medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2022-16-11-88-94medsovet-6960Research ArticleРЕВМАТОЛОГИЯRHEUMATOLOGYИнгибиторы интерлейкина-6: от терапии иммуновоспалительных ревматических заболеваний до использования при COVID-19Interleukin-6 inhibitors: from the therapy of immuno-inflammatory rheumatic diseases to use in COVID-19https://orcid.org/0000-0003-4327-6720МуравьеваН. В.MuravyevaN. V.

Муравьева Наталья Валерьевна, кандидат медицинских наук, научный сотрудник лаборатории коморбидных инфекций и  вакцинопрофилактики

115522, Москва, Каширское шоссе, д. 34А

Natalia V. Muravyeva, Cand. Sci. (Med.), Researcher at the Laboratory of Comorbid Infections and Vaccine Prevention

34а, Kashirskoe Shosse, Moscow, 115522

muravjeva@mail.ruhttps://orcid.org/0000-0001-7091-2054БеловБ. С.BelovB. S.

Белов Борис Сергеевич, доктор медицинских наук, заведующий лабораторией коморбидных инфекций и вакцинопрофилактики

115522, Москва, Каширское шоссе, д. 34А

Boris S. Belov, Dr. Sci. (Med.), Head of the Laboratory of Comorbid Infections and Vaccination

34а, Kashirskoe Shosse, Moscow, 115522

belovbor@yandex.ruНаучно-исследовательский институт ревматологии имени В.А. НасоновойРоссияNasonova Research Institute of RheumatologyRussian Federation2022060720220118894Copyright © Муравьева Н.В., Белов Б.С., 20222022Муравьева Н.В., Белов Б.С.Muravyeva N.V., Belov B.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/6960

Ключевую роль в  развитии хронического аутоиммунного воспаления играют провоспалительные цитокины, в  частности интерлейкин 6 (ИЛ-6). Внедрение в клиническую практику моноклональных антител, ингибирующих ИЛ-6, является значимым событием в ревматологии и в настоящее время рассматривается как перспективное направление в терапии иммуновоспалительных ревматических заболеваний. Первым ингибитором ИЛ-6 (иИЛ-6), вошедшим в практику ревматологов, стал тоцилизумаб (ТЦЗ), вторым – сарилумаб (САР). В многочисленных исследованиях показана высокая эффективность иИЛ-6: применение препаратов приводит к быстрому уменьшению клинических проявлений ревматоидного артрита (РА) и снижению лабораторных признаков воспаления, способствуя достижению низкой активности или ремиссии, улучшает качество жизни пациентов, а также замедляет рентгенологическое прогрессирование заболевания. В то же время иИЛ-6 обладают удовлетворительным профилем безопасности. Всеобщая проблема современности  – пандемия новой коронавирусной инфекции закономерно привела к попыткам использования иИЛ-6 у пациентов с тяжелым и критическим течением заболевания, поскольку в патогенезе COVID-19 важную роль играет именно ИЛ-6, что подтверждается результатами многочисленных исследований. Однако данные об эффективности и безопасности этих препаратов при COVID-19 противоречивы, что требует проведения более масштабных контролируемых исследований. В настоящем обзоре рассмотрены вопросы эффективности и безопасности ТЦЗ и САР у больных ревматологического профиля и у пациентов с COVID-19. Обзор иллюстрирован примерами из реальной клинической практики.

