Ustekinumab shows promise for reducing psoriasis-associated cardiovascular comorbidity

Initial results of an investigator-initiated phase 4 trial suggest that blocking interleukin-12 (IL-12) and IL-23 may reduce cardiovascular inflammation associated with psoriasis, researchers reported on Feb. 17 at the American Academy of Dermatology annual meeting in San Diego.

Previously, Gelfand et al. showed that patients with psoriasis, particularly severe psoriasis, face a higher likelihood of heart attacks, strokes and cardiovascular mortality independent of traditional risk factors for these events. Numerous groups worldwide subsequently confirmed these findings, said Joel M. Gelfand, M.D., director, Psoriasis and Phototherapy Treatment Center, University of Pennsylvania.

"At this point, we know that people with psoriasis, particularly when disease is extensive, have higher rates of cardiovascular disease, events and mortality, independent of traditional risk factors. We don't know for certain which treatments modify that risk in a meaningful way," he said.

Observational studies suggest that methotrexate and tumor necrosis factor (TNF) inhibitors may reduce cardiovascular events in patients with psoriasis, versus other treatments and no treatment. But because these are not randomized, controlled trials (RCTs), said Dr. Gelfand, "you can never be 100% certain whether the effect is due to the drug or some other factor you couldn't fully explore."

PASI AS PROXY

To better understand cardiovascular abnormalities in patients with psoriasis, Gelfand et al., collaborating with Nehal Mehta, MD MSCE, a cardiologist and scientist at NHLBI, discovered through PET-CT scans that these patients possess increased aortic inflammation equating to the impact of approximately a decade of aging. "We've also shown that the amount of inflammation in the aorta correlates with the amount of skin inflammation, measured by Psoriasis Area and Severity Index (PASI) scores." Aortic inflammation not only predicts future cardiovascular risk, he said, but it also improves within 4-12 weeks with therapies known to lower cardiovascular risk, such as statins.

Presently, said Dr. Gelfand, it's impractical to conduct a 5-year, 5,000-patient study to  definitively determine the impact of psoriasis treatments on cardiovascular events. Instead, "We're trying to do initial studies to understand which therapies hold promise for modulating important surrogate markers of cardiovascular risk such as aortic inflammation." Adalimumab has failed to do so, according to Gelfand et al.  (NCT01553058 and NCT01866592) and another group of researchers.

In a post-marketing trial, Gelfand et al. randomized 21 patients to placebo and 22 patients to ustekinumab. "We found that at week 12, those who got ustekinumab had a 6.6% reduction in aortic vascular inflammation, while the placebo group saw a 12% increase," resulting in an overall 19% improvement for ustekinumab-treated patients versus those who received placebo (p = 0.001).

As expected, "We showed that the drug is also highly effective in the skin – 77% of patients achieved PASI 75 in the treatment group," versus 10.5% in the placebo group (p<0.001). "We've shown that when you clear the skin with a drug that blocks interleukin 12 and 23, you also have significant improvements in aortic inflammation," to a level on par with a statin. Study investigators had images reviewed by a second imaging lab, which confirmed the results.

A STRIKING SURPRISE

The above information suggests that Stelara (Janssen) may hold promise for lowering vascular disease risk over time, said Dr. Gelfand. "What's surprising is that we all believed that TNF inhibitors would lower aortic vascular inflammation, but those studies were negative. The fact that this study is positive is striking. We'll see as other work emerges whether or not IL-12 and -23) may be particularly critical to cardiovascular disease in psoriasis."

Gelfand et al. hypothesized that people with psoriasis are more prone to atherosclerotic disease, particularly non-calcified plaque, which carries higher risk for cardiovascular events. "It may be that a type of cardiovascular disease people with psoriasis have is driven by cytokines that are more relevant in psoriasis. We know that IL-23, for example, is probably a master cytokine in psoriasis, whereas TNF doesn't seem to be as specific for psoriasis." A substantial body of literature suggests that IL-12 also may play an important cardiovascular role.

Regarding study limitations, Dr. Gelfand said it's important to remember that vascular inflammation is a surrogate marker. "When you improve a surrogate marker, you don't always know if you're also improving the events that matter most to patients. There are drugs that lower cholesterol, but don't lower heart attacks." Although results reached statistical significance, added Dr. Gelfand, the study's relatively small size begs for replication in a larger setting.

The trial was still ongoing at press time, with all patients being treated up to one year to see if improvements last or keep improving. The investigators also will examine ustekinumab's effects on several additional cardiovascular biomarkers in the pathways of inflammation, glucose metabolism and cholesterol function. "And we are thinking through the next generation of trials to more tightly hone in on the effect of our therapy in cardiovascular disease." Gelfand et al. also are studying whether secukinumab or apremilast can modulate aortic vascular inflammation.

DISCLOSURES: 

Dr. Gelfand is a consultant to several companies that market psoriasis treatments, including Janssen, which supported this study via a grant to the University of Pennsylvania.

REFERENCE

F061 - Late-breaking Research:  Clinical Trials. “A Phase IV, Randomized, Double-blind, Placebo-controlled Crossover Study of the Effects of Ustekinumab on Vascular Inflammation in Psoriasis (The VIP-U Trial).” Joel M. Gelfand, M.D., 2:20 p.m., Feb. 17, American Academy of Dermatology 2018 annual meeting.