Since its appearance on the market in the second half of 2002, the diagnostic properties of the CCP2 test have been studied by many laboratories. This resulted in more than 120 publications dealing with this subject. The accumulated data, including only papers that appeared in PubMed till December 2006, are given in Table 1. It is clear that the accumulated data confirm the earliest reports on specificity and sensitivity of the CCP2 test. The anti-CCP2 test demonstrates an RF-like sensitivity with a very high specificity for RA (see also recent reviews: [2, 3]). It is also commonly recognized that anti-CCP2 antibody may be present in up to 40% of RF-negative RA sera [4, 5].
The anti-CCP2 test enables clinicians to distinguish RA patients from other arthritic diseases, especially in cases where the RF test is not discriminative. This is, for example, the case with chronic hepatitis C virus (HCV) infection, a disease that can easily be misdiagnosed as it often reveals RA-like arthropathies and, in many cases, is accompanied by a positive RF. Several examples of such studies are given in recent reviews on this subject .
Recently, there is also an interest to compare the diagnostic potential of anti-CCP2 with novel tests based on the use of a citrullinated antigen (for example, MCV = anti-mutated citrullinated vimentin , CPA = citrullinated protein antibodies, VCP = anti-viral citrullinated protein , antihuman fibrinogen alpha [9, 10], and CCP3 ). For a reliable comparison of these tests, it is essential that their performance is assessed under the same conditions, e.g., the sensitivities of the tests should be determined at the same level of specificity. Good examples of such stratified studies have been carried out recently by van der Cruijssen et al.  and Dejaco et al. . For example, Dejaco et al.  showed, in a large cohort of patients (>600), that at a specificity of 98.7%, being the specificity of the anti-CCP2 test, the sensitivity of the anti-MCV test is 53.7% as opposed to 70.1% for the anti-CCP test. Coenen et al.  compared several commercial tests, including a very recent CCP3 test from Inova. At the cut-offs recommended by the various manufacturers, the positive predictive value of the three commercial CCP2 tests is about 90% with a specificity of around 96%. The specificity of the other tests (CCP3 = 88%, MCV = 90%, CPA = 94%) is lower as are their positive predictive values . These numbers may improve a little bit when the cut-off values are adjusted to more realistic data; nevertheless, the data allow the statement that, in absolute percentages, none of the tests performs better than the anti-CCP2 test. They also seem to indicate that some tests detect RA patient groups that are negative in the anti-CCP test, illustrating again that the autoantibody repertoire of RA patients is very heterogeneous.
Another risk for the specificity of a test that is based on a citrullinated antigen is the possibility that antibodies are not directed exclusively to the citrulline-containing epitope but also to other possibly overlapping epitopes present in the substrate antigen. This is particularly important when citrullinated versions of proteins like vimentin or fibrinogen are used. For example, it is known that antibodies to vimentin are present in several diseases different from RA [12, 13]. This particular problem has been addressed for CCP2 by Vannini et al. . They used ELISA plates containing the control CCP2 antigens (Arg instead of Cit in the same peptide context), produced and made available by Euro-Diagnostica, Arnhem, The Netherlands, in parallel to the normal CCP2 test. The results of these comparative studies showed that in RA and most non-RA rheumatic disease sera, anti-CCP reactivity indeed is citrulline-dependent. However, in some patients, particularly autoimmune hepatitis patients, citrulline-independent reactivity with the antigen may occur. A positive CCP test in a rheumatic disease (almost always citrulline-specific) may thus suggest the future development of RA as has been suggested by several studies [15, 16]. A positive test in a nonrheumatic disease (very often not citrulline-specific), for example, liver disease, should be interpreted with care .