Fitzpatrick’s Dermatology in General Medicine

Chapter 73 Diane Thiboutot John Strauss

Diseases of the Sebaceous Glands

ACNE VULGARIS MISCELLANEOUS TYPES OF ACNE

Anatomy of the Sebaceous Gland Neonatal Acne
Physiology of the Sebaceous Gland Acne Excoriée des Jeunes Filles
Lipid Composition of Sebum Steroid Folliculitis
Factors Regulating Sebaceous Gland Size and Halogen Acne
Sebum Production
Miscellaneous Drugs
Androgens
Occupational Acne
Retinoids
Tropical Acne
Melanocortins
Acne Aestivalis
Peroxisome Proliferator Activated Receptors
Acne Cosmetica
Acyl-CoA:Diacylglycerol Acyltransferase
(DGAT) Pomade Acne

Epidemiology of Acne Acne Mechanica

Etiology and Pathogenesis of Acne Acne with Facial Edema

Clinical Manifestations of Acne Acne Conglobata

Diagnosis and Differential Diagnosis Acne Fulminans

Laboratory Findings Steatocystoma Multiplex

Pathology
Treatment
Course and Prognosis REFERENCES
ACNE VULGARIS
Acne vulgaris is a self-limited disease, seen primarily in adolescents, involving the sebaceous
follicles. Most cases of acne are pleomorphic, presenting with a variety of lesions consisting of
comedones, papules, pustules, nodules, and, as sequelae to active lesions, pitted or hypertrophic
scars. Although classically classified as a sebaceous gland disease, it is actually a process that
involves the pilosebaceous unit.
Anatomy of the Sebaceous Gland
In the human fetus, sebaceous glands develop in the thirteenth to fifteenth week of gestation from
bulges on the developing hair follicles. When fully formed, the glands remain attached to the hair
follicles by a duct through which sebum flows into the follicular canal and eventually to the skin
surface. Sebaceous glands are associated with hair follicles all over the body. Only the palms and
soles, which have no hair follicles, are totally devoid of sebaceous glands. Sebaceous glands known
as Fordyce spots are sometimes present in the oral epithelium. In this location, the sebaceous ducts
open directly to the surface.
Sebaceous glands are unilobular or multilobular and vary considerably in size, even in the same
individual and in the same anatomic area. Fordyce spots are visible to the unaided eye because of
their large size (up to 2 to 3 mm) and the transparency of the oral epithelium. On the external body
surface, most glands are only a fraction of a millimeter in size. The largest glands and the greatest
density of glands are found on the face and scalp. The hairs associated with the large glands in these
areas are often tiny, and it has been suggested that the total structures be more properly termed
sebaceous follicles rather than hair follicles.
Physiology of the Sebaceous Gland
The sebaceous glands exude lipids by disintegration of entire cells, a process known as holocrine
secretion. The stages of this process are evident in the histology of the gland ( Fig. 73-1). 1 The
outermost cells, just inside the basement membrane, are small, nucleated, and devoid of lipid
droplets. This layer contains the dividing cells that replenish the gland as cells are lost in the process
of lipid excretion. As cells are displaced into the center of the gland, they begin to produce lipid,
which accumulates in droplets. Eventually the cells become greatly distended with lipid droplets
and the nuclei and other subcellular structures disappear. As the cells approach the sebaceous duct,
they disintegrate and release their contents. Only neutral lipids reach the skin surface. Proteins,
nucleic acids, and the membrane phospholipids are digested and apparently recycled during the
disintegration of the cells. Sebaceous gland activity is high at birth but then declines to become
almost nonexistent in children between ages 2 and 6 years. At about age 7, sebum secretion begins
to increase and continues to do so well into the teens. 2 From the twenties on, there is a decline of
approximately 23 percent per decade in men and approximately 32 percent per decade in women. 3
There is great individual variation and overlap between the sexes, although males have higher
values, on average, than females.

FIGURE 73-1 Electron micrograph of a rabbit sebaceous gland stained with uranyl acetate-lead
citrate. The peripheral cells (P) contain ellipsoidal nuclei (NuP) and no lipid droplets. As the cells
differentiate (D), lipid droplets accumulate and the nuclei (NuD) become irregularly shaped. In the
terminally differentiated cells (T), near the lumen (L) of the sebaceous duct, all subcellular
structures appear to break down. ( From Ito et al., 1 with permission. Copyright by Williams &
Wilkins, 1984.)
Lipid Composition of Sebum
Human sebum, as it leaves the sebaceous gland, contains squalene, cholesterol, cholesterol esters,
wax esters, and triglycerides ( Fig. 73-2). During passage of sebum through the hair canal, bacterial
enzymes hydrolyze some of the triglycerides, so that the lipid mixture reaching the skin surface
contains free fatty acids and small proportions of mono- and diglycerides in addition to the original
components. The wax esters and squalene distinguish sebum from the lipids of human internal
organs, which contain no wax esters and little squalene. Squalene that is synthesized in internal
tissues is quickly converted to lanosterol and eventually to cholesterol. Human sebaceous glands,
however, appear to be unable to cyclize squalene to sterols.

FIGURE 73-2 Human sebaceous gland lipids. The structures of the cholesterol ester, wax ester, and
triglyceride are representative of the many species that are present. Two sebaceous-type unsaturated
fatty acid moieties are shown: sapienic acid (16:1?6) (in the wax ester structure); and sebaleic acid
(18:2?5,8) (in the triglyceride structure). Anteiso branching is shown in the alcohol moiety of the
wax ester, and iso branching is shown in the triglyceride.

