Эффективность и безопасность генно-инженерных биологических препаратов для лечения анкилозирующего спондилита: систематический обзор и метаанализ препаратов, зарегистрированных в РФ

Цель исследования — оценить сравнительную эффективность и безопасность генно-инженерных биологических препаратов (ГИБП), зарегистрированных и применяемых в терапии взрослых пациентов с активным анкилозирующим спондилитом в условиях российской системы здравоохранения.

Материал и методы. Проведен систематический поиск рандомизированных клинических исследований в базах данных PubMed, Embase и eLIBRARY.RU. 17 публикаций по 16 исследованиям были отобраны для дальнейшего анализа. Основные критерии эффективности — ASAS 20/40 после 12—16 недель терапии, дополнительные - BASDAI 50, изменение BASDAI и BASFI относительного исходного уровня.

Безопасность оценена на основе частоты возникновения нежелательных явлений; дополнительно проанализирована доля пациентов с развитием серьезных нежелательных явлений. ГИБП были проранжированы на основе значений SUCRA.

Результаты. Анализ по классам ГИБП показал отсутствие статистически значимых различий между ингибиторами ИЛ-17 и ФНО-а, однако класс ингибиторов ИЛ-17 характеризовался более высокими значениями SUCRA. По совокупности всех анализируемых показателей эффективности первые три ранга представлены нетакимабом, инфликсимабом и иксекизумабом. Профили безопасности ГИБП, включенных в обзор, не имели статистически значимых различий с между собой.

Заключение. Результаты данного обзора могут быть полезны для специалистов сферы здравоохранения при принятии решений по выбору оптимальной терапии взрослых пациентов с активным анкилозирующим спондилитом.

1. Эрдес ШФ, Бадокин ВВ, Бочкова АГ. и др. О терминологии спондилоартритов. Научно-практическая ревматология. 2015;53(6):657-660. DOI: 10.14412/1995-4484-2015-657-660

2. Лила АМ, Древаль РО, Шипицын ВВ. Оценка организации медицинской помощи и лекарственного обеспечения при ревматических заболеваниях и социально-экономического бремени этих болезней в Российской Федерации. Современная ревматология. 2018;12(3):112-119.

3. van der Heijde D, Ramiro S, Landewe R, et al. 2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis. Ann Rheum Dis. 2017;76(6):978-991. DOI: 10.1136/annrheumdis-2016-210770

4. Bao C, Huang F, Khan MA, et al. Safety and efficacy of golimum-ab in Chinese patients with active ankylosing spondylitis: 1-year results of a multicentre, randomized, double-blind, placebo-controlled phase III trial. Rheumatology (Oxford). 2014;53(9):1654-1663. DOI: 10.1093/rheumatology/keu132

5. Inman RD, Davis Jr JC, Heijde DVD, et al. Efficacy and safety of golimumab in patients with ankylosing spondylitis: Results of a randomized, double-blind, placebo-controlled, phase III trial. Arthritis Rheum. 2008;58(11):3402-3412. DOI: 10.1002/art.23969

6. Landewc R, Braun J, Deodhar A, et al. Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study. Ann Rheum Dis. 2014;73(1):39-47.

7. Giardina AR, Ferrante A, Ciccia F, Impastato R, Miceli MC, Principato A, et al. A 2-year comparative open label randomized study of efficacy and safety of etanercept and infliximab in patients with ankylosing spondylitis. Rheumatol Int. 2010;30:1437-1440. DOI: 10.1007/s00296-009-1157-3

8. Sieper J, Poddubnyy D. Axial spondyloarthritis. Lancet. 2017;390(10089):73-84. DOI: 10.1016/S0140-6736(16)31591-4

9. Gravallese EM, Schett G. Effects of the IL-23-IL-17 pathway on bone in spondyloarthritis. Nat Rev Rheumatol. 2018;14:631-640. DOI: 10.1038/s41584-018-0091-8

10. Dougados M, Wei JCC, Landewc R, et al. Efficacy and safety of ixekizumab through 52 weeks in two phase 3, randomised, controlled clinical trials in patients with active radiographic axial spon-dyloarthritis (COAST-V and COAST-W). Ann Rheum Dis. 2020;79(2):176-185. DOI: 10.1136/annrheumdis-2019-216118

11. van der Heijde D, Wei JCC, Dougados M, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease-modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet. 2018;392(10163):2441-2451. DOI: 10.1016/S0140-6736(18)31946-9

12. Deodhar A, Poddubnyy D, Pacheco-Tena C, et al. Efficacy and safety of ixekizumab in the treatment of radiographic axial spondy-loarthritis: Sixteen-week results from a phase III randomized, double-blind, placebo-controlled trial in patients with prior inadequate response to or intolerance of tumor necrosis factor inhibitors. Arthritis Rheum. 2019;71(4):599-611. DOI: 10.1002/art.40753

