Workup and Management of Suspected Erythema Nodosum with Elevated C4
For a patient with suspected erythema nodosum and isolated C4 elevation, the diagnosis of erythema nodosum should be made clinically, and the elevated C4 is likely unrelated to the erythema nodosum itself, as EN does not cause complement abnormalities. 1
Clinical Diagnosis of Erythema Nodosum
The diagnosis is primarily clinical and does not require biopsy in typical presentations. 2, 1
Key diagnostic features to confirm:
- Raised, tender, red or violet subcutaneous nodules 1-5 cm in diameter 1
- Located on extensor surfaces, particularly anterior tibial areas 2, 1
- Bilateral and symmetrical distribution 3
- No ulceration (this distinguishes EN from other conditions) 2, 3
- Lesions evolve from bright red to livid/purplish to yellow-green (bruise-like appearance) 3
Associated systemic symptoms to assess:
- Fever, malaise, and extreme fatigue that may persist for weeks to months 1
- Symmetrical arthralgias affecting distal lower extremities without joint effusions 1
- Drenching night sweats and weight loss (suggests infectious etiology) 1
Diagnostic Workup for Underlying Causes
Initial laboratory screening should include: 4, 5, 6
- Complete blood count with differential 4
- Erythrocyte sedimentation rate and/or C-reactive protein 4, 6
- Throat culture or rapid streptococcal antigen test 4
- Anti-streptolysin O titer 4
- Chest radiograph (to evaluate for sarcoidosis, tuberculosis, or fungal infection) 4, 6
Common etiologies to consider: 1, 4, 5
- Streptococcal pharyngitis (most common identifiable cause) 4
- Inflammatory bowel disease (4.2-7.5% of IBD patients develop EN) 1
- Sarcoidosis 4, 5
- Behçet's disease (look for oral and genital ulcers) 1
- Tuberculosis (stratify patient by TB risk) 4
- Coccidioidomycosis or histoplasmosis (in endemic areas) 1, 4
- Medications (oral contraceptives, antibiotics) 4
Addressing the Elevated C4
The isolated C4 elevation is not consistent with erythema nodosum and warrants separate investigation. Erythema nodosum does not cause complement abnormalities. 2, 1
C4 elevation considerations:
- Normal C4 levels during an attack of hereditary angioedema strongly suggest HAE is unlikely 2
- Elevated C4 is not a feature of complement-mediated glomerulonephritis, which typically shows low C4 2, 7
- This finding may represent an acute phase reactant response or be incidental 2
If there are any features suggesting complement-related disease (recurrent angioedema, renal involvement), measure: 2, 7
However, in the context of isolated EN without angioedema or renal symptoms, extensive complement workup is not indicated. 2, 1
Treatment Strategy
Treatment should address the underlying cause when identified, as EN typically resolves when the precipitating condition is treated. 2, 1
First-line symptomatic management: 1, 3
- Bed rest and leg elevation 3, 6
- NSAIDs (indomethacin, naproxen, or oxyphenbutazone) for pain and inflammation 1, 3
For severe cases or IBD-associated EN: 2, 1
- Systemic corticosteroids may be required, but only after excluding infectious causes (particularly tuberculosis) 2, 3
- Corticosteroids are rarely indicated and should be used cautiously 3
For refractory or recurrent EN: 2, 1
- Colchicine (particularly effective when EN is the dominant lesion or associated with Behçet's disease) 2, 1
- Azathioprine for frequent relapses 2, 1
- TNF-alpha inhibitors (infliximab or adalimumab) for resistant cases, especially IBD-associated 2, 1
Common Pitfalls to Avoid
- Do not perform skin biopsy routinely - diagnosis is clinical; biopsy is reserved only for atypical presentations 2, 1
- Do not start corticosteroids before ruling out tuberculosis and other infections 3
- Do not attribute the elevated C4 to erythema nodosum - these are separate findings requiring independent evaluation 2
- Do not overlook inflammatory bowel disease - EN may be the presenting manifestation and occurs in up to 7.5% of IBD patients 1
- Monitor for recurrence - over half of patients experience subsequent attacks 8