The patterns of unsaturation of the fatty acids in the triglycerides, wax esters, and cholesterol esters
also distinguish human sebum from the lipids of other organs. The “normal” mammalian pathway
of desaturation involves inserting a double bond between the ninth and tenth carbon of stearic acid
(18:0) to form oleic acid (18:1?9). A ?6 double bond can be added only after the ?9 double bond is
in place. However, in human sebaceous glands, the predominant pattern is the insertion of a ?6
double bond into palmitic acid (16:0). The resulting sapienic acid (16:1?6) ( Fig. 73-2) is the major
fatty acid of adult human sebum. Elongation of the chain by two carbons and insertion of another
double bond between the fifth and sixth carbon gives sebaleic acid (18:2?5,8) ( Fig. 73-2), a fatty
acid thought to be unique to human sebum.
Sebaceous fatty acids and alcohols are also distinguished by chain branching. Methyl branches can
occur on the next to last (penultimate) carbon of a fatty acid chain (iso branching), on the third from
the last (antepenultimate) carbon (anteiso branching), or on any even-numbered carbon (internal
branching). Examples of these unusual unsaturated and branched-chain moieties are included in the
lipid structures in Fig. 73-2.
Factors Regulating Sebaceous Gland Size and Sebum Production
The exact mechanisms underlying the regulation of human sebum production have not been
defined. Clearly, sebaceous glands are regulated by androgens and retinoids, but recently, other
factors, such as melanocortins, peroxisome proliferator-activated receptors (PPARs), and acyl-
CoA:diacylglycerol acyl transferase (DGAT), have been postulated to play a role as well.
Androgens
It has long been recognized that sebaceous glands require androgenic stimulation to produce
significant quantities of sebum. Individuals with a genetic deficiency of androgen receptors
(complete androgen insensitivity) have no detectable sebum secretion. 4 However, there is still a
question as to which androgen is physiologically significant. Although the most powerful androgens
are testosterone and its end-organ reduction product dihydrotestosterone (DHT), levels of
testosterone do not parallel the patterns of sebaceous gland activity. For example, testosterone
levels are many-fold higher in males than in females, with no overlap between the sexes, while
average rates of sebum secretion are only slightly higher in males than in females, with considerable
overlap between the sexes. Also, sebum secretion starts to increase in children during adrenarche, a
developmental event that precedes puberty by about 2 years.
The weak adrenal androgen, dehydroepiandrosterone sulfate (DHEAS), might be a significant
regulator of sebaceous gland activity through its conversion to testosterone and dihydrotestosterone
in the sebaceous gland. Levels of DHEAS are high in newborns, very low in 2- to 4-year-old
children, and start to rise when sebum secretion starts to increase. In adulthood, DHEAS levels
show considerable individual variation, but are only slightly higher in men than in women on the
average. There is a decline in DHEAS levels in both sexes starting in early adulthood and
continuing throughout life, this decline parallels the decline of sebum secretion. DHEAS is present
in the blood in high concentration. The enzymes required to convert DHEAS to more potent
androgens are present in sebaceous glands. 5 These include 3ß-hydroxysteroid dehydrogenase, 17ß-
hydroxysteroid dehydrogenase and 5a-reductase. Each of these enzymes exists in two or more
isoforms that exhibit tissue-specific differences in their expression. The predominant isozymes in
the sebaceous gland include the type 1 3ß-hydroxysteroid dehydrogenase, the type 2 17ß-
hydroxysteroid dehydrogenase and the type 1 5a-reductase.
Retinoids
Isotretinoin (13- cis-retinoic acid) is the most potent known pharmacologic inhibitor of sebum
secretion. Significant reductions in sebum production can be observed as early as 2 weeks after use.
6 Histologically, sebaceous glands are markedly reduced in size and individual sebocytes appear
undifferentiated lacking the characteristic cytoplasmic accumulation of sebaceous lipids. The
mechanism by which 13- cis-retinoic acid lowers sebum secretion is unknown. It does not interact
with any of the known retinoid receptors. Isotretinoin may serve as a prodrug for the synthesis of
all- trans-retinoic acid or 9- cis-retinoic acid, which do interact with retinoid receptors, however, it
has greater sebosuppressive action than do all- trans- or 9- cis-retinoic acid. 7 Unfortunately 13- cis-
retinoic acid is teratogenic, so there is a continuing need for a nonteratogenic retinoid or retinoid-
like compound that would inhibit human sebaceous glands.
Melanocortins
Melanocortins include melanocyte-stimulating hormone (MSH) and adrenocorticotropic hormone
(ACTH). In rodents, melanocortins increase sebum production. Transgenic mice deficient in the
melanocortin-5 receptor have hypoplastic sebaceous glands and reduced sebum production. 8 The
melanocortin-5 receptor has been identified in human sebaceous glands where it may play a role in
the modulation of sebum production. 9 Further experimentation however is required to test this
hypothesis.
Peroxisome Proliferator Activated Receptors
Peroxisome proliferator activated receptors (PPARs) are orphan nuclear receptors that are similar to
retinoid receptors in many ways. Each of these receptors form heterodimers with retinoid X
receptors in order to regulate the transcription of genes involved in a variety of processes, including
lipid metabolism and cellular proliferation and differentiation. Rat preputial cells serve as a model
for human sebocytes. 10 In rat preputial cells, agonists of the PPAR-? receptor, such as drugs of the
thiazolidinedione class, increase lipid accumulation. 11 The PPAR-? receptor is strongly expressed
in human sebaceous glands, where it may play a role in mediating sebum production. 12
Acyl-CoA:Diacylglycerol Acyltransferase (DGAT)
Acyl-CoA:diacylglycerol acyltransferase an enzyme involved in the final step of triglyceride
synthesis, was recently shown to be important in sebaceous gland homeostasis in mice. 13 The
absence of DGAT leads to sebaceous gland atrophy and changes in the composition of surface lipid.
This effect does not appear to be mediated through androgens, and did not occur in the absence of
leptin, a peptide hormone secreted by adipocytes. The importance of these findings in human
sebaceous gland activity remains to be determined.
Epidemiology of Acne
Acne is sufficiently common that it often has been termed physiologic. Mild degrees of acne are
often seen at birth, probably resulting from follicular stimulation by adrenal androgens, and mild
cases may continue in the neonatal period. However, it is not until puberty that acne becomes a
common problem. Acne is often an early manifestation of puberty; in the very young patient the
predominant lesions are comedones. In girls, the occurrence of acne may precede menarche by
more than a year. The greatest number of cases is seen during the middle-to-late teenage period;
subsequently, the incidence decreases. However, particularly in women, acne may persist through
the third decade or even later. Acne seems to be familial, but owing to the high prevalence of the
disease this has been extremely difficult to assess. Nodulocystic acne has been reported to be more
common in white males than in black males, 14 and one group of investigators has found that acne
is more severe in patients with the XYY genotype. 15
Etiology and Pathogenesis of Acne
Although the basic cause of acne is unknown, there is considerable information on the various
factors concerned in its pathogenesis. Acne is a multifactorial disease, developing in the sebaceous
follicles. Its pathophysiology centers on the interplay of follicular hyperkeratinization, colonization
with P. acnes bacteria, increased sebum production, and inflammation.
FOLLICULAR HYPERKERATINIZATION The primary change in the sebaceous follicle in acne
is an alteration in the pattern of keratinization within the follicle. 16 Normally, the keratinous
material in the follicle is loosely organized ( Fig. 73-3A). On the ultrastructural level, there are
many lamellar granules and relatively few keratohyaline granules. The initial changes in comedo
formation are observed in the lower portion of the follicular infundibulum. The keratinous material
becomes more dense, the lamellar granules are less numerous, keratohyaline granules are increased,
and some of the cells contain amorphous material, which is probably lipid, generated during the
process of keratinization ( Fig. 73-3B). Kinetic studies demonstrate that there is an increase in
cellular turnover in comedones.

FIGURE 73-3 A. High magnification of the keratinized layer in the proximal infundibulum of a
normal sebaceous follicle. The cornified cells are thin and filamentous, and the cell membranes are
indistinct. Large clusters of lamellar granules (LG) fill the intracellular spaces. (×15,258) B. High
magnification of the infundibular region of an early comedo from the face. The keratinized cells
have thickened cell margins ( single arrows), and many layers accumulate. In comparison with the
normal follicle (see Fig. 73-3A), there are fewer small clusters of lamellar granules ( double arrows)
at the junction of the granular and cornified layers. Note intracellular lipid inclusions (L). (×8493). (
From Knutson, 16 with permission.)

The initiating factor in comedo formation still has not been definitely identified. Follicular
hyperkeratinization may relate to a local deficiency of linoleic acid, production of interleukin-1
within the follicle, or, possibly, the effects of androgens on follicular keratinization. Downing et al.
17 advanced the theory that the decreased concentrations of linoleic acid that accompany the high
sebum secretion rate found in patients with acne result in a localized essential fatty acid deficiency
of the follicular epithelium. This, in turn, theoretically induces follicular hyperkeratosis and
decreased epithelial barrier function, both of which are characteristic of the essential fatty acid
deficiency syndrome. Investigators have developed models using human infrainfundibular segments
to study the process of follicular hyperkeratinization. Guy et al. found that the addition of 1 ng/mL
of interleukin (IL)-1a to infrainfundibular segments caused hypercornification similar to that seen in
comedones. 18 This could be blocked by addition of an IL-1 receptor antagonist. These authors
suggest that changes in sebum secretion or composition could lead to the release of IL-1 by
follicular keratinocytes, which, in turn, may stimulate comedogenesis. Androgens are known to
regulate the development of the sebaceous gland and sebum production. In addition, androgens may
play a role in the follicular hyperkeratinization seen in acne. Indirect evidence in support of this
latter hypothesis includes these observations: (1) androgen receptors have been localized to the
outer root sheath of the infrainfundibular region of follicles; 19 (2) the formation of follicular casts
is reduced in patients treated with antiandrogens; 20 and (3) each of the key enzymes involved in
androgen metabolism has been identified in follicles. 21 No direct effect of androgens on follicular
hyperkeratinization has been demonstrated, however. Additional studies are needed to determine
whether androgens modulate follicular hyperkeratinization.
PROPIONIBACTERIUM ACNES The predominant organism in the follicular flora is the
anaerobic pleomorphic diphtheroid Propionibacterium acnes. In 11- to 15-year-olds, practically no
P. acnes are found in individuals without acne, whereas in patients with acne, the geometric mean
of P. acnes organisms is 114,800 per square centimeter. 22 Similar differences are found in 16- to
20-year-old groups, but in older individuals the number of organisms is the same in those with and
without acne. It is generally accepted that P. acnes are important in the pathogenesis of acne. While
the initial impression was that inflammation resulted from the production of free fatty acids, and it
was shown that P. acnes was the main source of follicular lipases, P. acnes also produces other
extracellular enzymes such as proteases and hyaluronidases, which may be important in the
inflammatory process. Furthermore, there are other ways in which P. acnes may produce
inflammation. 23 The organism has been shown to secrete chemotactic factors 24 and chemotactic
activity has been found in comedones. 25 The dialyzable, low molecular weight chemotactic factor
does not require serum complement for activation, and, because of its small size, it can probably
escape from the follicle and attract polymorphonuclear leukocytes. If the polymorphonuclear
leukocytes enter the follicle, they can ingest P. acnes organisms, resulting in the release of
hydrolytic enzymes, which, in turn, may be of importance in producing follicular epithelial damage.
26 In addition, the classical and alternative complement activation pathways are stimulated by P.
acnes, possibly also contributing to the inflammatory response. 27 The host response may also be
important. Circulating antibodies to P. acnes are elevated in patients with severe acne. 28 Whether
this has a direct effect is not proved, but it has been shown that the P. acnes induction of lysosomal
hydrolases by polymorphonuclear leukocytes is anti- P. acnes antibody dependent. 26 There is other
evidence of changes in the immune response as demonstrated by increased response to P. acnes
injections in patients with acne. 29
SEBUM PRODUCTION A connection between acne and high rates of sebum secretion is
supported by at least three types of evidence: (1) children do not get acne during the age range from
approximately 2 to 6 years, when sebum secretion is extremely low; (2) average rates of sebum
secretion are higher in individuals with acne than in those without acne; 30 and (3) treatments that
reduce sebum secretion (such as estrogen or 13- cis-retinoic acid) improve acne. 31 , 32 It is
unclear, however, why elevated rates of sebum secretion lead to acne. The triglyceride fraction of
sebum, which is unique to humans, is probably responsible for acne. The bacterial population of the
follicle hydrolyzes triglycerides to fatty acids, which eventually appear on the skin surface. In the
past, the free fatty acid fraction of sebum was considered to be important in the causation of
inflammation, but in recent years, it has become evident that there are probably other more
important causes of inflammation, as discussed below. Most studies have failed to detect any
changes in the composition of sebum in patients with acne as compared to age-matched controls.
However, there is a significant decrease in the levels of linoleic acid in patients with acne, and there
is an inverse relationship between sebum secretion and the linoleic acid concentration of sebum.
Linoleic acid cannot be synthesized in mammalian tissues, and so the linoleate concentration in
human sebum depends on the quantity of this essential fatty acid with which each cell is endowed
and the extent to which this initial endowment is diluted by subsequent endogenous lipid synthesis
in sebaceous cells. In individuals with high rates of sebum secretion, the fatty acids of the skin
surface may contain only about 0.5 percent linoleate. 2 During passage through the follicle, some of
the linoleate-deficient fatty acids may percolate through the follicular wall and dilute the linoleate
necessary for a healthy epithelium. Although this mechanism is speculative, the involvement of
follicular bacteria and free fatty acids in acne is supported by the fact that when the bacterial
population is reduced with oral antibiotics, free fatty acids are reduced and acne may thus be
alleviated.
Clinical Manifestations of Acne
The primary site of acne is the face and to a lesser degree the back, chest, and shoulders. On the
trunk, lesions tend to be numerous near the midline. The disease is characterized by a great variety
of clinical lesions. Although one type of lesion may be predominant, close observation usually
reveals the presence of several types of lesions ( Fig. 73-4). The lesions may be either
noninflammatory or inflammatory. The noninflammatory lesions are comedones, which may be
either open (blackheads) or closed (whiteheads). The open comedo appears as a flat or slightly
raised lesion with a central dark-colored follicular impaction of keratin and lipid. The closed
comedones, in contrast to the open comedones, may be difficult to visualize. They appear as pale,
slightly elevated, small papules and do not have a clinically visible orifice. Stretching of the skin is
an aid in detecting the lesions. Because the closed comedones are potential precursors for the large
inflammatory lesions, they are of considerable clinical importance. Although comedones are the
primary lesions of acne, they are not unique in this disease as they may be seen under other
conditions (e.g., so-called senile comedones, which are common, particularly in the periorbital area
of older persons, and comedones that are seen in atrophic skin resulting from x-ray therapy).

