What is the treatment approach for erythema nodosum?

Erythema Nodosum: Complete Illness Script

Clinical Presentation

Erythema nodosum presents as tender, raised, erythematous or violaceous subcutaneous nodules measuring 1-5 cm in diameter, characteristically appearing bilaterally and symmetrically on the anterior tibial surfaces of the lower extremities. 1, 2, 3

Key Clinical Features

• Acute onset of painful nodules that are warm to touch 2, 4
• Bilateral pretibial distribution is the hallmark location, though lesions can occur on extensor surfaces of arms 1, 3
• Does not ulcerate and resolves without scarring or atrophy 1, 2
• Lesions evolve through color changes resembling a bruise (red → purple → brown → yellow) over 3-6 weeks 3, 4
• Seasonal predominance in winter and spring 5
• Female predominance with a 6:1 female-to-male ratio 5

Associated Systemic Symptoms

• Fever, malaise, and extreme fatigue that may persist for weeks to months 6
• Arthralgias affecting multiple joints, typically symmetrical, involving distal lower extremities without joint effusions 6
• Drenching night sweats and weight loss in infectious etiologies 6

Pathophysiology

Erythema nodosum represents a type IV delayed hypersensitivity reaction to various antigenic stimuli, manifesting as septal panniculitis without vasculitis. 2, 3

• Histologically shows inflammatory infiltrate in the septa between fat lobules with radial granulomas 2
• Absence of vasculitis distinguishes it from other panniculitides 2
• Both neutrophilic and granulomatous inflammation are involved 7

Etiologies

Most Common Identifiable Causes (in order of frequency)

Streptococcal pharyngitis is the single most common identifiable cause of erythema nodosum. 2, 3, 5

1. Post-streptococcal infection (32%) - most frequent identified cause 5
2. Primary tuberculosis - particularly important in endemic areas 2, 3, 5
3. Sarcoidosis (11%) - second most common in hospitalized patients 5
4. Inflammatory bowel disease (ulcerative colitis and Crohn's disease) - occurs in 4.2-7.5% of IBD patients 6
5. Behçet's disease - colchicine is preferred when EN is the dominant lesion 6, 3
6. Medications - particularly oral contraceptives and antibiotics 2, 3
7. Pregnancy 3, 4
8. Coccidioidomycosis - in endemic southwestern United States 6
9. Histoplasmosis - associated with acute infection 6
10. Mycoplasma pneumoniae (3%) 5
11. Bartonella infection (3%) 5

Idiopathic Cases

• Approximately 32-50% of cases remain idiopathic after thorough evaluation 3, 4, 5

Diagnostic Approach

Diagnosis is primarily clinical based on characteristic appearance and distribution; biopsy is reserved for atypical presentations. 6, 1, 2

Initial Clinical Assessment

• Detailed exposure history: travel to endemic areas (tuberculosis, coccidioidomycosis, histoplasmosis), recent upper respiratory infection, new medications, tick exposure 6, 2, 3
• Temporal relationship: coccidioidomycosis should be considered if CAP develops within one month of endemic exposure 6
• Associated symptoms: respiratory symptoms, diarrhea, joint pain, eye inflammation, oral/genital ulcers 6, 3

Core Laboratory Evaluation

All patients should undergo basic screening studies including: 4, 5

• Complete blood count with differential - elevated in secondary causes 5
• Erythrocyte sedimentation rate and/or C-reactive protein - significantly elevated in secondary EN compared to idiopathic 5
• Throat culture or rapid streptococcal antigen test 2, 4
• Anti-streptolysin O (ASO) titers 2, 4, 5
• Chest radiograph - essential to evaluate for tuberculosis, sarcoidosis, hilar adenopathy, or fungal infection 2, 4, 5

Risk-Stratified Additional Testing

For patients at risk for tuberculosis: 6, 2

• Tuberculin skin test (PPD) or interferon-gamma release assay 5
• Chest CT if radiograph is abnormal 5

For patients with endemic fungal exposure: 6

• Coccidioides serology if travel to southwestern US within past month 6
• Histoplasma antigen testing if exposure to endemic areas 6

For patients with gastrointestinal symptoms: 6

• Stool cultures and inflammatory markers 5
• Consider colonoscopy if IBD suspected 6

For patients with recurrent episodes or multisystem involvement: 6, 3

• Pathergy test for Behçet's disease 6
• Autoimmune serologies guided by clinical presentation 5

When to Biopsy

Deep incisional or excisional biopsy should be obtained when: 2, 3

• Presentation is atypical (unilateral, ulcerating, or unusual distribution) 1, 2
• Lesions persist beyond 6-8 weeks 3
• Diagnosis remains uncertain after initial evaluation 2, 4

Treatment Strategy

Primary Principle

Treatment must address the underlying cause while providing symptomatic relief; erythema nodosum lesions themselves are self-limited and resolve without intervention in most cases. 1, 2, 3

First-Line Symptomatic Management

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the cornerstone of symptomatic treatment for pain and inflammation. 6, 1, 2, 7

• Bed rest and leg elevation to reduce discomfort 4
• NSAIDs (ibuprofen, naproxen, indomethacin) for 2-12 weeks based on symptom resolution 6, 1
• Relapse may occur after discontinuation, requiring reinstitution for another 4-8 weeks 6

Treatment of Underlying Conditions

Streptococcal infection: 2, 3

• Appropriate antibiotic therapy (penicillin or macrolide if allergic) 2

Tuberculosis: 2, 3

• Standard anti-tuberculous therapy 2, 5

Sarcoidosis: 3

• Hydroxychloroquine may be beneficial in addition to standard therapy 1

Inflammatory bowel disease: 6, 1

• EN typically parallels IBD activity and responds to treatment of underlying disease 6
• Systemic corticosteroids usually required 6

Coccidioidomycosis/Histoplasmosis: 6

• Antifungal therapy is NOT recommended for EN associated with acute fungal infection 6
• NSAIDs alone are sufficient 6

Behçet's disease: 6, 1

• Colchicine is preferred when EN is the dominant lesion 6, 1

Second-Line Therapies for Refractory Cases

Potassium iodide - effective for persistent lesions 7

Colchicine - particularly useful for recurrent EN or when associated with Behçet's syndrome 6, 1, 7

Systemic corticosteroids - reserved for severe cases with significant inflammation or IBD-associated EN 6, 1, 8

• Prednisone 30-60 mg daily or 1 mg/kg for 1 week with tapering over second week 6
• Should be used cautiously and only after excluding infectious causes 1, 8

Third-Line Therapies for Resistant Cases

For frequent relapses or IBD-associated EN: 6, 1

• Azathioprine for immunomodulation 6, 1
• TNF-alpha inhibitors (infliximab or adalimumab) for resistant cases associated with IBD 6, 1

Critical Pitfalls to Avoid

Never initiate corticosteroids before excluding active tuberculosis or other serious infections - this can lead to dissemination of infection 1, 8, 2

Do not assume idiopathic EN without completing core laboratory evaluation - missing an underlying systemic disease can result in progression and complications 1, 3, 4

Avoid prescribing antifungal therapy for EN associated with acute coccidioidomycosis or histoplasmosis - the skin manifestations are immunologic, not infectious, and do not require antifungal treatment 6

Do not neglect monitoring for disease activity in associated conditions like IBD or sarcoidosis, as EN recurrence may indicate persistent underlying disease 1

Recognize that extreme fatigue may persist for months and is often the last symptom to resolve, requiring patient counseling about prolonged convalescence 6

In endemic areas, consider coccidioidomycosis in any patient with CAP within one month of exposure - it accounts for 24% of community-acquired pneumonia in endemic regions 6