Rheumatoid Arthritis (RA) is a chronic progressive inflammatory autoimmune disease characterised primarily by joint damage and disability, although it may also be associated with vasculitis, lungs and heart disease with a significant increase in premature mortality (~10 years) . In the last two decades targeted biotherapeutics, namely monoclonal antibody therapies against TNF, the IL6 receptor and CD20 or small molecular inhibitors are highly successful in treated RA with significantly improved outcomes. Despite this a significant proportion of patients have sub-optimal responses, no response or suffer adverse events limiting the therapeutic impact. There are currently no biomarkers of who will develop RA, or the optimal time for treatment. Recent research has focussed on ‘individuals at-risk’ (IAR) of RA, positive for rheumatoid factor and/or anti-citrullinated protein antibodies but who have not developed clinical signs of arthritis, who may provide important clues in understanding the evolution of RA. Identifying those IAR remains problematic, with no good blood/tissue biomarkers identified to date. However, we have demonstrated that circulating immune cells are already primed in ‘at-risk’ patients, displaying hyperinflammatory and hypermetabolic profiles suggesting altered epigenetic regulation. This project will perform a comparative study of IAR of RA and those with established RA, with detailed mechanistic studies of synovial tissue and cells to define (i) immune cell function, (ii) transcriptional regulation and (iii) epigenetics. Discoveries from our project will provide further insight into the underlying mechanisms of disease onset and progression, and will identify new disease markers and drug candidates for the treatment of RA at the earliest stages, including potential prevention, of disease. This will allow selection of the correct treatment for specific patients (precision medicine) from the outset based on a sound, scientific rationale, which in turn will impact significantly on patient care, efficiency and cost effectiveness in our healthcare system.
