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Original Investigation
September 9, 2020

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

Author Affiliations
  • 1EA 7449 REPERES (Pharmacoepidemiology and Health Services Research), University of Rennes 1, Rennes, France
  • 2PEPS Research Consortium (Pharmacoepidemiology for Health Product Safety), Rennes, France
  • 3Department of Dermatology, CHU Rennes, Rennes, France
  • 4University of Bretagne Occidentale, Brest University, Brest, France
  • 5INSERM CIC 1412, CHRU Brest, Brest, France
  • 6Department of Clinical Pharmacology, CHU Nice, Nice, France
  • 7Department of Dermatology, Henri Mondor Hospital, APHP, Créteil, France
  • 8EA EpiDermE 7379, Paris Est Créteil University, Créteil, France
  • 9Department of Dermatology, CHU Montpellier, Montpellier, France
  • 10Université de Paris, Paris, France
  • 11INSERM UMR1163, Institut Imagine, Paris, France
  • 12Department of Dermatology, Saint-Louis Hospital, APHP, Paris, France
  • 13INSERM U970, Paris Cardiovascular Research Centre, Université de Paris, Paris, France
  • 14Department of Intensive Care, Saint-Antoine Hospital, APHP, Paris, France
JAMA Dermatol. Published online September 9, 2020. doi:10.1001/jamadermatol.2020.2977
Key Points

Question  Is the risk of severe cardiovascular events increased after the initiation of treatment with the anti–interleukin 12/23p40 (IL-12/23p40) monoclonal antibody ustekinumab?

Findings  This case-time-control analysis based on data from 9290 patients with records in the French national health insurance database from 2010 to 2016 suggests that the initiation of ustekinumab treatment is associated with increased risk of acute coronary syndrome or stroke in patients with a high baseline cardiovascular risk.

Meaning  The results of this case-time-control analysis suggest that ustekinumab should be prescribed with caution 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.

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