Autoantibodies binding to citrullinated telopeptide of type II collagen and to cyclic citrullinated peptides predict synergistically the development of seropositive rheumatoid arthritis Short running title: Autoantibodies to citrullinated collagens and anti-CCPs in RA patients

Objectives: To find out whether autoantibodies to citrullinated telopeptides of type I and II collagens and to cyclic citrullinated peptides (CCPs) predict the development of rheumatoid arthritis (RA). Methods: A case-control study (matched for sex, age and municipality) was nested within a Finnish cohort of 19072 adults who had neither arthritis nor a history of it at the baseline examination during 1973-77. 124 subjects developed RA by late 1989 and of them 89 were positive for rheumatoid factor (RF). Preillness serum specimens were analysed for autoantibodies against arginine (A) or citrulline (C) containing synthetic telopeptides using a chemiluminescence method and for anti-CCPs Mark2 with an ELISA method. Results: The mean levels of autoantibodies to citrulline-containing telopeptides and the C/A ratios of type I and II collagens and to CCP were higher in subjects who later developed RF-positive RA. In the highest tertiles of C/A (I), C/A (II) ratios and anti-CCPs levels the relative risk of RF-positive RA was significantly increased. In the multifactorial model only anti-CCPs retained its statistical significance. However, the interaction term of C/A (II) ratio and anti-CCPs proved statistically significant (p = 0.02). The subjects ranked into the highest tertiles of both C/A (II) ratio and antiCCPs had an odds ratio of 20.06 (95% confidence interval, 4.37-92.06) of developing RF-positive RA compared with those in the lowest tertiles of these antibodies. None of the autoantibodies predicted RF-negative RA. Conclusion: Autoantibodies to citrullinated telopeptides of type I and II collagen and to CCPs exert a synergistic effect on the risk of seropositive RA. Key Terms: Antibodies to cyclic citrullinated peptides (anti-CCPs) Antibodies to citrullinated type I and II collagens Rheumatoid arthritis (RA) group.bmj.com on October 14, 2017 Published by http://ard.bmj.com/ Downloaded from