AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

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Background

Erythema nodosum (EN) is an acute, nodular, erythematous eruption that usually is limited to the extensor aspects of the lower legs. Chronic or recurrent EN is rare but may occur. EN is presumed to be a hypersensitivity reaction and may occur in association with several systemic diseases or drug therapies, or it may be idiopathic. The inflammatory reaction occurs in the panniculus.

Pathophysiology

EN probably is a delayed hypersensitivity reaction to a variety of antigens; circulating immune complexes have not been found in idiopathic or uncomplicated cases but may be demonstrated in patients with inflammatory bowel disease.

Frequency

United States

Peak incidence occurs at age 18-34 years. Age and sex distributions vary according to etiology and geographic location.

International

Rates of EN vary according to country. In England, the rate is 2.4 cases per 10,000 per year.

Mortality/Morbidity

In most patients, EN resolves without any adverse reactions.

Sex

Women are affected more often than men, with a male-to-female ratio of 1:4.

Age

EN may occur in children and in patients older than 70 years, but it is more common in young adults aged 18-34 years. Age distribution varies with geographic location and etiology.

CLINICAL

Section 3 of 11  

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• Differentials
• Workup
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• Follow-up
• Miscellaneous
• Multimedia
• References

History

• The eruptive phase of EN begins with flulike symptoms of fever and generalized aching.
• Arthralgia may occur and precedes the eruption or appears during the eruptive phase.
• Most lesions in infection-induced EN heal within 7 weeks, but active disease may last up to 18 weeks. In contrast, 30% of idiopathic EN cases may last more than 6 months.
• Febrile illness with dermatologic findings includes abrupt onset of illness with initial fever, followed by a painful rash within 1-2 days.

Physical

• Pertinent physical findings are limited to the skin and joints.
• Primary skin lesions: Lesions begin as red tender nodules (see Image 1). Lesion borders are poorly defined, and lesions vary from 2-6 cm. During the first week, lesions become tense, hard, and painful; during the second week, they may become fluctuant, as in an abscess, but do not suppurate or ulcerate. Individual lesions last approximately 2 weeks, but occasionally, new lesions continue to appear for 3-6 weeks. Aching legs and swelling ankles may persist for weeks.
• Distribution of skin lesions: Characteristically, lesions appear on the anterior leg; however, they may appear on any surface.
• Color of skin lesions: Lesions change color in the second week from bright red to bluish or livid. As absorption progresses, the color gradually fades to a yellowish hue, resembling a bruise. This disappears in 1 or 2 weeks as the overlying skin desquamates.
• Hilar lymph nodes: Hilar adenopathy may develop as part of the hypersensitivity reaction of EN. Bilateral hilar lymphadenopathy is associated with sarcoidosis, while unilateral changes may occur with infections and malignancy.
• Joints: Arthralgia occurs in more than 50% of patients and begins during the eruptive phase or precedes the eruption by 2-4 weeks. Erythema, swelling, and tenderness occur over the joint, sometimes with effusions. Joint tenderness and morning stiffness may occur. Any joint may be involved, but the ankles, knees, and wrist are affected most commonly. Synovitis resolves within a few weeks, but joint pain and stiffness may last up to 6 months. No destructive joint changes occur. Synovial fluid is acellular, and the rheumatoid factor is negative.

Causes

Currently, the most common cause of EN is streptococcal infection in children and streptococcal infection and sarcoidosis in adults. Numerous other causes have been reported. The causes reported most often in the literature are as follows:

