Ustekinumab Shown to Reduce Aortic Inflammation

Joel M. Gelfand, MD, MSCE

Ustekinumab (Stelara), an FDA approved therapy for psoriasis, psoriatic arthritis, and Crohn’s Disease, has been shown to reduce aortic inflammation—a major marker for the risk of cardiovascular events.

In an ongoing, randomized, double-blind, placebo-controlled trial of 43 patients, those in the treatment group (n = 22) that was taking the Janssen product had a 19% improvement in aortic inflammation compared to the placebo group, confirmed by 18-FDG-PET/CT scans that were also independently confirmed by a second laboratory.

"The type of inflammation we see in psoriasis is similar to what we see in atherosclerosis - a type of heart disease that involves the build-up of fats, cholesterol, and inflammatory cells in the artery walls," Joel M. Gelfand, MD, MSCE, a professor of dermatology and epidemiology at the University of Pennsylvania, and the lead author, said in a statement. "Since ustekinumab blocks the specific pathways involved in both skin and cardiovascular inflammation, we wanted to test whether it can improve aortic vascular inflammation."

Gelfand told MD Magazine that at the moment, it is difficult to decipher the clinical impacts of this new finding.

“What’s important at this stage is the concept and the promise,” he said. “We know inflammation is an important risk factor for CVD—just recently, the CANTOS trial proved that blocking inflammation with an antibody against Il-1b lowers the risk of major cardiovascular events. Our study demonstrates that blocking IL12/23 not only improves inflammation in the skin, joints, and bowels, but also in the aorta, proving that it is capable of biologically hitting the target.”

These findings are an important proof of principle, Gelfand said, especially when put in the context of other studies. “It gives us more insight as to what’s going on with psoriasis and cardiovascular risk. It adds emphasis to what we’re finding now. It’s how you modulate the inflammation. It needs to be pretty specific.”

Psoriasis impacts an estimated 7.5 million Americans, according to the National Psoriasis Foundation. In moderate to severe cases, psoriasis carries an increased risk of heart attack, stroke, and premature death—a finding Gelfand was also involved in during a 2006 study.

The trial divided patients into a treatment group and a placebo group (n = 21), with imaging performed at baseline prior to treatment and week 12. The treatment group experienced a 6.6% decrease in aortic inflammation compared to a 12% increase in the placebo group (P <.0001).

As anticipated, skin inflammation was vastly improved in the treatment group, as 77% achieved a ≥75% improvement in psoriasis activity compared to 10.5% in the placebo group (P <.0001).

The trial results were consistent with a previous, smaller, uncontrolled trial of ustekinumab—but are in direct contrast with 2 larger trials of adalimumab (Humira, AbbVie). Gelfand said that this placebo-controlled trial, however, was the first of its kind to show a benefit in aortic inflammation. He called the effect “similar to what we would expect from a statin.”

“What we’re getting from this is more evidence that modulating inflammation can have cardiovascular benefits,” Gelfand said. “Now, we’re getting experimental data reading out to show these benefits. It moves the field forward and suggests that blocking IL 12 and 23 may reduce the risk of major cardiovascular events.”

The trial is still ongoing, with an open-label period planned for the participants, allowing them to take ustekinumab for up to 52 weeks. After that period, they will be rescanned and reassessed to determine if the improvement was more than temporary for the treatment group, as well as if the same improvement is seen in the placebo group post-switch.

Additionally, there are 2 other trials ongoing with secukinumab (Cosentyx, Novartis) and apremilast (Otezla, Celgene) to further determine which immune pathways are at play in aortic inflammation. “Ultimately, we’d like to do an event study, which would take 5000 patients and 5 years to do,” Gelfand said.

The findings were presented at the 2018 American Academy of Dermatology Annual Meeting in San Diego, California.

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