Serum Proteomic Signatures of RA Risk and Response: Analysis of the APIPPRA Trial

Objective 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 study participants were selected from baseline to RA onset for 46 RA progressors or to study end for 72 participants who did not develop RA. Samples were analysed using the SomaScan® 7k assay platform. Differential expression analysis was assessed by progression to RA (three pre‐RA time intervals to RA, RA progressors versus non‐progressors, baseline to RA), and by treatment allocation (abatacept versus placebo). Risk and response signatures were identified in the full 7k panel and two pre‐specified subpanels defined as Inflammatory Mediators and Adaptive Immune Cell panel. Results We observed significant changes in 80 proteins (68 downregulated and 12 upregulated) occurring between RA onset and 6‐24 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 non‐progressors at the end of treatment. Two upregulated proteins (CTLA4 and CD86), and seven downregulated 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, while 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. image