CLINICAL TRIAL: LIPITOR TO PREVENT AVASCULAR NECROSIS IN SYSTEMIC LUPUS ERYTHEMA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 研究人员此前报道，系统性红斑狼疮(SLE)的血管损伤以内皮细胞激活和黏附分子ICAM-1、VCAM-1和E-选择素上调为特征。他们还报道，SLE的恶化伴随着在内皮细胞iNOS上调的基础上一氧化氮水平的升高，以及循环内皮细胞(CEC)表达ICAM-1和iNOS的增加。典型的系统性红斑狼疮发作的内皮损伤可能是一种刺激事件，它易于导致与疾病相关的动脉粥样硬化的加速，并破坏微循环(例如，股骨头的末梢动脉)，从而易于发生骨缺血性坏死(AVN)。结果，这些患者的心肌梗死和脑血管意外的发生率比那些没有SLE的患者高出50倍。发生缺血性坏死的风险是其他使用皮质类固醇的患者的10-40倍。因此，在SLE患者中观察到的冠状动脉疾病(CAD)和AVN的增加可能与区分疾病的潜在血管损伤相一致。 在之前的一项研究中，研究人员观察到AVN本质上是多灶性的，与大剂量类固醇治疗活动期疾病有关，这与SLE中的AVN是骨间血管损伤和过度脂肪沉积引起的骨室综合征(即类似库辛戈德习惯症、月面脸、水牛驼峰和肺门脂肪增多症，可伴随高剂量类固醇治疗)共存的假设一致。 在动物模型中，脂肪生成增加和脂代谢异常与皮质类固醇诱导的骨坏死有关，越来越多的证据表明，脂肪骨髓含量与AVN之间的关系适用于人类。 阿托伐他汀是他汀类药物家族中的一员，它是胆固醇生物合成中高度调控的限速酶HMG-CoA还原酶的成员，它能降低血清中包括胆固醇和低密度脂蛋白在内的血脂水平，同时保持高密度脂蛋白水平。与他汀类药物相关的动物模型中骨髓脂肪转化的减少减少了AVN的发生，但这一益处尚未在人类受试者中得到证实。 这项研究假设阿托伐他汀通过防止骨髓脂肪堆积，将降低接受类固醇治疗的狼疮患者AVN的发生率。 90名需要类固醇治疗的活动期SLE患者将被纳入一项为期4个月的双盲随机安慰剂对照试验，比较阿托伐他汀和安慰剂预防AVN的效果。这项研究将确定阿托伐他汀是否有效降低SLE患者的血脂水平(例如，胆固醇、甘油三酯、低密度脂蛋白)；阿托伐他汀是否通过检测可溶性黏附分子(sICAM-1、sVCAM-1、sE-选择素)和CEC来抑制活动期SLE的内皮细胞激活；以及阿托伐他汀在活动期SLE是否具有抗炎作用，从而减少炎症反应的生物标志物(ESR、CRP和SAA)，并通过血清学(C3、C4、抗dsDNA)或临床仪器(系统性红斑狼疮活动指数[SLEDAI])来评估疾病的活动性。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The investigators have previously reported that vascular injury in systemic lupus erythematosus (SLE) is characterized by endothelial cell activation and the up-regulation of the adhesion molecules ICAM-1, VCAM-1, and E-selectin. They have also reported that exacerbated SLE is accompanied by increased levels of nitric oxide on the basis of up-regulated endothelial cell iNOS and by increased circulating endothelial cells (CEC) expressing ICAM-1 and iNOS. The endothelial injury typical of SLE flares may serve as an inciting event, which predisposes to the accelerated atherosclerosis that is associated with the disorder as well as disrupt the microcirculation (e.g., end artery of the femoral head) to predispose to avascular necrosis of bone (AVN). As a result, these patients exhibit rates of myocardial infarction and cerdbrovascular accident that are up to 50-fold higher than in those without SLE. The risk of developing avascular necrosis is 10-40 times greater than other patients on corticosteroids. Therefore, the increased frequency of coronary artery disease (CAD) and AVN observed in patients with SLE may be unified by the underlying vascular injury that distinguishes the disease. In a previous study the investigators observed that AVN is multifocal in nature and associated with high-dose steroid treatment of active disease, which is consistent with the hypothesis that AVN in SLE results from the co-occurrence of interosseous vascular injury and a bone compartment syndrome from excess lipid deposition (i.e., osseous lipomatosis akin to the Cushingoid habitus, moon face, buffalo hump, and hilar lipomatosis that can accompany high-dose steroid treatment). Increased adipogenesis and abnormal lipid metabolism has been shown to be associated with corticosteroid-induced osteonecrosis of bone in animal models, and there is increasing evidence to suggest that the relationship between fatty marrow content and AVN applies to humans. Atorvastatin is a member of the statin family of inhibitors of the highly regulated rate-limiting enzyme in the biosynthesis of cholesterol, HMG-CoA reductase, which lower the serum levels of blood lipids including cholesterol and LDL while maintaining HDL levels. The reduction in marrow fat conversion associated with statins in animal models reduces the development of AVN, but this benefit has yet to be established in human subjects. This study hypothesizes that atorvastatin, by preventing bone marrow fat accumulation, will reduce the incidence of AVN in steroid-treated lupus patients. Ninety SLE patients with active disease requiring steroid treatment will be recruited into a four-month double-blind randomized placebo-controlled trial comparing atorvastatin versus placebo to prevent AVN. The study will determine if atorvastatin is effective in lowering serum lipid levels (e.g., cholesterol, triglyceride, LDL) in SLE patients; if atorvastatin inhibits endothelial cell activation in active SLE by measuring soluble adhesion molecules (sICAM-1, sVCAM-1, sE-selectin) and CEC; and if atorvastatin has an anti-inflammatory effect in active SLE that reduces biological markers of the inflammatory response (ESR, CRP, and SAA) and reduces disease activity assessed by serology (C3, C4, anti-dsDNA) or clinical instrument (Systemic Lupus Erythematosus Activity Index [SLEDAI]).