Metabolic profiling reveals interleukin-17A monoclonal antibody treatment ameliorate lipids metabolism with the potentiality to reduce cardiovascular risk in psoriasis patients

Abstract

Background: Psoriasis is a common chronic inflammatory skin disease associated with overproduction of interleukin-17A (IL-17A). IL-17A monoclonal antibodies (mAbs) have shown clinical efficacy in psoriasis patients. Although a series of different overlapping mechanisms have been found to establish a link between psoriasis and cardiovascular diseases, the underlying mechanisms of the two types of diseases and the potential efficacy of IL-17A mAbs in amelioration of cardiovascular comorbidities remain unclear.

Methods: Serum samples from two study cohorts including 117 individuals were analyzed using a high-throughput UHPLC-MS platform. Non-targeted metabolic profiling analysis was first conducted with samples from 28 healthy individuals and from 28 psoriasis patients before and after 12-weeks of ixekizumab treatment in study cohort 1. Study cohort 2 was additionally recruited to validate the correlations of the identified metabolites with cardiovascular diseases.

Results: A total of 43 differential metabolites, including lysophospholipids, free fatty acids, acylcarnitines and dicarboxylic acids, were accurately identified in study cohort 1, and the analysis showed that lipid metabolism was impaired in psoriasis patients. Compared with healthy individuals, psoriasis patients had higher levels of lysophosphatidylcholines, lysophosphatidylinositols, lysophosphatidic acids and free fatty acids, but lower levels of acylcarnitines and dicarboxylic acids. The identified dicarboxylic acid levels were inversely correlated with psoriasis area and severity index (PASI) scores (P < 0.05). The results for study cohort 2 were largely consistent with the results for study cohort 1. Moreover, the levels of all identified lysophosphatidylcholines were higher in psoriasis patients with coronary heart diseases than in psoriasis without coronary heart disease. Notably, most of these lipidic changes were ameliorated by ixekizumab treatment.

Conclusion: The results of this non-targeted metabolomic analysis indicate that treatment with IL-17A mAbs can not only ameliorate psoriasis lesions but also restore dysregulated lipid metabolism to normal levels in psoriasis patients. Considering that dysregulated lipid metabolism has been regarded as the critical factor in cardiovascular diseases, the recovery of lipid metabolites in psoriasis patients indicates that IL-17A mAbs might have the potential protective effects against cardiovascular comorbidities.

Keywords: Cardiovascular diseases; IL-17A monoclonal antibody; Ixekizumab; Lipids; Lysophospholipids; Metabolism; Psoriasis.

Fig. 1

Workflow of this study. CON: group of healthy controls; PSO: group of psoriasis patients; IXE: group of ixekizumab-treated psoriasis patients; PC: group of psoriasis patients with coronary heart disease; CV: group of coronary heart disease patients without psoriasis

Fig. 2

Screening criteria for the differential metabolites identified in the PSO/CON comparison in study cohort 1. a. Volcano plot showing the variations in metabolites in the PSO/CON comparison according to the -log(P-value). b. S-plots for covariance and reliability correlations from OPLS-DA in the PSO/CON comparison. c. Thirty-seven identified differential metabolites in the PSO/CON comparison. The Bar plots represent, from left to right, the −log(P-value) outcomes from the t-test, the fold changes and the VIP values obtained from OPLS-DA. CON: group of healthy controls; PSO: group of psoriasis patients

Fig. 3

IL-17A mAb ameliorates dysregulated lipid metabolism in psoriasis patients. a. Heatmap of the 43 identified differential metabolites in the study cohort 1. The color represents the average normalized intensity of each metabolite. b. Box plots of highlighted metabolites in study cohort 1. *P < 0.05, **P < 0.01, ***P < 0.001. c. Correlation analysis between the identified DAs and PASI scores of psoriasis patients in study cohort 1. CON: group of healthy controls; PSO: group of psoriasis patients; IXE: group of ixekizumab-treated psoriasis patients; PASI: psoriasis area and severity index

Fig. 4

Common and specific metabolites in psoriasis patients with or without coronary heart disease. a. sPLS-DA score plots of the CON, PSO, PC and CV groups in study cohort 2. The CON group is indicated with green circles, the PSO group with red circles, the PC group with blue circles, and the CV group with yellow circles. b. Venn diagram of the 25 overlapping metabolites in the PSO, CV and PC groups compared with the CON group in study cohort 2. c. Heatmap of the 25 overlapping metabolites in the PSO, PC and CV groups (all compared with the CON group). d. The bar plots represent, from left to right, the log (fold change value) and -log(P-value) from t-test analysis in the PC/PSO comparison in study cohort 2. CON: group of healthy controls; PSO: group of psoriasis patients; PC: group of psoriasis patients with coronary heart disease; CV: group of coronary heart disease patients without psoriasis

Fig. 5

Scatter plots of highlighted metabolites in study cohorts 1 and 2. The metabolic changes in six ixekizumab-treated individuals from the PC group in the study cohort 2 conformed to previous observations in study cohort 1. *P < 0.05, **P < 0.01, ***P < 0.001. CON: group of healthy controls; PSO: group of psoriasis patients; IXE: group of ixekizumab-treated psoriasis patients; PC: group of psoriasis patients with coronary heart disease; CV: group of coronary heart disease patients without psoriasis