New possibilities of drug therapy for rheumatoid arthritis: focus at sarilumab

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Abstract

Rheumatoid arthritis (RA) is one of the most prevalent autoimmune diseases in humans and is a serious medical and social problem in the Russian Federation. Current synthetic and biological agents acting through specific molecular targets, play a significant role in the treatment of RA. Over the last few years, inhibitors of the biological effects of interleukin-6 (IL-6) have attracted increasing attention, being positioned as the first choice agents among the biologicals, especially if there is a need in monotherapy. IL-6 is a pleiotropic cytokine with a broad range of biological effects on immune cells, such as B and T lymphocytes, on hepatocytes, hematopoietic cells, vascular endothelial cells, and many others. In this regard, IL-6 is a good therapeutic target in RA. For several years, the group of inhibitors of IL-6 biological effects has been represented by one drug only, i.e. tocilizumab. The new drug of this group, sarilumab, is a human monoclonal antibody (IgG1 subtype) to the IL-6 receptor. Sarilumab binds specifically to both soluble and membrane IL-6 receptors (IL-6Rα), and inhibits IL-6-mediated signal transduction involving signal protein glycoprotein 130 (gp130) and signal proteins STAT-3. There is evidence that sarilumab has a higher affinity to the IL-6 receptor, and binds the receptor in a more stable manner than tocilizumab. Sarilumab has been approved for treatment of RA with moderate or high activity in adult patients with inadequate response or intolerability to one or several synthetic basic drugs, at a dose 150 mg or 200 mg subcutaneously biweekly in combination with methotrexate (MTX). It also can be prescribed as monotherapy in case of MTX intolerability or if treatment with MTX is inexpedient. Sarilumab is a highly active therapeutic agent with proven superiority in monotherapy over adalimumab. Therefore, sarilumab can be positioned as a first line biological agent in patients with high inflammatory activity, as well as in those resistant to tumor necrosis factor-α inhibitors. The safety profile of sarilumab is similar to that of tocilizumab; probably there is a slightly higher risk of neutropenia, but a lower risk of dyslipidemia, reactions at the injection site and gastrointestinal perforation for sarilumab than for tocilizumab.

About the authors

D. E. Karateev

Moscow Regional Research and Clinical Institute (MONIKI)

Author for correspondence.
Email: dekar@inbox.ru
ORCID iD: 0000-0002-2352-4080

Dmitry E. Karateev – MD, PhD, Head of Department of Rheumatology; Professor, Chair of Therapy, Postgraduate Training Faculty

61/2 Shchepkina ul., Moscow, 129110

Россия

E. L. Luchikhina

Moscow Regional Research and Clinical Institute (MONIKI)

Email: eleluch@yandex.ru
ORCID iD: 0000-0002-6519-1106

Elena L. Luchikhina – MD, PhD, Leading Research Fellow, Department of Rheumatology; Associate Professor, Chair of Therapy, Postgraduate Training Faculty