FIGURE 73-4 Acne vulgaris, mild to moderate. A. Close-up of the lower face with comedones,
papules, pustules, and scars. B. Close-up of the cheek, showing large open comedones, and
inflammatory papules and pustules that become confluent, forming an erythematous plaque.

The inflammatory lesions vary from small papules with an inflammatory areola to pustules to large,
tender, fluctuant nodules ( Fig. 73-4, Fig. 73-5, and Fig. 73-6). Some of the large nodules were
previously called “cysts” and the term nodulocystic has been used to describe severe cases of
inflammatory acne. True cysts are rarely found in acne, and this term should be abandoned and the
term severe nodular acne used instead ( Fig. 73-6). Whether the lesion appears as a papule, pustule,
or nodule depends on the extent and location of the inflammatory infiltrate in the dermis.

FIGURE 73-5 Acne vulgaris, nodular, moderate to severe. A. Many papules and nodules are seen
on the forehead and cheeks with little scarring apparent at this time. B. Nodular acne with scars on
the cheek. C. Larger nodules on the cheek and chin with significant scarring.

FIGURE 73-6 Acne vulgaris, nodular, severe. A. Large confluent nodules formed by confluence of
smaller lesions with interconnecting channels, associated with atrophic and hyperplastic scars. B.
Extensive nodules on the chest and arms with severe scarring. C. Close-up of nodules, crusted
ulcers, and scars on the shoulder. D. Severe nodular acne of the back with little residual normal
uninvolved skin.
In addition to the above-described lesions, patients may have scars of varying size ( Fig. 73-7). The
characteristic scar of acne is a sharply punched-out pit. These are ordinarily single, but where
inflammation has been marked, the pits may have multiple openings. Less commonly, broader pits
may occur, and in rare instances, especially on the trunk, the scars may be hypertrophic.

FIGURE 73-7 Acne vulgaris, scarring. A. “Punched out” and “ice-pick” scars are seen on the cheek
as a residual of burned-out nodular acne. B. Extensive atrophic scarring of the back associated with
recent nodular acne. C. Severe hypertrophic scarring of the back in a patient with history of nodular
acne.

It has been mentioned that seborrheic dermatitis is commonly seen in association with acne, but
there does not appear to be any relation between these two diseases.
Diagnosis and Differential Diagnosis
Although one type of lesion may predominate, the diagnosis of acne vulgaris is usually made from
the finding of a mixture of lesions of acne (comedones, pustules, papules, and nodules) on the face,
back, or chest. Diagnosis is usually easy, but acne may be confused with folliculitis, rosacea, and
the various miscellaneous acneiform disorders that are discussed subsequently. Lupus miliaris
disseminatus faciei may also have a similar appearance.
Laboratory Findings
In general, laboratory workup is not indicated for patients with acne unless hyperandrogenism is
suspected. There are numerous clinical studies relating acne to elevated serum levels of androgens
in both adolescents and adults. Varying results have been obtained based on the patient population
studied and the methodology used. Among 623 prepubertal girls followed over time, girls with acne
had increased levels of DHEAS as compared to aged-matched controls without acne. 33 DHEAS
can serve as a precursor for testosterone and dihydrotestosterone. Elevated serum levels of
androgens have been found in cases of severe cystic acne 34 and in acne associated with a variety of
endocrine conditions, including congenital adrenal hyperplasia (11ß- and 21ß-hydroxylase
deficiencies), ovarian or adrenal tumors, and polycystic ovarian disease. In the majority of acne
patients, however, serum androgens are within the normal range. Several studies indicate that the
mean serum levels of DHEAS, testosterone, or dihydrotestosterone may be higher (but still within
the normal range) in patients affected with acne as compared to normal controls. 35 It should be
stressed that most of these studies involved older patients with treatment-resistant acne, and that
other investigators, using a younger age group, either have not demonstrated increased androgens
36 , 37 or have shown that if increased blood androgens are found, the levels, at most, are variable.
At this time, a potential androgen excess should be considered, particularly in older female patients
who have treatment-resistant acne. However, there is no evidence that there are endocrinologic
changes in all patients with acne. For this reason, it is thought that the local production of androgens
within the skin may correlate more directly with the development of acne, 38 and it has been shown
that the skin possesses each of the enzymes required to convert precursor DHEAS into more potent
androgens. 21 , 39 Focus is also centering on the role of 5a-reductase in acne. Testosterone is
converted to dihydrotestosterone by the action of 5a-reductase. Skin biopsies from men and women
with acne have demonstrated increased 5a-reductase activity when compared to normal controls. 40
Two isozymes of 5a-reductase have been identified that differ in their tissue localization. 41 The
type 1 isozyme is active in human sebaceous glands and is more active in glands from areas that are
prone to acne such as the face, when compared to areas of the skin not predisposed to acne. 42
Hyperandrogenism should be considered to be a contributing factor to the development of acne in
female patients whose acne is severe, sudden in its onset, or associated with hirsutism or irregular
menstrual periods. A medical history and physical examination directed toward eliciting any
symptoms or signs of hyperandrogenism should be performed. The patient should be asked about
the frequency and character of her menstrual periods and whether her acne flares with changes in
her menstrual cycle. Hyperandrogenism can also result in deepening of the voice or an increase in
libido. In addition to acne, other skin signs of endocrine diseases associated with hyperandrogenism
include hirsutism, male pattern alopecia, acanthosis nigricans, and truncal obesity.
Acne can also result from the administration of exogenous androgens such as testosterone, other
anabolic steroids, gonadotrophins, glucocorticoids, and ACTH. The latter two agents are the cause
of steroid acne, an entity to be described later.
Many patients report that their acne flares during periods of stress. Although objective data are
limited, stress is known to increase the output of adrenal steroids, which may affect the sebaceous
gland. It has been shown that patients with acne have a greater increase in urinary glucocorticoid
levels after corticotropin administration.
Excess androgens may be produced by either the adrenal gland or ovary. The laboratory workup
should include measurement of serum DHEAS, total testosterone, free testosterone, and the
luteinizing hormone (LH) to follicle-stimulating hormone (FSH) ratio. Testing should be obtained
in the luteal phase of the menstrual cycle (within 2 weeks prior to the onset of menses), and patients
on oral contraceptives will need to discontinue their medication for at least 1 month prior to testing.
The above tests can be used to screen for the source of the hyperandrogenism. Values of DHEAS in
the range of 4000 to 8000 ng/mL may be associated with congenital adrenal hyperplasia. Patients
with a serum level of DHEAS > 8000 ng/mL could have an adrenal tumor and should be referred to
an endocrinologist for further evaluation. An ovarian source of excess androgens can be suspected
in cases where the serum total testosterone is > 150 ng/dL. Serum total testosterone in the range of
150 to 200 ng/dL or an increased LH/FSH ratio (greater than 2.0) can be found in cases of
polycystic ovary disease. Greater elevations in serum testosterone may indicate an ovarian tumor,
and appropriate referral should be made. There is a significant amount of variability in an
individual's serum androgen levels. In cases in which abnormal results are obtained, it may be wise
to repeat the test before proceeding with therapy or additional testing.
Pathology
As already stated, acne develops in the sebaceous follicles, and the primary lesion is the comedo.
Comedo development starts in the midportion of the follicle as an expanding mass of lipid-
impregnated keratinous material, resulting in thinning and ballooning-out of the follicular wall.
Gradually, more keratinous material accumulates, and, as it does, further thinning and dilatation of
the follicular wall occur. At the same time, the sebaceous glands begin to atrophy and are replaced
by undifferentiated epithelial cells. The fully formed comedo has a thin wall and a minimal number
of sebaceous cells, if they can be found at all. The open comedo has a patulous orifice, and the
keratinous material is arranged in a lamellar concentric fashion ( Fig. 73-8). With lipid stains, it can
be shown that the keratin is permeated by lipid. Diphtheroid bacteria are also present. In cross
section, the keratinous material consists of whorls of lamellar material centered on appendageal
structures such as the hairs. In fact, most comedones contain multiple hairs. The closed comedo
differs from the open comedo in that the keratinous material is not as compact and the follicular
orifice is narrow and not distended ( Fig. 73-9).
FIGURE 73-8 Open comedo. The mouth of the follicle is widely dilated. The comedo is composed
of a lamellar keratinous mass impregnated with lipid. Bacteria are also present. The sebaceous
glands have undergone atrophy. (From Strauss and Kligman, 80 with permission.)

