LIPITOR TO PREVENT AVASCULAR NECROSIS IN SYSTEMIC LUPUS ERYTHEMATOSUS

立普妥预防系统性红斑狼疮的血管坏死

基本信息

批准号：
7605699
负责人：
HOWARD M BELMONT
金额：
$ 0.12万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7605699
关键词：
Accidents Adrenal Cortex Hormones Animal Model Anti-Inflammatory Agents Anti-inflammatory Atherosclerosis Avascular necrosis of bone Biological Markers Blood Vessels Bone Marrow Bone necrosis Buffaloes Cell Adhesion Molecules Cholesterol Clinical Compartment syndromes Computer Retrieval of Information on Scientific Projects Database Coronary Arteriosclerosis Cushingoid facies Cushingoid habitus Deposition Development Disease Dose Double-Blind Method E-Selectin Endothelial Cells Enzymes Event Exhibits Family Fatty acid glycerol esters Flare Frequencies Funding Grant Head High Density Lipoproteins Hilar Human Hydroxymethylglutaryl-CoA reductase Incidence Inflammatory Response Injury Institution Intercellular adhesion molecule 1 LDL Cholesterol Lipoproteins Lipids Lipomatosis Lupus Marrow Measures Microcirculation Myocardial Infarction Nature Necrosis Nitric Oxide Patients Placebos Rate Recruitment Activity Reporting Research Research Personnel Resources Risk Selectins Serologic tests Serum Source Steroids Study of serum Systemic Lupus Erythematosus Time Transcriptional Activation Triglycerides United States National Institutes of Health Up-Regulation Vascular Cell Adhesion Molecule-1 atorvastatin base blood lipid bone cholesterol biosynthesis cysteine rich protein femoral artery human subject indexing inhibitor/antagonist instrument lipid biosynthesis lipid metabolism low density lipoprotein inhibitor member prevent randomized placebo controlled trial trial comparing

项目摘要

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]).

该子项目是利用该技术的众多研究子项目之一资源由 NIH/NCRR 资助的中心拨款提供。子项目及研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金，因此可以在其他 CRISP 条目中表示。列出的机构是对于中心来说，它不一定是研究者的机构。研究人员此前曾报道，系统性红斑狼疮 (SLE) 血管损伤的特点是内皮细胞活化以及粘附分子 ICAM-1、VCAM-1 和 E-选择素的上调。他们还报道，恶化的 SLE 伴随着基于内皮细胞 iNOS 上调的一氧化氮水平的增加，以及表达 ICAM-1 和 iNOS 的循环内皮细胞 (CEC) 的增加。 SLE 发作典型的内皮损伤可能是一种诱发事件，容易导致与该疾病相关的加速动脉粥样硬化，并扰乱微循环（例如股骨头末端动脉），从而容易导致骨缺血性坏死。 AVN）。因此，这些患者的心肌梗塞和脑血管意外发生率比没有 SLE 的患者高出 50 倍。发生股骨头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 频率增加可能与区分该疾病的潜在血管损伤有关。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，并且与活动性疾病的高剂量类固醇治疗有关，这与 SLE 中 AVN 是由骨间血管损伤和骨室综合征同时发生引起的假设是一致的来自过量的脂质沉积（即类似于库欣样习性、圆脸、水牛驼峰和可伴随的肺门脂肪增多症的骨性脂肪增多症）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已被证明与皮质类固醇诱导的骨坏死有关，并且越来越多的证据表明脂肪骨髓含量与 AVN 之间的关系也适用于人类。阿托伐他汀是他汀类药物家族的一员，是胆固醇生物合成中高度调控的限速酶 HMG-CoA 还原酶的抑制剂，可降低血清血脂水平，包括胆固醇和低密度脂蛋白，同时维持高密度脂蛋白水平。在动物模型中，与他汀类药物相关的骨髓脂肪转化减少可减少 AVN 的发生，但这种益处尚未在人类受试者中得到证实。本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性疾病 SLE 患者将被招募参加一项为期四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 的效果。该研究将确定阿托伐他汀是否能有效降低系统性红斑狼疮患者的血清脂质水平（例如胆固醇、甘油三酯、低密度脂蛋白）；阿托伐他汀是否通过测量可溶性粘附分子（sICAM-1、sVCAM-1、sE-选择素）和 CEC 来抑制活动性 SLE 中的内皮细胞活化；如果阿托伐他汀对活动性 SLE 具有抗炎作用，可降低炎症反应的生物标志物（ESR、CRP 和 SAA）并降低通过血清学（C3、C4、抗 dsDNA）或临床仪器（系统性狼疮）评估的疾病活动度红斑狼疮活动指数 [SLEDAI]）。