Summary Background There are safety concerns regarding immunomodulators (thiopurines and methotrexate) for treatment of inflammatory bowel disease (IBD). Aim To compare the long‐term tolerability, and persistence of thiopurine and methotrexate therapy in IBD. Methods A retrospective cohort study was performed at two hospitals between 1 January 2004 and 31 December 2016 for patients commenced on thiopurines or methotrexate for IBD. Treatment discontinuation rates, intolerances and disease activity were obtained from medical records. Results There were 782 patients commenced on immunomodulator therapy; 244 (31%) on methotrexate with folate (67% subcutaneous therapy) and 538 (69%) on thiopurine (73% azathioprine). Median follow‐up was 42 vs 47 months (P = 0.09). In patients on thiopurines, median 6‐TGN was 298 pmol/8 x 108 RBCs, while the median dose of methotrexate was 25 mg weekly. Methotrexate recipients had a higher rate of prior immunomodulator intolerance, were typically older and had a longer disease duration (54% vs 3%, median 43 vs 36 years, 6 vs 5 years, respectively, each P < 0.05). Overall, 208 (27%) discontinued therapy due to adverse events, (40% on methotrexate vs 19% on thiopurines, P < 0.001), including nausea (18% vs 4%), fatigue (7% vs 2%) and hepatotoxicity (8% vs 2%, each P < 0.001). Hospitalisations from adverse events (0.8% vs 0.9%) and serious infections (9% vs 12%), and deaths (1% vs 0%) were comparable between groups (all P > 0.05). Discontinuation due to adverse events occurred later in patients on methotrexate than on thiopurines (median 7 vs 5 months, P = 0.08). Conclusion Discontinuation of methotrexate occurred at rates twice that of dose‐optimised thiopurine therapy.

horts. 3 It is well established that smoking significantly increases the risk of developing and worsens the disease course of CD, yet is protective against the development and reduces the severity of ulcerative colitis (UC). 4,5 However, what is less clear is whether smoking impacts the efficacy of therapeutics in IBD. Given the increased choice and availability of therapies with differing mechanisms of action, it may be surmised that for patients who continue smoking (i.e., failing efforts at cessation as is often encountered) there may be a preferred treatment option given a potential differential impact (positive, negative, or neutral) of smoking on individual treatments. Hence, the aim of this paper was to review the literature regarding the relationship between smoking and the efficacy of medical and surgical therapies in IBD, with particular reference to CD. A proposed algorithm for the approach to the management of IBD in smokers is proposed based on this review (Fig. 1).

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