The CCP test is a chemiluminescent immunoassay (CLIA), for use on IDS automated analyzers. It is used for the quantitative determination of the specific IgG antibodies directed against cyclic citrullinated peptide (CCP), in human samples of serum or plasma (EDTA and Heparin).
Rheumatoid arthritis (RA) is a chronic, progressive, autoimmune inflammatory polyarthritis affecting the synovial joints. RA is one of the most widespread autoimmune disorders (1-2% of the European population) and in the majority of cases its clinical evolution leads to serious limitation of joint function and grave invalidity; early diagnosis of RA therefore has important clinical implications, since therapy begun in the early stages of the disease has been shown to be effective in limiting or reducing the progression of the lesions and in improving patients’ quality of life.
Use of the rheumatoid factor (RF),(1) a serologic marker that is sensitive but not particularly specific, has recently been flanked by assays for anti-citrullinated peptide autoantibodies (anti-citrulline or CCP),(2) which feature high sensitivity and a high diagnostic and prognostic predictive value in rheumatoid arthritis patients.
Citrullination is a biochemical process that targets the proteins present in the joint cavity as the result of phlogistic events. The reaction is catalyzed by the calcium-dependent peptidylarginine deiminase (PAD) enzyme, which deaminates the arginine residues of filaggrin (an aggregated filamentous protein involved in organization of the cytoskeleton of the squamous epithelia) and of the other cavity proteins. Following these modifications, the citrullinated residues are recognized by the specific antibodies.(3)
Citrullination of the proteins present in the joint cavity is a process common to all effusions,(4) but only subjects who are genetically predisposed to develop RA (HLA-DRB1) produce autoantibodies against the citrullinated peptides.(5)
These antibodies show a very high specificity for RA. First-generation peptides (CCP1) were used as coating in the early ELISA tests and showed good performance in terms of sensitivity for RA (50-60%) and of specificity (95-99%).(6) Use of second-generation cyclic citrullinated peptides (CCP2) has considerably improved sensitivity for RA (80 %) while maintaining high specificity (98-99%).(7)
The good performance of the second-generation CCP tests is reported in a highly significant number of recent scientific publications: specificity is probably actually higher than that reported in literature, since it has been demonstrated that positivity for anti-CCP can be manifested even 10 years prior to the appearance of RA symptoms(8); consequently, a high anti-CCP antibody titer in an asymptomatic subject should be considered predictive of RA rather than a false positive.
Anti-CCP antibodies have also been shown to possess a high predictive value for development of erosive joint lesions; the anti-CCP antibodies would in fact seem to represent the only early parameter (including clinical parameters) capable of indicating that a patient is evolving toward an erosive form of RA.(9)
Their determination is also useful in diagnosing RA in infancy and in differentiating RA from the collagenopathies with concomitant arthritis.(10)
Use of the anti-CCP assay in association with RF assay maximizes the sensitivity/specificity ratio. It must not be forgotten that 15-20% of RAs are positive for RF but negative for anti-CCP and that about half of the RAs negative for RF are anti-CCP positive. Simultaneous positivity for RF and CCP has a positive predictive value of 100%.
As regards monitoring of RA patients who are positive for anti-CCP, it would seem that serial assay of these autoantibodies does not correlate with clinical course and with response to drug treatment.
- Wener MH. Rheumatoid Factors. Manual of Clinical Laboratory Immunology, NR Rose et al. American Society of Microbiology Press, 961-972 ( 2002 ).
- Schellekens GA, Visser H, De Jong BA, Van de Hoogen FH, Hazens JM, Breedveld FC, et al. The diagnostic properties of rheumatoid arthritis recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000; 43: 155-63.
- Baeten D, Peene I, Union A, Sebbag M, Serre G, Veys EM, et al. Specific presence of intracellular citrullinate proteins in rheumatoid arthritis synovium: relevance to antifilaggrin antibodies. Arthritis Rheum 2001; 44: 2218-62.
- Asaga H, Yamada M, Senshu T. Selective determination of vimentin in calcium ionophore-induced apoptosis of mouse peritoneal macrophages. Biochem Biophys Res Commun 1998; 243: 641-6.
- Verpoort KN, van Gaalen FA, van der Helm-van et al. Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis. Arthritis Rheum 2005; 52:3058-62.
- Bizzaro N, Mazzanti G, Tonutti E et al. Diagnostic accuracy of the anti-citrulline antibody assay for rheumatoid arthritis. Clin Chem 2001; 47: 1089-93.
- Van Gaalen FA, Visser H, Huizinga TW. A comparison of the diagnostic accuracy and prognostic value of the first and second anti-cyclic citrullinated peptides autoantibody tests for rheumatoid arthritis. Ann Rheum Dis 2005; 64: 1510-2.
- Rantapaa-Dahlqvist S, de Jong BAW, Berglin E et al. Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. Arthritis Rheum 2003; 48: 2741-9.
- Visser H, le Cessie S, Vos K et al. How to diagnose rheumatoid arthritis early. A prediction model for persistent (erosive) arthritis. Arthritis Rheum 2002; 46: 357-65.
- Jansen LMA, van der Horst-Bruinsma IE, van Shaardenburg D, van de Stadt RJ, de Koning MHMT, Dukmans BAC. Rheumatoid factor and antibodies to cyclic citrullinated peptide differentiate rheumatoid arthritis from undifferentiated polyarthritis in patients with early arthritis. J Rheumatol 2002; 29( 10 ): 2074-2076.