Beyond rheumatology: Reconsidering methotrexate for Crohn’s disease in the biologic era

Abstract

In the pre-biologic era, immunomodulators such as azathioprine, 6-mercaptopurine, and methotrexate (MTX) were widely used as first-line maintenance therapies in Crohn’s disease. However, in the current era shaped by biologics, their role has shifted toward adjunctive use, primarily in combination with anti-tumor necrosis factor agents to reduce immunogenicity. Amid growing concerns about thiopurine-associated risks, MTX is receiving renewed attention for its favorable safety profile; however, this agent remains inconsistently utilized in gastroenterology despite its frontline status in rheumatology. This discrepancy was highlighted in a recent nationwide survey by Bonnaud et al published in the World Journal of Gastroenterology, which offers timely insights into MTX prescribing behaviors among French gastroenterologists. Although 71% of respondents reported using MTX, primarily via subcutaneous injection, it is still perceived as a secondary choice after thiopurines. Importantly, this underuse appears to be driven more by clinical inertia and limited guidance rather than by lack of efficacy or safety concerns. Clinicians increasingly recognize the value of MTX, particularly in patients with joint involvement, Epstein-Barr virus negativity, or increased malignancy risk. Notably, even non-prescribers viewed the drug favorably, suggesting that usage barriers may be modifiable. In light of evolving treatment goals that prioritize safety, cost-effectiveness, and individualized care, this editorial argues that MTX should no longer be viewed as a fallback but as a strategic first-line option in well-defined high-risk populations. The survey underscores a persistent gap between guidelines and real-world practice, reinforcing the urgent need for clearer algorithms and education to support the repositioning of MTX in modern Crohn’s disease management.

Keywords: Methotrexate; Crohn’s disease; Biologics; Immunosuppressants; Clinical practice

Core Tip: Methotrexate remains underutilized in Crohn’s disease management despite its favorable safety and established efficacy. The nationwide French survey by Bonnaud et al has shown that barriers are less about evidence than about clinical inertia and limited familiarity. Reconsidering methotrexate as a frontline immunomodulator, particularly in the biologic era, may provide a cost-effective and individualized therapeutic strategy.