Study of the Effects of N-acetylcysteine on Inflammatory Biomarkers and Disease Activity Score in Patients with Rheumatoid Arthritis
Abstract
Rheumatoid arthritis (RA) is considered as an autoimmune-related condition in which the overproduction of pro-inflammatory cytokines leads to an inflammatory cascade. N-acetylcysteine (NAC) is a potent anti-inflammatory and anti-oxidant agent. We aimed to explore the impact of oral NAC on cytokines activities and clinical indicators in RA patients.
In this placebo-controlled randomized double-blind clinical trial, 41 active RA patients were allocated in either NAC (600 mg, twice a day) or placebo group, as add-on therapy to the routine regimen, for 8 weeks. Disease activity score with an erythrocyte sedimentation rate (DAS28-ESR), and serum concentrations of interleukin (IL)-1β and IL-17 were assessed at baseline and end of the trial for all participants in the test and control groups.
The reduction of the DAS28-ESR was higher considerably in the NAC group compared to that of the control group. No statistically significant differences were seen in the reduction of IL-1β and IL-17 cytokines between the NAC and control groups. In addition, improvements in the patient global assessment, number of tender joints, number of swollen joints, and the ESR rates were in favor of the NAC group.
Our findings reveal that NAC may have a beneficial effect on all of the clinical features of RA. However, non-significant variations in the IL-1β and IL-17 levels suggest an alternative way of NAC effectiveness without influencing the measured cytokines. Nevertheless, these results need to be confirmed by further investigations.
1. Firestein G. Rheumatoid Arthritis, Kelley’s text book of Rhumatology, Harris E, Budd R, Firestein G. Elsevier.2005.
2. Koda-Kimble MA. Koda-Kimble and Young's applied therapeutics: the clinical use of drugs: Lippincot
Williams & Wilkins; 2012.
3. Bahadori S, Salamzadeh J, Kamalinejad M, Ardekani MRS, Keshavarz M, Ahmadzadeh A. Study of the Effect
of an Oral Formulation of Fig and Olive on Rheumatoid Arthritis (RA) Remission Indicators: A Randomized
Clinical Trial. Iran J Pharm Res. 2016;15(3):537-9.
4. Cutolo M, Kitas GD, van Riel PL, editors. Burden of disease in treated rheumatoid arthritis patients: going
beyond the joint. Semin Arthritis Rheum. 43(4):479-88.
5. Noack M, Miossec P, editors. Selected cytokine pathways in rheumatoid arthritis. Semin Immunopathol.
2017;39(4):363-5.
6. Eastgate J, Wood N, Di Giovine F, Symons J, Grinlinton F, Duff G. Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis. Lancet. 1988;332(8613):706-9.
7. Bazzazi H, Aghaei M, Memarian A, Asgarian-Omran H Behnampour N, Yazdani Y. Th1-Th17 ratio as a new
insight in rheumatoid arthritis disease. Iran J Allergy Asthma Immunol. 2018:68-77.
8. Van Den Berg WB, Miossec P. IL-17 as a future therapeutic target for rheumatoid arthritis. Nat Rev Rheumatol. 2009;5(10):549-53.
9. Kay J, Calabrese L. The role of interleukin-1 in the pathogenesis of rheumatoid arthritis. Rheumatology.
2004;43(suppl_3):iii2-iii9.
10. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF Kremer JM, et al. 2012 update of the 2008 American
College of Rheumatology recommendations for the use of disease‐modifying antirheumatic drugs and biologic
agents in the treatment of rheumatoid arthritis. Arthritis care Res. 2012;64(5):625-39.
11. Soeken K, Miller S, Ernst E. Herbal medicines for the treatment of rheumatoid arthritis: a systematic review. Rheumatology. 2003;42(5):652-9.
12. Van Vugt RM, Rijken PJ, Rietveld AG, Van Vugt AC, Dijkmans BA. Antioxidant intervention in rheumatoid
arthritis: results of an open pilot study. J Clin Rheumatol. 2008;27(6):771-5.
13. Oliver J, Silman A. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol. 2006;35(3):169- 74.
14. Ravipati AS, Zhang L, Koyyalamudi SR, Jeong SC, Reddy N, Bartlett J, et al. Antioxidant and anti-inflammatory activities of selected Chinese medicinal plants and their relation with antioxidant content. BMC
Complement Altern Med. 2012;12(1):1-14.
15. Mokhtari V, Afsharian P, Shahhoseini M, Kalantar SM, Moini A. A review on various uses of N-acetyl cysteine. Cell J. 2017;19(1):11-9.
