Erythema Nodosum

Erythema nodosum is an immune-mediated panniculitis (inflammation of the subcutaneous fat) caused by a type IV (delayed-type) hypersensitivity reaction. It commonly manifests in young women as tender, erythematous nodules on the shins. The underlying etiology varies and may be associated with infection, drug exposure, irritable bowel disease, pregnancy, or malignancy. The lesions often self-resolve within 8 weeks without scarring. Management focuses on identifying and treating the underlying cause.

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Epidemiology and Etiology

Epidemiology:

  • Erythema nodosum (EN) is most common in women in their second to fourth decades.
  • Women are affected 3–6 times more often than men. 
  • All ages and racial groups can be affected.
  • Most common form of panniculitis (inflammation of subcutaneous fat)

Etiology:

  • Half of cases have an unknown etiology.
  • Infection is the most commonly identified cause, especially streptococcal infection, but other bacteria, as well as fungi and viruses, are known etiologic agents, including coronavirus disease 2019 (COVID-19) (rare).
  • Drugs: oral contraceptives, penicillin, sulfonamides, others
  • Inflammatory bowel disease
  • Malignancy: hematologic malignancies and carcinoma
  • Miscellaneous: pregnancy, sarcoidosis, others
ClassificationEtiologiesExamples
Infectious causesBacterial
  • Streptococcal infections (most common), especially pharyngitis
  • Tuberculosis
  • Mycoplasma pneumonia
Viral
  • Infectious mononucleosis
  • Hepatitis B virus
Fungal
  • Coccidiomycosis
  • Histoplasmosis
  • Blastomycosis
Non-infectious causesDrugs
  • Penicillins
  • Sulfonamide
  • Oral contraceptive pills
Malignancy
  • Leukemia
  • Lymphoma
  • Solid malignancies
Inflammatory bowel disease
  • Ulcerative colitis
  • Crohn’s disease
Miscellaneous
  • Sarcoidosis: Lofgren’s syndrome
  • Pregnancy
  • Behcet’s disease

Pathophysiology

An immune-mediated reaction to various antigens results in subcutaneous fat inflammation.

  • Type IV hypersensitivity reaction (delayed-type hypersensitivity) to various antigens is considered to be the main immunologic mechanism, but other pathways may be involved, including immune complex deposition in subcutaneous fat.
  • Causes erythematous, tender nodules, typically on the shins, but other areas may be involved
  • Histology shows septal panniculitis without primary vasculitis, a mixed inflammatory infiltrate including eosinophils, Meischer’s “radial” granulomas in the early stages (such as histiocyte aggregates surrounding extracellular clefts with neutrophils at the periphery), and multinucleated giant cells in the later stages. Secondary vasculitis may be seen if there are dense neutrophil infiltrates.

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Clinical Presentation

  • Prodromal symptoms may precede the eruption of skin lesions and include:
    • Fatigue
    • Fever
    • Malaise
    • Arthralgia/arthritis 
  • Characteristic skin lesions:
    • Erythematous, tender nodules on both shins
      • Nonulcerated
      • Immobile
      • Slightly raised
      • Typically 25 cm
    • Develop over several days
      • Usually self-resolve without scarring within 8 weeks of presentation
      • Bruising or residual hyperpigmentation may occur during resolution.
    • Less common sites of nodules:
      • Ankles
      • Thighs
      • Buttocks
      • Calves
      • Face

Diagnosis and Management

Diagnosis

  • Erythema nodosum is usually diagnosed clinically by history and physical examination.
    • An acute onset of tender non-ulcerated nodules or plaques on both shins is typical.
    • Skin biopsy should be reserved for confirming the diagnosis if there are atypical lesions or the patient is immunosuppressed.
  • Patients should be evaluated for underlying disease.
    • Thorough history and physical examination should include:
      • Medication history
      • Travel history
      • Review of respiratory, gastrointestinal, and constitutional symptoms
      • Examination of the throat and tonsils (to rule out streptococcal infection)
    • Laboratory work-up may include:
      • CBC
      • Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP)
      • Throat culture and antistreptolysin-O (ASO) titers 
      • Tuberculin skin test/interferon-gamma release assay 
      • Pregnancy test
    • Imaging may include chest radiographs.

Management

  • Erythema nodosum is self-limiting and usually resolves within 8 weeks.
    • Symptomatic treatment includes:
      • Rest and leg elevation
      • Venous compression by stocking (if tolerated)
      • Analgesics, such as nonsteroidal anti-inflammatory drugs (NSAIDs)
      • Potassium iodide (inhibits neutrophil chemotaxis and generation of reactive oxygen species)
      • If infectious causes can be ruled out, systemic glucocorticoid therapy (prednisone 20 mg/day for 710 days) can improve both pain and the appearance of erythema nodosum.
  • The underlying causes should also be identified and treated.

Differential Diagnosis

  • Nodular vasculitis: a lobular panniculitis frequently associated with tuberculosis. Often occurs on the posterior calves with ulcerated, draining nodules. Patients would be expected to have a positive tuberculin skin test.
  • Subcutaneous infections: may be due to a bacterial, fungal, or mycobacterial infection. Often occurs on the legs/feet with fluctuant, ulcerated, draining lesions. Patients would be expected to have systemic signs of infection.
  • Cutaneous polyarteritis nodosa: characterized by painful subcutaneous nodules on the legs. However, these nodules are also associated with livedo racemosa, necrosis, and ulcerations. Histology shows segmental necrotizing medium artery vasculitis. 
  • Pancreatic panniculitis: These nodules differ in that they are fluctuant and ulcerative with oily fluid drainage. They often heal with scarring. Patients would be expected to have symptoms of pancreatitis including fever and abdominal pain. Laboratory results would reveal elevated lipase and amylase.
  • Alpha-1 antitrypsin deficiency: This genetic defect may be associated with subcutaneous nodules or plaques that frequently ulcerate and drain. 

Clinical Relevance

  • EN can offer clues to the presence of a serious underlying treatable disease, such as streptococcal infection, sarcoidosis, tuberculosis, and coccidioidomycosis.
  • EN may have prognostic value in a few situations because it is associated with the following:
    • A lower incidence of disseminated disease in coccidioidomycosis
    • A less aggressive form of sarcoidosis (Lofgren’s syndrome triad of EN, hilar lymphadenopathy, and acute arthritis/periarthritis)
  • EN may precede or be coincident with an acute flare of inflammatory bowel disease

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