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 (CD), while studies of its use in ulcerative colitis (UC) have been largely negative, 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.While 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, yet 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.
You et al. (Sun,) studied this question.