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.
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]
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.
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.
Prognosis
In patients with erythema nodosum, the prognosis is excellent. In most patients, erythema nodosum resolves without any adverse reactions.
Patient Education
Instruct patients that the restriction of physical activities may help shorten the course of erythema nodosum.
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Classic presentation of erythema nodosum with nodular red swellings over the shins.
