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. A prospective, longitudinal study of individuals at-risk for RA was performed to define molecular and cellular changes that contribute to the development and onset of rheumatoid arthritis (RA). We enrolled 45 subjects with elevated anti-citrullinated protein antibodies (ACPA) but no clinical signs of arthritis and followed them up to 3 years post-enrollment. Peripheral blood and metadata were collected 2-3 times per year and at the time of onset of clinical RA. During the study, 16 subjects progressed to clinical RA and were diagnosed with inflammatory arthritis (IA) by a rheumatologist . For comparison, 38 site-matched ACPA- healthy controls (CON1) and 11 site-matched ACPA+ early RA patients (ERA), within 1 year of clinical diagnosis and naive to biological and targeted synthetic disease modifying anti-rheumatic drugs (DMARDs), were enrolled. *_ARI: At Risk Individual Sample *_LONG: Longitudinal At Risk Sample *_ERA: Early RA Sample *_CON1: ACPA -ve Control Sample *_CON2: Healthy Controls ***Submitters state that raw data is subject to controlled access and thus will be submitted to dbGaP***