A systematic review with meta-analysis of the safety of Janus kinase inhibitors in relation to the risks of secondary bacterial infections


DOI: https://dx.doi.org/10.18565/therapy.2022.4.91-100

Gomon Yu.M., Kolbin A.S., Strizheletsky V.V., Ivanov I.G., Sultanova F.M., Balykina Yu.E., Verbitskaya E.V.

1) Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Healthcare of Russia; 2) Hospital of St. George the Great Martyr, Saint Petersburg; 3) Saint Petersburg State University
Abstract. Janus kinase (JAK) inhibitors are included in both domestic and a number of international guidelines for novel coronavirus infection treatment. In order to assess the safety of the use of this class of drugs for preventive pathogenetic therapy of COVID-19, a systematic review with a meta-analysis of the results was carried out.
Material and methods. Using queries in international and Russian databases, we searched for controlled trials of baricitinib and tofacitinib recommended for use in Russia as a preventive therapy for COVID-19 mild and moderate clinical cases.
Result. Data were obtained from three randomized clinical trials. A meta-analysis of their results regarding the total number of serious adverse events and adverse events belonging to the class «Infections and invasions» showed statistically significant data on the greater safety of baricitinib and tofacitinib in relation to the risks of these events compared with standard therapy. The risk ratio for serious adverse events in the control groups was 0,82 (95% CI: 0,69–0,96; p=0,02), the risk ratio for «Infections and invasions» was 0,78 (95% CI: 0,63–0,97, p=0,03); in both cases the result was in favor of the use of JAK inhibitors.
Conclusion. Performing of various design studies in a wider patient population will allow to make more accurate assessment of the risks of developing secondary bacterial infections against the background of short-term use of JAK inhibitors as part of the preventive pathogenetic therapy for COVID-19.
Keywords: baricitinib, novel coronaviral infection COVID-19, Janus kinase inhibitors, tofacitinib
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Literature

1. Meyer N.J., Gattinoni L., Calfee C.S. Acute respiratory distress syndrome. Lancet. 2021; 398(10300): 622–37. https://dx.doi.org/10.1016/S0140-6736(21)00439-6.


2. Camporota L., Chiumello D., Busana M. et al. Pathophysiology of COVID-19-associated acute respiratory distress syndrome. Lancet Respir Med. 2021; 9(1): e1. https://dx.doi.org/10.1016/S2213-2600(20)30505-1.


3. Babon J.J., Lucet I.S., Murphy J.M. et al. The molecular regulation of Janus kinase (JAK) activation. Biochem J. 2014; 462(1): 1–13. https://dx.doi.org/10.1042/BJ20140712.


4. Bousoik E., Montazeri Aliabadi H. «Do We Know Jack» about JAK? A closer look at JAK/STAT signaling pathway. Front Oncol. 2018; 8: 287. https://dx.doi.org/10.3389/fonc.2018.00287.


5. Zhang W., Zhao Y., Zhang F. et al. The use of anti-inflammatory drugs in the treatment of people with severe coronavirus disease 2019 (COVID-19): The perspectives of clinical immunologists from China. Clin Immunol. 2020; 214: 108393. https://dx.doi.org/10.1016/j.clim.2020.108393.


6. Stebbing J., Phelan A., Griffin I. et al. COVID-19: combining antiviral and anti-inflammatory treatments. Lancet Infect Dis. 2020; 20(4): 400–2. https://dx.doi.org/10.1016/S1473-3099(20)30132-8.


7. Временные методические рекомендации «Профилактика, диагностика и лечение новой коронавирусной инфекции (COVID-19)». Версия 14 (27.12.2021). Минздрав России. Доступ: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/059/041/original/ВМР_COVID-19_V14_27-12-2021.pdf (дата обращения – 10.04.2022). [Interim guidelines «Prevention, diagnosis and treatment of novel coronavirus infection (COVID-19)». Version 14 (12/27/2021). Ministry of Healthcare of Russia. URL: https://static-0.minzdrav.gov.ru/system/attachments/attaches/000/059/041/original/ВМР_COVID-19_V14_27-12-2021.pdf (date of access – 10.04.2022) (In Russ.)].


