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 a...