16. Holdiness MR. Clinical pharmacokinetics of Nacetylcysteine. Clin Pharmacokinet. 1991;20(2):123-34.
17. 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.
18. Pena LR, Hill DB, McClain CJ. Treatment with glutathione precursor decreases cytokine activity. J
Parenter Enteral Nutr. 1999;23(1):1-6.
19. Kim H-R, Kim K-W, Kim B-M, Lee K-A, Lee S-H. Nacetyl- l-cysteine controls osteoclastogenesis through
regulating Th17 differentiation and RANKL in rheumatoid arthritis. Korean J Intern Med. 2019;34(1):210-9.
20. Zafarullah M, Li W, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Molec Life Sci CMLS. 2003;60(1):6-20.
21. Funovits J, Aletaha D, Bykerk V, Combe B, Dougados M, Emery P, et al. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis:
methodological report phase I. Ann Rheum Dis. 2010;69(9):1589-95.
22. Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis
Care Res. 2012;64(5):640-7.
23. Bahadori S, Ahmadzadeh A, Ardekani MRS, Kamalinejad M, Keshavarz M, Salamzadeh J. Does regular use of a complementary medicine of Olea Europe and Ficus carica have adverse effects on lipid profile and
fasting blood glucose of Rheumatoid Arthritis (RA) patients under treatment with DMARD regimens
containing methotrexate? Iran J Pharm Res. 2016;15(4):933-9.
24. Magyari L, Varszegi D, Kovesdi E, Sarlos P, Farago B, Javorhazy A, et al. Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications. World J Orthop. 2014;5(4):516-8.
25. Joosten LA, Radstake TR, Lubberts E, van den Bersselaar LA, van Riel PL, van Lent PL, et al. Association of interleukin‐18 expression with enhanced levels of both interleukin‐1β and tumor necrosis factor α in knee synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 2003;48(2):339-47.
26. Dayer J-M, de Rochemonteix B, Burrus B, Demczuk S, Dinarello CA. Human recombinant interleukin 1
stimulates collagenase and prostaglandin E2 production by human synovial cells. J Clin Invest. 1986;77(2):645-8.
27. Cho MR. Targeting interleukin-17 and Th17 in immune inflammatory diseases. Hanyang Med Rev.
2013;33(1):17-26.
28. Pavlovic V, Dimic A, Milenkovic S, Krtinic D. Serum levels of IL-17, IL-4, and INFγ in Serbian patients with early rheumatoid arthritis. J Res Med Sci. 2014;19(1):18- 21.
29. Espersen G, Lervang H, Nielsen G, Thomsen B, Faarvang K, Dyerberg J, et al. Decreased interleukin-1
beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated fatty acids. J Clin Rheumatol. 1992;11(3):393-5.
30. Huang S, Wei JC, Wu D, Huang Y. Vitamin B 6 supplementation improves pro-inflammatory responses in
patients with rheumatoid arthritis. Eur J Clin Nutr. 2010;64(9):1007-13.
31. Abdollahzad H, Aghdashi MA, Jafarabadi MA, 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.
32. Veselinovic M, Vasiljevic D, Vucic V, Arsic A, Petrovic S, Tomic-Lucic A, et al. Clinical benefits of n-3 PUFA and ɤ-linolenic acid in patients with rheumatoid arthritis. Nutrients. 2017;9(4):325-9.
33. Jhun J, Lee SH, Byun J-K, Jeong J-H, Kim E-K, Lee J, et al. Coenzyme Q10 suppresses Th17 cells and osteoclast differentiation and ameliorates experimental autoimmune arthritis mice. Immunol Lett. 2015;166(2):92-102.
34. Kim H-R, Kim B-M, Won J-Y, Lee K-A, Ko HM, Kang YS, et al. Quercetin, a plant polyphenol, has potential for the prevention of bone destruction in rheumatoid arthritis. J Med Food. 2019;22(2):152-61.
35. Nakagawa S, Arai Y, Mazda O, Kishida T, Takahashi KA, Sakao K, et al. N‐acetylcysteine prevents nitric
oxide‐induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis. J
Orthop Res. 2010;28(2):156-63.
36. Roman-Blas JA, Contreras-Blasco MA, Largo R, Alvarez-Soria MA, Castaneda S, Herrero-Beaumont G.
Differential effects of the antioxidant N-acetylcysteine on the production of catabolic mediators in IL-1β-stimulated human osteoarthritic synoviocytes and chondrocytes. Eur J Pharmacol. 2009;623(1-3):125-31.
