Clinical applications to main durable remission, minimize relapse and prevent infection in ANCA GN.

ANCA肾小球肾炎（GN）治疗干预的目标已从预防死亡演变为 以最大限度地减少免疫抑制的副作用。减少并发症需要：1）尽量减少 完全持久缓解患者的免疫治疗持续时间和2） 需要持续免疫治疗的患者。该项目的目标是改善 ANCA GN患者通过维持持久缓解和最大限度地减少免疫治疗的并发症。 目的1通过寻找一种分子“缓解特征”来评估缓解和疾病治愈的概念， 可以用来识别那些复发风险很低的人。我们将测量免疫，细胞，遗传和 表观遗传学标志物在完全缓解的患者中至少有2年的治疗，与匹配的 活动性疾病患者。虽然目标1努力定义可能治愈疾病的患者，但目标2建立了 有证据表明，强大的调节性B细胞群可降低复发风险， 不需要维持免疫抑制的人我们提出了一个概念验证的前瞻性，随机， 一项开放标签临床试验，评估传统化疗方案缓解患者的至复发时间 诱导疗法高比例B调节细胞恢复的患者将接受预期治疗 没有进一步的免疫治疗。调节性B细胞比例较低的受试者将被随机分配至 维持免疫抑制治疗或密切的临床监测与免疫治疗的指导下，临床 活动性血管炎的迹象虽然目标1和目标2的重点是减少免疫抑制，但不可否认的是， 免疫抑制是所有ANCA GN患者的要求。目标3侧重于限制传染性 免疫抑制并发症是ANCA GN死亡的主要原因。知道呼吸道 感染是ANCA GN中全部和严重感染的主要原因，我们提出了一项可行性试验 其中患有活动性疾病的患者将随机接受安慰剂或每日阿奇霉素， 月，与标准免疫疗法结合。选择阿奇霉素是因为其抗菌和 抗炎特性。主要结局是呼吸道感染的发生率， 严重感染发生率、至复发时间、全因死亡率和不良事件的次要结局 与研究药物的相关性也进行了评价。总的来说，该项目旨在降低 ANCA GN通过消除疾病发作风险低的患者中不必要的免疫抑制， 寻找保护性策略，以减少需要免疫抑制的患者的感染负担。

The goals of therapeutic intervention in ANCA glomerulonephritis (GN) have evolved from preventing mortality to minimizing adverse effects of immunosuppression. Reduction of complications requires: 1) minimizing duration of immunotherapy for patients in complete durable remission and 2) prevention of infections in patients who need continued immunotherapy. The objective of this Project is to improve long-term outcomes of patients with ANCA GN by maintaining durable remission and minimizing complications of immunotherapy. Aim 1 evaluates the concept of remission and disease cure by seeking a molecular “remission signature” that can be used to identify those at very low relapse risk. We will measure immunologic, cellular, genetic and epigenetic markers in patients in complete remission off therapy for at least 2 years compared to matched patients with active disease. While Aim 1 strives to define patients who may be cured of disease, Aim 2 builds on the evidence that robust regulatory B cell populations impart a lower risk of relapse and identify patients who do not need maintenance immunosuppression. We propose a proof-of-concept prospective, randomized, open-label clinical trial evaluating time to relapse in patients who have attained remission with traditional induction therapy. Patients with recovery of a high proportion of B regulatory cells will be managed expectantly without further immunotherapy. Those with a low proportion of regulatory B cells will be randomized to maintenance immunosuppressive therapy or to close clinical monitoring with immunotherapy guided by clinical signs of active vasculitis. Although Aim 1 and Aim 2 focus on reducing immunosuppression, it is irrefutable that immunosuppression is a requirement for all patients with ANCA GN. Aim 3 focuses on limiting infectious complications of immunosuppression, the chief cause of death in ANCA GN. Knowing that respiratory infections are the leading cause of total and serious infections in ANCA GN, we propose a feasibility trial whereby patients with active disease will be randomized to receive placebo or daily azithromycin for 12 months, in in conjunction with standard immunotherapy. Azithromycin was selected for its antimicrobial and anti-inflammatory properties. The primary outcome will be incidence of respiratory tract infections, with secondary outcomes of incidence of serious infections, time to relapse, all-cause mortality, and adverse events associated with study medication also evaluated. Overall this Project aims to improve morbidity and mortality in ANCA GN through elimination of unnecessary immunosuppression in those with low risk of disease flare and to find protective strategies to reduce infectious burden in those requiring immunosuppression.