Erythema Nodosum

Background

Erythema nodosum (EN) is an acute, nodular, erythematous eruption that usually is limited to the extensor aspects of the lower legs.^[1] 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.^[2] The inflammatory reaction occurs in the panniculus.^[3]

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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 (IBD).^[4]

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Etiology

Bacterial infections

Streptococcal infection is one of the most common causes of EN overall^[5]  and is the single most common cause in children.^[6] Although tuberculosis was once an important cause of EN, it is now a much less common cause; however, it still must be excluded, especially in developing countries.^{[7, 8, 9]}  Yersinia enterocolitica, a gram-negative bacillus that causes acute diarrhea and abdominal pain, is a common cause of EN in Finland.^[10]  Mycoplasma pneumoniae, Salmonella, or Campylobacter infection may cause EN. Erythema nodosum leprosum clinically resembles EN, but the histologic picture is that of leukocytoclastic vasculitis. Lymphogranuloma venereum 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 may involve symptoms of upper respiratory tract 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 and blastomycosis may cause EN.

Viral infections

A case report described EN occurring as a manifestation of infection with human T-lymphotropic virus (HTLV)-1.^[11]

Drugs

Sulfonamides and halide agents are important causes of EN. Gold and sulfonylureas have also been described as causing EN. Oral contraceptive pills have been implicated in a number of reports.^[12]  

Enteropathies

Ulcerative colitis and Crohn disease may trigger EN.^[13] 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 treatment of the colitis. EN is the most frequent dermatologic symptom in IBD, and it is strongly associated with Crohn disease.^{[14, 15]}

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.^{[16, 17]}

Sarcoidosis

Sarcoidosis and streptococcal infection are the most common causes of EN in adults.^[6] Approximately 10-22% of all EN cases are caused by sarcoidosis,^[18]  and EN is the most common cutaneous manifestation of sarcoidosis.^[19] A characteristic form of acute sarcoidosis involves the association of EN, hilar lymphadenopathy, fever, arthritis, and uveitis (ie, Löfgren syndrome^[20] ). This presentation has a good prognosis, with most cases resolving completely within several months. 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.^[21]

Behçet disease

This condition is 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.

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Epidemiology

In the United States, the peak incidence of EN is between the ages of 18 and 34 years, though it has been known to occur in children and in individuals older than 70 years. Age and sex distributions vary according to etiology and geographic location.^[22]  Women are affected more often than men, with a male-to-female ratio of approximately 1:5.^[1] Globally, the incidence of EN varies by country. In England, the rate has been reported as 2.4 cases per 10,000 per year.

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Prognosis

The prognosis for patients with EN is generally excellent. In most cases, the condition resolves without any adverse reactions. Patients should be advised that restricting their physical activities may help shorten the course of EN.

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History

The eruptive phase of erythema nodosum (EN) begins with flulike symptoms of fever and generalized aching. Arthralgia may occur, appearing either before the eruption or during the eruptive phase. With infection-induced EN, most lesions heal within 7 weeks, though active disease may last as long as 18 weeks. In contrast, 30% of idiopathic EN cases may last longer 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

Skin lesions

Lesions begin as red tender nodules (see the image below). Their borders are poorly defined, and the range in size from 2 to 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.

Characteristically, lesions appear on the anterior leg; however, they may appear on any surface. In the second week, they change color from bright red to bluish or livid. As absorption progresses, the color gradually fades to a yellowish hue, resembling a bruise. This disappears in 1-2 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, whereas unilateral changes may occur with infections and malignancy.

Joints

Arthralgia occurs in more than 50% of patients and, as noted, may begin either during the eruptive phase or 2-4 weeks before the eruption. 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. Although synovitis resolves within a few weeks, joint pain and stiffness may last as long as 6 months. No destructive joint changes occur. Synovial fluid is acellular, and rheumatoid factor is negative.

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Laboratory Studies

Throat culture should be performed as part of the initial workup for erythema nodosum (EN) to exclude group A beta-hemolytic streptococcal infection.

The erythrocyte sedimentation rate (ESR) is often evaluated as part of the initial workup. In many cases, the ESR is very high.

The antistreptolysin titer is elevated in some patients with streptococcal disease, but normal values do not exclude streptococcal infection. Given that streptococcal disease is a common cause of EN, evaluation of the antistrepsolysin titer during the initial workup is warranted.

A stool examination should be ordered; in conjunction with an appropriate history of gastrointestinal complaints, this examination can exclude infection by Yersinia, Salmonella, and Campylobacter organisms.

Blood cultures should be ordered according to preliminary indications and findings.

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Imaging Studies

Chest radiographs should be ordered 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 EN frequently can be made on clinical grounds alone, 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 EN on histopathology include a septal panniculitis with slight superficial and deep perivascular inflammatory lymphocytic infiltrate.^{[23, 24]} The septa of subcutaneous fat usually are thickened. Early-stage lesions demonstrate vascular damage in the septa with neutrophils and eosinophils, similar to that seen in leukocytoclastic vasculitis.^[25] 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.

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Medical Care

In most patients, erythema nodosum (EN) is a self-limited disease that requires only symptomatic relief in the form of analgesics, cool wet compresses, elevation, and bed rest. If an underlying disease or drug is identified as the cause of EN, it should be eliminated.

Given that EN often regresses spontaneously, relief of symptoms through administration of nonsteroidal anti-inflammatory drugs (NSAIDs; eg, acetylsalicylic acid, ibuprofen, naproxen, and indomethacin) may be the only treatment necessary. Corticosteroids are effective but are seldom necessary in self-limited disease. Potassium iodide has been used with the aim of alleviating lesional tenderness, arthralgia, and fever. However, a study that included nine patients with EN found that only five of the nine derived benefit from potassium iodide and theat the remaining four derived no benefit at all.^[26]  Colchicine has been used in a few refractory cases with good results.^[27]

It should be noted that some of the medications used to treat EN have themselves been implicated as rare causes of EN in individuals with hypersensitivity to the drugs.^[28]

Recurrence of EN following discontinuance of treatment is common, and underlying infectious disease may be worsened.

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Activity

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

Compression stockings may be beneficial for reducing swelling and allowing patients to maintain their normal activity level.^[29]

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Prevention

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

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Consultations

Consultations with a dermatologist, an internist, or both may be necessary for evaluation of the underlying cause of EN.

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Long-Term Monitoring

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

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Aspirin (Acetylsalicylic acid, ASA, Bayer Advanced Aspirin)

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Ibuprofen (Advil, Motrin, PediaCare Children's Pain Reliever/Fever Reducer IB)

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Indomethacin (Indocin, Indocin SR (DSC), Tivorbex (DSC))

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Naproxen (Aleve, Anaprox, Anaprox DS)

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Colchicine (Colcrys, Gloperba, Lodoco)

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Potassium iodide (Iosat, Pima Syrup, SSKI)

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