Psoriasis and the risk of diabetes

描述(申请人提供)：牛皮癣和糖尿病的风险牛皮癣影响着美国700多万人(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。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。在动物和人类的糖尿病模型中，与牛皮癣的维持有关的慢性炎症途径已被证明促进胰岛素抵抗。此外，牛皮癣和糖尿病具有共同的易感基因(如CDKAL1)。这些共同的遗传和炎症途径表明，牛皮癣患者患糖尿病的风险增加的生物学合理性。然而，目前还不知道银屑病的临床方面(如受累的体表面积、受累的解剖部位等)如何影响糖尿病风险，也不知道银屑病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资助项目进行新的目标来解决这些关键的知识差距。首先，我们将在由R01 HL089744建立的名为突发健康结果和牛皮癣事件(IHOPE)研究的9000名牛皮癣患者的大型人群队列中确定糖尿病风险。其次，我们将在美国多中心临床队列中确定牛皮癣的临床特征与流行的糖尿病之间的关系，该队列包括1800名广泛表型的牛皮癣患者，其中200人患有普遍的糖尿病。该队列来源于由RC1AR058204建立的皮肤科临床有效性研究网络(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，全身肿瘤坏死因子抑制剂(阿达单抗)治疗牛皮癣是否能改善预测糖尿病未来发展的新生物标记物。这一新目标将在由R01 HL111293资助的正在进行的牛皮癣血管炎症(VIP)试验中进行研究，该试验旨在评估血管炎症和脂代谢结果。这些项目利用申请者进行的现有研究来开发非常有意义和创新的目标，这些目的将：1)为正在进行的研究提供附加值，同时帮助申请者在专注于糖尿病的流行病学和转化性研究中发展新的技能；2)通过确定哪些牛皮癣患者患糖尿病的风险最高，从而保证已被证明可以降低糖尿病风险的预防性干预，来解决一个重要问题；3)确定一类通常用于多种炎症性疾病适应症的药物(即肿瘤坏死因子抑制剂)是否通过在严格的随机对照试验中研究创新的生物标记物来预防糖尿病；以及，4)提供一个多样化的临床研究平台，在这个平台上指导年轻的内科科学家进行以患者为导向的研究，并促进他们成功地向独立研究过渡。

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.