ACP Medicine Online

ACP Medicine Online
3.
Dermatology
I
C U TA N E O U S M A N I F E S TAT I O N S O F
SYSTEMIC DISEASES
Mark Lebwohl, m.d.
The cutaneous manifestations of systemic diseases are so numerous and varied that a single chapter could not cover them
all, even in a cursory way. Instead, this chapter reviews key cutaneous manifestations of systemic diseases that should be recognized by most physicians, and it highlights recent developments in the diagnosis and management of such disorders. For
fuller discussions of specific diseases, including their cutaneous
manifestations, readers are referred to the chapters devoted to
these conditions.
In many of the disorders presented in this chapter, workup
and therapy of the underlying systemic condition are essential
to a favorable outcome. A finding of cutaneous sarcoidosis, for
example, should prompt a search for systemic sarcoidosis. In
other conditionsfor example, recessive dystrophic epidermolysis bullosatreatment of the skin disorder is key to the management of the systemic disease.
Cardiopulmonary and Vascular Diseases
sarcoidosis
Disease], saddle-nose deformity, nasal ulcerations, and septal

perforation should suggest the diagnosis of Wegener granulomatosis. Definitive diagnosis is made by demonstrating a necrotizing granulomatous vasculitis in a patient with upper and
lower respiratory tract disease and glomerulonephritis. Cytoplasmic antineutrophil cytoplasmic autoantibodies (c-ANCA)
are often present. Standard therapy is with cyclophosphamide
and corticosteroids. TNF- blockers have proved to be effective
for some patients with refractory Wegener granulomatosis.6
Lymphomatoid Granulomatosis
Lymphomatoid granulomatosis is a rare, destructive, angiocentric disorder that results from Epstein-Barr virusassociated
B cell lymphoproliferative disease.7 This condition can be associated with skin lesions. Typically, patients develop erythematous
papules or nodules that may or may not ulcerate.8 This disorder
is clinically distinguishable from Wegener granulomatosis by
the absence of upper respiratory tract involvement. Diagnosis is
established by demonstrating a granulomatous necrotizing infiltrate with atypical lymphoid cells around blood vessels. Lymphomatoid granulomatosis is usually fatal; however, rituximab
has been used successfully to treat this condition.9
Churg-Strauss Syndrome
The cutaneous manifestations of sarcoidosis are as varied as

its systemic manifestations [see 14:V Chronic Diffuse Infiltrative
Lung Disease]. Papules around the eyes or nose are most characteristic. The term lupus pernio refers to noncaseating granulomas that result in translucent, violaceous plaques of the ears,
cheeks, and nose [see Figure 1]. Involvement of underlying bone
can occur. Diagnosis is made by skin biopsy. Treatment with intralesional corticosteroids is traditional, and oral antimalarials
and methotrexate have been used with success. More recently,
infliximab has been successfully used for the treatment of sarcoidosis.1 Other tumor necrosis factor (TNF-) blockers such
as etanercept have been used to successfully treat arthritis and
skin lesions associated with sarcoidosis.2 Infliximab has also
been used to treat lupus pernio.3
There has been an increase in the use of interferon for the
treatment of hepatitis C and multiple sclerosis, and a number of
reports of sarcoidosis have been attributed to this treatment. Infliximab therapy has been found to effect a response in these
cases.4
In some patients with sarcoidosis, erythema nodosum, characterized by deep, tender erythematous nodules, occurs on the
lower extremities. Lupus pernio is associated with a more
chronic course of sarcoidosis, whereas erythema nodosum indicates a more acute and benign disease.5
Churg-Strauss syndrome, or allergic granulomatous angiitis,

most commonly presents as asthma and eosinophilia; however,
related skin lesions develop in up to 40% of patients. Symmetrical, palpable purpura and petechiae of the lower extremities are
the most common findings; these lesions show a leukocytoclastic vasculitis on skin biopsy. Cutaneous nodules caused by extravascular necrotizing granulomas and papules of the elbows
also occur.10 One of the clues to the diagnosis of this disorder is
the presence of perinuclear antineutrophil cytoplasmic antibodies (p-ANCA).11
granulomatous vasculitis
Wegener Granulomatosis
Wegener granulomatosis is associated with both distinctive
and nonspecific mucocutaneous signs. Palpable purpura is one
of the most common skin findings, but ulcers, papules, nodules,
and bullae have also been described. In addition to upper and
lower pulmonary symptoms [see 14:IV Focal and Multifocal Lung
2005 WebMD, Inc. All rights reserved.
April 2005 Update
Figure 1 Characteristic facial lesions of sarcoidosis, called lupus

pernio, are shown.
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DERMATOLOGY:I Cutaneous Manifestations of Systemic Diseases1
pseudoxanthoma elasticum
Pseudoxanthoma elasticum (PXE) is an autosomal recessively
inherited disorder of elastic tissue caused by mutations in the
ABCC6 transporter protein.16 PXE is associated with a wide array
of systemic manifestations. Angioid streaks, the ocular hallmark
of PXE, are breaks in the Bruch membrane. Retinal bleeding and
vision loss commonly occur. Calcification of the internal elastic
laminae of arteries can result in bleeding or occlusion of these vessels. As a result, patients develop intermittent claudication on
walking and occlusive coronary artery disease at an early age.
Cardiac valvular abnormalities have also been described.17 Skin lesions consist of yellow xanthomalike macules, papules, or redundant folds of skin in flexural areas, particularly the neck and axillae [see Figure 3]. Some patients may have systemic manifestations
of PXE without clinically apparent skin lesions.18 Diagnosis is established by biopsy of scar or normal-appearing flexural skin.19
There is no therapy for the skin lesions associated with PXE.
Figure 2 Xanthelasma and arcus senilis are shown in a patient with
hypercholesterolemia.
hyperlipoproteinemia
Xanthomas are cutaneous manifestations of hyperlipoproteinemias. Several types of xanthomas occur with different lipid
abnormalities. Xanthelasmas of the eyelids [see Figure 2] are the
most common manifestations of familial hypercholesterolemia;
however, in at least half the people who have eyelid lesions,
plasma lipid levels are normal. Planar xanthomas are flat yellow
plaques that can involve the palms, soles, neck, and chest. They
can occur in patients with primary biliary cirrhosis or multiple
myeloma. Tuberous xanthomas are large yellow or red nodules
that appear on the extensor surfaces of joints, such as on the elbows and hands, but are not attached to underlying tendons.
They can occur in patients with elevated triglyceride or cholesterol levels. In contrast, tendinous xanthomas, which can appear
in patients with familial hypercholesterolemia, are fixed to underlying tendons of the elbows, ankles, knees, and hands. Eruptive xanthomas occur when plasma triglyceride levels suddenly
become elevated. Skin lesions consist of small yellow papules
that often resolve with lowering of triglyceride levels.
kawasaki disease
Kawasaki disease, also called mucocutaneous lymph node
syndrome [see 15:VIII Systemic Vasculitis Syndromes], is a disorder
in children that can be complicated by coronary artery occlusion
and myocardial infarction, coronary artery aneurysms, ECG abnormalities, cardiac arrhythmias, or myocarditis.12 It has been
suggested that a toxin secreted by Staphylococcus aureus is responsible for this disease, but proof of the precise cause remains
elusive.13 Diagnosis is based on clinical criteria that include fever,
conjunctivitis, lymphadenopathy, and rash. In addition to a generalized erythematous eruption, abnormalities of the oral mucosa, as well as swelling and erythema of the hands and feet,
may develop. Striking desquamation of the palms and soles ultimately occurs. Perianal and scrotal erythema and scaling are
common as well. Thrombocytosis is a late finding, with platelet
counts increasing to more than one million over 2 weeks after
the onset of the disease. Approximately 15% to 25% of untreated
children develop coronary artery aneurysms that may lead to
sudden death.14 Treatment with intravenous immunoglobulin
reduces the frequency of coronary artery abnormalities.15
April 2005 Update
rheumatic fever
The two cutaneous manifestations of rheumatic fever are erythema marginatum and subcutaneous nodules. Erythema marginatum is a transient faint annular erythematous rash that often
develops over joints [see Figure 4]. The subcutaneous nodules
that appear with rheumatic fever are nontender, freely movable
nodules measuring approximately 1 cm in diameter; they occur
on the extensor surfaces of elbows, hands, or feet.
yellow nail syndrome
Yellow nail syndrome is caused by an abnormality of lymphatics [see Figure 5]. Affected patients develop lymphedema,
usually of the legs, and pleural effusions. Pulmonary symptoms
such as recurrent bronchitis are also common. Diagnosis is made
by finding evidence of abnormal lymphatic function associated
with yellow nails without other causes of nail pathology. Increased microvascular permeability with leakage of proteins may
play a role in the development of the yellow nail syndrome.20
Endocrinologic Diseases
diabetes mellitus
There are numerous cutaneous manifestations of diabetes
mellitus [see 9:VI Diabetes Mellitus]. Acanthosis nigricans can occur in patients with diabetes and other endocrinopathies, such as
Cushing syndrome, acromegaly, polycystic ovary syndrome,
and thyroid disease. Insulin resistance is an underlying factor in
several of the aforementioned endocrinopathies; it also may play
a role in the development of acanthosis nigricans. Skin lesions
consist of brown velvety patches in intertriginous areas, especially the neck and axillae [see Figure 6], and occur more commonly
in obese patients with diabetes.21 Acanthosis nigricans has also
been associated with internal malignancies, particularly gastric
adenocarcinoma or other gastrointestinal adenocarcinomas.
Necrobiosis lipoidica is a specific cutaneous manifestation of
diabetes. Lesions consist of chronic atrophic patches with enlarging erythematous borders. The legs are most commonly affected. The centers of the lesions appear yellow because of subcutaneous fat that is visible through the atrophic dermis and epidermis. Occasionally, the lesions ulcerate. Necrobiosis lipoidica
is often associated with diabetic nephropathy or retinopathy.22
Scleredema, another manifestation of diabetes, consists of induration of the skin of the back and posterior neck in obese pa-
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Figure 3 Xanthomalike papules are characteristic of pseudoxanthoma
Figure 6 Acanthosis nigricans, a dark velvety acanthosis that can
elasticum. The neck and axillae are the most common sites of
involvement.
occur in patients with diabetes mellitus and other endocrine disorders,

often appears on the neck.
Figure 4 Transient annular erythematous rashes (erythema

marginatum) typically occur in patients with rheumatic fever.
tients with type 2 (noninsulin-dependent) diabetes. Scleredema

may improve if diabetes is controlled.23 Less commonly, scleredema occurs in nondiabetic patients after streptococcal pharyngitis; in such patients, the disease is self-limited, resolving within 2 years of onset. High-dose corticosteroids,24 radiation,25 and
ultraviolet-A1 irradiation (UVA1)26 have all been used to treat
scleredema.
Diabetic bullae, neuropathic ulcers, and so-called waxy skin
and stiff joints occur in patients with diabetes. In the last condition mentioned, scleroderma-like induration of the skin over the
dorsal aspect of the hands prevents full flexion or extension of
the proximal interphalangeal joints.
Diabetic patients are prone to a number of infections, including erythrasma, a corynebacterial infection resulting in asymptomatic reddish-brown patches in intertriginous sites, especially
the groin and axillae. Patients are also prone to staphylococcal
infections and frequently develop furuncles and carbuncles.
Candidal infections are another risk, particularly when blood
glucose levels are poorly controlled.
graves disease
Graves disease consists of a triad of exophthalmos, hyperthyroidism, and pretibial myxedema [see 3:I Thyroid]. Pretibial
myxedema presents as skin-colored nodules and plaques that
extend from the pretibial area down to the dorsa of the feet. Lesions often develop after treatment of hyperthyroidism, although they can occur at any stage in the evolution of Graves
disease.
Onycholysis, the separation of the nail plate from the nail bed,
occurs in many patients with hyperthyroidism. Other autoimmune skin diseases, such as vitiligo and alopecia areata, are increased in patients with Graves disease. Manifestations of thyroid disease include the stigmata of hypothyroidism. Patients
can develop alopecia; specifically, they can lose the lateral third
of the eyebrows. Edematous thickening of the lips, tongue, and
nose occur as well.
Gastrointestinal Diseases
Figure 5 Yellow nails are a sign of underlying disease of the

lymphatics in patients with yellow nail syndrome.

April 2005 Update
Patients with any of a number of gastrointestinal diseases

may present with cutaneous manifestations; similarly, patients
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Figure 7 Aphthous stomatitis is a common
Figure 9 The patients nose and cheeks are

covered with small papules called
trichilemmomas, which represent the
cutaneous hallmark of Cowden disease.
finding in patients with ulcerative colitis.
Figure 8 Pyoderma gangrenosum is

characterized by ulcers that begin with craterlike
holes draining pus.
with certain cutaneous diseases can develop gastrointestinal
complications.
carcinoid syndrome
The carcinoid syndrome is characterized by episodic flushing
that can be associated with abdominal pain, diarrhea, and
wheezing. Ninety percent of carcinoid tumors originate in the
gastrointestinal tract; however, bronchial carcinoids occur occasionally. Less common cutaneous manifestations of carcinoid
tumors include sclerodermatous changes. Cutaneous metastases present as deep nodules; hyperkeratosis may occur; and
the patient may experience pigmentation changes similar to
those seen in pellagra.
inflammatory bowel disease
There are several specific and nonspecific cutaneous manifestations of inflammatory bowel disease [see 4:IV Inflammatory
Bowel Diseases]. In both Crohn disease and ulcerative colitis, disease can progress to a hypercoagulable stage, causing venous
and arterial thromboses that can lead to loss of digits and limbs.
Aphthous stomatitis is another nonspecific manifestation of in-
flammatory bowel disease [see Figure 7]. In patients with Crohn

disease, the lesions may appear as noncaseating granulomas,
whereas in patients with ulcerative colitis, they may be indistinguishable from canker sores.
Pyoderma gangrenosum occurs in patients with Crohn disease and ulcerative colitis and has also been reported in patients
with chronic active hepatitis, rheumatoid arthritis, and a number
of myeloproliferative disorders. The lesions are distinguishable
from other ulcers by the presence of craterlike holes, pustules,
and purulent drainage [see Figure 8]. Pyoderma gangrenosum
may occur at sites of trauma. Treatment with intralesionally injected or systemic corticosteroids may be required. Immunosuppressive agents such as cyclosporine have proved to be dramatically effective; in refractory cases, thalidomide has been shown
to be beneficial.27 Infliximab has proved to be highly effective in
the treatment of refractory pyoderma gangrenosum.28
Erythema nodosum is a septal panniculitis that is associated
with a number of conditions, including Crohn disease, ulcerative colitis, Behet syndrome, sarcoidosis, infection, and the ingestion of estrogens and other drugs. Other manifestations of
Crohn disease include inguinal abscesses and sinuses and anal
fistulas.
metastatic crohn disease
The term metastatic Crohn disease refers to histologically
proven noncaseating granulomas that are remote from the gastrointestinal tract in patients with Crohn disease. The clinical
presentation can be quite variable, and the diagnosis of this disorder is frequently missed. In some cases, patients present with
marked swelling of the scrotum or vulva.
cutaneous conditions with gastrointestinal
complications
Cowden Disease
Figure 10 The primary lesions of herpetiformis are vesicles that

quickly break to form crusts and erosions.

April 2005 Update
Cowden disease is an autosomal dominant disorder in which

gastrointestinal polyps develop along with numerous skin lesions. This disease has been attributed to mutations of the tumor
suppressor gene PTEN.29 Wartlike papules known as trichilemmomas occur, particularly around the nose, mouth, and ears but
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also on the hands and feet [see Figure 9]. Small papules can also
develop on the gingival mucosa, creating a cobblestone appearance. Hemangiomas and lipomas can occur.30 A distinctive nodule of the scalp known as Cowden fibroma has been described. Up
to 50% of women with Cowden disease develop breast cancer, a
finding that has been associated independently with the PTEN
mutation.31 Thyroid carcinomas, thyroid adenomas, and thyroid
goiters can occur as well.
Dermatitis Herpetiformis
Dermatitis herpetiformis is an immunobullous disease that is
associated with a gluten-sensitive enteropathy [see 2:IX Vesiculobullous Diseases]. Skin lesions begin as vesicles that are so pruritic
that they are quickly broken by scratching, leaving only excoriations and crusts [see Figure 10]. Like patients with celiac disease
who are not on a gluten-free diet, patients with dermatitis herpetiformis have an increased risk of gastrointestinal lymphoma.32
Peutz-Jegher Syndrome
In Peutz-Jegher syndrome, patients develop hamartomatous
polyps of the small intestine that are associated with pigmented
macules of the lips and oral mucosa [see 2:X Malignant Cutaneous
Tumors]. Also, pigmented macules can develop on the palms, fingers, soles, and toes and in areas around the mouth, nose, and
rectum. The disease is inherited as an autosomal dominant trait,
and a significant proportion of cases are associated with mutations in the serine/threonine protein kinase I1/LKB1 (STKI1/
LKB1) gene, although mutations in this gene do not account for
all cases.33
Recessive Dystrophic Epidermolysis Bullosa

Recessive dystrophic epidermolysis bullosa is a congenital
bullous disease with recurrent blistering and scarring, particularly on the hands and feet [see 2:IX Vesiculobullous Diseases].
The scarring results in pseudosyndactyly, giving rise to mittenlike hands. Ingestion of coarse food can result in mucosal bullae of the esophagus, which heal with scarring and stricture
formation. Dysphagia is a frequent complaint. Scarring of the
esophagus can lead to squamous cell carcinoma, which is a
leading cause of death in this disorder.34 Gastroenterologists
and dermatologists must play key roles in the management of
these patients. Liquid and pureed diets and appropriate skin
care are essential to the survival of patients with this debilitating disorder. Prenatal diagnosis can be made by sampling
DNA from the chorionic villus.35 All forms of dystrophic epidermolysis bullosa have been attributed to mutations in the
type VII collagen gene.36 Recently, through the use of a selfinactivating minimal lentivirus-based vector, the type VII collagen gene has been delivered and type VII collagen expressed
in immunodeficient mice, suggesting the possibility that, in the
future, gene therapy may be available to successfully treat this
devastating disorder.37
Because of amyloid deposits in blood vessels, spontaneous

bleeding occurs. Minimal trauma results in petechiae and purpura. Macroglossia also occurs in some patients with myelomaassociated amyloidosis and in some with primary systemic
amyloidosis. The systemic manifestations of myeloma-associated and primary systemic amyloidosis are quite varied. Hepatomegaly develops in 50% of patients. Amyloid can affect the
heart, resulting in heart failure or myocardial infarction. Survival of patients who undergo heart transplantations for cardiac
amyloidosis is lower than survival after cardiac transplantation
for other indications.38 Amyloidosis of the gastrointestinal tract
can result in malabsorption and protein-losing enteropathy.
Treatment with thalidomide (up to 400 mg daily) and intermittent dexamethasone is rapidly effective in some patients, but
side effects are frequent.39
mastocytosis
Mastocytosis is caused by the infiltration of mast cells into the
skin and other organs [see 4:XI Diseases Producing Malabsorption
and Maldigestion]. Urticaria pigmentosa refers to the skin lesions
that occur in most patients with mastocytosis. Reddish-brown
macules and papules resembling nevi are characteristic [see Figure 11]. Stroking of individual lesions results in urticarial
whealsa phenomenon known as the Darier sign. Pruritus,
flushing, abdominal pain, nausea, vomiting, and diarrhea are
common complaints.
Most patients with mastocytosis have an indolent form of the
disease, even when mast cells have infiltrated the bone marrow.40 Malignant or aggressive systemic mast cell disease can involve the spleen, liver, and lymph nodes in addition to the skin
and bone marrow. Histologically, infiltrates contain atypical
nonmetachromatic mast cells that are monoclonal in some patients.41 Children with urticaria pigmentosa usually have a better
prognosis than adults with the disease.42
The diagnosis of mastocytosis is made by the demonstration
of mast cells on skin biopsy. Because mast cells easily degranulate, making them difficult to identify, biopsies should be performed with a minimum of tissue manipulation.
porphyrias
The porphyrias result from defective hemoglobin synthesis,
leading to excess porphyrins in the blood and in body tissues
[see 9:V The Porphyrias].
Hematologic Diseases
amyloidosis
There are several forms of local and systemic amyloidosis [see
12:XV Chronic Lymphoid Leukemias and Plasma Cell Disorders]. In a
form associated with multiple myeloma, amyloid fibrils consisting of immunoglobulin light chains are deposited in the skin.
Shiny translucent papules develop, particularly on the eyelids.
April 2005 Update
Figure 11 Multiple brown macules resembling nevi occur in patients

with urticaria pigmentosa.
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Congenital Erythropoietic Porphyria

Congenital erythropoietic porphyria is a rare autosomal recessive disorder that has been attributed to mutations in the gene
for uroporphyrinogen III synthase.43 This condition is characterized by severe photosensitivity. Vesicles and bullae develop after
sun exposure; these lesions heal with scar formation. Erythrodontia (red-stained teeth) is a characteristic feature [see Figure
12]. Digit, ear, and nose loss is common in patients who manage
to survive to adulthood [see Figure 13]. Hypertrichosis is another
frequent complication. Formation of gallstones, splenomegaly,
and hemolytic anemia are also associated with this condition.
Porphyria Cutanea Tarda

Porphyria cutanea tarda is characterized by photosensitivity,
vesicle formation (especially on the dorsa of the hands) [see Figure 14], and hypertrichosis. The condition may be associated with
ingestion of alcohol or medications such as estrogens. Diagnosis
of the porphyrias can be established by elevated urinary porphyrin levels. Examination of the urine with a Wood lamp will
often reveal pink-red fluorescence attributable to the high level
of urinary porphyrins. Porphyria cutanea tarda can be associated with hepatitis C. Phlebotomy is effective therapy.
Figure 12 A reddish pigmentation (erythrodontia) occurs when

porphyrins are deposited in the teeth in congenital erythropoietic
porphyria.
Immunodeficiency Diseases
aids
AIDS may result in cutaneous infections and neoplasms that
are often dramatic in their extent and severity. This section focuses on selected cutaneous manifestations of infections and
other diseases associated with AIDS. (For a more comprehensive discussion of disorders associated with HIV infection, see
7:XXXIII HIV and AIDS and other chapters devoted to specific
conditions.)
Opportunistic Infections
Viral infections Banal viral infections, such as molluscum
contagiosum, that are ordinarily self-limited and easily curable
have become widespread, chronic, and enormous problems in
patients with AIDS. These umbilicated white papules, ordinarily only a few millimeters in diameter, can reach diameters of 1 to
2 cm in patients with AIDS. Similarly, condyloma acuminatum,
caused by human papillomavirus (HPV) infection, is often difficult to treat in patients with AIDS.
Herpes simplex virus infections become chronic and erosive,
forming large, nonhealing ulcers [see 7:XXVI Herpesvirus Infections]. Acyclovir-resistant strains of herpes simplex virus have
been reported in some patients with AIDS44; these patients require other antiviral agents, such as foscarnet. Mutations in
thymidine kinase and DNA polymerase genes of herpes simplex viruses can render them resistant to acyclovir and foscarnet.45 Topical cidofovir gel has been reported to be beneficial for
herpes infections in patients infected with HIV.46
Herpes zoster infections are a common sign of HIV infection.
In the nonHIV-infected host, herpes zoster is characterized by
grouped vesicles in a dermatomal distribution. The eruption is
self-limited, resolving within 1 to 2 weeks. In contrast, herpes
zoster infection can develop into a disseminated vesicular eruption in patients with AIDS; and in some AIDS patients, chronic
herpetic lesions develop and last for months.
Fungal infections Fungal infections are common in patients
April 2005 Update
Figure 13 Skin changes in congenital erythropoietic porphyria can

be severe; scarring and loss of digits are common in older patients.
with HIV infection. Monilial infections include oral thrush and

candidiasis of the groin. Several fungal infections that rarely
cause widespread infection in patients with normal immune
systems (e.g., cryptococcosis, histoplasmosis, aspergillosis, and
sporotrichosis) have emerged as serious pathogens in patients
with AIDS.
Bacterial infections Bacterial infections are more frequent
and severe in patients with AIDS than in patients with normal
immune systems. Bacillary angiomatosis, caused by Bartonella
henselae, presents as purple papules and nodules that can be
mistaken for Kaposi sarcoma (see below). Chronic fever and
chills can occur, as can bone lesions. Epidemiologic evidence
suggests that cats may be the source of human infection.47 Diag-
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nosis by serologic testing has been commonly used, but in the

future, polymerase chain reaction may offer a rapid and convenient way of establishing this diagnosis.48 The condition resolves
upon treatment with oral antibiotics [see 7:XI Infections Due to
Brucella, Francisella, Yersinia pestis, and Bartonella].
Scabies and other pruritic eruptions Scabies, a severely
pruritic eruption, has a predilection for the buttocks, the genitals, the periumbilical area, and the webs between the fingers.
Norwegian scabies, a thickly crusted psoriasislike form of the
parasitic disease, has been described in patients with Down syndrome and in other immunosuppressed persons. In recent
years, Norwegian scabies has been reported most commonly in
patients with AIDS. The scales of Norwegian scabies contain
thousands of mites that are easily seen with the microscope.
Burrows form linear lesions up to 1 cm long. The causative mite,
Sarcoptes scabiei, can be identified by microscopic examination of
scrapings from the burrows.
Eosinophilic pustular folliculitis and papular eruption of
AIDS are pruritic rashes that affect patients with HIV infection.
It has been suggested that pruritic papular eruption in patients
with HIV infection may represent a reaction to arthropod bites.49
Both eosinophilic pustular folliculitis and papular eruption of

AIDS are characterized by severe itching, and skin-colored
papules and excoriations are common in both. Patients with
eosinophilic pustular folliculitis can develop pustules and erythematous papules. Both conditions respond to treatment with
ultraviolet B.
Kaposi Sarcoma
Kaposi sarcoma, a slowly progressive vascular neoplasm,
was originally described in elderly Italian and Jewish men [see
2:X Malignant Cutaneous Tumors]. Subsequently, a more rapidly
progressive form of the disorder was described in immunosuppressed patients with lymphomas and in kidney transplant patients on immunosuppressive drugs. An aggressive form has
been described in patients with AIDS [see Figure 15]. Classic Kaposi sarcoma typically affects the lower extremities and only
gradually progresses to other sites. In contrast, AIDS-related Kaposi sarcoma can occur on any surface of the body, including
mucous membranes. Human herpesvirus type 8 has been implicated in both classic and AIDS-related Kaposi sarcoma.50 Treatments include radiation therapy, cryotherapy, and intralesional
injection with vinblastine; systemic chemotherapy can also be
effective. In patients with AIDS, Kaposi sarcoma is best treated
with antiretroviral regimens.
Oral Hairy Leukoplakia

Oral hairy leukoplakia, another condition that has been described in HIV-infected patients, consists of linear white papules
on the lateral surfaces of the tongue that result in the so-called
hairy appearance. Oral hairy leukoplakia can be distinguished
from oral thrush in that the lesions cannot be rubbed off, as they
can be in thrush.
Thanks to the development of effective antiretroviral therapy,
the frequency of opportunistic infections in patients with HIV
infection has diminished markedly.
other immunodeficient states
Figure 14 Crusting and scarring follow the appearance of vesicles

and bullae in porphyria cutanea tarda.
Other inherited or acquired immunodeficiency states share a

number of clinical features. Susceptibility to monilial infections
or bacterial infections is increased in disorders such as chronic
granulomatous disease and chemotherapy-induced neutropenia. Oral ulcers similarly occur in cyclic neutropenia and in
chemotherapy-induced immunosuppression.
Some immunosuppressive drugs have characteristic cutaneous effects. Corticosteroids, when used long-term, cause vascular fragility, resulting in steroid purpura. They can also cause
cutaneous atrophy, formation of striae, and acneiform eruptions.
Cyclosporine is associated with hypertrichosis. Aphthous stomatitis is a characteristic effect of numerous immunosuppressive
drugs, particularly agents that suppress bone marrow function.
Chronic immunosuppression can lead to the development of
lymphoma and nonmelanoma skin cancer. Avoidance of excessive exposure to sunlight may prevent development of the latter.
Infectious Diseases
Figure 15 Kaposi sarcoma is the most common malignancy of AIDS

patients. It often presents as purple patches, plaques, or papules. Purple
macules on the foot can be seen in patients with classic Kaposi sarcoma
but are seen here in a patient with AIDS-related Kaposi sarcoma.
April 2005 Update
Cutaneous manifestations can be major features of a number

of systemic infections; for example, patients with overwhelming
septicemia can develop disseminated intravascular coagulation
(DIC), which results in cutaneous infarcts and hemorrhage into
the skin. Key cutaneous features of selected systemic infections
follow.
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infective endocarditis
The cutaneous manifestations of infective endocarditis include petechiae, splinter hemorrhages (linear red streaks under
the nail), Osler nodes (tender purpuric nodules on the finger
pads and toes), and Janeway lesions (nontender purpuric macules of the palms and soles). Skin lesions are caused by either
septic emboli or vasculitis. Treatment of the underlying infection
results in resolution of the cutaneous manifestations [see 7:XVIII
Infective Endocarditis].
staphylococcal toxic-shock syndrome
Staphylococcal toxic-shock syndrome was first recognized in
menstruating women who used superabsorbent tampons [see 7:I
Infections Due to Gram-Positive Cocci]. It is caused by an exotoxin
produced by certain strains of S. aureus.51 Staphylococcal infections in bone, soft tissue, and other sites have been implicated.
Patients develop diffuse sunburnlike erythema, with swelling of
the hands and feet, followed by desquamation of the palms and
soles. Erythema of mucous membranes, fever, and hypotension
also occur. Gastrointestinal symptoms, impaired renal function,
elevated liver function values, thrombocytopenia, and myositis
can develop.
Figure 16 Several weeks after primary infection with Lyme disease,

hematogenous dissemination of spirochetes results in multiple patches
of erythema chronicum migrans.
Treatment with antibiotics and supportive care are essential aspects of therapy.
staphylococcal scalded skin syndrome
scarlet fever
Staphylococcal scalded skin syndrome (SSSS) is caused by a

circulating exfoliative toxin produced by S. aureus phage group
11. Generalized bulla formation with large areas of desquamation is characteristic of the disorder. Along with tenderness, erythema, and exfoliation of skin, patients have fever. The source of
the staphylococcal infection is not always apparent; occasionally, the infection arises in a wound or in an occult abscess. Because the staphylococcal infection is usually remote from the affected skin, culture of the skin does not grow S. aureus.
SSSS must be differentiated from toxic epidermal necrolysis.
Toxic epidermal necrolysis commonly affects adults and involves mucous membranes; SSSS usually affects children and
spares mucous membranes. In addition, toxic epidermal necrolysis can last for several weeks and has a high mortality, whereas
SSSS lasts a few days and usually has a good outcome. Histologically, SSSS shows bulla formation in the upper epidermis, and
the bulla cavity contains free-floating, normal-appearing, acantholytic cells. In toxic epidermal necrolysis, bulla formation occurs at the basal layer of the epidermis, and the epidermal cells
are necrotic. Treatment with antibiotics effective against S. aureus eliminates the underlying cause of SSSS.
Scarlet fever begins with pharyngitis caused by group A

Streptococcus [see 7:I Infections Due to Gram-Positive Cocci]. A generalized rash develops 1 to 2 days after onset of the pharyngitis.
The rash is characterized by pinpoint erythematous papules that
may be easier to palpate than to see. Other characteristic lesions
include a white strawberry tongue and linear petechial macules
occurring in body folds (Pastia lines). As the rash fades, desquamation of the palms and soles appears. Treatment with penicillin results in rapid resolution of all symptoms.
necrotizing fasciitis
Necrotizing fasciitis is caused by a mixed anaerobic infection
of an ulcer or a surgical or traumatic wound. The affected skin is
erythematous, warm, and tender and develops hemorrhagic
bullae that rupture to form rapidly enlarging areas of gangrene
that extend down to the fascia. Surgical debridement is essential
for this life-threatening infection.52
meningococcemia
Acute meningococcemia can occur either in epidemics or in
isolated cases [see 7:III Infections Due to Neisseria]. Fever, headache, and a hemorrhagic rash develop. If untreated, patients develop DIC, with extensive hemorrhage, hypotension, and ultimately death. The causative organism, Neisseria meningitidis, is
usually identified in cerebrospinal fluid but can also be identified by smear or cultures of skin lesions or by blood cultures.
April 2005 Update
VIBRIO
infection
Vibrio vulnificus infection arises from minor trauma sustained

while swimming in lakes or the ocean or while cleaning seafood.
Cellulitis occurs, with lymphangitis and bacteremia. In patients
with hepatic cirrhosis, infection can occur after eating raw oysters. These patients develop hemorrhagic bullae, with leukopenia and DIC.53 Treatment with antibiotics is necessary; management of complications may require intensive supportive care.
lyme disease
Lyme disease is caused by the spirochete Borrelia burgdorferi
and is transmitted primarily by the tick Ixodes scapularis [see
7:XVII Infections Due to Rickettsia, Ehrlichia, and Coxiella]. The
characteristic skin lesion, erythema chronicum migrans, begins
as an erythematous macule or papule at the site of the tick bite.
Over days and weeks, the erythematous lesion expands to form
a red ring, often with central clearing. If left untreated, lesions
last weeks or months. Hematogenous dissemination of spirochetes occurs after several weeks, resulting in multiple annular
patches of erythema chronicum migrans [see Figure 16]. Systemic
complications include an acute arthritis involving one or a few
large joints a few weeks after the onset of symptoms. A chronic
erosive arthritis develops in approximately 10% of patients.
Neurologic symptoms, including Bell palsy, can occur, as can
cardiac complications, including heart failure and cardiac conduction abnormalities.
Lyme disease can be prevented by the removal of ticks within
18 hours of attachment. Once symptoms have developed, oral
ACP Medicine
antibiotics are effective at destroying B. burgdorferi. A vaccine

containing a genetically engineered protein from the surface of
the bacteria was found to prevent infection in most vaccinated
people54; however, for a number of reasons, including lack of demand, the vaccine has been discontinued.55
rocky mountain spotted fever
Rocky Mountain spotted fever (RMSF) is a tick-borne illness
caused by Rickettsia rickettsii [see 7:XVII Infections Due to Rickettsia, Ehrlichia, and Coxiella]. It is characterized by the sudden onset of fevers, chills, and headache. Approximately 4 days later, a
characteristic erythematous rash develops on the wrists and ankles and becomes purpuric. The rash then spreads centrally to
involve the extremities, trunk, and face.
Because the mortality of RMSF is high, patients should be
treated immediately with intravenous chloramphenicol or tetracycline if RMSF is suspected. Diagnosis can then be established
by skin biopsy: immunofluorescence with antibodies against R.
rickettsii shows the organism in the walls of cutaneous blood
vessels. Serologic tests, such as the Weil-Felix reaction, can confirm the diagnosis after the acute phase of the illness.
Neurologic Diseases
basal cell nevus syndrome
The basal cell nevus syndrome is an autosomal dominant disorder attributed to mutational inactivation of the PTCH gene56 in
which patients develop basal cell carcinomas at an early age [see
2:X Malignant Cutaneous Tumors]. Multiple skeletal abnormalities are associated with the syndrome, and affected individuals
may also develop jaw cysts. Lamellar calcification of the falx
cerebri occurs, as well as other neurologic abnormalities, including medulloblastomas.
epidermal nevus syndrome
The epidermal nevus syndrome is characterized by systemic
manifestations, such as seizures, mental retardation, blindness,
and skeletal abnormalities in association with large epidermal
nevi. The nevi consist of long pigmented streaks that are linear
or whirled and involve large areas of the body [see Figure 17].
incontinentia pigmenti
Incontinentia pigmenti is an inherited syndrome that affects
the skin and nervous system. Mutations in the NEMO gene, an
essential component of the nuclear factorB signaling cascade,
account for 85% of cases.57 The inheritance pattern is X-linked
dominant and is lethal in male fetuses. The first skin manifestations begin within weeks after birth, occasionally occurring in
utero, and consist of linear patterns of vesiculobullous lesions.
Within weeks, these lesions evolve into verrucous papules and,
eventually, into pigmented whirls. Apart from neurologic symptoms, patients may have ocular abnormalities, scarring alopecia,
and skeletal malformations.
Hypomelanosis of Ito
Hypomelanosis of Ito, also called incontinentia pigmenti
achromians, consists of whirls of hypopigmentation that are associated with neurologic symptoms in 50% of patients. Skin lesions are present at birth or develop in early childhood. In addition to seizures and mental retardation, skeletal and ocular abnormalities occur.
April 2005 Update
neurofibromatosis
Neurofibromatosis is a common autosomal dominant disorder involving the skin and nervous system [see 2:XI Benign Cutaneous Tumors]. Skin lesions include cutaneous neurofibromas,
which are soft, skin-colored nodules that are often pedunculated
[see Figure 18]. Caf au lait macules are flat, evenly pigmented
patches up to several centimeters in diameter. Six or more caf
au lait macules greater than 1.5 cm in diameter are found in most
patients with neurofibromatosis type 1 (also called von Recklinghausen disease). Plexiform neuromas are larger, deeper tumors
that are associated with hypertrophy of bony and soft tissues. In
a small proportion of tumors, neurofibrosarcomas will arise. On
skin biopsy, caf au lait macules are found to contain macromelanosomesgiant granules of pigment in melanocytes and keratinocytes. Axillary and inguinal freckling also appear as pigmented macules that resemble small caf au lait spots in intertriginous sites. Lisch nodulespigmented iris hamartomasare
also found in most patients with neurofibromatosis.
Several variants of neurofibromatosis exist, including segmental neurofibromatosis, in which patients develop a segmental
distribution of caf au lait spots and cutaneous neurofibromas,
and neurofibromatosis type 2, which consists of acoustic neuromas, schwannomas, and meningiomas without Lisch nodules
and with fewer caf au lait macules than appear in type 1. Patients with neurofibromatosis type 2 may have some cutaneous
neurofibromas as well. Neurofibromatosis types 1 and 2 are
caused by different genetic defects. Neurofibromatosis type 1 is
caused by mutations in the NF1 gene for neurofibromin on chromosome 17.58 Neurofibromatosis type 2 has been attributed to inactivating mutations in the NF2 tumor suppressor gene whose
product, merlin, plays a number of roles in tumorigenesis.59
sneddon syndrome
Sneddon syndrome is a disease of the skin and nervous system caused by occlusion of small to medium-sized arteries in
persons younger than 45 years. The skin lesions resemble livedo
reticularis and have been called livedo racemosa. Transient ischemic attacks or strokes are common. Definitive diagnosis is
made by demonstrating characteristic vascular changes on skin
biopsy of patients with associated neurologic findings.
tuberous sclerosis
Tuberous sclerosis is an autosomal dominant disease that affects the skin and nervous system. Mutations that inactivate the
TSC1 or TSC2 tumor suppressor genes affect the respective gene
products, hamartin and tuberin, leading to tuberous sclerosis.60
Affected patients can develop seizures, mental retardation, and
brain lesions called tubers, which can be seen on CT scans. Adenoma sebaceum, the most characteristic cutaneous manifestation of tuberous sclerosis, consists of skin-colored papules of the
face [see Figure 19a]. Other skin lesions are hypopigmented macules referred to as ash-leaf macules [see Figure 19b], smaller hypopigmented lesions called confetti macules, periungual and
subungual fibromas (skin-colored nodules that arise around the
fingers and toenails) [see Figure 19c], and the shagreen patch (a
skin-colored plaque made of thick dermal connective tissue).
Renal Diseases
fabry disease
Fabry disease is caused by an abnormality of -galactosidase
ACP Medicine
Figure 17 The epidermal nevus syndrome is
Figure 18 Axillary freckling, caf au lait spots, and
characterized by linear or whirled streaks of pigmentation

that involve large areas of the body.
neurofibromas are evident in a patient with

neurofibromatosis type 1.
A, resulting in deposition of glycosphingolipids in body tissues.

The disorder is inherited as an X-linked recessive trait. A variety
of different mutations in the gene for -galactosidase A have
been found in unrelated families with Fabry disease.61 Affected
males often complain of severe pain in the extremities, with
burning of the palms and soles. Episodes of pain are transient,
but patients complain of persistent paresthesias in the hands
and feet.
Skin lesions consist of angiokeratomas, which are pinpoint
red or purple papules that resemble cherry hemangiomas [see
Figure 20]. Angiokeratomas are most commonly found in the
periumbilical area but can also occur on the palms, soles, trunk,
extremities, and mucous membranes. In adults, glycosphingolipids become deposited in blood vessels and organs, affecting the heart, heart valves, coronary arteries, and kidneys. Re-
placement therapy with recombinant human -galactosidase A

can improve cutaneous, gastrointestinal, neurologic, and psychiatric symptoms; it has been shown to be safe and can eliminate substrate storage of glycosphingolipids, but questions remain regarding optimal dosing.62
polyarteritis nodosa
Polyarteritis nodosa is an inflammatory condition that affects
muscular arteries [see 15:VIII Systemic Vasculitis Syndromes].
Aneurysms form in many arteries, including those leading to
the kidneys and subcutaneous tissue. Diagnosis of the systemic
form of polyarteritis can be made by demonstrating aneurysms
of the renal arteries on renal arteriograms.
A localized cutaneous form of polyarteritis nodosa most
commonly presents as painful nodules of the lower extremi-
Figure 19 Several of the characteristic cutaneous findings of tuberous sclerosis are shown: adenoma sebaceum (a); ash-leaf macule (b);
and periungual fibromas (c).

April 2005 Update
ACP Medicine
indurated plaques that may ulcerate, becoming necrotic [see Figure 21]. Calciphylaxis often eventuates in amputation or death.
Parathyroidectomy may result in healing of affected skin without amputation.66
Rheumatologic Diseases
dermatomyositis
Figure 20 Angiokeratomas are particularly common

in the periumbilical area of patients with Fabry disease.
ties.63 In mild cases, patients may only have livedo reticularis;

but in severe cases, skin lesions can ulcerate. A polyneuropathy
may be associated with the disorder. Patients with classic polyarteritis and microaneurysms have an increased incidence of
hepatitis B antigenemia; in contrast to patients with other vasculitides, they usually do not have antineutrophil cytoplasmic
antibodies.64
perforating disorders
Perforating disorders include several conditions characterized by extrusion of dermal material through the epidermis.
These lesions often develop in association with renal failure and
diabetes mellitus.65 Skin lesions are characterized by hyperkeratotic papules with central white craters that histologically can be
shown to contain dermal material. Reactive perforating collagenosis, perforating folliculitis, and Kyrle disease are all examples of perforating disorders associated with renal failure.
calciphylaxis
Calciphylaxis, also known as calcific uremic arteriolopathy, is
a condition of patients with renal failure in which localized areas
of skin become necrotic as a result of vascular calcification. Calciphylaxis begins with painful purpuric patches that may be reticulated, resembling livedo reticularis. These patches progress to
Figure 21 Calcification of arteries in patients with renal failure

results in calciphylaxis. Affected skin forms a black, necrotic eschar.
April 2005 Update
The best-known cutaneous manifestations of dermatomyositis, an inflammatory disorder of muscle and skin, are Gottron
papules and heliotrope erythema. Gottron papules are erythematous scaling macules and papules that occur on the dorsa of
the knuckles [see Figure 22]. Heliotrope erythema consists of periorbital erythema and edema. Scalp lesions, which can be associated with alopecia, have been described.67 The lesions are often
misdiagnosed as seborrheic dermatitis or psoriasis.
The association between dermatomyositis and malignancy
has been established68,69; one epidemiologic study indicates patients with dermatomyositis are at particular risk for ovarian
and lung cancer.69
Classifications of dermatomyositis include a juvenile variant
characterized by calcification of skin or muscle. A vasculitic
form in children is complicated by cutaneous infarcts and ulceration and by gastrointestinal vasculitis with abdominal pain,
bleeding, or perforation. The vasculitic form carries a poor prognosis, with many of the patients dying of this disease.
scleroderma and scleroderma-like diseases
The sclerodermas include a number of distinct syndromes
sharing a common feature, induration of the skin [see 15:V Scleroderma and Related Diseases].
Progressive Systemic Sclerosis and CREST Syndrome

Progressive systemic sclerosis, also known as systemic scleroderma, is a frequently fatal disease in which patients present
with Raynaud phenomenon and sclerodactyly (induration of
the skin of the digits) [see Figure 23]. Cutaneous induration can
become widespread. Involvement of the face can lead to a characteristic appearance with pursed lips and bound-down skin of
the nose that creates a beaklike appearance. Patients with antibodies to Scl-70 have a poor prognosis, often succumbing to renal disease and malignant hypertension. Pulmonary fibrosis can
Figure 22 Erythematous scaling papules on the dorsal aspects of the

knuckles (Gottron papules) are a sign of dermatomyositis.
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Eosinophilic Fasciitis
Scleroderma-like hardening of the skin also occurs in
eosinophilic fasciitis. Puckering of the skin on the extremities
typically develops and is associated with pain. In contrast to
progressive systemic sclerosis, Raynaud phenomenon does not
occur. Definitive diagnosis requires biopsy of skin and fascia
overlying the affected muscle. In some cases of eosinophilic
fasciitis, hematologic abnormalities develop, including aplastic
anemia, thrombocytopenia, Hodgkin disease, and leukemias.77
systemic lupus erythematosus
Figure 23 Sclerodactyly with a nonhealing digital ulcer commonly

occurs in progressive systemic sclerosis.
occur. Patients with anticentromere antibodies have a more
slowly progressive variant of scleroderma known as the CREST
syndrome, which is characterized by cutaneous calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and
telangiectasia. With time, pulmonary hypertension and rightsided heart failure develop.
There are many cutaneous manifestations of systemic lupus

erythematosus (SLE), including nonspecific manifestations such
as Raynaud phenomenon, photosensitivity, alopecia, and mucosal ulcers. More specific cutaneous manifestations of SLE include so-called discoid lupus (characterized by round scarred
skin lesions with central hypopigmentation and a rim of hyperpigmentation) and malar erythema [see 15:IV Systemic Lupus
Erythematosus]. As we learn more about lupus, the spectrum of
skin diseases associated with this disorder continues to expand.
Subacute cutaneous lupus, a variant characterized serologically
by anti-Ro and anti-La antibodies, is associated with annular or
psoriasiform skin lesions [see Figure 25].
Anticardiolipin Antibody Syndrome

The anticardiolipin antibody syndrome, which can occur in
patients with SLE, has been described in patients who suffer re-
Morphea
Morphea, also called localized scleroderma, is characterized
by sharply demarcated patches of indurated skin that can become generalized. It is distinguished from progressive systemic
sclerosis by the absence of Raynaud phenomenon, sclerodactyly, or the systemic complications of scleroderma. There have
been innovations in the treatment of both progressive systemic
sclerosis and morphea. Exposure to psoralen and longwave ultraviolet light (PUVA) has been reported to improve progressive
systemic sclerosis and morphea dramatically,70 and exposure to
UVA1 (the longer UVA spectrum, from 340 to 400 nm) has been
reported to benefit patients with localized scleroderma.71 Anecdotal evidence suggests that topical calcipotriene is an effective
treatment for morphea.72 Further studies must be done to confirm the efficacy of these treatments. Anecdotal reports have indicated that minocycline may benefit patients with progressive
systemic sclerosis, but controlled trials are needed.73
Figure 24 Flat-topped papules are seen in this chronic lichenoid graft

versus host reaction.
Graft versus Host Disease

As organ transplantation becomes more common, another
scleroderma-like illness, graft versus host disease, increases in frequency, particularly after bone marrow transplantation [see 5:X
Transfusion Therapy and 5:XI Hematopoietic Stem Cell Transplantation]. There are two stages of graft versus host disease. The first,
acute graft versus host disease, develops 10 to 40 days after transplantation and consists of an erythematous macular and papular
rash that is often associated with fever, hepatomegaly, lymphadenopathy, or gastrointestinal symptoms. Chronic graft versus host disease usually develops 3 months after transplantation
but can occur later; it consists of purple papules resembling lichen
planus [see Figure 24]. Sclerodermatous skin changes with telangiectasia, reticulated hyperpigmentation, and alopecia are most
characteristic. Both cyclosporine and PUVA have proved to be
useful in the prevention and treatment of graft versus host disease.74,75 Infliximab has been used very successfully to treat acute
graft versus host disease.76
April 2005 Update
Figure 25 Annular scaling erythematous patches are characteristic of

subacute cutaneous lupus erythematosus.
ACP Medicine
peated episodes of phlebitis, arterial thromboses, and repeated

miscarriages. Cutaneous infarcts are common manifestations,
and livedo reticularis can occur. Patients may have false positive
serologies for syphilis and have a circulating lupus anticoagulant. Circulating antiphospholipid antibodies are the serologic
hallmark of this syndrome; however, many asymptomatic persons have antiphospholipid antibodies,78 and antiphospholipid
antibody tests can have false negative results. In some patients, a
battery of tests may be needed to establish diagnosis; the dilute
Russell viper venom time, an assay for circulating lupus anticoagulant, has been found to be among the more sensitive tests.79
Livedo Vasculitis
Livedo vasculitis, another disorder that has been associated
with lupus, is characterized by painful recurrent ulcers over the
lower legs and ankles. The ulcers heal, leaving white sclerotic
scars. Affected patients often have livedo reticularis. This condition, also known as atrophie blanche, has been attributed to
thrombotic processes rather than immune complex deposition
or leukocytoclastic vasculitis.80
Neonatal Lupus
Neonatal lupus is a distinct syndrome of annular, erythematous macules and papules occurring on the face of newborn infants. The disorder has been attributed to transplacental passage
of anti-Ro and occasionally anti-La antibodies. Mothers are often
asymptomatic, but some may have lupus or Sjgren syndrome.
Congenital heart block is the most serious complication of this
disorder.81
The author has served as an investigator, consultant, or speaker for the following
companies: Abbott Laboratories, Inc., Allergen, Inc., Amgen, Inc., Biogen, Inc.,
Centocor, Inc., Connetics Corporation, Fujisawa Healthcare, Inc., Galderma
Laboratories, L.P., Genentech, Inc., Leo Pharmaceuticals, and Warner-Chilcott
Pharmaceuticals.
The FDA has not approved the following drugs for specific uses described in
this chapter: infliximab and TNF- blockers for the treatment of sarcoidosis and
Wegener granulomatosis; rituximab for the treatment of lymphomatoid granulomatosis; and calcipotriene for the treatment of morphea.
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diseases: from incontinentia pigmenti to ectodermal dysplasias and immune-deficiency
syndromes. Hum Mol Genet 11:2371, 2002
58. Dasgupta B, Dugan LL, Gutmann DH: The neurofibromatosis 1 gene product neurofibromin regulates pituitary adenylate cyclase-activating polypeptide-mediated signaling in astrocytes. J Neurosci 23:8949, 2003
59. Xiao GH, Chernoff J, Testa JR: NF2: the wizardry of Merlin. Genes Chromosomes
Cancer 38:389, 2003
60. Nellist M, Sancak O, Goedbloed MA, et al: Distinct effects of single amino-acid
changes to tuberin on the function of the tuberin-hamartin complex. Eur J Hum Genet
2004
61. Germain DP, Shabbeer J, Cotigny S, et al: Fabry disease: twenty novel alpha-galactosidase A mutations and genotype-phenotype correlations in classical and variant phenotypes. Mol Med 8:306, 2002
62. Desnick RJ, Brady R, Barranger J, et al: Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med 138:338, 2003
63. Daoud MS, Hutton KP, Gibson LE: Cutaneous periarteritis nodosa: a clinicopathological study of 79 cases. Br J Dermatol 136:706, 1997
64. Guillevin L, Lhote F, Amouroux J, et al: Antineutrophil cytoplasmic antibodies, abnormal angiograms and pathological findings in polyarteritis nodosa and Churg-Strauss

April 2005 Update
syndrome: indications for the classification of vasculitides of the polyarteritis nodosa

group. Br J Rheumatol 35:958, 1996
65. Poliak S, Lebwohl MG, Parris A, et al: Reactive perforating collagenosis associated
with diabetes mellitus. N Engl J Med 306:81, 1982
66. Arch-Ferrer JE, Beenken SW, Rue LW, et al: Therapy for calciphylaxis: an outcome
analysis. Surgery 134:941, 2003
67. Kasteler JS, Callen JP: Scalp involvement in dermatomyositis: often overlooked or
misdiagnosed. JAMA 272:1939, 1994
68. Buchbinder R, Forbes A, Hall S, et al: Incidence of malignant disease in biopsyproven inflammatory myopathy: a population-based cohort study. Ann Intern Med
134:1087, 2001
69. Hill CL, Zhang Y, Sigurgeirsson B, et al: Frequency of specific cancer types in dermatomyositis and polymyositis: a population based study. Lancet 357:96, 2001
70. Kanekura T, Fukumaru S, Matsushita S, et al: Successful treatment of scleroderma
with PUVA therapy. J Dermatol 23:455, 1996
71. Kerscher M, Volkenandt M, Gruss C, et al: Low-dose UVA phototherapy for treatment of localized scleroderma. J Am Acad Dermatol 38:21, 1998
72. Tay YK: Topical calcipotriol ointment in the treatment of morphea. J Dermatolog
Treat 14:219, 2003
73. Le CH, Morales A, Trentham DE: Minocycline in early diffuse scleroderma. Lancet
352:1755, 1998
74. Zikos P, van Lint MT, Frasoni F, et al: Low transplant mortality in allogeneic bone
marrow transplantation for acute myeloid leukemia: a randomized study of low-dose
cyclosporin versus low-dose cyclosporin and low-dose methotrexate. Blood 91:3503,
1998
75. Vogelsang GB, Wolff D, Altomonte V, et al: Treatment of chronic graft-versus-host
disease with ultraviolet irradiation and psoralen (PUVA). Bone Marrow Transplant
17:1061, 1996
76. Yamane T, Yamamura R, Aoyama Y, et al: Infliximab for the treatment of severe
steroid refractory acute graft-versus-host disease in three patients after allogeneic
hematopoietic transplantation. Leuk Lymphoma 44:2095, 2003
77. Kim SW, Rice L, Champlin R, et al: Aplastic anemia in eosinophilic fasciitis: responses to immunosuppression and marrow transplantation. Haematologia (Budap) 28:131,
1997
78. Tektonidou MG, Sotsiou F, Nakopoulou L, et al: Antiphospholipid syndrome
nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: prevalence, clinical associations, and long-term outcome. Arthritis Rheum
50:2569, 2004
79. Proven A, Bartlett RP, Moder KG, et al: Clinical importance of positive test results for
lupus anticoagulant and anticardiolipin antibodies. Mayo Clin Proc 79:467, 2004
80. McCalmont CS, McCalmont TH, Jorizzo JL, et al: Livedo vasculitis: vasculitis or
thrombotic vasculopathy? Clin Exp Dermatol 17:4, 1992
81. Brucato A, Franceschini F, Buyon JP: Neonatal lupus: long-term outcomes of mothers
and children and recurrence rate. Clin Exp Rheumatol 15:467, 1997
ACP Medicine
II
PA P U L O S Q U A M O U S D I S O R D E R S
ELIZABETH A. ABEL, M.D.
diagnosis
Papulosquamous disorders comprise a group of dermatoses

that have distinct morphologic features.1 The characteristic primary lesion of these disorders is a papule, usually erythematous, that has a variable amount of scale on the surface. Plaques
or patches form through coalescence of the primary lesions.
Some common papulosquamous dermatoses are pityriasis
rosea, lichen planus, seborrheic dermatitis, tinea corporis,
pityriasis rubra pilaris, psoriasis [see 2:III Psoriasis], and parapsoriasis. Drug eruptions, tinea corporis, and secondary
syphilis may also have a papulosquamous morphology. Some
papulosquamous disorders may be a cutaneous manifestation
of AIDS as well.2
The primary lesion, called a herald patch, appears first as a

slightly raised, salmon-colored oval patch with a fine, wrinkled
scale resembling cigarette paper. Typically, 7 to 10 days after
the appearance of the herald patch, there occurs a bilaterally
symmetrical eruption; this eruption occurs mainly on the trunk
and upper extremities [see Figure 1]. Lesions tend to fall in
cleavage planes in a so-called fir tree distribution and are occasionally pruritic. Atypical manifestations occur in 20% of those
affected. Such manifestations include a purpuric form of pityriasis rosea that resembles vasculitis, as well as papular, vesicular, pustular, and urticarial forms. An inverse variant of pityriasis rosea, more common in children than in adults, is characterized by lesions on the face and extremities, with relatively
few lesions appearing on the trunk.4
Pityriasis Rosea
differential diagnosis
Pityriasis rosea is a relatively common, self-limited, exanthematous disease characterized by oval papulosquamous lesions
on the trunk and proximal areas of the extremities. Pityriasis
rosea typically appears during the spring and fall; its incidence
is highest in persons between 10 and 35 years of age.3,4
A population-based, 10-year epidemiologic survey identified
939 patients with pityriasis rosea, about one third of whom had
antecedent acute infection or atopy.5 It also showed that peak incidence occurred at 20 to 24 years of age, that the incidence was
higher in colder months, and that recurrences were rare. Occurrences among household contacts are uncommon. This study
also noted that the incidence of disease had appeared to decline.
Because lesions of pityriasis rosea may closely resemble those

of secondary syphilis, a serologic test for syphilis may be indicated. Lesions may also resemble tinea corporis or tinea versicolor and should be examined by fungal scrapings and potassium hydroxide (KOH) wet mounts. A careful drug history must
be obtained to exclude the possibility of a drug eruption.
etiology
A viral etiology has been suggested for pityriasis rosea on
the basis of immunologic and histologic data. The superficial
dermis contains aggregates of CD4+ helper T cells in perivascular locations and increased numbers of Langerhans cells. It has
been postulated that IgM antibodies to keratinocytes cause the
secondary form of the eruption. An association between human herpesvirus type 7 (HHV-7) and pityriasis rosea was initially reported in 1997.6 More recent studies, however, suggested that pityriasis rosea was not associated with HHV-7; these
studies used polymerase chain reaction and immunohistochemical analyses of tissue samples to detect HHV-7 DNA sequences and antigens. In a retrospective study of 13 patients
and 14 control subjects, the prevalence of HHV-7 was lower in
lesional skin of patients with pityriasis rosea than in control
subjects.7 A subsequent seroepidemiologic study of HHV-6
and HHV-7 was conducted in 44 patients with pityriasis rosea
and in 25 patients with other skin eruptions. Although in this
study several patients with pityriasis rosea had antibody titers
consistent with active infection, the overall prevalence of HHV6 and HHV-7 was no greater in patients with pityriasis rosea
than in control subjects.8 A viral etiology of pityriasis rosea thus
remains elusive.
Certain drugs that cause a pityriasis rosealike eruption
have been implicated in the etiology of this disorder. These
drugs include the antihypertensive agent captopril, metronidazole, isotretinoin (13-cis-retinoic acid), penicillamine, arsenic,
gold, bismuth, barbiturates, and clonidine.4
2002 WebMD Inc. All rights reserved.
June 2002 Update
treatment
Pityriasis rosea lesions resolve spontaneously after 6 to 8
weeks. The patient should be reassured that the disorder is benign and self-limited; such reassurance, together with educating the patient about the disease, is the most important aspect
of treatment. Lesions are variably pruritic. Symptoms should
be treated with bland emollients or systemic antipruritics. Sun
exposure may accelerate clearing. Irradiation with ultraviolet B
(UVB) sunlamps is beneficial in decreasing the severity of disease, especially when treatment is initiated within the first
week of the eruption. One study found that 10 erythemogenic
exposures of UVB substantially decreased the extent of pityriasis rosea, although it neither altered the duration of the disorder nor improved the itching.9
Figure 1 Pityriasis rosea commonly presents with a single large

salmon-colored plaque called a herald patch (arrow). Appearance of the
isolated lesion is followed in a week to 10 days by a bilaterally
symmetrical papulosquamous eruption, mainly on the trunk and upper
extremities.
ACP Medicine
DERMATOLOGY:II Papulosquamous Disorders1
Lichen Planus
Lichen planus is a localized or generalized eruption with
violaceous, flat-topped, polygonal papules and little or no observable scale [see Figure 2]. It is often localized to the oral
mucosa; 25% of patients with oral lichen planus have skin involvement as well.11 The incidence is highest in young to
middle-aged persons. Lichen planus usually appears in the
fifth or sixth decade and affects women more than men.
etiology
In a double-blind, placebo-controlled study in India, oral

erythromycin administered in divided doses for 14 days was
effective in treating patients with pityriasis rosea.10 In this cohort, upper respiratory tract infections preceded the skin
eruption in 68.8% of the 90 patients. A complete response,
with complete resolution of skin lesions occurring within 2
weeks, was reported in 33% of the treatment group, as compared with 0% in the placebo group. The duration of disease
was comparable for both groups of patients. Although not
all patients with pityriasis rosea are benefited by erythromycin therapy, a trial of erythromycin is a safe treatment approach.
The etiology of lichen planus is unknown. An alteration in

basal keratinocytes that induces humoral and cell-mediated
immune responses has been postulated as a mechanism. Skin
and mucous membrane lesions resembling lichen planus have
been observed in patients with graft versus host disease
(GVHD) [see 2:VI Cutaneous Adverse Drug Reactions]. Lichen
planus has also been associated with other immune-mediated
diseases, including ulcerative colitis, bullous pemphigoid,
myasthenia gravis with thymoma, primary biliary cirrhosis,
and chronic active hepatitis.12 There is an increased prevalence
of viral hepatitis, especially hepatitis C,13 in patients with lichen
planus. In an epidemiologic study of 30 sequential patients
with lichen planus in Miami (a geographic area of high reactivity), the prevalence of hepatitis C virus was 23%, compared
with 4.8% in control subjects. Two patients with lichen planus
and hepatitis C recovered after treatment with interferon alfa.
There are a number of reports of lichen planus occurring after
administration of different types of hepatitis B vaccine.14 This is
a rare occurrence, considering the widespread use of this vaccine; several cases have been reported from France and Italy,
and one case has been reported from the Middle East. As with
GVHD, an immunologic mechanism has been postulated as
the cause. The latency period ranges from several days to 3
months after any one of the three usual injections of vaccine.
A variety of drugs have been reported to cause lichenoid reactions in the skin, usually sparing the mucous membranes.
Such drugs include beta blockers, methyldopa, penicillamine,
quinidine, and quinine. Other drugs that have been implicated
but for which causal evidence is insufficient include angiotensin-converting enzyme inhibitors, sulfonylurea agents,
carbamazepine, gold, and lithium.15 In one study, the administration of penicillamine for primary biliary cirrhosis was followed by the development of lichen planus in 17 of 24 patients16;
Figure 3 The Koebner phenomenon, the appearance of lesions along
Figure 4 Lichen planus of the mucous membrane assumes a white,
a scratch line, may be seen in patients with lichen planus.
reticulated mosaic pattern, as seen above on the buccal mucosa.
Figure 2 Violaceous, flat-topped, polygonal papules are typical of

lichen planus. A common location is the flexor aspect of the wrists and
forearms.

June 2002 Update
ACP Medicine
in addition, after treatment with penicillamine, the skin eruption became worse in three of seven patients with biliary cirrhosis and preexisting lichen planus. Nonsteroidal anti-inflammatory agents have been documented to cause a lichenoid drug
eruption; these drugs include naproxen, indomethacin, diflunisal, ibuprofen, acetylsalicylic acid, and salsalate.17 Although
the latency period is highly variable, symptoms usually develop
within a few months after drug initiation and resolve within
weeks to months after discontinuance of the offending agent.
diagnosis
Lichen planus appears as flat-topped, shiny, violaceous
papules, often with a fine, reticulated scale on the surface.
Common sites of involvement include the skin, nails, mucous
membranes, vulva, and penis. Wickham striaewhite lacy
patterns on the papule surfaceare apparent on magnification
with a hand lens.18 The occurrence of papules along a scratch
line, as in linear lichen planus, is referred to as the Koebner
phenomenon [see Figure 3]. In the hypertrophic form of the disease, papules coalesce to form thick plaques or nodules that are
often found on the lower extremities. Pruritus may be severe,
particularly in the generalized or hypertrophic forms of the disease. Common sites of involvement are the flexor surfaces of
the wrists, the sacrum, the mucous membranes of the mouth,
the medial thighs, and the genitalia. Mucous membrane lesions
show a white, reticulated mosaic pattern [see Figure 4]. A severe
erosive form of lichen planus can involve the oral mucous
membranes. In rare cases, lesions occur in the esophagus, causing esophageal stricture and dysphagia.19
A follicular form known as lichen planopilaris may result in
scarring alopecia. Variants of lichen planus with distinct morphologic features include actinic, annular, bullous, hypertrophic, linear, ulcerative, and zosteriform forms. The nails
may also be involved [see 2:XIV Disorders of Nails]. The clinical
features of some forms of lichen planus may resemble those of
lupus erythematosus.18
Skin biopsy confirms the clinical diagnosis of lichen planus.
Typically, the epidermis shows hyperkeratosis, a prominent
granular layer, liquefaction degeneration of the basal cell layer,
and an intense upper dermal inflammatory infiltrate. Immunoperoxidase studies using monoclonal antibodies to cell surface
antigens have shown that most cells in the infiltrate are of
the helper-inducer T cell subset. Colloid bodies (Civatte bodies)
coated with immunoglobulin are frequently seen in the dermal
papillae. On ultrastructural examination, numerous Langerhans cells can be observed at the dermoepidermal junction.
treatment
Patients who experience an acute outbreak of lichen planus
have a good prognosis; in most cases, the papules clear within
several months to a year. The chronic form, however, may last
for 10 years or longer. The long-term course of lichen planus
was followed in 214 patients for 8 to 12 years. In two thirds of
the patients, lichen planus had cleared within 1 year. The recurrence rate was 49%, which was higher than recurrence rates reported in previous studies; the authors attributed the high rate
of recurrence to treatment with potent topical corticosteroids.20
Emollients, topical glucocorticoids, a short course of systemic corticosteroids, and systemic antipruritics have been
used to treat the symptoms of lichen planus. Oral metronidazole is an alternative therapy that may have immunomodulatory and antimicrobial action.21 In a trial of oral psoralen pho 2002 WebMD Inc. All rights reserved.
June 2002 Update
tochemotherapy for widespread recalcitrant lichen planus,

clinical remission occurred in six of seven patients and correlated with the disappearance of the upper dermal infiltrate.22 Systemic retinoids, such as acitretin, are beneficial in some patients
with oral and cutaneous forms of lichen planus. Azathioprine
has been used for its steroid-sparing effect in erosive and generalized lichen planus.23 Recombinant interferon alfa-2b, administered subcutaneously every other day, was successful in
the treatment of generalized lichen planus in three patients
with no evidence of hepatitis, further supporting the cell-mediated immunologic etiology of this disease.24 Oral cyclosporine
has also been effective, but potential renal toxicity and hypertension limit its long-term use.18
For lichen planus that is localized to the oral mucosa, a highpotency corticosteroid such as clobetasol in a vehicle that is adherent to the mucosal surface (Orabase) is helpful.25 Intralesional injections of corticosteroids may be used to treat localized,
recalcitrant lesions. Use of miconazole gel in combination with
chlorhexidine mouth rinses is effective for prophylaxis against
oral candidiasis.25 Topical isotretinoin gel is an effective alternative to corticosteroids, although relapses often occur after discontinuance of this medication.26 In a double-blind, placebocontrolled study of 22 patients with biopsy-proven oral lichen
planus, an 8-week course of 0.1% isotretinoin gel was found to
be effective.26 Cyclosporine mouth rinses have been helpful for
some patients. Topical tacrolimus, a macrolide that suppresses
T cell activation, was used to treat erosive mucosal lichen
planus in six patients whose conditions were resistant to conventional treatment. In three of the patients, disease resolved
completely; the other three patients experienced significant improvement of the symptoms of pain and burning.27 A 6-month
course of hydroxychloroquine, 200 to 400 mg daily, was successful as monotherapy in nine of 10 patients with oral lichen
planus; ulcers healed and pain decreased after 1 to 2 months.28
Seborrheic Dermatitis
Seborrheic dermatitis is a papulosquamous condition that is
often associated with excessive oiliness or seborrhea, dandruff,
and well-defined red, scaly patches on the face, trunk, and intertriginous areas.29 Some cases may progress to a severe exfoliative erythroderma. Seborrheic dermatitis is a common skin
disorder that occurs in otherwise healthy adults. It is increasingly prevalent in middle-aged and elderly persons. Seborrheic dermatitis does not occur before puberty except during infancy (usually between 2 and 12 weeks of age), at which time
transplacentally derived maternal hormones are present. The
prognosis in adults is one of lifelong recurrence, with each
episode lasting weeks to months.
etiology
The cause of seborrheic dermatitis is unknown. An occasional association with neurologic abnormalities, especially parkinsonism, has been observed. Genetic predisposition, emotional
stress, diet, hormones, and climatic factors may also influence
this disorder. Infection with the yeastlike organism Pityrosporum has also been implicated.
Patients with classic seborrheic dermatitis may have normal
or reduced rates of sebum excretion; therefore, seborrhea is not
essential for the development of this disorder.30 However, seborrhea may play a role in the seborrheic dermatitis present in
certain patients, such as those with parkinsonism. Reduction of
ACP Medicine
of eczema. Seborrheic dermatitis of the face may resemble the

facial lesions found in lupus erythematosus or other photosensitivity dermatoses. Lesions on the trunk may be confused with
tinea versicolor, but the latter is easily excluded by skin scraping and KOH preparation or Wood light examination. Atopic
dermatitis and psoriasis, especially when partially treated, are
also included in the differential diagnosis.
seborrheic dermatitis associated with aids
Severe seborrheic dermatitis can be one of the most common
and earliest manifestations of AIDS. From 30% to 80% of patients with AIDS have seborrheic dermatitis, compared with
3% to 5% of HIV-negative young adults.31 Lesions may be explosive in onset and are often resistant to therapy. Clinical features include a predominantly inflammatory papular eruption
on the face, with a tendency to spare the scalp, in contrast to the
mild erythema and scaling of the scalp typical of seborrheic
dermatitis in persons without AIDS. Truncal involvement in
seborrheic areas is common in AIDS patients, and the lesions
may resemble psoriasis. Although the cause of the association
of seborrheic dermatitis with AIDS is unknown, immunologic
dysfunction may lead to an overgrowth of the yeast P. orbiculare in seborrheic areas.
Skin biopsy specimens from AIDS patients with seborrheic
dermatitis have distinct histologic features, including keratinocyte necrosis, leukoexocytosis, a superficial perivascular
infiltrate of plasma cells, and, frequently, neutrophils.32
Figure 5 Seborrheic dermatitis seen on the face of this patient
involves sites of sebaceous gland activity.
seborrhea with improvement of the dermatitis has been observed after a favorable neurologic response to levodopa treatment for parkinsonism.
diagnosis
The scale associated with seborrheic dermatitis may be yellowish and either dry or greasy. Sites of predilection are in areas of sebaceous gland activity [see Figure 5], such as the scalp,
eyebrows, eyelids, forehead, nasolabial folds, and presternal or
interscapular regions. Blepharitis involves granular inflammation of the lid margin with scaling and shedding of debris into
the eye, which may cause conjunctivitis. Seborrheic dermatitis
is the most common cause of otitis externa. When the scalp is
involved, lesions often extend along the frontal hairline, forming a band of erythema. The postauricular area is a common
site of involvement. Lesions of the trunk may consist of erythematous follicular papules covered by greasy scales, which may
coalesce to form large plaques or circinate patches. Seborrheic
dermatitis can be seen in areas of male pattern baldness, but it
is not a cause of hair loss unless there has been a severe intervening secondary infection resulting in a scarring alopecia.
Seborrheic dermatitis should be considered in the differential diagnosis of chronic eczematous dermatitis and in that of
papulosquamous disorders, particularly psoriasis. The clinical
features of seborrheic dermatitis limited to the scalp and face
may resemble those associated with psoriasis, giving rise to the
term sebopsoriasis. Histologic features range from psoriasiform changes of acanthosis and parakeratosis to the spongiosis
June 2002 Update
treatment
The condition on the scalp usually responds well to frequentas often as dailyshampooing with a preparation containing 3% to 5% sulfur and 2% to 3% salicylic acid. For the face
and nonhairy areas, a mild cream containing precipitated 3%
sulfur and 3% salicylic acid is effective. Involved areas also respond well to low-potency topical glucocorticoids, such as 1%
hydrocortisone cream or desonide cream. Caution, however,
must be exercised in the use of high-potency fluorinated steroid
preparations, especially on the face and in skin folds; prolonged
application may lead to chronic skin changes, such as atrophy
and telangiectasia. Wet dressings followed by a topical antibiotic
preparation are helpful in treating intertriginous areas, in which
maceration and superficial secondary infection may occur.
Ketoconazole has a potent antifungal effect on the lipophilic
yeast Pityrosporum, which is an etiologic factor in seborrheic
dermatitis. In one study, 575 patients with seborrheic dermatitis underwent twice-weekly treatments with 2% ketoconazole
shampoo; an excellent response was seen in 88% of the patients.33 Continued prophylactic treatment once weekly over 6
months was helpful in preventing relapse of the disorder in a
significant number of patients.
In a study of the effect of ketoconazole on living and killed
Staphylococcus aureus in an animal model, ketoconazole was
found to have antibacterial and anti-inflammatory effects when
compared with hydrocortisone acetate. The anti-inflammatory
effect was caused by ketoconazoles inhibition of the lipoxygenase pathway, which resulted in a decrease in the production
of leukotrienes. Ketoconazole inhibits keratinocytes by interfering with cholesterol biosynthesis.34
In a trial of 38 patients with seborrheic dermatitis, 1%
metronidazole gel was found to be effective. Improvement was
noted after 2 weeks, and marked improvement or complete
clearing was noted at 8 weeks.35
ACP Medicine
Seborrheic blepharitis may be treated by applying baby

shampoo with a cotton-tipped applicator to debride scales. If
topical corticosteroids are required, the patient should be referred to an ophthalmologist to monitor potential side effects to
the eye, such as increased intraocular pressure, glaucoma,
cataracts, and activation of latent herpes infection.1
Treatment of HIV-associated seborrheic dermatitis is similar
to that of seborrheic dermatitis in general, although HIV-associated seborrheic dermatitis is apt to be recalcitrant, requiring
intensive, prolonged therapy. Treatment of the underlying HIV
infection may lead to improvement of the associated seborrheic dermatitis.
Pityriasis Rubra Pilaris
Figure 7 Plantar hyperkeratosis and confluent erythematous
Pityriasis rubra pilaris is a relatively uncommon chronic inflammatory dermatosis that is considered to be a disorder of
keratinization. The age distribution is bimodal, occurring either
in childhood or in the fifth decade; the clinical course is variable. An autosomal dominant inheritance has been postulated
for the juvenile form of the disease.36 Patients with the classic
adult form of the disease have the best prognosis; resolution
usually occurs over a 3-year period.
follicular papules typical of pityriasis rubra pilaris are seen on the

ankle and foot of this patient.
diagnosis
Typically, pityriasis rubra pilaris initially manifests as a seborrheic dermatitislike eruption that occurs in sun-exposed areas of the body; there then occurs the development of follicular papules that coalesce into psoriasiform patches on the
trunk and extremities, with progression to erythroderma.
Generalized involvement is characterized by yellow-orange
erythema with desquamation. Diffuse areas of involvement
Figure 6 Islands of spared skin within a background of diffuse

erythema are present on the legs of this patient with pityriasis rubra
pilaris.

June 2002 Update
generally show islands of spared skin [see Figure 6]. Additional

features are palmoplantar hyperkeratosis [see Figure 7] and
prominent follicular plugging over the dorsal aspects of the
fingers. Pruritus is usually mild or absent. A pityriasis rubra
pilarislike eruption with follicular hyperkeratosis is a littleknown but distinctive cutaneous manifestation of dermatomyositis.37
treatment
The response of patients with pityriasis rubra pilaris to
conventional antipsoriatic therapies, such as topical corticosteroids, tars, and oral methotrexate, is often unsatisfactory;
some patients, however, have shown a favorable response to
topical calcipotriene (known outside the United States as calcipotriol).38 Ultraviolet B phototherapy may exacerbate the
disease.39 High-dose vitamin A in excess of 200,000 IU daily
has been used but can cause liver or central nervous system
toxicity. An oral retinoid such as etretinate or, more recently,
acitretin is indicated for the treatment of pityriasis rubra pilaris in men and postmenopausal women. In an early study
involving 45 patients with pityriasis rubra pilaris, isotretinoin
produced definite improvement in 50% of the patients after 4
weeks of therapy.40 Remission of up to 6 months was sustained in some patients after the drug was withdrawn. Longterm use of this drug in patients with keratinizing disorders
has been associated with irreversible skeletal toxicity. Because
teratogenicity is a concern, women of childbearing age must
use effective birth control with either agent. Although acitretin has a shorter half-life and is, therefore, less teratogenic
than etretinate, ingestion of alcohol can convert acitretin to
the prodrug etretinate; thus, the risk of birth defects associated with acitretin would be the same as that incurred with
etretinate.
In one study, retinoid therapy consisting mainly of etretinate,
25 to 75 mg/day, or isotretinoin resulted in 25% to 75% improvement in 17 of 24 patients after 16 weeks of therapy.41 Concomitant or subsequent methotrexate therapy was used in 11 of
these patients who had recalcitrant disabling disease. There is
concern, however, about potential hepatotoxicity in patients receiving this combination. Cyclosporine, 5 mg/kg/day, was effective in the treatment of three adult patients with pityriasis
rubra pilaris. A favorable response was noted within 2 to 4
weeks of initiation of therapy, but relapse occurred when the
dose was decreased to 1.2 mg/kg/day.42
ACP Medicine
Parapsoriasis
Parapsoriasis encompasses a variety of relatively uncommon chronic inflammatory dermatoses of unknown etiology
that are resistant to conventional treatment. Despite the designation parapsoriasis, the clinical appearance of the noninfiltrated scaly patches or plaques is distinct from that of psoriatic lesions. Classification of these disorders is controversial and further complicated by the use of several terms to denote a single
entity and by the use of various systems of nomenclature. A
proposed standard nomenclature divides parapsoriasis into
two distinct subgroups: pityriasis lichenoides, which may be
acute or chronic, and small- and large-plaque parapsoriasis.43
pityriasis lichenoides
Diagnosis
Figure 9 The digitate variant of small-plaque parapsoriasis is seen

in this patient.
The acute form of pityriasis lichenoides, also known as

pityriasis lichenoides et varioliformis acuta (PLEVA) or
Mucha-Habermann disease, is characterized by the abrupt onset of a generalized eruption of reddish-brown maculopapules
that evolve during a period of weeks to months. Lesions are
typically present at all stages of evolution and may be vesicular, hemorrhagic, crusted, or necrotic [see Figure 8]. Healing
with varioliform scarring is common. Nonspecific histologic
features include intraepidermal lymphocytes and erythrocytes,
dermal hemorrhage, and a lymphocytic vasculitis.44 Skin lesions of PLEVA may resemble those of lymphomatoid papulosa, which has immunohistologic features of a CD30+ cutaneous T cell lymphoma. Lymphomatoid papulosa occurs as a
chronic, recurrent, self-healing papulonodular eruption; an association with mycosis fungoides has been observed in some
patients. T cell clonality has been documented by PCR in 20 patients with PLEVA; similar findings have been made in patients with lymphomatoid papulosis.45 Investigators have suggested that PLEVA is a lymphoproliferative process rather
Figure 10 Large-plaque parapsoriasis as seen on the buttocks of this

patient may eventuate in cutaneous T cell lymphoma.
than an inflammatory reaction to various trigger factors, such
as infectious agents.
A chronic form of pityriasis lichenoides, pityriasis lichenoides
chronica, shows milder skin changes without necrosis. Lesions
evolve during a period of weeks and may recur over many years.
Treatment
Figure 8 Hemorrhagic brown-crusted varioliform papules are

present on the lower legs of this patient with the acute form of
pityriasis lichenoides.

June 2002 Update
Treatment of both acute and chronic forms of pityriasis

lichenoides is generally unsatisfactory. Topical corticosteroids,
tars, and systemically administered methotrexate have all been
tried, with variable success. Ultraviolet radiation from sunlamps46 and oral psoralen photochemotherapy47 may have a
beneficial effect on the course of disease. Treatment with highdose tetracycline, 2 g/day for 1 month or more, has also been
effective in clearing the condition.48 Minocycline, 100 mg once
or twice daily, is also beneficial. A rare type of PLEVA known
as Degos disease (also called malignant atrophic papulosis),
characterized by fever and hemorrhagic and papulonecrotic lesions, responds rapidly to the administration of methotrexate
[see 15:VIII Systemic Vasculitis Syndromes].49
ACP Medicine
parapsoriasis; such findings suggest a similarity to lesions of

mycosis fungoides, although epidermotropism is absent.51 Patients with this form of the disease should be evaluated with repeated biopsies of untreated lesions. Once a definitive diagnosis of mycosis fungoides has been established, specific treatment of this disease may be instituted.
Treatment
Treatment of large- and small-plaque parapsoriasis is similar
to that of pityriasis lichenoides chronica [see Pityriasis Lichenoides, above].
Erythroderma
Papulosquamous and psoriasiform eczematous dermatitis
may progress to generalized skin involvement with erythema
and scaling, known as exfoliative erythroderma. Other causes
of erythroderma include drug eruption, contact dermatitis, and
pityriasis rubra pilaris. Eyrthroderma is a rare skin disorder
that occurs more often as an exacerbation of a preexisting skin
disorder; less commonly, it is idiopathic. There are no accurate
studies on the incidence of erythroderma. However, on the basis of a survey of all dermatologists in The Netherlands, the annual incidence was estimated to be 1 to 2 patients per 100,000
inhabitants.52
Figure 11 Erythroderma, which appears as total skin erythema and
scaling, can occur as a result of papulosquamous and eczematous
disorders caused by a variety of diseases. Cutaneous T cell lymphoma,
as seen in this patient with Szary syndrome, can result in erythroderma.
small- and large-plaque parapsoriasis
Diagnosis
Small-plaque parapsoriasis consists of slightly scaly, thin,
oval erythematous plaques of less than 5 cm in diameter, commonly located on the trunk and proximal extremities. The variantdigitate dermatosisshows elongated lesions falling
along lines of skin cleavage. The two diseases follow similar
chronic, benign courses [see Figure 9].
Clinically, large-plaque parapsoriasis consists of slightly
thickened, red-brown, scaly plaques that are more than 10 cm
in diameter and have ill-defined borders; such lesions are present mainly on the proximal extremities and the buttocks and
on the breasts of women [see Figure 10]. Frequently, there is a
component of poikiloderma, which includes mottled hyperpigmentation and hypopigmentation, atrophy, and telangiectasia.
Early lesions may show a nonspecific histology; late lesions
show atypical lymphocytes within the epidermis.
It is important to differentiate large-plaque parapsoriasis
from the small-plaque form because about 10% of cases of
large-plaque parapsoriasis result in a cutaneous T cell lymphoma (mycosis fungoides).43 Large-plaque lesions may be present for many years before malignant transformation is recognized histologically. The malignant change is suggested clinically by increased pruritus and progressive induration of lesions. The retiform variant may show prominent poikiloderma
with atrophy and has a greater potential for malignant transformation.50 Studies of T cell subsets using monoclonal antibodies to membrane markers have shown a variable predominance of helper T cells in the cutaneous infiltrates in atrophic
June 2002 Update
diagnosis
Most cases of exfoliative erythroderma are associated with
exacerbation of an underlying dermatosis, such as psoriasis,
pityriasis rubra pilaris, seborrheic dermatitis, drug eruptions,
atopic dermatitis, or contact dermatitis. Some patients have idiopathic erythroderma, also called red man syndrome.51 Common associated skin findings include palmoplantar keratoderma, alopecia, and nail dystrophy. Skin biopsy usually shows
nonspecific inflammation. Lymph node biopsy may reveal dermatopathic lymphadenopathy. In some patients, idiopathic
erythroderma may progress to cutaneous T cell lymphoma
(e.g., erythrodermic mycosis fungoides and Szary syndrome)
[see Figure 11] [see 2:X Malignant Cutaneous Tumors].
Systemic symptoms associated with erythroderma include
fever and chills, dehydration from transepidermal water loss,
and high-output cardiac failure.
treatment
Nonspecific treatment includes restoration of fluid and electrolyte balance and supportive measures such as administration of antipruritics, application of cool compresses and mild
topical corticosteroids, and bed rest. Antibiotics may be required for treatment of secondary bacterial infection. Generally, more aggressive topical and systemic therapies are avoided
until the inflammation subsides. More specific treatment depends on the underlying diagnosis and cause of the erythroderma. For example, in patients with erythroderma that is secondary to Szary syndrome, treatment would be directed toward the underlying cutaneous T cell lymphoma [see 2:X
Malignant Cutaneous Tumors]. For erythroderma caused by a
drug eruption, the offending drug must be discontinued. Systemic agents such as acitretin and methotrexate may be used to
treat psoriatic erythroderma [see 2:III Psoriasis].
The author has no commercial relationships with manufacturers of products or
providers of services discussed in this subsection.
ACP Medicine
References
1. Fox BJ, Odom RB: Papulosquamous diseases: a review. J Am Acad Dermatol 12:597,
1985
2. Sadick NS, McNutt NS, Kaplan MH: Papulosquamous dermatoses of AIDS. J Am
Acad Dermatol 22:1270, 1990
3. Allen RA, Janniger CK, Schwartz RA: Pityriasis rosea. Cutis 56:198, 1995
4. Chuang T-Y, Ilstrup DM, Perry HO, et al: Pityriasis rosea in Rochester, Minnesota,
1969 to 1978: a 10-year epidemiologic study. J Am Acad Dermatol 7:80, 1982
5. Parsons JM: Pityriasis rosea update: 1986. J Am Acad Dermatol 15:159, 1986
6. Drago F, Ranieri E, Malaguti F, et al: Human herpesvirus 7 in 7 patients with pityriasis rosea. Dermatology 195:374, 1997
7. Kempf W, Adams V, Kleinhans M, et al: Pityriasis rosea is not associated with human
herpesvirus 7. Arch Dermatol 135:1070, 1999
8. Kosuge H, Tanaka-Taya K, Miyoshi H, et al: Epidemiological study of human herpesvirus6 and human herpesvirus7 in pityriasis rosea. Br J Dermatol 143:795, 2000
9. Leenutaphong V, Jiamton S: UVB phototherapy for pityriasis rosea: a bilateral comparison study. J Am Acad Dermatol 33:996, 1995
10. Sharma PK, Yadav TP, Gautam RK, et al: Erythromycin in pityriasis rosea: a doubleblind placebo-controlled clinical trial. J Am Acad Dermatol 42:241, 2000
11. Bricker SL: Oral lichen planus: a review. Semin Dermatol 13:87, 1994
12. Shai A, Halevy S: Lichen planus and lichen planus-like eruptions: pathogenesis and
associated diseases. Int J Dermatol 31:379, 1992
13. Bellman B, Reddy R, Falanga V: Generalized lichen planus associated with hepatitis
C virus immunoreactivity. J Am Acad Dermatol 35:770, 1996
14. Al-Khenaizan S: Lichen planus occurring after hepatitis B vaccination: a new case. J
Am Acad Dermatol 45:614, 2001
15. Thompson DF, Skaehill PA: Drug-induced lichen planus. Pharmacotherapy 14:561,
1994
16. Powell FC, Rogers RS III, Dickson ER: Primary biliary cirrhosis and lichen planus. J
17. Powell ML, Ehrlich A, Belsito DV: Lichenoid drug eruption to salsalate. J Am Acad
Dermatol 45:616, 2001
18. Boyd AS, Neldner KH: Lichen planus. J Am Acad Dermatol 25:593, 1991
19. Abraham SC, Ravich WJ, Anhalt GJ, et al: Esophageal lichen planus: case report and
review of the literature. Am J Surg Pathol 24:1678, 2000
20. Irvine C, Irvine F, Champion RH: Long-term follow-up of lichen planus. Acta Derm
Venereol 71:242, 1991
21. Byk AY, Kavala M: Oral metronidazole treatment of lichen planus. J Am Acad
Dermatol 43:260, 2000
22. Ortonne JP, Thivolet J, Sannwald C: Oral photochemotherapy in the treatment of
lichen planus (LP): clinical results, histological and ultrastructural observations. Br J
Dermatol 99:77, 1978
23. Lear JT, English JS: Erosive and generalized lichen planus responsive to azathioprine. Clin Exp Dermatol 21:56, 1996
24. Hildebrand A, Kolde G, Luger TA, et al: Successful treatment of generalized lichen
planus with recombinant interferon alfa-2b. J Am Acad Dermatol 33:880, 1995
25. Carbone M, Conrotto D, Carrozzo M, et al: Topical corticosteroids in association
with miconazole and chlorhexidine in the long-term management of atrophic-erosive
oral lichen planus: a placebo-controlled and comparative study between clobetasol and
fluocinonide. Oral Dis 5:44, 1999
26. Giustina TA, Stewart JB, Ellis CN, et al: Topical application of oral isotretinoin gel
improves oral lichen planus: a double-blind study. Arch Dermatol 122:534, 1986
27. Vente C, Reich K, Rupprecht R, et al: Erosive mucosal lichen planus: response to topical treatment with tacrolimus. Br J Dermatol 140:338, 1999

June 2002 Update
28. Eisen D: Hydroxychloroquine sulfate (Plaquenil) improves oral lichen planus: an

open trial. J Am Acad Dermatol 28:609, 1993
29. Plewig G: Seborrheic dermatitis. Dermatology in General Medicine, 4th ed, Vol 1.
Fitzpatrick TB, Eisen AZ, Wolff K, et al, Eds. McGraw-Hill Book Co, New York, 1993,
p 1569
30. Burton JL, Pye RJ: Seborrhoea is not a feature of seborrhoeic dermatitis. Br Med J
26:1169, 1983
31. Odom RB: Common superficial fungal infections in immunosuppressed patients. J
Am Acad Dermatol 31:S56, 1994
32. Soeprono FF, Schinella RA, Cockerell CJ, et al: Seborrheic-like dermatitis of acquired
immunodeficiency syndrome: a clinicopathologic study. J Am Acad Dermatol 14:242,
1986
33. Peter RU, Richarz-Barthauer U: Successful treatment and prophylaxis of scalp seborrhoeic dermatitis and dandruff with 2% ketoconazole shampoo: results of a multicentre, double-blind, placebo-controlled trial. Br J Dermatol 132:441, 1995
34. Van Cutsem J, Van Gerven F, Cauwenbergh G, et al: The anti-inflammatory effects
of ketoconazole. J Am Acad Dermatol 25:257, 1991
35. Parsad D, Pandhi R, Negi KS, et al: Topical metronidazole in seborrheic dermatitis
a double-blind study. Dermatology 202:35, 2001
36. Dicken CH: Treatment of classic pityriasis rubra pilaris. J Am Acad Dermatol 31:997,
1994
37. Requena L, Grilli R, Soriano L, et al: Dermatomyositis with a pityriasis rubra pilarislike eruption: a little-known distinctive cutaneous manifestation of dermatomyositis. Br
J Dermatol 136:768, 1997
38. Van de Kerkfho PC, Steijlen PM: Topical treatment of pityriasis rubra pilaris with
calcipotriol. Br J Dermatol 130:675, 1994
39. Yaniv R, Barzilai A, Trau H: Pityriasis rubra pilaris exacerbated by ultraviolet B phototherapy (letter). Dermatology 189:313, 1994
40. Goldsmith LA, Weinrich AE, Shupack J: Pityriasis rubra pilaris response to 13-cisretinoic acid (isotretinoin). J Am Acad Dermatol 6:710, 1982
41. Clayton BD, Jorizzo JL, Hitchcock MG, et al: Adult pityriasis rubra pilaris: a 10-year
case series. J Am Acad Dermatol 36:959, 1997
42. Usuki K, Sekiyama M, Shimada S, et al: Three cases of pityriasis rubra pilaris successfully treated with cyclosporin A. Dermatology 200:324, 2000
43. Lambert WC, Everett MA: The nosology of parapsoriasis. J Am Acad Dermatol
5:373, 1981
44. Hood AF, Mark EJ: Histopathologic diagnosis of pityriasis lichenoides et varioliformis acuta and its clinical correlation. Arch Dermatol 118:478, 1982
45. Dereure O, Levi E, Kadin ME: T-cell clonality in pityriasis lichenoides et varioliformis acuta: a heteroduplex analysis of 20 cases. Arch Dermatol 136:1483, 2000
46. LeVine MJ: Phototherapy of pityriasis lichenoides. Arch Dermatol 119:378, 1983
47. Satra KH, DeLeo VA: PUVA for photosensitivity and other skin diseases. Photochemotherapy in Dermatology. Abel EA, Ed. Igaku-Shoin Medical Publishers, New
York, 1991, p 159
48. Humbert P, Treffel P, Chapuis J-F, et al: The tetracyclines in dermatology. J Am
49. Fink-Puches R, Soyer HP, Kerl H: Febrile ulceronecrotic pityriasis lichenoides et varioliformis acuta. J Am Acad Dermatol 30:261, 1994
50. Kikuchi A, Naka W, Harada T, et al: Parapsoriasis en plaques: its potential for progression to malignant lymphoma. J Am Acad Dermatol 29:419, 1993
51. Thestrup-Pedersen K, Halkier-Sorensen L, Sogaard H, et al: The red man syndrome:
exfoliative dermatitis of unknown etiology: a description and follow-up of 38 patients. J
52. Sigurdsson V, Steegmans PH, van Vloten WA: The incidence of erythroderma: a
survey among all dermatologists in The Netherlands. J Am Acad Dermatol 45:675, 2001
ACP Medicine
III
PSORIASIS
Elizabeth A. Abel, m.d.

