Citrullinated (cit-) epitope detection is an evolving science with different substrates being proposed continuously1–4. Given all the published enthusiasm with anti-cyclic citrullinated peptide (CCP), why does the test need to be improved? It is assumed that the cit-epitopes targeted in cit-peptides/proteins are all detected by anti-CCP and are invariable in the various individuals during the phases of disease. That premise may be incorrect.
Recent objective critical evaluation of anti-CCP is severe. Its added value in rheumatoid arthritis (RA) diagnostics, over and above previously existing clinical and laboratory tools, is deemed marginal5. The huge anti-CCP literature contains recurring inconsistencies suggesting that authors are using the same test to measure different things in a very heterogeneous disease. Moreover, it is difficult to understand how a test can be associated with more severe evolution in early RA6 and also be positive without arthritis for 10 to 15 years before people get sick7–10. How does one reconcile that?
The solution of Chibnik, et al in this issue of The Journal7 is to pay more attention to titers of anti-CCP to explain the transition from pre-RA to RA. Just having anti-CCP is not sufficient; also important is how much one has. The higher the titer, the shorter the interval to disease onset! Titers rise steadily until disease onset and then stabilize, as is the current experience in established disease. That the titers rise near RA onset has already been suggested8 and is convincingly confirmed here7. What does that mean exactly? Either the disease manifests itself only when a sufficient level of autoantibody is reached (quantitative change) or when a given autoantibody emerges whose specificity is associated with disease onset (qualitative change). The 2 explanations are not mutually exclusive, as maturation of an immune response is accompanied by rising titers and epitope dominance.
http://jrheum.org/content/36/4/663.full