SLE Treatment with N-acetylcysteine

系统性红斑狼疮（SLE）是一种病因不明的自身免疫性疾病， 5年内接近10%。SLE死亡的主要原因是由于药物毒性引起的感染。 免疫抑制剂因此，存在对有效且无毒的药物组合物的显著未满足的需求。 治疗SLE的药物。我们的中心假设是基于有效的治疗方法 应该针对发病机制的关键检查点，如还原型谷胱甘肽（GSH）的消耗， 是雷帕霉素机制靶点（mTOR）激活和炎症谱系特化的基础 SLE中T细胞、B细胞活化和抗核自身抗体的产生。这项研究的基本原理是 证据支持：1）SLE患者外周血淋巴细胞（PBL）中GSH耗尽; 2）GSH 消耗有助于mTOR活化，其驱动SLE中的T细胞功能障碍; 3）施用N- 乙酰半胱氨酸（NAC）作为GSH的细胞渗透性氨基酸前体， 初步研究表明NAC是安全的，可逆转GSH耗竭和mTOR 激活并改善SLE患者的疾病活动性。在我们完成的双盲安慰剂对照试验中， 在一项研究中，100%的患者对1.2 g/天和2.4 g/天剂量的NAC耐受，而33%的患者对1.2 g/天和2.4 g/天剂量的NAC耐受。 接受4.8 g/天的患者出现可逆性恶心。安慰剂和1.2 g/天NAC不影响疾病活动。 虽然2.4 g/天和4.8 g/天NAC剂量均显示出临床疗效的初步证据，但4.8 g/天NAC剂量的临床疗效仍优于4.8 g/天NAC剂量。 g/天的NAC使SLEDAI和BILAG评分下降幅度更大。NAC升高GSH，阻断mTOR， 扩展的T拟议的II期试验将采用SLE应答者指数（SRI）作为临床指标， 有意义的主要结局指标，提供易于解释的结果并产生可行的样本 与足够的功效相关的尺寸，以检测1年内的治疗获益。尽量减少潜在 为了避免NAC不耐受和受试者退出，研究设计包括开放标签剂量滴定期。 耐受每日2.4-4.8 g NAC持续3个月的患者将以1：1的比例随机分配， 他们的耐受剂量的NAC或匹配的安慰剂额外9个月。超越验证的前提 临床疗效和持久性，该疗法在SLE，拟议的研究将测试假设，消耗 GSH和半胱氨酸的增加以及mTOR的活化可预测对NAC的免疫生物学和临床反应性。 这些研究将大大促进我们对免疫代谢途径的理解， T细胞谱系特化与狼疮发病机制和治疗的翻译相关性。的 这种方法是创新的，因为它将采用安全的治疗干预来确定半胱氨酸耗竭在 狼疮患者体内氧化还原依赖性mTOR活化和促炎性T细胞发育。的 结果将为我们理解疾病发病机制带来新的视角， SLE患者的临床管理的相关性。

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology with mortality still approaching 10% in 5 years. The leading cause of death in SLE are infections due to the toxicity of immunosuppressant medications. Therefore, a significant unmet need exists for effective and non-toxic medications to treat SLE. Our central hypothesis has been formulated on the basis that effective treatment should target key checkpoints of pathogenesis, such as the depletion of reduced glutathione (GSH), which underlies the activation of the mechanistic target of rapamycin (mTOR) and inflammatory lineage specification of T cells, B-cell activation and antinuclear autoantibody production in SLE. The rationale for this study is supported by evidence that 1) GSH is depleted in peripheral blood lymphocytes (PBL) of SLE patients; 2) GSH depletion contributes to mTOR activation that drives T-cell dysfunction in SLE; 3) administration of N- acetylcysteine (NAC), which serves as a cell-permeable amino acid precursor of GSH, blocks the development of murine lupus; and 4) the preliminary studies suggest that NAC is safe, reverses GSH depletion and mTOR activation and improves disease activity in SLE patients. In our completed double-blind placebo-controlled pilot study, NAC was tolerated by 100% of patients on 1.2 g/day and 2.4 g/day dosages, while 33% of those receiving 4.8 g/day had reversible nausea. Placebo and 1.2 g/day NAC did not influence disease activity. Although both 2.4 g/day and 4.8 g/day NAC dosages showed preliminary evidence for clinical efficacy, 4.8 g/day NAC achieved greater drops in SLEDAI and BILAG scores. NAC raised GSH, blocked mTOR, and expanded T regs. The proposed phase II trial will employ the SLE Responder Index (SRI), as a clinically meaningful primary outcome measure that provides easily interpretable results and yields a feasible sample size that is associated with adequate power to detect therapeutic benefit over 1 year. To minimize potential intolerance of NAC and subject withdrawal, the study design includes an open-label dosage titration period. Patients who tolerate 2.4-4.8 g daily NAC for 3 months will be randomly assigned 1:1 to continue treatment on their tolerated dosage of NAC or matching placebo for 9 additional months. Beyond the premise of validating clinical efficacy and durability of this therapy in SLE, the proposed studies will test the hypothesis that depletion of GSH and cysteine and activation of mTOR predict immunobiological and clinical responsiveness to NAC. The proposed studies will significantly advance our understanding of immune-metabolic pathways that control T-cell lineage specification with translational relevance for the pathogenesis and treatment of lupus. The approach is innovative as it will employ a safe therapeutic intervention to define the role of cysteine depletion in redox-dependent mTOR activation and pro-inflammatory T-cell development in lupus patients in vivo. The results will bring new perspectives to our understanding of disease pathogenesis with broad translational relevance for clinical management of patients with SLE.