Mark Lebwohl, m.d.
Psoriasis is an immune-mediated inflammatory cutaneous disorder characterized by chronic, scaling, erythematous patches
and plaques of skin. It can begin at any age and can vary in
severity. Psoriasis can manifest itself in several different forms,
including pustular and erythrodermic forms. In addition to involving the skin, psoriasis frequently involves the nails, and
some patients may experience inflammation of the joints (psoriatic arthritis). Because of its highly visible nature, psoriasis
can compromise both the personal and the working lives of its
victims.
Breakthroughs in the treatment of psoriasis have led to a better understanding of its pathogenesis. This chapter reviews current knowledge of the genetics, pathogenesis, and treatment of
psoriasis.
Epidemiology
The estimated prevalence of psoriasis ranges from 0.5% to
4.6% worldwide. The reasons for the geographic variation in
prevalence are unknown, but climate and genetics may play a
role. Psoriasis is uncommon in blacks in tropical zones, but it is
more often seen in blacks in temperate zones. It occurs commonly in Japanese persons but rarely in persons native to North and
South America. In the United States, studies have variously reported that 4.5 million adults1 or 7 million adults and children2
have psoriasis.
Psoriasis can occur at any age, with some cases being reported
at birth and others being reported in patients older than 100
years. In Farber and Nalls pioneer study of 5,600 patients, the
average age of onset of psoriasis was 27.8 years; in 35% of patients, onset occurred before 20 years of age, and in 10%, onset
occurred before 10 years of age.3 Psoriasis occurs with equal frequency in men and women, but in Farber and Nalls study, onset occurred later in men. In populations in which there is a high
prevalence of psoriasis, onset tends to occur at an earlier age. In
the Faroe Islands, for example, the prevalence is 3%, and the average age of onset is 12.5 years. The average age of onset is 23
years in the United States. In persons with earlier age of onset,
psoriasis is more likely to be severe, with involvement of a large
area of skin surface.
Pathogenesis
Psoriasis was once thought to be caused by an abnormality in
epidermal cell kinetics; it is now thought that an abnormality in
the immune system triggers epidermal proliferation. The role of
activated lymphocytes in the development of psoriasis was first
proved through investigations of DAB389 interleukin-2 (IL-2), a
fusion protein consisting of molecules of IL-2 fused to diphtheria
toxin. This fusion protein binds to high-affinity IL-2 receptors on
activated T cells, destroying those cells. In a study of DAB389
IL-2 treatment in 10 patients, four patients showed dramatic clinical improvement and four others showed moderate improvement.4 Unfortunately, the side effects of DAB389 IL-2 have precluded its approval for the treatment of psoriasis.5
April 2005 Update
The skin of patients with lesional psoriasis has higher numbers of antigen-presenting cells that can activate T cells. For T cell
activation to occur, antigen-presenting cells must deliver at least
two signals to resting T cells. The first signal occurs when major
histocompatibility complex (MHC) class II molecules of the antigen-presenting cells present antigens to the T cells. A second costimulatory signal must be delivered through the interaction of
ligands on the surface of the antigen-presenting cells with receptors on the surface of T cells. Examples of this process include the
interaction of B7 molecules with CD28 on the surface of resting T
cells and the interaction of lymphocyte functionassociated antigen 3 (LFA-3) with CD2 or intercellular adhesion molecule1
(ICAM-1) with LFA-1 on the surface of T cells.6,7 Blockade of any
of these steps results in clearing of psoriasis.8,9 Upon activation, T
cells release Th1 (T helper type 1) cytokines, IL-2, and interferon
gamma, which together induce proliferation of keratinocytes
and further stimulation of T cells. Inflammatory cytokines such
as tumor necrosis factor (TNF-) are found in psoriatic skin lesions and joints, and treatment with TNF- blockers results in
clearing of psoriasis and of psoriatic arthritis.10
Etiology
genetic factors
Several lines of evidence suggest that psoriasis has a genetic
etiology. One third of persons affected have a positive family
history. Studies have found a higher concordance rate in
monozygotic twins than in dizygotic twins or siblings (70% versus 23%).11
Current evidence suggests genetic heterogeneity. Both autosomal dominant inheritance with incomplete penetrance and
polygenic or multifactorial inheritance have been described. The
most important psoriasis susceptibility gene appears to be
PSORS1, which has been mapped to the region on chromosome
6p21 that codes for the MHC; seven other PSORS genes have
been found on other chromosomes.12 Psoriasis is also associated
with a single-nucleotide polymorphism on chromosome 17q25
that impairs binding of a runt-related protein (RUNX1).13
contributing factors
The course and severity of psoriasis can be affected by a number of endogenous and exogenous factors, including stress, climate, concurrent infections, and medications.
Psychological Stress
Many patients believe that anxiety or psychological stress has
an adverse effect on the course of their psoriasis. The etiologic
significance of stress in psoriasis is difficult to evaluate, however,
because of the subjective nature of the evidence used in many of
the investigations into this question.14 In a prospective study, a
multivariate statistical method revealed a positive correlation between severity of psoriasis symptoms and psychological stress
related to adverse life events.15 Psoriasis itself can be a source of
stress: the effects of psoriasis on physical and mental function
have been compared with the effects of cancer, heart disease, diabetes, and depression.16
ACP Medicine
DERMATOLOGY:III Psoriasis1
Climate
It has long been known that psoriasis improves when patients
are exposed to sunny climates and to regions of lower latitude.
In northern latitudes, exacerbation of psoriasis commonly occurs
during the fall and winter.
Infection
Viral or bacterial infections, especially streptococcal pharyngitis or tonsillitis, may precipitate the onset or exacerbation of psoriasis.17 Guttate psoriasis, in particular, is often attributed to a
previous streptococcal infection. Attempts to reverse psoriasis
by treatment with oral antibiotics have not proved effective in
double-blind trials.18 Nevertheless, some investigators advocate
antibiotic therapy for psoriasis.19
Infection with HIV has also been associated with psoriasis. In
some patients with HIV infection, preexisting psoriasis becomes
exacerbated; in other patients, psoriasis develops within a few
years after HIV infection. Often, HIV-infected patients present
with symptoms similar to those of Reiter syndrome.20
genitals are also commonly affected, but psoriasis can involve

any part of the body. Lesions frequently occur in a symmetrical
pattern of distribution.
Many patients have only one or a few lesions that persist for
years and that occasionally resolve after exposure to sunlight.
Other patients can be covered with plaques that become confluent, affecting nearly 100% of the body surface area. Nail involvement is common, particularly in patients with severe disease.
The second most common form of psoriasis, guttate psoriasis,
affects fewer than 10% of patients and is characterized by the development of small, scaling, erythematous papules on the trunk
and the extremities [see Figure 6]. This form of psoriasis often follows streptococcal infection. Patients with plaque-type psoriasis
can develop guttate psoriasis. Conversely, patients with guttate
psoriasis frequently develop plaque-type psoriasis. Occasionally, guttate lesions enlarge and become confluent, resulting in the
formation of plaques.
Drugs
Numerous drugs can worsen psoriasis.21 Antimalarial agents
such as chloroquine can cause exfoliative erythroderma or pustular psoriasis. Up to 31% of patients experience new onset or
worsening of psoriasis as a result of antimalarial therapy. Lithium and beta blockers such as propranolol may precipitate the
onset of psoriasis or cause exacerbations of psoriasis.22 Some
nonsteroidal anti-inflammatory drugs (NSAIDs) also exacerbate
psoriasis, although this effect is sufficiently minor to allow
NSAIDs to be used in the treatment of psoriatic arthritis.23 Flares
of pustular psoriasis may be precipitated by withdrawal from
systemic corticosteroids or withdrawal from high-potency topical corticosteroids. Interferon therapy has been associated with
development or exacerbation of psoriasis, presumably because
of the Th1 effects of this therapy.24
Other Factors
Trauma to the clinically uninvolved skin of patients with psoriasis can cause a lesion to appear at the exact site of injury; this
phenomenon is known as the Kbner response. Cuts, abrasions,
injections, burns resulting from phototherapy, and other forms
of trauma can elicit this reaction.
Smoking may be an exacerbating factor in psoriasis.25 Alcohol
use has also been implicated in the exacerbation of psoriasis.26
Surveys have suggested that diet plays a role in the development of psoriasis, and attempts have been made to affect the clinical course of psoriasis through modification of diet.27 Doubleblind studies, however, have failed to show that diet has either a
beneficial or a detrimental effect on the severity of psoriasis.
Figure 1 Involvement of the elbows is characteristic of plaque

psoriasis.
Diagnosis
The diagnosis of psoriasis is usually made on clinical
grounds. If unusual features are present, biopsy of affected skin
can be done to confirm the diagnosis.
clinical variants
Nearly 90% of patients with psoriasis have plaque type, a
form that is characterized by sharply demarcated, erythematous,
scaling plaques. The elbows [see Figure 1], knees, and scalp [see
Figure 2] are the most commonly affected sites. The intergluteal
cleft [see Figure 3], palms [see Figure 4], soles [see Figure 5], and
April 2005 Update
Figure 2 The scalp is affected in the majority of patients with plaque

psoriasis.
ACP Medicine
Erythrodermic psoriasis can develop de novo or evolve from

typical plaque-type or guttate psoriasis. Erythrodermic psoriasis can occur after withdrawal of systemic corticosteroids, after
phototherapy burns, as a result of antimalarial treatment, as a
result of a drug-induced hypersensitivity reaction, or for no apparent reason. Cutaneous T cell lymphoma may also present as
erythroderma and needs to be differentiated from erythrodermic psoriasis.
Pustular psoriasis, another severe form of the disease, can
occur in patients with preexisting psoriasis or can arise de
novo. Pustular psoriasis can be generalized (von Zumbusch
type) or localized to the palms and soles [see Figure 8]. In either
case, the condition is severe and debilitating. In generalized
Figure 3 The intergluteal cleft is a common site of involvement in
patients with plaque psoriasis.
Figure 6 Guttate psoriasis is characterized by small scaly papules

and plaques.
Figure 4 Psoriasis of the palms is shown in this patient.
Figure 5 Sharply demarcated, erythematous, scaling plaques on the

feet are apparent in this patient with psoriasis of the soles.
Erythrodermic psoriasis is a severe form of psoriasis that often

affects the entire cutaneous surface. Patients present with an exfoliative erythroderma in which the skin is very red and inflamed and is constantly scaling [see Figure 7]. Patients are acutely ill, their skin having lost all protective function. Loss of temperature control, loss of fluids and nutrients through the
impaired skin, and susceptibility to infection make this a potentially life-threatening condition.
April 2005 Update
Figure 7 Erythrodermic psoriasis is characterized by

generalized erythema and desquamation.
ACP Medicine
Other changes include subungual hyperkeratosisan accumulation of keratinous debris under the nailas well as transverse and longitudinal ridging. These findings, however, are
much less specific because they also occur secondary to dermatitis, fungal infection, vascular insufficiency, and other conditions.
Occasionally, a patient shows typical psoriatic nail changes without any other cutaneous signs at initial examination; all such patients are probably psoriatic and may eventually manifest psoriatic lesions.
Psoriatic Arthritis
Figure 8 Pustular psoriasis can be localized to the palms and soles or

generalized.
Figure 9 Involvement of the nails is common in psoriasis.

pustular psoriasis, the body is covered with sterile pustules. As
with erythrodermic psoriasis, the protective functions of the
skin are lost, and patients may succumb to infection or hypovolemia and electrolyte imbalance caused by loss of fluid
through the skin. Although fever and leukocytosis are common features in pustular psoriasis, the possibility of infection
should not be overlooked; patients with pustular psoriasis
have died of staphylococcal sepsis.28
As with erythrodermic psoriasis, pustular psoriasis is most
commonly precipitated by withdrawal of systemic corticosteroids. However, it can also result from therapy with antimalarial drugs or lithium, and it can develop spontaneously.
Nail Psoriasis
Nail changes can be of immeasurable value when the diagnosis is in doubt [see Figure 9]. In one study, 55% of patients with
psoriasis experienced such changes.29 The most common change
consists of the appearance of tiny pits, as might be made with an
ice pick, which often occur in groups. This characteristic pitting
of the nails is highly specific for psoriasis, although a few isolated pits may be seen in healthy nails or as a result of past trauma.
Yellowish discoloration is common in psoriatic toenails and may
appear in fingernails as well. Onycholysis, or distal separation of
the nail plate from its bed, frequently occurs.
April 2005 Update
Psoriatic arthritis has been estimated to occur in 7% to 42% of

patients with psoriasis.30 Joint inflammation in psoriatic arthritis
is chronic, with occasional remissions.31 There are five classic
subtypes. The most common presentation is an oligoarthritis in
which one or a few joints are affected. This form accounts for approximately 70% of cases of psoriatic arthritis. Skin lesions of
psoriasis usually precede articular disease by 5 to 10 years, but
joint inflammation develops before skin lesions in some patients.
If a diagnosis of psoriatic arthritis is suspected, the physician
should carefully examine the scalp, nails, intergluteal cleft, external ear canal, and genital region for psoriasis lesions.
The second most common type of psoriatic arthritis is virtually
identical to rheumatoid arthritis. This form is characterized by
symmetrical involvement of the joints with ulnar deviation and
typical deformities, such as swan-neck deformity and boutonnire deformity. The only distinguishing features are the presence of psoriasis and the absence of circulating rheumatoid factor.
Arthritis mutilans is a rare, severely destructive form of psoriatic arthritis in which the interphalangeal joints of the hands and
feet are destroyed, resulting in deformed digits. Ankylosing
spondylitis accounts for 5% of cases of psoriatic arthritis. As in
other forms of ankylosing spondylitis, the genetic marker HLAB27 is usually present.
Distal interphalangeal joint involvement is the most characteristic form of psoriatic arthritis. It is usually associated with nail
involvement.
histopathology
The classic microscopic features of a psoriatic plaque include
the following:
A markedly thickened stratum corneum, with layered
zones of parakeratosis (retention of nuclei).
A moderately to markedly hyperplastic epidermis, with
broadening of rete projections and elongation to a uniform
depth in the dermis.
Increased mitotic activity in the lower epidermis.
Epidermal thinning over the dermal papillae.
A scant amount of inflammatory infiltrate from mononuclear cells in the superficial dermis.
Intracorneal or subcorneal collections of polymorphonuclear leukocytes (Munro microabscesses)
Differential Diagnosis
The differential diagnosis of psoriasis includes other scaling
dermatoses [see 2:II Papulosquamous Disorders]. Such dermatoses
include the following:
Seborrheic dermatitis that involves the scalp, nasolabial
folds, and retroauricular folds.
Pityriasis rosea, which begins with a herald patch and is
self-limited.
ACP Medicine
Lichen simplex chronicus, which is caused by repeated

rubbing or scratching.
Parapsoriasis, which is characterized by atrophy, telangiectasia, and pigmentary abnormalities.
Pityriasis rubra pilaris, which is characterized by psoriasiform patches that often begin in sun-exposed areas.
Other conditions (e.g., discoid eczema or secondary
syphilis) that can be differentiated by clinical and pathologic criteria.
Treatment
More treatments are available for psoriasis than perhaps for
any other dermatologic disease. New topical therapies, new systemic therapies, and new forms of phototherapy have been introduced, and additional treatments are in development. Biologic therapies that target specific molecules are likely to change the
treatment of psoriasis in the future. Topical therapy will continue to be used by most patients, however.
topical therapy
The 1990s saw the development of many new therapies for
psoriasis.32 Topical therapy is the mainstay of treatment for most
patients, particularly those with mild disease. Topical corticosteroids are the most commonly prescribed class of medication,
but they are now often used together with topical calcipotriene, a
vitamin D3 analogue, or topical tazarotene, a retinoid; both calcipotriene and tazarotene have approval by the Food and Drug
Administration for the treatment of psoriasis.33 Tar and salicylic
acid are available by prescription and as over-the-counter products. Use of anthralin has declined as effective nonsteroidal
agents have become available.
Emollients are an important part of any topical regimen for
psoriasis. Application of petrolatum alone may be sufficient
therapy for some patients. More elegant creams and lotions are
helpful but are somewhat less effective than greasy ointments.
Tar and salicylic acid shampoos are valuable in the treatment of
patients with scalp involvement. These preparations are available without prescription.
Corticosteroids
Topical corticosteroids are indicated for limited plaques of
psoriasis. Because of their ease of use and their wide availability,
topical corticosteroids are the most commonly prescribed medication for treatment of psoriasis. They have anti-inflammatory,
antiproliferative, and antipruritic effects. Corticosteroids are
more potent when they are applied under occlusion, which increases their percutaneous penetration. Unfortunately, occlusion
also increases side effects.
Topical steroids have been ranked in seven categories in decreasing order of potency, with potency determined by a vasoconstriction assay [see Table 1]. Superpotent corticosteroids are in
group I, and weak over-the-counter topical corticosteroids are in
group VII.34
Side effects The most commonly encountered side effects
of topical corticosteroids are local cutaneous reactions. Development of cutaneous atrophy, telangiectasia, and irreversible
striae are the most common side effects. Perioral dermatitis,
which is characterized by erythematous papules and pustules
on the face, is caused by chronic use of topical corticosteroids.
Tachyphylaxis, with habituation to topical corticosteroids and
April 2005 Update
loss of response to them, is noted by most patients. Flare or rebound of psoriasis upon sudden withdrawal of topical corticosteroids can occur. Finally, suppression of the hypothalamicpituitary-adrenal axis can occur, especially with use of superpotent topical corticosteroids, the widespread application of
corticosteroids, occlusion, or chronic use. Because of concern
over side effects, the package inserts for some superpotent corticosteroids suggest that use be limited to 2 weeks duration. A
number of regimens have been developed in which, after the
initial weeks of continuous treatment with superpotent topical
corticosteroids, psoriasis plaques are subsequently treated only
on weekends.35
Vitamin D Analogues
Calcipotriene The first topical vitamin D analogue to receive FDA approval for use in the United States, calcipotriene
has rapidly gained acceptance, despite the fact that it is not as effective as superpotent topical corticosteroids. Calcipotriene is
available in ointment and cream form and as a solution. The primary reason for its success is its freedom from any corticosteroid
side effectsnamely, cutaneous atrophy, telangiectasia, striae,
or suppression of the hypothalamic-pituitary-adrenal axis. Calcipotriene is comparable in efficacy to a group II corticosteroid. It
is applied twice daily.
Calcipotriene has been used very successfully in combination
with several other medications. It is most effective when used in
combination with a superpotent topical corticosteroid. A regimen of calcipotriene ointment and halobetasol propionate ointment, each applied once daily, has been found to be more effective than monotherapy with either calcipotriene twice daily or
halobetasol propionate twice daily.36 Up to 90% of patients
achieve marked improvement within 2 weeks of combination
therapy with once-daily calcipotriene and once-daily halobetasol
propionate ointment. For long-term maintenance of remission, a
regimen has been developed in which halobetasol propionate is
applied only on weekends and calcipotriene is applied on weekdays.37 Using this regimen, 76% of patients achieved marked improvement for at least 6 months; this level of improvement was
achieved in only 40% of patients receiving halobetasol propionate ointment on weekends only. Calcipotriene has also been
shown to improve the response to ultraviolet B light (UVB)38 and
to psoralen plus ultraviolet A light (PUVA).39
Caution must be used when combining calcipotriene ointment with other medications, because it is easily inactivated. Salicylic acid, for example, completely inactivates calcipotriene on
contact. Several other topical medications, including topical corticosteroids, can inactivate calcipotriene. In contrast, halobetasol
propionate ointment is compatible with calcipotriene even when
one medication is applied on top of the other.40 UVA has been
shown to inactivate calcipotriene,41 so calcipotriene should be applied after PUVA therapy, not before. Use of calcipotriene
should be limited to a maximum of 120 g a week because of isolated reports of hypercalcemia.42
A combination product containing calcipotriene and betamethasone dipropionate is now available in Europe and Canada. It appears to be more effective than the individual medications applied separately.43
Other vitamin D analogues Several new vitamin D analogues are under investigation in the United States or are in use
elsewhere. Tacalcitol and maxacalcitol are promising medications for the treatment of psoriasis. The only common side effect
ACP Medicine
Table 1 Ranking of Topical Steroids for Psoriasis in Order of High to Low Potency
Group
Generic Name
Trade Name
Strength (%)
Betamethasone dipropionate in optimized vehicle

Clobetasol propionate
Diflorasone diacetate
Diprolene ointment
Temovate cream, ointment
Psorcon ointment
0.05
0.05
0.05
II
Amcinonide
Betamethasone dipropionate, augmented
Betamethasone dipropionate
Mometasone furoate
Halcinonide
Fluocinonide
Desoximetasone
Cyclocort ointment
Diprolene AF cream
Diprosone ointment
Elocon ointment
Florone ointment, Maxiflor ointment
Halog cream
Lidex cream, ointment; Topsyn gel
Topicort cream, ointment
0.1
0.05
0.05
0.1
0.05
0.1
0.05
0.25
III
Triamcinolone acetonide
Betamethasone valerate
Aristocort cream (HP)

Diprosone cream
Florone cream, Maxiflor cream
Valisone ointment
0.5
0.05
0.05
0.1
Betamethasone benzoate
Flurandrenolide
Mometasone furoate
Fluocinolone acetonide
Aristocort ointment, Kenalog ointment

Benisone ointment
Cordran ointment
Elocon cream
Synalar-HP cream
Synalar ointment
0.1
0.025
0.05
0.1
0.2
0.025
Betamethasone benzoate
Flurandrenolide
Fluticasone propionate
Hydrocortisone butyrate
Betamethasone valerate
Hydrocortisone valerate
Benisone cream
Cordran cream
Cutivate cream
Diprosone lotion
Kenalog cream, lotion
Locoid cream
Synalar cream
Valisone cream, lotion
Westcort cream
0.025
0.05
0.05
0.02
0.1
0.1
0.025
0.1
0.2
VI
Alclometasone dipropionate
Desonide
Flumethasone pivalate
Aclovate cream
Tridesilon cream, ointment; DesOwen cream, ointment
Locorten cream
Synalar solution
0.05
0.05
0.03
0.01
VII
Hydrocortisone
2.5
1.0
IV
is irritation, which occurs in up to 20% of patients, most often on

the face and in intertriginous areas. Topical calcitriol has FDA
approval for the treatment of psoriasis in several countries
around the world44; it may be less irritating than calcipotriene in
intertriginous sites.
Tazarotene
Tazarotene is a retinoid that has been developed for the treatment of psoriasis. It is available in 0.05% and 0.1% gels and in
cream formulations. Tazarotene is comparable in efficacy to a
group II corticosteroid cream. Patients receiving tazarotene 0.1%
gel experience longer periods of remission after discontinuance
of therapy than patients receiving corticosteroids.
Tazarotene has several advantages over the corticosteroids.
First, it is not associated with cutaneous atrophy, telangiectasia,
or the development of striae. In fact, tazarotene, like other retinoids, may actually prevent corticosteroid atrophy. Tazarotene
has been shown to enhance the efficacy of UVB phototherapy.45
It does, however, increase the ability of ultraviolet light to induce
erythema.46 Doses of UVB and UVA should therefore be reduced
in patients who are also receiving tazarotene.
April 2005 Update
Hytone cream, lotion, ointment

Hytone, Penecort, Synacort, Cort-Dome, Nutracort
Side effects The main side effect of tazarotene is local irritation, which has caused many patients to discontinue its use. The
combination of tazarotene and a topical corticosteroid reduces irritation and enhances the efficacy of both agents.
Tars
Tar has been used since the 19th century to treat psoriasis.
Crude coal tar, a complex mixture of thousands of hydrocarbon
compounds, affects psoriatic epidermal cells through enzyme inhibition and antimitotic action.47 Crude coal tar is messy to apply,
has a strong odor, and stains skin and clothing. It is applied in
conjunction with UVB phototherapy in the Goeckerman regimen [see Phototherapy, below]. More refined tar preparations,
which are cosmetically acceptable, are available by prescription
and over the counter in the form of gels, creams, bath oils, shampoos, and solutions (liquor carbonis detergens). Tar is often used
in combination therapies and as maintenance therapy after psoriasis plaques have resolved.
Anthralin
Anthralin (dithranol) has been used to treat psoriasis since
ACP Medicine
1916.48 It is an extremely effective topical agent for psoriasis,

probably because it inhibits enzyme metabolism and reduces
epidermal mitotic turnover.48
Indications Because of the staining and irritation associated
with the use of anthralin, this agent is usually prescribed for patients who do not respond to other topical therapies.
Formulations and regimens A modified Ingram regimen
combines the daily application of anthralin in a stiff paste with
tar baths and with exposure to ultraviolet light. This therapy involves application of progressively higher concentrations of anthralin for 6 to 8 hours at a time; it was introduced in the United
States for hospitalized psoriatic patients44 and for ambulatory patients in a psoriasis day care center.49
Modified anthralin formulations have been used to minimize
the staining from anthralin, to decrease irritation, and to promote home use of the medication. Short-contact therapy consists
of the application of anthralin to localized plaques for 30 minutes
to 2 hours, after which time the anthralin must be thoroughly removed to minimize irritation of the surrounding skin.50 Anthralin in a cream base, which can be removed by washing with
water, is suitable for home use; it is available in 1% and 0.5% concentrations, for application to localized lesions on the skin and
the scalp.
A formulation of 1% anthralin cream, composed of microencapsulated lipid crystals that release anthralin for absorption at
skin temperature, is available. When used as short-contact therapy, this preparation carries a low risk of staining and irritation.51
Anthralin is most effective therapeutically when it is compounded in the form of a hard paste containing paraffin; this
form is most commonly used in ambulatory psoriasis treatment
centers. Anthralin ointment is less effective than anthralin paste,
and anthralin cream is even less effective. With regard to patient
compliance, this order is reversed. The end point of treatment is
resolution of plaques to a macular state; this is usually associated
with residual postinflammatory hyperpigmentation and temporary staining from anthralin. Resolution of symptoms usually occurs within 2 to 3 weeks after a modified Ingram regimen; remissions last for weeks to months.
Side effects Staining of skin, clothing, and the home is common with anthralin, as is irritation at the site of application.
sunlight
Ultraviolet radiation has a beneficial effect on psoriasis. Sunbathing for 2 to 4 weeks lessens the morbidity associated with
the disorder, and climatotherapy at the Dead Sea is an effective alternative therapy for psoriasis for those who can travel
to that part of the world. Because of its unique geographic location, 300 m below sea level, patients are exposed to naturally filtered ultraviolet light, which results in significant improvement or complete resolution of symptoms in 83% of patients over several weeks.52 The sunlight at the Dead Sea
accounts for most of the response, with little additional improvement resulting from bathing in the Dead Sea. Not surprisingly,
patients treated at the Dead Sea have higher rates of nonmelanoma skin cancer.53
phototherapy
Phototherapy with UVB is an important therapeutic option
for patients with extensive psoriasis. UVB irradiation can be
April 2005 Update
used alone, but it has traditionally been combined with topical

application of tar. Daily in-hospital application of crude coal tar
and exposure to ultraviolet light (the Goeckerman regimen) can
lead to a resolution of symptoms in widespread psoriasis within
3 or 4 weeks and can effect remissions that last for weeks to
months.
In a reevaluation of the Goeckerman regimen, application of a
1% tar preparation was found to be as effective as a 6% preparation. Furthermore, application of the tar preparation for 2 hours
before irradiation was equivalent to longer periods of application.54 Contraindications to the use of the Goeckerman regimen
include the presence of severely excoriated or inflamed psoriasis,
erythrodermic and pustular forms of the disease, folliculitis, and
a history of photosensitivity.
Newer regimens, which are more convenient and aesthetically acceptable, combine UVB with emollients. The emollient or
vehicle decreases reflectance of the psoriatic scale, thereby increasing light transmission. According to a report by Lowe and
colleagues, results with emollients are equivalent to those with
tar, when used in regimens that utilize UVB in doses sufficient to
cause erythema (erythemogenic); however, tar may have an additive effect when combined with a less aggressive regimen of
suberythemogenic UVB.55
In a comparison study, outpatient UVB phototherapy was administered three times weekly, along with the application of either a tar oil or an emollient twice a day. This approach led to
clearing of psoriatic lesions in 78% of patients [see Figure 10]. No
difference in response was observed between the tar oil and the
emollient.56 Although the Lowe study had shown an additive effect for tar combined with UVB irradiation when patients were
evaluated after 3 to 4 weeks (before their lesions had cleared),57
this comparison study showed no such advantage in patients
who were evaluated at the time of lesion clearing. Remission
lasted longer in patients who received maintenance UVB phototherapy twice weekly for 1 to 2 months and then once weekly
for up to 4 months than in patients who stopped receiving UVB
phototherapy after the initial clearing.
Narrow-Band UVB
Narrow-band UVB, which comprises wavelengths of approximately 311 nm (as opposed to the 295 to 320 nm range of broadband UVB), is a newer approach that is more effective than
broad-band UVB.58 Like other forms of phototherapy, narrowband UVB works through local effects; therefore, covered areas,
such as the scalp, do not respond.59
photochemotherapy
Photochemotherapy with PUVA is indicated for patients with
extensive, disabling psoriasis that has failed to respond to conventional forms of therapy, including conventional or narrowband UVB phototherapy. PUVA therapy entails the administration of the photosensitizing drug methoxsalen (8-methoxypsoralen)in an oral dose or by soaking in a tub containing
methoxsalen or applying topical methoxsalenfollowed by exposure of the patient to high-intensity longwave ultraviolet light
in a walk-in irradiation chamber. The initial UVA dose (in
joules/cm2) is based on the patients skin type and calculated in
accordance with established protocols.60
Although its therapeutic effect is local, PUVA is a systemic
treatment in which photoactivated methoxsalen binds to epidermal DNA, forming monofunctional and bifunctional adducts. It
has been postulated that the resulting interference with epiderACP Medicine
Figure 10 Psoriasis in a child before (a) and after (b) phototherapy.
mal mitosis is one of the mechanisms of action of PUVA therapy

for psoriasis, although effects on immune function in the skin
play an important role.
The efficacy of oral PUVA therapy has been established by
several multicenter clinical trials.61 A course of PUVA therapy
administered two or three times weekly resulted in significant
clearing of psoriasis lesions in approximately 90% of patients
within a mean of 25 total treatments. After the initial course, a tapering maintenance regimen is instituted, and PUVA therapy is
eventually discontinued. In most patients, psoriasis recurs
months to years after PUVA is discontinued, indicating that this
therapy is palliative rather than curative.
Side Effects
Acute side effects caused by phototoxicity, such as erythema
and blistering, are dose related and can therefore be controlled.
Pruritus, usually associated with dryness of the skin, is fairly
common and can be alleviated by the use of emollients and oral
antihistamines. Nausea may follow ingestion of methoxsalen. Of
greater concern are the potential long-term side effects, particularly carcinogenicity. Although the FDA has approved the use of
PUVA to treat psoriasis, patients must be closely monitored for
long-term side effects. A multicenter study of more than 1,300
PUVA-treated patients in the United States who were evaluated
after 1 to 3 years of follow-up revealed a significant increase in
the number of squamous cell carcinomas (SCCs) in those patients with a history of exposure to ionizing radiation or a history
of skin cancer.62 A higher-than-expected ratio of SCCs to basal
cell epitheliomas and an excess of SCCs in areas of the body that
were not exposed to the sun were significant findings of the
study. A 5.7-year follow-up study of the original cohort group
revealed a dose-dependent increase in the risk of SCC.63 There
was only a slight increase in the risk of basal cell carcinoma in
these patients. The risk of SCC was almost 13-fold higher in patients who had received high cumulative doses of PUVA than in
patients who received low-dose therapy.
April 2005 Update
A follow-up study of the surviving members of that cohort, at

least 15 years after original treatment, again assessed the risk of
skin cancers. Of great concern was a small but statistically significant increase in the incidence of malignant melanoma.64 Because
that increase did not become apparent until after a period of at
least 15 years, there is great concern that high rates of melanoma
will occur in patients who began PUVA therapy years ago. Fortunately, this has not happened thus far.
Studies in animals suggest that PUVA may have ocular side
effects. Methoxsalen has been detected in the lenses of rats after
they have ingested the drug; subsequent exposure to UVA enhances such ultraviolet-induced changes as cataracts.65 The risk
of ocular toxicity and possible retinal damage is of particular
concern in young persons, whose lenses transmit more UVA
than the more opaque lenses of older persons, and in aphakic
persons, in whom lenses are absent.66 The use of UVA-opaque
goggles during PUVA treatment sessions is extremely important. Glasses that block UVA must be worn from the time that
methoxsalen is administered throughout the rest of the day.
Some investigators advise protection of the eyes the day after
therapy. Thus far, studies of patients treated with PUVA have
not revealed an increase in the incidence of cataracts.
systemic therapy
Methotrexate
Short-term use of the antimetabolite methotrexate can be an
extremely effective treatment for psoriasis. Methotrexate is indicated for patients who do not respond adequately to phototherapy and for patients with psoriatic arthritis.
The source of methotrexates efficacy against psoriasis was
once thought to be its antimitotic effect on proliferating keratinocytes. However, tissue culture studies have suggested that
activated lymphoid cells in the lymph nodes, blood, and skin are
a likely target of methotrexate; proliferating macrophages and T
cells are 100 times more sensitive to methotrexate than are prolifACP Medicine
erating epithelial cells.67 These findings may be relevant to the

mechanism of action of methotrexate in other immunologically
based disorders, including psoriatic arthritis, rheumatoid arthritis, and Crohn disease.
Dosage Methotrexate is best given in a single weekly oral
dose of up to 30 mg or in three divided doses at 12-hour intervals
during a 24-hour period (e.g., at 8:00 A.M., at 8:00 P.M., and
again at 8:00 A.M.).
Hepatoxicity and liver biopsy The use of liver biopsy has
been advocated for monitoring patients with psoriasis who are
receiving methotrexate. This recommendation is controversial,
however; critics point out that liver biopsies are not routinely
performed in patients with rheumatoid arthritis who are undergoing treatment with methotrexate.68 Nevertheless, a review of
the literature clearly shows that patients with psoriasis who are
treated with methotrexate are more likely to develop hepatic fibrosis, possibly because of their underlying disease or because of
the concomitant treatments they are given.
Current guidelines call for the use of liver biopsy in patients
with psoriasis who have received a cumulative dose of 1 to 1.5
g of methotrexate and who do not have a history of liver disease or alcoholism. Biopsy should be performed early in the
course of treatment in patients with a history of hepatitis C, alcoholism, or other liver disease. Other risk factors for hepatotoxicity are obesity, diabetes, and abnormalities on liver function testing.
Pathologic liver changes caused by methotrexate therapy
have been graded as follows: grade I, normal liver histology or
mild fatty infiltration; grade II, moderate to severe fatty infiltration with portal tract inflammation and necrosis; grade IIIA,
mild fibrosis; grade IIIB, moderate to severe fibrosis; and grade
IV, cirrhosis. Methotrexate should be discontinued in patients
with grade IIIB or IV pathologic liver changes. The importance
of strict adherence to current guidelines for the administration of
methotrexate is emphasized by the occurrence of methotrexateinduced cirrhosis necessitating liver transplantation in three patients with long-term psoriasis who did not undergo serial liver
biopsies.69
Other side effects In addition to hepatotoxicity, other side
effects of methotrexate therapy include bone marrow suppression, nausea, diarrhea, and stomatitis. Methotrexate is teratogenic and can cause reversible oligospermia. Pneumonitis can
occur early in the course of treatment if methotrexate is administered in oncologic doses. Evaluation by tests of liver function, renal function, and blood elements must be made before and
throughout the course of methotrexate therapy.
Certain drugs increase the toxicity of methotrexate by reducing renal tubular secretion; these drugs include salicylates, sulfonamides, probenecid, and penicillins. Other drugs increase
toxicity by displacing methotrexate from its binding sites on
plasma proteins; these drugs include salicylates, probenecid,
barbiturates, and phenytoin. Many of the NSAIDs and trimethoprim-sulfamethoxazole enhance methotrexate toxicity.68 Cases of
pancytopenia after low-dose methotrexate therapy underscore
the hazards of using this drug in patients with renal insufficiency or in patients who are concomitantly receiving drugs that increase methotrexate toxicity.70
Contraindications to treatment with methotrexate and indications for stopping treatment should be heeded. Constant med 2005 WebMD, Inc. All rights reserved.
April 2005 Update
ical supervision is necessary, and therapy must be stopped at

once if toxicity develops.
Acitretin
Indications and dosage Acitretin, an oral retinoid, has FDA
approval for the treatment of plaque psoriasis. It is highly effective in the treatment of pustular psoriasis and can be very effective as monotherapy for erythrodermic psoriasis. For plaquetype and guttate psoriasis, however, acitretin is most useful in
combination with other treatments, particularly UVB and PUVA
phototherapy.71,72 Acitretin is initiated 1 to 2 weeks before UVB or
PUVA therapy is started. With combination treatment, symptoms resolve much more quickly. Doses of only 10 to 25 mg daily are effective, thus minimizing retinoid side effects.71,72 When
used as monotherapy, acitretin is prescribed in doses of 25 mg
daily, which can be increased to 50 mg a day or higher.
Side effects Acitretin side effects are dose related and are
common with doses above 25 mg daily. Hair loss, cheilitis,
desquamation of the palms and soles, sun sensitivity, and periungual pyogenic granulomas are among the mucocutaneous
side effects. Hyperlipidemia is common but is easily controlled
with lipid-lowering agents. Elevations in liver enzyme levels can
occur, and enzyme levels must be monitored. Serial liver biopsies have not demonstrated hepatic fibrosis in patients treated
with oral retinoids.73
Acitretin poses a significant risk of teratogenicity. Characteristic retinoid birth defects occur in a high proportion of fetuses exposed to even small amounts of the drug in utero. Acitretin is
eliminated from the body much more quickly than its prodrug
etretinate. In the presence of alcohol, however, acitretin is converted back to etretinate,74 raising concerns that women of childbearing age who take acitretin and who later become pregnant
would then be at risk for exposing their fetus to acitretins teratogenic effects. The FDA therefore requires that acitretin not be
given to women planning a pregnancy within 3 years.
Long-term side effects of oral retinoids include calcification of
ligaments and tendons and osteoporosis.75,76 The long-term safety of etretinate, acitretins prodrug, was examined in a 5-year
prospective study of 956 patients with psoriasis. The investigators concluded that with appropriate patient selection and monitoring, there was no substantially increased risk of side effects
related to cardiovascular disease, cancer, diabetes, cataracts, and
inflammatory bowel disease. Although joint symptoms improved in some patients, more patients had joint problems associated with etretinate. Etretinate also caused short-term changes
in liver enzyme levels in some patients and, in rare cases, caused
acute hepatitis. The long-term risk of liver disease and cirrhosis
with etretinate, however, was less than that associated with comparable periods of methotrexate.77
Cyclosporine
Cyclosporine in a microemulsion formulation was approved
by the FDA for the treatment of psoriasis after extensive worldwide experience. In dosages of 2.5 to 5 mg/kg/day, cyclosporine
is highly effective for psoriasis. Even at such doses, however, it
may be associated with significant side effects, which have limited its use in patients with severe or refractory disease.
Indications and dosage Cyclosporine is indicated for patients in whom phototherapy or methotrexate therapy has failed.
The microemulsion formulation of cyclosporine is better abACP Medicine
sorbed than earlier formulations. It is available in gel capsules of

25 and 100 mg and is most commonly taken in divided doses
twice daily. At dosages of 5 mg/kg/day, a response is usually
seen within 4 weeks, and some patients respond as quickly as 1
week. It should be noted that in the United States, the package
insert for cyclosporine recommends an upper dosage limit of 4
mg/kg/day, although worldwide experience regarding the efficacy and safety of this drug has established an upper limit of 5
mg/kg/day.78 In the United States, the maximum FDA-approved duration of treatment of cyclosporine is 1 year.
Side effects Cyclosporine is associated with a number of
side effects that are easily managed; other side effects are of
greater concern. Hypertrichosis, tremors, paresthesias, headache,
gingival hyperplasia, joint pain, and fatigue can occur. Elevations in serum lipid levels and minor elevations in liver enzyme
levels are also common. Hypomagnesemia may require magnesium supplementation. The most serious common side effects
are hypertension and nephrotoxicity. Hypertension can be managed by lowering the dose or by instituting treatment with calcium channel blockers such as amlodipine besylate. There is some
evidence that in normotensive patients receiving cyclosporine,
amlodipine therapy may prevent some of the nephrotoxicity
that has been associated with this potent psoriasis treatment.79
Renal interstitial fibrosis and renal tubular atrophy are common in patients on long-term therapy with cyclosporine.80,81 Consequently, serum creatinine levels must be monitored on a regular basis. If the serum creatinine level rises more than 30% above
baseline (or more than 25%, according to the United States package insert), the dosage may have to be reduced.78
Organ transplant patients taking cyclosporine, as well as other immunosuppressive drugs, to prevent rejection have experienced an increase in lymphoproliferative diseases and skin cancers.82,83 It is hoped that the lower doses and intermittent usage of
cyclosporine in psoriasis patients will not be associated with an
increase in malignancies, but caution must be exercised. In one
study, no increase in lymphoproliferative disorders was found
in rheumatoid arthritis patients who were treated with cyclosporine for a short period (median, 1.6 years), compared with
a parallel group of rheumatoid patients who were not treated
with cyclosporine.84 Nevertheless, caution must be used with this
powerful new psoriasis treatment.
Tacrolimus
Although tacrolimus does not have FDA approval for use in
psoriasis, it is a potent immunosuppressive agent that may be
substituted for cyclosporine in patients who cannot tolerate the
hypertrichosis associated with this agent. Tacrolimus has proved
to be effective in the treatment of psoriasis. In a double-blind trial, 50 patients with severe recalcitrant psoriasis were given either
oral tacrolimus or placebo.85 In the tacrolimus group, starting
dosages were 0.5 mg/kg/day, and the dosages could be increased to 0.10 mg/kg at week 3 or 6 if patient response was
judged to be insufficient. After 9 weeks of treatment, patients receiving tacrolimus had an 84% reduction in Psoriasis Area and
Severity Index (PASI) scores.
As with cyclosporine, there are concerns about hypertension,
nephrotoxicity, and immunosuppressive effects with tacrolimus.
This drug is not associated with hypertrichosis or gingival hyperplasia. Tacrolimus has not been studied as extensively as cyclosporine for the treatment of psoriasis, and further investigations are warranted for this very effective antipsoriatic agent.
April 2005 Update
Hydroxyurea
Hydroxyurea may be considered for the treatment of psoriasis in patients with hepatic disease, because hepatotoxicity is uncommon with this agent.86 Response is slower and less complete
than with methotrexate, however, and resistance to hydroxyurea
may develop more frequently. Hydroxyurea is administered
orally at a dosage of 1 to 2 g/day. Careful monitoring of blood
counts is necessary during therapy.
Sulfasalazine
Sulfasalazine does not have FDA approval for the treatment
of psoriasis but is highly effective in selected patients. It is typically given in dosages of 3 to 4 g daily. In one study, over 25% of
patients given sulfasalazine stopped the treatment because of
side effects (cutaneous eruptions or nausea). In clinical practice,
results have been less promising than in studies.87
Combination Therapy
Combinations of various psoriasis treatments have proved to
be superior in efficacy to monotherapy. Acitretin is routinely
used with UVB and PUVA, a combination that allows the use of
smaller doses and minimizes toxicities of both retinoid therapy
and phototherapy.71,72 The combination of methotrexate and acitretin has been used successfully despite some concern that both
drugs are hepatotoxic.88 Careful monitoring of liver enzyme levels is essential. Methotrexate and cyclosporine can be used together, and their concurrent administration in small doses can
result in greater efficacy and less toxicity than that which can be
achieved with higher doses of either agent used alone.89
Methotrexate has also been used very successfully in combination with UVB90 and PUVA,91 although there is some concern
that methotrexate may potentiate the carcinogenic effect of
PUVA.92 Because cyclosporine has been associated with skin cancers, it is not routinely used in combination with PUVA. It can be
used in combination with retinoids and mycophenolate mofetil.
Other Systemic Therapies

Mycophenolate mofetil, a drug that has FDA approval for the
prevention of organ transplant rejection, is highly effective for
some patients with psoriasis.93 Mycophenolate mofetil is the prodrug of mycophenolic acid, a medication that was tested for psoriasis in the 1970s.94 Although mycophenolic acid was found to
be highly effective in the treatment of psoriasis, the manufacturers did not pursue FDA approval for that indication because of
its side effects, which included gastrointestinal toxicity and an
immunosuppressive effect that resulted in herpes zoster infections in more than 10% of treated patients.
6-Thioguanine is another anticancer chemotherapeutic agent
that is highly effective for psoriasis. Unfortunately, it has been
associated with bone marrow suppression in approximately
50% of patients.95 Bone marrow toxicity from 6-thioguanine can
be reduced by administering the drug two to three times a week
rather than daily.96
Biologic Therapies
The ability to create molecules that target specific steps in the
pathogenesis of psoriasis has led to the development of biologic
agents that can treat psoriasis without the nephrotoxicity associated with cyclosporine and without the bone marrow and liver
toxicities associated with methotrexate. Biologic agents are immunosuppressive, and their long-term toxicity is not known. As
ACP Medicine
with other immunosuppressive agents, there is concern about

the potential to predispose patients to infections or malignancies.
Several biologic agents have FDA approval for use in psoriasis
namely, alefacept, efalizumab, and etanercept. Others have been
approved for use in other diseases but are undergoing clinical
trials for use in psoriasisnamely, adalimumab and infliximab.
Still other agents, such as onercept, a TNF- blocking agent, and
antiIL-12, are at earlier stages of development.
Alefacept Alefacept is a fusion protein consisting of LFA-3
fused to the Fc portion of human IgG1. The LFA-3 portion of the
molecule attaches to its naturally occurring receptor, CD2, on the
surface of a resting T cell, thereby blocking T cell activation. The
Fc portion of the molecule attaches to Fc receptors on natural
killer cells and macrophages, resulting in apoptosis of the bound
T cell.97
Alefacept originally received FDA approval as intravenous
and intramuscular formulations, but it is now available only in
the intramuscular form. Alefacept is administered weekly for 12
weeks in a dose of 15 mg. In one study, by 14 weeks after the
start of therapy, 21% of patients achieved PASI 75 (75% reduction in disease from baseline) and 42% of patients achieved PASI
50 (50% reduction in disease from baseline). Improvement typically progresses after the completion of treatment, with maximal
disease reduction 8 weeks after a second course of therapy; in
one study, 33% of patients achieved PASI 75 and 57% achieved
PASI 50 by this point.98 The most striking benefit of alefacept
therapy is the long duration of remission achieved in a subgroup
of patients. In patients who achieved PASI 75, the median time
to recurrence of psoriasis (as defined by maintenance of PASI 50)
was 7 months after a single 12-week course of therapy and more
than a year after two courses of therapy.99
Drawbacks of alefacept therapy include the high cost of the
drug and the need for weekly CD4+ T cell counts because the
drug tends to reduce the number of these cells. The onset of action of alefacept is slow, with many patients achieving maximal
response weeks after completing the 12-week course. Moreover,
only a proportion of patients achieve a satisfactory response.
Efalizumab Efalizumab is a humanized monoclonal antibody directed against the CD11a portion of LFA-1. Efalizumab
blocks the interaction between LFA-1 and ICAM-1, an interaction that is responsible for T cell activation and trafficking of T
cells into inflamed skin. After a conditioning dose of 0.7 mg/kg
the first week, patients self-administer subcutaneous injections
of efalizumab at a dose of 1 mg/kg weekly. In double-blind,
placebo-controlled trials, 22% to 39% of patients treated with
weekly efalizumab for 12 weeks achieved PASI 75,100-102 and nearly 60% of patients achieved PASI 50. With longer therapy, higher
proportions of patients achieve greater degrees of improvement.
Like the other biologic agents, efalizumab does not cause the
nephrotoxicity associated with cyclosporine or the bone marrow
or liver toxicity associated with methotrexate. The drug is fairly
expensive, however, and flulike symptoms may develop after
the first or second injection; a serious concern is the development
of psoriasis rebound (defined as a worsening of psoriasis over
baseline), which occurs in up to 15% of patients. To avoid psoriasis rebound, efalizumab should not be stopped abruptly but,
rather, slowly converted to alternative therapies.
Etanercept Etanercept is a recombinant fusion protein that
includes the p75 TNF receptor that binds to TNF-, blocking its
April 2005 Update
interaction with cell surface receptors. Etanercept originally received FDA approval for a dosage of 25 mg administered subcutaneously by the patient at home twice weekly for the treatment of psoriatic arthritis. Subsequently, etanercept received
approval for the treatment of psoriasis at a dosage of 50 mg administered subcutaneously twice weekly for 3 months and then
once weekly. In a double-blind, placebo-controlled, four-arm
trial comparing placebo with three dosage regimens, analysis
after 12 weeks of treatment showed that PASI 75 was achieved
in 14% of patients who received 25 mg once a week, in 34% who
received 25 mg twice a week, and in 49% who received 50 mg
twice a week. Response rates were even higher at 24 weeks of
therapy.103
The drawbacks of etanercept include its cost and the need to
self-inject the medication on a long-term basis. Injection-site reactions, although common, are almost always minor and seldom
require any treatment other than temporarily using a different
site for injections. There is evidence that TNF- blockers can
cause an exacerbation of multiple sclerosis, so the drug should
be avoided in patients with a personal or family history of demyelinating disease. Some controversy exists as to whether
TNF- blockers exacerbate chronic heart failure, and there is
concern that the immunosuppressive effects of TNF- blockers
may contribute to an increase in the development of lymphoproliferative diseases.104 Antinuclear antibodies also develop in etanercept-treated patients, but they are of questionable physiologic
significance.
Infliximab Infliximab is a chimeric monoclonal antibody
directed against TNF-. In the short term (12 weeks), it is the
most effective treatment for psoriasis, but it does not yet have
FDA approval for this indication. It is administered by slow intravenous infusion at baseline, at weeks 2 and 6, and then every
8 weeks thereafter. In a double-blind, placebo-controlled trial
evaluating patients at week 10, after only three infusions, 82% of
patients achieved PASI 75.105 Moreover, 55% of patients maintained PASI 50 or higher during 6 months of follow-up.
Like the other TNF- blockers, infliximab is associated with
worsening of chronic heart failure, multiple sclerosis, and lymphoproliferative diseases. In addition, infusion reactions develop in a significant proportion of patients; these appear to be related to the development of human antichimeric antibodies. Although infusion reactions are mild in the majority of patients,
they can be severe, resulting in chest pain and hypotension. Pretreating patients with antibiotics is beneficial. TNF- blocking
plays a significant role in the control of mycobacterial infection,
and an increase in reactivation of latent tuberculosis has been
observed in patients treated with infliximab. Consequently, patients should undergo tuberculosis testing before starting on
this medication.106
Adalimumab Adalimumab is a fully human monoclonal
antibody against TNF-. It has FDA approval for the treatment
of rheumatoid arthritis and has been successfully tested for
psoriasis.107 Like the other biologics, adalimumab is not toxic to
kidneys, liver, or bone marrow; however, also like the other biologic agents, it is quite expensive. The same concerns about
heart failure, multiple sclerosis, and lymphoproliferative diseases that exist with etanercept and infliximab are also described in adalimumabs package insert. In a three-arm, placebo-controlled trial, PASI 75 was achieved by 53% of patients
who received adalimumab every other week and by 80% of paACP Medicine
tients who received it weekly. An even greater number of patients achieved PASI 50. Adalimumab, 40 mg, is given by subcutaneous injection.
Prognosis
Psoriasis is usually lifelong, but the severity of the disease
may vary, with periodic exacerbations and relative remissions in
some patients. Although pustular psoriasis and erythrodermic
psoriasis can be life-threatening, even stable plaque psoriasis can
have a negative impact on overall health, possibly because of comorbid conditions such as psoriatic arthritis or obesity or because of complications of therapy.
Severe exacerbation of psoriasis taxes the ingenuity of even
the most skilled clinician. Fortunately, because of the wide range
of psoriasis therapies now available, clinicians are able to successfully treat almost all patients with psoriasis. The goal of therapy must be to minimize toxicity while achieving satisfactory
improvement both in physical signs and symptoms and in patients quality of life.
Elizabeth A. Abel, M.D., has been an investigator, consultant, or speaker for
Abbott Laboratories, Allergan, Inc., Amgen, Inc., Biogen, Inc., Centocor, Inc.,
Connetics Corp., Genentech, Inc., and 3M.
Mark Lebwohl, M.D., has been an investigator, consultant, or speaker for Abbott Laboratories, Allergan, Inc., Amgen, Inc., Biogen, Inc., Centocor, Inc.,
Connetics Corp., Fujisawa Healthcare, Inc., Galderma Laboratories, Genentech,
Inc., Novartis AG., and Warner Chilcott.
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April 2005 Update
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36. Lebwohl M, Siskin SB, Epinette W, et al: A multicenter trial of calcipotriene ointment and halobetasol ointment to either agent alone for the treatment of psoriasis. J Am
37. Lebwohl M, Yoles A, Lombardi K, et al: Calcipotriene ointment and halobetasol
ointment in the long-term treatment of psoriasis: effects on the duration of improvement. J Am Acad Dermatol 39:447, 1998
38. Ramsay CA, Schwartz BE, Lowson D, et al: Calcipotriol cream combined with twice
weekly broad-band UVB phototherapy: a safe, effective and UVB-sparing antipsoriatric
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39. Speight EL, Farr PM: Calcipotriol improves the response of psoriasis to PUVA. Br J
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40. Patel B, Siskin S, Krazmien BA, et al: Compatibility of calcipotriene with other topical medications. J Am Acad Dermatol 38:1010, 1998
41. Lebwohl M, Hecker D, Martinez J, et al: Interactions between calcipotriene and ultraviolet light. J Am Acad Dermatol 37:93, 1997
42. Georgiou S, Tsambaos D: Hypercalcaemia and hypercalciuria after topical treatment of psoriasis with excessive amounts of calcipotriol. Acta Derm Venereol 79:86,
1999
43. Guenther LC: Fixed-dose combination therapy for psoriasis. Am J Clin Dermatol
5:71, 2004
44. Franssen ME, de Jongh GJ, van Erp PE, et al: A left/right comparison of twice-daily
calcipotriol ointment and calcitriol ointment in patients with psoriasis: the effect on keratinocyte subpopulations. Acta Derm Venereol 84:195, 2004
45. Koo JY: Tazarotene in combination with phototherapy. J Am Acad Dermatol
39:S144, 1998
46. Hecker D, Worsley J, Yueh G, et al: Interactions between tazarotene and ultraviolet
light. J Am Acad Dermatol 41:927, 1999
47. Lowe NJ, Breeding J, Wortzman MS: The pharmacological variability of crude coal
tar. Br J Dermatol 126:608, 1992
48. Fiore M: Practical aspects of anthralin therapy. Cutis 46:351, 1990
49. Abel EA, OConnell BM, Farber EM: Psoriasis Day Care Center treatment at Stanford: part-time and full-time programs. Int J Dermatol 26:500, 1987
50. Schaefer H, Farber EM, Goldberg L, et al: Limited application period for dithranol
in psoriasis: preliminary report on penetration and clinical efficacy. Br J Dermatol
102:571, 1980
51. Volden G, Bjornberg A, Tegner E, et al: Short-contact treatment at home with micanol. Acta Derm Venereol Suppl (Stockh) 172:20, 1992
52. Even-Paz Z, Gumon R, Kipnis V, et al: Dead Sea sun vs. Dead Sea water in the treatment of psoriasis. Dermatol Treat 7:83, 1996
53. Frentz G, Olsen JH, Avrach WW: Malignant tumours and psoriasis: climatotherapy
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54. Petrozzi JW, Barton JO, Kaidbey KH, et al: Updating the Goeckerman regimen for
psoriasis. Br J Dermatol 98:437, 1978
55. Lowe NJ, Wortzman MS, Breeding J, et al: Coal tar phototherapy for psoriasis
reevaluated: erythemogenic versus suberythemogenic ultraviolet with a tar extract in
oil and crude coal tar. J Am Acad Dermatol 8:781, 1983
56. Stern RS, Gange RW, Parrish JA, et al: Contribution of topical tar oil to ultra-violet B
phototherapy for psoriasis. J Am Acad Dermatol 14:742, 1986
57. Lowe NJ, Stern RS: Contribution of topical tar oil to ultraviolet B phototherapy for
psoriasis. J Am Acad Dermatol 15:1053, 1986
58. Barbagallo J, Spann CT, Tutrone WD, et al: Narrowband UVB phototherapy for the
treatment of psoriasis: a review and update. Cutis 68:345, 2001
59. Dawe RS, Cameron H, Yule S, et al: UV-B phototherapy clears psoriasis through local effects. Arch Dermatol 138:1071, 2002
60. Abel EA: Administration of PUVA therapy: protocols, indications, and cautions.
Photochemotherapy in Dermatology. Abel EA, Ed. Igaku-Shoin Medical Publishers,
New York, 1992, p 75
61. Stern RS, Laird N: The carcinogenic risk of treatments for severe psoriasis. Cancer
73:2759, 1994
62. Stern RS, Thibodeau LA, Kleinerman RA, et al: Risk of cutaneous carcinoma in patients treated with oral methoxsalen photochemotherapy for psoriasis. N Engl J Med
300:809, 1979
63. Stern RS, Laird N, Melski J, et al: Cutaneous squamous-cell carcinoma in patients
treated with PUVA. N Engl J Med 310:1156, 1984
64. Stern RS, Nichols KT, Vakeva LH: Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study.N Engl J Med 336:1041, 1997
65. Lerman S, Borkman RF: A method for detecting 8-methoxypsoralen in the ocular
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66. Lerman S: Ocular phototoxicity and psoralen plus ultraviolet radiation (320400
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67. Jeffes EB III, McCullough JL, Pittelkow MR, et al: Methotrexate therapy of psoriasis:
differential sensitivity of proliferating lymphoid and epithelial cells to the cytotoxic and
growth-inhibitory effects of methotrexate. J Invest Dermatol 104:183, 1995
68. Roenigk HH Jr, Auerbach R, Maibach H, et al: Methotrexate in psoriasis: consensus
conference. J Am Acad Dermatol 38:478, 1996
69. Gilbert SC, Lintmalm G, Menter A, et al: Methotrexate-induced cirrhosis requiring
liver transplantation in three patients with psoriasis: a word of caution in light of the expanding use of this steroid-sparing agent. Arch Intern Med 150:889, 1990
70. Al-Awadhi A, Dale P, McKendry RJ: Pancytopenia associated with low dose
methotrexate therapy: a regional survey. J Rheumatol 20:1121, 1993
71. Lebwohl M: Acitretin in combination with UVB or PUVA. J Am Acad Dermatol
4:S22, 1999
72. Lebwohl M, Drake L, Menter A, et al: Consensus conference: acitretin in combination with UVB or PUVA in the treatment of psoriasis. J Am Acad Dermatol 45:544, 2001
73. Roenigk HH Jr, Callen JP, Guzzo CA, et al: Effects of acitretin on the liver. J Am
74. Larsen FG, Jakobsen P, Knudsen J, et al: Conversion of acitretin to etretinate in psoriatic patients is influenced by ethanol. J Invest Dermatol 100:623, 1993
75. DiGiovanna JJ, Sollitto RB, Abangan DL, et al: Osteoporosis is a toxic effect of longterm etretinate therapy. Arch Dermatol 131:1263, 1995
76. Wilson DJ, Kay V, Charig M, et al: Skeletal hyperostosis and extraosseous calcification in patients receiving long-term etretinate (Tigason). Br J Dermatol 119:597, 1988
77. Stern RS, Fitzgerald E, Ellis CN, et al: The safety of etretinate as long-term therapy
for psoriasis: results of the Etretinate Follow-Up Study. J Am Acad Dermatol 33:44, 1995
78. Lebwohl M, Ellis C, Gottlieb A, et al: Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. J Am Acad Dermatol 39:464, 1998
79. Raman GV, Campbell SK, Farrer A, et al: Modifying effects of amlodipine on cyclosporin Ainduced changes in renal function in patients with psoriasis. J Hypertens
Suppl 16:S39, 1998

April 2005 Update
80. Zachariae H, Kragballe K, Hansen HE, et al: Renal biopsy findings in long-term cyclosporin treatment of psoriasis. Br J Dermatol 136:531, 1997
81. Lowe NJ, Wieder JM, Rosenbach A, et al: Long-term low-dose cyclosporine therapy
for severe psoriasis: effects on renal function and structure. J Am Acad Dermatol 35:710,
1996
82. Jensen P, Hansen S, Moller B, et al: Skin cancer in kidney and heart transplant recipients and different long-term immunosuppressive therapy regimens. J Am Acad Dermatol 40:177, 1999
83. Srivastava T, Zwick DL, Rothberg PG, et al: Posttransplant lymphoproliferative disorder in pediatric renal transplantation. Pediatr Nephrol 13:748, 1999
84. van den Borne BE, Landewe RB, Houkes I, et al: No increased risk of malignancies
and mortality in cyclosporin Atreated patients with rheumatoid arthritis. Arthritis
Rheum 41:1930, 1998
85. Systemic tacrolimus (FK 506) is effective for the treatment of psoriasis in a doubleblind, placebo-controlled study. The European FK 506 Multicenter Psoriasis Study
Group. Arch Dermatol 132:419, 1996
86. Smith CH: Use of hydroxyurea in psoriasis. Clin Exp Dermatol 24:2, 1999
87. Gupta AK, Ellis CN, Siegel MT, et al: Sulfasalazine improves psoriasis: a doubleblind analysis. Arch Dermatol 126:487, 1990
88. Roenigk HH Jr: Acitretin combination therapy. J Am Acad Dermatol 41:S18, 1999
89. Wong KC, Georgouras K: Low dose cyclosporin A and methotrexate in the treatment of psoriasis. Acta Derm Venereol 79:87, 1999
90. Paul BS, Momtaz K, Stern RS, et al: Combined methotrexateultraviolet B therapy
in the treatment of psoriasis. J Am Acad Dermatol 7:758, 1982
91. Morison WL, Momtaz K, Parrish JA, et al: Combined methotrexatePUVA therapy
in the treatment of psoriasis. J Am Acad Dermatol 6:46, 1982
92. Stern RS, Laird N: The carcinogenic risk of treatments for severe psoriasis. Photochemotherapy Follow-up Study. Cancer 73:2759, 1994
93. Kirby B, Yates VM: Mycophenolate mofetil for psoriasis. Br J Dermatol 139:357,
1998
94. Epinette WW, Parker CM, Jones EL, et al: Mycophenolic acid for psoriasis: a review
of pharmacology, long-term efficacy, and safety. J Am Acad Dermatol 17:962, 1987
95. Zackheim HS, Glogau RG, Fisher DA, et al: 6-Thioguanine treatment of psoriasis:
experience in 81 patients. J Am Acad Dermatol 30:452, 1994
96. Silvis NG, Levine N: Pulse dosing of thioguanine in recalcitrant psoriasis. Arch Dermatol 135:433, 1999
97. Krueger GG: Selective targeting of T cell subsets: focus on alefacept: a remittive
therapy for psoriasis. Expert Opin Biol Ther 2:431, 2002
98. Hodak E, David M: Alefacept: a review of the literature and practical guidelines for
management. Dermatol Ther 17:383, 2004
99. Gordon KB, Langley RG: Remittive effects of intramuscular alefacept in psoriasis. J
Drugs Dermatol 2:624, 2003
100. Lebwohl M, Tyring SK, Hamilton TK, et al: A novel targeted T-cell modulator,
efalizumab, for plaque psoriasis. Efalizumab Study Group. N Engl J Med 349:2004, 2003
101. Leonardi CL: Efalizumab in the treatment of psoriasis. Dermatol Ther 17:393, 2004
102. Gordon KB, Papp KA, Hamilton TK, et al: Efalizumab for patients with moderate
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JAMA 290:3073, 2003
103. Leonardi CL, Powers JL, Matheson RT, et al: Etanercept as monotherapy in patients with psoriasis. Etanercept Psoriasis Study Group. N Engl J Med 349:2014, 2003
104. Brown SL, Greene MH, Gershon SK, et al: Tumor necrosis factor antagonist therapy and lymphoma development: twenty-six cases reported to the Food and Drug Administration. Arthritis Rheum 46:3151, 2002
105. Chaudhari U, Romano P, Mulcahy LD, et al: Efficacy and safety of infliximab
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106. Keane J, Gershon S, Wise RP, et al: Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 345:1098, 2001
107. Patel T, Gordon KB: Adalimumab: efficacy and safety in psoriasis and rheumatoid
arthritis. Dermatol Ther 17:427, 2004
ACP Medicine
IV
E C Z E M AT O U S D I S O R D E R S , AT O P I C
D E R M AT I T I S , A N D I C H T H Y O S E S
Seth R. Stevens, m.d.
Kevin D. Cooper, m.d.
Kefei Kang, m.d.
sides of fingers, although more extensive involvement can occur.

Treatment is with compresses and soaks, antipruritics, topical
steroids, and, in severe recalcitrant cases, systemic corticosteroids. Photochemotherapy with topical psoralen and ultraviolet A irradiation (PUVA) may also be effective.
Eczematous Disorders
Eczematous dermatitis, or eczema, is a skin disease that is
characterized by erythematous vesicular, weeping, and crusting
patches. Although the term eczema is often used as a diagnosis,
it can in fact be used appropriately to describe lesions seen in
several diseases. Itching is a characteristic symptom, and epidermal intercellular edema (spongiosis) is a characteristic histopathologic finding of eczematous conditions. The term eczema is
also commonly used to describe atopic dermatitis [see Atopic
Dermatitis, below].
Atopic Dermatitis
Atopic dermatitis (AD) is a common chronic inflammatory
dermatosis. The term atopy was coined in the early 1920s to describe the associated triad of asthma, allergic rhinitis, and dermatitis.3 The role of reaginic antibodies and allergies in the etiology of AD is controversial; in 80% of patients with AD, however,
serum immunoglobulin IgE is elevated, sometimes markedly.
contact dermatitis
etiology and pathogenesis
Contact dermatitis, a paradigmatic example of an eczematous

disorder, is common and well studied [see 2:V Contact Dermatitis
and Related Disorders]. Contact dermatitis can be either allergic or
irritant in etiology. Allergic contact dermatitis differs from other
eczematous disorders in that determination of the offending contactant is an important part of the evaluation. If the patients history does not provide the answer, the body site of the lesion may
(e.g., head involvement in allergy to paraphenylenediamine in
hair dye). Patch testing may be required to confirm the diagnosis.1
The manifestations of irritant contact dermatitis are similar to
those of allergic contact dermatitis2; in the irritant form, however,
the mechanism is not immunologic. Given sufficient concentration and duration of contact, offending agents will induce irritation in anyones skin. Detergents, acids, alkalis, solvents, formaldehyde, and fiberglass are common causes.
The expression of AD is a complex integration of environmental and genetic factors. The lifetime prevalence is estimated
to be 30% of the population,4-6 possibly because of increasing contact with causative agents in the environment. Epidemiologic
data suggest a genetic influence25% of dizygotic twins and
75% of monozygotic twins are concordant for AD.7 The condition develops in 60% of children who have one affected parent
and in 80% of children with two affected parents.8 The defect is
likely carried in the immune system, because both antigenspecific IgE reactivity and AD have been transplanted from an
AD-affected bone marrow donor to a previously unaffected
recipient.9 Candidate genes continue to be investigated.
AD can be quickly exacerbated by environmental trigger factors.10 Wool, lanolin, and harsh detergents are particularly irritating. Emotional stress can also lead to flares. The role of airborne
and foodborne allergens is difficult to assess. Although patients
with AD frequently have circulating dust mite antigen-specific
IgE and TH2 CD4+ T cells,11 hyposensitization infrequently results
in improvement. Contact urticaria to food occurs in AD,12 but
generalized exacerbation after eating is rare. In the absence of a
strong supporting history, elimination diets are rarely effective in
treating AD. A role has been frequently suggested for cows milk
in inducing AD; however, such an association was not supported
in a study of AD in infants fed breast milk rather than cows
milkbased formula.13 Mechanisms have been proposed to explain a link between Staphylococcus aureus and exacerbations of
AD,14 including effects of cell wall constituents to increase expression of IgE, IgE receptor, and enterotoxin B, a superantigen that
activates T cells in an antigen-independent fashion.15
The apparent paradox of reduced cell-mediated immunity16,17
and hyperimmunoglobulinemia E seen in AD is addressed by
the so-called TH1/TH2 model of helper T cells. In this model of the
murine immune system, CD4+ cells are divided into two mutually exclusive classes on the basis of cytokine secretion: TH1 cells,
which secrete cytokines that promote cell-mediated immunity
(e.g., interleukin-2 [IL-2], interferon gamma), and TH2 cells,
which secrete cytokines that promote humoral immunity and
eosinophil function (e.g., IL-4 and IL-5). Atopy, including AD,
has been seen as the paradigmatic condition of a so-called TH1deficient state. Refinements have shown a heterogeneity of re-
seborrheic dermatitis
Seborrheic dermatitis is another common eczematous condition [see 2:II Papulosquamous Disorders]. Clinically, seborrheic dermatitis may exist without vesicle formation. Lesional morphology is usually a greasy scale on erythematous patches; however,
the scale may be dry and the patches may have an orange hue.
Scalp, eyebrows, mustache area, nasolabial folds, and chest are
typical areas of involvement. Psoriasis may be in the differential
diagnosis. Treatment is with shampoos containing selenium sulfide, zinc pyrithione, tar, or ketoconazole; emollients; and mild
(nonfluorinated) topical steroids. Antimicrobial therapy directed
at the commensal yeast Pityrosporum ovale can be effective, although a causative role of the organism remains unproved.
other eczematous dermatitides
Two other eczematous dermatitides are nummular eczema
and dyshidrotic eczema (pompholyx). Nummular eczema describes well-demarcated, coin-shaped eczematous patches that
are usually 2 to 4 cm (rarely more than 10 cm) in diameter. The
lesions are quite pruritic and require potent topical steroids, antihistamines, and, occasionally, intralesional or systemic corticosteroids for treatment. Dyshidrotic eczema presents as a vesicular
eruption of the hands and feet, accompanied on rare occasions
by hyperhidrosis. Typically, 1 to 2 mm vesicles appear on the
March 2002 Update
ACP Medicine
DERMATOLOGY:IV Eczematous Disorders, Atopic Dermatitis, and Ichthyoses1
Table 1 Diagnostic Criteria for

Atopic Dermatitis11
Major criteria
Personal or family history of atopy (atopic dermatitis, allergic
rhinitis, allergic conjunctivitis, allergic blepharitis, or asthma)
Characteristic morphology and distribution of lesions
Pruritus
Chronic or chronically recurring dermatosis
Minor features
Hyperimmunoglobulinemia E
Food intolerance
Intolerance to wool and lipid solvents
Recurrent skin infections
Xerosis
Sweat-induced pruritus
White (not red) dermatographism
Ichthyosis
Chronically scaling scalp
Accentuation of hair follicles
Recurrent conjunctivitis
Anterior subcapsular cataracts and keratoconus
Morgan line, or Dennie sign (single or double creases in the
lower eyelids)
Periorbital darkening (allergic shiner)
Pityriasis alba (hypopigmented, scaling patches, typically on
the cheeks)
Cheilitis
Anterior neck folds
Keratosis pilaris (perifollicular papules with keratotic plugs,
typically on the arms and thighs)
Nipple eczema
Hyperlinear palms (increased folds, typically on the thenar
or hypothenar eminence)
Recurrent hand and foot dermatitis
Exacerbation of symptoms by environmental or emotional
factors
sponses within different AD lesions, however. The current model is that blood and acute lesions of AD patients are more often
dominated by TH2 cells, whereas chronic lesions are more often
dominated by TH1 cells.18
Hyperstimulatory dendritic antigen-presenting cells (Langerhans cells) are present in patients with AD.19 One proposed
mechanism for the augmented function of Langerhans cells in
AD is the binding of antigen-specific IgE and antigen to the IgE
receptors on Langerhans cells as a means of antigen focusing.20
Another antigen-presenting cell, the monocyte, also manifests altered function in AD. Cyclic adenosine monophosphate (cAMP)
phosphodiesterase has increased activity in monocytes of patients with ADleading to hyperproduction of prostaglandin
E2, among other effects. Increased cAMP phosphodiesterase in
AD may explain aberrant adrenergic responses, and the increased prostaglandin E2 leads to diminished interferon-gamma
production. Additionally, monocytes secrete IL-10 in AD, which
further augments the so-called TH2 responses.21 Altered cyclic nucleotide metabolism leads to excessive release of histamine by
basophils and, potentially, to mast cell degranulation. High levels of cAMP phosphodiesterase are found in the umbilical cord
blood of infants of AD-affected parents.22 This finding may indicate an early, if not primary, defect in the disease that may become the basis of a diagnostic laboratory test.
Because IL-5 is a critical eosinophil growth factor and activating cytokine, blood eosinophilia may be expected to occur in a
March 2002 Update
TH2 disease such as AD23; tissue eosinophilia, however, is variable. Cutaneous endothelial cells are also activated in AD, leading to increased expression of adhesion molecules and recruitment of leukocytes into the skin (i.e., dermatitis).
diagnosis
AD remains a clinical diagnosis. Major diagnostic criteria are
(1) personal or family history of atopy (AD, allergic rhinitis, allergic conjunctivitis, allergic blepharitis, or asthma); (2) characteristic morphology and distribution of lesions; (3) pruritus; and (4)
chronic or chronically recurring dermatosis. Several minor features can be added [see Table 1].12 Pruritus is a consistent feature
of AD. The lack of itching or of another major diagnostic criterion should prompt consideration of alternative diagnoses [see
Differential Diagnosis, below]. Cutaneous signs can vary, depending on the age of the lesions.
Acute lesions of AD are eczematouserythematous, scaling,
and papulovesicular. Weeping and crusted lesions may develop
[see Figure 1]. Scratching results acutely in linear excoriations,
presenting as erosions or a hemorrhagic crust. In extremely severe cases, exfoliative dermatitis (erythroderma) may occur,
with generalized redness, scaling, weeping, and crusting. There
may be accompanying systemic toxicity, sepsis, lymphadenopathy, altered thermoregulation (either hyperthermia or hypothermia), and high-output cardiac failure. Erythroderma is a potentially life-threatening condition.
Figure 1 Extensive, severe, weeping, crusted acute eczematous patches

on the face of this infant are characteristic of patients in this age group.
Figure 2 Lichenified patches appear after chronic rubbing of

eczematous patches. These lesions are characteristic of chronic allergic
contact dermatitis and atopic dermatitis.
ACP Medicine
Chronic lesions tend not to be eczematous (thus, atopic

eczema is not an ideal synonym for AD). Instead, lichenified
plaques [see Figure 2] or nodules predominate. Lichenification
denotes areas of thickened skin divided by deep linear furrows.
Lichenified plaques result from repeated rubbing or scratching
and thus often occur in areas of predilection, such as the
popliteal and cubital fossae. As is typical of lesions in AD,
lichenification is poorly demarcated. There may be accompanying acute signs. Lichenified lesions are very difficult to treat; once
established, they may persist for months even with adequate
therapy and avoidance of rubbing or scratching.
Clinical expression of AD also varies with the age of the patient. The infantile stage of AD occurs up to approximately 2
years of age. Of all cases of AD, approximately 90% arise before
the fifth year and 60% in the first year of life; onset before 2
months of age is unusual, however.7 During infancy, ill-defined,
erythematous scaling patches and confluent, edematous papules
and vesicles are typical. These lesions may become crusted and
exudative. Intense pruritus leads to scratching, which induces
linear excoriations and, with time, lichenification. Before the infant begins to crawl, the scalp and face are most often involved
[see Figure 1], although lesions may be seen anywhere. After the
child begins crawling, the extensor surfacesparticularly the
kneesbecome involved. Involvement of fingers can be severe if
the child sucks them frequently. Intense pruritus can lead to
sleep disturbances of child and parents. Other features may arise
[see Table 1]. Perifollicular accentuation and papules are commonly seen at any point in the life of an atopic patient, particularly in persons of Asian or African ancestry.
During childhood, the clinical features evolve into those seen
in adults. Lesions tend to become less eczematous and drier,
with increasing flexural and neck involvement. Scaling, fissured,
and crusted hands may become especially troublesome. Infraorbital folds (sometimes called Morgan lines or the Dennie sign)
and pityriasis alba can appear. Chronic or chronically relapsing
pruritic, erythematous, papulovesicular eruptions that progress
to scaling, lichenified dermatitis in a flexural distribution typify
adult AD. Extensive areas of skin may be involved, including the
face, chest, neck, flanks, and hands. Areas of dyspigmentation
may result from repeated skin trauma. Approximately 10% to
15% of childhood AD persists after puberty.7
AD that begins after 20 years of age has been termed adultonset atopic dermatitis.24 This condition should be considered in
patients with characteristic features of AD.
There are many associated features of AD. Asthma and allergic rhinitis, the major and minor criteria, respectively, have already been mentioned. Another important association, cutaneous infection, is related to diminished cutaneous cell-mediated
immunity and defective chemotaxis. S. aureus is usually found on
AD skin, and its density correlates with lesion severity. Although
such observations have implicated S. aureus as a cause of AD,14,25 it
is also clear that reduction in AD lesions reduces bacterial colonization.26 Regardless, the high bacterial counts in lesional skin
and the relative ease of their reduction suggest the desirability of
extra efforts (e.g., use of topical steroids) to reduce the presence of
S. aureus before elective procedures are performed through involved skin. Frank infection also occurs more commonly in AD,
which results in pustules and oozing, crusted lesions.
Cutaneous fungal and viral infections also occur frequently
and with increased severity in patients with AD. Eczema herpeticum, an extensive eruption of 2 to 3 mm vesicles, pustules,
and punched-out erosions caused by herpes simplex virus,
March 2002 Update
may coalesce into extensive areas of eroded skin. Frequently,

the condition is most severe on the face (where it often arises
from a herpetic lesion) and diminishes as it progresses to the
trunk and extremities. Secondary bacterial infection is common. Lymphadenopathy, fever, and malaise may develop. Antiviral and antibiotic therapy can be lifesaving and should be
started empirically upon presentation. Tzanck test, viral culture, and direct fluorescent antibody detection of viral antigens
can confirm the diagnosis.
Molluscum contagiosum and common warts are also problematic in patients with AD, as are dermatophyte infections.
Because of similar appearance, foot eczema must be distinguished from tinea pedis by potassium hydroxide preparation
or fungal culture.
Numerous ocular complications of AD exist.27 These include
anterior subcapsular cataracts, retinal detachment, keratoconus,
blepharitis, conjunctivitis, and iritis.
The differential diagnosis of AD includes the eczematous conditions and ichthyoses described in this subsection and other immunologic, metabolic, neoplastic, and rheumatologic disorders
[see Table 2]. Because 80% to 85% of patients with occupational
hand dermatitis have AD, the possibility of coexisting AD and
contact dermatitis needs to be considered. Another important element of the differential diagnosis is cutaneous T cell lymphoma. Cutaneous T cell lymphoma can arise clinically as scaling, erythematous patches or exfoliative erythroderma. The classic
distributionnear axillae, buttocks, and groinis distinct from
that of AD, and patches are frequently well demarcated. There is
often sufficient clinical overlap between the two conditions,
however, to necessitate further investigation, including histology, immunophenotyping, and gene rearrangement analysis of
T cell receptors. Cutaneous T cell lymphoma can arise in patients
with AD, and the lack of conclusive clinical or laboratory tests
for either disease can make distinction difficult. Reassessment
from time to time in such cases is recommended.
Table 2 Differential Diagnosis of Atopic Dermatitis

Type
Disorders
Dermatitides
Allergic contact dermatitis

Dermatitis herpetiformis
Irritant contact dermatitis (may be
concomitant with atopic dermatitis)
Nummular eczema
Seborrheic dermatitis
Ichthyoses
Ichthyosis vulgaris
Immunologic disorders
Graft versus host disease

HIV-associated dermatosis
Hyperimmunoglobulinemia E syndrome
Wiskott-Aldrich syndrome
Infectious diseases
Scabies
Dermatophytosis
Metabolic disorders
Zinc deficiency
Various inborn errors of metabolism
Neoplastic disorders
Cutaneous T cell lymphoma
Rheumatologic disorders
Dermatomyositis
ACP Medicine
treatment
Reduction of Trigger Factors

Reduction of trigger factors (e.g., harsh chemicals, detergents,
and wool) and avoidance of occupations that require contact with
trigger factors (e.g., hairdressing, nursing, and construction) can
be helpful. Appropriate behaviors should be taught to patients and
parents early during life, when habits are more easily formed.28,29
The use of mild, nonalkali soaps and frequent use of emollients are important elements in the long-term management of
AD. Because moisture evaporating off the skin can trigger flares,
bathing is sometimes discouraged. A better approach is the
prompt application of an emollient such as petrolatum (finishing
within 3 minutes of the end of the bath), which can serve to seal
the moisture from the bath. Lotions and creams containing high
amounts of water are usually inadequate, however, and can actually worsen AD. Products containing hydroxy acids, phenol, or
urea can reduce dryness and scaling, but these can sting inflamed
skin and should therefore be used with caution. Because of a specific reduction of ceramides in AD, a lotion that provides excess
ceramides relative to other lipids has been tried in AD and appears to have a therapeutic advantage.30 Bubble baths and scented
salts and oils can be irritating. Scalp care should include a bland
shampoo. Topical tar products, such as shampoos and bath solutions, and topical creams and lotions containing 5% to 10% liquor
carbonis detergens can help. Baths, soaks, and compresses with
Burow solution can ameliorate crusted, infected, eczematous
patches. Cotton clothing, washed to remove finishing (which often releases formaldehyde), is preferable to wool or synthetics.
Corticosteroids
Topical corticosteroids are another mainstay of therapy. Application immediately after bathing improves cutaneous penetration. Lowering the risk of side effects with less potent preparations
must be balanced against gaining control of a flare quickly with
more potent preparations. Long-term use of inadequately potent
topical corticosteroids may pose a greater risk of adverse effects
than brief use of more potent agents followed by a rapid taper to
bland emollients. Because steroid-induced cutaneous atrophy is a
greater risk on the face, in intertriginous areas (e.g., groin, axillae,
and inframammary folds), and under diapers, less potent steroids
(e.g., hydrocortisone and desonide) should be used in these areas,
and they should be used with particular caution. For the remainder of the body, midpotency preparations, such as 0.1% triamcinolone acetonide, are helpful. More potent ointments, such as
fluocinonide and desoximetasone, are useful for lichenified
plaques. Flurandrenolide tape is useful for nodular prurigo (socalled pickers nodules) because it also physically protects the
area from manipulation. For the scalp, solutions are preferred.
Systemic corticosteroids (e.g., prednisone, 20 to 80 mg/day
orally) may be useful to treat severe, acute flares. Because of the
risks of gastrointestinal, endocrine, skeletal, central nervous system, and cardiovascular complications, however, they should
not be used more than twice yearly.
Other Therapies
Antihistamines can sometimes be helpful in breaking the itchscratch cycle in AD. Sedating antihistamines, such as hydroxyzine
and diphenhydramine, are particularly usefulespecially when
itching prevents sleep. Nonsedating antihistamines are less useful.
Doxepin, a tricyclic antidepressant known to have antihistaminic
effects, can be beneficial when applied topically in a 5% cream.
March 2002 Update
Virtually every phototherapy regimen has been reported to

ameliorate AD. Some patients cannot tolerate the heat generated by the equipment, howeverparticularly that used in UVB
irradiation. In addition to UVB, the following can be beneficial:
UVA, longwave UVA1, narrow-band UVB, UVA-UVB, and
PUVA. Extracorporeal photochemotherapy (photopheresis) is
also emerging as an effective therapy for recalcitrant disease.31
Although some patients may benefit from natural sunlight, the
risk of sunburn and induction of malignancy by ultraviolet
light must be considered.
The macrolide antibiotic tacrolimus has been approved for
use in both pediatric (0.03% ointment) and adult (0.1% ointment)
atopic dermatitis.32 Current labeling is for use in steroid-unresponsive disease. However, because this medication appears to
have a much-improved therapeutic index, its position in the armamentarium is still being determined. The ascomycin macrolactam derivative, SDZ ASM 981, also shows promise in AD33
and may be widely available shortly.
Antimicrobials are obviously important for patients with infection. Less clear is whether antimicrobial agents can directly
treat AD by reducing bacterial products thought to exacerbate
the condition. Antistaphylococcal therapy has been advocated
for use in patients with AD; however, a double-blind, placebocontrolled study of flucloxacillin did not show improvement in
AD despite reduced bacterial counts.34 Ketoconazole, likewise,
has been used; its success, however, may be the result of anti-inflammatory, rather than antifungal, effects.
More advanced therapeutic options exist for severe, recalcitrant AD. The altered expression of cytokines in AD [see Etiology and Pathogenesis, above] has led investigators to explore
the use of interferon gamma. Clinical trials have demonstrated
that for some patients, daily subcutaneous administration of
interferon gamma is effective in reducing both signs and
symptoms of AD35,36 and that long-term treatment can maintain the benefit.37
Oral cyclosporine (2.5 to 5 mg/kg/day orally),38,39 methotrexate (15 to 25 mg/wk orally), and azathioprine (100 to 200
mg/day orally) can be used in severe, recalcitrant disease provided that patients are monitored for adverse effects specific to
those agents.
Traditional Chinese herbal medicine has been found to be effective in the treatment of AD, both in children40 and in adults,41
although the efficacy of this treatment remains controversial.42
The mechanisms of action of these preparations are unclear. Patients should be cautioned that herbal remedies are not risk free
and may carry a potential for hepatotoxicity, cardiomyopathy,
and other adverse effects; such remedies should be monitored,
as should any other treatment.
Although evening primrose oil has for many years been proposed to be effective in AD, a well-controlled study failed to
show any benefit to patients taking either evening primrose oil
or a combination of evening primrose oil and fish oil compared
with those receiving placebo.43 The importance of well-controlled studies to assess efficacy of treatments must be stressed
because AD patients on the placebo arms of most controlled
studies tend to show benefit from the placebo. The cAMP
phosphodiesterase inhibitor CP80633 shows promise as an
emerging therapy.44 These new agents, which are based on the
emerging pathogenic concepts of altered cytokine production
and cyclic nucleotide regulation, may prove to reduce pruritus
and dermatitis effectively without producing unacceptable
side effects.
ACP Medicine
Ichthyoses
The ichthyoses are a group of diseases of cornification that are
characterized by excessive scaling.45 Etiologies of the ichthyoses
are diverse, including genetic defects of structural proteins and
enzymes as well as acquired forms. Only the major clinical variants will be discussed here.
major variants
Ichthyosis Vulgaris
Ichthyosis vulgaris, the most common form of ichthyosis, is
found in approximately one in 300 births. This autosomal dominant condition presents as dry skin with fine scaling. The extensor surfaces of extremities are the most commonly affected areas.
Ichthyosis vulgaris can occur concomitantly with keratosis pilaris
and can also be associated with AD. Age at onset is typically between 3 months and 12 months. Implicated etiologic factors include reduced filaggrin (filament-aggregating protein) and its
precursor profilaggrin, whose normal functions are to allow for
aggregation of keratin filaments and to serve as sources of compounds that hydrate the skin. The clinical severity of ichthyosis
vulgaris correlates with the degree of reduction in filaggrin and
profilaggrin. Another possible etiologic factor is the reduced activity of proteases that normally lead to dissociation of keratinocytes.46
X-Linked Ichthyosis
Recessive X-linked ichthyosis occurs in approximately one in
2,000 to one in 6,000 male infants. Although collodion membrane
may be present at birth, the skin is usually normal, with fine scaling beginning at 1 to 3 weeks of life. Typically, the scales are
thick and dark, giving the skin a dirty appearance. Extensor distributioncombined with involvement of the sides of the neck
and preauricular skin and sparing the flexural areasis typical.
Steroid sulfatase deficiency is an etiologic factor, causing an increase in cholesterol sulfate and a decrease in cholesterol in the
stratum corneum.47 The accumulated cholesterol sulfate may inhibit proteolysisa process similar to the inhibition seen in
ichthyosis vulgaris. Prenatal diagnosis is available, and gene
therapy may be on the horizon.
Lamellar Ichthyosis
Lamellar ichthyosis occurs in one in 300,000 births. It is inherited in an autosomal recessive pattern. Collodion membrane
Figure 4 This patient developed marked scaling (acquired ichthyosis)

over a 6-month period. Investigation revealed non-Hodgkin lymphoma.
may be present at birth but is then shed, revealing characteristic
large, platelike scales. Erythroderma may be present, albeit difficult to discern because of the thickness of the scales. Ectropion is
present in most patients and can give rise to ophthalmic complications. The leading candidate for the etiologic genetic disorder
is defective transglutaminase, which normally cross-links the
structural proteins that give rise to the cornified envelope of stratum corneum cells that is critical to cutaneous barrier function.48
Congenital Ichthyosiform Erythroderma