The key role in the development of chronic autoimmune inflammation is played by pro-inflammatory cytokines, in particular, interleukin 6 (IL-6). The introduction into clinical practice of monoclonal antibodies inhibiting IL-6 is a significant event in rheumatology and is currently considered as a promising direction in the treatment of immuno-inflammatory rheumatic diseases. The first inhibitor of IL-6 (IL-6), which entered the practice of rheumatologists, was tocilizumab (TCZ), the second – sarilumab (SAR). Numerous studies have shown the high effectiveness of iIL-6: the use of drugs leads to a rapid decrease in the clinical manifestations of rheumatoid arthritis (RA) and a decrease in laboratory signs of inflammation, contributing to the achievement of low activity or remission, improves the quality of life of patients, and also slows down the X-ray progression of the disease. At the same time, iIL-6 has a satisfactory safety profile. The universal problem of our time – the pandemic of a new coronavirus infection – has led to attempts to use IL-6 in patients with severe and critical disease, since IL-6 plays an important role in the pathogenesis of COVID-19, which is confirmed by the results of numerous studies. However, data on the efficacy and safety of these drugs in COVID-19 are contradictory, which requires conducting larger-scale controlled studies. This review examines the issues of the effectiveness and safety of TCZ and SAR in rheumatological patients and in patients with COVID-19. The review is illustrated with examples from real clinical practice.

интерлейкин 6тоцилизумабсарилумабиммуновоспалительные ревматические заболеванияревматоидный артритCOVID-19синдром цитокинового штормаinterleukin 6tocilizumabsarilumabimmuno-inflammatory rheumatic diseasesrheumatoid arthritisCOVID-19cytokine storm syndromeReferencesНасонов Е.Л., Лила А.М. Ингибиция интерлейкина 6 при иммуновоспалительных заболеваниях: достижения, перспективы и надежды. Научнопрактическая ревматология. 2017;(6):590–599. Режим доступа: https://rsp.mediar-press.net/rsp/article/view/2461.Nasonov E.L., Lila A.M. Inhibition of interleukin 6 in immune inflammatory rheumatic diseases: achievements, prospects, and hopes. Rheumatology Science and Practice. 2017;(6):590–599. (In Russ.) Available at: https://rsp.mediar-press.net/rsp/article/view/2461.Hunter C.A., Jones S.A. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448–457. https://doi.org/10.1038/ni.3153.Hunter C.A., Jones S.A. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16(5):448–457. https://doi.org/10.1038/ni.3153.Calabrese L.H., Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10(12):720–727. https://doi.org/10.1038/nrrheum.2014.127.Calabrese L.H., Rose-John S. IL-6 biology: implications for clinical targeting in rheumatic disease. Nat Rev Rheumatol. 2014;10(12):720–727. https://doi.org/10.1038/nrrheum.2014.127.Насонов Е.Л., Станислав М.Л., Раскина Т.А., Куропаткин Г.В., Ширинский И.В., Ребров А.П. и др. 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;(2):142–148. Режим доступа: https://rsp.mediar-press.net/rsp/article/view/2696.Nasonov E.L., Stanislav M.L., Raskina T.A., Kuropatkin G.V., Shirinsky I.V., Rebrov A.P. et al. Efficacy and safety of sarilumab in combination with methotrexate in patients with active rheumatoid arthritis and inadequate effect of methotrexate monotherapy (results of phase III MOBILITY study). Rheumatology Science and Practice. 