13. Wang R, Dasgupta A, Ward MM. Comparative efficacy of tumor necrosis factor-а inhibitors in ankylosing spondylitis: A systematic review and Bayesian network metaanalysis. J Rheumatol. 2018;45(4):481-490. DOI: 10.3899/jrheum.170224

14. Yin Y, Wang M, Liu M. Efficacy and safety of IL-17 inhibitors for the treatment of ankylosing spondylitis: A systematic review and meta-analysis. Arthritis Res Ther. 2020;22:1-11. DOI: 10.1186/s13075-020-02208-w

15. Chen C, Zhang X, Xiao L, et al. Comparative effectiveness of biologic therapy regimens for ankylosing spondylitis: A systematic review and a network meta-analysis. Medicine (Baltimore). 2016;95(11):e3060. DOI: 10.1097/MD.0000000000003060

16. Deodhar A, Chakravarty SD, Cameron C, et al. A systematic review and network meta-analysis of current and investigational treatments for active ankylosing spondylitis. Clin Rheumatol. 2020;39:2307-2315. DOI: 10.1007/s10067-020-04970-3

17. Tolkacheva D, Sokolova V, Mladov V. A systematic review and network meta-analysis of comparative efficacy and safety of biologics for radiographic axial spondyloarthritis (ankylosing spondylitis) in the Russian Federation. PROSPERO 2020 CRD42020192389. URL: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020192389 (Date accessed: 2020).

18. European Medicines Agency. Guideline on the Clinical Investigation of Medicinal Products for the Treatment of Axial Spondyloarthritis. Revision 1. URL: https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-clinical-investigation-medicinal-products-treatment-axial-spondyloarthritis-revision-1_en.pdf (Date accessed: 2020).

19. Sterne JAC, Savovic J, Page MJ, et al. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. DOI: 10.1136/bmj.l4898

20. Омельяновский ВВ, Авксентьева МВ, Сура МВ, и др. Методические рекомендации по оценке сравнительной эффективности и безопасности лекарственного препарата. 2016. URL: https://rosmedex.ru/hta/recom/ (Date accessed: 2020)

21. Higgins JPT, Green S (editors). Cochrane handbook for systematic reviews of interventions. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. URL: www.handbook.cochrane.org (Date accessed: 2020)

22. Dias S, Welton NJ, Sutton AJ, et al. NICE DSU Technical support document 2: A generalised linear modelling framework for pairwise and network meta-analysis of randomised controlled trials. URL: http://nicedsu.org.uk/wp-content/uploads/2016/03/A-general-linear-modelling-framework-for-pair-wise-and-network-meta-analysis-of-randomised-controlled-trials..pdf (Date accessed: 2020)

23. Turner RM, Jackson В, Wei Y, et al. Predictive distributions for between-study heterogeneity and simple methods for their application in Bayesian meta-analysis. Statistics in Medicine. 2014;34:984-998.

24. Dias S, Sutton AJ, Welton NJ, Ades AE. NICE DSU Technical support document 5: Evidence synthesis in the baseline natural history model. URL: http://nicedsu.org.uk/wp-content/uploads/2016/03/TSD5-Baseline.final-report.08.05.12.pdf (Date accessed: 2020)

25. Mbuagbaw L, Rochwerg B, Jaeschke R, et al. Approaches to interpreting and choosing the best treatments in network meta-analyses. Systematic reviews. 2017;6(1):1-5. DOI: 10.1186/s13643-017-0473-z

26. Мазуров ВИ, Гайдукова ИЗ, Эрдес ШФ, и др. Эффективность и безопасность нетакимаба, моноклонального антитела против интерлейкина-17, у пациентов с активным анкилозирующим спондилитом. Результаты международного многоцентрового рандомизированного двойного слепого клинического исследования III фазы BCD-085-5/ASTERA. Научнопрактическая ревматология. 2020;58(4):376-386. DOI: 10.47360/1995-4484-2020-376-386

27. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: A randomised controlled multicentre trial. Lancet. 2002;359(9313):1187-1193. DOI: 10.1016/s0140-6736(02)08215-6

28. Calin A, Dijkmans BAC, Emery P, et al. Outcomes of a multicentre randomised clinical trial of etanercept to treat ankylosing spondylitis. Ann Rheum Dis. 2004;63(12):1594-1600. DOI: 10.1136/ard.2004.020875

29. Davis Jr JC, van der Heijde D, Braun J, et al. Recombinant human tumor necrosis factor receptor (etanercept) for treating ankylosing spondylitis: A randomized, controlled trial. Arthritis Rheum. 2003;48(11):3230-3236. DOI: 10.1002/art.11325

30. Dougados M, Braun J, Szanto S, et al. Efficacy of etanercept on rheumatic signs and pulmonary function tests in advanced ankylosing spondylitis: Results of a randomised double-blind placebo-controlled study (SPINE). Ann Rheum Dis. 2011;70(5):799-804. DOI: 10.1136/ard.2010.139261

31. Erdes S, Nasonov E, Kunder E, et al. Primary efficacy of netakimab, a novel interleukin-17 inhibitor, in the treatment of active ankylosing spondylitis in adults. Clin Exp Rheumatol. 2020;38(1):27-34.

