Rheumatoid Arthritis (RA) is a chronic autoimmune disease which causes joint destruction, disability, and increased mortality. While treatment has improved, currently only 1:4 patients achieve full reMsion and predicting who will develop severe disease or who will respond to treatment is difficult. Therefore, this research will examine immune mechanisms which drive the initiation of RA in well-defined patient cohorts which will encompass the evolution of the disease across multiple stages from “pre-RA, early and established RA, as well as those receiving immunotherapy treatment. This approach will aim to identify new candidate treatments for those suffering with RA, but also allow stratification of patients, thus facilitating early and more personalised treatment interventions. In turn this will impact on patient care, efficiency, and cost effectiveness in our healthcare system. This research will involve extensive mechanistic studies using synovial tissue/synovial fluid and peripheral blood from well-defined patient cohorts, to focus on (i) immune-cell function, (ii) Immune checkpoint-inhibitor (ICI) pathway regulation and (iii) metabolism. Specifically, we will examine the PD-1:PD-L1 pathway, in RA development, at the site of inflammation and how immune cells such as Dendritic cells (DC) and T cells drive inflammation despite the presence of these negative regulators. Moreover, we will examine how metabolism influences this pathway and contributes to disease progression. Finally, it has emerged that oncology patients undergoing anti-PD-1/PD-L1 immunotherapy can develop various autoimmune diseases referred to as immune-related adverse events (irAEs) such as RA. Therefore, we will examine in parallel, the PD-1/PDL-1 pathway in oncology patients (ICI-induced RA) and the “pre-RA”, early and established RA groups. This will give significant insight into the evolution of RA from a genetic/environmental perspective compared to immunotherapy induced RA providing much needed insight into the mechanism of disease development and progression.