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

确定银屑病治疗对心脏代谢疾病影响的试验

• 批准号: 8218835
• 负责人: JOEL M GELFAND
• 金额: $ 78.52万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-08 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8218835
• 关键词: 2-Fluoro-2-deoxyglucose; Address; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Biological Markers; Blood; Blood Vessels; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Cessation of life; Chronic; Clinical; Critical Pathways; Data; Deoxyglucose; Development; Disease; Dyslipidemias; Epidemiologic Studies; Ethics; Event; Functional disorder; Future; Grant; Helper-Inducer T-Lymphocyte; High Density Lipoproteins; Human; Image; Imaging Techniques; Immune; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Insulin Resistance; Intervention; Joints; Knowledge; Lesion; Link; Lipoproteins; Liver; Measurement; Measures; Mediating; Medical; Metabolic; Metabolic Pathway; Metabolism; Modality; Modeling; Myocardial Infarction; Nature; Observational Study; Organ; Pathogenesis; Pathway interactions; Patients; Perception; Pharmaceutical Preparations; Phenotype; Phototherapy; Placebos; Play; Population; Positron-Emission Tomography; Process; Psoriasis; Research; Rheumatoid Arthritis; Risk; Risk Factors; Skin; Spleen; Stroke; T-Lymphocyte; Testing; Tumor Necrosis Factor-alpha; X-Ray Computed Tomography; adalimumab; arm; base; cardiovascular risk factor; clinically significant; cytokine; fluorodeoxyglucose positron emission tomography; immune activation; immunoregulation; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; lipid metabolism; macrophage; patient population; premature; randomized placebo controlled trial; randomized trial; reverse cholesterol transport; tumor necrosis factor-alpha inhibitor; ultraviolet; vascular inflammation

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.

描述（由申请人提供）：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，牛皮癣与独立于传统危险因素的主要心血管（CV）事件和由CV疾病引起的过早死亡的风险增加有关。目前尚不清楚牛皮癣的成功治疗是否能调节CV风险。此外，使用肿瘤坏死因子α抑制剂（TNF-I）治疗牛皮癣和其他炎性疾病状态的人数已超过100万人，并且有观察性研究表明这些药物可以调节脂蛋白和CV风险，然而，需要对这些终点进行随机试验来证实这些发现。鉴于炎症是心血管代谢疾病的一个重要致病过程，通过治疗银屑病系统性地减少炎症提供了一个人体体内模型，以了解慢性炎症调节与心血管疾病之间的联系，在这种疾病的治疗是选择性的人群中，提供了一个伦理安慰剂组。最近使用正电子发射断层扫描(PET)/计算机断层扫描（CT）测量血管炎症的18[F]-2-氟-2-脱氧-d -葡萄糖（FDG）成像技术的发展为在体内验证这一假设提供了一种方式。此外，FDG PET CT解决了该领域进展的一个关键障碍，因为它允许以一种高度敏感、可重复、在干预后短期内可修改的方式动态测量血管炎症，并预测临床重要的心血管事件。我们汇集了高技能、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领域的领导者，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的相互关系问题的跨学科性质。因此，我们建议进行一项随机、安慰剂对照试验，以确定银屑病的治疗是否能改善FDG PET CT测量的血管炎症和已知CV生物标志物（包括血脂异常、HDL功能、代谢和基于炎症的测量）测量的心脏代谢疾病，采用三种治疗方法：用TNF-I进行全身免疫调节；紫外线B （UVB）光疗皮肤定向治疗；和安慰剂。通过提出的研究，我们将提高对体内和体外与安慰剂相比，TNF-I和UVB光疗如何调节血管炎症和心脏代谢疾病的科学认识。这些结果将是确定银屑病治疗如何影响这一易感患者群体心血管风险的关键一步，同时也将提高对常用TNF-I脱靶效应的科学认识。