IL23-axis cytokines and C-reactive protein as dissociable biomarkers of vascular recovery in psoriasis: A hypothesis

Abstract Biologic therapy has transformed psoriasis into a clinically controllable disease, yet skin clearance does not guarantee resolution of the systemic inflammation and vascular dysfunction that drive cardiovascular risk in this population. We hypothesize that interleukin (IL)-23-axis-proximal cytokines and C-reactive protein (CRP) mark two distinct, dissociable inflammatory compartments in psoriasis: IL23-axis-proximal signaling predominantly governs cutaneous disease activity and microvascular endothelial function, whereas CRP integrates a broader cardiometabolic burden and tracks macrovascular recovery. We distinguish IL23-axis-proximal cytokines (IL23, IL17a, IL22), whose production is largely confined to lesional skin, from shared effector cytokines (TNF-α, IFN-γ, IL1, and IL6), which also arise from adipose tissue and other systemic sources. This model generates two falsifiable predictions: (1) IL23 blockade will improve cutaneous microvascular endothelial function in proportion to suppression of IL23-axis-proximal signaling and out of proportion to any change in CRP, and (2) persistent CRP elevation despite adequate skin clearance will identify patients with blunted macrovascular recovery even when IL23-axis-proximal signaling is suppressed. Because IL6 is a node shared by cutaneous and adipose inflammation, the two compartments are coupled, and we therefore state the model in relative rather than absolute terms: quantitative dissociation, not statistical independence. If confirmed, this compartmentalized model would explain why near-complete skin clearance under biologic therapy, including IL23 blockade, does not uniformly normalize cardiovascular risk, and would offer two complementary, mechanism-specific biomarkers, rather than skin clearance alone, for monitoring vascular recovery after psoriasis treatment. We outline the rationale for this hypothesis and a longitudinal biomarker-imaging design capable of refuting it.