These antibodies and anti-perinuclear factor and antifilaggrin antibodies target citrulline, a modified form of arginine produced through the action of pepitidyl-arginine-deaminase.
Called anti-cyclic citrullinated peptide antibodies (anti-CCP) test has a sensitivity of 50-70% and a specificity of 95-98% for rheumatoid arthritis.
A meta-analysis reports sensitivity and specificity of the anti-CCP test for rheumatoid arthritis of 67% and 95%, respectively (Nishimura).
Anti-CCP first highly specific biomarker with rheumatoid arthritis.
Has a greater specificity for rheumatoid arthritis.
Anti-cyclic citrullinated peptide (anti-CCP) antibodies are autoantibodies that target citrullinated proteins in the joints and are highly specific markers for rheumatoid arthritis (RA), with specificity exceeding 95% and sensitivity of approximately 67-70%.
Anti-CCP antibodies are part of the broader family of anti-citrullinated protein antibodies (ACPAs).
Citrullination is a post-translational modification where the enzyme peptidyl arginine deiminase converts arginine to citrulline in proteins.
In RA, ACPAs recognize various citrullinated proteins including fibrinogen, fibronectin, enolase, collagen type II, and histones.
Anti-CCP antibodies demonstrate superior specificity compared to rheumatoid factor (RF) for RA diagnosis.
In patients with early RA (<2 years), second-generation anti-CCP2 testing shows:
Sensitivity: 57% (range 51-63%)
Specificity: 96% (range 93-97%)
Positive likelihood ratio: 12.46
This compares favorably to RF, which has 69% sensitivity but only 85% specificity.
Anti-CCP antibodies are found in more than 75% of RA patients and are almost never found in those without the disease.
Anti-CCP positivity carries important prognostic implications:
Predicts radiographic progression and erosive disease more reliably than RF.
Associated with extra-articular manifestations.
Precedes clinical disease by several years when titers reach 3 times the upper limit of normal in at-risk persons, there is a 30-50% chance of RA diagnosis within 3-5 years.
IgA anti-CCP antibodies may predict diminished response to anti-TNF biologics.
The development of ACPAs represents a break in immune tolerance and is strongly associated with HLA-DRB1 shared epitope alleles.
Environmental factors, particularly cigarette smoking and periodontitis, promote protein citrullination and ACPA production.
For ACPA-positive smokers with two copies of the susceptibility shared epitope, the risk of RA is 20 times that of nonsmokers.
Initial ACPA production may occur at mucosal sites-periodontium, gut, or lung, distant from the joints, transitioning from localized IgA-mediated to systemic IgG-mediated autoimmunity before clinical arthritis develops.
Anti-CCP testing is recommended in the workup of patients with early symptoms of RA and is included in the ACR classification criteria for RA.
While highly specific for RA, anti-CCP antibodies can occasionally be detected in other conditions including psoriatic arthritis (10.6%), primary Sjogren syndrome (33.3%), systemic lupus erythematosus (16.6%), and unclassified rheumatism (20.9%).
The combination of anti-CCP and RF testing provides additional diagnostic value, with positive predictive values for RA reaching 74.3% when both are positive.