PPAR-y agonists, RA and cardiovascular disease

描述(申请人提供)：类风湿性关节炎(RA)是一种影响1%人口的慢性炎症性疾病，主要由于动脉粥样硬化加速而导致死亡率升高。全身性炎症对内皮功能有很强的影响，并导致动脉粥样硬化和斑块破裂的增加。因此，对于像RA这样的疾病，理想的治疗方法是通过减少炎症和预防或逆转内皮功能异常来解决多种病理过程。过氧化物酶体增殖物激活受体-y(PPAR-y)激动剂是一类对血管和炎症级联反应具有明显趋向性作用的药物，这使得它们成为预防动脉粥样硬化/内皮功能障碍和治疗类风湿关节炎的非常有吸引力的治疗选择。拟议项目的主要目标是评估PPAR-y激动剂吡格列酮在改善类风湿关节炎患者内皮功能障碍和动脉粥样硬化风险的标志物方面的疗效。作为次要目标，我们将评估吡格列酮在改善RA疾病活动性和炎症标志物方面的疗效。拟议的临床试验将是一项随机、安慰剂对照的双盲交叉研究，对象为144名RA患者，随机接受吡格列酮或安慰剂治疗。患者将接受3个月的吡格列酮或安慰剂治疗，经历8周的冲洗期，然后接受另一只手臂的交叉治疗3个月。将通过以下方式研究吡格列酮对内皮生物学和功能的作用：1)在吡格列酮治疗前和治疗后，分别验证内皮依赖和独立功能的替代标志物--臂动脉血流介导的扩张和硝酸甘油介导的扩张；2)动脉顺应性，因为动脉僵硬是心血管损害的一个重要预测因子；3)在吡格列酮治疗前后检测内皮损伤和心血管风险的特定血清生物标志物。对炎症和RA疾病活动的影响将通过：1)疾病活动量表(DAS-28)；以及2)研究全身炎症和炎性细胞因子的标记物来评估。如果吡格列酮治疗能改善类风湿性关节炎患者的内皮功能，减轻炎症反应，则可能为预防早期动脉粥样硬化和维持炎症提供一种安全、有效、相对廉价的辅助治疗方法。这项研究也将进一步阐明类风湿关节炎血管内皮细胞损伤的生物学机制。

DESCRIPTION (provided by applicant): Rheumatoid arthritis (RA), a chronic inflammatory disease affecting 1% of the population, is associated with heightened mortality predominantly due to accelerated atherosclerosis. Systemic inflammation has powerful effects on endothelial function and contributes to increased atherosclerosis and plaque rupture. Therefore, the ideal therapy for a disease like RA is one in which multiple pathologic processes are addressed by reducing inflammation and preventing or reversing abnormalities of endothelial function. Peroxisome proliferator-activated receptor-y (PPAR-y) agonists are drugs with profound pleitropic effects on the vasculature and on inflammatory cascades which make them very attractive therapeutic options for both atherosclerosis/endothelial dysfunction prevention and for treatment of inflammation in RA. The primary goal of the proposed project is to evaluate the efficacy of pioglitazone, a PPAR-y agonist, in improving markers of endothelial dysfunction and atherosclerosis risk in RA. As a secondary aim-point, we will evaluate the efficacy of pioglitazone in improving RA disease activity and markers of inflammation. The proposed clinical trial will be a randomized, placebo controlled double blinded, cross-over study of 144 RA patients, randomized to receive pioglitazone or placebo. Patients will be treated for 3 months with either pioglitazone or placebo, undergo a washout period of 8 weeks, and then undergo crossover to the other arm for an additional 3 months. The role of pioglitazone on endothelial biology and function will be studied by: 1) Brachial artery flow mediated dilatation and nitroglycerin-mediated dilatation, validated surrogate markers of endotheliumdependent and independent function, respectively, before and after therapy with pioglitazone; 2) Arterial compliance, as arterial stiffness is an important predictor of cardiovascular damage, before and after treatment with pioglitazone; 3) Examination of specific serum biomarkers of endothelial damage and cardiovascular risk, before and after treatment with pioglitazone. The effect on inflammation and RA disease activity will be assessed, by: 1) The Disease Activity Scale (DAS-28); and 2) Studying markers of systemic inflammation and inflammatory cytokines. If therapy with pioglitazone improves endothelial function and decreases inflammation in RA it may provide a safe, effective, relatively inexpensive adjuvant therapy both for the prevention of premature atherosclerosis and the persistence of inflammation in this disease. This study will also shed further light on the biology of endothelial cell injury in RA.