2019;(2):142–148. (In Russ.) Available at: https://rsp.mediar-press.net/rsp/article/view/2696.Nishimoto N., Hashimoto J., Miaysaka 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 randomized controlled trial of tocilizumab. Ann Rheum Dis. 2007;66(9):1162–1167. https://doi.org/10.1136/ard.2006.068064.Nishimoto N., Hashimoto J., Miaysaka 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 randomized controlled trial of tocilizumab. Ann Rheum Dis. 2007;66(9):1162–1167. https://doi.org/10.1136/ard.2006.068064.Genovese M.C., McKay J.D., Nasonov E.L., Mysler E.F., da Silva N.A., 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;58(10):2968–2980. https://doi.org/10.1002/art.23940.Genovese M.C., McKay J.D., Nasonov E.L., Mysler E.F., da Silva N.A., 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;58(10):2968–2980. https://doi.org/10.1002/art.23940.Smolen J., Beaulieu A., Ruddert-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 randomized trial. Lancet. 2008;371(9617):987–997. https://doi.org/10.1016/S0140-6736(08)60453-5.Smolen J., Beaulieu A., Ruddert-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 randomized trial. Lancet. 2008;371(9617):987–997. https://doi.org/10.1016/S0140-6736(08)60453-5.Emery P., Keystone E., Tony H.-P., Cantagrel A., van Vollenhoven R., Sanchez A. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-TNF biologics: results from a 24-week multicenter randomized placebocontrolled trial. Ann Rheum Dis. 2008;67(11):1516–1523. https://doi.org/10.1136/ard.2008.092932.Emery P., Keystone E., Tony H.-P., Cantagrel A., van Vollenhoven R., Sanchez A. et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-TNF biologics: results from a 24-week multicenter randomized placebocontrolled trial. Ann Rheum Dis. 2008;67(11):1516–1523. https://doi.org/10.1136/ard.2008.092932.Nishimoto N., Miaysaka N., Yamamoto K., Kawai S., Takeuchi T., Azuma J., Kishimoto T. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19(1):12–19. https://doi.org/10.1007/s10165-008-0125-1.Nishimoto N., Miaysaka N., Yamamoto K., Kawai S., Takeuchi T., Azuma J., Kishimoto T. Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL-6 receptor inhibition therapy. Mod Rheumatol. 2009;19(1):12–19. https://doi.org/10.1007/s10165-008-0125-1.Jones G., Sebba A., Gu J., Lowenstein M.B., Calvo A., Gomez-Reino J.J. et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69(1):88–96. https://doi.org/10.1136/ard.2008.105197.Jones G., Sebba A., Gu J., Lowenstein M.B., Calvo A., Gomez-Reino J.J. et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis. 2010;69(1):88–96. https://doi.org/10.1136/ard.2008.105197.Kremer J.L., Blanco R., Brzosko M., Burgos-Vargas R., Halland A.-M., Vernon E. et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate response to methotrexate at 1 year; LITHE study. Arthritis Rheum. 2011;63(3):609–621. https://doi.org/10.1002/art.30158.Kremer J.L., Blanco R., Brzosko M., Burgos-Vargas R., Halland A.-M., Vernon E. et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate response to methotrexate at 1 year; LITHE study. Arthritis Rheum. 2011;63(3):609–621. https://doi.org/10.1002/art.30158.Yazici Y., Curtis J.R., Ince A., Baraf H., Malamet R.L., Teng L.L., Kavanaughet A. Efficacy of tocilizumab in patients with moderate to severe rheumatoid arthritis and previously inadequate response to disease-modifying antirheumatic drug: the ROSE study. Ann Rheum Dis. 2012;71(2):198–205. https://doi.org/10.1136/ard.2010.148700.Yazici Y., Curtis J.R., Ince A., Baraf H., Malamet R.L., Teng L.L., Kavanaughet A. Efficacy of tocilizumab in patients with moderate to severe rheumatoid arthritis and previously inadequate response to disease-modifying antirheumatic drug: the ROSE study. Ann