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