Emerging mechanistic trends and clinical efficacy for methotrexate: Applications to inflammatory bowel disease

Methotrexate (MTX) was among the first steroid-sparing agents introduced for the treatment of inflammatory bowel disease (IBD). Its efficacy is well established for Crohn's disease, though studies of its use in ulcerative colitis have largely reported negative results, with only some, although inconsistent, findings suggesting limited benefit. In this review, we provide a comprehensive and up-to-date evaluation of MTX's use in IBD, including its key mechanisms of action(s), therapeutic value, as well as emerging targets that underscore the complexity of this drug and the biological landscape it alters. Despite its longstanding use, the full spectrum of MTX's effects contributing to its efficacy in IBD remains incompletely understood. Although multiple pathways have been implicated, the relative importance of each remains nebulous, and additional, unidentified functions may play a role, particularly in contexts not pertaining to immunomodulation. We highlight recent findings that poise MTX as an unexpected but promising agent for mucosal healing. We also provide a detailed evaluation of clinical studies, encompassing randomized controlled trials and observational data, highlighting MTX's effectiveness, differences in route of administration, safety profile, and limitations as they pertain to the management of IBD. As therapeutic targets for IBD evolve, we discuss MTX's future positioning by exploring clinical perspectives regarding its utility and examine the latest evidence that indicates there may be novel, previously unexplored, therapeutic potential. By bridging mechanistic insights with clinical evidence, this review underscores MTX's enduring, albeit niche, position in IBD therapy and highlights key areas for future investigation to optimize its use. SIGNIFICANCE STATEMENT: Methotrexate remains a valuable, though underutilized, therapeutic option for the management of inflammatory bowel disease. This review provides a comprehensive overview of methotrexate's pharmacology, integrating emerging mechanistic insights and clinical data to reframe its role beyond immunomodulation, particularly at the gastrointestinal mucosal interface, thereby identifying novel avenues for future research that may expand its clinical utility in inflammatory bowel disease.