What is the diagnostic approach for a patient with suspected rheumatoid arthritis?

Diagnosing Rheumatoid Arthritis

Diagnose rheumatoid arthritis by identifying definite clinical synovitis in at least one joint not explained by another disease, then confirm with serologic testing (RF and anti-CCP antibodies) and baseline imaging of hands, wrists, and feet. 1

Immediate Referral Criteria

Refer to a rheumatologist within 6 weeks of symptom onset if any of the following are present: 1, 2

• Small joints of hands or feet are affected 1
• More than one joint is involved 1
• Delay of 3 months or longer between symptom onset and seeking medical advice 1

Do not delay referral based on negative RF or normal inflammatory markers—these can be absent in 20-30% of RA cases. 3

Clinical Examination: The Foundation of Diagnosis

Focus on identifying definite synovitis (joint swelling), which is the cornerstone of RA diagnosis. 1, 3 Perform a systematic 28-joint examination assessing: 3

• Proximal interphalangeal joints (PIPs) 3
• Metacarpophalangeal joints (MCPs) 3
• Wrists 3
• Elbows 3
• Shoulders 3
• Knees 3

Morning stiffness lasting more than 30 minutes in and around joints is characteristic of RA and distinguishes it from osteoarthritis. 4, 5 The squeeze test of MCPs and metatarsophalangeal joints (MTPs) helps assess for clinical synovitis. 3

When Clinical Examination is Inconclusive

If inflammatory arthritis is suspected but swelling is not evident on examination, use ultrasound with Power Doppler to confirm synovitis—it detects synovitis 2.18-fold more frequently than clinical examination. 1 MRI detects synovitis 2.20-fold more frequently than clinical examination and is more sensitive than ultrasound in early stages. 1

Laboratory Testing Algorithm

First-Line Essential Tests

Order simultaneously at initial presentation: 3, 2

• Rheumatoid factor (RF) - sensitivity 60%, specificity 70% 3
• Anti-cyclic citrullinated peptide antibodies (anti-CCP/ACPA) - sensitivity 60%, specificity 90% 3, 2
• C-reactive protein (CRP) - preferred over ESR as it is more reliable and not age-dependent 1, 3
• Erythrocyte sedimentation rate (ESR) - for baseline inflammatory marker assessment 3, 2
• Complete blood count with differential - to assess for cytopenias before starting treatment 3, 2
• Comprehensive metabolic panel - including liver function, renal function, glucose, and urate levels 3, 2

Critical Clinical Pearls About Serology

Both RF and anti-CCP should be ordered simultaneously—do not wait for RF results before ordering anti-CCP. 2 High-positive RF or ACPA carries more diagnostic weight (3 points) than low-positive results (2 points) in the 2010 ACR/EULAR Classification Criteria. 2

Seronegative RA accounts for 20-30% of cases, so negative RF does not exclude RA. 3 If RF is negative and combination therapy is being considered, anti-CCP testing provides important prognostic information. 1, 2

Conditional Testing Based on Clinical Presentation

• Antinuclear antibodies (ANA) - if diagnosis remains uncertain to screen for other connective tissue diseases like lupus 3, 2
• HLA-B27 - if spondyloarthropathy is suspected (axial or entheseal involvement) 3, 2
• Urinalysis - part of standard initial workup 3, 2

Pre-Treatment Screening (If Biologic Therapy Anticipated)

Test for hepatitis B, hepatitis C, and tuberculosis before starting any biologic therapy. 3, 5

Imaging Studies: Structured Approach

Initial Imaging

Obtain conventional radiographs of hands, wrists, and feet bilaterally at baseline—this is the initial imaging technique to detect damage. 6, 1 Radiographic features in early disease include: 4

• Soft tissue swelling 4
• Periarticular osteopenia 4
• Uniform joint space narrowing 3
• Osseous erosions (if present, highly predictive for RA diagnosis and disease persistence) 3, 2

Advanced Imaging When Radiographs Are Normal

If conventional radiographs do not show damage and diagnostic doubt remains, use ultrasound or MRI—these can detect damage at an earlier time point, especially in early RA. 6, 1

Ultrasound with Power Doppler is superior to clinical examination for detecting inflammation and structural damage, and can detect synovitis that predicts disease progression. 6, 1, 3 It is particularly useful when patients with early arthritis do not meet the 2010 ACR/EULAR criteria. 6, 3

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. 6, 1, 3 The presence of bone marrow edema or both synovitis and erosion on MRI increases likelihood of developing RA (positive likelihood ratio 4.5 and 4.8, respectively). 6, 3

Applying the 2010 ACR/EULAR Classification Criteria

A score of ≥6/10 points is needed for definite RA classification. 3 The scoring system includes: 3

Joint Involvement (0-5 points):

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

• 10 joints = 5 points 3

Serology (0-3 points):

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

Acute Phase Reactants (0-1 point):

• Normal CRP and ESR = 0 points 3
• Abnormal CRP or ESR = 1 point 3

Duration of Symptoms (0-1 point):

• <6 weeks = 0 points 3
• ≥6 weeks = 1 point 3

Risk Stratification for Undifferentiated Arthritis

If a definite diagnosis cannot be reached and the patient has early undifferentiated arthritis, the following risk factors predict progression to RA: 1

• Number of swollen joints 1
• Elevated acute phase reactants (CRP/ESR) 1
• Positive rheumatoid factor 1
• Positive anti-CCP antibodies 1
• Imaging findings showing inflammation or early damage 1

Patients at risk of persistent arthritis should be started on disease-modifying antirheumatic drugs (DMARDs) as early as possible—ideally within 3 months—even if they do not fulfill classification criteria. 1

Critical Pitfalls to Avoid

Do not delay treatment waiting for positive serology—seronegative RA is common and has similar prognosis. 3 Do not dismiss the diagnosis based on normal ESR/CRP, as acute phase reactants are poor predictors and can be normal even in active disease. 3

Do not use CT, bone scan, or arthrography for RA diagnosis—these do not contribute to diagnosis or management. 6 MR arthrography and CT arthrography similarly do not contribute to diagnosis. 6

Differential Diagnosis Considerations

Distinguish osteoarthritis by usage-related pain, short morning stiffness (<30 minutes), age >40, and characteristic radiographic features (osteophytes, joint space narrowing) rather than inflammatory pattern. 1 Distal interphalangeal joints, first carpometacarpal joints, and first metatarsophalangeal joints are typically spared in RA but affected in osteoarthritis. 3

Exclude psoriatic arthritis, gout, and hemochromatosis, which can present with similar symptoms. 3 Normal uric acid effectively excludes gout as the primary diagnosis. 3