Professional Documents
Culture Documents
114
Etiology
Erythema nodosum may be associated with a wide variety of
disease processes, and its observation must always be followed by a search for underlying etiology. A review of the
literature reveals that the list of etiologic factors that can lead
to erythema nodosum is long and varied, including infections, drugs, malignant diseases, and a wide group of miscellaneous conditions (Table 1).1-104 Although there are considerable geographic variations related to endemic infections, in
our country streptococcal infections are the most frequent
Erythema nodosum
Table 1 Etiologic Factors in Erythema Nodosum
Infections
Bacterial infections
Atypical mycobacterial infections2
Borrelia burgdorferi infections3
Boutonneuse fever4
Brucellosis5
Campylobacter infections6
Cat-scratch disease7
Chancroid2
Chlamydia psittaci infections8
Corynebacterium diphteriae infections2
Escherichia coli infections104
Gonorrhea9
Klebsiella pneumoniae infections10
Leptospirosis11
Lymphogranuloma venereum12
Meningococcemia13
Moraxella catarrhalis infections14
Mycoplasma pneumoniae infections15
Pasteurella pseudotuberculosis infections16
Propionibacterium acnes17
Pseudomona aeruginosa infections18
Q fever19
Salmonella infections20
Shigella infections21
Streptococcal infections22
Syphilis23
Tuberculosis24
Tularemia25
Yersinia infections26
Viral infections
Cytomegalovirus infections27
Hepatitis B28
Hepatitis C29
Herpes simplex2
HIV infection30
Infectious mononucleosis31
Measles32
Milkers nodules33
Parvovirus B19 infections34
Varicella35
Fungal infections
Aspergillosis36
Blastomycosis37
Coccidioidomycosis38
Dermatophytes39
Histoplasmosis40
Protozoal infections
Amebiasis41
Ascariasis42
Giardiasis41
Hydatidosis43
Hookworm infestation2
Sparganum larva44
Toxoplasmosis45
Trichomoniasis46
Drugs
Acetaminophen47
Actinomycin-D48
All-trans retinoic acid48
Aminopyrine2
115
Table 1 Continued
Amiodarone47
Amoxicillin104
Ampicillin104
Antimony2
Arsphenamine9
Azathioprine47
Bromides49
Busulfan47
Carbamazepine47
Carbenicillin50
Carbimazole47
Cefdinir47
Chlordiazepoxide47
Chlorotrianisene47
Chlorpropamide47
Ciprofloxacin47
Clomiphene47
Codeine47
Cotrimoxazole47
D-penicillamine51
Dapsone47
Diclofenac47
Dicloxacillin47
Diethylstilbestrol52
Disopyramide47
Echinacea herbal therapy52
Enoxacin47
Erythromycin104
Estrogens47
Fluoxetine47
Furosemide47
Glucagon47
Gold salts53
Granulocyte colony-stimulating factor47
Hepatitis B vaccine54
Hydralazine47
Ibuprofen47
Indomethacin47
Interleukin-255
Iodides49
Isotretinoin56
Leukotriene modifying agents (zileuton and
rafirlukast)57
Levofloxacin47
Meclofenamate47
Medroxyprogesterone47
Meprobamate47
Mesalamine47
Methicillin47
Methimazole47
Methyldopa47
Mezlozillin47
Minocycline58
Naproxen47
Nifedipine47
Nitrofurantoin2
Ofloxacin47
Omeprazole59
Oral contraceptives60
Oxacillin47
Paroxetine47
116
Table 1 Continued
Penicillin54
Phenylbutazone36
Phenytoin33
Piperacillin47
Progestins47
Propylthiouracil61
Pyritinol9
Sparfloxacin47
Streptomycin47
Sulfamethoxazole47
Sulfixoxazole47
Sulfonamides62
Sulfosalazine47
Thalidomide63
Ticarcilin47
Trimethoprim64
Typhoid vaccination65
Verapamil47
Malignant diseases
Adenocarcinoma of the colon66
Carcinoid tumor67
Carcinoma of the uterine cervix68
Hepatocellular carcinoma69
Hodgkins disease70
Leukemia71
Lung cancer72
Non-Hodgkins lymphoma73
Pancreatic carcinoma74
Post-radiotherapy for pelvic carcinoma1
Renal carcinoma55
Sarcoma9
Stomach cancer104
Miscellaneous conditions
Acne fulminans75
Acupunture therapy and flu-like infection76
Adult Stills disease77
Ankylosing spondylitis78
Antiphospolipid antibodies syndrome79
Behets syndrome80
Bergers disease81
Breast abscesses82
Chronic active hepatitis83
Coeliac disease84
Colon diverticulosis9
Crohns disease85
Diverticulitis86
Granulomatous mastitis87
IgA nephropathy88
Jellyfish sting89
Lupus erythematosus90
Pregnancy91
Radiotherapy92
Recurrent polychondritis93
Reiters syndrome94
Rheumatoid arthritis95
Sarcoidosis96
Sjgrens syndrome97