8. COVID-19 treatment guidelines panel. Coronavirus disease 2019 (COVID-19) treatment guidelines. National Institutes of Health. URL: https://www.covid19treatmentguidelines.nih.gov (date of access – 10.04.2022).


9. Agarwal A., Rochwerg B., Lamontagne F. et al. A living WHO guideline on drugs for Covid-19. BMJ. 2020; 370: m3379. https://dx.doi.org/10.1136/bmj.m3379.


10. Food and Drug Administration. Fact sheet for healthcare providers: Emergency Use Authorization (EUA) of baricitinib. 2021. URL: https://www.fda.gov/media/143823/download (date of access – 10.04.2022).


11. Food and Drug Administration. FDA requires warnings about increased risk of serious heart-related events, cancer, blood clots, and death for JAK inhibitors that treat certain chronic inflammatory conditions. 2021. URL: https://www.fda.gov/drugs/drug-safety-and-availability/fda-requires-warnings-about-increased-risk-serious-heart-related-events-cancer-blood-clots-and-death (date of access – 10.04.2022).


12. Penman S., Kiy R.T., Jensen R.L. et al. Safety perspectives on presently considered drugs for the treatment of COVID-19. Br J Pharmacol. 2020; 177(19): 4353–74. https://dx.doi.org/10.1111/bph.15204


13. Государственный реестр лекарственных средств Минздрава России. Доступ: https://grls.rosminzdrav.ru (дата обращения – 10.04.2022). [State Register of Medicines of the Ministry of Healthcare of Russia. URL: https://grls.rosminzdrav.ru (date of access – 10.04.2022) (In Russ.)].


14. Реброва О.Ю., Федяева В.К., Хачатрян Г.Р. Адаптация и валидизация вопросника для оценки риска систематических ошибок в рандомизированных контролируемых испытаниях. Медицинские технологии. Оценка и выбор. 2015; 1: 9–17. [Rebrova O.Yu., Fedyaeva V.K., Khachatryan G.R. Adaptation and validation of the questionnaire to assess the risk of systematic errors in randomized controlled trials. Meditsinskiye tekhnologii. Otsenka i vybor = Medical Technologies. Assessment and Choice. 2015; 1: 9–17 (In Russ.)].


15. Реброва О.Ю., Федяева В.К. Вопросник для оценки риска систематических ошибок в нерандомизированных сравнительных исследованиях: русскоязычная версия шкалы Ньюкасл-Оттава. Медицинские технологии. Оценка и выбор. 2016; 3: 14–19. [Rebrova O.Yu., Fedyaeva V.K. Questionnaire for assessing the risk of systematic errors in randomized comparative studies: the Russian version of the Newcastle–Ottawa scale. Meditsinskiye tekhnologii. Otsenka i vybor = Medical Technologies. Assessment and Choice. 2016; 3: 14–19 (In Russ.)].


16. Cantini F., Niccoli L., Nannini C. et al. Beneficial impact of Baricitinib in COVID-19 moderate pneumonia; multicentre study. J Infect. 2020; 81(4): 647–79. https://dx.doi.org/10.1016/j.jinf.2020.06.052.


17. Hasan M.J., Rabbani R., Anam A.M. et al. Impact of high dose of baricitinib in severe COVID-19 pneumonia: a prospective cohort study in Bangladesh. BMC Infect Dis. 2021; 21(1): 427. https://dx.doi.org/10.1186/s12879-021-06119-2.


18. Iglesias Gomez R., Mendez R., Palanques-Pastor T. et al. Baricitinib against severe COVID-19: effectiveness and safety in hospitalised pretreated patients. Eur J Hosp Pharm. 2021: ejhpharm-2021-002741. https://dx.doi.org/10.1136/ejhpharm-2021-002741.