37. Remans P, Zuijderduin W, Levahrt N, Schuitemaker J, Tak P, Breedveld F, et al. High dose intravenous Nacetyl- L-cysteine (NAC) therapy in rheumatoid arthritis, results from a pilot study. Role of reactive oxygen species in rheumatoid arthritis synovial t lymphocytes. 1997:97.
38. Jonsson H, Wollheim F, Svensson B. No effect of acetylcystein on refractory rheumatoid arthritis. Clin Exp
Rheumatol. 1986;4(4):363-4.
39. Batooei M, Tahamoli-Roudsari A, Basiri Z, Yasrebifar F, Shahdoust M, Eshraghi A, 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.
40. Truini A, Piroso S, Pasquale E, Notartomaso S, Stefano GD, Lattanzi R, et al. N-acetyl-cysteine, a drug that enhances the endogenous activation of group-II metabotropic glutamate receptors, inhibits nociceptive
transmission in humans. Mol Pain. 2015;11:s12990-015- 0009-2.
41. Amini Y, Moloudi R, Izadpanah E, Hassanzadeh K. NAcetylcysteine Provides Analgesic Effect in Rats. J
Isfahan Med Sch. 2013;31(257):140-9.
42. Ozcamdalli M, Misir A, Kizkapan TB, Uzun E, Duygulu F, Yazici C, et al. Comparison of intra-articular injection of hyaluronic acid and N-acetyl cysteine in the treatment of knee osteoarthritis: A pilot study. Cartilage. 2017;8(4):384-90.
43. Hashemi G, Mirjalili M, Basiri Z, Tahamoli-Roudsari A, Kheiripour N, Shahdoust M, et al. A pilot study to
evaluate the effects of oral N-acetyl cysteine on inflammatory and oxidative stress biomarkers in
rheumatoid arthritis. Curr Rheumatol Rev. 2019;15(3):246-53.
44. 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.
45. Nascimento MM, Suliman ME, Silva M, Chinaglia T, Marchioro J, Hayashi SY, et al. Effect of oral Nacetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo-controlled study. Peritoneal dialysis international. 2010;30(3):336-42.
46. Mahmoud K, Ammar A. Effect of N‐acetylcysteine on cardiac injury and oxidative stress after abdominal aortic aneurysm repair: A randomized controlled trial. Acta Anaesthesiol Scand. 2011;55(8):1015-21.
2. Koda-Kimble MA. Koda-Kimble and Young's applied therapeutics: the clinical use of drugs: Lippincot
Williams & Wilkins; 2012.
3. Bahadori S, Salamzadeh J, Kamalinejad M, Ardekani MRS, Keshavarz M, Ahmadzadeh A. Study of the Effect
of an Oral Formulation of Fig and Olive on Rheumatoid Arthritis (RA) Remission Indicators: A Randomized
Clinical Trial. Iran J Pharm Res. 2016;15(3):537-9.
4. Cutolo M, Kitas GD, van Riel PL, editors. Burden of disease in treated rheumatoid arthritis patients: going
beyond the joint. Semin Arthritis Rheum. 43(4):479-88.
5. Noack M, Miossec P, editors. Selected cytokine pathways in rheumatoid arthritis. Semin Immunopathol.
2017;39(4):363-5.
6. Eastgate J, Wood N, Di Giovine F, Symons J, Grinlinton F, Duff G. Correlation of plasma interleukin 1 levels with disease activity in rheumatoid arthritis. Lancet. 1988;332(8613):706-9.
7. Bazzazi H, Aghaei M, Memarian A, Asgarian-Omran H Behnampour N, Yazdani Y. Th1-Th17 ratio as a new
insight in rheumatoid arthritis disease. Iran J Allergy Asthma Immunol. 2018:68-77.
8. Van Den Berg WB, Miossec P. IL-17 as a future therapeutic target for rheumatoid arthritis. Nat Rev Rheumatol. 2009;5(10):549-53.
9. Kay J, Calabrese L. The role of interleukin-1 in the pathogenesis of rheumatoid arthritis. Rheumatology.
2004;43(suppl_3):iii2-iii9.
10. Singh JA, Furst DE, Bharat A, Curtis JR, Kavanaugh AF Kremer JM, et al. 2012 update of the 2008 American
College of Rheumatology recommendations for the use of disease‐modifying antirheumatic drugs and biologic
agents in the treatment of rheumatoid arthritis. Arthritis care Res. 2012;64(5):625-39.
11. Soeken K, Miller S, Ernst E. Herbal medicines for the treatment of rheumatoid arthritis: a systematic review. Rheumatology. 2003;42(5):652-9.