• Bacterial infections
• • Streptococcal infections are one of the most common causes of EN.
  • Tuberculosis was an important cause in the past, but it has decreased dramatically as a cause for EN; however, it still must be excluded, especially in developing countries.
  • Yersinia enterocolitica is a gram-negative bacillus that causes acute diarrhea and abdominal pain; it is a common cause of EN in France and Finland.
  • Mycoplasma pneumoniae infection may cause EN.
  • EN leprosum clinically resembles EN, but the histologic picture is that of leukocytoclastic vasculitis.
  • Lymphogranuloma venereum may cause EN.
  • Salmonella infection may cause EN.
  • Campylobacter infection may cause EN.
• Fungal infections
• • Coccidioidomycosis (San Joaquin Valley fever) is the most common cause of EN in the American Southwest. In approximately 4% of males and 10% of females, the primary fungal infection (which may be asymptomatic or involve symptoms of upper respiratory infection) is followed by the development of EN. Lesions appear 3 days to 3 weeks after the end of the fever caused by the fungal infection.
  • Histoplasmosis may cause EN.
  • Blastomycosis may cause EN.
• Drugs: Sulfonamides and halide agents are an important cause of EN. Drugs more recently described to cause EN include gold and sulfonylureas. Oral contraceptive pills are implicated in an increasing number of reports.
• Enteropathies: Ulcerative colitis and Crohn disease may trigger EN. EN associated with enteropathies correlates with flares of the disease. The mean duration of chronic ulcerative colitis before the onset of EN is 5 years, and EN is controlled with adequate therapy of the colitis.
• Hodgkin disease and lymphoma: EN associated with non-Hodgkin lymphoma may precede the diagnosis of lymphoma by months. Reports of EN preceding the onset of acute myelogenous leukemia have been published.
• Sarcoidosis: The most common cutaneous manifestation of sarcoidosis is EN. A characteristic form of acute sarcoidosis involves the association of EN, hilar lymphadenopathy, fever, arthritis, and uveitis, which has been termed Lofgren syndrome. This presentation has a good prognosis with complete resolution within several months in most patients.
• Behçet disease (associated with EN)
• Pregnancy: Some patients develop EN during pregnancy, most frequently during the second trimester. Repeated episodes occur with subsequent pregnancies or with the use of oral contraceptives.

DIFFERENTIALS

Section 4 of 11  

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Other Problems to be Considered

Familial Mediterranean fever
Superficial migratory thrombophlebitis
Thrombophlebitis

WORKUP

Section 5 of 11  

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Lab Studies

• Perform throat culture as part of the initial workup to exclude group A beta-hemolytic streptococcal infection.
• Perform erythrocyte sedimentation rates often as part of the initial workup. The rate often is very high.
• Antistreptolysin titer is elevated in some patients with streptococcal disease, but normal values do not exclude streptococcal infection. Evaluate titer levels during the initial workup, since streptococcal disease is a common cause of EN.
• Order stool examination, since along with the appropriate history of gastrointestinal complaints, a stool examination can exclude infection by Yersinia, Salmonella, and Campylobacter organisms.
• Order blood cultures according to preliminary indications and findings.

Imaging Studies

• Order chest radiographs as part of the initial workup to exclude sarcoidosis and tuberculosis and to document hilar adenopathy.

Other Tests

• Intradermal skin tests can be used to exclude tuberculosis and coccidioidomycosis.

Procedures

• Since a clinical diagnosis of EN often can be made, biopsy is reserved for diagnostically difficult cases. Punch biopsies usually are not adequate. Deep skin incisional biopsies are required to sample the subcutaneous tissue adequately. Findings are localized to the subcutaneous tissue.

Histologic Findings

The classic features of EN on histopathology include a septal panniculitis with slight superficial and deep perivascular inflammatory lymphocytic infiltrate. The septa of subcutaneous fat usually are thickened. As lesions evolve, periseptal fibrosis, giant cells, and granulation tissue appear. Miescher granulomas are a hallmark feature of EN. Small well-defined nodular aggregates of histiocytes around a central stellate cleft are scattered throughout the lesions. A lymphohistiocytic infiltrate is noted in the septum and in small and medium-sized vessels.

TREATMENT

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Medical Care

In most patients, EN is a self-limited disease and requires only symptomatic relief using nonsteroidal anti-inflammatory drugs (NSAIDs), cool wet compresses, elevation, and bed rest.

Consultations

• Dermatologist - For evaluation of the underlying cause of EN
• Internist - For evaluation of the underlying cause of EN

Activity

Patient mobility is restricted in the acute stages if pain and swelling are significant.

MEDICATION

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If the underlying disease or drug is identified, it should be eliminated. Since EN often regresses spontaneously, symptomatic relief using NSAIDs (eg, acetyl salicylic acid, ibuprofen, naproxen, indomethacin) usually is all that is required. Corticosteroids are effective but seldom necessary in self-limited disease. Recurrence of EN following discontinuation of treatment is common, and underlying infectious disease may be worsened. Potassium iodide may relieve lesional tenderness, arthralgia, and fever. Colchicine has been used in a few refractory cases with good results. Note that some of the medications used to treat EN have been implicated as rare causes of EN in individuals with hypersensitivity to the drugs.

