Rheumatoid arthritis (RA) is a chronic autoimmune disease causing joint destruction and disability. Autoantibodies against citrullinated proteins are among the robust risk factors for bone destruction. ACPA expression can be present years before clinical disease, suggesting that autoimmunity precedes inflammation. This implicates a direct link between autoantibody response and structural bone damage in RA. In this study we propose to improve the early diagnosis and prognostication of RA patients, by examining the effect of ACPA positivity on immune cell function and synovial invasiveness. Specifically we aim to (i) stratify pre-RA and RA patients using ACPA positivity, erosive status and immunopathological phenotype of synovial T and B cells in high-risk, poor outcome or good prognosis groups, (ii) examine the functional role of T cell and B cell isolated from the site of inflammation in ACPA+ vs ACPA- patients, and investigate their reciprocal interactions and subsequent effect on synovial invasive mechanisms, and finally (iii) identification of new targets/biomarkers using functional genomics and systems biology approach for disease onset, progression and response. Combining clinical status, immunopathology, immune function and transcriptomic analysis from ACPA+ vs ACPA- patients will provide valuable insight into the diagnosis and prognosis of RA patients at an earlier stage of disease than is currently possible and this will allow selection of treatment for specific patients based on a sound, scientific rationale. This will impact significantly on patient care, efficiency and cost effectiveness in our healthcare system.