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

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.

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.

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).

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.