IL-6 inhibition improves nitric oxide in rheumatoid arthritis

Authors

  • Jaspreet Kaur Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab.
  • Ashit Syngle Director, Cardio-Rheuma & Healing Touch City Clinic, Chandigarh & Senior Consultant Physician and Rheumatologist, Fortis Hospital, Mohali, Punjab.
  • Pawan Krishan Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab
  • Kanchan Vohra Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab
  • Nidhi Garg Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab
  • Ladbans Kaur Consultant Radiologist, Prime Diagnostics, Chandigarh
  • Monica Chhabra Consultant Radiologist, Fortis Multispecialty Hospital, Mohali, Punjab

DOI:

https://doi.org/10.15305/ijrci/v2i1/78

Keywords:

Serum nitrite, Endothelial dysfunction, Rheumatoid Arthritis, Tocilizumab, IL-6 antagonist.

Abstract

Aim

To investigate the serum nitrite levels in patients with active rheumatoid arthritis (RA) after treatment with tocilizumab, an IL-6 antagonist, and to correlate between inflammatory disease activity measures and endothelial dysfunction.

Materials and methods

Eleven anti-IL-6-naive RA patients with high disease activity (DAS28 >5.1) were investigated. Inflammatory disease activity (DAS28 and HAQ-DI scores, ESR and CRP), serum nitrite concentration and flow mediated dilation (FMD) of the brachial artery were measured before and after 12 weeks of therapy with tocilizumab 8mg/kg intravenous infusion every 4 weeks. Serum nitrite levels and FMD were also estimated in 10 age- and sex- matched healthy controls.

Results

Serum nitrite levels in RA patients at baseline were significantly higher when compared to healthy volunteers (P <0.01). Level of serum nitrite significantly decreased (P <0.001), inflammatory disease activity measures and FMD significantly improved (P <0.001) after treatment. There was a significant correlation of serum nitrite with FMD, CRP, and DAS 28 both at baseline (P <0.05) and after 12 weeks therapy (P <0.05).

Conclusion

Nitrite production is enhanced to a greater extent in patients with RA compared to controls. Reduction in nitrite level after treatment is associated with the improvement in disease activity and endothelial dysfunction. Serum nitrite level may serve as a good predictor of both inflammatory disease activity and response to therapy in RA.

 

References

Van Leuven SI, Franssen R, Kastelein JJ, Levi M, Stroes ESG, Tak PP. Systemic inflammation as a risk factor for atherothrombosis. Rheumatology (Oxford). 2008 Jan;47(1):3–7.

Taylor PC. Serum vascular markers and vascular imaging in assessment of rheumatoid arthritis disease activity and response to therapy. Rheumatology. 2005 Jun 1;44(6):721–8.

Del Rincón ID, Williams K, Stern MP, Freeman GL, Escalante A. High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors. Arthritis Rheum. 2001 Dec;44(12):2737–45.

Sattar N, McCarey DW, Capell H, McInnes IB. Explaining How “High-Grade” Systemic Inflammation Accelerates Vascular Risk in Rheumatoid Arthritis. Circulation. 2003 Dec 16;108(24):2957–63.

Endemann DH, Schiffrin EL. Endothelial Dysfunction. JASN. 2004 Aug 1;15(8):1983–92.

FischerP, Hilfiker-Kleiner D. Survival pathways in hypertrophy and heart failure: The gp130-STAT3 axis. Basic Res. Cardiol. 2007;102:393–411.

Cesari M, Penninx BWJH, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation. 2003 Nov 11;108(19):2317–22.

Peters MJL, Symmons DPM, McCarey D, Dijkmans BAC, Nicola P, Kvien TK, et al. EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. Ann Rheum Dis. 2010 Feb;69(2):325–31.

Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, Vazquez-Rodriguez TR, Miranda-Filloy JA, Gonzalez-Juanatey C, et al. Short-term effect of anti-TNF-alpha therapy on nitric oxide production in patients with severe rheumatoid arthritis. Clin Exp Rheumatol. 2009 Jun;27(3):452–8.

Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2010 Sep 1;69(9):1580–8.

Koike R, Harigai M, Atsumi T, Amano K, Kawai S, Saito K, et al. Japan College of Rheumatology 2009 guidelines for the use of tocilizumab, a humanized anti-interleukin-6 receptor monoclonal antibody, in rheumatoid arthritis. Mod Rheumatol. 2009;19(4):351–7.

Van Gestel AM, Prevoo ML, van ’t Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum. 1996 Jan;39(1):34–40.

Kumar A, Malaviya AN, Pandhi A, Singh R. Validation of an Indian version of the Health Assessment Questionnaire in patients with rheumatoid arthritis. Rheumatology (Oxford). 2002;41:1457–9.

ClancyMC, AminAR, AbramsonSB. The role of nitric oxide in inflammation and immunity.Arthritis Rheum.1998;41:1141-51.