Smoke inhalation in a house fire98
Sweets syndrome99
Systemic lupus erythematosus-like syndrome due to
C4 deficiency100
Table 1 Continued
Takayasus arteritis101
Ulcerative colitis102
Vogt-Koyanagi disease97
Wegeners granulomatosis103
Erythema nodosum
Many patients with Behet disease develop lesions that
clinically resemble those of erythema nodosum.81 Histopathologic studies, however, have demonstrated that a significant proportion of these patients with Behet syndrome
and erythema nodosum-like lesions showed a mostly lobular
panniculitis with the frequent finding of leukocytoclastic or
lymphocytic vasculitis110,111 and therefore some patients with
Behet disease show a panniculitis different from that of erythema nodosum.
The simultaneous occurrence of Sweets syndrome and
erythema nodosum have been considered a rare association.112-117 In these patients, the concomitant development of
Sweets syndrome and erythema nodosum is associated with
sarcoidosis,113 upper respiratory tract infection,113,114 acute
myelogenous leukemia,115,116 and Crohns disease.116 However, recently Ginarte and Toribio117 commented that the
association between Sweets syndrome and erythema nodosum is not as rare as the review of the literature seems to
indicate, because 15% to 30% of patients of several series of
Sweets syndrome showed biopsy-proved erythema nodosum.118-122 On the basis of these data, Ginarte and Toribio
concluded that the simultaneous occurrence of these 2 reactive processes is a frequent feature that may be caused by a
common underlying mechanism of pathogenesis (streptococcal upper respiratory tract infection or inflammatory
bowel disease) and they respond to the same treatment (corticosteroids, potassium iodide), also supporting a close relationship between them.117 The same opinion has been recently supported by other authors.123
Despite thorough clinical and laboratory investigations,
the etiology of erythema nodosum remained uncertain in a
significant percentage of the cases that ranged from 37% to
60% of the cases in all reported series.36,104,106,124-127
Pathogenesis
Erythema nodosum is considered to be a hypersensitivity
response to a wide variety of inciting factors. The variability
of possible antigenic stimuli that can induce erythema nodosum indicates that this disorder is a cutaneous reactive process and that the skin has limited responses to different provoking agents. Erythema nodosum probably results from the
formation of immune complexes and their deposition in and
around venules of the connective tissue septa of the subcutaneous fat. Circulating immunocomplexes128 and complement activation129,130 have been recorded in patients with
erythema nodosum. Histopathologic features in fully developed lesions also suggest a delayed hypersensitivity mechanism131 and direct immunofluorescence studies have shown
deposits of immunoglobulins in the blood vessels walls of the
septa of subcutaneous fat.132 However, other authors failed to
demonstrate circulating immunocomplexes in patients with
erythema nodosum,133 and a type IV delayed hypersensitivity
reaction may also play an important role in the pathogenesis
of the disorder.
Early lesions of erythema nodosum are histopathologically
characterized by a neutrophilic inflammatory infiltrate involving the septa of the subcutaneous tissue. Recent investi-
117
gations have demonstrated that patients suffering from erythema nodosum had a fourfold higher percentage of reactive
oxygen intermediates (ROIs) produced by activated neutrophils in their peripheral blood compared with healthy volunteers. Furthermore, the percentage of ROI-producing cells in
patients with erythema nodosum correlated with the clinical
severity. These data support the fact that ROI might play a
role in the pathogenesis of erythema nodosum. ROI might
exert their effects by oxidative tissue damage and by promoting tissue inflammation.134
Patients with erythema nodosum associated with sarcoidosis produce an uncommon tumor necrosis factor (TNF)-II.
