LIPITOR TO PREVENT AVASCULAR NECROSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。研究者先前报道系统性红斑狼疮（SLE）血管损伤的特征是内皮细胞活化和粘附分子ICAM-1、VCAM-1和E-选择素的上调。他们还报道，恶化的SLE伴随着基于上调的内皮细胞iNOS的一氧化氮水平的增加和表达ICAM-1和iNOS的循环内皮细胞（CEC）的增加。典型的SLE发作的内皮损伤可以作为一种激发事件，其倾向于加速与该病症相关的动脉粥样硬化以及破坏微循环（例如，股骨头末端动脉）易发生骨缺血性坏死（AVN）。因此，这些患者表现出心肌梗死和脑血管意外的发生率比没有SLE的患者高50倍。发生缺血性坏死的风险比其他使用皮质类固醇的患者高10-40倍。因此，在SLE患者中观察到的冠状动脉疾病（CAD）和AVN的频率增加可能与区分疾病的潜在血管损伤相统一。 在先前的研究中，研究人员观察到AVN本质上是多灶性的，并且与活动性疾病的高剂量类固醇治疗相关，这与SLE中的AVN由骨间血管损伤和过量脂质沉积引起的骨室综合征（即，类似于库欣样体型、月亮脸、布法罗驼峰和肺门脂肪增多症的骨质脂肪增多症，可伴随高剂量类固醇治疗）。 在动物模型中，脂肪生成增加和脂质代谢异常与皮质类固醇诱导的骨坏死相关，越来越多的证据表明脂肪骨髓含量和AVN之间的关系适用于人类。 阿托伐他汀是胆固醇生物合成中高度调节的限速酶HMG-CoA还原酶抑制剂的他汀类家族的成员，其降低血脂（包括胆固醇和LDL）的血清水平，同时维持HDL水平。在动物模型中，与他汀类药物相关的骨髓脂肪转化的减少减少了AVN的发展，但这种益处尚未在人类受试者中确立。 这项研究假设阿托伐他汀，通过防止骨髓脂肪堆积，将减少类固醇治疗狼疮患者的AVN的发生率。 将招募90名患有需要类固醇治疗的活动性疾病的SLE患者参加为期4个月的双盲随机安慰剂对照试验，比较阿托伐他汀与安慰剂预防AVN。该研究将确定阿托伐他汀是否有效降低血清脂质水平（例如，胆固醇、甘油三酯、LDL）;如果阿托伐他汀通过测量可溶性粘附分子抑制活动性SLE中的内皮细胞活化，sICAM-1、sVCAM-1、sE-选择素和CEC;如果阿托伐他汀在活动性SLE中具有抗炎作用，（ESR、CRP和SAA）并降低通过血清学（C3、C4、抗dsDNA）或临床仪器（系统性红斑狼疮活动指数[SLEDAI]）评估的疾病活动性。

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]).