How should I evaluate and manage a patient with symmetric polyarthralgia, elevated C‑reactive protein, and negative rheumatoid factor?

Approach to Symmetric Polyarthralgia with Negative RF and Elevated CRP

In a patient with symmetric polyarthralgia, elevated CRP, and negative rheumatoid factor, you should urgently pursue a diagnosis of seronegative rheumatoid arthritis or other inflammatory arthropathy through immediate anti-CCP antibody testing, comprehensive joint examination, baseline imaging, and rheumatology referral within 6 weeks—while simultaneously excluding septic arthritis, psoriatic arthritis, and reactive arthritis. 1

Immediate Diagnostic Workup

Essential Laboratory Tests (Order Today)

• Anti-CCP antibody testing is critical, as it has 90-98% specificity for RA and remains positive in 60-70% of RF-negative RA patients 1, 2
• Order ESR to complement CRP for baseline inflammatory assessment 1
• Complete blood count with differential to assess for cytopenias before starting any DMARDs 1
• Comprehensive metabolic panel including liver function, renal function, glucose, and urate levels 1
• Urinalysis as part of standard workup 1
• If any single joint is disproportionately swollen, perform arthrocentesis urgently to exclude septic arthritis with synovial fluid cell count, Gram stain, and cultures 3

Additional Serologic Testing Based on Clinical Features

• ANA and extractable nuclear antigens if systemic features suggest lupus (though symmetric polyarthritis with elevated CRP favors RA over SLE) 1
• HLA-B27 if axial pain, enthesitis, or asymmetric pattern suggests spondyloarthropathy 1, 3
• Hepatitis B, C, and tuberculosis screening before any biologic therapy 1

Baseline Imaging (Order Within 1 Week)

• Bilateral hand, wrist, and foot X-rays to detect erosions, which predict RA diagnosis and disease persistence 1
• If clinical examination shows no definite synovitis but suspicion remains high, order ultrasound with Power Doppler or MRI to detect subclinical synovitis 1

Critical Physical Examination Findings

Joint Assessment (28-Joint Count)

• Examine PIPs, MCPs, wrists, elbows, shoulders, and knees for soft tissue swelling (not bony enlargement) and tenderness 1
• Perform squeeze test of MCPs and MTPs to assess for clinical synovitis 1
• Document morning stiffness duration—>30 minutes strongly suggests inflammatory arthritis 3
• Look for symmetric involvement of small joints, which is characteristic of RA 1

Skin and Nail Examination

• Carefully examine for psoriatic plaques, nail pitting, or onycholysis to distinguish psoriatic arthritis from seronegative RA 4, 1
• Check for rheumatoid nodules, though these are less common in seronegative disease 1

Understanding Seronegative RA

Key Clinical Pearls

• Seronegative RA accounts for 20-30% of all RA cases and has similar prognosis to seropositive disease 1
• Negative RF does NOT exclude RA—clinical synovitis and disease activity take precedence over serology 1
• Anti-CCP has superior specificity (96%) compared to RF (70%), making it invaluable when positive 2
• Dual negativity (RF and anti-CCP both negative) substantially reduces but does not eliminate RA probability 2

Prognostic Significance of Elevated CRP

• CRP of 93.3 mg/L represents severe systemic inflammation far beyond non-inflammatory conditions 1
• Persistently elevated CRP predicts aggressive disease with high risk of radiographic progression if untreated 1
• Even patients with 0-1 swollen joints can have CRP >10 mg/L, indicating subclinical inflammation 5

Differential Diagnosis to Exclude

High-Priority Alternatives

• Psoriatic arthritis: Can present with polyarticular involvement, elevated CRP, and negative RF—skin/nail findings are key differentiators 4, 1
• Reactive arthritis: Consider if recent conjunctivitis, urethritis, or GI/GU infection; HLA-B27 testing recommended 1, 3
• Polymyalgia rheumatica: Proximal muscle pain without true weakness, normal CK, absence of definite synovitis 1
• Viral arthritis: Parvovirus B19, hepatitis B/C, EBV can mimic early RA—symptoms resolving within 6 weeks suggest viral etiology 1
• Adult-onset Still's disease: High-spiking fevers, salmon-pink rash, ferritin >1,000 ng/mL 1

Initial Management Strategy

Symptomatic Treatment (Start Today)

• NSAIDs for symptomatic relief in mild inflammatory arthritis 3, 6
• Intra-articular corticosteroid injections if only 1-2 joints predominantly affected 3
• Avoid NSAIDs if inflammatory bowel disease suspected 3

Disease Activity Assessment

• Calculate Simplified Disease Activity Index (SDAI) using tender joint count, swollen joint count, patient global assessment, evaluator global assessment, and CRP 1
• SDAI targets: remission ≤3.3, low disease activity ≤11, moderate ≤26, high >26 1
• Document functional status using Health Assessment Questionnaire 1

Monitoring and Follow-Up

• Clinical reassessment every 2-4 weeks to monitor disease trajectory 3
• Repeat ESR and CRP at each visit 1
• If symptoms persist beyond 6 weeks with continued elevated inflammatory markers, probability of chronic inflammatory arthritis increases significantly 3

Rheumatology Referral (Urgent)

Referral Criteria

• Refer within 6 weeks of symptom onset if inflammatory arthritis suspected—early treatment prevents irreversible joint damage 1
• Refer earlier (within 2 weeks) if:
  • Any joint with disproportionate swelling (after excluding septic arthritis) 3
  • High disease activity (multiple swollen joints, markedly elevated CRP) 1
  • Poor prognostic features present (erosions on X-ray, high CRP, symmetric disease) 3

Information to Provide Rheumatology

• 28-joint count with specific documentation of tender and swollen joints 1
• Morning stiffness duration 3
• All serologic results (RF, anti-CCP, ANA, inflammatory markers) 1
• Baseline X-ray results 1
• SDAI or CDAI score 1

Treatment Escalation Plan (If RA Confirmed)

First-Line DMARD Therapy

• Methotrexate 15 mg weekly as first-line DMARD, escalating to 20-25 mg weekly 1, 7
• Add short-term low-dose prednisone (10-20 mg daily) as bridge therapy while awaiting DMARD effect 1, 8
• Folate supplementation 1 mg twice daily 7

Treatment Targets

• Target remission (SDAI ≤3.3) or low disease activity (SDAI ≤11) 1
• Reassess disease activity every 4-6 weeks 1
• If inadequate response after 3 months of methotrexate, consider triple DMARD therapy or adding biologic agent (TNF inhibitor) 1

Repeat Imaging Schedule

• Hand, wrist, and foot X-rays at 6 months and 12 months to monitor radiographic progression 1

Critical Pitfalls to Avoid

• Do NOT delay treatment waiting for positive serology—seronegative RA is common and has similar prognosis 1
• Do NOT dismiss diagnosis based on normal ESR/CRP alone—acute phase reactants can be normal even in active disease 1
• Do NOT rely solely on RF testing—anti-CCP is more specific and should always be ordered 2
• Do NOT miss psoriatic arthritis—always examine skin and nails thoroughly 4, 1
• Do NOT delay rheumatology referral beyond 6 weeks—early treatment prevents irreversible joint damage 1