Etiology

A variety of immunologic triggers can result in erythema nodosum (EN). A patient’s geographic location and travel history are both key considerations.

Tuberculosis is the most common etiology in developing countries. Streptococcal infection, Behcet disease, systemic mycoses, drugs, and underlying malignancies, coccidioidomycosis, and medications are potential causes.[3]

While the majority of EN cases are idiopathic, streptococcal infection is currently the most common identifiable cause.[3][4][5] Other leading bacterial infections are Salmonella enteritidis, Salmonella typhimurium, Campylobacter jejuni, Yersinia enterocolitica, Mycoplasma, and Bartonella.[6][7]

In Behcet disease, cutaneous manifestation, including EN, is seen in 40% to 90% of patients.[8] Behcet disease is an important consideration in the Middle East, the Mediterranean region, and East Asia.[9]

EN is one of the most common skin manifestations of histoplasmosis, which is seen mainly in the southern and midwestern US, the Mississippi valley, Central America, and parts of South America.[10] Coccidioidomycosis predominates in the western and southwestern regions of the US.[11][12] EN is rarely described in blastomycosis, but may be the cause in the Mississippi and Ohio River valleys, Midwestern US, and parts of Canada.[13]

Drugs such as sulfonamides, bromides, and oral contraceptives have been identified as the cause of EN in 3% to 5% of patients.[3] The following vaccines have been associated with subsequent EN development: tetanus, diphtheria, acellular pertussis, BCG, hepatitis B, human papillomavirus, malaria, rabies, smallpox, typhoid, and cholera.[14] Patients should be questioned about recent medications or vaccines.

An underlying malignancy may be responsible for patients with unexplained, recurrent, or treatment-resistant EN, and constitutional symptoms. Hematologic malignancies such as leukemia and lymphoma are the most common malignancies associated with EN lesions.[3][15][16] Radiation therapy can precipitate EN.[3]

Erythema nodosum-like lesions are the most frequently encountered cutaneous lesions in brucellosis, which is seen in dairy workers and farmers.[17]

EN may be a presenting feature in patients with sarcoidosis.[18] More commonly seen in northern Europe.

Pregnancy causes EN in 2% to 6% of patients.[3]

EN is the most common cutaneous manifestation of inflammatory bowel disease.[19][20]

Pathophysiology

Regardless of cause, the lesions are analogous in their gross and microscopic appearance, suggesting a common but unclear pathogenesis. There is serum macrophage activation and immune complex deposition in the subcutaneous fat. The development of lesions may be a secondary effect of a primary cellular reaction. Patients with tuberculosis and coccidioidomycosis do not develop these lesions until they are skin-positive. In sarcoidosis, lesions are associated with HLA-DRB1*0301 and HLA-DQB1*0201.[21]

Classification

Types of erythema nodosum

Idiopathic in 60% of cases.

Secondary disease

  1. Bacterial

    • Streptococcal infection

    • Tuberculosis

    • Leprosy

    • Tularemia

    • Yersinia enterocolitica

    • Mycoplasma pneumonia

    • Leptospirosis

    • Brucellosis.

  2. Fungal

    • Coccidioidomycosis

    • Histoplasmosis

    • Blastomycosis

    • Dermatophytosis.

  3. Viral and chlamydial agents

    • Psittacosis

    • Lymphogranuloma venereum

    • Infectious mononucleosis

    • Cat-scratch disease

    • Hepatitis B

    • Paravaccinia.

  4. Drug-induced

    • Sulfonamides

    • Oral contraceptives

    • Bromides and iodides.

  5. Ulcerative diseases of the gastrointestinal tract

    • Crohn disease

    • Ulcerative colitis

    • Behcet disease.

  6. Malignant diseases

    • Lymphoma

    • Leukemia

    • Paraneoplastic associated with internal carcinoma.

  7. Miscellaneous

    • Sarcoidosis

    • Whipple disease

    • Sweet syndrome.

Erythema nodosum variants

Erythema nodosum migrans, erythema nodosum chronicum, and nodose erythema are rare variants of erythema nodosum that constitute a very small percentage of all erythema nodosum cases.

Erythema nodosum migrans, also referred to as subacute migratory nodular panniculitis, consists of multiple smaller nodules that migrate centrifugally and demonstrate areas of coalescence. Erythema nodosum chronicum refers to clinically typical but persistent lesions; nodose erythema refers to those lesions that demonstrate an atypical clinical presentation.

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