RITUXIMAB THERAPY

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究的主要目的是确定与常规治疗相比，利妥昔单抗对ANCA相关血管炎患者缓解诱导的影响，并比较利妥昔单抗与常规治疗的安全性。其他目的包括确定利妥昔单抗在诱导缓解后是否会诱导持久效果，从而在利妥昔单抗停药后维持缓解（临床耐受性），以及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。韦格纳肉芽肿病（WG）和显微多血管炎是与抗中性粒细胞胞浆抗体（ANCA）相关的系统性血管炎的两种主要形式。在美国，这些疾病的发病率每年约为6000例新病例，估计患病率在25 - 3万之间。这些情况被称为anca相关性血管增生症（AAV），因为它们与这些高度特异性的自身抗体密切相关。AAV是一种自身免疫性疾病，其对两种自身抗原（蛋白酶3 （PR3）或髓过氧化物酶（MPO））之一的耐受性丧失，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，这是由这些特异性抗体与活化的中性粒细胞和单核细胞表面的靶抗原相互作用产生的。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的结果是死亡。常规疗法与治疗失败、疾病复发和严重毒性的高比例相关。该研究是一项随机、多中心、双盲、安慰剂对照试验。共有228名参与者将以1:1的比例随机分配到对照组或试验组。两个治疗组的患者将接受为期3天的甲基强的松龙静脉注射，然后是强的松。在缓解诱导阶段，对照组将接受每周利妥昔单抗安慰剂输注（4次）和每日环磷酰胺（CYC） 3至6个月，随后在缓解维持阶段接受硫唑嘌呤（AZA） 12个月。在缓解诱导阶段，实验组将接受每周利妥昔单抗输注（4次）和每日CYC安慰剂，持续3 - 6个月，随后在缓解维持阶段接受AZA安慰剂，持续12个月。被定义为治疗失败的患者（在随机化后的前6个月内）将被转移到另一个治疗组。

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.