Serum Proteomic Signatures of Rheumatoid Arthritis Risk and Response: Analysis of a Rheumatoid Arthritis Interception Trial

OBJECTIVE: Our study objective was to identify serum protein signatures associated with progression to rheumatoid arthritis (RA) and response to abatacept in at-risk individuals. METHODS: A total of 440 serum samples from 118 APIPPRA (Arthritis Prevention In the Preclinical Phase of RA with Abatacept) study participants were selected from baseline to RA onset for 46 progressors of RA or to study end for 72 participants who did not develop RA. Samples were analyzed using the SomaScan 7k assay platform. Differential expression analysis was assessed by progression to RA (three pre-RA time intervals to RA, progressors of RA vs nonprogressors, baseline to RA), and by treatment allocation (abatacept vs placebo). Risk and response signatures were identified in the full 7k panel and two prespecified subpanels defined as Inflammatory Mediators and Adaptive Immune Cell panel. RESULTS: We observed significant changes in 80 proteins (68 down-regulated and 12 up-regulated) occurring between RA onset and 6 to 24 months before developing disease. Progression to RA was associated with increased levels of acute-phase reactants SAA1 and SAA2 and reductions in CTLA4, when compared to nonprogressors at the end of treatment. Two up-regulated proteins (CTLA4 and CD86) and seven down-regulated proteins (CXCL13, FCRL4, FCER2, CCL21, LTA|LTB, FDCSP, and IL22RA2) were observed in participants receiving abatacept compared to placebo regardless of RA outcome. CONCLUSION: Protein signatures dominated by acute-phase proteins define progression to RA, whereas changes associated with abatacept therapy highlight potential mechanisms of treatment response. Such signatures provide a better understanding of the immune landscape of the at-risk phase, opening up the possibility of new treatment modalities for RA prevention.