title: 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.
abstract: 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).
  
  
  CONCLUSIONS
  This pilot study suggests that NAC safely improves lupus disease activity by blocking mTOR in T lymphocytes.
authors.affiliation: State University of New York, Upstate Medical University, College of Medicine, Syracuse, New York 13210, USA.
authors.forename: Zhi-Wei
authors.initials: ZW
authors.lastname: Lai
authors.forename: Robert
authors.initials: R
authors.lastname: Hanczko
authors.forename: Eduardo
authors.initials: E
authors.lastname: Bonilla
authors.forename: Tiffany N
authors.initials: TN
authors.lastname: Caza
authors.forename: Brandon
authors.initials: B
authors.lastname: Clair
authors.forename: Adam
authors.initials: A
authors.lastname: Bartos
authors.forename: Gabriella
authors.initials: G
authors.lastname: Miklossy
authors.forename: John
authors.initials: J
authors.lastname: Jimah
authors.forename: Edward
authors.initials: E
authors.lastname: Doherty
authors.forename: Hajra
authors.initials: H
authors.lastname: Tily
authors.forename: Lisa
authors.initials: L
authors.lastname: Francis
authors.forename: Ricardo
authors.initials: R
authors.lastname: Garcia
authors.forename: Maha
authors.initials: M
authors.lastname: Dawood
authors.forename: Jianghong
authors.initials: J
authors.lastname: Yu
authors.forename: Irene
authors.initials: I
authors.lastname: Ramos
authors.forename: Ioana
authors.initials: I
authors.lastname: Coman
authors.forename: Stephen V
authors.initials: SV
authors.lastname: Faraone
authors.forename: Paul E
authors.initials: PE
authors.lastname: Phillips
authors.forename: Andras
authors.initials: A
authors.lastname: Perl
mesh_terms: D000111:Acetylcysteine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000328:Adult; D004311:Double-Blind Method; D005260:Female; D016166:Free Radical Scavengers / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008875:Middle Aged; D010865:Pilot Projects; D010919:Placebos; D012720:Severity of Illness Index; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D016166:Free Radical Scavengers; D010919:Placebos; D058570:TOR Serine-Threonine Kinases; D000111:Acetylcysteine