Background: Patients with rheumatoid arthritis (RA) commonly use glucocorticoids (GCs) despite their toxicity and the risk of adverse symptoms when they are tapered. Such symptoms pose a major barrier to GC tapering for many, but are minimal or well-tolerated by others. Clinicians cannot predict how a patient will respond to GC dose reduction and rely on trial and error when tapering GCs, encouraging extended GC exposure. Personalized medicine based on patient phenotyping is a cornerstone of RA management, yet current GC tapering strategies remain “one size fits all”. Significance/Impact: This application proposes a career development and research plan to characterize and phenotype responses to GC dose reduction among Veterans with RA. This research agenda is well-aligned with Clinical Science Research and Development priority research focus on individual treatment response and treatment optimization. In the short-term, the results of this proposal will lead to a Merit award proposal to test GC tapering protocols tailored to specific phenotypes, in a sequential multi-assignment randomized clinical trial (SMART). Long-term, Dr. Wallace will expand this line of research to personalize a) GC tapering in other conditions common among Veterans (e.g. chronic obstructive pulmonary disease, asthma, gout, etc). b) other high-risk treatment regimens where data to guide optimization are limited (e.g. biologic drugs, opioids). Dr. Wallace is a VHA rheumatologist and research investigator who is committed to improving treatment outcomes for Veterans using high-risk medications Her long-term goal is to become an independent physician- scientist focused on developing personalized sequential treatment strategies to optimize medication use in the Veteran population. Innovation: The proposed work will apply personalized medicine approaches to GC tapering to understand why, and for whom, current GC tapering strategies fail. Short-term, this line of research will generate new hypotheses surrounding etiology and management of GC taper-related symptoms in Veterans with RA, as well as critical data on GC response phenotypes and associated effect sizes. Long-term, this work will inform other innovative trials to guide optimization of high-risk medications across medical specialties within VHA. Specific Aims: Focusing on Veterans with RA as a test case, this proposal aims to (1) Evaluate response to (a) 15-day and (b) 6-month GC dose reduction strategies; (2) Identify multi-dimensional phenotypes of patient response to GC dose reduction, that can be used to develop tailored GC tapering strategies (SA2). Training Aims: Dr. Wallace and her mentorship team have developed a program of targeted coursework, seminars, directed readings, and mentored research that will provide her with necessary training in: a) selecting and interpreting appropriate endpoints for measuring treatment change; b) quantitative methods required for clinical phenotyping; c) clinical trial design and analysis, with specific training in SMART and adaptive methodologies. Deliverables from Aims: The proposed aims will prepare Dr. Wallace to write and submit a Merit proposal (Year 4) that uses SMART methods to test tailored GC tapering strategies in Veterans with RA. In addition to conference presentations and publications, she will work with an array of partners to disseminate her research findings throughout VHA and develop strategies to implement her work and maximize impact.

Patients with rheumatoid arthritis frequently use glucocorticoids (GCs) despite their known toxicity and the risk of adverse symptoms when they are tapered. Clinicians cannot predict how a given patient will respond to GC dose reduction, as existing studies do not examine taper-related symptoms as predictors of taper success, or evaluate how patient factors may affect such symptoms. The proposed research will a) prospectively evaluate tolerance to GC dose reduction among RA patients; b) develop multi-dimensional phenotypes of GC taper response that can be used to design tailored GC tapering strategies.