12. Van Vugt RM, Rijken PJ, Rietveld AG, Van Vugt AC, Dijkmans BA. Antioxidant intervention in rheumatoid
arthritis: results of an open pilot study. J Clin Rheumatol. 2008;27(6):771-5.
13. Oliver J, Silman A. Risk factors for the development of rheumatoid arthritis. Scand J Rheumatol. 2006;35(3):169- 74.
14. Ravipati AS, Zhang L, Koyyalamudi SR, Jeong SC, Reddy N, Bartlett J, et al. Antioxidant and anti-inflammatory activities of selected Chinese medicinal plants and their relation with antioxidant content. BMC
Complement Altern Med. 2012;12(1):1-14.
15. Mokhtari V, Afsharian P, Shahhoseini M, Kalantar SM, Moini A. A review on various uses of N-acetyl cysteine. Cell J. 2017;19(1):11-9.
16. Holdiness MR. Clinical pharmacokinetics of Nacetylcysteine. Clin Pharmacokinet. 1991;20(2):123-34.
17. 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.
18. Pena LR, Hill DB, McClain CJ. Treatment with glutathione precursor decreases cytokine activity. J
Parenter Enteral Nutr. 1999;23(1):1-6.
19. Kim H-R, Kim K-W, Kim B-M, Lee K-A, Lee S-H. Nacetyl- l-cysteine controls osteoclastogenesis through
regulating Th17 differentiation and RANKL in rheumatoid arthritis. Korean J Intern Med. 2019;34(1):210-9.
20. Zafarullah M, Li W, Sylvester J, Ahmad M. Molecular mechanisms of N-acetylcysteine actions. Cell Molec Life Sci CMLS. 2003;60(1):6-20.
21. Funovits J, Aletaha D, Bykerk V, Combe B, Dougados M, Emery P, et al. The 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for rheumatoid arthritis:
methodological report phase I. Ann Rheum Dis. 2010;69(9):1589-95.
22. Anderson J, Caplan L, Yazdany J, Robbins ML, Neogi T, Michaud K, et al. Rheumatoid arthritis disease activity measures: American College of Rheumatology recommendations for use in clinical practice. Arthritis
Care Res. 2012;64(5):640-7.
23. Bahadori S, Ahmadzadeh A, Ardekani MRS, Kamalinejad M, Keshavarz M, Salamzadeh J. Does regular use of a complementary medicine of Olea Europe and Ficus carica have adverse effects on lipid profile and
fasting blood glucose of Rheumatoid Arthritis (RA) patients under treatment with DMARD regimens
containing methotrexate? Iran J Pharm Res. 2016;15(4):933-9.
24. Magyari L, Varszegi D, Kovesdi E, Sarlos P, Farago B, Javorhazy A, et al. Interleukins and interleukin receptors in rheumatoid arthritis: Research, diagnostics and clinical implications. World J Orthop. 2014;5(4):516-8.
25. Joosten LA, Radstake TR, Lubberts E, van den Bersselaar LA, van Riel PL, van Lent PL, et al. Association of interleukin‐18 expression with enhanced levels of both interleukin‐1β and tumor necrosis factor α in knee synovial tissue of patients with rheumatoid arthritis. Arthritis Rheum. 2003;48(2):339-47.
26. Dayer J-M, de Rochemonteix B, Burrus B, Demczuk S, Dinarello CA. Human recombinant interleukin 1
stimulates collagenase and prostaglandin E2 production by human synovial cells. J Clin Invest. 1986;77(2):645-8.
27. Cho MR. Targeting interleukin-17 and Th17 in immune inflammatory diseases. Hanyang Med Rev.
2013;33(1):17-26.
28. Pavlovic V, Dimic A, Milenkovic S, Krtinic D. Serum levels of IL-17, IL-4, and INFγ in Serbian patients with early rheumatoid arthritis. J Res Med Sci. 2014;19(1):18- 21.
29. Espersen G, Lervang H, Nielsen G, Thomsen B, Faarvang K, Dyerberg J, et al. Decreased interleukin-1
beta levels in plasma from rheumatoid arthritis patients after dietary supplementation with n-3 polyunsaturated fatty acids. J Clin Rheumatol. 1992;11(3):393-5.
30. Huang S, Wei JC, Wu D, Huang Y. Vitamin B 6 supplementation improves pro-inflammatory responses in
patients with rheumatoid arthritis. Eur J Clin Nutr. 2010;64(9):1007-13.
