Inflammation and lymphocyte activation during longitudinal progression to rheumatoid arthritis in at-risk individuals

Rheumatoid Arthritis is a chronic immune-mediated disease characterized by joint inflammation, autoantibodies, and systemic inflammatory features. Autoantibodies, including anti-citrullinated protein antibodies are highly predictive biomarkers that pre-date clinical disease and can be used to identify individuals “at-risk” for RA. We performed a prospective, longitudinal multi omic study of at-risk individuals at multiple timepoints to characterize their immune state. One-third of patients progressed to clinically active RA during the study. We show that at-risk RA subjects have systemic inflammation with features like those observed in active RA despite having no clinical disease. Progression to active disease was especially apparent in the T and B cells compartments, with pro-pathogenic features recognized in naive cells. We identify key molecular and cellular alterations in innate and adaptive immunity that accompany this inflammatory state.