FIGURE 73-9 Closed comedo. The structure of the lesion is similar to that of the open comedo.
However, the orifice is small, and the contents of the comedo are not as compact. ( From Strauss
and Kligman, 80 with permission.)

The fully developed open comedo is not usually the site of inflammatory changes, unless it is
traumatized by the patient. The developing microcomedo and, to a lesser degree, the closed comedo
are the major sites for the development of inflammatory lesions. The initial event appears to be
escape of lipid through an edematous comedo wall, with the development of a cellular reaction in
the adjacent dermis. Once complete rupture has occurred, the entire contents of the comedo are
extruded into the dermis ( Fig. 73-10). This reaction is much greater, and giant cells are common,
reflecting the escape of the keratinous material. Within the inflammatory infiltrate, gram-positive
diphtheroid bacteria with the morphologic characteristics of P. acnes may be observed free and
within polymorphonuclear leukocytes. Depending upon the site and extent of inflammation, these
ruptured lesions may appear as a pustule, a nodule, or as a nodule surmounted by a pustule.

FIGURE 73-10 Pustule following rupture of a sebaceous follicle. The original walls of the follicle
can be seen at the follicular orifice. New strands of epithelial cells are migrating from the epidermis
to encapsulate the inflammatory mass, making the inflammatory material appear to be within the
follicle.