31. Abdollahzad H, Aghdashi MA, Jafarabadi MA, 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.
32. Veselinovic M, Vasiljevic D, Vucic V, Arsic A, Petrovic S, Tomic-Lucic A, et al. Clinical benefits of n-3 PUFA and ɤ-linolenic acid in patients with rheumatoid arthritis. Nutrients. 2017;9(4):325-9.
33. Jhun J, Lee SH, Byun J-K, Jeong J-H, Kim E-K, Lee J, et al. Coenzyme Q10 suppresses Th17 cells and osteoclast differentiation and ameliorates experimental autoimmune arthritis mice. Immunol Lett. 2015;166(2):92-102.
34. Kim H-R, Kim B-M, Won J-Y, Lee K-A, Ko HM, Kang YS, et al. Quercetin, a plant polyphenol, has potential for the prevention of bone destruction in rheumatoid arthritis. J Med Food. 2019;22(2):152-61.
35. Nakagawa S, Arai Y, Mazda O, Kishida T, Takahashi KA, Sakao K, et al. N‐acetylcysteine prevents nitric
oxide‐induced chondrocyte apoptosis and cartilage degeneration in an experimental model of osteoarthritis. J
Orthop Res. 2010;28(2):156-63.
36. Roman-Blas JA, Contreras-Blasco MA, Largo R, Alvarez-Soria MA, Castaneda S, Herrero-Beaumont G.
Differential effects of the antioxidant N-acetylcysteine on the production of catabolic mediators in IL-1β-stimulated human osteoarthritic synoviocytes and chondrocytes. Eur J Pharmacol. 2009;623(1-3):125-31.
37. Remans P, Zuijderduin W, Levahrt N, Schuitemaker J, Tak P, Breedveld F, et al. High dose intravenous Nacetyl- L-cysteine (NAC) therapy in rheumatoid arthritis, results from a pilot study. Role of reactive oxygen species in rheumatoid arthritis synovial t lymphocytes. 1997:97.
38. Jonsson H, Wollheim F, Svensson B. No effect of acetylcystein on refractory rheumatoid arthritis. Clin Exp
Rheumatol. 1986;4(4):363-4.
39. Batooei M, Tahamoli-Roudsari A, Basiri Z, Yasrebifar F, Shahdoust M, Eshraghi A, 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.
40. Truini A, Piroso S, Pasquale E, Notartomaso S, Stefano GD, Lattanzi R, et al. N-acetyl-cysteine, a drug that enhances the endogenous activation of group-II metabotropic glutamate receptors, inhibits nociceptive
transmission in humans. Mol Pain. 2015;11:s12990-015- 0009-2.
41. Amini Y, Moloudi R, Izadpanah E, Hassanzadeh K. NAcetylcysteine Provides Analgesic Effect in Rats. J
Isfahan Med Sch. 2013;31(257):140-9.
42. Ozcamdalli M, Misir A, Kizkapan TB, Uzun E, Duygulu F, Yazici C, et al. Comparison of intra-articular injection of hyaluronic acid and N-acetyl cysteine in the treatment of knee osteoarthritis: A pilot study. Cartilage. 2017;8(4):384-90.
43. Hashemi G, Mirjalili M, Basiri Z, Tahamoli-Roudsari A, Kheiripour N, Shahdoust M, et al. A pilot study to
evaluate the effects of oral N-acetyl cysteine on inflammatory and oxidative stress biomarkers in
rheumatoid arthritis. Curr Rheumatol Rev. 2019;15(3):246-53.
44. 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.
45. Nascimento MM, Suliman ME, Silva M, Chinaglia T, Marchioro J, Hayashi SY, et al. Effect of oral Nacetylcysteine treatment on plasma inflammatory and oxidative stress markers in peritoneal dialysis patients: a placebo-controlled study. Peritoneal dialysis international. 2010;30(3):336-42.
46. Mahmoud K, Ammar A. Effect of N‐acetylcysteine on cardiac injury and oxidative stress after abdominal aortic aneurysm repair: A randomized controlled trial. Acta Anaesthesiol Scand. 2011;55(8):1015-21.
| Files | ||
| Issue | Vol 20 No 5 (2021) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v20i5.7407 | |
| Keywords | ||
| Acetylcysteine Cytokines Rheumatoid arthritis | ||
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How to Cite
1.
Jamali F, Ahmadzadeh A, Sahraei Z, Salamzadeh J. Study of the Effects of N-acetylcysteine on Inflammatory Biomarkers and Disease Activity Score in Patients with Rheumatoid Arthritis. Iran J Allergy Asthma Immunol. 2021;20(5):574-583.
