A Pilot Study to Evaluate the Effects of Oral N-Acetyl Cysteine on Inflammatory and Oxidative Stress Biomarkers in Rheumatoid Arthritis

Author(s): Ghazal Hashemi, Mahtabalsadat Mirjalili, Zahra Basiri, Ahmad Tahamoli-Roudsari, Nejat Kheiripour, Maryam Shahdoust, Akram Ranjbar, Maryam Mehrpooya*, Sara Ataei.

Journal Name: Current Rheumatology Reviews

Volume 15 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Rheumatoid Arthritis (RA) is a common inflammatory disease of the joints. Due to the importance of inflammation and oxidative stress in the pathogenesis of RA, drugs that have anti-oxidant and anti-inflammatory properties, such as N-acetyl Cysteine (NAC), can be used as adjunctive therapy in patients with RA.

Aims: The aim of this study was to evaluate the effects of oral NAC on inflammatory cytokines and oxidative stress in patients with RA.

Methods: Adjunct to standard treatment, the NAC group (23 patients) received 600 mg of NAC twice daily and the placebo group (19 patients) received identical placebo twice daily for 12 weeks. Serum levels of Total Oxidant Status (TOS), Total Antioxidant Capacity (TAC), nitric oxide (NO), Total Thiol Groups (TTG), Malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), interleukin- 6 (IL-6), C-reactive Protein (CRP), and Erythrocyte Sedimentation Rate (ESR) were measured at baseline and at the end of the study.

Results: Results showed that in the NAC group, the serum levels of MDA, NO, IL-6, TNF-α, ESR and CRP were significantly lower than the baseline. Also, the serum level of TAC and TTG, as antioxidant parameters, increased significantly. However, only NO, MDA and TTG showed a significant difference in the NAC group as compared to the placebo group at the end of study.

Conclusion: According to the results of this study, oral NAC can significantly reduce the several oxidative stress factors and inflammatory cytokines. These results need to be confirmed in larger studies while considering clinical outcomes of RA patients.

Keywords: N-acetylcysteine, rheumatoid arthritis, oxidative stress, nitrosative stress, inflammatory cytokines, antioxidants.

