Ustekinumab’s short-term effect on aortic vascular inflammation points to possible role of IL-12, IL-23 in cardiovascular disease, but more research is needed.
In a recent 39-patient trial, week 12 reductions in aortic vascular inflammation (AVI) achieved by patients on ustekinumab did not persist through week 52. Nevertheless, it's the first biologic drug to show temporary impact on vascular inflammation, while reductions in some systemic markers of inflammation did last 52 weeks.
"In psoriasis, there is intense interest in understanding if therapies will lower cardiovascular risk over time. And there's interest in this phenomenon in cardiovascular medicine in general, because we know that many patients have heart attacks or strokes that are related to chronic inflammation, not necessarily to traditional cardiovascular risk factors,” says lead author Joel M. Gelfand, M.D., MSCE. “So, there is a need to identify therapies that can lower cardiovascular risk by lowering inflammation in blood vessels in a way that will reduce heart attacks and strokes."
Dr. Gelfand says it is clear from previous research that TNF inhibitors and secukinumab do not alter AVI versus placebo. In the Vascular Inflammation in Psoriasis (VIP)-U trial, however, 18F-2-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) showed that at week 12, ustekinumab-treated patients had an 18.65% reduction in AVI versus placebo-treated patients (P = 0.001).
"But when we followed people for a total of 52 weeks on the drug, they were back to their baseline levels of aortic vascular inflammation,” he says.
Like the changes in AVI, statistically significant reductions in VCAM-1 that appeared at 12 weeks did not last until week 52. This protein mediates adhesion of lymphocytes to vascular endothelium and is believed to be important in atherosclerosis.
"Reducing VCAM-1 seems to suggest potential benefits in vascular health because essentially it would help limit the ability of immune cells to enter the vasculature and promote vascular disease," says Dr. Gelfand.
At week 52, researchers observed statistically significant decreases in TNF alpha, IL-1b, IL-17a, IL-18 and IL-6. Reductions in IL-1b and IL-6 are believed to be especially important as they are causally related to the risk of major cardiovascular events (lower levels are associated with lower risk). Most other inflammation-related biomarkers examined in the study, including CRP, did not change significantly. "We saw some very mild impairments in cholesterol that we don't believe are clinically important.”
The VIP-U trial establishes proof of principle that antibody-based therapies can causally decrease AVI. "These are very large molecules," says Dr. Gelfand. Before, it was unknown whether they could penetrate the aorta. This trial shows that previously tested biologics failed to influence AVI not due to their molecular size, but for biological reasons that remain unknown.
Overall, says Dr. Gelfand, the findings are reassuring in light of the small imbalance in cardiovascular events versus placebo that surfaced in early ustekinumab trials. "And this study suggests that, if anything, it seems to have cardioprotective benefits by lowering aortic vascular inflammation, even if it's only short-term."
Biomarkers seem to reflect ustekinumab's safety, he adds. "We don't see much change in systemic markers of inflammation. That may be part of the reason why we don't see higher rates of atypical and serious infections with therapies targeting the IL-12/23 pathway."
It's impossible to discern whether the effects on AVI stem from targeting IL-12 or IL-23, he notes. Rigorous trials with TNF inhibitors, ustekinumab and secukinumab are providing detailed phenotyping of these therapies' effects on pathways important to cardiovascular disease, adds Dr. Gelfand, whose group is investigating such effects with apremilast in an open-label trial.
"We'll need to study these things in the IL-23 drugs risankizumab, guselkumab and tildrakizumab, as well as newer therapies that come to market, to more fully understand what they do beyond the skin,” he says.
Dr. Gelfand is professor of dermatology and epidemiology, vice chair of clinical research, medical director of the Dermatology Clinical Studies Unit and director of the Psoriasis and Phototherapy Treatment Center at the University of Pennsylvania Perelman School of Medicine.
This study was funded by a grant to the University of Pennsylvania from Janssen Pharmaceuticals. Dr. Gelfand has served and received honoraria as a consultant for BMS, Boehringer Ingelheim, Janssen, Novartis, Sanofi, Pfizer and UCB. He has also received research grants (made to the University of Pennsylvania) from AbbVie, Boehringer Ingelheim, Celgene, Janssen, Novartis, Ortho Dermatologics and Pfizer.
1. Gelfand JM, Shin DB, Alavi A, et al. A phase IV, randomized, double-blind, placebo-controlled crossover study of the effects of ustekinumab on vascular inflammation in psoriasis (the VIP-U Trial). J Invest Dermatol. 2020;140:85-93.