Psoriasis and the Risk of Diabetes

银屑病在美国影响超过700万人（全球1.25亿人），是人类最常见的辅助性t细胞(Th)-1和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。新出现的数据表明，牛皮癣患者患糖尿病的风险也可能增加。在动物和人类糖尿病模型中，参与牛皮癣维持的慢性炎症途径已被证明可促进胰岛素抵抗。此外，牛皮癣和糖尿病有共同的易感基因（如CDKAL1）。这些共同的遗传和炎症途径提示银屑病患者糖尿病风险增加的生物学合理性。然而，目前尚不清楚牛皮癣的临床方面（如受损伤的体表面积、受损伤的解剖部位等）如何影响糖尿病的风险，也不知道牛皮癣的成功治疗是否会降低糖尿病的风险。我们将通过对正在进行的NIH资助项目实施新的目标来解决这些关键的知识差距。首先，我们将确定9000名牛皮癣患者的糖尿病风险，称为事件健康结局和牛皮癣事件（iHOPE）研究，由R01 h089744建立。其次，我们将确定牛皮癣的临床方面如何与流行糖尿病在美国多中心临床为基础的队列1800广泛表型的牛皮癣患者，其中200人患有流行糖尿病。该队列来源于RC1 AR058204建立的皮肤病临床疗效研究网络（DCERN）。第三，我们将确定与皮肤靶向治疗（紫外线B光疗）或安慰剂相比，使用系统性tnf抑制剂（阿达木单抗）治疗牛皮癣是否能改善预测未来糖尿病发展的新生物标志物。这一新目标将在R01 HL111293资助的正在进行的银屑病血管炎症（VIP）试验中进行研究，该试验旨在评估血管炎症和脂质代谢结果。这些项目利用申请人进行的现有研究来制定高度重要和创新的目标，这些目标将：1)为正在进行的研究提供附加价值，同时帮助申请人开发以糖尿病为重点的流行病学和转化研究的新技能；2)通过确定哪些牛皮癣患者患糖尿病的风险最高，从而保证已经证明可以降低糖尿病风险的预防性干预措施，解决一个重要问题；3)确定一类通常用于多种炎症疾病适应症的药物（即TNF抑制剂）是否有希望通过严格的随机对照试验中创新生物标志物的研究来预防糖尿病，这可能产生新的临床实践范例；4)提供一个多样化的临床研究平台，指导年轻的内科科学家进行以患者为导向的研究，并促进他们成功过渡到独立。

DESCRIPTION (provided by applicant): Psoriasis and the risk of diabetes Psoriasis affects over 7 million people in the US (125 million people worldwide) and is the most common helper T-cell (Th)-1 and 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. Emerging data suggest that patients with psoriasis may also be at increased risk for developing diabetes as well. The chronic inflammatory pathways involved in the maintenance of psoriasis have been shown to promote insulin resistance in animal and human models of diabetes. Furthermore, psoriasis and diabetes share susceptibility genes (such as CDKAL1). These shared genetic and inflammatory pathways suggest biologic plausibility for an increased risk of diabetes in patients with psoriasis. However, it is not known how clinical aspects of psoriasis (such as body surface area of involvement, anatomic sites of involvement, etc) impact diabetes risk nor is it known if successful treatment of psoriasis will lower the risk of diabetes. We will address these key knowledge gaps by conducting new aims to ongoing NIH funded projects. First, we will determine the risk of diabetes in a large population-based cohort of 9000 patients with psoriasis called the incident health outcomes and psoriasis events (iHOPE) study, established by R01 HL089744. Second we will determine how clinical aspects of psoriasis are associated with prevalent diabetes in a United States multi-centered clinic-based cohort of 1800 extensively phenotyped patients with psoriasis, 200 of whom have prevalent diabetes. This cohort was derived from the Dermatology Clinical Effectiveness Research Network (DCERN) established by RC1 AR058204. Third, we will determine if treatment of psoriasis with a systemic TNF-inhibitor (adalimumab) improves novel biomarkers which predict future development of diabetes compared to skin targeted treatment (ultraviolet B phototherapy) or placebo. This new aim will be investigated in the ongoing Vascular Inflammation in Psoriasis (VIP) trial funded by R01 HL111293, which is designed to evaluate vascular inflammation and lipid metabolism outcomes. These projects leverage existing studies conducted by the applicant to develop highly significant and innovative aims which will: 1) provide added value to ongoing studies while aiding the applicant to develop new skills in epidemiological and translational research focusing on diabetes; 2) address an important problem by determining which patients with psoriasis are at highest risk for developing diabetes thus warranting preventive interventions already proven to reduce the risk of diabetes; 3) determine if a class of medicines (i.e., TNF inhibitors) which are commonly used across multiple inflammatory disease indications hold promise for diabetes prevention through the study of innovative biomarkers in a rigorous randomized controlled trial which may yield new clinical practice paradigms; and, 4) provide a diverse clinical research platform in which to mentor young physician scientists in patient oriented research and promote their successful transition to independence.