Rheum Dis. 2012;71(2):198–205. https://doi.org/10.1136/ard.2010.148700.Dougados M., Kissel K., Sheeran T., Tak P.P., Conaghan P.G., Mola E.M. et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72(1):43–50. https://doi.org/10.1136/annrheumdis-2011-201282.Dougados M., Kissel K., Sheeran T., Tak P.P., Conaghan P.G., Mola E.M. et al. Adding tocilizumab or switching to tocilizumab monotherapy in methotrexate inadequate responders: 24-week symptomatic and structural results of a 2-year randomised controlled strategy trial in rheumatoid arthritis (ACT-RAY). Ann Rheum Dis. 2013;72(1):43–50. https://doi.org/10.1136/annrheumdis-2011-201282.Burmester G.R., Feist E., Kellner H., Braun J., Iking-Konert C., Rubbert-Roth A. Effectiveness and safety of the interleukin 6 receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA). Ann Rheum Dis. 2011;70(5):755–759. https://doi.org/10.1136/ard.2010.139725.Burmester G.R., Feist E., Kellner H., Braun J., Iking-Konert C., Rubbert-Roth A. Effectiveness and safety of the interleukin 6 receptor antagonist tocilizumab after 4 and 24 weeks in patients with active rheumatoid arthritis: the first phase IIIb real-life study (TAMARA). Ann Rheum Dis. 2011;70(5):755–759. https://doi.org/10.1136/ard.2010.139725.Huizinga T.W.J., Fleischmann R.M., Jasson M., Radin A.R., Adelsberg J., Fiore S. et al. 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 randomized SARIL-RAMOBILITY Part A trial. Ann Rheum Dis. 2014;73(9):1626–1634. https://doi.org/10.1136/annrheumdis-2013-204405.Huizinga T.W.J., Fleischmann R.M., Jasson M., Radin A.R., Adelsberg J., Fiore S. et al. 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 randomized SARIL-RAMOBILITY Part A trial. Ann Rheum Dis. 2014;73(9):1626–1634. https://doi.org/10.1136/annrheumdis-2013-204405.Genovese M.C., Fleischmann R., Kivitz A.J., Rell-Bakalarska M., Martincova R., Fiore S. et al. 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):1424–1437. https://doi.org/10.1002/art.39093.Genovese M.C., Fleischmann R., Kivitz A.J., Rell-Bakalarska M., Martincova R., Fiore S. et al. 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):1424–1437. https://doi.org/10.1002/art.39093.Genovese M.C., Adelsberg J., Fan C., Graham N.M.H., Hoogstraten H., Parrino J. et al. 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):1423–1431. https://doi.org/:10.1093/rheumatology/key121.Genovese M.C., Adelsberg J., Fan C., Graham N.M.H., Hoogstraten H., Parrino J. et al. 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):1423–1431. https://doi.org/:10.1093/rheumatology/key121.Genovese M.C., Heijde D., Lin Y., John G., Wang S., Hoogstraten H. et al. Long-term safety and efficacy of sarilumab plus methotrexate on disease activity, physical function and radiographic progression: 5 years of sarilumab plus methotrexate treatment. RMD Open. 2019;5(2):e000887. https://doi.org/10.1136/rmdopen-2018-000887.Genovese M.C., Heijde D., Lin Y., John G., Wang S., Hoogstraten H. et al. Long-term safety and efficacy of sarilumab plus methotrexate on disease activity, physical function and radiographic progression: 5 years of sarilumab plus methotrexate treatment. RMD Open. 2019;5(2):e000887. https://doi.org/10.1136/rmdopen-2018-000887.Tanaka Y., Wada K., Takahashi Y. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a randomized, placebo-controlled phase III trial in Japan. Arthritis Res Ther. 2019;21(1):79. https://doi.org/10.1186/s13075-019-1856-4.Tanaka Y., Wada K., Takahashi Y. Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a randomized, placebo-controlled phase III trial in Japan. Arthritis Res Ther. 2019;21(1):79. https://doi.org/10.1186/s13075-019-1856-4.Fleischmann R., Adelsberg J., Lin Y., Castelar-Pinheiro G., Brzezicki J., Hrycaj P. et al. 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):277–290. https://doi.org/10.1002/art.39944.Fleischmann R., Adelsberg J., Lin Y., Castelar-Pinheiro G., Brzezicki J., Hrycaj P. et al. 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):277–290. https://doi.org/10.1002/art.39944.Burmester G.R., Lin Y., Patel R., Adelsberg J., Mangan E.K., Graham N.M.H. et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomized, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):8400–8847. https://doi.org/10.1136/annrheumdis-2016-210310.Burmester G.R., Lin Y., Patel R., Adelsberg J., Mangan E.K., Graham N.M.H. et al. Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomized, double-blind, parallel-group phase III trial. Ann Rheum Dis. 2017;76(5):8400–8847. https://doi.org/10.1136/annrheumdis-2016-210310.Strand V., Kosinski M., Chen C.-I., Joseph G., Rendas-Baum R., Graham N.M.H. et al. Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther. 2016;18(1):198. https://doi.org/10.1186/s13075-016-1096-9.Strand V., Kosinski M., Chen C.-I., Joseph G., Rendas-Baum R., Graham N.M.H. et al. Sarilumab plus methotrexate improves patient-reported outcomes in patients with active rheumatoid arthritis and inadequate responses to methotrexate: results of a phase III trial. Arthritis Res Ther. 2016;18(1):198. https://doi.org/10.1186/s13075-016-1096-9.Панасюк Е.Ю., Амирджанова В.Н., Авдеева А.С., Лучихина Е.Л., Александрова Е.Н., Новиков А.А., Насонов Е.Л. Опыт применения тоцилизумаба у больных ревматоидным артритом (по данным многоцентрового исследования ЛОРНЕТ). Научно-практическая ревматология. 2013;(2):104–110. Режим доступа: https://rsp.mediar-press.net/rsp/article/view/773.Panasyuk E.Yu., Amirdzhanova V.N., Avdeyeva A.S., Lushichina E.L., Alexandrova E.A., Novikov A.A., Nasonov E.L. Experience with tocilizumab in patients with rheumatoid arthritis (according to the data of the LORNET multicenter trial). Rheumatology Science and Practice. 2013;(2):104–110. (In Russ.) Available at: https://rsp.mediar-press.net/rsp/article/view/773.Masui-Ito A., Okamoto R., Ikejiri K., Fujimoto M., Tanimura M., Nakamoriet S. et al. Tocilizumab for uncontrollable systemic inflammatory response syndrome complicating adult-onset Still disease: case report and review of literature. Medicine (Baltimore). 2017;96(29):e7596. https://doi.org/10.1097/MD.0000000000007596.Masui-Ito A., Okamoto R., Ikejiri K., Fujimoto M., Tanimura M., Nakamoriet S. et al. Tocilizumab for uncontrollable systemic inflammatory response syndrome complicating adult-onset Still disease: case report and review of literature. Medicine (Baltimore). 2017;96(29):e7596. https://doi.org/10.1097/MD.0000000000007596.Koster M.J., Matteson E.L., Warrington K.J. Recent advances in the clinical management of giant cell arteritis and Takayasu arteritis. Curr Opin Rheumatol. 2016;28(3):2111–2117. https://doi.org/10.1097/BOR.0000000000000265.Koster M.J., Matteson E.L., Warrington K.J. Recent advances in the clinical management of giant cell arteritis and Takayasu arteritis. Curr Opin Rheumatol. 2016;28(3):2111–2117. https://doi.org/10.1097/BOR.0000000000000265.Khanna D., Denton C.P., Jahreis A., van Laar J.M., Frech T.M., Andersonet M. et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630–2640. https://doi.org/10.1016/S0140-6736(16)00232-4.Khanna D., Denton C.P., Jahreis A., van Laar J.M., Frech T.M., Andersonet M. et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet. 2016;387(10038):2630–2640. https://doi.org/10.1016/S0140-6736(16)00232-4.Campbell L., Chen C., Bhagat S.S., Parker R.A., Östör A.J.K. Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systemic literature review and meta-analysis of randomized controlled trials. Rheumatology (Oxford). 2011;50(3):552–562. https://doi.org/10.1093/rheumatology/keq343.Campbell L., Chen C., Bhagat S.S., Parker R.A., Östör A.J.K. Risk of adverse events including serious infections in rheumatoid arthritis patients treated with tocilizumab: a systemic literature review and meta-analysis of randomized controlled trials. Rheumatology (Oxford). 2011;50(3):552–562. https://doi.org/10.1093/rheumatology/keq343.Lang V., Englbrecht M., Rech J., Nüsslein H., Manger K., Schuchet F. et al. Risk of infections in rheumatoid arthritis patients treated with tocilizumab. Rheumatology (Oxford). 2012;51(5):852–857. https://doi.org/10.1093/rheumatology/ker223Lang V., Englbrecht M., Rech J., Nüsslein H., Manger K., Schuchet F. et al. Risk of infections in rheumatoid arthritis patients treated with tocilizumab. Rheumatology (Oxford). 2012;51(5):852–857. https://doi.org/10.1093/rheumatology/ker223Насонов Е.Л. (ред.). Ревматология: российские клинические рекомендации. М.; 2017. 464 с.Nasonov E.L. (ed.). Rheumatology: Russian clinical guidelines. Moscow; 2017. 464 p. (In Russ.)Насонов Е.Л. Иммунопатология и иммунофармакотерапия коронавирусной болезни 2019 (COVID-19): фокус на интерлейкин 6. Научно-практическая ревматология. 2020;(3):245–261. Режим доступа: https://rsp.mediar-press.net/rsp/article/view/2890.Nasonov E.L. Immunopathology and immunopharmacotherapy of coronavirus disease (COVID-19): focus on interleukin 6. Rheumatology Science and Practice. 2020;(3):245–261. (In Russ.) Available at: https://rsp.mediar-press.net/rsp/article/view/2890.Michot J.M., Albiges L., Chaput N., Saada V., Pommeret F., Griscelli F. et al. Tocilizumab, an anti-IL6 receptor antibody, to treat COVID-19-related respiratory failure: a case report. Ann Oncol. 2020;31(7):961–964. https://doi.org/10.1016/j.annonc.2020.03.300.Michot J.M., Albiges L., Chaput N., Saada V., Pommeret F., Griscelli F. et al. Tocilizumab, an anti-IL6 receptor antibody, to treat COVID-19-related respiratory failure: a case report. Ann Oncol. 2020;31(7):961–964. https://doi.org/10.1016/j.annonc.2020.03.300.Fontana F., Alfano G., Mori G., Amurri A., Tei L., Ballestri M. et al. COVID-19 pneumonia in a kidney transplant recipient successfully treated with Tocilizumab and Hydroxychloroquine. Am J Transplant. 2020;20(7):1902– 1906. https://doi.org/10.1111/ajt.15935.Fontana F., Alfano G., Mori G., Amurri A., Tei L., Ballestri M. et al. COVID-19 pneumonia in a kidney transplant recipient successfully treated with Tocilizumab and Hydroxychloroquine. Am J Transplant. 2020;20(7):1902– 1906. https://doi.org/10.1111/ajt.15935.Zhang X., Song K., Tong F., Fei M., Guo H., Luet Z. et al. First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Adv. 2020;4(7):1307–1310. https://doi.org/10.1182/bloodadvances.2020001907.Zhang X., Song K., Tong F., Fei M., Guo H., Luet Z. et al. First case of COVID-19 in a patient with multiple myeloma successfully treated with tocilizumab. Blood Adv. 2020;4(7):1307–1310. https://doi.org/10.1182/bloodadvances.2020001907.De Luna G., Habibi A., Deux J.F., Colard M., d’Orengiani A.-L., Schlemmer F. et al. Rapid and severe COVID-19 pneumonia with severe acute chest syndrome in a sickle cell patient successfully treated with Tocilizumab. Am J Hematol. 