Sex differences in serum proteomic profiles in psoriatic arthritis

Abstract Objectives Sex-related differences exist in the clinical presentation and treatment outcomes of patients with PsA. The biological pathways driving these differences remain unknown. We conducted an untargeted proteomic study to identify sex-specific serum proteins and biological pathways in males and females with PsA. Methods We used an aptamer-based panel to measure 6402 serum proteins in 50 male and 50 female patients with active PsA and 50 age- and sex-matched non-psoriatic controls. Differential expression and pathway enrichment analysis identified differentially expressed proteins (DEPs) and enriched pathways between male and female PsA patients. Machine learning classifiers were used to develop sex-specific multi-biomarker models to distinguish PsA patients from controls. Proteins with the highest predictive performances were highlighted from random forest models. Results The differential analysis revealed over 20 times more sex-specific DEPs in PsA males vs controls (n = 741) than in PsA females vs controls (n = 31). The enriched pathways among DEPs in PsA males vs PsA females were related to intracellular signalling, vascular function, cytokine signalling and immune cell functions. All models discriminated PsA from controls for both sexes with an area under the curve of 0.85–0.99. Variable importance analysis identified leukotriene A-4 hydrolase as a significant predictor in PsA females vs controls, whereas IL-36 alpha, NEK7 and PIK3CA/PIK3R1 were significant in PsA males vs controls. Conclusion Significantly more dysregulated proteins and biological pathways were found in males than in females with PsA. The identified proteins and pathways offer potential new targets for sex-based research in PsA.