Knight TM, Forman D, Al-Dabbagh SA, Doll R. Estimation of dietary intake of nitrate and nitrite in Great Britain. Food Chem Toxicol. 1987 Apr;25(4):277–85.

Sastry KVH, Moudgal RP, Mohan J, Tyagi JS, Rao GS. Spectrophotometric determination of serum nitrite and nitrate by copper-cadmium alloy. Anal Biochem. 2002 Jul 1;306(1):79–82.

Himeno M, Ishibashi T, Nakano S, Furuya K, Kigoshi T, Uchida K, et al. A practical procedure for achieving a steady state of NOx concentration in plasma: with special reference to the NOx content of Japanese daily food. Tohoku J Exp Med. 2003 Feb;199(2):95–110.

Hürlimann D, Forster A, Noll G, Enseleit F, Chenevard R, Distler O, et al. Anti-tumor necrosis factor-alpha treatment improves endothelial function in patients with rheumatoid arthritis. Circulation. 2002 Oct 22;106(17):2184–7.

Nagy G, Koncz A, Telarico T, Fernandez D, Ersek B, Buzás E, et al. Central role of nitric oxide in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus. Arthritis Res Ther. 2010;12(3):210.

Saura M, Zaragoza C, Bao C, Herranz B, Rodriguez-Puyol M, Lowenstein CJ. Stat3 Mediates Interelukin-6 Inhibition of Human Endothelial Nitric-oxide Synthase Expression. J Biol Chem. 2006 Oct 6;281(40):30057–62.

Vila E, Salaices M. Cytokines and Vascular reactivity in resistance arteries. Am. J. Physiol. Heart Circ. Physiol.2005;288: H1016-H1021.

Wassmann S, Stumpf M, Strehlow K, Schmid A, Schieffer B, Böhm M, et al. Interleukin-6 induces oxidative stress and endothelial dysfunction by overexpression of the angiotensin II type 1 receptor. Circ Res. 2004 Mar 5;94(4):534–41.

Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, et al. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone. J Clin Invest. 1996 Apr 15;97(8):1916–23.

Didion SP, Kinzenbaw DA, Faraci FM. Critical role for CuZn-superoxide dismutase in preventing angiotensin II-induced endothelial dysfunction. Hypertension. 2005;46:1147-1153.

Hou T, Tieu BC, Ray S, Recinos III A, Cui R, Tilton RG, et al. Roles of IL-6-gp130 Signaling in Vascular Inflammation. Curr Cardiol Rev. 2008 Aug;4(3):179–92.

Ersoy Y, Ozerol E, Baysal O, Temel I, MacWalter RS, Meral U, et al. Serum nitrate and nitrite levels in patients with rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. Ann Rheum Dis. 2002 Jan;61(1):76–8.

Syngle A, Vohra K, Kaur L, Sharma S. Effect of spironolactone on endothelial dysfunction in rheumatoid arthritis.Scan J Rheumatol. 2009;38:15-22.

Farrell AJ, Blake DR, Palmer RM, Moncada S. Increased concentrations of nitrite in synovial fluid and serum samples suggest increased nitric oxide synthesis in rheumatic diseases.Ann. Rheum. Dis.1992;51:1219-1222.

Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet. 2008 Mar 22;371(9617):987–97.

Gabay C, Emery P, van Vollenhoven R, Dikranian A, Alten R, Pavelka K, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. The Lancet. 2013 May;381(9877):1541–50.

Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50:1761–1769.

Venugopal SK, Devaraj S, Yuhanna I, Shaul P, Jialal I. Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells. Circulation. 2002 Sep 17;106(12):1439–41.

Pasceri V, Cheng JS, Willerson JT, Yeh ET, Chang J. Modulation of C-reactive protein-mediated monocyte chemoattractant protein-1 induction in human endothelial cells by anti-atherosclerosis drugs. Circulation. 2001 May 29;103(21):2531–4.

Syngle A, Vohra K, Garg N, Kaur L, Chand P. Advanced glycation end products inhibition improves endothelial dysfunction in rheumatoid arthritis.Int J Rheum Dis. 2012;15:45–55.

Protogerou AD, Zampeli E, Fragiadaki K, Stamatelopoulos K, Papamichael C, Sfikakis PP. A pilot study of endothelial dysfunction and aortic stiffness after interleukin-6 receptor inhibition in rheumatoid arthritis. Atherosclerosis. 2011 Dec;219(2):734–6.

Nishimoto N, Hashimoto J, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, et al. Study of active controlled monotherapy used for rheumatoid arthritis, an IL-6 inhibitor (SAMURAI): evidence of clinical and radiographic benefit from an x ray reader-blinded randomised controlled trial of tocilizumab. Ann Rheum Dis. 2007 Sep;66(9):1162–7.

Genovese MC, McKay JD, Nasonov EL, Mysler EF, da Silva NA, Alecock E, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease-modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum. 2008 Oct;58(10):2968–80.

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Published

27-05-2014

Issue

Vol. 2 No. 1 (2014)

Section

Original Articles

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