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

描述（由申请人提供）：银屑病影响美国超过700万人（全球1.25亿人），是人类最常见的辅助T细胞（Th）-1，Th-17介导的炎症性疾病。流行病学研究表明，银屑病与主要心血管（CV）事件和CV疾病导致的过早死亡的风险增加相关，与传统风险因素无关。尚不清楚银屑病的成功治疗是否会调节CV风险。此外，使用肿瘤坏死因子α抑制剂（TNF-1）治疗银屑病和其他炎症性疾病状态的患者已超过100万人，并且有观察性研究表明这些药物可调节脂蛋白和CV风险，但是，需要对这些终点进行随机试验以证实这些发现。鉴于炎症是心脏代谢疾病中的重要致病过程，通过治疗银肩病全身性减少炎症为人类提供了一种，体内模型，以了解慢性炎症和CV疾病的调节之间的联系，在人群中，疾病的治疗是选择性的，提供了一个道德的安慰剂手臂。用于测量血管炎症的发射断层扫描（PET）/计算机断层扫描（CT）提供了在体内检验该假设的模式。此外，FDG PET CT解决了该领域进展的关键障碍，因为它允许以高度灵敏、可重复、在干预后短期内可修改的方式动态体内测量血管炎症，并预测临床重要的CV事件。我们聚集了高技能，多样化的合作者，他们是银屑病心血管研究，PET/CT血管成像，脂蛋白代谢和心血管转化的领导者，专注于代谢和动脉粥样硬化疾病的炎症病理机制。该团队提供了一个重要的机会，以解决研究两种常见但表型不同的疾病之间相互关系的问题的跨学科性质。因此，我们提出了一项随机、安慰剂对照试验，以确定银屑病治疗是否改善血管炎症（通过FDG PET CT测量）和心脏代谢疾病（通过已知的CV生物标志物测量）（包括血脂异常、HDL功能、代谢和基于炎症的测量），使用三个治疗组：TNF-1的全身免疫调节;紫外线B（UVB）光疗的皮肤定向治疗;和安慰剂。通过所提出的研究，我们将提高对TNF-I和UVB光疗与安慰剂相比如何在体内和体外调节血管炎症和心脏代谢疾病的科学理解。这些结果将是确定银屑病治疗如何影响这一脆弱患者人群CV风险的关键一步，同时将提高对常用TNF-1脱靶效应的科学认识。 公共卫生相关性：拟议的项目将确定银屑病和其他炎症性疾病常用的疗法如何影响血管炎症和心血管风险的血液标志物。这项研究将有助于确定治疗银屑病是否可以降低主要心血管问题的风险，并将对我们了解抑制炎症如何影响脂质代谢和心血管疾病产生广泛的影响。

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. PUBLIC HEALTH RELEVANCE: The proposed project will determine how therapies commonly used for psoriasis and other inflammatory diseases impact vascular inflammation and blood markers of cardiovascular risk. This research will help determine if treating psoriasis may lower the risk of major cardiovascular problems and will have broad implications for our understanding of how suppressing inflammation affects lipid metabolism and cardiovascular disease.