clinvestКачественная клиническая практикаKachestvennaya Klinicheskaya Praktika = Good Clinical Practice2588-05192618-8473ООО «Издательство ОКИ10.37489/2588-0519-2023-4-96-10clinvest-693Research ArticleСИСТЕМАТИЧЕСКИЙ ОБЗОР И МЕТААНАЛИЗSYSTEMATIC REVIEW AND META-ANALYSISЭффективность ингибиторов Янус-киназ при ревматоидном артрите: систематический обзор и  метаанализEffectiveness of  Janus kinase  inhibitors in  rheumatoid  arthritis:  systematic review  and  meta-analysisЧебердаА. Е.CheberdaA. E.

Москва

Alexey E. Cheberda

Moscow

БелоусовД. Ю.BelousovD. Yu.

Москва

Dmitry Yu. Belousov

Moscow

ООО «Центр фармакоэкономических исследованияРоссияCenter for Pharmacoeconomics Research LLCRussian Federation2023280220240496107Copyright © Чеберда А.Е., Белоусов Д.Ю., 20242024Чеберда А.Е., Белоусов Д.Ю.Cheberda A.E., Belousov D.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.clinvest.ru/jour/article/view/693

Цель. Оценить профили эффективности различных режимов дозирования тофацитиниба, барицитиниба и  упадацитиниба  — новых селективных пероральных ингибиторов Янус-киназы, при ревматоидном артрите (РА). Материалы и методы.  Рандомизированные контролируемые исследования тофацитиниба, барицитиниба и упадацитиниба при РА были выявлены в  базах данных MEDLINE и  Cochrane. Для оценки относительных рисков (ОР) эффективности и средней разницы в оценке качества жизни (КЖ) в метаанализе были использованы модели случайных эффектов. Для оценки эффективности был использован критерий ACR20, а для оценки показателей КЖ — индекс  HAQ-DI. Результаты.  Было отобрано двадцать исследований с общим низким риском систематической ошибки. Тофацитиниб, барицитиниб и упадацитиниб улучшали контроль РА по критерию ACR20 (ОР 2,03; 95 % ДИ 1,87–2,20) и по индексу HAQ-DI (средняя разница –0,31; 95  % ДИ –0,34 — –0,28) по сравнению с плацебо. Заключение. Тофацитиниб, барицитиниб и упадацитиниб значительно улучшают контроль РА и КЖ пациентов. Для принятия дальнейших решений необходимы сравнительные клинические исследования изученных ингибиторов Янус-киназы в условиях реальной клинической практики.

Aim.  To assess the efficacy profiles of different dosing regimens of tofacitinib, baricitinib, and upadacitinib — novel selective oral Janus activated kinase inhibitors, in rheumatoid arthritis (RA). Materials and methods.  Randomized controlled trials of tofacitinib, baricitinib and upadacitinib in RA were identified from MEDLINE, and Cochrane databases. Random- effects models were used to estimate pooled mean differences (MD) and relative risks (RRs). American College of Rheumatology 20 % (ACR20), Health Assessment Questionnaire–Disability Index (HAQ-DI) were calculated.  Results. Twenty trials with an overall low risk of bias were identified. Tofacitinib, baricitinib, and upadacitinib improved RA control as deter -mined by ACR20 (RR, 2.03; 95 % CI, 1.87 to 2.20) and HAQ-DI (MD, −0.31; 95% CI, −0.34 to −0.28) compared with placebo.  Conclusion.  Tofacitinib, baricitinib, and upadacitinib significantly improve RA control. To make further decisions, comparative clinical trials of the Janus kinase inhibitors in the real-world clinical practice are necessary.

