Interleukin-6 blocking agents for treating COVID-19: a living systematic review.

BACKGROUND It has been reported that people with COVID-19 and pre-existing autoantibodies against type I interferons are likely to develop an inflammatory cytokine storm responsible for severe respiratory symptoms. Since interleukin 6 (IL-6) is one of the cytokines released during this inflammatory process, IL-6 blocking agents have been used for treating people with severe COVID-19. OBJECTIVES To update the evidence on the effectiveness and safety of IL-6 blocking agents compared to standard care alone or to a placebo for people with COVID-19. SEARCH METHODS We searched the World Health Organization (WHO) International Clinical Trials Registry Platform, the Living OVerview of Evidence (L·OVE) platform, and the Cochrane COVID-19 Study Register to identify studies on 7 June 2022. SELECTION CRITERIA We included randomized controlled trials (RCTs) evaluating IL-6 blocking agents compared to standard care alone or to placebo for people with COVID-19, regardless of disease severity. DATA COLLECTION AND ANALYSIS Pairs of researchers independently conducted study selection, extracted data and assessed risk of bias. We assessed the certainty of evidence using the GRADE approach for all critical and important outcomes. In this update we amended our protocol to update the methods used for grading evidence by establishing minimal important differences for the critical outcomes. MAIN RESULTS This update includes 22 additional trials, for a total of 32 trials including 12,160 randomized participants all hospitalized for COVID-19 disease. We identified a further 17 registered RCTs evaluating IL-6 blocking agents without results available as of 7 June 2022.  The mean age range varied from 56 to 75 years; 66.2% (8051/12,160) of enrolled participants were men. One-third (11/32) of included trials were placebo-controlled. Twenty-two were published in peer-reviewed journals, three were reported as preprints, two trials had results posted only on registries, and results from five trials were retrieved from another meta-analysis. Eight were funded by pharmaceutical companies.  Twenty-six included studies were multicenter trials; four were multinational and 22 took place in single countries. Recruitment of participants occurred between February 2020 and June 2021, with a mean enrollment duration of 21 weeks (range 1 to 54 weeks). Nineteen trials (60%) had a follow-up of 60 days or more. Disease severity ranged from mild to critical disease. The proportion of participants who were intubated at study inclusion also varied from 5% to 95%. Only six trials reported vaccination status; there were no vaccinated participants included in these trials, and 17 trials were conducted before vaccination was rolled out. We assessed a total of six treatments, each compared to placebo or standard care. Twenty trials assessed tocilizumab, nine assessed sarilumab, and two assessed clazakizumab. Only one trial was included for each of the other IL-6 blocking agents (siltuximab, olokizumab, and levilimab). Two trials assessed more than one treatment. Efficacy and safety of tocilizumab and sarilumab compared to standard care or placebo for treating COVID-19 At day (D) 28, tocilizumab and sarilumab probably result in little or no increase in clinical improvement (tocilizumab: risk ratio (RR) 1.05, 95% confidence interval (CI) 1.00 to 1.11; 15 RCTs, 6116 participants; moderate-certainty evidence; sarilumab: RR 0.99, 95% CI 0.94 to 1.05; 7 RCTs, 2425 participants; moderate-certainty evidence). For clinical improvement at ≥ D60, the certainty of evidence is very low for both tocilizumab (RR 1.10, 95% CI 0.81 to 1.48; 1 RCT, 97 participants; very low-certainty evidence) and sarilumab (RR 1.22, 95% CI 0.91 to 1.63; 2 RCTs, 239 participants; very low-certainty evidence). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score (WHO-CPS) of level 7 or above remains uncertain at D28 (RR 0.90, 95% CI 0.72 to 1.12; 13 RCTs, 2117 participants; low-certainty evidence) and that for sarilumab very uncertain (RR 1.10, 95% CI 0.90 to 1.33; 5 RCTs, 886 participants; very low-certainty evidence). Tocilizumab reduces all cause-mortality at D28 compared to standard care/placebo (RR 0.88, 95% CI 0.81 to 0.94; 18 RCTs, 7428 participants; high-certainty evidence). The evidence about the effect of sarilumab on this outcome is very uncertain (RR 1.06, 95% CI 0.86 to 1.30; 9 RCTs, 3305 participants; very low-certainty evidence). The evidence is uncertain for all cause-mortality at ≥ D60 for tocilizumab (RR 0.91, 95% CI 0.80 to 1.04; 9 RCTs, 2775 participants; low-certainty evidence) and very uncertain for sarilumab (RR 0.95, 95% CI 0.84 to 1.07; 6 RCTs, 3379 participants; very low-certainty evidence). Tocilizumab probably results in little to no difference in the risk of adverse events (RR 1.03, 95% CI 0.95 to 1.12; 9 RCTs, 1811 participants; moderate-certainty evidence). The evidence about adverse events for sarilumab is uncertain (RR 1.12, 95% CI 0.97 to 1.28; 4 RCT, 860 participants; low-certainty evidence).  The evidence about serious adverse events is very uncertain for tocilizumab (RR 0.93, 95% CI 0.81 to 1.07; 16 RCTs; 2974 participants; very low-certainty evidence) and uncertain for sarilumab (RR 1.09, 95% CI 0.97 to 1.21; 6 RCTs; 2936 participants; low-certainty evidence). Efficacy and safety of clazakizumab, olokizumab, siltuximab and levilimab compared to standard care or placebo for treating COVID-19 The evidence about the effects of clazakizumab, olokizumab, siltuximab, and levilimab comes from only one or two studies for each blocking agent, and is uncertain or very uncertain. AUTHORS' CONCLUSIONS In hospitalized people with COVID-19, results show a beneficial effect of tocilizumab on all-cause mortality in the short term and probably little or no difference in the risk of adverse events compared to standard care alone or placebo. Nevertheless, both tocilizumab and sarilumab probably result in little or no increase in clinical improvement at D28. Evidence for an effect of sarilumab and the other IL-6 blocking agents on critical outcomes is uncertain or very uncertain. Most of the trials included in our review were done before the waves of different variants of concern and before vaccination was rolled out on a large scale. An additional 17 RCTs of IL-6 blocking agents are currently registered with no results yet reported. The number of pending studies and the number of participants planned is low. Consequently, we will not publish further updates of this review.

