Background/Purpose: Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology with mortality still approaching 10% in 5 years. The major causes of death in SLE include infections due to the toxicity of immunosuppressant medications. Our study design has been formulated on the premise that safe and effective treatment should target key checkpoints of pathogenesis. The depletion of cysteine and reduced glutathione (GSH) underlie mitochondrial oxidative stress, activation of the mechanistic target of rapamycin (mTOR), inflammatory lineage specification and antinuclear autoantibody production in SLE. An earlier completed double-blind, placebo-controlled study provided preliminary evidence that replacement of cysteine and GSH with amino acid precursor, N-acetylcysteine (NAC), can safely reduce mTOR activation, anti-DNA antibody production, and disease activity in SLE (PMID: 22549432; PMID: 23400548).

Methods: The study is a multicenter randomized, double-blind, placebo-controlled clinical trial, using an innovative enriched enrollment randomized withdrawal (EERW) design that allows participants to use an individualized dosage of study medication, which mimics clinical practice in terms of how NAC would be administered. Eligibility criteria required clinically active disease with ≥6 SLE Disease Activity Index (SLEDAI) and British Isles Lupus Assessment Group (BILAG) organ domain scores ≥1 BILAG A or ≥2 BILAG B (clinicaltrials.gov NCT00775476). All participants received NAC for 3 months, titrated up to a maximally tolerated dosage between 2.4 g/day and 4.8 g/day. Subjects tolerating ≥2.4 g/day NAC have been randomized to receive either NAC or placebo at the subject’s tolerated dosage for the remaining 9 months of treatment. Our preliminary analysis evaluated the BILAG and SLEDAI scores in 68 patients, and validated Fatigue Assessment (FAS) and ADHD Self-Report Scales (ASRS) (PMID: 23400548) in 54 SLE patients, before and after a 3-month open-label dose titration phase. Statistical analysis included two-tailed paired t-tests and correlations corrected for multiple comparisons using the Bonferroni correction in GraphPad software.

Results: We observed a significant reduction of SLE disease activity as measured by the reduction of SLEDAI and BILAG muco-cutaneous and musculoskeletal organ domain scores. ASRS cognition/inattention and fatigue scores also improved (Table 1). Adverse events—including headache, nausea, gastrointestinal upset, constipation, and diarrhea—were all transient and reversible. By month 3, 18 participants had withdrawn: 1 due to adverse events, 1 due to scheduling conflicts, 6 were lost to follow-up, 3 were unwilling to continue, 5 withdrew consent, and 2 experienced serious adverse events unrelated to the study drug.

Conclusion: This preliminary analysis supports the notion that NAC may serve as a safe and effective treatment for patients with SLE, but these observations could be affected by the absence of blinding in the open-label phase and regression-to-the-mean. The double-blind phase of the ongoing multicenter trial will confirm whether NAC is efficacious in treating SLE.

Table 1: Clinical assessment as measured by SLEDAI, BILAG, ASRS Inattention and Hyperactivity, and FAS Physical and Mental Fatigue scores. BILAG organ domain scores were converted to numerical values: A=12, B=8, C=1, D/E=0. Data are presented as mean ± standard deviation (STDEV). P values indicate comparisons between pretreatment (Month 0) and 3-month post-treatment measurements (Month 3) using a two-tailed paired t-test, corrected for multiple comparisons; differences (∆) between Month 0 and Month 3 are also reported.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/preliminary-analysis-of-open-label-dose-titration-phase-of-sle-treatment-with-n-acetylcysteine-snac-shows-evidence-for-potential-improvement-of-sledai-bilag-adhd-and-fatigue-scores-in-patients-wit-2/