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

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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]).