2020;95(7):876–878. https://doi.org/10.1002/ajh.25833.De Luna G., Habibi A., Deux J.F., Colard M., d’Orengiani A.-L., Schlemmer F. et al. Rapid and severe COVID-19 pneumonia with severe acute chest syndrome in a sickle cell patient successfully treated with Tocilizumab. Am J Hematol. 2020;95(7):876–878. https://doi.org/10.1002/ajh.25833.Wong S.Y., Leong K.H., Ng K.S., Tan S., Lo P.L.C., Chan K. An elderly couple with COVID-19 pneumonia treated in Singapore: contrasting clinical course and management. Singapore Med J. 2020;61(7):392–394. https://doi.org/10.11622/smedj.2020064.Wong S.Y., Leong K.H., Ng K.S., Tan S., Lo P.L.C., Chan K. An elderly couple with COVID-19 pneumonia treated in Singapore: contrasting clinical course and management. Singapore Med J. 2020;61(7):392–394. https://doi.org/10.11622/smedj.2020064.Holzhauser L., Lourenco L., Sarswat N., Kim G., Chung B., Nguyen A. Early experience of COVID-19 in two heart transplant recipients: case reports and review of treatment options. Am J Transplant. 2020;20(10):2916–2922. https://doi.org/10.1111/ajt.15982.Holzhauser L., Lourenco L., Sarswat N., Kim G., Chung B., Nguyen A. Early experience of COVID-19 in two heart transplant recipients: case reports and review of treatment options. Am J Transplant. 2020;20(10):2916–2922. https://doi.org/10.1111/ajt.15982.Blanco J.L., Ambrosioni J., Garcia F., Martínez E., Soriano A., Mallolas J., Miro J.M. COVID-19 in patients with HIV: clinical case series. Lancet HIV. 2020;7(5):e314–e316. https://doi.org/10.1016/S2352-3018(20)30111-9.Blanco J.L., Ambrosioni J., Garcia F., Martínez E., Soriano A., Mallolas J., Miro J.M. COVID-19 in patients with HIV: clinical case series. Lancet HIV. 2020;7(5):e314–e316. https://doi.org/10.1016/S2352-3018(20)30111-9.Gupta S., Wang W., Hayek S.S., Chan L., Mathews K.S., Melamedet M.L. et al. Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med. 2021;181(1):41–51. https://doi.org/10.1001/jamainternmed.2020.6252.Gupta S., Wang W., Hayek S.S., Chan L., Mathews K.S., Melamedet M.L. et al. Association between early treatment with tocilizumab and mortality among critically ill patients with COVID-19. JAMA Intern Med. 2021;181(1):41–51. https://doi.org/10.1001/jamainternmed.2020.6252.Narain S., Stefanov D.G., Chau A.S., Weber A.G., Marder G., Kaplanet B. et al. Northwell COVID-19 Research Consortium. Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease 2019 Cytokine Storm. Chest. 2020;159(3):933–948. https://doi.org/10.1016/j.chest.2020.09.275.Narain S., Stefanov D.G., Chau A.S., Weber A.G., Marder G., Kaplanet B. et al. Northwell COVID-19 Research Consortium. Comparative Survival Analysis of Immunomodulatory Therapy for Coronavirus Disease 2019 Cytokine Storm. Chest. 2020;159(3):933–948. https://doi.org/10.1016/j.chest.2020.09.275.Моисеев С.В., Авдеев С.Н., Тао Е.А., Бровко М.Ю., Яворовский А.Г., Умбетова К.Т. и др. Эффективность тоцилизумаба у пациентов с COVID-19, госпитализированных в ОРИТ: ретроспективное когортное исследование. Клиническая фармакология и терапия. 2020;(4):17–25. https://doi.org/10.32756/0869-5490-2020-4-17-25.Moiseev S.V., Avdeev S.N., Tao E.A., Brovko M.Yu., Yavorovsky A.G., Umbetova K.T. et al. Efficacy of tocilizumab in the intensive care unit patients with COVID-19: a retrospective cohort study. Clinical Pharmacology and Therapy. 2020;(4):17–25. (In Russ.) https://doi.org/10.32756/0869-5490-2020-4-17-25.Salama C., Han J., Yau L., Reiss W.G., Kramer B., Neidhartet J.D. et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;384(1):20–30. https://doi.org/10.1056/NEJMoa2030340.Salama C., Han J., Yau L., Reiss W.G., Kramer B., Neidhartet J.D. et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;384(1):20–30. https://doi.org/10.1056/NEJMoa2030340.Hermine O., Mariette X., Tharaux P., Resche-Rigon M., Porcher R., Ravaud Ph. