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经常被认为是积极的细胞毒治疗的有力指征，但最近的数据表明，这些患者中有相当大一部分人患有未被发现的无症状心血管疾病(CVD)，最终可能导致重要的发病率和死亡率。我们中心进行了一项大型病例对照研究，以记录系统性红斑狼疮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。尽管系统性红斑狼疮患者和对照组在心血管危险因素方面具有可比性，但动脉粥样硬化(颈动脉斑块)在系统性红斑狼疮患者中更为常见(37vs.15%，p&lt；0.001)。为了阐明这些患者过早动脉粥样硬化的潜在机制，我们评估了一组外周血中的促炎介质。这些数据没有揭示相关的机制，因为无论有或没有颈动脉斑块的SLE患者都表达了高水平的细胞因子、可溶性黏附分子和可溶性CD154。然而，基于对SLE研究对象子集的微阵列数据的分析，揭示了关于潜在疾病机制的重要线索。这些数据支持了一种假设，即血小板-单核细胞-内皮细胞轴的激活导致了SLE的过早动脉粥样硬化。初步数据表明，在有颈动脉斑块的SLE患者中，可能是血管损伤重要中介的特定基因产物的表达增加。这项拟议的研究将调查这些血管介质在我们的以颈动脉疾病为特征的SLE和RA患者队列中的表达，并将研究表达这些因子的细胞之间的功能关系。其具体目的是：1)研究CD154在风湿性疾病伴早发动脉粥样硬化患者中的表达；2)探讨风湿性疾病伴早发动脉粥样硬化患者中潜在的血管疾病生物标志物的表达；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。早期识别那些将继续发展为过早动脉粥样硬化性疾病的患者的生物标志物，以及建立那些将继续发展为早期动脉粥样硬化性疾病的患者的生物标志物，并制定适当的治疗措施，将对患者的健康和生存产生重大影响。

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.