Formerly, congenital ichthyosiform erythroderma [see Figure
3] was considered a variant of lamellar ichthyosis. Both are inherited as autosomal recessive traits, and collodion membrane
may be present at birth in both conditions. Ectropion, eclabion
(eversion of the lip), and erythroderma can also occur. Although
patients with congenital ichthyosiform erythroderma, like patients with lamellar ichthyosis, may have platelike scales on the
lower extremities, elsewhere the scales are fine and white. Also
in contrast to lamellar ichthyosis, X-linked ichthyosis, and
ichthyosis vulgaris, whose lesions are scaly because of an abnormal ability to desquamate (so-called retention hyperkeratoses),
the lesions of congenital ichthyosiform erythroderma are scaly
because of increased production of keratinocytes (so-called hyperproliferative ichthyosis).
Epidermolytic Hyperkeratosis
Epidermolytic hyperkeratosis (formerly called bullous congenital ichthyosiform erythroderma) is autosomal dominant in
inheritance. The combinations of large blisters and erythema
with denuded skin that appear at birth may be confused with epidermolysis bullosa, staphylococcal scalded skin syndrome, or toxic epidermal necrolysis. Several months to 1 year after birth, the
blisters become less prominent, and thick, verrucous plaques
comprising rows of hyperkeratotic ridges develop. Flexural skin
is usually involved, but the disease can be more extensive. Bacterial colonization leads to a clinically significant foul odor. Abnormal keratin gene expression is the etiologic basis of this condition.49
Acquired Ichthyosis
Figure 3 Erythroderma (total body erythema) and extensive scaling are

seen in this infant with congenital ichthyosiform erythroderma.
March 2002 Update
Acquired ichthyoses have been associated with numerous systemic diseases and medications. Although the onset of scaling is
commonly a manifestation of dryness or ichthyosis vulgaris, patients with unusual manifestations or with severe or recalcitrant
disease warrant further investigation. Endocrinopathies (e.g., thyroid disease), autoimmune diseases, infectious diseases (e.g.,
ACP Medicine
HIV), and malignancies such as lymphomas [see Figure 4] and

other carcinomas have been associated with the onset of ichthyosiform dermatosis.
treatment
The standard therapy for the ichthyoses is emollients (e.g.,
petrolatum) and keratolytics (e.g., lactic acid with or without propylene glycol). Lactic acid should be used cautiously in neonates
to avoid causing excess absorption. Oral retinoids (which require
lipid monitoring) can be helpful, particularly in the management
of X-linked ichthyosis, congenital ichthyosiform erythroderma,
and lamellar ichthyosis. Epidermolytic hyperkeratosis is the
most difficult of these conditions to treat because of the risk of
blistering induced by therapeutic agents. Antimicrobial agents
can be useful to reduce the odor caused by bacterial colonization.
The authors have no commercial relationships with manufacturers of products or
22. Heskel NS, Chan SC, Thiel ML, et al: Elevated umbilical cord blood leukocyte cyclic
adenosine monophosphate-phosphodiesterase activity in children with atopic parents.
J Am Acad Dermatol 11:422, 1984
23. Uehara M, Izukura R, Sawai T: Blood eosinophilia in atopic dermatitis. Clin Exp
Dermatol 15:264, 1990
24. Bannister MJ, Freeman S: Adult-onset atopic dermatitis. Australas J Dermatol
41:225, 2000
25. Hofer MF, Lester MR, Schlievert PM, et al: Upregulation of IgE synthesis by staphylocococcal toxic shock syndrome toxin-1 in peripheral blood mononuclear cells from
patients with atopic dermatitis. Clin Exp Allergy 25:1218, 1995
26. Nilsson EJ, Henning CG, Magnusson J: Topical corticosteroids and Staphylococcus
aureus in atopic dermatitis. J Am Acad Dermatol 27:29, 1992
27. Rich LF, Hanifin JM: Ocular complications of atopic dermatitis and other eczemas.
Int Ophthalmol Clin 25:61, 1985
28. McHenry PM, Williams HC, Bingham EA: Management of atopic eczema. Joint
Workshop of the British Association of Dermatologists and the Research Unit of the
Royal College of Physicians of London. BMJ 310:843, 1995
29. Guidelines of care for atopic dermatitis. American Academy of Dermatology. J Am
30. Chamlin SL, Frieden IJ, Fowler A, et al: Ceramide-dominant, barrier-repair lipids
improve childhood atopic dermatitis. Arch Dermatol 137:1110, 2001
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March 2002 Update
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1998
32. Alaiti S, Kang S, Fiedler VC, et al: Tacrolimus (FK506) ointment for atopic dermatitis: a phase I study in adults and children. J Am Acad Dermatol 38:69, 1998
33. Van Leent EJ, Graber M, Thurston M, et al: Effectiveness of the ascomycin macrolactam SDZ ASM 981 in the topical treatment of atopic dermatitis. Arch Dermatol
134:805, 1998
34. Ewing CI, Ashcroft C, Gibbs AC, et al: Flucloxacillin in the treatment of atopic dermatitis. Br J Dermatol 138:1022, 1998
35. Hanifin JM, Schneider LC, Leung DY, et al: Recombinant interferon gamma therapy
for atopic dermatitis. J Am Acad Dermatol 28:189, 1993
36. Ellis CN, Stevens SR, Blok BK, et al: Interferon-gamma therapy reduces blood
leukocyte levels in patients with atopic dermatitis: correction with clinical improvement. Clin Immunol 92:49, 1999
37. Stevens SR, Hanifin JM, Hamilton T, et al: Long-term effectiveness and safety of recombinant human interferon gamma therapy for atopic dermatitis despite unchanged
serum IgE levels. Arch Dermatol 134:799, 1998
38. Berth-Jones J, Graham-Brown RA, Marks R, et al: Long-term efficacy and safety of
cyclosporin in severe adult atopic dermatitis. Br J Dermatol 136:76, 1997
39. Berth-Jones J, Finlay AY, Zaki I, et al: Cyclosporine in severe childhood atopic dermatitis: a multicenter study. J Am Acad Dermatol 34:1016, 1996
40. Sheehan MP, Atherton DJ: A controlled trial of traditional Chinese medicinal plants
in widespread non-exudative atopic eczema. Br J Dermatol 126:179, 1992
41. Sheehan MP, Atherton DJ: One-year follow up of children treated with Chinese
medicinal herbs for atopic dermatitis. Br J Dermatol 130:488, 1994
42. Fung AY, Look PC, Chong LY, et al: A controlled trial of traditional Chinese herbal
medicine in Chinese patients with recalcitrant atopic dermatitis. Int J Dermatol 38:387,
1999
43. Berth-Jones J, Graham-Brown RA: Placebo-controlled trial of essential fatty acid
supplementation in atopic dermatitis. Lancet 341:1557, 1993
44. Hanifin JM, Chan SC, Cheng JB, et al: Type 4 phosphodiesterase inhibitors have
clinical and in vitro anti-inflammatory effects in atopic dermatitis. J Invest Dermatol
107:51, 1996
45. Williams ML, Elias PM: Genetically transmitted, generalized disorders of cornification: the ichthyoses. Dermatol Clin 5:155, 1987
46. Rabinowitz LG, Esterly NB: Atopic dermatitis and ichthyosis vulgaris. Pediatr Rev
15:220, 1994
47. Paller AS: Laboratory tests for ichthyosis. Dermatol Clin 12:99, 1994
48. Epstein EH Jr: The genetics of human skin diseases. Curr Opin Genet Dev 6:295,
1996
49. Fuchs E, Coulombe P, Cheng J, et al: Genetic bases of epidermolysis bullosa simplex
and epidermolytic hyperkeratosis. J Invest Dermatol 103(5 suppl):25S, 1994
ACP Medicine
V
C O N TA C T D E R M AT I T I S A N D R E L AT E D
DISORDERS
James S. Taylor, m.d.
Contact dermatitis is an acute or chronic skin inflammation resulting from interaction with a chemical, biological, or physical
agent.1 It is one of the most common conditions seen by physicians, accounting for an estimated 6.5 million physician visits in
1994 and 95% of all reported occupational skin diseases.2 Substances that produce contact dermatitis after single or multiple
exposures may be irritant or allergic. Direct tissue damage results
from contact with irritants. Tissue damage by allergic substances
is mediated through immunologic mechanisms. Eczema or dermatitis is the most common clinical expression of this induced inflammation. Of the more than 85,000 chemicals in our environment, most can be irritants, depending on the circumstances of
exposure.1 More than 3,700 substances have been identified as
contact allergens.3 The potential for these substances to cause contact dermatitis varies greatly, and the severity of the dermatitis
ranges from a mild, short-lived condition to a severe, persistent,
job-threatening, and possibly life-threatening disease.
Major Types of Contact Dermatitis
irritant contact dermatitis
allergic contact dermatitis

Allergic contact dermatitis is a type 4, T cellmediated, delayed hypersensitivity reaction in the skin. The disorder affects
only certain sensitized individuals, typically after two or more exposures, and accounts for about 20% of contact dermatitis cases.
Predisposing Factors
Irritants cause as much as 80% of contact dermatitis, act by direct nonimmunologic chemical or physical action on the skin,
and are divided into marginal and acute types. Marginal irritants
are the most common. Repeated insults by low-grade irritants
such as soap, detergents, surfactants, organic solvents, and oils
may not cause clinical changes for days or months. Dryness of the
skin with a glazed, parched appearance are often the initial signs;
erythema, hyperkeratosis, and fissuring may supervene.
In contrast, acute irritants cause a more immediate reaction.
Some irritants, such as strong acids and alkalis, aromatic amines,
phosphorus, and metallic salts, produce a marked observable effect within minutes.4-6 Others, such as hydrofluoric acid, ethylene
oxide, podophyllin, and anthralin, produce a reaction within 8 to
24 hours after exposure.4 Acute irritant contact dermatitis (ICD) is
usually easily diagnosed by the patient history and often results
from occupational accidents. The clinical appearance varies depending on the irritant and ranges from burns and deep-red ulcerations with sharp circumspection of the dermatitis, sometimes
with a gravitational, dripping effect, to a vesicular dermatitis that
is indistinguishable from acute allergic contact dermatitis.
Almost any substance can be an irritant, depending on the
conditions of exposure [see Figure 1]. The nature of the irritant (i.e.,
its pH, solubility, physical state, and concentration), the duration
of contact, and the nature of the vehicle affect disease severity.
Host factors that predispose to ICD include preexisting dermatitis, skin dryness, sweating, and decreased thickness or breaks in
the stratum corneum; environmental factors include high temperature, low humidity, friction, and pressure.
The causative factors are complex and usually involve exposure to a combination of irritants. The sentinel event for irritant
hand eczema in hairdressers is dermatitis developing in moist areas that are difficult to rinse and dry, such as under rings and in
the web spaces of the fingers.7 Dermatitis may spread to the dor 2001 WebMD Inc. All rights reserved.
March 2001 Update
sum of the hand, where the skin is thinner and less resistant than
on the palms.
ICD may become chronic if it is not treated early. Even when
the skin appears to be healed, its protective capacity remains impaired for weeks or months. Additionally, ICD impairs the barrier function of the skin, allowing penetration of potential contact
allergens. Individuals who had childhood atopic eczema are more
likely than others to develop ICD of the hands when their jobs involve wet work.
No universally accepted test exists for diagnosing ICD, which
is often diagnosed by excluding allergic contact dermatitis (ACD).
Because of the clinical similarity of allergic and irritant contact
dermatitis, it is important that patients thought to have either disorder undergo patch testing, which is positive with ICD and negative with ACD.6
Immunologic status Predisposing factors to ACD include

the patients immunologic status, which in turn is influenced by
genetics, age, gender, and the presence of systemic disease. Patients with AIDS, severe combined immunodeficiency, advanced
lymphoma or other malignancy, sarcoidosis, lepromatous leprosy, cachexia, and atopic dermatitis may have impaired cell-medi-
Figure 1 Wearing a plastic bib resulted in irritant dermatitis in an

18-month-old child.
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DERMATOLOGY:V Contact Dermatitis and Related Disorders1
Table 1 Body Sites Often Affected by 10 Common Contact Allergens

Allergen
Common Uses
Localization Site
Nickel
Costume jewelry
Earlobes, neck, fingers, wrists, abdomen
Neomycin
Topical antibiotics (dermatologic; ophthalmologic; ear,

nose, throat)
Face, neck, trunk, extremities
Balsam of Peru
Fragrances, cosmetics, medications, flavorings
Face, trunk, extremities, perianal area
Fragrance mix
Toothpaste, fragrances, toiletries, cosmetics
Same as for balsam of Peru
Thimerosal
Topical antiseptic, contact lens solutions, eye cosmetics,

nasal sprays
Eyelids, face, neck (relevance hard to prove)
Gold
Jewelry
Eyelids, earlobes, wrists, fingers
Formaldehyde
Cosmetics (preservative), shampoos, nail enamel
Eyelids, face, neck, trunk (especially intertriginous areas)
Quaternium-15
Cosmetics (preservative), shampoos, soaps, lotions
Face, trunk, extremities, hands
Cobalt
Metal-plated objects, jewelry
Earlobes, neck, fingers, wrists
Bacitracin
Topical antibiotics (dermatologic; ophthalmologic; ear,

nose, throat)
Face, neck, trunk, extremities
ated immunity or anergy.8 However, contact allergy should not be

excluded in these individuals, especially those with atopic eczema. In experimental models, agents that affect the immune system, such as ultraviolet light (ultraviolet B or psoralen and ultraviolet A [PUVA]), glucocorticoids, cyclosporine, and various other
drugs, may downregulate ACD.8 Administration of systemic corticosteroids below certain dosages (e.g., prednisone, 20 mg or less
daily), however, does not inhibit strong patch-test reactions.9
In patients with occupational dermatitis, a form of natural hyporeactivity termed hardening may occur with diminished but
continued exposure to chemical irritants. The process is inducible
and is not localized.10 This acquired state of unresponsiveness
is called tolerance. Tolerance may be achieved in guinea pigs
through intravenous administration of a dilute allergen or through
repeated topical administration of a dilute allergen before a sensitizing exposure.8
Environment The chemical environment in which we live
defines opportunities for exposure to various allergens. A patients age, gender, occupation, avocation, habits, and nationality
determine the environment and thus the chemicals to which an
individual is exposed. The most common source of contact allergen in the United States is Toxicodendron, a plant genus that includes poison ivy, poison oak, and poison sumac. In addition to
Toxicodendron, there are 10 sources of contact allergens that are
commonly encountered in North America [see Table 1].11
Other cutaneous disorders Skin that is infected, inflamed,
burned, or eczematous predisposes a patient to ACD. Patients
with stasis, hand and foot eczema, or chronic actinic dermatitis
are at high risk for ACD. ACD occasionally occurs with other
skin disorders, including seborrheic dermatitis, psoriasis, prurigo
nodularis, and benign familial pemphigus (Hailey-Hailey disease).12 Noneczematous contact reactions have also been reported: purpuric reactions caused by black rubber; lichen planuslike
eruptions caused by color-film developers, gold, and other dental
metals (oral mucosa); and granulomas caused by beryllium and
zirconium.13
March 2001 Update
Pathogenesis
Despite their different pathogenesis, ACD and ICD, especially
of the chronic type of ICD, show remarkable similarities with respect to clinical appearance, histology, and immunohistology.
Some inflammatory immune reactions are the same for ICD and
ACD, with similar cytokine (tumor necrosis factor and interferon gamma) and accessory molecule (HLA-DR and intercellular
adhesion molecule-1) activity that produces the cascade of inflammation. However, there is no memory T cell function in ICD,14 and
the extent of reaction is directly related to the amount of irritant
and duration of exposure.15
In contrast, even small amounts of an allergen can trigger the T
cell reaction in ACD. Minor variations in an allergens physical
and chemical properties may affect its ability to induce sensitization.8 Most environmental allergens are haptens, small (<500 daltons) molecules that penetrate the skin and undergo in vivo conjugation with tissue, or carrier, protein. Once the complex forms,
the carrier protein is no longer recognized by the immune system
as self. ACD represents a delayed-type hypersensitivity reaction
to this complex.
During the sensitization phase, which usually takes a minimum of 5 to 21 days, an individual acquires a specific hypersensitivity to a particular contact allergen. Sensitization not only can
evoke a type 4 delayed hypersensitivity response (mediated by
lymphocytes) but also can produce a type 1 immediate hypersensitivity reaction (mediated by circulating antibodies).
During the elicitation phase, on re-exposure to an allergen, a
hapten-carrier complex capable of eliciting a specific reaction reforms. The reaction timethe time required for a previously sensitized individual to manifest a clinical dermatitis after reexposure to the antigenis usually 12 to 48 hours but may range from
8 to 120 hours.
A spontaneous flare may occur within 10 to 21 days without
reexposure, possibly because enough allergen remains at the site
to cause a reaction once the sensitization phase has occurred.
Cross-sensitization occurs when a patient allergic to one chemical also reacts when exposed to structurally related chemicals.
Examples include Toxicodendron antigens (poison ivy, oak and
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Table 2 Common Misconceptions about ACD12

Fallacy
Truth
Rash quickly follows contact
Rash is often delayed 1 to 2 days and may not appear for 1 wk after
contact
Allergy develops only to new substances
Allergy can develop years after contact; an induction period may

last virtually a lifetime
Allergy is dose-dependent
Allergy is not, within a wide range, dose-dependent
If changes in medications or cosmetics do not lead to clearing of the

rash, those products are not the cause
Many products contain the same or cross-reacting allergens; also, the

composition of the product may be altered without a change in the
trade name of the product
Contact allergy occurs only at the site of exposure to the offending

agent
Contact allergy can spread by direct or indirect contact, airborne

exposure, connubial contact, or autoeczematization
Expensive products are not allergenic
Allergy is not related to cost
Negative prick or scratch test or RAST exclude ACD
Only patch testing is diagnostic of ACD
ACD is always bilateral if allergen exposure is bilateral
Shoe and glove allergy are often bilateral but may be unilateral
ACD is of the same intensity at all areas of exposure
Body sites may differ in responsiveness to allergens; ACD may be

patchy (e.g., hand dermatitis from gloves)
ACD does not affect the palms and soles
ACD may occur on the palms and soles (e.g., from gloves, topical
medicaments, shoes)
ACDallergic contact dermatitis
RASTradioallergosorbent test
sumac Japanese lacquer, mango, cashew nutshell oil), aromatic

amines (p-phenylenediamine, procaine, benzocaine, and p-aminobenzoic acid), and perfumes or flavors (balsam of Peru, benzoin,
cinnamates, and vanilla). This phenomenon may explain persistence or reactivation of dermatitis when such exposures are
unknown.8,13
Diagnosis
Diagnosis of ACD is based on the patient history; on the appearance, periodicity, and localization of the eruption; and on the
clinical course. The history is especially important in cases of
chronic dermatitis and putative occupational contact dermatitis.
The history alone may be accurate only 50% of the time, on average, ranging from 80% correct for nickel to 50% correct for moderately common allergens to about 10% correct for less common
allergens. Even with causes considered obvious, the specific allergen may not be known, and ACD caused by other chemicals may
also be present. Skillful history taking is required to differentiate
ACD from contact urticaria and ICD, with differentiation being
especially difficult in chronic cases [see Table 2]. Published history
forms may be utilized.16 Detailed questioning of the patient about
all topical medications (over-the-counter and prescription), systemic medication, cosmetics, other lotions and creams, occupation, hobbies, travel and clothing is also important. A history of
ACD caused by one or more of the major contact allergens, such
as nickel, rubber, topical medicaments, and cosmetics (fragrances, preservatives, and dyes), or obvious occupational or avocational exposures to substances or chemicals, such as chrome,
epoxy, acrylics, gloves, clothing, first-aid creams, preservatives,
and plants, may point to inadvertent ACD in an otherwise unexplained eruption.17
Clinical features In the acute stage, papules, oozing vesicles,
and crusting lesions that are surrounded by inflammation pre 2001 WebMD Inc. All rights reserved.
March 2001 Update
dominate. These clinical features may occur anywhere, but they

are best visualized on the palms, sides of the fingers, periungual
areas, and soles of the feet. Frequently occurring or persistent episodes of ACD often become chronic, with thickening associated
with lichenification, scaling, and fissuring [see Figures 2 and 3].
Postinflammatory hyperpigmentation or hypopigmentation may
occur. Features of both the acute and the chronic stages characterize the subacute form. All forms of contact dermatitis frequently
cause pruritus. Acute dermatitis is more likely to be caused by recent exposure, and accordingly, the cause is more obvious. On
the other hand, the onset of ACD is often more subtle. A lowgrade, subacute to chronic eczema may appear as primarily a
scaly or chapped eruption, especially on the face or on the dorsa
of the hands.6,13,17
The distribution of dermatitis is often the single most important clue to the diagnosis of ACD. The area of most intense dermatitis usually corresponds to the site of most intense contact
with the allergen. Exceptions occur, such as nail-polish allergy,
which typically appears on ectopic sites, especially the eyelids,
face, and neck. In addition to the transfer of allergens to distant
sites, volatile airborne chemicals may cause dermatitis on exposed body areas. Regional differences in susceptibility to contact
allergens exist. Thinner eyelid and genital skin is more susceptible to both allergic and irritant contact dermatitis. Scalp hair is often protective, with allergic reactions to hair cosmetics involving
the upper face, eyelids, postauricular area, and neck. Other areas
of the body have higher or lower exposures to allergens; these exposures are not always clear and are reflected in unusual distributions of dermatitis. Allergens in lotions and creams applied all
over the body sometimes produce reactions in skin folds and intertriginous areas, where the chemicals tend to concentrate. Recognition of ACD on the basis of the physical examination alone
may be only partially accurate. Linear vesicular streaks are commonly seen in poison ivy, poison oak, and poison sumac der-
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Patch test The patch test is the only useful and reliable methodthe gold standardfor the diagnosis of ACD. The proper
performance and interpretation of this bioassay require considerable experience. Because the procedure is subject to patient
variability and observer error, the technique has been standardized by the North American Contact Dermatitis Group. First, the
allergen is diluted in petrolatum or water to a concentration that
does not produce active sensitization or irritation. A widely used
patch-test system consists of strips of paper tape, onto which are
fixed aluminum disks 8 mm in diameter (Finn Chambers on Scanpor tape). A small amount of allergen is placed within these disks,
covering slightly more than one half of its diameter [see Figure 8].
Figure 2 Exposure to poison oak produced this acute Toxicodendron

dermatitis with erythema, edema, and linear vesicles and bullae.
Figure 3 Chronic eczematous dermatitis, with scaling, lichenification,

and hyperpigmentation, was caused by an allergy to leather components
in a hatband.
matitis, but contact with other plants can give a similar picture.
Contact with liquids may also produce linear vesicles. Failure to
examine the entire skin surface may result in misdiagnosis. Eczema on the trunk and arms may in fact represent autoeczematization from contact or stasis dermatitis of the legs. Significant
regional variations are associated with contact dermatitis, and
knowledge of substances that cause dermatitis of specific body
sites facilitates the diagnosis. Three such areas are the hands, face
and neck, and feet [see Figures 4 through 7]. It is helpful to know
the occupations when determining which patients with ACD
should be given patch tests [see Table 3]. Also helpful is a list of
blind spots in the diagnosis of ACD, with specific examples [see
Table 4].
Histopathology Biopsies are of limited help in diagnosing
contact dermatitis. Microscopic findings vary according to the
stage of the process: acute, subacute, or chronic. The hallmark of
eczema is spongiosis, or intercellular edema, associated with
spongiotic vesicles. Intracellular edema may cause reticular degeneration of the epidermis with multilocular bullae formation.
Most types of eczema show similar pathologic changes and cannot be distinguished with certainty.18
March 2001 Update
Figure 4 Acute contact dermatitis caused by wearing sandals typically

involves the dorsal surface of the feet.
Figure 5 Hairdresser with acute allergic contact dermatitis of the

hands, caused by glyceryl thioglycolate.
ACP Medicine
reading between 4 and 7 days after the patches are initially applied. Otherwise, almost 20% of positive reactions will be missed.
Neomycin, formaldehyde and formaldehyde-releasing preservatives, and tixocortol pivolate are often late reactors. Results at
both readings are graded according to intensity of the reaction
covering at least 50% of the patch-test site on a scale of 0 to 3+, as
follows:
0 = no reaction
? (doubtful) = weak erythema only
1+ = erythema and edema
2+ = erythema, edema, and papules
3+ = vesicles or bullae
Figure 6 Ectopic allergic contact dermatitis of the eyelids from tosylamide formaldehyde resin in nail polish.
Currently, the only commercially available patch-test system

in the United States is the thin-layer rapid-use epicutaneous
(T.R.U.E.) test. The T.R.U.E. test contains 23 preloaded allergens
that are crystallized, micronized, or emulsified into gels that are
affixed to paper tape.
With both systems the tests are applied to the upper back or
midback, which must be free of dermatitis. The patches are left in
place and kept dry. When removed at 48 hours, the first reading
is performed after 20 to 30 minutes, which allows time for pressure erythema to resolve. It is important to perform a second
Both false positive and false negative reactions can result. Thus,
patch testing is best done by physicians who are familiar with the
intricacies of the procedure and who have been trained to advise
patients about allergen substitution, relevance of the test, and
prognosis. Reading test results and interpreting relevance are as
important as performing the test. Any reaction must be evaluated
with regard to the individual patient. Thus, when an allergen is
found to be positive, it cannot always be assumed to be the cause
of ACD.8,13,16 The relevance of positive reactions to present or past
episodes of ACD ranges from a low of 16.7% for thimerosal to
93.4% for DMDM hydantoin [see Table 5]. Thus, relevance is determined by correlating the patch-test results with chemicals,
products, and processes encountered in the environment. Occasionally, when patients are allergic to chemicals in products they
use, the allergen may be present in only minimal amounts and
may not be responsible for the dermatitis.8 In these cases, repeat
Figure 7 Allergic contact dermatitis of the hands (a) and neck (b), with a positive patch test to rosin (colophony) (c), which
is used by violinists on their bows (d).

March 2001 Update
ACP Medicine
series approved by the Food and Drug Administration. However, since there are over 3,700 environmental contact allergens, and
this series identifies only 20% to 50% of patients with ACD, testing with additional chemicals is imperative for a thorough diagnosis of ACD. These additional substances can be obtained from
chemical suppliers and prepared by a compounding pharmacist
in appropriate concentrations, as detailed in a standard text, for
testing with the Finn Chamber system. As an alternative, many
centers in the United States use individual patch-test chemicals or
series (e.g., corticosteroid, plastics and glues, acrylic, dental, machinist, hairdresser) that are available in Europe but have not
been approved in the United States.11,19
Table 3 Criteria* for Determining Which ACD

Patients Should Be Given a Patch Test12
Presence of a specific type of eczema that places patient at higher
risk for ACD (stasis, hand, foot, or chronic)
Patient is in a high-risk occupation
Health care worker
Cosmetologist (hairdresser)
Rubber compounder
Plastics processor
Chemical worker
Printer
Machinist
Woodworker
Specific allergen or substance is suspected
Patient has a highly suggestive history or distribution of
dermatitis
Dermatitis flares or does not respond to treatment
Patient has previously undiagnosed dermatoses and erythroderma
Patient has putative occupational dermatitis
Special situation applies, such as photosensitivity or systemic
contact dermatitis
*Test is ordered if any one of the risk factors is present.
open application testing (ROAT), in which the patient applies the

commercial product to normal skin twice daily for several days,
can be helpful. ROAT is typically used with products that are left
on rather than washed off after application.
In the United States, patch testing is often initially performed
with 23 T.R.U.E. test allergens, the standard screening diagnostic
Table 4
Fallacy
Reproducibility and validity of patch testing In a study in

which 383 patients received simultaneous duplicate patch tests
on opposite sides of the upper back, 8% of patients had completely discordant results: positive on one side of the back and negative on the other. The intensity of the reactions was not disclosed,
and clinical relevance of this problem was considered small. The
most reproducible positive patch tests were for fragrance mix,
nickel, and balsam of Peru. Formaldehyde and lanolin were the
least reproducible positive reactors, both of which may be weak
irritants.20 The sensitivity, specificity, and validity of a standard
screening series has been estimated at about 70%,21 indicating that
about 30% of these patch-test results were not valid. However,
patch tests are diagnostically very useful, and the patients whose
screening results were negative later had positive results to other
allergens. It was assumed that the earlier screening results had
been false negative. The positive predictive value of a diagnosis
of ACD is a function of the prevalence of ACD in the population
and a function of the sensitivity and specificity of the patch test.22
Blind Spots in the Diagnosis of ACD

Truth
ACD may be identical to another disease
Seborrheic dermatitislike ACD caused by hair tonic

Tinea pedis misdiagnosed as ACD; a positive potassium hydroxide preparation made the
diagnosis
Psoriasis of the soles mimicking ACD caused by shoes; patch tests were negative
Factitial eczema of the dorsal hand, from an unknown cause, mimicking ACD; cured
with an Unna occlusive dressing
ACD caused by fragrances and preservatives; misdiagnosed for 5 years as lupus
erythematosus
ACD caused by sunscreen; misdiagnosed as sunburn
Failure to make a second diagnosis
ACD caused by neomycin; misdiagnosed as worsening atopic eczema

Chronic actinic dermatitis of face, with ACD caused by fragrance
Morphea of the leg, with ACD caused by a topical corticosteroid cream
Occult exposure to an allergen
Keys in pants pocket caused ACD of the lateral thigh in a man allergic to nickel
ACD caused by the preservative imidazolidinyl urea, present in a sunscreen with a label
that listed only the active ingredients
Chronic hand eczema from ACD caused by red dye in window curtains
Inadequate or deceptive history (patient does not

recall exposure to specific allergens)
Patient with chronic eczema worsened by use of a prescription topical cream (doxepin)
identified only from a pharmacy prescription list
Patient allergic to neomycin had periorbital contact eczema caused by an ophthalmic
ointment that contained tobramycin, which was not recognized as a cross-reacting
allergen
Failure of patch testing
Occupational contact dermatitis of the hands attributed to a false positive irritantpatch-test reaction to a cleanser.
Occupational contact dermatitis of the hands with a false negative patch-test reaction to
latex surgical gloves; further patch-testing indicated an allergy to thiurams, which
were present as accelerators in the gloves

March 2001 Update
ACP Medicine
a dose-response study that tested the impact of seasonal

A large
Topical Therapy
Figure 8 Patch-test allergens to be tested, usually in petrolatum and

occasionally aqueous, are placed on Finn Chambers on Scanpor tape (a)
for application to the patients back (b) for 48 hours. See patch testing in
text and Figure 7c for a positive patch test.
variation on the irritant susceptibility of skin identified a stronger

reaction to irritants in winter.23
prevention and treatment of irritant and allergic
contact dermatitis
Prevention
Most cases of contact dermatitis can be effectively treated and
controlled once the offending irritant or allergen is identified and
eliminated. Identifying hidden sources of allergens is important,
and patients who have positive patch-test results are given exposure lists identifying various names of allergens, cross-reacting
substances, lists of potential products and processes containing
the allergen, and nonsensitizing substitutes. Standard texts should
be consulted for detailed information.13,16 Examples of allergen alternatives include topical erythromycin or mupirocin ointments as
substitutes for neomycin.24 Neomycin may cross-react with gentamicin and tobramycin. Bacitracin should generally be avoided for
neomycin-sensitive patients because of coreactivity.
Reasons for persistence of ACD include unidentified sources
of allergens or irritants at home or at work, exposure to cross-reacting allergens, presence of underlying endogenous (e.g., atopic)
eczema, and adverse reactions to therapy [see Topical Medication
Allergy, below].
In the case of hand dermatitis, practical management must include protective measures as well as the use of topical corticosteroids and lubrication. The use of vinyl gloves with cotton liners to
avoid the accumulation of moisture that often occurs during ac 2001 WebMD Inc. All rights reserved.
March 2001 Update
tivities involving exposure to household or other irritants and

foods (e.g., peeling or chopping fruits or vegetables) may be helpful. However, it is important to verify that gloves are safe to use
in the workplace around machinery before recommending them.
Protective devices themselves may introduce new allergic or irritant hazards in the form of rubber in gloves and solvents in waterless cleansers. Automation of industrial processes may reduce
exposure but is the most expensive preventive measure. Barrier
creams are generally the last resort and are probably best for workers with no dermatitis.25 A barrier agent containing quaternium18 bentonite has been shown to be effective with exposure to a
specific allergen, such as poison ivy.26 Principles of treatment of
atopic dermatitis [see Subsection IV] may also be applied to treatment of contact dermatitis.
In the acute vesicular stage, apply cool, wet compresses for
15 minutes two to three times daily. Isotonic saline or Domeboro powder dissolved in tap water to make a 1:40 dilution
(aluminum acetate) may be used. A soft cloth, such as Kerlex
gauze or a towel, is immersed in the solution. The cloth is
wrung slightly and applied to the affected area of the skin. The
solution should not be poured directly on the dressing. Lukewarm to cool water baths or sitz baths are antipruritic and antiinflammatory; they also aid in cleansing and removing crusts
and medications. Oatmeal in the form of Aveeno Oilated (colloidal powdered oatmeal with oils) may be added to the bath
for its antipruritic and drying effects.
In acute dermatitis such as that caused by poison ivy, a lotion of camphor, menthol, and hydrocortisone (Sarnol-HC) is
soothing, drying, and antipruritic. Pramoxine, a topical anesthetic in a lotion base (Prax), may also relieve pruritus. In the
subacute and chronic stages of contact dermatitis, an emollient
lotion (Eucerin) or ointment (Aquaphor) may be applied to
moist skin after bathing for lubrication. Oil in water emulsions
that contain perfluoropolyethers have been shown to significantly inhibit irritation caused by a wide variety of hydrophilic
and lipophilic irritants.27
Corticosteroid creams and ointments are effective anti-inflammatory agents for treating subacute and chronic contact dermatitis. Hydrocortisone is effective topically in a 1% concentration.
The high-potency fluorinated corticosteroids act more rapidly
but should be used with discretion. Frequent and prolonged use
in skin-fold areas may cause atrophy, telangiectasia, or striae, and
their use on the face may cause steroid rosacea. For patients with
chronic dermatitis, crude coal tar preparations may be used to
control eczema. Bath PUVA may be effective for contact dermatitis of the palms and soles.28
Systemic Therapy
Intense itching may be relieved with sedating antihistamines
such as diphenhydramine hydrochloride (Benadryl), hydroxyzine
hydrochloride (Atarax), and doxepin hydrochloride (Sinequan),
administered at night. Most cases of ICD and ACD are effectively
managed without the use of systemic corticosteroids. However,
short courses of systemic corticosteroids are indicated for patients
with severe vesiculobullous eruptions of the hands and feet or the
face [see Figure 9] or severe disseminated ACD, such as poison ivy.
Attempts at desensitization have generally been unsuccessful.8
Secondary infection sometimes arises as a complication of ICD
and ACD, and systemic antibiotics may be indicated.27
ACP Medicine
Table 5 Patch Test Results in North America from 1996 through 199811
Test Substance*
TT
Use
Allergic (%)
Test Substance
Nickel sulfate 2.5%
TT
Metal
14.2
49.1
Neomycin sulfate 20%
TT
Antibiotic
13.1
46.2
Balsam of Peru (Myroxylon pereirae) 25%
TT
Fragrance
11.8
82.9
Fragrance mix 8%
TT
Fragrance
11.7
86.9
Thimerosal 0.1%
TT
Preservative
10.9
16.8
Metal
9.5
40.6
Gold sodium thiosulfate 0.5%

Formaldehyde 1% aq
TT
Preservative
9.2
63.2
Quaternium-15 2%
TT
Preservative
9.0
88.7
Cobalt chloride 1%
TT
Metal
9.0
55.1
Bacitracin 20%
Antibiotic
8.7
50.4
Methyldibromaglutaronitrile/phenoxyethanol 2.5%
Preservative
7.6
59.1
Rubber accelerators
7.3
71.7
Fabric finish resin
7.2
65.9
Carba mix 30%
TT
Ethyleneurea melamine-formaldehyde resin 5%

Thiuram mix 1%
TT
Rubber accelerators
6.9
79.8
p-Phenylenediamine 1%
TT
Hair dye
6.0
53.1
Propylene glycol 30% aq
Medicine/cosmetic solvent
3.8
82.8
Diazolidinyl urea 1%
Preservative
3.7
91.5
Cosmetic emollient
3.3
78.9
Imidazoldinyl urea 2%
Preservative
3.2
91.7
2-Bromo-2-nitropropane-1,3-diol 0.5%
Preservative
3.2
68.5
Preservative
2.9
87.2
Diazolidinyl urea 1% aq
Preservative
2.9
85.0
Cinnamic aldehyde 1%
Fragrance
2.8
83.2
Metal
2.8
54.3
Preservative
2.7
73.8
Medicine/cosmetic stabilizer
2.6
23.9
DMDM hydantoin 1%
Preservative
2.6
93.4
Glutaraldehyde 1%
Antibacterial
2.6
48.1
Imidazolidinyl urea 2% aq
Preservative
2.5
86.1
Tixocortol-21-pivalate 1%
Corticosteroid
2.3
91.7
Anesthetic
2.0
34.3
Lanolin 30%
Methylchloroisothiazolinone/methylisothiazolinone
100 ppm aq
Potassium dichromate 0.25%
TT
TT
TT
Methyldibromoglutaronitrile/phenoxyethanol 1%
Ethylenediamine dihydrochloride 1%
Benzocaine 5%
TT
TT (as caine
mix)
Colophony (rosin) 20%
TT
Adhesive, etc.
2.0
36.2
Epoxy resin 1%
TT
Industrial coating/adhesive
1.9
55.2
DMDM hydantoin 1% aq
Preservative
1.9
82.0
Glyceryl thioglycolate 1%
Permanent wave chemical
1.9
39
Rubber accelerator
1.8
75.8
Mercaptobenzothiazole 1%

March 2001 Update
TT
ACP Medicine
Table 5 (continued)
Test Substance*
TT
Use
Allergic (%)
Test Substance
p-Tert-butylphenol formaldehyde resin 1%
TT
Adhesives
1.8
46
Mercapto mix 1%
TT
Rubber accelerators
1.8
77.1
Paraben mix 15%
TT
Preservative
1.7
86.8
Glutaraldehyde 0.2%
Antibacterial
1.7
59.4
Methyl methacrylate 2%
Resin/adhesive
1.6
67.2
Rubber antioxidant
1.5
58.5
Tosylamide formaldehyde resin 10%
Nail polish resin
1.5
67.7
Mixed dialkyl thiourea 1%
Rubber adhesive/accelerator
1.3
69.1
Ethyl acrylate 0.1%
Acrylic nails/resin
1.3
72.8
Budesonide 0.1%
Corticosteroid
1.2
78
Chloroxylenol 1%
Preservative
1.0
63.4
Sesquiterpene lactone mix 0.1%
Plant oleoresins
0.7
44.8
Oxybenzone 3%
Sunscreen
0.5
73.7
Butylated hydroxyanisole 2%
Antioxidant
0.2
85.7
N-Isopropyl-N-phenyl paraphenylene-diamine 0.1%
TT (as black
rubber mix)
*Allergens in petrolatum unless noted aqueous (aq).

Allergens present on the thin-layer rapid-use epicutaneous (T.R.U.E) test series.
Definite, probable, or possible relevance to patients dermatitis at time of testing.
TT T.R.U.E. test.
Specific Etiologic Forms of Contact Dermatitis

topical medication allergy
Reactions to topically applied medications include allergic and
irritant contact dermatitis, photosensitivity, airborne contact dermatitis, and contact urticaria and anaphylaxis. ACD is the most
common skin reaction to topically applied drugs. The three most
important contact allergens are topical antibiotics, anesthetics, and
antihistamines. Neomycin and bacitracin are among the most frequently prescribed medications and are common causes of ACD.
Mupirocin ointment infrequently causes ACD.24 Benzocaine, the
most common topical anesthetic allergen, is still widely used in
topical agents, and there have been a number of reports of contact
allergy to topical doxepin, which was initially marketed in 1994.29
ACD from topical corticosteroids is most often caused by the
steroid itself rather than the vehicle. In a series of 2,073 patients
screened for contact dermatitis, the prevalence of allergy to one or
more corticosteroids ranged from 2.9% to 4.8%. Patch testing for
allergy to tixocortol pivolate and budesonide detects a great majority of cases of ACD caused by topical corticosteroids. Further patch
or ROAT with commercial preparations from the major cross-reacting classes may identify additional allergenic steroids or, alternatively, nonreacting steroids. Delayed readings are important at 5
to 7 days. Allergy to inhaled corticosteroids may present as perinasal or perioral itching or dermatitis, mimicking impetigo and
herpes simplex or worsening asthma or allergic rhinitis. In these
cases, prior sensitization by the cutaneous route is usual, although
allergy from mucosal exposure is possible.30,31
Topical drug allergy is particularly common in patients with
other dermatitis, especially stasis dermatitis [see Figure 10]. Often,
March 2001 Update
this allergy appears as a nonhealing dermatitis, masking its presentation. A detailed history is important and should include the
patients use of nonprescription preparations, topical agents meant
for animal use, medicated bandages, borrowed medications, transdermal devices, and herbal medicines. Patch testing with the standard screening tray and the patient's topical medications is invaluable in diagnosing ACD caused by topical medications.
Figure 9 For this patient with allergic contact dermatitis with marked
facial edema, a short course of therapy with systemic corticosteroids is
indicated.
ACP Medicine
systemic contact dermatitis

Systemic contact dermatitis occurs in individuals with contact
allergy to a hapten when they are exposed systemically to the
hapten via the oral, subcutaneous, transcutaneous, intravenous,
inhalation, intra-articular, or intravesicular route. The disorder
has been caused by a number of medications, metals, and other
allergens, including food components, but occurs infrequently
compared with allergic and irritant contact dermatitis. Systemic
contact dermatitis presents with the following clinically characteristic features32,33:
1. Flare-up of previous dermatitis or of prior positive-patch-test
sites.
2. Skin disorders in previously unaffected skin, such as vesicular
hand eczema, dermatitis in the elbow and knee flexures, nonspecific maculopapular eruption, vasculitis with palpable purpura, and the so-called baboon syndrome. This syndrome includes a pink-todark-violet eruption that is well demarcated
on the buttocks and genital area and is V-shaped on the inner
thighs. It may occupy the whole area or only part of it.
3. General symptoms of headache, malaise, arthralgia, diarrhea,
and vomiting.
Systemic contact dermatitis may start a few hours or 1 to 2
days after experimental provocation, suggesting that more than
one type of immunologic reaction is involved. Documentation
rests on patch testing and investigational oral-challenge studies.
Well-controlled oral-challenge studies in sensitized individuals
have been performed with medications but are more difficult to
perform with ubiquitous contact allergens, such as metals and

natural flavors. A relatively high dose of hapten is usually needed. Other variables include route of administration, bioavailability, individual sensitivity to the allergen, and interaction with amino acids and other allergens.32 When 12 leg ulcer patients with
neomycin allergy were challenged with an oral dose of the hapten, 10 reacted.33 However, of 29 patients with confirmed localized ACD caused by transdermal clonidine, only one had a skin
reaction to oral clonidine.34
clothing and textile dermatitis
ACD from clothing is usually not caused by the fibers but rather by the dyes used to color the garments or by formalin finish
resins added to make them wrinkle-resistant, shrinkproof, or
wash-and-wear. Disperse blue dyes (especially blue 106 and blue
124) were designated allergen of the year for 2000.35 These dyes
are highly valuable screening agents for diagnosing an important
cause of textile dermatitis. The distribution of dermatitis corresponds to areas where garments fit snugly, such as the upper and
inner anterior thighs, popliteal fossae, buttocks, and waistband
areas. Other areas include, in men, the parts of the neck that come
in contact with stiff collars and, in women, the anterior or posterior axillary folds, vulva, and suprapubic area. Diagnosis is confirmed by patch testing with disperse dyes (especially blue 106
and blue 124) and formaldehyde-releasing fabric-finish resins
(e.g., dimethyloldihydroxyethyleneurea and ethyleneurea melamine formaldehyde). Patch testing with the clothing (particularly
acetate and polyester liners) of patients with dye allergy may yield
positive results.
Textile dye dermatitis can be managed in the following ways:
1. Avoiding clothes with the offending dye (especially 100% acetate or 100% polyester liners).
2. Avoiding nylon hose (especially beige tones) and tight synthetic spandex/Lycra exercise clothing.
3. Wearing 100% natural fabrics (i.e., cotton, linen, silk, wool) or
100% silk long-sleeved undershirts and slip pants.
4. Wearing loose-fitting clothing that has been washed (three
times) before wearing.36
Many of these principles also apply to managing fabric-finish allergy, especially avoiding wrinkle-resistant, shrinkproof, and washand-wear clothing.
occupational contact dermatitis
Contact dermatitis, particularly of the hands, is one of the most
common types of occupational skin disorders. Special issues associated with these disorders include the following:
Figure 10 Patients with stasis dermatitis are at high risk for allergic
contact dermatitis, especially from topical medications. Bacitracin was
the cause in this case.

March 2001 Update
1. Inadequate workplace data, especially job descriptions and

material-safety data sheets that include information on workplace chemicals and other substances.
2. Objective information on exposure history (a factory visit is
ideal) is important. Direct exposure to chemicals can occur because of spills or routine work levels; indirect exposure can
come from contaminated tools, rags, and gloves; and airborne
exposures can result from mists, droplets, and sprays.
3. The skin is an important portal of entry for a number of toxic
chemicals that may or may not have a direct effect on skin.
These chemicals include aniline, carbon disulfide, ethylene glycol ethers, certain pesticides, tetrachloroethylene, and toluene.
4. Patch testing with industrial chemicals should be performed
very carefully. Irritants should not be tested, and many require
ACP Medicine
Table 6Topical and Systemic

Photosensitizers18,38,39
Agent
Topical photosensitizers
Psoralens
Pitch, creosote, and coal tar
derivatives
Halogenated salicylanilides
(e.g., bithionol, dibromosalicylanilide)
Musk ambrette
Oxybenzone/padimate O
Phenothiazines
Ketoprofen
Systemic photosensitizers
Thiazides
Phenothiazines
Dimethylchlorotetracycline
Griseofulvin
Nalidixic acid
Sulfonamides
Psoralens
Piroxicam
PT/PA
PT
PT
PA
Common Sources/Forms
Plants and drugs

Medications/industrial
products
Antibacterials in soaps
and detergents
droplike patches on the neck, face, and breast. This reaction is

caused by exposure to 5-methoxypsoralen present in perfumes or
colognes containing oil of bergamot, and the hyperpigmentation
may persist for many months. Photo-onycholysis has been reported with tetracyclines, psoralen, and other phototoxic drugs.
Not all cases exhibit obvious skin phototoxicity.18 Most cases of
phototoxicity are caused by administration of phototoxic systemic drugs [see Table 6].
Photoallergy
PA
PA
PA
PA
Fragrance
Sunscreens
Topical drugs
Nonsteroidal antiinflammatory drugs
PT
PT
PT
PT
PT
PT
PT
PT?
Diuretics
Tranquilizers
Antibiotic
Antifungal
Antibiotic
Antibiotic
Photosensitizing drug
Nonsteroidal antiinflammatory drugs,
especially in thimerosalsensitive patients
PAphotoallergenic reaction PTphototoxic reaction
dilution to nonirritating concentrations. Testing with individual

chemical components of mixtures is preferable in many cases.
5. Establishing occupational causation for ACD is often a challenge, and recommendations have been published.
Prevention and treatment of occupational contact dermatitis is
the same as for ACD.17
Photoallergy is analogous to ACD and is an immunologic reaction in which exposure of the photosensitizing compound to
UV light plays a role in formation of a complete antigen. A delayed eruption, usually eczematous, appears in sun-exposed
body areas, usually the face and dorsal hands, typically sparing
the submental and retroauricular areas [see Figure 11]; shaded areas and covered areas remain relatively clear but occasionally are
involved. Most cases are caused by topical photoallergens [see
Table 6], and the most common photocontact allergens are sunscreen chemicals, which act by absorbing ultraviolet light, especially oxybenzone. Other sunscreen chemicals, such as padimate
O and the dibenzoylmethanes, have also been reported to cause
photoallergic contact dermatitis.37 Photoallergic contact dermatitis is reproduced and diagnosed by photopatch testing in which
ultraviolet light (usually ultraviolet A) is combined with patch
testing. This procedure is particularly helpful in separating patients with eruptions caused by polymorphous light from patients with photoallergic contact dermatitis. Photopatch testing is
not indicated in phototoxic drug eruptions. Photoallergic reactions can persist in some individuals as chronic actinic dermatitis
(CAD), which can be a difficult management problem. Patients
with photoallergic contact dermatitis often have contact allergy
and should also be patch tested.
Treatment of Phototoxicity and Photoallergy

Elimination of exposure to the photoallergen or phototoxic
agent is effective for most patients, except for a few with CAD.
Broad-spectrum sunscreens or sunblocks, especially those con-
Subtypes of Contact Dermatitis

photosensitivity
Photosensitivity refers to a condition in which ultraviolet light
in combination with endogenous or exogenous substances, usually drugs or chemicals, evokes an eruption on sun-exposed skin.
Most cases are evoked by ultraviolet A, but on occasion, eruptions are caused by ultraviolet B (sunburn irradiation) or by visible light. The most common causes are systemic exposure to photosensitizing drugs [see Table 6] or cutaneous exposure, usually
accidental, to psoralen in plants.
Photosensitivity reactions are of two types: phototoxicity and
photoallergy. Many substances that are photoallergic at low concentrations may be phototoxic at high concentrations.37,38
Phototoxicity
Phototoxicity is analogous to irritation and occurs in any individual after one exposure to sufficient amounts of chemical and
light. Phototoxicity has been likened to an exaggerated sunburn
response, consisting of delayed erythema and edema followed by
pigmentation and desquamation. Asphalt workers and roofers
working with pitch develop the so-called smarts when exposed to
sufficient sunlight. Phytophotodermatitis, or meadow dermatitis,
is a particularly striking phototoxicity characterized by streaky
bullae after contact, sometimes while sunbathing, with psoralen
containing umbelliferones. Berloque dermatitis is a phototoxic
dermatitis characterized by the appearance of hyperpigmented,
March 2001 Update
Figure 11 Photocontact dermatitis characteristically involves areas

exposed to the sun.
ACP Medicine
Predisposing Risk Factors

Predisposing risk factors are hand eczema, allergic rhinitis,
allergic conjunctivitis, or asthma in individuals who frequently
wear NRL gloves; mucosal exposure to NRL; and multiple surgical procedures.39,40
Clinical Features
Figure 12 Contact urticaria of the hands in a nurse allergic to her

powdered natural rubber latex gloves (latex allergy). She also experienced allergic rhinitis and asthma while at work. Urticaria is often shortlived after gloves are used and may be absent at the time of examination.
taining micronized titanium, along with sun-protective clothing,

may be helpful. Topical steroids are helpful for mildly affected
patients, but severely affected patients with CAD may require
azathioprine, with or without systemic steroids; psoralen ultraviolet A therapy and cyclosporine have also been used in some severe cases.18
latex allergy
Latex allergy is an IgE-mediated hypersensitivity to one or
more of a number of proteins present in raw or uncured natural
rubber latex (NRL). The paradigm for immunologic contact urticaria is latex allergy, which, over the past decade, has become a
significant medical and occupational health problem.
Populations at Risk
Individuals at highest risk are patients with spina bifida (30%
to 65% prevalence), health care workers, and other workers with
significant NRL exposure. Most reported series of occupational
cases involve health care workers, affecting 5% to 11% of those
studied. Studies of populations of nonhealth care workers are
infrequent and include kitchen workers; cleaners; rubber-band,
surgical-glove, and latex-doll manufacturing workers; and miscellaneous other occupations in which NRL is utilized.
Clinical signs of NRL allergy include contact urticaria [see Figure 12], generalized urticaria, allergic rhinitis, allergic conjunctivitis, angioedema, asthma, and anaphylaxis.39 More than 600 serious reactions to NRL, including 16 fatal anaphylactic reactions,
were reported to the FDA by the early 1990s.
The majority of cases involve reactions from wearing NRL
gloves or being examined by individuals wearing NRL gloves.
Reactions from other medical and nonmedical NRL devices have
occurred; these include balloons, rubber bands, condoms, vibrators, dental dams, anesthesia equipment, and toys for animals or
children. The route of exposure to NRL proteins includes direct
contact with intact or inflamed skin and mucosal exposure, such
as inhalation of powder from NRL gloves, especially in medical
facilities and in operating rooms.40 Most immediate-type NRL reactions result from exposure to dipped NRL products (gloves,
condoms, balloons, and tourniquets). Dry-molded rubber products (syringes, plungers, vial stoppers, and baby-bottle nipples)
contain lower residual protein levels or have less easily extracted
proteins than do dipped NRL products.
NRL allergy is sometimes associated with allergic reactions to
fruit, especially bananas, kiwi, and avocados, and to chestnuts.
This allergic reaction results from cross-reactivity between proteins in NRL and those found in some fruits and nuts. Symptoms
range from oral itching and angioedema to asthma, gastrointestinal upset, and anaphylaxis.
Diagnosis
Diagnosis of NRL allergy is strongly suggested by a history of
angioedema of the lips when inflating balloons and by a history of
itching, burning, urticaria, or anaphylaxis when donning gloves;
when undergoing surgical, medical, and dental procedures; or after exposure to condoms or other NRL devices. Diagnosis is confirmed by a positive wear or use test with NRL gloves, a valid
positive intracutaneous prick test with NRL, or a positive serum
radioallergosorbent test with NRL.39 Severe allergic reactions
have occurred from prick and wear tests; epinephrine latex-safe
resuscitation equipment free of NRL should be available during
these procedures.39
Table 7Dermatitis and Latex Allergy Information Sources

Condition
Contact Dermatitis
Latex Allergy

March 2001 Update
Organization
Web Address
American Contact Dermatitis

Society
www.contactderm.org
American Academy of Dermatology
www.aad.org
National Institute for Occupational

Safety and Health
www.cdc.gov/NIOSH
A.L.E.R.T. Inc
www.latexallergyresources.org
Elastic Inc
www.latexallergyhelp.com
Spina Bifida Association of America
www.sbaa.org
ACP Medicine
Treatment and Prevention

Hyposensitization to NRL is not yet feasible, and NRL avoidance and substitution is imperative. Because many patients
with NRL allergy have hand eczema or have immediate allergic
symptoms or both, the most important issues for physicians are
accurate diagnosis, appropriate treatment, and counseling.
Prevention and control of NRL allergy includes latex avoidance in health care settings for affected workers and patients.
Synthetic non-NRL gloves should be available to replace latex
gloves. Also, in many cases, low-allergen NRL gloves should be
worn by coworkers so as to minimize symptoms and decrease
induction of NRL allergy in those with NRL allergy. Allergen
content of gloves should be requested from manufacturers and
suppliers; lists of glove allergen levels have also been published.
Patients with NRL allergy should also obtain Medic-Alert
bracelets and inform health care providers of their sensitivity.
These patients should be given lists of substitute gloves, other
non-NRL devices, potentially allergenic fruits, latex-safe anesthesia protocols, occult sources of NRL exposure such as toys
(for animals and children), and dental prophylaxis cups. Some
of this information is available in published sources, government agencies, and latex allergy support groups that publish
newsletters and other relevant information. Some sources have
Web sites [see Table 7].
References
1. Rietschel RR, Adams RM, Daily AD, et al: Guidelines of care for contact dermatitis.
2. Schappert SM: National Ambulatory Medical Care Survey: 1994 Summary. Adv Data
273:1, 1996
3. De Groot AC: Patch Testing: Test Concentrations and Vehicles for 3700 Chemicals, 2nd
ed. Elsevier, Amsterdam, 1994
4. Wigger-Alberti W, Elsner P: Contact dermatitis due to irritation. Handbook of Occupational Dermatology. Kanerva L, Elsner P, Wahlberg JE, et al, Eds. Springer Verlag,
Berlin, 2000, p 99
5. Iliev D, Elsner P: Clinical irritant contact dermatitis syndromes. Immunol Allergy Clin
North Am 17:365, 1997
6. Andersen KE, Maibach HI: Contact dermatitis. Dermatology. Orkin M, Maibach HI,
Dahl MV, Eds. Appleton & Lange, Norwalk, 1991, p 405
7. Schwanitz HJ, Uter W: Interdigital dermatitis: sentinel skin damage in hairdressers.
Br J Dermatol 142:1011, 2000
8. Belsito DV: Allergic contact dermatitis. Fitzpatricks Dermatology in General Medicine, 5th ed. Freedberg IM, Eisen AZ, Wolff, K, et al, Eds. McGraw-Hill, New York, 1999,
p 1447
9. Condie MW, Adams RM: Influence of oral prednisone on patch test reaction to Rhus
antigen. Arch Dermatol 107:540, 1973
10. Wulfhorst B: Skin hardening in occupational dermatology. Handbook of Contact Dermatology. Kanerva L, Elsner P, Wahlberg J, et al, Eds. Springer Verlag, Berlin, 2000, p 115
11. Marks JG Jr, Belsito DV, DeLeo VA, et al: North American contact dermatitis group
test results 19961998. Arch Dermatol 136:272, 2000
12. Marks JG, DeLeo V: Contact and Occupational Dermatology, 2nd ed. Mosby, St. Louis,
1997
13. Rietschel RL, Fowler JF: Fishers Contact Dermatitis, 4th ed. Williams & Wilkins, Baltimore, 1995

March 2001 Update
14. Gaspari AA: The role of keratinocytes in the pathophysiology of contact dermatitis.
Immunol Allergy Clin North Am 17:377, 1997
15. Corsini E, Galli CL: Cytokines and irritant contact dermatitis. Toxicol Lett 102:277,
1998
16. Adams RM: Occupational Skin Disease, 3rd ed. WB Saunders, Philadelphia, 1999
17. Taylor JS: Recognizing allergic contact dermatitis. Practical Contact Dermatitis. Guin
JD, Ed. McGraw Hill, New York, 1995, p 31
18. Wilkinson JD, Shaw S: Contact dermatitis: allergic. Rook/Wilkinson/Ebling Textbook of Dermatology. Champion RH, Burton JL, Burns DA, et al, Eds. Blackwell Science,
London, 1998, p 733
19. Rietschel RL: Experience with supplemental allergens in the diagnosis of contact dermatitis. Cutis 65:27, 2000
20. Bourke JF, Batta K, Prais L, et al: The reproducibility of patch tests. Br J Dermatol 140:
102, 1999
21. Nethercott JR, Holness DL: Validity of patch test screening trays in the evaluation of
patients with allergic contact dermatitis. J Am Acad Dermatol 21:568, 1989
22. Diepgen TL, Coenraads PJ: Sensitivity, specificity and positive predictive value of
patch testing: the more you test, the more you get? Contact Dermatitis 42:315, 2000
23. Basketter DA, Griffiths HA, Wang XM, et al: Individual, ethnic, and seasonal variation in irritant susceptibility of skin: the implications for a predictive human patch test.
Contact Dermatitis 35:208, 1996
24. Zappi E, Brancaccio RR: Allergic contact dermatitis from mupirocin ointment. J Acad
Derm 36:266, 1977
25. Wigger-Alberti W, Elsner P: Preventive measures in contact dermatitis. Clin Dermatol
15:661, 1997
26. Marks JG Jr, Fowler JF Jr, Sherertz EF, et al: Prevention of poison ivy and poison oak
allergic contact dermatitis by quaternium-18 bentonite. J Am Acad Dermatol 33:212, 1995
27. Elsner P, Wiggerti-Alberti W, Pantini G: Perfluoropolyethers in the prevention of irritant contact dermatitis. Dermatology 197:141, 1998
28. Taylor JS: Occupational dermatoses. Conns Current Therapy. Rakel RE, Ed. WB Saunders, Philadelphia, 1996, p 823
29. Taylor JS, Praditsuwan P, Handel D, et al: Allergic contact dermatitis from doxepin
cream: a one-year patch test clinic experience. Arch Dermatol 132:515, 1996
30. Isakkson M, Dooms-Goosens A: Corticosteroids. Clin Dermatol 15:527, 1997
31. Rietschel RL: Patch testing for corticosteroid allergy in the United States. Arch Dermatol 131:91, 1995
32. Veien NK: Ingested food in systemic contact dermatitis. Clin Dermatol 15:547, 1997
33. Menne T, Veien N, Sjolin K-E, et al: Systemic contact dermatitis. Am J Contact Dermatitis 5:1, 1994
34. Maibach HI: Oral substitution in patients sensitized by transdermal clonidine treatment. Contact Dermatitis 16:1, 1987
35. Storrs FJ: Contact allergen of the year: disperse blue dyes. Am J Contact Dermatitis
11:1, 2000
36. Pratt M, Taraska V: Disperse blue dyes 106 and 124 are common causes of textile dermatitis and should serve as screening allergens for this condition. Am J Contact Dermatitis 11:30, 2000
37. Isaksson M, Bruze M: Photocontact dermatitis: photopatch testing. Clin Dermatol
15:615, 1997
38. Harber LC, Bickers DR: Photosensitivity Diseases. BC Decker, Toronto, 1989
39. Taylor JS, Wattanakrai P, Charous L, et al: Latex allergy. 1999 Yearbook of Dermatology and Dermatologic Surgery. Thiers BH, Lang PG, Eds. Mosby, St. Louis, 1999, p 1
40. Fink JN, Ed: Latex allergy. Immunol Allergy Clin North Am 15:1, 1995
41. Taylor JS: Occupational dermatoses. Conns Current Therapy. Rakel RE, Ed. WB
Saunders, Philadelphia, 1996, p 823
42. Shelley WB, Shelly ED: Contact dermatitis. Advanced Dermatologic Diagnosis. WB
Saunders Co, Philadelphia, 1992, p 437
Acknowledgments
Figure 7 Courtesy of James R. Nethercott, M.D. (deceased), Department of Dermatology, University of Maryland, Baltimore.
Figure 11 Courtesy of Kristina Turjanmaa, M.D., and Arto Lahti, M.D., Tampere and
Oulu, Finland.
ACP Medicine
VI
C U TA N E O U S A D V E R S E D R U G
REACTIONS
Neil H. Shear, m.d.
Sandra Knowles, b.sc. pharm.
Lori Shapiro, m.d.
drome reaction). Fever is associated with the more serious cutaneous ADRs.
An adverse drug reaction (ADR) is defined as any noxious, unintended, and undesired effect of a drug that occurs at doses
used in humans for prophylaxis, diagnosis, or therapy.1 An ADR
may range from a cutaneous eruption to severe syndromes
(e.g., drug hypersensitivity syndrome, Stevens-Johnson syndrome [SJS], toxic epidermal necrolysis [TEN], and serum sicknesslike reaction). Over the past 20 years, a dramatic shift has
occurred in our understanding of drug-induced cutaneous
eruptions. It is now believed that many severe cutaneous adverse drug reactions are caused by the formation of reactive oxidative metabolites and perhaps the formation of antibodies to
drug-protein complexes and skin proteins, cytochrome P-450
enzymes, or both. The predisposition to drug-induced eruptions may be genetic, and family counseling and in vitro testing
are being used in certain centers to manage patients and their
families. This chapter reviews the pathophysiology and clinical
manifestations that are important for correct diagnosis and
treatment of cutaneous ADRs.
Differential diagnoses can include viral exanthems (e.g., infectious mononucleosis and parvovirus B19 infection), bacterial infections, Kawasaki syndrome, collagen vascular disease,
and neoplasia.7
laboratory tests
Penicillin skin testing with major and minor determinants is
useful for confirmation of an IgE-mediated immediate hypersensitivity reaction to penicillin.8 Skin tests are performed 6
weeks to 6 months after complete healing of the cutaneous
drug reaction.9 Oral rechallenges may be useful in the diagnosis of ADRs; however, they should not be used if a serious reaction, such as SJS or TEN, previously occurred. Patch testing
may be helpful in the diagnosis of fixed drug eruptions or contact dermatitis.10
Exanthematous Eruptions
simple eruptions
Epidemiology
The morphology of cutaneous eruptions may be exanthematous, urticarial, blistering, or pustular. The extent of the reaction is variable. For example, once the morphology of the reaction has been documented, a specific diagnosis (e.g., fixed
drug eruption or acute generalized exanthematous pustulosis)
can be made. The reaction may also present as a syndrome
(e.g., serum sicknesslike reaction or hypersensitivity syn-
Exanthematous eruptions, also known as morbilliform, maculopapular, or scarlatiniform eruptions, are the most common
cutaneous ADRs.4 Simple exanthems are erythematous changes in the skin without blistering or pustulation.
Many drugs can cause exanthematous eruptions, including
the penicillins, sulfonamides, barbiturates, antiepileptic medications, nonnucleoside reverse transcriptase inhibitors (e.g.,
nevirapine), and antimalarials.4,11 Exanthematous eruptions occur in 3% to 7% of patients receiving such aminopenicillins as
ampicillin and amoxicillin. However, these eruptions may occur in 60% to 100% of patients taking ampicillin or amoxicillin
who are receiving concurrent allopurinol therapy or who have
concomitant lymphocytic leukemia, infectious mononucleosis,
cytomegalovirus infection, or hyperuricemia.
Studies suggest that some exanthematous eruptions represent
cell-mediated hypersensitivity.12,13 The etiology of the ampicillin
rash concurrent with a viral infection is unknown, but the rash
does not appear to be IgE mediated, and patients can tolerate all
-lactam antibiotics, including ampicillin, once the infectious
process has resolved. A similar reaction was seen in 50% of HIVinfected patients exposed to sulfonamide antibiotics.14 Recent
studies have shown that drug-specific T cells play a major role
in exanthematous, bullous, and pustular drug reactions.15
Simple exanthems are symmetrical and often become generalized. Pruritus is the most frequently associated symptom.
Fever is not associated with simple exanthematous eruptions.
These eruptions usually occur within 1 week after the beginning of therapy and generally resolve within 7 to 14 days.16 The
exanthems turning from bright red to brownish red marks resolution. Resolution may be followed by scaling or desquamation.17 Some patients with ampicillin- or amoxicillin-induced
exanthematous eruptions may have a positive result on a patch
test or on a delayed intradermal test.13,14 In general, however,

March 2004 Update
ACP Medicine
DERMATOLOGY:VI Cutaneous Adverse Drug Reactions1
Epidemiologic studies have shown that ADRs occur in 6.7%

of all hospitalized patients,2 and 3% to 6% of all hospital admissions are the result of ADRs.3 In the Boston Collaborative Drug
Surveillance Program,4 the prevalence of cutaneous ADRs in
hospitalized patients was 2.2%. Antibiotics were responsible
for 75% of detected reactions. In the Harvard Medical Practice
Study, approximately 14% of ADRs in hospital patients were
cutaneous or allergic in nature.5 The cost of drug-related morbidity and mortality has been estimated at $30 billion a year,6
and ADRs are thought to be between the fourth and sixth leading cause of death in the United States.2,6
Etiology
Cutaneous reactions to drugs often occur in complicated
clinical scenarios that may include exposure to multiple agents.
New drugs started within the preceding 6 weeks are potential
causative agents, as are drugs that have been used intermittently, including over-the-counter preparations and herbal and
naturopathic remedies.
Diagnosis
clinical manifestations
skin testing is not considered helpful in the diagnosis of an exanthematous eruption.

The differential diagnosis of drug-induced exanthematous
eruption includes viral exanthem (patients should be tested for
mononucleosis), collagen vascular disease, bacterial infection,
and rickettsial infection. Hypersensitivity syndrome should be
considered in the differential diagnosis.
The treatment of simple exanthematous eruptions is generally
supportive. For example, oral antihistamines used in conjunction
with soothing baths may help relieve pruritus. Topical corticosteroids are indicated when antihistamines do not provide relief.
Systemic corticosteroids are used only in severe cases. Discontinuance of the offending agent is recommended in most cases.
complex eruptions
Hypersensitivity Syndrome Reaction

Hypersensitivity syndrome reaction is a complex drug reaction that affects various organ systems. A triad of fever, skin eruption, and internal organ involvement signals this potentially lifethreatening syndrome. It occurs in approximately one in 3,000
exposures to such agents as aromatic anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine), lamotrigine, sulfonamide antibiotics, dapsone, minocycline, and allopurinol.18
It has been suggested that the metabolism of aromatic anticonvulsants by cytochrome P-450 plays a pivotal role in the development of the hypersensitivity syndrome reaction with these
drugs.19 In most people, the chemically reactive metabolites that
are produced are detoxified by epoxide hydroxylases. If detoxification is defective, however, one of the metabolites may act as a
hapten and initiate an immune response, stimulate apoptosis, or
cause cell necrosis directly.
In one study, 75% of patients with hypersensitivity syndrome
reactions to one aromatic anticonvulsant showed in vitro cross-reactivity to the other two aromatic anticonvulsants.19 In addition, in
vitro testing has shown that there is a familial occurrence of hypersensitivity to anticonvulsants.19 Although lamotrigine is not an
aromatic anticonvulsant, it too can cause a hypersensitivity syndrome reaction.20,21 There is no evidence that lamotrigine cross-reacts with the aromatic anticonvulsants. Lamotrigine and other anticonvulsants are also associated with more severe reactions (e.g.,
SJS and TEN) [see Complex Eruptions, below].
Sulfonamide antibiotics can cause hypersensitivity syndrome reactions in susceptible persons. The primary metabolic
pathway for sulfonamides involves acetylation of the drug to a
nontoxic metabolite and renal excretion. An alternative metabolic pathway, quantitatively more important in patients who
are slow acetylators, engages the cytochrome P-450 mixedfunction oxidase system. These enzymes transform the parent
compound to reactive metabolitesnamely, hydroxylamines
and nitroso compounds, which produce cytotoxicity independently of preformed drug-specific antibody. In most people,
detoxification of the metabolite occurs. However, hypersensitivity syndrome reactions may occur in patients who are unable to detoxify this metabolite (e.g., those who are glutathione
deficient).22 Although the detoxification defect is present in 2%
of the population, only one in 10,000 people will manifest a hypersensitivity syndrome reaction in response to sulfonamide
antibiotics. Siblings and other first-degree relatives of patients
with the detoxification defect are at increased risk (perhaps one
in four) for having a similar defect.
Other aromatic amines, such as procainamide, dapsone, and
acebutolol, are also metabolized to chemically reactive compounds.
We recommend that patients who develop symptoms compatible with a sulfonamide hypersensitivity syndrome reaction avoid
these aromatic amines, because the potential exists for cross-reactivity. However, cross-reactivity should not occur between
sulfonamides and drugs that are not aromatic amines (e.g., sulfonylureas, thiazide diuretics, furosemide, and acetazolamide).
Hypersensitivity syndrome reaction occurs most frequently
on first exposure to the drug, with initial symptoms starting 1
to 6 weeks after exposure [see Table 1]. Fever and malaise,
which can be accompanied by pharyngitis and cervical lymphadenopathy, are the presenting symptoms in most patients.
This is often followed by edema and swelling of the face, especially upon rising in the morning. Atypical lymphocytosis,
with subsequent eosinophilia, may occur during the initial
phases of the reaction in some patients. A cutaneous eruption,
which occurs in approximately 85% of patients, can range from
an exanthematous eruption [see Figure 1] to the more serious
SJS or TEN. The liver is often involved, resulting in hepatitis,
although other internal organs may be affected, such as the
kidney (e.g., interstitial nephritis and vasculitis), the central
nervous system (e.g., encephalitis and aseptic meningitis), and
the lungs (e.g., interstitial pneumonitis, respiratory distress
syndrome, and vasculitis). A subgroup of patients may become
hypothyroid as part of an autoimmune thyroiditis within 2
months after the initiation of symptoms.23
After hypersensitivity syndrome reaction has been recognized from the symptom complex of fever, rash, and lymphadenopathy, some laboratory tests can be used to evaluate
internal organ involvement, which may be asymptomatic. A
complete blood count, urinalysis, and measurements of liver
transaminase and serum creatinine levels should be per-
Table 1Clinical Features of Hypersensitivity Syndrome Reaction and Serum Sicknesslike Reaction
Rash
Hypersensitivity syndrome reaction
Serum sicknesslike reaction
Exanthem
Exfoliative dermatitis
Pustular eruptions
Erythema multiforme
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Urticaria
Exanthem

March 2004 Update
Fever
Internal Organ
Involvement
Arthralgia
Lymphadenopathy
Present
Present
Absent
Present
Present
Absent
Present
Present
ACP Medicine
Figure 1 This 35-year-old woman developed hypersensitivity

syndrome reaction, characterized by fever, rash, and hepatitis, 14 days
after starting trimethoprim-sulfamethoxazole therapy. The rash is an
extensive, symmetrical, red edematous eruption.
formed. In addition, the clinician should be guided by symptoms that may suggest specific internal organ involvement
(e.g., respiratory symptoms). Thyroid function should be evaluated on presentation of hypersensitivity syndrome reaction
and then 2 to 3 months after presentation. A skin biopsy may
help confirm the diagnosis when the patient has a blistering or
a pustular eruption. Unfortunately, diagnostic or confirmatory
tests are not readily available. An in vitro test employing a
mouse hepatic microsomal system is used for research purposes to characterize patients who develop hypersensitivity syndrome reaction.19,24 Because of the severity of the reaction, oral
rechallenges are not recommended.
Although the role of corticosteroids is controversial, most
clinicians choose to start prednisone at a dosage of 1 to 2
mg/kg/day when symptoms are severe. Antihistamines, topical corticosteroids, or both can be used to alleviate symptoms.
Because the risk of hypersensitivity syndrome reaction in firstdegree relatives of patients who have had reactions is substantially higher than in the general population, counseling of family members regarding their risk of hypersensitivity syndrome
reaction is advised.
Urticarial Eruptions
radiocontrast media, and narcotic analgesics27 may directly cause

release of histamine from mast cells, independently of IgE. Angiotensin-converting enzyme (ACE) inhibitors are frequent
causes of angioedema.28 The mechanism of this reaction is unclear but may relate to accumulation of bradykinin or activation
of the complement system.
Although medications tend to cause urticaria, angioedema,
or both, other causal agents are food [see 6:XVI Food Allergies],
physical factors (e.g., dermatographism and cholinergic urticaria) [see 6:XIII Urticaria, Angioedema, and Anaphylaxis], and idiopathic factors. Certain foods containing proteins that can
cross-react with latex proteins, such as bananas, kiwifruit, avocados, and chestnuts, can cause oral itching and swelling, hives,
or wheezing after ingestion. People at greatest risk for latex allergy include children with spina bifida and health care workers.29,30 Latex allergy can present as contact urticaria at sites of latex exposure, such as lip swelling in a person who has blown up
a balloon or sucked on a pacifier. Contact with aerosolized powder from latex gloves to which the latex protein has adhered
may cause mucosal symptoms, such as itchy, swollen eyes; runny nose; sneezing; or wheezing. Anaphylaxis may also occur.31
Signs and symptoms of IgE-mediated allergic reactions are
typically pruritus, urticaria, cutaneous flushing, angioedema,
nausea, vomiting, diarrhea, abdominal pain, nasal congestion,
rhinorrhea, laryngeal edema, and bronchospasm or hypotension or both. Fever is not associated with urticaria or angioedema reactions. In general, individual lesions of urticaria last for
less than 24 hours, although new lesions can continually develop. With ACE-inhibitor therapy, the onset of the adverse reaction is usually within hours but can occur as late as 1 week to
several months into therapy.32 With treatment, the resulting angioedema usually resolves within 48 hours.
Skin testing may be helpful in cases of IgE-mediated urticaria. For example, penicillin skin testing with the major and
minor determinants identifies approximately 99% of patients
who have had an IgE-mediated reaction to penicillin.10 A latex
skin test is a sensitive indicator of IgE sensitization.31 For largemolecular-weight agents, such as insulin,33 protamine,34 and
egg-containing vaccines, positive immediate skin-test reactions
identify patients at risk for IgE-mediated reactions.
Withdrawal of the causative agent is recommended. When
angioedema or anaphylaxis occurs, immediate therapy with
epinephrine and systemic steroids may be needed. Symptomatic relief can generally be achieved with antihistamines (H1
receptor blockers).
simple eruptions
Urticaria and Angioedema
Urticaria is characterized by pruritic red wheals of varying

sizes that can occur with any medication. When deep dermal
and subcutaneous tissues are also swollen, the reaction is
known as angioedema.
Urticaria and angioedema usually result from a type I immediate hypersensitivity reaction. This mechanism is typified by
immediate reactions to penicillin and other antibiotics. Binding
of the drug or its metabolite to IgE bound to the surfaces of cutaneous mast cells leads to activation, degranulation, and release of vasoactive mediators such as histamine, leukotrienes,
and prostaglandins.25
Urticarial reactions may also result from nonimmunologic
activation of inflammatory mediators. Drugs such as acetylsalicylic acid and nonsteroidal anti-inflammatory drugs (NSAIDs),26
Allergic urticaria must be differentiated from urticaria

caused by physical factors. Cold urticaria, for example, is precipitated by exposure to cold, occurring within minutes after
immersion of hands or body in cold water or after exposure to
cold air. In severe cases, systemic symptoms, including wheezing and syncope, can occur. A rare familial form of cold urticaria that is autosomal dominant has been linked to chromosome 1q44.35
Cold urticaria can be differentiated from other forms of urticaria by eliciting an urticarial reaction with an ice cube applied to the skin for 5 to 10 minutes. Other physical urticarias
also have distinguishing causes or features. Solar urticaria occurs within minutes of exposure to sunlight and can be produced by exposing limited areas of skin to sunlight or to appro-

March 2004 Update
ACP Medicine
priate wavelengths of ultraviolet light in a phototherapy response to physical pressure. Cholinergic urticaria, which is
characterized by small urticarial papules, can be induced by exposure to heat or by exercise.
Histologically, all the urticarias are characterized by an increase in mast cells in the dermis. Edema, vascular changes,
and mononuclear infiltrates are more striking in the dermis of
patients with cold urticaria. Mononuclear infiltrates are also
more prominent in the deep dermis of patients with delayed
pressure urticaria.36
As with drug-induced urticaria, first-line therapy of most urticarias consists of oral antihistamines and avoidance of precipitating factors. Psoralen plus ultraviolet A (PUVA) has been
used successfully to treat patients with solar urticaria. Montelukast has been used successfully to treat delayed pressure
urticaria,37 and cyclosporine is promising for cases of severe refractory chronic urticaria.38
Figure 2 This 28-year-old man taking tetracycline for acne vulgaris

developed a fixed drug eruption.
complex eruptions
Serum Sicknesslike Reactions

Serum sicknesslike reactions are defined by fever, rash
(usually urticarial), and arthralgias occurring 1 to 3 weeks after
drug initiation. Other symptoms, such as lymphadenopathy
and eosinophilia, may also be present. In contrast to true serum
sickness, serum sicknesslike reactions are without immune
complexes, hypocomplementemia, vasculitis, and renal lesions
[see Table 1].
Epidemiologic studies in children suggest that the risk of
serum sicknesslike reactions is greater with cefaclor than with
other antibiotics, including other cephalosporins.39,40 The overall
incidence of cefaclor serum sicknesslike reactions has been estimated to be 0.024% to 0.2% per course of cefaclor prescribed.
Although the pathogenesis is unknown, it has been postulated that in genetically susceptible hosts, metabolism of cefaclor
produces a reactive metabolite that may bind to tissue proteins
and elicit an inflammatory response that manifests as a serum
sicknesslike reaction.41
Other drugs that have been implicated in serum sicknesslike
reactions are cefprozil,42 bupropion,43 and minocycline.18,44 The
incidence of serum sicknesslike reactions caused by these
drugs is unknown.
Discontinuance of the culprit drug and symptomatic treatment with antihistamines and topical corticosteroids are recommended for patients with serum sicknesslike reactions. A
short course of oral corticosteroids may be required for patients
with more severe symptoms. The drug that caused the serum
sicknesslike reaction should be avoided. For cefaclor and cefprozil, the risk of cross-reaction with -lactam antibiotics is
small, and the administration of another cephalosporin is usually well tolerated.45 However, some clinicians recommend that
patients who experience serum sicknesslike reactions from cefaclor avoid all -lactam drugs.46
into an edematous plaque [see Figure 2]. In some patients, multiple lesions may be present. Blistering and erosion may occur
on mucosal surfaces.
Fixed drug eruptions recur in the same skin area after readministration of the causative medication. Many drugs have
been implicated in fixed drug eruptions, including phenolphthalein, ibuprofen, sulfonamides, tetracyclines, and barbiturates.47 The pathogenesis of fixed drug eruptions has not been
fully elucidated. A haplotype linkage in the setting of trimethoprim-sulfamethoxazoleinduced fixed drug eruptions was recently documented.48
Fixed drug eruptions are most common on the genitalia and
in the perianal area, although they can occur anywhere on the
skin surface. The onset of a fixed drug eruption can be sudden,
developing within 30 minutes to 8 to 16 hours after ingestion of
the medication. In patients who continue to take the offending
drug, the number of eruption sites may gradually increase.48
After the initial acute phase, which lasts days to weeks, residual hyperpigmentation develops. Some patients may complain
of burning or stinging on the affected skin sites. Systemic manifestations, which are present in approximately 25% of cases, can
include fever, malaise, and abdominal symptoms.48
No conclusive diagnostic tests are available, but a challenge
or provocation test with the suspected drug may be useful in
confirming the diagnosis. Patch testing at the site of a previous
lesion yields a positive response in up to 43% of patients. Prick
and intradermal skin tests are reported to yield positive reactions in 24% and 67% of patients, respectively, but results vary
with different drugs and reaction patterns. Patients with maculopapular rashes are more likely to have positive patch tests
than patients with urticarial rashes.49
Treatment includes discontinuance of the causative agent
and symptomatic therapy (e.g., topical corticosteroids).
Pseudoporphyria
Fixed drug eruptions usually appear as solitary pruritic, erythematous, bright-red or dusky-red macules that may evolve
Pseudoporphyria is a cutaneous phototoxic disorder that

can resemble either porphyria cutanea tarda (PCT) or erythropoietic protoporphyria (EPP). Tetracycline, furosemide, and
naproxen have been implicated in PCT- and EPP-pseudoporphyria.50 The eruption may begin within 1 day after initiation of
therapy or may be delayed for as long as 1 year. PCT-pseudoporphyria is characterized by skin fragility, blister formation,
and scarring in areas exposed to sunlight; it occurs with normal

March 2004 Update
ACP Medicine
Blistering Eruptions
simple eruptions
Fixed Drug Eruptions
disease, immune deposits disappear from the skin once the lesions resolve. Steroids and dapsone do not influence the healing
process in drug-induced disease, whereas these agents have
proved effective in treatment of idiopathic linear IgA disease.52
Drug-Induced Pemphigus
Figure 3 Pemphigus foliaceus developed in this 64-year-old man

taking enalapril.
Pemphigus may be drug induced or drug triggered (i.e., the

latent disease is unmasked by the drug exposure).
Drugs that cause pemphigus are penicillin, rifampin, phenylbutazone, propranolol, progesterone, piroxicam, interferon beta,
interleukin-2, and levodopa.53 An active amide group found in
masked thiol drugs such as penicillin and cephalosporins and
in nonthiol drugs such as enalapril may contribute to the pathogenesis of pemphigus.53,54 Pemphigus foliaceus [see Figure 3]
caused by penicillamine and other thiol drugs tends to resolve
spontaneously in 35% to 50% of cases.53 The average interval to
onset is 1 year. Antinuclear antibodies are detected in 25% of affected patients.
Nonthiol druginduced pemphigus manifests clinical, histologic, immunologic, and evolutionary aspects similar to those
of idiopathic pemphigus vulgaris [see Figure 4]. Drug-induced
pemphigus is associated with mucosal involvement. Spontaneous recovery after drug withdrawal occurs in 15% of affected
patients.
Treatment of drug-induced pemphigus begins with drug withdrawal. Systemic corticosteroids are often required until all symptoms of active disease disappear. Vigilant follow-up is required
after remission for an early relapse to be detected. The patients
serum should be monitored regularly for autoantibodies.53
Erythema Multiforme, Stevens-Johnson Syndrome,

and Toxic Epidermal Necrolysis
Figure 4 Pemphigus vulgaris developed in this 59-year-old woman

who took penicillamine as treatment for rheumatoid arthritis.
porphyrin metabolism. The second clinical pattern mimics EPP

and presents as cutaneous burning, erythema, vesiculation, angular scars, and waxy thickening of the skin.
Because of the risk of permanent facial scarring, the implicated drug should be discontinued when skin fragility, blistering,
or scarring occurs. In addition, broad-spectrum sunscreen and
protective clothing should be recommended to the patient.
The eruptions of erythema multiforme (EM), SJS, and TEN may

represent variants of the same disease process. Reactions encompass a spectrum ranging from the less serious eruptions seen in
EM to more serious reactions seen in SJS and TEN [see Figure 5].
A large percentage of EM and SJS cases are not drug related
and may develop after a variety of predisposing factors, including infections, neoplasia, and autoimmune diseases. The
drugs most frequently cited as causes of EM, SJS, and TEN are
anticonvulsants, antibiotics (e.g., sulfonamides), allopurinol,
and NSAIDs (e.g., piroxicam).55 With anticonvulsants, risk appears to be greatest during the first 8 weeks of therapy.56
complex eruptions
Drug-Induced Linear IgA Disease

Linear IgA disease is an autoimmune bullous dermatosis
that is identified on the basis of the linear deposition of IgA at
the basement membrane zone.51 This disease can be induced by
such drugs as vancomycin, lithium, diclofenac, and amiodarone. The drug-induced disease probably represents an immunologic response to the offending drug.
Drug-induced linear IgA disease is heterogeneous in clinical
presentation. Cases have shown morphologies resembling erythema multiforme, bullous pemphigoid, and dermatitis herpetiformis. Drug-induced disease cannot be distinguished from the
idiopathic variety either clinically, histologically, or immunologically; however, the clinical courses of these presentations
differ. In drug-induced disease, spontaneous remission occurs
once the offending agent is withdrawn; in idiopathic linear IgA
March 2004 Update
Figure 5 This 50-year-old woman developed toxic epidermal

necrolysis 17 days after starting phenytoin therapy.
ACP Medicine
Figure 6 Acute generalized exanthematous pustulosis (small
Figure 7 Coumarin-induced skin necrosis in a 57-year-old woman
nonfollicular pustules on a red base) in a 70-year-old man who took

cloxacillin as treatment for cellulitis.
who was given coumarin as treatment for atrial fibrillation.
The pathogenesis of severe cutaneous ADRs is unknown, although a metabolic basis has been hypothesized. Sulfonamides
and anticonvulsants, the two groups of drugs most frequently
associated with SJS and TEN, are metabolized to toxic metabolites that are subsequently detoxified in most persons. However, in predisposed patients with a genetic defect, the metabolite
may bind covalently to proteins. In some of these patients, the
metabolite-protein adducts may trigger an immune response
that leads to a cutaneous ADR.57
Clinically, the reaction patterns of EM, SJS, and TEN are
characterized by the triad of mucous membrane erosions, target lesions, and epidermal necrosis with skin detachment. SJS
is characterized by mucous membrane erosions and blisters on
less than 10% of the total body surface area, whereas TEN involves more than 30% of the total body surface area.58 The
more severe the reaction, the more likely it is that it was druginduced. Cases of severe cutaneous ADRs to lamotrigine (e.g.,
SJS and TEN) have been reported.59 The prevalence of severe
cutaneous ADRs associated with lamotrigine has been reported to be as high as one in 1,000 in adults and is higher in children. The risk is increased in the presence of valproic acid.
Complete blood counts, liver enzyme measurements, and
chest x-rays should be performed to rule out concurrent internal organ involvement.
Treatment of EM, SJS, and TEN includes discontinuance of a
suspected drug and such supportive measures as careful
wound care, hydration, and nutritional support.60 The use of
corticosteroids in SJS and TEN is controversial.61 Intravenous
immunoglobulin (IVIg, 0.4 to 1.0 g/kg/day for 2 to 4 days),
which contains naturally occurring Fas ligand (FasL)blocking
antibodies, has been shown in most reports to halt progression
of TEN, especially when IVIg is started early.62-64 Patients who
have developed a severe cutaneous ADR (EM, SJS, or TEN)

should not be rechallenged with the drug or undergo desensitization with the medication.
Table 2
Pustular Eruptions
simple eruptions
Acneiform Eruptions
Eruptions morphologically mimicking acne vulgaris may be
associated with drug ingestion. Iodides, bromides, adrenocorticotropic hormone, corticosteroids, isoniazid, androgens, lithium, dactinomycin, and phenytoin are reported to induce acnelike lesions.65 Acne fulminans was induced by testosterone in
1% to 2% of adolescent boys who were treated for excessively
tall stature.66
Drug-induced acne often appears on the face and back, but it
may appear in atypical areas, such as arms and legs, and is
usually monomorphous. Comedones are usually absent. Fever
is absent. Acneiform eruptions do not affect prepubertal children, indicating that previous hormonal priming is a prerequisite. Topical tretinoin may be useful when the drug cannot be
stopped.
complex eruptions
Acute Generalized Exanthematous Pustulosis