32. Huang F, Gu J, Zhu P, et al. Efficacy and safety of adalimumab in Chinese adults with active ankylosing spondylitis: Results of a randomised, controlled trial. Ann Rheum Dis. 2014;73(3):587-594. DOI: 10.1136/annrheumdis-2012-202533

33. Kivitz AJ, Wagner U, Dokoupilova E, et al. Efficacy and safety of secukinumab 150 mg with and without loading regimen in ankylosing spondylitis: 104-week results from MEASURE 4 study. Rheumatology and Therapy. 2018;5(2):447-462. DOI: 10.1007/s40744-018-0123-5

34. Sieper J, Deodhar A, Marzo-Ortega H, et al. Secukinumab efficacy in anti-TNF-naive and anti-TNF-experienced subjects with active ankylosing spondylitis: Results from the MEASURE 2 study. Ann Rheum Dis. 2017;76(3):571-592. DOI: 10.1136/ann-rheumdis-2016-210023

35. van der Heijde D, Kivitz A, Schiff MH, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: Results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2006;54(7):2136-2146. DOI: 10.1002/art.21913

36. van der Heijde D, Da Silva JC, Dougados M, et al. Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis. Ann Rheum Dis. 2006;65(12):1572-1577. DOI: 10.1136/ard.2006.056747.

37. Maneiro JR, Souto A, Salgado E, et al. Predictors of response to TNF antagonists in patients with ankylosing spondylitis and psoriatic arthritis: systematic review and meta-analysis. RMD open. 2015;1(1):1-11. DOI: 10.1136/rmdopen-2014-000017.

38. Arends S, Brouwer E, van der Veer E, et al. Baseline predictors of response and discontinuation of tumor necrosis factor-alpha blocking therapy in ankylosing spondylitis: A prospective longitudinal observational cohort study. Arthritis Res Ther. 2011;13(3):R94. DOI: 10.1186/ar3369

39. Davis JC, van der Heijde DM, Dougados M, et al. Baseline factors that influence ASAS 20 response in patients with ankylosing spondylitis treated with etanercept. J Rheumatol. 2005;32(9):1751-1754.

40. Emperiale V, Sanchez-Piedra C, Bolidique'z C, et al. FRI0389 Effectiveness of biologic therapy on disease activity in ankylosing spondylitis: A BIOBADASER III observational study. Ann Rieum Dis. 2019;78:879-880.

41. van der Linden SM, Valkenburg HA, De Jongi BM, et al. Tie risk of developing ankylosing spondylitis in HLA-B27 positive individuals. A comparison of relatives of spondylitis patients witi tie general population. Artiritis Rieum. 1984;27(3):241-249. DOI: 10.1002/art.1780270301

42. Bropiy S, Mackay K, Al-Saidi A, et al. Tie natural iistory of ankylosing spondylitis as defined by radiological progression. J Rieumatol. 2002;29(6):1236-1243.

43. Spoorenberg A, van der Heijde D, de Klerk E. A comparative study of tie usefulness of tie Bati Ankylosing Spondylitis Functional Index and tie Dougados Functional Index in tie assessment of ankylosing spondylitis. J Rieumatol. 1999;26(4):961-965.

44. Davis JC, Dougados M, Braun J, et al. Definition of disease duration in ankylosing spondylitis: reassessing tie concept. Ann Rieum Dis. 2006;65(11):1518-1520. DOI: 10.1136/ard.2005.044834

45. Ikawa EN, de Carvalio JF, Silva CAA, et al. Immunogenicity of anti-TNF-alpia agents in autoimmune diseases. Clin Rev Allergy Immunol. 2010;38(2-3):82-89.

46. Plasencia C, Pascual-Salcedo D, Nuno L, et al. Influence of immunogenicity on the efficacy of longterm treatment of spon-dyloarthritis with infliximab. Ann Rheum Dis. 2012;71(12):1955-1960.

47. De Vries MK, Wolbink GJ, Stapel SO, et al. Decreased clinical response to infliximab in ankylosing spondylitis is correlated with anti-infliximab formation. Ann Rheum Dis. 2007;66(9):1252-1254.

48. Kneepkens EL, Wei JC, Nurmohamed MT, et al. Immunogenicity, adalimumab levels and clinical response in ankylosing spondylitis patients during 24 weeks of follow-up. Ann Rheum Dis. 2015;74(2):396-401. DOI: 10.1136/annrheumdis-2013-204185