Laboratory Evaluation for Rheumatoid Arthritis
Order rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPA/anti-CCP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), complete blood count with differential, comprehensive metabolic panel, and urinalysis as the essential initial laboratory workup for suspected rheumatoid arthritis. 1, 2
Core Serologic Tests
RF and ACPA/anti-CCP testing are mandatory for all patients with suspected RA, as these provide both diagnostic and prognostic information. 3, 2
- Anti-CCP antibodies have the highest specificity (90%) with moderate sensitivity (60%) and should be ordered in all suspected cases 1, 2
- Rheumatoid factor has lower specificity (70%) but similar sensitivity to anti-CCP and remains an important diagnostic marker 1, 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
- Combined detection of RF and anti-CCP achieves 90.2% sensitivity and 83.3% specificity for RA diagnosis 4
Critical Caveat About Seronegative Disease
Seronegative RA accounts for 20-30% of cases, so negative RF does not exclude the diagnosis. 1, 5 Do not delay treatment or dismiss the diagnosis based solely on negative serology, as seronegative RA has similar prognosis and requires the same aggressive management. 5
Inflammatory Markers
CRP is preferred over ESR because it is more reliable, not age-dependent, and provides a simple, validated, reproducible test. 1, 2
- ESR and CRP should both be performed at baseline for diagnostic and prognostic purposes 3, 2
- Elevated CRP, especially at high levels, has diagnostic value for predicting RA 3
- Repeat ESR and CRP when clinically relevant to monitor disease activity and treatment response 3, 5
Critical Caveat About Normal Inflammatory Markers
Approximately 40-50% of patients with active RA can have normal acute phase reactants—do not dismiss the diagnosis based solely on normal ESR/CRP. 1, 6 ESR and CRP are poor predictors of RA and can be normal even in active disease. 5, 6 The 2010 ACR/EULAR criteria assign only 1 point for abnormal CRP or ESR, while joint involvement can contribute up to 5 points, emphasizing that clinical synovitis is more important than inflammatory markers. 5
Baseline Laboratory Assessment
Complete blood count with differential should be ordered to assess for cytopenias before starting treatment and calculate neutrophil-to-lymphocyte ratio. 1, 2
Comprehensive metabolic panel including liver function tests, renal function, glucose, and uric acid levels should be ordered. 1, 2 This establishes baseline organ function before initiating disease-modifying antirheumatic drugs (DMARDs). 1
Urinalysis should be performed as part of standard initial workup. 3, 1, 2
Conditional Testing Based on Clinical Context
Antinuclear antibodies (ANA) can be used to screen for other connective tissue diseases if the diagnosis is uncertain or if features suggest overlap syndromes. 3, 5
HLA-B27 typing may be considered if spondyloarthropathy is being considered based on axial or entheseal involvement. 3, 5
Pre-Treatment Screening (Once Diagnosis Established)
Before initiating biologic or targeted synthetic DMARDs:
- Tuberculosis screening with tuberculin skin test or interferon-gamma release assay should be performed regardless of risk factors 1
- Hepatitis B surface antigen, surface antibody, and core antibody should be tested 1, 7
- Hepatitis C antibody should be tested 1, 7
Algorithmic Approach to Laboratory Interpretation
If RF and/or ACPA positive with elevated CRP/ESR and clinical synovitis: High probability of RA—proceed with treatment planning 2, 4
If RF and ACPA both negative but elevated CRP/ESR with clinical synovitis: Consider seronegative RA (20-30% of cases)—do not delay treatment 1, 5
If RF and/or ACPA positive but normal CRP/ESR: RA remains possible as 40-50% have normal inflammatory markers—prioritize clinical examination findings 1, 6
If all serologies negative and normal inflammatory markers but persistent clinical synovitis: Consider advanced imaging (ultrasound or MRI) to detect subclinical inflammation 2, 5
Common Pitfalls to Avoid
Do not wait for positive serology to initiate treatment, as seronegative RA is common and has similar prognosis. 5
Do not dismiss RA based on normal ESR/CRP alone, as these are poor predictors and can be normal in 40-50% of active disease. 1, 6
Do not order only RF without anti-CCP, as combined testing improves diagnostic accuracy to 90.2% sensitivity and 83.3% specificity. 4
Do not forget pre-treatment screening for hepatitis B, hepatitis C, and tuberculosis before starting biologic agents, as this is mandatory. 1, 7