Acute generalized exanthematous pustulosis is characterized by acute onset, fever, and a cutaneous eruption with nonfollicular sterile pustules on an edematous erythema, generally
starting within days of drug ingestion67 [see Figure 6]; leukocy-
Clinical Pearls to Identify Anticoagulant-Induced Skin Necrosis

Interval to Onset
Location
Other
Coumarin-induced skin necrosis
35 days
Adipose-rich sites
Heparin-induced thrombocytopenia and thrombosis
414 days
Extremities
Thrombocytopenia occurs concurrently
Purple-toe syndrome
38 wk
Acral location
Often occurs after angiography

March 2004 Update
ACP Medicine
ing infection, such as pneumonia, viral infection, or erysipelas,

may occur in as many as 25% of patients. Purple-toe syndrome
occurs 3 to 8 weeks after initiation of coumarin therapy.
Treatment entails the discontinuance of coumarin, administration of vitamin K, and infusion of heparin at therapeutic
doses. Fresh frozen plasma and purified protein C concentrates
have been used.71 Supportive measures for the skin are recommended. Plastic surgery for remediation is necessary in 60% of
affected patients.
drug-induced lichenoid eruptions
Figure 8 Leukocytoclastic vasculitis developed in this 47-year-old

woman taking hydrochlorothiazide.
tosis is another common finding. Generalized desquamation

occurs 2 weeks later. Differential diagnosis includes pustular
psoriasis, subcorneal pustular dermatosis (Sneddon-Wilkinson
disease), hypersensitivity syndrome reaction with pustulation,
and pustular eruptions of infancy.
Acute generalized exanthematous pustulosis is most commonly associated with -lactam and macrolide antibiotic usage. Many other drugs have been implicated, however, including calcium channel blockers and analgesics. The estimated incidence rate is approximately one to five cases per million per
year.68 Discontinuance of therapy is usually the extent of treatment necessary in most patients, although some patients may
require the use of corticosteroids. Patch testing to the putative
drug is often positive, resulting in a localized pustular reaction.
Drug-induced lichen planus produces lesions that are clinically and histologically indistinguishable from those of idiopathic lichen planus. Many drugs, including beta blockers,
penicillamine, NSAIDs, gold, and ACE inhibitors, especially
captopril, have been reported to produce this reaction.
The latent period between the start of administration of the
drug and appearance of the eruption is variable. The mean latent period is between 2 months and 3 years for penicillamine,
approximately 1 year for beta-adrenergic blocking agents, and
3 to 6 months for ACE inhibitors. The latent period may be
shorter if the patient was previously exposed to the drug.72 In
general, resolution usually occurs within 2 to 4 months.
Rechallenge with the culprit drug has been attempted in a
few patients, with reactivation of symptoms within 4 to 15
days.73 Patch testing has not proved helpful in most cases of
drug-induced lichen planus. However, results of patch tests
performed with contact inducers of lichen drug eruptions (e.g.,
color-film developers and dental restorative materials) are usually positive.72
drug-induced vasculitis
Anticoagulant drugs may induce hypercoagulable states

with subsequent vascular infarction and cutaneous necrosis
[see Figure 7]. Both coumarin and heparin can induce skin
necrosis. Clinical pearls that can help differentiate these reactions are the location, timing, platelet count, and primary diagnosis [see Table 2].
The pathogenesis of coumarin-induced skin necrosis is the
paradoxical development of occlusive thrombi in cutaneous and
subcutaneous venules caused by a transient hypercoagulable
state. This condition results from the suppression of the natural
anticoagulant protein C at a greater rate than natural procoagulant factors. Coumarin-induced skin necrosis is associated with
protein C and protein S deficiency, but pretreatment screening
is not warranted. An association with a heterozygote for the
factor V Leiden mutation has been recently reported.69
It is estimated that one in 10,000 persons who take coumarin
are at risk for this adverse event.70 The prevalence is four times
higher in women than in men. In both sexes, the peak incidence
occurs in the sixth and seventh decades of life. Afflicted patients tend to be obese.
Coumarin-induced skin necrosis begins 3 to 5 days after initiation of treatment. Painful red plaques develop in adipose-rich
sites such as breasts, buttocks, and hips. These plaques may
blister, ulcerate, or develop into necrotic areas. An accompany-
Drug-induced vasculitis represents approximately 10% of

the acute cutaneous vasculitides and usually affects small vessels [see Figure 8].74 Drug-induced vasculitis should be considered in any patient with small vessel vasculitis that is usually
confined to the skin.75 Drugs that are most frequently associated with vasculitis include propylthiouracil, hydralazine, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), allopurinol, cefaclor, minocycline, penicillamine, phenytoin, and isotretinoin.73 The average interval to
onset of drug-induced vasculitis is 7 to 21 days.76
The clinical hallmark of cutaneous vasculitis is palpable purpura, classically found on the lower extremities, although any
cutaneous site may be affected. Urticaria can be a manifestation
of small vessel vasculitis. Unlike nonvasculitic allergic urticaria,
vasculitic urticaria lasts longer than 1 day, may evolve into purpuric lesions, and may be accompanied by hypocomplementemia.77 Other features are hemorrhagic bullae, urticaria, ulcers,
nodules, Raynaud disease, and digital necrosis. The same vasculitic process may also affect internal organs, such as the liver,
kidney, gut, and CNS, and is potentially life threatening.
Histologically, the small blood vessels of the dermis display
fibrinoid necrosis, polymorphonuclear infiltration into the
blood vessel wall, extravasation of red blood cells, and nuclear
dust. Direct immunofluorescence may show deposits of IgM
and C3 in the blood vessel walls. Therefore, these reactions are
immune complexdependent drug reactions. The immune
complexes may be composed of antibodies directed against
drug-related haptens, but this has not been proved.
Drug-induced vasculitis can be difficult to diagnose, and diagnosis is often one of exclusion.78 Alternative causes of cuta-

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ACP Medicine
Other Eruptions
anticoagulant-induced skin necrosis
1. Karch FE, Lasagna L: Adverse drug reactions: a critical review. JAMA 234:1236, 1975
2. Lazarou J, Pomeranz BH, Corey PN: Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. JAMA 279:1200, 1998
3. Lakshmanan M, Hershey C, Breslau D: Hospital admissions caused by iatrogenic
disease. Arch Intern Med 146:1391, 1986
4. Bigby M, Jick S, Jick H, et al: Drug-induced cutaneous reactions: a report from the
Boston Collaborative Drug Surveillance Program on 15,438 consecutive inpatients, 1975
to 1982. JAMA 256:3358, 1986
5. Leape LL, Brennan TA, Laird N, et al: The nature of adverse events in hospitalized
patients. Results of the Harvard Medical Practice Study II. N Engl J Med 324:377, 1991
6. Classen DC, Pestotnik SL, Evans RS, et al: Adverse drug events in hospitalized patients: excess length of stay, extra costs and attributable mortality. JAMA 277:301, 1997
7. Shear NH: Diagnosing cutaneous adverse reactions to drugs. Arch Dermatol 126:94,
1990
8. Sogn DD, Evans R, Shepherd GM, et al: Results of the National Institute of Allergy
and Infectious Diseases Collaborative Clinical Trial to test the predictive value of skin
testing with major and minor penicillin derivatives in hospitalized adults. Arch Intern
Med 152:1025, 1992
9. Barbaud A, Goncalo M, Bruynzeel D, et al: Guidelines for performing skin tests with
drugs in the investigation of cutaneous adverse drug reactions. Contact Derm 45:321,
2001
10. Alanko K, Stubb S, Reitamo S: Topical provocation of fixed drug eruption. Br J Dermatol 116:561, 1987
11. Smith HR, Croft AM, Black MM: Dermatological adverse effects with the antimalarial drug mefloquine: a review of 74 published case reports. Clin Exp Dermatol
24:249, 1999
12. Vega JM, Blanca M, Carmona MJ, et al: Delayed allergic reactions to beta-lactams.
Allergy 46:154, 1991
13. Romano A, Quaratino D, Papa G, et al: Aminopenicillin allergy. Arch Dis Child
76:513, 1997
14. Coopman S, Johnson R, Platt R, et al: Cutaneous disease and drug reactions in HIV
infection. N Engl J Med 328:1670, 1993
15. Pichler W, Yawalkar N, Schmid S, et al: Pathogenesis of drug-induced exanthems.
Allergy 57:884, 2002
16. Nigen S, Knowles SR, Shear NH: Drug eruptions: approaching the diagnosis of
drug-induced skin diseases. J Drugs Dermatol 2:278, 2003
17. Prussick R, Knowles S, Shear N: Cutaneous drug reactions. Curr Probl Dermatol
6:81, 1994
18. Knowles SR, Shapiro L, Shear NH: Serious adverse reactions induced by minocycline: a report of 13 patients and review of the literature. Arch Dermatol 132:934, 1996
19. Shear NH, Spielberg SP: Anticonvulsant hypersensitivity syndrome: in vitro assessment of risk. J Clin Invest 82:1826, 1988
20. Calabrese JR, Sullivan JR, Bowden CL: Rash in multicenter trials of lamotrigine in
mood disorders: clinical relevance and management. J Clin Psychiatry 63:1010, 2002
21. Wadelius M, Karlsson T, Wadelius C, et al: Lamotrigine and toxic epidermal necrolysis. Lancet 348:1041, 1996
22. Shear NH, Spielberg SP, Grant DM, et al: Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity. Ann Intern Med 105:179, 1986
23. Gupta A, Eggo M, Uetrecht J, et al: Drug-induced hypothyroidism: the thyroid as a
target organ in hypersensitivity reactions to anticonvulsants and sulfonamides. Clin
Pharmacol Ther 51:56, 1992
24. Rieder MJ: In vivo and in vitro testing for adverse drug reactions. Pediatr Clin
North Am 44:93, 1997
25. Anderson J: Allergic reactions to drugs and biologic agents. JAMA 268:2845, 1992
26. Simon RA, Namazy J: Adverse reactions to aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs). Clin Rev Allergy Immunol 24:239, 2003
27. Fisher MM, Harle DG, Baldo BA: Anaphylactoid reactions to narcotic analgesics.
Clin Rev Allergy 9:309, 1991
28. Oudit G, Girgrah N, Allard J: ACE inhibitor-induced angioedema of the intestine:

case report, incidence, pathophysiology, diagnosis and management. Can J Gastroenterol 15:827, 2001
29. Archambault S, Malo JL, Infante-Rivard C, et al: Incidence of sensitization, symptoms, and probably occupational rhinoconjunctivitis and asthma in apprentices starting
exposure to latex. J Allergy Clin Immunol 107:921, 2001
30. Mazon A, Nieto A, Linana JJ, et al: Latex sensitization in children with spina bifida:
follow-up comparative study after two years. Ann Allergy Asthma Immunol 84:207,
2000
31. Turjanmaa K, Alenius H, Reunala T, et al: Recent developments in latex allergy.
Curr Opin Allergy Clin Immunol 2:407, 2002
32. Pavletic AJ: Late angioedema in patients taking angiotensin-converting-enzyme inhibitors. Lancet 360:493, 2002
33. deShazo RD, Mather P, Grant W, et al: Evaluation of patients with local reactions to
insulin with skin tests and in vitro techniques. Diabetes Care 10:330, 1987
34. Dykewicz M, Kim HW, Orfan N, et al: Immunologic analysis of anaphylaxis to protamine component in neutral protamine Hagedorn human insulin. J Allergy Clin Immunol 93:117, 1994
35. Hoffman HM, Wright FA, Broide DH, et al: Identification of a locus on chromosome
1q44 for familial cold urticaria. Am J Hum Genet 66:1693, 2000
36. Haas N, Toppe E, Henz BE: Microscopic morphology of different types of urticaria.
Arch Dermatol 134:41, 1998
37. Erbagci Z: The leukotriene receptor antagonist montelukast in the treatment of
chronic idiopathic urticaria: a single-blind, placebo-controlled, cross-over clinical study.
J Allergy Clin Immunol 110:484, 2002
38. Ilter N, Gurer MA, Akkoca MA: Short-term oral cyclosporine for chronic idiopathic
urticaria. J Eur Acad Dermatol Venereol 12:67, 1999
39. Heckbert SR, Stryker WS, Coltin KL, et al: Serum sickness in children after antibiotic exposure: estimates of occurrence and morbidity in a health maintenance organization population. Am J Epidemiol 132:336, 1990
40. Joubert GI, Hada K, Matsui D, et al: Selection of treatment of cefaclor-associated urticarial, serum sicknesslike reactions and erythema multiforme by emergency pediatricians: lack of a uniform standard of care. Can J Clin Pharmacol 6:197, 1999
41. Kearns GL, Wheeler JG, Childress SH, et al: Serum sicknesslike reactions to cefaclor: role of hepatic metabolism and individual susceptibility. J Pediatr 125:805, 1994
42. Lowery N, Kearns GL, Young RA, et al: Serum sicknesslike reactions associated
with cefprozil therapy. J Pediatr 125:325, 1994
43. McCollom RA, Elbe DH, Ritchie AH: Bupropion-induced serum sicknesslike reaction. Ann Pharmacother 34:471, 2000
44. Shapiro LE, Knowles SR, Shear NH: Comparative safety and risk management of
tetracycline, doxycycline and minocycline. Arch Dermatol 133:1224, 1997
45. Vial T, Pont J, Pham E, et al: Cefaclor-associated serum sicknesslike disease: eight
cases and review of the literature. Ann Pharmacother 26:910, 1992
46. Grammer LC: Cefaclor serum sickness. JAMA 275:1152, 1996
47. Lee AY: Fixed drug eruptions: incidence, recognition and avoidance. Am J Clin Dermatol 1:277, 2000
48. Ozkaya-Bayazit E, Akar U: Fixed drug eruption induced by trimethoprim-sulfamethoxazole: evidence for a link to HLA-A30 B13 Cw6 haplotype. J Am Acad Dermatol 45:712, 2001
49. Barbaud A, Reichert-Penetrat S, Trechot P, et al: The use of skin testing in the investigation of cutaneous adverse drug reactions. Br J Dermatol 139:49, 1998
50. Al-Khenaizan S, Schecter JF, Sasseville D: Pseudoporphyria induced by propionic
acid derivatives. J Cutan Med Surg 3:162, 1999
51. Kuechle MK, Stegemeir E, Maynard B, et al: Drug-induced linear IgA bullous dermatosis: report of six cases and review of the literature. J Am Acad Dermatol 30:187,
1994
52. Neughebauer BI, Negron G, Pelton S, et al: Bullous skin disease: an unusual allergic
reaction to vancomycin. Am J Med Sci 323:273, 2002
53. Brenner S, Bialy-Gohan A, Ruocco V: Drug-induced pemphigus. Clin Dermatol
16:393, 1998
54. Wolf R, Brenner S: An active amide group in the molecule of drugs that induce
pemphigus: a casual or causal relationship? Dermatology 189:1, 1994
55. Roujeau JC, Kelly JP, Naldi L, et al: Medication use and the risk of Stevens-Johnson
syndrome or toxic epidermal necrolysis. N Engl J Med 333:1600, 1995
56. Rzany B, Correia O, Kelly JP, et al: Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis during first weeks of antiepileptic therapy: a case-control study.
Study Group of the International Case Control Study on Severe Cutaneous Adverse Reactions. Lancet 353:2190, 1999
57. Wolkenstein P, Charue D, Bagot M, et al: Metabolic predisposition to cutaneous adverse drug reactions. Arch Dermatol 131:544, 1995
58. Bastuji-Garin S, Rzany B, Stern RS, et al: Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 129:92, 1993
59. Schlienger RG, Shapiro LE, Shear NH: Lamotrigine-induced severe cutaneous adverse reactions. Epilepsia 39:S22, 1998
60. Garcia-Doval I, LeCleach L, Bocquet H, et al: Toxic epidermal necrolysis and
Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk
of death? Arch Dermatol 136:323, 2000
61. Patterson R, Miller M, Kaplan M, et al: Effectiveness of early therapy with corticosteroids in Stevens-Johnson syndrome: experience with 41 cases and a hypothesis regarding pathogenesis. Ann Allergy 73:27, 1994

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ACP Medicine
neous vasculitis, such as infection or autoimmune disease,

must be eliminated.
Treatment consists of drug withdrawal.Therapy for patients
with severe manifestations includes hemodialysis, pulse corticosteroids, cyclophosphamide, and plasmapheresis.73
Neil H. Shear, M.D., has received grants for clinical research and educational
purposes and served as advisor for Roche, Galderma SA, GlaxoSmithKline,
Novartis AG, and Fujisawa Healthcare Inc. He has also received grants for
clinical research and served as advisor for Genesoft Co. Ltd.
Sandra Knowles, B.Sc. Pharm., has no commercial relationships with manufacturers of products or providers of services discussed in this chapter.
Lori Shapiro, M.D., has no commercial relationships with manufacturers
of products or providers of services discussed in this chapter.
References
62. Prins C, Kerdel FA, Padilla RS, et al: Treatment of toxic epidermal necrolysis with
high-dose intravenous immunoglobulins. Arch Dermatol 139:26, 2003
63. Trent JT, Kirsner RS, Romanelli P, et al: Analysis of intravenous immunoglobulin for
the treatment of toxic epidermal necrolysis using SCORTEN. Arch Dermatol 139:39,
2003
64. Bachot N, Revuz J, Roujeau JC: Intravenous immunoglobulin treatment for StevensJohnson syndrome and toxic epidermal necrolysis. Arch Dermatol 139:33, 2003
65. Remmer H, Falk W: Successful treatment of lithium-induced acne. J Clin Psychiatry
47:48, 1986
66. Traupe H, von Muhlendahl K, Bramswig J, et al: Acne of the fulminans type following testosterone therapy in three excessively tall boys. Arch Dermatol 124:414, 1988
67. Beylot C, Doutre MS, Beylot-Barry M: Acute generalized exanthematous pustulosis.
Semin Cutaneous Med Surg 15:244, 1996
68. Sidoroff A, Halevy S, Bavinck JN, et al: Acute generalized exanthematous pustulosis (AGEP): a clinical reaction pattern. J Cutan Pathol 28:113, 2001
69. Freeman BD, Schmieg RE, McGrath S, et al: Factor V Leiden mutation in a patient
with warfarin-associated skin necrosis. Surgery 127:595, 2000
70. Bauer KA: Coumarin-induced skin necrosis. Arch Dermatol 129:766, 1993

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ACP Medicine
71. Schramm W, Spannagel M, Bauer KA, et al: Treatment of coumarin-induced skin

necrosis with a monoclonal antibody purified protein C concentrate. Arch Dermatol
19:753, 1993
72. Thompson DF, Skaehill A: Drug-induced lichen planus. Pharmacotherapy 14:561,
1994
73. ten Holder SM, Joy MS, Falk RJ: Cutaneous and systemic manifestations of drug-induced vasculitis. Ann Pharmcother 36:130, 2002
74. Sanchez NP, Van Hale HM, Su WP: Clinical and histopathologic spectrum of necrotizing vasculitis: reports of findings in 101 cases. Arch Dermatol 121:220, 1985
75. Jennette J, Falk K: Small-vessel vasculitis. N Engl J Med 337:1512, 1997
76. Merkel PA: Drugs associated with vasculitis. Curr Opin Rheumatol 10:45, 1998
77. Mehregan D, Hall M, Gibson E: Urticarial vasculitis: a histopathologic and clinical
review of 72 cases. J Am Acad Dermatol 26:441, 1992
78. Wolkenstein P, Revuz J: Drug-induced severe skin reactions: incidence, management and prevention. Drug Safety 13:56, 1995
VII
FUNGAL, BACTERIAL, AND VIRAL
INFECTIONS OF THE SKIN
Jan V. Hirschmann, m.d.
Despite its large surface area and constant exposure to the environment, the skin resists infection well. The most important
protective factor is an intact stratum corneum, the tough barrier of protein and lipid formed on the cutaneous surface by the
underlying epidermis.1 This barricade impedes invasion by environmental pathogens, and its dryness discourages colonization and growth of the many organisms that require moisture
to survive, such as gram-negative bacilli. Furthermore, the constant shedding of cells of the epidermis impedes most microbes
from establishing permanent residence.
Some organisms, however, can attach to skin cells and reproduce there; the normal cutaneous flora comprises primarily aerobic, gram-positive cocci and bacilli in densities ranging from
about 102 organisms/cm2 on dry skin to 107 organisms/cm2 in
moist areas, such as the axilla.2 This resident population inhibits
harmful organisms from colonizing the skin by occupying binding sites on the epidermal cells, competing for nutrients, producing antimicrobial substances, and maintaining the skin surface at a low pH (about 5.5). Anaerobes are sparse except in areas with abundant sebaceous glands, such as the face and chest;
in the deeper portions of these sites, as well as in hair follicles,
anaerobes reach concentrations of 104 to 106 organisms/cm2.
Cutaneous infections occur when the skins protective mechanisms fail, especially when trauma, inflammation, maceration
from excessive moisture, or other factors disrupt the stratum
corneum. The organisms causing infection may originate from
the victims own resident flora, either on the skin or on adjacent
mucous membranes, but many come from other people, animals, or the environment.
Dermatophyte Infections
Dermatophytes are fungi (molds) that can infect the skin,
hair, and nails. These organisms, which include Trichophyton,
Microsporum, and Epidermophyton species, are classified as anthropophilic, zoophilic, or geophilic, depending on whether
their primary source is humans, animals, or the soil, respectively.3 Geophilic dermatophyte infections occur sporadically, primarily among gardeners and farm workers. Zoophilic dermatophytes (Trichophyton and Microsporum species) may have
a restricted range of hosts (e.g., M. persicolor infects only voles)
or may afflict many different animals (e.g., T. mentagrophytes
can infect mice and other rodents, dogs, cats, and horses). Human infections with zoophilic species have occurred after exposure to dogs, cats, horses, cattle, pigs, rodents, poultry,
hedgehogs, and voles.
Anthropophilic dermatophytes are the most common cause
of fungal skin infections in humans. Transmission of these infections occurs from direct contact between people or from exposure to desquamated skin cells present in the environment
arthrospores can survive for months. Direct inoculation of the
spores through breaks in the skin can lead to germination and
subsequent invasion of the superficial cutaneous layers.
Dermatophyte infections occur more frequently in certain
March 2003 Update
ethnic groups and in people with impaired cell-mediated immunity. Many of the anthropophilic dermatophyte infections
occur more often in one gender or age group.4
Infection of the scalp, for example, is primarily a disease of
children. Involvement of the feet and groin is most common in
adolescents and young adults, especially males, but is unusual
in children. Nail infection is more frequent in both men and
women of advancing age. The reasons for these differences are
unknown.
The anthropophilic dermatophytes also have unique geographic distribution patterns. The most common cause of scalp
infection in the United States, for example, is T. tonsurans, but
in Southeast Asia and the Middle East, it is T. violaceum. These
differences may relate to climatic or racial factors.
The various forms of dermatophytosis, also called ringworm, are named according to the site involved. These infections include tinea capitis (scalp), tinea corporis (body), tinea
barbae (beard area of men), tinea faciei (face), tinea cruris
(groin), tinea pedis (feet), tinea unguium (nails), and tinea
manuum (hands). The characteristic skin lesion is an annular
scaly patch [see Figure 1], though the clinical appearance varies
not only with the site involved but also with the hosts immune
status and the type of infecting organism. In general, anthropophilic species elicit little inflammation and cause chronic infections. Zoophilic and geophilic species, however, often provoke intense inflammation, which sometimes leads to eradication of the organisms and healing without treatment.
clinical presentations
Tinea Capitis
Tinea capitis occurs primarily in children but may develop
in adultsespecially the elderly, those who are unkempt, and
the impoverished. Transmission can occur between humans by
the sharing of combs, brushes, or headgear. Only Microsporum
and Trichophyton species cause tinea capitis. Infection begins
with invasion of the stratum corneum of the scalp skin. The
hairs then become infected, in one of three microscopic patterns: ectothrix, endothrix, or favus. In ectothrix, the spores are
Figure 1 Classic annular lesion of tinea corporis shows a raised or

vesicular margin with central clearing.
ACP Medicine
DERMATOLOGY:VII Fungal, Bacterial, and Viral Infections of the Skin1
Figure 2 A typical kerion presenting as a zoophilic Microsporum

canis infection of the scalp (tinea capitis).
ters from the epidermis in this endothrix infection, the scalp

sometimes appears to be marked by small black dots. Like all
infections with Trichophyton species, these scalp lesions do not
fluoresce under a Wood light.
T. schoenleinii causes favus, characterized by an inflammatory crust (scutulum) in which hair appears to be matted in the
dried, yellow exudate. Hair shedding late in the infection is
common because the hair shaft is not damaged until the infection is well advanced.
M. audouinii, which causes an ectothrix infection, produces
well-delineated, noninflammatory patches of alopecia in which
the hair breaks at the epidermal surface and is often dull gray
because of the presence of numerous spores on the surface of
the hair shaft. As in all Microsporum infections, these lesions fluoresce under a Wood light. The most severe inflammation,
usually from a zoophilic species, results in a kerion, a painful,
boggy mass in which follicles may discharge pus and in which
sinus tracts form [see Figure 2]. Crusting and matting of adjacent hairs are common, and cervical lymph nodes may enlarge.
Tinea Corporis
outside the hair shaft and destroy the cuticle; in endothrix, they
lie within the hair and do not affect the cuticle; and in favus,
broad hyphae and air spaces form within the hair, but spores
are absent. In all three types, scaling, hair loss, and inflammation of varying degrees are present.5
T. tonsurans, the major cause of tinea capitis in adults, characteristically produces a noninflammatory infection with either
well-demarcated or irregular and diffuse areas of scaling and
alopecia. Because the swollen hairs may fracture a few millime-
Tinea corporis typically appears as a single lesion or multiple circular lesions with scaling, well-delineated margins, and
a raised, erythematous edge. Often, they have an area of central clearing. The amount of inflammation varies; when the inflammation is intense, pustules, vesicles, and even bullae may
occur. Sometimes, involvement of the hair follicles in the middle of a patch of scaling erythema leads to perifollicular nodules, a condition called Majocchi granuloma. This condition
usually occurs on the legs of patients infected with T. rubrum.
Figure 3 (a) The scaling of tinea pedis appears between and under the toes and on the plantar surface. (b) Tinea pedis may also
present as vesicles.

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ACP Medicine
In immunocompromised hosts, subcutaneous abscesses may

develop.
Tinea Barbae
Tinea barbae occurs in adult men and involves the skin and
coarse hairs of the beard and mustache area. The usual cause is a
zoophilic species, primarily T. verrucosum and T. mentagrophytes,
which are organisms that commonly infect cattle and horses.
The victims are generally farm workers, and the infection usually causes erythema, scaling, and follicular pustules. Many hairs
become loose and are easily removed with a forceps.
Tinea Faciei
Tinea faciei occurs as an infection of the face in women and
children and infection of the area outside the mustache and
beard in men. The usual causes are T. rubrum and T. mentagrophytes; these organisms reach the face through direct inoculation or by spreading from another site of infection on the body.
Patients often complain of itching and burning, and symptoms
may worsen after exposure to sunlight. The lesions may be
scaly, annular erythematous patches, but often they are indistinct red areas with little or no scaling.
Tinea Cruris
Tinea cruris, infection of the groin, is much more common
in men than women and is often associated with infection of
the feet. T. rubrum and E. floccosum are the most common causes. The lesions are usually red, scaling, sharply demarcated areas with raised, erythematous borders. The infection, which affects the medial portion of the upper thighs but consistently
spares the scrotum, may extend to the buttocks, abdomen, and
lower back. Vesicles, nodules, pustules, and maceration may be
present.
Tinea Pedis
Tinea pedis is most frequently caused by T. rubrum, E. floccosum, and T. mentagrophytes. The most common form consists of
fissuring, scaling, and maceration in the interdigital spaces, especially between the fourth and fifth toes. A second type involves scaling, hyperkeratosis, and erythema of the soles, heels,
and sides of the feet. In this kind of tinea pedis, the lesions occur
in a so-called moccasin distribution pattern [see Figure 3a]. The
plantar skin may become very thick and scaly. A third form
demonstrates an inflammatory pattern characterized by vesicles, pustules, or even bullae, usually on the soles [see Figure 3b].
An important complication of tinea pedis is streptococcal cellulitis of the lower leg. Streptococci do not ordinarily survive on
normal skin, but the presence of fungal disease apparently permits streptococci of various groups, including A, B, C, and G, to
colonize the toe webs.6 From this location, these bacteria may
invade the skin damaged by the tinea pedis or migrate to locations higher up the leg and enter the skin through any defects.
Tinea Unguium
Nail involvement usually occurs from adjacent fungal infection of the hands or feet. The organisms typically invade the
nail from the distal or lateral borders, and infection spreads
proximally. The nails are thickened, opaque, and yellowish to
brownish. They may crack or crumble, and often, subungual
hyperkeratosis lifts the nail plate from the underlying bed (a
condition known as onycholysis) [see Figure 4]. Splinter hemorrhages are common.
March 2003 Update
Figure 4 Nails are usually thickened, cracked, and crumbly in tinea

unguium; subungual debris may be present, as shown.
Tinea Manuum
Tinea manuum is an infection of the hands. Most cases
have accompanying involvement of the feet; inexplicably,
usually only one hand is affected (so-called two-feet, onehand disease). The most common finding is scaling or hyperkeratosis of the palms and fingers. Occasionally, vesicles,
papules, or follicular nodules form on the dorsal surface of
the hands.
diagnosis
Clinicians should suspect dermatophyte infection in patients
with any scaling, erythematous eruption and in patients whose
nails exhibit the characteristics of tinea unguium (see above).
The diagnosis can be confirmed by microscopy or culture of
properly obtained specimens. The optimal method of obtaining specimens from the skin is by scraping the scaly lesions;
specimens from the nails are best obtained by taking fragments
of subungual debris.
The specimen is prepared for microscopic examination by
first placing it on a glass slide and treating it with potassium
hydroxide (KOH), which digests the keratin of the skin, nails,
and hair, and then heating it to hasten the process. The basic
culture medium for isolating dermatophytes is an agar containing Sabouraud medium, often combined with antibiotics
to eliminate bacteria and with cycloheximide to inhibit saprophytic fungi. Growth is usually apparent in 3 to 14 days. Dermatophyte test medium culture can be used in the office and is
both accurate and inexpensive.7 When both KOH preparations
and cultures are negative, a biopsy may be useful in identifying the infecting organism, usually by special tissue stains
such as periodic acidSchiff or Gomori methenamine-silver
stains.
ACP Medicine
treatment
Tinea corporis, tinea cruris, tinea pedis, and tinea faciei respond to topical agents applied once or twice daily to the affected area, usually for 2 to 4 weeks. Good choices include
azoles (e.g., miconazole, econazole, or clotrimazole) or
terbinafine. The cost of the preparation can dictate which agent
to prescribe. Tinea pedis often recurs after effective therapy, especially in cases of the moccasin form of the disease. When infection reappears, the previous therapy can be resumed without loss of effectiveness.
Oral therapy is necessary for extensive lesions, for infection
involving the hair or hair follicles (e.g., tinea capitis and tinea
barbae), for tinea unguium, and, often, for tinea manuum and
various forms of dermatophytoses in immunocompromised
hosts. Five oral agents are currently available: griseofulvin, ketoconazole, itraconazole, fluconazole, and terbinafine. Griseofulvin, a fungistatic agent, is the oldest oral treatment available
and is still useful, primarily in infections not involving the
nails. Griseofulvin reduces the serum levels of barbiturates and
warfarin. Some patients receiving griseofulvin note a diminished tolerance to alcohol.
The azoles include ketoconazole, itraconazole, and fluconazole; like griseofulvin, they are fungistatic. Ketoconazole is
usually well tolerated, but hepatotoxicity occurs in about 1 in
10,000 patients, typically after several weeks of use. Fluconazole and itraconazole are very expensive, but they provide protracted levels of antibiotic in the nails, allowing short or intermittent courses of therapy for tinea unguium. Both fluconazole
and itraconazole can cause gastrointestinal disorders, rashes,
and, occasionally, hepatotoxicity and can have serious interactions with several medications, including cyclosporine, digoxin, and quinidine. Ketoconazole, itraconazole, and fluconazole
can interact with other medications; pharmacologic sources
should be consulted for potential interactions.
Terbinafine, also an expensive medication, is an allylamine.
Unlike both griseofulvin and the azoles, which are fungistatic,
terbinafine is fungicidal. It achieves high levels of drug in the
nails, and the drug persists for many weeks after discontinuance. Its few side effects include gastrointestinal reactions and,
occasionally, skin rashes. Hepatotoxicity and hematologic abnormalities are rare, and drug interactions are uncommon.
These oral antifungals are quite effective for tinea capitis.
The adult dosage for griseofulvin is 500 mg twice daily for 8
weeks. The other agents are effective when given for 1 to 3
weeks. Daily doses are as follows: itraconazole, 200 mg; fluconazole, 200 mg; and terbinafine, 250 mg. Of these, griseofulvin is the least expensive, but some T. tonsurans isolates are resistant to it. All these medications are effective in cases of tinea
barbae, Majocchi granuloma, extensive tinea corporis, and
tinea manuum that are unresponsive to topical agents. Griseofulvin and terbinafine appear to be superior to fluconazole and
itraconazole for the treatment of tinea capitis.8
Tinea unguium is difficult to eradicate, particularly in the
toenails. The most effective agent is terbinafine, administered
at a dosage of 250 mg daily for 6 weeks for fingernail infections
and for 12 weeks for toenail involvement.9 Because terbinafine
persists in the nails for many weeks, it continues to exert antifungal effects long after it is discontinued. The terbinafine regimens produce short-term eradication of infection in about 70%
to 90% of patients with fingernail infection and in about 50% to
80% of patients with toenail infection. Relapse is common, and
patients often require a second course of treatment. About 75%
March 2003 Update
of patients who receive one or more courses of terbinafine will

have a clinical cure 5 years later. This therapy is very expensive, and clinicians must decide in each case whether treatment
is warranted.
Yeast Infections
Yeasts are unicellular fungi that reproduce by budding.
They may form filamentous projections, which, unlike the hyphae of molds, do not contain separate cells. Accordingly, they
are called pseudohyphae. Candida species are not part of the
normal skin flora, but they commonly reside in the oropharynx, vagina, and colon. From these locations, they may cause
infections in adjacent traumatized skin. Alternatively, with reduction in the other flora or with impaired host defense mechanisms, these yeasts may proliferate in large numbers to produce lesions on the mucosal surfaces of the mouth and vagina.
Malassezia furfur (also called Pityrosporum orbiculare or P.
ovale) is a yeast that requires lipids for growth. It normally colonizes the skin of adults, especially of the scalp and upper
trunk, where the presence of sebum is highest. For unknown
reasons, these organisms, which are ordinarily commensals,
can become pathogenic and cause tinea versicolor (also known
as pityriasis versicolor) or folliculitis. Cogent evidence suggests that these organisms cause seborrheic dermatitis and
dandruff.
candidiasis
Clinical Presentations
Oral candidiasis One form of oral candidiasis, thrush, appears as white to gray patches (pseudomembranes) on the
tongue, soft palate, gingiva, oropharynx, and buccal mucosa.
Removing the material from the mucosal surface reveals an underlying erythematous base. Predisposing factors in adults include diabetes mellitus, use of systemic or local corticosteroids,
use of broad-spectrum antibiotics, use of radiotherapy or
chemotherapy, and impaired cell-mediated immunity, especially from HIV infection. Acute atrophic candidiasis especially
follows antibiotic therapy and causes painful, red, denuded lesions of the mucous membranes; the tongue may have erythematous areas with atrophic filiform papillae. In chronic
atrophic candidiasis, contamination of dentures with Candida
causes painful, red, and sometimes edematous lesions with a
shiny, atrophic epithelium and well-demarcated borders
where the dentures contact the mucous membranes. Poor dental hygiene and prolonged use of dentures are common predisposing factors. Some patients with these predisposing factors
have angular cheilitis (perleche), characterized by erythema
and fissuring of the corners of the mouth. Other contributing
conditions are maceration from excessive salivation or licking,
poorly fitting dentures, and a larger fold from diminished alveolar ridge height. Candida is present in most, but not all, patients with this disorder.
Chronic hyperplastic candidiasis (candidal leukoplakia)
consists of irregular, white, persistent plaques on the tongue or
mucous membranes that are difficult to remove; this form of
candidiasis occurs especially in male smokers. Soreness, burning, and roughness of the affected areas are the usual symptoms. Candidiasis of the tongue can also take the form of median rhomboid glossitis, a diamond-shaped area of atrophic
papillae in the central portion of the lingual surface.
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Candidal intertrigo Candida infection may occur in any

skin fold, causing soreness and itching. Obese patients are especially vulnerable. Commonly affected areas include the
groin, inframammary regions, and folds of the abdominal pannus. The lesions are patches of bright erythema accompanied
by maceration and an irregular, scalloped border, beyond
which papules and pustules (satellite lesions) commonly form
[see Figure 5].
Candidal vulvovaginitis and balanitis Most women with
candidal vulvovaginitis have no underlying disease, but candidal vulvovaginitis may accompany diabetes mellitus and HIV
infection. Candidal vulvovaginitis causes white plaques on a
swollen, red vaginal mucosa; a creamy vaginal discharge; and
erythema, sometimes with pustules, on the vulvar skin. Soreness and burning are common symptoms. Male sexual partners of women with candidal vulvovaginitisespecially male
sexual partners who are uncircumcisedmay develop balanitis, characterized by erythema, pustules, and erosions on the
glans of the penis. Balanitis may occur spontaneously as well.
Candidal paronychia and nail infection Maceration of the
tissue surrounding the nail, typically caused by excessive moisture, may cause paronychia, which is characterized by erythema, swelling, and pain of the nail fold with loss of the cuticle
[see Figure 6]. Candida organisms often colonize the area but are
probably pathogenic only when pus forms. With chronic colonization, nail involvement may occur, producing yellowish
discoloration and separation of the nail plate from the nail bed
(onycholysis). For chronic paronychia without purulence, topical corticosteroids, such as triamcinolone cream applied twice
daily for 3 weeks, are the best therapy.10
Figure 6 In a Candida paronychia, seen on this patients thumb, the

nail fold becomes red, swollen, and painful. Nail dystrophy is also seen.
Diagnosis
Scrapings from cutaneous or mucous membrane lesions
may be mixed with KOH solution and examined under the microscope for budding yeasts with pseudohyphae. Gram stains
of the same specimen are easier to evaluate because they disclose very large, oval, gram-positive cocci that may demonstrate budding or pseudohyphal formation. These organisms
are much larger than bacteria and are much easier to see on
Gram stain than on KOH preparation. Culture of specimens
may be useful if the microscopy is normal or ambiguous. These
organisms grow rapidly on both fungal and conventional bacterial media.
Treatment
Oral candidiasis For oral candidiasis, topical nystatin suspension, 200,000 to 400,000 units three to five times a day, is
usually effective; an alternative treatment is clotrimazole
troches. For patients in whom topical treatment is ineffective or
poorly tolerated, systemic therapies include ketoconazole, 200
mg/day; fluconazole, 100 mg/day; and itraconazole, 100 mg
twice a day. Angular cheilitis usually responds to an azole
cream, such as miconazole or clotrimazole. Dentures should be
cleaned carefully with an effective disinfectant, such as
chlorhexidine.
Candidal intertrigo and balanitis Candidal intertrigo and
balanitis respond to a topical azole cream, such as miconazole
or clotrimazole.
Candidal vulvovaginitis Treatment of vulvovaginitis includes a topical azole in the form of a cream, suppository, or
ointment, administered intravaginally, typically once daily for
7 days. A cream may be used for vulvar involvement. An alternative to suppositories is treatment with a single oral dose (150
mg) of fluconazole, which is at least as effective as topical therapy and is often preferred by patients.
Figure 5 Prominent satellite lesions of discrete vesicles are seen in a

patient with candidiasis.

March 2003 Update
Candidal paronychia Patients with candidal paronychia

should keep their fingers dry; when wet work is unavoidable,
patients should use cotton liners under rubber gloves. Prolonged topical therapy with creams or solutions of various
azole preparations, such as clotrimazole, is often necessary to
eradicate the infection.
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MALASSEZIA
infections
Clinical Presentations
Tinea versicolor (pityriasis versicolor) Because the term
tinea traditionally refers to dermatophyte infection, some clinicians prefer the term pityriasis, which means scaling, for this
yeast infection. Usually asymptomatic, tinea versicolor may
cause itching or skin irritation. The lesions are small, discrete
macules that tend to be darker than the surrounding skin in
light-skinned patients and hypopigmented in patients with
dark skin. They often coalesce to form large patches of various
colors (versicolor) ranging from white to tan [see Figure 7].
Scratching the lesions produces a fine scale. This infection most
commonly involves the upper trunk, but the arms, axillae, abdomen, and groin may also be affected. Most lesions fluoresce
a yellowish color under a Wood light.
Malassezia folliculitis (Pityrosporum folliculitis) In folliculitis, inflammation of the hair follicle causes red papules and
pustules that surround individual hairs. One cause of folliculitis is M. furfur. Lesions appear predominantly on the trunk but
occasionally occur on the arms as well. The lack of comedones
distinguishes the lesion from acne. Pruritus and stinging may
be present.
Diagnosis
In patients with tinea versicolor, KOH preparations of scrapings from the lesions demonstrate pseudohyphae and yeasts,
which resemble spaghetti and meatballs. This technique is sufficient to establish the diagnosis. The yeast form prevails in folliculitis and is easily seen on Gram stain of purulent material
from a pustule, appearing as a large, oval, gram-positive coccus that is much larger than bacteria. Biopsies of these lesions
show organisms around and within the hair follicle, with accompanying neutrophilic inflammation. The yeasts are best
seen with periodic acidSchiff or Gomori methenamine-silver
stain. Because these yeasts form part of the normal cutaneous
flora, growth of the organism on cultures from scrapings of the
skin surface is not very helpful diagnostically. Culture of the
yeast from the pus of folliculitis, however, is definitive, but it
requires special media, such as Sabouraud agar with olive oil,
to provide the necessary lipids for growth. Growth typically
occurs in 3 to 5 days.
Figure 8 Vesicopustules or bullae of impetigo rupture quickly and

leave an erythematous base covered with a thin, seropurulent exudate.
The exudate dries, forming layers of honey-colored crusts.
Treatment
Simple treatment of tinea versicolor and Malassezia folliculitis involves applying selenium sulfide shampoo from the chin
to the waist and from the shoulders to the wrist, allowing the
shampoo to dry, and then washing it off after 10 to 15 minutes.
Repeating this regimen after 1 week is usually effective; reapplication once every few weeks as necessary should prevent relapses, which are otherwise common. With tinea versicolor,
scaling resolves promptly, but the pigmentary changes may
take weeks to months to disappear. Topical azoles, such as ketoconazole, miconazole, and clotrimazole, are also effective,
but the expense of these drugs makes their use impractical except for small or isolated lesions. For patients who have difficulty applying a topical agent because of physical disabilities or
other factors, oral ketoconazole or fluconazole in a single 400
mg dose is an effective alternative. This oral program can be repeated for recurrences.
Bacterial Infections
skin infections caused by streptococci,
staphylococci, or both
Impetigo
Figure 7 Tinea versicolor appears on the chest of this patient as

oval, hypopigmented, finely scaling macules.
March 2003 Update
Initially a vesicular infection of the skin, impetigo rapidly

evolves into pustules that rupture, with the dried discharge
forming honey-colored crusts on an erythematous base [see Figure 8]. The lesions are often itchy. Impetigo characteristically
occurs on skin damaged by previous trauma, such as abrasions
or cuts. Exposed areas are most commonly involved, typically
the extremities or the areas around the mouth and nose. Impetigo is usually a disease of young children and is more frequent in hot, humid climates than in temperate ones.
The usual cause is Staphylococcus aureus, but sometimes,
Streptococcus pyogenes (group A streptococci) is also present; occasionally, S. pyogenes is the sole organism cultured.11 Some
strains of S. aureus elaborate a toxin that causes a split in the
epidermis and the development of thin-roofed bullae. In this
disorder, known as bullous impetigo, superficial, fragile, and
flaccid vesiculopustules form and then rupture, with the exu-
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date drying into a thin, brown, varnishlike crust. Sometimes,

the vesiculopustules are not apparent, and erythematous erosions are the only evident disturbance.
Growth of S. aureus, S. pyogenes, or both from the skin lesions
confirms the diagnosis, but cultures are unnecessary in characteristic cases. For treatment of sparse, nonbullous lesions, topical mupirocin ointment applied three times daily for 7 days is
as effective as oral antimicrobials. Systemic antibiotics active
against both S. aureus and S. pyogenes, such as cephalexin or dicloxacillin, represent an alternative to topical treatment. For extensive lesions, these antibiotics are preferred to topical therapy, and they are the treatment of choice for bullous impetigo.
Because of the superficial nature of these infections, the lesions
heal without scarring.
Ecthyma
Ecthyma (from the Greek word ekthyma, meaning pustule) is
a deeper infection than impetigo. As with impetigo, S. aureus,
S. pyogenes, or both may be the cause. Ecthyma commonly occurs in patients with poor hygiene or malnutrition or patients
who have had skin trauma. The lesions, which are often multiple and are most common on the lower extremities, begin as
vesicles that rupture, creating circular, erythematous lesions
with adherent crusts. Beneath the scabs, which may spontaneously slough, are ulcers that leave a scar when healing occurs. Culture of the ulcer base yields the causative organisms.
Treatment should be with an oral antistaphylococcal agent,
such as dicloxacillin or cephalexin.
skin infections caused by streptococci
Cellulitis and Erysipelas

Cellulitis and erysipelas are acute, spreading infections of
the skin caused by streptococci of groups A, B, C, and G.
Erysipelas involves the superficial dermis, especially the dermal lymphatics, and cellulitis affects the deeper dermis and
subcutaneous fat. Erysipelas has an elevated, sharply demarcated border, but differences in the clinical appearances of
erysipelas and cellulitis are unimportant and often unclear. The
most common sites of infection are the face and lower extremities. The causative organisms may enter the skin at obvious areas, such as traumatic wounds and leg ulcers, or through cutaneous inflammation (e.g., eczema); often, however, no point of
entry is apparent. Edema from any cause, including venous insufficiency, hypoalbuminemia, and lymphatic damage, is a
predisposing factor. Infection commonly occurs on skin that
has been permanently damaged by burns, trauma, radiotherapy, or surgery. For example, cellulitis may occur at the site of a
saphenous vein removal for cardiac or vascular surgery
months to years after the procedure.12 An important predisposing factor in patients with cellulitis or erysipelas is tinea pedis,
especially interdigital involvement; streptococci can invade the
skin at sites of tinea pedis through adjacent skin surface disrupted by the fungal infection or can migrate to more proximal
locations on the leg and enter through abnormal skin there.
Obesity is also a predisposing condition.13
Diagnosis Cutaneous findings include rapidly expanding
erythema and swelling of the skin [see Figure 9], sometimes accompanied by proximal streaks of redness, representing lymphangitis, and tender, enlarged regional lymph nodes. Vesicles, bullae, petechiae, and ecchymoses may occur. The cuta 2003 WebMD Inc. All rights reserved.
March 2003 Update
Figure 9 Erythema, edema, and sharp demarcation of the lesion

from the normal surrounding skin characterize facial erysipelas.
neous surface may resemble the skin of an orange (peau dorange) because the hair follicles remain tethered to the deeper
structures, keeping their openings below the surrounding superficial edema and creating the characteristic dimpling of the
skin. On the face, the typical location is on one or both cheeks,
with a butterfly pattern of erythema and swelling. Extension to
the eyelids, ears, or neck is common. Systemic symptoms, such
as fever, headache, and confusion, can accompany these infections; sometimes, such symptoms precede by hours any cutaneous findings on examination. Other patients have no systemic features despite severe skin abnormalities.
The diagnosis is largely clinical; in a typical case, cultures are
unnecessary and usually unrewarding. Needle aspiration of the
lesion yields an isolate in about 5% of specimens, as do blood
cultures in febrile patients. Because of their low yield, blood
cultures are unrewarding in typical cases of cellulitis.14 Punch
biopsies of the skin are culture-positive in about 20% of cases.15
These results, together with serum antibody tests for streptococci16 and immunofluorescent studies of skin biopsies,17 indicate that streptococci cause the vast majority of cases of cellulitis
and erysipelas. S. aureus is often suspected but rarely implicated in cellulitis in the absence of an abscess or penetrating injury.
Additional circumstances in which organisms other than streptococci are likely to be responsible for cases of cellulitis include
immunodeficiency, penetrating trauma, immersion injuries in
freshwater or saltwater, granulocytopenia, and animal bites or
scratches. Cultures are appropriate in these situations.
Treatment Treatment consists of elevation of the affected
area to help reduce edema and administration of systemic antibiotic therapy. For patients who do not have serious systemic
illness, oral treatment is satisfactory. Penicillin is the drug of
choice for streptococcal infections; for outpatients who may not
take an oral medication as prescribed, I.M. benzathine penicillin
G in an adult dose of 1.2 million units provides a complete
course. Instead of penicillin, many clinicians prescribe an antistaphylococcal agenteither a first-generation cephalosporin or
a penicillinase-resistant penicillinbecause of concerns about S.
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aureus. Patients often get worse shortly after therapy, with further extension of the cellulitis, higher fever, greater toxicity, and
increased white blood cell counts, presumably because rapid
killing of the organisms releases potent enzymes, such as streptokinase and hyaluronidase, that cause many of the clinical features. Oral prednisolone, taken for 8 days in doses of 30 mg, 15
mg, 10 mg, and 5 mg, with each dose taken for 2 days, decreases
the duration of cellulitis and shortens hospital stay; it is a reasonable regimen in those with no contraindications to systemic
corticosteroids.18
In patients with leg cellulitis, treatment of tinea pedis is useful in preventing further episodes, which are likely to cause
permanent lymphatic damage and can lead to lymphedema
and further risk of infection. Other measures to diminish the
frequency of future attacks include control of edema by diuretics or mechanical means, such as elastic stockings, and, for
those with frequent episodes, prophylactic antibiotics. The easiest approach is the administration of oral penicillin or erythromycin, 250 mg twice daily.19,20
infections due to STAPHYLOCOCCUS AUREUS
Furunculosis
A furuncle is a deep-seated inflammatory nodule with a
pustular center that develops around a hair follicle [see Figure
10]. With involvement of several adjacent follicles, a mass
called a carbuncle may form, with pus discharging from multiple follicular orifices. This infection typically develops on the
back of the neck and appears more commonly in patients with
diabetes than in the general population. Moist heat is usually
adequate for small furuncles, which ordinarily drain spontaneously. Incision and drainage are appropriate for large or
multiple furuncles and for all carbuncles. Systemic antibiotics
are unnecessary unless there is fever or substantial surrounding cellulitis.
Some patients have recurrent episodes of furunculosis. Although a few patients have definable abnormalities in host defenses, such as neutrophil disorders, most are otherwise
healthy people who, like 20% to 40% of the population, carry S.
aureus in the anterior nares. From this site or occasionally from
the perineum or axilla, organisms can spread and enter the
skin, presumably through minor, usually inapparent, trauma.
Successful prevention of recurrent infection requires eradication of these bacteria from their site of residence, but most sys-
temic antibiotics do not achieve adequate levels of drug in the

anterior nares. An exception is clindamycin, which, when given as a single daily dose of 150 mg for 3 months, is very effective in preventing subsequent episodes.21 A less effective alternative is mupirocin ointment, applied in the anterior nares
twice daily for 5 days each month.22
skin infections caused by the resident cutaneous flora
The normal cutaneous flora helps prevent infection by other
organisms through the mechanisms mentioned above: occupying available sites of residence, competition for nutrients, establishment of a low pH, and the elaboration of antibacterial substances. Occasionally, however, the resident skin flora causes cutaneous infections, especially with trauma or alterations in the
stratum corneum. Examples are erythrasma, pitted keratolysis,
trichomycosis axillaris, and most cases of cutaneous abscesses.
Cutaneous Abscesses
Cutaneous abscesses are collections of pus within the dermis
and deeper skin tissues. They probably occur as a result of
trauma. Sites of trauma associated with cutaneous abscesses
may be apparent, as with sites of injections in illicit-drug
users,23 or they may be minor and unnoticed. S. aureus, usually
in pure culture, causes about 25% of cutaneous abscesses, especially in the axillae, on the hand, and on the breasts of women
after childbirth.24 In other sites, however, the predominant organisms are anaerobes. Anaerobes occur either alone or in the
mixture of anaerobes and aerobes that constitutes the normal
regional flora; they are sometimes accompanied by microbes
from adjacent mucous membranes. In anogenital infections,
such as scrotal, inguinal, vaginal, buttock, and perirectal abscesses, the organisms are commonly fecal bacteria, including
streptococci, anaerobic gram-positive cocci, and anaerobic
gram-negative bacilli, such as Bacteroides fragilis. On the extremities, trunk, neck, and head, the usual microbes include coagulase-negative staphylococci, anaerobic gram-positive cocci,
and Propionibacterium acnes, an anaerobic gram-positive bacillus. These organisms ordinarily possess little virulence, but
when introduced into the dermis or subcutaneous tissue by
trauma or through a disrupted cutaneous surface, they may become pathogenic.
Cutaneous abscesses usually cause a painful, fluctuant, red,
tender swelling, on which may rest a pustule. Treatment is incision and drainage of the area. Gram stain and culture of the
pus are ordinarily unnecessary, as are topical antimicrobials.
Systemic antibiotics are reserved for patients with extensive
surrounding cellulitis, neutropenia, cutaneous gangrene, or
systemic manifestations of infection, such as high fever.
Erythrasma
Figure 10 A furuncle, or boil, occurs as an acute, painful, localized

staphylococcal abscess surrounding a hair follicle.

March 2003 Update
Porphyrin-producing coryneform bacteria, which are grampositive bacilli that constitute part of the normal cutaneous flora, cause a superficial, usually asymptomatic, skin disorder
called erythrasma. One particular species, Corynebacterium
minutissimum, has often been cited as the sole cause of this infection, but its precise role, if any, remains unclear. The most
common site of erythrasma is between the toes, especially in
the fourth interdigital space, where it causes fissuring, maceration, and scaling, resembling tinea pedis. Other locations are intertriginous areas, such as the axillae, groin, submammary
area, and intergluteal cleft. In these regions, the lesions are usually scaly, brownish-red, sharply circumscribed patches. In hot,
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humid climates, more extensive disease may occur. The definitive diagnostic technique is examination of the skin with a
Wood light, which, because the organisms produce porphyrins, reveals a coral-red fluorescence. Culture of the lesions,
which requires special media, is unnecessary. Because they
possess some activity against gram-positive bacteria, topical
azoles, such as miconazole and clotrimazole, are effective in the
treatment of this infection. Topical erythromycin or clindamycin is also effective. Oral erythromycin (250 mg q.i.d. for 2
weeks) is an alternative.25
Pitted Keratolysis
C. minutissimum and a gram-positive coccus, Micrococcus
sedentarius, either alone or together, cause a disorder that may
affect the solestypically in pressure-bearing areasor, occasionally, the palms.26 Pitted keratolysis consists of small pitted
erosions about 1 to 7 mm in diameter that may be present on
reddened plaques and are often more apparent after soaking in
water for a few minutes. This infection occurs with increased
moisture, such as caused by excessive sweating, occlusive
footwear, or frequent contact with water. It appears more commonly in hot, humid climates than in more temperate ones. An
impressive malodor of the feet is often apparent, and although
the disorder may cause no symptoms, some patients complain
of itching, tenderness, or sliminess of the feet. As in erythrasma, topical azoles, such as clotrimazole and miconazole, are effective, as are topical erythromycin and clindamycin.
Trichomycosis axillaris
Trichomycosis axillaris is characterized by colored concretions of axillary hair that result from infection of the hair shafts
by large colonies of various species of Corynebacterium. The
nodules may be yellow, black, or red; and because the organisms may invade the cuticle, the hair can become brittle. The
same process occasionally affects the facial or pubic hair.27 Excessive sweating, poor hygiene, and failure to use an axillary
deodorant are predisposing factors. Shaving the hair is effective treatment; other options include topical erythromycin or
clindamycin.
infections due to other bacteria
Necrotizing Fasciitis
Necrotizing fasciitis, a necrotizing infection of the subcutaneous tissue, can be caused by streptococci; more often, however, the responsible organisms are a combination of aerobic bacteriasuch as gram-negative enteric organisms (e.g., Escherichia
coli) and gram-positive cocciand anaerobes, including B. fragilis.28 Necrotizing fasciitis usually occurs after a penetrating
wound to the extremities. The injury is typically deep, but
sometimes, infection occurs after apparently trivial trauma,
such as abrasions or lacerations. The necrotizing process may
develop from extension of an adjacent infection, especially in
the second most common location, the anogenital area. There,
infection typically arises from a perianal abscess; as an extension of a periurethral gland infection, especially in men with
urethral strictures; through retroperitoneal suppuration from
perforated abdominal viscera; or as a complication of a preceding surgery. Necrotizing infection involving the genitalia is
called Fournier gangrene.
These infections typically begin with fever, systemic toxicity,
severe pain in the affected site, and the development of a
March 2003 Update
painful, red swelling that rapidly progresses to necrosis of the

subcutaneous tissue and overlying skin. Early on, the pain may
appear disproportionate to the clinical findings. In some cases
involving S. pyogenes infection, the characteristics of the streptococcal toxic-shock syndrome may appear29 [see 7:I Infections
Due to Gram-Positive Cocci]. When anaerobes or certain aerobic
gram-negative bacilli cause the infection, gas may form in tissues, evident as crepitus on physical examination or visible on
radiographic studies. Although the disease may resemble uncomplicated cellulitis, the following signs and symptoms
should suggest the presence of a necrotizing subcutaneous infection: edema beyond the apparent limits of the infection;
rapid development of bullae and ecchymoses; cutaneous gangrene; fluctuance; crepitus; and radiographically visible gas.
Computed tomography or magnetic resonance imaging may
be helpful in some cases in detecting the infection and defining
its extent. Aspiration of the affected tissue may yield purulent
fluid, which on Gram stain demonstrates only gram-positive
cocci in chains when S. pyogenes is responsible or reveals a variety of many different organisms when a mixed infection is present. The findings on Gram stain and culture of pus should dictate antibiotic choice, but a good initial program is gentamicin
in combination with clindamycin. Most important is incision
and drainage of the affected area, which should include removal of any necrotic tissue. Often, the amount of disease revealed at surgery is much greater than was apparent on the
preoperative clinical examination, because the infection typically extends far beyond the borders of cutaneous inflammation. Repeat operation after 24 hours is typically prudent to detect new areas of infection and necrotic tissue.
Folliculitis
Folliculitis is an inflammation at the opening of the hair follicle that causes erythematous papules and pustules surrounding individual hairs [see Figure 11]. The most common location
is the trunk. The initiating factor seems to be occlusion of the
opening of the follicle, which may occur from contact with
chemicals, such as oils or cosmetics; overhydration of the skin
from excessive moisture; or repetitive trauma, such as friction
from tight-fitting clothing, which elicits hyperkeratosis and follicular plugging. Subsequently, inflammation develops, which
may be provoked by bacteria, yeast, or other nonmicrobial substances trapped beneath the occluded ostium.
Among bacteria, S. aureus is often suspected but rarely
found. When bacteria are present in the pustules, the culture
usually yields normal skin flora. In these patients, oral erythromycin or doxycycline may be effective in eradicating the lesions. Another cause is M. furfur, a yeast that is a normal resident on the skin. In other patients, the avoidance of oily substances on the skin or tight clothing leads to resolution of the
problem.
Occasionally, Pseudomonas aeruginosa is responsible, as a consequence of inadequate disinfection of hot tubs, swimming
pools, or whirlpools.30 This gram-negative bacillus grows well
in hot water. Outbreaks occur an average of 48 hours after exposure, with a range of several hours to several days. Erythematous, pruritic papules, often with a pinpoint central pustule,
appear in areas exposed to the contaminated water; lesions are
particularly numerous in regions occluded by tight-fitting
swimming suits. The lesions disappear spontaneously over
several days, leaving no scars; ordinarily, no topical or systemic therapy is necessary. Some patients have sore throat,
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regional lymph nodes, but bacteremia is uncommon. After an

incubation period of about 1 to 7 days, a painless, pruritic
papule forms at the entry site, most commonly the head, neck,
and extremities. Over the next few hours the lesion enlarges,
and a ring of erythema may form around it. In 1 to 2 days, vesicles appear, surrounding the papule and containing numerous
bacteria but few neutrophils. Painless, gelatinous, nonpitting
edema then encircles the lesion, often spreading extensively to
adjacent skin and soft tissue [see Figure 12]. This pronounced
edema is especially characteristic of anthrax. After enlarging,
the vesicles become hemorrhagic and rupture. In the depressed
center of the lesion, a black eschar forms and sloughs within 1
to 2 weeks, leaving a shallow ulcer that heals with minimal, if
any, scarring. In the early days of illness, patients commonly
have headache, malaise, and fever. Regional lymph nodes often enlarge, causing pain and tenderness.
Diagnosis B. anthracis, a broad, encapsulated gram-positive rod, is visible on Gram stains of material from a skin lesion
as single organisms or chains of two or three bacilli. It grows
readily at 37 C on blood agar media. Skin biopsies reveal
necrosis, hemorrhage, and massive edema. Organisms are
demonstrable with tissue Gram stain or immunohistochemical
staining for the bacterias cell wall antigen. Because it requires
acute and convalescent blood specimens, serologic testing for
antibodies to B. anthracis is unhelpful for immediate diagnosis
but may establish a retrospective diagnosis of suspected but
unconfirmed cases.
Figure 11 Folliculitis is a superficial or deep inflammation of the

hair follicles, appearing at follicular openings as small pustules
surrounded by erythema (a). Folliculitis may also occur as an isolated
lesion (b).
rhinitis, earache, and headache, but fever or bacteremia is very
rare. Cultures of the skin lesions and the contaminated water
usually yield the organism.
Treatment Treatment for cutaneous anthrax unassociated

with bioterrorism is penicillin V (500 mg q.i.d. orally) or amoxicillin (500 mg t.i.d. orally) for mild cases and, for more severe
disease, penicillin G (6 to 8 million units I.V. daily). For penicillin-allergic patients or cases arising from bioterrorism, the
recommended therapy is oral ciprofloxacin (500 mg b.i.d.) or
doxycycline (100 mg b.i.d). Antibiotic therapy does not alter
the course of eschar formation and healing, but it does decrease
the risk of systemic disease. Ordinarily, the duration of therapy
is 7 to 10 days, but the recommended regimen for cases associated with bioterrorism is 60 days because of the possibility of
simultaneous aerosol exposure.31
Cutaneous Anthrax
Spores of Bacillus anthracis sent through the mail in the fall
of 2001 as an act of bioterrorism caused cases of inhalational
and cutaneous anthrax in several states. Otherwise, anthrax
has been very rare in the United States over the past few
decades. Ordinarily, this bacterium resides in the soil, where
it forms spores that can persist for years. When ingested
primarily by herbivores (cattle, horses, sheep, and goats) grazing on contaminated landthese spores may cause infection.
This veterinary disease is most frequent in tropical and subtropical areas, but extensive vaccination can markedly diminish its frequency.
Except for cases associated with bioterrorism [see 8:V Bioterrorism], humans usually develop anthrax from exposure to affected animals or their products, such as hides. Occasional laboratory-acquired cases also occur. The cutaneous form develops when spores enter the skin through abrasions and then
transform into bacilli, which produce toxins that cause local tissue edema and necrosis. Macrophages can transport spores to
March 2003 Update
Figure 12 Cutaneous anthrax lesion, seen on the seventh day after

infection.
ACP Medicine
Viral Infections
warts
Warts, or verrucae, are caused by human papillomaviruses
(HPVs), a subgroup of DNA-containing papovaviruses, of
which there are more than 70 types. Humans are the only
known reservoir; transmission probably occurs from close contact with infected people or possibly from exposure to
sloughed, infected epidermal cells. The virus presumably enters through small breaks in the skin. The incubation period is
difficult to discern but is probably several months. Autoinoculation from one portion of the body to another also occurs. Cellmediated immunity appears important in controlling these infections, which can be very extensive and refractory to treatment in immunocompromised patients.
Verrucae vary according to location. They include the common, elevated wart (verruca vulgaris), typically appearing on
the hands; the flat wart (verruca plana), on the face and legs;
the moist wart (condyloma acuminatum), in the anogenital
area; and the callus-covered plantar wart (verruca plantaris),
on the sole of the foot. A histologic feature that distinguishes
a wart from other papillomas is the presence in the upper epidermis of large, vacuolated cells that contain numerous viral
particles.
Verruca Vulgaris
The common wart consists of single or multiple skin-colored
papules, which often have a hyperkeratotic, papillary surface.
They are commonly present on the fingers. The estimated nationwide prevalence of hand warts is 3.5% for people 18 to 64
years of age; the greatest frequency (5.5%) occurs in men 18 to
24 years of age. The warts may be filiform, with a small base
and a thin projection of several millimeters, especially on the
face.
Liquid nitrogen is a common initial treatment of choice for
many warts. Administered with a cotton-tipped applicator or
cryospray device, liquid nitrogen freezes the lesion, causing it
to blister and subsequently dissolve. More than one application
at 2- to 3-week intervals may be necessary for large or periungual warts. Electrodesiccation and curettage or laser surgery
are effective for persistent or recurrent lesions.
Verruca Plana
The flat wart is a skin-colored or light-brown, slightly elevated, smooth papule commonly seen on the face and the dorsum
of the hand. These may be difficult to treat, but freezing with
liquid nitrogen, application of trichloroacetic acid, or painting
the lesions with 10% salicylic acid and 10% lactic acid in flexible
collodion may be effective.
Verruca Plantaris
The plantar wart is often painful and disabling. A mosaic
wart, a variant of verruca plantaris, consists of multiple discrete or confluent superficial lesions and is often difficult
to treat. A plantar wart that is covered by a callus can be distinguished from an ordinary callus by paring off the surface
keratin; multiple, pinpoint dots, representing thrombosed
vessels, or bleeding points from surface capillaries will become apparent if it is a wart. Paring of the wart can be followed by immediate treatment with liquid nitrogen, the application of strong acid (50% trichloroacetic acid), or the nightly
administration of salicylic acid in plasters, an acrylic vehicle,
or collodion.
March 2003 Update
Figure 13 Condyloma acuminatum may appear as a large

cauliflower-like mass that resembles a malignant tumor.
Condyloma Acuminatum
Anogenital warts consist of skin-colored or gray, discrete or
confluent cauliflower-like excrescences that may cause no
symptoms or produce itching, burning, pain, or tenderness [see
Figure 13]. The incidence is highest in young adults; most often,
it is a sexually transmitted disease, though some anogenital
warts may develop from autoinoculation or may be acquired
in other ways.32
Infection with some types of HPV predisposes to malignancy. Most cases of squamous carcinoma of the cervix are caused
by HPV, especially HPV-16 and HPV-18, but fortunately, these
types represent only a small percentage of the isolates from
anogenital warts. Genital verrucous carcinoma, also called giant condyloma acuminatum of Buschke-Lwenstein, is a lowgrade genital malignancy caused by HPV-6 and HPV-11.
Squamous carcinoma of the anus is associated primarily with
HPV-16.
Anogenital warts may be difficult to eradicate, and several
treatments are often necessary.33 Therapies administered by
clinicians include liquid nitrogen, podophyllin resin, trichloroacetic or bichloroacetic acid, surgical removal, laser therapy, or
intralesional interferon. Patient-applied treatments are podophyllotoxin, which the patient applies twice daily for 3 days, or
imiquimod cream, used at bedtime three times a week for up to
16 weeks. Another approach involves fluorouracil (5-FU) cream
administered twice daily for 1 to 3 weeks. This medication is
particularly suitable for large wart plaques and warts of the urethral meatus, but side effects, including discomfort and painful
erosions, are common.
ACP Medicine
Figure 14 Benign lesions of bowenoid papulosis, as seen on the

shaft of the penis, may histologically resemble carcinoma in situ.
Bowenoid Papulosis
Bowenoid papulosis consists of benign-appearing erythematous or pigmented papules in the anogenital area that histologically resemble Bowen disease (squamous cell carcinoma in
situ) [see Figure 14]. Its course, however, is not aggressive, and
the papules should be treated as anogenital warts (see above).
HPV-16 is a common cause, however, and malignancy does occasionally develop, especially in women.
The author has no commercial relationships with manufacturers of products or
References
1. Roth RR, James WD: Microbiology of the skin: resident flora, ecology, infection. J Am
2. Leyden JJ, McGinley KJ, Nordstrom KM, et al: Skin microflora. J Invest Dermatol
88(suppl):65s, 1987
3. Macura AB: Dermatophyte infections. Int J Dermatol 32:313, 1993
4. DeVroey C: Epidemiology of ringworm. Semin Dermatol 4:185, 1985
5. Elewski BE: Tinea capitis: a current perspective. J Am Acad Dermatol 45:320, 2001
6. Semel JD, Goldin H: Association of athletes foot with cellulitis of the lower extremities: diagnostic value of bacterial cultures of ipsilateral interdigital space samples. Clin
Infect Dis 23:1162, 1996
7. Elewski BE, Leyden J, Rinaldi MG, et al: Office practicebased confirmation of onychomycosis: a US nationwide prospective survey. Arch Intern Med 162:2133, 2002
8. Gupta AK, Adam P, Dlova N, et al: Therapeutic options for the treatment of tinea
capitis caused by Trichophyton species: griseofulvin versus the new oral antifungal

March 2003 Update
agents terbinafine, itraconazole, and fluconazole. Pediatr Dermatol 18:433, 2001

9. Evans EV, Sigurgeirsson B: Double blind, randomized study of continuous
terbinafine compared with intermittent itraconazole in treatment of toenail onychomycosis. The LION Study Group. BMJ 318:1031, 1999
10. Tosti A, Piraccini BM, Ghetti E, et al: Topical steroids versus systemic antifungals in
the treatment of chronic paronychia: an open, randomized double-blind and double
dummy study. J Am Acad Dermatol 47:73, 2002
11. Demidovich CW, Wittler RR, Ruff ME, et al: Impetigo: current etiology and comparison of penicillin, erythromycin, and cephalexin therapies. Am J Dis Child 144:1313,
1990
12. Dan M, Heller K, Shapira I, et al: Incidence of erysipelas following venectomy for
coronary artery bypass surgery. Infection 15:107, 1987
13. Dupuy A, Benchikhi H, Roujeau JC, et al: Risk factors for erysipelas of the leg (cellulitis): case-control study. BMJ 318:1591, 1999
14. Perl B, Gottehrer NP, Raveh D, et al: Cost-effectiveness of blood cultures for adult
patients with cellulitis. Clin Infect Dis 29:1483, 1999
15. Hook EW, Hooton TM, Horton CA, et al: Microbiologic evaluation of cutaneous cellulitis in adults. Arch Intern Med 146:295, 1986
16. Eriksson B, Jorup-Rnstrom C, Karkkonen K, et al: Erysipelas: clinical and bacteriologic spectrum and serological aspects. Clin Infect Dis 23:1091, 1996
17. Bernard P, Bedane C, Mounier M, et al: Streptococcal cause of erysipelas and cellulitis in adults: a microscopic study using a direct immunofluorescence technique. Arch
Dermatol 125:779, 1989
18. Bergkvist PI, Sjbeck K: Antibiotic and prednisolone therapy of erysipelas: a randomized, double blind placebo-controlled study. Scand J Infect Dis 29:377, 1997
19. Kremer M, Zuckerman R, Avraham Z, et al: Long-term antimicrobial therapy in the
prevention of recurrent soft-tissue infections. J Infect 22:37, 1991
20. Hirschmann JV: Antimicrobial prophylaxis in dermatology. Semin Cutan Med Surg
19:2, 2000
21. Klempner MS, Styrt B: Prevention of recurrent staphylococcal skin infections with
low-dose oral clindamycin therapy. JAMA 260:2682, 1988
22. Raz R, Miron D, Colodner R, et al: A 1-year trial of nasal mupirocin in the prevention of recurrent staphylococcal nasal colonization and skin infection. Arch Intern Med
156:1109, 1996
23. Ebright JR, Pieper B: Skin and soft tissue infections in injection drug users. Infect Dis
Clin North Am 16:697, 2002
24. Meislin HW, Lerner SA, Graves MH, et al: Cutaneous abscesses: anaerobic and aerobic bacteriology and outpatient management. Ann Intern Med 87:145, 1977
25. Holdiness MR: Management of cutaneous erythrasma. Drugs 62:1131, 2002
26. Takama H, Tamada Y, Yano K, et al: Pitted keratolysis: clinical manifestations in 53
cases. Br J Dermatol 137:282, 1997
27. White SW, Smith J: Trichomycosis pubis. Arch Dermatol 115:444, 1979
28. Stone DR, Gorbach SL: Necrotizing fasciitis: the changing spectrum. Dermatol Clin
15:213, 1997
29. Dahl PR, Perniciaro C, Holmkvist KA, et al: Fulminant group A streptococcal necrotizing fasciitis: clinical and pathologic findings in 7 patients. J Am Acad Dermatol
47:489, 2002
30. Agger WA, Mardan A: Pseudomonas aeruginosa infections of intact skin. Clin Infect
Dis 20:302, 1995
31. Inglesby TV, OToole T, Henderson DA, et al: Anthrax as a biological weapon, 2002.
Updated recommendations for management. JAMA 287:2236, 2002
32. Von Krogh G, Gross G: Anogenital warts. Clin Dermatol 15:355, 1997
33. Gross G, Von Krogh G: Therapy of anogenital HPV-induced lesions. Clin Dermatol
15:457, 1997
Acknowledgment
Figure 12 Centers for Disease Control and Prevention Public Health Image Library.
ACP Medicine
VIII
PA R A S I T I C I N F E S T A T I O N S

Ectoparasites may cause severely pruritic infectious diseases of
the skin. With early detection and treatment, parasitic infestations can be cured and their spread to other persons can be prevented. The most common parasitic diseases of the skin that occur in nontropical environments are scabies, which is caused
by itch mites, and pediculosis capitis, pediculosis corporis, and
pediculosis pubis, which are caused by bloodsucking lice.
An increase in international travel, including vacation travel
to tropical destinations and immigration from such areas, has
led to the occurrence of parasitic disorders endemic to tropical
regions in persons living in temperate climates. The differential
diagnosis of skin disorders in patients treated at a tropical disease clinic in Paris over a 2-year period included cutaneous larva migrans, pyodermas, arthropod-reactive dermatitis, myiasis, tungiasis, urticaria, and cutaneous leishmaniasis.1
Scabies
Scabies is caused by infestation with Sarcoptes scabiei, an ectoparasite that bores into the corneal layer of human skin, forming burrows in which it deposits its eggs. The incubation period
is 2 to 6 weeks in a person who has not been previously exposed.
During this time, the host develops delayed hypersensitivity to
mite antigens. Upon reinfestation, symptoms occur in sensitized
persons within 24 to 48 hours after exposure.2 The incidence of
scabies follows a 30-year cycle: 15 years of high incidence alternates with 15 years of low incidence. The current pandemic,
however, has exceeded 15 years.
The scabies mite does not survive for more than 48 hours away
from the host. Therefore, most infestations are transmitted through
direct personal skin-to-skin and sexual contact.2 However, transfer of organisms can occur by exposure to fomites in contaminated bedding, clothing, or furniture and is a common cause of epidemics of scabies in nursing homes and other institutions.2,3
in those who are using topical steroids. Secondary bacterial infection with impetiginization is common, especially in children
and in elderly patients who actively excoriate their lesions.
Atypical presentations of scabies have been described in immunosuppressed persons, including organ transplant recipients,
patients with lymphoma or leukemia, and patients with AIDS.
Itching and scratching, with elimination of mites and burrows,
may be minimal in patients who lack an immunologic host response, allowing for thousands of mites to reproduce and
thrive.2 Crusted scabies, which was originally described in Norway, is associated with widespread hyperkeratotic lesions and
deep fissures in the skin. Crusted scabies can develop in patients
with malnutrition or severe mental deficiency and in institutionalized patients. The condition is highly contagious because of the
large number of mites present in the exfoliating skin.
A severe form of scabies with unusual clinical features consisting of crusted lesions and a widespread pruritic papular dermatitis has been described in HIV-infected patients.2,4 In these patients,
multiple treatment applications may be needed because of the
large mite population as well as the patients impaired immunologic response.
Skin Scrapings
A skin scraping that demonstrates the presence of mite eggs
or mite products can confirm a diagnosis of scabies. A No. 15
surgical blade is used to scrape across one or more burrows. Saline solution or mineral oil is used to remove scrapings
from the blade. The scrapings are then placed on a glass slide
with a coverslip and examined under a microscope at low-power magnification. The scraping is positive if the gravid female,
eggs, or scybala (fecal pellets) are seen [see Figure 3]. The yield is
greatest in burrows that are not yet excoriated, which may be
difficult to find. For this reason, if the scraping is negative but
the clinical suspicion of scabies is high, the patient should be
treated empirically. Histopathologic examination of a skin biopsy sample is also diagnostic if it reveals the mite or the superficial skin burrow and its contents.5
diagnosis
Clinical Features
Scabies causes severe itching, which is usually worse at night.
Characteristic sites of infestation are the webs of the fingers, the
flexor aspects of the wrists, the axillae, the buttocks, the umbilicus, the penis and scrotum of males, and the breasts and nipples
of females. The disease is more generalized in infants and children than in adults.
The burrow of the female Sarcoptes may be seen as an irregular zigzag line in the stratum corneum, with a black dot at one
end that indicates the presence of the mite [see Figure 1]. Secondary lesions represent immunologic reactions to the mites
and usually appear as small erythematous papules and vesicles with surrounding edema and scratch marks [see Figure 2].
The type and number of lesions depend predominantly on the
immune status of the host. Occasionally, nodular lesions,
which may resemble lesions of histiocytosis X (Langerhans cell
granulomatosis) or lymphoma, occur as a hypersensitivity reaction to retained mite parts. Fewer lesions occur in people
who practice good hygiene, and the condition may be masked
March 2001 Update
Figure 1 Typical scabies lesions are small erythematous papules and

vesicles with surrounding edema.
ACP Medicine
DERMATOLOGY:VIII Parasitic Infestations1
treatment
Initial Treatment
Figure 2 The burrow of the female Sarcoptes frequently appears as an

irregular line several millimeters to a few centimeters long in the
stratum corneum.
Figure 3 Observation of the Sarcoptes scabiei or its eggs and feces

confirms the diagnosis of scabies. Magnification is 400 times.
Clinical differential diagnosis includes drug eruption, papular
urticaria, follicullitis, atopic dermatitis, dermatitis herpetiformis,
and contact dermatitis, particularly from fiberglass. Papular urticaria is an intensely itchy eruption caused by a hypersensitivity
reaction to bites from such insects as fleas, bedbugs, and animal
scabies. Lesions occur as small papules that may have a central
punctum, often occurring in groups on exposed skin.
March 2001 Update
After a cleansing bath or shower, the patient should allow the

skin to dry and cool and then apply a scabicide over the entire
body, excluding the face and scalp. Care must be taken to include
skin folds such as toe webs and the skin under the nails. The
medication is left in place for 8 to 12 hours, usually overnight. In
the morning, the patient showers and changes clothes. All clothing worn within 2 days after treatment, in addition to towels and
bed linens, is laundered in hot water or dry-cleaned. Chairs and
mattresses should be vacuumed.
Available scabicides include 5% permethrin cream (Elimite,
Acticin); lindane, or gamma benzene hexachloride, lotion or
cream (Kwell, Gamene); 10% to 20% benzyl benzoate lotion;
crotamiton cream (Eurax); and 6% precipitated sulfur ointment.
Permethrin, a synthetic pyrethroid with low toxicity, is considered the first line of therapy.6 Natural pyrethrins, which are
derived from chrysanthemum flowers, have greater toxicity
and less insecticidal activity than the synthetic pyrethroids. The
low toxicity of the drug is a result of its rapid breakdown into
inactive metabolites. Permethrin cream can be safely used in
children and infants older than 2 months and in the elderly.
Acticin is a form of permethrin in a base that has a lower viscosity to promote ease of application. Alternative scabicides
that can be used for young children and pregnant or lactating
women include crotamiton cream and sulfur ointment. Six percent precipitated sulfur ointment is applied three times: at diagnosis, after 24 hours, and at 1 week. Crotamiton cream is applied for 2 or more consecutive days but is less effective than
permethrin.
Lindane is lipophilic and can accumulate in fat and bind to
brain tissue. Toxic reactions may occur in patients who have increased absorption; infants and young children, who have a
higher ratio of skin surface to body volume than do adults, are
especially susceptible. Excessive treatment with lindane has
been reported to cause central nervous system toxicity resulting
in convulsions.7,8 Nevertheless, low cost, ease of application, and
experience with the drug have made lindane one of the most
commonly prescribed scabicides.
Oral ivermectin is another option that may increase compliance to treatment because oral administration is easier than
whole body therapy. A single oral dose of 200 g/kg of ivermectin was used to treat uncomplicated scabies in 11 otherwise
healthy patients and in 11 patients with HIV infection.9 Clearing
was documented by negative skin scrapings at 2 weeks and 4
weeks after treatment, and cure was achieved in all of the otherwise healthy patients and in eight of the HIV-infected patients.
In a comparative study of oral ivermectin and topical permethrin, a single application of permethrin was found to be superior to a single dose of ivermectin. Two doses of ivermectin were
required for eradication of scabies. The lack of ovicidal activity of
ivermectin may explain the difference in effectiveness between
the two drugs.10 Ivermectin is toxic to invertebrate nerve and
muscle cells but may not be effective against younger stages of
the parasite that do not have a developed nervous system. Permethrin acts at all stages of the life cycle of the parasite, and topical application ensures adequate drug concentration in the skin.10
Topical ivermectin has also been investigated for treatment
of scabies. A total of 75 patients were found to be cured, on the
basis of clinical and parasitologic examinations, within 48
hours after a single application of ivermectin. Postscabies itchACP Medicine
ing, which persisted in 50% of the patients, was effectively

treated by a second application of ivermectin within 5 days.11
Postscabies Itch
Postscabies itch is thought to represent a hypersensitivity reaction to the mite or mite products and is not caused by active
infestation. The pruritus may persist for weeks to months and
can be treated with an antipruritic or anti-inflammatory agent,
such as a low-potency to midpotency corticosteroid cream, in
addition to oral antihistamines. Overtreatment with the scabicide may result in a primary irritant dermatitis that may be confused with persistent infestation. The use of bland emollients
and a corticosteroid cream and avoidance of skin irritants may
reduce the dermatitis. Patients should be evaluated at 4 weeks,
the time required for viable eggs to mature to the adult stage, to
determine the efficacy of treatment. If lesions are healed and no
new outbreaks have occurred, the patient is considered cured.2
Resistant Scabies
Pyrethroids are effective in cases of resistant scabies that
may be associated with overuse of lindane.12 Treatment failures
can also occur in cases involving impetiginized or crusted scabies. In these cases, treatment with the appropriate oral antibiotic is initiated along with application of the scabicide and is
followed within a week by a second application of the scabicide. Keratolytics are useful as an aid in removal of the crusts.
Oral ivermectin has been used to treat resistant scabies. Although it has not been approved by the FDA for this purpose,
oral ivermectin is rapidly gaining acceptance as first-line therapy
for scabies. Combination treatment with one or two doses of
ivermectin 8 days apart, in addition to permethrin and mechanical removal of subungual debris, has been advocated for outbreaks of crusted scabies in the geriatric population.13
Combination therapy with oral ivermectin, 200 mg/kg, and
benzylbenzoate, 15% solution applied twice daily for 3 days, is
more effective than either agent alone for the treatment of
crusted scabies in patients with HIV.14
Cases of apparent resistant scabies may be the result of reinfestation. Therefore, family members and sexual partners of persons with scabies should be treated because they may be asymptomatic carriers. Scabies occurring in patients and personnel in
long-term health care facilities may be difficult to diagnose and
manage. In this setting, it is extremely important to treat all nursing contacts, as well as family members and other visitors of
affected patients. In addition to the patients with scabies, other
patients in the facility need to be assessed, and care must be coordinated to treat all affected persons simultaneously. In cases of
crusted scabies, the head and neck must be treated, as well as
subungual areas, which may also harbor the mites.3
animal scabies
Animal scabies is a common disorder in farm animals and domestic animalsespecially dogs, in which the external ear is frequently infested with a species-specific mite. In persons who
handle affected animals, an extremely pruritic papular eruption
can develop that differs from ordinary scabies in several ways:
distribution of lesions is proximal, with involvement of the
thighs, abdomen, and forearms. Burrows are usually absent. The
course is self-limited provided there is no reexposure. Other persons in the household do not have to be treated, because humanto-human transmission of animal scabies does not occur.
The Cheyletiella mite is an ectoparasite that resides in the fur of
March 2001 Update
dogs, cats, and rabbits. Persons who hold infested house pets, especially cats, are susceptible to a dermatitis from the mite bites.
However, the mites do not live on humans, so diagnosis requires
a high index of suspicion. Lesions may appear as urticarial
papules, vesicles, or bullae on the arms, trunk, and legs. Cases
most commonly occur in the fall or winter. An important part of
the overall treatment of Cheyletiella infestation is treatment of the
household pets by a veterinarian.15
Pediculosis
The three types of bloodsucking lice that cause pediculosis
are Pediculus humanus var. capitis (head louse), Pediculus humanus var. corporis (body louse), and Phthirus pubis (pubic, or
crab, louse). The first two types are closely related. The third is
a separate genus and is distinctive not only in appearance and
in location on the body but also in its characteristic attachment
to the skin for long periods. Any form of pediculosis causes intense pruritus, aggravated by scratching and often complicated
by secondary bacterial infection.16
The most common infestation is pediculosis capitis, except under conditions of overcrowding and poor sanitation or in wartime,
when pediculosis corporis is widespread. The lice may be transmitted directly from person to person or indirectly through contact with contaminated personal objects such as combs and brushes, clothing, and bedding. Pediculosis pubis (also called crabs) is
usually transmitted sexually; only occasionally are the lice transmitted through contact with fomites such as contaminated bedding or toilet seats.
The natural history of lice is important because it suggests specific preventive measures. The life expectancy of the organism is
about 1 month. Eggs live up to 10 days but need the body heat of
the host to hatch. Eggs ordinarily hatch in 7 to 8 days, and organisms reach adulthood and attain sexual reproductive capacity in 3
to 4 weeks. Lice can survive 48 hours without a blood meal.
diagnosis
Pediculosis capitis is confined to the scalp and is most prevalent in women and children. Examination of the itchy scalp may
reveal the lice, which look like tiny black dots that are barely visible to the naked eye, and lice eggs (nits), which are white and
are attached to the hair shafts [see Figure 4]. Viable nits are attached close to the scalp. Those that occur several millimeters
away from the surface on hairs that have grown out are empty
egg cases. The hair may become matted because of exudation
and secondary infection of lesions, and the cervical glands may
become enlarged and painful.
Pediculosis corporis, also called vagabond disease, affects areas of the body covered by clothing. Body lice live in the seams
of clothing, and they attach to the body only to feed [see Figure
5]. They may serve as vectors of infectious disease under conditions of overcrowding or poor hygiene, as in wartime or during
natural disasters. Characteristic lesions include erythematous
macules and wheals. Lesions are most common on the shoulders, buttocks, and abdomen; furunculosis is an occasional complication. Excoriations and secondary infection may result from
intense scratching. After the eggs hatch, the organisms reach
adulthood in 10 days and complete their life cycle in approximately 1 month. Adult lice lay about 10 eggs a day.
Pediculosis pubis, which is caused by infestation with Phthirus
pubis [see Figure 6], tends to be limited to the pubic area but occasionally affects the axillae, eyelashes, or other hairy parts of the
ACP Medicine
Over-the-counter preparations available for the treatment of

pediculosis capitis include synergized pyrethrin products such
as RID, R&C Spray, A-200, and a 1% permethrin cream rinse
(Nix). These products are cosmetically acceptable and require
only 10 minutes to apply but may not always be effective. Repeat treatment in 7 to 10 days is advisable because the initial
treatment does not kill all the eggs.
Resistance to lindane has emerged over the past 2 decades.
More recently, treatment of lice infestation has been complicated
by the development of resistance to permethrin.17 Mechanical
methods of removing head lice and nits18 and application of occlusive oils or ointments19 have been advocated for treatment of
resistant head lice. Oral ivermectin has been administered as a
single dose of 12 mg (2 to 6 mg tablets) followed by a second dose
7 to 10 days later.16
Pediculosis Pubis and Pediculosis Corpis

Figure 4 Pediculosis capitis is caused by infestation of the scalp with
Pediculus humanus var. capitis. Magnification is 10 times.
To treat hairy areas of the body infested with P. pubis, a cleansing bath or shower should first be taken and the skin dried with a
towel. One ounce of lindane cream or lotion is applied to the affected and surrounding areas and left on for 12 to 24 hours. After
another bath or shower, freshly laundered clothing should be
donned; bedsheets and towels should also be changed. Lindane
may be applied a second time after 1 week if infestation continues. Lindane should not be applied to the face and eyelids, because it causes irritation; eyelash infestation may be treated by local application of 0.25% physostigmine ophthalmic ointment. An
alternative treatment for eyelash infestation that is effective and
nonirritating is the application of a thick layer of petrolatum twice
a day, followed by mechanical removal of the nits.
Neurologic complications can ensue from absorption of lindane after extensive or prolonged topical application [see Scabies, above]. Alternative treatments are therefore indicated in infants (who are especially susceptible), in young children, in pregnant women, and in the elderly. No serious side effects have
been reported from the use of lindane for head lice.
A combination of pyrethrins with piperonyl butoxide (RID or
A-200) has been shown to be considerably less toxic than lindane
in animal experiments and in clinical experience. However, this
combination irritates the eyes and mucous membranes and may
also cause allergic contact dermatitis in susceptible people.
General Treatment Measures

Figure 5 Pediculosis corporis is caused by infestation with Pediculus
humanus var. corporis organisms, which live in the seams of clothing.
body. Examination will reveal lice attached to the skin and lice
eggs attached to the hair shafts [see Figure 7]. Blue macules,
which are caused by the lices sucking blood from the dermis,
may be seen on the thighs or pubic area.
treatment
Pediculosis Capitis
One of the most widely used remedies for pediculosis in the
United States is 1% lindane (Kwell, Gamene). For the treatment of
Pediculus capitis, 2 tbsp (30 ml) of the shampoo is applied to affected and adjacent areas of the scalp for at least 4 minutes, followed
by thorough rinsing and drying. Adherent nits may be removed
with a fine-tooth comb. Distilled white vinegar can be used to
soften the nit cementing material to aid in removal of the nits.
March 2001 Update
All family members should be carefully examined for

pediculosis and treated, if necessary, to avoid spread or reinfection of previously treated persons. In the case of pediculosis
pubis, sexual contacts should be examined and treated. Because sexually transmitted diseases are frequently present in
persons infested with P. pubis, a serologic test for syphilis and
screening for HIV are usually done. To prevent spread of
pediculosis, contaminated clothing and other articles, such as
towels and bedding, should be boiled, machine washed in hot
water, and placed in a dryer using a 20-minute hot cycle or
should be dry-cleaned. Items such as combs and brushes may
be cleaned with medicated shampoo or soaked in 5% Lysol. To
eradicate P. corporis, the patients clothing must be put through
the same decontamination process as that used for P. pubis. A
hot iron with pressure applied, especially to the seams of clothing, may also be used to kill P. corporis. Systemic antibiotics
should be prescribed for concomitant secondary bacterial infections such as furunculosis and impetigo, both of which are
commonly associated with pediculosis capitis.
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days and under ideal conditions to as long as 20 months.20

Eradication of the fleas may require consultation with a veterinarian. Pets must be treated more than once to kill the eggs,
larvae, and pupae, as well as the residual fleas. A household
flea spray should be combined with a fogger to fumigate the
house. Proper extermination procedure includes vacuuming
the furniture and vacuuming or steam cleaning carpets or rugs.
The yard should be sprayed and cleared of organic debris.
Treatment of flea bites consists of cool-water compresses,
application of a corticosteroid cream and an antipruritic lotion,
and oral antihistamines in the case of allergic hypersensitivity
reaction. Systemic antibiotics are prescribed for secondary bacterial infection.
Tungiasis
Figure 6 Pediculosis pubis, also called crabs, is caused by infestation
Cutaneous infestation by the sandflea Tunga penetrans is endemic in Central and South America, parts of Mexico, tropical
Africa, Pakistan, and the west coast of India. Isolated cases have
been reported in the United States, Australia, and New Zealand.
Tungiasis is more prevalent in poverty-stricken areas and is associated with domestic animals such as pigs, dogs, and cattle,
which serve as intermediaries in the biologic life cycle.21 The female adult sandflea exists in sandy soils and requires a warmblooded host to complete its life cycle. The organism penetrates
the stratum corneum, resulting in erythematous nodules with a
central dark spot. Common sites of skin involvement are the
soles of the feet, the web spaces between fingers and toes, the ankles, the perineal area, and the buttocks.
Infestation can be prevented by wearing shoes and proper
clothing and by the use of insecticides.
with Phthirus pubis. Magnification is 100 times.
myiasis
Miscellaneous Infestations
Myiasis is caused by the larvae (maggots) of feeding flies of

the order Diptera. The larvae may invade the skin primarily or
become secondarily implanted in a preexisting skin wound.22
Many species of the genus Cuterebra can cause myiasis, but in
flea infestations
Fleas are small (approximately 3 mm), bloodsucking, wingless ectoparasites of the insect order Siphonaptera. Fleas are
medically significant because they are vectors of infectious disease [see Section 7, Subsections II and XVII]. They can also cause
considerable cutaneous symptoms, particularly if the symptoms are associated with an allergic hypersensitivity reaction,
as seen in papular urticaria. There are approximately 250 species of flea, 20 of which can infest humans. Two common species that infest cats and dogs are Ctenocephalides felis and C. canis. They are not host specific and can therefore infest humans as
well. Pulex irritans, the house flea, infests humans and is not a
problem for pets. Flea bites appear as erythematous edematous
papules with hemorrhagic puncta in clusters or groups on the
lower extremities, especially on the ankles. Occasionally, vesicles and bullae can appear, as well as larger urticarial lesions.
Secondary impetiginization may occur because of scratching.20
Fleas are difficult to eradicate because of their unpredictable
life cycle, which consists of egg, larva, pupa, and adult stages.
The eggs are laid on the host but can drop to the ground; onto
carpets, pet bedding , and furniture; and into floor cracks. Eggs
hatch in 2 to 21 days into larvae. A larva molts twice and, in the
third larval stage, spins a cocoon, in which it becomes a pupa.
Within 7 days to 1 year or more, the adult emerges, depending on
various trigger factors (e.g., a vibration caused by a nearby pet or
human). The life cycle from egg to adult can range from 14 to 21
March 2001 Update
Figure 7 Lice attached to the skin and lice eggs attached to the hair
shafts can be seen on a patient with pediculosis pubis.
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washed ashore by ocean currents, have been identified as the

cause of seabather eruption in southern Florida and the
Caribbean. Similar outbreaks on Long Island, New York, are
thought to be caused by larvae of Edwardsiella lineata.26
Treatment is symptomatic and includes antihistamines, topical antipruritic agents, and steroids.
swimmers itch
Figure 8 Seabathers eruption is characterized by the development of

pruritic papules on areas covered by the patients bathing suit.
North America, C. cuterebra and C. dermatobia cause furuncular

cutaneous infestations.
The skin lesions appear as nonhealing single or multiple
nodules on the upper trunk, usually at the site of a painful bite
wound. Skin lesions may be misdiagnosed as cellulitis, boils, or
sebaceous cysts. Myiasis is commonly reported in travelers to
endemic areas such as Central and South America and tropical
and subtropical Africa. Preventive measures include the use of
insect repellents, the wearing of protective clothing to prevent
mosquito bites, and the avoidance of direct skin contact with
sand that may be infested with eggs.
The condition is effectively treated by removal of the larvae
by incision and drainage with debridement. Antibiotics are
prescribed for secondary bacterial infection. Occlusion with
such agents as liquid paraffin, lubricating jelly, and even the
fatty portion of raw bacon has been suggested to cause suffocation of the larvae or migration of the larvae from the wound.23
cutaneous larva migrans
Cutaneous larva migrans is caused by penetration and migration of larval hookworms (usually Ancylostoma braziliense)
within the skin. Patients are usually travelers returning from
seawater beaches in tropical areas and commonly present to
the dermatologist with pruritic skin lesions. The abdomen or
feet are most often involved, with a characteristic eruption consisting of one or several erythematous linear to serpiginous
thin lines in the skin.
Treatment includes oral thiabendazole, 25 to 60 mg/kg for 2 to
4 days only. This drug may cause side effects such as headaches,
nausea, and vomiting. Oral albendazole has a high cure rate in a
dosage of 400 mg for 5 consecutive days. Oral ivermectin is reportedly effective in a single dose of 150 to 200 g/kg.24
Cercarial dermatitis, known as swimmers itch, is caused by

an avian schistosome, Microbilharzia variglandis. The skin eruption appears approximately 12 hours after contact with seawater as a pruritic papulovesicular dermatitis on exposed skin
sites.27 The inflammatory response is attributed to dermatologic penetration by cercariae, which are the free-swimming larvae of M. variglandis and other bird schistosomes.
Treatment is symptomatic and includes antihistamines, topical antipruritic agents, topical corticosteroids, and antibiotic
treatment of superimposed bacterial infection.
cutaneous and mucocutaneous leishmaniasis
There are distinctive skin lesions associated with the cutaneous and mucocutaneous forms of leishmaniasis [see Figure 9].
Leishmaniasis is caused by an obligate intracellular parasite introduced by the Phlebotomus sandfly that feeds on infected animals. Leishmania braziliensis and L. mexicana are the most common causes of American, or New World, leishmaniasis. L.
donovani causes Old World leishmaniasis, which is endemic in
Asia and West Africa [see Section 7, Subsection XXXIV].
Cutaneous leishmaniasisthe initial, or primary, form of the
diseaseappears as a localized, usually single, lesion involving
the mouth and nose. A red-brown papule develops at the site of
inoculation into a nodule that becomes verrucous or ulcerates,
and satellite nodules may form. Spontaneous healing with an atrophic scar occurs in most cases. Old World leishmaniasis is usually limited to the skin, whereas New World leishmaniasis can
cause mutilating mucocutaneous involvement.28 After a period of
months to years, the mucocutaneous, or secondary, form of the
disease may develop, depending on host immunologic factors.
Lesions in this stage range from edema of the lips and nose to
perforation of the nasal cartilage. A rare form, disseminated cutaneous leishmaniasis, which has widespread nodules resembling
lepromatous leprosy, may occur in immunosuppressed patients.
The differential diagnosis includes various inflammatory and
seabathers eruption
Seabathers eruption, also known as sea lice by laypersons, is
an acute pruritic dermatitis that occurs within 24 hours of seawater exposure and resolves spontaneously after 3 to 5 days.25
Lesions affect areas of the skin covered by swimwear, particularly those that are subjected to pressure or friction, such as the
waistline, axillae, neck, and inner thighs [see Figure 8]. The larvae of the thimble jellyfish Linuche unguiculata, which are
March 2001 Update
Figure 9 Leishmaniasis can present as chronic cutaneous ulcerations.