[1]
PJW Venables M, MB BChir, MD, FRCPRavinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS.. Diagnosis and differential diagnosis of rheumatoid arthritis. UpToDate Post TW ed UpTo- Date,Waltham, MA (Accessed on February 23, 2018)
[2]
Shokri A, Yarmohammadian MH, Mottaghi P, Karimi S. Customer Quality and Rheumatoid Arthritis in the Iranian Patient’s Perspective: A Cross-Sectional Study. Journal of Patient Safety & Quality Improvement 2014; 2(3): 110-5.
[3]
Davatchi F, Sandoughi M, Moghimi N, et al. Epidemiology of rheumatic diseases in Iran from analysis of four COPCORD studies Int J Rheum Dis 2016; 19(11): 1056-62.
[http://dx.doi.org/10.1111/1756-185X.12809] [PMID: 26620687]
[4]
Myasoedova E, Crowson CS, Turesson C, Gabriel SE, Matteson EL. Incidence of extraarticular rheumatoid arthritis in Olmsted County, Minnesota, in 1995-2007 versus 1985-1994: a populationbased study. J Rheumatol 2011; 38(6): 983-.
[http://dx.doi.org/10.3899/jrheum.101133] [PMID: 21459933]
[5]
McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis N Engl J Med 2011; 365(23): 2205-19.
[http://dx.doi.org/10.1056/NEJMra1004965] [PMID: 22150039]
[6]
Wei S-T, Sun Y-H, Zong S-H, Xiang Y-B. Serum levels of IL-6 and TNF-α may correlate with activity and severity of rheumatoid arthritis. Med Sci Monit: international medical journal of experimental and clinical research 2015; 21(4030)
[7]
Angiolilli C, Grabiec AM, Ferguson BS, et al. Inflammatory cytokines epigenetically regulate rheumatoid arthritis fibroblast-like synoviocyte activation by suppressing HDAC5 expression. Ann Rheum Dis 2016; 75(2): 430-8.
[http://dx.doi.org/10.1136/annrheumdis-2014-205635] [PMID: 25452308]
[8]
Niu X, Chen G. Clinical biomarkers and pathogenic-related cytokines in rheumatoid arthritis. J Immunol Res 2014 2014.
[9]
Oztürk HS, Cimen MY, Cimen OB, Kaçmaz M, Durak I. Oxidant/ antioxidant status of plasma samples from patients with rheumatoid arthritis. Rheumatol Int 1999; 19(1-2): 35-7.
[http://dx.doi.org/10.1007/s002960050097] [PMID: 10651080]
[10]
Preedy V, Reilly M, Mantle D, Peters T. Oxidative damage in liver disease. J Int Fed Clin Chem 1998; 10: 16-20.
[11]
Pincemail J. Free radicals and antioxidants in human diseases Analysis of free radicals in biological systems. Springer 1995; pp. 83-98.
[http://dx.doi.org/10.1007/978-3-0348-9074-8_7]
[12]
Ghezzi P, Dinarello CA, Bianchi M, Rosandich ME, Repine JE, White CW. Hypoxia increases production of interleukin-1 and tumor necrosis factor by human mononuclear cells Cytokine 1991; 3(3): 189-94.
[http://dx.doi.org/10.1016/1043-4666(91)90015-6] [PMID: 1883957]
[13]
Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis Arthritis Rheum 2008; 59(6): 762-84.
[http://dx.doi.org/10.1002/art.23721] [PMID: 18512708]
[14]
SUTTER FT. Natural Therapies for Rheumatoid Arthritis and Other Chronic Inflammatory Conditions 2000.
[15]
Atmaca G. Antioxidant effects of sulfur-containing amino acids. Yonsei Med J 2004; 45(5): 776-88.
[http://dx.doi.org/10.3349/ymj.2004.45.5.776] [PMID: 15515186]
[16]
Dean O, Giorlando F, Berk M. N-acetylcysteine in psychiatry: current therapeutic evidence and potential mechanisms of action. J Psychiatry Neurosci 2011; 36(2): 78-86.
[http://dx.doi.org/10.1503/jpn.100057] [PMID: 21118657]
[17]
Dekhuijzen PN. Antioxidant properties of N-acetylcysteine: their relevance in relation to chronic obstructive pulmonary disease. Eur Respir J 2004; 23(4): 629-36.
[http://dx.doi.org/10.1183/09031936.04.00016804] [PMID: 15083766]
[18]
Tepel M, van der Giet M, Schwarzfeld C, Laufer U, Liermann D, Zidek W. Prevention of radiographic-contrast-agent-induced reductions in renal function by acetylcysteine. N Engl J Med 2000; 343(3): 180-4.
[http://dx.doi.org/10.1056/NEJM200007203430304] [PMID: 10900277]
[19]
