A trial to determine the effect of psoriasis treatment on cardiometabolic disease

描述(申请人提供)：牛皮癣在美国影响超过700万人(全球1.25亿人)，是人类最常见的辅助性T细胞(Th)-1，Th-17介导的炎症性疾病。流行病学研究表明，牛皮癣与发生重大心血管事件和因心血管疾病导致的过早死亡的风险增加有关，而不受传统危险因素的影响。目前尚不清楚银屑病的成功治疗是否会调节心血管风险。此外，肿瘤坏死因子α抑制剂(肿瘤坏死因子-I S)治疗牛皮癣和其他炎症性疾病的患者已达100多万人，有观察性研究表明这些药物可以调节脂蛋白和心血管风险，然而，需要对这些终点进行随机试验来证实这些发现。鉴于炎症是心脏代谢性疾病的一个重要致病过程，通过治疗牛皮癣系统地减少炎症提供了一个人体活体模型，以了解慢性炎症的调节与心血管疾病之间的联系，在这个人群中，疾病的治疗是选择性的，提供了一种合乎道德的安慰剂。18[F]-2-氟-2-脱氧-D-葡萄糖(FDG)正电子发射断层扫描(PET)/计算机断层扫描(CT)用于测量血管炎症的最新进展为在体内验证这一假说提供了一种方法。此外，FDG PET CT解决了该领域取得进展的关键障碍，因为它允许以一种高度敏感、可重复性、在干预后短期内可修改的方式对血管炎症进行动态体内测量，并可预测临床上重要的心血管事件。我们汇集了技术精湛的多样化合作者，他们是牛皮癣心血管研究、PET/CT血管成像、脂蛋白代谢和心血管翻译的领导者，专注于代谢和动脉粥样硬化疾病的炎症病理机制。这个团队提供了一个重要的机会来解决这一问题的跨学科性质，研究两种常见但表型截然不同的疾病之间的相互关系。因此，我们提出了一项随机、安慰剂对照试验，以确定银屑病的治疗是否改善了FDGPET CT测量的血管炎症和已知CV生物标记物(包括血脂异常、高密度脂蛋白功能、代谢和基于炎症的测量)测量的心脏代谢疾病，使用三种治疗方案：肿瘤坏死因子-I S的全身免疫调节；中波紫外线B光疗的皮肤定向治疗；以及安慰剂。通过提出的研究，我们将提高对与安慰剂相比，肿瘤坏死因子-I、S和UVB光疗如何在体内和体外调节血管炎症和心脏代谢性疾病的科学理解。这些结果将是确定牛皮癣的治疗如何影响这一脆弱患者群体的心血管风险的关键一步，同时将提高对常用肿瘤坏死因子-I S的非靶向作用的科学知识。

DESCRIPTION (provided by applicant): Psoriasis affects over 7 million people in the US (125 million people worldwide) and is the most common helper T-cell (Th)-1, Th-17 mediated inflammatory disease in humans. Epidemiological studies indicate that psoriasis is associated with an increased risk for major cardiovascular (CV) events and premature death due to CV disease independent of traditional risk factors. It is not know if successful treatment of psoriasis modulates CV risk. Furthermore, treatment of psoriasis and other inflammatory disease states with tumor necrosis factor alpha inhibitors (TNF-I s) has reached over 1 million people and there are observational studies demonstrating modulation of lipoproteins and CV risk with these drugs, however, a randomized trial of these endpoints is necessary to confirm these findings. Given that inflammation is an important pathogenic process in cardiometabolic disease, reduction of inflammation systemically by treating psoriasis provides a human, in vivo model to understand the link between modulation of chronic inflammation and CV disease in a population where treatment of the disease is elective providing an ethical placebo arm. The recent development of 18[F]-2-fluoro-2-deoxy-D-glucose (FDG) imaging using positron-emission tomography (PET)/computed tomography (CT) for measuring vascular inflammation provides a modality to test this hypothesis in vivo. Furthermore, FDG PET CT addresses a critical barrier to progress in the field as it allows for dynamic in vivo measurement of vascular inflammation in a manner which is highly sensitive, reproducible, modifiable over a short term following intervention, and predictive of clinically important CV events. We have assembled highly skilled, diverse collaborators who are leaders in psoriasis cardiovascular research, PET/CT vascular imaging, lipoprotein metabolism and cardiovascular translational focused on inflammatory patho-mechanisms of metabolic and atherosclerotic disease. This team provides a significant opportunity to address the interdisciplinary nature of the problem of studying the interrelationship of two common, but phenotypically distinct diseases. We therefore propose a randomized, placebo controlled trial to determine if treatment of psoriasis improves vascular inflammation measured by FDG PET CT and cardiometabolic disease measured by known CV biomarkers (including dyslipidemia, HDL function, metabolic, and inflammatory-based measures) using three treatment arms: systemic immunomodulation with TNF-I s; skin-directed therapy with ultraviolet B (UVB) phototherapy; and placebo. Through the studies proposed, we will improve scientific understanding of how treatment with TNF-I s and UVB phototherapy modulate vascular inflammation and cardiometabolic disease in vivo and ex vivo compared to placebo. These results will be a critical step in determining how treatment of psoriasis affects CV risk in this vulnerable patient population and will concurrently improve scientific knowledge of off target effects of the commonly used TNF-I s.