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Meta-Analysis
. 2021 Mar 18;3(3):CD013881.
doi: 10.1002/14651858.CD013881.

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

Lina Ghosn  1   2   3 , Anna Chaimani  3 , Theodoros Evrenoglou  3 , Mauricia Davidson  1   2   3 , Carolina Graña  1   2   3 , Christine Schmucker  4   5 , Claudia Bollig  4   5 , Nicholas Henschke  6 , Yanina Sguassero  6 , Camilla Hansen Nejstgaard  7   8 , Sonia Menon  1   2   3 , Thu Van Nguyen  3 , Gabriel Ferrand  1   2   3 , Philipp Kapp  1   2   3 , Carolina Riveros  1   2   3 , Camila Ávila  9 , Declan Devane  10   11 , Joerg J Meerpohl  4   5 , Gabriel Rada  9   12 , Asbjørn Hróbjartsson  7   8 , Giacomo Grasselli  13   14   15 , David Tovey  1 , Philippe Ravaud  1   2   3 , Isabelle Boutron  1   2   3
Affiliations
Meta-Analysis

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

Lina Ghosn et al. Cochrane Database Syst Rev. .

Update in

  • Interleukin-6 blocking agents for treating COVID-19: a living systematic review.
    Ghosn L, Assi R, Evrenoglou T, Buckley BS, Henschke N, Probyn K, Riveros C, Davidson M, Graña C, Bonnet H, Jarde A, Ávila C, Nejstgaard CH, Menon S, Ferrand G, Kapp P, Breuer C, Schmucker C, Sguassero Y, Nguyen TV, Devane D, Meerpohl JJ, Rada G, Hróbjartsson A, Grasselli G, Tovey D, Ravaud P, Chaimani A, Boutron I. Ghosn L, et al. Cochrane Database Syst Rev. 2023 Jun 1;6(6):CD013881. doi: 10.1002/14651858.CD013881.pub2. Cochrane Database Syst Rev. 2023. PMID: 37260086 Free PMC article.

Abstract

Background: Interleukin 6 (IL-6) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19). Their immunosuppressive effect might be valuable in patients with COVID-19 characterised by substantial immune system dysfunction by controlling inflammation and promoting disease tolerance.

Objectives: To assess the effect of IL-6 blocking agents compared to standard care alone or with placebo on efficacy and safety outcomes in COVID-19. We will update this assessment regularly.

Search methods: We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (up to 11 February 2021) and the L-OVE platform, and Cochrane COVID-19 Study Register to identify trials up to 26 February 2021.

Selection criteria: We included randomised controlled trials (RCTs) evaluating IL-6 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity.

Data collection and analysis: We followed standard Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two review authors independently collected data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence with the GRADE approach for the critical outcomes such as clinical improvement (defined as hospital discharge or improvement on the scale used by trialists to evaluate clinical progression or recovery) (day (D) 28 / ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28 / ≥ D60); all-cause mortality (D28 / ≥ D60); incidence of any adverse events; and incidence of serious adverse events.