[1]  G. Guyatt,et al.  GRADE Guidance article 35: Update on rating imprecision for assessing contextualized certainty of evidence and making decisions. , 2022, Journal of clinical epidemiology.

[2]  E. Petkova,et al.  A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation* , 2022, Critical care medicine.

[3]  I. Douglas,et al.  Tocilizumab in patients hospitalised with COVID-19 pneumonia: Efficacy, safety, viral clearance, and antibody response from a randomised controlled trial (COVACTA) , 2022, eClinicalMedicine.

[4]  Miyoung Choi,et al.  Clinical efficacy and safety of interleukin-6 receptor antagonists (tocilizumab and sarilumab) in patients with COVID-19: a systematic review and meta-analysis , 2022, Emerging microbes & infections.

[5]  S. Jamal,et al.  Reduced fixed dose tocilizumab 400 mg IV compared to weight-based dosing in critically ill patients with COVID-19: A before-after cohort study , 2022, The Lancet Regional Health - Americas.

[6]  E. Löyttyniemi,et al.  Early administration of tocilizumab in hospitalized COVID-19 patients with elevated inflammatory markers; COVIDSTORM—a prospective, randomized, single-centre, open-label study , 2022, Clinical Microbiology and Infection.

[7]  R. Dhond,et al.  Subcutaneous sarilumab for the treatment of hospitalized patients with moderate to severe COVID19 disease: A pragmatic, embedded randomized clinical trial , 2022, PloS one.

[8]  R. Guleria,et al.  Tocilizumab for COVID-19: A systematic review and meta-analysis of randomized controlled trials. , 2022, Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace.

[9]  P. Ravaud,et al.  Effect of interleukin-6 receptor antagonists in critically ill adult patients with COVID-19 pneumonia: two randomised controlled trials of the CORIMUNO-19 Collaborative Group , 2022, European Respiratory Journal.

[10]  Guanzhao Liang,et al.  Association between tocilizumab treatment and clinical outcomes of COVID-19 patients: a systematic review and meta-analysis , 2022, Aging.

[11]  G. McComsey,et al.  Safety and Efficacy of Tocilizumab 4 or 8 mg/kg in Hospitalized Patients With Moderate to Severe Coronavirus Disease 2019 Pneumonia: A Randomized Clinical Trial , 2021, Open forum infectious diseases.

