Aim-for-RA - rheumatoid arthritis (RA) affects approximately 1% of the population and is characterized by inflammation and joint damage, often leading to considerable disability and pain in both early…

Aim-for-RA - rheumatoid arthritis (RA) affects approximately 1% of the population and is characterized by inflammation and joint damage, often leading to considerable disability and pain in both early and established stages. Key areas of unmet need in the field include the: 1) highly heterogeneous and unpredictable disease course, 2) rarity of lasting remissions, 3) failure of currently available treatments to achieve low disease activity and/or limit progressive joint damage in many patients, and 4) lack of robust biomarkers necessary to personalize appropriate treatment strategies. We propose that cellular and molecular variation in synovial tissue underlies this heterogeneity and that understanding the basis for this will improve the prediction of disease course and provide a rationale for the timely selection of precision treatment strategies with higher rates of sustained RA control. Through sustained collaborative global team-science, the aim-for-RA team has already developed state-of- the-art protocols that deconstructed RA synovial biopsy tissues - an innovation that profoundly advanced knowledge in cells and pathways involved in RA pathogenesis, identified novel treatment targets, identified disease biomarkers, and opened new opportunities in disease prevention. However, IT remains unclear how molecular interactions in the synovium relate to the evolution of defined clinical outcomes, from the at-risk preclinical period to arthritis onset, and then through to synovitis outcome. Therefore, aim-for-RA disease team (DT) aims to relate disease-relevant synovial cellular pathways and dynamic crosstalk to environmental exposures, disease outcomes and treatment response, thereby reconstructing the disease pathogenesis trajectory. In a dmard-naïve RA cross- sectional synovial biopsy-based study of 50 RA patients across 9 sites using harmonized protocols and integrated technologies, aim 1 will deliver high-quality multimodal clinical phenotype and histology data, along with synovial tissue and other biosamples, to evaluate how synovial cellular and molecular pathways relate to disease onset. With longitudinal follow-up and repeat biopsy of these individuals after methotrexate monotherapy, aim 2 will address whether synovial signatures and multi-modal data predict first-line methotrexate response, or failure in patients with early previously untreated disease. Finally, in aim 3, in patients with methotrexate inadequate response we will address whether distinct synovial cellular or molecular features predict a positive response to biologic therapies directly targeting these features. The outcomes of this program will have potential for rapid translational application to improve treatment outcomes at all RA disease stages. Collectively, the collaborative, global aim-for-RA team that has made seminal observations regarding RA disease pathogenesis is ideally suited to inform the key questions and meet major unmet needs in the field.