Противоревматические препараты и COVID-19: разочарования и надежды

В соответствии с полученными данными о патогенезе новой коронавирусной инфекции, некоторые противоревматические препараты рассматриваются в качестве терапевтических агентов для подавления гипервоспалительной реакции при тяжелом течении COVID-19. В обзоре представлены литературные данные об эффективности и безопасности отдельных базисных противовоспалительных и генно-инженерных биологических препаратов у пациентов с COVID-19. Гидроксихлорохин не показан для лечения инфекции SARS-CoV-2 любой степени тяжести в связи с отсутствием терапевтических преимуществ, вероятностью ухудшения прогноза у более тяжелых пациентов и развития нежелательных реакций, особенно при одновременном применении с азитромицином. Применение системных глюкокортикоидов (ГК) у пациентов с COVID-19, нуждающихся в кислородной поддержке, ведет к снижению смертности и улучшению прогноза заболевания. Однако оптимальное время назначения, доза и продолжительность приема ГК остаются предметом дальнейших исследований. Несмотря на обнадеживающие данные, окончательные выводы о целесообразности применения тоцилизумаба при COVID-19 делать пока рано, поскольку ни в одном рандомизированном клиническом исследовании не продемонстрировано явное преимущество препарата в плане уменьшения смертности. Применение анакинры не снижает потребность в неинвазивной/инвазивной вентиляции легких или смертность пациентов с COVID-19. В качестве возможных вариантов лечения COVID-19 в настоящее время рассматриваются два препарата из группы ингибиторов фактора некроза опухоли-а - инфликсимаб и адалимумаб. Одобрено применение комбинации барицитиниба и ремдесивира для лечения больных COVID-19, нуждающихся в кислородной поддержке. Требуются новые РКИ для изучения эффективности других противоревматических препаратов при COVID-19.

1. Cao B., Wang Y., Wen D., Liu W., Wang J., Fan G. et al. A trial of Lopinavir-Ritonavir in adults hospitalized with severe Covid-19. N Engl J Med. 2020;382:1787-1799. https://doi.org/10.1056/NEJMoa2001282.

2. Beigel J.H., Tomashek K.M., Dodd L.E., Mehta A.K., Zingman B.S., Kalil A.C. et al. Remdesivir for the Treatment of Covid-19 - Final Report. N Engl J Med. 2020;383:1813-1826. https://doi.org/10.1056/NEJMoa2007764.

3. Pan H., Peto R., Henao-Restrepo A.M., Preziosi M.P., Sathiyamoorthy V., Abdool Karim Q. et al. Repurposed antiviral drugs for Covid-19 - interim who solidarity trial results. N Engl J Med. 2021;384:497-511. https://doi.org/10.1056/NEJMoa2023184.

4. Devaux C.A., Rolain J.-M., Colson P, Raoult D. New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19? Int J Antimicrob Agents. 2020;55:105938. https://doi.org/10.1016/j.ijantimi-cag.2020.105938.

5. Mitja O., Corbacho-Monne M., Ubals M., Tebe C., Penafiel J., Tobias A. et al. Hydroxychloroquine for early treatment of adults with mild coronavirus disease 2019: a randomized, controlled trial. Clin Infect Dis. 2020;ciaa100. https://doi.org/10.1093/cid/ciaa1009.

6. Skipper C.P, Pastick K.A., Engen N.W., Bangdiwala A.S., Abassi M., Lofgren S.M. et al. Hydroxychloroquine in nonhospitalized adults with early COVID-19: a randomized trial. Ann Intern Med. 2020;173(8):623-631. https://doi.org/10.7326/M20-4207.

7. Abd-Elsalam S., Esmail E.S., Khalaf M., Abdo E.F., Medhat M.A., Abd El. et al. Hydroxychloroquine in the treatment of COVID-19: a multicenter randomized controlled study. Am J Trop Med Hyg. 2020;103(4):1635-1639. https://doi.org/10.4269/ajtmh.20-0873.

8. Lyngbakken M.N., Berdal J.E., Eskesen A., Kvale D., Olsen I.C., Rangberg A. et al. Norwegian coronavirus disease 2019 (NO COVID-19) pragmatic open label study to assess early use of hydroxychloroquine sulphate in moderately severe hospitalised patients with coronavirus disease 2019: a structured summary of a study protocol for a randomised controlled trial. Trials. 2020;21(1):485. https://doi.org/10.1186/s13063-020-04420-0.

9. Horby P, Mafham M., Linsell L., Bell J.L., Staplin N., Emberson J.R. et al. Effect of hydroxychloroquine in hospitalized patients with Covid-19. N Engl J Med. 2020;383:2030-2040. https://doi.org/10.1056/NEJMoa2022926.

10. Cavalcanti A.B., Zampieri F.G., Rosa R.G., Azevedo L.C.P, Veiga V.C., Avezum A. et al. Hydroxychloroquine with or without azithromycin in mild-to-moderate Covid-19. N Engl J Med. 2020;383:2041-2052. https://doi.org/10.1056/NEJMoa2019014.

