A patient with erythema nodosum, normal CBC and CMP, positive rheumatoid factor and isolated complement C4 elevation, and no clinical synovitis—what are the most likely diagnoses and what targeted work‑up and management should be pursued?

Diagnostic Approach to Erythema Nodosum with Positive Rheumatoid Factor and Isolated C4 Elevation

Most Likely Diagnoses

The most likely diagnosis is idiopathic erythema nodosum with an incidental positive rheumatoid factor, as the absence of clinical synovitis effectively excludes rheumatoid arthritis and the isolated C4 elevation is unrelated to EN. 1, 2

Key Diagnostic Considerations

• Erythema nodosum does not cause complement abnormalities; an isolated C4 rise should be regarded as unrelated to EN and investigated separately. 1

• The positive rheumatoid factor in the absence of clinical synovitis has zero diagnostic value for rheumatoid arthritis—the 2010 ACR/EULAR classification criteria require definite clinical synovitis in at least one joint as an absolute prerequisite for RA diagnosis. 2

• RF positivity occurs in approximately 15% of first-degree relatives of RA patients and can be present in healthy individuals, particularly when mildly elevated. 3, 2

• Seronegative spondyloarthropathies (psoriatic arthritis, ankylosing spondylitis) are RF-negative by definition, making the positive RF inconsistent with these diagnoses. 4

Targeted Work-Up

For Erythema Nodosum Etiology

First-line investigations to identify the underlying trigger:

• Streptococcal testing: throat culture, rapid antigen test, or anti-streptolysin-O titer (most common cause in children and adults). 5, 6

• Chest radiography: to evaluate for sarcoidosis (second most common cause in adults) or tuberculosis. 5, 3

• Tuberculosis screening: purified protein derivative test or interferon-gamma release assay, especially in high-risk populations. 5

• Inflammatory bowel disease evaluation: if gastrointestinal symptoms present (occurs in 4.2–7.5% of IBD patients). 1

• Coccidioidomycosis or histoplasmosis serology: only if endemic exposure history (southwestern United States for coccidioidomycosis). 3, 1

For Isolated C4 Elevation

• Do not perform extensive complement testing (C3, C1q, C1-inhibitor) in EN patients without angioedema or renal involvement. 1

• An isolated C4 rise may represent an acute-phase reactant response or be an incidental finding; it is not characteristic of complement-mediated disease. 1

• If recurrent angioedema or renal signs develop, then measure C3, C1q, and C1-inhibitor antigen plus function. 1

For Rheumatoid Factor Positivity

• No additional rheumatologic work-up is indicated in the absence of clinical synovitis. 2

• Monitor clinically and consider advanced imaging (ultrasound with Power Doppler or MRI) only if joint symptoms develop. 2

• Do not order anti-CCP antibodies, hand radiographs, or rheumatology referral without objective joint swelling. 2

Management Strategy

Symptomatic Treatment of Erythema Nodosum

NSAIDs are the cornerstone of treatment:

• First-line: indomethacin, naproxen, or ibuprofen for pain and inflammation. 1, 5, 6

• Bed rest and leg elevation provide additional symptomatic relief. 1

• Systemic corticosteroids are reserved for severe cases with significant inflammation or IBD-associated EN, and should be used only after infectious causes—particularly tuberculosis—have been excluded. 1, 3

Treatment of Underlying Condition

• Address the identified trigger: treat streptococcal infection with antibiotics, manage IBD flares, or treat sarcoidosis if symptomatic. 1, 5

• Antifungal therapy is not recommended for histoplasmosis-associated EN or coccidioidomycosis-associated EN; NSAIDs alone are sufficient. 3, 1

For Refractory or Recurrent EN

• Colchicine is especially effective when EN is the dominant lesion or associated with Behçet's disease. 1

• Azathioprine can be considered for patients with frequent relapses. 1

• TNF-α inhibitors (infliximab or adalimumab) are options for resistant cases, particularly when linked to inflammatory bowel disease. 1

Common Pitfalls to Avoid

• Do not perform routine skin biopsy for typical EN; reserve it for atypical presentations (ulceration, asymmetric distribution, or lack of resolution). 1

• Do not attribute the elevated C4 level to EN; it requires independent evaluation if clinically indicated. 1

• Do not diagnose or treat rheumatoid arthritis based on positive RF alone—clinical synovitis is mandatory for RA diagnosis. 2

• Do not use systemic corticosteroids before excluding tuberculosis and other treatable infections. 3, 1

• Do not delay treatment of an identified underlying condition (e.g., streptococcal pharyngitis) while awaiting EN resolution. 1, 5

• Recognize that EN is self-limited in most cases; over 50% of patients have subsequent attacks, but the condition resolves without permanent sequelae. 5, 7