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，其死亡率仍然很高。 5年后接近10%。系统性红斑狼疮的主要死因是由于其毒性引起的感染。 免疫抑制药物。因此，存在着对有效和无毒的重大未得到满足的需求 治疗系统性红斑狼疮的药物。我们的中心假设是建立在有效治疗的基础上的 应针对发病机制的关键检查点，如还原型谷胱甘肽(GSH)的耗竭，这是 雷帕霉素(MTOR)机制靶点的激活和炎性谱系的规范 SLE患者的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 有证据表明，1)SLE患者外周血淋巴细胞(PBL)中的GSH被耗尽；2)GSH 耗竭有助于mTOR激活，从而导致SLE患者T细胞功能障碍；3)给予N- 乙酰半胱氨酸(NAC)作为GSH的细胞通透性氨基酸前体，阻碍了GSH的发育 4)初步研究表明NAC是安全的，可以逆转GSH耗竭和mTOR 激活和改善SLE患者的疾病活跃度。在我们完成的双盲安慰剂对照试验中 研究表明，NAC在每天1.2克和2.4克剂量下的耐受率为100%，而33%的患者 每天服用4.8g的患者出现可逆性恶心。安慰剂和1.2g/天的NAC不影响疾病活动。 尽管2.4g/天和4.8g/天的NAC剂量都显示出临床疗效的初步证据，4.8 NAC的SLEDAI和BILAG得分下降幅度更大。NAC提高GSH，阻止mTOR，以及 扩展的T规则。拟议的II期试验将使用SLE Responder Index(SRI)作为临床 有意义的初步结果衡量标准，提供易于解释的结果并产生可行的样本 大小与检测一年以上的治疗效果的足够能力相关。将潜力降至最低 由于对NAC和受试者停药不耐受，该研究设计包括开放标签剂量滴定期。 每日耐受2.4-4.8克NAC持续3个月的患者将被随机分配为1：1继续治疗 他们的耐受量NAC或匹配的安慰剂额外9个月。超越了验证的前提 这种疗法在系统性红斑狼疮中的临床有效性和持久性，拟议的研究将检验耗竭的假设 GSH和半胱氨酸水平及mTOR活性可预测NAC的免疫生物学和临床疗效。 拟议中的研究将显著提高我们对免疫代谢途径的理解 T细胞谱系特征与狼疮发病机制和治疗的翻译相关性。这个 方法是创新的，因为它将使用一种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的mTOR激活和促炎T细胞发育。这个 研究结果将为我们对疾病发病机制的理解带来新的视角，具有广泛的翻译意义 与系统性红斑狼疮患者临床治疗的相关性。

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.