These patients showed a nucleotide exchange, (G-A) at position 308 in the human TNF- gene promoter, whereas patients with erythema nodosum without underlying sarcoidosis displayed a similar allele frequency compared with
controls. These results support the notion that erythema nodosum in association with sarcoidosis might be pathogenetically linked to altered TNF-alpha production due to a genetic
promoter polymorphism.135 In contrast, other authors have
found that the proinflammatory cytokine pattern showed increased interleukin-6 serum concentrations both in infectious and non infectious disease-related erythema nodosum,
whereas a minor involvement of TNF was found in these
patients.100
The reason why the anterior aspects of the legs are so
susceptible for the development of lesions of erythema nodosum is unknown. Some authors have proposed that there is
no other site in the skin surface where the combination of a
relatively sparse arterial supply is associated with a venous
system subject to gravitational effects and cooling and a lymphatic system which is hardly rich enough to meet the requirements of any increase in fluid load and which has no
mechanical stimulus. The skin of the shins has no underlying
muscle pump and receives little in the way of massage. All
these local anatomic factors would favor the location of the
lesions of erythema nodosum on the shins.1
Clinical Features
Erythema nodosum can occur at any age, but most cases
appear between the second and fourth decades of the life,
with the peak of incidence being between 20 and 30 years of
age, probably attributable to the high incidence of sarcoidosis
at this age.136 Several studies have demonstrated that erythema nodosum occurs 3 to 6 times more frequently in
women than in men,137 although the sex incidence before
puberty is approximately equal.124 Racial and geographic differences of incidence vary depending on the prevalence of
diseases that are etiologic factors. Prevalence of erythema
nodosum in a semirural area of England during a 2-year
period gave a figure of 2.4 per 1000 population per year.138
Prevalence varies also according to the type of the patients
attended to in a clinic: the average hospital incidence was
approximately 0.5% of new cases seen in Departments of
Dermatology in England1 and approximately 0.38% of all
patients seen in a Department of Internal Medicine in
Spain.139 In a recent study, the average annual incidence rate
118
of biopsy-proven erythema nodosum in a hospital of the
northwestern Spain for the population 14 years and older
was 52 cases per million of persons,104 although certainly this
rate underestimated the authentic incidence of the disease
because only included cases confirmed by biopsy. Most cases
of erythema nodosum occur within the first half of the
year,104 probably because of the more frequent incidence of
streptococcal infections in this period of the year, and there is
no difference in distribution between urban and rural areas.1
Familial cases are usually due to an infectious etiology.
The typical eruption is quite characteristic and consists of
a sudden onset of symmetrical, tender, erythematous, warm
nodules and raised plaques usually located on the shins, ankles and knees. The nodules, which range from 1 to 5 cm or
more in diameter, are usually bilaterally distributed (Fig. 1).
Nodules may become confluent resulting in erythematous
plaques. In rare instances, more extensive lesions may appear, involving the thighs, extensor aspects of the arms, neck,
and even the face. At first, the nodules show a bright red color
and are raised slightly above the skin. Within a few days, they
become flat, with a livid red or purplish color. Finally, they
exhibit a yellow or greenish appearance often taking on the
look of a deep bruise (erythema contusiformis). This contusiform color evolution is quite characteristic of erythema
nodosum and allows a specific diagnosis in late stage lesions.
Laboratory Anomalies
Because the list of possible etiologic factors in erythema nodosum is extensive, a rational, cost-effective diagnostic approach in patients with erythema nodosum is desirable. A
complete clinical history should be elicited in all patients,
with reference of previous diseases, medications, foreign
travel, pets and hobbies, as well as familial cases.
Initial evaluation should include complete blood count,
determination of the sedimentation rate, ASO titer, urinalysis, throat culture, intradermal tuberculin test and chest
roentgenogram. The white blood count is normal or only
slightly increased, but the erythrocyte sedimentation rate is
often very high, returning to normal when the eruption fades.
In children, the elevation of the erythrocyte sedimentation
rate correlates significantly with the number of cutaneous
lesions.142 The rheumatoid factor is usually negative, and
there is a temporary increase in the 2-globulin. A high antistreptolysin titer is seen in those cases of erythema nodosum
associated with a sore throat streptococcal infection. Usually,
a significant change, at least 30%, in ASO titer in two con-
Erythema nodosum
119
Histopathology
Histopathologically, erythema nodosum is the stereotypical
example of a mostly septal panniculitis with no vasculitis.
