How to manage a patient with symmetric polyarthritis of 2 weeks duration, elevated Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP), and negative Anti-Streptolysin O (ASO) titre, Anti-Cyclic Citrullinated Peptide (Anti-CCP) antibodies, and Rheumatoid Factor (RF)?

Management of Seronegative Symmetric Polyarthritis with Elevated Inflammatory Markers

This patient requires urgent evaluation to exclude septic arthritis and other infectious causes, followed by initiation of symptomatic treatment with NSAIDs and close monitoring for disease evolution, as the 2-week duration is too early to definitively diagnose rheumatoid arthritis or initiate disease-modifying therapy.

Immediate Diagnostic Priorities

Rule Out Infectious Causes First

• Arthrocentesis should be performed urgently if any single joint is disproportionately affected to exclude septic arthritis, which requires immediate treatment 1
• Synovial fluid analysis must include cell count with differential, Gram stain, and aerobic/anaerobic cultures 1
• Blood cultures should be obtained if fever is present or acute onset symptoms suggest bacteremia 1
• In patients from endemic areas or with atypical presentations, infectious causes including tuberculosis and leprosy must be considered before starting immunosuppression, even when the presentation mimics rheumatoid arthritis 2

Complete the Diagnostic Workup

• All possible causes of arthritis (autoimmune, infectious, malignancy, crystal arthropathy, viral) must be considered through complete history and thorough physical examination 3
• Complete blood count with differential to assess for leukocytosis, anemia, or other hematologic abnormalities 4, 1
• Plain radiographs of hands, wrists, and feet should be performed at baseline, as the presence of erosions is predictive for rheumatoid arthritis development and disease persistence 3
• Repeat radiographs within 1 year to assess for progression 3
• Consider testing for additional autoantibodies (ANA) if connective tissue disease is suspected 3
• Serum uric acid and consider joint aspiration for crystal analysis to exclude gout or pseudogout 3

Clinical Context and Differential Diagnosis

Understanding the 2-Week Timeline

• At 2 weeks duration, this represents undifferentiated peripheral inflammatory arthritis (UPIA), as definitive diagnosis of rheumatoid arthritis requires longer observation 3
• Disease duration ≥6 weeks is a predictor of persistent inflammatory arthritis 3
• Negative RF, anti-CCP, and ASO titre do not exclude progression to rheumatoid arthritis, as approximately 20-30% of RA patients remain seronegative 3, 5

Key Prognostic Features to Document

• Morning stiffness duration (>30 minutes suggests inflammatory arthritis) 3
• Number of joints involved (≥3 joints predicts persistence) 3
• Pattern of joint involvement (symmetric small joint involvement suggests RA) 3, 4
• Functional impairment using standardized assessment 3
• Presence of extra-articular manifestations 3

Initial Management Strategy

Symptomatic Treatment

• NSAIDs should be initiated for symptomatic relief in patients with mild inflammatory arthritis 3
• Analgesics may be added for pain control 3
• Intra-articular corticosteroid injections are an option if only one or two joints are predominantly affected 3

When to Avoid Premature DMARD Initiation

• At 2 weeks duration without confirmed diagnosis, disease-modifying antirheumatic drugs (DMARDs) should NOT be initiated 3, 6
• Methotrexate is indicated only after diagnosis is established and inadequate response to NSAIDs is documented 6
• The critical pitfall is starting immunosuppression before excluding infectious causes, particularly in patients from endemic areas 2

Monitoring and Follow-Up Protocol

Short-Term Monitoring (First 6 Weeks)

• ESR and CRP should be repeated when clinically relevant to assess disease trajectory 3, 1
• Clinical reassessment every 2-4 weeks to monitor for disease persistence or resolution 3
• If symptoms persist beyond 6 weeks with continued elevated inflammatory markers, this significantly increases probability of chronic inflammatory arthritis 3

Disease Activity Assessment

• Document number of tender and swollen joints at each visit 3
• Assess morning stiffness duration 3
• Monitor functional status 3
• Disease activity should be monitored, though no specific tool can be recommended for UPIA 3

When to Escalate Treatment

Criteria for Rheumatology Referral

• Early referral to rheumatology should be considered at grade 2 symptoms (moderate disease activity) before starting corticosteroids 3
• Persistence of symptoms beyond 6 weeks with elevated inflammatory markers 3
• Development of erosions on radiography 3
• Significant functional impairment despite NSAIDs 6

Indications for Systemic Corticosteroids

• Most patients with confirmed inflammatory arthritis will require systemic corticosteroids at moderate doses of 10-20 mg prednisone daily 3
• Corticosteroids should be tapered as rapidly as possible according to clinical situation 3
• For grade 2 inflammatory arthritis, prednisone 10-20 mg/day is recommended 3

DMARD Initiation Criteria

• Methotrexate should only be started after RA diagnosis is established and patient has had insufficient response to adequate trial of NSAIDs 6
• Combined use of methotrexate with other DMARDs has not been fully studied in early disease 6
• If diagnosis evolves to confirmed RA with poor prognostic markers (positive anti-CCP if it converts, erosions, high disease activity), biological DMARDs may be considered in addition to synthetic DMARDs 3

Critical Pitfalls to Avoid

• Do NOT start immunosuppressive therapy at 2 weeks without excluding infectious causes 2
• Do NOT assume seronegative status excludes rheumatoid arthritis—20-30% of RA patients are seronegative for both RF and anti-CCP 5, 7
• Normal inflammatory markers do not exclude inflammatory arthritis, particularly in seronegative disease 5
• Elevated ESR and CRP at this stage are useful for diagnosis and prognosis but do not establish specific etiology 3
• Anti-CCP antibodies can be helpful in differential diagnosis as they are rarely detected in non-RA inflammatory arthritis but almost constant in RA 3
• Repeat autoantibody testing may be warranted if initial tests are negative but clinical suspicion remains high, as seroconversion can occur 8