ACP Medicine
neoplastic disorders, including squamous cell carcinoma. Diagnosis is made by skin biopsy with histopathologic examination. Appropriate therapy depends on species identification. A
pentavalent antimony compound, such as sodium stibogluconate, is the drug of choice for New World leishmaniasis, which
tends to be more aggressive. Lesions acquired in the Middle
East and North Africa may spontaneously involute or may respond to local therapy, including cryosurgery, heat therapy, or
intralesional injection of antimonials.
Delusions of Parasitosis
Patients with delusions of parasitosis express the conviction
that there are scabies, insects, lice, fleas, worms, or other vermin
infesting their skin and producing a crawling, itching, or prickling sensation.29 They may have excoriations or skin inflammation and erosions consistent with factitial dermatitis. Frequently, patients will bring small containers filled with lint, hairs,
pieces of skin, fibers, or other debris for examination. Despite
the lack of objective evidence for infestationincluding negative results from clinical examination, microscopic examination
of skin scrapings, and skin biopsythe delusions persist. Associated underlying psychiatric disturbances may range from a
phobic-obsessive state or anxiety reaction to a frank psychosis
with either depression or paranoia. Not infrequently, the delusion is shared by the spouse or other family members, as in the
classic folie deux or folie famille. The patient usually functions in a highly organized manner in other aspects of his or her
life. Such patients typically resist seeking psychiatric evaluation.
Treatment with pimozide, a high-potency antipsychotic
neuroleptic of the diphenylbutylpiperidine group, has been
used successfully.29 The effectiveness of the drug may be mediated by its ability to specifically block central dopamine receptors. As is characteristic of high-potency antipsychotic drugs,
pimozide has fewer cardiovascular and anticholinergic effects
but greater neurologic toxicity, especially with long-term use,
than does low-potency antipsychotic drugs. Tardive dyskinesia, an extrapyramidal syndrome characterized by involuntary
movements of facial muscles and extremities, may occur in
10% to 20% of patients on antipsychotic drugs. Other side effects may include skin discoloration, dermatitis, and blurred
vision. Thorough medical and psychiatric evaluation should be
obtained before antipsychotic medication is instituted.

March 2001 Update
References
1. Lucchina LC, Wilson ME, Drake LA: Dermatology and the recently returned traveler: infectious diseases with dermatologic manifestations. Int J Dermatol 36:167, 1997
2. Hoke AW, Maibach HI: Scabies management: a current perspective. Cutis 64:2, 1999
3. Holness DL, DeKoven JG, Nethercott JR: Scabies in chronic health care institutions.
4. Orkin M: Scabies in AIDS. Semin Dermatol 12:9, 1993
5. Head ES, Macdonald EM, Ewert A, et al: Sarcoptes scabiei in histopathologic sections
of skin in human scabies. Arch Dermatol 126:1475, 1990
6. Taplin D, Meinking TL: Pyrethrins and pyrethroids in dermatology. Arch Dermatol
126:213, 1990
7. Schultz MW, Gomez M, Hansen RC, et al: Comparative study of 5% permethrin
cream and 1% lindane lotion for the treatment of scabies. Arch Dermatol 126:167, 1990
8. Tenenbein M: Seizures after lindane therapy. J Am Geriatr Soc 39:394, 1991
9. Meinking TL, Taplin D, Hermida JL, et al: The treatment of scabies with ivermectin.
N Engl J Med 333:26, 1995
10. Usha V, Gopalakrishnan Nair TV: A comparative study of oral ivermectin and topical permethrin cream in the treatment of scabies. J Am Acad Dermatol 42:236, 2000
11. Youssef MYM, Sadaka HAH, Eissa MM, et al: Topical application of ivermectin for
human ectoparasites. Am J Trop Hyg 53:652, 1995
12. Purvis RS, Tyring SK: An outbreak of lindane-resistant scabies treated successfully
with permethrin 5% cream. J Am Acad Dermatol 26(pt 1):1015, 1991
13. Paasch U, Haustein U-F: Management of endemic outbreaks of scabies with allethrin, permethrin, and ivermectin. Int J Dermatol 39:463, 2000
14. Alberici F, Pagani L, Ratti G, et al: Ivermectin alone or in combination with benzyl
benzoate in the treatment of human immunodeficiency virus-associated scabies. Br J
Dermatol 142:969, 2000
15. Lee BW: Cheyletiella dermatitis: a report of fourteen cases. Cutis 47:111, 1991
16. Elston DM: Whats eating you? Pediculus humanus (head louse and body louse).
Cutis 63:259, 1999
17. Downs AM, Stafford KA, Harvey I, et al: Evidence for double resistance to permethrin and malathion in head lice. Br J Dermatol 141:508, 1999
18. Roberts RJ, Casey D, Morgan DA, et al: Comparison of wet combing with
malathion for treatment of head lice in the UK: a pragmatic randomised controlled trial.
Lancet 356:540, 2000
19. Mumcuoglu KY: Prevention and treatment of head lice in children. Paediatr Drugs
1:211, 1999
20. Hutchins ME, Burnett JW: Fleas. Cutis 51:241, 1993
21. Campos Macias P, Mendez Sashida P: Cutaneous infestation by Tunga penetrans. Int
J Dermatol 39:296, 2000
22. Burnett JW: Myiasis. Cutis 46:51, 1990
23. Brewer TF, Wilson ME, Gonzalez MD, et al: Bacon therapy and furuncular myiasis.
JAMA 270:2087, 1993
24. Caumes E, Carriere J, Datry A, et al: A randomized trial of ivermectin versus albendazole for the treatment of cutaneous larva migrans. Am J Trop Med Hyg 49:641, 1993
25. Tomchik RS, Russell MT, Szmant AM, et al: Clinical perspectives on seabathers
eruption, also known as sea lice. JAMA 269:1669, 1993
26. Freudenthal AR, Joseph PR: Seabathers eruption. N Engl J Med 329:542, 1993
27. Cercarial dermatitis outbreak at a State ParkDelaware, 1991. JAMA 267:2581,
1992
28. Koff AB, Rosen T: Treatment of cutaneous leishmaniasis. J Am Acad Dermatol
31:693, 1994
29. Driscoll MS, Rothe MJ, Grant-Kels JM, et al: Delusional parasitosis: a dermatologic,
psychiatric, and pharmacologic approach. J Am Acad Dermatol 29:1023, 1993
ACP Medicine
IX
VESICULOBULLOUS DISEASES

Jean-Claude Bystryn, m.d.
Vesiculobullous diseases, which number more than 50, are characterized by fluid-filled blisters in the skin. Blisters smaller than
0.5 cm are called vesicles, and larger ones are called bullae. Vesicles and bullae are reaction patterns of skin to injury and thus
can be caused by a wide variety of conditions.
Most primary vesiculobullous diseases are either immunologic or genetic. They are caused by autoimmune reactions to components of skin, by allergic reactions to external agents in which
the skin is the major organ system affected, and by genetic conditions in which some components of the skin are missing or abnormal. The final common pathway is disadhesion: one or more
of the structures that hold the skin together separate, and a fluidfilled cavity appears. The different diseases are classified by the
structure or structures affected and the mechanism or mechanisms by which disadhesion occurs [see Table 1]. In this subsection, several paradigmatic vesiculobullous diseases are discussed in the context of a general diagnostic approach to the patient with blistering lesions.
General Clinical Assessment
Diagnosis is based on clinical features, histologic findings, and
immunologic findings. Clinical features of diagnostic importance include the following:
1. The history. Is the condition acute or chronic? Is it aggravated by sun or physical trauma?
2. The appearance of individual lesions [see Table 2]. Is the lesion
a vesicle or bulla? Is it tense, flaccid, or umbilicated? Does the
skin at the base of the blister appear normal, urticarial, or
scarred? Is the border of each urticarial lesion annular or oval
or is it irregular? Is the blister in the middle of urticarial
plaques or on the periphery? Do more than one bulla arise
from the same plaque?
3. The grouping of individual lesions. Are the lesions in closely spaced groups (as occurs in herpes simplex), or are they
randomly distributed?
4. Sites of involvement. Are lesions on mucosal surfaces as
well as on the skin? Are they predominantly on flexural or
extensor surfaces; on the palms and soles or on the dorsa of
the hands and feet; on the scalp, face, and upper torso; or
on areas exposed to trauma?
The most important histologic finding is the layer of skin
where the blister forms. If the blister forms in the epidermis,
does it form immediately above the basal cell layer or higher up
(beneath the stratum corneum)? If it forms in the basement
membrane zone, is it within the lamina lucida or below the lamina densa? The precise location may be determined by immunofluorescence or by electron microscopic procedures.
The most important immunologic finding is the presence or
absence of abnormal circulating or tissue-fixed antibodies to
skin. These are usually detected by immunofluorescence techniques: (1) indirect immunofluorescence to detect circulating antibodies and (2) direct immunofluorescence on skin biopsy specimens to detect tissue-fixed antibodies. Recently, enzyme-linked
immunosorbent assays (ELISAs) using purified antigens have
July 2003 Update
become available to detect the antibodies that occur in some of

the bullous diseases, such as pemphigus.
Pemphigus
definition and pathogenesis
Pemphigus is characterized by blisters that arise within the
epidermis and by a loss of cohesion of the epidermal cells (acantholysis) that results in the formation of clefts above the basal cell
layer. Autoantibodies directed against adhesion molecules cause
epidermal keratinocytes to separate, resulting in intraepidermal
bullae. There are two types of pemphigus: deep (e.g., pemphigus
vulgaris) and superficial (e.g., pemphigus foliaceus). They differ
in the epidermal layers that are injured, in the clinical manifestations of the diseases, and in the associated immunologic abnormalities.1 In the deep forms, the blisters form immediately above
the basal cell layer and are associated with autoantibodies to
desmoglein 3; about half the cases are associated with antibodies
to desmoglein 1 glycoprotein keratinocyte adhesion molecules.2
In the superficial forms, the bullae form immediately below the
stratum corneum. The superficial forms of pemphigus are associated with antibodies to desmoglein 1.
clinical features
Pemphigus Vulgaris
Pemphigus vulgaris is the most common form of pemphigus. It can develop at any age but usually occurs in persons between 30 and 60 years old. The disorder tends to affect persons
of Mediterranean ancestry but can occur in persons of any ethnicity. Pemphigus is more common in persons with certain
HLA allotypes. The occurrence of the disease in first-degree
relatives, although rare, suggests an inherited susceptibility
transferred as a dominant trait. However, other unknown factors are required for expression of the disorder in predisposed
persons.3 Studies of HLA class II alleles in Japanese patients as
well as in other ethnic groups show an association with HLADRB1*04 and HLA-DRB1*14 in patients with pemphigus vulgaris across racial lines.4
Pemphigus vulgaris usually, but not invariably, begins with
chronic, painful, nonhealing ulcerations in the oral cavity [see
Figure 1]. Bullae are rarely seen because they rupture easily, leaving ulcerated bases. The ulcerations are usually multiple, superficial, and irregular in shape. Any oral mucosal surface can be involved, but the most common sites are the buccal and labial mucosae, the palate, and the gingiva. The occurrence of multiple
ulcerations differentiates these lesions from ulcerated malignant
tumors of the oral cavity, which are usually single. A diagnosis
of pemphigus is usually considered only after lesions have been
present for weeks to months.
Skin lesions can also be the initial manifestation, beginning
as small fluid-filled bullae on otherwise normal-looking skin.
The blisters are usually flaccid because the thin overlying epidermis cannot sustain much pressure. Bullae therefore rupture
rapidly, usually in several days, and may be absent when a patient is examined. Sharply outlined, coin-sized, superficial erosions with a collarette of loose epidermis around the periphery
of the erosions may appear instead. The upper chest, back,
ACP Medicine
DERMATOLOGY:IX Vesiculobullous Diseases1
scalp, and face are common sites of involvement, but lesions

can occur on any part of the body. The condition progresses
over weeks to months [see Figure 2]. Sites often overlooked in-
clude the periungual areas (manifested as painful, erythematous, paronychial swelling), the pharynx and larynx (pain on
swallowing and hoarseness), and the nasal cavity (nasal con-
Table 1 Differentiating Features and Standard Therapy for Selected Blistering Diseases
Disease
Features
Therapy
Chronic, painful ulcerations in the oral cavity; small, flaccid bullae or

coin-sized superficial erosions arising from normal skin; positive
Nikolsky sign; IgG and C3 at intercellular spaces; serum antidesmoglein 1 or 3 antibodies
Hypertrophic proliferation of epidermis in intertriginous areas; IgG
and C3 at intercellular spaces; serum antidesmoglein 3 antibodies
Localized: Intralesional or topical corticosteroids, low-dose systemic corticosteroids

Extensive or rapidly progressive disease: corticosteroids, adjuvant therapy with cytotoxic and immunosuppressive agents
Refractory disease: plasmapheresis, IVIg,
pulse therapy with megadoses of I.V.
methylprednisolone
Small, pruritic, crusted lesions on upper torso, face, or scalp; chronic

superficial erosions; rare oral involvement; immunopathology
higher in epidermis
Erythematous scaly to crusted eruption on face and upper chest;
lupuslike immunologic abnormalities (granular deposits of IgG
and C3 at epidermal-dermal junction)
Features similar to pemphigus foliaceus (primarily affects persons
< 30 yr in rural areas of Brazil, Colombia, Tunisia)
Localized: Intralesional or topical corticosteroids, low-dose systemic corticosteroids

Extensive or rapidly progressive disease: corticosteroids, adjuvant therapy with cytotoxic and immunosuppressive agents
Paraneoplastic mixed
bullous disease (paraneoplastic pemphigus)
Large, tense bullae; target lesions on skin; oral erosions; keratinocyte

necrosis; clinical features overlap between pemphigus and erythema multiforme; subepidermal separation; IC and BMZ antibodies
on direct IF
Difficult (standard treatments for autoimmune blistering diseases fail in most

patients)
Hailey-Hailey disease
Multiple vesicles on inflammatory bases in intertriginous areas and

other areas subject to friction or pressure; loss of bridges between
epidermal cells; no circulating or tissue-fixed autoantibodies
Involved areas kept dry and free of friction;

administration of topical and systemic
antibiotics; topical, intralesional corticosteroids; ablation of involved areas
Bullous pemphigoid
Crops of large, tense blisters recurring from urticarial plaques on

torso and flexures; negative Nikolsky sign; oral lesions (10%25%
of patients); circulating BMZ antibodies; IgG and C3 at BMZ in a
linear pattern on direct IF
Administration of systemic corticosteroids

at doses lower than those used for pemphigus ( 80 mg/day prednisone) [see also
Bullous Pemphigoid, Treatment, in text]
Cicatricial pemphigoid
Blisters on mucosal surfaces (oral cavity, esophagus, eyes) that heal

with scarring, often occurring repeatedly at same site; diffuse, painful erythema and atrophy of the gingival mucosa; IgG and C3 at
BMZ in a linear pattern on direct IF
Combination therapy with systemic corticosteroids and dapsone or azathioprine;

long-term therapy with systemic corticosteroids, sometimes combined with immunosuppressive agents; intralesional
corticosteroids
Herpes gestationis
Pruritic urticarial plaques occurring in pregnancy (beginning around

the umbilicus, spreading to abdomen and thighs); laminal blisters
with linear deposits of C3 or IgG at the epidermal-dermal junction;
circulating complement-fixing BMZ antibodies on indirect IF
Normally clears after delivery
Clusters of intensely pruritic, small, polymorphic vesicles on elbows,

knees, buttocks, scapular area, and scalp; accumulations of neutrophils and eosinophils in dermal papillae; granular deposits of IgA
in BMZ; no circulating antibodies to normal skin components
Administration of sulfones (dapsone, 100

200 mg/day; sulfapyridine, 13 g/day in
divided doses; or sulfamethoxypyridazine); reduction of gluten intake
Linear IgA dermatosis
Blisters resembling those of dermatitis herpetiformis or erythema

multiforme; linear deposition of IgA in BMZ on direct IF
Administration of sulfones
Erythema multiforme
Sudden eruption of crops of lesions on elbows, knees, hands, and

feet; target papule or vesicle with halo of erythema; subepidermal
edema, deep perivascular inflammatory infiltrate
Elimination of underlying causes (e.g., infectious agents, drugs); in mild cases, topical glucocorticoids, anti-inflammatories,
antipruritics, antibiotics; in severe cases,
prednisone 40120 mg/day in divided
doses
Toxic epidermal
necrolysis
Rapidly progressive painful denudation of epithelium (usually a drug

reaction); full-thickness epidermal necrosis; absence of immune
reactants within skin blood vessels; little dermal inflammation
Meticulous wound care with debridement

of necrotic tissue, fluid and electrolyte
replacement, and prevention of sepsis;
IVIg 56
Staphylococcal scalded
skin syndrome
Scarlatiniform eruption accompanied by skin tenderness, fever, and

irritability; lack of mucous membrane involvement or target lesions
Intravenous penicillinase-resistant
penicillins
Epidermolysis bullosa
[See Epidermolysis Bullosa, in text]
Supportive therapy; counseling; promotion

of wound healing; prevention of
complications
Pemphigus vulgaris
Pemphigus vegetans
Subepidermal
Epidermal
Pemphigus foliaceus
Pemphigus
erythematosus
Fogo selvagem
BMZbasal membrane zone ICintercellular IFimmunofluorescence IVIgintravenous immunoglobulin

July 2003 Update
ACP Medicine
Table 2 Pathologic Typology of Blisters57

Blister Type
Mode of Formation
Site of Formation
Disease
Subcorneal blister
Detachment of horny layer
Epidermis (subcorneal layer)
Miliaria crystallina
Impetigo
Blister due to intracellular

degeneration
Separation of cells from one another
Upper epidermis
Friction blisters
Spongiotic blister
Intercellular edema
Epidermis
Dermatitis (eczema)
Miliaria rubra
Acantholytic blister
Dissolution of intercellular bridges
Epidermis (suprabasal layer)
Keratosis follicularis (Darier disease)

Pemphigus vulgaris
Epidermis (subcorneal layer)
Pemphigus foliaceus
Ballooning degeneration leading to

acantholysis
Epidermis
Herpes simplex
Herpes zoster
Varicella
Cytolysis of basal cells
Basal cell layer
Epidermolysis bullosa simplex

Erythema multiforme (epidermal type)
Loss of dermal contact by damaged

basal cells
Basal cell layer
Lichen planus
Lupus erythematosus
Blister due to degeneration

of basement membrane
zone
Damage in the structures that cause

coherence of basal cells
Basement membrane zone
Bullous pemphigoid
Erythema multiforme (dermal type)
Dermolytic blister
Anchoring fibrils are decreased and

rudimentary
Dermis
Dystrophic epidermolysis bullosa

Acquired epidermolysis bullosa
Viral blister
Blister due to degeneration

of basal cells
gestion and a bloody mucous discharge, particularly noticeable

upon blowing the nose in the morning).
A characteristic feature of all severe active forms of pemphigus is the Nikolsky sign, in which sliding firm pressure on normal-appearing skin causes the epidermis to separate from the
dermis. The Nikolsky sign is elicited most easily on clinically uninvolved skin adjacent to an active lesion.
If left untreated, the erosions and bullae of pemphigus vulgaris gradually spread, involving an increasing surface area,
and can become complicated by severe infections and metabolic disturbances. Before the advent of corticosteroids, pemphigus was almost invariably fatalapproximately 75% of patients died within a year.5 However, as better techniques have
permitted the diagnosis of earlier, milder forms of the disease,
the prognosis has improved significantly.6 Mild forms may
regress spontaneously, and the progression of even the most
severe forms can be reversed in most cases. With treatment (see
below), lesions normally heal without scarring. Most patients
treated for pemphigus will enter a partial remission within 2 to
5 years. They can then be maintained lesion-free with minimal
doses of corticosteroids (approximately 15 mg of prednisone
daily). In a longitudinal study of outcome in 40 patients with
pemphigus vulgaris, 45% entered a complete and long-term remission after 5 years and 71% after 10 years. Patients in remission remained lesion-free without any therapy.7 The hyperpigmentation that is commonly associated with pemphigus usually resolves after several months.
In pregnancy, pemphigus appears to be associated with an
increased incidence of premature delivery and fetal death.8
The lesions of pemphigus can appear on the skin of the
neonate; however, they normally resolve spontaneously in
several weeks.
July 2003 Update
Pemphigus Foliaceus
Pemphigus foliaceus is the second most common form of
pemphigus. It usually begins with small (approximately 1 cm),
pruritic, crusted lesions resembling corn flakes on the upper torso and face. The crusts are easily removed, leaving chronic, superficial erosions.
Over weeks to months, the condition progresses, with an increasing number of lesions appearing on the upper torso, face,
and scalp. In extensive cases, lesions develop over the entire
body, become confluent, and can progress to an exfoliative erythroderma. In contrast to the deep forms of pemphigus, oral involvement in pemphigus foliaceus is very rare.
The prognosis of untreated pemphigus foliaceus is more favorable than that of pemphigus vulgaris. The lesions of pemphi-
Figure 1 Painful ulcerations or erosions in the mouth may be present

many months before the onset of generalized pemphigus vulgaris.
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Paraneoplastic Mixed Bullous Disease

Paraneoplastic pemphigus is an autoimmune disease of the
skin and oral mucosa that develops in patients with an underlying neoplasm. It is characterized by large, tense bullae. Unfortunately, standard treatments for autoimmune blistering diseases
fail in most cases. Paraneoplastic pemphigus shares clinical features of both pemphigus and severe erythema multiforme.12
Hailey-Hailey Disease
Familial benign chronic pemphigus, or Hailey-Hailey disease,
is an autosomal dominant disorder marked by multiple vesicles
on inflammatory bases in skin subject to friction or pressure,
such as intertriginous areas. In addition to pharmacologic treatment (see below), therapy includes keeping involved areas dry
and free of friction.
Figure 2 Flaccid bullae of pemphigus vulgaris have broken down to
form erosions and crusts, particularly under the breasts.
gus foliaceus are not as deep, and there is less chance for infection, fluid loss, and metabolic disturbance. Although pemphigus
foliaceus is less severe, the doses of medications required for
control are similar to those used for pemphigus vulgaris. There
are two clinical variants: pemphigus erythematosus and fogo
selvagem. Pemphigus erythematosus (also known as SenearUsher syndrome) has features of lupus erythematosus. Fogo selvagem (Portuguese for wild fire; also known as endemic pemphigus and Brazilian pemphigus) [see Table 1] may be triggered
by exposure to one or more environmental antigens.9
Drug-Related Pemphigus
Both pemphigus vulgaris and pemphigus foliaceus can be either induced or triggered (i.e., latent disease unmasked) by certain drugs. Pemphigus that continues after a patient stops using
a drug is referred to as triggered, whereas lesions that clear soon
after withdrawal are referred to as induced. Although drug-related pemphigus is uncommon, its possibility must be excluded
in all patients with newly diagnosed disease. The clinical, histologic,10 and immunofluorescence abnormalities11 of drug-induced
pemphigus are similar to those of the idiopathic variety. However, pemphigus caused by drugs containing a sulfhydryl radical
(thiol drugs) is clinically distinct from pemphigus caused by
nonthiol drugs. The presence or absence of a sulfhydryl radical
appears to influence both the type of pemphigus that is expressed and the prognosis of the drug-induced condition. Thiol
drugs are more likely to induce pemphigus foliaceus, which is
more likely to regress spontaneously when the drug is discontinued [see 2:VI Cutaneous Adverse Drug Reactions]. Nonthiol drugs
are more likely to trigger pemphigus vulgaris, which can persist
even after the drug is stopped. The most commonly implicated
agents are thiol drugs such as penicillamine and captopril. Other
responsible drugs include sulfur-containing drugs such as penicillins and cephalosporins. These undergo metabolic changes to
form thiol groups and are termed masked thiol drugs. Nonthiol
drugs that contain an amide group (e.g., dipyrone and enalapril)
can provoke a disease that is indistinguishable from spontaneously occurring pemphigus vulgaris.11
Endemic Pemphigus
Epidemiologic features of fogo selvagem in rural areas of
Brazil suggest that the production of pathologic antibodies to
desmoglein 1 is linked to exposure to one or more environmental antigens.9
July 2003 Update
histologic and immunologic findings

The diagnosis should always be confirmed by histopathologic
examination and immunofluorescence studies.13 Biopsies for
pemphigus and all other bullous diseases should be performed at
the edge of a lesion, so as to include clinically uninvolved adjacent skin. Acantholysis (the separation of keratinocytes from each
other) is the fundamental abnormality in all forms of pemphigus.
All forms of pemphigus are associated with circulating and
tissue-fixed intercellular (IC) autoantibodies that react against
cell-surface keratinocyte antigens. The detection of these antibodies is very helpful in establishing the diagnosis, because
they rarely appear in other conditions. Circulating IC autoantibodies are detected by indirect immunofluorescence assays on
serum, and tissue-fixed IC autoantibodies are detected by direct immunofluorescence on skin biopsies. In both cases, they
cause a lacelike pattern of fluorescence within the epidermis.
Low titers of IC autoantibodies may also be present in burns,
fungal infections, and allergic drug reactions. Antibodies against
ABO blood group antigens, which are present in approximately 5% of the normal population, are the most common cause of
false positive tests for IC autoantibodies. Tissue-fixed IC autoantibodies are present in lesions and adjacent normal skin
in approximately 90% of patients with pemphigus and are
more sensitive and specific for the diagnosis of pemphigus
than are circulating IC autoantibodies. The most common autoantibodies are IgG, but IgM and IgA (with or without C3)
may also be deposited.
treatment
Initial Therapy
Initial therapy is determined by the extent and rate of progression of lesions. Localized, slowly progressive disease can be
treated with intralesional injections of corticosteroids (triamcinolone acetonide, 10 to 20 mg/ml) or topical application of highpotency corticosteroids. New lesions that continue to appear in
increasing numbers can be controlled in some cases with lowdose systemic corticosteroids (prednisone, 20 mg/day). Patients
with extensive or rapidly progressive disease are treated with
moderately high doses of corticosteroids (prednisone, 70 to 90
mg/day). This dose is rapidly escalated every 4 to 14 days in
50% increments until disease activity is controlled, as evidenced
by an absence of new lesions and the disappearance of skin pain
or itching. If the disease remains active despite high doses of corticosteroids (e.g., 120 to 160 mg/day of prednisone), one of the
following approaches should be considered for rapid control:
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1. Plasmapheresis, normally performed three times a week

for removal of 1 to 2 L of plasma per procedure.14
2. Intravenous immunoglobulin (IVIg), usually given at a
dosage of 400 mg/kg/day for 5 days or in higher doses for
3 days.15 The procedure may need to be repeated every 2 to
3 weeks for several cycles. It is very expensive. The use of
IVIg for the treatment of skin diseases has recently been reviewed.16 With both IVIg and plasmapheresis it is important to concurrently administer an immunosuppressive
agent such as cyclophosphamide or azathioprine to minimize rebound in the level of pemphigus antibodies,14 and it
is also important to monitor the level of these antibodies to
ensure that the patient is responding to treatment.
3. Pulse therapy with megadoses of intravenous methylprednisolone, given at a dosage of 1 g/day for 5 days.17
No comparative studies have yet evaluated the relative effectiveness of these procedures. On the basis of such limited experience, IVIg may be preferred because it has fewer side effects than
the other procedures and is associated with a significantly higher
response rate. Once disease activity is controlled, the patient is
maintained on the type and dose of medications required to establish control until approximately 80% of lesions are healed.
Therapy should not be tapered while new lesions are appearing.
Rituximab, an anti-CD20 chimeric monoclonal antibody, is
approved for use in non-Hodgkin lymphoma. However, there is
a case report of partial remission from recalcitrant, life-threatening pemphigus vulgaris after treatment with rituximab.18
Adjuvant Therapy
The role of adjuvants in the treatment of pemphigus remains
controversial. Because of a lack of controlled studies, it is not
known whether the potential benefits of adjuvants outweigh the
additional toxicities.5 Indications for adjuvant therapy include
the presence of relative contraindications to systemic corticosteroids, development of serious corticosteroid side effects, and
repeated flares of disease activity that make it undesirable to reduce corticosteroid doses.7 Because they require 4 to 6 weeks to
become effective, adjuvants are not used to control active, rapidly progressive disease.
Adjuvant treatments for pemphigus include a variety of cytotoxic and immunosuppressive agents (e.g., cyclophosphamide, azathioprine, cyclosporine, methotrexate, and mycophenolate mofetil19);
dapsone; anti-inflammatory agents (e.g., gold); antimalarials; and
certain antibiotics (e.g., tetracycline and minocycline).
Bullous Pemphigoid
pathogenesis
The immediate cause of bullous pemphigoid (BP) appears to
be an autoantibody response to the 180 kd (BP180) and 230 kd
(BP230) basement membrane zone antigens.20 Passive transfer of
these antibodies into animals can cause lesions of the disease21;
anti-BP180 autoantibodies have been found to be a poor prognostic factor in a study of 94 elderly patients.22
clinical features
BP is a nonscarring, subepidermal blistering disease that is
characterized by recurrent crops of large, tense blisters arising
from urticarial bases. Lesions normally appear on the torso and
flexures, particularly on the inner thighs. Blisters can range in size
from a few millimeters to several centimeters [see Figure 3]. They
July 2003 Update
Figure 3 Tense bullae characteristically occur in bullous

pemphigoid.
are usually filled with a clear fluid, but they can be hemorrhagic.
Erosions are much less common than in pemphigus, and the
Nikolsky sign is negative. A characteristic feature is that multiple
bullae usually arise from large (palm-sized or larger), irregular,
urticarial plaques. This is in contrast to the bullae of erythema
multiforme (see below); in erythema multiforme, a single bulla
arises from the center of a smaller (coin-sized) urticarial base.
In acute flares of BP, bullae may arise from normal-appearing
skin. Oral lesions occur in 10% to 25% of patients; ocular involvement, however, is rare. Without treatment, the disease may become very extensive.
BP is a sporadic disease that occurs mainly in the elderly but
can occur at any age and in any race. It has been reported in a 2month-old infant.23 Precipitating factors include trauma, burns,
ionizing radiation, ultraviolet light, and certain drugs. In a casecontrol study of 116 incident cases, neuroleptics and diuretics
particularly aldosterone antagonistswere more commonly
used by patients who developed BP than by control subjects.24
There is still controversy as to whether BP is associated with an
increased incidence of cancer25; however, correlations between
flare in disease activity and recurrence of underlying cancer suggest such an association in individual patients.
BP is characterized by spontaneous remissions followed by
flares in disease activity that can persist for years. Even without
therapy, BP is often self-limited, resolving after a period of many
months to years. The disease is nonetheless serious, particularly
in older patients who have been treated with high doses of oral
corticosteroids.26 Mortality is low in younger persons but is significant in the elderly. In one study of patients older than 68
years, nearly a third died of the disease or complications (mainly
sepsis and cardiovascular disease) within 1 year.22
The earliest lesion of BP is a blister arising in the lamina lucida, between the basal membrane of keratinocytes and the lamina
densa. This is associated with loss of anchoring filaments and
hemidesmosomes. Histologically, there is a superficial inflammatory cell infiltrate and a subepidermal blister without necrotic
keratinocytes. The infiltrate consists of lymphocytes and histiocytes and is particularly rich in eosinophils. There is no scarring.
Approximately 70% to 80% of patients with active BP have
circulating antibodies to one or more basement membrane zone
antigens. On direct immunofluorescence, the antibodies are deACP Medicine
posited in a thin linear pattern; and on immune electron microscopy, they are present in the lamina lucida. By contrast, the
antibodies to basement membrane zone antigens that are
present in the skin of patients with systemic lupus erythematosus are deposited in a granular pattern.
Two less common subepidermal blistering diseases that are
closely related to BP are cicatricial mucous membrane pemphigoid and herpes gestationis [see Table 1]. The differential diagnosis also includes dermatitis herpetiformis and acquired epidermolysis bullosa (see below). Scar formation in mucous membrane pemphigoid and acquired epidemolysis bullosa can lead
to major disability.27
treatment
Treatment of BP is generally similar to that of pemphigus.28
The differences are as follows: (1) BP normally, but not invariably, responds to lower doses of systemic corticosteroids (alone
or combined with other oral or topical agents), with most patients improving on prednisone at a dosage of 80 mg/day or less;
(2) in an open prospective study of 18 cases, low-dose methotrexate was shown to be effective for maintenance of clinical
remission induced by initial short-term use of potent topical
steroids29; and (3) BP is more likely to respond to dapsone30 or
to the combination of tetracycline and niacinamide.31,32 Considering that the prognosis of untreated BP is better than that of
pemphigus, side effects of treatment are of greater concern.
Two small studies of severe ocular mucous membrane pemphigoid suggest that this condition responds more favorably
to treatment with cyclophosphamide combined with prednisone, whereas dapsone suppresses some cases of mild to
moderate disease.27
Dermatitis Herpetiformis
Dermatitis herpetiformis (DH) is a rare vesiculobullous disease characterized by intensely pruritic, small vesicles that are
grouped in small clusters and typically appear on the extensor

aspects of the extremities and on the buttocks, scalp, and back.
The condition is believed to be an immune-mediated disorder
and is associated with abnormal granular deposits of IgA at the
basement membrane zone and with asymptomatic, gluten-sensitive, spruelike enteropathy. The disease is chronic, with periods of exacerbation and remission. Lesions may clear if patients
follow a strict gluten-free diet. Linear IgA dermatosis [see Table 1]
is an uncommon subepidermal blistering disease that may clinically resemble DH or erythema multiforme (see below).
pathogenesis
The cause of DH is unknown. It may be related to gluten-sensitive celiac disease; there is a strong association between the
two conditions, and they share a similar genetic basis (both are
associated with HLA-B8 and HLA-DR3). DH is thought to result from an abnormal IgA immune response to an unidentified
antigen (possibly found in gluten) that contacts the gut. Skin lesions may result from deposition of immune complexes against
this antigen in skin.
clinical features
Skin lesions of DH are polymorphic. They usually begin as
small, very pruritic urticarial papules or vesicles that are grouped
in a herpetiform pattern [see Figure 4]. Actual vesicles or other
primary lesions are rarely seen because they are excoriated by
patients scratching. The distribution of lesions is characteristic:
they occur most commonly on the elbows, knees, buttocks, scapular area, and scalp. Sometimes, lesions are scattered over the
entire body. The lesions tend to appear suddenly and symmetrically, sometimes after ingestion of large amounts of gluten. Lesions heal, leaving hyperpigmentation; scarring may result from
scratching or secondary infection. Involvement of mucous membranes is rare.
The disease is twice as common in men as in women. It predominantly affects persons between the ages of 20 and 50 years.
There may be an associated patchy duodenal and jejunal atrophy that resembles the gluten-sensitive enteropathy of adult celiac disease.33,34 The enteropathy is usually asymptomatic and, like
celiac disease, responds to gluten restriction. Because celiac disease is associated with gastrointestinal lymphoma, there is concern that the same may be true for DH. However, although lymphomas of the small intestine have been reported in DH,35 the association appears to be rare.
Figure 4 Dermatitis herpetiformis, an extremely pruritic eruption,

commonly presents as excoriated, grouped papulovesicles, often in a
symmetrical distribution.
July 2003 Update
Two characteristic laboratory features of DH are used for diagnosis. First, the disease is characterized histologically by accumulations of neutrophils and eosinophils in microabscesses at
the tips of dermal papillae. In more severe cases, edema appears
and can progress to subepidermal blisters appearing just below
the lamina densa. Secondly, granular deposits of IgA are found
at the basement membrane zone in almost all patients. These are
often associated with granular deposits of C3 and, occasionally,
of IgG and IgM. When found alone, IgA is one of the most sensitive and specific diagnostic markers for DH. When IgA is found
with deposits of IgG, IgM, or C3, immune complex vasculitis
and systemic lupus erythematosus are added to the differential
diagnosis. Although basement membrane zone deposits of IgA
alone also occur in linear IgA disease,36 the deposits in that condition are linear rather than granular. There are no circulating
antibodies to normal skin components in DH.
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treatment
DH responds rapidly and dramatically to sulfones. Dapsone
at a dosage of 100 to 200 mg/day is most commonly used for
treatment. Glucose-6-phosphate dehydrogenase (G6PD) deficiency must be excluded before starting therapy, because lack
of this enzyme can result in severe drug-induced anemia. Sulfapyridine at a dosage of 1 to 3 g/day in divided doses (or sulfamethoxypyridazine) can be used in patients who cannot tolerate dapsone. Doses of these drugs are gradually reduced to
the lowest amount that will suppress pruritus and development of new lesions. As indicated, patients also respond to a
gluten-free diet; however, such diets are difficult to follow.
Nevertheless, even a partial decrease in gluten intake will result in a decreased requirement for sulfones and should therefore be encouraged.
Erythema Multiforme
Erythema multiforme is an acute, recurrent, self-limiting disease that affects all age groups and races. It is characterized by
the sudden eruption of crops of lesions, which represent a cellmediated hypersensitivity reaction of the skin and mucous
membranes to a variety of precipitating factors, including infectious agents and drugs [see Table 3].37 Recent or recurrent infection with herpes simplex virus is a principal risk factor for erythema multiforme.38
Table 3 Precipitating Factors in

Erythema Multiforme
Viral diseases
Herpes simplex
Hepatitis
Influenza A
Vaccinia
Mumps
Fungal diseases
Dermatophytoses
Histoplasmosis
Coccidioidomycosis
Bacterial diseases
Hemolytic streptococcal infections

Tuberculosis
Leprosy
Typhoid
Collagen vascular disorders
Rheumatoid arthritis
Systemic lupus erythematosus
Dermatomyositis
Allergic vasculitis
Polyarteritis nodosa
Malignant tumors
Carcinoma
Lymphoma after radiation therapy
Hormonal changes
Pregnancy
Menstruation
Drugs
Penicillins
Sulfonamides
Barbiturates
Salicylates
Halogens
Phenolphthalein
Miscellaneous
Rhus dermatitis
Dental extractions
Mycoplasma pneumoniae infection
clinical features
Lesions may be localized or widespread and may affect both
the skin and the mucous membranes. The eruption often occurs
bilaterally and symmetrically on the extensor surfaces of the extremities and on both the dorsal and the volar areas of the hands
and feet. Lesions vary from well-defined, red or purple, edematous macules and papules to vesicular or bullous lesions that
may ulcerate, encrust, erode, and become infected. A target lesion consisting of a papule or vesicle surrounded by a region of
normal skin and a halo of erythema at the periphery [see Figure 5]
is characteristic.
Stevens-Johnson syndrome is a severe form of erythema multiforme that is usually disseminated, fulminant, and multisystemic [see Figure 6]. The syndrome may be accompanied by high
fever, malaise, chills, headache, tachycardia, tachypnea, and prostration. Drugs are more commonly the underlying etiologic agent
than infection. Some of these include long-acting sulfonamides
(particularly trimethoprim-sulfamethoxazole), anticonvulsants,
barbiturates, and nonsteroidal anti-inflammatory drugs. The mucous membranes in the mouth, the anus, and the vagina contain
round or oval erythematous macules that form vesicles, bullae,
and ulcers. Ocular lesions are bilateral yellowish-gray papules
that often ulcerate and become secondarily infected, resulting in
conjunctivitis. Ocular involvement has produced blindness.
Toxic epidermal necrolysis (TEN) has a potentially fatal outcome because of detachment of large areas of epidermis. TEN is
considered by some to be a form of erythema multiforme, usually a reaction to medication. However, the absence of immune reactants within the blood vessels in the skin and the paucity of
dermal inflammation have led other researchers to consider
TEN a separate disease.
Staphylococcal scalded skin syndrome also causes large areas
of epidermal necrosis. This syndrome, which results from toxins
produced by Staphylococcus aureus,39 is sometimes confused with
TEN [see Table 1].
July 2003 Update

Characteristic cutaneous histologic findings of erythema multiforme include subepidermal edema, bulla formation, epidermal cell necrosis, and a deep perivascular inflammatory infiltrate
composed of mononuclear cells involving vessels in the upper
dermis. The chemokine profile, with dominance of lymphocytic
attractant chemokines at the dermoepidermal junction, is a feature of the interface dermatitis.40 There are no specific immunofluorescence findings and no circulating antibodies, although direct immunofluorescence may show granular deposits of C3 and
fibrin at the dermoepidermal junction and deposits of IgM, C3,
and fibrin in the dermal blood vessels.
In vitro studies suggest that different immunopathogenic
processes may be involved in herpes-mediated erythema multiforme and the drug-mediated forms of the disease.41
treatment
Erythema multiforme eruptions may recur without warning,
despite preventive measures. It is therefore important to identify
and eliminate underlying causes. Mild cases are treated symptomatically with topical glucocorticoids and topical anti-inflammatory, antipruritic, or antibiotic preparations. Oral acyclovir may
be effective in the prophylaxis of recurrent postherpetic erythema multiforme. In more severe cases, treatment with prednisone, 40 to 120 mg/day in divided doses, is indicated. If the eyes
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EB is classified primarily on the basis of an ultrastructural level of skin cleavage in the basement membrane zone [see Figure 7].
Three major subtypes include EB simplex or epidermolytic (intraepidermal), junctional EB (intralamina lucida), and dystrophic or dermolytic EB (sublamina densa). Electron microscopy
examination localizes the lesions to a specific layer.44 Because this
technology may not be widely available, immunofluorescence
mapping with monoclonal antibodies can be used to target components of the basement membrane layers such as BP antigen
(basal cell layer), laminin (lamina lucida), and type IV collagen
(lamina densa).45 The prenatal diagnosis may be made by immunocytochemical probes for antigenic components of the basement membrane in fetal skin biopsy, such as in the junctional EB
pyloric atresia syndrome.46
epidermolysis bullosa simplex
Figure 5 Target lesions are characteristic of erythema multiforme.

are involved, prompt ophthalmologic consultation should be obtained. Patients with large areas of epidermal necrosis (e.g., those
with Stevens-Johnson syndrome) may require specialized intensive care, such as in a burn unit.
Early treatment with high-dose IVIg has been reported to be
safe and effective in improving survival of patients with TEN.42
However, there is no standard treatment of TEN that can be
used as a basis for comparative studies.43
Epidermolysis Bullosa
Epidermolysis bullosa (EB) comprises a group of genetically
based disorders with a prevalence of approximately one in
500,000 persons. There are more than 20 different phenotypes of
EB, which may be inherited as an autosomal recessive trait.
These disorders are characterized by blistering and erosions that
arise after minor skin trauma or friction and heal with or without
scarring. Extent of involvement ranges from localized blisters
(e.g., on the palms and soles) to severe widespread sloughing of
the skin, with a risk of severe morbidity and mortality from secondary infection, fluid and electrolyte imbalance, anemia, or other complications.
Figure 6 Stevens-Johnson syndrome is a fulminating form of

erythema multiforme associated with marked mucocutaneous
involvement, eye involvement, and severe constitutional symptoms.

July 2003 Update
There are three major forms of EB simplex.47 The most common type is a mild autosomal dominant form that appears at birth
or shortly thereafter as either localized or generalized blisters
that do not usually result in scarring. A second type is WeberCockayne disease, which can be either localized or generalized.
In the localized form, blisters appear acrally on the palms and
soles during childhood or adolescence. In the generalized form,
disease activity is usually greater in a warm climate.
The Dowling-Meara variant (EB herpetiformis) is a less common form of EB simplex that presents as severe generalized blistering in infancy; it resembles recessive junctional and dystrophic EB. EB herpetiformis becomes less severe with age.
junctional epidermolysis bullosa
Junctional EB is a recessively inherited group of disorders that
exhibit a decreased number of hemidesmosomes and hypoplasia of hemidesmosomes, as revealed by electron microscopy,
and separation at the level of the lamina lucida. Mucosal involvement and dystrophic nails are common. The most severe
form, EB letalis, occurs within the first few days or months of life
and has a high mortality. Patients with EB letalis have a high incidence of respiratory arrest at an early age because of laryngeal
and tracheal involvement. Less severe forms of junctional EB exhibit severe generalized blistering at birth that gradually improves. Esophageal strictures may develop.
dystrophic epidermolysis bullosa
There are two forms of dystrophic EB that are inherited in
an autosomal dominant fashion. Hyperplastic EB dystrophica
(Cockayne-Touraine syndrome) appears in early infancy or
childhood as serosanguineous blisters, predominantly on extensor aspects of the lower extremities, in association with nail dystrophy. The albopapuloid type of EB dystrophica is characterized by white papules that develop during adolescence on the
trunk or extremities; however, blistering is present in the perinatal period. In both forms, ultrastructural examination reveals
sublaminal dermal separation, with abnormalities in anchoring
fibrils or a decrease in their number.
Recessive forms of EB dystrophica appear during the neonatal period as severe serosanguineous blistering that is either localized to sites of skin trauma or generalized. Milium formation
is uncommon, but lesional scarring may result. Other complications include dental abnormalities, nail dystrophy or loss, digital
fusion, flexion contractures, and esophageal strictures [see Figure
8]. Growth retardation, malnutrition, and chronic anemia also
occur. Patients with recessive EB dystrophica are at increased
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economic and social aspects of EB, and to register patients willing to participate in various research protocols.
acquired epidermolysis bullosa
Figure 7 Three major forms of epidermolysis bullosa (EB) have been

recognized: EB simplex, in which a split occurs within the basal cell
layer; junctional EB, which is characterized by separation within the
lamina lucida; and dystrophic EB, in which separation occurs below
the basement membrane zone.
risk for squamous cell carcinoma, with a high incidence of fatal

metastases.
Prenatal diagnosis of recessive dystrophic EB may be made
by fetoscopy and skin biopsy; ultrastructural analysis of the tissue reveals dermolytic blister formation. An alternative method
for prenatal diagnosis of recessive dystrophic EB involves testing
of chorionic villus samples for mutation and haplotype analysis
in the type VII collagen gene.48
Supportive treatment of EB is directed toward promotion of
wound healing and prevention of complications. Daily skin care
may include wet dressings or whirlpool baths, antibiotic ointment,
and nonadhesive dressings, such as fine-mesh gauze (N-terface).
A multidisciplinary approach that includes genetic counseling,
psychological or psychiatric counseling, and support systems for
the patient and family is essential, particularly for managing the
severe forms of the disease.
A national registry has been established by the Dystrophic
Epidermolysis Bullosa Research Association of America
(http://www.debra.org) to collect epidemiologic data, to assess
Figure 8 Recessive dystrophic epidermolysis bullosa may cause

severe scarring and syndactyly.

July 2003 Update
Acquired epidermolysis bullosa, or epidermolysis bullosa acquisita (EBA), is a trauma-induced blistering disorder in adults
who have no genetic basis for disease. Both circulating and tissuebound IgG antibasement membrane zone antibodies may be
demonstrated by immunohistology. The blisters develop below
the epidermis and heal with atrophic scars and malformation.
They are usually confined to the extremities at sites of mechanical
trauma. Oral lesions and nail dystrophy may be associated with
EBA. Underlying malignant, autoimmune, and inflammatory
diseases may be associated with this condition. The presence of
ulcerative colitis or Crohn disease in approximately 30% of cases
suggests that EBA should be included among the extraintestinal
manifestations of inflammatory bowel disease.49
The diagnosis is made by excluding other bullous disorders,
particularly BP (see above) and porphyria cutanea tarda. Immunoelectron microscopy may be used as an additional diagnostic
aid, although this technique may not be widely available. Direct
immunofluorescence with the use of salt-split skin to separate the
lamina lucida aids in the differential diagnosis. With this method,
the IgG antibodies appear on the dermal side of the split specimens in EBA and on the epidermal side in pemphigoid.50 The
antigen of EBA has been identified as the globular carboxyl terminus of type VII procollagen,51 a major constituent of anchoring
fibrils.12 EBA may also be triggered by certain drugs, such as penicillin, cephalosporins, diclofenac, and captopril.52
Differential Diagnosis of Vesiculobullous Disorders
The major forms of bullous diseases occurring on an autoimmune or inherited basis have been discussed. The differential diagnosis includes a number of additional conditions in which
vesicles or bullae are less common or appear secondary to other
disease processes.
Acantholytic blisters occur in keratosis follicularis (Darier disease) as well as in pemphigus. Such blisters are a histologic
rather than a clinical finding. Darier disease is an autosomal
dominant disorder that manifests as greasy papules and plaques
on seborrheic areas and in the flexures; almost all patients have
nail abnormalities. Unlike pemphigus vulgaris, Darier disease is
most effectively treated with oral retinoids.53
A fixed drug eruption may produce localized bullae that appear after ingestion of a particular drug [see 2:VI Cutaneous Adverse Drug Reactions]. Eczematous dermatitis results in spongiotic vesicles caused by intercellular edema [see 2:IV Eczematous Disorders, Atopic Dermatitis, and Ichthyoses]. This is manifested
clinically by large bullae in acute allergic contact dermatitis triggered by poison ivy or poison oak. Systemic lupus erythematosus [see 15:IV Systemic Lupus Erythematosus] occasionally produces bullae by causing degeneration of basal cells.
A bullous eruption on the dorsa of the hands and other sunexposed sites in patients receiving long-term hemodialysis may
resemble porphyria cutanea tarda [see 9:V The Porphyrias].54 Porphyrin levels are usually within normal limits. Intraepidermal or
subepidermal bullae, primarily on the extremities, may be a cutaneous sign of diabetes mellitus.55 Bacterial infections of the
skin, such as impetigo, may be associated with subcorneal bulla
formation. Bullae may occur on the feet in patients with severe
dermatophytosis.
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Various viral infections, including varicella (chickenpox), herpes simplex, and herpes zoster, also must be considered in the
differential diagnosis [see 2:VII Fungal, Bacterial, and Viral Infections of the Skin, 7:XXVI Herpesvirus Infections, and 7:XXXIII HIV
and AIDS]. Lastly, blisters from physical trauma, burns, or cold
must also be considered.
Elizabeth A. Abel, M.D., has received research support from Allergan Inc. and is
a consultant for Centocor, Inc. Jean-Claude Bystryn, M.D., has no commercial
relationships with manufacturers of products or providers of services discussed
in this subsection.
References
1. Korman NJ, Eyre RW, Klaus-Kovtun V, et al: Demonstration of an adhering-junction
molecule (plakoglobin) in the autoantigens of pemphigus foliaceus and pemphigus vulgaris. N Engl J Med 321:631, 1989
2. Amagai M: Desmoglein as a target in autoimmunity and infection. J Am Acad Dermatol 48:244, 2003
3. Starzycki Z, Chorzelski TP, Jablonska S: Familial pemphigus vulgaris in mother and
daughter. Int J Dermatol 37:211, 1998
4. Miyagawa S, Higashimine I, Iida T, et al: HLA-DRB1*04 and DRB1*14 alleles are associated with susceptibility to pemphigus among Japanese. J Invest Dermatol 109:615, 1997
5. Bystryn JC, Steinmen NM: The adjuvant therapy of pemphigus: an update. Arch
Dermatol 132:203, 1996
6. Ljubojevic S, Lipozencic J, Brenner S, et al: Pemphigus vulgaris: a review of treatment
over a 19-year period. J Eur Acad Dermatol Venereol 16:599, 2002
7. Herbst A, Bystryn JC: Remissions in pemphigus. J Invest Dermatol 106:850, 1996
8. Ruach M, Ohel G, Rahav D, et al: Pemphigus vulgaris and pregnancy. Obstet Gynecol Surv 50:755, 1995
9. Warren SJ, Lin MS, Giudice GJ, et al: The prevalence of antibodies against
desmoglein 1 in endemic pemphigus foliaceus in Brazil. N Engl J Med 343:23, 2000
10. Landau M, Brenner S: Histopathologic findings in drug-induced pemphigus. Am J
Dermatopathol 19:411, 1997
11. Brenner S, Bialy-Golan A, Anhalt GJ: Recognition of pemphigus antigens in drug-induced pemphigus vulgaris and pemphigus foliaceus. J Am Acad Dermatol 36:919, 1997
12. Anhalt GJ, Kim SC, Stanley JR, et al: Paraneoplastic pemphigus: an autoimmune
mucocutaneous disease associated with neoplasia. N Engl J Med 323:1729, 1990
13. Mutasim DF, Adams BB: Immunofluorescence in dermatology. J Am Acad Dermatol 45:803, 2001
14. Turner MS, Sutton D, Sauder DN: The use of plasmapheresis and immunosuppression in the treatment of pemphigus vulgaris. J Am Acad Dermatol 43:1058, 2000
15. Bystryn JC, Jiao D, Natow S: Treatment of pemphigus with intravenous immunoglobulin. J Am Acad Dermatol 47:358, 2002
16. Dahl MV, Bridges AG: Intravenous immune globulin: fighting antibodies with antibodies. J Am Acad Dermatol 45:690, 2001
17. Werth VP: Treatment of pemphigus vulgaris with brief, high-dose intravenous glucocorticoids. Arch Dermatol 132:1435, 1996
18. Salopek TG, Logsetty S, Tredget EE: Anti-CD20 chimeric monoclonal antibody (rituximab) for the treatment of recalcitrant, life-threatening pemphigus vulgaris with implications in the pathogenesis of the disorder. J Am Acad Dermatol 47:785, 2002
19. Chams-Davatchi C, Nonahal Azar R, Daneshpazooh M, et al: Open trial of mycophenolate mofetil in the treatment of resistant pemphigus vulgaris. Ann Dermatol
Venereol 129:23, 2002
20. Moll R, Moll I: Epidermal adhesion molecules and basement membrane components as target structures of autoimmunity. Virchows Arch 432:487, 1998
21. Lin MS, Mascaro JM Jr, Liu Z, et al: The desmosome and hemidesmosome in cutaneous autoimmunity. Clin Exp Immunol 107(suppl 1):9, 1997
22. Bernard P, Bedane C, Bonnetblanc JM: Anti-BP180 autoantibodies as a marker of
poor prognosis in bullous pemphigoid: a cohort analysis of 94 elderly patients. Br J Dermatol 136:694, 1997
23. Cunha PR, Thomazeski PV, Hipolito E, et al: Bullous pemphigoid in a 2-month-old
infant. Int J Dermatol 37:935, 1998
24. Bastuji-Garin S, Joly P, Picard-Dahan C, et al: Drugs associated with bullous pemphigoid: a case-control study. Arch Dermatol 132:272, 1996
25. Ogawa H, Sakuma M, Morioka S, et al: The incidence of internal malignancies in
pemphigus and bullous pemphigoid in Japan. J Dermatol Sci 9:136, 1995
26. Joly P, Roujeau JC, Benichou J, et al: A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 346:321, 2002
27. Kirtschig G, Murrell D, Wojnarowska F, et al: Interventions for mucous membrane

July 2003 Update
pemphigoid/cicatricid pemphigoid and epidermolysis bullosa acquisita: a systemic literature review. Arch Dermatol 138:380, 2002
28. Yancey KB, Egan CA: Pemphigoid: Clinical, histologic, immunopathologic, and
therapeutic considerations. JAMA 284:350, 2000
29. Dereure O, Bessis D, Guillot B, et al: Treatment of bullous pemphigoid by low-dose
methotrexate associated with short-term potent topical steroids: an open prospective
study of 18 cases. Arch Dermatol 138:1255, 2002
30. Bouscarat F, Chosidow O, Picard-Dahan C, et al: Treatment of bullous pemphigoid
with dapsone: retrospective study of thirty-six cases. J Am Acad Dermatol 34:683, 1996
31. Hornschuh B, Hamm H, Wever S, et al: Treatment of 16 patients with bullous pemphigoid with oral tetracycline and niacinamide and topical clobetasol. J Am Acad Dermatol 36:101, 1997
32. Thornfeldt CR, Menkes AW: Bullous pemphigoid controlled by tetracycline. J Am
33. Brow JR, Parker F, Weinstein WM, et al: The small intestinal mucosa in dermatitis
herpetiformis: I. Severity and distribution of the small intestinal lesion and associated
malabsorption. Gastroenterology 60:355, 1971
34. Katz SI, Hall RP III, Lawley TJ, et al: Dermatitis herpetiformis: the skin and the gut.
Ann Intern Med 93:857, 1980
35. Jenkins D, Lynde CW, Stewart WD: Histiocytic lymphoma occurring in a patient
with dermatitis herpetiformis. J Am Acad Dermatol 9:252, 1983
36. Guide SV, Marinkovich MP: Linear IgA bullous dermatosis. Clin Dermatol 19:719,
2001
37. Fine JD: Management of acquired bullous skin diseases. N Engl J Med 333:1475,
1995
38. Auquier-Dunant A, Mockenhaupt M, Naldi L, et al: Correlations between clinical
patterns and causes or erythema multiforme majus, Stevens-Johnson syndrome, and
toxic epidermal necrolysis: results of an international prospective study. Arch Dermatol
138:1019, 2002
39. Manders SM: Toxin-mediated streptococcal and staphylococcal disease. J Am Acad
Dermatol 39:383, 1998
40. Spandau U, Brocher EB, Kampgen E, et al: CC and CXC chemokines are differentially expressed in erythema multiforme in vivo. Arch Dermatol 138:1027, 2002
41. Kokuba H, Aurelian L, Burnett J: Herpes simplex virus associated erythema multiforme (HAEM) is mechanistically distinct from drug-induced erythema multiforme: interferon V is expressed in HAEM lesions and tumor necrosis factoralpha in drug-induced erythema multiforme lesions. J Invest Dermatol 113:808, 1999
42. Prins C, Kerdel FA, Padilla RS, et al: Treatment of toxic epidermal necrolysis with
high-dose intravenous immunoglobulins: multicenter retrospective analysis of 48 consecutive cases. Arch Dermatol 139:26, 2003
43. Wolff K, Tappeiner G: Treatment of toxic epidermal necrolysis. Arch Dermatol
139:85, 2003
44. Fine JD, Eady RA, Bauer EA, et al: Revised classification system for inherited epidermolysis bullosa: report of the Second International Consensus Meeting on diagnosis
and classification of epidermolysis bullosa. J Am Acad Dermatol 42:1051, 2000
45. Hintner H, Stingl G, Schuler G, et al: Immunofluorescence mapping of antigenic determinants within the dermal-epidermal junction in the mechanobullous diseases. J Invest Dermatol 76:113, 1981
46. Shimizu H, Fine JD, Suzumori K, et al: Prenatal exclusion of pyloric atresia-junctional epidermolysis bullosa syndrome. J Am Acad Dermatol 31:429, 1994
47. Okulicz JF, Kihiczak NI, Janniger CK: Epidermolysis bullosa simplex. Cutis 70:19,
2002
48. Christiano AM, LaForgia S, Paller AS, et al: Prenatal diagnosis for recessive dystrophic epidermolysis bullosa in 10 families by mutation and haplotype analysis in the
type VII collagen gene (COL7A1). Mol Med 2:59, 1996
49. Raab B, Fretzin DF, Bronson DM, et al: Epidermolysis bullosa acquisita and inflammatory bowel disease. JAMA 250:1746, 1983
50. Vaillant L, Bernard P, Joly P, et al: Evaluation of clinical criteria for diagnosis of bullous pemphigoid. Arch Dermatol 134:1075, 1998
51. Woodley DT, Burgeson RE, Lunstrum G, et al: The epidermolysis bullosa acquisita
antigen is the globular carboxyl terminus of type VII procollagen. J Clin Invest 81:683,
1988
52. Delbaldo C, Chen M, Friedli A, et al: Drug-induced epidermolysis bullous acquisita
with antibodies to type VII collagen. J Am Acad Dermatol 46(5 suppl):S161, 2002
53. Cooper SM, Burge SM: Dariers disease: epidemiology, pathophysiology, and management. Am J Clin Dermatol 4:97, 2003
54. Glynne P, Deacon A, Goldsmith D, et al: Bullous dermatoses in end-stage renal failure: porphyria or pseudoporphyria? Am J Kidney Dis 34:155, 1999
55. Perez MI, Kohn SR: Cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 30:519, 1994
56. Viard I, Wehrli P, Bullani R, et al: Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science 282:490, 1998
57. Elder D, Elenitsas R, Jaworsky C, et al: Levers Histopathology of the Skin, 8th ed.
Lippincott-Raven, Philadelphia, 1997
ACP Medicine
M A L I G N A N T C U TA N E O U S T U M O R S
Allan C. Halpern, m.d.

Patricia L. Myskowski, m.d.
Malignant tumors can arise from cells of any layer of the skin
keratinocytes, melanocytes, fibroblasts, endothelial cells, adipocytesas well as from cells such as lymphocytes, which normally transit through the skin. Cutaneous metastases may also arise
from other primary sites. In this subsection, we review the most
common malignant cutaneous tumors in their order of frequency.
nonmelanoma skin cancer

Nonmelanoma skin cancer (NMSC) typically occurs as pink
lesions on the sun-exposed skin surface. Any pink skin lesion
that persists or recurs in the same location, especially if easily irritated by minor trauma, should raise the suspicion of NMSC.
Some forms of NMSC will fade with changes in season (i.e., with
reduced sun exposure) or with the application of topical
steroids, and the clinician should advise patients that any lesion
that recurs warrants further attention.
Basal Cell Carcinoma

Malignant Tumors of the Epidermis
Epidermal skin cancers are the most common cancers in humans. They arise in the keratinocytes and the melanocytes of the
epidermis. Epidermal skin cancers present a unique opportunity
for effective intervention with both early detection and primary
prevention. They are amenable to clinical diagnosis by simple visual inspection and to pathologic diagnosis by minimally invasive biopsy.
Basal cell carcinoma and squamous cell carcinoma originate
from the keratinocytes of the epidermis. Because these two cancers share many features, they are often lumped together under
the term nonmelanoma skin cancer.
Malignant melanoma is a malignancy arising from a melanocyte. Although malignant melanomas can arise in any melanocyte of the body, including the eye, the vast majority occur in the
skin. Cutaneous malignant melanoma has been categorized into
four major histogenetic types: lentigo maligna melanoma, superficial spreading melanoma, nodular melanoma, and acral lentiginous melanoma.
Basal cell carcinoma (BCC) is a malignant cutaneous tumor

arising from the basal keratinocytes of the epidermis.
Epidemiology BCC is the most common skin cancer. Reported incidence ranges from 3.4 per 100,000 per year in African
Americans to over 1,100 per 100,000 per year in Townsville,
Queensland, Australia.4,5 Although rare, metastases and death
from BCC do occur.
sun exposure and skin cancer
Etiology UV radiationspecifically, intense intermittent

sun exposureappears to play an important role in the development of BCC. Recent studies of basal cell nevus syndrome
(Gorlin syndrome) are yielding dramatic new insights into the
genetics of BCC. A gene named patched, which was first recognized as a developmental gene in the fruit fly Drosophila, has
been identified as playing a critical role in the development of
BCC. Almost all patients with basal cell nevus syndrome appear to inherit a mutated copy of the patched gene, and studies
of sporadic BCC suggest that mutations in the patched gene
pathway are a necessary, if not sufficient, step in the development of most BCCs.6
Several lines of evidence implicate ultraviolet (UV) radiation

in the pathogenesis of all three of the major epidermal skin cancers.1 Epidemiologic data implicate chronic cumulative sun exposure in the development of squamous cell carcinoma and intense intermittent sun exposure in basal cell carcinoma and
melanoma. Laboratory studies indicate that both UVA (320 nm
to 400 nm) and UVB (290 nm to 320 nm) radiation from sunlight
can damage DNA both directly and through oxidative damage.
In addition, UV radiation can suppress the cutaneous immune
system.2 The association of some squamous cell carcinomas with
chemical carcinogens and the occurrence of acral lentiginous and
mucosal melanomas in unexposed areas of the body underscore
the need for studies to identify additional etiologic agents.
Recognition of the important role of sunlight in the etiology of
skin cancer affords an opportunity for primary prevention
through the use of sun protection. Unfortunately, the timing and
doses of UV exposure involved in the development of skin cancer in humans are not yet known. Accordingly, patients should
be educated about the deleterious effects of sun exposure and
tanning. Sun-protection efforts should be geared to an overall reduction of sun exposure through the avoidance of sun-seeking
behavior and the use of sun-protective clothing. Broad-spectrum
sunscreens with a sun protection factor (SPF) of 15 or greater are
a useful adjunct to sun protection, but they should not be used to
increase the amount of time spent in direct sunlight.3
Diagnosis Approximately 90% of BCCs occur on the head

and neck. They occur in nodular and superficial forms.
Nodular BCC appears as a raised, pearly, translucent, pink
bump on the skin surface. It is often easily irritated, fragile, and
associated with episodes of superficial ulceration or hemorrhage. When ulceration is prominent, it can lead to the appearance of a so-called rodent ulcer, in which the pearly translucent
border is barely appreciable. Such lesions can also appear more
white than pink and, on close observation, often demonstrate
small telangiectasias. They tend to have a smoother, shinier surface and firmer texture than common dermal nevi [see Figure 1].
Superficial BCC appears as a pink patch of skin. On close inspection, most superficial BCCs demonstrate a thready translucent border, with areas of seemingly normal or slightly fibrotic
skin within the lesion. Superficial BCC is usually found on the
upper trunk, arms, and legs.
Less common clinical variants of BCC include morpheaform,
pigmented, and cystic lesions. Morpheaform BCCs have an infiltrative pattern that histologically and clinically resembles a scar.
Pigmented BCCs typically contain specks of blue-black pigment,
but they may be deeply pigmented throughout. Pigment is most
commonly a variant of nodular BCC. Cystic BCCs tend to be
softer than typical nodular BCCs and may have a clear to bluegray appearance.

October 2002 Update
ACP Medicine
DERMATOLOGY:X Malignant Cutaneous Tumor1
Figure 1 Nodular basal cell carcinomashown here above a patients lip, with a so-called rodents ulcer (a)commonly
presents as a raised, pearly, translucent pink bump on the skin surface (b). A superficial form appears as a pink patch of skin (c).
Patient history plays a critical role in the diagnosis of BCC.
When questioned about lesions that become easily irritated or
bleed from minor trauma, patients can often alert the clinician to
early lesions that would otherwise elude detection. With the patient under local anesthesia, a biopsy should be obtained of any
suspicious lesion.
Differential diagnosis Nodular BCC can be confused with
angiofibromas, dermal nevi, amelanotic melanoma, cutaneous
metastases, and a host of benign adnexal tumors (e.g., trichoepithelioma). Superficial BCCs mimic several inflammatory dermatoses (e.g., eczema and tinea) and share several clinical features with actinic keratoses. Pigmented BCC can easily be confused with a primary melanocytic neoplasm. Cystic BCCs can be
confused with cystic adnexal tumors and inflammatory lesions.
Treatment The goal of therapy is to adequately eradicate the
lesion and ensure the best cosmetic and functional outcome.
Multiple factorssuch as the size, location, and histologic subtype of the lesions and attributes of the patient, including age,
general health, skin color, and skin laxityshould be taken into
consideration in choosing an optimal therapy.
The vast majority of BCCs are amenable to surgical treatment. The primary options include curettage and electrodesiccation, excision, cryotherapy, radiotherapy, and Mohs micrographic surgery.
A small but significant subset of BCCs benefit from Mohs micrographic surgery, which entails microscopic examination of
frozen sections of the entire undersurface of the excised specimen
at the time of surgery. The technique may be indicated for recurrent lesions and lesions with a high likelihood of recurrence.
These include ill-defined lesions, large lesions (> 2 cm), lesions
with a high-risk histology (i.e., aggressive growth pattern, sclerosing pattern, or perineural involvement), and lesions overlying
embryonal fusion planes (e.g., ocular canthi or nasofacial sulcus).
The Mohs micrographic technique has significantly higher cure
rates than other treatments for these high-risk lesions.7
Radiation therapy can be an effective, painless, and well-tolerated alternative that is typically reserved for older patients who
are poor surgical candidates. Radiation therapy should be avoided, however, in patients with basal cell nevus syndrome.
Experimental therapies under investigation include intralesional chemotherapy, topical immune modulators, and photodynamic therapy.
October 2002 Update
All patients treated for BCC are at risk for local recurrence as
well as at significant risk for the development of additional skin
cancers. Patients should be instructed in the self-examination of
their skin as well as in methods of sun protection, and they
should receive routine professional follow-up.
Prognosis As noted (see above), the risk of local recurrence
relates to the lesions size, location, and histology. Metastases are
very rare: a prevalence of 0.0028% was reported in a series of
50,000 Australians.8 Metastases occur through both the lymphatic and the hematogenous routes; risk factors include basal cell
nevus syndrome, immunosuppression, and previous exposure
to ionizing radiation. Metastases that are not amenable to surgical management are associated with a poor outcome.
Squamous Cell Carcinoma

Like BCC, cutaneous squamous cell carcinoma (SCC) arises
from the keratinocytes of the epidermis. Histologically, the cells
of well-differentiated SCC resemble the cells of the superior portion of the epidermis.
Epidemiology An estimated 150,000 to 250,000 new cases of
cutaneous SCC were diagnosed in the United States in 1994.9 The
estimated mortality from SCC in the United States in 1988 was
approximately 0.5 per 100,000. Several lines of data suggest significant recent increases in SCC incidence. In Australia, for example, SCC incidence increased by 51% between the years 1985
and 1990.10
Etiology In addition to sunlight, other known etiologic
agents that contribute to the development of cutaneous SCC are
ionizing radiation, chemical carcinogens, thermal burns, and chronic nonhealing wounds. Sun-related SCCs demonstrate a lower
risk of metastases and death than SCCs related to other exposures.
Factors involved in predisposition to SCC from sun exposure include light skin color, tendency to burn, and inability to tan.
Pathophysiology and pathogenesis Sun-related SCC is often associated with a precursor lesion called an actinic keratosis.
Such lesions occur on the scalp, face, extensor surfaces of the
forearms, and backs of the hands. They tend to be rough-surfaced, irregularly shaped, and pink. They are often more readily
felt than seen. The majority of patients with actinic keratoses
have multiple lesions. The risk of SCC in these individuals has
ACP Medicine
Figure 2 A squamous cell

carcinoma is shown on an arm (a)
and lower lip (b).
been estimated to be as high as 20%.11 SCC may also appear on

normal-looking skin.
SCC of the oral or genital mucosa may arise in precursor lesions termed leukoplakia or erythroplakia. Mucosal SCCs are associated with a significant risk of metastases.
Immune surveillance affects the progression of SCC. Immunosuppression as occurs in transplant recipients and patients with lymphoma is associated with a high incidence of
SCC. In these patients, infection with human papillomavirus
appears to play an etiologic role in conjunction with sun exposure. SCCs tend to be more aggressive in immunosuppressed
persons.
Diagnosis Most lesions occur in areas of the body that are
usually exposed to the sun. The lesions are pinkish, firm plaques
that often have a rough, scaly surface [see Figure 2]. Biopsy is required for definitive diagnosis.
Differential diagnosis The differential diagnosis of SCC includes keratoacanthoma, Bowen disease, verrucous carcinoma,
BCC, hypertrophic actinic keratosis, and common warts.
Keratoacanthomas share many features with SCC both clinically and histologically. They arise de novo on normal-looking
skin and grow very rapidly. They are typically pink, domeshaped, shiny bumps on the surface of the skin with a central
crateriform keratotic plug. They may become very large. Although keratoacanthomas are not associated with a risk of
metastasis, they can be locally destructive. Spontaneous regression of keratoacanthoma over the course of months has been
well documented.
Bowen disease is SCC that is confined to the epidermis. It appears as red, scaly, minimally elevated plaques with well-defined, irregular borders. The previously reported association of
Bowen disease with internal malignancy has not held up to closer scrutiny.
SCCs that lack a scaly keratotic surface can be confused with a
host of other adnexal and dermal skin tumors.
Treatment Small SCCs evolving from an actinic keratosis
can be adequately treated with simple curettage and electrodesiccation. Larger actinic lesions, as well as lesions arising in
nonsun-exposed areas of skin, are best treated with definitive
surgical excision with confirmation of negative margins. Highrisk, ill-defined lesions, especially those occurring in the surgically sensitive areas of the face, genitalia, hands, and feet, are often
best treated by Mohs micrographic surgery.
October 2002 Update
Fractionated radiation therapy is an alternative treatment for

primary SCC in older patients who are poor surgical candidates.
The benefits of adjuvant radiation therapy are less clear, as are
the benefits of elective lymph node dissection for patients with
high-risk SCC of the head and neck.
Cytotoxic chemotherapy and biologic response modifiers have
been used in patients who have advanced SCC, with complete response rates of 25% to 46% but with few long-term survivors.
Actinic keratoses are treated with cryotherapy, curettage, topical chemotherapy with fluorouracil, chemical peels, and laser
resurfacing to prevent progression to SCC.
Treatment guidelines from the National Comprehensive Cancer Network have recently been published.12
Prognosis Regardless of the therapy employed, high-risk lesions have a significant rate of local recurrence at 5 years. Highrisk SCCs include those in specific anatomic sites (e.g., ears, lips,
genitalia and other nonsun-exposed areas), those greater than 2
cm in diameter, those with aggressive histologic features (depth
> 4 mm, Clark level IV and above, and poorly differentiated histology), and those in immunosuppressed patients.13 The primary
route of SCC metastasis is via lymphatic spread to regional
lymph nodes. Reported rates of metastasis vary from as low as
0.3% in small, sun-derived lesions to 33% in larger, poorly differentiated lesions.13 Reported overall 5-year survival for patients
with regionally metastatic SCC has ranged from 25% to 47%.13
malignant melanoma
Epidemiology
In the United States, a persons lifetime risk for developing
melanoma is about 1 in 75 (1.3%).14 Between 1973 and 1994, the
incidence of melanoma rose by 121%, and the mortality rose by
39%.14 Encouraging trends include a shift toward the detection of
earlier disease as well as a stabilization of incidence rates in some
segments of the population. In terms of both morbidity and mortality, however, the burden of melanoma-related disease continues to increase. Although melanoma can occur in anyone, it is
primarily a disease of whites. Melanomas occurring in blacks are
typically of the acral lentiginous variety.
Etiology
Although strong epidemiologic and basic-science evidence
supports an association between melanoma and sun exposure,
the relationship appears to be complex. Lentigo maligna
melanoma is associated with chronic cumulative sun exposure.
ACP Medicine
Figure 3 Superficial spreading malignant melanoma begins as a small, irregular brown lesion (a).
Variation in color and contour is characteristic of lentigo maligna melanoma (b). Nodular melanoma
often grows more in thickness than in diameter (c). Acral lentiginous melanoma can resemble a
hematoma under the nail (d).
Superficial spreading melanoma and nodular melanoma appear

to be associated with intense intermittent sun exposure, especially in youth. Acral lentiginous melanoma has no apparent association with sun exposure. Basic-science studies and animal models have implicated different wavelengths of UV in melanoma
carcinogenesis; UV wavelength may vary among types of
melanoma.
Approximately 5% of patients with melanomas have a family
history of melanoma. Mutations in the cell-cycle regulatory gene
p16 (cyclin-dependent kinase inhibitor2a) are associated with
melanoma in approximately 40% of familial-melanoma families,
with linkage of the gene to chromosome 9p.15 Abnormalities of
DNA repair found in patients with dysplastic nevi suggest this
as another mechanism of genetic predisposition to melanoma.
Diagnosis
As a pigmented lesion occurring on the surface of the skin,
melanoma is amenable to early detection by simple visual inspection at an easily curable stage. Left untreated, melanoma is
among the deadliest and most therapeutically unresponsive
forms of cancer.
Early recognition of melanoma requires attention to pigmented lesions on all body surfaces. Despite the strong association of
melanoma with sun exposure, melanomas can occur anywhere
on the cutaneous surface. Patients self-examination, as well as
physician examination, must therefore include all skin surfaces,
including the scalp, genitalia, and soles of the feet. Any pigmented skin lesion with recent change or with features described by
the ABCD mnemonic (asymmetry, border irregularity, color
variation, diameter > 6 mm) warrants consideration of the possi 2002 WebMD Inc. All rights reserved.
October 2002 Update
bility of melanoma. Although any mole may change gradually

over time, any that change color, shape, or size relative to a patients other moles deserve special attention [see Figure 3].
Among whites, several additional risk factors have been identified, such as fair complexion, tendency to burn, inability to tan,
freckling, and family history of melanoma. The strongest phenotypic markers of melanoma risk are moles (nevi)more specifically, increased numbers of moles and the presence of atypical
moles (dysplastic nevi). Melanoma can arise in a preexisting
mole or may arise de novo on normal-appearing skin.
Screening of the family members of patients with melanoma
(particularly multiple melanoma) may be a useful preventive
and diagnostic measure.16
Dysplastic nevi Several epidemiologic studies have correlated dysplastic nevi with melanoma risk. Clinically, dysplastic nevi
are large (> 5 mm) moles with variegate pigmentation and ill-defined borders [see Figure 4]. Histologically, dysplastic nevi are
characterized by the presence of architectural atypia and random
cytologic atypia.17 The degree of melanoma risk associated with
dysplastic nevi depends on the genetic context. In families with
familial melanomadysplastic nevus syndrome, the abnormal
mole phenotype appears to be inherited in an autosomal dominant fashion. Members of these families with dysplastic nevi
have a lifetime melanoma risk that approaches 100%.18 Outside
the context of familial melanoma, dysplastic nevi occur in approximately 5% to 10% of whites. In this general population, dysplastic nevi are markers of increased melanoma risk [see Table 1]. 19
Dysplastic nevi present both opportunity and challenge in
melanoma detection. On one hand, their recognition allows effiACP Medicine
Figure 4 Dysplastic nevi typically are larger than common moles (a) and have variegate pigmentation and illdefined borders (b).
cient targeting of a high-risk group. On the other, they can complicate attempts at melanoma detection by clinically mimicking
early melanomas. Although some dysplastic nevi may progress
to melanoma, the overwhelming majority remain benign. Furthermore, not all melanomas arising in patients with dysplastic
nevi develop in a preexisting mole. Wholesale removal of dysplastic nevi is an impractical approach to melanoma prevention.
In patients with dysplastic nevi, melanoma detection is predicated on specialized visual examination aided by self-examination
and professional follow-up to identify changing lesions.
Several specialized aids to diagnosis of melanoma in patients
with dysplastic nevi are under development. Epiluminescent
microscopy (ELM), which is also known as dermatoscopy, entails the use of a handheld otoscopelike device to magnify a pigmented lesion while applying pressure and oil to the surface.
The technique allows the visualization of pigment patterns and
features not apparent with simple visual inspection. With experience and training, ELM can be a useful aid in distinguishing
Table 1 Adjusted Estimated Relative Risks of

Melanoma by Nevus Type and Number17
Type
Number
Adjusted Relative
Risk*
Nevi > 2 mm and < 5 mm
024
2549
5099
100
1.0
1.8 (1.32.5)
3.0 (2.14.4)
3.4 (2.05.7)
Nondysplastic nevi > 5 mm
0
1
24
59
10
1.0
0.9 (0.71.3)
1.3 (1.01.8)
1.7 (1.02.7)
2.3 (1.24.3)
Dysplastic nevi
None
Indeterminate
1
24
59
10
1.0
1.0 (0.71.6)
2.3 (1.43.6)
7.3 (4.612.0)
4.9 (2.59.8)
12.0 (4.431.0)
*Mutually adjusted and adjusted for age, sex, center, referral pattern, morphologic
dysplastic nevi < 5 mm, sunburns, freckles, solar damage, scars, nevus excisions,
and family history of melanoma (confidence interval = 95%).