61/2 Shchepkina ul., Moscow, 129110

Россия

References

  1. Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH; National Arthritis Data Workgroup. Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum. 2008;58(1): 15– 25. doi: 10.1002/art.23177.
  2. Насонов ЕЛ, Каратеев ДЕ. Ревматоидный артрит. В: Насонов ЕЛ, ред. Российские клинические рекомендации. Ревматология. М.: ГЭОТАР-Медиа; 2017. 464 с.
  3. Pedersini R, Karateev DE, Vasilescu RS, Alvir JM, Spurden D, Smolen JS. The burden of rheumatoid arthritis in Russia. Value Health. 2015;18(7):A651. doi: 10.1016/j.jval.2015.09.2344.
  4. Smolen JS, Landewe R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, Nam J, Ramiro S, Voshaar M, van Vollenhoven R, Aletaha D, Aringer M, Boers M, Buckley CD, Buttgereit F, Bykerk V, Cardiel M, Combe B, Cutolo M, van Eijk-Hustings Y, Emery P, Finckh A, Gabay C, Gomez-Reino J, Gossec L, Gottenberg JE, Hazes JMW, Huizinga T, Jani M, Karateev D, Kouloumas M, Kvien T, Li Z, Mariette X, McInnes I, Mysler E, Nash P, Pavelka K, Poor G, Richez C, van Riel P, Rubbert-Roth A, Saag K, da Silva J, Stamm T, Takeuchi T, Westhovens R, de Wit M, van der Heijde D. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6): 960–77. doi: 10.1136/annrheumdis-2016-210715.
  5. Насонов ЕЛ, Каратеев ДЕ. Применение генно-инженерных биологических препаратов для лечения ревматоидного артрита: общая характеристика (лекция). Научно-практическая ревматология. 2013;51(2): 163–9. doi: 10.14412/1995-4484-2013-645.
  6. Панасюк ЕЮ, Амирджанова ВН, Александрова ЕН, Губарь ЕГ, Лукина ГВ, Лучихина ЕЛ, Цветкова ЕС, Гавва ТН, Федоренко ЕФ, Авдеева АС, Климова НВ, Насонов ЕЛ. Быстрый эффект тоцилизумаба при ревматоидном артрите. Научно-практическая ревматология. 2011;49(4): 11–6. doi: 10.14412/19954484-2011-55.
  7. Pascart T, Philippe P, Drumez E, Deprez X, Cortet B, Duhamel A, Houvenagel E, Flipo RM. Comparative efficacy of tocilizumab, abatacept and rituximab after non-TNF inhibitor failure: results from a multicentre study. Int J Rheum Dis. 2016;19(11): 1093–102. doi: 10.1111/1756-185X.12845.
  8. Gottenberg JE, Morel J, Perrodeau E, Bardin T, Combe B, Dougados M, Flipo RM, Saraux A, Schaeverbeke T, Sibilia J, Soubrier M, Vittecoq O, Baron G, Constantin A, Ravaud P, Mariette X; French Society of Rheumatology and the investigators participating in AIR, ORA, and REGATE registries. Comparative effectiveness of rituximab, abatacept, and tocilizumab in adults with rheumatoid arthritis and inadequate response to TNF inhibitors: prospective cohort study. BMJ. 2019;364:l67. doi: 10.1136/bmj.l67.
  9. Kang S, Tanaka T, Kishimoto T. Therapeutic uses of anti-interleukin-6 receptor antibody. Int Immunol. 2015;27(1): 21–9. doi: 10.1093/intimm/dxu081.
  10. Wong PK, Campbell IK, Egan PJ, Ernst M, Wicks IP. The role of the interleukin-6 family of cytokines in inflammatory arthritis and bone turnover. Arthritis Rheum. 2003;48(5): 1177– 89. doi: 10.1002/art.10943.
  11. Chung SJ, Kwon YJ, Park MC, Park YB, Lee SK. The correlation between increased serum concentrations of interleukin-6 family cytokines and disease activity in rheumatoid arthritis patients. Yonsei Med J. 2011;52(1): 113–20. doi: 10.3349/ymj.2011.52.1.113.