Drug Category: Anti-inflammatory agents

Provide symptomatic relief for lesional tenderness, arthralgia, and fever.

Drug Category: Antithyroid agents

Relieve lesional tenderness, arthralgia, and fever. Relief may occur within 24 h. Most lesions completely subside within 10-14 d. Potassium iodide is not effective for all patients with EN. Patients who receive medication shortly after the initial onset of EN respond more satisfactorily than patients with chronic EN.

FOLLOW-UP

Section 8 of 11  

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Further Outpatient Care

• The course of EN is benign and self-limited. Bed rest and restriction of physical activities is encouraged during the active phase.

Deterrence/Prevention

• Restriction of physical activities while EN is active may prevent exacerbations of the disease.

Prognosis

• In patients with EN, the prognosis is excellent.

Patient Education

• Instruct patients that the restriction of physical activities may help shorten the course of EN.

MISCELLANEOUS

Section 9 of 11  

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Medical/Legal Pitfalls

• Failure to exclude significant underlying diseases or drugs that cause EN may result in morbidity and mortality associated with the causes

MULTIMEDIA

Section 10 of 11  

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• Multimedia
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Media file 1:  Classic presentation of erythema nodosum with nodular red swellings over the shins.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
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• Differentials
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• References

• Bottone EJ. Yersinia enterocolitica: the charisma continues. Clin Microbiol Rev. Apr 1997;10(2):257-76. [Medline].
• Hassink RI, Pasquinelli-Egli CE, Jacomella V, et al. Conditions currently associated with erythema nodosum in Swiss children. Eur J Pediatr. Nov 1997;156(11):851-3. [Medline].
• Kakourou T, Drosatou P, Psychou F, et al. Erythema nodosum in children: a prospective study. J Am Acad Dermatol. Jan 2001;44(1):17-21. [Medline].
• Labbe L, Perel Y, Maleville J, Taieb A. Erythema nodosum in children: a study of 27 patients. Pediatr Dermatol. Nov-Dec 1996;13(6):447-50. [Medline].
• Marshall JK, Irvine EJ. Successful therapy of refractory erythema nodosum associated with Crohn''s disease using potassium iodide. Can J Gastroenterol. Sep 1997;11(6):501-2. [Medline].
• Mert A, Ozaras R, Tabak F, Ozturk R. Primary tuberculosis cases presenting with erythema nodosum. J Dermatol. Jan 2004;31(1):66-8. [Medline].
• Mert A, Ozaras R, Tabak F, et al. Erythema nodosum: an experience of 10 years. Scand J Infect Dis. 2004;36(6-7):424-7. [Medline].
• Moraes AJ, Soares PM, Zapata AL, et al. Panniculitis in childhood and adolescence. Pediatr Int. Feb 2006;48(1):48-53. [Medline].
• Nguyen GC, Torres EA, Regueiro M, et al. Inflammatory bowel disease characteristics among African Americans, Hispanics, and non-Hispanic Whites: characterization of a large North American cohort. Am J Gastroenterol. May 2006;101(5):1012-23. [Medline].
• Puavilai S, Sakuntabhai A, Sriprachaya-Anunt S, et al. Etiology of erythema nodosum. J Med Assoc Thai. Feb 1995;78(2):72-5. [Medline].
• Requena L, Yus ES. Panniculitis. Part I. Mostly septal panniculitis. J Am Acad Dermatol. Aug 2001;45(2):163-83. [Medline].
• Stolk-Engelaar VM, Hoogkamp-Korstanje JA. Clinical presentation and diagnosis of gastrointestinal infections by Yersinia enterocolitica in 261 Dutch patients. Scand J Infect Dis. 1996;28(6):571-5. [Medline].
• Sullivan R, Clowers-Webb H, Davis MD. Erythema nodosum: a presenting sign of acute myelogenous leukemia. Cutis. Aug 2005;76(2):114-6. [Medline].
• Tseng S, Pak G, Washenik K, et al. Rediscovering thalidomide: a review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol. Dec 1996;35(6):969-79. [Medline].

Article Last Updated: Oct 19, 2006