Association Between Early Severe Cardiovascular Events and the Initiation of Treatment With the Anti-Interleukin 12/23p40 Antibody Ustekinumab

Florence Poizeau (1, 2, 3) , Emmanuel Nowak (4, 3) , Sandrine Kerbrat (1, 3) , Béranger Le Nautout (1, 3) , Catherine Droitcourt (1, 2, 3) , M.-D. Drici (5) , Emilie Sbidian (6, 7) , Bernard Guillot (8) , Hervé Bachelez (9) , Hafid Ait-Oufella (10, 11) , André Happe (1, 3) , Emmanuel Oger (1, 3) , Alain Dupuy (1, 2, 3)

1 REPERES - Recherche en Pharmaco-épidémiologie et Recours aux Soins
2 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
3 PEPS - Pharmaco-Épidémiologie des Produits de Santé
4 CIC Brest
5 CHU - Hôpital Pasteur [Nice]
6 EpiDermE - Epidemiology in Dermatology and Evaluation in Therapeutics
7 CHU Henri Mondor [Créteil]
8 CHU - Hôpital Lapeyronie [Montpellier]
9 AP-HP - Hopital Saint-Louis [AP-HP]
10 PARCC (UMR_S 970/ U970) - Paris-Centre de Recherche Cardiovasculaire
11 CHU Saint-Antoine [AP-HP]

Importance: Ustekinumab, a monoclonal antibody targeting interleukin 12/23p40 (IL-12/23p40), is effective in the treatment of moderate to severe psoriasis, psoriatic arthritis, and Crohn disease. In 2011, a meta-analysis of randomized clinical trials reported a potential risk of severe cardiovascular events (SCEs) within the first few months after the initiation of anti-IL-12/23p40 antibodies. Objective: To assess whether the initiation of ustekinumab treatment is associated with increased risk of SCEs. Design, setting, and participants: This case-time-control study used data from the French national health insurance database, covering 66 million individuals, on all patients exposed to ustekinumab between April 1, 2010, and December 31, 2016, classified according to their cardiovascular risk level (high- and low-risk strata). The risk period was the 6 months before the SCE, defined as acute coronary syndrome or stroke, and the reference period was the 6 months before the risk period. Statistical analysis was performed from September 20, 2017, to July 6, 2018. Exposure: The initiation of ustekinumab treatment was screened during the risk and reference periods. Main outcomes and measures: Odds ratios for the risk of SCE after the initiation of ustekinumab treatment were calculated. Results: Of the 9290 patients exposed to ustekinumab (4847 men [52%]; mean [SD] age, 43 [14] years), 179 experienced SCEs (65 cases of acute coronary syndrome, 68 cases of unstable angina, and 46 cases of stroke). Among patients with a high cardiovascular risk, a statisically significant association between initiaton of ustekinumab treatment and SCE occurrence was identified (odds ratio, 4.17; 95% CI, 1.19-14.59). Conversely, no statistically significant association was found among patients with a low cardiovascular risk (odds ratio, 0.30; 95% CI, 0.03-3.13). Conclusions and relevance: This study suggests that the initiation of ustekinumab treatment may trigger SCEs among patients at high cardiovascular risk. In line with the current mechanistic models for atherosclerotic disease, the period after the initiation of anti-IL-12/23p40 may be associated with atherosclerotic plaque destabilization via the inhibition of helper T cell subtype 17. Although the study interpretation is limited by its observational design, these results suggest that caution may be needed in the prescription of ustekinumab to patients at high cardiovascular risk.

Domaines: Sciences du Vivant [q-bio]; Dermatologie

Florence Poizeau, Emmanuel Nowak, Sandrine Kerbrat, Béranger Le Nautout, Catherine Droitcourt, et al.. Association Between Early Severe Cardiovascular Events and the Initiation of Treatment With the Anti-Interleukin 12/23p40 Antibody Ustekinumab. JAMA Dermatology, 2020, 156 (11), pp.1208-1215. ⟨10.1001/jamadermatol.2020.2977⟩. ⟨hal-02960093⟩