Erythema Nodosum

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 erythema nodosum is rare but may occur. Erythema nodosum 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.

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Pathophysiology

Erythema nodosum 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.^[1]

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Etiology

Currently, the most common cause of erythema nodosum is streptococcal infection in children and streptococcal infection and sarcoidosis in adults.^[2] Numerous other causes have been reported.^[3] The causes reported most often in the literature are described below.

Bacterial infections

Streptococcal infections are one of the most common causes of erythema nodosum.^[4] Tuberculosis was an important cause in the past, but it has decreased dramatically as a cause for erythema nodosum; however, it still must be excluded, especially in developing countries.^{[5, 6]} Yersinia enterocolitica is a gram-negative bacillus that causes acute diarrhea and abdominal pain; it is a common cause of erythema nodosum in France and Finland.^{[7, 8, 9]} Mycoplasma pneumoniae infection may cause erythema nodosum. Erythema nodosum leprosum clinically resembles erythema nodosum, but the histologic picture is that of leukocytoclastic vasculitis. Lymphogranuloma venereum may cause erythema nodosum. Salmonella infection may cause erythema nodosum. Campylobacter infection may cause erythema nodosum.

Fungal infections

Coccidioidomycosis (San Joaquin Valley fever) is the most common cause of erythema nodosum 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 erythema nodosum. Lesions appear 3 days to 3 weeks after the end of the fever caused by the fungal infection. Histoplasmosis may cause erythema nodosum. Blastomycosis may cause erythema nodosum.

Drugs

Sulfonamides and halide agents are an important cause of erythema nodosum. Drugs more recently described to cause erythema nodosum include gold and sulfonylureas. Oral contraceptive pills are implicated in an increasing number of reports.^[10]  

Enteropathies

Ulcerative colitis and Crohn disease may trigger erythema nodosum. Erythema nodosum associated with enteropathies correlates with flares of the disease. The mean duration of chronic ulcerative colitis before the onset of erythema nodosum is 5 years, and erythema nodosum is controlled with adequate therapy of the colitis. Erythema nodosum is the most frequent dermatologic symptom in inflammatory bowel diseases, and it is strongly associated with Crohn disease.^{[11, 12]}

Hodgkin disease and lymphoma

Erythema nodosum associated with non-Hodgkin lymphoma may precede the diagnosis of lymphoma by months. Reports of erythema nodosum preceding the onset of acute myelogenous leukemia have been published.^{[13, 14]}

Sarcoidosis

Approximately 10-22% of all erythema nodosum cases are caused by sarcoidosis.^[15]  The most common cutaneous manifestation of sarcoidosis is erythema nodosum.^[16] A characteristic form of acute sarcoidosis involves the association of erythema nodosum, hilar lymphadenopathy, fever, arthritis, and uveitis, which has been termed Löfgren syndrome. This presentation has a good prognosis, with complete resolution within several months in most patients. HLA-DRB1*03 is associated with Löfgren syndrome. Most DRB1*03-positive patients have resolution of their symptoms within 2 years; however, nearly half of DRB1*03-negative patients have an unremitting course.^[17]

Behçet disease

This condition is associated with erythema nodosum.

Pregnancy

Some patients develop erythema nodosum during pregnancy, most frequently during the second trimester. Repeated episodes occur with subsequent pregnancies or with the use of oral contraceptives.

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Epidemiology

Frequency

United States

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

International

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

Sex

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

Age

Erythema nodosum 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.

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Prognosis

In patients with erythema nodosum, the prognosis is excellent. In most patients, erythema nodosum resolves without any adverse reactions.

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Patient Education

Instruct patients that the restriction of physical activities may help shorten the course of erythema nodosum.

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History

The eruptive phase of erythema nodosum 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 erythema nodosum heal within 7 weeks, but active disease may last up to 18 weeks. In contrast, 30% of idiopathic erythema nodosum 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.

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Physical Examination

Pertinent physical findings are limited to the skin and joints.

