Rheumatoid Arthritis (RA) is a chronic progressive autoimmune disease characterized by joint damage and disability. Targeted biotherapeutics have significantly improved outcomes, however a significant proportion of patients have sub-optimal responses, no response and suffer adverse events. 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 programme 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 obtained from these well-defined patient cohorts. Specifically, we will (i) phenotypically characterize circulating monocytes 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 alters their pathogenic phenotype in ‘at-risk’ ACPA+ individuals and RA patients, and (iii) are circulatory monocytes in ‘at-risk’ ACPA+ individuals already transcriptionally different and epigenetically primed compared to healthy control subjects? Discoveries from our project will provide further insight into the underlying mechanisms of disease onset and progression, and will help to identify new disease markers, drug targets, and drug candidates for the treatment of RA at an earlier stage of disease. This will allow the selection of the right treatment for specific patients from the beginning based on a sound, scientific rationale, which in turn will impact significantly on patient care, efficiency and cost effectiveness in our healthcare system.