[12]  OUP accepted manuscript , 2022, Clinical Infectious Diseases.

[13]  R. León-López,et al.  Early Use of Sarilumab in Patients Hospitalized with COVID-19 Pneumonia and Features of Systemic Inflammation: the SARICOR Randomized Clinical Trial , 2021, Antimicrobial agents and chemotherapy.

[14]  E. Vicaut,et al.  Sarilumab in adults hospitalised with moderate-to-severe COVID-19 pneumonia (CORIMUNO-SARI-1): An open-label randomised controlled trial , 2021, The Lancet Rheumatology.

[15]  J. Buades,et al.  Efficacy and Safety of Sarilumab in patients with COVID19 Pneumonia: A Randomized, Phase III Clinical Trial (SARTRE Study) , 2021, Infectious Diseases and Therapy.

[16]  K. Blyth,et al.  Prognostic and Predictive Biomarkers in Patients With Coronavirus Disease 2019 Treated With Tocilizumab in a Randomized Controlled Trial* , 2021, Critical care medicine.

[17]  B. Lambrecht,et al.  Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial , 2021, The Lancet Respiratory Medicine.

[18]  V. Mazurov,et al.  The efficacy and safety of levilimab in severely ill COVID-19 patients not requiring mechanical ventilation: results of a multicenter randomized double-blind placebo-controlled phase III CORONA clinical study , 2021, Inflammation research : official journal of the European Histamine Research Society ... [et al.].

[19]  M. Netea,et al.  Early treatment of COVID-19 with anakinra guided by soluble urokinase plasminogen receptor plasma levels: a double-blind, randomized controlled phase 3 trial , 2021, Nature Medicine.

[20]  I. Boutron,et al.  Secondary electronic sources demonstrated very good sensitivity for identifying studies evaluating interventions for COVID-19 , 2021, Journal of Clinical Epidemiology.

[21]  Peter J. Godolphin,et al.  Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. , 2021, JAMA.

[22]  M. Polymeropoulos,et al.  Assessing the potential correlation of polymorphisms in the IL6R with relative IL6 elevation in severely ill COVID-19 patients’ , 2021, Cytokine.

[23]  A. Verma,et al.  Managing drug shortages during a pandemic: tocilizumab and COVID-19 , 2021, Canadian Medical Association Journal.

[24]  Eric A. Meyerowitz,et al.  EFFECT OF TOCILIZUMAB ON CARDIAC INJURY AND DYSFUNCTION IN COVID-19 , 2021, Journal of the American College of Cardiology.

[25]  Steve B Jones,et al.  Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial , 2021, Lancet.

[26]  R. Gans,et al.  Timely Administration of Tocilizumab Improves Survival of Hospitalized COVID-19 Patients , 2021, SSRN Electronic Journal.

[27]  I. Boutron,et al.  Day-to-day discovery of preprint–publication links , 2021, Scientometrics.

[28]  B. Wiratama,et al.  Immunomodulation as a Potent COVID-19 Pharmacotherapy: Past, Present and Future , 2021, Journal of inflammation research.

[29]  I. Boutron,et al.  Interleukin-6 blocking agents for treating COVID-19: a living systematic review. , 2021, The Cochrane database of systematic reviews.

[30]  M. Biehl,et al.  Severe covid-19 pneumonia: pathogenesis and clinical management , 2021, BMJ.

[31]  Xiaojing Wang,et al.  Tocilizumab in patients with moderate or severe COVID-19: a randomized, controlled, open-label, multicenter trial , 2021, Frontiers of Medicine.

[32]  Y. Mehta,et al.  Tocilizumab plus standard care versus standard care in patients in India with moderate to severe COVID-19-associated cytokine release syndrome (COVINTOC): an open-label, multicentre, randomised, controlled, phase 3 trial , 2021, The Lancet Respiratory Medicine.

[33]  G. Canonica,et al.  Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial , 2021, The Lancet Respiratory Medicine.

[34]  L. Amato,et al.  [The praise of uncertainty: a systematic living review to evaluate the efficacy and safety of drug treatments for patients with covid-19.] , 2021, Recenti progressi in medicina.

[35]  M. Cortón,et al.  IL-6–based mortality prediction model for COVID-19: Validation and update in multicenter and second wave cohorts , 2021, Journal of Allergy and Clinical Immunology.

