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Methotrexate has been used an immunomodulator in many autoimmune diseases, including inflammatory bowel disease. However, many physicians are unfamiliar or uncomfortable with its use in the management of inflammatory bowel disease. We summarize the data for use of methotrexate in common clinical scenarios: (1) steroid dependant Crohn's disease (CD); (2) maintenance of remission in steroid free CD; (3) azathioprine failures in CD; (4) in combination therapy with Anti-TNF agents in CD; (5) decreasing antibody formation to Anti-TNF therapy in CD; (6) management of fistulizing disease in CD; and (7) as well as induction and maintenance of remission in ulcerative colitis. An easy to use algorithm is provided for the busy clinician to access and safely prescribe methotrexate for their inflammatory bowel disease patients.

Although antagonists of tumor necrosis factor have resulted in major therapeutic benefits in inflammatory bowel disease, the magnitude and durability of response are variable. Similar to previously available drugs such as 5-aminosalicylates and immunomodulators, the therapeutic effect is not universal leaving many people searching for options. The development of newer agents has benefited from advances in the understanding of the pathophysiology of the disease. Uncontrolled activation of the acquired immune system has an important role, and lymphocytes, cytokines, and adhesion molecules are broadly targeted for therapeutic intervention. There is increasing evidence of an important role of the innate immune system and the intestinal epithelium, and the therapeutic paradigm is also shifting from immunosuppression to the reinforcement of the intestinal barrier, and modification of the disease process. In this review, we explore the limitation of current therapy as well as mechanisms of actions of new drugs and the efficacy and adverse events from data from clinical trials.