Sochman J. N-acetylcysteine in acute cardiology: 10 years later: what do we know and what would we like to know?! J Am Coll Cardiol 2002; 39(9): 1422-8.
[http://dx.doi.org/10.1016/S0735-1097(02)01797-7] [PMID: 11985902]
[20]
Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine--a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol 2007; 7(4): 355-9.
[http://dx.doi.org/10.1016/j.coph.2007.04.005] [PMID: 17602868]
[21]
Kim HR, Kim KW, Kim BM, Lee KA, Lee SH. N-acetyl-l-cysteine controls osteoclastogenesis through regulating Th17 differentiation and RANKL in rheumatoid arthritis. Korean J Intern Med (Korean Assoc Intern Med) 2017.
[PMID: 28286938]
[22]
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62(9): 2569-81.
[http://dx.doi.org/10.1002/art.27584] [PMID: 20872595]
[23]
van Riel PL, Fransen J. DAS28: a useful instrument to monitor infliximab treatment in patients with rheumatoid arthritis. Arthritis Res Ther 2005; 7(5): 189-90.
[http://dx.doi.org/10.1186/ar1820] [PMID: 16207346]
[24]
Benzie IF, Szeto YT. Total antioxidant capacity of teas by the ferric reducing/antioxidant power assay. J Agric Food Chem 1999; 47(2): 633-6.
[http://dx.doi.org/10.1021/jf9807768] [PMID: 10563944]
[25]
Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005; 38(12): 1103-11.
[http://dx.doi.org/10.1016/j.clinbiochem.2005.08.008] [PMID: 16214125]
[26]
Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95(2): 351-8.
[http://dx.doi.org/10.1016/0003-2697(79)90738-3] [PMID: 36810]
[27]
Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959; 82(1): 70-7.
[http://dx.doi.org/10.1016/0003-9861(59)90090-6] [PMID: 13650640]
[28]
Westergren A. On the Clinical Import of the Red Cell Sedimentation Reaction in Diseases of the Joints. J Intern Med 1926; 64(S16): 343-54.
[29]
Purwanto B, Prasetyo DH. Effect of oral N-acetylcysteine treatment on immune system in continuous ambulatory peritoneal dialysis patients. Acta Med Indones 2012; 44(2): 140-4.
[PMID: 22745145]
[30]
Feldmann M, Brennan FM, Maini RN. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996; 14: 397-440.
[http://dx.doi.org/10.1146/annurev.immunol.14.1.397] [PMID: 8717520]
[31]
Isomäki P, Punnonen J. Pro- and anti-inflammatory cytokines in rheumatoid arthritis. Ann Med 1997; 29(6): 499-507.
[http://dx.doi.org/10.3109/07853899709007474] [PMID: 9562516]
[32]
Lubberts E, Berg WB. Cytokines in the pathogenesis of rheumatoid arthritis and collagen-induced arthritis. Cytokines and Chemokines in Autoimmune Disease 2003; pp. 194-202.
[http://dx.doi.org/10.1007/978-1-4615-0171-8_11]
[33]
Hadjigogos K. The role of free radicals in the pathogenesis of rheumatoid arthritis. Panminerva Med 2003; 45(1): 7-13.
[PMID: 12682616]]
[34]
Hassan SZ, Gheita TA, Kenawy SA, Fahim AT, El-Sorougy IM, Abdou MS. Oxidative stress in systemic lupus erythematosus and rheumatoid arthritis patients: relationship to disease manifestations and activity. Int J Rheum Dis 2011; 14(4): 325-31.
[http://dx.doi.org/10.1111/j.1756-185X.2011.01630.x] [PMID: 22004228]
[35]
Bracht A, Silveira SS, Castro-Ghizoni CV, et al. Oxidative changes in the blood and serum albumin differentiate rats with monoarthritis and polyarthritis. Springerplus 2016; 5: 36.
[http://dx.doi.org/10.1186/s40064-016-1671-1] [PMID: 26835218]
[36]
Jaswal S, Mehta HC, Sood AK, Kaur J. Antioxidant status in rheumatoid arthritis and role of antioxidant therapy. Clin Chim Acta 2003; 338(1-2): 123-9.
[http://dx.doi.org/10.1016/j.cccn.2003.08.011] [PMID: 14637276]
[37]
Abdollahzad H, Aghdashi MA, Asghari Jafarabadi M, Alipour B. Effects of coenzyme Q10 supplementation on inflammatory cytokines (TNF-α, IL-6) and oxidative stress in rheumatoid arthritis patients: a randomized controlled trial. Arch Med Res 2015; 46(7): 527-33.
[http://dx.doi.org/10.1016/j.arcmed.2015.08.006] [PMID: 26342738]
[38]
