RITUXIMAB THERAPY FOR THE INDUCTION REMISSION AND TOLERANCE IN ANCA-ASSOCIATE

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。 本研究的主要目的是确定利妥昔单抗与传统疗法相比对ANCA相关性小血管炎患者的缓解诱导作用，并比较利妥昔单抗与传统疗法的安全性。其他目的包括确定利妥昔单抗在诱导缓解后是否会产生持久的影响，从而在停用利妥昔单抗后维持缓解(临床耐受性)，并通过一系列详细的机制研究确定利妥昔单抗对特定免疫参数的影响。 韦格纳肉芽肿(WG)和显微镜下的多血管炎是与抗中性粒细胞胞浆抗体(ANCA)相关的两种主要形式的系统性血管炎。在美国，这些疾病的发病率约为每年6000例新病例，估计患病率为25-30,000人。这些疾病被称为ANCA相关性血管炎(AAV)，因为它们与这些高度特异的自身抗体有很强的相关性。AAV是一种自身免疫性疾病，对两种自身抗原(蛋白酶3(PR3)或髓过氧化物酶(MPO))中的一种失去耐受性，导致PR3-ANCA或MPO-ANCA的产生。临床观察表明，内皮损伤和组织损伤依赖于ANCA的促炎作用，ANCA是由于这些特异性抗体与其在激活的中性粒细胞和单核细胞表面的靶抗原相互作用而产生的。有初步证据表明，抗CD20治疗(利妥昔单抗)可以重建对ANCA靶抗原的耐受性。 如果不治疗，AAV的结果就是死亡。传统疗法与高比例的治疗失败、疾病复发和严重毒性有关。 这项研究是一项随机、多中心、双盲、安慰剂对照试验。总共228名参与者将被1：1随机分配到控制组或试验组。两个治疗组的患者都将接受为期3天的甲基强的松龙静脉脉冲治疗，随后是强的松。在缓解诱导阶段，对照组将接受每周一次的利妥昔单抗安慰剂输注(4次)和每天3-6个月的环磷酰胺(CyC)治疗，然后在缓解维持阶段接受12个月的硫唑嘌呤(AZA)治疗。在缓解诱导阶段，试验组将接受每周一次的利妥昔单抗(4次)和每日3-6个月的环磷酰胺安慰剂治疗，随后在缓解维持阶段接受为期12个月的AZA安慰剂治疗。被定义为治疗失败的患者(在随机分组后的前6个月内)将被交叉到另一治疗臂。

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 primary objectives of this study are to determine the effect of rituximab on remission induction in patients with ANCA associated vasculitis as compared with conventional therapy and to compare the safety profile of rituximab with conventional therapy. Other aims include to determine if rituximab will induce a lasting effect after remission induction, thereby maintaining remission after rituximab is discontinued (clinical tolerance), and to determine the effect of rituximab on specific immune parameters through a series of detailed mechanistic studies. Wegener's granulomatosis (WG) and microscopic polyangiitis are the two major forms of systemic vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA). The incidence of these disorders in the US is about 6,000 new cases per year, with the estimated prevalence at 25 - 30,000. These conditions are termed ANCA-associated vasculitides (AAV) because of their strong associations with these hightly specific autoantibodies. AAV are autoimmune disorders in which tolerance for one of two self-antigens (proteinase 3 (PR3) or myeloperoxidase (MPO), has been lost, leading to the production of PR3-ANCA or MPO-ANCA. Clinical observations indicate that endothelial injury and tissue damage are dependent upon the proinflammatory effects of ANCA that result from the interaction of these specific antibodies with their target antigens on the surface of activated neutrophils and monocytes. There is preliminary evidence that anti-CD20 therapy (rituximab) may reestablish tolerance to the ANCA target antigens. If untreated, the outcome of AAV is death. Conventional therapies are associated with a high percentage of treatment failures, disease relapses and substantial toxicity. The study is a randomized, multicenter, doublemasked, placebo controlled trial. A total of 228 participants will be randomized 1:1 to either the control arm or the experimental arm. Patients in both treatment arms will receive a 3 day intravenous pulse of methylprednisolone followed by prednisone. During the remission induction phase, the control arm will receive weekly rituximab placebo infusions (times 4) and daily cyclophosphamide (CYC) for between 3 and 6 months, followed by azathioprine (AZA) for 12 months in the remission maintenance phase. During the remission induction phase, the experimental arm will receive weekly rituximab infusions (times 4) and daily CYC placebo for 3 - 6 months, followed by AZA placebo for 12 months in the remission maintenance phase. Patients who are defined as treatment failures (within the first 6 months after randomization) will be crossed over to the other treatment arm.