How to diagnose and treat a patient with bilateral hand joint swelling, shoulder pain, limited range of motion, and bilateral knee pain, with elevated C-reactive protein (CRP) and Rheumatoid factor (RF), but normal Uric acid, Antistreptolysin O antibody (ASO), and Erythrocyte Sedimentation Rate (ESR)?

Diagnosis and Management of Bilateral Polyarthritis with Elevated Inflammatory Markers

Immediate Diagnostic Approach

This patient most likely has seronegative rheumatoid arthritis (RA) or undifferentiated peripheral inflammatory arthritis (UPIA), and requires urgent rheumatology referral with baseline imaging and consideration of disease-modifying therapy after excluding infection.

The clinical presentation of acute-onset bilateral symmetric polyarthritis involving hands, shoulders, and knees with significantly elevated CRP (78 mg/L) indicates active inflammatory arthritis requiring immediate evaluation 1. The elevated rheumatoid factor (14.1), while technically positive, is only mildly elevated and combined with negative anti-CCP antibodies (8) makes classic seropositive RA less likely—however, seronegative RA accounts for 20-30% of cases and has similar prognosis to seropositive disease 2.

Critical First Steps

Before initiating any immunosuppressive therapy, infection must be excluded through arthrocentesis of at least one swollen joint for cell count, Gram stain, culture, and crystal analysis 1. This is essential given the acute 4-5 day onset and elevated inflammatory markers, which could represent septic arthritis or post-streptococcal reactive arthritis despite the normal ASO titer 1.

Additional infectious workup should include 1:

• Blood cultures if febrile
• Throat culture or rapid strep test
• Hepatitis B, Hepatitis C, and tuberculosis screening (required before any biologic therapy) 2

Additional Laboratory Testing Required

The following tests should be ordered immediately 3:

• Complete blood count with differential - to assess for cytopenias and calculate neutrophil-to-lymphocyte ratio 3
• Comprehensive metabolic panel - including liver function tests, renal function, glucose, and urate (already done) 2
• Baseline hand, wrist, and foot X-rays bilaterally - erosions predict RA diagnosis and disease persistence, and baseline imaging is essential for monitoring structural damage progression 3, 2
• Urinalysis - part of standard UPIA workup 3
• Repeat ESR and CRP - for monitoring disease activity over time 3

Do not delay treatment waiting for positive serology or dismiss the diagnosis based on negative RF/anti-CCP, as seronegative RA is common 2. The normal ESR (29 mm/h) despite markedly elevated CRP (78 mg/L) represents discordance that occurs in 28% of cases, and when discordance occurs, CRP is the better measure of disease activity 4.

Diagnostic Classification

Using the 2010 ACR/EULAR Classification Criteria for RA, this patient's score is calculated as 2:

• Joint involvement: Bilateral hands (small joints), shoulders (large joints), and knees (large joints) = likely 3-5 points depending on exact joint count
• Serology: Low positive RF with negative ACPA = 2 points
• Acute phase reactants: Abnormal CRP = 1 point
• Duration: 4-5 days = 0 points (requires ≥6 weeks for 1 point)

Current score: 6-8 points, meeting criteria for definite RA if ≥6 points 2. However, the short symptom duration (<6 weeks) means this currently represents UPIA that may evolve into definite RA.

Treatment Strategy

Immediate Management (First 1-2 Weeks)

Once infection is excluded, initiate bridging therapy with prednisone 0.5-1 mg/kg/day (typically 10-20 mg daily for most adults) to rapidly control severe inflammation and functional impairment 1, 5. This serves as bridge therapy while awaiting DMARD effect 2.

Add NSAIDs at therapeutic doses (e.g., naproxen 500 mg twice daily) for additional pain control 1, 6. Naproxen has been shown comparable to aspirin and indomethacin in controlling RA disease activity with fewer gastrointestinal and nervous system adverse effects 6.

Disease-Modifying Therapy (Within 2 Weeks)

Start methotrexate 15 mg weekly as first-line DMARD immediately after infection is excluded, with plan to escalate to 20-25 mg weekly based on response 1, 2, 7. Add folic acid 1 mg daily to reduce methotrexate toxicity 1.

The rationale for early DMARD initiation despite short symptom duration includes 3, 1:

• Bilateral symmetric small joint involvement with functional impairment
• Markedly elevated inflammatory markers (CRP 78 mg/L)
• Positive RF (even if low-titer)
• High probability of progression to persistent erosive disease

Baseline monitoring before methotrexate 7:

• Complete blood count
• Liver function tests
• Renal function (creatinine clearance)
• Hepatitis B, C, and tuberculosis screening

Glucocorticoid Tapering Strategy

Plan to taper prednisone over 4-8 weeks as methotrexate takes effect, with goal of discontinuation or maintenance below 7.5 mg/day 2, 5. The FDA label notes that alternate-day therapy may minimize adverse effects in patients requiring long-term corticosteroids 5.

Monitoring and Follow-Up

Immediate Rheumatology Referral

Refer immediately to rheumatology given definite synovitis with severe functional impairment (unable to move arms, unable to walk properly) and diagnostic uncertainty 1. Fast-track evaluation within 24-48 hours is appropriate for this level of functional impairment.

Disease Activity Monitoring

Reassess every 4-6 weeks using composite disease activity measures 1, 2:

• Simplified Disease Activity Index (SDAI) - preferred when CRP is elevated 3
• Target: Remission (SDAI ≤3.3) or low disease activity (SDAI ≤11) 2
• Monitor: 28-joint count, patient global assessment, evaluator global assessment, CRP 3, 2

Repeat inflammatory markers (CRP and ESR) at each visit 3. CRP is more sensitive than ESR for monitoring acute phase response, though ESR may better reflect general disease severity due to sensitivity to immunoglobulins and RF 4.

Radiographic Monitoring

Repeat hand, wrist, and foot X-rays at 6 months and 12 months 3. Studies show that radiological deterioration continues during the first 6 months regardless of clinical response, but further deterioration is less likely when ESR and CRP are consistently controlled below 30 mm/h and 20 mg/L respectively 8.

Treatment Escalation Strategy

If inadequate response after 3 months of methotrexate (failure to achieve low disease activity), consider 2:

• Triple DMARD therapy (methotrexate + hydroxychloroquine + sulfasalazine), OR
• Adding a biologic agent (TNF inhibitor preferred as first biologic)

Critical Pitfalls to Avoid

• Do not delay DMARD therapy waiting for 6 weeks of symptoms - early aggressive treatment prevents irreversible joint damage 1, 2
• Do not dismiss RA diagnosis based on negative anti-CCP or low RF - seronegative RA is common and has similar prognosis 2
• Do not ignore normal ESR (29) in context of high CRP (78) - CRP is the more reliable acute phase marker 4
• Do not start immunosuppression before excluding infection - arthrocentesis is mandatory 1
• Do not use preserved methotrexate formulations for high-dose or intrathecal therapy - use preservative-free formulations 7
• Monitor for methotrexate hepatotoxicity with liver function tests every 4-8 weeks - chronic hepatotoxicity can occur after cumulative doses >1.5 grams 7