19. Titanji B.K., Farley M.M., Mehta A. et al. Use of baricitinib in patients with moderate to severe coronavirus disease 2019. Clin Infect Dis. 2021; 72(7): 1247–50. https://dx.doi.org/10.1093/cid/ciaa879.


20. Hasan M.J., Rabbani R., Anam A.M., Huq S.M.R. Additional baricitinib loading dose improves clinical outcome in COVID-19. Open Med (Wars). 2020; 16(1): 41–46. https://dx.doi.org/10.1515/med-2021-0010.


21. Abizanda P., Calbo Mayo J.M., Mas Romero M. Baricitinib reduces 30-day mortality in older adults with moderate-to-severe COVID-19 pneumonia. J Am Geriatr Soc. 2021; 69(10): 2752–58. https://dx.doi.org/10.1111/jgs.17357.


22. Hayek M.E., Mansour M., Ndetan H. et al. Anti-inflammatory treatment of COVID-19 pneumonia with tofacitinib alone or in combination with dexamethasone is safe and possibly superior to dexamethasone as a single agent in a predominantly African American cohort. Mayo Clin Proc Innov Qual Outcomes. 2021; 5(3): 605–13. https://dx.doi.org/10.1016/j.mayocpiqo.2021.03.007.


23. Singh P.K., Lalwani L.K., Govindagoudar M.B. et al. Tofacitinib associated with reduced intubation rates in the management of severe COVID-19 pneumonia: A preliminary experience. Indian J Crit Care Med. 2021; 25(10): 1108–12. https://dx.doi.org/10.5005/jp-journals-10071-23964.


24. Моисеев С.В., Буланов Н.М., Зыкова А.С. с соавт. Эффективность и безопасность тофацитиниба у пациентов с COVID-19: многоцентровое нерандомизированное контролируемое исследование. Клиническая фармакология и терапия. 2021; 2: 22–30. [Moiseev S.V., Bulanov N.M., Zykova A.S. et al. Efficacy and safety of tofacitinib in patients with COVID-19: a multicenter, non-randomized controlled trial. Klinicheskaya farmakologiya i terapiya = Clinical Pharmacology and Therapy. 2021; 2: 22–30 (In Russ.)]. https://dx.doi.org/10.32756/0869-5490-2021-2-22-30.


25. Kalil A.C., Patterson T.F., Mehta A.K. et al. Baricitinib plus remdesivir for hospitalized adults with Covid-19. N Engl J Med. 2021; 384(9): 795–807. https://dx.doi.org/10.1056/NEJMoa2031994.


26. Marconi V.C., Ramanan A.V., de Bono S. et al. Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): A randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. Lancet Respir Med. 2021; 9(12): 1407–18. https://dx.doi.org/10.1016/S2213-2600(21)00331-3. Erratum in: Lancet Respir Med. 2021; 9(10): e102.


27. Garcia-Garcia J.A., Perez-Quintana M., Ramos-Giraldez C. et al. Anakinra versus baricitinib: Different strategies for patients hospitalized with COVID-19. J Clin Med. 2021; 10(17): 4019. https://dx.doi.org/10.3390/jcm10174019.


28. Guimaraes P.O., Quirk D., Furtado R.H. et al. Tofacitinib in patients hospitalized with Covid-19 pneumonia. N Engl J Med. 2021; 385(5): 406–15. https://dx.doi.org/10.1056/NEJMoa2101643.


29. Allen E.N., Chandler C.I., Mandimika N., Leisegang C, Barnes K. Eliciting adverse effects data from participants in clinical trials. Cochrane Database Syst Rev. 2018; 1(1): MR000039. https://dx.doi.org/10.1002/14651858.MR000039.pub2.