It should be realized that the skin is always attempting to repair itself, and sheaths of cells will grow
out from the epidermis or appendageal structures in an attempt to encapsulate the inflammatory
reaction. This encapsulation may be complete so that the inflammatory infiltrate appears to be
within the follicle, but often it is far from complete, and further rupture may occur leading to
multichanneled tracts, as can be seen in many acne scars. Fibrous contraction also contributes to
scar formation.
Treatment
There may be great fluctuations in the natural course of acne; furthermore, the response to placebo
therapy is considerable. Therefore, the determination of the therapeutic efficacy of medications used
in acne is not a simple task, and it is possible to find many favorable therapeutic reports for agents
that are obviously of little value in the treatment of acne. In this section, no attempt is made to be
all-inclusive; only the more commonly used or useful modalities are discussed.
In general, there are four major principles governing the therapy of acne, and the individual
therapeutic modalities listed below are related to these principles, where possible. These principles
are: (1) correct the altered pattern of follicular keratinization; (2) decrease sebaceous gland activity;
(3) decrease the follicular bacterial population, particularly the P. acnes population, and inhibit the
production of extracellular inflammatory products (either directly or indirectly) by inhibiting the
bacterial organisms; and (4) produce an anti-inflammatory effect. The first of these treatment
principles, namely, changing the altered pattern of follicular keratinization, should be the primary
form of therapy in noninflammatory acne; the rest of the modalities are primarily designed for use
in inflammatory acne. Nonetheless, because altered follicular keratinization is the starting point for
the development of inflammatory acne, therapy directed at this abnormality also should be of value
in inflammatory acne.
LOCAL THERAPY
Cleansing There is no evidence that either surface sebum or surface bacteria aggravates acne.
Therefore, in order for a soap or topical antibacterial agent to be of aid in the therapy of acne, the
topical agent would have to remove the lipids or the bacteria (or both) from within the follicle.
Certainly, the action of a soap will not remove open or closed comedones. Any dermatologist can
readily describe cases of acne that he or she has seen in compulsive washers. It would appear that
washing as a therapeutic measure is often overemphasized, but many acne patients do not have a
pronounced seborrhea, and washing or cleansing to remove this excessive oil, if not overdone,
provides subjective benefit.
Topical agents Topical therapy of acne has undergone periodic change. Many years ago, empirical
reliance was placed on the use of sulfur- and resorcinol-containing products, and to a degree, they
are still used in the over-the-counter market. Their mechanism of action has not been defined.
Products containing salicylic acid, a keratolytic agent, have also enjoyed some popularity. However,
the major topical agents now in use are retinoids and antimicrobials such as benzoyl peroxide and
topical antibiotics. Topical retinoids, such as tretinoin and tazarotene, and agents with retinoid
activity, such as adapalene, are used extensively for their comedolytic activity. These agents can be
irritants; in general, the order of irritancy increases as one progresses from the use of cream
preparations to gels to the solution. Most patients can use low-potency tretinoin or adapalene cream
daily without developing an irritant reaction. Patients must also be cautioned about sun exposure,
because an exaggerated burn may follow what previously was an easily tolerated sun exposure.
Unlike tretinoin, adapalene and tazarotene are specific for a subset of retinoic acid receptors
(RARs). These two drugs selectively activate RAR-ß and RAR-?, but not RAR-a receptors. The
binding of these agents to nuclear retinoic acid receptors affects the expression of genes involved in
cell proliferation, cell differentiation, and inflammation. At the cellular level, the result may be a
modification of several acne pathogenic factors, including corneocyte accumulation and cohesion,
and inflammation. Topical retinoids are comedolytic, and reversal of the altered pattern of follicular
keratinization has been seen at an ultrastructural level. Epidermal cell turnover is increased in
comedones. Salicylic acid is also comedolytic but is not as effective as topical retinoids. Benzoyl
peroxide preparations are among the most common topical medications prescribed by
dermatologists, and benzoyl peroxide is a major therapeutic agent in the over-the-counter acne
market. Benzoyl peroxide is a powerful antibacterial agent, and its effect is probably related to a
decrease in the bacterial population and an accompanying decrease in the hydrolysis of
triglycerides. Benzoyl peroxide preparations are available in both lotion and gel forms, the latter
generally being considered more active. The compound can produce significant dryness and
irritation, and allergic contact dermatitis has occurred, but this is an uncommon event. Topical
antibiotics are also used for the treatment of acne, the most popular preparations containing
erythromycin or clindamycin. These two agents have also been used in combination preparations
with benzoyl peroxide. Increased levels of P. acnes resistance have been reported in patients who
are being treated with antibiotics. However, the development of resistance is less likely in patients
who are treated with a combination of benzoyl peroxide/erythromycin or clindamycin. 43
Therefore, these combination products are preferable over topical antibiotics alone. Another topical
agent is a cream containing 20% azelaic acid. Azelaic acid is a naturally occurring dicarboxylic acid
found in cereal grains. It is available as a topical cream, which is effective in inflammatory and
comedonal acne. The activity of azelaic acid against inflammatory lesions may be greater than its
activity against comedones. Azelaic acid is applied twice daily and its use is reported to have fewer
local side effects than topical retinoids. In addition, it may help to lighten postinflammatory
hyperpigmentation. Because comedolytic agents, such as topical retinoids or salicylic acid, and
antimicrobial agents, such as benzoyl peroxide or antibiotics, have different modes of action, they
are often used together in an individual patient. However, they should be applied at separate times.
SYSTEMIC THERAPY Over the years, many different agents have been used systemically. The
major systemic modalities that are currently being used include antibiotics and antibacterial agents,
hormones, and an oral synthetic retinoid.
Antibiotics and antibacterial agents Currently, the broad-spectrum antibiotics are widely used in the
treatment of acne. Although the oral administration of tetracycline does not alter sebum production,
it does decrease the concentration of free fatty acids while the esterified fatty acid content increases.
This decrease in free fatty acids is seen with dosages ranging from 250 mg/day to 1 g/day. The free
fatty acids are probably not the major irritants in sebum, but their level is an indication of the
metabolic activity of the organism and its secretion of other proinflammatory products. The
decrease in free fatty acids may take several weeks to become evident. This, in turn, is reflected in
the clinical course of the disease during antibiotic therapy, as several weeks are often required for
maximal clinical benefit. The effect, then, is one of prevention; the individual lesions require their
usual time to undergo resolution. However, the fact that a decrease in free fatty acids does occur
strengthens the rationale for the use of tetracycline. Tetracycline may act through direct suppression
of the number of P. acnes, but part of its action may also be due to its anti-inflammatory activity.
Decreases in free fatty acid formation also have been reported with erythromycin,
demethylchlortetracycline, clindamycin, and minocycline. Most studies support the efficacy of
tetracycline and its derivatives in the treatment of acne. In clinical practice, tetracycline is usually
given initially in dosages of 500 mg/day to 1000 mg/day. While the dose is often decreased as
improvement occurs and may be continued at a level of 250 mg/day or less, there is increasing
concern that this may generate resistant strains. Tetracycline should be taken on an empty stomach
to promote absorption. Erythromycin has been used in the past in patients who have difficulty in
taking tetracycline on an empty stomach, but there is increasing evidence of the development of
erythromycin-resistant strains of P. acnes from both the topical and systemic use of erythromycin.
Therefore, it is wise to limit the use of oral erythromycin to those cases where tetracyclines are
contraindicated, that is, in pregnant women and young children. Increasingly, doxycycline and
minocycline are being used as alternatives for tetracycline or in tetracycline-unresponsive cases.
These two drugs appear to be more effective than tetracycline, and drug resistance is less likely to
occur, especially with minocycline. Doxycycline should be administered in dosages of 50 to 100 mg
twice daily. The major disadvantage of the use of doxycycline is that it can produce photosensitivity
reactions, and patients should be switched to another antibiotic, if possible, during the summer
months. Minocycline is given in divided dosages at a level of 100 mg/day to 200 mg/day. Patients
on minocycline should be monitored carefully as the drug can cause blue-black pigmentation,
especially in the acne scars, as well as the hard palate, alveolar ridge, and anterior shins.
Minocycline-induced autoimmune hepatitis and a systemic lupus erythematosus-like syndrome
have been reported during minocycline therapy, but to date, these side effects are very rare. 44 , 45
Oral clindamycin has been used in the past, but because of the potential of pseudomembranous
colitis, it is now rarely used for acne. Although long-term, low-dosage antibiotic therapy is often
continued for many months, very few side effects have been observed. Tetracyclines have an
affinity for rapidly mineralizing tissues and are deposited in developing teeth, where they may
cause irreversible yellow-brown staining; also, tetracyclines have been reported to inhibit skeletal
growth in the fetus. Therefore, they should not be administered to pregnant women, especially after
the fourth month of gestation, or to babies. The tetracyclines also should not be given to children
younger than 8 years of age. The only safe antibiotic to administer to pregnant women or children is
erythromycin. A rare complication, but one that can easily be missed, is the development of a gram-
negative folliculitis. 46 With prolonged antibiotic therapy, gram-negative organisms may proliferate
in the anterior nares and spread out onto the surrounding skin. The physician should be alerted to
this diagnosis if there is a sudden flare with pustules or nodules in a patient who is otherwise
improving. Two types of lesions are seen. Most commonly there are multiple pustules with an
intense inflammatory areola. This type of lesion is often caused by Enterobacter or Klebsiella. The
patient may also have deep indolent nodules from which Proteus organisms are most often isolated.
Culture confirmation is necessary, and antibiotic therapy should be governed by the results of
sensitivity studies. Ampicillin is often the antibiotic of choice. Patients who do not show a response
to antibiotics should be treated with a full course of isotretinoin (see below). Tetracycline in
dosages ranging from 1500 mg/day to 3500 mg/day has been used in patients with very severe acne.
The results of this form of therapy are encouraging, particularly because the treated patients have
otherwise been resistant to therapy. Patients under treatment with high-dose tetracycline should be
carefully monitored with frequent laboratory evaluation. Trimethoprim-sulfamethoxazole
combinations are also effective in acne. In general, because the potential for side effects is greater
with their use, they should be used only in patients with severe acne who do not respond to other
antibiotics. If trimethoprim-sulfamethoxazole is used, the patient must be monitored for potential
hematologic suppression approximately monthly.
Hormonal therapy of acne Sebum secretion is increased by agents with androgenic activity,
including synthetic anabolic steroids, and decreased by agents that counteract or interfere with
androgen action, namely estrogens and antiandrogens. The goal of hormonal therapy is to
