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负担得起 临床改善，它们不是治愈的，而且与显著的副作用相关。我们之前 发现一种天然抗氧化剂谷胱甘肽(GSH)在SLE患者的淋巴细胞中耗尽。我们也 研究发现，作为氧化应激感应器的雷帕霉素机械靶点(MTOR)的激活有助于 系统性红斑狼疮患者的T细胞谱系异常和功能障碍。在狼疮易感小鼠中，N-乙酰半胱氨酸(NAC)，它 ACTS是谷胱甘肽的前体，本身也是一种抗氧化剂，可以根除这种疾病。虽然静脉注射NAC已经被 在人类安全地用于其他适应症，它不能作为处方的口服药物。因此，我们 启动了一项随机、双盲、安慰剂对照的试点研究，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学及治疗的影响在这项研究中，NAC被发现是安全的，它 3个月后，疾病活跃度改善，GSH耗竭逆转，促炎症mTOR激活受阻。 这些结果显然需要在一项治疗时间更长的试验中得到证实。要解决这一关键差距， 知识，我们建议对多中心、随机、双盲、安慰剂对照的U34规划拨款 NAC治疗系统性红斑狼疮的安全性和有效性的II期临床试验。这项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，具有连贯的管理结构和 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； 根据审查和NIAMS的输入，试验构思已经重新设计，以确保临床上有意义的 使用新方法和最近验证的SLE响应器进行前提、高效且经济实惠的试验规模 评价初步临床疗效的指标(SRI)；3)规范临床评估技术，以 确保协作中心的主要和次要结果衡量标准的可靠性；4)设计 以及实施符合21 CRF第11部分标准的电子数据采集系统，该系统将基于 现有病例报告表(CRF)；5)建立数据收集和集中监测程序 管理；6)最终确定数据和安全监控计划、标准操作程序、手册 操作程序和调查手册，以满足FDA、OHRP和NIAMS对U01的要求 (多站点)临床试验实施合作协议。未来的初步具体目标 临床试验将：1)确认NAC相对于安慰剂在210名SLE患者中的安全性和有效性， (每支手臂105名患者，建议增加多达20名受试者参加NAC的滴定，以在一年内耐受 剂量范围为2.4克/天至4.8克/天，最初的3个月开放标签期)在12个月期间 干预后进行为期1个月的冲刷；2)确定逆转GSH耗竭和阻断 MTOR持续12个月以上，预测对NAC的反应性。这项研究将确立新来港儿童的角色 作为一种新的、安全、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.