Florence Poizeau1,2,3, Emmanuel Nowak2,4,5, Sandrine Kerbrat1,2, Béranger Le Nautout1,2, Catherine Droitcourt1,2,3, Milou-Daniel Drici6, Emilie Sbidian7,8, Bernard Guillot9, Hervé Bachelez10,11,12, Hafid Ait-Oufella13,14, André Happe1,2, Emmanuel Oger1,2, Alain Dupuy1,2,3. 1. EA 7449 REPERES (Pharmacoepidemiology and Health Services Research), University of Rennes 1, Rennes, France. 2. PEPS Research Consortium (Pharmacoepidemiology for Health Product Safety), Rennes, France. 3. Department of Dermatology, CHU Rennes, Rennes, France. 4. University of Bretagne Occidentale, Brest University, Brest, France. 5. INSERM CIC 1412, CHRU Brest, Brest, France. 6. Department of Clinical Pharmacology, CHU Nice, Nice, France. 7. Department of Dermatology, Henri Mondor Hospital, APHP, Créteil, France. 8. EA EpiDermE 7379, Paris Est Créteil University, Créteil, France. 9. Department of Dermatology, CHU Montpellier, Montpellier, France. 10. Université de Paris, Paris, France. 11. INSERM UMR1163, Institut Imagine, Paris, France. 12. Department of Dermatology, Saint-Louis Hospital, APHP, Paris, France. 13. INSERM U970, Paris Cardiovascular Research Centre, Université de Paris, Paris, France. 14. Department of Intensive Care, Saint-Antoine Hospital, APHP, Paris, France.
Abstract
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.
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.
Authors: Pablo A Olivera; Stephane Zuily; Paulo G Kotze; Veronique Regnault; Sameer Al Awadhi; Peter Bossuyt; Richard B Gearry; Subrata Ghosh; Taku Kobayashi; Patrick Lacolley; Edouard Louis; Fernando Magro; Siew C Ng; Alfredo Papa; Tim Raine; Fabio V Teixeira; David T Rubin; Silvio Danese; Laurent Peyrin-Biroulet Journal: Nat Rev Gastroenterol Hepatol Date: 2021-08-27 Impact factor: 46.802
Authors: K B Gordon; M Lebwohl; K A Papp; H Bachelez; J J Wu; R G Langley; A Blauvelt; B Kaplan; M Shah; Y Zhao; R Sinvhal; K Reich Journal: Br J Dermatol Date: 2021-11-24 Impact factor: 11.113