30. Фармаконадзор. Под общ. ред. А.С. Колбина, С.К. Зырянова, Д.Ю. Белоусова, О.А. Логиновской. 2-е изд. (дополненное). М.: Издательство ОКИ: Буки Веди. 2022; 256 с. [Pharmacovigilance. Ed by Kolbin A.S., Zyryanov S.K., Belousov D.Yu., Loginovskaya O.A. 2nd ed. (supplemented). -Moscow: OKI Publishing House: Buki Vedi. 2022; 256 pp. (In Russ.)]. ISBN: 978-5-4465-2373-3.


31. Charan J., Dutta S., Kaur R. et al. Tocilizumab in COVID-19: A study of adverse drug events reported in the WHO database. Expert Opin Drug Saf. 2021; 20(9): 1125–36. https://dx.doi.org/10.1080/14740338.2021.1946513.


32. Jung S.Y., Kim M.S., Li H. et al. Cardiovascular events and safety outcomes associated with remdesivir using a World Health Organization international pharmacovigilance database. Clin Transl Sci. 2022; 15(2): 501–13. https://dx.doi.org/10.1111/cts.13168.


33. Kim M.S., Jung S.Y., Lee S.W. et al. Hepatobiliary adverse drug reactions associated with remdesivir: The WHO international pharmacovigilance study. Clin Gastroenterol Hepatol. 2021; 19(9): 1970–72.e3. https://dx.doi.org/10.1016/j.cgh.2021.04.039.


34. Gerard A.O., Laurain A., Fresse A. et al. Remdesivir and acute renal failure: a potential safety signal from disproportionality analysis of the WHO safety database. Clin Pharmacol Ther. 2021; 109(4): 1021–24. https://dx.doi.org/10.1002/cpt.2145.


About the Autors

Yuliya M. Gomon, Dr. med. habil., professor of the Department of clinical pharmacology and evidence-based medicine, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Healthcare of Russia, clinical pharmacologist at Hospital of St. George the Great Martyr. Address: 197022, Saint Petersburg, 6–8 Lva Tolstogo Str. E-mail: gomonmd@yandex.ru. ORCID: https://orcid.org/0000-0001-7704-9900
Alexey S. Kolbin, Dr. med. habil., professor, head of the Department of clinical pharmacology and evidence-based medicine, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Healthcare of Russia, professor of the Department of pharmacology of the medical faculty, Saint Petersburg State University. Address: 197022, Saint Petersburg, 6–8 Lva Tolstogo Str. E-mail: Alex.kolbin1971@gmail.com.
ORCID: https://orcid.org/0000-0002-1919-2909
Valery V. Strizheletsky, Dr. med. habil., professor of the Department of faculty surgery of the Faculty of medicine, Saint Petersburg State University, chief physician of Hospital of St. George the Great Martyr. Address: 194354, Saint Petersburg, 1 Severny Avenue. E-mail: B4@zdrav.spb.ru
Igor G. Ivanov, assistant at the Department of propaedeutics of internal diseases of the Faculty of medicine, Saint Petersburg State University, deputy chief physician of Hospital of St. George the Great Martyr. Address: 194354, Saint Petersburg, 1 Severny Avenue. E-mail: B4@zdrav.spb.ru
Flora M. Sultanova, surgeon at Hospital of St. George the Great Martyr. Address: 194354, Saint Petersburg, 1 Severny Avenue. E-mail: B4@zdrav.spb.ru
Yuliya E. Balykina, PhD in physics and mathematics, associate professor of the Department of mathematical modeling of energy systems of the Faculty of applied mathematics and control processes, Saint Petersburg State University. Address: 198504, Saint Petersburg 35 Universitetsky Avenue. E-mail: julia.balykina@gmail.com.
ORCID: https://orcid.org/0000-0003-2143-0440:
Elena V. Verbitskaya, PhD in biology, associate professor, associate professor of the Department of clinical pharmacology and evidence-based medicine, Academician I.P. Pavlov First Saint Petersburg State Medical University of the Ministry of Healthcare of Russia. Address: 197022, Saint Petersburg, 6–8 Lva Tolstogo Str. E-mail: elena.verbitskaya@gmail.com. ORCID: https://orcid.org/0000-0003-3770-993X


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