RA disability stems from structural damage of cartilage and bone due to erosions in synovial joints, if not treated early and aggressively. Treatment guidelines are based on clinical factors such as rheumatoid factor (RF), and more recently, presence of the autoantibodies anti-citrullinated peptide antibodies (ACPA), which may provide improved prediction of outcome in RA. The association with ACPA appears to be highly specific to RA, indeed these antibodies may be present before the onset of clinical arthritis, in some cases several years before, suggesting that autoimmunity precedes inflammation. Autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. This implies a direct link between autoantibody response and structural bone damage in RA. In this study we propose to improve the early diagnosis and prognosis of RA patients by examining the role of ACPA positivity on immune cell function and synovial invasiveness. Specifically, we are stratifying pre-RA and RA patients using ACPA positivity, erosive status and immunopathology of synovial T and B cells in high-risk, poor outcome or good prognosis groups. Phenotype and functional characterisation of T cells and B cells isolated from the site of inflammation in ACPA+ vs ACPA- patients, and their reciprocal interactions and subsequent effect on synovial invasive mechanisms are being examined. Finally, a functional genomics and systems biology approach for disease onset, progression and response is being utilised. Combining clinical status, immunopathology, immune function and transcriptomics analysis from ACPA+ vs ACPA- patients will provide valuable insight into the diagnosis and prognosis of patients with RA 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.