October 2002 Update
melanoma from benign pigmented lesions; however, when used

inexpertly, ELM may actually decrease diagnostic accuracy.20,21
Another aid to melanoma detection in high-risk individuals is
photographically assisted follow-up.22 A baseline set of whole
body photographs of the skin are used during self-examination
and follow-up professional examination to assess change in the
lesions. This procedure helps to prevent unnecessary excision of
stable lesions and improves the sensitivity of examinations in detecting change. New imaging technologies such as in vivo confocal scanning laser microscopy hold promise for future improvements in the noninvasive diagnosis of melanoma.23
Any lesion that raises a clinical suspicion of melanoma requires definitive diagnosis. Full-thickness excision is the preferred technique for biopsy of a suspicious pigmented lesion.
Partial biopsy can lead to misdiagnosis through sampling error
or by depriving the pathologist of a view of the overall architecture and cytology of the lesion. Incisional biopsies with good
clinical-pathologic correlation may be appropriate, however, in
the assessment of large lesions and of lesions occurring in surgically sensitive areas. There is no evidence to suggest that incisional biopsy increases the risk of metastasis.
Dysplastic nevi share many features with early superficial
spreading melanoma. Other common lesions that may mimic
melanoma include lentigines, sunburn freckles, traumatized
nevi, thrombosed angiomas, pigmented BCCs, pigmented
Bowen disease, dermatofibromas, and atypical seborrheic keratoses. Two other challenges in the differential diagnosis of
melanoma deserve special mention. Amelanotic melanomas
(melanomas without pigment) present as pink lesions that may
be misdiagnosed as BCCs or Spitz nevi. Spitz nevi can be difficult to differentiate from melanoma both clinically and histologically. Spitz nevi occur most commonly in children, but they also
occur in adults. Like nodular melanomas, Spitz nevi tend to appear suddenly and range in color from red to reddish brown.
Treatment
Primary site Primary cutaneous melanoma is managed surgically with definitive reexcision. The wide excisions of the past
have given way to more modest resection margins. Data from
two prospective, randomized trials of surgical margins for primary cutaneous melanoma have demonstrated the safety of 1
ACP Medicine
cm margins for melanomas less than 1 mm in thickness and of 2

cm margins for melanomas between 1 and 4 mm in thickness.24,25
Randomized trials of resection margins for melanomas more
than 4 mm thick have not been conducted. Most authors recommend a 2 to 4 cm margin for these thicker primary melanomas.
Primary closure and reconstructive flaps are preferable, cosmetically and functionally, to skin grafts and should be used instead
of grafts whenever possible.
men approved by the Food and Drug Administration for the

treatment of metastatic melanoma.30 Objective responses to
DTIC are seen in approximately 5% to 20% of patients; durable
complete responses are rare. Radiation therapy can play an important palliative role. In the absence of more effective clinically
proven therapy, patients with distant metastases should be offered the opportunity to participate in clinical trials of experimental therapy when appropriate.
Lymph nodes Patients with clinically evident regional

lymph node disease are treated with therapeutic lymph node
dissection. The performance of elective lymph node dissection
(ELND) has long been controversial in patients with intermediate-thickness primary cutaneous melanoma but no clinical evidence of regional nodal disease. Overall, the data on survival
benefit suggest that ELND is not warranted, given the morbidity
associated with this procedure.
Sentinel lymph node biopsy is being increasingly used as an
alternative to ELND in patients with primary cutaneous
melanoma. This technique utilizes lymphoscintigraphy to identify the draining regional lymph node basins for the skin at the
site of the primary melanoma. At the time of definitive reexcision of the melanoma, a blue dye and radioisotope are injected
into the dermis around the melanoma site. A small incision is
made over the spot that has been identified on lymphoscintigraphy as the proximal area of drainage of the regional lymph node
basin. The first lymph node identified as taking up the blue dye
and radioisotope (the sentinel node) is then excised.
The sentinel node is then histologically evaluated, often with
the use of immunohistochemical techniques and occasionally
with the use of polymerase chain reaction, which is more sensitive. The absence of melanoma in the sentinel node is highly
sensitive for ruling out the presence of metastases in the remainder of the lymph node basin when the procedure is performed by an experienced team. When the sentinel node is
found to be positive for melanoma, a full ELND is typically
performed. Prospective studies have demonstrated sentinel
node status to be strongly correlated with 5-year survival.26 Patients with positive sentinel nodes are appropriate candidates
for consideration of adjuvant therapy (see below). Several multicenter trials are currently under way to assess the clinical utility of this procedure.27,28
Adjuvant therapy Patients with cutaneous or regional disease who have been surgically rendered free of disease but are at
high risk for recurrence or metastasis are potential candidates for
adjuvant therapy.31 Various adjuvant therapies have been used
in melanoma, including immunostimulants such as bacillus Calmette-Gurin, Corynebacterium parvum, and levamisole. Several
chemotherapeutic agents have been tried as well. More recently,
immunotherapy with cytokines, such as interferons, and active
immunization with vaccines have been studied. A high-dose
regimen of interferon alfa (20 million units/m2 I.V. daily for 1
month followed by 10 million units/m2 S.C. three times a week
for 48 weeks) has been approved by the FDA for use as adjuvant
therapy for melanoma. Two studies have demonstrated a small
but statistically significant improvement in overall survival with
this regimen. Multiple studies have failed to demonstrate improved long-term overall survival with the use of adjuvant interferon in intermediate-dose or low-dose regimens.32,33
A host of novel strategies, including active immunization,
passive immunization, and myriad biologic therapies, are currently being studied and may provide opportunities for patients
who are appropriate candidates for trials.34
In-transit metastases In-transit metastases can remain confined to a single limb for prolonged periods. Amputation does
not appear to provide a long-term survival benefit in this setting. Slow-growing individual in-transit metastases can be
managed surgically. More extensive disease can be treated
with sensitization therapy with dinitrochlorobenzene (DNCB).
For extensive in-transit metastases confined to an extremity,
limb perfusion therapy can result in dramatic palliation and
limb salvage. The procedure entails isolation of the vasculature
of the involved extremity from the systemic vasculature and
perfusion of the isolated limb with chemotherapeutic agents,
biologic agents, or both at doses that could not be tolerated if
given systemically.29
Distant metastases Despite the development of several novel approaches to the treatment of patients with metastatic
melanoma, including multidrug chemotherapy, biologic therapy, immunotherapy, and combinations of these treatments,
monotherapy with dacarbazine (DTIC) remains the only regi 2002 WebMD Inc. All rights reserved.
October 2002 Update
Prognosis
Stage The single strongest prognostic factor for melanoma is
stage of disease. Various staging classifications have been used
over the years. All staging systems for melanoma take into account the classic TNM classification of tumor size (T), lymph node
involvement (N), and distant metastases (M). The differences
across staging systems relate largely to the staging of the primary
site. New staging systems attempt to use the attributes of the primary tumor that strongly correlate with outcome. These attributes
include thickness, ulceration, and, in the case of thin melanomas
less than 1 mm, the Clark level of invasion. The advent of sentinel
node biopsy has led to the inclusion of microstaging of lymph
nodes in the new staging system [see Tables 2 and 3].35,36
Attributes of the primary tumor Several attributes of the
primary tumor have been identified as predictors of outcome
from primary cutaneous melanoma. The single strongest, most
consistent predictor of outcome is the Breslow tumor thickness.
Other important histologic parameters are the Clark level of tumor invasion, extent of ulceration, rate of mitosis, presence of tumor-infiltrating lymphocytes, and vascular invasion. For thin
primary melanomas, one of the strongest predictors of outcome
is growth phase.37 Radial-growth-phase melanoma does not appear to metastasize, whereas vertical-growth-phase melanoma
(characterized by the formation of a tumor nodule in the dermis)
is associated with significant risk of metastasis even in lesions
less than 1 mm thick.38 Patient characteristics associated with improved survival from melanoma include young age (< 60 years),
female sex, and location of the melanoma on an extremity. Multivariable models for predicting outcome from melanoma have
been developed [see Table 4].39
ACP Medicine
Malignant Tumors of the Dermis

metastatic tumors
Cutaneous metastases occur in approximately 5% of patients
with solid tumors and are usually associated with widespread
disease. The relative frequency of skin metastases is gender specific, reflecting the rates of the primary cancers.40 In women, two
thirds of metastases are from breast cancer, but lung, colorectal,
melanoma, and ovarian cancers are also frequent. In men, lung
cancer is most common, followed by cancer of the large intestine, melanoma, SCC of the head and neck, and cancer of the
kidneys.40 The anatomic distribution of skin metastases is not
random. Cutaneous metastases from breast cancer often involve
the chest wall and may appear as nodules, lymphedema, or cellulitis. The scalp is a common site for metastasis, especially of
cancer from the lung and kidney (in men) and breast (in
women). Head and neck cancers may invade the skin by local
extension, giving rise to a firm, dusky-red edema of the skin that
resembles cellulitis. Abdominal wall metastases, often called Sister Josephs nodules, may occur with GI or ovarian malignancies.40 Clinically, cutaneous metastases are often minimally
symptomatic dermal papules or nodules and are flesh-colored
or pink; dissemination occurs via lymphatic or vascular path-
ways. Cutaneous metastases may clinically reflect the histology

of the primary tumor (e.g., black, brown, or gray nodules with
metastatic melanoma, and vascular nodules with renal cell or
thyroid carcinoma).
primary tumors
Primary malignancies of the dermis may develop from any of
the myriad structures of the skin, including sebaceous glands
(sebaceous carcinoma), connective tissue (dermatofibrosarcoma
protuberans), smooth muscle (leiomyosarcoma), and other adnexal tissue (eccrine carcinoma).41 Most of these primary dermal
neoplasms are rare; they may exhibit aggressive biologic behavior. Although these neoplasms are quite varied histologically,
many share a common clinical presentation of a rapidly growing
flesh-colored to pink or red subcutaneous nodule that occasionally resembles a sebaceous cyst.
Merkel cell carcinoma This neoplasm is a dermal malignancy of neuroendocrine origin. It usually appears as a red to violaceous dermal papule or nodule on the head and neck of elderly patients, although all age groups are affected.41 The treatment of choice is wide local excision with or without ELND.
Local recurrences are frequent, and distant metastases occur in
Table 2 AJCC 2002 TNM Classification35
T classification
T1
Characteristics
Node Size, Number, or Site
TNM Classification
1.0 mm
a: Without ulceration and Clark

level II or III
b: With ulceration or Clark level
IV or V
T2
1.012.0 mm
a: Without ulceration
b: With ulceration
T3
2.014.0 mm
b: With ulceration
T4
> 4.0 mm
b: With ulceration
One lymph node
a: Micrometastasis*
b. Macrometastasis
N2
23 lymph nodes
a: Micrometastasis*
b. Macrometastasis
c: In-transit met(s)/satellites(s)
without metastatic lymph nodes
N3
4 or more metastatic lymph nodes, matted lymph nodes,

or combination of in-transit met(s)/satellite(s) with
metastatic lymph nodes
N classification
N1
M classification
M1a
Distant skin, subcutaneous, or lymph node mets
Normal LDH
M1b
Lung mets
Normal LDH
M1c
All other visceral mets

Any distant mets
Normal LDH
Elevated LDH with any M
*Micrometastases are diagnosed after sentinel or elective lymphadenectomy.

Macrometastases are defined as clinically detectable nodal metastases confirmed
by therapeutic lymphadenectomy; the term also

applies to nodal metastases that exhibit gross extracapsular extension.
AJCCAmerican Joint Committee on Cancer LDlactic dehydrogenase metsmetastases

October 2002 Update
ACP Medicine
Table 3 AJCC 2002 Staging System35

No. + Nodes
Node Size
Distant Metastasis 5-Year Survival 10-Year Survival
Pathologic Stage
TNM
IA
T1a
<1
No
95.3 0.4
87.9 1.0
IB
T1b
T2a
<1
1.012.0
Yes or level IV, V

No
0
0
90.9 1.0
89.0 0.7
83.1 1.5
79.2 1.1
IIA
T2b
T3a
1.012.0
2.014.0
Yes
No
0
0
77.4 1.7
78.7 1.2
64.4 2.2
63.8 1.7
IIB
T3b
T4a
2.014.0
> 4.0
Yes
No
0
0
63.0 1.5
67.4 2.4
50.8 1.7
53.9 3.3
IIC
T4b
> 4.0
Yes
45.1 1.9
32.3 2.1
IIIA
N1a
N2a
Any
Any
No
No
1
23
Micro
Micro
69.5 3.7
63.3 5.6
63.0 4.4
56.9 6.8
IIIB
N1a
N2a
N1b
N2b
Any
Any
Any
Any
Yes
Yes
No
No
1
23
1
23
Micro
Micro
Macro
Macro
52.8 4.1
49.6 5.7
59.0 4.8
46.3 5.5
37.8 4.8
35.9 7.2
47.7 5.8
39.2 5.8
IIIC
N1b
N2b
N3
Any
Any
Any
Yes
Yes
Any
1
23
4
Macro
Macro
Micro/macro
29.0 5.1
24.0 4.4
26.7 2.5
24.4 5.3
15.0 3.9
18.4 2.5
IV
M1a
M1b
M1c
Any
Any
Any
Any
Any
Any
Any
Any
Any
Any
Any
Any
18.8 3.0
6.7 2.0
9.5 1.1
15.7 2.9
2.5 1.5
6.0 0.9
Ulceration
Thickness (mm)
AJCCAmerican Joint Committee on Cancer
Skin, S.C.
Lung
Other visceral
S.C.subcutaneous
more than one third of patients. Chemotherapy of metastases is

generally disappointing.41
Paget disease A rare malignancy of the skin associated with
an underlying adenocarcinoma,40,41 Paget disease usually presents as an erythematous, often weeping unilateral dermatitis of
the breast that involves the nipple and areola. The differential diagnosis includes eczema, psoriasis, contact dermatitis, and impetigo. For this reason, biopsy of an inflammatory, nonresolving
dermatitis of the nipple or areola is imperative. In Paget disease,
the biopsy will reveal typical pale-staining Paget cells in the epidermis. Appropriate surgical resection of the cutaneous and underlying neoplasm is the treatment of choice; lymph node metastases often occur.41
Extramammary Paget disease Extramammary Paget disease is even more uncommon than Paget disease. It typically
presents as red, often ulcerated, plaques in the perineal areas of
elderly persons.40,41 Lesions may be pruritic or asymptomatic, are
often long-standing, and may have been misdiagnosed as psoriasis, contact dermatitis, or chronic fungal infections. Underlying
associated tumors include rectal and genitourinary carcinomas.
Even without an associated internal malignancy, extramammary Paget disease is difficult to treat, and it is associated with a
high local recurrence rate.41
Angiosarcoma A rare, often highly aggressive vascular malignancy,41 angiosarcoma may appear as multicentric reddishpurple patches or nodules in a lymphedematous limb, such as on
a lymphedematous arm after a mastectomy (Stewart-Treves syndrome). Another presentation is violaceous patches or plaques on
October 2002 Update
the head or neck (especially scalp) of elderly persons. Patients

with angiosarcoma have a poor prognosis, with pulmonary
metastases frequently developing despite surgery or radiation.41
Dermatofibrosarcoma protuberans Dermatofibrosarcoma
protuberans is a slow-growing, locally aggressive malignancy
that rarely metastasizes but often recurs. Lesions typically present as firm reddish-brown or purple nodules, usually on the
trunk or nonsun-exposed extremities. The differential diagnosis
includes keloids and benign dermatofibroma. Young adults are
most often affected, although the tumor may occur at any age.
Wide local excision with or without Mohs micrographic surgery
offers the best chance of cure.41
kaposi sarcoma
Kaposi sarcoma (KS) is a multicentric cutaneous neoplasm that
has several distinct clinical variants.42,43 In spite of its name, KS is
not a true sarcoma. Although the cell of origin has not been clearly established, lymphatic endothelium is a likely candidate.42,43
Epidemiology
In its classic form, KS is an indolent disease of elderly men of
Mediterranean or eastern European background, in which violaceous nodules and plaques develop on the lower extremities.42,43
Before the advent of AIDS, the disorder was rare in the United
States, with an age-adjusted annual incidence of 0.29 per 100,000
population in men and 0.07 per 100,000 population in women.43
In the mid-1960s, a second, endemic form of KS was recognized
in central Africa. African KS, which typically affects young adults
and children, pursues a more aggressive course than classic KS,
with frequent bone, lymph node, and visceral involvement.42,43
ACP Medicine
In 1981, KS became the first tumor to be recognized as part of

AIDS. Primarily affecting homosexual men, KS was an AIDSdefining illness for 30% to 40% of patients in the earliest years of
the HIV epidemic.42 HIV-infected homosexual men have a
73,000-fold increased incidence of KS, and HIV-infected women
and nonhomosexual men have a 10,000-fold increase, compared
with the general United States population.42,43 A fourth variant of
KS has been recognized in iatrogenically immunosuppressed
patients, especially organ transplant recipients. Men are affected
slightly more often than women.42,43
Etiology
The epidemiology of KS has long suggested a transmissible infectious agent or cofactor.42,43 Kaposi sarcomaassociated herpesvirus (KSHV), also known as human herpesvirus type 8 (HHV8), has been detected44 and propagated45 in all variants of KS.
HHV-8 has also been found in patients with body cavitybased
lymphoma, Castleman disease, and angioblastic lymphadenopathy, as well as in certain skin lesions of organ transplant recipients.42 There is a high risk of KS in HIV-infected individuals who
are coinfected with HHV-8; up to half of such patients will develop
KS during long-term (i.e., 10-year) follow-up.46 The mechanism
by which HHV-8 infection leads to KS tumorigenesis is unclear
but probably involves a complex combination of inflammation,
angiogenesis, and neoplastic proliferation.42,43 The prevalence of KS
largely parallels the rate of HHV-8 infection in various populations.43 Although the incidence of HHV-8 infection may be as high
as 2% to 10% in the general population, the incidence of KS is very
low, suggesting that the majority of infections are subclinical.42,43
Host factors, particularly immunosuppression, are crucial in
some populations with KS.42,43 HIV may play an indirect role in
the development of KS through CD4+ T cell depletion and stimulated production of cytokines such as interleukin-1 (IL-1) and IL6.42,43 Immunosuppressive drugs, especially cyclosporine, azathioprine, and prednisone, increase the risk of developing KS, especially in kidney and liver transplant recipients.43 Spontaneous
KS regression has been observed after withdrawal of cyclosporine and corticosteroids.43
Table 4
Despite the prevalence of KS in some ethnic groups, the role

of any possible genetic factors is unclear. An increased incidence
of HLA-DR5 in classic KS patients has been debated.43 Familial
KS is extremely rare, suggesting that genetic factors alone are not
responsible.
Finally, gender appears to be a significant risk factor, especially in classic KS, in which the male-to-female ratio may range
from 3:1 to 10:1.42,43 The reasons for this male predominance remain unclear.42,43
Diagnosis
The clinical manifestations of KS differ among the variants of
the disorder.42,43 In classic KS, faint reddish-purple macules or
patches or purple nodules first appear on the feet, especially the
soles. Lymphadenopathy (especially inguinal) is present on rare
occasions. Lesions may also occasionally develop on the arms
and genital areas. As the disease progresses, the lesions coalesce
into violaceous plaques.
HIV-associated KS usually presents as cutaneous lesions, but
the first lesions may appear in the oral mucosa or lymph nodes.
In contrast to classic KS lesions, HIV-associated KS lesions often
begin on the upper body (face, trunk, or arms). Most typically,
HIV-associated KS lesions are purple-red, often oval, papules
that follow the skin lines in a pityriasis rosealike distribution.42,43
Lesions vary from pink macules to deep-purple plaques [see Figure 5] or may resemble ecchymoses, especially in patients with
low CD4+ T cell counts. Oral lesions are typically red-purple
plaques or nodules on the palate, gingiva, or buccal mucosa. Patients with darker skin may have dark-purple to black lesions or
hyperpigmented plaques.43
As HIV-associated KS progresses, lymphedema may develop
in the feet, scrotum, genitalia, and periorbital regions, and lymphadenopathy (especially inguinal) may occur. Gastrointestinal
lesions are usually submucosal and asymptomatic but may result in gastrointestinal hemorrhage. Pulmonary KS carries a
poor prognosis.43
Laboratory workup of patients with KS should include HIV
antibody testing, complete blood count, fecal occult blood test-
Estimated Probability of 10-Year Survival in Patients with Primary Cutaneous Melanoma37

Probability of 10-Year Survival*
Tumor Thickness/Age
of Patient
Tumor with Extremity Location

Female Patients
Male Patients
Tumor with Axis Location

Female Patients
Male Patients
< 0.76 mm
60 yr
> 60 yr
0.99 (0.981.0)
0.98 (0.950.99)
0.98 (0.950.99)
0.96 (0.890.98)
0.97 (0.930.99)
0.92 (0.820.96)
0.94 (0.880.97)
0.84 (0.700.93)
0.761.69 mm
60 yr
> 60 yr
0.96 (0.920.98)
0.90 (0.800.95)
0.93 (0.850.97)
0.81 (0.640.91)
0.86 (0.760.92)
0.67 (0.500.81)
0.75 (0.620.84)
0.50 (0.330.67)
1.703.60 mm
60 yr
> 60 yr
0.89 (0.800.94)
0.73 (0.570.85)
0.80 (0.650.89)
0.57 (0.380.75)
0.65 (0.500.77)
0.38 (0.240.55)
0.48 (0.350.61)
0.24 (0.140.37)
> 3.60 mm
60 yr
> 60 yr
0.74 (0.530.87)
0.48 (0.280.69)
0.58 (0.360.77)
0.32 (0.160.53)
0.39 (0.210.60)
0.18 (0.080.35)
0.24 (0.130.40)
0.10 (0.040.20)
*Confidence interval = 95%.

Axis location includes the trunk, head, neck, and volar and subungual sites.

October 2002 Update
ACP Medicine
Figure 5 HIV-associated Kaposi sarcoma lesions vary from pink

patches (shown) to deep-purple plaques.
ing, and chest radiograph. CD4+ T cell counts are indicated in

HIV-positive patients. A complete medical history and physical
examination should be performed, with special attention paid to
the presence of opportunistic infections in HIV-infected or otherwise immunosuppressed patients.
Skin biopsy should be obtained in patients with suspected KS.
The histopathologies of all KS variants are similar: spindleshaped cells in the dermis, with extravasated red blood cells present in slits between irregular vascular spaces.47
The clinical differential diagnosis of KS includes dermatofibroma,
purpura, pyogenic granuloma, bacillary angiomatosis, metastatic
melanoma, and BCC. Other histopathologic entities that may resemble KS include angiosarcoma and stasis dermatitis.42,43
Treatment
Classic Kaposi sarcoma The therapy for KS is palliative. In
classic KS, where the disease is indolent and the patients are elderly, aggressive systemic therapy is rarely warranted.42,43 Instead, radiation therapy is the treatment of choice.43,48 KS is very
radiosensitive: single doses of 800 cGy have been used for rapid
palliation in patients with poor prognoses.49 Total doses of 800 to
3,500 cGy have yielded 50% complete responses and 46% partial
responses, with more than half of patients needing no follow-up
treatment for as long as 13 years.48 A treatment regimen equivalent to 3,000 cGy in 10 fractions over 2 weeks has been advocated.48
For patients with classic KS who have only one or two papules,
excisional biopsy may be sufficient for both diagnosis and treatment. Cryotherapy with liquid nitrogen may be useful for isolated
papules. Systemic therapy for classic KS may be indicated in cases of
extensive cutaneous disease or visceral involvement. Single-agent
chemotherapy with vinca alkaloids (vincristine or vinblastine) is
most commonly used. Low-dose recombinant interferon alfa may
also be effective in classic KS; however, side effects (fever, chills, myalgias, and fatigue) may not be well tolerated by elderly patients.42,43
HIV-associated Kaposi sarcoma Although KS is more aggressive in HIV-infected patients, the extent of immune suppression and the presence of opportunistic infections or other
systemic illnesses may be of equal importance in staging, determining prognosis, and choosing appropriate therapy.42,43 Clinical features that were traditionally associated with a more fa+
vorable outcome included a CD4 T cell count higher than 200
October 2002 Update
cells/mm3, a lack of systemic illness, KS limited to the skin or

lymph nodes, and minimal (i.e., not nodular) oral KS; poor risk
factors included a CD4+ T cell count below 200 cells/mm3, KSassociated lymphedema, visceral KS, ulcerated KS, nodular
oral KS, and opportunistic infection.50 With the advent of highly active antiretroviral therapy (HAART), however, physicians
treating patients with HIV-associated KS now have the opportunity to influence and even reverse immune suppression by
affecting both HIV viral load and CD4+ T cell count. Regression
of KS has been observed after initiation of HAART, often during the first few months of therapy51; consequently, this is often
first-line therapy in HIV-associated KS.43
Local therapy is a reasonable approach in KS patients with
limited disease, those with infectious complications, and those
who cannot tolerate systemic therapy.49 Specific antitumor therapy has not been shown to improve overall survival.42,43 Radiation
therapy is effective in HIV-associated KS in doses similar to those
for classic KS (see above). Responses in HIV-associated KS are
generally short-lived, however.43 Topical alitretinoin (9-cis-retinoic
acid) gel may be effective in HIV-associated KS and has been approved by the FDA for this use.52 Intralesional injections of vinblastine or interferon have also been useful in selected lesions.42,43
Cryotherapy with liquid nitrogen is effective for small lesions49;
however, cryotherapy is contraindicated in dark-skinned patients
in whom posttreatment hypopigmentation may appear much
worse cosmetically than the original KS lesion.
Systemic therapy has included conventional chemotherapy
and biologic response modifiers. Single-agent chemotherapeutic
regimens have response rates of 30% to 70%.42,43 In the past, combination chemotherapy (e.g., doxorubicin, bleomycin, and vincristine) was complicated by profound bone marrow suppression and frequent opportunistic infections. The advent of
hematopoietic colony-stimulating factors (e.g., granulocyte
colony-stimulating factor) and Pneumocystis carinii prophylaxis
reduced these complications.
The development of liposomally encapsulated anthracyclines
(e.g., doxorubicin and daunorubicin) represents an important new
option in KS treatment. In a randomized study of 258 patients
with advanced AIDS-associated KS, those who received pegylated liposomal doxorubicin had significantly higher response rates
than those who received standard combination chemotherapy
with doxorubicin, bleomycin, and vincristine.53 Paclitaxel has also
had good responses in patients with advanced KS.54
Promising investigative approaches for HIV-associated KS include combination therapy with antiretroviral agents and specific
antitumor therapyand, potentially, therapy targeting HHV-8.42,43
Complications
Bacterial infections and sepsis are common with ulcerated tumors of the legs and feet. Opportunistic infections may intervene, especially in patients with very low CD4+ T cell counts.
Prognosis
The total CD4+ T cell count is the most important predictor of
survival in HIV-associated KS.50 Large tumor burdens,50 lymphedema, and pulmonary KS are also predictive of poorer outcomes.50,54
Cutaneous Lymphoma
Lymphomas may be of B cell or T cell lineage and may involve the skin primarily or secondarily [see 12:IV Principles of
Cancer Treatment]. B cell lymphomas, particularly non-Hodgkin
ACP Medicine
Figure 6 Cutaneous T cell lymphoma is shown in the large-patch stage (a) and as tumor-stage mycosis fungoides (b).
lymphomas, may involve the skin secondarily in advanced disease. They typically appear as reddish-purple subcutaneous
plaques or nodules. Primary B cell lymphomas of the skin are
even rarer. They appear as reddish nodules that often remain localized to the skin but may progress to systemic disease. The
vast majority of primary cutaneous lymphomas fall into the
spectrum of cutaneous T cell lymphoma (CTCL).
CTCL is a rare skin disorder that is often still referred to as mycosis fungoides (MF).55,56 MF is actually the largest subset of
CTCL; the two terms, however, are often used interchangeably.
The leukemic variant of MF is termed Szary syndrome.55 Another variant of CTCL is associated with human T cell lymphotropic
virus type I (HTLV-I) and is part of the spectra of adult T cell lymphoma/leukemia and peripheral T cell lymphoma.55
epidemiology
Approximately 1,000 new cases of CTCL are diagnosed in the
United States each year.55,56 From 1973 to 1984, the incidence of
CTCL rose from 0.19 per 100,000 population to 0.42 per 100,000
population. CTCL primarily affects middle-aged adults; the median
age at presentation is 50 years.57 The male-to-female ratio is approximately 2:1; blacks are twice as likely as whites to develop CTCL.55,57
etiology
Host susceptibility and an environmental antigen, perhaps
viral, are hypothesized as playing important roles in the pathogenesis of CTCL.55 Genetic factors may be related to major histocompatibility antigens, such as an increase in HLA-DR5 in
CTCL patients.58 Chronic antigenic stimulation (e.g., infection)
may play an etiologic role.55 For example, HTLV-I infection
may be associated with a peripheral T cell lymphoma with cutaneous involvement; it has unique clinical features, including
hypercalcemia and bone lesions.55
diagnosis
Clinical Manifestations
The clinical manifestations of MF typically evolve over
many months to years. In one study, the mean duration of
symptoms before diagnosis was 7.5 years.59 Flat erythematous
patches, often scaling and occasionally atrophic, begin most
commonly on the trunk and thighs, especially in a so-called
bathing-trunk distribution [see Figure 6]. Lesions are asymptomatic or mildly pruritic and may spontaneously remit or re 2002 WebMD Inc. All rights reserved.
October 2002 Update
spond to topical corticosteroid therapy. Patients may also report improvement after sun exposure.
As MF progresses, patches tend to enlarge and thicken into
plaques. The color may become darker red; in dark-skinned persons, lesions may initially be hyperpigmented or hypopigmented and may acquire an erythematous or violaceous hue. In advanced MF, tumors may develop or transform to a large-cell
lymphoma.55,60,61 In approximately 10% of cases, tumors are the
initial presentation of CTCL (tumor dembl). Generalized erythroderma with circulating atypical T cells (in Szary syndrome) is
the presentation in 5% of CTCL patients.55
Physical examination of patients with suspected CTCL includes complete skin examination, including classification of lesions (patch, plaque, or tumor) and extent of body surface area
involved. Lymph nodes, liver, and spleen should be palpated.
Skin Biopsy
Skin biopsy is necessary for the definitive diagnosis of MF. The
presence of atypical lymphoid cells with hyperconvoluted cerebriform nuclei in clusters in the epidermis (Pautrier microabscesses)
and a bandlike lymphocytic infiltrate in the upper dermis are diagnostic of CTCL.55,56,61 The malignant cell is a T cell, with most of the
cells expressing the panT cell markers CD2, CD3, and CD5.55 The
use of T cell receptor gene rearrangement studies to confirm clonality
in early disease may be an aid to diagnosis.55 Neither immunophenotypic studies nor electron microscopy may be considered as definitively diagnostic of MF; clinicopathologic correlation is necessary.
Laboratory Studies
The laboratory evaluation for CTCL includes complete blood
count, eosinophil count, Szary cell count, assessment of lactic dehydrogenase level, and liver function tests. Bone marrow biopsy
is unnecessary in the absence of circulating leukemic cells. HTLVI testing should be considered for patients with risk factors or
atypical presentations. Lymph node biopsy should be considered
for palpable nodes, especially those larger than 2 cm. Abdominal
computed tomography or chest radiography may be important
in patients with tumors or suspected visceral involvement.
In its early stages, MF may resemble any of a number of benign inflammatory disorders (e.g., drug reaction, eczema, psoriasis, or contact dermatitis). These disorders should be ruled out
before contemplating therapy.
ACP Medicine
treatment
Topical Therapy
Topical therapy is the mainstay of the treatment of early (stage
IA, IB, and IIA), patch, or plaque disease. Early aggressive therapy with radiation and chemotherapy has not proved to be superior to local approaches in controlling disease or improving survival in patients with limited disease.55,56 A rational approach for
early limited (or histologically equivocal) disease is topical corticosteroids.62 Topical nitrogen mustard (mechlorethamine), in either aqueous or ointment form, is the most frequently used topical
chemotherapy and leads to complete remission in patch and plaque
disease in up to 60% to 80% of patients.55,63 Therapy must continue
for prolonged periods (up to 3 years after clearing of lesions). Contact dermatitis develops in about one third of patients.55
Carmustine (BCNU) solution, applied daily to lesions, is another useful regimen. Treatment generally lasts 8 to 16 weeks but
has been continued for up to 6 months. Because systemic absorption can result in bone marrow suppression, complete blood
counts must be monitored.55,63 Recently, a topical retinoid,
bexarotene, was shown to be effective in CTCL; it is approved by
the FDA for use in CTCL.64
Ultraviolet Radiation
Radiation therapy for CTCL takes several forms, from ultraviolet light to ionizing radiation. UVB is useful in stage I disease. In
one study, it resulted in a 71% complete clinical remission rate.
Median time to remission was 5 months, and median duration
was 22 months.65
Another effective approach in MF is the combination of psoralen and UVA (PUVA). In one study, 95% of patients with stage
I CTCL had complete clinical clearing, with a median response
duration of 43 months.66
Radiation Therapy
Total skin electron beam (TSEB) radiation delivers radiotherapy to the skin surface without a significant internal dose. It is especially useful with plaque diseases. Typical doses are 2,400 to 3,600
cGy, fractionated over several weeks with 4 to 9 MeV electron
beam radiation.67 Complete skin remissions are related to stage as
follows: IA, 84% to 96%; IB, 56% to 81%; IIA, 63% to 74%; IIB, 24%
to 53%; III, 26% to 50%; and IVA, 8% to 33%. A 50% relapse-free
survival at 5 years was achieved with IA disease, but most patients
with more advanced disease experienced relapse by 5 years.67
Systemic Therapy
Systemic therapy for CTCL has been undertaken as primary
therapy in advanced disease (stages III through IVB) and as sequential therapy to promote more durable responses in earlier
disease.55,56 Oral bexarotene has yielded response rates of up to
45%, and it is approved by the FDA for use in this disease.68 Another recently approved systemic therapy for CTCL is denileukin
diftitox [DAB(389) IL-2].69 This receptor-targeted cytotoxic fusion
protein binds to the IL-2 receptor on T cells; it achieved a 30% response rate in heavily-pretreated patients with CTCL.70
Extracorporeal photopheresis appears most useful in erythrodermic CTCL and Szary syndrome.49,62 In this treatment, the patient undergoes extracorporeal photopheresis with UVA irradiation to leukocytes after oral ingestion of 8-methoxypsoralen.
Advanced tumor and visceral CTCL have also been treated
with single-agent and combination chemotherapy, including
methotrexate, adenosine analogues, interferon alfa, and retinoids.
October 2002 Update
Combination Therapy
Early aggressive treatment of CTCL (TSEB followed by combination chemotherapy with cyclophosphamide, doxorubicin,
etoposide, and vincristine) provides no survival advantage over
sequential topical therapy.55 Similarly, the addition of systemic
chemotherapy (doxorubicin and cyclophosphamide) or extracorporeal photopheresis after a complete response to TSEB appears to have no impact on survival on early MF and no impact
on relapse-free survival for all stages.69 Other regimens include
interferon alfa and retinoids (isotretinoin) with TSEB, followed
by topical nitrogen mustard. The heterogeneity of reported combination therapy regimens in CTCL makes it virtually impossible to compare results.
complications
The most serious complications of CTCL are infections. Sepsis
from ulcerated cutaneous tumors is a common cause of death.
Visceral CTCL may occur, as may transformation to large cell
lymphoma in some CTCL patients (39% probability after 12
years).60 In long-term survivors with early disease, local therapies (e.g., TSEB or PUVA) may contribute to the development of
other skin cancers (e.g., BCC or SCC) and cataracts.
prognosis
Staging of CTCL is based on an evaluation of type and extent
of skin lesions and extent of lymph node, peripheral blood, and
visceral involvement.55,56,59,61 Many different attempts have been
made to classify CTCL into useful prognostic groups. An early
and still valid study that used the TNM system identified three
major groups: good-risk patients (stages IA, IB, and IIA, with
plaque-only skin disease and no lymph node, blood, or visceral
involvement [median survival, > 12 years]); intermediate-risk patients (stages IIB, III, and IVA, with cutaneous tumors, erythroderma, or plaque disease and node or blood involvement but
no visceral disease or node effacement [median survival, 5
years]); and poor-risk patients (stage IVB, with visceral involvement or node effacement [median survival, 2.5 years]).59
Eosinophilia is also associated with shortened survival.59 Other long-term studies have revealed that stage IA patients do not
have a reduced life expectancy and that fewer than 10% of these
patients experience disease progression to more advanced
stages.71 Survival of patients with generalized patch/plaque MF
(stages IB or IIA), at a median of 11.7 years, is significantly worse
than that of a race-, age-, and sex-matched control population.72
Gender and race appear to have no effect on survival, but older
patients (> 58 years) have shorter disease-specific survivals.55,57
Allan C. Halpern, M.D., has no commercial relationships with manufacturers of
products or providers of services discussed in this subsection.
Patricia L. Myskowski, M.D., has received grant or reseach support from
MedImmune, Inc., and Schering-Plough Corp. and is a consultant for Ligand
Pharmaceuticals, Inc.
Interferon alfa has not been approved by the FDA for use in cutaneous T cell
lymphoma or mycosis fungoides.
References
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2. Grossman D, Leffell DJ: The molecular basis of nonmelanoma skin cancer: new understanding. Arch Dermatol 133:1263, 1997
3. Naylor MF, Farmer KC: The case for sunscreens: a review of their use in preventing
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10. Staples M, Marks R, Giles G: Trends in the incidence of non-melanocytic skin cancer
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11. Elder D, Elenitsas R, Jaworsky C, et al: Tumors and cysts of the epidermis. Levers
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12. Miller SJ: The National Comprehensive Cancer Network (NCCN) guidelines of care
for nonmelanoma skin cancers. Dermatol Surg 26:289, 2000
13. Rowe DE, Carroll RJ, Day CL Jr: Prognostic factors for local recurrence, metastasis,
and survival rates in squamous cell carcinoma of the skin, ear, and lip: implications for
treatment modality selection. J Am Acad Dermatol 26:976, 1992
14. Hall HI, Miller DR, Rogers JD, et al: Update on the incidence and mortality from
melanoma in the United States. J Am Acad Dermatol 40:35, 1999
15. Haluska FG, Hodi FS: Molecular genetics of familial cutaneous melanoma. J Clin
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16. Blackwood MA, Holmes R, Synnestvedt M, et al: Multiple primary melanoma revisited. Cancer 94:2248, 2002
17. Elder DE, Clark WH Jr, Elenitsas R, et al: The early and intermediate precursor lesions of tumor progression in the melanocytic system: common acquired nevi and atypical (dysplastic) nevi. Semin Diagn Pathol 10:18, 1993
18. Carey WP Jr, Thompson CJ, Synnestvedt M, et al: Dysplastic nevi as a melanoma
risk factor in patients with familial melanoma. Cancer 74:3118, 1994
19. Tucker MA, Halpern A, Holly EA, et al: Clinically recognized dysplastic nevi: a central risk factor for cutaneous melanoma. JAMA 277:1439, 1997
20. Binder M, Puespoeck-Schwarz M, Steiner A, et al: Epiluminescence microscopy of
small pigmented skin lesions: short-term formal training improves the diagnostic performance of dermatologists. J Am Acad Dermatol 36:197, 1997
21. Binder M, Schwarz M, Winkler A, et al: Epiluminescence microscopy: a useful tool
for the diagnosis of pigmented skin lesions for formally trained dermatologists. Arch
Dermatol 131:286, 1995
22. Halpern AC: The use of whole body photography in a pigmented lesion clinic. Dermatol Surg 26:1175, 2000
23. Busam KJ, Charles C, Lee G, et al: Morphologic features of melanocytes, pigmented
keratinocytes, and melanophages by in vivo confocal scanning laser microscopy. Mod
Pathol 14:862, 2001
24. Balch CM, Soong SJ, Smith T, et al: Long-term results of a prospective surgical trial
comparing 2 cm vs. 4 cm excision margins for 740 patients with 14 mm melanomas.
Ann Surg Oncol 8:101, 2001
25. Veronesi U, Cascinelli N, Adamus J, et al: Thin stage I primary cutaneous malignant
melanoma: comparison of excision with margins of 1 or 3 cm. N Engl J Med 318:1159,
1988
26. Gershenwald JE, Thompson W, Mansfield PF, et al: Multi-institutional melanoma
lymphatic mapping experience: the prognostic value of sentinel lymph node status in
612 stage I or II melanoma patients. J Clin Oncol 17:976, 1999
27. Kelley MC, Ollila DW, Morton DL: Lymphatic mapping and sentinel lymphadenectomy for melanoma. Semin Surg Oncol 14:283, 1998
28. Chan AD, Morton DL: Sentinel node detection in malignant melanoma. Recent Results Cancer Res 157:161, 2000
29. Thompson JF, Hunt JA, Shannon KF, et al: Frequency and duration of remission after isolated limb perfusion for melanoma. Arch Surg 132:903, 1997
30. Houghton A, Coit D, Bloomer W, et al: NCCN melanoma practice guidelines. Oncology 12:153, 1998
31. Agarwala SS, Kirkwood JM: Adjuvant interferon treatment for melanoma. Hematol
Oncol Clin North Am 12:823, 1998
32. Kirkwood JM, Strawderman MH, Ernstoff MS, et al: Interferon alfa-2b adjuvant
therapy of high-risk resected cutaneous melanoma: the Eastern Cooperative Oncology
Group Trial EST 1684. J Clin Oncol 14:7, 1996
33. Kirkwood JM, Ibrahim JG, Sosman JA, et al: High-dose interferon alfa-2b significantly prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21
vaccine in patients with resected stage IIB-III melanoma: results of intergroup trial
E1694/S9512/C509801. J Clin Oncol 19:2370, 2001
34. Brinckerhoff LH, Thompson LW, Slingluff CL Jr: Melanoma vaccines. Curr Opin
Oncol 12:163, 2000
35. Balch CM, Buzaid AC, Soon SJ, et al: Final version of the American Joint Committee
on Cancer staging system for cutaneous melanoma. J Clin Oncol 19:3635, 2001
36. Balch CM, Soong SJ, Gershenwald JE, et al: Prognostic factors analysis of 17,600
melanoma patients: validation of the American Joint Committee on Cancer melanoma
staging system. J Clin Oncol 19:3622, 2001
37. Guerry D 4th, Synnestvedt M, Elder DE, et al: Lessons from tumor progression: the
invasive radial growth phase of melanoma is common, incapable of metastasis, and indolent. J Invest Dermatol 100:342S, 1993
38. Elder DE, Van Belle P, Elenitsas R, et al: Neoplastic progression and prognosis in

October 2002 Update
melanoma. Semin Cutan Med Surg 15:336, 1996

39. Schuchter L, Schultz DJ, Synnestvedt M, et al: A prognostic model for predicting 10year survival in patients with primary melanoma. Ann Intern Med 125:369, 1996
40. Schwartz RA: Cutaneous metastatic disease. J Am Acad Dermatol 33:161, 1995
41. Demetrius RW, Randle HW: High-risk nonmelanoma skin cancers. Dermatol Surg
24:1272, 1998
42. Antman K, Chang Y: Kaposis sarcoma. N Engl J Med 342:1027, 2000
43. Myskowski PL, Krown SE: Kaposis sarcoma. Sober AJ, Haluska FG, Ed. Skin Cancer. American Cancer Society Atlas of Clinical Oncology. BC Decker, Ontario, 2001
44. Moore PS, Change Y: Detection of herpesvirus-like DNA sequences in Kaposis sarcoma in patients with and without HIV infection. N Engl J Med 332:1181, 1995
45. Foreman KE, Friborg J Jr, Kong WP, et al: Propagation of a human herpesvirus from
AIDS-associated Kaposis sarcoma. N Engl J Med 336:163, 1997
46. Gao SJ, Kingsley L, Hoover DR, et al: Seroconversion to antibodies against Kaposis
sarcomaassociated herpesvirus-related latent nuclear antigen before the development
of Kaposis sarcoma. N Engl J Med 335:233, 1996
47. Niedt GW, Myskowski PL, Urmacher C, et al: Histologic predictors of survival in
acquired immunodeficiency syndromeassociated Kaposis sarcoma. Hum Pathol
23:1419, 1992
48. Cooper JS, Sacco J, Newall J: The duration of local control of classic (nonAIDS-associated) Kaposis sarcoma by radiotherapy. J Am Acad Dermatol 19:59, 1988
49. Dezube BJ: AIDS-related Kaposi sarcoma: the role of local therapy for a systemic
disease. Arch Dermatol 136:1554, 2000
50. Krown SE, Testa MA, Huang J: AIDS-related Kaposis sarcoma: prospective validation of the AIDS Clinical Trials Group staging classification. J Clin Oncol 15:3085, 1997
51. Krischer J, Rutschmann O, Hirschel B, et al: Regression of Kaposis sarcoma during
therapy with HIV-I protease inhibitors: a prospective pilot study. J Am Acad Dermatol
38:594, 1998
52. Duvic M, Friedman-Kien AE, Looney DJ, et al: Topical treatment of cutaneous lesions of acquired immunodeficiency syndromerelated Kaposi sarcoma using alitretinoin gel: results of phase 1 and 2 trials. Arch Dermatol 136:1461, 2000
53. Northfelt DW, Dezube BJ, Thommes JA, et al: Pegylated-liposomal doxorubicin
versus doxorubicin, bleomycin, and vincristine in the treatment of AIDS-related Kaposis sarcoma: results of a randomized phase III clinical trial. J Clin Oncol 16:2445, 1998
54. Welles L, Saville MW, Lietzau J, et al: Phase II trial with dose titration of paclitaxel
for the therapy of human immunodeficiency virusassociated Kaposis sarcoma. J Clin
Oncol 16:1112, 1998
55. Seigel RS, Pandolfino T, Guitart J, et al: Primary cutaneous T-cell lymphoma: review
and current concepts. J Clin Oncol 18:2908, 2000
56. Duvic M, Cather JC: Emerging new therapies for cutaneous T-cell lymphoma. Dermatol Clin 18:147, 2000
57. Weinstock MA, Reynes JF: The changing survival of patients with mycosis fungoides: a population-based assessment of trends in the United States. Cancer 85:208,
1999
58. Jackow CM, McHam JB, Friss A, et al: HLA-DR5 and DQB1*03 class II alleles are associated with cutaneous T-cell lymphoma. J Invest Dermatol 107:373, 1996
59. Sausville EA, Eddy JL, Makuch RW, et al: Histopathologic staging at initial diagnosis of mycosis fungoides and the Szary syndrome: definition of three distinctive prognostic groups. Ann Intern Med 109:372, 1988
60. Diamandidou E, Colome-Grimmer M, Fayad L, et al: Transformation of mycosis
fungoides/Szary syndrome: clinical characteristics and prognosis. Blood 92:1150, 1998
61. Fung MA, Murphy MJ, Hoss DM, et al: Practical evaluation and management of cutaneous lymphoma. J Am Acad Dermatol 46:325, 2002
62. Zackheim HS, Kashani-Sabet M, Amin S: Topical corticosteroids for mycosis fungoides: experience in 79 patients. Arch Dermatol 134:949, 1998
63. Ramsay DL, Meller JA, Zackheim HS: Topical treatment of early cutaneous T-cell
lymphoma. Hematol Oncol Clin North Am 9:1031, 1995
64. Breneman D, Duvic M, Kuzel T, et al: Phase 1 and 2 trial of bexarotene gel for skindirected treatment of patients with cutaneous T-cell lymphoma. Arch Dermatol
138:398, 2002
65. Ramsay DL, Lish KM, Yalowitz CB, et al: Ultraviolet-B phototherapy for early-stage
cutaneous T-cell lymphoma. Arch Dermatol 128:931, 1992
66. Herrmann JJ, Roenigk HH Jr, Hurria A, et al: Treatment of mycosis fungoides with
photochemotherapy (PUVA): long-term follow-up. J Am Acad Dermatol 33:234, 1995
67. Jones GW, Hoppe RT, Glatstein E: Electron beam treatment for cutaneous T-cell
lymphoma. Hematol Oncol Clin North Am 9:1057, 1995
68. Duvic M, Hymes K, Heald P, et al: Bexarotene is effective and safe for treatment of
refractory advanced-stage cutaneous T-cell lymphoma: multinational phase IIIII trial
results. J Clin Oncol 19:2456, 2001
69. Wilson LD, Licata Al, Braverman IM, et al: Systemic chemotherapy and extracorporeal photochemotherapy for T3 and T4 cutaneous T-cell lymphoma patients who have
achieved a complete response to total skin electron beam therapy. Int J Radiat Oncol
Biol Phys 32:987, 1995
70. Olsen E, Duvic M, Frankel A, et al: Pivotal phase III trial of two dose levels of denileukin diftitox for the treatment of cutaneous T-cell lymphoma. J Clin Oncol 19:376,
2001
71. Kim YH, Jensen RA, Watanabe GL, et al: Clinical stage IA (limited patch and
plaque) mycosis fungoides: a long-term outcome analysis. Arch Dermatol 132:1309,
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72. Kim YH, Chow S, Varghese A, et al: Clinical characteristics and long-term outcome
of patients with generalized patch and/or plaque (T2) mycosis fungoides. Arch Dermatol 135:26, 1999
ACP Medicine
XI
B E N I G N C U TA N E O U S T U M O R S

General Considerations
classification
Tumors of the cutaneous surface may arise from the epidermis, dermis, or subcutaneous tissue or from any of the specialized cell types in the skin or its appendages. Broad categories
include tumors derived from epithelial, melanocytic, or connective tissue structures. Within each location or cell type, lesions are classified as benign, malignant, or, in certain cases,
premalignant.1,2
Benign epithelial tumors include tumors of the surface epidermis that form keratin; tumors of the epidermal appendages;
and cysts of the skin.
Melanocytic, or pigment-forming, lesions are very common.
One of the most frequently encountered forms is the nevus cell
nevus. The term nevus has two meanings: a malformation commonly involving the entire skin layer (tissue nevus) and a benign growth of melanocytic cells (nevus cells).
Nevus cells are closely related to melanocytes and may be
defined as modified neuroectodermal melanin-producing elements. The word mole, often used as a synonym for nevus, is an
imprecise term because it refers to birthmarks that may or may
not contain nevus cells. Neural tumors, such as neurofibromas,
are related to melanocytic tumors because both are of neuroectodermal origin.
Tumors that are derived from connective tissue include fibromas, histiocytomas, lipomas, leiomyomas, and hemangiomas.
histologic evaluation
For cases in which it is not possible to distinguish clinically
between benign and malignant cutaneous tumors, histopathologic examination is extremely important. The type of biopsy
performed depends on the location, size, and nature of the lesion and on cosmetic considerations. In all cases, the clinical features must be correlated with the distinctive microscopic appearance of the tumor to confirm or exclude the diagnosis on
the basis of physical examination.
Epithelial Tumors
ic keratosesthe sign of Leser-Trelatwhich are associated

with internal malignancy, particularly adenocarcinoma. The
true value of the sign of Leser-Trelat as a marker of underlying
malignancy is a subject of debate.
Dermatosis papulosa nigra is similar to seborrheic keratosis,
but it is seen in dark-skinned races; it usually appears on the
face and presents at an earlier age than seborrheic keratosis [see
Figure 2].
The differential diagnosis of seborrheic keratosis and dermatosis papulosa nigra includes lentigo, wart, and nevus cell
nevus. A biopsy may be required to rule out a pigmented basal
cell carcinoma or, in the case of an inflamed seborrheic keratosis, malignant melanoma or squamous cell carcinoma. A shave
biopsy that includes the base of the lesion may be performed before treatment with curettage.
Treatment
Curettage is a satisfactory treatment. When multiple lesions
are present, anesthesia may be achieved by freezing the affected
area with an ethyl chloride spray before performing curettage.
For larger lesions, electrodesiccation is unnecessary and may
cause scarring. Smaller lesions may be successfully treated with
electrodesiccation, cryotherapy, or topical application of 50%
trichloroacetic acid.
epidermal nevus
Diagnosis
Epidermal nevus consists of closely set, skin-colored or hyperpigmented papules that either may be localized to one side
of the body and arranged in linear fashion or may be widespread. When localized, the condition is termed nevus unius lateris [see Figure 3]. When widespread, it is called systematized
nevus. Lesions affect about one in 1,000 people; they are present
at birth or appear in early childhood. The lesions have no malignant potential but may constitute a serious cosmetic problem.
Histologically, epidermal nevi exhibit hyperplasia of the epidermis; the structure or maturation of these lesions is not significantly different from that of normal epidermis. One variant, the
inflammatory linear verrucous epidermal nevus, shows psori-
seborrheic keratosis
Diagnosis and Classification

Seborrheic keratosis (seborrheic wart) consists of a sharply
circumscribed, rough or smooth papule or plaque that is 1 mm
to several centimeters in size and dirty yellow or light to dark
brown in color. The lesions often have the appearance of being
stuck on and are characterized by prominent follicular plugging. They are most common in light-skinned races, first appearing in adults on the face and upper trunk and occurring
more frequently with increasing age [see Figure 1].
Transient eruptive seborrheic keratoses have been associated
with inflammatory skin conditions, including erythroderma associated with psoriasis and drug eruptions. These keratoses
tend to resolve when the skin inflammation clears.3 These transient keratoses should be distinguished from eruptive seborrhe 2002 WebMD Inc. All rights reserved.
June 2002 Update
Figure 1 Verrucous, hyperpigmented lesions of seborrheic keratosis

with a stuck-on appearance are present on the trunk of this patient.
ACP Medicine
DERMATOLOGY:XI Benign Cutaneous Tumors1
skeletal, urogenital, cardiovascular, and nervous systems.5 This

rare syndrome is apparent at birth; the presence of widespread
epidermal nevi should trigger a search for associated anomalies.
Nevus comedonicus is a variant of an epidermal nevus affecting the pilosebaceous structures; it occurs as clusters of
comedonelike papules, usually in a linear pattern on the face,
neck, upper arms, and trunk.5
Nevus sebaceous is a benign tumor that shows sebaceous differentiation. The lesion has a yellow hue and a granular surface
and occurs in a linear pattern on the face or scalp. At puberty,
nevus sebaceous may become more elevated; in adulthood,
there is an associated risk of basal cell carcinoma.
Treatment
Figure 2 Dermatosis papulosa nigra, as seen on the face, appears in
dark-skinned races at a younger age than seborrheic keratosis.
Treatment of epidermal nevi with electrodesiccation and

curettage is often unsuccessful and may cause scarring. Surgical
or laser removal may be indicated for localized lesions. Disturbances involving other organ systems must be evaluated and
managed appropriately through a multidisciplinary approach.
Tumors of the Epidermal Appendages
There are a large number of benign tumors of the hair follicles, the sebaceous glands, and the apocrine and eccrine glands.
Solitary skin tumors of these epidermal appendages are typically nonhereditary, whereas multiple neoplasms may show an
autosomal dominant inheritance pattern.6
sebaceous hyperplasia
Figure 3 Epidermal nevus with discrete and confluent brown papillomas is present in a somewhat linear arrangement.
Figure 4 Skin-colored or yellowish, often umbilicated papules of

sebaceous hyperplasia, as seen on the forehead, may clinically resemble
basal cell carcinomas.
asiform hyperplasia. Another variant, which is common in systematized nevi, shows granular degeneration of epidermolytic
hyperkeratosis histologically. This type of epidermal nevus is a
mosaic genetic disorder of suprabasal keratin. Mutations in the
K10 gene are associated with lesions of the skin, whereas the
normal gene is found in unaffected skin.4
Variants
The epidermal nevus syndrome involves a spectrum of different types of epidermal nevi associated with disturbances in the
June 2002 Update
Sebaceous hyperplasia is a common clinical condition that

appears as multiple skin-colored or yellowish, often umbilicated papules or plaques, usually on the forehead, nose, or cheeks
of persons after the fifth decade of life. These lesions consist of
enlarged sebaceous gland lobules with a central dilated duct.
Sebaceous hyperplasia may respond to cryotherapy with liquid
nitrogen or the application of a dilute solution of trichloroacetic
or bichloroacetic acid. Lesions may sometimes be confused clinically with basal cell carcinoma [see Figure 4]. In the familial
form of this disorder, onset occurs in puberty; with the passage
of time, the lesions increase in extent over the face, neck, and
upper thorax. This condition must be distinguished from acne
vulgaris, rosacea, and the angiofibromas of tuberous sclerosis.
Three patients with this condition responded favorably to oral
isotretinoin at a dosage of 1 mg/kg/day. To maintain the response, this dosage was tapered after 6 weeks.7 Isotretinoin is a
known teratogen that cannot be given to women of childbearing age unless strict precautions are observed [see 2:XII Acne
Vulgaris and Related Disorders].
trichoepitheliomas
Trichoepitheliomas usually present as multiple yellowishpink, translucent papules distributed symmetrically on the
cheeks, eyelids, and nasolabial areas [see Figure 5]. Often inherited as an autosomal dominant trait, the papules first appear at
puberty and grow slowly for years. The gene for multiple familial trichoepitheliomas has been mapped to chromosome 9p21.8
Lesions may be confused both clinically and histologically with
basal cell carcinoma, though trichoepithelioma usually shows
differentiation toward the formation of hair. A single or localized trichoepithelioma may be removed by electrodesiccation
and curettage. Multiple lesions are difficult to treat and may be
a cosmetic problem.
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may be a recurrence of the lesion. Occasionally, the entire cyst

has to be excised. Preliminary treatment with a systemic antibiotic, such as erythromycin, and warm-water compresses applied three or four times daily may be instituted if the cyst is inflamed and infected. When the inflammation and infection resolve, the lesion can be removed. Repeated episodes of
infection may cause fibrosis, after which the cyst may have to
be surgically excised.
Other Cysts
Figure 5 Symmetrical papules of trichoepithelioma appear on the

eyelids and nasolabial areas and may be inherited as an autosomal
dominant trait.
The pilar cyst, which is less common, has a wall that contains
keratin similar to that found in hair. The contents of these cysts
are semifluid and often have a rancid odor.
A milium is similar to an epidermoid cyst but differs mainly
in size. Milia are white, hard subepidermal keratin cysts, 1 to 2
mm in diameter, that commonly arise spontaneously on the
face [see Figure 8]. They may also arise secondarily in scars or in
association with certain bullous diseases. Incision and expression of contents with a comedo extractor may be performed.
Familial Tumor Syndromes
Multiple cutaneous neoplasms may be a feature of familial
tumor syndromes that are thought to be mediated by inactiva-
Figure 6 Syringomasbenign tumors of eccrine ductsare commonly

seen on the face, especially on the lower eyelids.
syringomas
Syringomas usually present in groups of multiple small
papules that are distributed symmetrically over the face, especially on the lower eyelids [see Figure 6]. Eruptive syringoma, a
rare condition, is characterized by widespread lesions.
Histologically, there is a benign proliferation of the eccrine
ducts.
Figure 7 This large epidermoid cyst has a central pore, contains thick
keratinous material, and has a lining that resembles the epidermis.
epidermoid cyst
Diagnosis
Commonly called wens, epidermoid cysts have a lining that
resembles the epidermis. Several types of cyst exist, but they are
usually clinically indistinguishable from one another. On histologic examination, most of these cysts appear to be derived
from hair follicles.
The epidermoid cyst is commonly located on the back and
consists of one or more slow-growing, elevated, firm nodules,
often with a central pore [see Figure 7]. The diameters of the lesions vary from 0.2 to 5.0 cm.
Treatment
The epidermoid cyst may be incised with a pointed scalpel
to express its wall and contents, which consist of a thick keratinous material. If the cyst wall is not completely removed, there
June 2002 Update
Figure 8 Milia, which are multiple small subepidermal inclusion

cysts, can be observed in the periorbital area of this patient.
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tion of tumor suppressor genes. It is important to recognize

these syndromes because they may be associated with underlying malignancies.
muir-torre syndrome
Muir-Torre syndrome (MTS), previously known as Torre syndrome, consists of sebaceous gland neoplasms that are associated with visceral carcinoma and that arise from colonic epithelium.
Sebaceous gland tumors may include, in decreasing order of frequency, adenomas, epitheliomas, and carcinomas.9 Keratoacanthomas and sebaceous hyperplasia are also seen in patients with
MTS. Colorectal cancer develops in 51% of patients with MTS a
decade earlier than it develops in the general population. Genitourinary cancer develops in 24% of MTS patients. A germline
mutation in the DNA mismatch repair gene hMSH2 has been
identified in patients with MTS. Predictive diagnosis in family
members should be preceded by careful genetic counseling.9
gardner syndrome
Gardner syndrome consists of the triad of intestinal polyposis, bony tumors, and soft tissue lesions; it has an autosomal
dominant inheritance. The colonic polyps eventually become
malignant if left untreated. Soft tissue lesions include epidermoid cysts, sebaceous cysts, desmoid tumors, and scattered
lentigines on the head and extremities.10
cowden syndrome
Cowden syndrome is characterized by facial trichilemmomas and acral fibromas, and it is associated with an increased
risk of cancer of the breast, thyroid, and gastrointestinal tract.
This rare genodermatosis, which is also known as multiple
hamartoma syndrome, is inherited as an autosomal dominant
trait. It is important to make a prompt diagnosis of this syndrome because of the high risk of malignancy, particularly cancer of the breast in women.
birt-hogg-dub syndrome
Birt-Hogg-Dub syndrome (BHDS) is an autosomal dominant multisystem disorder characterized by the cutaneous triad
of fibrofolliculomas, trichodiscomas, and acrochordons. Fibrofolliculomas are benign tumors of the hair follicle. Fibrofolliculomas are firm, pink or skin-colored papules measuring 1 to 3
mm that appear on the face, particularly the nose, earlobes, and
forehead. In the original kindred described by Birt (a dermatologist), Hogg (a pathologist), and Dub (a pathologist), family
members were afflicted with medullary carcinoma of the thyroid. Subsequently, there appeared reports of patients with
BHDS who had intestinal polyps, adenocarcinoma of the colon,
parathyroid adenomas, and renal cell carcinoma. The skin tumors begin in early adulthood; systemic tumors appear years
later. In families with recognized renal cell carcinoma, BHDS
may account for 6% of the cases.11,12
Melanocytic (Pigment-Forming) Tumors
Benign tumors of pigment-forming cells, including those
containing nevus cells (melanocytic nevi) and those of epidermal or dermal melanocytes, are of neuroectodermal origin.
melanocytic nevus
Melanocytic nevus, also called nevus cell nevus, has a characteristic life history of evolution and involution. Melanocytic nevi
June 2002 Update
are the most common of all skin tumors; each young adult has
an average of 20 to 40 of them. Their incidence increases with
age up to the second or third decade of life, after which they occur less commonly.
Risk Factors for Melanoma

An increase in the total number of melanocytic nevi is a risk
factor for melanoma.13 In a study of 716 patients with newly diagnosed melanoma, an increased number of small nevi (25 to
49) was associated with a twofold increase in risk of melanoma;
greater numbers of nevi were associated with further increased
risk.14 The presence of one clinically dysplastic nevus was associated with a twofold increase in risk of melanoma; and 10 or
more, with a 12-fold increase in risk. Criteria for dysplastic nevi
included large size (over 5 mm), flatness (entirely macular or
having a macular component), and at least two of the following:
irregular pigmentation, asymmetry, and indistinct borders [see
2:X Malignant Cutaneous Tumors]. The presence of freckling conferred additional risk of melanoma for all types of nevi.
The relation between sun exposure and melanocytic nevi has
been investigated to determine what environmental factors influence melanoma and to facilitate preventive measures. Studies suggest that melanocytic nevi are more common on sun-exposed skin sites and reach a peak incidence earlier in age on
these sites than on covered areas of the body.15 A study of Australian schoolchildren showed an increasing prevalence of nevi
with decreasing latitude, particularly in children 6 and 9 years
of age.16 Sun exposure during childhood was considered to be a
factor in the development of melanocytic nevi and an associated
risk factor for melanoma.16 In Australia, however, sun exposure
may be sufficient to maximally induce nevi regardless of latitude. Further studies need to be performed on persons living at
higher latitudes to see whether the relation between sun exposure and nevi continues into adulthood.
Diagnosis
A melanocytic nevus that is present at birth or appears during the first year of life is considered to be congenital. Certain
syndromes are associated with congenital nevi, including epidermal (linear sebaceous) nevus syndrome, neurocutaneous
melanosis, premature-aging syndrome, and occult spinal dysraphism or tethered cord syndrome.17 Various neuroectodermal
defects and multisystem abnormalities may also be present. Giant congenital melanocytic nevi are associated with an increased risk of melanoma (see below).
Acquired melanocytic nevi vary considerably in form, ranging from flat to pedunculate. They may be hairy or hairless and
may be skin colored, dark brown, or even black. Nevi that are
flat and darkly pigmented are called junctional nevi. Slightly
raised nevi are often compound; that is, they contain both epidermal and dermal components. Nevi that are predominantly
intradermal are usually more elevated and contain less pigment
than compound or junctional nevi. Nevi that are papillomatous,
dome shaped, or pedunculate are usually intradermal [see Figures 9 through 11].
The differential diagnosis of melanocytic nevi includes
ephelis (freckle), lentigo, caf au lait spot (see below), wart, seborrheic keratosis, and skin tag (a small pedunculate protrusion
of skin that does not contain nevus cells). Ephelis is a tan macule, commonly seen in children after sun exposure; it often disACP Medicine
lowed for up to 13 years had no adverse developments, a finding indicative of the benign nature of this lesion.
Treatment
Figure 9 A flat junctional nevus with dark pigmentation is

seen in this patient.
No treatment is required for melanocytic nevi. However,

shave biopsy or excisional biopsy may be performed for cosmetic reasons or when a nevus is subject to irritation because of
pressure from clothing or because it is located in an intertriginous area. Patients should be followed with serial photographs. Biopsy should be performed for nevi that appear
prone to malignant transformation; nevi that show severe dysplasia should be removed. Removal of mildly or moderately
dysplastic nevi is advocated by some but not all experts [see
2:XI Malignant Cutaneous Tumors].
caf au lait spots
Caf au lait spots are common benign congenital or acquired
birthmarks. They are tan, round to oval macules ranging in size
from several millimeters to 10 to 20 cm. They can occur on any
area of the body but are more common on the trunk, buttocks,
and lower extremities. The presence in a prepubertal child of
five or more caf au lait spots larger than 0.5 cm may be a
marker for neurofibromatosis-1 (NF-1) (see below).19 Histologically, caf au lait spots show an increased number of dihydroxyphenylalanine (DOPA)-positive melanocytes that produce an
increased concentration of melanosomes. The caf au lait spots
seen in Albright hereditary osteodystrophy are usually unilateral and show jagged rather than smooth margins. An association of juvenile xanthogranulomas with caf au lait macules
carries an increased risk of underlying systemic disorders, including leukemia.20
halo nevus
Figure 10 This slightly raised compound nevus typically has

less pigmentation than a junctional nevus.
A halo nevus consists of an acquired zone of hypopigmentation surrounding a pigmented tumor, most commonly a compound nevus [see Figure 12]; other tumors, even malignant
melanoma, may also be surrounded by a depigmented halo.
The halo lesion typically involutes during a period of months in
the absence of clinical signs of inflammation. Histologically, a
chronic lymphocytic infiltrate surrounds the nevus cells, which
may represent an autoimmune phenomenon.
spindle cell nevus
Formerly called benign juvenile melanoma, spindle cell nevus usually arises in childhood as a pink or reddish-brown,
smooth or slightly scaly, firm papule with a predilection for the
face, especially the cheeks [see Figure 13].21 Although benign,
spindle cell nevus may closely resemble a malignant melanoma.
Excisional biopsy is therefore advisable in many cases.
mongolian spot
Figure 11 A skin-colored intradermal nevus with a dome-shaped

configuration is seen on the face.
appears in the winter. Lentigo, also called senile lentigo or liver

spot, is a tan or brown macule commonly seen on exposed skin
areas, such as the face, the backs of the hands, and the neck. The
labial melanotic macule is a distinct entity that appears in adults
as a well-defined brown or black pigmented macule on the lip.
In a study of 79 patients, the majority of melanocytic lesions
(94%) were on the central third of the lower lip, suggesting that
exposure to ultraviolet light has a causative role.18 Patients fol 2002 WebMD Inc. All rights reserved.
June 2002 Update
The mongolian spot is a bluish macule that is seen in newborns of dark-skinned races. The discoloration is caused by
persistence of dermal melanocytes, often in the lumbosacral region [see Figure 14]. The lesion usually disappears by 3 or 4
years of age.
blue nevus
The common blue nevus occurs as a solitary, sharply circumscribed, blue-black papule [see Figure 15]. This malformation consists of a group of melanocytes with long, thin surface
projections in the middle and lower thirds of the dermis and
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nevus of ota
The nevus of Ota occurs in infancy or appears in adolescence
as a blue-gray macule in the distribution of the trigeminal nerve.
The lesion is unilateral in 90% of cases. Asian females are most
commonly affected. Histologically, a benign dendritic melanocytosis is present in the papillary and upper reticular dermis. Highenergy fluences of the Q-switched ruby laser results in lightening of the lesion, without scarring, after a few treatments.22
becker nevus
Figure 12 The halo nevus may represent an autoimmune phenomenon;

a zone of hypopigmentation may appear around a nevus, with subsequent involution of the pigmented tumor.
A malformation of epidermal melanocytes, Becker nevus occurs as a large area of hyperpigmentation and increased hair
growth and is usually located on one shoulder. It appears most
commonly in males during adolescence [see Figure 16]. Underlying bony and soft tissue abnormalities may be associated with
this disorder.23
Light microscopy reveals hyperpigmentation of the basal layer of the epidermis, with melanin-containing phagocytes in the
dermis but no nevus cells.
congenital giant pigmented nevus
Figure 13 The spindle cell nevus is an active compound nevus that

may be difficult to distinguish histologically from a melanoma.
Giant pigmented nevus is an uncommon birthmark appearing sporadically in one in 20,000 live births. Its features are different from those of an ordinary acquired nevus. Lesions are often
darkly pigmented, hairy, and slightly infiltrated, eventually becoming verrucous or nodular. They tend to occur in the distribution of a dermatome and may be quite extensive, as in bathing
trunk nevus [see Figure 17]. Satellite lesions may be present. The
condition not only is of cosmetic concern but also has a high association with malignant melanoma, with a reported 10% to 15%
of nevus patients developing melanoma. Histologic features of
an ordinary compound nevus, an intradermal nevus, a neural
nevus, or a blue nevus may be present.1 Treatment consists of
multiple operations to excise as much of the lesion as possible.
neurocutaneous melanosis
Figure 14 The bluish pigmentation of a mongolian spot is seen in

the lumbosacral area and is caused by the persistence of dermal
melanocytes.
in subcutaneous fat. The common blue nevus does not show
a tendency toward malignant transformation. The cellular
blue nevus, which appears as a blue-black nodule or an indurated plaque, contains two types of cells: spindle shaped
and rounded. The cellular blue nevus may in rare instances
become malignant.
June 2002 Update
Lesions on the scalp and neck may be associated with neurocutaneous melanosis of the leptomeninges that can be complicated by epilepsy, mental retardation, or central nervous system
melanoma. Large congenital melanocytic nevi (LCMN) carry a
poor prognosis in the presence of CNS signs or symptoms such
as abnormal reflexes, hydrocephalus, and papilledema. Posterior axial LCMN, especially in association with satellite nevi, is a
risk factor for CNS melanosis. Magnetic resonance imaging
should be considered in the evaluation of newborns with these
findings. In one study, CNS involvement occurred in 33 of 289
patients with LCMN. All the patients with CNS involvement
had nevi in the posterior axial location. Satellite nevi were present in 31 of the 33 patients.24 These findings suggest that melanocytic malformation occurs during the migration of neural crest
cells that give rise to cutaneous leptomeningeal melanocytes.
Malformation resulting in LCMN on the extremities occurs after
migration from the neural crest and is not associated with
CNS melanosis.
Neural Tumors
Neural tumors, such as neurofibromas, are of neuroectodermal origin, as are melanocytic tumors. Neurilemmomas (also
called schwannomas) are benign nerve sheath tumors that extend subcutaneously adjacent to a peripheral nerve. They usually occur in solitary form but may occur as multiple lesions in the
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Figure 15 The presence of melanocytes in the middle and lower

dermis is responsible for the color of the blue nevus.
Figure 17 This form of congenital giant pigmented hairy nevus is

associated with an increased risk of malignant melanoma, which
develops within the lesion.
Figure 16 Becker nevus, an acquired localized malformation of

epidermal melanocytes that may be associated with hypertrichosis, is
seen on the shoulder.
syndrome of neurilemmomatosis.25 These tumors are usually

painful and may be associated with nerve compression. Other
benign tumors that must be considered in the differential diagnosis of painful skin nodules are neuromas, angiolipomas and
angiomyolipomas, leiomyomas, eccrine spiradenomas, glomus
tumors, and the blue rubber bleb nevus.
neurofibromatosis
Neurofibromatosis represents a spectrum of disorders involving the skin, central and peripheral nervous systems, bones, and
blood vessels. This neurocutaneous syndrome is transmitted via
an autosomal dominant gene at an estimated frequency of one in
3,000 persons with almost complete penetrance.26

Two distinct forms of neurofibromatosis are recognized, but
variant forms also exist.
Neurofibromatosis-1 The most common form (occurring in
85% to 90% of all cases) is NF-1, or von Recklinghausen disease
[see Figure 18]. This is a common autosomal disorder, with an incidence of one in 3,500 persons. It is characterized by the presence of caf au lait spots, intertriginous freckling, multiple spinal
and peripheral neurofibromas, plexiform neuromas, bilateral iris
hamartomas (also known as Lisch nodules), neurologic impair 2002 WebMD Inc. All rights reserved.
June 2002 Update
Figure 18 Multiple neurofibromas, as seen in von Recklinghausen

disease, usually appear in late childhood and increase in size and
number with age.
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ment, and bone abnormalities. The disease is progressive and is

associated with a predisposition to a malignant state.
Sarcomatous degeneration of skin lesions is rare but may occur in extracutaneous tumors. Caf au lait spots of NF-1 may be
present at birth and may be best visualized under a Wood light.
Neurofibromas begin to appear at puberty as soft, globoid, and
pedunculated tumors that are skin colored or violaceous. Lesions may be large and numerous, causing complications resulting from impingement on surrounding structures.
Neurofibromatosis-2 A second form of the disease, neurofibromatosis-2 (NF-2), is characterized by bilateral acoustic neuromas, which are Schwann cell tumors that arise from vestibular
nerves.27 Associated features may include meningiomas, gliomas,
paraspinal neurofibromas, and subcapsular cataracts. Skin tumors
and caf au lait spots are less commonly seen in NF-2 than in NF-1.
Variants Other forms of neurofibromatosis include segmental cases in which caf au lait spots or neurofibromas are localized
to a single dermatome. The gene for NF-2 is located on chromosome 22. In this autosomal dominant disorder, the merlin tumor
suppressor gene encoded in chromosome band 22q12 is inactivated. This results in an alteration in DNA with substitution of
tyrosine for asparagine at position 220 of the merlin cytoskeletal
associated protein.28
Genetic Counseling
skin tag
Skin tag, also called acrochordon, commonly occurs as multiple skin-colored or tan, filiform or smooth-surfaced papules that
are 2 to 3 mm in diameter. Lesions are often located on the neck
or axillae but may also appear in the groin or on the extremities,
often as isolated larger polypoid growths [see Figure 19]. The fibrous stalk consists of loose connective tissue with dilated capillaries. Lesions may become inflamed if they are irritated or are
traumatized from twisting of the stalk. Biopsy is performed if
the clinical diagnosis is uncertain. Skin tags may be removed for
cosmetic reasons by using scissors to clip the pedunculate lesions at the base.
dermatofibroma
Dermatofibroma, also called histiocytoma, is a firm, skin-colored or reddish-brown sessile papule or nodule that arises spontaneously or after minor trauma, usually in adults [see Figure 20].
A dermatofibromatous lesion may occur, for example, after an
insect bite on an extremity. A solitary lesion is most common,
though multiple or eruptive histiocytomas have been reported.
It may be necessary to perform a biopsy when the diagnosis is
uncertain. Treatment is necessary only for cosmetic reasons.
keloid and hypertrophic scar
Normal wound healing in response to tissue injury involves
several integrated processes: inflammation, production of granulation tissue, formation of the extracellular matrix, wound con-
Patients with either NF-1 or NF-2 should seek genetic counseling because there is a 50% risk that their offspring will also be
affected with neurofibromatosis. In NF-1, optic glioma can appear in early childhood; patients with NF-1 may also have scoliosis. In NF-2, bilateral acoustic neuromas can cause deafness.
The genes for the two distinct forms of neurofibromatosis have
been located on two separate chromosomes. This finding may
lead to improved diagnosis, which would facilitate genetic
counseling and enable prenatal testing.27
Treatment
For treatment of selected neurofibromas, surgical excision is
more successful than scalpel removal or electrodesiccation and
curettage. In a preliminary study, the use of ketotifen, a benzocycloheptathiophene compound that acts as a mast cell stabilizer, was evaluated in the treatment of patients with neurofibromatosis.29 All treated patients showed a decrease in symptoms
of pruritus, pain, or skin tenderness and experienced a decreased rate of neurofibroma growth. Long-term double-blind
studies are required, however, to confirm and extend these preliminary findings.
The bilateral acoustic neuromas of NF-2 may be visualized
by computed tomography or MRI. Hearing loss is an early
symptom that may begin in the second or third decade of life;
it can be detected by an audiologic study with brain stem auditory-evoked response. Unilateral acoustic neuromas that
are not associated with neurofibromatosis and that are not inherited are more common in older persons and pose fewer
management problems.27 Surgical removal of small acoustic
neuromas may improve neurologic or audiologic status.
Connective Tissue Tumors
Fibroma of the skin comprises multiple conditions that may
represent reactions to hemorrhage, infection, or chronic irritation.
June 2002 Update
Figure 19 Skin tags, also called acrochordons or soft fibromas, are

skin-colored or tan papules. They are commonly seen in such
intertriginous areas as the groin or axillae.
Figure 20 Dermatofibroma appears as a firm skin-colored or reddishbrown papule and may arise spontaneously or follow minor trauma to
the skin.
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traction, and, finally, scar formation. In the final phases of

wound healing, fibroblasts degrade and produce bundles of
collagen fibers. These bundles become thicker and are aligned
along the lines of tension to which the tissues are exposed. As a
result of these changes, wound tensile strength gradually increases. The resulting scar is relatively acellular and has fewer
macrophages, blood vessels, and fibroblasts than the unwounded tissue.

Scars may be normotrophic, atrophic, hypertrophic, or
keloidal. Both hypertrophic and keloidal scars are abnormal responses to tissue injury. Hypertrophic scars mature and flatten
over time, usually after 6 months. The keloid appears as a shiny,
smooth, raised proliferation of scar tissue with typical crablike
extensions beyond the site of the original injury [see Figure 21].
Keloids differ from hypertrophic scars in that their development is delayed, sometimes occurring months after tissue injury. Keloids do not regress, and they frequently cause pain,
itching, and burning. Keloids are more common in African
Americans, Hispanics, and persons with a personal or family
history of keloids. Other factors associated with the development of keloids include wound tension, especially in skin sites
such as the chest, shoulders, and back; ear piercing; healing by
second intention; pregnancy; young age; and deep laceration.30
In atrophic scars, there is thinning of the skin and loss of normal architecture. Striae distensae, a so-called stretch mark, is a
common dermal atrophic scar that tends to appear during periods of rapid weight gain and in the presence of excess glucocorticoid, as well as late in gestation.
Treatment
Treatment with intralesional steroids, 10 to 40 mg/ml once a
month for up to 6 months, can effectively flatten keloid and hypertrophic scars. Cryotherapy (a 30-second application once a
month for 3 months) has been found to be safe and effective.31
Topical silicone gel sheeting, which was first used for burn
scars, has been used in the treatment of keloids and hypertrophic scars.32 There is no release of silicone into the skin, and
there are no adverse side effects from this treatment. The mechanism of action is unknown. Potential side effects of intralesional corticosteroid treatment include atrophy, depigmentation,
telangiectasia, and ulceration and dose-related systemic effects.
Vascular Birthmarks
Vascular proliferations are broadly classified as hyperplasias
that show a tendency to regress or as benign vascular tumors
that persist.33,34 Vascular hyperplasias include pyogenic granuloma and pseudo-Kaposi sarcoma. Vascular hemangiomas can be
further subdivided according to their histologic cell of origin
(endothelial cell, pericyte, glomus cell), depth of tissue involvement (superficial or deep), and size of involved vessels (capillaries, venules, arterioles, veins, or arteries). Vascular birthmarks
such as nevus flammeus and salmon patch may resemble angiomas but are nonproliferative malformations that usually do
not involute.
epidemiology
Hemangiomas (see below) occur in a female-to-male ratio of
5:1, whereas vascular malformations occur with equal frequency in males and females. A rare familial occurrence of heman 2002 WebMD Inc. All rights reserved.
June 2002 Update
Figure 21 The proliferation of scar tissue in a keloid may extend

beyond the original site of injury.
giomas, vascular malformations, or both has been reported in
six kindreds, suggesting autosomal dominant inheritance in
these cases.35
Vascular malformations are congenital developmental defects that are generally of unknown etiology. Port-wine stains
may result from progressive ectasia of the superficial vascular
plexus in the skin as a result of abnormal neural regulation of
blood flow.36 In the Klippel-Trnaunay-Weber syndrome, a
mesodermal abnormality affecting differentiation of the limb
bud may occur during the third to sixth week of gestation.37
pathogenesis
The etiopathogenesis of hemangiomas and vascular malformations is not well understood. Hemangiomas arise in response to an angiogenic stimulus that may begin in utero.
Through use of immunohistochemical techniques, infantile hemangiomas and placental microvessels were found to coexpress the vascular antigens GLUT-1 and Lewis Y antigen
(LeY).38 These antigens are not present in other vascular tumors,
such as pyogenic granulomas, or in vascular malformations. A
pathogenic link involving aberrant differentiation of vascular
precursor cells or embolization of placental cells to fetal tissue
has been hypothesized.38 These antigens are also absent in congenital nonprogressive hemangioma, a distinctive hemangioma
consisting of lesions that are fully formed at birth and that either
remain static or rapidly involute.39
overview of management
Evaluation and management of hemangiomas and malformations require a multidisciplinary approach. Specific diagnosis
may be aided by imaging techniques such as CT and MRI to assess depth of involvement and extension to adjacent structures
and to evaluate associated abnormalities. Laboratory evaluation
for associated systemic disease may be required in addition to
ophthalmologic, neurologic, and cardiologic assessment for
complications of vascular tumors and dysmorphic syndromes.
hemangiomas
Hemangiomas are proliferating vascular tumors that are not
necessarily present at birth. The vascular lesion may appear in
neonates as a faint pink patch that subsequently undergoes
rapid proliferation over a period of months to years before the
lesion stabilizes and regresses.
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Treatment
Figure 22 The strawberry, or capillary, hemangioma appears between

the second and fifth weeks of life and undergoes spontaneous involution over a period of several years.
It is important to realize that most hemangiomas are uncomplicated and regress without treatment early in life with minimal residual scarring. Follow-up studies have shown that in
90% of patients, hemangiomas regress by 9 years of age.41 Parents may require considerable reassurance that the best course
is to refrain from treatment. Care must be taken to prevent trauma and infection, which may lead to scarring.
There is considerable controversy as to when to intervene in
the treatment of complicated hemangiomas because of potential
side effects, such as scarring. The ideal time to treat would be at
the beginning of the period of rapid growth, but this is difficult
to predict. Indications for treatment include involvement of a
vital orifice, infection, ulceration, ocular involvement, and severe cosmetic deformity. Medical options include intralesional
or systemic steroids, the latter at a dose of 1 to 3 mg/kg/day.
Antimetabolites have been used for their antiproliferative effect.
Interferon alfa has been used for severe hemangiomatosis, but
its use is associated with systemic side effects and the potential
risk of spastic diplegia. Laser surgery with 585 nm pulsed dye
laser may be used to treat the superficial proliferative component.41 Radiation therapy may lead to scarring and is discouraged in children because of long-term radiation effects, including
risk of malignancy. Interventional techniques involving embolization of vessels may be required in cases involving airway
obstruction or other life-threatening complications. A multidisciplinary team approach involving the dermatologist, pediatrician, radiologist, surgeon, and other specialists is needed for optimal management of complicated cases.42
vascular malformations
Vascular malformations are usually present at birth. They are
permanent or progress in the form of ectasias but do not proliferate. Vascular malformations may be subdivided into the following groups: venous, lymphatic, combined arteriovenous,
and capillary (such as port-wine stain).43 Dysmorphic syndromes such as Sturge-Weber and Klippel-Trnaunay-Weber
syndromes are more commonly associated with vascular malformations than with hemangiomas.
Figure 23 A nevus flammeus is present at birth as a reddish or

violaceous macular discoloration, often in a unilateral and segmental
distribution; it shows little tendency to involute later in life.
The biologic classification of hemangiomas is very different

from that of vascular malformations. Vascular tumors can be
classified according to their cell or origin, the size of the involved vessels, and the depth of involvement. Such classifications have led to refinement in terminology.40 The terms strawberry hemangioma and cavernous hemangioma are descriptive clinical terms that do not specify the type of vessels that
are involved.

