A Systemic Immune State Axis Distinguishes Psoriatic Arthritis from Psoriasis

Psoriasis and psoriatic arthritis (PsA) are systemic immune-mediated diseases, but the features that distinguish cutaneous-dominant psoriasis from musculoskeletal involvement remain unclear. We analyzed four core public cross-sectional datasets spanning whole-blood methylation, PBMC single-cell RNA sequencing summarized at the subject level, skin RNA sequencing, and purified CD4+ T-cell methylation, and used two additional public skin cohorts for external contextual checks to define a disease inflammatory response axis (DIR) and a contrast-resolved systemic state coordinate (CRS) representing systemic immune state variation associated with PsA. In whole-blood methylation, DIR primarily separated healthy controls from psoriasis, whereas CRS separated psoriasis from PsA with minimal correlation to DIR. In untreated-only PBMC single-cell reanalysis, CRS separated PsA from PsO; the source-defined PSX subgroup (joint pain without CASPAR-classified PsA) showed heterogeneous subject-level positioning, with above-band enrichment concentrated at the cell-type level. Cell-type-resolved analyses localized CRS-related shifts to T-cell, monocyte, B-cell, and regulatory compartments and identified multicompartment pathway state remodeling along the CRS continuum. In contrast, skin RNA sequencing mainly captured lesional inflammatory burden and showed only limited additional PsA-related separation within the same tissue state. These findings support a model in which PsA is distinguished from psoriasis by an additional systemic immune state axis rather than by skin inflammatory burden alone.