counteract the effects of androgens on the sebaceous gland. This can be accomplished with the use
of estrogens, antiandrogens, or agents designed to decrease the endogenous production of androgens
by the ovary or adrenal gland, including oral contraceptives, glucocorticoids, or gonadotropin-
releasing hormone (GnRH) agonists.
ESTROGENS Any estrogen given in sufficient amounts will decrease sebum production. The dose
of estrogen required to suppress sebum production, however, is greater than the dose required to
suppress ovulation. Although some patients will respond to lower-dose agents containing 0.035 to
0.050 µg of ethinyl estradiol or its esters, higher doses of estrogen are often required. 47 If estrogen
therapy is indicated and if the physician is unfamiliar with its usage or side effects, it is best to work
with a gynecologist. Breast examinations and Pap smears are recommended for women receiving
estrogen therapy. The incidence of more serious side effects such as clotting and hypertension that
follow the use of estrogens is, fortunately, rare in young healthy females. Nevertheless, the
physician and patient should be aware of the possibilities, and the risk/benefit ratio should be
carefully considered before undertaking estrogen therapy. Although the use of estrogen therapy for
acne has decreased dramatically since oral isotretinoin has been available, there are specific patients
in whom its use is still appropriate. As mentioned below, estrogens can be used in combination with
glucocorticoids.
ORAL CONTRACEPTIVES With the use of estrogen-progestin-containing oral contraceptives
rather than estrogen alone, side effects such as delayed menses, menorrhagia, and premenstrual
cramps are uncommon. However, other side effects such as nausea, weight gain, spotting, breast
tenderness, amenorrhea, and melasma can occur. The third-generation progestins, desogestrel,
norgestimate, and gestodene (not available in the United States), have the lowest intrinsic
androgenic activity. 48 Two oral contraceptives are currently FDA approved for the treatment of
acne (Ortho Tri-Cyclen and Estrostep). Ortho Tri-Cyclen is a triphasic oral contraceptive comprised
of a norgestimate-ethinyl estradiol (35 µg) combination. 49 In an effort to reduce the estrogenic side
effects of oral contraceptives, preparations with lower doses of estrogen (20 µg) have been
developed and are being studied for the treatment of acne. Estrostep contains a graduated dose of
ethinyl estradiol (20 to 35 µg) in combination with norethindrone acetate. 50 An oral contraceptive
containing a low dose of estrogen (20 µg) in combination with levonorgestrel (Alesse) has also
demonstrated efficacy in acne. 51 Side effects from oral contraceptive use include nausea, vomiting,
abnormal menses, weight gain, and breast tenderness. Rare but more serious complications include
thrombophlebitis, pulmonary embolism, and hypertension.
GLUCOCORTICOIDS Because of their anti-inflammatory activity, high-dose systemic
glucocorticoids may be of benefit in the treatment of acne. In practice, their use is usually restricted
to the severely involved patient. Furthermore, because of the potential side effects, these drugs are
ordinarily used for limited periods of time, and recurrences are common after therapy is
discontinued. Prolonged use may result in the appearance of steroid acne. Glucocorticoids in low
dosages are also indicated in those female patients who have an elevation in serum DHEAS
associated with an 11- or 21-hydroxylase deficiency or in other individuals with demonstrated
androgen excess. Low-dose prednisone (2.5 mg or 5 mg) or dexamethasone can be given orally at
bedtime to suppress adrenal androgen production. 34 The combined use of glucocorticoids and
estrogens has been used in recalcitrant acne in women, based upon the inhibition of sebum
production by this combination. 52 The mechanism of action is probably related to a greater
reduction of plasma androgen levels by combined therapy than is produced by either drug alone.
GONADOTROPIN-RELEASING HORMONE AGONISTS GnRH agonists act on the pituitary
gland to disrupt its cyclic release of gonadotropins. The net effect is suppression of ovarian
steroidogenesis in women. These agents are used in the treatment of ovarian hyperandrenogenism.
GnRH agonists have demonstrated efficacy in the treatment of acne and hirsutism in females both
with and without endocrine disturbance. 53 Their use, however, is limited by their side-effect
profile, which includes menopausal symptoms and bone loss.
ANTIANDROGENS Cyproterone acetate is a progestational antiandrogen that blocks the androgen
receptor. It is combined with ethinyl estradiol in an oral contraceptive formulation that is widely
used in Europe for the treatment of acne. Cyproterone acetate is not available in the United States.
Spironolactone functions both as an androgen receptor blocker and inhibitor of 5a-reductase. In
doses of 50 to 100 mg twice a day, it has been shown to reduce sebum production and to improve
acne. 54 Side effects include potential hyperkalemia, irregular menstrual periods, breast tenderness,
headache, and fatigue. As an antiandrogen, there is a risk of feminization of a male fetus if this
medication is taken by a pregnant female. Risk to a fetus and the symptoms of irregular menstrual
bleeding can be alleviated by combining spironolactone treatment with an oral contraceptive.
Flutamide, an androgen receptor blocker, has been used at doses of 250 mg twice a day in
combination with oral contraceptives for treatment of acne or hirsutism in females. 55 Liver
function tests should be monitored as cases of fetal hepatitis have been reported. 56 Pregnancy
should be avoided. Use of flutamide in the treatment of acne may be limited by its side effect
profile.
ENZYME INHIBITORS The development of 5a-reductase inhibitors, such as finasteride, that block
the conversion of testosterone to DHT in the prostate suggested the possibility of an approach to
interfering with androgen action on the sebaceous glands that would be appropriate for use in males.
However, finasteride does not inhibit sebum secretion. 4 Its lack of action is attributed to the
existence of two different 5a-reductases, with the enzyme in the prostate being blocked by the drug
while that in the skin is unaffected. 42 , 57 Specific inhibitors of the type 1 5a-reductase are being
developed. 58 If these agents reduce sebum production, they may be efficacious in the treatment of
acne.
ISOTRETINOIN (See also Chap. 257) The use of the oral retinoid, isotretinoin, has revolutionized
the management of severe treatment-resistant acne. 59 Isotretinoin, like vitamin A, produces side
effects, but, as discussed below, these are not usually severe enough to necessitate interruption of
therapy in most cases. The remarkable aspects of isotretinoin therapy are the completeness of the
remission in almost all cases and the longevity of the remission, which lasts for months to years in
the great majority of patients. Isotretinoin therapy, for all practical purposes, is always accompanied
by side effects that may mimic those seen in the chronic hypervitaminosis A syndrome. 60 Thus,
side effects related to the skin and mucous membranes are most common. Cheilitis of varying
degrees is found in almost all cases. Other side effects that are likely to be seen in over 50 percent
of patients are dryness of the mucous membranes, xerosis, conjunctivitis, and pruritus. Side effects
seen with lesser degrees of frequency include bone and joint pain; thinning of hair; headache and
accompanying symptoms associated with increased intracranial pressure; palmoplantar
desquamation; and nausea and vomiting. The laboratory abnormalities that have occurred include
elevations in triglycerides, erythrocyte sedimentation rate, platelet count, liver function tests, and
white blood cells in the urine and decreases in red blood cell parameters, white cell counts, and
high-density lipoprotein levels. The elevation of triglycerides, which is dose-related, is of particular
concern because it is often accompanied by a decrease in the high-density lipoprotein levels, which
may increase the risk of coronary artery disease. There are also reports of the development of bony
hyperostoses after isotretinoin therapy, but these are more likely to be seen in patients who receive
the drug for longer periods of time in higher dosages for diseases of keratinization. 61 The issue of
isotretinoin and psychiatric effects has come to the forefront. From 1982 to May 2000, 37 cases of
suicide, 110 cases of hospitalized depression, suicidal ideation or suicide attempt, and 284 cases of
nonhospitalized depression in patients on isotretinoin were reported to the FDA's Adverse Event
Reporting System. 62 In one population-based cohort study comparing isotretinoin users with oral
antibiotic users, the relative risk for development of depression or psychosis was approximately 1.0,
indicating no increased risk. 63 Further studies are needed to resolve this issue of causality. Until
then, a careful review for signs and symptoms of depression and suicidal ideation should be
performed in all patients for whom isotretinoin therapy is considered, and the patients must be
carefully monitored during therapy. Studies show that some of the side effects are dosage related.
These same studies demonstrate that clinical results can be obtained with dosages as low as 0.1
mg/kg per day. However, with such dosages, the incidence of relapses after therapy is greater. The
recommended daily dosage of isotretinoin is in the range of 0.5 to 1 mg/kg per day. Because back
and chest lesions show less of a response than facial lesions, dosages as high as 2 mg/kg per day
may be necessary in those patients who have very severe trunk involvement. Patients with severe
acne, particularly those with granulomatous lesions, will often develop marked flares of their
disease when isotretinoin is started. Therefore, the initial dosing should be low, even below 0.5
mg/kg per day. These patients often need pretreatment for 1 to 2 weeks with prednisone (40 to 60
mg per day), which may have to be continued for the first 2 weeks of therapy. Isotretinoin is usually
given for 20 weeks, but the length of the course of treatment is not absolute; in patients who have
not shown an adequate response, therapy can be extended, if necessary. Some improvement is
usually seen for 1 to 2 months after isotretinoin is discontinued, so that total clearing is not a
necessary endpoint for determining when to discontinue therapy. Approximately 10 percent of
patients treated with isotretinoin require a second course of the drug. The likelihood for repeat
therapy is increased in patients younger than 16 to 17 years of age. It is best to allow at least 2 to 3
months between courses of isotretinoin. Studies suggest that the chances of inducing a long-term
remission are greatest if the patient has received a total dose of 120 to 150 mg/kg of isotretinoin
during a course of therapy. 64 Isotretinoin should be used only in those patients with severe acne.
Furthermore, laboratory monitoring is indicated. It is appropriate to obtain a baseline complete
blood count and liver function tests, but the greatest attention should be paid to following serum
triglyceride levels. Baseline values for serum triglycerides should be obtained and repeated at 3 to 4
weeks and 6 to 8 weeks of therapy. If the values are normal at 6 to 8 weeks, there is no need to
repeat the test during the remaining course of therapy unless there are risk factors. If serum
triglycerides increase above 500 mg/dL, the levels should be monitored frequently. Levels above
700 to 800 mg/dL are a reason for interrupting therapy or treating the patient with a lipid-lowering
drug such as gemfibrozil. Eruptive exanthemas or pancreatitis can occur at higher serum
triglyceride levels. In rare instances, exuberant granulation tissue has appeared in some lesions. If
this occurs, the dosage of drug may have to be decreased or the drug may have to be discontinued.
Glucocorticoids may have to be administered either systemically or intralesionally to control the
granulation tissue. The greatest concern during isotretinoin therapy is the risk of the drug being
administered during pregnancy and thereby inducing teratogenic effects in the fetus. 65 , 66 The
drug is not mutagenic; its effect is on organogenesis. Therefore, the production of retinoic
embryopathy occurs very early in pregnancy, with a peak near the third week of gestation. 65 , 66
Theoretically, based on animal studies and the pharmacokinetics of the drug, there should be more
safety in the use of isotretinoin than either vitamin A or etretinate. 67 , 68 However, that is not the