ревматоидный артриттофацитиниббарицитинибупадацитинибингибиторы янус-киназсистематический обзорметаанализHAQ-DIACR20rheumatoid arthritistofacitinibbaricitinibupadacitinibJanus kinase inhibitorssystematic reviewmeta-analysisHAQ-DIACR20ReferencesНасонов Е.Л., Каратеев Д.Е., Балабанова Р.М. Ревматоидный артрит. В кн.: Ревматология. Национальное руководство. Под ред. Е.Л. Насонова, В.А. Насоновой. Москва: ГЭОТАР-Медиа; 2008.С. 290–331.Nasonov EL, Karateev DE, Balabanova RM. Rheumatoid arthritis. In the book: Rheumatology. National leadership. Ed.by EL Nasonov, VA Nasonova. Moscow: GEOTAR-Media; 2008.Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016; 22;388(10055):2023-2038. doi:10.1016/S0140-6736(16)30173-8.Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet 2016; 22;388(10055):2023-2038. doi:10.1016/S0140-6736(16)30173-8.Cutolo M, Kitas GD, van Riel PLCM. Burden of disease in treated rheumatoid arthritis patients: going beyond the joint. Semin Arthritis Rheum 2014; 43:479–488.Cutolo M, Kitas GD, van Riel PLCM. Burden of disease in treated rheumatoid arthritis patients: going beyond the joint. Semin Arthritis Rheum 2014; 43:479–488.Фоломеева O.M., Галушко Е.А., Эрдес Ш.Ф. Распространенность ревматических заболеваний в популяциях взрослого населения России и США. Научно-практическая ревматология. 2008;46(4):4-13. doi: 10.14412/1995-4484-2008-529.Folomeeva OM, Galushko EA, Erdes SF. Prevalence of rheumatic diseases in adult populations of Russian Federation and USA. Rheumatology Science and Practice. 2008;46(4):4-13. (In Russ.). doi: 10.14412/1995-4484-2008-529.Общая заболеваемость взрослого населения России в 2017 г. Статистические материалы, часть IV, Москва. 2018. The general morbidity of the adult population of Russia in 2017 Statistical materials, part IV, Moscow. 2018The general morbidity of the adult population of Russia in 2017 Statistical materials, part IV, Moscow. 2018Государственный реестр лекарственных средств. URL: http://grls.rosminzdrav.ru (дата обращения: 01.10.2023).The State Register of Medicines. URL: http://grls.rosminzdrav.ru (date of application: 01.10.2023).Новиков П.И., Шевцова Т.П., Щеголева Е.М., Моисеев С.В. Ингибиторы янус-киназ: фармакологические свойства и сравнительные клиническая эффективность и безопасность. Клиническая фармакология и терапия. 2021;30(1):51-60. doi: 10.32756/0869-5490-2021-1-51-60.Novikov P, Shevtsova T, Shchegoleva E, Moiseev S. JAK-inhibitors: pharmacological properties and comparative clinical efficacy and safety. Klinicheskaya farmakologiya i terapiya = Clin Pharmacol Ther. 2021;30(1):51-60. (In Russ.). doi: 10.32756/0869-5490-2021-1-51-60.Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315-24. doi: 10.1002/art.1780310302.Arnett FC, Edworthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum. 1988 Mar;31(3):315-24. doi: 10.1002/art.1780310302.Kosinski M, Zhao SZ, Dedhiya S, et al. Determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis. Arthritis Rheum. 2000 Jul;43(7):1478-87. doi: 10.1002/1529-0131(200007)43:7.Kosinski M, Zhao SZ, Dedhiya S, et al. Determining minimally important changes in generic and disease-specific health-related quality of life questionnaires in clinical trials of rheumatoid arthritis. Arthritis Rheum. 2000 Jul;43(7):1478-87. doi: 10.1002/1529-0131(200007)43:7.Wells GA, Tugwell P, Kraag GR, et al. Minimum important difference between patients with rheumatoid arthritis: the patient's perspective. J Rheumatol. 1993 Mar;20(3):557-60.Wells GA, Tugwell P, Kraag GR, et al. Minimum important difference between patients with rheumatoid arthritis: the patient's perspective. J Rheumatol. 1993 Mar;20(3):557-60.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Режим доступа: http://prisma-statement.org/.Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Режим доступа: http://prisma-statement.org/.Библиографическая база MEDLINE®. Режим доступа: https://pubmed.ncbi.nlm.nih.gov/. MEDLINE® bibliographic database. Access mode: https://pubmed.ncbi.nlm.nih.gov/.