N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial

Arthritis Rheum. 2012 Sep;64(9):2937-46. doi: 10.1002/art.34502.


Objective: Systemic lupus erythematosus (SLE) patients exhibit T cell dysfunction, which can be regulated through mitochondrial transmembrane potential (Δψm) and mammalian target of rapamycin (mTOR) by glutathione (GSH). This randomized, double-blind, placebo-controlled study was undertaken to examine the safety, tolerance, and efficacy of the GSH precursor N-acetylcysteine (NAC).

Methods: A total of 36 SLE patients received either daily placebo or 1.2 gm, 2.4 gm, or 4.8 gm of NAC. Disease activity was evaluated monthly by the British Isles Lupus Assessment Group (BILAG) index, the SLE Disease Activity Index (SLEDAI), and the Fatigue Assessment Scale (FAS) before, during, and after a 3-month treatment period. Mitochondrial transmembrane potential and mTOR were assessed by flow cytometry. Forty-two healthy subjects matched to patients for age, sex, and ethnicity were studied as controls.

Results: NAC up to 2.4 gm/day was tolerated by all patients, while 33% of those receiving 4.8 gm/day had reversible nausea. Placebo or NAC 1.2 gm/day did not influence disease activity. Considered together, 2.4 gm and 4.8 gm NAC reduced the SLEDAI score after 1 month (P = 0.0007), 2 months (P = 0.0009), 3 months (P = 0.0030), and 4 months (P = 0.0046); the BILAG score after 1 month (P = 0.029) and 3 months (P = 0.009); and the FAS score after 2 months (P = 0.0006) and 3 months (P = 0.005). NAC increased Δψm (P = 0.0001) in all T cells, profoundly reduced mTOR activity (P = 0.0009), enhanced apoptosis (P = 0.0004), reversed expansion of CD4-CD8- T cells (mean ± SEM 1.35 ± 0.12-fold change; P = 0.008), stimulated FoxP3 expression in CD4+CD25+ T cells (P = 0.045), and reduced anti-DNA production (P = 0.049).

Conclusion: This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.

Trial registration: ClinicalTrials.gov NCT00775476.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / adverse effects
  • Acetylcysteine / pharmacology
  • Acetylcysteine / therapeutic use*
  • Adult
  • Double-Blind Method
  • Female
  • Free Radical Scavengers / adverse effects
  • Free Radical Scavengers / pharmacology
  • Free Radical Scavengers / therapeutic use*
  • Humans
  • Lupus Erythematosus, Systemic / drug therapy*
  • Lupus Erythematosus, Systemic / metabolism
  • Male
  • Membrane Potential, Mitochondrial / drug effects
  • Middle Aged
  • Pilot Projects
  • Placebos
  • Severity of Illness Index
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / metabolism
  • TOR Serine-Threonine Kinases / metabolism*
  • Treatment Outcome


  • Free Radical Scavengers
  • Placebos
  • TOR Serine-Threonine Kinases
  • Acetylcysteine

Associated data

  • ClinicalTrials.gov/NCT00775476