Systematic review: Methotrexate—A poorly understood and underused medication in inflammatory bowel disease

Summary Background Methotrexate, an immunosuppressant used for the treatment of inflammatory bowel disease (IBD) for over 30 years, remains underused compared to thiopurines. Aims To review the efficacy, safety, optimal dosing and delivery regimens of methotrexate in adults with IBD. Methods We conducted a systematic review of studies involving patients with IBD treated with methotrexate from inception to August 2023. All studies were included from the MEDLINE database via PubMed. Results For Crohn's disease, we included eight randomised controlled trials (RCTs) and 17 observational studies. Parenteral methotrexate effectively increased remission rates in steroid‐dependent patients at 25 mg/week for 16 weeks and at 15 mg/week for maintenance. Methotrexate can be used in combination with anti‐tumour necrosis factor (TNF) agents to reduce immunogenicity. Data comparing thiopurines and methotrexate remain scarce. For ulcerative colitis (UC), we included five RCTs and 10 observational studies were included; there was no evidence to support the use of methotrexate in (UC). We extracted safety data from 17 studies; mild‐to‐moderate adverse effects were common. The incidence of liver fibrosis or cirrhosis was low. Conclusion Methotrexate is effective at inducing and maintaining remission in steroid‐refractory Crohn's disease and can reduce anti‐TNF‐induced immunogenicity when used in combination therapy. Data regarding tolerance and safety are reassuring. These findings challenge preconceived ideas on methotrexate and suggest that it is a valid first‐line conventional option for the treatment of mild‐to‐moderate Crohn's disease.