Библиографическая база MEDLINE®. Режим доступа: https://pubmed.ncbi.nlm.nih.gov/. MEDLINE® bibliographic database. Access mode: https://pubmed.ncbi.nlm.nih.gov/.Кокрейновский регистр контролируемых исследований (Cochrane Control Trials Registry, CENTRAL). Режим доступа: https://www.cochranelibrary.com/central/about-central.Cochrane Register of Controlled Trials (Cochrane Control Trials Registry, CENTRAL). Access mode: https://www.cochranelibrary.com/central/about-central.Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012 Mar;64(3):617-29. doi: 10.1002/art.33383.Fleischmann R, Cutolo M, Genovese MC, et al. Phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modifying antirheumatic drugs. Arthritis Rheum. 2012 Mar;64(3):617-29. doi: 10.1002/art.33383.Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6):495-507. doi: 10.1056/NEJMoa1109071.Fleischmann R, Kremer J, Cush J, et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6):495-507. doi: 10.1056/NEJMoa1109071.Keystone EC, Taylor PC, Drescher E, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015 Feb;74(2):333-40. doi: 10.1136/annrheumdis-2014-206478.Keystone EC, Taylor PC, Drescher E, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015 Feb;74(2):333-40. doi: 10.1136/annrheumdis-2014-206478.Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009 Jul;60(7):1895-905. doi: 10.1002/art.24567. Erratum in: Arthritis Rheum. 2012 May;64(5):1487.Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009 Jul;60(7):1895-905. doi: 10.1002/art.24567. Erratum in: Arthritis Rheum. 2012 May;64(5):1487.Kremer J, Li ZG, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013 Aug 20;159(4):253-61. doi: 10.7326/0003-4819-159-4-201308200-00006.Kremer J, Li ZG, Hall S, et al. Tofacitinib in combination with nonbiologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis: a randomized trial. Ann Intern Med. 2013 Aug 20;159(4):253-61. doi: 10.7326/0003-4819-159-4-201308200-00006.Tanaka Y, Takeuchi T, Yamanaka H, et al. Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. Mod Rheumatol. 2015 Jul;25(4):514-21. doi: 10.3109/14397595.2014.995875.Tanaka Y, Takeuchi T, Yamanaka H, et al. Efficacy and safety of tofacitinib as monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week, randomized, phase 2 study. Mod Rheumatol. 2015 Jul;25(4):514-21. doi: 10.3109/14397595.2014.995875.Kremer JM, Kivitz AJ, Simon-Campos JA, et al. Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial. Arthritis Res Ther. 2015 Apr 6;17(1):95. doi: 10.1186/s13075-015-0612-7.Kremer JM, Kivitz AJ, Simon-Campos JA, et al. Evaluation of the effect of tofacitinib on measured glomerular filtration rate in patients with active rheumatoid arthritis: results from a randomised controlled trial. Arthritis Res Ther. 2015 Apr 6;17(1):95. doi: 10.1186/s13075-015-0612-7.Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken). 2011 Aug;63(8):1150-8. doi: 10.1002/acr.20494.Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken). 2011 Aug;63(8):1150-8. doi: 10.1002/acr.20494.van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6):508-19. doi: 10.1056/NEJMoa1112072. Erratum in: N Engl J Med. 2013 Jul 18;369(3):293.van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012 Aug 9;367(6):508-19. doi: 10.1056/NEJMoa1112072. Erratum in: N Engl J Med. 2013 Jul 18;369(3):293.Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012 Apr;64(4):970-81. doi: 10.1002/art.33419.Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIb dose-ranging study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012 Apr;64(4):970-81. doi: 10.1002/art.33419.van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013 Mar;65(3):559-70. doi: 10.1002/art.37816.van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013 Mar;65(3):559-70. doi: 10.1002/art.37816.Boyle DL, Soma K, Hodge J, et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2015 Jun;74(6):1311-6. doi: 10.1136/annrheumdis-2014-206028.Boyle DL, Soma K, Hodge J, et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signalling in rheumatoid arthritis. Ann Rheum Dis. 2015 Jun;74(6):1311-6. doi: 10.1136/annrheumdis-2014-206028.Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013 Feb 9;381(9865):451-60. doi: 10.1016/S0140-6736(12)61424-X.Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013 Feb 9;381(9865):451-60. doi: 10.1016/S0140-6736(12)61424-X.Tanaka Y, Emoto K, Cai Z, et al. Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study. J Rheumatol. 2016 Mar;43(3):504-11. doi: 10.3899/jrheum.150613. Epub 2016 Feb 1. Erratum in: J Rheumatol. 2016 May;43(5):998.Tanaka Y, Emoto K, Cai Z, et al. Efficacy and Safety of Baricitinib in Japanese Patients with Active Rheumatoid Arthritis Receiving Background Methotrexate Therapy: A 12-week, Double-blind, Randomized Placebo-controlled Study. J Rheumatol. 2016 Mar;43(3):504-11. doi: 10.3899/jrheum.150613. Epub 2016 Feb 1. Erratum in: J Rheumatol. 2016 May;43(5):998.Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med. 2017 Feb 16;376(7):652-662. doi: 10.1056/NEJMoa1608345.Taylor PC, Keystone EC, van der Heijde D, et al. Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis. N Engl J Med. 2017 Feb 16;376(7):652-662. doi: 10.1056/NEJMoa1608345.Genovese MC, Kremer J, Zamani O, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016 Mar 31;374(13):1243-52. doi: 10.1056/NEJMoa1507247.Genovese MC, Kremer J, Zamani O, et al. Baricitinib in Patients with Refractory Rheumatoid Arthritis. N Engl J Med. 2016 Mar 31;374(13):1243-52. doi: 10.1056/NEJMoa1507247.Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017 Jan;76(1):88-95. doi: 10.1136/annrheumdis-2016-210094. Epub 2016 Sep 29. Erratum in: Ann Rheum Dis. 2017 Sep;76(9):1634.Dougados M, van der Heijde D, Chen YC, et al. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017 Jan;76(1):88-95. doi: 10.1136/annrheumdis-2016-210094. Epub 2016 Sep 29. Erratum in: Ann Rheum Dis. 2017 Sep;76(9):1634.Burmester GR, Kremer JM, Van den Bosch F, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018 Jun 23;391(10139):2503-2512. doi: 10.1016/S0140-6736(18)31115-2.Burmester GR, Kremer JM, Van den Bosch F, et al. Safety and efficacy of upadacitinib in patients with rheumatoid arthritis and inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs (SELECT-NEXT): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet. 2018 Jun 23;391(10139):2503-2512. doi: 10.1016/S0140-6736(18)31115-2.Genovese MC, Fleischmann R, Combe B, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet. 2018 Jun 23;391(10139):2513-2524. doi: 10.1016/S0140-6736(18)31116-4.Genovese MC, Fleischmann R, Combe B, et al. Safety and efficacy of upadacitinib in patients with active rheumatoid arthritis refractory to biologic disease-modifying anti-rheumatic drugs (SELECT-BEYOND): a double-blind, randomised controlled phase 3 trial. Lancet. 2018 Jun 23;391(10139):2513-2524. doi: 10.1016/S0140-6736(18)31116-4.Fleischmann R, Pangan AL, Song IH, et al. Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol. 2019 Nov;71(11):1788-1800. doi: 10.1002/art.41032.Fleischmann R, Pangan AL, Song IH, et al. Upadacitinib Versus Placebo or Adalimumab in Patients With Rheumatoid Arthritis and an Inadequate Response to Methotrexate: Results of a Phase III, Double-Blind, Randomized Controlled Trial. Arthritis Rheumatol. 2019 Nov;71(11):1788-1800. doi: 10.1002/art.41032.Методические рекомендации по оценке сравнительной клинической эффективности и безопасности лекарственного препарата. Утверждены приказом ФГБУ «ЦЭККМП» Минздрава России от 23.12.2016 № 145-од.Metodicheskie rekomendacii po ocenke sravnitel'noj klinicheskoj effektivnosti i bezopasnosti lekarstvennogo preparata. Utverzhdeny prikazom FGBU «CEKKMP» Minzdrava Rossii ot 23.12.2016 № 145-od. (In Russ.).Методические рекомендации по проведению сравнительной клинико-экономической оценки лекарственного препарата. Утверждены приказом ФГБУ «ЦЭККМП» Минздрава России от 23.12.2016 № 145-од.Metodicheskie rekomendacii po provedeniyu sravnitel'noj klinikoekonomicheskoj ocenki lekarstvennogo preparata. Utverzhdeny prikazom FGBU «CEKKMP» Minzdrava Rossii ot 23.12.2016 № 145-od. (In Russ.).

The authors declare that there are no conflicts of interest present.