EFFECT OF GOLIMUMAB ON IMMUNOLOGICAL MARKERS FOR BONE METABOLISM AND ON ARTERIAL STIFFNESS IN PATIENTS WITH RHEUMATOID ARTHRITIS

Objective: to evaluate the effect of golimumab (GLM) on the receptor activator of NF-κB ligand (RANKL)/osteoprotegerin (OPG) transmembrane molecular system and arterial stiffness in patients with rheumatoid arthritis (RA).

Subjects and methods. Thirty-six patients with RA were examined and randomized into 2 groups based on disease duration (less than or more than 2 years). The serum levels of OPG, and RANKL, were investigated. Dual-energy X-ray absorptiometry and pulse wave contour analysis were performed before and 52 weeks after GLM treatment.

Results and discussion. Group 1 patients demonstrated increased serum OPG levels that were on average 3.6 times higher than in the controls (р=0.005) and 2.1 times higher than in Group 2 (р=0.01). In Group 2 patients, the RANKL concentration was 9-fold higher than that in the controls (p=0.001) and 30.6% higher than in Group 1 (p=0.01). The examinees were found to be diagnosed with subclinical damage to the great arteries (increases in augmentation index (AIp), stiffness index (SI), and reflection (RI) index), which progressed with a longer RA duration. After GLM treatment, serum OPG and RANKL levels decreased in Group 1 patients by 2.1- (p<0.001) and 1.7-fold (p<0.01), respectively. In Group 2, the level of RANKL dropped by 32.2% (p<0.01), without significant OPG concentration changes. After GLM treatment, the pulse wave contour analysis parameters in Group 1 did not differ from those in the controls; Group 2 showed significant decreases in AIp by an average of 1.8 times (p<0.01), in SI by 1.2 times (p<0.01), and in RI by 1.6 times (p<0.01).

Conclusion. GLM treatment in RA patients is accompanied by a lower imbalance in the RANKL/OPG transmembrane molecular system and exerts a vasoprotective effect on the large elastic vessels (reductions in AIp and SI) and small muscular arteries (a decrease in RI). 

1. Firesteinb GS. Evolving concepts of rheumatoid arthritis. Nature. 2003 May 15;423(6937):356-61. doi: 10.1038/nature01661

2. Schett G, Hayer S, Zwerina J, et al. Mechanisms of disease: the link between RANKL and arthritic bone disease. Nat Clin Pract Rheumatol. 2005 Nov;1(1):47-54. doi: 10.1038/ncprheum0036

3. Alissa EM, Alnahdi WA, Alama N, et al. Bone mineral density and cardiovascular risk factors in postmenopausal women with coronary artery disease. Bonekey Rep. 2015 Nov 11;4:758. doi: 10.1038/bonekey.2015.127

4. Ye C, Xu M, Wang S, et al. Decreased Bone Mineral Density Is an Independent Predictor for the Development of Atherosclerosis: A Systematic Review and Meta-Analysis. PLoS One. 2016 May 5;11(5):e0154740. doi: 10.1371/journal.pone.0154740

5. Долженко АТ, Сагаловски С. Клеточно-молекулярные механизмы развития остеопороза: современные концепции и будущее направление терапии. Современная ревматология. 2016;10(2):56- 63 [Dolzhenko AT, Sagalovsky S. Cellular and molecular mechanisms of osteoporosis: current concepts and future direction treatment. Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2016;10(2):56-63 (In Russ.)]. doi: 10.14412/1996-7012-2016-2-56-63

6. Demer LL, Tintut J. Vascular calcification: pathobiology of a multifaceted disease. Circulation. 2008;117(22):2938-48. doi: 10.1161/CIRCULATIONAHA.107.743161

7. Lutgens SP, Cleutjens KB, Daemen MJ, Heeneman S. Cathepsin cysteine proteases in cardiovascular disease. FASEB J. 2007;21(12):3029-41. doi: 10.1096/fj.06-7924com

8. Langdahl BL. New treatment of osteoporosis. Osteoporos Sarcopenia. 2015;1(1):4-21. doi: 10.1016/j.afos.2015.07.007

9. Periard D, Folly A, Meyer MA, et al. Aortic calcification and risk of osteoporotic fractures. Rev Med Suisse. 2010;6(271):2200-3 (In French).

10. Tabas I, Garcia-Cardena G, Owens GK. Recent insights into the cellular biology of atherosclerosis. J Cell Biol. 2015;209(1):13-22. doi: 10.1083/jcb.201412052

11. Ndip A, Williams A, Jude EB, et al. The RANKL/RANK/ОПГ signaling pathway mediates medial arterial calcification in diabetic Charcot neuroarthropathy. Diabetes. 2011 Aug;60(8):2187-96. doi: 10.2337/db10-1220. Epub 2011 Jun 9.

