What is anti-CCP (anti-cyclic citrullinated peptide)?

Anti-CCP: A Highly Specific Biomarker for Rheumatoid Arthritis

Anti-CCP (anti-cyclic citrullinated peptide) is a highly specific antibody biomarker for rheumatoid arthritis with approximately 96% specificity and 66% sensitivity, making it significantly more specific than rheumatoid factor for diagnosing RA. 1

Definition and Basic Characteristics

• Anti-CCP antibodies are autoantibodies that target citrullinated proteins, which are proteins containing the modified amino acid citrulline 2
• These antibodies are a collection of anti-citrullinated protein antibodies (ACPA) that can recognize multiple citrullinated proteins in the body 3
• Anti-CCP testing measures antibodies directed against synthetic cyclic citrullinated peptides designed to detect these autoantibodies 4
• The concentration of anti-CCP IgG antibodies can be substantial, estimated at least 30 μg/ml in patients with high anti-CCP levels 3

Diagnostic Performance

• Anti-CCP has superior specificity (96%, 95% CI 0.94-0.97) compared to rheumatoid factor (70-85%) 5, 1
• The sensitivity of anti-CCP is moderate at approximately 66% (95% CI 0.60-0.71) 5, 1
• The diagnostic odds ratio for anti-CCP is 43.05 (95% CI 32.00-57.93), indicating that a person with RA is 43 times more likely to test positive than someone without RA 5
• Positive likelihood ratio is 15.39, making a positive result highly reliable for confirming RA diagnosis 5, 1
• Negative likelihood ratio is 0.35, meaning a negative result doesn't strongly rule out RA 5

Clinical Significance

• Anti-CCP antibodies can be detected very early in the disease course, often before clinical manifestations are fully apparent 1, 4
• Anti-CCP positivity is associated with more severe disease progression and worse radiographic outcomes 1
• The presence of anti-CCP increases the probability of developing persistent synovitis 2
• Anti-CCP is included in the 2010 American College of Rheumatology/EULAR classification criteria for rheumatoid arthritis 2

Isotype Distribution

• While IgG anti-CCP is most commonly measured, IgA and IgM isotypes also exist 6
• IgG, IgA, and IgM anti-CCP antibodies have been found in 74.8%, 52.9%, and 44.5% of RA patients, respectively 6
• IgM anti-CCP antibodies are more frequently found in early RA compared to longstanding disease, suggesting they are generated during the initial immune response 6

Clinical Applications

• Both anti-CCP and RF should be performed in the evaluation of patients with undifferentiated peripheral inflammatory arthritis 1, 2
• Anti-CCP testing is particularly valuable when RF is negative but clinical suspicion for RA remains high 2
• The European League Against Rheumatism (EULAR) recommends measuring anti-CCP in every patient presenting with early arthritis as a predictor of persistent and erosive disease 2
• Anti-CCP positivity helps identify patients who should start disease-modifying antirheumatic drugs (DMARDs) early, even before fulfilling all classification criteria for RA 2

Important Caveats

• Anti-CCP can occasionally be positive in other conditions, including:
  • Primary Sjögren syndrome (22.1% in one study) 7
  • Bronchiectasis (particularly in those who may later develop RA) 5
• A negative anti-CCP result does not exclude RA diagnosis due to its moderate sensitivity 1
• Approximately 30-40% of RA patients may be anti-CCP negative 1
• Both anti-CCP and RF should be used together for optimal diagnostic accuracy 1, 8

Relationship with Genetic Factors

• Anti-CCP antibody presence is significantly associated with HLA-DRB1 shared epitope alleles 6
• The combination of genetic factors and anti-CCP positivity may help identify patients at higher risk for aggressive disease 2