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):32–40. https://doi.org/10.1001/jamainternmed.2020.6820.Hermine O., Mariette X., Tharaux P., Resche-Rigon M., Porcher R., Ravaud Ph. Effect of tocilizumab vs usual care in adults hospitalized with COVID-19 and moderate or severe pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):32–40. https://doi.org/10.1001/jamainternmed.2020.6820.Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637–1645. https://doi.org/10.1016/S0140-6736(21)00676-0.Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637–1645. https://doi.org/10.1016/S0140-6736(21)00676-0.Gordon A.C., Mouncey P.R., Al-Beidh F., Rowan K.R., Nichol A.D., Arabiet Y.M. et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491–1502. https://doi.org/10.1056/NEJMoa2100433.Gordon A.C., Mouncey P.R., Al-Beidh F., Rowan K.R., Nichol A.D., Arabiet Y.M. et al. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384(16):1491–1502. https://doi.org/10.1056/NEJMoa2100433.Mariette X., Hermine O., Tharaux P.L., Resche-Rigon M., Steg Ph.G., Porcher R., Ravaud Ph. A follow-up of the CORIMUNO-TOCI-1 randomized clinical trial. JAMA Intern Med. 2021;181(9):1241–1243. https://doi.org/10.1001/jamainternmed.2021.2209.Mariette X., Hermine O., Tharaux P.L., Resche-Rigon M., Steg Ph.G., Porcher R., Ravaud Ph. A follow-up of the CORIMUNO-TOCI-1 randomized clinical trial. JAMA Intern Med. 2021;181(9):1241–1243. https://doi.org/10.1001/jamainternmed.2021.2209.Rosas I.O., Bräu N., Waters M., Go R.C. , Hunter B.D. , Bhagani S. et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med. 2021;384(16):1503–1516. https://doi.org/10.1056/NEJMoa2028700.Rosas I.O., Bräu N., Waters M., Go R.C. , Hunter B.D. , Bhagani S. et al. Tocilizumab in hospitalized patients with severe Covid-19 pneumonia. N Engl J Med. 2021;384(16):1503–1516. https://doi.org/10.1056/NEJMoa2028700.Hariyanto T.I., Hardyson W., Kurniawan A. Efficacy and safety of tocilizumab for coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis. Drug Res (Stuttg). 2021;71(5):265–274. https://doi.org/10.1055/a-1336-2371.Hariyanto T.I., Hardyson W., Kurniawan A. Efficacy and safety of tocilizumab for coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis. Drug Res (Stuttg). 2021;71(5):265–274. https://doi.org/10.1055/a-1336-2371.Rezaei S., Fatemi B., Karimi M.Z., Minaei H., Peikanpour M., Anjidani N. et al. Efficacy and safety of Tocilizumab in severe and critical COVID-19: A systematic review and meta-analysis. Expert Rev Clin Immunol. 2021;17(5):499–511. https://doi.org/10.1080/1744666X.2021.1908128.Rezaei S., Fatemi B., Karimi M.Z., Minaei H., Peikanpour M., Anjidani N. et al. Efficacy and safety of Tocilizumab in severe and critical COVID-19: A systematic review and meta-analysis. Expert Rev Clin Immunol. 2021;17(5):499–511. https://doi.org/10.1080/1744666X.2021.1908128.Chen C.-X., Hu F., Wei J., Yuan L.-T., Wen T.-M., Gale R.P., Liang Y. Systematic review and meta-analysis of tocilizumab in persons with coronavirus disease-2019 (COVID-19). Leukemia. 2021;35(6):1661–1670. https://doi.org/10.1038/s41375-021-01264-8.Chen C.-X., Hu F., Wei J., Yuan L.-T., Wen T.-M., Gale R.P., Liang Y. Systematic review and meta-analysis of tocilizumab in persons with coronavirus disease-2019 (COVID-19). Leukemia. 2021;35(6):1661–1670. https://doi.org/10.1038/s41375-021-01264-8.

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