case, and a significant number of fetal abnormalities have been reported after the use of isotretinoin.
For this reason, it should be emphasized that isotretinoin should be given only to patients who have
not responded to other therapy. Furthermore, women who are of childbearing age must be fully
informed of the risk of pregnancy. The patient must either avoid sexual exposure totally or should
employ two highly effective contraception techniques such as the use of an oral contraceptive and
condoms with a spermicidal jelly. Contraception must be started at least 1 month before isotretinoin
therapy. The patient must have a negative serum pregnancy test at the time when therapy is decided
upon and on the second or third day of the next menstrual period or 11 days after the last
unprotected intercourse in a woman who is amenorrheic. The woman must thoroughly understand
the contraception techniques she is using and continue them throughout the course of isotretinoin
and for 1 month after stopping treatment. No more than 1 month's supply of drug should be given to
a female patient so that she can be counseled on a monthly basis on the hazards of pregnancy during
isotretinoin therapy. The pregnancy test should be repeated monthly to maintain patient awareness.
The manufacturer and the FDA have recently instituted a verification process requiring that
authorization stickers be affixed to prescriptions to insure that pregnancy-prevention procedures are
followed. As stated above, retinoic acid embryopathy results from the effect of isotretinoin on early
organogenesis. Therefore, because the drug is not mutagenic, there is no risk to a fetus conceived by
a male who is taking isotretinoin. Although it may seem obvious, it is important to remind men who
are taking isotretinoin not to give any of their medication to female companions under any
circumstances. The mechanism of action of isotretinoin is not completely known. The drug
produces profound inhibition of sebaceous gland activity, and this undoubtedly is of great
importance in the initial clearing. 69 , 70 In some patients, sebaceous gland inhibition continues for
at least a year, but in the majority of patients, sebum production returns to normal after 2 to 4
months. 69 Thus, this action of the drug cannot be used to explain the long-term remissions. The P.
acnes population is also decreased during isotretinoin therapy, but this decrease is not often long
lasting. 70 , 71 Isotretinoin has no inhibitory effect on P. acnes in vitro. Therefore, the effect on the
bacterial population is probably indirect, resulting from the decrease in intrafollicular lipids
necessary for organism growth. Isotretinoin also has anti-inflammatory activity and probably has an
effect on the pattern of follicular keratinization. Once again, it has not been demonstrated that these
effects are long lasting. Thus, while the drug may influence the course of severe acne through
several different mechanisms, the explanation for the long-term remissions remains obscure.
DIET Currently, there is little enthusiasm for the elimination of various foods such as shellfish,
chocolate, sweets, milk, and fatty foods from the diet of patients with acne. There is no evidence to
support the value of elimination of these foods, although some patients will attest to flares of their
disease after ingestion of certain foods. This is especially true with chocolate. Because patients will
cling to their beliefs, it is best to restrict those dietary agents that they feel produce flares.
PHYSICAL THERAPY Superficial x-ray therapy, ultraviolet light therapy, and cryotherapy have
been used extensively in the past for the treatment of acne. Superficial x-ray therapy was helpful in
that it produced temporary suppression of the sebaceous glands, but the hazards associated with this
procedure, including thyroid carcinoma, far outweigh the gains, and it is rarely, if ever, used now.
There is no proof that ultraviolet light therapy is effective, other than the masking produced by the
tan, and cryotherapy is rarely used.
ACNE SURGERY This modality, used for the removal of comedones and superficial pustules, aids
in bringing about involution of individual acne lesions. Acne surgery was a mainstay of therapy in
the past. However, with the advent of comedolytic agents such as topical vitamin A acid, it is not
needed as often. Its use is primarily restricted to those patients who do not respond to comedolytic
agents. Even in those patients, the comedones are removed with greater ease and less trauma if the
patient is treated first with topical vitamin A acid or a similar topical agent for 3 to 4 weeks. This
pretreatment should be done in all patients who are going to undergo mechanical comedo removal.
Acne surgery is helpful only when properly done, and inaccurate placement of the comedo extractor
may serve only to push the inflammatory material further into the skin. Therefore, it is inadvisable
to have the patient do acne surgery at home. The Unna type of comedo extractor, which has a broad
flat plate and no narrow sharp edges, is preferable. The removal of open comedones does not
materially influence the course of the disease because these lesions do not become inflammatory.
However, it is desirable to remove them for cosmetic purposes. In contrast, closed comedones
should be removed to prevent their rupture. Unfortunately, the orifice of closed comedones is often
very small, and usually the material contained within the comedo can be removed only after the
orifice is gently enlarged with a no. 25 needle or other suitable sharply pointed instrument.
INTRALESIONAL GLUCOCORTICOIDS Intralesional injection of glucocorticoids, either by the
use of a syringe or by the use of an automatic needleless injector, usually dramatically decreases the
size of deep nodular lesions. The injection of 0.05 to 0.25 mL per lesion of a triamcinolone acetate
suspension (2.5 to 10 mg/mL) is recommended as the anti-inflammatory agent. This is a very useful
form of therapy in the patient with nodular acne, but it often has to be repeated every 2 to 3 weeks.
A major advantage is that it can be done without incising or draining the lesions, thus avoiding the
possibility of scar formation.
Course and Prognosis
The age of onset of acne varies considerably. It may start as early as 6 to 8 years of age or it may
not appear until the age of 20 or later. The course is one of several years' duration followed by
spontaneous remission, the cause of which is unknown. While most patients will clear by their early
twenties, some have acne extending well into the third or fourth decades. The extent of involvement
varies, and spontaneous fluctuations in the degree of involvement are the rule rather than the
exception. In the northern sections of the United States, where seasonal differences are great,
relative clearing occurs in the summer for reasons that are not understood. Also, in women there is
often a fluctuation in association with menses, with a flare just before the onset of menstruation.
This flare is not due to a change in sebaceous gland activity as there is no increase in sebum
production in the luteal phase of the menstrual cycle.
The prognosis of acne vulgaris is favorable, and almost all cases undergo spontaneous resolution as
mentioned above. The only physical sequela is scarring which, with proper care, can often be
minimized. Several different procedures are available to correct the scarring. Dermabrasion, laser
resurfacing and deeper chemical peels seek to reduce the variability of the skin surface area and
smooth out pitted complexions. The scar may be treated by superficial peeling with agents such as
phenol or trichloroacetic acid, but it is unlikely that the technique will eliminate more than the most
superficial scars. For discreet, depressed scars, soft tissue augmentation can be temporarily
beneficial. Filler substances used include bovine collagen, autologous fat, silicone, and dermal
grafts. Hypersensitivity to xenographic fillers should be ruled out prior to their use. For larger
hypertrophic or aggregated pitted scars, full thickness surgical excision may result in improved scar
placement and a better cosmetic outcome.
Many scars are erythematous, and the redness may be decreased by treatment with a pulsed dye
laser. However, the most definitive treatment for scars is the use of deep abrasive therapy with
motor-driven brushes or wheels to remove the epidermis and upper dermis down to the level of the
scars. Potential patients for dermabrasive therapy must be carefully screened. Because the
sebaceous glands are suppressed by the administration of isotretinoin, procedures such as
dermabrasion or laser resurfacing, which are dependent upon intact appendageal structures for
resurfacing, should be delayed at least 6 months. It should be noted that emotionally unstable
individuals are poor risks because they likely will blame their appearance for their underlying
difficulties. The improvement from dermabrasion is unlikely to solve these difficulties, and such
patients are often not satisfied with the results. Persistent erythema, hyperpigmentation or
hypopigmentation may follow dermabrasion or resurfacing, and, very rarely, hypertrophic scarring
may occur. When deep scars exist, more than one dermabrasion may be necessary. For all these
reasons, the patient must give considerable thought to the pros and cons before undertaking this
surgical procedure. If there is no medical contraindication to dermabrasion, the decision to undergo
the procedure should rest with the patient and not with the physician.
It is important, however, to look beyond the physical scarring, for, as has been stated, there is no
disease that has caused more insecurity and feelings of inferiority than acne. 72 Indeed, acne is
perceived by adolescents as having negative personal and social consequences. 73 The psychiatric
morbidity associated with acne can assume many varied forms, including impaired self-image and
self-esteem, social impairment, depression, or even anger.
MISCELLANEOUS TYPES OF ACNE
In the past, acne was divided into various minor subgroups on the basis of the predominant lesions.
Thus, there are references to, for example, comedonal, papular, and pustular acne. As stated earlier,
this classification has limited value because close scrutiny usually discloses an admixture of lesions.
Nevertheless, there are a few varieties of acne that warrant presentation as separate entities.
Neonatal Acne
An acneiform eruption may occur in newborns or infants. This is often seen on the nose and
adjacent portions of the cheeks. The appearance of acne at this time is probably related to the
glandular development that occurs during fetal life. Clearing usually occurs, even without
treatment. Recent studies suggest that neonatal cephalic pustulosis, a condition confused with
neonatal acne, may be due to an inflammatory reaction against Malassezia species. 74 Acne can
also start after birth and persist for a few months. This is called infantile acne.
Acne Excoriée des Jeunes Filles
Mild acne may be accompanied by extensive excoriations. As a result of the depth of the lesions,
linear scarring may occur in these patients. Because this is most frequently seen in young adult
women, the above name has been used to describe these cases. Excoriated acne is usually very
difficult to treat and may even require supportive psychotherapy.
Steroid Folliculitis
Following administration of glucocorticoids or corticotropin, a folliculitis may appear. This is very
uncommon in children but may occur in any adult as early as 2 weeks after steroids are started.
Similar lesions may follow the prolonged application of topical glucocorticoids to the face. For this
reason, topical glucocorticoids have no place in the treatment of acne, and their use on the face, in
general, should be limited. The pathology of steroid acne is that of a focal folliculitis with a
neutrophilic infiltrate in and around the follicle. On histologic examination, hyperkeratinization is
not a prominent feature, which is consistent with the clinical findings. This type of acne clearly
differs from acne vulgaris in its distribution and in the type of lesions observed. The lesions, which
are usually all in the same stage of development, consist of small pustules and red papules. In
contrast to acne vulgaris, they appear mainly on the trunk, shoulders, and upper arms, with lesser
involvement of the face. Postinflammatory hyperpigmentation may occur, but comedones, cysts,
and scarring are unusual.
Halogen Acne
Iodides and bromides may induce an acneiform eruption similar to that observed with steroids. With
iodides, in particular, inflammation may be marked. The iodine content of iodized salt is low and,
therefore, it is extremely unlikely that enough iodized salt could be ingested to cause this type of
