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.
Systemic lupus erythematosus (SLE) is a life-threatening disease of the immune system that primarily affects women in childbearing age with death rates approaching 10% in 5 years. The major causes of death include infections due to the toxicity of immunosuppressant medications. Therefore, a significant unmet need exists for non-toxic medications in SLE. Our research has been directed to develop safe and effective treatments that are focused on the very causes of lupus pathogenesis, such as the depletion of a natural antioxidant, reduced glutathione (GSH), which underlies inflammation in SLE through activating a regulatory protein called the mechanistic target of rapamycin (mTOR). Along this line, we have initiated a clinical trial in SLE patients aimed at the replenishment of GSH with an amino acid precursor, N-acetylcysteine (NAC). As shown by our pilot study completed in 2011, NAC was tolerated by all patients at the 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 the 2.4 g/day and 4.8 g/day NAC dosages showed preliminary evidence for therapeutic efficacy, 4.8 g/day NAC achieved greater clinical improvements. NAC raised GSH, blocked mTOR, and expanded anti-inflammatory cells. Importantly, the safety of NAC has been widely confirmed and efficacy has been noted in follow-up case reports. While NAC is inexpensive compared to current therapies burdened with serious side-effects and widely accessible in health food stores, it is unavailable as an oral medication by prescription. Therefore, the proposed phase II trial will employ the SLE Responder Index (SRI), as a clinically meaningful primary outcome to evaluate the efficacy of NAC over 1 year. To minimize potential intolerance of NAC and subject withdrawal during the trial, the design includes an open-label dosage titration period. Patients who tolerate 2.4-4.8 g daily NAC for 3 months will be randomized or 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, the proposed studies will test the assumption that depletion of GSH and activation of mTOR predict clinical responsiveness to NAC in SLE. The proposed studies are expected to lead to the development of a novel, uniquely safe, and affordable medication with the potential to favorably alter the long-term outcomes of SLE.