Capillary hemangioma, also known as strawberry hemangioma, appears as a single vascular lesion or multiple lesions
during the second to the fifth week of life. Infantile hemangiomas are bright-red, soft, lobulated tumors that increase in
size for a period of months [see Figure 22]. Lesions spontaneously involute, sometimes with fibrosis, over a period of several
years.33 Histologically, the capillary hemangioma shows a proliferation of endothelial cells that form many new small vessels.
June 2002 Update

Salmon patch The salmon patch, one of the most common
vascular birthmarks, is a dull-pink macule that appears on the
nape of the neck, central forehead, or eyelids. Although the
salmon patch is sometimes classified as a nevus flammeus, it is
distinguished from the latter by its tendency to fade in early life.
The salmon patch is caused by the persistence of fetal capillary
ectasia in the dermis.33
Port-wine stain Port-wine stain, also called nevus flammeus, appears at birth as a reddish or violaceous macular discoloration, usually in a unilateral, segmental distribution [see Figure
23]. Mature dilated capillaries are present in the dermis. After
puberty, nevus flammeus lesions may become thickened and
nodular or papular. There is little tendency toward involution.
Nevus flammeus lesions may be associated with abnormalities
of the larger vessels and with neurologic manifestations.
Sturge-Weber syndrome A facial port-wine stain that involves the skin innervated by the first branch of the trigeminal
nerve is a feature of the Sturge-Weber syndrome (also known as
encephalotrigeminal angiomatosis). Other features of the SturgeACP Medicine
Acquired Vascular Disorders

diagnosis and classification
Spider Angioma
Spider angioma, also called spider nevus or arterial spider,
appears as a central red punctum from which fine vessels radiate; the appearance of the lesion is suggestive of a red spider [see
Figure 24]. The central arteriole may be pulsatile. These telangiectasias (dilated capillaries) are commonly seen on the face,
neck, trunk, and upper extremities and occur most commonly
in middle-aged or elderly persons. They may arise spontaneously or in association with pregnancy or hepatic dysfunction. Spider angiomas may be treated with laser therapy for cosmetic reasons.
Figure 24 A spider angioma, which has a central arteriole from which
fine vessels radiate, blanches with pressure.
Weber syndrome include ipsilateral congenital glaucoma and
contralateral seizures caused by leptomeningeal angiomatosis.
Ophthalmologic and neurologic evaluation may be warranted in
patients with the Sturge-Weber syndrome.
Klippel-Trnaunay-Weber syndrome The triad of findings
seen in Klippel-Trnaunay-Weber syndrome includes a portwine stain, usually in a patchy distribution on the involved extremity; varicose veins; and soft tissue or bony hypertrophy. The
most common site of involvement is the lower leg; the next most
common sites of involvement are the arms and trunk.37
Venous malformation Formerly referred to as cavernous
hemangiomas, vascular malformation consists of a collection of
abnormal veins and venous pouches that commonly occur
around the head and neck but can occur anywhere on the body.
They are frequently multiple or have satellite lesions. Superficially, they appear as a subcutaneous swelling with a bluish hue on
the skin surface or mucous membrane. Deeper components may
be invisible on clinical examination. Lesions enlarge for several
months, become stationary for an indefinite period, and spontaneously resolve.
Treatment
Because vascular malformations do not proliferate, treatment
may be cosmetic and can be postponed to later in life. However,
a multidisciplinary approach is needed to treat potential complications of vascular malformations associated with dysmorphic syndromes. Salmon patch tends to fade in early life and
usually requires no treatment.
Treatment of port-wine stains by excision, tattooing, ionizing
radiation, cryosurgery, or dermabrasion is largely unsatisfactory. Use of the argon laser has resulted in lightening of vascular
lesions; however, there is wide variability in response. The effectiveness of this treatment results from the selective absorption of the monochromatic 585 nm laser light by red hemoglobin pigment, which produces thermal energy with resultant
photocoagulation of tissue.44 Thinner lesions are more responsive than thicker lesions that have undergone progressive vascular ectasia. In a study of 100 patients of different age groups
who had port-wine stains of the head and neck and who were
treated with a flashlamp pulsed dye laser, treatment was no
more effective when given in early childhood than when given
at a later date.45
June 2002 Update
Unilateral Telangiectasia
Acquired unilateral telangiectatic nevi are uncommon, but
those that have been reported resulted from mechanical or
physical trauma, including sun damage.46
Cherry Angioma
Cherry angioma, also called senile angioma, appears as multiple bright-red, soft, dome-shaped papules on the trunk of middle-aged or older persons. Trauma produces slight bleeding.
Electrodesiccation may be performed for cosmetic purposes.
Pyogenic Granuloma and Other Vascular Tumors

The pyogenic granuloma is a soft red lesion that is solitary,
raised, and nonpulsatile; it often appears after minor skin trauma, such as a puncture wound. Other predisposing factors include hormonal effects, infection, viral oncogenes, microscopic
arteriovenous anastomoses, and growth factors.47 Epulis gravidarum is a variant of a pyogenic granuloma. The lesion was formerly believed to be caused by a pyogenic infection of a small
wound; histologically, however, an early lesion resembles a
capillary hemangioma. The thin, sometimes verrucous epidermis is friable and apt to become eroded or ulcerated. Lesions
rapidly reach a size of 1 to 2 cm and then remain static. Common sites of involvement are the fingers, feet, and face [see Figure 25]. Biopsy is performed to rule out malignant tumors, such
as Kaposi sarcoma and amelanotic melanoma.
Other benign tumors with a vascular component include angiofibroma, angioleiomyoma, and angiolipoma. Some of these
can be painful. Differential diagnosis of painful skin tumors includes glomus tumor, angiolipoma, angioleiomyoma, neuromas, and eccrine spiradenoma.34 Lesions are usually easily removed by electrodesiccation and curettage. If they recur or if
satellite lesions appear after such treatment, excisional biopsy is
recommended.
Kimura Disease
Kimura disease and angiolymphoid hyperplasia with eosinophilia are rare tumors of unknown cause that occur mainly on
the head and neck in young adults and may resemble pyogenic
granuloma.48 Kimura disease, which was first reported in Korea,
is most common in Asians. It appears as a granulomatous proliferation of lymphoid tissue that may be accompanied by peripheral eosinophilia and contiguous lymphadenopathy. Lesions may occasionally be seen on the trunk, extremities, and
genitalia in addition to the head and neck. Angiolymphoid hyACP Medicine
Leiomyoma
The leiomyoma is an uncommon tumor of smooth muscle
that appears as a single brownish-red papule or as multiple
papules or small nodules, which are sometimes painful [see Figure 26]. Leiomyomas may arise from the arrector pili (the
smooth muscle attached to the hair follicle sheath) or from the
smooth muscle surrounding cutaneous blood vessels (angioleiomyoma). Painful lesions can be excised.
Lymphangioma Circumscriptum
Figure 25 The pyogenic granuloma, which may show a smooth,

verrucous, eroded, or friable surface, may be confused with a
malignant tumor.
Lymphangioma circumscriptum is characterized by groups

of persistent localized or diffuse translucent vesicles. Indications
for treatment include severe cosmetic problems, persistent leakage of lymphatic fluid or blood, and recurrent infection. The
vesicles frequently recur after surgery, radiotherapy, electrocautery, or cryosurgery because of the persistence of deep lymphatic cisterns. Carbon dioxide laser in a vaporization mode has
been used to ablate superficial cutaneous lesions in patients
with lymphangioma circumscriptum.50 The major advantage of
this technique is that it may reduce the frequency of recurrences
because it seals the communicating channels to the deeper cisterns by vaporizing the superficial lymphatics.
The author has no commercial relationships with manufacturers of products
or providers of services discussed in this subsection.
References
Figure 26 Leiomyomas are sometimes painful papules that arise

from smooth muscle of blood vessels or the arrector pili.
perplasia with eosinophilia, which may or may not represent a

different disease, appears as localized single or multiple nodules. Infectious, allergic, hormonal, and traumatic mechanisms
have been postulated. Immunodermatopathologic studies suggest an unusual distribution of adhesion molecules, IgE, and
CD23 in these angioproliferating tumors.49
Lipoma
The lipoma, which is a soft, rounded to lobulated subcutaneous tumor of mature fat cells, is commonly seen on the trunk,
neck, or forearms. Lesions are rubbery in consistency and freely
movable under the overlying skin, which appears normal.
There may be a single lesion or multiple lesions, and they are
usually asymptomatic unless they impinge on a nerve. Lipomas
are of variable size and grow slowly. Histologically, the tumors
are usually encapsulated and show fat cells that are indistinguishable from normal adipose tissue. Admixture of other tissue components may result in fibrolipomas (fibrous tissue), angiolipomas (blood vessels), and myolipomas (smooth muscle).
Excision may be performed for cosmetic reasons. If a lesion
grows rapidly, biopsy should be performed, though lipomas
rarely become malignant.
June 2002 Update
1. Levers Histopathology of the Skin. Elder D, Elenitsas R, Jaworsky C, et al, Eds. Lippincott-Raven Publishers, Philadelphia, 1997
2. Dermatology in General Medicine. Fitzpatrick TB, Eisen AZ, Wolff K, et al, Eds. McGraw-Hill Book Co, New York, 1993
3. Flugman SL, McClain SA, Clark RF: Transient eruptive seborrheic keratoses associated with erythrodermic psoriasis and erythrodermic drug eruption: report of two cases. J Am Acad Dermatol 45:S212, 2001
4. Paller AS, Syder AJ, Chan YM, et al: Genetic and clinical mosaicism in a type of epidermal nevus. N Engl J Med 331:1408, 1994
5. Seo YJ, Piao, YJ, Suhr KB, et al: A case of nevus comedonicus syndrome associated
with neurologic and skeletal abnormalities. Int J Dermatol 40:648, 2001
6. Brownstein MH: Basaloid follicular hamartoma: solitary and multiple types. J Am
7. Grimalt R, Ferrando J, Mascaro JM: Premature familial sebaceous hyperplasia: successful response to oral isotretinoin in three patients. J Am Acad Dermatol 37:996, 1997
8. Sidhu SK, Wakelin SH, Wilkinson JD: Multiple familial trichoepitheliomas. Cutis
63:239, 1999
9. Esche C, Kruse R, Lamberti C, et al: Muir-Torre syndrome: clinical features and molecular genetic analysis. Br J Dermatol 136:913, 1997
10. Parks ET, Caldemeyer KS, Mirowski GW: Radiologic images in dermatology: Gardner syndrome. J Am Acad Dermatol 45:940, 2001
11. Liu V, Kwan T, Page EH: Parotid oncocytoma in the Birt-Hogg-Dub syndrome. J
12. Lindor NM, Hand J, Burch PA, et al: Birt-Hogg-Dube syndrome: an autosomal
dominant disorder with predisposition to cancers of the kidney, fibrofolliculomas, and
focal cutaneous mucinosis. Int J Dermatol 40:653, 2001
13. Grob JJ, Gouvernet J, Aymar D, et al: Count of benign melanocytic nevi as a major
indicator of risk for nonfamilial nodular and superficial spreading melanoma. Cancer
66:387, 1990
14. Tucker MA, Halpern A, Holly EA, et al: Clinically recognized dysplastic nevi: a central risk factor for cutaneous melanoma. JAMA 277:1439, 1997
15. Augustsson A, Stierner U, Rosdahl I, et al: Melanocytic naevi in sun-exposed and
protected skin in melanoma patients and controls. Acta Derm Venereol (Stockh) 71:512,
1991
16. Kelly JW, Rivers JK, MacLennan R, et al: Sunlight: a major factor associated with the
development of melanocytic nevi in Australian schoolchildren. J Am Acad Dermatol
30:40, 1994
17. Marghoob AA, Orlow SJ, Kopf AW: Syndromes associated with melanocyti nevi. J
18. Gupta G, Williams REA, Mackie RM: The labial melanotic macule: a review of 79
cases. Br J Dermatol 136:772, 1997
19. Cohen JB, Janniger CK, Schwartz RA: Caf-au-lait spots. Cutis 66:22, 2000
ACP Medicine
20. Thami GP, Kaur S, Kanwar A: Association of juvenile xanthogranuloma with cafau-lait macules. Int J Dermatol 40:281, 2001
21. Mooney MA, Barr RJ, Buxton MG: Halo nevus or halo phenomenon: a study of 142
cases. J Cutan Pathol 22:342, 1995
22. Lowe NJ, Wieder JM, Sawcer D, et al: Nevus of Ota: treatment with high energy fluences of the Q-switched ruby laser. J Am Acad Dermatol 29:997, 1993
23. Glinick SE, Alper JC, Bogaars H, et al: Beckers melanosis: associated abnormalities.
24. DeDavid M, Orlow SJ, Provost N, et al: Neurocutaneous melanosis: clinical features
of large congenital melanocytic nevi in patients with manifest central nervous system
melanosis. J Am Acad Dermatol 35:529, 1996
25. Buenger KM, Porter NC, Dozier SE, et al: Localized multiple neurilemmomas of the
lower extremity. Cutis 51:36, 1993
26. Riccardi VM: Von Recklinghausen neurofibromatosis. N Engl J Med 305:1617, 1981
27. Martuza RL, Eldridge R: Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 318:684, 1988
28. MacCollin M, Mohney T, Trofatter J, et al: DNA diagnosis of neurofibromatosis 2:
altered coding sequence of the merlin tumor suppressor in an extended pedigree.
JAMA 270:2316, 1993
29. Riccardi VM: Mast-cell stabilization to decrease neurofibroma growth: preliminary
experiences with ketotifen. Arch Dermatol 123:1011, 1987
30. Sahl WJ, Clever H: Cutaneous scars: part I. Int J Dermatol 33:681, 1994
31. Zouboulis CC, Blume U, Buttner P, et al: Outcomes of cryosurgery in keloids and
hypertrophic scars: a prospective consecutive trial of case series. Arch Dermatol
129:1146, 1993
32. Gold MH: Topical silicone gel sheeting in the treatment of hypertrophic scars and
keloids. J Dermatol Surg Oncol 19:912, 1993
33. Requena L, Sangueza OP: Cutaneous vascular proliferations. Part II: hyperplasias
and benign neoplasms. J Am Acad Dermatol 37:887, 1997
34. Requena L, Sanqueza MD: Cutaneous vascular proliferations. Part III: malignant
neoplasms, other cutaneous neoplasms with significant vascular component, and disorders erroneously considered as vascular neoplasms. J Am Acad Dermatol 38:143,
1998
35. Blei F, Walter J, Orlow SJ, et al: Familial segregation of hemangiomas and vascular
malformations as an autosomal dominant trait. Arch Dermatol 134:718, 1998

June 2002 Update
36. Smoller BR, Rosen R: Port-wine stains: a disease of altered neural modulation of
blood vessels. Arch Dermatol 122:177, 1986
37. Meine JG, Schwartz RA, Janniger CK: Klippel-Trnaunay-Weber syndrome. Cutis
60:127, 1997
38. North PE, Waner M, Mizeracki A, et al: A unique microvascular phenotype shared
by juvenile hemangiomas and human placenta. Arch Dermatol 137:559, 2001
39. North PE, Waner M, James CA, et al: Congenital nonprogressive hemangioma: a
distinct clinicopathologic entity unlike infantile hemangioma. Arch Dermatol 137:1607,
2001
40. Mulliken JB, Young AE: Vascular Birthmarks: Hemangiomas and Malformations.
WB Saunders Co, Philadelphia, 1988, p 77
41. Barlow RJ, Walker NJ, Markey AC: Treatment of proliferative haemangiomas with
the 585 nm pulsed dye laser. Br J Dermatol 134:700, 1996
42. Donnelly LF, Adams DM, Bisset GS 3rd: Vascular malformations and hemangiomas: a practical approach in a multidisciplinary clinic. AJR Am J Roentgenol 174:597,
2000
43. Requena L, Sangueza OP: Cutaneous vascular anomalies. Part I. Hamartomas, malformations, and dilatation of preexisting vessels. J Am Acad Dermatol 37:523, 1997
44. Fitzpatrick RE, Lowe NJ, Goldman MP, et al: Flashlamp-pumped pulsed dye laser
treatment of port-wine stains. J Dermatol Surg Oncol 20:743, 1994
45. van der Horst CM, Koster PL, de Borgie CM, et al: Effect of the timing of treatment
of port-wine stains with the flash-lamp-pumped pulsed-dye laser. N Engl J Med
338:1028, 1998
46. Pasyk KA: Acquired lateral telangiectatic nevus: port-wine stain or nevus flammeus. Cutis 51:281, 1993
47. Mooney MA, Janniger CK: Pyogenic granuloma. Pediatr Dermatol 55:133, 1995
48. Chun SI, Ji HG: Kimuras disease and angiolymphoid hyperplasia with eosinophilia: clinical and histopathologic differences. J Am Acad Dermatol 27:954, 1992
49. von den Driesch P, Gruschwitz M, Schell H, et al: Distribution of adhesion molecules, IgE, and CD23 in a case of angiolymphoid hyperplasia with eosinophilia. J Am
50. Bailin PL, Kantor GR, Wheeland RG: Carbon dioxide laser vaporization of lymphangioma circumscriptum. J Am Acad Dermatol 14:257, 1986
ACP Medicine
XII
A C N E V U L G A R I S A N D R E L AT E D
DISORDERS
Mark Lebwohl, m.d.
Acne and its clinical variants are among the most common causes of patient visits to the physician for cutaneous disorders. Severe forms of these disorders can be disfiguring and debilitating;
and because the face is the primary site of involvement, patients
will often seek therapy for even mild forms. Therapeutic approaches will therefore be stressed in this chapter.
Epidemiology and Etiology
Acne vulgaris is the most common dermatologic problem
of adolescent years; it usually begins in puberty. Age of onset
and severity of disease are affected by sex, genetics, and external factors such as cosmetics and medications. Acne is usually
more severe in males than in females and often begins earlier
(in early adolescence) in males. Acne often subsides after the
teenage years, but the disease can remain a problem for
adults in the third and fourth decades and beyond. A significant portion of women experience premenstrual flares of
acne; this phenomenon may be more common in older
women.1
Genetic factors clearly play a role in severe acne. A family history of severe acne can often be elicited during the workup of affected patients. Various external factors, such as occlusive cosmetics, can contribute to acne, and certain medications (e.g., corticosteroids, adrenocorticotropic hormone [ACTH], phenytoin
sodium, isoniazid, lithium, progestins, potassium iodide, bromides, actinomycin D) can cause acnelike lesions [see II:VI Cutaneous Adverse Drug Reactions].
Pathogenesis
Multiple factors contribute to the development of acne in susceptible persons. Among the most significant are alterations in
keratinization, accumulation of sebum, and inflammation. Androgenic influences may contribute to some of these factors.
Modified keratinization of the follicular infundibulum leads
to proliferation and increased cohesiveness of keratinocytes,
which causes plugs to form. These plugs block follicular outlets,
allowing cellular debris in sebum to form comedones (the noninflammatory lesions of acne).
The composition of sebum does not appear to be altered in
patients with acne; however, sebaceous glands are often larger
and sebum production is often greater in persons affected with
acne than in unaffected persons.2 Sebum is comedogenic and inflammatory, which may account for its role in acne.3 Inflammation in acne has also been attributed to the anaerobic diphtheroid
Propionibacterium acnes. The presence of P. acnes correlates with
the occurrence of acne in adolescents.4 The microbes role in inflammation has been attributed to lipases, proteases, and
hyaluronidases, as well as chemotactic factors.
Androgens play a role in the development of acne, as evidenced by increased levels of dehydroepiandrosterone sulfate
(DHEAS) in girls with acne5 and an association of acne with endocrinopathies characterized by increased levels of circulating
androgens. For example, the occurrence of acne is increased in
November 2002 Update
patients with congenital adrenal hyperplasia, polycystic ovaries,

and some ovarian and adrenal tumors. Androgens act to increase sebum production and enlarge sebaceous glands; they
may also contribute to the follicular hyperkeratinization that
leads to acne. However, serum androgens are usually within the
normal range in patients with acne. Some researchers have postulated that local production of androgens in the skin can lead to
acne. Skin biopsies from patients with acne show increases in 5reductase activity.6 This increased androgenic activity may result
in the conversion of testosterone to dihydrotestosterone in the
skin, leading to the development of acne.
Diagnosis
clinical features
The characteristic skin lesions of acne include open and closed
comedones, erythematous papules, pustules, nodules, cysts, and
scars. The most commonly affected site is the face, but in more
severely affected individuals, the back and chest can be involved
as well.
Comedonal Acne
Comedones consist of keratinized cells and sebum. Comedonal acne consists of a predominance of open and closed comedones. Open comedones (blackheads) are black papules measuring 0.1 to 2 mm that are easily extruded with gentle pressure.
The material that is removed is greasy and has a gray-white color. Contrary to popular belief, the dark color of open comedones
is caused by melanin, not by dirt or oxidized fatty acids. Closed
comedones (whiteheads) consist of white papules measuring 0.1
to 2 mm. Unless extracted, they persist somewhat longer than
open comedones, often for weeks to months.
Inflammatory Acne
Erythematous papules, pustules, nodules, and cysts are the
predominant lesions in inflammatory acne [see Figure 1]. Erythematous papules range in size from 3 to 10 mm and can develop
Figure 1 Inflammatory acne is characterized by erythematous papules

and pustules.
ACP Medicine
DERMATOLOGY:XII Acne Vulgaris and Related Disorders1
into pustules or resolve into an erythematous macule that fades.

Postinflammatory hyperpigmentation can occur. Pustules are
superficial and usually dry in a few days. Nodules, which are 1
cm or larger, are erythematous and tender. They can be firm at
onset but often become fluctuant. In severely affected individuals, these lesions form fluctuant sinuses that open to the surface
through multiple tracts. Postinflammatory pigmentary changes
and scarring commonly occur.
Clinical Variants of Acne

Acne conglobata Acne conglobata is a severe, scarring form
of acne in which large cysts and abscesses become confluent to
form draining sinus tracts. Scarring is often severe. Topical acne
therapy and oral antibiotics are frequently ineffective; patients
may require treatment with oral isotretinoin [see Treatment, below]. Intralesional injection of corticosteroids and drainage of abscesses are temporarily helpful.
been suggested that affected infants may be predisposed to severe acne later in life.
laboratory tests
The clinical features of acne are so commonly recognized that
laboratory investigation is usually not necessary. Laboratory
tests should be considered, however, for female patients who
have other signs of hyperandrogenism, such as hirsutism or irregular menses. Serum for determining DHEAS and free testosterone levels and for the ratio of luteinizing hormone to follicle
stimulating hormone (LH:FSH) should be obtained 2 weeks before the onset of menses [see Table 1]. Tests should also be undertaken in patients whose conditions do not respond to adequate
doses of isotretinoin, the most potent treatment available for
acne [see Treatment, below].
Acne cosmetica A persistent, low-grade form of acne can result from the use of greasy, occlusive cosmetics, moisturizers,
and sunscreens. Women are most commonly affected.
Clinical features of acne are sufficiently distinctive that diagnosis is usually obvious. Nevertheless, a number of disorders
can be mistaken for acne.
Acne excorie Picking of minor acne lesions can cause large

ulcers and erosions that heal with scarring. Young women are
most typically affected.
Acne mechanica An acneiform eruption can result from repeated trauma associated with the wearing of sports helmets,
shoulder pads, and bras and from the chin rests of violins and violas (so-called fiddlers neck).
Folliculitis The perifollicular pustules of folliculitis can be

distinguished from the lesions of acne by their distribution. Folliculitis can affect the trunk and extremities and is not limited to
the usual sites of acne on the face, back, and chest. Malassezia
folliculitis is characterized by erythematous acneiform papules
that do not respond to typical acne therapies. Gram stain of pus
from the lesions reveals gram-positive budding yeast [see 2:VII
Fungal, Bacterial, and Viral Infections of the Skin].
Pomade acne A form of acne results from the use of thick

oils in the hair. Comedones, papules, and pustules are usually
found close to the hairline. Black men and women are most commonly affected.
Gram-negative folliculitis In patients on long-term antibiotics, superficial pustules or nodules can develop at the anterior
nares and spread outward on the face. This condition responds
promptly to oral ampicillin.
Acne in neonates and children Neonatal acne has been attributed to maternal androgens, as well as androgens secreted
by the neonatal adrenal gland. Erythematous papules and pustules may last for 2 to 3 months after birth but usually resolve
spontaneously.
Infantile acne develops between 3 and 6 months after birth.
This condition is characterized by inflamed papules and pustules and signals early secretion of androgens by the gonads,
particularly in boys. This condition may last until age 5. It has
Milia Milia are white pinpoint cysts that resemble closed

comedones. They frequently occur around the eyes but can develop anywhere on the face. If untreated, they last for months or
years. Milia can be opened with a small surgical blade and their
contents easily drained.
Table 1 Laboratory Evaluation for Women with

Acne and Signs of Hyperandrogenism
Finding
Suspected Condition
DHEAS
4,0008,000 ng/ml
> 8,000 ng/ml
Congenital adrenal hyperplasia

Adrenal tumor
LH:FSH ratio > 2.0
Polycystic ovary disease
Testosterone (unbound)
2040 yr, > 107.5 pmol/L
4160 yr, > 86.7 pmol/L
6180 yr, > 69.3 pmol/L
Polycystic ovary disease; ovarian tumor

DHEASdehydroepiandrosterone sulfate FSHfollicle-stimulating hormone

LHluteinizing hormone

Perioral dermatitis Long-term use of topical corticosteroids on the face can result in acneiform, erythematous, inflamed papules on the chin and cheeks. Despite the name, the
area immediately around the mouth is typically spared in perioral dermatitis.
Chloracne Cysts and closed comedones that resemble acne
lesions can be caused by exposure to halogenated hydrocarbons.
Hidradenitis suppurativa Hidradenitis suppurativa is a
chronic condition in which inflamed cysts in the axillae and
groin form fluctuant sinuses with draining tracts.
Favre-Racouchot disease Numerous open and closed
comedones can appear around the eyes of elderly patients, especially men who have worked out of doors for much of their lives.
This condition has been attributed to a lifetime of sun exposure.
Rosacea Rosacea is a common condition that usually begins
after 30 years of age. It is so similar to acne in some individuals
ACP Medicine
Figure 2 Erythematous papules, pustules, telangiectasia, and

flushing are features of rosacea.
tracts and other surgical procedures are best performed by

physicians with expertise in dermatologic surgery [see Table 2].
Scars can be treated with dermabrasion, laser abrasion, or intralesional injection of fluorouracil.8 The appearance of depressed scars can be improved by chemical peels and other
resurfacing procedures, as well as the injection of filler substances such as injectable collagen.9
Numerous over-the-counter cleansing agents are available to
help patients remove seborrhea and oily debris from the skin, resulting in subjective improvements. Overmanipulation of lesions by picking, squeezing, or excessive washing can lead to exacerbation of lesions and even scarring.
Topical preparations, including sunscreens, soaps, and cosmetics, should be oil-free and noncomedogenic. Numerous
over-the-counter oil-free, noncomedogenic moisturizers are
available for persons who have dry skin and acne.
There is no role for dietary change in the management of acne.
Previous beliefs that chocolate or oily foods cause acne have
been disproved.
topical therapy
that it has been called acne rosacea. Skin lesions consist of erythematous papules, pustules, and telangiectasia [see Figure 2]. Facial
flushing is a common feature. In patients with a predominance of
inflamed papules and pustules, differentiation from acne can be
difficult. Presence of telangiectasia and the occurrence of flushing
help distinguish this common condition from acne.
Recently, it has been suggested that Helicobacter pylori plays a
role in the pathogenesis of rosacea.7 Further work must be done,
however, to confirm the contribution of H. pylori to this antibiotic-responsive condition.
Treatment
Treatment of acne depends on the type and severity of lesions and on the patients response to treatment. Comedonal
acne is usually best managed with topical retinoids and acne
surgery; inflammatory acne is treated with a range of topical
therapies and may require oral therapy in moderate to severe
cases. Because nodules and cysts are more likely than comedones to scar, they are treated more quickly with oral antibiotics and, if necessary, isotretinoin (see below). Intralesional
corticosteroids administered by dermatologists can prevent
scarring from cysts. Incision and drainage of infected cysts may
be necessary but can contribute to scarring. Unroofing of sinus
Table 2 Surgical Treatments for Acne Lesions

and Acne Scars
Lesions
Scars
Extraction of comedones
Drainage of pustules and cysts
Intralesional injection of corticosteroids in cysts
Excision and unroofing of sinus tracts and cysts
Dermabrasion
Laser abrasion
Acid peels
Injection of filling materials (e.g., collagen)
Excision
Punch autographs
Intralesional injection of 5-fluorouracil

Comedonal Acne
Topical retinoids are among the most effective therapies
for comedonal acne; these preparations unplug follicles and
allow penetration of topical antibiotics and benzoyl peroxide.
Retinoids can be used in combination with antibacterial
agents and are also effective in the management of inflammatory acne. They are often irritating when first applied; patients can reduce the irritation by reducing the frequency of
application. Significant improvement is evident within 6
weeks and can continue for 3 to 4 months, at which time the
frequency of application can be reduced, depending on the
patients response.
Newer formulations of retinoids that are purportedly less irritating are a tretinoin microsponge vehicle and adapalene, but
few comparative studies examining irritation have been performed.10,11 Tazarotene, a topical retinoid used for acne and psoriasis, can be used effectively in a short-contact method, in which
it is applied for seconds to minutes.12
Inflammatory Acne
Topical antibiotics are not as effective as retinoids or benzoyl
peroxide for inflammatory acne, but they are less irritating and
better tolerated. The resistance of P. acnes to antibiotics has
been well documented; such resistance threatens the usefulness of this form of acne therapy in the future.13,14 It is therefore
useful to use antibiotics in combination with benzoyl peroxide.
A new combined formulation of clindamycin 1% and benzoyl
peroxide 5% produced faster and greater reductions in P. acnes
than formulations containing clindamycin alone.15 Moreover,
the combination of benzoyl peroxide and clindamycin resulted
in greater improvement in acne than either of its individual
components alone.16
A commonly used regimen includes the combined antibioticbenzoyl peroxide gel in the morning and topical retinoid in
the evening. Azelaic acid, a recently introduced anticomedonal and antibacterial agent, offers yet another choice for the
topical treatment of acne. It, too, can be used in combination
with topical retinoids, benzoyl peroxide, or topical antibiotics.17 Salicylic acid, an over-the-counter comedolytic agent,
plays a minor role in the treatment of acne. Skin-colored sulACP Medicine
Table 3 Topical Therapies for Acne

Medication
Formulation
Frequency of
Application
Primary
Mechanism
of Action
Adverse Effects
Azelaic acid
20% cream
b.i.d.
Anticomedonal,
antibacterial
Stinging, irritation
Benzoyl peroxide
2.5%, 5%, 10% creams, gels, lotions, washes
b.i.d.
Antibacterial
Dryness, irritation, allergic contact dermatitis
1% solutions, lotions, gels

2% solutions, creams, gels, pledgets, wipes
3% erythromycin5% benzoyl peroxide gel
b.i.d.
b.i.d.
b.i.d.
Antibacterial
Antibacterial
Antibacterial
10% sodium sulfacetamide, 5% sulfur lotions
b.i.d.
Antibacterial
Antibiotic resistance
Antibiotic resistance
Dryness, irritation, allergic contact dermatitis;
deteriorates if not refrigerated
Dryness, irritation, allergic contact dermatitis
0.1% gels
0.05%, 0.1% gels
0.025%, 0.05%, 0.1% creams; 0.01%, 0.025%
gels; 0.05% solutions
q.d.
q.d.
q.d.
Comedolytic
Comedolytic
Comedolytic
Dryness, irritation, photosensitivity

Sulfur and resorcinol
2% resorcinol, 8% sulfur lotions, creams
q.d., b.i.d.
Comedolytic
Dryness, peeling, allergic contact dermatitis
Salicylic acid
0.5%2% gels, pads, soaps
q.d., b.i.d.
Comedolytic
Dryness, irritation
Antibiotics
Clindamycin
Erythromycin
Erythromycin
benzoyl peroxide
Sodium
sulfacetamide
sulfur
Retinoids
Adapalene
Tazarotene
Tretinoin
fur-resorcinol lotions are available; these very effective drying

and peeling agents can be useful for treating individual lesions
[see Table 3].
cycline, symptoms resolve, but upon retreatment, the syndrome recurs.
systemic therapy
Oral isotretinoin is the most effective agent available for the

treatment of acne. It results in long-lasting remissions or cures in
the majority of patients treated. Because of its serious potential
adverse effects, however, isotretinoin is not generally used as
first-line therapy except for unusual cases.
Most of the side effects of isotretinoin are dose related and affect a majority of patients treated. For example, cheilitis uniformly occurs in patients treated with significant doses. Myalgias,
dryness of mucous membranes, dry eczematous skin changes,
and hyperlipidemia frequently occur. Total serum cholesterol
levels can rise in patients taking isotretinoin, and triglyceride levels can rise sufficiently to cause pancreatitis.
Teratogenicity occurs with even a single dose of isotretinoin
administered to pregnant women. Birth control counseling is
an essential part of the management of women for whom
isotretinoin is prescribed. The use of two forms of contraception is advised. Despite major educational efforts, pregnancies
in women receiving isotretinoin continue to occur, resulting in
severe birth defects.21 Consequently, the manufacturers of
isotretinoin have started a program in which physicians and
pharmacists prescribing and administering isotretinoin must
be registered and agree to require pregnancy tests on a regular basis.
There have been several instances of suicide and depression occurring in patients receiving oral isotretinoin.22 However, teenagers with severe acne may be at increased risk of suicide, regardless of the treatment they are using. A study compared the risk of depression, psychotic symptoms, suicide,
and attempted suicide in acne patients receiving isotretinoin
and in similar patients being treated with oral antibiotics. The
relative risk of depression or psychosis for isotretinoin-treated
patients was 1.0, and the relative risk for suicide and attempt-
Systemic agents are warranted for patients with nodulocystic

acne or inflammatory acne that is not responsive to topical therapy. Oral antibiotics are usually the first line of systemic treatment.
Isotretinoin has generally been reserved for patients whose acne
is refractory to antibiotics. To prevent scarring, patients with particularly severe acne are occasionally started on isotretinoin, as
are patients with a history of antibiotic intolerance.
Antibiotics
Antibiotics have both antibacterial and anti-inflammatory effects that are beneficial in treating acne. The antibiotics most
commonly used for acne are doxycycline, erythromycin,
minocycline, tetracycline, and trimethoprim-sulfamethoxazole
[see Table 4]. Because antibiotic resistance is a major problem with
many of the older antibiotics, minocycline has been prescribed
for many acne patients even though it is considerably more expensive. Most recently, strains of P. acnes that are resistant to
minocycline have begun to emerge, and this may limit the usefulness of this drug in the future.18 The duration of treatment
with oral antibiotics depends on patient response. For example,
azithromycin given at a dosage of 500 mg/day for 4 days, repeated at 10-day intervals for four cycles, is as effective as
minocycline given at a dosage of 100 mg/day for 6 weeks.19 Further refinements of regimens with these newer antibiotics will
undoubtedly be performed before they achieve more widespread usage.
In recent years, a lupuslike syndrome has been reported in
patients taking oral minocycline. Synovitis, the presence of antinuclear antibodies, and elevations in hepatic transaminase
levels were reported, but renal disease and central nervous
system disease do not occur.20 Upon discontinuance of mino 2002 WebMD Inc. All rights reserved.
Isotretinoin
ACP Medicine
Table 4 Commonly Prescribed Systemic Therapies for Acne

Medication
Antibiotics
Doxycycline
Erythromycin
Minocycline
Tetracycline
Trimethoprimsulfamethoxazole
Other Agents
Isotretinoin
Norgestimateethinyl
estradiol
Dosage
50100 mg p.o., b.i.d.

250500 mg p.o., b.i.d.
50 mg p.o., q.d.100 mg p.o., b.i.d.
Advantages
Adverse Effects
Inexpensive
Alternative to tetracyclines
Highly effective; antibiotic resistance rare at 200 mg/day
Inexpensive
Photosensitivity, GI symptoms, candidiasis

GI symptoms, candidiasis
GI symptoms, candidiasis, vertigo, lupuslike
syndrome (rare), autoimmune hepatitis (rare)
Photosensitivity, GI symptoms, candidiasis
Alternative to tetracyclines and

erythromycin
Bone marrow suppression, drug eruption
0.52.0 mg/kg/day, in two divided

doses
Most effective treatment; longlasting remissions
0.18 mg norgestimate, 0.035 mg ethinyl estradiol p.o., q.d., for 21 days,

repeat every 4 wk
Alternative to antibiotics and

isotretinoin; less androgenic
activity than progestins in
other contraceptives
Teratogenicity, hyperlipidemia, cheilitis,

alopecia, pyogenic granulomas, dry eyes,
epistaxis, rare pseudotumor cerebri (especially
with concomitant antibiotics)
Thromboembolic disorders, ?antibiotic interaction, ?increased breast carcinoma, gallbladder
disease, reduced glucose tolerance, headache,
fluid retention, hypertension, breakthrough
bleeding, breast swelling and tenderness
250 mg p.o., q.d.500 mg p.o., q.i.d.

(b.i.d. dosing preferred)
160 mg trimethoprim800 mg
sulfamethoxazole b.i.d.
ed suicide was 0.9, suggesting that isotretinoin does not cause

depression.23
Pseudotumor cerebri, a rare side effect of isotretinoin, occurs
more commonly in patients who are concomitantly given oral
antibiotics. Extensive counseling and monitoringincluding
complete blood counts, chemistry screens, and pregnancy tests
when appropriateshould be done before treatment with
isotretinoin, at 2-week intervals during the first month of treatment, and monthly thereafter. Depending on patient response,
treatment with 1 to 2 mg/kg/day in two divided doses should
be continued for 4 to 6 months. Some clinicians have continued
low-dose isotretinoin therapy for more than 6 months. Rarely, a
second course of therapy is indicated when acne recurs. A new
micronized formulation of isotretinoin is more bioavailable than
other acne treatments and requires taking the medicine only
once daily.24
Other Therapies
Estrogens in the form of oral contraceptives can be beneficial
for patients with acne; progestins, however, can exacerbate the
condition. The newer progestinsdesogestrel, norgestimate,
and gestodenehave less androgenic activity and therefore are
less likely to exacerbate acne. A combination of ethinyl estradiol
and norgestimate has been shown to be beneficial in the treatment of acne.25 These agents are ideal in women who are seeking
birth control methods and in women who are not candidates for
or who have not responded to oral antibiotics or isotretinoin.
Oral contraceptives can be particularly helpful to women with
the polycystic ovarian syndrome. It is noteworthy that the beneficial effects of combined oral contraceptives are diminished in
patients who are obese.26
Some concerns have been raised about the concomitant use
of antibiotics and oral contraceptives because of the possibility
that some antibiotics interfere with contraceptive activity.
Reviews of large numbers of patients treated concomitantly
with oral contraceptives and antibiotics have not revealed
significant increases in pregnancies.27 Nevertheless, caution is
advisable when a patient uses an antibiotic and an oral contraceptive together, especially one of the new low-dose estrogen
contraceptives.
Additional Information
Additional information about acne and its related disorders is
available from the American Academy of Dermatology
(http://www.aad.org) and the National Rosacea Society
(http://www.rosacea.org).
The author is an investigator for Hoffmann-La Roche, Inc., Allergan, Inc.,
Medicis, and Ortho-McNeil Pharmaceutical, Inc.
References
1. Stoll S, Shalita AR, Webster GF, et al: The effect of the menstrual cycle on acne. J Am
2. Harris HH, Downing DT, Stewart ME, et al: Sustainable rates of sebum secretion in
acne patients and matched normal control subjects. J Am Acad Dermatol 8:200, 1983
3. Tucker SB, Rogers RS III, Winkelmann RK, et al: Inflammation in acne vulgaris:
leukocyte attraction and cytotoxicity by comedonal material. J Invest Dermatol 74:21,
1980
4. Leyden JJ, McGinley KJ, Mills OH, et al: Propionibacterium levels in patients with
and without acne vulgaris. J Invest Dermatol 65:382, 1975
5. Lucky AW, Biro FM, Huster GA, et al: Acne vulgaris in premenarchal girls: an early
sign of puberty associated with rising levels of dehydroepiandrosterone. Arch Dermatol 130:308, 1994
6. Sansone G, Reisner RM: Differential rates of conversion of testosterone to dihydrotestosterone in acne and in normal human skin: a possible pathogenic factor in acne.
J Invest Dermatol 56:366, 1971
7. Utas S, Ozbakir O, Turasan A, et al: Helicobacter pylori eradication treatment reduces the severity of rosacea. J Am Acad Dermatol 40:433, 1999
8. Fitzpatrick RE: Treatment of inflamed hypertrophic scars using intralesional 5-FU.
Dermatol Surg 25:224, 1999
9. Hirsch RJ, Lewis AB: Treatment of acne scarring. Semin Cutan Med Surg 20:190,
2001
10. Leyden J, Grove GL: Randomized facial tolerability studies comparing gel formulations of retinoids used to treat acne vulgaris. Cutis 67(6 suppl):17, 2001
11. Dunlap FE, Baker MD, Plott RT, et al: Adapalene 0.1% gel has low skin irritation potential even when applied immediately after washing. Br J Dermatol 139(suppl):52,
1998
12. Bershad S, Kranjac Singer G, Parente JE, et al: Successful treatment of acne vulgaris
using a new method: results of a randomized vehicle-controlled trial of short-contact
therapy with 0.1% tazarotene gel. Arch Dermatol 138:481, 2002
13. Leyden JJ: The evolving role of Propionibacterium acnes in acne. Semin Cutan Med
Surg 20:139, 2001
14. Dreno B, Reynaud A, Moyse D, et al: Erythromycin-resistance of cutaneous bacterial flora in acne. Eur J Dermatol 11:549, 2001
15. Leyden J, Kaidbey K, Levy SF: The combination formulation of clindamycin 1%
plus benzoyl peroxide 5% versus 3 different formulations of topical clindamycin alone
in the reduction of Propionibacterium acnes: an in vivo comparative study. Am J Clin Dermatol 2:263, 2001
ACP Medicine
16. Leyden JJ, Berger RS, Dunlap FE, et al: Comparison of the efficacy and safety of a
combination topical gel formulation of benzoyl peroxide and clindamycin with benzoyl
peroxide, clindamycin and vehicle gel in the treatments of acne vulgaris. Am J Clin Dermatol 2:33, 2001
17. Webster G: Combination azelaic acid therapy for acne vulgaris. J Am Acad Dermatol 43(2 pt 3):S47, 2000
18. Ross JI, Snelling AM, Eady EA, et al: Phenotypic and genotypic characterization of
antibiotic-resistant Propionibacterium acnes isolated from acne patients attending dermatology clinics in Europe, the U.S.A., Japan and Australia. Br J Dermatol 144:339, 2001
19. Gruber F, Grubisic-Greblo H, Kastelan M, et al: Azithromycin compared with
minocycline in the treatment of acne comedonica and papulo-pustulosa. J Chemother
10:469, 1998
20. Lawson TM, Amos N, Bulgen D, et al: Minocycline-induced lupus: clinical features
and response to rechallenge. Rheumatology (Oxford) 40:329, 2001
21. Honein MA, Paulozzi LJ, Erickson JD: Continued occurrence of Accutane-exposed
pregnancies. Teratology 64:142, 2001
22. Wysowski DK, Pitts M, Beitz J: An analysis of reports of depression and suicide in
patients treated with isotretinoin. J Am Acad Dermatol 45:515, 2001

23. Jick SS, Kremers HM, Vasilakis-Scaramozza C: Isotretinoin use and risk of depression, pyschotic symptoms, suicide, and attempted suicide. Arch Dermatol 136:1231,
2000
24. Strauss JS, Leyden JJ, Lucky AW, et al: A randomized trial of the efficacy of a new
micronized formulation versus a standard formulation of isotretinoin in patients with
severe recalcitrant nodular acne. J Am Acad Dermatol 45:187, 2001
25. Lucky AW, Henderson TA, Olson WH, et al: Effectiveness of norgestimate and
ethinyl estradiol in treating moderate acne vulgaris. J Am Acad Dermatol 37:746, 1997
26. Cibula D, Hill M, Fanta M, et al: Does obesity diminish the positive effect of oral
contraceptive treatment on hyperandrogenism in women with polycystic ovarian syndrome? Hum Reprod 16:940, 2001
27. London BM, Lookingbill DP: Frequency of pregnancy in acne patients taking oral
antibiotics and oral contraceptives. Arch Dermatol 130:392, 1994
Reviews
Brown SK, Shalita AR: Acne vulgaris. Lancet 351:1871, 1998
Munro CS: Acne. J R Coll Physicians Lond 31:360, 1997
ACP Medicine
XIII
DISORDERS OF HAIR
David A. Whiting, m.d.

Physiology and Evaluation of Hair Growth
A basic knowledge of the hair growth cycle is needed to evaluate disorders of hair growth.1,2 Scalp hair follicles cycle independently of one another. On average, of 100,000 scalp hairs, approximately 90% are in the anagen (growing) phase and 10% in
the telogen (resting) phase at any given time. Anagen lasts an average of 3 years, with a range of 1 to 7 years. Telogen usually
lasts 3 months, after which the resting hairs are shed and new
hairs grow in. The average rate of scalp hair growth is approximately 0.35 mm/day, or 1 cm/month (1 in. every 2 to 3 months).
An average loss of 100 hairs a day is normal, with larger numbers of hairs being lost on shampoo days. When obtaining a history, it is important to determine whether shedding is abnormal
and whether the shed hairs break off or come out by the roots.3
Hair normally comes out by the roots; however, trauma or excessive fragility may cause hair to break.
Examination of the patient should include a routine check for
broken-off hairs and the performance of hair-pull tests on the
top, sides, and back of the scalp. The hair-pull test is performed
by grasping groups of 10 to 20 hairs between the index finger
and thumb and pulling steadily.4,5 Extraction of more than 20%
of the grasped hairs indicates a potential for abnormal shedding,
usually involving telogen hairs. Telogen hairs (club hairs) are
easily recognized by their whitish club-shaped bulbs and lack of
root sheaths. Anagen hairs are normally difficult to detach and
have blackish, indented roots with intact root sheaths.
Androgenetic Alopecia
Androgenetic alopecia is the common type of nonscarring hair
loss affecting the crown. It results from a genetically determined
end-organ sensitivity to androgens. It is often referred to as common baldness, male-pattern alopecia, and female-pattern alopecia.
epidemiology and pathogenesis
Androgenetic alopecia affects at least 50% of men by 50 years
of age and 50% of women by 60 years of age.6,7 Males have more
androgen than females and therefore are usually affected earlier
and more severely. Male-pattern alopecia often starts between 15
and 25 years of age. Male-pattern alopecia has two characteristic
components, bitemporal recession and vertex balding [see Figure
1], which in pronounced cases can progress to complete balding
of the crown.6,7 Female-pattern alopecia is more likely to start between 25 and 30 years of age (or sometimes later, after menopause). It is characterized by an intact frontal hairline and an
oval area of diffuse thinning over the crown [see Figure 2]. Bitemporal recession in women is much less obvious than it typically
is in men, or it can be nonexistent. In general, androgenetic
alopecia in women progresses to mild, moderate, or severe thinning but not to complete baldness. The best predictor of outcome
is the degree of progression in affected relatives.
Androgenetic alopecia is an autosomal dominant disorder
with variable penetrance. Susceptible hairs on the crown are
predisposed to miniaturize under the influence of androgens,
notably dihydrotestosterone. In both sexes, miniaturization re 2003 WebMD Inc. All rights reserved.
January 2003 Update
sults from a shortening of the anagen cycle, from years to

months or weeks. Miniaturized hairs are characterized by reduced length and diameter; this accounts for the appearance of
hair loss.8 Androgenetic alopecia largely spares the back and
sides of the scalp.
diagnosis
The diagnosis of androgenetic alopecia is usually obvious
from the clinical pattern of hair loss from the top of the head.9 In
some men, a female pattern of alopecia (see above) causes diagnostic confusion but has no other significance. In women, a male
pattern of alopecia (i.e., bitemporal recession and vertex balding)
occurring with menstrual irregularities, acne, hirsutism, and a
deep voice is significant. The virilism indicates significant hyperandrogenism, the cause of which must be identified and treated
[see 3:III Ovary and 3:IV The Adrenal].
Scalp biopsies are rarely necessary to diagnose androgenetic
alopecia. Biopsies cut horizontally are sometimes useful, however, in differentiating female-pattern alopecia from chronic telogen effluvium (see below).
treatment
Depending on the severity of the condition, management of
androgenetic alopecia ranges from watchful inactivity to medical and surgical treatment, or a hairpiece or wig may be used in
the most refractory cases.
Topical Therapy
The Food and Drug Administration approved topical 2% minoxidil for use in men in 1987 and in women in 1989. Minoxidil
is applied twice daily with a dropper, spread over the top of the
scalp, and gently rubbed in. The drug should be tried for at least
a year. Minoxidil acts by initiating and prolonging anagen. It
produces visible hair growth in approximately one third of male
and female patients, fine-hair growth in approximately one
third, and no growth in approximately one third. It is more effective as a preventive agent, retarding hair loss in approximately
80% of patients.6
Figure 1 Bitemporal recession and vertex balding are present in this

patient with male pattern androgenetic alopecia.
ACP Medicine
DERMATOLOGY:XIII Disorders of Hair1
female pattern hair loss unless other signs of hyperandrogenism

are present.16
Therapy for Refractory Cases

In patients who do not respond to the treatments listed above,
the next step may be hair transplantation. Micrografts and minigrafts can produce a good cosmetic appearance in patients who
have a sufficient reserve of hair on the back and sides of the
scalp.17 If all therapies fail, a hairpiece may be an option.
Diffuse Alopecia
Figure 2 Intact frontal hairline and diffuse thinning over the crown
are characteristic of female pattern androgenetic alopecia.
Topical 5% minoxidil, which was approved for use in men in

1997, produces visible hair growth in 45% of patients in less time
than the 2% solution. Both concentrations are available over the
counter. Side effects are not significant and include scalp irritation and increased facial hair.10 The medication has to be continued indefinitely.11
Systemic Therapy
Oral finasteride, at a dosage of 1 mg/day, was approved by
the FDA for the treatment of male-pattern alopecia in 1997. Finasteride is a powerful type II 5-reductase inhibitor that prevents formation of dihydrotestosterone in the prostate gland and
in the hair follicle. It reduces circulating dihydrotestosterone by
65% to 70%. When administered at a dosage of 1 mg/day for 2
years to male patients with androgenetic alopecia who are between 18 and 41 years of age, finasteride grew visible hair in 66%
and prevented further hair loss in 83%.12 The efficacy of finasteride was maintained in a 5-year study.13 Hair-weight studies
have shown that finasteride increases hair length and diameter,
producing better coverage from existing hairs.14
Side effects in men are minimal and include lack of libido, lack
of potency, and mild reduction in semen in approximately 0.5%
of patients. These effects are reversed when the drug is stopped
and often disappear as the drug is continued. A 1-year trial of
finasteride at a dosage of 1 mg/day in postmenopausal women
failed to show any positive effects.
Because of the likelihood of finasteride to cause severe side effects in the male fetus, the drug is contraindicated in premenopausal women.
Therapy for Hair Loss in Women

Topical minoxidil is currently the best available treatment for
androgenetic alopecia in women.10,15 However, various antiandrogenic drugs have been used. Oral contraceptives (e.g., ethinyl
estradiolethynodiol diacetate [Demulen], desogestrelethinyl
estradiol [Desogen], and ethinyl estradiolnorgestimate [Ortho
Tri-Cyclen]) can reduce hair loss and occasionally lead to slight
hair growth.6 Oral spironolactone (Aldactone) in dosages of 75
mg/day to 200 mg/day can produce androgen blockade. Dexamethasone in dosages of 0.125 mg/day to 0.5 mg/day can suppress adrenal overactivity. Cyproterone acetate, which is not
available in the United States, is not as effective as minoxidil in
January 2003 Update
Diffuse alopecia is generalized hair loss over the entire scalp.

Because the loss is so diffuse, it is often unnoticeable until 30% to
50% of scalp hair is shed. Causes of diffuse alopecia include telogen effluvium, anagen arrest, drug reactions, and a number of
systemic and nonsystemic conditions [see Table 1].18,19
telogen effluvium
Telogen effluvium is the most common form of diffuse alopecia.20 It presents as a generalized shedding of telogen hairs from
normal resting follicles. The basic cause of telogen effluvium is a
premature interruption of anagen, leading to an increase in the
number of hairs cycling into telogen. When the 3-month telogen
period ends, new anagen hairs grow in and numerous telogen
hairs fall out. Patients may need reassurance that this apparent
loss of hair is actually a sign of regrowth.
Acute telogen effluvium can be caused by childbirth, febrile
illnesses, surgery, chronic systemic diseases, crash diets, traction,
severe emotional stress, and drug reactions [see Table 2]. It can
also be a physiologic reaction in neonates.21
During acute telogen effluvium, pull tests are positive all over
the scalp, yielding two to 10 club hairs. Telogen effluvium is often accompanied by bitemporal recession; this is a useful diagnostic sign in women [see Figure 3]. The acute form usually ends
within 3 to 6 months. The diagnosis is usually made on the basis
of the history of an initiating event 3 months before the onset of
shedding. No treatment is needed for acute telogen effluvium,
because the hair invariably regrows within a short time.
Chronic telogen effluvium has a long, fluctuating course of 6
months to 7 years or more. Very often, no identifiable cause can
be found.
Diagnosis
The diagnosis of telogen effluvium is usually clinical; biopsies
may be necessary to distinguish telogen effluvium from an acute
onset of widespread androgenetic alopecia.22 Other causes of
Table 1 Causes of Diffuse Alopecia45

Telogen effluvium (acute and chronic)
Anagen arrest
Reactions to drugs and other chemicals
Thyroid disorder
Iron deficiency and other nutritional deficiencies
Malabsorption
Renal failure
Hepatic failure
Systemic disease
Miscellaneous causes (e.g., diffuse alopecia areata, congenital
hypotrichosis) and idiopathic causes
ACP Medicine
Table 2 Categories of Drugs

That Can Cause Alopecia5
Category
Selected Agents
Alpha blockers
Doxazosin, prazosin, terazosin
Angiotensin converting
enzyme inhibitors
Captopril, enalapril
Anticancer drugs
Bleomycin, cyclophosphamide, cytarabine,

dactinomycin, daunorubicin, doxorubicin,
etoposide, floxuridine, fluorouracil,
methotrexate, mitomycin, mitoxantrone,
procarbazine, thioguanine, vinblastine,
vincristine
Anticoagulant drugs
Dicumarol, heparin, warfarin
Anticonvulsant drugs
Ethotoin, mephenytoin, paramethadione,

phenytoin, trimethadione, valproate sodium
Antithyroid drugs
Carbimazole, methylthiouracil, methimazole, propylthiouracil
Beta blockers
Acebutolol, atenolol, labetalol, metoprolol,

nadolol, pindolol, propranolol, timolol
Calcium channel
blockers
Diltiazem, verapamil
Cholesterol reducers
Clofibrate, lovastatin
H 2 receptor blockers
Cimetidine, famotidine, ranitidine
Nonsteroidal antiinflammatory drugs
Fenoprofen, ibuprofen, indomethacin,

ketoprofen, meclomen, naproxen,
piroxicam, sulindac
Retinoids and retinol
Acitretin, etretinate, isotretinoin, vitamin A

overdose
Tricyclic
antidepressants
Amitriptyline, amoxapine, desipramine,

doxepin, imipramine, nortriptyline,
protriptyline, trimipramine
vere protein calorie malnutrition. Because 90% of scalp hairs are

in anagen at any given time, this condition causes obvious and
severe baldness [see Figure 4].
Diagnosis
The diagnosis of anagen arrest is easily made by the history,
evidence of extensive hair loss, and hair-pull tests that yield easily broken hairs with proximal tapering.
Treatment
Treatment of anagen arrest lies in elimination of the underlying cause. Once the antimitotic influence is removed, the anagen
Figure 3 In women, marked bitemporal recession is often a sign of

telogen effluvium.
hair loss should be excluded by a careful drug history and tests

for iron deficiency, syphilis, and disorders of the thyroid, kidney,
and liver.
Treatment
As mentioned above, no treatment is needed for acute telogen
effluvium because the hair invariably regrows within a short
time. In chronic telogen effluvium, topical minoxidil in a 2% or
5% solution may be indicated. The patient should be reassured
that telogen effluvium rarely causes permanent baldness.
anagen arrest (anagen effluvium)
So-called anagen effluvium represents a diffuse loss of anagen
hairs from growing follicles.23 The term anagen effluvium is a
misnomer. Normally, hairs pass through a brief transition phase
(catagen) between the anagen and telogen phases before falling
out by the roots. In anagen arrest, inhibition of cell division in the
hair bulb matrix leads to a progressive narrowing of the hair
shaft and sometimes failure of hair formation. As the growing
hair narrows near the skin surface, it may break off. The resultant shedding can occur within a few weeks, unlike in telogen effluvium, in which shedding takes 3 months to occur.
Causes of anagen arrest include reactions to cytostatic drugs
and other toxic agents, radiation therapy, endocrine diseases,
alopecia areata, cicatricial alopecia, trauma and pressure, and se 2003 WebMD Inc. All rights reserved.
January 2003 Update
Figure 4 Anagen arrest causes severe, diffuse hair loss.

ACP Medicine
Table 3 Miscellaneous Chemicals

That Can Cause Alopecia45
Abrin
Plant source (Abrus precatorius [rosary pea,

jequirity bean, or precatory bean])
Arsenic
Pesticides
Bismuth
Old treatment for syphilis
Boric acid
Mouthwashes, occupational exposure
Chloroprene dimers
Occupational exposure (synthetic-rubber

manufacturing)
Some 5% of alopecia areata casesusually those occurring in

middle-aged patientsare associated with autoimmune disease,
either in the patient or in the patients family. Some 10% of these
patients will experience loss of all scalp hair in the course of the
disorder. Approximately 20% to 25% of casesoften those occurring in childhoodmay be associated with atopic disease
(e.g., hay fever, asthma, or eczema). The incidence of complete
scalp hair loss is much higher in these patients.
Despite its long course, often recurring over many years, the
prognosis of alopecia areata is often favorable. Most patients will
regrow hair at one time or another. In cases of extensive alopecia
areata, alopecia totalis, and alopecia universalis, however, hair
loss may be permanent.
Lead
Paints
diagnosis
Mercury
Cosmetics, teething powders, antiseptics
Mimosine
Plant source (Leucaena glauca)
Selenocystothione
Plant source (Lecythis species)
Thallium salts
Rodenticides
Active alopecia areata is characterized by a spreading, annular area of hair loss; a smooth, depressed area of scalp that is slick
to the touch is surrounded by hairs that often include so-called
exclamation-point hairs (i.e., broken hairs 3 to 4 mm long, usually with an expanded tip and a telogen bulb). These hairs are not
always seen but are diagnostic when present. They delineate the
active spreading margin of alopecia areata. The bald patches
generally affect the scalp but can also involve eyebrows, eyelashes, beard hair, and body hair. Spontaneous regrowth is common.
This condition is extremely unpredictable, often fluctuating
without any obvious reason. However, seasonal outbreaks are
noted in many patients. The initial patch may enlarge, or additional patches may develop and become confluent [see Figure 5].
The condition can progress to large irregular areas of baldness.
In severe cases, patients lose all scalp hair or all body hair.
Ophiasis is a chronic and difficult to treat form of alopecia
areata in which a band of baldness circles the scalp, very often
around the inferior margin. This slowly extending lesion is often
present for several years before any regrowth occurs. Permanent
hair loss may result in some areas.
Chemical
Common Source
hair will regrow promptly with a normally tapering shaft. Unbroken hairs that regrow often show the Pohl-Pinkus deformity
(i.e., a constriction that results in a dumbbell shape).
alopecia caused by drugs and chemicals
Substance-induced alopecia is relatively common but is often
hard to diagnose because of the large number of drugs and
chemicals that can cause hair loss [see Tables 2 and 3]. It often
takes time to identify the underlying cause by trial and error:
many patients are exposed to several alopecia-inducing substances, and removal of the causative agent may not result in immediate regrowth of hair.
other causes of diffuse alopecia
Hypothyroidism and iron deficiency should be excluded in
patients with diffuse hair loss [see Table 1]. Appropriate treatment may lead to hair regrowth.
Alopecia Areata
Alopecia areata is typically characterized by patchy hair loss;
however, involvement can vary from a single patch on the scalp
or elsewhere to total body baldness (alopecia universalis).24
epidemiology and pathogenesis
In the United States, alopecia areata affects 1.7% of the population younger than 50 years.25 Some 70% to 75% of cases are not
associated with any other disease. In these patients, alopecia
areata often starts in the 20s and 30s, although it can occur at any
age. In only about 6% of these patients with alopecia areata does
the disease progress to total loss of scalp hair. Even total alopecia
can reverse itself.
Alopecia areata is currently regarded as an autoimmune disease. A positive family history in 20% of alopecia areata patients
indicates a genetic predisposition to this disease. Certain HLA
groups have been associated with mild or severe cases of alopecia areata.26 Although the exact cause is unknown, many researchers presume that an infectious agent such as a virus is the
offending agent. Stress, seasonal factors, and infection are
among the trigger factors for active episodes of hair loss.
January 2003 Update
treatment
The treatment of alopecia areata depends on the severity of
the disease.27 Small patches of alopecia areata often regrow hair
without treatment. If not, they usually respond to medium- or
high-potency topical corticosteroids or to intralesional injections
of triamcinolone acetonide at a concentration of 5 mg/ml.
In more severe cases, intralesional corticosteroids may be
tried; however, these may not be feasible in extensive hair loss.
Daily, short-contact topical therapy with 0.25% to 1% anthralin
cream for up to an hour at a time may help and is suitable for
children and adults. Psoralen and ultraviolet A (PUVA) therapy
has also been used with some success.
Topical 5% minoxidil can be tried to speed hair regrowth and
lengthen existing hairs. Minoxidil has no effect on the course of
the disease but may improve hair coverage. It has few side effects
and is often used in older children; however, the FDA has approved minoxidil for use only in persons 18 years of age and older. Systemic steroids are effective; however, they have shown a
potential for side effects and do not prevent future recurrences.28
Prednisone (20 to 40 mg daily in the morning for 1 or 2 months
followed by slow tapering) has controlled the disease in adults; a
change to alternate-day therapy is advisable whenever possible.
Topical immunotherapy with the sensitizing chemical diphencyprone has been used in some centers; it has a response rate
comparable to that of systemic corticosteroids.29 Success with this
treatment usually requires supervision in a specialized clinic.27
ACP Medicine
sulting from sibling rivalry, lack of attention, divorce of parents,

learning disabilities, or unhappiness or teasing at school. In adolescents and adults, trichotillomania may be accompanied by
mood disorders, anxiety disorders, or mental retardation and is
often harder to treat than in children.
The diagnosis is based on the presence of irregular, broken-off
hairs in patches on the scalp [see Figure 6]. The hairs are irregular
in length because they are broken off at different times. The scalp
itself is normal. Occasionally, biopsies are necessary to confirm
the diagnosis. The best treatment is to explain cause and remedy
to the patient in a nonconfrontational manner; usually, reassurance and understanding go a long way in the treatment of this
condition. In more difficult cases, psychiatric consultation may be
indicated.33 If habit tics or head rolling and banging are found to
be causing traumatic hair loss, those behaviors should be treated.
other causes of traumatic alopecia
Figure 5 Circumscribed patches of hair loss are present in alopecia
areata.
Sulfasalazine has been reported to have a 23% success rate in the

treatment of severe alopecia areata.30 Other immunosuppressive
drugs, such as oral cyclosporine, have been used experimentally.
Such therapies are risky and expensive, however, and have not
been approved in the United States for alopecia areata.
traumatic alopecia
Traumatic alopecia may be caused by a variety of physical or
chemical injuries to the hair and scalp. These injuries may be deliberate or accidental, inflicted by self or others, and acute or
repetitive. The cause may be obvious or unclear.31 Potential causes include trichotillomania, habit tics, pruritic dermatoses, traction, pressure and friction, heat, radiation, and chemicals. In
most cases of traumatic alopecia, management is removal of the
underlying cause. In areas with permanent damage, hair transplantation may be necessary.
trichotillomania
Trichotillomania is a compulsion to pull out ones hair. It is
characterized by an increasing sense of tension before, and a
sense of relief after, the hair is pulled. Trichotillomania is now
classified as a specific disorder of impulse control.31,32 It is more
common in children, in whom it is often caused by insecurity re-
Pruritic Dermatoses
Pruritic dermatoses such as acne necrotica, folliculitis, lichen
simplex chronicus, pediculosis capitis, prurigo nodularis, psoriasis, seborrheic dermatitis, and neurotic excoriations can lead to
hair loss from excoriation. They need to be identified and treated.
Traction Alopecia and Loose Anagen Syndrome

Traction alopecia may be acute (caused by accidental or deliberate avulsion of the scalp) or may arise from a familial condition, the loose anagen syndrome. Common causes of traction
alopecia are excessive brushing and combing; backcombing and
pulling the hair into braids, cornrows, and ponytails; weaving;
and application of rollers.31
Loose anagen syndrome is usually seen in fair-haired children
2 to 5 years of age.34 It often presents as patchy hair loss following
an incident of hair tugging. Prompt hair regrowth is the rule. The
condition becomes asymptomatic with gentle hair care. Diagnosis is made on the basis of positive hair pull tests showing many
anagen hairs.
Alopecia Caused by Pressure and Friction

Prolonged pressure on a localized area of the scalp in immobilized neonates or patients under anesthesia, in coma, or with debilitating illness may result in ischemia leading to pressure
alopecia. The hair usually regrows with time, but if the damage
is severe, permanent hair loss and scarring may result.31 Alopecia
caused by friction from vigorous massage has been described
but is easily remedied.
Alopecia Caused by Heat, Radiation, and Chemicals
Figure 6 Irregular, broken-off hairs are seen in trichotillomania.

January 2003 Update
Excessive heat from hot oils and pomades, hot combs, and hot
rollers is a common cause of chronic hair loss. Overheated hair
dryers frequently cause the fluid droplets in wet hair shafts to
expand, leading to the formation of bubble hairs.35 These brittle
hairs are a frequent cause of follicle damage. The source of the
overheating needs to be identified and removed.
Radiation dermatitis can cause hair loss. Permanent scarring
alopecia is still seen in patients who were overtreated with x-rays
for tinea capitis before oral antifungal agents became available.
Many chemicals, such as hair dyes, moisturizers, oils and pomades, permanent waves, relaxers and straighteners, setting lotions, certain cationic and detergent shampoos, and saltwater,
are possible causes of hair loss.36 A careful history of hair care
and grooming is needed to uncover these causes.
ACP Medicine
Cicatricial Alopecia
Cicatricial alopecia results from permanent scarring of the hair
follicles. It may be widespread or localized and is sometimes difficult to identify. The causes of cicatricial alopecia may be primary or secondary.37 It can result from hereditary or congenital conditions, infections, injuries, neoplasms, and dermatoses [see Table 4].
diagnosis
On clinical examination, scarring is detected by the absence of
follicular orifices and a pearly or scarred appearance of the skin.
The scar may be depressed or hypertrophic. Associated lesions
such as folliculitis, follicular plugs, scales, and telangiectasias
may be found, along with broken, twisted, or easily extractable
hairs. Other lesions may be present on skin or mucous membranes. If the disease is active, a specific diagnosis may be possible; but in an inactive case, the initial cause is often inapparent.
Table 4 Causes of Cicatricial Alopecia46

Dermatoses
Cicatricial pemphigoid, dermatomyositis,

folliculitis decalvans, lichen planopilaris,
lupus erythematosus, neurotic excoriations,
pseudopelade, scleroderma
Hereditary and
congenital disorders
Aplasia cutis, epidermal nevi, epidermolysis bullosa
Infections
Bacterial
Fungal
Protozoan
Viral
Injuries
Burns, mechanical trauma, radiodermatitis
Neoplasms
Angiosarcoma, basal cell epithelioma, lymphoma, melanoma, metastatic tumors,

squamous cell carcinoma
Clinical Variants
The common variants of primary cicatricial alopecia of the
scalp include discoid lupus erythematosus, lichen planopilaris,
folliculitis decalvans, and pseudopelade.38,39 The end phases of
these conditions are similar; they are characterized by a lack of
pores and by inflammation in white, scarred areas. For an accurate diagnosis, an early biopsy from an area of activity might
show the identifying pathology. In the final scarring stage, it is
usually not possible to identify the original cause.
Discoid lupus erythematosus Lesions are often itchy at onset and lead to erythema, scaling, telangiectasia, follicular spines,
and atrophy [see Figure 7]. They often occur centrally in bare
patches of scarring with an inactive border [see 15:IV Systemic Lupus Erythematosus].
Acne keloidalis, dissecting cellulitis, folliculitis, syphilis

Favus (tinea capitis), kerion, mycetoma
Leishmaniasis
Herpes zoster, varicella
This eponym is rarely used nowadays except perhaps for a small

cohort of cases with no inflammatory phase at all, particularly
occurring in children. Most cases of so-called pseudopelade of
Brocq are explainable as an end stage of lichen planopilaris or
other causes.37
treatment
Treatment depends on the level of activity of the underlying disease. Discoid lupus erythematosus and lichen planopilaris may
respond to topical, intralesional, or systemic steroids or oral chloroquine therapy. Topical minoxidil is sometimes helpful in regrowing any surviving hairs, which may be normal, dystrophic,
or in a resting stage. The application of a 2% or 5% solution twice
daily should be tried for at least a year on scarred areas that show
Lichen planopilaris Central scarring characterizes these lesions. The condition generally starts with bare, white patches that
bud out from one another like pseudopods. Prominent follicular
hyperkeratosis is present around the residual terminal hairs at
the edges of the lesion, and varying degrees of erythema, scaling,
and telangiectasia may occur. Itching may be present.
Folliculitis decalvans Crops of follicular pustules surrounding multiple, slowly expanding, and round or oval areas of
alopecia characterize this condition. It may involve large areas of
the skin. Secondary infection may be severe, with crusting and
oozing. Eventually this condition gradually loses activity and
looks like other forms of chronic cicatricial alopecia.
Pseudopelade (nonspecific cicatricial alopecia) The majority of cases classified as pseudopelade are in fact cases of nonspecific cicatricial alopecia in which the initial cause has not been established. In general, there is an insidious spread of a scarring
process, which is apparently noninflammatory. It often involves
the crown and occurs mainly in middle-aged women. It may
represent the final common pathway of various causes, such as
lichen planopilaris in particular or discoid lupus erythematosus.
It is characterized by patchy areas of alopecia with irregular extensions. The affected skin is smooth, white, and devoid of erythema, scaling, or pores, causing the so-called footprints in the
snow. The course is variable and may last for a few years or several decades.
The original cases were described as a specific entity in the
late 19th century and were reported as pseudopelade of Brocq.
January 2003 Update
Figure 7 Atrophic scarring with erythema, scaling, telangiectasia, and

follicular spines are characteristic of discoid lupus erythematosus.
ACP Medicine
Figure 8 In endothrix tinea capitis, black dots represent brittle,

infected hairs snapped off flush with the scalp.
agnosed by Woods light or by a finding of fungal spores around

the hair shaft with KOH. Suitable oral antifungal treatments include griseofulvin, itraconazole, terbinafine, and fluconazole.
Secondary syphilis can cause a somewhat nondescript, motheaten type of diffuse alopecia [see Figure 9]. In such cases, a routine serologic test for syphilis is indicated.
Scalp lice should always be sought in cases of hair loss accompanied by pruritus. Lice are most likely to be found around and
behind the ears and on the nape of the neck. Lymphadenopathy
may also be present. Suitable treatment with permethrin shampoo or 0.5% malathion can be given.
Hair shaft abnormalities frequently present as broken-off
hairs. Structural abnormalities of the hair shaft include fractures,
irregularities, coiling and twisting, and extraneous matter.41,42
There are many different types of congenital and inherited
hair loss.43 These include congenital hypotrichosis with or without associated defects, congenital triangular alopecia, and many
ectodermal dysplasias that affect the hair, teeth, nails, and sweat
glands. One major form of congenital hypotrichosis is the MarieUnna syndrome, which affects large families that have a dominant gene.44 Minor forms of hypotrichosis can occur in patients
with other hereditary syndromes and chromosomal abnormalities. In most of these conditions, a reduction of hair follicles accounts for the hair loss. Some patients have surviving hairs that
are often in telogen and may benefit from topical minoxidil.
The author is a consultant and participates in the speakers bureaus for Pharmacia & Upjohn, Merck & Co., Inc., and GlaxoSmithKline.
Oral contraceptives and antiandrogens discussed in this subsection have not
been approved by the FDA for use in androgenetic alopecia; topical minoxidil discussed in this subsection has not been approved by the FDA for use in chronic
telogen effluvium and cicatricial alopecia; diphencyprone, sulfasalazine, and cyclosporine discussed in this subsection have not been approved by the FDA for
use in alopecia areata; and rifampin discussed in this subsection has not been approved by the FDA for use in folliculitis decalvans.
Figure 9 The characteristic irregular, so-called moth-eaten diffuse

alopecia caused by syphilis is seen here.
some hair. Folliculitis decalvans may respond to treatment with

long-term antibiotics such as tetracycline (500 mg), minocycline
(100 mg), erythromycin (250 mg), trimethoprim-sulfamethoxazole (regular strength), or rifampin (300 mg, with regularstrength trimethoprim-sulfamethoxazole, given twice daily for at
least 3 months). When the conditions have burned themselves
out, either scalp reduction or hair transplants may be helpful.
Miscellaneous Causes of Hair Loss
As mentioned earlier, less common causes of hair loss include
infections (e.g., tinea capitis),40 infestations, hair shaft abnormalities, hereditary and congenital conditions, and various dermatoses involving the scalp.
In the United States, tinea capitis is now largely caused by Trichophyton tonsurans, an endothrix that infects the inside of the hair
shaft. This makes the shaft brittle, which causes it to snap off
flush with the skin, leaving a characteristic black dot of hair [see
Figure 8]. The clinical diagnosis depends on this finding of black
dots in patchy areas of hair loss. Removing the black dot with a
small scalpel blade and dissolving it in potassium hydroxide
(KOH) should reveal many spores that were packed inside the
affected hair shaft. Ectothrix ringworm caused by Microsporum
canis and M. audouinii is much less common; it can usually be di 2003 WebMD Inc. All rights reserved.
January 2003 Update
References
1. Abell E: Embryology and anatomy of the hair follicle. Disorders of Hair Growth: Diagnosis and Treatment. Olsen EA, Ed. McGraw-Hill, New York, 1994, p 1
2. Stenn KS, Paus R: Controls of hair follicle cycling. Physiol Rev 81:449, 2001
3. Olsen EA: Clinical tools for assessing hair loss. Disorders of Hair Growth: Diagnosis
and Treatment. Olsen EA, Ed. McGraw-Hill, New York, 1994, p 59
4. Rietschel RL: A simplified approach to the diagnosis of alopecia. Dermatol Clin
14:691, 1996
5. Whiting DA, Howsden FL: Assessment of patient with hair loss. Color Atlas of Differential Diagnosis of Hair Loss, rev. Whiting DA, Howsden FL, Eds. Canfield Publishing, Fairfield, New Jersey, 1998, p 8
6. Olsen EA: Androgenetic alopecia. Disorders of Hair Growth: Diagnosis and Treatment. Olsen EA, Ed. McGraw-Hill, New York, 1994, p 257
7. Sawaya ME: Clinical updates in hair. Dermatol Clin 15:37, 1997
8. Birch MP, Messenger JF, Messenger AG: Hair density, hair diameter and the prevalence of female pattern hair loss. Br J Dermatol 144:297, 2001
9. Whiting DA, Howsden FL: Androgenetic alopecia. Color Atlas of Differential Diagnosis of Hair Loss, rev. Whiting DA, Howsden FL, Eds. Canfield Publishing, Fairfield,
New Jersey, 1998, p 18
10. Shapiro J, Price VH: Hair regrowth: therapeutic agents. Dermatol Clin 16:341, 1998
11. Olsen EA, DeLong ER, Weiner MS: Long-term follow-up of men with male pattern
baldness treated with topical minoxidil. J Am Acad Dermatol 16:688, 1987
12. Kaufman KD, Olsen EA, Whiting DA, et al: Finasteride in the treatment of men
with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group. J Am
13. Kaufman KD: Long-term (5-year) multinational experience with finasteride 1 mg in
the treatment of men with androgenetic alopecia. Eur J Dermatol 12:38, 2002
14. Price VH, Menefee E, Sanchez M, et al: Changes in hair weight and hair count in
men with androgenetic alopecia after treatment with finasteride, 1 mg, daily. J Am
15. Tosti A, Piraccini BM: Androgenetic alopecia. Int J Dermatol 38(suppl 1):1, 1999
16. Vexiau P, Chaspoux C, Boudou P, et al: Effects of minoxidil 2% vs. cyproterone acetate treatment on female androgenetic alopecia: a controlled, 12-month randomized
trial. Br J Dermatol 146:992, 2002
ACP Medicine
17. Unger WP: Whats new in hair replacement surgery. Dermatol Clin 14:783, 1996
18. Fiedler VC, Hafeer A: Diffuse alopecia: Telogen hair loss. Disorders of Hair Growth:
Diagnosis and Treatment. Olsen EA, Ed. McGraw-Hill, New York, 1994, p 241
19. Sinclair R: Diffuse hair loss. Int J Dermatol 38(suppl 1):8, 1999
20. Headington JE: Telogen effluvium: new concepts and review. Arch Dermatol
129:356, 1993
21. Kligman AM: Pathologic dynamics of human hair loss 1: telogen effluvium. Arch
Dermatol 83:175, 1961
22. Whiting DA: Chronic telogen effluvium. Dermatol Clin 14:723, 1996
23. Grossman KL, Kvedar JC: Anagen hair loss. Disorders of Hair Growth: Diagnosis
and Treatment. Olsen EA, Ed. McGraw-Hill, New York, 1994, p 223
24. Hordinsky MK: Alopecia areata. Disorders of Hair Growth: Diagnosis and Treatment. Olsen EA, Ed. McGraw-Hill, New York, 1994, p 195
25. Safavi KH, Muller SA, Suman VJ, et al: Incidence of alopecia areata in Olmsted
County, Minnesota, 1975 through 1989. Mayo Clin Proc 70:628, 1995
26. Price VH, Colombe BW: Heritable factors distinguish two types of alopecia areata.
Dermatol Clin 14:679, 1996
27. Shapiro J, Madani S: Alopecia areata: diagnosis and management. Int J Dermatol
38(suppl 1):19, 1999
28. Shapiro J, Price VH: Hair regrowth: therapeutic agents. Dermatol Clin 16:341, 1998
29. Madani S, Shapiro J: Alopecia areata update. J Am Acad Dermatol 42:549, 2000
30. Ellis CN, Brown MF, Voorhees JJ: Sulfasalazine for alopecia areata. J Am Acad Dermatol 46:541, 2002
31. Whiting DA: Traumatic alopecia. Int J Dermatol 38(suppl 1):34, 1999
32. Walsh KH, McDougle CJ: Trichotillomania: presentation, etiology, diagnosis and
therapy. Am J Clin Dermatol 2:327, 2001
33. Hautmann G, Hercogova J, Lotti T: Trichotillomania. J Am Acad Dermatol 46:807,
2002
34. Price VH, Gummer CL: Loose anagen syndrome. J Am Acad Dermatol 20:249, 1989
35. Detwiler SP, Carson JL, Woosley JT, et al: Bubble hair: case caused by overheating
hair dryer and reproducibility in normal hair with heat. J Am Acad Dermatol 30:54,
1994

January 2003 Update
36. Wilborn WS: Disorders of hair growth in African Americans. Disorders of Hair
Growth: Diagnosis and Treatment. Olsen EA, Ed. McGraw-Hill, New York, 1994, p 389
37. Amato L, Mei S, Massi D, et al: Cicatricial alopecia: a dermatopathologic and immunopathologic study of 33 patients (pseudopelade of Brocq is not a specific clinicopathologic entity). Int J Dermatol 41:8, 2002
38. Headington JT: Cicatricial alopecia. Dermatol Clin 14:773, 1996
39. Whiting DA: Cicatricial alopecia: clinico-pathological findings and treatment. Clin
Dermatol 19:211, 2001
40. DeVillez RL: Infectious, physical and inflammatory causes of hair and scalp abnormalities. Disorders of Hair Growth: Diagnosis and Treatment. Olsen EA, Ed. McGrawHill, New York, 1994, p 71
41. Whiting DA: Hair shaft defects. Disorders of Hair Growth: Diagnosis and Treatment. Olsen EA, Ed. McGraw-Hill, New York, 1994, p 134
42. DeBerker D, Sinclair R: Defects of the hair shaft. Diseases of the Hair and Scalp, 3rd
ed. Dawber R, Ed. Blackwell Science, Oxford, 1997, p 239
43. Sinclair R, DeBerker D: Hereditary and congenital alopecia and hypotrichosis. Diseases of the Hair and Scalp, 3rd ed. Dawber R, Ed. Blackwell Science, Oxford, 1997, p
151
44. Roberts JL, Whiting DA, Henry D, et al: Marie Unna congenital hypotrichosis: clinical description, histopathology, scanning electron microscopy of a previously unreported large pedigree. J Invest Dermatol Symp Proc 4:261, 1999
45. Dawber RR, Simpson NB, Barth JH: Diffuse alopecia: endocrine, metabolic and
chemical influences on the follicular cycle. Diseases of the Hair and Scalp, 3rd ed. Dawber R, Ed. Blackwell Science, Oxford, 1997, p 123
46. Dawber RR, Fenton DA: Cicatricial alopecia. Diseases of the Hair and Scalp, 3rd ed.
Dawber R, Ed. Blackwell Science, Oxford, 1997, p 370
Acknowledgments
Figures 2, 4, 7, and 8: D. A. Whiting and F. L. Howsden: Color Atlas of Differential Diagnosis
of Hair Loss, rev. Canfield Publishing, Fairfield, New Jersey, 1998. Used with permission.
ACP Medicine
XIV
DISEASES OF THE NAIL

these racial backgrounds may present more commonly with
diffuse or banded nail-plate or nail-bed hyperpigmentation.
James Q. Del Rosso, d.o.

C. Ralph Daniel iii, m.d.
The human nail is a complex unit composed of five major modified cutaneous structures: the nail matrix, nail bed, nail plate,
nail folds, and cuticle (eponychium).1 These components are
structurally supported by specialized mesenchyme, which provides a ligamentlike function, anchoring the soft tissue structures of the nail to the underlying phalangeal bone. The primary function of the human nail is to provide protection for the
distal digits. Nails also assist in performance of fine touch and
digital dexterity. For many individuals, nails serve as an important aesthetic symbol of optimal appearance, enhanced self-image, or individuality; several cosmetic techniques are available
to modify the appearance of the nail plate. The basic anatomic
components of the nail unit are diagrammed [see Figure 1].
Nail Structure, Function, and Pathophysiology
nail matrix
The nail matrix is the dynamic, germinative portion of the
nail unit that produces the nail plate.2-4 The lunula is the visible
portion of the nail matrix, appearing under the proximal nail
plate as a gray-white half moon projecting just distal to the
proximal nail-fold cuticle. That lunula decreases with age in
approximately 20 % of persons.5
Nails are usually devoid of pigmentation because of the relatively sparse number of melanocytes present in matrix epithelium.1,2 Because nail-matrix or nail-bed melanocytes tend to be
more numerous in blacks, Asians, and Hispanics, persons of
Pathophysiology Affecting the Nail Matrix

Because of the diagonal orientation of the ventral nail matrix, the proximal portion of the nail matrix produces the superior portion of the nail plate.6 As a result, disorders of the proximal matrix produce surface abnormalities of the nail plate. A
characteristic example is nail-plate pitting secondary to psoriasis. Diseases of the distal nail matrix result in abnormalities of
the undersurface of the nail plate, changes that are visible at the
free edge of the nail, or both. Permanent damage to the matrix
as the result of trauma, surgical intervention, or disease may result in permanent nail-plate dystrophy.
nail bed
The nail bed is a layer of epithelium lying between the
lunula and the hyponychium (the distal epithelium at the free
edge of the nail). The surface epithelium of the nail bed is longitudinally ridged, with small superficially oriented vessels
coursing along the same axis, interdigitating with a complementary array of ridges on the undersurface of the nail plate.3
This anatomic feature explains the longitudinal linearity of
splinter hemorrhages, which are foci of extravasation wedged
between the bed and the plate. As outgrowth of the nail plate
occurs, splinter hemorrhages progress distally.
Pathophysiology Affecting the Nail Bed

The epidermis of the nail bed is thin and minimally keratinized, without a granular layer. If there is prolonged loss of
nail plate as a result of disease or surgical intervention, in-
Proximal Nail
Fold
Eponychium
Bed
Bed Horny Layer
Plate
Matrix
Hyponychium
Phalanx
Distal Nail
Fold
Figure 1 Longitudinal section of the

fingernail. Major components of the nail
include the nail matrix, nail plate,
eponychium, hyponychium, nail bed,
and the proximal and lateral nail folds.

February 2003 Update
ACP Medicine
DERMATOLOGY:II Diseases of the Nail1
creased nail-bed keratinization with development of a granular

layer prevents the firm attachment of the ingrowing nail plate
to the underlying nail bed. Melanocytes are more sparsely distributed in nail-bed epithelium than in the nail matrix [see Nail
Matrix, above]. The dermal layer of the nail bed is very thin and
is supported by very sparse subcutaneous tissue; it is firmly attached to the underlying bony phalanx.
nail plate
The nail plate, which is composed of densely compacted
keratinized epithelial cells, is produced by the matrix and
progesses distally toward the free edge of the nail as newly
formed plate slowly pushes forward in a distal direction. Formation and outgrowth of the nail plate is a continual process. A
fully formed nail plate extends from below the proximal nailfold cuticle to beyond the hyponychium and extends laterally
below the cuticle of the lateral nail folds. Nail-plate abnormalities frequently occur secondary to changes or disorders affecting function of the nail matrix; infections such as onychomycosis; or trauma.
Age-Related Nail-Plate Findings

The growth rate of an adult fingernail plate is approximately
3 mm/mo, with marked variability among individuals.2 Toenail plate growth occurs at one third to one half the rate of fingernail growth. A general rule is that adult fingernails take approximately 6 months to grow out fully; adult toenails, 12 to 18
months. Nail-plate growth is faster in children, peaking between 10 and 14 years of age; there is a slowly progressive decline after the second decade of life.2 Linear nail-plate growth
decreases by 50 % over a lifetime, with periods of slow decline
alternating with periods of rapid decline in approximate 7-year
increments.7 Nail-plate growth increases during pregnancy
and decreases during lactation, after use of chemotherapeutic
agents, and in conditions characterized by limb paralysis, persistently diminished circulation, or malnutrition.2,3,8 Yellow nail
syndrome is characterized by very slow or absent growth of
nail plate; it usually affects both fingernails and toenails and is
seen in association with several underlying conditions, such as
lymphedema, respiratory disorders (e.g., bronchiectasis and
pleural effusions), and nephrotic syndrome.9
Constitutional age-related findings in the nail plate include
changes in nail color and luster, longitudinal ridging, changes
in convexity, and brittle nails.8,10 Nail plates, especially of toenails, often develop a yellow or gray color with a dull, opaque
appearance. Longitudinal ridging may affect some or all nails
and may present as slightly indented grooves or projection
ridges or as beading. Over time, the surface of the nail plate
may become flattened (platyonychia) or spooned (koilonychia). Temporary koilonychia, especially of the toenails, is also
seen in infants.6
Pathophysiology Affecting the Nail Plate

Brittle nails is a common complaint; its incidence is 20% in
the overall population (27% in female patients) and increases
with advancing age.10 When nail water content falls below 16%,
nail plates become brittle; when the water content rises above
25%, nail plates become soft. The most common cause of brittle
nails is dehydration, which can be caused or exacerbated by external factors such as use of nail-polish remover or exposure to
dry climate. Onychoschizia, which presents as a layered, superficial splitting of the nail plate, may increase in incidence with
age. This condition is seen much more frequently in female patients. It is likely related to recurrent exposures to water or irritants, such as during nail-care procedures.
Fingernails demonstrate a tendency to become thinner and
more fragile over time. Toenails usually become thicker and
harder. Onychogryphosis is a marked thickening, usually of
the large toenail, resulting in a compacted mass of heaped-up
dystrophic nail plate.8 Contributing factors appear to be advanced age, poor nail care, chronic trauma, decreased peripheral circulation, and neuropathy. Poor-fitting shoewear causes
long-term exposure to lateral pressure and friction, resulting in
gryphotic changes (marked thickening or heaping of nail
plate), usually of the first and fifth toenails.
nail folds
The nail folds are the cutaneous soft tissue that houses the
nail unit, invaginating proximally and laterally to encompass
the emerging nail plate. The proximal nail fold, with the exception of the lunula, covers the underlying matrix and is devoid
of sebaceous glands and dermatoglyphic skin markings.11 The
term paronychia describes inflammation of the nail folds.
Paronychia may be acute or chronic and may occur secondary
to a variety of conditions, including contact dermatitis, psoriasis, bacterial infection, and fungal infection.12,13 The cuticle
(eponychium) is a thin, keratinized membrane of modified
stratum corneum that extends from the distal portion of the
nail fold, reflecting onto the nail-plate surface. Intact cuticle
serves as a seal that protects the space between the nail folds
and the nail plate from exposure to external irritants, allergens,
and pathogens. Loss of cuticle allows for exposure and trapping of these deleterious external agents, providing an environment in which either inflammatory or infectious paronychia can develop.
Nail Findings Associated with Disease States
Several nail findings have been associated with both underlying systemic and dermatologic conditions. The following is a
review of selected, recognized associations. Diagnosis is based
on proper evaluation of clinical findings; treatment is based on
a confirmed etiology or the recognition of an underlying systemic association.
Special care must be taken when performing biopsy of the
nail bed or matrix to avoid trauma to the tissue specimen and
surrounding structures upon specimen removal. The most appropriate plane of dissection during nail-bed or nail-matrix
biopsy is subdermal. The sampled tissue should be manipulated very gently throughout the biopsy procedure to avoid crush
artifact, which may interfere significantly with histopathologic
evaluation. It is also important to carefully dissect along the undersurface of the specimen, ensuring nontraumatic separation
of the biopsy tissue from its underlying firm attachment to
bone.
splinter hemorrhages
Splinter hemorrhages may be secondary to trauma, high altitude, primary dermatoses (i.e., psoriasis), or several underlying conditions (e.g., arterial emboli, collagen vascular disease,
or thromboangiitis obliterans). The simultaneous appearance
of splinter hemorrhages in several nails should raise suspicion
of a possible underlying systemic disorder, especially in female
patients.14
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koilonychia
Koilonychia may be found in association with other conditions, including congenital conditions, iron deficiency anemia,
cardiac disease, endocrinopathy, occupational exposures, and
trauma.3,15
transverse nail-plate depressions (beau lines)
Beau lines present as well-delineated, transverse depressions
in the nail plate. They are believed to occur secondary to temporary growth arrest of the nail matrix. The grooves become
evident weeks after the occurrence of an abrupt, stressful
event, such as an acute febrile illness. The width of the groove
reflects the duration of interrupted nail-matrix function. When
limited to one or a few digits, Beau lines may be associated
with trauma, carpal tunnel syndrome, or Raynaud disease, or
they may occur subsequent to tourniquet application during
hand surgery.15 Approximately 1 to 2 months after birth, infants may demonstrate physiologic Beau lines, which mark the
transition from intrauterine to extrauterine life.16 Multiple
transverse grooves (stepladder appearance) may be seen in as-
sociation with repeated cycles of chemotherapy, or they may

be related to zinc deficiency. Multiple Beau lines should not be
confused with the multiple transverse depressions that are
stacked longitudinally along the central nail plate (washboard
nails), resulting from the obsessive habit of repeatedly pushing
back the cuticle or picking at the proximal nailfold margin
(habit-tic deformity) [see Figure 2].15,17 There is no specific treatment for Beau lines. They grow out over time after resolution
of the growth-arrest period.
onycholysis
Onycholyis is defined as the separation of the nail plate
from the nail bed. In most cases, onycholysis begins distally; it
is often related to acute or chronic trauma that produces a
lever effect, lifting the nail plate upward and away from its
bed. Other causes of onycholysis are chemical exposure (allergic or irritant dermatitis), onychomycosis, and primary dermatoses (e.g., psoriasis or lichen planus).13 Associations with
underlying systemic disease (e.g., thyroid disease) have been
sporadically reported but are less commonly encountered in
clinical practice. When moisture accumulates under onycholytic nail plate, bacterial proliferation may occur. This can
cause a green discoloration of the nail plate as a result of a pigment produced by certain organisms (e.g., Pseudomonas aeruginosa) [see Figure 3].
Treatment requires avoidance of precipating factors for onycholysis, debridement of separated nail plate, and the twicedaily topical application of diluted acetic acid solution (consisting of equal parts white vinegar and water), gentamicin, or the
combination of polymyxin B and bacitracin.18
leukonychia
Figure 2 Stacking of transverse linear grooves traversing the entire

length of the central nail plate, resulting from the repeated picking of
the proximal nail fold margin (habit-tic deformity). Note the marked
hypertrophy of the lunula, which is typical of this disorder.
Figure 3 Colonization of the closed space between the nail bed and
nail plate with Pseudomonas aeruginosa, causing a green nail. Moisture
trapped in the onycholytic space provides an optimal environment for
proliferation of this bacterium.

