PCSK9 inhibition tied to decreased psoriasis risk

Inhibition of the proprotein convertase subtilisin/kexin type 9 (PCSK9) pathway appears to be causally associated with a lower risk of psoriasis, regardless of the concentration levels of circulating low-density lipoprotein (LDL), according a two-sample Mendelian randomization study.

Data from population-level genome-wide association studies of psoriasis in the UK Biobank showed that genetically proxied inhibition of PCSK9 with alirocumab exerted a protective effect on the risk of developing psoriasis. Each standard deviation reduction in LDL was associated with 31-percent lower odds of psoriasis (odds ratio, 0.69, 95 percent confidence interval [CI], 0.55–0.88; p=0.003). [JAMA Dermatol 2023;159:275-280]

“This association appeared to be independent of circulating LDL levels, since we did not observe an overall association of LDL with psoriasis risk,” according to the investigators.

The result was replicated using data from the Finnish FinnGen database (OR, 0.71, 95 percent CI, 0.57–0.88; p=0.002).

Meanwhile, genetically proxied inhibition of 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR; as targeted by statins) and of Niemann-Pick C1–like 1 (NPC1L1; as targeted by ezetimibe) had a null association with psoriasis risk.

The UK Biobank analysis included 6,495 patients with psoriasis and 25,980 randomly selected individuals without psoriasis, while the FinnGen analysis involved 5,621 patients with psoriasis and a control group of 252,323 individuals.

Therapeutic target for psoriasis prevention

PCSK9, a member of proprotein convertase family, promotes LDL receptor degradation, with higher PCSK9 level being associated with greater incidence of cardiovascular events, the investigators pointed out. Moreover, circulating PCSK9 levels have been shown to be higher in patients with psoriasis than healthy controls and may be associated with atherosclerosis and cardiovascular risk in psoriasis. [Circulation 2016;133:1230-1239; J Invest Dermatol 2021;141:308-315]

In a recent study, PCSK9 expression was found to be higher in psoriatic plaques vs normal skin in keratinocytes and epithelial cells of dermis blood vessels. Further analysis using an imiquimod-induced mouse model of psoriasis indicated that PCSK9 knockout mice had suppressed imiquimod reaction and that reduced PCSK9 expression suppressed the imiquimod reaction. [Invest Dermatol 2019;139:859-867]

“Taken together, these results provide compelling evidence that PCSK9 is implicated in psoriasis pathophysiology. Although the results of the current analysis only provide inference for psoriasis prevention, [previous studies using] animal models support PCSK9 as a potential target for treatment,” according to the investigators. [Immune Netw 2019;19:e41; Invest Dermatol 2019;139:859-867]

“Existing PCSK9 inhibitors hold potential as therapeutic targets for prevention, and possibly treatment, of psoriasis, although further clinical studies are needed,” they added.