  12. Kotake S, Sato K, Kim KJ, Takahashi N, Udagawa N, Nakamura I, Yamaguchi A, Kishimoto T, Suda T, Kashiwazaki S. Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J Bone Miner Res. 1996;11(1): 88–95. doi: 10.1002/jbmr.5650110113.
  13. Avci AB, Feist E, Burmester GR. Biologicals in rheumatoid arthritis: current and future. RMD Open. 2015;1(1):e000127. doi: 10.1136/rmdopen2015-000127.
  14. Scott LJ. Tocilizumab: A Review in Rheumatoid Arthritis. Drugs. 2017;77(17): 1865–79. doi: 10.1007/s40265-017-0829-7.
  15. Emery P, Keystone E, Tony HP, Cantagrel A, van Vollenhoven R, Sanchez A, Alecock E, Lee J, Kremer J. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebocontrolled trial. Ann Rheum Dis. 2008;67(11): 1516–23. doi: 10.1136/ard.2008.092932.
  16. Панасюк ЕЮ, Амирджанова ВН, Авдеева АС, Лучихина ЕЛ, Александрова ЕН, Новиков АА, Насонов ЕЛ. Опыт применения тоцилизумаба у больных ревматоидным артритом (по данным многоцентрового исследования ЛОРНЕТ). Научно-практическая ревматология. 2013;51(2): 104–10. doi: 10.14412/1995-4484-2013-635.
  17. Lauper K, Nordstrom DC, Pavelka K, Hernandez MV, Kvien TK, Kristianslund EK, Santos MJ, Rotar Ž, Iannone F, Codreanu C, Lukina G, Gale SL, Sarsour K, Luder Y, Courvoisier DS, Gabay C. Comparative effectiveness of tocilizumab versus TNF inhibitors as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis after the use of at least one biologic disease-modifying antirheumatic drug: analyses from the pan-European TOCERRA register collaboration. Ann Rheum Dis. 2018;77(9): 1276–82. doi: 10.1136/annrheumdis-2017-212845.
  18. Инструкция по применению препарата Кевзара [Интернет]. Доступно на: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=5b781c69-9631-4661-87a4-3b3bd96a20d9&t=.
  19. Инструкция по применению препарата Актемра [Интернет]. Доступно на: https://grls.rosminzdrav.ru/Grls_View_v2.aspx?routingGuid=968b8fda-c0ba-46c8-8913-c4b5d92f6941&t=.
  20. McCarty D, Robinson A. Efficacy and safety of sarilumab in patients with active rheumatoid arthritis. Ther Adv Musculoskelet Dis. 2018;10(3): 61–7. doi: 10.1177/1759720X17752037.
  21. Huizinga TW, Fleischmann RM, Jasson M, Radin AR, van Adelsberg J, Fiore S, Huang X, Yancopoulos GD, Stahl N, Genovese MC. Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY Part A trial. Ann Rheum Dis. 2014;73(9): 1626–34. doi: 10.1136/annrheumdis-2013-204405.
  22. Rafique A, Martin J, Blome M, Huang T, Ouyang A, Papadopoulos N. AB0037 Evaluation of the binding kinetics and functional bioassay activity of sarilumab and tocilizumab to the human il-6 receptor (il-6r) alpha. Ann Rheum Dis. 2014;72 Suppl 3:A797. doi: 10.1136/annrheumdis-2013-eular.2360.
  23. Xu C, Nolain P, Lu Q, Paccaly A, Iglesias-Rodriguez M, St John G, Nivens C, Maldonado R, Ishii T, Choy E, Kanamaluru V. FRI0106 Sarilumab and tocilizumab receptor occupancy (RO), and effects on C-reactive protein (CRP) levels, in patients with rheumatoid arthritis (RA). Ann Rheum Dis. 2019;78:719–20. doi: 10.1136/annrheumdis2019-eular.3324.
  24. European Medicines Agency. Committee for Medicinal Products for Human Use (CHMP). Assessment report. Kevzara. International non-proprietary name: sarilumab [Internet]. Available from: https://www.ema.europa.eu/en/documents/assessment-report/kevzara-epar-public-assessment-report_en.pdf.
