Plasma Exchange and Glucocorticoids for Treatment of ANCA-Associated Vasculitis

描述（由申请人提供）： 韦格纳肉芽肿病和显微镜下多血管炎是罕见的（在美国合并患病率<200，000），多系统疾病，通常称为抗中性粒细胞胞质抗体（ANCA）相关性血管炎（AAV）。AAV虽然罕见，但如果不治疗，几乎普遍致命。现代治疗策略利用有效的免疫抑制药物和高剂量的糖皮质激素（GC）。虽然治疗已经改善了AAV患者的生存率，但严重形式仍然与不可接受的高不良结局率相关，高达40%的患者在诊断后5年内达到终末期肾病（ESRD）或死亡。AAV患者的不良结局似乎是由于疾病控制不足以及治疗相关毒性和不良事件所致。 这项研究的主要目的是通过提高治疗效果同时减少治疗相关不良事件来改善AAV患者的ESRD和死亡率。血浆置换是一种去除潜在致病性抗体、凝血因子和炎症介质的方法，已显示出改善AAV患者预后的前景。早期治疗期间的高剂量GC与严重感染的发生率增加相关，严重感染是AAV患者死亡的主要原因。本研究将通过两个具体目标实现：1）进行一项多国随机临床试验，比较使用强制性血浆置换与单独标准治疗AAV的情况; 2）进行一项多国随机临床试验，比较AAV的低剂量GC方案与标准剂量GC方案。假设增加连续性血浆置换可改善AAV患者的治疗功效，而假设减少GC剂量可减少治疗相关不良事件。这些目标将在一项大型、多国、2 × 2析因设计的随机对照试验中实现，其中研究者将对患者的GC方案设盲。将在5年内招募500名受试者，并以1：1的方式随机分配至每种干预措施，并随访至少2年（最长7年），以确定ESRD或死亡的主要结局。本申请寻求资金支持在美国的5个研究站，并将联合收割机资源与英国的资金相结合。

DESCRIPTION (provided by applicant): Wegener's granulomatosis and microscopic polyangiitis are rare (combined prevalence <200,000 in U.S.), multi-system diseases commonly referred to as anti-neutrophil cytoplasm antibody (ANCA) -associated vasculitis (AAV). AAV, although rare, is almost universally fatal if left untreated. Modern treatment strategies utilize potent immunosuppressive medications and high doses of glucocorticoids (GC). While treatment has resulted in improved survival for patients with AAV, severe forms are still associated with unacceptably high rates of poor outcomes with up to 40% of patients reaching end-stage renal disease (ESRD) or death within 5 years of diagnosis. Poor outcomes in patients with AAV appear due to both inadequate disease control and as a result of treatment related toxicities and adverse events. The broad aim of this research is to improve ESRD and mortality rates for patients with AAV by improving the efficacy of treatment while reducing treatment-related adverse events. Plasma exchange, a method of removing potentially pathogenic antibodies, coagulation factors and inflammatory mediators has shown promise in improving outcomes for patients with AAV. High-dose GC during early treatment is associated with increased rates of serious infections, a principle cause of death in patients with AAV. This research will be achieved through two specific aims: 1) to conduct a multi-national randomized clinical trial comparing the use of adjunctive plasma exchange to standard treatment alone for AAV and 2) to conduct a multi-national randomized clinical trial of a low-dose GC regimen to a standard dose GC regimen for AAV. The addition of adjunctive plasma exchange is hypothesized to improve the efficacy of treatment in patients with AAV while the reduction in GC dose is hypothesized to reduce treatment related adverse events. These aims will be achieved in the context of a large, multinational, two-by-two factorial design randomized control trial in which investigators will be blinded to the GC regimen of patients. 500 will be recruited over 5 years and randomized in a 1:1 fashion to each intervention and followed for a minimum of 2 years (maximum 7) for the development of the primary outcome of ESRD or death. This application seeks funding to support 5 study sties in the United States and combine resources with funding from the United Kingdom.