Rheumatoid Arthritis (RA) is a common, systemic autoimmune disease affecting 0.5-1% of the population. It is characterized by chronic inflammation of the synovium, which commonly leads to progressive joint destruction and in most cases, to disability and reduction of quality of life. Evidence gained over the last few years suggests that aggressive therapy given early in the disease has the greatest therapeutic potential.
The serum of RA patients contains a variety of antibodies directed against self-antigens. The most widely known of these autoantibodies is the rheumatoid factor (RF) antibody directed against the constant domain of IgG molecules. The presence of RF is one of the American College of Rheumatology’s criteria for the classification of RA. Although the RF test has good sensitivity for RA, it is not very specific for the disease as it can also be detected in the serum of patients with other rheumatic or inflammatory diseases and even in a substantial percentage of the healthy (elderly) population. For several years it has been recognized that antibodies to anti-perinuclear factor and anti-keratin are highly specific for RA. It was subsequently reported that both of these antibodies reacted with native filaggrin and are now referred to as anti-filaggrin antibodies. More recently it has been shown that all of these antibodies are directed to citrulline-containing epitopes. Citrulline is a nonstandard amino acid, as it is not incorporated into proteins during protein synthesis. It can, however, be generated via post-translational modification of arginine residues by the enzyme peptidyl arginine deiminase. In 1998, Schellekens and colleagues reported that linear peptides containing citrulline (CP) were very specific for RA antibodies (96%) in an ELISA based assay. Subsequent work demonstrated that cyclic variants of these peptides, termed cyclic citrullinated peptides (CCP), were equally specific for RA, but with a higher sensitivity than linear peptides. To improve the sensitivity of the CCP test further, several dedicated libraries of citrulline-containing peptides were screened with RA sera and a new set of peptides (CCP2) were discovered which gave superior performance compared to the CCP1 test. Over the last few years, many independent studies have confirmed the diagnostic performance of the CCP2 test. In 2007, the European League against Rheumatism (EULAR) published guidelines for the diagnosis of early RA, and the measurement of antibodies to anti-CCP was included as a serology marker.
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