[36]  I. Douglas,et al.  Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia , 2021, The New England journal of medicine.

[37]  Christopher M. Horvat,et al.  Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19 - Preliminary report , 2021, medRxiv.

[38]  E. Vicaut,et al.  Effect of anakinra versus usual care in adults in hospital with COVID-19 and mild-to-moderate pneumonia (CORIMUNO-ANA-1): a randomised controlled trial , 2021, The Lancet Respiratory Medicine.

[39]  Á. Avezum,et al.  Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial , 2021, BMJ.

[40]  L. Fabbri,et al.  Systematic review and meta-analysis of anakinra, sarilumab, siltuximab and tocilizumab for COVID-19 , 2021, Thorax.

[41]  W. Lim,et al.  Dexamethasone in Hospitalized Patients with Covid-19 , 2021 .

[42]  J. Casanova,et al.  Life-Threatening COVID-19: Defective Interferons Unleash Excessive Inflammation , 2020, Med.

[43]  G. Criner,et al.  Tocilizumab in Patients Hospitalized with Covid-19 Pneumonia , 2020, The New England journal of medicine.

[44]  Cameron R. Wolfe,et al.  Baricitinib plus Remdesivir for Hospitalized Adults with Covid-19 , 2020, The New England journal of medicine.

[45]  N. Koulouris,et al.  Untuned antiviral immunity in COVID-19 revealed by temporal type I/III interferon patterns and flu comparison , 2020, Nature Immunology.

[46]  I. Boutron,et al.  Changes in evidence for studies assessing interventions for COVID-19 reported in preprints: meta-research study , 2020, BMC Medicine.

[47]  J. Jakobsen,et al.  Interventions for treatment of COVID-19: Second edition of a living systematic review with meta-analyses and trial sequential analyses (The LIVING Project) , 2020, medRxiv.

[48]  I. Tleyjeh,et al.  Efficacy and safety of tocilizumab in COVID-19 patients: a living systematic review and meta-analysis , 2020, Clinical Microbiology and Infection.

[49]  I. Boutron,et al.  Interventions for the prevention and treatment of COVID-19: a living mapping of research and living network meta-analysis , 2020, Cochrane Database of Systematic Reviews.

[50]  G. Mutlu,et al.  IL-6 Inhibition in Critically Ill COVID-19 Patients Is Associated With Increased Secondary Infections , 2020, Frontiers in Medicine.

[51]  Eric A. Meyerowitz,et al.  Efficacy of Tocilizumab in Patients Hospitalized with Covid-19 , 2020, The New England journal of medicine.

[52]  R. Porcher,et al.  Effect of Tocilizumab vs Usual Care in Adults Hospitalized With COVID-19 and Moderate or Severe Pneumonia: A Randomized Clinical Trial. , 2020, JAMA internal medicine.

[53]  M. Massari,et al.  Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial. , 2020, JAMA internal medicine.

[54]  T. Hirano,et al.  How COVID-19 induces cytokine storm with high mortality , 2020, Inflammation and regeneration.

[55]  T. Cavero,et al.  IL-6 serum levels predict severity and response to tocilizumab in COVID-19: An observational study , 2020, Journal of Allergy and Clinical Immunology.

[56]  Samuel M. Brown,et al.  Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study , 2020, The Lancet Rheumatology.

[57]  G. Criner,et al.  Preliminary predictive criteria for COVID-19 cytokine storm , 2020, Annals of the Rheumatic Diseases.

[58]  Steven M. Holland,et al.  Autoantibodies against type I IFNs in patients with life-threatening COVID-19 , 2020, Science.

[59]  I. Boutron,et al.  The COVID-NMA Project: Building an Evidence Ecosystem for the COVID-19 Pandemic , 2020, Annals of Internal Medicine.

[60]  I. González-Álvaro,et al.  Subcutaneous Sarilumab in hospitalised patients with moderate-severe COVID-19 infection compared to the standard of care (SARCOVID): a structured summary of a study protocol for a randomised controlled trial , 2020, Trials.

[61]  C. Wellington,et al.  Confronting the controversy: interleukin-6 and the COVID-19 cytokine storm syndrome , 2020, European Respiratory Journal.

[62]  C. Wellington,et al.  The Association of Inflammatory Cytokines in the Pulmonary Pathophysiology of Respiratory Failure in Critically Ill Patients With Coronavirus Disease 2019 , 2020, Critical care explorations.

