What is the most likely diagnosis and recommended work‑up and treatment for a patient with a positive rheumatoid factor, elevated complement C4, and erythema nodosum?

Diagnostic Approach to Positive RF, Elevated C4, and Erythema Nodosum

This presentation most likely represents erythema nodosum (EN) as a manifestation of an underlying systemic inflammatory condition—most commonly sarcoidosis, Behçet's disease, or inflammatory bowel disease—rather than rheumatoid arthritis, despite the positive RF. The elevated C4 is atypical for RA and suggests either an acute-phase response or a distinct immunologic process.

Understanding the Clinical Triad

Erythema Nodosum Characteristics

• EN presents as tender, erythematous, subcutaneous nodules of 1-5 cm diameter, typically bilateral and symmetrical on the anterior tibial areas, without ulceration or scarring 1
• The diagnosis is clinical based on these characteristic features; biopsy is unnecessary in typical presentations 1
• EN represents a type IV delayed hypersensitivity response involving inflammation of subcutaneous fat septa without vasculitis 2

The Elevated C4 Paradox

• Elevated C4 is NOT characteristic of RA, which typically shows normal or mildly elevated acute-phase reactants 3
• In contrast, SLE characteristically shows reduced C3 and C4 levels, making this pattern inconsistent with lupus 3
• Elevated C4 in the context of EN may represent an acute-phase reactant response during early sarcoidosis, where circulating immune complexes and C3 breakdown products are frequently detected 4
• The isolated C4 elevation should be regarded as unrelated to EN itself and investigated separately 1

Rheumatoid Factor Context

• RF positivity occurs in approximately 15% of first-degree relatives of RA patients and can be present without clinical RA 5
• RF can be positive in multiple conditions beyond RA, including sarcoidosis, Behçet's disease, and other systemic inflammatory states 6
• Negative RF does not exclude RA, and positive RF does not confirm it—clinical synovitis is the cornerstone of RA diagnosis 5

Most Likely Diagnoses (in Order of Probability)

1. Sarcoidosis with EN (Löfgren Syndrome)

• Sarcoidosis is the second most common cause of EN in rheumatology clinics (15.9% of cases) 7
• Early acute sarcoidosis with EN is associated with circulating immune complexes and elevated C3 breakdown products in 14 of 18 tested patients 4
• This would explain both the EN and the elevated C4 as part of the acute-phase immune response 4

2. Behçet's Disease

• Behçet's disease is the most common cause of EN in rheumatology clinics (37.4% of cases) 7
• EN can be the dominant cutaneous manifestation, often preceding other features 1
• Look specifically for oral ulcers, genital ulcers, and ocular inflammation 1

3. Inflammatory Bowel Disease (IBD)

• EN occurs in 4.2-7.5% of IBD patients (ulcerative colitis and Crohn's disease) 1
• IBD-associated EN may precede gastrointestinal symptoms 1
• Assess for diarrhea, abdominal pain, weight loss, and rectal bleeding 1

4. Rheumatoid Arthritis (Less Likely)

• While RA can rarely present with EN, this is an atypical manifestation 8
• The elevated C4 makes RA less likely, as RA typically shows elevated CRP with normal or mildly elevated complement levels 3
• RA diagnosis requires definite clinical synovitis in at least one joint, not just positive serology 5

Essential Diagnostic Work-Up

Immediate Clinical Assessment

• Examine for definite synovitis: Look for soft, boggy joint swelling (not bony enlargement) in MCPs, PIPs, wrists, elbows, shoulders, and knees 5
• Perform a squeeze test of MCPs and MTPs to assess for inflammatory arthritis 5
• Document morning stiffness duration (>30 minutes suggests inflammatory arthritis) 5
• Skin examination: Look for psoriatic plaques, oral/genital ulcers (Behçet's), or other rashes 5
• Ocular examination: Assess for uveitis (Behçet's, sarcoidosis) and dry eyes (Sjögren's) 5

Laboratory Testing

• Anti-CCP antibodies: High specificity (90%) for RA; if negative with positive RF, consider alternative diagnoses 5
• ESR and CRP: Quantify systemic inflammation; markedly elevated levels suggest active inflammatory disease 5, 3
• Complete blood count with differential: Assess for cytopenias and eosinophilia 5
• Comprehensive metabolic panel: Including liver and renal function 5
• Complement levels: Measure C3 (if not already done) to assess for consumption pattern; low C3 with elevated C4 would be unusual and warrant further investigation 1, 3
• ACE level: Elevated in 60% of active sarcoidosis cases (not mentioned in evidence but standard practice)
• Tuberculosis screening: PPD or IGRA, especially before considering immunosuppression 2
• Stool studies: If diarrhea or GI symptoms suggest IBD 2

Imaging Studies

• Chest X-ray: Essential to evaluate for bilateral hilar lymphadenopathy (sarcoidosis) or pulmonary tuberculosis 2, 4
• Bilateral hand, wrist, and foot X-rays: If clinical synovitis is present, to assess for erosions that predict RA 5
• Ultrasound with Power Doppler or MRI: If clinical examination is equivocal but suspicion for inflammatory arthritis remains high 5

Treatment Strategy

Address the Underlying Condition First

• Do not initiate DMARD therapy for presumed RA without confirming clinical synovitis 5
• EN typically resolves once the precipitating condition is treated 1
• Exclude tuberculosis before starting any immunosuppression, particularly if considering corticosteroids 2

Symptomatic Management of EN

• First-line: NSAIDs (indomethacin or naproxen) for pain and inflammation 1, 2
• Supportive care: Bed rest and leg elevation 1
• Systemic corticosteroids: Reserved for severe cases or IBD-associated EN, only after excluding infectious causes 1

Disease-Specific Treatment

• If Behçet's disease confirmed: Colchicine is preferred when EN is the dominant lesion 1
• If IBD-associated EN: Treat underlying IBD; consider azathioprine or TNF-α inhibitors (infliximab, adalimumab) for refractory cases 1
• If sarcoidosis confirmed: Most cases of Löfgren syndrome resolve spontaneously; NSAIDs are usually sufficient 1
• If RA confirmed with clinical synovitis: Start methotrexate 15 mg weekly as first-line DMARD, escalating to 20-25 mg weekly 5

Critical Pitfalls to Avoid

• Do not diagnose RA based solely on positive RF—clinical synovitis is mandatory for diagnosis 5
• Do not attribute elevated C4 to EN—it requires independent evaluation and may indicate sarcoidosis or another immune complex-mediated process 1, 4
• Do not perform routine skin biopsy for typical EN—diagnosis is clinical 1
• Do not start immunosuppression before excluding tuberculosis, especially in endemic areas or high-risk patients 2
• Do not dismiss the diagnosis of inflammatory arthritis based on normal ESR/CRP alone—these are poor predictors and can be normal even in active disease 5
• Do not delay rheumatology referral if clinical synovitis is present—refer within 6 weeks of symptom onset to prevent irreversible joint damage 5

Monitoring and Follow-Up

• Reassess in 4-6 weeks to evaluate EN resolution and monitor for development of additional features that may clarify the underlying diagnosis 1
• Repeat inflammatory markers (CRP, ESR) to track disease activity 5
• Serial clinical examinations to detect emergence of synovitis, oral ulcers, or other systemic manifestations 5
• If RA is ultimately diagnosed: Use SDAI or CDAI every 4-6 weeks to guide treatment, targeting remission (SDAI ≤3.3) or low disease activity (SDAI ≤11) 5