What is the appropriate work‑up and management for an adult presenting with new‑onset painful erythema nodosum on the anterior shins?

Erythema Nodosum: Work-up and Management

Clinical Diagnosis

Erythema nodosum is diagnosed clinically based on the characteristic appearance of tender, raised, red or violet subcutaneous nodules (1–5 cm diameter) that are bilateral and symmetrical on the anterior tibial areas; skin biopsy is reserved only for atypical presentations. 1, 2

The nodules typically:

• Appear suddenly with a bright red color initially, then evolve to livid red/purplish, and finally take on a yellow-greenish bruise-like appearance 3
• Never ulcerate and heal without scarring or atrophy 3, 4
• Are accompanied by systemic symptoms including fever, malaise, extreme fatigue (lasting weeks to months), and symmetrical arthralgias of distal lower extremities without effusions 2

Initial Work-up

Core Laboratory Studies (Obtain in All Patients)

• Complete blood count with differential (look for eosinophilia, leukocytosis) 5, 4
• Erythrocyte sedimentation rate and/or C-reactive protein (elevated in active inflammation) 5, 4
• Throat swab culture or rapid antigen test plus anti-streptolysin O titer (streptococcal pharyngitis is the most common identifiable cause) 5, 4, 6
• Chest radiograph (to screen for sarcoidosis, tuberculosis, hilar adenopathy) 5, 4

Risk-Stratified Additional Testing

For patients with tuberculosis risk factors (endemic area exposure, immunosuppression, night sweats, weight loss):

• Tuberculin skin test or interferon-gamma release assay 4, 7
• Sputum cultures if pulmonary symptoms present 4

For patients with respiratory symptoms or endemic area exposure (southwestern United States, Ohio/Mississippi River valleys):

• Serologic testing for coccidioidomycosis or histoplasmosis 2

For patients with gastrointestinal symptoms (diarrhea, abdominal pain, rectal bleeding):

• Stool studies and consider colonoscopy to evaluate for inflammatory bowel disease (IBD occurs in 4.2–7.5% of EN cases) 1, 2, 4

For patients with oral/genital ulcers:

• Evaluate for Behçet's disease 2, 6

Treatment Algorithm

Step 1: Address the Underlying Cause

Treat any identified trigger first—EN typically resolves once the precipitating condition is managed. 2, 8

• Streptococcal infection: appropriate antibiotics 4
• Tuberculosis: standard anti-tuberculous therapy 7
• IBD flare: treat underlying bowel inflammation 1
• Drug-induced: discontinue offending medication 4, 6

Step 2: Symptomatic Management (First-Line)

NSAIDs (indomethacin, naproxen) combined with bed rest and leg elevation are the cornerstone of symptomatic treatment. 2, 8, 3

• Most cases are self-limited and resolve within weeks with supportive care alone 3, 5
• Potassium iodide may enhance analgesia and resolution 3

Step 3: Severe Cases

Systemic corticosteroids are reserved for severe cases with significant inflammation or IBD-associated EN, but only after infectious causes—particularly tuberculosis—have been excluded. 1, 2, 8, 3

Step 4: Refractory or Recurrent Disease

For resistant cases or frequent relapses, escalate therapy in this order:

1. Colchicine (especially effective when EN is the dominant lesion or associated with Behçet's disease) 2
2. Azathioprine for frequent relapses 1, 2, 8
3. TNF-α inhibitors (infliximab or adalimumab) for IBD-associated EN that is resistant to conventional therapy 1, 2, 8

Common Pitfalls to Avoid

• Do not perform routine skin biopsy for typical EN presentations; reserve it only for atypical cases where the diagnosis is uncertain 1, 2, 5
• Do not prescribe systemic corticosteroids before excluding tuberculosis and other infections, as steroids can worsen underlying infections 2, 3, 4
• Do not assume idiopathic EN without completing the core work-up, as EN may be the first sign of serious systemic disease (tuberculosis, sarcoidosis, IBD, malignancy) 4, 6
• Do not neglect to monitor for disease activity in associated conditions like IBD or sarcoidosis, as recurrent EN indicates persistent underlying disease 2