There is a knowledge gap in the understanding of mechanisms and predictors of flare in remission RA and we hypothesize that synovial tissue in disease remission exhibits heterogeneity in cellular and molecular pathways, and this determines clinical outcome after treatment tapering/cessation (remission maintenance or flare). Dissecting this heterogeneity will provide: (i) biomarkers to develop testable machine-learning (ML) models that accurate predict disease flares, and uncover (ii) cellular mechanisms responsible for maintenance of remission or flare. To test this hypothesis, we will establish a comprehensive cellular and molecular synovial tissue atlas of remission RA, achieved with different therapeutics. This will aid discovery of (a) cell clusters/pathways driving flare or sustaining remission, and (b) provide an evidence-base to develop ML tools to predict flares that will be tested longitudinally in a biopsy-driven clinical study. To test the functional roles of distinct cell clusters that distinguish synovium of those who flared from those who maintained in remission, we will investigate their pathogenic or inflammation resolving functions using human synovial organoid system. In summary, this project will uncover tissue biomarkers of flare that will help in management of patients’ flares with current therapeutics and provide novel targets for therapeutic intervention to enhance the resolution/repair processes that could transform remission into long-term state.
Project LeadDr. S Alivernini
This study proposal will have the following research objectives:
A) To establish the cellular and molecular atlas of remission RA achieved with different therapeutics aimed to identify (i) cell clusters/pathways driving disease flare or maintaining remission and (ii) provide an evidence base for developing ML tools for predicting flares.
B) To test the performance of a ML-derived algorithm on longitudinal remission RA cohort in a biopsy-driven study.
C) To dissect the cellular and molecular mechanisms of remission maintenance and joint flares.
Milestone 1: To establish the cellular and molecular atlas of remission RA achieved with different therapeutics, providing (i) biomarkers fordeveloping ML-based algorithm predicting disease flare, and (ii) molecular mechanisms driving maintenance of remission versus flare.
Milestone 2: Biopsy-driven study will validate power of the ML algorithm in predicting maintenance of remission or onset of flare.
Milestone 3: To establish the role of tissue resident and infiltrating myeloid-stromal cell interactions in induction of flare or maintenance of remission.
Two PRP from Associazione Persone con Malattie Reumatiche e Rare and from the CONARTRITIS were recruited. They will provide their insight into project progression at biannual meetings. For example, they will help in preparation of the factsheet describing this study, which we will be given to patients during consenting for biopsy and testing ML tool. To develop the communication skills of research fellows and to maintain the focus of the project onto the priorities of the patient, each research fellow will be allocated a PRP. The PRPs will also have an important role in providing lay language for effective dissemination of discoveries at educational meetings for patients and public.