12. Герштейн ЕС, Тимофеев ЮС, Зуев АА, Кушлинский НЕ. Лиганд-рецепторная система RANK/RANKL/ОПГ и ее роль при первичных новообразованиях костей (анализ литературы и собственные результаты). Успехи молекулярной онкологии. 2015:2(3);51-9 [Gershtein ES, Timofeev YuS, Zuev AA, Kushlinskii NE. RANK/RANKL/OPG ligand-receptor system and its role in primary bone neoplasms (literature analysis and own data). Uspekhi Molekulyarnoi Onkologii = Advances in Molecular Oncology. 2015;2(3):51-9 (In Russ.)]. doi: 10.17650/2313-805X2015-2-3-51-59

13. Дыдыкина ПС, Дыдыкина ИС, Насонов ЕЛ. Влияние терапии генно-инженерными биологическими препаратами на костную ткань больных ревматоидным артритом. Научнопрактическая ревматология. 2014;52(6):669-77 [Dydykina PS, Dydykina IS, Nasonov EL. Impact of biological therapy on bone in patients with rheumatoid arthritis. Sovremennaya Revmatologiya = Modern Rheumatology Journal. 2014;52(6):669-77 (In Russ.)]. doi: 10.14412/1995-4484-2014-669-677

14. Vis M, Havaardsholm EA, Haugeberg G, et al. Evaluation of bone mineral density, bone metabolism, osteoprotegerin and receptor activator of the NFkappaB ligand serum levels during treatment with infliximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:1495-9. doi: 10.1136/ard.2005.044198

15. Perpetuo IP, Caetano-Lopes J, Rodrigues AM, et al. Effect of Tumor Necrosis Factor Inhibitor Therapy on Osteoclasts Precursors in Rheumatoid Arthritis. Biomed Res Int. 2017;2017:2690402. doi: 10.1155/2017/2690402

16. Aguilar Del Rey FJ, Garcia Portales R, Haro Liger M, et al. Effect of tumour necrosis factor α blockade on bone metabolism in chronic inflammatory joint diseases. Med Clin (Barc). 2016 Jul 15;147(2):56-62. doi: 10.1016/j.medcli.2016.03.029

17. Князева ЛА, Мещерина НС. Влияние инфликсимаба на параметры ремоделирования артериального русла, уровень RANKL и остеопротегерина у больных ревматоидным артритом. Научно-практическая ревматология. 2013;51(6):666-70 [Knyazeva LA, Meshcherina NS. Effect of infliximab on parameters of remodeling of arterial bloodstream, RANKL and osteoprotegerin levels in patients with rheumatoid arthritis. NauchnoPrakticheskaya Revmatologiya = Rheumatology Science and Practice. 2013;51(6):666-70 (In Russ.)]. doi: 10.14412/1995-4484- 2013-666-70

18. Парфенов АС. Экспресс-диагностика сердечно-сосудистых заболеваний. Мир измерений. 2008;(6):74-82 [Parfenov AS. Express diagnostics of cardiovascular zabolevaniy. World Measurements. 2008;(6):74-82 (In Russ.)].

19. Van Tuyl LHD, Voskuyl AE, Boers M, et al. Baseline RANKL:OPG ratio and markers of bone and cartilage degradation predict annual radiological progression over 11 years in rheumatoid arthritis. Ann Rheum Dis. 2010;69:1623-8. doi: 10.1136/ard.2009.121764

20. Vik A, Mathiesen EB, Brox J, et al. Serum osteoprotegerin is a predictor for incident cardiovascular disease, and mortality in a general population: the Troms? Study. J Thromb Haemostatic. 2011;9(4):638-44. doi: 10.1111/j.153 8- 7836.2011.04222.x

21. Van Compenhout A, Golledge J. Osteoprotegerin, vascular calcification and atherosclerosis. Atherosclerosis. 2009;204(2):321-9. doi: 10.1016/j.atherosclerosis.2008.09.033

22. Caidahl K, Ueland T, Aukrust P. Osteoprotegerin: a biomarker with many faces. Atheroscler Thromb Vasc Biol. 2010;30(9):1684-6. doi: 10.1161/ATVBAHA.110.208843

23. Lieb W, Gona P, Larson MG, et al. Biomarkers of the osteoprotegerin pathway: clinical correlates, subclinical disease, incident cardiovascular disease, and mortality. Artherioscler Thromb Vasc Biol. 2010;30(9):1849-54. doi: 10.1161/ATVBAHA.109.199661

24. Townsend RR, Wilkinson IB, Schiffrin EL, et al. American Heart Association Council on Hypertension. Recommendations for Improving and Standardizing Vascular Research on Arterial Stiffness. A Scientific Statement from the American Heart Association. J Hypertension. 2015;66(3):698-722. doi: 10.1161/HYP.0000000000000033

25. Labovsky V, Vallone VB, Martinez LM, et al. Expression of osteoprotegerin, receptor activator of nuclear factor kappa-B ligand, tumor necrosis factor-related apoptosis-inducing ligand, stromal cell-derivated factor-1 and their receptors in epithelial metastatic breast cancer cell lines. Cancer Cell Internat. 2012;12(1):29. doi: 10.1186/1475-2867-12-29

26. Nelson CA, Warren JT, Wang MW, et al. RANKL employs distinct binding modes to engage RANK and the osteoprotegerin decoy receptor. Structure. 2012;20(11):1971-82. doi: 10.1016/j. str.2012.08.030

27. Kirkham BW, Wasko MC, Hsia EC, et al. Effects of golimumab, an anti-tumour necrosis factor-α human monoclonal antibody, on lipids and markers of inflammation. Ann Rheum Dis. 2014 Jan;73(1):161-9. doi: 10.1136/annrheumdis-2012-202089

28. Bathon J, Wasko MC, Kirkham B, et al. Golimumab and cardiovascular disease: carotid artery ultrasound evaluation and cardiovascular adverse events. Ann Rheum Dis. 2010;69 Suppl 3:464.

29. Wasko MC, Hsia EC, Kirkham B, et al. Effect of Golimumab on Carotid Atherosclerotic Disease Measures and Cardiovascular Events in Inflammatory Arthritides. J Clin Rheumatol. 2014 Jan;20(1):1-10. doi: 10.1097/RHU.0000000000000053