Erythema Nodosum: A Practical Approach and Diagnostic Algorithm

Daniela Michelle Pérez-Garza; Sonia Chavez-Alvarez; Jorge Ocampo-Candiani; Minerva Gomez-Flores


Am J Clin Dermatol. 2021;22(3):367-378. 

In This Article


The etiology varies according to the affected population, the geographical area, and the seasonal period, although according to the literature 32–72% of EN cases remain with an unknown etiology.[4,19,22] Erythema nodosum may be the first sign of a systemic disease, triggered by a large group of processes, such as infections, inflammation, neoplasias, and/or drugs (Table 1). The most common identifiable causes are streptococcal infections, primary TB, sarcoidosis, Behçet disease, drugs, pregnancy, and inflammatory bowel disease.[19]

Behçet Disease

Patients diagnosed with Behçet disease present with EN lesions in about 44% of the cases, with EN being the initial manifestation of the disease in up to 5.7% of the cases.[23] Several diagnostic criteria have been proposed for Behçet disease, and in the International Study Group International Criteria for Behçet's Disease, EN is included as a criterion.[24] Based on the histopathology, two forms of presentation are found: (1) the EN type with the typical septal panniculitis pattern in 27% of these cases and with a possible association with mild symptoms and (2) an EN-like with a lobular-mixed panniculitis pattern and vasculitis, representing 73% of cases, with an apparent association with severe disease.[25]

Inflammatory Bowel Disease

Inflammatory bowel disease (IBD) can present as ulcerative colitis or as Crohn's disease. In addition to the gastrointestinal symptoms, up to 40% of these patients can have a variety of extraintestinal manifestations.[26] Erythema nodosum occurs in 4–15% of patients with Crohn's disease and in 3–10% of patients with ulcerative colitis,[27,28] with a female predilection.[29,30]


In sarcoidosis, the most common skin lesion is EN.[31] Löfgren syndrome, an acute presentation of sarcoidosis, is characterized by EN, bilateral hilar lymphadenopathy, and fever. In conjunction with the EN lesions, patients can have periarticular ankle inflammation and papular lesions on the knees and elbows.[17] Diagnosis of sarcoidosis is usually made when clinical and radiological data are confirmed by a tissue biopsy (noncaseating granulomas).[32]


Erythema nodosum can present as a reactive cutaneous manifestation of infections, such as bacterial, viral, fungal, and protozoal.

Streptococcal Infection. After a pharyngeal streptococcal infection, skin lesions appear in about 2–3 weeks.[10] A throat culture, a rapid antigen Streptococcus test, or antistreptolysin O titers should be ordered when this etiology is suspected.[33] The antibody response is first seen during the second or third week of the acute episode and usually peaks in 4–5 weeks. Pharyngeal culture is still the gold standard for documenting the presence of group A β-hemolytic Streptococcus in these patients. Leukocytosis with neutrophilia and mild normochromic anemia can also occur.[34]

Tuberculosis. In some developing countries in which the prevalence of TB is high, Mycobacterium tuberculosis infection is a contributing etiologic factor in EN development. A Chinese study reported a positive polymerase chain reaction analysis and interferon-γ-release assay in 30.4% and 59.4% of patients with EN, respectively.[35] Furthermore, another study suggests that EN among patients with M. tuberculosis infection is common, and EN appears to be a strong predictor or an early symptom of TB. Almost 50% of individuals with EN were diagnosed with TB within 1 month of their EN diagnoses, thus patients should be examined carefully and followed closely.[36] Chest radiography, sputum acid-fast bacilli smear, mycobacterial culture, and nucleic acid amplification testing should be obtained to rule out pulmonary TB. Additionally a tuberculin skin test or interferon-γ release assay should be performed.[37] These studies are mandatory in endemic regions. Furthermore, infection with an atypical mycobacteria species has been associated with EN.[10]

Other Infections. Among other leading bacterial infections are Salmonella enteritidis, Salmonella typhimurium, Campylobacter jejuni, Yersenia enterocolitica, Mycoplasma, and Bartonella.[38,39] Fungal infections, such as coccidioidomycosis[40] blastomycosis,[41] and histoplasmosis,[42] have been implicated in EN development. Patients' geographical locations and history of travel to these mycosis-endemic regions can provide diagnostic clues. An association between Coronavirus Disease 2019 and EN has been recently reported.[43,44] Other infections that can develop EN are summarized in Table 1.

Drugs and Vaccines

Drugs are another frequent etiologic factor of EN and have been identified as the cause of EN in 2.9–5% of patients.[4,19,45] Sulfonamides, bromides, and oral contraceptives are the most commonly associated medications.[10] Some vaccines, such as tetanus, diphtheria, and acellular pertussis, BCG, hepatitis B, human papillomavirus, malaria, rabies, smallpox, typhoid, and cholera have been associated with subsequent development of EN.[46] All patients should be carefully questioned about recent medications or vaccines.

A role for different hormones in the development of EN has been described. Pregnancy represents the etiologic cause in 2–6% of patients.[6,19,45] Oral contraceptive pills and aromatase inhibitors are associated with EN development.[47,48]


An underlying malignancy can be responsible for EN symptoms in patients with unexplained EN and constitutional symptoms. Hematologic malignancies (leukemia and lymphoma) are most frequently associated with EN lesions,[49–52] and more rarely, solid neoplasms (lung, colon, cervix, hepatic, pancreatic, parathyroid, and carcinoid tumors) have been implicated.[53–59] In some cases, EN lesions indicate disease relapse.[60] Radiation can precipitate EN, this must be taken into account in patients undergoing this treatment.[61–63] Patients with recurrent EN or poor response to conventional treatments should be investigated for an underlying malignancy.