JAK inhibitor effective in Crohn’s disease

Review by Prof. Eamonn Quigley (USA)

Study Summary 

Janus kinases (JAK) mediate T cell responses; JAK inhibitors, such as upadacitinib, have efficacy in autoimmune disorders and are FDA-approved for use in ulcerative colitis. Here, patients with moderate-to-severe Crohn’s disease were enrolled in two parallel trials, and received induction upadacitinib therapy (45 mg/day) or placebo for 12 weeks; for the second trial, all enrolled had previously failed at least one biologic. Responders were then enrolled in a 52-week maintenance trial. Clinical remission occurred in 50% and 39% with upadacitinib, compared to 29% and 21% on placebo; endoscopic response rates were 46% and 35%, vs 13% and 4%. 48% of those on maintenance upadacitinib were remission, vs 15% on placebo. Herpes Zoster infections, neutropenia and creatine kinase elevations were more frequent in the active treatment groups, and GI perforations occurred in 6 patients. (133)

Commentary 

Benefits of upadacitinib include oral administration and rapid onset of action, many achieved clinical remission in 2-4 weeks. The decision to treat Crohn’s disease patients failing an anti-TNF agent with upadacitinib vs. another biologic will in part hinge on adverse event profiles: JAK inhibitors have received a black box warning from the FDA, highlighting an increased risk of stroke, myocardial infarction, and thrombosis, and caution is advised when using these agents in smokers, those with risk factors for cardiovascular disease, and those who have a history of malignancy other than non-melanoma skin cancer. Patients should be screened for chronic infections and should be up-to-date with vaccinations. (107)

Citation

Loftus EV, et al. Upadacitinib induction and maintenance therapy for Crohn’s disease. NEJM 2023;388:1966-80, DOI: 10.1056/NEJMoa2212728

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