During this project, worldwide the largest Clinically Suspect Arthralgia (CSA) cohort has been established; it now includes >900 patients with CSA that are longitudinally followed on the development of rheumatoid arthritis (RA). Using clinical, serological and imaging data several novel discoveries were made. Novel autoantibody characteristics were studied, among which aberrant ACPA-F(ab)glycosylation, this appeared not to be predictive for RA development in patients with CSA. However, anti-APAA antibodies were found predictive, independent of the known IgM RF and ACPA autoantibodies. Anti-CarP autoantibodies were not independently predictive. Many autoantibody characteristics (AntiCCP2, RF, antiCarp, Anti-APAA, and level and isotypes from all of these autoantbodies) and markers of systemic inflammation were studied in serial serum samples during progression from CSA to RA, and were shown completely stable. This suggests that changes in the systemic autoimmune response are not related to the final hit or final process of RA development. The imaging studies however discovered several new tissues that are inflamed in RA , that occur even before arthritis development and that progressed during RA development. The most specific novel feature is tenosynovitis at the level of small joints, which is also highly predictive of RA development. Other early inflammatory features are intermetatarsal bursitis in the forefeet and interossei tendinitis in the hands, that also occur very early after CSA onset. Hence these imaging studies deepened our understanding of the tissues inflamed in RA and increased the predictive accuracy in the at risk stage of CSA. Moreover, these data show that the concept of RA, which has always been considered as an exclusive disease of synovitis, should be changed. The finding that these tissues are inflamed before arthritis develops suggests that that RA development follows the outside-in hypothesis. It starts with changes in the systemic autoimmune response which mostly develop in the asymptomatic risk stage, before CSA onset. This is followed by local inflammation in periarticular structures, and finally intraarticular synovitis develops. Finally using all clinical, serological and clinical data, a risk stratification method for RA development was derived at the end of the project and this was validated in international cohort data.
