Genetically mimicked effects of evinacumab on psoriasis: a drug target Mendelian randomization study.

Background And Objectives: Dyslipidemia has been reported to contribute to the psoriasis pathogenesis. Thus, evinacumab, a novel lipid-lowering drug targeting angiopoietin-like 3, may have therapeutic potential to treat and/or manage psoriasis.

Methods And Study Design: Summary statistics were obtained from genome-wide association studies addressing psoriasis (FinnGen Consortium; n=216,752) and serum lipid concentrations (United Kingdom Biobank; n=403,943-440,546). Two-sample Mendelian randomization analyses were conducted to evaluate the associations of serum lipid concentrations and genetically mimicked effects of evinacumab, respectively, with the risks of psoriasis and its subtypes.

Results: Genetically determined per standard deviation increase in triglyceride concentrations was associated with increased risk of psoriasis (OR: 1.17, 95% CI: 1.03-1.32, p=0.018), whereas that in low-density lipoprotein-cholesterol (LDL-C) was associated with both psoriasis (OR: 1.22, 95% CI: 1.05-1.43, p=0.011) and its subtypes, including arthropathic psoriasis (OR: 1.30, 95% CI: 1.02-1.65, p=0.032), psoriasis vulgaris (OR: 1.87, 95% CI: 1.16-2.99, p=0.0095), and guttate psoriasis (OR: 2.19, 95% CI: 1.17-4.07, p=0.014). Moreover, genetically mimicked effects of evinacumab, via angiopoietin-like 3 inhibition, significantly reduced the risk of psoriasis (OR: 0.752 per standard deviation reduction in triglycerides, 95% CI: 0.577-0.982, p=0.036) and arthropathic psoriasis (OR: 0.266 per standard deviation reduction in LDL-C, 95% CI: 0.0886-0.799, p=0.018).

Conclusions: The genetically mimicked effect of evinacumab has the potential to reduce the risk of psoriasis and arthropathic psoriasis by lowering circulating triglyceride and LDL-C concentrations, respectively. These findings suggest that evinacumab may help prevent psoriasis and psoriatic arthritis progression in clinical practice.