What is the appropriate workup and treatment for a patient presenting with symptoms suggestive of rheumatoid arthritis (RA), including joint pain, swelling, and stiffness, particularly in the hands and feet?

Rheumatoid Arthritis Workup

For a patient with joint pain, swelling, and stiffness in the hands and feet, immediately order RF, anti-CCP antibodies, CRP, ESR, CBC with differential, comprehensive metabolic panel, and bilateral X-rays of hands, wrists, and feet, then refer to rheumatology within 6 weeks of symptom onset. 1

Initial Clinical Assessment

Key Physical Examination Findings

• Identify definite clinical synovitis (soft, boggy joint swelling from inflammation, not hard bony enlargement) in at least one joint not explained by another disease—this is the cornerstone of RA diagnosis. 1, 2

• Perform a squeeze test of MCPs and MTPs to assess for tenderness, which indicates inflammatory synovitis. 1, 2

• Document symmetric involvement of small joints, particularly MCPs, PIPs, wrists, and MTPs—this pattern is characteristic of RA. 1, 2

• Assess morning stiffness duration—stiffness lasting ≥30 minutes (typically ≥1 hour) strongly suggests inflammatory arthritis rather than osteoarthritis where stiffness lasts <30 minutes. 2, 3

• Examine for spared joints—DIPs, first carpometacarpal joints, and first MTPs are typically spared in RA, which helps differentiate from osteoarthritis. 1

• Perform a 28-joint count examining PIPs, MCPs, wrists, elbows, shoulders, and knees for tenderness and swelling to quantify disease activity. 1, 4

Essential Laboratory Workup

First-Line Serologic Tests

• Order both RF and anti-CCP (ACPA) simultaneously at initial presentation—these are cornerstone autoantibody tests for RA diagnosis and prognosis. 1, 5, 6

  • Anti-CCP has high specificity (90%) with moderate sensitivity (60%). 1
  • RF has lower specificity (70%) with similar sensitivity to anti-CCP. 1
  • Do not delay treatment waiting for positive serology—seronegative RA accounts for 20-30% of cases and has similar prognosis. 1

• Measure CRP and ESR at baseline for diagnostic and prognostic purposes, with CRP preferred for ongoing monitoring as it is more reliable and not age-dependent. 1, 5, 6

  • Critical pitfall: Do not dismiss RA diagnosis based on normal CRP/ESR—acute phase reactants can be normal even in active disease. 1

Additional Laboratory Tests

• CBC with differential to assess for cytopenias before starting treatment and calculate neutrophil-to-lymphocyte ratio. 1

• Comprehensive metabolic panel including liver function tests, renal function, glucose, and urate levels for baseline assessment and monitoring. 1

• Urinalysis as part of standard initial workup. 1

• ANA testing if diagnosis remains uncertain to screen for other connective tissue diseases like lupus. 1

• HLA-B27 typing if spondyloarthropathy is being considered (axial or entheseal involvement). 1

Pre-Treatment Screening (Before Starting Biologics)

• Screen for hepatitis B, hepatitis C, and tuberculosis before initiating any biologic therapy—this is mandatory per ACR guidelines. 1, 5, 6

Imaging Studies

Baseline Radiographs

• Obtain bilateral hand, wrist, and foot X-rays at initial presentation to assess for erosions and establish baseline for monitoring structural damage progression. 1

  • Look for periarticular osteopenia, uniform joint space narrowing, and marginal erosions. 1
  • Erosions on baseline radiographs are highly predictive for RA diagnosis and disease persistence. 1

• Repeat X-rays at 6 months and 12 months to monitor radiographic progression. 1

Advanced Imaging (When Diagnosis Uncertain)

• Ultrasound with Power Doppler is superior to clinical examination for detecting subclinical synovitis when diagnosis is uncertain—it is 75% more accurate than physical examination alone. 1

• MRI with IV contrast is more sensitive than ultrasound in early stages and detects bone marrow edema (osteitis), which is the best single predictor of future disease progression and functional deterioration. 1

Diagnostic Scoring System

2010 ACR/EULAR Classification Criteria

A score of ≥6/10 points is needed for definite RA classification. 1

• Joint involvement scoring: 1

  • 1 large joint = 0 points
  • 2-10 large joints = 1 point
  • 1-3 small joints = 2 points
  • 4-10 small joints = 3 points

  • 10 joints = 5 points

• Serology scoring: 1

  • Negative RF and ACPA = 0 points
  • Low positive RF or ACPA = 2 points
  • High positive RF or ACPA = 3 points

• Acute phase reactants: 1

  • Normal CRP and ESR = 0 points
  • Abnormal CRP or ESR = 1 point

• Duration of symptoms: 1

  • <6 weeks = 0 points
  • ≥6 weeks = 1 point

Rheumatology Referral Timing

Urgent Referral (Within 6 Weeks)

• Refer any patient with joint swelling in more than one joint to rheumatology within 6 weeks of symptom onset—early treatment prevents irreversible joint damage. 1, 3, 5, 6

• Immediate referral criteria: 3

  • Morning stiffness ≥30 minutes
  • Elevated inflammatory markers (CRP or ESR) with joint symptoms
  • Positive RF or anti-CCP, especially if high-titer
  • Persistent joint swelling beyond 4 weeks with inflammatory features

Initial Treatment Strategy (If RA Confirmed)

First-Line DMARD Therapy

• Start methotrexate 15 mg weekly immediately as first-line DMARD without delaying for complete serologic workup—this is the anchor drug for RA treatment. 1, 7, 5, 6, 8

  • Plan to escalate to 20-25 mg weekly based on response. 1
  • Maximum dose should not ordinarily exceed 30 mg/week. 7

• Add short-term low-dose prednisone (10-20 mg daily) as bridge therapy while awaiting DMARD effect. 1

• Methotrexate precautions: 1, 7

  • Use with caution in patients with hematologic abnormalities
  • Use with caution in patients with active infections
  • Ensure adequate renal function (creatinine clearance >60 mL/min for high-dose therapy)

Treatment Target and Monitoring

• The primary target is remission (SDAI ≤3.3) or low disease activity (SDAI ≤11). 1, 4

• Reassess disease activity every 4-6 weeks using composite measures (SDAI, CDAI, or DAS28). 1, 4

  • SDAI is preferred over DAS28 when CRP is elevated as it provides more stringent disease activity assessment. 1
  • CDAI can be used when acute phase reactants are normal. 1

• If inadequate response after 3 months of methotrexate, consider triple DMARD therapy or adding a biologic agent such as a TNF inhibitor. 1, 8

Critical Pitfalls to Avoid

• Do not delay treatment waiting for positive serology—20-30% of RA cases are seronegative with similar prognosis. 1

• Do not dismiss diagnosis based on normal ESR/CRP—inflammatory markers are poor predictors and can be normal even in active disease. 1

• Do not rely solely on clinical examination—ultrasound and MRI may reveal subclinical inflammation not detected on physical exam. 1, 2

• Do not wait beyond 6 weeks to refer—multiple studies show better outcomes when treatment starts earlier, preventing irreversible joint damage. 1, 3