Importance: Ustekinumab, a monoclonal antibody targeting interleukin (IL)-12/23, is effective in the treatment of moderate-to-severe psoriasis, psoriatic arthritis and Crohn’s disease. In 2011, a meta-analysis of randomized trials alerted on a potential risk of major adverse cardiovascular event (MACE) within the first months after the initiation of anti-IL-12/23 antibodies. 
Objective: To assess whether ustekinumab initiation triggers MACE.
Design: We conducted a case-time-control study. We defined the ‘risk’ period as the 6 months before the MACE, defined as acute coronary syndrome or stroke, and the ‘reference’ period as the 6 months before the risk period.
Setting: French National Health Insurance database, covering 66 million subjects.
Participants: All patients exposed to ustekinumab between 2010 and 2016, classified according to their cardiovascular risk level (high and low risk strata).
Exposure: The initiation of ustekinumab was screened in both periods.
Main outcome and measures: We assessed the odds-ratios (OR) between the initiation of ustekinumab and MACE.
Results: Among the 9290 patients exposed to ustekinumab, 179 experienced MACEs: 65 cases of acute coronary syndrome, 68 unstable angina and 46 stroke. Among patients with high cardiovascular risk, a significant association between ustekinumab initiation and MACE occurrence was identified (OR, 4.17; 95% CI, 1.19-14.59). Conversely, no association was found among patients with low cardiovascular risk (OR, 0.30; 95% CI, 0.03-3.13). 
Conclusions and relevance: From real-world data, we suggest that ustekinumab initiation could trigger MACE among patients with high cardiovascular risk, in line with the current mechanistic models for atherosclerotic disease, in which the period following ustekinumab initiation is associated with high risk for MACE. These results should call for caution in the prescription of ustekinumab to patients with high cardiovascular risk.

Early major adverse cardiovascular events following the initiation of the anti-interleukin 12/23 antibody ustekinumab. A population-based case-time-control study.