Premature Atherosclerosis in Rheumatic Diseases

描述（由申请人提供）： 虽然系统性红斑狼疮（SLE）的肾脏和中枢神经系统表现通常是积极的细胞毒性治疗的强制性指征，但最近的数据表明，这些患者中有相当一部分患有无症状的心血管疾病（CVD），这些疾病无法识别，最终可能导致严重的发病率和死亡率。我们中心已经进行了一项主要的病例对照研究，以记录SLE患者中过早动脉粥样硬化的患病率，并将该研究扩展到类风湿关节炎（RA）患者。尽管SLE患者和对照组在CVD危险因素方面相当，但SLE患者中动脉粥样硬化（颈动脉斑块）更普遍（37%对15%，p<0.001）。为了阐明导致这些患者过早动脉粥样硬化的潜在机制，评估了外周血中的一组促炎介质。这些数据未揭示相关机制，因为SLE患者无论有无颈动脉斑块，细胞因子、可溶性粘附分子和可溶性CD 154水平均升高。然而，关于潜在疾病机制的重要线索是基于对SLE研究受试者子集的微阵列数据的分析而揭示的。这些数据刺激了血小板-单核细胞-内皮细胞轴的激活导致SLE患者过早动脉粥样硬化的假设。初步数据表明，特定的基因产物，可能是血管损伤的重要介质，在SLE患者颈动脉斑块的表达增加。拟议的研究将调查这些血管介质的表达在我们的队列SLE和RA患者的特征为颈动脉疾病，并将研究表达这些因子的细胞之间的功能关系。具体目标是：1）研究CD 154在具有过早动脉粥样硬化的风湿性疾病患者中的表达; 2）研究具有过早动脉粥样硬化的风湿性疾病患者中血管疾病的潜在生物标志物的表达;以及3）确定血小板和单核细胞在产生促动脉粥样硬化介质中的作用。在那些将继续发展为过早的动脉粥样硬化疾病的患者中早期鉴定生物标志物，在那些将继续发展为过早的动脉粥样硬化疾病的患者中建立生物标志物，以及建立适当的治疗应该对患者的健康和生存具有重大影响。

DESCRIPTION (provided by applicant): While the renal and central nervous system manifestations of systemic lupus erythematosus (SLE) often present as compelling indications for aggressive cytotoxic therapy, recent data demonstrate that a significant proportion of those patients have asymptomatic cardiovascular disease (CVD) that goes unrecognized and can eventually result in important morbidity and mortality. Our center has performed a major case-control study to document the prevalence of premature atherosclerosis among patients with SLE and is extending that study to patients with rheumatoid arthritis (RA). Although SLE patients and controls were comparable in CVD risk factors, atherosclerosis (carotid plaque) was more prevalent in SLE patients (37 vs. 15%, p<0.001). To elucidate the underlying mechanisms that account for premature atherosclerosis in these patients, a panel of proinflammatory mediators in peripheral blood was assessed. The data were unrevealing of relevant mechanisms, as SLE patients either with or without carotid plaque expressed elevated levels of cytokines, soluble adhesion molecules, and soluble CD154. However, important clues regarding potential disease mechanisms were revealed based on analysis of microarray data from a subset of the SLE study subjects. The data have stimulated the hypothesis that activation of the platelet-monocyte-endothelial cell axis contributes to premature atherosclerosis in SLE. Preliminary data suggest that specific gene products that may be important mediators of vascular damage are increased in expression in SLE patients with carotid plaque. The proposed research will investigate the expression of these vascular mediators in our cohort of SLE and RA patients characterized for carotid disease and will study the functional relationship among the cells that express these factors. The specific aims are: 1) to investigate the expression of CD154 in rheumatic disease patients with premature atherosclerosis; 2) to investigate the expression of potential biomarkers of vascular disease in rheumatic disease patients with premature atherosclerosis; and 3) to determine the role of platelets and monocytes in generating pro-atherogenic mediators. Early identification of biomarkers in those patients who will go on to develop premature atherosclerotic disease and institution of biomarkers in those patients who will go on to develop premature atherosclerotic disease and institution of appropriate therapy should have a major impact on patient health and survival.