N-acetylcysteine & Autoimmunity

Therapeutic Potential in SLE, MS & Systemic Sclerosis

Kimberly M. Sanders, ND

N-acetylcysteine (NAC) is an amino acid derivative that is a well-known mucolytic and antioxidant. Its therapeutic use ranges from detoxification support to chronic sinusitis and neurotransmitter balance. NAC may also be a useful adjunctive therapy for autoimmune diseases, including neuropsychiatric systemic lupus erythematosus (SLE), multiple sclerosis, and systemic sclerosis, through a number of different mechanisms.

Systemic Lupus Erythematosus

Patients with neuropsychiatric SLE may experience depression, irritability, memory loss, and fatigue as part of their disease process. Neuropsychiatric SLE is associated with anti-NMDA receptor antibodies, which are extremely pathogenic due to their ability to stimulate the glutamate receptor and cause neuron excitotoxicity and, ultimately, neuronal death.1,2 N-acetylcysteine is a natural precursor to glutathione, thus has the ability to modulate glutamate levels, improve depression, and promote neurogenesis.3 A small 2013 study investigated the use of NAC therapy (at both 2.4 g and 4.8 g per day for 3 months) for ADHD and impaired concentration in 24 SLE patients.4 The study showed significant improvements in the patients after treatment with both dosages of NAC.

N-acetylcysteine may also be a useful therapy for SLE by modulating the high levels of oxidative stress found in these patients. A 2013 article explains that oxidative stress contributes to SLE pathogenesis via autoantibody production and immune dysregulation.5 The glutathione levels within T cells isolated from SLE patients are depleted, and the mitochondrial activity in these T cells promotes excess oxidative stress and activates mTOR (a cellular protein that modulates several functions). Activation of mTOR leads to reduced autophagy and accumulation of misfolded proteins intracellularly, potentially inducing autoimmune reactions. NAC has demonstrated positive effects in lupus-prone mice and has shown promise in human trials by modifying these factors as well.5 A 2012 human trial involving 36 SLE patients investigated the effects of placebo versus 1.2 g, 2.4 g, or 4.8 g of NAC supplementation.6 The study found that 2.4 g of NAC was well tolerated, while 4.8 g caused nausea in 33% of subjects. Both dosages were found to significantly improve disease activity scores, improve T-cell mitochondrial membrane potential, enhance apoptosis, and block mTOR activation.6Though this human trial was small, its results are encouraging and show that NAC is safe and well-tolerated in this patient population.

Two of the major causes of mortality in SLE patients are lupus nephritis and cardiovascular disease; NAC supplementation may be useful for the treatment of both of these complications. A 2010 case study, published in the Journal of Clinical Pharmacology and Therapeutics, presented the results of NAC supplementation in a 46-year-old lupus nephritis patient.7 She received 1.8 g of NAC daily for 3 months and showed improved kidney glutathione levels, reduced fatigue, and reduced proteinuria. More trials are warranted in the future investigating the therapeutic effect of NAC for this purpose. A 2011 study investigated the effects of NAC (with and without atorvastatin) on endothelial dysfunction in 32 SLE patients, as measured by arterial stiffness, C-reactive protein (CRP), and malondialdehyde (MDA) levels.8 Arterial stiffness was reduced in the NAC/atorvastatin treatment group, and CRP and MDA levels were reduced in those treated with NAC alone. The authors conclude that improved endothelial function may prevent cardiovascular incidents in these patients.

Multiple Sclerosis

A 2014 in-vivo study showed that glutamate excitotoxicity may be linked to the pathogenesis of multiple sclerosis.9 This study and others suggest that excess glutamate levels are associated with elevated markers of disease progression in multiple sclerosis.9,10A study utilizing an animal model of experimental autoimmune encephalitis with optic neuritis (the accepted animal model for MS) showed preservation of retinal ganglion cells, reduced demyelination, and axonal protection with NMDA blockade agents.11 While no human trials currently exist, there is therapeutic potential for NAC in MS and other neurological disorders linked to glutamate excitotoxicity.12

Systemic Sclerosis

Patients with systemic sclerosis are at risk for organ failure, including renal failure and pulmonary fibrosis. Pulmonary fibrosis may lead to cor pulmonale secondary to increased pulmonary vascular resistance. NAC supplementation has been studied in the treatment of pulmonary fibrosis in these patients. A 2011 study evaluated carbon monoxide diffusing capacity (DLCO) levels at baseline vs 24 months.13 High-dose IV NAC was supplemented at a dose of 15 mg/kg/h for 5 hours every 14 days. The treatment led to significant improvements in DLCO, as well as improvements in vital capacity and total lung capacity.13A 2009 small open-label study evaluated the effects of NAC infusion on renal artery resistance in 40 systemic sclerosis patients.14 Renal arterial resistance was significantly reduced, and the authors concluded that NAC is useful for those with low disease severity, for the preservation of renal function. NAC may also help preserve hepatic function in systemic sclerosis patients. An open-label 2009 study of 40 patients evaluated the effects of IV NAC at 15 mg/kg/h for 5 consecutive hours.15 The authors conclude that IV NAC can increase hepatic flow volume and total liver perfusion in those with low disease severity.

