Long-Term Efficacy And Safety Of Ustekinumab In Refractory Crohn'S Disease Patients: A Multicenter Retrospective Experience

Background: Ustekinumab has been shown to be effective in Crohn's disease (CD) in phase III trials. However, long-term outcome of ustekinumab has never been evaluated in CD. The aim of the present study was to evaluate the long-term efficacy and safety of ustekinumab and to identify predictive factors of ustekinumab failure-free survival in a multicenter cohort of anti-TNF refractory CD patients. Methods: We performed a retrospective observational study in 20 tertiary centers from the GETAID, including all patients who received subcutaneous ustekinumab induction for an active CD from March 2011 to December 2014 and were followed until November 2016. The primary outcome was ustekinumab failure-free; failure was defined as withdrawal of ustekinumab due to loss of response, intolerance or need of surgery. Predictive factors of ustekinumab failure-free survival at 2 years and safety data were also evaluated. Results: Until December 2014, 122 CD patients received subcutaneous ustekinumab induction. Eighty-eight patients responded to ustekinumab during the first year and were followed until November 2016. Among these 88 patients (64 females, median age: 32.5 years, median disease duration: 11.8 years), all patients have failed to at least one anti-TNF agent and two-third underwent prior intestinal resection. At time of ustekinumab introduction, 13 (15%) patients received immunosuppressant (IS) and 13 (15%) steroids. Median time on ustekinumab was 2.2 (1.1–2.9) years and 42 (48%) patients experienced ustekinumab failure. Ustekinumab failure-free survival was observed in 78.4% at 1 year, 65.8% at 2 years and 54.7% at 3 years. Ustekinumab discontinuation was observed for loss of response in 32 (36%) patients, for intolerance in 4 (5%) patients, for remission in 5 (6%) patients, and for pregnancy in one patient. Five patients underwent intestinal resection during the follow-up. In univariate analysis, concomitant IS at time of ustekinumab introduction and female sex were associated with ustekinumab failure-free survival at 2 years (p=0.07;IC95% (1.2–24.8) and p=0.05;IC95% (0.11–1.05), respectively). In multivariate analysis, none predictive factor of ustekinumab failure-free survival was identified. An adverse event occurred in 21 (24%) patients. One anal adenocarcinoma was reported during follow-up. Conclusions: We here report the first real-life experience of long-term outcome of ustekinumab treatment in CD refractory patients, with a median follow-up of more than 2 years. More than 50% of patients maintained ustekinumab during the follow-up without loss of response, intolerance or surgery, with a good safety profile. No predictive factor of ustekinumab failure-free survival was identified in multivariate analysis.