11. Huang H.D., Jneid H., Aziz M., Ravi V., Sharma PS., Larsen T. et al. Safety and effectiveness of hydroxychloroquine and azithromycin combination therapy for treatment of hospitalized patients with COVID-19: a Propensity-Matched study. Cardiol Their. 2020;9:523-534. https://doi.org/10.1007/s40119-020-00201-7.

12. Tang W., Cao Z., Han M., Wang Z., Chen J., Sun W. et al. Hydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial. BMJ. 2020;369:m1849. https://doi.org/10.1136/bmj.m1849.

13. Horby P, Lim W.S., Emberson J.R., Mafham M., Bell J.L., Linsell L. et al. Dexamethasone in hospitalized patients with Covid-19 - preliminary report. N Engl J Med. 2021;384:693-704. https://doi.org/10.1056/NEJMoa2021436.

14. Tomazini B.M., Maia I.S., Cavalcanti A.B., Berwanger O., Rosa R.G., Veiga V.C. et al. Effect of dexamethasone on days alive and Ventilator-Free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the Codex randomized clinical trial. JAMA. 2020;324(13):1307. https://doi.org/10.1001/jama.2020.17021.

15. Jeronimo C.M.P., Farias M.E.L., Val F.F.A., Sampaio V.S., Alexandre M.A.A., Melo G.C. et al. Methylprednisolone as adjunctive therapy for patients hospitalized with COVID-19 (Metcovid): a randomised, double-blind, phase IIb, placebo-controlled trial. Clin Infect Dis. 2021;72(9):e373-e381. https://doi.org/10.1093/cid/ciaa1177.

16. Edalatifard M., Akhtari M., Salehi M., Naderi Z., Jamshidi A., Mostafaei S. et al. Intravenous methylprednisolone pulse as a treatment for hospitalised severe COVID-19 patients: results from a randomised controlled clinical trial. Eur Respir J. 2020;56:2002808. https://doi.org/10.1183/13993003.02808-2020.

17. Angus D.C., Berry S., Lewis RJ., Al-Beidh F., Arabi Y., van Bentum-Puijk W. et al. The REMAP-CAP (randomized embedded multifactorial adaptive platform for community-acquired pneumonia) study. Rationale and design. Ann Am Thorac Soc. 2020;17(7):879-891. https://doi.org/10.1513/AnnalsATS.202003-192SD.

18. Dequin P.F., Heming N., Meziani F., Plantefeve G., Voiriot G., Badie J. et al. Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial. JAMA. 2020;324(13):1298-1306. https://doi.org/10.1001/jama.2020.16761.

19. Tomazini B.M., Maia I.S., Cavalcanti A.B., Berwanger O., Rosa R.G., Veiga V.C. et al. Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients with Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial. JAMA. 2020;324(13):1307-1316. https://doi.org/10.1001/jama.2020.17021.

20. Biran N., Ip A., Ahn J., Go R.C., Wang S., Mathura S. et al. Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study. Lancet Rheumatol. 2020;2(10):e603-e612. https://doi.org/10.1016/S2665-9913(20)30277-0.

21. Somers E.C., Eschenauer G.A., Troost J.P., Golob J.L., Gandhi T.N., Wang L. et al. Tocilizumab for Treatment of Mechanically Ventilated Patients With COVID-19. Clin Infect Dis. 2020:ciaa954. https://doi.org/10.1093/cid/ciaa954.

22. Guaraldi G., Meschiari M., Cozzi-Lepri A., Milic J., Tonelli R., Menozzi M. et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol. 2020;2(8):e474-e484. https://doi.org/10.1016/S2665-9913(20)30173-9.

23. Salama C., Han J., Yau L., Reiss W.G., Kramer B., Neidhart J.D. et al. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021;384:20-30. https://doi.org/10.1056/NEJMoa2030340.

24. Hermine O., Mariette X., Tharaux P.L., Resche-Rigon M., Porcher R., Ravaud P. et al. 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/jamain-ternmed.2020.6820.

25. Stone J.H., Frigault MJ., Serling-Boyd NJ., Fernandes A.D., Harvey L., Foulkes A.S. et al. Efficacy of tocilizumab in patients hospitalized with Covid-19. N Engl J Med. 2020;383:2333-2344. https://doi.org/10.1056/NEJMoa2028836.

26. Salvarani C., Dolci G., Massari M., Merlo D.F., Cavuto S., Savoldi L. et al. Effect of tocilizumab vs standard care on clinical worsening in patients hospitalized with COVID-19 pneumonia: a randomized clinical trial. JAMA Intern Med. 2021;181(1):24-31. https://doi.org/10.1001/jamain-ternmed.2020.6615.

27. Gordon A.C., Mouncey P.R., AL-Beidh F., Rowan K.M., NichoL A.D. Arabi Y.M. et aL. Interleukin-6 receptor antagonists in critically ill patients with Covid-19. N Engl J Med. 2021;384:1491-1502. https://doi.org/10.1056/NEJMoa2100433.

