Despite advances in therapies over the past 3 decades, up to 30% of RA patients continue to live with uncontrolled disease even with frequent switching of DMARD and biological therapies suggesting that RA is a heterogeneous disease that may evolve over a lifetime. The cellular and molecular mechanisms that underlie the heterogeneity of RA are largely unknown. A detailed understanding of the pathways responsible for the differential responses of RA patients to treatment would be invaluable to facilitate the optimization of treatment regimens for individual RA patients and allow the implementation of effective `treat-to-target" approaches. This proposal will take advantage of unique cohorts of RA patients and a well-integrated multidisciplinary team of clinicians and scientists at the Hospital for Special Surgery (HSS), the New York Genome Center (NYGC) and Mount Sinai Hospital (MSH) at the University of Toronto to gain a broad understanding of the molecular pathways that control the function of these distinct cellular compartments in different clinical settings. Or major goals are to: a) utilize the unparalleled access of HSS physicians to over 26,000 surgical cases/year to obtain paired samples of peripheral blood and synovial tissues from RA and control patients undergoing surgical procedures to perform detailed cellular, molecular, and histological analyses aimed at uncovering molecular pathways whose deregulation is shared between peripheral blood samples and tissue specimens, b) exploit the phenomenon of disease worsening or flare in patients discontinuing DMARDs and biologics during the perioperative period, to perform longitudinal studies to unmask pathways that distinguish flaring vs. non-flaring patients, and c) extend the results obtained from these initial studies to cohorts of early RA patients observed longitudinally who are DMARD and/or TNF responders versus non-responders.

Public Health Relevance

These studies will provide essential information enabling a more accurate subsetting of RA patients and leading to the development of cellular/molecular signatures that can predict the responses of RA patients to therapy and guide personalized therapeutic regimens.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Exploratory/Developmental Cooperative Agreement Phase I (UH2)
Project #
1UH2AR067691-01
Application #
8851814
Study Section
Special Emphasis Panel (ZAR1-KM (M1))
Program Officer
Serrate-Sztein, Susana
Project Start
2014-09-24
Project End
2016-05-31
Budget Start
2014-09-24
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$350,001
Indirect Cost
$119,960
Name
Hospital for Special Surgery
Department
Type
DUNS #
622146454
City
New York
State
NY
Country
United States
Zip Code
10021