Plasma Exchange and Glucocorticoids for Treatment of ANCA-Associated Vasculitis

描述(由申请人提供)： 韦格纳肉芽肿和显微镜下的多血管炎很少见(在美国合并患病率为20万)，通常被称为抗中性粒细胞胞浆抗体(ANCA)相关性小血管炎(AAV)的多系统疾病。AAV虽然罕见，但如果不治疗，几乎普遍是致命的。现代治疗策略使用有效的免疫抑制药物和大剂量的糖皮质激素(GC)。虽然治疗提高了AAV患者的存活率，但严重的AAV患者预后不良的比率仍然高得令人无法接受，高达40%的患者在确诊后5年内患上终末期肾病(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与治疗相关的毒性和不良事件的结果。这项研究的广泛目标是通过提高治疗效果同时减少与治疗相关的不良事件来改善AAV患者的ESRD和死亡率。血浆置换是一种清除潜在致病抗体、凝血因子和炎症介质的方法，已显示出在改善AAV患者预后方面的前景。在早期治疗期间使用大剂量GC与严重感染率的增加有关，严重感染率是AAV患者死亡的主要原因。这项研究将通过两个具体目标实现：1)进行一项多国家随机临床试验，比较使用辅助血浆置换与标准治疗AAV的情况；2)进行一项低剂量GC方案与标准剂量GC方案治疗AAV的多国家随机临床试验。增加辅助血浆交换被认为是为了改善AAV患者的治疗效果，而减少GC剂量是为了减少与治疗相关的不良事件。这些目标将在一项大型、多国、二乘二析因设计随机对照试验的背景下实现，在该试验中，研究人员将对患者的GC方案视而不见。500人将在5年内被招募，并以1：1的方式随机分配到每次干预中，并跟踪调查最少2年(最多7年)，以制定终末期肾病或死亡的主要结果。本申请寻求资助美国的5个留学基金，并将资源与来自英国的资金结合起来。

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.