28. Gupta S., Wang W., Hayek S.S., Chan L., Mathews K.S., MeLamed 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.

29. Fajgenbaum D.C., June C.H. Cytokine storm. N Engl J Med. 2020;383:2255-2273. https://doi.org/10.1056/NEJMra2026131.

30. Stone J.H., FrigauLt MJ., SerLing-Boyd NJ., Fernandes A.D., Harvey L., FouLkes A.S. et aL. Efficacy of tociLizumab in patients hospitaLized with Covid-19. N Engl J Med. 2020;383:2333-2344. https://doi.org/10.1056/NEJMoa2028836.

31. Pasin L., CavaLLi G., NavaLesi P., SeLLa N., Landoni G., Yavorovskiy A.G. et aL. Anakinra for patients with COVID-19: a meta-anaLysis of non-randomized cohort studies. Eur J Intern Med. 2021;86:34-40. https://doi.org/10.1016/j.ejim.2021.01.016.

32. Richardson P., Griffin I., Tucker C., Smith D., OechsLe O., PheLan A. et aL. Baricitinib as potentiaL treatment for 2019-nCoV acute respiratory disease. Lancet. 2020;395:e30-e31. https://doi.org/10.1016/S0140-6736(20)30304-4.

33. Stebbing J., PheLan A., Griffin I., Tucker C., OechsLe O., Smith D. et aL. COVID-19: combining antiviraL and anti-infLammatory treatments. Lancet Infect Dis. 2020;20:400-402. https://doi.org/10.1016/S1473-3099(20)30132-8.

34. Titanji B.K., FarLey M.M., Mehta A., Connor-SchuLer R., Moanna A., Cribbs S.K. et aL. Use of baricitinib in patients with moderate and severe COVID-19. Clin Infect Dis. 2021;72(7):1247-1250. https://doi.org/10.1093/cid/ciaa879.

35. Cantini F., NiccoLi L., Nannini C., Matarrese D., NataLe M.E.D., Lotti P. et aL. BeneficiaL impact of Baricitinib in COVID-19 moderate pneumonia; muLticentre study. J Infect. 2020;81(4):647-679. https://doi.org/10.1016/j.jinf.2020.06.052.

36. Rodriguez-Garcia J.L., Sanchez-Nievas G., ArevaLo-Serrano J., Garcia-Gomez C., Jimenez-Vizuete J.M., Martinez-ALfaro E. Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observationaL cohort study. Rheumatology (Oxford). 2021;60(1): 399-407. https://doi.org/10.1093/rheumatoLogy/keaa587.

37. KaLiL A.C., Patterson T.F., Mehta A.K., Tomashek K.M., WoLfe C.R., Ghazaryan V. et aL. Baricitinib pLus remdesivir for hospitaLised aduLts with COVID-19. N Engl J Med. 2021;384:795-807. https://doi.org/10.1056/NEJMoa2031994.

38. ALunno A., Najm A., Machado P.M., Bertheussen H., Burmester G.R., Carubbi F. et aL. EULAR points to consider on pathophysioLogy and use of immunomoduLatory therapies in COVID-19. Ann Rheum Dis. 2021. https://doi.org/10.1136/annrheumdis-2020-219724.

39. D’SiLva K.M., SerLing-Boyd N., WaLLwork R., Hsu T., Fu X., GravaLLese E.M. et aL. CLinicaL characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) and rheumatic disease: a comparative cohort study from a US “hot spot”. Ann Rheum Dis. 2020;79(9):1156-1162. https://doi.org/10.1136/annrheumdis-2020-217888.

40. Mahase E. Covid-19: Anti-TNF drug adaLimumab to be triaLLed for patients in the community. BMJ. 2020;371:m3847. https://doi.org/10.1136/bmj.m3847.

41. Scarsi M., Piantoni S., CoLombo E., Airo P., Richini D., MicLini M. et aL. Association between treatment with coLchicine and improved survivaL in a singLe-centre cohort of aduLt hospitaLised patients with COVID-19 pneumonia and acute respiratory distress syndrome. Ann Rheum Dis. 2020;79(10):-1286-1289. https://doi.org/10.1136/annrheumdis-2020-217712.

42. Chen I.Y., Moriyama M., Chang M.F., Ichinohe T. Severe Acute Respiratory Syndrome Coronavirus Viroporin 3a Activates the NLRP3 InfLammasome. Front. Microbiol. 2019;10:50. https://doi.org/10.3389/fmicb.2019.00050.

43. Brunetti L., Diawara O., Tsai A., Firestein B.L., Nahass R.G., Poiani G., SchLesinger N. CoLchicine to Weather the Cytokine Storm in HospitaLized Patients with COVID-19. J Clin Med. 2020;9(9):2961. https://doi.org/10.3390/jcm9092961.

44. Deftereos S.G., GiannopouLos G., Vrachatis D.A., Siasos G.D., Giotaki S.G., GargaLianos P. et aL. Effect of CoLchicine vs Standard Care on Cardiac and InfLammatory Biomarkers and CLinicaL Outcomes in Patients HospitaLized With Coronavirus Disease 2019: The GRECCO-19 Randomized CLinicaL TriaL. JAMA Netw Open. 2020;3(6):e2013136. https://doi.org/10.1001/jamanet-workopen.2020.13136.