Treatment of Systemic Lupus Erythematosus (SLE) with N-acetylcysteine (NAC)

摘要 系统性红斑狼疮（SLE）是一种潜在的致命性自身免疫性疾病。尽管目前的治疗方法 虽然它们不能改善临床症状，但它们不是治愈性的，并且与显著的副作用相关。我们之前 发现一种天然的抗氧化剂，谷胱甘肽（GSH），在SLE患者的淋巴细胞中被耗尽。我们也 发现雷帕霉素（mTOR）的机制靶点（氧化应激传感器）的激活有助于 SLE中T细胞谱系特异性异常和功能障碍。在狼疮易感小鼠中，N-乙酰半胱氨酸（NAC）， 作为谷胱甘肽的前体和抗氧化剂本身，消除了疾病。虽然静脉注射NAC已经 安全地用于人类的其他适应症，它是不可用的作为口服药物的处方。所以我们 启动了一项随机、双盲、安慰剂对照的初步研究，以评估安全性、耐受性以及 NAC对36例系统性红斑狼疮患者免疫和治疗影响在这项研究中，NAC被发现是安全的， 在3个月内改善疾病活动性、逆转GSH耗竭并阻断促炎性mTOR活化。 这些结果显然需要在治疗持续时间较长的试验中得到证实。为了解决这一关键差距， 知识，我们提出了一个U34计划补助金，用于多中心，随机，双盲，安慰剂对照 NAC在SLE患者中的安全性和有效性的II期临床试验。U34应用程序的目标包括： 1)将狼疮临床试验专家聚集在一个多中心研究中，具有一致的管理结构和 明确的沟通策略; 2）完善确定NAC安全性和有效性的临床方案; 为了响应审查和NIAMS的输入，重新设计了试验概念，以确保临床上有意义的 使用新方法和最近经过验证的SLE应答者， 评价主要临床疗效结局的SRI指数; 3）标准化临床评估技术， 确保合作中心的主要和次要结局指标的可靠性; 4）设计 并实施符合21 CRF第11部分的电子数据采集系统（eDC），该系统将基于 现有病例报告表（CRF）; 5）建立数据收集的集中监测程序， 管理; 6）最终确定数据和安全监测计划，标准操作程序， 符合FDA、OHRP和NIAMS对U 01要求的操作规程和研究者手册 （多中心）临床试验实施合作协议。未来的初步具体目标 临床试验将用于：1）在210名SLE患者中确认NAC相对于安慰剂的安全性并确定其疗效， (105每组最多20例受试者，计划在2015年1月至2016年1月期间入组NAC滴定至耐受水平的额外受试者。 剂量范围为2.4 g/天至4.8 g/天，直至最初的3个月开放标签期）， 干预后1个月洗脱; 2）确定是否逆转GSH耗竭和阻断 mTOR持续超过12个月，并预测对NAC的反应性。这项研究将确定国家咨询委员会的作用， 作为一种新的、安全的、有效的、生物标志物驱动的治疗SLE的方法。

ABSTRACT Systemic lupus erythematosus (SLE) is a potentially fatal autoimmune disease. Although current therapies afford clinical improvement, they are not curative and are associated with significant side-effects. We previously discovered that a natural antioxidant, glutathione (GSH), is depleted in lymphocytes of SLE patients. We also found that the activation of mechanistic target of rapamycin (mTOR), a sensor of oxidative stress, contributes to abnormal T-cell lineage specification and dysfunction in SLE. In lupus-prone mice, N-acetylcysteine (NAC), which acts a precursor of GSH and an antioxidant by itself, abrogated the disease. While intravenous NAC has been safely used in humans for other indications, it is unavailable as an oral medication by prescription. Therefore, we initiated a randomized, double-blind, placebo-controlled pilot study to evaluate the safety, tolerance, as well as immunological and therapeutic impact of NAC in 36 SLE patients. In this study, NAC was found to be safe, and it improved disease activity, reversed GSH depletion and blocked pro-inflammatory mTOR activation over 3 months. These results clearly warrant confirmation in a trial with longer treatment duration. To address this critical gap in knowledge, we propose a U34 planning grant for a multi-center, randomized, double-blind, placebo-controlled phase II clinical trial of the safety and efficacy of NAC in SLE patients. The aims for this U34 application include: 1) Bringing together lupus clinical trial experts in a multi-center study with a coherent management structure and a clear communication strategy; 2) Refining the Clinical Protocol for determining the safety and efficacy of NAC; the trial conception has been, in response to reviews and NIAMS input, re-designed to ensure a clinically meaningful premise and efficient and affordable trial size using a novel approach and the recently validated SLE Responder Index (SRI) to evaluate primary clinical efficacy outcome; 3) Standardizing clinical assessment techniques to ensure reliability of the primary and secondary outcome measures across the collaborating centers; 4) Designing and implementing a 21 CRF part 11 compliant electronic data capture system (eDC), which will be based on the existing case report forms (CRFs); 5) Establishing centralized monitoring procedures for data collection and management; 6) Finalizing the Data and Safety Monitoring Plan, Standard Operating Procedures, Manual of Operating Procedures, and Investigators Brochure to meet FDA, OHRP and NIAMS requirements for a U01 (multi-site) Clinical Trial Implementation Cooperative Agreement. The preliminary specific aims for the future clinical trial will be to: 1) Confirm safety and determine efficacy of NAC relative to placebo in 210 SLE patients, (105 patients per arm, with up to 20 additional subjects proposed to enroll for titration of NAC to tolerance within a dosage range of 2.4 g/day to 4.8 g/day through an initial 3-month open label period) during a 12-month intervention followed by a 1-month washout; 2) Determine whether the reversal of GSH depletion and blockade of mTOR are sustained over 12 months and predict responsiveness to NAC. This study will establish the role of NAC as a novel, safe, effective, and biomarker-driven approach in the treatment of SLE.