Effectiveness and safety of tocilizumab for COVID-19
a systematic review and meta-analysis of randomized clinical trials
Keywords:
COVID-19, SARS-CoV-2, Tocilizumab [supplementary concept]Abstract
BACKGROUND: Tocilizumab is an anti-human interleukin 6 receptor monoclonal antibody that has been used to treat coronavirus disease 2019 (COVID-19). However, there is no consensus on its efficacy for the treatment of COVID-19. OBJECTIVE: To evaluate the effectiveness and safety of tocilizumab for treating COVID-19. DESIGN AND SETTING: Systematic Review of randomized controlled trials (RCTs), Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil. METHODS: We searched MEDLINE via PubMed, EMBASE, CENTRAL, and IBECS for RCTs published up to March 2021. Two authors selected studies and assessed the risk of bias and the certainty of the evidence following Cochrane Recommendations. RESULTS: Eight RCTs with 6,139 participants were included. We were not able to find differences between using tocilizumab compared to standard care on mortality in hospitalized patients with COVID-19 (risk ratio (RR) 0.97, 95% confidence interval (CI) 0.84 to 1.13; 8 trials; 5,950 participants; low-certainty evidence). However, hospitalized patients under tocilizumab plus standard care treatment seemed to present a significantly lower risk of needing mechanical ventilation (risk ratio = 0.78; 95% CI 0.64−0.94 moderate-certainty of evidence). CONCLUSIONS: To date, the best evidence available shows no difference between using tocilizumab plus standard care compared to standard care alone for reducing mortality in patients with COVID-19. However, as a finding with a practical implication, the use of tocilizumab in association to standard care probably reduces the risk of progressing to mechanical ventilation in those patients. REGISTRATION: osf.io/qe4fs.
Downloads
References
World Health Organization. Coronavirus disease (COVID-19) pandemic. WHO: 2021, Available from: http://who.int/emergencies/diseases/novel-coronavirus-2019. Accessed in 2021 (Jun16).
Vabret N, Britton GJ, Gruber C, et al. Immunology of COVID-19: current state of the science. Immunity. 2020:52(6):910-41. PMID: 32505227; https://doi.org/10.1016/j.immuni.2020.05.002.
Zeng F, Huang Y, Guo Y, et al. Association of inflammatory markers with the severity ofCOVID-19: a meta-analysis. Int J Infect Dis. 2020;96:467-74. PMID: 32425643; https://doi.org/10.1016/j.ijid.2020.05.055.
Aziz M, Fatima R, Assaly R. Elevated interleukin-6 and severe COVID-19: a meta-analysis. J Med Virol. 2020;9 (11):2283-5. PMID: 32343429; https://doi.org/10.1002/jmv.25948.
Zhu J, Pang J, Ji P, et al. Elevated interleukin-6 is associated with severity of COVID-19: a meta-analysis. J Med Virol. 2021;93(1):35-7. PMID: 32470146; https://doi.org/10.1002/jmv.26085.
Herold T, Jurinovic V, Arnreich C, et al. Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19. J Allergy Clin Immunol. 2020;146(1): 128-136.e4. PMID: 32425269; https://doi.org/10.1016/j.jaci.2020.05.008.
Hermine O, Mariette X, Tharaux PL, 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):144, PMID: 33080017; https://doi.org/10.1001/jamainternmed.2020.6820.
Xu X, Han M, Li T, et al. Effective treatment of severe COVID-19 patients with tocilizumab. Proc Natl Acad Sci U S A. 2020;117(20):10970-5. PMID: 32350134; https://doi.org/10.1073/pnas.200561511717.
Roumier M, Paule R, Groh M, Vallée. A, Ackermann F. Interleukin-6 blockade for severe COVID-19. MedRxiv preprint. 2020. https://doi.or g/10.1101/2020.04.20.20061861.
Guaraldi G, Meschiari M, Cozzi-Lepri A, et al. Tocilizumab in patients with severe COVID-19: a retrospective cohort study. Lancet Rheumatol. 2020;2(8):e474-e484. PMID: 32835257; https://doi.org/10.1016/S2665-9913(20)30173-9.
Higgins JPT, Thomas J, Chandler J, et al. Cochrane Handbook for Systematic Reviews of Interventions version 6.2 (updated February 2021). Cochrane, 2021. Available from: www.training.cochrane.org/handbook.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557-60. PMID: 12958120; https://doi.org/10.1136/bmj.327.7414.557.
Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ. 2004;328(7454):1490. PMID: 15205295; https://doi.org/10.1136/bmj.328.7454.1490.
Stone JH, Frigault MJ, Serling-Boyd NJ, et al. Efficacy of Tocilizumab in Patients Hospitalized with Covid-19. N Engl J Med. 2020; 383(24):2333-
PMID: 33085857; https://doi.org/10.1056/NEJMoa2028836.
Veiga VC, Prats JAGG, Farias DLC, et al. Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial. BMJ. 2021;372:n84. PMID: 33472855; https://doi.org/10.1136/bmj.n84.
RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10285):1637-45. PMID: 33933206; https://doi.org/10.1016/S0140-6736(21)00676-0.
REMAP-CAP Investigators et al. Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19. N Engl J Med. 2021; 384(16):1491-502. PMID: 33631065; https://doi.org/10.1056/NEJMoa2100433.
Salama C, Han J, Yau L, etal. Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia. N Engl J Med. 2021; 384(1):20-30. PMID: 33332779; https://doi.org/10.1056/NEJMoa2030340.
Rosas IO, Bräu N, Waters M, et al. Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia. N Engl J Med. 2021;384(16):1503-16. PMID: 33631066; https://doi.org/10.1056/NEJMoa2028700.
Salvarani C, Dolci G, Massari M, 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. PMID: 33080005; https://doi.org/10.1001/jamainternmed.2020.6615.
Cortegiani A, Ippolito M, Greco M, et al. Rationale and evidence on the use of tocilizumab in COVID-19: a systematic review. Pulmonology. 2021;27(1):52-66. https://doi:10.1016/j.pulmoe.2020.07.003.
Higgins JPT, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons; 2022. Available from: https://training.cochrane.org/handbook/current. Accessed in 2022 (Jul 18).
Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112(10):3959-64. PMID: 18784373; https://doi.org/10.1182/blood-2008-05-155846.