The septa of subcutaneous fat are always thickened and infiltrated by inflammatory cells that extend to the periseptal
areas of the fat lobules. Usually, a superficial and deep
perivascular inflammatory infiltrate predominantly composed of lymphocytes is also seen in the overlying dermis.
The composition of the inflammatory infiltrate in the septa
varies with age of the lesion. In early lesions, edema, hemorrhage, and neutrophils (Fig. 2) are responsible for the septal
thickening,126 whereas fibrosis, periseptal granulation tissue,
lymphocytes, histiocytes (Fig. 3) and multinucleated giant
cells (Fig. 4) are the main findings in late stage lesions of
erythema nodosum. In rare instances eosinophils are the predominant inflammatory cells in early lesions of erythema
nodosum.154 Sometimes, in these early lesions, the inflammatory cell infiltrate may be more apparent in the fat lobules
than in the septa, because inflammatory cells extend into the
periphery of the fat lobules between individual fat cells in a
lace-like fashion, and the process appears as a predominantly
lobular panniculitis. However, in contrast with authentic lobular panniculitis, necrosis of the adipocytes at the center of
the fat lobule is not seen. A histopathologic hallmark of erythema nodosum is the presence of the so-called Mieschers
radial granulomas,155-157 that consist of small, well-defined
nodular aggregations of small histiocytes around a central
stellate or banana shaped cleft (Fig. 3). The nature of the
central cleft is unknown and, although some authors have
considered them as lymphatic spaces,1 our immunohistochemical and ultrastructural studies of cases of Mieschers
radial granulomas have failed to demonstrate endothelial or
other cellular lining of these clefts.
In early lesions, Mieschers radial granulomas appear scattered in the septa and surrounded by neutrophils. In older
nodules of erythema nodosum, histiocytes coalesce to form
multinucleated giant cells, many of which still keep in their
cytoplasm a stellate central cleft reminiscent of those centers
of Mieschers radial granuloma. Sometimes Mieschers radial
granulomas are conspicuous in the septa, but occasionally
serial sections may be necessary to identify them. In our
experience, these Mieschers radial granulomas are present in
all stages of the evolution of erythema nodosum lesions and
they should be searched for to make a specific diagnosis.157
However, other authors consider that similar granulomas
may be present in lesions of Sweets syndrome, erythema
induratum of Bazin, Behet disease, and necrobiosis lipoidica.149 Recent immunohistochemical studies have demonstrated that the central cleft of Mieschers radial granulomas express myeloperoxidase, which suggest that myeloid
cells were present in some stage of the Mieschers radial granuloma formation.158 Myeloperoxidase immunoexpression
has been also described in the small, elongated, twisted ap-
120
Figure 3 Histopathologic features of a fully developed lesion of erythema nodosum. (A) Scanning power showing thickened septa of the
subcutaneous tissue with inflammatory infiltrate. (B) Higher magnification shows that the inflammatory infiltrate of the septa extends to
the periphery of the adjacent fat lobules. (C) Higher magnification
shows the characteristic features of Mieschers radial granuloma: Aggregations of small histiocytes around a central cleft.
Erythema nodosum
121
Prognosis
Most cases of erythema nodosum regress spontaneously in 3
to 4 weeks. More severe cases need about 6 weeks. Relapses
are not exceptional, and they are more common in patients
with idiopathic erythema nodosum and erythema nodosum
associated with nonstreptococcal or streptococcal upper respiratory tract infections. Complications are uncommon. A
patient developed retrobulbar optic nerve neuritis during the
acute episode of erythema nodosum,166 and another patient
with chronic hepatitis C had erythema nodosum with concomitant erythema multiforme and lichen planus that coincided with the reactivation of viral replication.167
Treatment
Treatment of erythema nodosum should be directed to the
underlying associated condition, if identified. Usually, nodules of erythema nodosum regress spontaneously within a
122
Systemic corticosteroids are rarely indicated in erythema
nodosum and before these drugs are administered an underlying infection should be ruled out. When administered,
prednisone in a dosage of 40 mg per day has been followed by
resolution of the nodules in few days. Intralesional injection
of triamcinolone acetonide, in a dosage of 5 mg/mL, into the
center of the nodules may cause them to resolve. Some patients may respond to a course of colchicine, 0.6 to 1.2 mg
twice a day,177,178 and hydroxychloroquine 200 mg twice a
day has been also reported to be useful in a recent report.179
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