Recent research has focused on people ‘at-risk’ of RA with circulating autoantibodies (ACPA/RF) but no clinical signs of RA currently. These subjects may provide important clues in understanding the evolution of RA. Identifying those ‘at-risk’ remains problematic, with no good blood or tissue biomarkers identified to date. However, we and others, have demonstrated that circulating monocytes are already primed in ‘at-risk’ patients, displaying hyperinflammatory and hypermetabolic profiles, suggesting the immune system is already activated. Thus, in this program of research we will perform a comparative study of individuals ’at-risk’ of RA, established RA, and healthy controls, along with extensive mechanistic studies using circulating monocytes and synovial tissue macrophages obtained from these well-defined patient cohorts. Specifically, we will (i) phenotypically characterize circulating monocytes and MoM1/MoM2 in ‘at-risk’ individuals, active RA, and healthy controls, and analyze in relation to their clinical inflammation, progression and erosive status, (ii) examine if metabolic reprogramming of inflammatory monocytes/macrophages alters their pathogenic phenotype, and (iii) are these cells are epigenetically primed compared to healthy control subjects?