acne. Rather, when it occurs, it is due to ingestion of halogen-containing sedatives, expectorants,
drugs, vitamins, and the like.
Miscellaneous Drugs
Acne resembling steroid acne has been reported after the use of isonicotinic acid hydrazide, and
there is a report that patients in whom inactivation of this drug is slow are prone to develop this type
of acne. 75 Acne also occurs in patients taking diphenylhydantoin, and it has been reported in
individuals taking lithium carbonate.
Occupational Acne
Several different groups of industrial compounds may cause acne. These include coal tar
derivatives, insoluble cutting oils, and chlorinated hydrocarbons (chlornaphthalenes,
chlordiphenyls, and chlordiphenyloxides). Acne from these agents tends to be quite inflammatory
and, in addition to large comedones, is characterized by papules, pustules, large nodules, and true
cysts. Tar acne is often accompanied by hyperpigmentation. The lesions of industrial acne are not
restricted to the face and, in fact, are more common on covered areas where intimate contact with
clothing saturated with the offending compound is maintained. Because the cutting oils are so
widely used, they are the most common cause of industrial acne. However, the chlorinated
hydrocarbons have posed a more difficult problem because of the severity of the disease induced
with these compounds. Many cases have occurred as the result of massive exposure in industrial
accidents. 76
Tropical Acne
Acne vulgaris may flare, and a severe folliculitis may develop, in tropical climates. These skin
conditions are a major cause of dermatologic disability in the Armed Forces. Tropical acne, which
occurs mainly on the trunk and buttocks, has many deep, large, inflammatory nodules with multiple
draining areas. It resembles acne conglobata (see below). The pathogenesis of this type of acne is
unknown, although secondary infection with coagulase-positive staphylococci almost always
ensues. Systemic antibiotics must be given, but often more important is the necessity to remove the
patient to a cooler environment.
Acne Aestivalis
This monomorphous eruption consists of multiple, uniform, red, papular lesions and is reported to
occur after sun exposure. It is referred to as Mallorca acne because it occurred in many
Scandinavians after they had been in southern Europe. Almost all cases have occurred in women,
mainly 20 to 30 years old. The lesions are common on the shoulders, arms, neck, and chest.
Histologically, the lesions resemble steroid acne in that they show a focal follicular destruction with
neutrophilic infiltrate. Comedones are not part of the clinical or histologic picture. The pathogenesis
is unknown.
Acne Cosmetica
In the past, various cosmetic compounds were found to induce comedo formation when applied to
the external ear canal of rabbits, and cosmetics were considered to be a major cause of adult acne in
women. However, new guidelines for interpretation of assays using the rabbit ear model for
comedogenesis are now available 77 and cosmetic companies are testing their compounds
adequately for comedogenicity before marketing. Consequently, with the exception of very greasy,
occlusive products, cosmetics are infrequent etiologic agents for acne.
Pomade Acne
This form of acne is seen most often in black men and women. Some of the pomade that is applied
to the scalp is also applied to the forehead and is responsible for the development of multiple,
closely packed comedones close to the hairline. If the pomade is spread over greater areas of the
face, the lesions themselves may be more extensive and may appear on areas such as the cheek.
Pomades are comedogenic in the rabbit ear canal model.
Acne Mechanica
Acneiform eruptions have been observed after repetitive physical trauma to the skin such as
rubbing. This can occur from clothing (belts and straps) or sports equipment (football helmets and
shoulder pads). It has been induced by occluding the skin with adhesive tape. These extrinsic
factors probably produce flares of preexisting acne, and it is uncertain whether they can produce
acne in otherwise uninvolved skin. Probably the most common location to see this form of acne is
on the forehead and the chin area in those wearing football helmets.
Acne with Facial Edema
Acne may uncommonly be associated with a peculiar inflammatory edema of the mid-third of the
face. The edema is unresponsive to high-dose oral antibiotics, but sometimes responds to oral
glucocorticoids, often in combination with isotretinoin. However, recurrences are common when
glucocorticoids are stopped.
Acne Conglobata
This is a highly inflammatory disease with comedones, nodules, abscesses, and draining sinus
tracts. Healing occurs with severe scarring, which is often keloidal in nature. This type of acne is
rare and usually starts in adult life.
EPIDEMIOLOGY Males predominate, but a few cases have been reported in females. There may
be an antecedent history of acne vulgaris, but this is not invariable.
ETIOLOGY AND PATHOGENESIS Acne conglobata is generally considered to be a separate
entity from acne vulgaris because of its occurrence at a later age and its chronic unremitting course.
Its true pathogenesis is unknown, but because of the frequent recovery of coagulase-positive
staphylococci, and sometimes ß-hemolytic streptococci, it is often considered to be a true
pyoderma.
CLINICAL MANIFESTATIONS The patients with acne conglobata have a mixture of comedones,
papules, pustules, nodules, abscesses, and scars on the back, buttocks, chest, and, to a lesser extent,
on the abdomen, shoulders, neck, face, upper arms, and thighs. The comedones often have multiple
openings. The inflammatory lesions are large, tender, and dusky-colored. The draining lesions
discharge a foul-smelling serous, purulent, or mucoid material. Subcutaneous dissection with the
formation of multichanneled sinus tracts is common. Healing results in an admixture of depressed
and keloidal scars.
LABORATORY FINDINGS Although some lesions may be sterile or show only the presence of
resident coagulase-negative staphylococci and anaerobic diphtheroids, is common to isolate
coagulase-positive staphylococci. Occasionally, ß-hemolytic streptococci are found. The presence
of a chronic infection may be reflected by the presence of a normochromic, normocytic anemia, an
elevated white blood count with an increased percentage of polymorphonuclear leukocytes, and an
increased sedimentation rate. There is no evidence that these patients have decreased ?-globulins; in
fact, ?-globulins may be elevated. The fasting blood sugar and glucose tolerance tests are normal.
PATHOLOGY This disease is highly inflammatory, resulting in the destruction of the normal
architecture of the appendageal structures. Where follicles can be identified, there is a dense
perifollicular inflammatory infiltrate of lymphocytes, polymorphonuclear leukocytes, and plasma
cells. Abscess formation is common. Many proliferating tongues of epithelial cells permeate the
inflammatory masses, leading eventually to the formation of interconnecting sinus tracts.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The highly inflammatory nature of the lesions,
their distribution on the trunk, and the usual age of onset are aids in establishing the diagnosis and
differentiating this disease from cystic acne vulgaris. Acne conglobata may also be confused with
tropical acne, acne fulminans, and chloracne. Because lesions may occur in the axillary and inguinal
regions, the disease may resemble hidradenitis suppurativa. In fact, acne conglobata, hidradenitis
suppurativa, and perifolliculitis capitis abscedens et suffodiens of the scalp are often seen in the
same patient.
TREATMENT The management of these patients is very difficult and the effect of treatment is
often temporary. Several medications have been used including intensive high-dose therapy with
antibiotics governed by in vitro antibiotic sensitivity studies, intralesional glucocorticoids, systemic
glucocorticoids, x-ray therapy, surgical debridement, surgical incision, and surgical excision. The
use of isotretinoin has produced dramatic results in some of these patients. In severe cases, dosages
as high as 2 mg/kg per day for a 20-week course may be necessary. However, because severe flares
may occur when isotretinoin is started, the initial dose should be 0.5 mg/kg per day or less, and
systemic glucocorticoids are often required either before initiating isotretinoin therapy or as
concomitant therapy.
COURSE AND PROGNOSIS This disease tends to run a recalcitrant, chronic course, and patients
often have emotional disturbances. However, the prognosis is much better now as isotretinoin can
be used to control the active disease, although in many instances significant scarring may remain.
Slow-growing, well-differentiated squamous cell carcinoma has been reported in the lesions of acne
conglobata. 78 To date, no metastases have been reported. Spondyloarthropathy has also been
reported. 79
Acne Fulminans
This catastrophic disease has also been called acute febrile ulcerative acne. It is characterized by the
sudden appearance of massive, inflammatory, tender lesions of the back and chest that rapidly
become ulcerative and heal with scarring. The disease is reported to occur exclusively in teenage
boys. The face is often not involved. The patients are febrile, have a leukocytosis of 10,000 to
30,000/mm 3 white blood cells, and usually have polyarthralgia, myalgia, and other systemic
symptoms. X-ray examination may disclose the presence of osteolytic areas in parts of bone
tenderness. Although this disease is often classified with acne conglobata, there are basic
differences. The onset of acne fulminans is more explosive; nodules and polyporous comedones are
less common; the face is not involved as frequently and the neck is usually spared; ulcerative and
crusted lesions are unique; and systemic symptoms are more common. Systemic glucocorticoid
therapy, along with intensive use of oral antibiotics and intralesional glucocorticoids, is the
treatment regimen required for these patients. Isotretinoin is also of benefit in these patients, but in
order to prevent explosive flares, systemic glucocorticoids must be started before isotretinoin and
continued during the first few weeks of isotretinoin therapy. The initial dosing of isotretinoin must
also be small. The daily dose of glucocorticoids should be slowly decreased as tolerated.
Steatocystoma Multiplex
This is a disorder characterized by multiple, varying sized, cystic lesions of the trunk.
EPIDEMIOLOGY Both men and women may be affected. The disease starts in early adult life. It is
familial and has been said to be inherited as a dominant characteristic.
ETIOLOGY AND PATHOGENESIS The exact pathogenesis of these lesions is unknown. It has
been proposed that this is a cystic sebaceous nevus, and it has also been proposed that the lesions
are a result of blockage of the follicular orifice. Relationship to the development of the sebaceous
glands is indicated by their location in the midline and the appearance of the lesions at puberty.
CLINICAL MANIFESTATIONS The cutaneous lesions appear chiefly on the upper anterior trunk.
They may also be found on the back, arms, forearms, thighs, and scrotum. The individual lesions
vary from 1 to 2 mm up to 1 to 2 cm in diameter. They may be flesh-colored or distinctly yellow.
The lesions are soft and freely movable. The contents may be either a clear oily liquid or a cheesy
white material. There are no systemic manifestations. No laboratory abnormalities have been
reported.
PATHOLOGY Serial sections will disclose the presence of a follicular duct that is filled with
keratinous material. The cysts are filled with keratin and lipid. Usually, however, there is much less
keratin than is found in keratinous cysts. The follicular wall is atrophic, but appendageal remnants
may be visible. Some of the cells of the cyst walls may show lipid differentiation. Lanugo hairs may
be seen. The surrounding dermis is compressed by the expanding lesions.
DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS The appearance of the multiple cystic lesions,
varying in size, particularly on the anterior chest, is essential for diagnosis. Any confusion with
solid epithelial tumors or infiltrates into the skin can be eliminated by incising one of the lesions.
TREATMENT None is indicated, but the lesions can be drained by incision or aspiration. They may
be excised, although the number of lesions usually precludes any significant overall improvement.
COURSE AND PROGNOSIS The number of lesions, as well as their size, may increase slowly.
Except for the cosmetic appearance, this disease poses no threat to the person's health. Malignant
degeneration has not been reported.