Ustekinumab associated with increased cardiovascular risk in some patients

A study of nearly 9,300 people who had taken the anti-interleukin-12/23p40 monoclonal antibody ustekinumab found people with high baseline cardiovascular risk were at increased risk for developing severe cardiovascular events within 6 months after starting ustekinumab treatment.

People with low baseline cardiovascular risk did not have increased risk of severe cardiac events in the months following ustekinumab (Stelara, Janssen Biotech) initiation.

Authors of the paper, published September 9 in JAMA Dermatology, pointed out the risk seems to concern psoriasis patients the most, and the findings suggest “… ustekinumab should be prescribed with caution to patients at high cardiovascular risk.”

Preliminary reports of major adverse cardiovascular events among psoriasis patients receiving anti-IL-12/23 medications ustekinumab and briakinumab prompted a metanalysis published in 2011 in JAMA.

Researchers reviewing 22 randomized controlled trials concluded “Compared with placebo, there was no significant difference in the rate of [major adverse cardiovascular events] observed in patients receiving anti–IL-12/IL-23 antibodies or anti–TNF- treatments.”

Concerns remained, with authors of the JAMA study noting that limitations of their work prevented them from determining whether the drugs exposed psoriasis patients to increased cardiovascular risk. The authors also wrote they were concerned with the major adverse cardiovascular event rate in the placebo-controlled phase of the phase 3 briakinumab study. Abbott discontinued all briakinumab clinical trials in 2011 and stopped the drug’s development.

Another reason for potential concern about cardiovascular risk with ustekinumab, according to authors of the new study, is the short-term triggering of severe cardiac events in the early months of ustekinumab use makes sense.

“Ustekinumab inhibits the p40 subunit shared by IL-12, a helper T cell subtype 1 (TH1) inducer, and IL-23, which maintains TH17 cell homeostasis. Several experimental studies have shown that IL-12 and associated TH1 responses are proatherogenic,” they wrote.

To assess whether there was an association between initiation of ustekinumab and serious cardiac events, French researchers conducted a case-time-control study using data from the French national health insurance database. They looked for patients who had been exposed to ustekinumab between April 1, 2010 and Dec. 31, 2016, focusing on the first six months of treatment.

The study included 9290 patients who had taken ustekinumab. Eighty-six percent had been prescribed the drug to treat psoriasis, and 12% for Crohn’s disease.

“Of the 9290 patients exposed to ustekinumab (4847 men [52%]; mean [SD] age, 43 [14] years), 179 experienced [severe cardiovascular events] (65 cases of acute coronary syndrome, 68 cases of unstable angina, and 46 cases of stroke),” according to the study’s abstract. “Among patients with a high cardiovascular risk, a statistically significant association between initiation of ustekinumab treatment and [serious cardiovascular event] 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).”

Among the 179 patients, 98 had acute coronary syndrome requiring stays in the intensive care unit or suffered strokes. Of these, 78% were at high cardiovascular risk, defined as having at least two risk factors or a personal history of atherothrombotic disease, before starting ustekinumab. More than 90% of those patients had psoriasis.

Dermatologists weigh in

Scott Worswick, MD, dermatologist with Keck Medicine of USC and clinical associate professor of dermatology at the Keck School of Medicine of USC, says this study will make him think twice about prescribing ustekinumab to psoriasis patients with cardiovascular risk factors.

“I have been prescribing ustekinumab for the last 10 years and remember when it first came out there was a big buzz about a similar drug, briakinumab. Briakinumab had the same mechanism of action as ustekinumab and got pulled due to potential cardiovascular events,” says Dr. Worswick. “The same concerns didn’t show up in the initial trials for ustekinumab, but this study shows that maybe there is a slight increase with ustekinumab, as well.”

Recent research on other systemic psoriasis agents IL-17 inhibitors and tumor necrosis factor (TNF) inhibitors suggests these agents might lower risk of cardiovascular events.

“If I have a patient that has cardiovascular risk factors, I might think about prescribing one of those other agents rather than ustekinumab,” he says.

Still, ustekinumab might be the most appropriate therapy for some patients, and he will counsel those about the potential risks.

