Does a positive anti-CCP test identify a distinct arthritis entity?

A new era began when analyses identifying 'anti-citrullinated protein antibodies' (ACPA) were introduced for the diagnosis of arthritis. The question of whether ACPA-positive patients constitute a distinct clinical entity presently attracts great interest. In a previous issue of Arthritis Research and Therapy Annette van der Helm-van Mil and colleagues give a detailed description of clinical characteristics in very early rheumatoid arthritis (RA) at presentation and during 4 years, comparing patients with and without antibodies to cyclic citrullinated peptide (CCP) [1].ACPA constitute a growing family of autoantibodies, in which the first member (anti-perinuclear factor) was described over 40 years ago. However, the major breakthrough came with the important series of investigations by Walther van Venrooij and colleagues, who discovered the crucial role of post-translationally citrullinated peptide epitopes and developed the anti-CCP test. These workers also described the test's remarkable diagnostic specificity for RA, with a sensitivity comparable with that for rheumatoid factor (RF) (reviewed in [2]).Although the aetiology is unknown, several genetic and environmental factors are obviously important in RA. The HLA-DRB1 product 'shared epitope' (SE) is the best known genetic factor associated with RA, and cigarette smoking is the best described environmental susceptibility factor. A gene–environment interaction has been shown for SE and smoking regarding susceptibility to RF-positive RA [3,4], and the presence of anti-CCP antibodies (CCP+) correlates strongly with the presence of the SE [5]. It has been demonstrated that major histocompatibility complex class II molecules expressing the SE can bind and present citrullinated peptides to T cells [6], and that a combination of SE-positive (SE+) and CCP+ is highly predictive of future RF-positive RA [7]. Contrary to nonsmokers, bronchoalveolar lavage cells from cigarette smokers have been reported to express citrullin