A Functional Genetic Score in the ZMIZ1/TGF-β/STAT Pathway Predicts Early Biologic Discontinuation in Psoriasis Patients Treated with Anti-TNF and Anti-IL12/23 Agents.

INTRODUCTION

Biologic drug survival in psoriasis is variable. While clinical factors such as obesity and comorbidities contribute to early discontinuation, genetic predictors are less defined. The ZMIZ1/TGF-β/STAT axis regulates immune-metabolic responses and represents a promising pharmacogenetic target.

METHODS

We retrospectively analyzed 875 biologic treatment courses from 312 patients with moderate-to-severe psoriasis (NCT07041112). A pathway-based genetic score was derived from seven single nucleotide polymorphisms (SNPs) in the ZMIZ1/TGF-β/STAT axis and dichotomized at the median. The primary outcome was time to biologic discontinuation, assessed with Kaplan-Meier curves and Cox proportional hazards models adjusted for demographic, clinical, and inflammatory covariates.

RESULTS

Patients with a high genetic score had significantly longer drug survival (hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.62-0.89; p = 0.0015), despite elevated baseline tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-15, and leptin. This indicates that genetic background simultaneously conditioned immune-metabolic activation and treatment persistence. Predictive value was strongest for anti-IL12/23 agents (HR = 0.44; 95% CI: 0.26-0.75; p = 0.002) and anti-TNF therapies (HR = 0.79; 95% CI: 0.62-0.99; p = 0.045), but absent for anti-IL17/IL-23 agents after adjustment. None of the circulating biomarkers independently predicted survival.

CONCLUSION

A functional genetic score in the ZMIZ1/TGF-β/STAT pathway independently predicted long-term biologic persistence in psoriasis, particularly with anti-TNF and anti-IL12/23 therapies. Its association with immune-metabolic activation suggests that genetic background shapes both inflammatory status and treatment durability. Incorporating such profiling into predictive algorithms may improve treatment personalization and biologic retention.

TRIAL REGISTRATION: Trial Registration NCT07041112.