[63]  X. Yao,et al.  Tocilizumab Ameliorates the Hypoxia in COVID-19 Moderate Patients with Bilateral Pulmonary Lesions: A Randomized, Controlled, Open-Label, Multicenter Trial , 2020 .

[64]  M. Singer,et al.  COVID-19-associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study , 2020, The Lancet Rheumatology.

[65]  C. Campochiaro,et al.  The conundrum of interleukin-6 blockade in COVID-19 , 2020, The Lancet Rheumatology.

[66]  G. Guyatt,et al.  Drug treatments for covid-19: living systematic review and network meta-analysis , 2020, BMJ.

[67]  Eric Song,et al.  Longitudinal analyses reveal immunological misfiring in severe COVID-19 , 2020, Nature.

[68]  N. Laura,et al.  Interleukin-6-based mortality risk model for hospitalised COVID-19 patients , 2020, Journal of Allergy and Clinical Immunology.

[69]  R. Fumagalli,et al.  Safety and efficacy of anti-il6-receptor tocilizumab use in severe and critical patients affected by coronavirus disease 2019: A comparative analysis , 2020, Journal of Infection.

[70]  J. Jordán,et al.  A systematic review on the efficacy and safety of IL-6 modulatory drugs in the treatment of COVID-19 patients. , 2020, European review for medical and pharmacological sciences.

[71]  M. Massari,et al.  Tocilizumab in patients with severe COVID-19: a retrospective cohort study , 2020, The Lancet Rheumatology.

[72]  Mike Clarke,et al.  A minimal common outcome measure set for COVID-19 clinical research , 2020, The Lancet Infectious Diseases.

[73]  Jing Liu,et al.  Ruxolitinib in treatment of severe coronavirus disease 2019 (COVID-19): A multicenter, single-blind, randomized controlled trial , 2020, Journal of Allergy and Clinical Immunology.

[74]  B. Lipworth,et al.  Elevated levels of IL-6 and CRP predict the need for mechanical ventilation in COVID-19 , 2020, Journal of Allergy and Clinical Immunology.

[75]  T. Kishimoto,et al.  Historical overview of the interleukin-6 family cytokine , 2020, The Journal of experimental medicine.

[76]  Y. Ho,et al.  SARS-CoV-2: A Storm is Raging. , 2020, The Journal of clinical investigation.

[77]  P. Mehta,et al.  COVID-19: consider cytokine storm syndromes and immunosuppression , 2020, The Lancet.

[78]  Gerta Rücker,et al.  How to perform a meta-analysis with R: a practical tutorial , 2019, Evidence-Based Mental Health.

[79]  Natalie S Blencowe,et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials , 2019, BMJ.

[80]  D. Altman,et al.  Outcome reporting bias in trials: a methodological approach for assessment and adjustment in systematic reviews , 2018, British Medical Journal.

[81]  Dimitris Mavridis,et al.  Allowing for Informative Missingness in Aggregate Data Meta-Analysis with Continuous or Binary Outcomes: Extensions to Metamiss , 2018, The Stata journal.

[82]  L. Scott Tocilizumab: A Review in Rheumatoid Arthritis , 2017, Drugs.

[83]  J. Stone,et al.  Trial of Tocilizumab in Giant‐Cell Arteritis , 2017, The New England journal of medicine.

[84]  Hossam M. Hammady,et al.  Rayyan—a web and mobile app for systematic reviews , 2016, Systematic Reviews.

[85]  Dimitris Mavridis,et al.  Allowing for uncertainty due to missing continuous outcome data in pairwise and network meta‐analysis , 2015, Statistics in medicine.

[86]  G. Salanti,et al.  Missing outcome data in meta-analysis , 2014, Evidence Based Journals.

[87]  Richard D Riley,et al.  Interpretation of random effects meta-analyses , 2011, BMJ : British Medical Journal.

[88]  Wolfgang Viechtbauer,et al.  Conducting Meta-Analyses in R with the metafor Package , 2010 .

[89]  Ian R White,et al.  Allowing for uncertainty due to missing data in meta‐analysis—Part 1: Two‐stage methods , 2008, Statistics in medicine.

[90]  M. Sydes,et al.  Practical methods for incorporating summary time-to-event data into meta-analysis , 2007, Trials.