A Mendelian randomization study employing data from nearly 300,000 individuals has linked elevated levels of the PCSK9 enzyme with an increased risk of psoriasis, suggesting it might be targetable as an intervention.
. Conversely, psoriasis risk did not appear to be affected when LDL-C was reduced by other pathways of lipid control.
This study “suggests that PCSK9 inhibition is causally associated with reduced risk of psoriasis,” reported a team of investigators led by Sizheng Steven Zhao, MD, PhD, of the division of musculoskeletal and dermatological sciences, University of Manchester (England). “Existing PCSK9 inhibitors hold potential as therapeutic targets for prevention, and possibly treatment, of psoriasis, although further clinical studies are needed,” they concluded.
In an interview, Dr. Zhao also noted that it will be interesting to look at psoriasis susceptibility in post hoc analyses of large randomized controlled trials of PCSK9 inhibitors for cardiovascular disease.
“Genetically proxied” inhibition of HMG-CoA reductase, which is targeted by statins, and NPC1L1 which is targeted by ezetimibe, “were not associated with psoriasis risk,” the investigators reported in the study, published in JAMA Dermatology.
Abnormal lipid metabolism is sufficiently common among people with psoriasis that screening in patients with moderate to severe disease is recommended in 2019 psoriasis guidelines from the American Academy of Dermatology and the National Psoriasis Foundation. However, the link between these diseases is unclear. This study was launched to explore genetically proxied relationships between psoriasis and LDL-C reductions as well as specific treatments for elevated LDL-C.
Mendelian randomizations were applied to deidentified data from two sources, a UK biobank and FinnGen, a Finnish-based project for identifying genotype-to-phenotype correlations. Genetic proxies for these variables were established on the basis of genomewide association studies on large population samples.
Ultimately, 34 genetic variants were selected to proxy for lipid lowering by PCSK9, 19 were selected to proxy for HMG-CoA reductase, and 9 for NPC1L1. In the Mendelian analyses performed on the two sources, genetically proxied PCSK9 inhibition was associated with about a 30% reduction in the odds ratio of psoriasis (OR, 0.69; P = .003). There were no robust associations with proxies for reductions in either HMG-CoA reductase or NPC1L1.
In sensitivity analyses, there was no evidence of bias from pleiotropy or genetic confounding, according to Dr. Zhao and his coauthors, who noted that the relationship between reductions in PCSK9 and reduced risk of psoriasis appeared to be independent of change in circulating LDL-C.
Given the prior evidence implicating the PCSK9 enzyme in psoriasis risk, “this is an exciting study that really highlights the importance of studying and targeting lipid metabolism in psoriasis for a few reasons,” according to Michael S. Garshick, MD, a researcher, cardiologist, and director of the cardio-rheumatology program, New York University Langone Health.
An investigator who has participated in several studies evaluating the relationship between cardiovascular risk and psoriasis, Dr. Garshick said there is increasing interest in PCSK9 as a biomarker or even a mediator of inflammation independent of blood lipid levels.
“In psoriasis regarding PCSK9, we and others have shown PCSK9 is elevated in psoriatic lesion skin, and studies are starting to investigate the unique lipidomic profile in psoriasis,” Dr. Garshick said in an interview. The study he led that showed elevated PCSK9 levels in psoriatic skin was published in 2021 in the Journal of Investigative Dermatology.
While the Mendelian randomization provides only “an inference” that PCSK9 plays a role in mediating risk of psoriasis, Dr. Zhao and coauthors cited numerous studies linking elevated PCSK9 to psoriasis pathophysiology. This not only includes the elevated PCSK9 expression in psoriatic plaques as shown by Dr. Garshick and others but several sets of experimental evidence linking PCSK9 to inflammatory pathways, including upregulation of interleukin-17 and stimulation of macrophage activation.
While Dr. Zhao and coauthors suggested that clinical trials are now needed to test the potential of PCSK9 inhibitors to modify the risk of psoriasis, Dr. Garshick indicated that there are numerous variables to unravel in the relationship between elevated lipids, PCSK9, and psoriasis.
“In our own studies, we did see a statistical correlation between circulating PCSK9 and psoriasis severity,” Dr. Garshick said. But he added, “I think we are just beginning to understand the functions of circulating (extrahepatic) PCSK9 independent of lipid metabolism.”
While he is intrigued by the evidence that PCSK9 is linked to systemic inflammation, he pointed out that several medications used to treat dyslipidemias, such as statins, are associated with an anti-inflammatory effect.
This study “further emphasizes the need to conduct clinical trials treating dyslipidemia in psoriasis, including the targeting of PCSK9, whether it is with statins with lipid lowering and potential pleiotropic anti-inflammatory properties or PCSK9 inhibition,” he said. If positive, “both would be exciting.“
From a cardiologist’s point of view, there is an upside for including patients with psoriasis in lipid-lowering trials even if the effect on psoriasis is modest. Either way, “you still get the lipid-lowering benefit, which is important for reducing atherosclerotic cardiovascular disease,” Dr. Garshick said.
Dr. Zhao reported financial relationships with UCB, although UCB did not provide funding for this study. One author reported grants from Versus Arthritis and the National Institute for Health Research Manchester Biomedical Research Centre during the study, grants from Bristol Myers Squibb, Galapagos, and Pfizer, and personal fees from Chugai Roche outside the submitted work. No other disclosures were reported. The study was supported by grants from Versus Arthritis and the NIHR Manchester Biomedical Research Centre. Dr. Garshick reported financial relationships with AbbVie and Horizon Therapeutics.