Primary skin lesions

Lesions begin as red tender nodules (see the image below). 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.

View Image

Classic presentation of erythema nodosum with nodular red swellings over the shins.

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 erythema nodosum. 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.

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Laboratory 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 erythema nodosum.

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.

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Imaging Studies

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

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Other Tests

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

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Procedures

Because the diagnosis of erythema nodosum often is clinical, 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.

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Histologic Findings

The classic features of erythema nodosum on histopathology include a septal panniculitis with slight superficial and deep perivascular inflammatory lymphocytic infiltrate.^{[19, 20]} The septa of subcutaneous fat usually are thickened. Early-stage lesions demonstrate vascular damage in the septae with neutrophils and eosinophils similar to a leukocytoclastic vasculitis.^[21] As lesions evolve, periseptal fibrosis, giant cells, and granulation tissue appear. Miescher granulomas are a hallmark feature of erythema nodosum. 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.

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Medical Care

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

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Consultations

Consultations with a dermatologist and/or internist may be necessary for evaluation of the underlying cause of erythema nodosum.

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Activity

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

Compression stockings may be beneficial to decrease swelling and allow patients to maintain their normal activity level.^[22]

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Prevention

Restriction of physical activities while erythema nodosum is active may prevent exacerbations of the disease.

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Long-Term Monitoring

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

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Medication Summary

If the underlying disease or drug is identified, it should be eliminated. Since erythema nodosum 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 erythema nodosum following discontinuation of treatment is common, and underlying infectious disease may be worsened. Potassium iodide may relieve lesional tenderness, arthralgia, and fever.^[23] Colchicine has been used in a few refractory cases with good results. Note that some of the medications used to treat erythema nodosum have been implicated as rare causes of erythema nodosum in individuals with hypersensitivity to the drugs.^[24]

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Aspirin (Anacin, Ascriptin, Bayer Aspirin)

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Clinical Context:  Aspirin is a salicylate used for anti-inflammatory, analgesic, and antipyretic properties. It treats mild-to-moderate pain and headache. Aspirin inhibits prostaglandin synthesis, which prevents the formation of platelet-aggregating thromboxane A2. It acts on the heat-regulating center of the hypothalamus, and it vasodilates peripheral vessels to reduce fever. Enteric-coated and extended-release tablets are available.

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Naproxen (Naprelan, Naprosyn, Aleve, Anaprox)

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Clinical Context:  Naproxen has analgesic, anti-inflammatory, and antipyretic properties. It inhibits inflammatory reactions and pain by decreasing the activity of cyclooxygenase, which is responsible for prostaglandin synthesis.

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Indomethacin (Indocin, Indochron E-R)

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Clinical Context:  Indomethacin is rapidly absorbed; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation; it inhibits prostaglandin synthesis.

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Colchicine

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Clinical Context:  Colchicine reduces the formation of uric acid crystals in affected joints, thereby reducing the amount of acute inflammation and pain; it also decreases uric acid levels in the blood.

Colchicine can be used in combination with probenecid on a long-term basis to prevent gout or it can be used alone to treat the pain and inflammation of acute gout attacks. Discontinue usage when the pain of a gout attack begins to subside, when the maximum dose is reached, or when GI tract symptoms (eg, nausea, vomiting, diarrhea) indicate cellular poisoning.

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Class Summary

Anti-inflammatory agents provide symptomatic relief for lesional tenderness, arthralgia, and fever.

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Potassium iodide (Pima, SSKI)

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Clinical Context:  The mechanism of action for potassium iodide in erythema nodosum is unknown, but it is known to enhance response by potentiating neutrophil activity.

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Class Summary

Antithyroid agents relieve lesional tenderness, arthralgia, and fever. Relief may occur within 24 hours. Most lesions completely subside within 10-14 days. Potassium iodide is not effective for all patients with erythema nodosum. Patients who receive medication shortly after the initial onset of erythema nodosum respond more satisfactorily than patients with chronic erythema nodosum.

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