Main results: We identified 10 RCTs with available data including one platform trial comparing tocilizumab and sarilumab with standard of care. These trials evaluated tocilizumab (nine RCTs including two platform trials; seven were reported as peer-reviewed articles, two as preprints; 6428 randomised participants); and two sarilumab (one platform trial reported as peer reviewed article, one reported as preprint, 880 randomised participants). All trials included were multicentre trials. They were conducted in Brazil, China, France, Italy, UK, USA, and four were multi-country trials. The mean age range of participants ranged from 56 to 65 years; 4572 (66.3%) of trial participants were male. Disease severity ranged from mild to critical disease. The reported proportion of participants on oxygen at baseline but not intubated varied from 56% to 100% where reported. Five trials reported the inclusion of intubated patients at baseline. We identified a further 20 registered RCTs of tocilizumab compared to placebo/standard care (five completed without available results, five terminated without available results, eight ongoing, two not recruiting); 11 RCTs of sarilumab (two completed without results, three terminated without available results, six ongoing); six RCTs of clazakisumab (five ongoing, one not recruiting); two RCTs of olokizumab (one completed, one not recruiting); one of siltuximab (ongoing) and one RCT of levilimab (completed without available results). Of note, three were cancelled (2 tocilizumab, 1 clazakisumab). One multiple-arm RCT evaluated both tocilizumab and sarilumab compared to standard of care, one three-arm RCT evaluated tocilizumab and siltuximab compared to standard of care and consequently they appear in each respective comparison. Tocilizumab versus standard care alone or with placebo a. Effectiveness of tocilizumab for patients with COVID-19 Tocilizumab probably results in little or no increase in the outcome of clinical improvement at D28 (RR 1.06, 95% CI 1.00 to 1.13; I2 = 40.9%; 7 RCTs, 5585 participants; absolute effect: 31 more with clinical improvement per 1000 (from 0 fewer to 67 more); moderate-certainty evidence). However, we cannot exclude that some subgroups of patients could benefit from the treatment. We did not obtain data for longer-term follow-up (≥ D60). The effect of tocilizumab on the proportion of participants with a WHO Clinical Progression Score of level of 7 or above is uncertain at D28 (RR 0.99, 95% CI 0.56 to 1.74; I2 = 64.4%; 3 RCTs, 712 participants; low-certainty evidence). We did not obtain data for longer-term follow-up (≥ D60). Tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo (RR 0.89, 95% CI 0.82 to 0.97; I2 = 0.0%; 8 RCTs, 6363 participants; absolute effect: 32 fewer deaths per 1000 (from 52 fewer to 9 fewer); high-certainty evidence). The evidence suggests uncertainty around the effect on mortality at ≥ D60 (RR 0.86, 95% CI 0.53 to 1.40; I2 = 0.0%; 2 RCTs, 519 participants; low-certainty evidence). b. Safety of tocilizumab for patients with COVID-19 The evidence is very uncertain about the effect of tocilizumab on adverse events (RR 1.23, 95% CI 0.87 to 1.72; I2 = 86.4%; 7 RCTs, 1534 participants; very low-certainty evidence). Nevertheless, tocilizumab probably results in slightly fewer serious adverse events than standard care alone or placebo (RR 0.89, 95% CI 0.75 to 1.06; I2 = 0.0%; 8 RCTs, 2312 participants; moderate-certainty evidence). Sarilumab versus standard care alone or with placebo The evidence is uncertain about the effect of sarilumab on all-cause mortality at D28 (RR 0.77, 95% CI 0.43 to 1.36; 2 RCTs, 880 participants; low certainty), on all-cause mortality at ≥ D60 (RR 1.00, 95% CI 0.50 to 2.0; 1 RCT, 420 participants; low certainty), and serious adverse events (RR 1.17, 95% CI 0.77 to 1.77; 2 RCTs, 880 participants; low certainty). It is unlikely that sarilumab results in an important increase of adverse events (RR 1.05, 95% CI 0.88 to 1.25; 1 RCT, 420 participants; moderate certainty). However, an increase cannot be excluded No data were available for other critical outcomes.

Authors' conclusions: On average, tocilizumab reduces all-cause mortality at D28 compared to standard care alone or placebo and probably results in slightly fewer serious adverse events than standard care alone or placebo. Nevertheless, tocilizumab probably results in little or no increase in the outcome clinical improvement (defined as hospital discharge or improvement measured by trialist-defined scales) at D28. The impact of tocilizumab on other outcomes is uncertain or very uncertain. With the data available, we were not able to explore heterogeneity. Individual patient data meta-analyses are needed to be able to identify which patients are more likely to benefit from this treatment. Evidence for an effect of sarilumab is uncertain and evidence for other anti-IL6 agents is unavailable. Thirty-nine RCTs of IL-6 blocking agents with no results are currently registered, of which nine are completed and seven trials were terminated with no results available. The findings of this review will be updated as new data are made available on the COVID-NMA platform (covid-nma.com).

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Conflict of interest statement

Lina Ghosn has no interest to declare.

