What is Anti-CCP (Anti-Cyclic Citrullinated Peptide)?
Anti-CCP is an autoantibody test used to diagnose rheumatoid arthritis with high specificity (96%) but moderate sensitivity (66%), making it excellent for ruling in RA when positive but less useful for ruling out disease when negative. 1
Clinical Utility and Test Characteristics
Anti-CCP antibodies are highly specific markers for rheumatoid arthritis, with pooled specificity of 96% (95% CI 0.94–0.97) and sensitivity of 66% (95% CI 0.60–0.71) compared to reference standards. 1 The diagnostic odds ratio of 43.05 means a patient with RA is 43 times more likely to test positive than someone without the disease. 1
Key Performance Metrics:
- Positive likelihood ratio of 15.39 - when anti-CCP is positive, the patient is 15.39 times more likely to be a true positive than false positive, meeting the threshold of >10 for clinical utility to rule in RA. 1
- Negative likelihood ratio indicates patients with negative anti-CCP are only 2.8 times more likely to be true negatives, falling short of the >10 threshold needed to reliably rule out disease. 1
- Specificity of 90% with moderate sensitivity of 60% according to ACR guidelines. 2
Role in Diagnosis and Prognosis
Anti-CCP should be ordered simultaneously with rheumatoid factor at initial presentation for any patient with suspected inflammatory arthritis, as these are cornerstone autoantibody tests for RA diagnosis. 2
Diagnostic Scoring:
- Negative RF and anti-CCP = 0 points in the 2010 ACR/EULAR classification criteria. 2
- Low positive RF or anti-CCP (≤3x upper limit normal) = 2 points. 2
- High positive RF or anti-CCP (>3x upper limit normal) = 3 points. 2
- A total score ≥6/10 across all criteria (joint involvement, serology, acute phase reactants, symptom duration) indicates definite RA. 2
Prognostic Implications:
- Anti-CCP positivity predicts more aggressive disease with higher risk of erosive joint damage and radiographic progression. 2, 3, 4
- Radiological defects occur significantly more often in anti-CCP positive patients (68.9% with defects were anti-CCP positive, p=0.001). 3
- Anti-CCP titer correlates with deformed joint count (r=0.224, p<0.05) and radiographic score (r=0.308, p<0.05). 4
- Higher baseline anti-CCP concentrations associate with better treatment response to abatacept, with significant improvements in patient-reported outcomes at 6 months. 5
Clinical Context and Interpretation
Seronegative RA (negative RF and anti-CCP) accounts for 20-30% of cases, so negative antibodies do not exclude the diagnosis. 2 The presence of clinical synovitis in at least one joint not explained by another disease remains the cornerstone of RA diagnosis, regardless of antibody status. 2
Important Caveats:
- Anti-CCP can be positive in 2.2% of Behçet's disease patients and rarely in other conditions, though specificity remains excellent at 97.8%. 4
- Different anti-CCP assays show variable performance - anti-CCP3 assays demonstrate slightly higher sensitivity (75%) compared to anti-CCP2 assays (63-72%) at fixed 92% specificity. 6
- RF positivity significantly co-occurs with anti-CCP positivity (p=0.002), and both together predict more severe disease. 3
When to Order Anti-CCP
Order anti-CCP testing for any patient presenting with:
- Symmetrical polyarthritis involving small joints (MCPs, PIPs, wrists, MTPs). 2
- Morning stiffness lasting >30 minutes with joint swelling. 2
- Elevated inflammatory markers (ESR, CRP) with clinical synovitis. 2
- Suspected inflammatory arthritis requiring differentiation from osteoarthritis, crystal arthropathy, or other conditions. 1, 2
Do not delay treatment waiting for positive serology - seronegative RA has similar prognosis and requires equally aggressive management. 2 Clinical synovitis with elevated inflammatory markers warrants DMARD therapy even with negative antibodies. 2