What is erythema nodosum?

What is Erythema Nodosum

Erythema nodosum is a painful inflammatory condition of the subcutaneous fat (panniculitis) that presents as tender, raised, red or violet nodules of 1-5 cm diameter, typically appearing bilaterally and symmetrically on the anterior tibial areas (shins), and represents a hypersensitivity reaction to various antigenic triggers rather than a primary infectious process. 1

Clinical Presentation

Characteristic Skin Lesions

• The nodules appear suddenly as bright red, tender, warm, raised lesions primarily on the shins, ankles, and knees 2, 3
• Within days, the lesions evolve from bright red to livid red or purplish, and finally take on a yellow or greenish appearance resembling a deep bruise 2
• Crucially, the lesions never ulcerate and heal without atrophy or scarring, which distinguishes them from other conditions 2, 4
• The nodules are typically bilateral and symmetrical, ranging from 1-5 cm in diameter 1, 3

Systemic Symptoms

• Fever, malaise, and extreme fatigue that may persist for weeks to months are common 1
• Arthralgias affecting multiple joints symmetrically, typically involving distal lower extremities without joint effusions, occur in approximately 70% of cases 1, 5
• Drenching night sweats and weight loss may occur when infectious etiologies like coccidioidomycosis are present 1

Pathophysiology

Erythema nodosum represents a type IV delayed hypersensitivity response to numerous antigens rather than a direct infection of the skin. 4 Histopathologically, it is characterized by:

• Septal panniculitis (inflammation of the septa between fat lobules) without vasculitis 2, 4
• Miescher's radial granulomas—small nodular aggregations of histiocytes arranged radially around a central cleft—which are pathognomonic 2
• Early lesions show edema, hemorrhage, and neutrophils; late lesions show fibrosis, granulation tissue, lymphocytes, and multinucleated giant cells 2

Common Etiologies

Infectious Causes

• Streptococcal pharyngitis is the most common identifiable infectious cause 4, 3
• Primary tuberculosis, particularly in endemic areas 4, 6
• Coccidioidomycosis in endemic regions (southwestern United States) 1, 5
• Histoplasmosis 1

Inflammatory Conditions

• Sarcoidosis 4, 3, 6
• Inflammatory bowel disease (ulcerative colitis and Crohn's disease) occurs in 4.2-7.5% of IBD patients 1
• Behçet's disease, characterized by oral and genital ulcers 1, 6

Other Causes

• Medications, including oral contraceptives and certain antibiotics 4, 3
• Pregnancy 2, 6
• Malignancies 4, 3
• Approximately 50% of cases are idiopathic despite thorough evaluation 3, 6

Diagnostic Approach

Clinical Diagnosis

• Diagnosis is primarily made on clinical grounds based on the characteristic appearance and location of lesions 1, 4
• Biopsy is not usually necessary except in atypical cases where the diagnosis is uncertain 7, 1

Initial Laboratory Evaluation

• Complete blood count with differential 4, 3
• Erythrocyte sedimentation rate and/or C-reactive protein 4, 3
• Throat culture, rapid antigen test, antistreptolysin-O titer for streptococcal infection 4, 3
• Chest radiograph to evaluate for tuberculosis, sarcoidosis, or fungal infections 4, 3

Risk-Stratified Additional Testing

• Purified protein derivative (PPD) test or interferon-gamma release assay in patients at risk for tuberculosis 4
• Stool cultures if inflammatory bowel disease is suspected 4
• Coccidioides serology in endemic areas 1
• Further testing should be guided by specific clinical findings rather than performed routinely 4, 3

Key Differential Diagnosis

Gnathostomiasis must be excluded in patients with travel history to Southeast Asia, as it presents with recurrent painful or pruritic subcutaneous nodules that migrate over time, unlike erythema nodosum which remains fixed bilaterally on the anterior tibial areas. 8 The migration pattern of gnathostomiasis nodules—moving to different locations over days to weeks—is the key distinguishing feature 8.

Treatment Strategy

Address Underlying Cause

• Treatment should be directed primarily at the underlying associated condition if identified 1, 2
• Treat streptococcal infection with appropriate antibiotics 1
• Manage inflammatory bowel disease flares 1
• Notably, antifungal therapy is not recommended for erythema nodosum associated with coccidioidomycosis or histoplasmosis 1

Symptomatic Management

• Bed rest and leg elevation are generally recommended to reduce discomfort 2, 3
• Nonsteroidal anti-inflammatory drugs (NSAIDs) are the cornerstone of symptomatic treatment for pain and inflammation 1, 2, 3
• Aspirin, indomethacin, or naproxen may be used 2
• Potassium iodide may enhance analgesia and resolution 2

Advanced Therapies for Severe or Refractory Cases

• Systemic corticosteroids are reserved for severe cases with significant inflammation or IBD-associated erythema nodosum, and should be used cautiously after excluding infectious causes 1, 2
• Colchicine is preferred when erythema nodosum is associated with Behçet's syndrome 1
• Azathioprine for frequent relapses 1
• TNF-alpha inhibitors (infliximab or adalimumab) for resistant cases associated with inflammatory bowel disease 1
• Hydroxychloroquine may be beneficial when erythema nodosum is associated with sarcoidosis 1

Clinical Course and Prognosis

• Most cases are self-limited and resolve spontaneously within 3-6 weeks 2, 3
• Over half of patients experience subsequent attacks, and some have recurrent episodes for months to years 5
• Recurrent erythema nodosum may indicate persistent underlying disease activity and warrants reassessment 1

Important Pitfalls to Avoid

• Never assume erythema nodosum is idiopathic without completing the basic diagnostic work-up to exclude treatable underlying conditions 4, 6
• Do not initiate systemic corticosteroids before ruling out tuberculosis and other infectious causes 2, 4
• Neglecting to monitor for disease activity in associated conditions like inflammatory bowel disease or sarcoidosis can lead to missed opportunities for disease-modifying treatment 1
• Remember that erythema nodosum itself is not a complication but rather a manifestation; the underlying disease determines long-term outcomes 5