Conclusions

N-acetylcysteine has therapeutic potential for certain autoimmune diseases, including SLE, MS, and systemic sclerosis. In SLE patients, NAC may help reduce glutamate excitotoxicity in neuropsychiatric lupus. It may also reduce oxidative stress in these patients by enhancing glutathione status, enhancing autophagy, and improving mitochondrial function. Additionally, there is evidence that glutamate excitotoxicity is linked to multiple sclerosis, and animal models have demonstrated improvements using NMDA-blockade agents. Systemic sclerosis patients are at risk for organ damage, including lung, kidney, and liver. High-dose NAC has demonstrated benefits in these patients by improving organ function, improving DLCO in the lungs, reducing renal arterial resistance, and preserving hepatic blood flow.

Kim headshotKimberly M. Sanders, ND, is a licensed naturopathic physician in Connecticut. She graduated from the University of Bridgeport, and completed her CNME-accredited residency training there as well. She was named 3-time MVP of the ZRT Cup Competition as a medical student. Dr Sanders currently owns ArthroWell Naturopathic, a specialty practice in rheumatology. She has undergone extensive pediatric and rheumatology training, and has lectured on the topic of autoimmunity and autism at the annual CNPA and NHAND conferences. Her passion in practice is finding the underlying cause of immune dysfunction and restoring balance to the immune system with functional medicine.

References:

  1. Levite M. Glutamate receptor antibodies in neurological diseases: anti-AMPA-GluR3 antibodies, anti-NMDA-NR1 antibodies, anti-NMDA-NR2A/B antibodies, anti-mGluR1 antibodies or anti-mGluR5 antibodies are present in subpopulations of patients with either: epilepsy, encephalitis, cerebellar ataxia, systemic lupus erythematosus (SLE) and neuropsychiatric SLE, Sjogren’s syndrome, schizophrenia, mania or stroke.J Neural Transm. 2014;121(8):1029-1075.
  2. Gono T. [Anti-NMDA receptor antibody in systemic lupus erythematosus]. Nihon Shinkei Seishin Yakurigaku Zasshi.2013;33(5-6):225-230. [Article in Japanese]
  3. Berk M, Dean OM, Cotton SM, et al. The efficacy of adjunctive N-acetylcysteine in major depressive disorder: a double-blind, randomized, placebo-controlled trial. J Clin Psychiatry.2014;75(6):628-636.
  4. Garcia RJ, Francis L, Dawood M, et al. Attention deficit and hyperactivity disorder scores are elevated and respond to N-acetylcysteine treatment in patients with systemic lupus erythematosus. Arthritis Rheum. 2014;65(5):1313-1318.
  5. Perl A. Oxidative stress in the pathology and treatment of systemic lupus erythematosus. Nat Rev Rheumatol.2013;9(11):674-686.
  6. Lai ZW, Hanczko R, Bonilla E, et al. N-acetylcysteine reduces disease activity by blocking mTOR in T cells of systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2012;64(9):2937-2946.
  7. Tewthanom K, Janwitayanujit S, Totemchockcyakam K, et al. The effect of high dose of N-acetylcysteine in lupus nephritis: a case report and literature review. J Clin Pharm Ther. 2010;35(4):483-485.
  8. Kudaravalli J. Improvement in endothelial dysfunction in patients with systemic lupus erythematosus with N-acetylcysteine and atorvastatin. Indian J Pharmacol.2011;43(3):311-315.
  9. Azevedo CJ, Komak J, Chu P, et al. In vivo evidence of glutamate toxicity in multiple sclerosis. Ann Neurol. 2014;76(2):269-278.
  10. Vallejo-Illarramendi A, Domercq M, Perez-Cerda F, et al. Increased expression and function of glutamatetransporters in multiple sclerosis, Neurobiol Dis. 2006;21(1):154-164.
  11. Suhs KW, Fairless R, Williams SK, et al. N-methyl-D-aspartate receptor blockade is neuroprotective in experimental autoimmune optic neuritis. J Neuropathol Exp Neurol.2014;73(6):507-518.
  12. Bavarsad Shahripour R, Harrigan MR, Alexandrov AV. N-acetylcysteine (NAC) in neurological disorders: mechanisms of action and therapeutic opportunities. Brain Behav. 2014;4(2):108-122.
  13. Rosato E, Rossi C, Molinaro I, et al. Long-termN-acetylcysteine therapy in systemic sclerosis interstitial lung disease: a retrospective study. Int J Immunopathol Pharmacol. 2011;24(3):727-733.
  14. Rosato E, Cianci R, Barbano B, et al. N-acetylcysteine infusion reduces the resistance index of renal artery in the early stage of systemic sclerosis. Acta Pharmacol Sin. 2009;30(9):1283-1288.
  15. Rosato E, Zardi EM, Barbano B, et al. N-acetylcysteineinfusion improves hepatic perfusion in the early stages of systemic sclerosis. Int J Immunopathol Pharmacol. 2009;22(3):763-72.
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