  25. Boyce EG, Rogan EL, Vyas D, Prasad N, Mai Y. Sarilumab: Review of a Second IL-6 Receptor Antagonist Indicated for the Treatment of Rheumatoid Arthritis. Ann Pharmacother. 2018;52(8): 780–91. doi: 10.1177/1060028018761599.
  26. Raimondo MG, Biggioggero M, Crotti C, Becciolini A, Favalli EG. Profile of sarilumab and its potential in the treatment of rheumatoid arthritis. Drug Des Devel Ther. 2017;11:1593– 603. doi: 10.2147/DDDT.S100302.
  27. Genovese MC, Fleischmann R, Kivitz AJ, Rell-Bakalarska M, Martincova R, Fiore S, Rohane P, van Hoogstraten H, Garg A, Fan C, van Adelsberg J, Weinstein SP, Graham NM, Stahl N, Yancopoulos GD, Huizinga TW, van der Heijde D. Sarilumab Plus Methotrexate in Patients With Active Rheumatoid Arthritis and Inadequate Response to Methotrexate: Results of a Phase III Study. Arthritis Rheumatol. 2015;67(6): 1424–37. doi: 10.1002/art.39093.
  28. Strand V, Kosinski M, Chen CI, Joseph G, RendasBaum R, Graham NM, van Hoogstraten H, Bayliss M, Fan C, Huizinga T, Genovese MC. Sarilumab plus methotrexate improves patientreported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther. 2016;18:198. doi: 10.1186/s13075-016-1096-9.
  29. Насонов ЕЛ, Станислав МЛ, Раскина ТА, Куропаткин ГВ, Ширинский ИВ, Ребров АП, Шостак НА, Алиханов БА, Ушакова ЕН, Камалова РГ, Смакотина СА, Симаненков ВИ, Повзун АС, Захарьян ИИ, Якушин СС, Сандин МЮ. Эффективность и безопасность сарилумаба в комбинации с метотрексатом у пациентов с активным ревматоидным артритом и неадекватным эффектом монотерапии метотрексатом (результаты исследования III фазы по протоколу MOBILITY). Научно-практическая ревматология. 2019;57(2): 142–8. doi: 10.14412/1995-44842019-142-148.
  30. Boyapati A, Msihid J, Fiore S, van Adelsberg J, Graham NM, Hamilton JD. Sarilumab plus methotrexate suppresses circulating biomarkers of bone resorption and synovial damage in patients with rheumatoid arthritis and inadequate response to methotrexate: a biomarker study of MOBILITY. Arthritis Res Ther. 2016;18(1): 225. doi: 10.1186/s13075-016-1132-9.
  31. Fleischmann R, van Adelsberg J, Lin Y, CastelarPinheiro GD, Brzezicki J, Hrycaj P, Graham NM, van Hoogstraten H, Bauer D, Burmester GR. Sarilumab and Nonbiologic Disease-Modifying Antirheumatic Drugs in Patients With Active Rheumatoid Arthritis and Inadequate Response or Intolerance to Tumor Necrosis Factor Inhibitors. Arthritis Rheumatol. 2017;69(2): 277–90. doi: 10.1002/art.39944.
  32. Gabay C, Msihid J, Zilberstein M, Paccard C, Lin Y, Graham NMH, Boyapati A. Identification of sarilumab pharmacodynamic and predictive markers in patients with inadequate response to TNF inhibition: a biomarker substudy of the phase 3 TARGET study. RMD Open. 2018;4(1):e000607. doi: 10.1136/rmdopen2017-000607.
  33. Burmester GR, Lin Y, Patel R, van Adelsberg J, Mangan EK, Graham NM, van Hoogstraten H, Bauer D, Ignacio Vargas J, Lee EB. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5): 840–7. doi: 10.1136/annrheumdis2016-210310.
  34. Strand V, Gossec L, Proudfoot CWJ, Chen CI, Reaney M, Guillonneau S, Kimura T, van Adelsberg J, Lin Y, Mangan EK, van Hoogstraten H, Burmester GR. Patient-reported outcomes from a randomized phase III trial of sarilumab monotherapy versus adalimumab monotherapy in patients with rheumatoid arthritis. Arthritis Res Ther. 2018;20(1): 129. doi: 10.1186/s13075-018-1614-z.