Huang SC, Wei JC, Wu DJ, Huang YC. Vitamin B(6) supplementation improves pro-inflammatory responses in patients with rheumatoid arthritis. Eur J Clin Nutr 2010; 64(9): 1007-13.
[http://dx.doi.org/10.1038/ejcn.2010.107] [PMID: 20571496]
[39]
Veselinovic M, Vasiljevic D, Vucic V, et al. Clinical Benefits of n-3 PUFA and ɤ-Linolenic Acid in Patients with Rheumatoid Arthritis. Nutrients 2017; 9(4): E325.
[http://dx.doi.org/10.3390/nu9040325] [PMID: 28346333]
[40]
Millea PJ. N-acetylcysteine: multiple clinical applications. Am Fam Physician 2009; 80(3): 265-9.
[PMID: 19621836]
[41]
Gürer H, Ozgünes H, Neal R, Spitz DR, Erçal N. Antioxidant effects of N-acetylcysteine and succimer in red blood cells from lead-exposed rats. Toxicology 1998; 128(3): 181-9.
[http://dx.doi.org/10.1016/S0300-483X(98)00074-2] [PMID: 9750041]
[42]
Kumar A, Takada Y, Boriek AM, Aggarwal BB. Nuclear factor-kappaB: its role in health and disease. J Mol Med (Berl) 2004; 82(7): 434-48.
[http://dx.doi.org/10.1007/s00109-004-0555-y] [PMID: 15175863]
[43]
Park JH, Kang S-S, Kim JY, Tchah H. The antioxidant N-acetylcysteine inhibits inflammatory and apoptotic processes in human conjunctival epithelial cells in a high-glucose environment. Invest Ophthalmol Vis Sci 2015; 56(9): 5614-21.
[http://dx.doi.org/10.1167/iovs.15-16909] [PMID: 26305534]
[44]
Guo Z, Xia Z, Jiang J, McNeill JH. Downregulation of NADPH oxidase, antioxidant enzymes, and inflammatory markers in the heart of streptozotocin-induced diabetic rats by N-acetyl-L-cysteine. Am J Physiol Heart Circ Physiol 2007; 292(4): H1728-36.
[http://dx.doi.org/10.1152/ajpheart.01328.2005] [PMID: 17122189]
[45]
Lee K-A, Kim H-R, Lee SH, Kim B, Kim K-W, Eds. NAcetylcysteine Regulates Osteoclastogenesis and Th17 Cell Differentiation in Rheumatoid ArthritisArthritis & Rheumatology. Hoboken 07030-5774, NJ USA: Wiley 111 River St 2016.
[46]
Jonsson H, Wollheim FA, Svensson B. No effect of acetylcystein on refractory rheumatoid arthritis. Clin Exp Rheumatol 1986; 4(4): 363-4.
[PMID: 3791720]
[47]
Remans P, Zuijderduin W, Levahrt N, Schuitemaker J, Tak P, Breedveld F, et al. High dose intravenous N-acetyl-L-cysteine (NAC) therapy in rheumatoid arthritis, results from a pilot study. Role Of Reactive Oxygen Species In Rheumatoid Arthritis Synovial T Lymphocytes97
[48]
Batooei M, Tahamoli-Roudsari A, Basiri Z, et al. Evaluating the effect of oral N-acetylcysteine as an adjuvant treatment on clinical outcomes of patients with rheumatoid arthritis: a randomized, double blind clinical trial. Rev Recent Clin Trials 2018; 13(2): 132-8.
[http://dx.doi.org/10.2174/1574887113666180307151937] [PMID: 29521247]
[49]
Nascimento MM, Suliman ME, Silva M, et al. Effect of oral N-acetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo-controlled study. Perit Dial Int 2010; 30(3): 336-42.
[http://dx.doi.org/10.3747/pdi.2009.00073] [PMID: 20190028]
[50]
Csontos C, Rezman B, Foldi V, et al. Effect of N-acetylcysteine treatment on oxidative stress and inflammation after severe burn. Burns 2012; 38(3): 428-37.
[http://dx.doi.org/10.1016/j.burns.2011.09.011] [PMID: 21978796]
[51]
Tossios P, Bloch W, Huebner A, et al. N-acetylcysteine prevents reactive oxygen species-mediated myocardial stress in patients undergoing cardiac surgery: results of a randomized, double-blind, placebo-controlled clinical trial. J Thorac Cardiovasc Surg 2003; 126(5): 1513-20.
[http://dx.doi.org/10.1016/S0022-5223(03)00968-1] [PMID: 14666027]
[52]
Allameh Z, Karimi A, Rafiei Tabatabaei S, Sharifian M, Salamzadeh J. Effect of N-acetylcysteine on inflammation biomarkers in pediatric acute pyelonephritis: a randomized controlled trial. Iran J Kidney Dis 2015; 9(6): 454-62.
[PMID: 26552352]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [246 - 253]
Pages: 8
DOI: 10.2174/1573403X14666180926100811
Price: $58

Article Metrics

PDF: 31
HTML: 2
EPUB: 1
PRC: 1