Anna Chaimani has no interest to declare.

Theodoros Evrenoglou has no interest to declare.

Mauricia Davidson has no interest to declare.

Carolina Graña has no interest to declare.

Christine Schmucker has no interest to declare.

Claudia Bollig has no interest to declare.

Nicholas Henschke has been an employee of Cochrane Response since 2016. Cochrane Response was commissioned by the WHO to perform parts of this systematic review.

Yanina Sguassero been an employee of Cochrane Response since 2019. Cochrane Response was commissioned by the WHO to undertake tasks relevant to this systematic review.

Camilla Hansen Nejstgaard has no interest to declare.

Sonia Menon works as a systematic reviewer for p95 consultancy company.

Thu Van Nguyen has no interest to declare.

Gabriel Ferrand has no interest to declare.

Philip Kapp has no interest to declare.

Carolina Riveros has no interest to declare.

Camila Ávila has no interest to declare.

Declan Devane is Principal Investigator for a grant from the Health Research Board (HRB, Ireland) and the Health and Social Care, Research and Development (HSC R&D) Division of the Public Health Agency in Northern Ireland to establish Evidence Synthesis Ireland within which Cochrane Ireland is hosted. The funds are received by his institution. Declan's position as Director of Cochrane Ireland and Director of Cochrane Ireland is paid 0.5FTE from this grant.

Joerg J Meerpohl has no interest to declare.

Gabriel Rada has no interest to declare.

Asbjørn Hróbjartsson has no interest to declare.

Giacomo Grasselli has received personal fees for lectures from Getinge, Fisher&Paykel, Draeger Medical, Biotest, Thermofisher and MSD; support for travel‐meeting expenses from Biotest and Getinge (all outside the present work). I also received an unrestricted research grant from Fisher&Paykel (unrelated to the present work).

David Tovey is a paid editorial advisor to Cochrane France.

Philippe Ravaud is minority shareholder of INATO and SAVANA. He is also principal investigator of the CORIMUNO platform (funding: French Ministry of Health, Programme Hospitalier de Recherche Clinique [PHRC COVID‐19‐20‐0143, PHRC COVID‐19‐20‐0029], Foundation for Medical Research (FRM), AP‐HP Foundation and the Reacting program).

Isabelle Boutron has no interest to declare.

Figures

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Flowchart of included RCTs of interleukin 6 (IL‐6) blocking agents (last search date 11 February 2021). COVID‐NMA is a living systematic review of all trials assessing treatment and preventive interventions for COVID‐19 (Boutron 2020b). This review is a sub‐review of COVID‐NMA. *two multiple‐arm RCTs evaluated both tocilizumab and sarilumab, one three‐arm RCT evaluated tocilizumab and siltuximab and consequently they appear twice. §one multi‐arm RCT evaluated both tocilizumab and sarilumab
2
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Tociliuzumab compared to standard care/placebo for mild/moderate/severe/critical COVID‐19: Clinical improvement D28
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Tociliuzumab compared to standard care/placebo for mild/moderate/severe/critical COVID‐19: WHO progression score (level 7 or above) D28
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Tociliuzumab compared to standard care/placebo for mild/moderate/severe/critical COVID‐19: All‐cause mortality D28
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Tociliuzumab compared to standard care/placebo for mild/moderate/severe/critical COVID‐19: All‐cause mortality D60 or above
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Tociliuzumab compared to standard care/placebo for mild/moderate/severe/critical COVID‐19: Adverse events
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Tociliuzumab compared to standard care/placebo for mild/moderate/severe/critical COVID‐19: Serious adverse events
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Sarilumab compared to standard care for severe/critical COVID‐19: All‐cause mortality D28
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Sarilumab compared to standard care for severe/critical COVID‐19:All‐cause mortality D60 or above
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Sarilumab compared to standard care for severe/critical COVID‐19: Adverse events
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Sarilumab compared to standard care for severe/critical COVID‐19:Serious adverse events
See this image and copyright information in PMC

Comment in

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