Leukonychia, a white discoloration of the nail plate or subungual tissue, has multiple presentations. Small 1 to 3 mm white
spots (punctate leukonychia) or irregular transverse streaks
(leukonychia variegata) of the nail plate are the most common
varieties.15 These two presentations are generally secondary to
repeated microtrauma to the matrix, growing out distally with
outgrowth of the nail plate. Mee lines specifically refer to transverse 1 to 2 mm white bands, which usually are demonstrated
at the same site in multiple nails and reported in association
with arsenic intoxication, Hodgkin disease, sickle cell anemia,
renal failure, and cardiac insufficiency. Leukonychia is also associated with systemic infection and chemotherapy.19-21
Half-and-half nails (Lindsay nails) present as a diffuse, dull
whitening of the proximal nail bed that obscures the lunula
and as a distal region of pink or reddish-brown discoloration
that occupies from 20% to 60% of the nail length.15,22 The most
commonly reported association with half-and-half nails is
chronic renal failure. When the distal brown band of discoloration constitutes less than 20% of the total nail length, the
anomaly is known as Terry nails, which occurs in association
with chronic congestive heart failure, hepatic cirrhosis, type 2
(noninsulin-dependent) diabetes mellitus, and advanced age.
In both half-and-half nails and Terry nails, the proximal portion of the nail bed may be light pink, exhibiting a more normal
appearance, rather than white.
Muehrcke nails present as paired, white, narrow transverse
bands of the nail bed, separated by normal-appearing thin pink
bands.15,22 Muehrcke nails have been associated with chronic
hypoalbuminemia. Resolution of this nail finding correlates
with normalization of serum albumin levels.15
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clubbing
When the normal angle between the proximal nail fold and
the nail plate exceeds 180, digital clubbing is present. The morphologic changes of clubbing typically include hypertrophy of
the surrounding soft tissue of the nail folds as a result of hyperplasia of dermal fibrovasculature and edematous infiltration of
the pulp tip.21 Radiologic changes are identified in fewer than
20% of cases.15
Clubbing may be hereditary, or it may be seen in association
with several underlying disease states, such as hypertrophic
pulmonary osteoarthropathy, chronic congestive heart failure,
congenital heart disease associated with cyanosis, polycythemias associated with hypoxia, Graves disease, chronic hepatic cirrhosis, lung cancer, Crohn disease, and irritable bowel
disease.15,22,23 When clubbing is unilateral, consideration should
be given to underlying causes of obstructed circulation, such as
aneurysm, arteriovenous fistula, and a pulmonary sulcus tumor (Pancoast tumor); disorders producing soft tissue edema;
and diseases causing localized changes in underlying digital
bone (e.g., sarcoidosis). Unilateral clubbing can also be found
in cases of hemiplegia,24 and a case of subungual perineurioma
caused by unilateral clubbing has been reported.25 Paronychia
and distal phalangeal resorption may cause changes that simulate true clubbing (pseudoclubbing).
nail-plate pitting
Nail-plate pitting (onychia punctata) develops as a result of
focal defects in nail-plate formation from the proximal nail matrix. The number, size, and shape of the superficial depressions
may vary.15 The extent and duration of involvement with nail
pitting correlates with the duration of nail-matrix abnormality.
Psoriasis, the most common association with nail pitting, may
produce a random array of shallow or deep pitted indentations, usually affecting one or more fingernails.26,27
Psoriasis of the nails often responds poorly to treatment, and
it tends to recur. Topical corticosteroids, topical tazarotene, and
intralesional corticosteroid injection may help in some cases.28,29
It is a common misconception that nail pitting is pathognomonic for psoriasis.27 Nail pitting may also be seen in association with alopecia areata, punctate keratoderma, idiopathic trachyonychia, occasionally in normal nails, and rarely in association with collagen vascular disease or syphilis. Fingernail
pitting occurs in one third of children with alopecia areata;
mild disease involving only a few nails is observed in approximately 20% of cases.27 Compared to psoriasis, nail pitting seen
in alopecia areata is typically more uniform and patterned, often presenting as orderly rows of shallow pitted depressions.
Currently, there is no available treatment for this type of nail
pitting.
Figure 4 Melanonychia striata (longitudinal pigmented band)

produced by a melanocytic nevus of the nail matrix. A high index of
suspicion for subungual melanoma is very important when a
longitudinal pigmented band of the nail is identified.
eration of matrix melanocytes.30 Melanonychia striata affecting

a single nail may result from a benign melanocytic nevus or a
subungual melanoma. Thus, it is important to distinguish between a benign cause and a malignant cause of a longitudinal
pigmented band. Factors suggesting the presence of melanoma
or an atypical melanocytic proliferation are (1) single digit involvement; (2) periungual spread of pigment onto the nail-fold
region (Hutchinson sign); (3) border irregularity or variegated
color within the linear streak; and (4) changes in appearance
(e.g., color or borders) involving an established longitudinal
band.32 Because of the severity of subungual melanoma and the
importance of making a prompt diagnosis, the index of suspicion must be high. A simple biopsy of the nail plate is not satisfactory in establishing the diagnosis, because it will only
demonstrate the presence of melanin. An appropriate biopsy
inclusive of the nail matrix, as well as the nail bed if clinically
indicated, should be performed by a surgeon who is familiar
with the intricacies of performing a nail biopsy.33 Because of
limited experience and the difficulties that are commonly con-
longitudinal pigmented bands

Longitudinal pigmented bands (melanonychia striata), also
referred to as longitudinal melanonychia, is the presence of single or multiple longitudinally oriented brown or black bands
[see Figure 4]. Homogeneous longitudinal bands occur in approximately 75% of African Americans older than 20 years. It
usually affects the thumb and index finger.30,31 Melanonychia
striata is also commonly seen in Hispanics, may be found in up
to 20% of Japanese, and is rare in whites.30
The deposition of melanin in the nail plate may result from
increased melanin synthesis by matrix melanocytes that are
usually nonfunctional; it may also occur as a result of a prolif 2003 WebMD Inc. All rights reserved.
Figure 5 Psoriasis of the nail, characterized by subungual

hyperkeratosis and loss of distal onycholytic nail plate. This patient
was unsuccessfully treated with oral antifungal therapy after an
erroneous diagnosis of onychomycosis was made on the basis of
clinical diagnosis alone. Careful examination of the proximal intact nail
plate reveals pitting, a feature characteristic for psoriasis and not
onychomycosis.
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Figure 6 (a) When obtaining a nail specimen for potassium hydroxide (KOH) preparation, it is important to expose the affected nail bed by
first trimming away and discarding the distal, separated (onycholytic) nail plate. (b) Small specimen fragments of subungual hyperkeratosis of
the nail bed and exposed undersurface of the nail plate are effectively obtained using a small curette. The smaller fragments are more easily
dissolved by KOH, allowing for more accurate microscopic visualization, and can be easily plated on fungal culture medium.
fronted in the histologic interpretation of nail specimens,

biopsies of melanonychia striata are best interpreted by a
dermatopathologist.34
When nail-bed pigmentation is noted, other causes such as
systemic drugs (e.g., antimalarials, zidovudine, bleomycin,
doxorubicin, minocycline, and hydroxyuria) or systemic disease (e.g., Addison disease and HIV infection) must be considered; however, these causes usually result in a broader, more
diffuse pigmentation, often involving multiple nails.35 Another
reported association with melanonychia striata is systemic lupus erythematosus.36 Frictional melanonychia resulting from
trauma from athletic activities or poorly fitting shoewear may
cause nail pigmentation, including pigmentation of the nail
fold, especially in dark-skinned persons (pseudo-Hutchinson
sign).32
Bacterial and Fungal Nail Infections

bacterial paronychia
Bacterial infection of the nail folds (bacterial paronychia) is
usually acute in nature. It is is characterized by swelling, erythema, discomfort, and sometimes purulence. The most common etiologic pathogen is Staphylococcus aureus. Treatment requires drainage of a focal abscess, if present, and oral antibiotic
therapy.37
chronic paronychia
Chronic paronychia results from persistent or frequently recurrent nail-fold inflammation, which is usually the result of
chronic irritant dermatitis and loss of cuticle from trauma or
nail-care practices. Secondary candidal infection may occur.29,38
Table 1 Oral Antifungal for Toenail Onychomycosis*46

Drug
Dosage
Comments
Griseofulvin tablets or
liquid
500 mg 1 g daily
12 18 mo
Generally not recommended because of limited efficacy and because more effective agents are
available; only active against dermatophyte organisms
Itraconazole capsules
Pulse therapy:
200 mg twice daily
1 wk/mo for 3 consecutive mo
Contraindications include specific drug interactions and congestive heart failure; potential hepatotoxicity (rare); effective for dermatophytes, Candida species, and some nondermatophytic
molds; should be administered with food; absorption may be decreased by increased gastric
pH (as might result from use of H2 blockers, antacids, proton pump inhibitors); blood clearance in 1 2 wk; therapeutic nail levels 9 mo posttherapy
Continuous therapy:
200 mg daily 3 mo
250 mg daily 3 mo
Most active for dermatophytes; some efficacy for certain nondermatophytic molds; limited activity against most Candida species; potential hepatotoxicity (rare); sporadic reports of blood
dyscrasias (rare); reversible change or loss of taste (< 2%); blood clearance in 1 2 mo; therapeutic nail levels 9 mo posttherapy
150 300 mg 9 12 mo
Effective against dermatophytes and Candida species; potential hepatotoxicity (rare); some significant drug interactions; limited therapeutic drug reservoir in nail posttherapy
Terbinafine tablets
Fluconazole tablets
*Topical ciclopirox 8% nail lacquer is FDA approved for onychomycosis caused by Trichophyton rubrum. Treatment involves application once daily for 12 mo (or until outgrowth of clear nail occurs), combined with debridement/trimming of onycholytic nail plate. Efficacy is lower than that seen with newer oral agents (e.g., itraconazole,
terbinafine). No oral or topical agent is currently FDA approved for nondermatophytic onychomycosis (e.g., Candida species, molds).
Pulse itraconazole is FDA approved for fingernail tinea unguium; established efficacy has been demonstrated for toenail disease.
Fluconazole is not FDA approved for onychomycosis; established efficacy has been demonstrated for tinea unguium.

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Table 2 Selected Dermatologic Disorders Affecting the Nail Unit

Disease State
Disease Features
Nail Findings
Inflammatory diseases
Psoriasis
Nail findings in 10% 50% of patients; 39% of children with

psoriasis with nail changes (usually pitting); nail disease
present in 50% 85% of patients with psoriatic arthritis
Proximal matrix involvement: pitting, transverse grooving,

deeply ridged plate surface (onychorrhexis)
Distal matrix involvement: plate thinning, lunula erythema
Nail bed: subungual hyperkeratosis, oil drop sign, splinter
hemorrhages
Nail folds: cutaneous lesions of psoriasis
Phalangeal/joint involvement: psoriatic arthritis
Lichen planus
Nail changes occur in up to 10% of patients with lichen

planus; may occur in childhood or adulthood; nail involvement may be present with or without skin or mucosal disease; potentially reversible in early inflammatory
stage; irreversible in cicatricial (later stage) of disease; may
present as ridged, rough-surfaced, lusterless plates (trachyonychia) or 20-nail dystrophy in children
Matrix involvement: combination of nail-plate ridging, splitting, and progressive uniform thinning; distal-edge splitting, fragility, crumbling, brittleness, nail-plate shedding
(onychomadesis)
Focal matrix scarring: pterygium formation (scarring bridge
between proximal nail fold and subungual epidermis with
focal loss of nail plate)
Nail-bed involvement: subungual hyperkeratosis, onycholysis
Diffuse matrix/nail-bed disease: total nail-plate loss, atrophy, scarring
Alopecia areata
Nail changes in 10% of patints with alopecia areata; nail

changes in over 40% of children with alopecia areata; fingernail involvement most common; may present in children as 20-nail dystrophy
Matrix involvement: orderly nail pitting arranged in a crosshatched pattern (glen-plaid sign); roughened nail-plate
surface (trachyonychia); fragility; splitting; longitudinal
ridging; spotted or red lunula (erythema); nail-plate shedding (onychomadesis)
75% occur on the hand, usually subungual (nail bed); a benign vascular hamartoma
Visible through plate as a light-red, reddish-blue spot; rarely

exceeds 1 cm in size; characteristic symptom of intense or
pulsatile pain; pain is spontaneous or provoked by slight
trauma or pressure
Digital myxoid
(mucus) cyst
A form of focal mucinosis; not a true cyst (no epithelial lining); contains clear, viscous, jellylike fluid; usually seen in
adults
Soft, domed, translucent, pink or skin-colored, shiny, soft

neoplasm of proximal nail fold or overlying distal interphalangeal joint; those over fold may compress matrix,
producing flattening of plate; those over joint may connect
to underlying joint space
Subungual exostoses
Outgrowths of calcified cartilage or normal bone; most seen

on great toe; most frequent in adolescents and young
adults; benign lesions
Emerge from the dorsal digit at distal phalanx; may erode

through plate or project from under distal or lateral edge
of plate; often painful; may become eroded
Periungual
angiofibromas
Arise out of nail fold; often multiple; seen in 50% of cases of

tuberous sclerosis (Borneville-Pringle disease); usually
arise in early teenage years; benign neoplasm
Small, round, flesh-colored or pink, firm papules with shiny,

smooth surface arising from nail-fold region; may partially
cover nail plate; usually asymptomatic
Nail tumors
Glomus tumor
onychomycosis
Onychomycosis, the most common infection of the nail, is a
fungal infection characterized by nail-bed and plate involvement. Dermatophyte onychomycosis (tinea unguium) is the
most common type of fungal nail infection.39 It is seen far more
commonly in adults than in children and most frequently affects one or more toenails. The mode of fungal invasion usually
presents as distal-lateral subungual onychomycosis, occurring
as dermatophyte organisms migrate from pedal skin to below
the nail plate and invade nail-bed tissue.40 Tinea pedis and onychomycosis frequently coexist in a patient.41,42
The dermatophytes that most commonly cause onychomycosis are Trichophyton rubrum and T. mentagrophytes.43 The tendency to harbor dermatophytes (especially T. rubrum), predominantly on pedal skin, has been noted in some kindreds. As a result, patients with such a tendency are prone to tinea pedis,
tinea unguium, tinea cruris, and diffuse tinea corporis. They
may present with dermatophyte infections earlier in life than
usually seen and often experience recurrence of dermatophyte
infection after completion of initially effective therapy.
The most characteristic clinical features of dermatophyte
onychomycosis are distal onycholysis, subungual hyperkeratosis, and a dystrophic, discolored nail plate.42 Because this combination of features is also seen in persons with nail psoriasis,
accurate diagnosis may require performance of a potassium
hydroxide (KOH) preparation and fungal culture [see Figure 5].
It is important that specimens be obtained from the nail bed
[see Figure 6] and that culture specimens be transported and
plated appropriately, because different culture media are required for identification of dermatophyte and nondermatophyte fungal nail pathogens.42 Dermatophyte test medium
(DTM) may be used as an in-office culture technique that has
no special incubation requirements. DTM is inexpensive and
accurate in the diagnosis of dermatophyte onychomycosis.44
The clinical presentation of proximal white subungual onychomycosis, another presentation of dermatophyte onychomycosis, has been reported in association with systemic immunosuppression, including HIV disease.45
Candida onychomycosis is far less common than dermatophyte onychomycosis. Candida onychomycosis is often associated with immunosuppression (e.g., HIV disease and chronic mucocutaneous candidiasis). The Candida organisms may invade
ACP Medicine
the nail as a secondary pathogen, and they more frequently affect the fingernails.42 Nondermatophyte molds, including Aspergillus species, Scopulariopsis brevicaulis, Fusarium species, Scytalidium hyalinum, and Scytalidium dimidiatum, have been reported to cause fingernail or toenail infection; however, such
infections are relatively uncommon.42,46 Associated paronychia
may be seen when nondermatophytic fungi cause onychomycosis. Effective therapy for onychomycosis includes the use of
an oral antifungal agent [see Table 1].47 Because nails grow slowly, clinical response is delayed.46 Infections with Scytalidium species are rare in the United States, and such infections respond
poorly to currently available antifungal agents.
dermatologic disorders affecting the nail
Complete reviews of dermatologic, systemic, neoplastic, and
exogenous disorders affecting the nail are beyond the scope of
this subsection. An overview of selected dermatologic disorders affecting the nail unit and their associated clinical findings
is provided [see Table 2].
James Q. Del Rosso, D.O., participates in the speakers bureaus and is a consultant for Allergan, Inc., Janssen Pharmaceutica Products, L.P., Dermik Laboratories, Inc., Novartis Pharmaceuticals Corp., and Medicis Co.
C. Ralph Daniel III, M.D., has no commercial relationships with manufacturers of products or providers of services discussed in this subsection.
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41. Lauritz B: Dermatoses of the feet. Am J Clin Dermatol 1:181, 2000
42. Elewski BE, Charif MA, Daniel CR III: Onychomycosis. Nails: Therapy, Diagnosis,
Surgery. Scher RK, Daniel CR, Eds. WB Saunders Co, Philadelphia, 1997, p 152
43. Jennings MB, Weinberg JM, Koestenblatt EK, et al: Study of clinically suspected onychomycosis in a podiatric population. J Am Podiatr Med Assoc 92:327, 2002
44. Pariser D, Opper C: An in-office diagnostic procedure to detect dermatophytes in a
nationwide study of onychomycosis patients. Manag Care 11:43, 2002
45. Baran R, Dawber RPR, Tosti A: Onychomycosis and its treatment. A Text Atlas of
Nail Disorders. Baran R, Dawber RPR, Tosti A, Eds. Martin Dunitz, London, 1996, p 157
46. Del Rosso JQ: Current management of onychomycosis and dermatomycoses. Curr
Infect Dis Rep 2:438, 2000
47. Crawford F, Young P, Godfrey C, et al: Oral treatments for toenail onychomycosis: a
systematic review. Arch Dermatol 138:811, 2002
Acknowledgment
Figure 1 Tom Moore.
ACP Medicine
XV
D I S O R D E R S O F P I G M E N TAT I O N
Pearl E. Grimes, m.d.

Disorders of Hyperpigmentation
melasma
Definition
Melasma is a common acquired symmetrical hypermelanosis
characterized by irregular light-brown to gray-brown macules
involving the face. There is a predilection for the cheeks, forehead, upper lips, nose, and chin [see Figure 1]. Lesions may occasionally occur in other sun-exposed areas, including the forearms and back.1-3
Epidemiology
Melasma is most commonly observed in females. Men constitute only 10% of the cases but usually demonstrate the same clinicopathologic features as women do. The condition affects all
racial and ethnic groups but is most prevalent in persons with
darker complexions (skin types IV through VI). It is also more
common in geographic areas with intense ultraviolet radiation
(sunlight), such as tropical and subtropical regions.
Etiology and Pathogenesis

Although the precise cause of melasma is unknown, multiple
factors have been implicated in the etiology and pathogenesis of
this condition. These factors include genetic influences, intense
ultraviolet radiation exposure, pregnancy, oral contraceptive
use, hormone replacement therapy, cosmetics, and phototoxic
and antiseizure medications.1
Endocrinologic studies of patients with melasma have shown
varying results. Although a detailed study of nine women with
melasma showed significantly increased levels of luteinizing
hormone (LH) and low levels of estradiol, suggesting a role for
subclinical mild ovarian dysfunction, a study of 26 women
found no difference in LH, follicle-stimulating hormone (FSH),
and -melanocytestimulating hormone (-MSH) levels between patients with melasma and control subjects.3 Another
study reported increased expression of -MSH in the affected
skin areas of 10 women with melasma. -MSH stimulates tyrosinase and melanin synthesis.4
Clinically, the light-brown patches are commonly evident on
the malar prominences, forehead, chin, nose, and upper lip. The
patches may have a malar, centrofacial, or mandibular distribution. Histologically, an epidermal, epidermal-dermal, or dermal
pattern of increased pigmentation occurs. Histologic studies
document an increase in epidermal pigmentation, increased
numbers of melanocytes, and increased activity of melanogenic
enzymes.5 A Wood-light examination enhances the epidermal
pattern of pigment deposition. Such epidermal lesions are most
amenable to treatment.
The differential diagnosis of melasma includes other conditions that cause facial hyperpigmentation, such as postinflammatory hyperpigmentation, drug-induced hyperpigmentation,
lichen planus actinicus, and photosensitivity disorders.
quinone formulations, azelaic acid, kojic acid formulations, hydroxyacid products, retinoic acid, retinol, superficial chemical
peels, and microdermabrasion.1,6-9 A triple-combination product
containing 4% hydroquinone, 0.01% fluocinolone, and 0.05%
retinoic acid has enhanced efficacy. This product was previously compounded by pharmacists, but it is now available as a commercial preparation (Tri-Luma cream, Galderma Laboratories)
that has been approved by the Food and Drug Administration
for treatment of melasma. Because the combination contains a
fluorinated steroid, treatment should be limited to 8 weeks.
Laser therapy offers minimal long-term success and, instead,
may worsen the condition. Intense pulsed light therapy may offer some improvement in patients with melasma.10,11
Although all of these therapies reduce the severity of melasma, none are curative. Hence, it is essential for patients to rigidly
adhere to a regimen of daily sun protection (e.g., using sunscreen or wearing protective clothing) to control the progression
of melasma.
postinflammatory hyperpigmentation
Definition
Postinflammatory hyperpigmentation is characterized by an
acquired increase in cutaneous pigmentation secondary to an inflammatory process [see Figure 2]. Excess pigment deposition may
occur in the epidermis or in both the epidermis and the dermis.
Treatment
Current treatments for melasma include broad-spectrum sunscreens, 2% (over the counter) and 4% (prescription) hydro 2003 WebMD Corp. All rights reserved.
August 2003 Update
Figure 1 Melasma is characterized by hyperpigmentation of the

cheek, forehead, and upper lip.
ACP Medicine
DERMATOLOGY:XV Disorders of Pigmentation 1
Epidemiology
All racial and ethnic groups are susceptible to postinflammatory hyperpigmentation, but the incidence of the condition is
higher in persons with darker complexions. In a diagnostic survey of 2,000 African-American patients seeking dermatologic
care, the third most common diagnosis was pigmentary disorders, of which postinflammatory hyperpigmentation was the
most prevalent.1

Pigmentary changes may be a result of production of inflammatory mediators and altered cytokine production.12,13 Such
changes may lead to an increase in the number and size of epidermal melanocytes. In addition, hyperpigmentation may be a
consequence of pigmentary incontinence, with deposition of
pigment in the upper dermis. Postinflammatory hyperpigmentation may be a sequela of conditions such as acne, allergic reactions, drug eruptions, papulosquamous disorders, eczematoid
disorders, and vesiculobullous disorders.14
Figure 2 Postinflammatory hyperpigmentation of the face may be

secondary to acne vulgaris.
Diagnosis
Clinically, postinflammatory pigmentary changes may be localized, circumscribed, or generalized. Lesions range in color
from brown to black to ashen gray and usually follow the distribution of the primary dermatosis.
Treatment
Therapies for postinflammatory hyperpigmentation include
over-the-counter and prescription hydroquinone preparations.
Higher concentrations are indicated for moderate to severe involvement. Other treatments include azelaic acid, kojic acid,
retinoic acid [see Melasma, above], and adapalene.15
drug-induced hyperpigmentation
Medications are a common cause of cutaneous hyperpigmentation. Lesions may be localized or generalized. Medications can
also cause hyperpigmentation of the oral mucosa and nails.
There may be some improvement upon withdrawal of the offending agent; however, drug-induced hyperpigmentation can
persist for many years.
Medications causing drug-induced hyperpigmentation include oral contraceptives, hormone replacement therapies, antibiotics, antidepressants, antiviral agents, antimalarials, antihypertensives, and chemotherapeutic agents. Such medications include progesterone, estrogen, zidovudine (AZT), minocycline,
tetracycline, bleomycin, hydrochlorothiazide, hydantoin, amiodarone, chlorpromazine, quinacrine, hydroxychloroquine,
chloroquine, imipramine, amitriptyline, diltiazem, citalopram,
hydroxyurea, doxorubicin, busulfan, daunorubicin, cisplatin, cyclophosphamide, thiotepa, vinblastine, and vincristine.16-23
Heavy-metal preparations can also cause hyperpigmentation.
These preparations include arsenic, gold, silver, mercury, and
bismuth.
Treatment with the Q-switched alexandrite laser has proven
to be an effective treatment for drug-induced pigmentation.19,24
erythema dyschromicum perstans
Definition
Erythema dyschromicum perstans (EDP, or ashy dermatosis)
is an acquired benign condition characterized by slate-gray to violaceous macules. It was first described in 1957.
2003 WebMD Corp. All rights reserved.
August 2003 Update
Epidemiology
EDP is reported most commonly in dark-skinned persons.
However, cases have been reported globally and in all skin
types. The disease appears to have a relatively equal frequency
in men and women. It has also been reported in children.

The precise cause of EDP is unknown. Studies suggest that
pollutants, pesticides, hair dyes, chemicals, and drug exposure
may play a role in the pathogenesis.23-28 Findings in light microscopic, ultrastructural, and immunofluorescent studies of EDP
have been similar to those in studies of lichen planus, leading
some investigators to postulate that EDP may be a variant of
lichen planus. Other studies suggest that EDP is a distinct entity.
Expression of intercellular adhesion moleculeI (ICAM-I) and
major histocompatibility complex (MHC) class II molecules
(HLA-DR) has been reported.29 These findings suggest that aberrant cell-mediated immunity may be involved in the pathogenesis of EDP.
Diagnosis
Clinically, the macules of EDP are ashen and may have an
erythematous, slightly raised border during the early stages of
the disease. Erythematous macules have also been described
during the early stages. Areas of erythema eventually resolve,
leaving slate-gray areas of pigmentation. The lesions are usually
symmetrically distributed and vary in size from small macules
to very large patches. Common sites of involvement include the
face, neck, trunk, and upper extremities. Mucous membranes,
palms, soles, and nails are usually spared. Light microscopic
findings are slight epidermal atrophic changes, spongiosis, lymphocytic exocytosis, and basal vacuolopathy in the epidermis, as
well as lymphohistiocytic, lichenoid dermal infiltrates. In later
stages, the lesions lack the epidermal changes and show increased deposition of dermal pigment.
Postinflammatory hyperpigmentation, idiopathic eruptive
macular pigmentation, pityriasis rosea, lichen planus, fixed
drug eruption, Addison disease, pinta, syphilis, macular amyloidosis, hemochromatosis, and argyria must be distinguished
from EDP.
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Treatment
Treatment
Therapies for EDP have been minimally effective. They include

sunscreens, hydroquinone, topical corticosteroids, systemic steroids,
griseofulvin, clofazamine, antibiotics, and antimalarials.30
The treatment of lentigines includes hydroquinone-containing

bleaching agents, cryotherapy, Q-switched neodymium:yttriumaluminum-garnet (Nd:YAG) laser, and intense pulsed light.33,34
lentigines
confluent and reticulated papillomatosis of

gougerot and carteaud
Definition
A lentigo is a well-circumscribed, brown to brown-black macule, usually less than 1 cm in size, that appears at birth or in early
childhood. Lentigines occur in all skin types and may be found
on any cutaneous surface, including the palms, soles, and mucous membranes. They do not darken with sun exposure.
Lentigines can be localized and must be distinguished from
freckles (ephelides). Clinical differentiating features include the
later appearance of freckles (at 4 to 6 years of age) and their predominance on sun-exposed skin and increased frequency in redheads and fair-skinned persons. Freckles also tend to fade in
winter and with advancing age.
Epidemiology
Multiple lentigines have been reported in 18.5% of black newborns and 0.04% of white newborns. Solar lentigines have been
reported in 90% of whites older than 60 years.
Diagnosis
Several types of lentigines are recognized, including lentigo
simplex, solar lentigines, nevus spilus, lentigines induced by
psoralens plus ultraviolet A (PUVA), generalized lentiginosis,
and syndrome-related lentiginosis.
Lentigo simplex lesions may occur as solitary localized macules or may be numerous and widespread. They often occur
during the first decade of life and can be found on any cutaneous
surface.
Solar (senile) lentigines, or so-called liver spots, are brown
macules that appear late in adult life on chronically sun-exposed
skin. These lesions are present in 90% of whites older than 70
years and occur in response to solar exposure. Solar lentigines
correlate with the tendency to freckle and with two or more sunburns after 20 years of age.
Nevus spilus, or speckled lentiginous nevus, is a congenital
brown patch on which dotted brown macules develop during
childhood. Histologically, the brown patch has features of a
lentigo, whereas the dotted brown macules most often reveal
features of junctional nevi. Zosteriform patterns have also been
described. Generalized lentiginosis is characterized by innumerable lentigines unassociated with other abnormalities.
Syndromes characterized by multiple lentiginosis include multiple lentigines (LEOPARD [multiple lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary
stenosis, abnormal genitalia, retardation of growth, sensorineural
deafness]) syndrome, Moynahan syndrome, centrofacial lentiginosis, Carney complex, Laugier-Hunziker disease, Peutz-Jeghers
syndrome, and Bannayan-Ruvalcaba-Riley syndrome.31,32
The histopathology of lentiginosis shows elongated rete ridges,
increased numbers of basal melanocytes, and increased basal
melanization. In contrast, freckles result from hypermelanization of basal melanocytes without a concomitant increase in
number.
Lentigo must be distinguished from other flat, pigmented lesions, including freckles, junctional nevi, postinflammatory hyperpigmentation, and pigmented actinic keratoses.
August 2003 Update
Definition
The eruption of confluent and reticulated papillomatosis was
initially described by Gougerot and Carteaud in 1927 and 1932.
The condition consists of 2 to 5 mm hyperpigmented papules
that have a predilection for the sternal area and midline of the
back and neck.
Epidemiology
Confluent and reticulated papillomatosis occurs in equal frequency in men and women and shows no racial or ethnic
predilections. The disease usually begins during the third
decade of life.

The precise cause of confluent and reticulated papillomatosis
is unknown. Abnormal host response to Pityrosporum orbiculare
(Malassezia furfur; the fungus that causes tinea versicolor), abnormal response to colonization by follicular bacteria, and genetically determined defects of keratinization have been suggested.35,36
The disease has been associated with Cushing syndrome, diabetes, hypopigmentation, and thyroid disorders.
Diagnosis
Patients present with 2 to 5 mm hyperpigmented, slightly verrucoid papules that have a predilection for the back, scapula,
and inframammary areas. The papules become confluent near
the midline and possess a reticulated pattern near the periphery.
The lesions do not form a true scale but, rather, a mealy deposit
that can be easily removed with the fingertips.
Histologically, studies show hyperkeratosis, decreased granular cell layers, papillomatosis, absence of sweat glands, and fragmentation of elastic fibers. Electron microscopic studies have
shown increased numbers of transitional cells between the stratum granulosum and stratum corneum. This finding suggests
premature keratinization. In addition, increased expression of
keratin 16 has been reported, suggesting abnormal proliferation,
differentiation, or both.36
Other conditions that simulate confluent and reticulated papillomatosis are tinea versicolor and acanthosis nigricans.
Treatment
Minocycline is reportedly beneficial.37 Other treatments that
have shown some efficacy include selenium sulfide shampoo,
salicylic acid, urea, vitamin A, corticosteroids, calcipotriol, tetracycline, erythromycin, doxycycline, retinoids, and PUVA.38-41
dowling-degos disease
Definition
Dowling-Degos disease, or reticulated pigmented anomaly of
the flexures, is an autosomal dominant disorder with variable
penetrance characterized by brownish-black macules of the flexures that develop in a reticulated pattern. It may be caused by an
underlying defect in follicular epithelial proliferation.
ACP Medicine
Diagnosis
Dowling-Degos disease presents as symmetrical, reticulated
hyperpigmentation of the groin, axilla, antecubital area, inframammary areas, and neck.42 The lesions begin as 1 to 3 mm macules that gradually become confluent, assuming a reticulated
lacelike pattern. In addition, perinasal and facial involvement is
common. Pigmented pinhead-sized comedones are frequently
observed in the affected areas, and perinasal, pitted acneiform
scars can occur around the mouth.
Lesions of Dowling-Degos disease begin in early adult life
and are slowly progressive. The condition has been reported in
association with reticulated acropigmentation of Kitamura and
hidradenitis suppurativa,43 suggesting an underlying defect in
follicular epithelial proliferation. In addition, the disease has
been reported in a large kindred with reticulate acropigmentation of Kitamura and acropigmentation of Dohi, suggesting an
association between and overlap of these conditions.44 Histologically, thin, pigmented epithelial strands of downgrowth extend
from the epidermis and follicular wall in a filiform pattern resembling adenoid seborrheic keratoses.42,45
Treatment
In general, there is no effective treatment for Dowling-Degos
disease. Adapalene and the erbium:YAG laser have been reported to offer some benefit.46
Disorders of Hypopigmentation
vitiligo
Definition
Vitiligo is a common acquired, idiopathic skin disorder characterized by one or more patches of depigmented skin. The depigmentation results from loss of cutaneous melanocytes. These
lesions are cosmetically disfiguring and usually cause emotional
trauma in both children and adults [see Figure 3].
Epidemiology
Vitiligo affects 1% to 2% of the population. Onset may begin
at any age, but peak incidence is in the second or third decade of
life. The disease shows no racial or ethnic predilection, but because of the stark contrast between depigmented and darker
skin tones, it is more cosmetically disfiguring in darker racial
and ethnic groups. Females are affected more often than males.
The disease has a familial incidence of 25% to 30%. Genetic studies suggest a polygenic inheritance pattern.
HLA studies have reported increases in a variety of haplotypes of class I and class II antigens in patients with vitiligo.
However, results vary significantly by race and ethnicity of the
population studied. The reported HLA associations include increased frequencies of HLA A30, CW6, CW7, DR1, DR3, DR4,
and DQW3.47

The precise cause of vitiligo is unknown. Multiple theories
have been proposed, including genetic, autoimmune, neural,
biochemical, and viral mechanisms. Reviews addressing the etiology of vitiligo suggest that vitiligo is probably a heterogeneous
disease encompassing multiple etiologies.47,48
An immune-mediated pathogenesis is the most popular theory. This theory is predicated on the increased frequency of a
August 2003 Update
Figure 3 Vitiligo is indicated by generalized patches of depigmentation

of the trunk.
plethora of immunologic diseases in patients with vitiligo, including hypothyroidism (Hashimoto thyroiditis), Graves disease, pernicious anemia, diabetes mellitus, and alopecia areata.
Thyroid diseases are the most common associated diseases. Other disorders reported in association with vitiligo include Addison disease, atopic dermatitis, asthma, lichen planus, morphea,
lichen sclerosus et atrophicus, mucocutaneous candidiasis, biliary cirrhosis, myasthenia gravis, Down syndrome, AIDS, and
cutaneous T cell lymphoma.
Humoral and cell-mediated immunologic defects are a common phenomenon in vitiligo.47,48 Numerous studies have documented an increased frequency of organ-specific autoantibodies.
Antithyroid, gastric antiparietal cell, and antinuclear antibodies
are most commonly demonstrated. Patients with positive organspecific autoantibodies unassociated with autoimmune disease
have an increased risk of subsequent subclinical or overt autoimmune disease.
Antimelanocyte antibodies, often demonstrated in the sera of
patients with vitiligo, induce the destruction of cultured
melanocytes by complement-mediated lysis and antibody-dependent cellular cytotoxicity. The presence and titer of antimelanocyte antibodies correlate with the severity and activity of vitiligo. These antibodies are directed against melanocyte cell surface antigens with molecular weights of 25, 35 to 40, 75, 90, and
150 kd. Studies suggest that the antimelanocyte antibody may
mediate the destruction of melanocytes in vitiligo. Tyrosinase
antibodies have also been reported in patients with localized and
generalized disease.49
Cellular immune-mediated defects include diminished contact
sensitization and quantitative and qualitative alterations in T cells
and natural-killer cells. Skin-homing cytotoxic T cells have also
been implicated in the destruction of melanocytes. Immunohistochemical studies have demonstrated abnormal expression of
MHC class II and ICAM-I by melanocytes in vitiligo, which may
contribute to the aberrant cellular immune response. In addition,
there is increased expression of the antiadhesive matrix component tenasin in perilesional and lesional vitiliginous skin. Increased tenasin expression may be a consequence of elevated cytokine production and cellular infiltrates in vitiligo.47 Studies have
documented alterations in cytokine production in patients with
vitiligo. Studies of affected skin showed a significantly lower expression of granulocyte-macrophage colony-stimulating factor
ACP Medicine
(GM-CSF), basic fibroblast growth factor (bFGF), and stem cell

factor.50 In contrast, expression of interleukin 6 (IL-6) and tumor
necrosis factor (TNF- ) was greater in lesional skin than in
perilesional or normal skin. Another study reported increased expression of TNF-, interferon gamma, and IL-10 in the lesional
and adjacent skin of vitiligo patients.51
Cytomegalovirus DNA has been demonstrated in the involved
and uninvolved skin of patients with vitiligo. No viral DNA was
detected in matched control subjects.52 These findings suggest
that in some cases, vitiligo may be triggered by a viral infection.
The neural theory is supported by several clinical, biochemical, and ultrastructural observations. These observations include
the occurrence of segmental vitiligo; the demonstration of lesional autonomic dysfunction, such as increased sweating; and the
demonstration of nerve endingmelanocyte contact. The last observation is rare in normal skin.
Several studies suggest that oxidative stress may be the initial
event in the destruction of melanocytes.53,54 Defective recycling of
tetrahydrobiopterin, increased production of hydrogen peroxide, and decreased catalase have been demonstrated in the skin
of patients with vitiligo.55,56 In addition, lesional catecholamine
biosynthesis and release are increased. Thus, abnormal release of
catecholamines from autonomic nerve endings and oxidative
stress may damage melanocytes by altering the free radical defense of the epidermis.
The self-destruction hypothesis proposes that melanocytes
may be destroyed by phenolic compounds formed during the
synthesis of melanin. In vivo and in vitro studies have demonstrated the destruction of melanocytes by phenols and catechols.
In addition, industrial workers who are exposed to catechols and
phenols may experience depigmentation of areas of skin.
A variety of environmentally ubiquitous compounds containing catechols, phenols, and sulfhydryls can induce hypopigmentation, depigmentation, or both. These compounds are most often encountered in industrial chemicals and cleaning agents.
Possible mechanisms for altered pigment production by these
compounds include melanocyte destruction via free radical formation, inhibition of tyrosinase activity, and interference with
the production or transfer of melanosomes.
Diagnosis
Clinical manifestations Vitiliginous lesions are typically
asymptomatic depigmented macules without clinical signs of inflammation. However, inflammatory vitiligo with erythematous
borders has been reported. Hypopigmented lesions may coexist
with depigmented lesions. The patches are occasionally pruritic.
Macules frequently begin on sun-exposed or perioral facial skin
and either remain localized or disseminate to other cutaneous
sites. Areas of depigmentation vary in size from a few millimeters to many centimeters, and their borders are usually distinct.
Trichrome lesions are most often observed in darker-complexioned persons. These lesions are characterized by zones of white,
light-brown, and normal skin color. Depigmented hairs are often
present in lesional skin and do not preclude repigmentation of a
lesion. In addition, there is a high incidence of premature graying of scalp hair in patients with vitiligo and in their families. Vitiliginous lesions can remain stable or can slowly progress for
years. In some instances, patients undergo almost complete
spontaneous depigmentation over a few years.
Vitiligo is subclassified into different types on the basis of the
distribution of skin lesions. These subclassifications include the
generalized or vulgaris, acral or acrofacial, localized, and seg 2003 WebMD Corp. All rights reserved.
August 2003 Update
mented types. The generalized pattern is characterized by symmetrical macules or patches occurring in a random distribution.
Acral or acrofacial vitiligo consists of depigmented macules confined to the extremities or to the face and extremities, respectively. A subcategory of the acrofacial type is the lip-tip variety, in
which lesions are confined to the lips and the tips of the digits.
The generalized and acrofacial varieties are the most common.
Segmental vitiligo occurs in a dermatomal or quasidermatomal
distribution; lesions rarely spread beyond the affected dermatome. This type is the less common variety of vitiligo and
most often occurs along the distribution of the trigeminal nerve.
Melanocytes of the eye, ear, and leptomeninges may also be
involved in vitiligo. Depigmented areas of the retinal pigment
epithelium and choroid have been reported in 39% of patients
studied. These lesions usually do not interfere with vision. Vitiligo is also a manifestation of the Vogt-Koyanagi-Harada syndrome, which is characterized by poliosis, chronic uveitis, alopecia, dysacusis, vitiligo, and signs of meningeal irritation. It usually begins in the third decade of life, and although no race is
spared, the disease tends to be more severe in darker-complexioned races, especially Asians.
The syndrome has been divided into stages. The first, or
meningeal, stage, is associated with headache, nausea, vomiting,
fever, confusion, cranial nerve palsies, hemiparesis, and cerebrospinal fluid pleocytosis. Usually, there are a few neurologic sequelae. In the second stage, ophthalmic and auditory changes predominate, including photophobia, ocular pain, visual loss, anterior or posterior uveitis, and sometimes retinal detachment, tinnitus,
and dysacusis. Cutaneous lesions are dominant in the third, or
convalescent, stage, occurring as the uveitis begins to subside.
Common features are vitiligo, which frequently involves the eyelids and periorbital region [see Figure 4]; poliosis of the scalp, hair,
eyelashes, and eyebrows; and diffuse or patchy alopecia.
Patients with malignant melanoma frequently experience a
vitiligolike depigmentation surrounding melanoma lesions and
at distant sites. The presence of depigmentation in melanoma
patients portends a longer survival.
Laboratory findings Histologically, the predominant finding in vitiligo is an absence of melanocytes in lesional skin. Light
microscopy and ultrastructural studies have also revealed vacuolar degeneration of basal and parabasal keratinocytes and revealed epidermal and dermal lymphohistiocytic cell infiltrates.
Figure 4 A patient with Vogt-Koyanagi-Harada syndrome shows

periorbital depigmentation.
ACP Medicine
Immunohistochemical staining has confirmed the presence of a

predominantly T cell infiltrate in vitiliginous and adjacent skin.
In view of the association of vitiligo with myriad other autoimmune diseases, the routine baseline evaluation of a patient
should include a thorough history and physical examination.
Recommended laboratory tests include a complete blood count;
sedimentation rate; comprehensive metabolic panel, including
liver function tests; and autoantibody tests (antinuclear antibody, thyroid peroxidase, and parietal cell antibodies).
Table 1 Therapeutic Approaches for Vitiligo
Other disorders characterized by depigmentation may occasionally mimic vitiligo clinically. These include piebaldism, nevus
depigmentosus, nevus anemicus, postinflammatory depigmentation or hypopigmentation, pityriasis alba, tinea versicolor, discoid lupus erythematosus, scleroderma, hypopigmented mycosis
fungoides, and sarcoidosis. Therefore, in some instances, a skin
biopsy may be necessary to substantiate a diagnosis of vitiligo.
Stages I and II disease*
Treatment Selection
Therapeutic objectives in vitiligo should include both stabilization of the disease and repigmentation of vitiliginous skin lesions.
Repigmentation can be accomplished medically57-59 or, in patients
with localized stable lesions, surgically.60 The choice of repigmentation therapies should be predicated on the age of the patient, extent of cutaneous surface involvement (severity), and activity or
progression of the disease. The disease can be divided into four
stages: limited (less than 10% involvement), moderate (10% to
25% involvement), moderately severe (26% to 50% involvement),
and severe (greater than 50% involvement) [see Table 1].
Medical Treatment
Medical therapies for vitiligo include topical and systemic
steroids, topical and systemic PUVA, narrow-band ultraviolet
light therapy (UVB), excimer laser therapy, nutritional vitamin
supplementation, immunomodulators, calcipotriol, phenylalanine, and khellin.57-59
Steroids Mid- to high-potency steroids are indicated in patients with limited involvement. Low-potency topical steroids
are usually ineffective. Topical mid- to high-potency steroids can
be used safely for 2 to 3 months, then interrupted for 1 month or
tapered to low-potency preparations. Patients must be closely
monitored for topical steroid side effects, which include skin atrophy, telangiectasias, hypertrichosis, and acneiform eruptions.
Since the introduction of topical immunomodulators (tacrolimus
and pimecrolimus), topical steroids are used less often in vitiligo
patients.
Short courses of oral prednisone for 1 to 2 weeks or intramuscular triamcinolone acetonide injections, 40 mg/month for 2 to 3
months, are often extremely helpful for stabilizing rapidly progressive vitiligo. However, prolonged use of systemic steroids is
not indicated.57-59
Photochemotherapy Until recently, topical and systemic
PUVA therapies were the mainstay for repigmenting vitiliginous
lesions.57,58 However, in the past several years, these therapies
have been overshadowed by new ones, including narrow-band
UVB phototherapy, lasers, and topical immunomodulators.
Topical photochemotherapy can be administered in the office
or outside the office in combination with sunlight. The choice of
topical PUVA is predicated on the severity of vitiligo, patient
August 2003 Update
Stages III and IV disease*
Topical steroids
Topical photochemotherapy
PUVA-sol
In-office PUVA
Bath photochemotherapy
Pseudocatalase/UVB
UVB phototherapy
Narrow band
Broad band
Excimer laser
Topical immunomodulators
Tacrolimus
Pimecrolimus
l-phenylalanine/UV
Topical khellin/UVA
Melagenina
Calcipotriol/PUVA
Tar emulsions
Vitamin supplementation
Autologous melanocyte grafting
(stable lesions)
Oral photochemotherapy
Systemic steroids (oral, I.M.) (for
stabilization)
Bath photochemotherapy
UVB phototherapy
Narrow band
Broad band
Oral khellin/UVA
l-phenylalanine/UV
Immunomodulators
Isoprinosine
Levamasole
Immunosuppressives
Cyclosporine
Cyclophosphamide
Nitrogen mustard
Depigmentation (severe, recalcitrant
lesions)
*Stage I, < 10% involvement; stage II, 10%25% involvement; stage III, 26%50%
involvement; stage IV, > 50% involvement.
PUVApsoralens plus ultraviolet A UVultraviolet UVAultraviolet A
UVBultraviolet B
lifestyle, and convenience for the patient. Topical in-office PUVA

is appropriate for patients with less than 20% cutaneous surface
involvement. A thin coat of 0.01% to 0.1% methoxsalen ointment
is applied to affected areas 30 minutes before UVA exposure.
Treatments are weekly or twice weekly. For patients with less
than 10% involvement, an alternative approach involves the use
of 0.001% methoxsalen ointment applied 30 minutes before sunlight exposure. Patients are allowed to expose the affected areas
for 10 minutes, gradually increasing exposure time to 30 minutes. Treatments are daily or every other day.
Oral photochemotherapy is indicated in patients with greater
than 20% to 25% cutaneous surface involvement. The standard
dose of 8-methoxypsoralen (8-MOP) is usually 0.3 to 0.4 mg/kg
ingested 1.5 hours before UVA exposure. The treatments are administered twice weekly. Broad-spectrum sunscreen protection
is essential after PUVA treatments. In addition, because of the
ocular pharmacokinetics of 8-MOP, protective UVA sunglasses
should be worn indoors and outdoors for 18 to 24 hours after ingestion of 8-MOP.
Contraindications to oral PUVA treatment include liver disease and photosensitivity disorders. Side effects include headaches, nausea, vomiting, xerosis, pruritus, photoaging, diffuse
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hyperpigmentation, and hypertrichosis. Compared with topical

PUVA, the major advantages of oral PUVA include its effectiveness in controlling the progression of active disease and its lower
frequency of blistering reactions. Oral PUVA therapy has been
associated with an increase in nonmelanoma and melanoma skin
cancer in patients with psoriasis. However, similar documentation has not been reported in patients with vitiligo.
Factors that portend enhanced PUVA-induced repigmentation include young age (children), patient motivation, maintenance of adequate lesional phototoxicity, and location of lesions.
Maximal repigmentation occurs on the face and neck, and minimal responses occur in the hands and feet. Overall, mean repigmentation of 60% to 65% of the affected areas can be achieved.58
Narrow-band UVB Recent studies have reported the benefits of narrow-band UVB phototherapy (NB-UVB).61 NB-UVB
treatment was shown to be as effective as topical PUVA, with
fewer side effects. In a study of NB-UVB phototherapy versus
oral PUVA, 56% of the UVB group had greater than 25% repigmentation, compared with 63% of the oral PUVA group. The difference was not statistically significant. Because of its efficacy
and safety profile, NB-UVB has emerged as the therapy of choice
for patients with moderate to severe disease.
NB-UVB phototherapy offers several advantages over oral
psoralen photochemotherapy, including ease of treatment, lack
of need for posttreatment ocular protection, lack of the side effects (e.g., nausea, headaches, and gastritis) associated with oral
methoxsalen, and minimal phototoxic reactions. Furthermore,
NB-UVB phototherapy can be used to treat young children who
have extensive, progressive vitiligo. Disadvantages include the
need for more treatments for maximal efficacy (three times
weekly for NB-UVB, compared with twice weekly for PUVA)
and the lack of data concerning the possible long-term carcinogenic effects of NB-UVB phototherapy.
Dermatologists continue to treat patients with PUVA, and it
remains the gold standard despite its inherent difficulties. Patients whose vitiligo does not respond to NB-UVB phototherapy
are often switched to oral PUVA.
Repigmentation occurs gradually and requires many treatments: 16 to 24 treatments are usually needed for new pigment
to become evident. In general, maximal repigmentation involves
6 to 12 months of NB-UVB or PUVA therapy.
Laser therapy The excimer laser (308 nm UVB), recently approved by the FDA for treatment of psoriasis, also shows
promise as a therapy for vitiligo.62,63 This laser can be used as
monotherapy or in combination with other modalities. Laser
therapy targets the lesional area and theoretically reduces UV
exposure. In addition, because the laser provides a focused,
high-intensity dose of NB-UVB, treatment duration, in theory,
may be reduced. Long-term, controlled studies are needed to
further define the efficacy, risks, and benefits of the excimer laser
for treatment of vitiligo.
Pseudocatalase The beneficial effects of pseudocatalase and
calcium applied twice daily and UVB exposure twice weekly
have also been reported. The rationale for this therapy is derived
from previous studies that demonstrated aberrant catalase and
calcium homeostasis in patients.64
Vitamins Preliminary open-label studies have documented
stabilization and repigmentation in vitiligo patients treated with
August 2003 Update
high-dose vitamin supplementation, including daily doses of ascorbic acid (1,000 mg), vitamin B12 (1,000 g), and folic acid (1 to 5 mg).57
Topical immunomodulators Abnormalities of both humoral and cell-mediated immunity have been well documented
in patients with vitiligo,47-52 which explains the apparent efficacy
of several immunomodulators for this disease. Preliminary investigations have reported repigmentation of vitiliginous lesions with
isoprinosine, levamisole, suplatast tosilate, and cyclosporine.57
Tacrolimus ointment is a novel topical immunomodulatory
drug for treatment of adult and pediatric atopic dermatitis.
Tacrolimus exerts its therapeutic effect via inhibition of the production of proinflammatory cytokines. Moderate to excellent
repigmentation was reported in five of six patients treated with
tacrolimus. Patients ranged in age from 6 to 32 years. Repigmentation responses did not correlate with disease duration.58, 65
Calcipotriol Several studies have documented the efficacy
of calcipotriol for repigmentation of vitiligo. Used in combination with UV exposure, calcipotriol was well tolerated and effective in both children and adults.58 Melanocytes are thought to express 1,25-dihydroxyvitamin D3 receptors, which may play a
role in stimulating melanogenesis.
Depigmentation Since the 1950s, monobenzylether of hydroquinone (MBEH, or monobenzene) has been used as a depigmenting agent for patients with extensive vitiligo. In general,
MBEH causes permanent destruction of melanocytes and induces depigmentation locally and remotely from the sites of application. Hence, the use of MBEH for other disorders of pigmentation is contraindicated.
Depigmentation is a viable therapeutic alternative in patients
with greater than 50% cutaneous depigmentation who have demonstrated recalcitrance to repigmentation or in patients with
extensive vitiligo who have no desire to undergo repigmentation therapies.55,58 The major side effects of MBEH therapy are
dermatitis and pruritus, which usually respond to topical and
systemic steroids. Other side effects include severe xerosis,
alopecia, premature graying, and suppression of lymphoproliferative responses.
Surgical Treatment
Surgical treatment is appropriate for patients with localized,
stable areas of vitiligo that have been recalcitrant to medical treatment.60 Such approaches are contraindicated in patients with
keloids or hypertrophic scars. Techniques for surgical grafting include suction blister grafts, punch grafts, sheet grafts, pure melanocyte cultures, and cocultures of melanocytes and keratinocytes.
These techniques are indeed beneficial for localized lesions.
Micropigmentation is often associated with the induction of
koebnerization; therefore, its use should be limited to treatment
of mucous membrane lesions.
albinism
Definition
Albinism is an uncommon, complex congenital disorder characterized by hypopigmentation of the hair, eyes, and skin. Albinism is generally subclassified as oculocutaneous albinism
(OCA) and ocular albinism (OA); in the latter, reduction of
melanin is limited to the eye.66-71 Sometimes, different mutations
in the same gene can cause OCA or OA.
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Epidemiology
OCA has been reported by investigators in all mammalian
orders and in all human ethnic groups. It is one of the most
widely distributed genetic abnormalities in the animal kingdom. Human albinism has been noted throughout history.
OCA is the most common inherited disorder of generalized
hypopigmentation.

Albinism may result from primary defects that are specific for
the melanin synthetic pathway or from defects that are not specific for melanin synthesis. Mutations in seven genes have been
reported to cause OCA or OA.67,68 They include the tyrosinase
gene (OCA1 on chromosome 12q1), the oculocutaneous albinism
gene (OCA2, a missed mutation of the P gene on 15q11), the tyrosinase-related protein 1 gene (OCA3), the HPS gene (Hermansky-Pudlak syndrome at 10q23 and mutations of the 3Aadaptin gene), the CHS gene (Chdiak-Higashi syndrome), and
the OA1 gene (X-linked ocular albinism).
Diagnosis
Clinically, the most severe disease is observed in OCA1A,
which is OCA resulting from mutations in the tyrosinase gene. It
is characterized by absent tyrosinase activity, which results in
complete absence of melanin in the eyes, skin, and hair. There is
no improvement with age. Affected individuals have marked
photophobia, nystagmus, and profound sun sensitivity because
of the inability to tan.
OCA1B, or yellow albinism, is less severe. Tyrosinase activity
is low or absent, and pigmentation of the hair and skin improves
with age. In contrast to OCA1A, pigmented freckles and lentigines develop with age.
OCA1-MP, or minimal-pigment OCA, is characterized by
white skin and hair at birth. Iris pigment is present at birth, or it
appears during the first decade of life. All reported cases have
been in white persons. The tyrosinase gene mutation produces a
less active enzyme.
Temperature-sensitive OCA (OCA1-TS) is characterized by
white skin and hair and blue eyes at birth and by development
of patterned pigmentation by puberty. Darker hair develops in
cooler areas (extremities), and white hair is retained in warmer
areas (axilla and scalp). The pattern results from a tyrosinase
mutation that causes a temperature-sensitive enzyme.
OCA2, tyrosinase-positive OCA with normal tyrosinase activity, is the most common variety. The hair darkens with age, but
the skin remains white. Pigmented nevi, lentigines, and freckles
develop and are especially pronounced in sun-exposed areas.
This type has recently been ascribed to mutation of the P gene,
which encodes the tyrosinase-transporting membrane protein.
The P gene is on chromosome 15q.
OCA3 encompasses the Rufous variety and some cases of
brown albinism. Clinically, there is minimal pigment reduction in
the hair, eyes, and skin.
The secondary varieties of albinism in which the primary defect is not specific for the melanin synthetic pathway include Hermansky-Pudlak syndrome,71 Chdiak-Higashi syndrome, CrossMcKusick-Breen syndrome, Prader-Willi syndrome, and Angelman syndrome.
The autosomal recessive Hermansky-Pudlak syndrome is
characterized by low to absent tyrosinase activity. The HPS gene
has been mapped to chromosome 10q23.71-73 Skin and hair color
varies from white to light brown. Freckles and lentigines develop
August 2003 Update
Figure 5 A patient with piebaldism has the classic midextremity areas

of depigmentation with islands of hyperpigmentation.
with age. Iris pigment correlates with hair and skin pigmentation.
Affected individuals experience a hemorrhagic diathesis secondary to a platelet-storage-pool deficiency. Their platelets lack
storage granules (i.e., sites of storage for serotonin, calcium, and
adenine nucleotides). Ceroidlike deposits are present in macrophages of the bone marrow, lungs, liver, spleen, and gastrointestinal tract. These patients bruise easily and are subject to epistaxis and gingival bleeding. Pulmonary fibrosis and granulomatous colitis develop as a consequence of the ceroid deposits.
Chdiak-Higashi syndrome consists of hypopigmentation, recurrent sinopulmonary bacterial infections, peripheral neuropathy, and giant lysosomal granules, with death occurring at an
early age as a result of lymphoreticular malignancies. The CHS
gene locus is on chromosome 1q29. Chdiak-Higashi syndrome
must be distinguished from Griscelli syndrome, which is characterized by partial albinism, lymphohistiocytosis, immunodeficiency, neutropenia, and thrombocytopenia. Griscelli syndrome
has been mapped to chromosome15q21, around the myosin-Va
gene. However, the presence of giant lysosomal granules is
pathognomonic for Chdiak-Higashi syndrome.74,75
Cross-McKusick-Breen syndrome includes hypopigmentation, microphthalmia, nystagmus, and severe mental and physical retardation.
ACP Medicine
Prader-Willi syndrome is a developmental syndrome characterized by mental retardation, neonatal hypotonia, and poor feeding, followed by hyperphagia and obesity later in life. Short stature,
hypogonadism, and inappropriate emotional behavior constitute
the syndrome. Fifty percent of patients have a deletion on the
long arm of chromosome 15. Patients have ocular abnormalities
and skin and hair hypopigmentation consistent with OCA.
Mutation of the P gene has been reported in Angelman syndrome and is also characterized by mental retardation, abnormal
behavior, and hypopigmentation. The pattern of hypopigmentation is similar to that in Prader-Willi syndrome. In addition, Angelman syndrome is associated with a deletion on chromosome
15. However, in contrast to Prader-Willi syndrome, the deletion
occurs on the maternal chromosome.
Treatment
The management of patients with albinism should include genetic counseling and patient education regarding the use of sunscreens and clothing for protection against ultraviolet radiation
induced damage. Magnifiers are beneficial for ocular symptoms.
Complications
The long-term consequences of albinism are solar keratoses
and basal and squamous cell carcinomas. Malignant melanoma
is uncommon.
piebaldism
Definition
Piebaldism is a rare autosomal dominant congenital disorder
of pigmentation. It is a stable leukoderma and is characterized by
patches of white skin and white hair. The affected areas are principally the frontal scalp, forehead, ventral chest, abdomen, and
extremities. A white forelock occurs in 80% to 90% of patients.
Epidemiology
Although rare, piebaldism occurs in all ethnic groups worldwide. Its estimated occurrence is one in 100,000 persons. It is
found with equal frequency in males and females.

Molecular genetics studies have shown that piebaldism results from mutations of the KIT proto-oncogene, which encodes
the cell surface receptor tyrosine kinase for mast cell or stem
cell factor located on chromosome segment 4q12. Mutations
occur in the highly conserved tyrosinase domain of KIT. A
number of different mutations in the KIT gene can cause
piebaldism.76-80 The locations of the KIT gene mutation correlates with severity of disease. Mutations of the intracellular tyrosine kinase domain are associated with the most severe phenotypes.77 Reduced KIT function arrests the migration of
melanocytes into affected hair follicles and epidermis during
embryonal development.76-78
In general, patients with piebaldism are healthy and do not
have associated systemic abnormalities. However, the disorder
occasionally has been associated with heterochromia irides,
mental retardation, osteopathia striata, Woolf syndrome, and
Hirschsprung disease.
Diagnosis
Cutaneous depigmentation is the only manifestation of
piebaldism in 10% to 20% of cases. Amelanotic macules are usu 2003 WebMD Corp. All rights reserved.
August 2003 Update
ally present on the ventral surface of the thorax and abdomen

and extend to the back but spare the midline. Characteristic extremity lesions extend from midarm to wrist and occur on the
midleg [see Figure 5]. White patches of the mucous membranes
have also been reported. Hyperpigmented macules may appear
within the areas of depigmentation.
Light and electron microscopic studies of the white macules
have typically revealed an absence of melanocytes. However,
melanocytes have been demonstrated in the white forelock and
amelanotic skin of three patients studied.
Piebaldism is sometimes confused with vitiligo, but in
piebaldism, the leukodermic patches are both congenital and relatively static in shape and size.
Treatment
The lesions of piebaldism are usually stable throughout life,
although some patients have reported spontaneous repigmentation. In general, therapeutic approaches, including psoralen photochemotherapy and grafting, are unsatisfactory. Autologous
melanocyte grafting procedures may offer some benefit for localized or limited areas of involvement.
idiopathic guttate hypomelanosis
Definition
Idiopathic guttate hypomelanosis (IGH) is a common asymptomatic disorder characterized by hypopigmentation and depigmented polygonal macules ranging from approximately 2 to 8
mm in diameter.
Epidemiology
IGH appears to be a very common, benign dermatosis. It occurs in all races, with a frequency ranging from 46% to 70%, but
is more prevalent in darker-skinned racial and ethnic groups.
Macules may begin to appear during the third or fourth decade
of life and gradually increase in number thereafter.

The precise pathogenesis has not been established for IGH.
Long-term sun exposure, trauma, genetic influences, and aging,
with a gradual loss of melanocytes, have been implicated in the
pathogenesis of this disorder.81
Diagnosis
The lesions of IGH are macules that are punctate to polygonal
in shape, 2 to 8 mm in diameter, and hypopigmented to depigmented. They are most commonly observed on the lower extremities. There is no atrophy or change in the overlying skin.
Histologic evaluation of lesions reveals hyperkeratosis, epidermal atrophy, and decreased epidermal melanin. Melanocytes
may be normal or decreased. Immunoperoxidase studies show a
markedly reduced number of melanocytes. Melanocyte differentiation appears to be unaffected.82
IGH must be differentiated from other hypopigmentary disorders, such as vitiligo, scleroderma, leukodermic guttate parapsoriasis, tinea versicolor, hypopigmented sarcoidosis, pityriasis alba, chemical depigmentation, and postinflammatory
hypopigmentation.
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Treatment
No definitive treatment is currently available. Patients often
need reassurance regarding the banality of lesions. For patients
concerned about the cosmetic appearance of lesions, clinicians
have used camouflage, intralesional steroids, and topical photochemotherapy. Localized superficial dermabrasion may offer
some improvement.83
The author has received grants for clinical research from Allergan Inc., Fujisawa
Healthcare, Inc., and Galderma Laborotories, L.P., during the past 12 months.
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78. Syrris P, Malik N, Murday VA, et al: Three novel mutations of the proto-oncogene
KIT cause human piebaldism. Am J Med Genet 95:79, 2000
79. Spritz RA: Piebaldism, Waardenburg syndrome and related disorders of
melanocyte development. Semin Cutan Med Surg 16:15, 1997
80. Spritz RA, Hearing VJ Jr: Genetic disorders of pigmentation. Adv Hum Genet 22:1,
1994
81. Falabella R: Idiopathic guttate hypomelanosis. Dermatol Clin 6:241, 1988
82. Wallace ML, Grichnik JM, Prieto VG, et al: Numbers and differentiation status of
melanocytes in idiopathic guttate hypomelanosis. J Cutan Pathol 25:375, 1998
83. Hexsel DM: Treatment of idiopathic guttate hypomelanosis by localized superficial
dermabrasion. Dermatol Surg 25:917, 1999
ACP Medicine
XVI
APPROACH TO THE DIAGNOSIS OF
SKIN DISEASE
Robert T. Brodell, m.d.
Stephen E. Helms, m.d.
Patients frequently see their primary care physician for skin disease1; however, compared with dermatologists, primary care
physicians treat substantially fewer patients with common skin
conditions, and the types of cutaneous disease they treat tend to
be few in number.2,3 One study reported that dermatologists had
728 and 352 office visits a year for acne and contact dermatitis,
respectively; by contrast, internists averaged three and nine visits, a year, respectively, and family physicians averaged eight
and 27 visits a year.2 The relative inexperience with cutaneous
presentations gives rise to possible error in the dermatologic care
offered by nondermatologists. Some studies have reported that
nondermatologists perform poorly in the diagnosis and treatment of skin disease.4 One area of concern is the apparent low
proficiency among nondermatologists in the diagnosis of skin
cancer.5,6 The root of most problems encountered by primary
care physicians in the treatment of skin disease rests in establishing the accurate diagnosis of cutaneous presentations.
Diagnosis of a cutaneous disease is most reliably achieved by
a stepwise approach to patient evaluation, beginning with an examination of the morphologic features of the skin lesions and
frequently culminating in diagnostic testing. This chapter reviews the primary skin lesions that allow categorization of dermatologic disease (e.g., papulosquamous diseases, blistering diseases, nonscaling erythematous and infiltrative diseases, and tumors) and presents a method by which the physician can
narrow the possible causes of a specific presentation and arrive
at a diagnosis in a cost-effective manner.
Approach to the Patient with a Dermatologic Lesion
Dermatology is a visual specialty, and physical examination
is primarily oriented toward observing the skin. Dermatologists approach skin disease in a manner that has been tested
over time and perpetuated in the training of medical students
and residents. A simple diagnostic evaluation based on the approach preferred by dermatologists allows primary care physicians to narrow the possible causes of a cutaneous presentation
and arrive at an accurate diagnosis.
diagnostic evaluation
Diagnostic evaluation of a cutaneous presentation begins with
a brief patient history that is directed at the nature of the chief
complaint and its onset; factors that aggravate and alleviate
symptoms; and responses to over-the-counter or prescription
medications. This is followed by careful inspection of the skin. In
examining a patient with a rash, the first step is to try to identify
primary lesions (i.e., lesions that appear early in the disease
process) [see Morphologic Classification of Skin Disorders, Primary Lesions, below]); these lesions help to categorize the disease
and provide the basis for diagnosis. Information derived from
the identification of primary lesions is augmented by an examination of primary lesions that have undergone change. Secondary changes to primary lesions may occur naturally or after
trauma, such as scratching [see Morphologic Classification of

Skin Disorders, Secondary Changes, below]. The location, distribution, and configuration of primary lesions and their secondary
changes are analyzed, and the findings are categorized to promote the development of a differential diagnosis.
After an examination of the lesions, a more complete patient history is obtained, including the patients family history, social history, and medical history. The expanded patient history is followed
by a focused general medical examination. In the context of a detailed patient history, the general medical examination often provides diagnostic clues that further narrow the differential diagnosis.
The final step in a dermatologic examination comprises various forms of testing (e.g., dermatologic testing, skin biopsy,
and laboratory tests) [see Arriving at a Diagnosis, below] to confirm the diagnosis or sufficiently narrow the differential diagnosis to permit selection of the most appropriate treatment. If
the diagnosis remains uncertain after testing, consultation with
a dermatologist may be useful in establishing the diagnosis.
The patient is typically scheduled for a follow-up visit after initiation of treatment. The purpose of the follow-up visit is to assess the response to therapy and to confirm that the proper diagnosis was rendered.
suboptimal methods of diagnosis and management
Errors in dermatologic diagnosis can be classified into several
categories. It is worth exploring these problems to avoid falling
into predictable traps.
Treating Symptoms Rather than Diseases

Establishing the underlying cause of symptoms is a guiding
principle in medicine; however, the treatment of dermatologic
presentations frequently focuses on symptom management
without addressing the underlying cause. This approach is seldom an efficient or effective form of management. For example,
treatment of pruritus with antihistamines is a poor substitute for
establishing a definitive diagnosis of the underlying condition
that is the cause of the symptom. In the case of a patient with severe itching associated with dermatitis herpetiformis, treatment
with a topical corticosteroid may give temporary relief from pruritus; however, a careful examination would most likely reveal
grouped papulovesicles on the extensor surfaces of the extremities, and a biopsy would confirm the diagnosis of dermatitis herpetiformis. Treatment of dermatitis herpetiformis with a
gluten-free diet and oral dapsone would lead to dramatic, longlasting remission.
Snapshot Approach to Diagnosis

A snapshot diagnosis is rendered on the basis of physical appearance of a rash or other form of lesion in the absence of any
other data. This method of examination is quick; however, it can
lead to inaccurate diagnosis and imprecise and inadequate treatment. For example, a patient with widespread scaling, erythema,
lichenification, and excoriations may appear to have eczema. On
careful examination, the finger webs disclose burrows. The patient reports that itching is more severe at night, and that family
members are also experiencing itching. A scabies preparation
test discloses the presence of mites, confirming the diagnosis as
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DERMATOLOGY:XVI Approach to the Diagnosis of Skin Disease1
Table 1 Primary Lesions: Consensus Definitions

of Dermatologic Morphologic Terms7
Morphologic
Term
DLP Proposed Definition
Bulla
A fluid-filled blister greater than 0.5 cm in diameter;

fluid can be clear, serous, hemorrhagic, or pus-filled
Comedo
An enlarged hair follicular infundibulum primarily

containing keratin and lipids and having a plugged,
dilated follicular opening (blackhead) or a clinically
unapparent follicular opening (whitehead)
Macule
A flat area of skin or mucous membranes having a color

different from the surrounding tissue and a diameter
generally less than 0.5 cm; macules may have nonpalpable, fine scales
Nodule
A dermal or subcutaneous firm, well-defined lesion

usually greater than 0.5 cm in diameter
Papule
A discrete, solid, elevated body usually less than 0.5 cm

in diameter; papules are further classified by shape,
size, color, and surface change
Patch
A flat area of skin or mucous membranes having a color

different from the surrounding tissue and a diameter
generally greater than 0.5 cm; patches may have nonpalpable, fine scales
Plaque
A discrete, solid, elevated body usually broader than it

is thick and measuring more than 0.5 cm in diameter;
plaques may be further classified by shape, size, color,
and surface change
Pustule
A circumscribed elevation that contains pus; pustules

are usually less than 0.5 cm in diameter
Vesicle
Fluid-filled cavity or elevation less than 0.5 cm in

diameter; fluid may be clear, serous, hemorrhagic,
or pus-filled
Wheal
An edematous, transitory papule or plaque
DLPDermatology Lexicon Project
scabies infestation. A snap diagnosis of eczema and treatment

with topical steroids would have been inappropriate.
Scattershot Management
A suboptimal approach to the management of a dermatologic presentation is touted by physicians who delude themselves
into believing that all rashes look alike. This leads to the scattershot approach to management, which advocates increasing the
potential for successful treatment of an unknown skin disease
by treating all possible causes. For example, the use of a topical
steroid/antifungal preparation for a papulosquamous process
may seem a prudent treatment of two possible disorders
namely, eczema and superficial fungal infection; however, if the
patient has a dermatophyte-induced fungal infection, the topical steroid may decrease local immunity and slow the healing
process. This management strategy is expensive, increases
the risk of iatrogenic disease, and delays appropriate diagnosis
and treatment.
A scattershot approach may also be used in diagnostic evaluation; such an approach entails the ordering of a broad battery of
tests in the hope of stumbling upon the correct diagnosis. This
inefficient method can lead to false positive results that confuse
rather than confirm the diagnosis.
All rashes present physical diagnostic clues that are useful in
establishing a diagnosis. A careful evaluation of the lesions morphologic characteristics, coupled with a thorough patient history
and examination, will most likely provide an accurate diagnosis.
If the diagnosis remains uncertain, the morphologic condition of
the lesion will suggest which specific tests are appropriate for arriving at the diagnosis.
Morphologic Classification of Skin Disorders
primary lesions
The first step in the diagnosis of a rash is to identify primary
lesions [see Table 1]. Primary lesions are those physical characteristics of skin disease that appear initially and are most useful in
developing a differential diagnosis. The characterizing features
of primary lesions include whether they are flat or raised, solid
or fluid filled, dark or light in color, large or small, smooth or
rough. Lesions may be few or numerous, localized or widespread. The newly erupted and undisturbed lesions are most often helpful in categorizing skin conditions in a manner that leads
to a correct diagnosis.
Primary skin lesions can be defined simply. Flat lesions are referred to as macules when they are smaller than 0.5 cm and as
patches when they are greater than 0.5 cm in diameter [see Figure 1].
Figure 1 (a) Schematic drawing of macules (lesions < 0.5 cm) or patches (lesions > 0.5 cm). Macules and patches are flat areas of skin
for which the color and texture differ from that of the surrounding tissue. (b) Nonblanching erythematous macules and patches are
present in a patient with a drug eruption. (c) Depigmented macules are noted on the face of a patient with vitiligo.

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Figure 2 (a) Schematic drawing of papules (lesions < 0.5 cm) or nodules (lesions > 0.5 cm). Papules and
nodules are discrete, solid, elevated lesions. (b) A raised, dome-shaped, erythematous papule is seen in a
case of dermatofibroma. (c) A raised, flat-topped, erythematous, and hyperkeratotic nodule with scalloped
edges is present in a patient with squamous cell carcinoma. (d) Large, erythematous plaques of psoriasis
have an annular appearance, owing to their elevated margins.
Small raised bumps are referred to as papules [see Figures 2a and
b], and large lesions of this type are referred to as nodules; nodules typically have a deeper dermal component [see Figure 2c].
Discrete, broad, raised eruptions are referred to as plaques [see
Figure 2d]. Raised lesions containing fluid (commonly known as
blisters) are referred to as vesicles when smaller than 0.5 cm [see
Figures 3a and b] and as bullae when larger than 0.5 cm in diameter [see Figure 3c]. Vesicles and bullae are usually clear but may
be turbid. White or yellow fluid-filled lesions are called pustules.
Atrophic lesions exhibit a thinned epidermis that is often depressed; they have a scaly, shiny surface that has the texture of
cigarette paper. An edematous transitory papule or plaque is
called a wheal [see Figure 4].
The shape of primary lesions often provides diagnostic clues.
Primary lesions may be round, oval, angular, or irregular; flat-topped or domed; or umbilicated or verrucous. The borders of primary
lesions may be well circumscribed or poorly defined; the presence or absence of an elevated border may be a useful finding.
secondary changes
Secondary changes to lesions provide valuable diagnostic information; however, they are not as useful as primary lesions in
arriving at a specific diagnosis [see Table 2]. Secondary changes
may represent a late stage in the natural history of primary lesions, or they may be the result of trauma such as from scratching or rubbing of the skin. Secondary changes to lesions include
the following:
Scales: small flakes of superficial skin.

Scale crusts: scales combined with serous exudate.
Excoriations: abrasions resulting from the scratching of elevated lesions.
Erosions: localized loss of epithelium.
Ulcers: denuded areas of epidermis and some portion of
dermis. Ulcers may be open or covered with a black eschar
[see Figure 5].
Scars: raised or depressed fibrous lesions caused by trauma
or disease.
Cutaneous horns: keratotic projections extending from a
skin lesion.
Fissures: cracks that extend through the epidermis into the
dermis.
Numerous additional terms are helpful in characterizing the
morphologic presentation of skin lesions [see Table 3]. It is critical
that exacting definitions of descriptive terms be used by all clinicians if a reproducible method of diagnosis is to be promulgated.
The Dermatology Lexicon Project (DLP) has provided an expert
consensus of definitions for dermatologic terms [see Tables 1
through 3].7
morphologic patterns of presentation
Once the patient has been examined for primary and secondary lesions, the diagnostician must consider the overall presentation of the rash and determine its location, distribution, and
configurationthree factors essential in determining a diagnosis.
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Figure 3
(a) Schematic drawing of a vesicle (lesions < 0.5 cm) or bulla (lesions > 0.5 cm). Vesicles, bullae, and pustules are fluidfilled elevations or cavities in the skin. Vesicles and bullae are clear; pustules are turbid and pus filled. (b) Small, clear, fluid-filled
vesicles on an erythematous base are present in a patient who has herpes zoster. (c) Large, clear, fluid-filled bullae are present in a
patient with bullous pemphigoid. The bullae are associated with erythematous patches.
Location
The location refers to the particular site where the lesion or lesions are found. The location should be carefully defined because some skin diseases target specific anatomic areas. Notation
of involved anatomic sites should be as specific as possible, listing not only the involved sites but the affected aspects of those
sites. For example, facial lesions may occur in the periorbital or
perioral areas; hand lesions may occur on the fingers or palm;
and foot lesions may occur on the toes or sole. Lesions might also
be found on the upper arm or the forearm, the lower leg or the
thigh, and the trunk. It is important to further describe the affected areas as being on the right or left side and on the proximal or
distal, medial or lateral, dorsal or ventral, and flexural or extensor surfaces of the involved anatomic sites.
Distribution
The distribution of lesions describes the overall pattern of an
eruption in relation to the entire cutaneous surface. The rash
may be localized to one area of the body, may involve several

areas, or may extend over much of the body surface. Rashes
may be symmetrical or asymmetrical, and they may be present
primarily on the trunk or on the extremities. Rashes may be
present on exposed skin (i.e., skin that is not covered by clothing) or unexposed skin. These characteristics should be carefully noted because a particular distribution will narrow the differential diagnosis.
Configuration
The configuration of lesions refers to the pattern exhibited by
multiple lesions within a defined area. Because the configuration
of lesions may vary according to the disorder, any detectable
pattern may be helpful in arriving at a definitive diagnosis. Some
of the more common configurations include the following:
Grouped or herpetiform configuration: multiple small lesions appearing within a small, defined area [see Figure 6].
Zosteriform configuration: lesions occurring within a
dermatone.
Linear configuration: lesions oriented along a line [see Figure 7].
Annular configuration: lesions appearing in a ringlike pattern.
Target (iris) configuration: lesions appearing in concentric
rings.
Table 2 Selected Secondary Lesions: Consensus

Definitions of Dermatologic Morphologic Terms7
Morphologic
Term
Figure 4
Multiple linear, erythematous wheals secondary to

scratching are noted on the back of a patient with chronic urticaria and
dermatographism.

Horn
Abnormally keratinized cutaneous projection taller

than it is broad
Erosion
A localized loss of the epidermal or mucosal epithelium
Fissure
A linear crack or cleavage within the skin usually

found with thickened skin
Ulcer
A circumscribed loss of the epidermis and at least the

upper dermis; ulcers are further classified by their
depth, border/shape, edge, and tissue at their base
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Figure 5 (a) Schematic drawing of a skin ulceration. A

skin ulceration is a circumscribed lesion denuded of
epidermis and at least some dermis. (b) A well-defined
3.5 by 4.0 cm ulceration with an erythematous
granulating base is present in a patient who has early
evolving pyoderma gangrenosum.
Arcuate configuration: lesions appearing in a semicircular

pattern.
Polycyclic configuration: lesions appearing as interlocking
rings.
Serpiginous configuration: lesions appearing in snakelike
whorls.
Digitate configuration: lesions resembling the size and shape
of a fingertip.
When lesions coalesce over large areas, they are termed confluent. Erythroderma describes a widespread confluence of rash
covering nearly all of the cutaneous surface.
Color
The color of cutaneous lesions also provides important diagnostic clues. Lesions may be flesh-colored, hyperpigmented or
hypopigmented, erythematous, or virtually any color of the rainbow. Purpuric rashes caused by the extravasation of red blood
cells show no blanching on diascopy (i.e., a test in which a glass
slide or lens is pressed against the skin).
Table 3 Other Important Morphologic Terms:

Consensus Definitions of Dermatologic
Morphologic Terms7
Morphologic
Term
Abscess
A localized accumulation of pus in the dermis or subcutaneous tissue; frequently red, warm, and tender
Atrophy
A thinning of tissue defined by the location (e.g., epidermal atrophy, dermal atrophy, or subcutaneous
atrophy)
Burrow
A threadlike linear or serpiginous tunnel in the skin

typically made by a parasite
Carbuncle
An inflammatory nodule composed of coalescing

furuncles
Ecchymosis
A discoloration of the skin or mucous membranes

resulting from extravasation of blood that exhibits
color change over time; the characteristic transition
is from blue-black to brown-yellow to green
Erythema
Localized, blanchable redness of the skin or mucous

membranes
Exfoliation
Desquamation of the superficial epidermis appearing

as a fine scaling or as peeling sheets
Furuncle
A follicle-centered nodule caused by a suppurative

infection characterized by pain, redness, and perhaps
visible pus; usually greater than 1 cm in diameter
Induration
Hardening of the skin beneath the epidermis, usually

caused by edema, dermal sclerosis, inflammation,
or infiltration
Petechiae
Purpuric nonblanchable macules resulting from tiny

hemorrhages, initially measuring 1 to 2 mm
Poikiloderma
An area of variegated pigmentation, atrophy, and

telangiectasia
Purpura
Hemorrhaging into skin or mucous membranes

that varies in size, color, and duration; types of purpura include palpable purpura, ecchymosis, and
petechiae
Telangiectasia
Visible, persistent dilation of small, superficial cutaneous blood vessels
Categories of Skin Diseases

The appearance of individual lesions on the skin (e.g., primary lesions and their secondary changes) classifies a rash or
growth within a major category of skin disease. The most common skin diseases and many important rare conditions can be
classified into one of five disease categories on the basis of their
characteristic lesions. Once the category is determined, the diseases within that category are considered in the differential diagnosis of the presenting disorder [see Table 4].
As a clinicians dermatologic knowledge becomes more
sophisticated, additional categories can be mastered, including (but not limited to) diseases of the hair, nails, or mucous
membranes; photosensitivity diseases; diseases of vascular
reactivity; ulcerative skin conditions; and conditions typical
of specific distributions, such as diseases of the genitalia, feet
and hands, and eyelids. Manuals of differential diagnosis
based on the morphology of lesions and other physical features are plentiful and can be quite helpful in determining
a diagnosis.
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Table 4 Categories of Skin Disease
Papulosquamous diseases
(discrete papules or plaques
with scaling)
Figure 6 Close-up view of a herpetiform pattern of vesicles on an
Blistering diseases (vesicles,

bullae, pustules)
Acute allergic contact dermatitis

Bullous pemphigoid
Pemphigus vulgaris
Herpesvirus infections
Bacterial folliculitis
Nonscaling erythematous
(macules, patches, wheals)
and infiltrative diseases
(plaques)
Urticaria
Morbilliform drug eruptions
Viral exanthems
Sarcoidosis
Leukemia and lymphoma cutis
Amyloidosis
Diseases of pigmentation
(macules or patches of
various colors)
Vitiligo
Tinea versicolor
Pityriasis alba
Caf au lait macules
Lentigines
Benign and premalignant

tumors (macules, papules,
nodules, tumors)
Actinic keratosis
Basal cell carcinoma
Squamous cell carcinoma
Melanoma
Acrochordons
Dermatofibroma
Neurofibroma
Melanocytic nevi
Adnexal tumors
erythematous base within a dermatome in a patient with herpes zoster.
Arriving at a Diagnosis
It is important to begin the assessment of a skin condition
with a broad differential diagnosis, noting the presentation as
characteristic of one of the categories of skin disease [see Table 4].
Using physical findings, patient history, and diagnostic testing,
the differential diagnosis is gradually narrowed until a diagnosis
is determined. For example, scaling conditions, including rashes
composed of both papules and plaques, are characterized as
papulosquamous skin diseases; each papulosquamous condition [see Table 4] should be considered in the differential diagnosis of a scaling rash. The specific features of each of the papulosquamous conditions are compared with the patients lesions
to systematically identify the disorder. It is critical that the initial
differential diagnosis be broadly determined. Jumping to an early conclusion and not systematically considering all of the possible papulosquamous disorders can result in an incorrect diagnosis. In fact, if the actual diagnosis is not among the diseases ini-
Figure 7 Linear arrangement of papules in a patient with contact

dermatitis caused by poison ivy.

Psoriasis vulgaris
Chronic atopic dermatitis
Lichen planus
Pityriasis rosea
Fungal infections
Secondary syphilis
Mycosis fungoides
tially considered, it is much more difficult to determine the correct diagnosis.

Diagnosis is almost always more difficult than treatment. Consultation with a dermatologist is recommended when the diagnosis is uncertain, particularly in cases in which treatment may
fail or may lead to iatrogenic disease. The dermatologist may
help define the primary lesions that permit the accurate categorization of the disease process and, in turn, suggest the diagnosis.
If a diagnosis remains in doubt, a follow-up visit with the patient should be scheduled because, as the disease progresses, the
development of primary lesions and lesion distribution may
make the diagnosis more apparent. In addition, single, confirmatory tests often prove helpful in the diagnosis of cutaneous presentations; tests used to confirm a diagnosis include a Wood
light examination, potassium hydroxide (KOH) preparation,
sampling for fungal culture, scabies preparation, Tzanck preparation, patch testing, skin biopsy, dark-field microscopic examination, microscopic hair-shaft analysis, Gram stain, and viral or
bacterial cultures.
A Wood light examination is performed by shining a black
light on the skin in a dimly lit room. Epidermal pigmentation
(e.g., lentigines) is highlighted by this examination, whereas dermal pigmentation (e.g., Mongolian spot) disappears. A search
for depigmented spots such as ash-leaf macules in babies with
tuberous sclerosis is also aided by the Wood lamp.
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A KOH test for fungal infections involves applying KOH to

scales of skin or hair shafts to clear the keratin so that fungal
hyphae and spores can be identified. For example, scales can be
lightly scraped onto a glass slide after placing the slide on the
advancing margin of an annular plaque with central clearing.
After a coverslip is applied, 2.5% KOH preparation is applied
to the slide next to the coverslip. The KOH preparation spreads
under the coverslip by capillary action. After gentle heating,
excess KOH is blotted away, and the specimen is examined under a microscope. Fungal infections can also be confirmed by
obtaining scales by lightly scraping papulosquamous lesions
and sprinkling the scales onto Sabouraud dextrose agar. This
agar preparation is then incubated at room temperature for
several weeks, after which it is analyzed for colony growth, color, and morphology.
A scabies preparation test involves applying oil to excoriated
lesionsfrequently found on wrists and finger websand lightly scraping the burrows to obtain their contents. The scrapings
are placed on a slide with coverslip; the test is positive if scabies
mites, eggs, or feces are visible on microscopic examination.
Tzanck preparations are smears obtained from the base of intact vesicles and stained with one of a variety of nuclear stains. A
finding of multinucleated giant cells suggests a diagnosis of herpes simplex or herpes zoster infection.
Patch testing is performed to objectively elucidate the specific
cause of an allergic contact dermatitis. Standard allergens are applied under patches for 24 hours, and the reactions are read 48
hours and 1 week later.
Skin biopsies are helpful in confirming the diagnosis of a variety of inflammatory and neoplastic diseases. Dark-field microscopic examination of serous fluid from genital ulcers identifies spirochetes in lesions of primary syphilis. Hair-shaft
analysis is helpful when alopecia is caused by hair-shaft abnormalities. Finally, viral and bacterial cultures using specific

swabs can provide laboratory confirmation of a variety of viral

and bacterial diseases.
The authors have no commercial relationships with manufacturers of products or
providers of services discussed in this chapter.
References
1. Lowell BA, Froelich CW, Federman DG, et al: Dermatology in primary care: prevalence and patient disposition. J Am Acad Dermatol 45:250, 2001
2. Fleischer AB Jr, Herbert CR, Feldman SR, et al: Diagnosis of skin disease by nondermatologists. Am J Manag Care 6:1149, 2000
3. Feldman SR, Fleischer AB Jr, McConnell RC: Most common dermatologic problems
identified by internists, 19901994. Arch Intern Med 158:1952, 1998
4. Federman D, Hogan D, Taylor JR, et al: A comparison of diagnosis, evaluation, and
treatment of patients with dermatologic disorders. J Am Acad Dermatol 32:726, 1995
5. Whited JD, Hall RP, Simel DL, et al: Primary care clinicians performance for detecting actinic keratoses and skin cancer. Arch Intern Med 157:985, 1997
6. Gerbert B, Maurer T, Berger T, et al: Primary care physicians as gatekeepers in managed care: primary care physicians and dermatologists skills at secondary prevention
of skin cancer. Arch Dermatol 132:1030, 1996
7. Morphologic terminology. Dermatology Lexicon Project, 2002
http://www.dermatologylexicon.org
Reviews
Ashton R, Leppard B: Differential Diagnosis in Dermatology. Radcliffe Medical Press,
Oxford, 1993
Ghatan HEY: Dermatological Differential Diagnosis and Pearls, 2nd ed. CRC Press,
New York, 2002
Kusch SL: Clinical Dermatology: A Manual of Differential Diagnosis, 3rd ed. TaroPharma, 2003
http://www.taropharmadermatology.com
Lawrence CM, Cox NH: Physical Signs in Dermatology: Color Atlas and Text, 2nd ed.
Mosby-Wolfe, London, 2001
Lazarus GS, Goldsmith LA: Diagnosis of Skin Disease. FA Davis Co, Princeton, 1980
Pocket Guide to Cutaneous Medicine and Surgery. Dover JS, Ed. Harcourt Brace,
Philadelphia, 1996
White GM: Color Atlas of Regional Dermatology. Mosby, London, 1997
Acknowledgment
Figures 1a, 2a, 3a, and 5a Dragonfly Media Group.
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Disease], saddle-nose deformity, nasal ulcerations, and septal

The cutaneous manifestations of sarcoidosis are as varied as

Churg-Strauss syndrome, or allergic granulomatous angiitis,

Figure 1 Characteristic facial lesions of sarcoidosis, called lupus

Figure 3 Xanthomalike papules are characteristic of pseudoxanthoma

Figure 6 Acanthosis nigricans, a dark velvety acanthosis that can

occur in patients with diabetes mellitus and other endocrine disorders,

Figure 4 Transient annular erythematous rashes (erythema

tients with type 2 (noninsulin-dependent) diabetes. Scleredema

Figure 5 Yellow nails are a sign of underlying disease of the

2005 WebMD, Inc. All rights reserved.

Patients with any of a number of gastrointestinal diseases

Figure 7 Aphthous stomatitis is a common

Figure 9 The patients nose and cheeks are

finding in patients with ulcerative colitis.

Figure 8 Pyoderma gangrenosum is

flammatory bowel disease [see Figure 7]. In patients with Crohn

Figure 10 The primary lesions of herpetiformis are vesicles that

2005 WebMD, Inc. All rights reserved.

Cowden disease is an autosomal dominant disorder in which

Recessive Dystrophic Epidermolysis Bullosa

Because of amyloid deposits in blood vessels, spontaneous

Figure 11 Multiple brown macules resembling nevi occur in patients

Congenital Erythropoietic Porphyria

Porphyria Cutanea Tarda

Figure 12 A reddish pigmentation (erythrodontia) occurs when

Figure 13 Skin changes in congenital erythropoietic porphyria can

with HIV infection. Monilial infections include oral thrush and

nosis by serologic testing has been commonly used, but in the

Both eosinophilic pustular folliculitis and papular eruption of

Oral Hairy Leukoplakia

Figure 14 Crusting and scarring follow the appearance of vesicles

Other inherited or acquired immunodeficiency states share a

Figure 15 Kaposi sarcoma is the most common malignancy of AIDS

Cutaneous manifestations can be major features of a number

Figure 16 Several weeks after primary infection with Lyme disease,

staphylococcal scalded skin syndrome

Staphylococcal scalded skin syndrome (SSSS) is caused by a

Scarlet fever begins with pharyngitis caused by group A

Vibrio vulnificus infection arises from minor trauma sustained

antibiotics are effective at destroying B. burgdorferi. A vaccine

Figure 17 The epidermal nevus syndrome is

Figure 18 Axillary freckling, caf au lait spots, and

characterized by linear or whirled streaks of pigmentation

neurofibromas are evident in a patient with

A, resulting in deposition of glycosphingolipids in body tissues.

placement therapy with recombinant human -galactosidase A

2005 WebMD, Inc. All rights reserved.

Figure 20 Angiokeratomas are particularly common

ties.63 In mild cases, patients may only have livedo reticularis;

Figure 21 Calcification of arteries in patients with renal failure

Progressive Systemic Sclerosis and CREST Syndrome

Figure 22 Erythematous scaling papules on the dorsal aspects of the

Figure 23 Sclerodactyly with a nonhealing digital ulcer commonly

There are many cutaneous manifestations of systemic lupus

Anticardiolipin Antibody Syndrome

Figure 24 Flat-topped papules are seen in this chronic lichenoid graft

Graft versus Host Disease

Figure 25 Annular scaling erythematous patches are characteristic of

peated episodes of phlebitis, arterial thromboses, and repeated

2005 WebMD, Inc. All rights reserved.

2005 WebMD, Inc. All rights reserved.

syndrome: indications for the classification of vasculitides of the polyarteritis nodosa