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.

Grant Number: 5UC2AR081025-04
NIH Institute/Center: NIH
Principal Investigator: Jennifer Anolik