“If you look at the data, ustekinumab is a very effective drug for psoriasis and the other diseases,” says Dr. Worswick.

Dermatologist Jashin J. Wu, MD, founder and course director of the Symposium for Inflammatory Skin Disease and the San Diego Dermatology Symposium, he says he is surprised by these findings.

“Most of the observational data involving biologics (in particular TNF inhibitors) are associated with a reduction in cardiovascular events, and a few studies show no association,” says Dr. Wu. “This is the only study that shows an increased association in cardiovascular events with ustekinumab.”

There was an earlier study which showed that ustekinumab had a numerically higher risk of major adverse cardiovascular events. But the risk, according to Dr. Wu, was not significant and likely due to a small number of patients.

Like Dr. Worswick, Dr. Wu says the findings are enough to give him pause in prescribing ustekinumab to those at high cardiovascular risk.

Not all dermatologists agree with the study’s findings.

Joel M. Gelfand, MD, MSCE, professor of dermatology and epidemiology and director, Psoriasis and Phototherapy Treatment Center, at the University of Pennsylvania Perelman School of Medicine, says results of the Poizeau et al study in JAMA Dermatology are methodologically flawed, making the results unreliable.

The results of the study should not impact clinical practice, according to Dr. Gelfand.

“Poizeau and colleagues used a method called the case-crossover design to test their hypothesis. This design makes a fundamental assumption: that the exposure and its effects are transient. Clearly, this assumption is violated with ustekinumab, a drug taken chronically with a long half-life,” says Dr. Gelfand. “Indeed, it is known from the CANTOS trial that it takes more than 6 months to see a reduction of major adverse cardiovascular events compared to placebo when using a biologic to treat inflammation. One could therefore conclude the opposite based on Poizeau’s results, that ustekinumab treatment for 6 to 12 months is protective of cardiovascular events compared to less than 6 months of treatment where the effect is expected to be null based on CANTOS data.”

References:

1. Poizeau F, Nowak E, Kerbrat S, et al. Association Between Early Severe Cardiovascular Events and the Initiation of Treatment With the Anti–Interleukin 12/23p40 Antibody Ustekinumab. JAMA Dermatol. Published online September 09, 2020. doi:10.1001/jamadermatol.2020.2977

2. Ryan C, Leonardi CL, Krueger JG, et al. Association Between Biologic Therapies for Chronic Plaque Psoriasis and Cardiovascular Events: A Meta-analysis of Randomized Controlled Trials. JAMA. 2011;306(8):864–871. doi:10.1001/jama.2011.1211

3. Ahlehoff O, Skov L, Gislason G, Gniadecki R, Iversen L, Bryld LE, Lasthein S, Lindhardsen J, Kristensen SL, Torp-Pedersen C, Hansen PR. Cardiovascular outcomes and systemic anti-inflammatory drugs in patients with severe psoriasis: 5-year follow-up of a Danish nationwide cohort. J Eur Acad Dermatol Venereol. 2015 Jun;29(6):1128-34. doi: 10.1111/jdv.12768. Epub 2014 Oct 10. PMID: 25303139.

Disclosures:

Dr. Worswick: None

Dr. Wu is or has been an investigator, consultant, or speaker for AbbVie, Almirall, Amgen, Arcutis, Boehringer Ingelheim, Bristol-Myers Squibb, Dermavant, Dr. Reddy's Laboratories, Eli Lilly, Galderma, Janssen, LEO Pharma, Novartis, Regeneron, Sanofi Genzyme, Sun Pharmaceutical, UCB, Valeant Pharmaceuticals North America LLC.

Dr Gelfand served as a consultant for Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Janssen Biologics, Novartis Corp, Regeneron, UCB (Data Safety and Monitoring Board), and Sanofi and Pfizer Inc, receiving honoraria; in addition, he receives research grants (to the Trustees of the University of Pennsylvania) from Abbvie, Janssen, Novartis Corp, Sanofi, Celgene, OrthoDermatologics, and Pfizer Inc, and he has received payment for CME work related to psoriasis that was supported indirectly by Eli Lilly and Company and Ortho Dermatologics.