Abstract
OBJECTIVES: Frailty is associated with numerous chronic conditions, but its relationship with psoriasis remains poorly understood. This study investigated whether baseline frailty predisposes individuals to incident psoriasis. Secondary analyses evaluated inflammatory markers, shared genetic architecture, and circulating proteins as supporting evidence to contextualize this association.
STUDY DESIGN: Baseline frailty was assessed using both the physical frailty phenotype and a multidimensional frailty index, classifying participants as non-frail, pre-frail, or frail. Cox proportional hazards models with stratified analyses were used to quantify associations with psoriasis onset. Multi-marker Analysis of Genomic Annotation was applied to identify genes common to both frailty and psoriasis. To examine causality, we employed two-sample and generalized summary-data-based Mendelian randomization. Additionally, circulating inflammatory markers and plasma proteomic data were analyzed as secondary exploratory analyses to identify candidate biological correlates rather than to establish definitive mechanisms.
RESULTS: Compared with non-frail individuals, both pre-frail and frail participants had a higher risk of developing psoriasis. Specifically, pre-frail individuals had hazard ratios of 1.22 (95% confidence intervals 1.13-1.32) for physical frailty and 1.40 (95% confidence intervals 1.30-1.52) for the frailty index. Frail participants had hazard ratios of 1.42 (95% confidence intervals 1.18-1.73) and 1.87 (95% confidence intervals 1.62-2.15), respectively, with stronger associations observed in those with higher polygenic risk scores (P for interaction <0.05). Gene analysis identified 81 genes shared between frailty and psoriasis, providing supporting evidence of overlapping genetic architecture. Circulating inflammatory markers, such as neutrophil count and C-reactive protein, were found to partially mediate the frailty-psoriasis relationship, with mediating effects ranging from 0.89% to 18.21%. Proteomic analyses identified PCSK9 as a potential candidate protein associated with psoriasis risk in frail individuals.
CONCLUSIONS: Overall, frailty was associated with an increased long-term risk of psoriasis, particularly in participants with higher genetic susceptibility. Inflammatory cell measures and circulating proteins, including PCSK9, should be interpreted as potential candidate markers requiring further validation in pre-frail and frail populations.