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.

IF 4 3区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Advances in Therapy Pub Date : 2025-10-06 DOI:10.1007/s12325-025-03350-0

Juan de Luque, Carmen Mochón-Jiménez, Irene Rivera-Ruiz, Jesús Gay-Mimbrera, Judilyn Fuentes-Duculan, Israel Coats, Macarena Aguilar-Luque, Beatriz Isla-Tejera, Antonio Vélez-García Nieto, Manuel Galán-Gutiérrez, Teresa López-Viñau López, Mayte Suarez-Fariñas, James G Krueger, Juan Ruano

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引用次数: 0

Abstract

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.

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ZMIZ1/TGF-β/STAT通路的功能遗传评分预测抗tnf和抗il - 12/23药物治疗的银屑病患者的早期生物停药

简介：银屑病的生物药物生存率是可变的。虽然肥胖和合并症等临床因素有助于早期停药，但遗传预测因素尚未明确。ZMIZ1/TGF-β/STAT轴调控免疫代谢反应，是一个很有前景的药理学靶点。方法：回顾性分析312例中重度牛皮癣（NCT07041112）患者的875个生物治疗疗程。根据ZMIZ1/TGF-β/STAT轴上的7个单核苷酸多态性（snp）得出基于途径的遗传评分，并在中位数处进行二分。通过Kaplan-Meier曲线和Cox比例风险模型对人口统计学、临床和炎症协变量进行调整，评估主要终点为生物停药时间。结果：尽管基线肿瘤坏死因子(TNF)-α、白细胞介素(IL)-1β、IL-15和瘦素升高，但遗传评分高的患者的药物生存期明显延长（风险比[HR] = 0.74； 95%可信区间[CI]: 0.62-0.89; p = 0.0015）。这表明遗传背景同时影响免疫代谢激活和治疗持久性。抗il - 12/23药物（HR = 0.44; 95% CI: 0.26-0.75; p = 0.002）和抗tnf治疗（HR = 0.79; 95% CI: 0.62-0.99; p = 0.045）的预测值最强，但调整后抗il - 17/IL-23药物的预测值缺失。没有一种循环生物标志物能独立预测生存率。结论：ZMIZ1/TGF-β/STAT通路的功能遗传评分独立预测银屑病的长期生物持续性，特别是抗tnf和抗il 12/23治疗。它与免疫代谢激活的关联表明，遗传背景决定了炎症状态和治疗持久性。将这种分析纳入预测算法可以提高治疗的个性化和生物保留率。试验注册：试验注册号NCT07041112。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Advances in Therapy 医学-药学

CiteScore

7.20

自引率

2.60%

发文量

353

审稿时长

6-12 weeks

期刊介绍： Advances in Therapy is an international, peer reviewed, rapid-publication (peer review in 2 weeks, published 3–4 weeks from acceptance) journal dedicated to the publication of high-quality clinical (all phases), observational, real-world, and health outcomes research around the discovery, development, and use of therapeutics and interventions (including devices) across all therapeutic areas. Studies relating to diagnostics and diagnosis, pharmacoeconomics, public health, epidemiology, quality of life, and patient care, management, and education are also encouraged. The journal is of interest to a broad audience of healthcare professionals and publishes original research, reviews, communications and letters. The journal is read by a global audience and receives submissions from all over the world. Advances in Therapy will consider all scientifically sound research be it positive, confirmatory or negative data. Submissions are welcomed whether they relate to an international and/or a country-specific audience, something that is crucially important when researchers are trying to target more specific patient populations. This inclusive approach allows the journal to assist in the dissemination of all scientifically and ethically sound research.