  35. Genovese MC, van Adelsberg J, Fan C, Graham NMH, van Hoogstraten H, Parrino J, Mangan EK, Spindler A, Huizinga TWJ, van der Heijde D; EXTEND study investigators. Two years of sarilumab in patients with rheumatoid arthritis and an inadequate response to MTX: safety, efficacy and radiographic outcomes. Rheumatology (Oxford). 2018;57(8): 1423–31. doi: 10.1093/rheumatology/key121.
  36. Gossec L, Strand V, Proudfoot C, Chen CI, Guillonneau S, Kimura T, van Hoogstraten H, Mangan E, Reaney M. Effects of Sarilumab on Rheumatoid Arthritis as Reported by Patients Using the Rheumatoid Arthritis Impact of Disease Scale. J Rheumatol. 2019;46(10): 1259–67. doi: 10.3899/jrheum.180904.
  37. Kameda H, Wada K, Takahashi Y, Hagino O, van Hoogstraten H, Graham N, Tanaka Y. Sarilumab monotherapy or in combination with non-methotrexate disease-modifying antirheumatic drugs in active rheumatoid arthritis: A Japan phase 3 trial (HARUKA). Mod Rheumatol. 2019:1–10. doi: 10.1080/14397595.2019.1639939. [Epub ahead of print].
  38. Choy E, Freemantle N, Proudfoot C, Chen CI, Pollissard L, Kuznik A, Van Hoogstraten H, Mangan E, Carita P, Huynh TM. Evaluation of the efficacy and safety of sarilumab combination therapy in patients with rheumatoid arthritis with inadequate response to conventional disease-modifying antirheumatic drugs or tumour necrosis factor α inhibitors: systematic literature review and network meta-analyses. RMD Open. 2019;5(1):e000798. doi: 10.1136/rmdopen-2018-000798.
  39. Fournier M, Chen CI, Kuznik A, Proudfoot C, Mallya UG, Michaud K. Sarilumab monotherapy compared with adalimumab monotherapy for the treatment of moderately to severely active rheumatoid arthritis: an analysis of incremental cost per effectively treated patient. Clinicoecon Outcomes Res. 2019;11:117–28. doi: 10.2147/CEOR.S183076.
  40. Muszbek N, Proudfoot C, Fournier M, Chen CI, Kuznik A, Kiss Z, Gal P, Michaud K. Economic Evaluation of Sarilumab in the Treatment of Adult Patients with Moderately-to-Severely Active Rheumatoid Arthritis Who Have an Inadequate Response to Conventional Synthetic Disease-Modifying Antirheumatic Drugs. Adv Ther. 2019;36(6): 1337–57. doi: 10.1007/s12325-019-00946-1.
  41. Mahajan TD, Mikuls TR. Recent advances in the treatment of rheumatoid arthritis. Curr Opin Rheumatol. 2018;30(3): 231–7. doi: 10.1097/BOR.0000000000000496.
  42. Emery P, Rondon J, Parrino J, Lin Y, Pena-Rossi C, van Hoogstraten H, Graham NMH, Liu N, Paccaly A, Wu R, Spindler A. Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis. Rheumatology (Oxford). 2019;58(5): 849–58. doi: 10.1093/rheumatology/key361.
  43. June RR, Olsen NJ. Room for more IL-6 blockade? Sarilumab for the treatment of rheumatoid arthritis. Expert Opin Biol Ther. 2016;16(10): 1303–9. doi: 10.1080/14712598.2016.1217988.
  44. Onuora S. Rheumatoid arthritis: Sarilumab more effective than adalimumab. Nat Rev Rheumatol. 2017;13(1): 2. doi: 10.1038/nrrheum.2016.207.
  45. Lee EB. A review of sarilumab for the treatment of rheumatoid arthritis. Immunotherapy. 2018;10(1): 57–65. doi: 10.2217/imt-2017-0075.

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