Anti-CCP antibodies: the past, the present and the future

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by autoantibodies against citrullinated antigens. The importance of citrulline for the epitopes bound by these autoantibodies, referred to as ACPA (anti-citrullinated peptide/protein antibodies), was first described in 1998. In addition to citrullinated proteins, cyclic citrullinated peptides (CCP) can also be used as test substrates for detecting ACPA. The standard test for these antibodies is the second-generation CCP (CCP2) test, which is one of the best in terms of sensitivity and specificity. The generation of ACPA is an early event in the disease course, and is dependent on the presence of certain MHC class II alleles. ACPA in the inflamed synovium have been shown to associate with citrullinated antigens to form immune complexes, resulting in progression of the inflammatory process. The involvement of ACPA in the chronicity of RA is probably the reason why ACPA-positive patients have a more erosive disease course than ACPA-negative patients. The presence of ACPA has been included in the 2010 RA classification criteria. Thus, it is important to further standardize ACPA testing, for example by including an internal serum standard, which may lead to a better distinction between low and high ACPA levels.

Key Points

  • Anti-citrullinated peptide/protein antibodies (ACPA) are present in early disease, and are highly specific for rheumatoid arthritis (RA)

  • Data from the literature show that the second-generation anti-cyclic citrullinated peptide antibody (CCP2) test is one of the best tools for detecting ACPA

  • The CCP2 test enables the clinician to distinguish two subclasses of patients with early RA (ACPA-positive and ACPA-negative), each with their own genetic background and future disease course

  • ACPA have recently been added to the RA classification criteria jointly developed by the American College of Rheumatology and the European League Against Rheumatism

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Figure 1: Typical immunofluorescence staining pattern of a buccal mucosa cell by APF-positive RA serum.
Figure 2: Citrullination of proteins.
Figure 3: The hypothesized role of citrullination in RA.

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Acknowledgements

Our work was supported in part by the Dutch Arthritis Association and the Dutch Technology Foundation (STW).

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All authors took part in researching data for the article. W. J. van Venrooij and G. J. M. Pruijn discussed the content. All authors contributed equally to writing the article and reviewing/editing the manuscript before submission.

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Correspondence to Walther J. van Venrooij.

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van Venrooij, W., van Beers, J. & Pruijn, G. Anti-CCP antibodies: the past, the present and the future. Nat Rev Rheumatol 7, 391–398 (2011). https://doi.org/10.1038/nrrheum.2011.76

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