RITUXIMAB IN SUBJECTS WITH MODERATE TO SEVERE 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。假设：系统性红斑狼疮（SLE）是一种自身免疫性风湿性疾病，主要发生在育龄妇女。其特征在于多系统受累和总体免疫异常，其中大部分组织损伤被认为是通过自身抗体形成和免疫复合物沉积而发生的。这种疾病在临床表现、病程和预后上具有异质性。然而，大多数患者表现为关节受累、皮疹、口腔溃疡、雷诺现象和/或严重疲劳。心包和胸膜组织的炎症也可能存在。严重的表现包括中枢神经系统和肾脏受累。通常，该疾病遵循复发-缓解过程，具有各种发作率。在纵向队列中，已报告了该疾病的三种主要模式：复发-缓解型、慢性活动型和长期静止型。 治疗SLE的药物有限，在过去的30年里没有新的药物被批准用于治疗狼疮。治疗的支柱仍然是皮质类固醇用于中度至重度疾病的发作。非甾体类抗炎药（NSAID）、抗疟药、皮质类固醇和其他免疫抑制剂（如环磷酰胺、硫唑嘌呤或6-巯基嘌呤、甲氨蝶呤（MTX）和吗替麦考酚酯（MMF））可单独或联合用于治疗该疾病的多种表现。 这项研究涉及一种新的治疗方法，研究B细胞在SLE病理学中的作用。B细胞通过自身抗体依赖性机制和包括狼疮性肾炎（LN）在内的所有SLE表现所共有的机制而对SLE起中心作用。几种自身抗体与终末器官损伤相关。 目标：本研究的主要目的是评估利妥昔单抗与安慰剂相比在中重度SLE受试者中实现和维持主要临床应答（MCR）或部分临床应答（PCR）方面的疗效。 本研究的次要目的（比较利妥昔单抗与安慰剂）将评价以下内容：利妥昔单抗降低总体SLE疾病活动性的能力，通过52周内不列颠群岛狼疮评估组BILAG评估的时间校正曲线下面积减去基线（AUCMB）评分测量;利妥昔单抗诱导MCR的能力（不包括项目完成报告）或项目完成报告（包括MCR）;利妥昔单抗的安全性和耐受性;利妥昔单抗治疗的受试者在第24周达到BILAG C或更好的能力;利妥昔单抗延长中度或重度发作时间的能力;利妥昔单抗改善生活质量的能力，如通过SLE扩展健康调查（SF-36指数，具有狼疮特异性的额外元素）测量的;接受利妥昔单抗的受试者中的皮质类固醇节省;以及利妥昔单抗在SLE受试者中的药代动力学。 实验设计：这是一项II/III期、随机化、双盲、安慰剂对照、多中心研究，旨在评价利妥昔单抗与安慰剂相比联合单一稳定背景免疫抑制药物治疗中重度SLE受试者的疗效和安全性。将在第52周时评价试验的主要疗效终点。本研究将在美国约55家临床试验机构入组受试者。受试者将以2：1的比例随机接受利妥昔单抗+泼尼松或安慰剂+泼尼松。随机化受试者将接受静脉（IV）研究药物，间隔15天，每6个月重复一次。此外，受试者将在每次研究药物（利妥昔单抗或安慰剂）输注前30-60分钟接受100 mg IV Solumedrol。

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. Hypothesis: Systemic lupus erythematosus (SLE) is an autoimmune rheumatic disease that occurs primarily in women of childbearing age. It is characterized by multi-system involvement and gross immunological abnormality where much of the tissue damage is thought to occur through autoantibody formation and immune complex deposition. The disease is heterogenous in its clinical presentation, course, and prognosis. However, most patients present with joint involvement, skin rashes, mouth ulcers, Raynaud's phenomenon, and/or severe fatigue. Inflammation of pericardial and pleural tissues may also be present. Serious manifestations include central nervous system and renal involvement. Typically, the disease follows a relapsing-remitting course, with a variety of flare rates. Three major patterns of the disease have been reported in longitudinal cohorts: relapsing-remitting, chronic activity, and long quiescence. Medications for the treatment of SLE are limited, and no new medication for lupus has been approved in the past 30 yrs. The mainstay of therapy continues to be corticosteroids for flares of moderate to severe disease. Nonsteroidal anti-inflammatory drugs (NSAIDs), antimalarials, corticosteroids, and other immunosuppressive agents such as Cyclophosphamide, Azathioprine or 6-Mercaptopurine, Methotrexate (MTX), and Mycophenolate Mofetil (MMF) are used alone or in combination for the many manifestations of this disease. This study involves a new therapeutic approach which investigates the role of B-cells in SLE symptomology. B-cells are central to SLE through autoantibody-dependent mechanisms and mechanisms that are common to all manifestations of SLE, including lupus nephritis (LN). Several autoantibodies are correlated with end organ damage. Goals: The primary objective of this study is to assess the efficacy of Rituximab compared with placebo in achieving and maintaining a major clinical response (MCR) or partial clinical response (PCR) in subjects with moderate to severe SLE. The secondary objectives of this study (comparing Rituximab with placebo) will be to evaluate the following: ability of Rituximab to decrease overall SLE disease activity as measured by time-adjusted area under the curve minus baseline (AUCMB) scoring with the British Isles Lupus Assessment Group BILAG assessment over 52 weeks; ability of Rituximab to induce MCRs (excluding PCRs) or PCRs (including MCRs); safety and tolerability of rituximab; ability of Rituximab-treated subjects to achieve a BILAG C or better at week 24; ability of Rituximab to prolong the time to a moderate or severe flare; ability of Rituximab to improve quality of life as measured by SLE Expanded Health Survey (SF-36 index with additional elements specific to lupus); corticosteroid-sparing in subjects receiving Rituximab; and pharmacokinetics of rituximab in subjects with SLE. Experimental Design: This is a Phase II/III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of Rituximab compared with placebo when combined with a single stable background immunosuppressive medication in subjects with moderate to severe SLE. The primary efficacy endpoint of the trial will be evaluated at 52 weeks. The study will enroll subjects at approximately 55 centers in the United States. Subjects will be randomized in a 2:1 ratio to receive Rituximab + Prednisone or placebo + Prednisone. Randomized subjects will receive intravenous (IV) study drug ¿ 2 separated by 15 days that is repeated at 6 months. In addition, subjects will receive 100 mg IV Solumedrol 30-60 min prior to each study drug (Rituximab or placebo) infusion.