CoChat
Sign Up
Cited by 678COVID-19 Clinical Research StudiesRespiratory Support and MechanismsSARS-CoV-2 and COVID-19 Research

Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis

Open access
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Domingo, Pere, Mur, Isabel, Mateo, Gracia María, Gutierrez, Maria del Mar, Pomar, Virginia, de Benito, Natividad, Corbacho, Noemí +345 more·2021·JAMA
DOI 10.1001/jama.2021.11330PMC PMC8261689
Open this paper in CoChat — free account

Abstract

Importance: Clinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm. Objective: To estimate the association between administration of IL-6 antagonists compared with usual care or placebo and 28-day all-cause mortality and other outcomes. Data Sources: Trials were identified through systematic searches of electronic databases between October 2020 and January 2021. Searches were not restricted by trial status or language. Additional trials were identified through contact with experts. Study Selection: Eligible trials randomly assigned patients hospitalized for COVID-19 to a group in whom IL-6 antagonists were administered and to a group in whom neither IL-6 antagonists nor any other immunomodulators except corticosteroids were administered. Among 72 potentially eligible trials, 27 (37.5%) met study selection criteria. Data Extraction and Synthesis: In this prospective meta-analysis, risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance-weighted fixed-effects meta-analysis of odds ratios (ORs) for 28-day all-cause mortality. Main Outcomes and Measures: The primary outcome measure was all-cause mortality at 28 days after randomization. There were 9 secondary outcomes including progression to invasive mechanical ventilation or death and risk of secondary infection by 28 days. Results: A total of 10 930 patients (median age, 61 years [range of medians, 52-68 years]; 3560 [33%] were women) participating in 27 trials were included. By 28 days, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo (summary OR, 0.86 [95% CI, 0.79-0.95]; P = .003 based on a fixed-effects meta-analysis). This corresponds to an absolute mortality risk of 22% for IL-6 antagonists compared with an assumed mortality risk of 25% for usual care or placebo. The corresponding summary ORs were 0.83 (95% CI, 0.74-0.92; P < .001) for tocilizumab and 1.08 (95% CI, 0.86-1.36; P = .52) for sarilumab. The summary ORs for the association with mortality compared with usual care or placebo in those receiving corticosteroids were 0.77 (95% CI, 0.68-0.87) for tocilizumab and 0.92 (95% CI, 0.61-1.38) for sarilumab. The ORs for the association with progression to invasive mechanical ventilation or death, compared with usual care or placebo, were 0.77 (95% CI, 0.70-0.85) for all IL-6 antagonists, 0.74 (95% CI, 0.66-0.82) for tocilizumab, and 1.00 (95% CI, 0.74-1.34) for sarilumab. Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16). Conclusions and Relevance: In this prospective meta-analysis of clinical trials of patients hospitalized for COVID-19, administration of IL-6 antagonists, compared with usual care or placebo, was associated with lower 28-day all-cause mortality. Trial Registration: PROSPERO Identifier: CRD42021230155.

Integrity signals

Registry

Crossref · 10.1001/jama.2021.11330

Cites

29 of 29 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 11 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Among patients not receiving corticosteroids at randomization, sarilumab compared with usual care or placebo was not associated with lower 28-day all-cause mortality (summary OR 1.18, 95% CI 0.88-1.58).

    “The corresponding summary ORs for sarilumab (8 trials, 2406 patients, and 538 deaths) were 1.18 (95% CI, 0.88-1.58)and 0.92 (95% CI, 0.61-1.38),respectively.”
    Quote in the paperSubstantial claim
  • Findingown data

    IL-6 antagonists were not associated with secondary infections by 28 days (21.9% vs 17.6%; OR 0.99, 95% CI 0.85-1.16).

    “Secondary infections by 28 days occurred in 21.9% of patients treated with IL-6 antagonists vs 17.6% of patients treated with usual care or placebo (OR accounting for trial sample sizes, 0.99; 95% CI, 0.85-1.16).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Among patients not receiving corticosteroids at randomization, tocilizumab compared with usual care or placebo was not associated with lower 28-day all-cause mortality (summary OR 1.06, 95% CI 0.85-1.33).

    “The summary OR for the association with mortality for tocilizumab (15 trials, 7490 patients, and 1951 deaths) was 1.06 (95% CI, 0.85-1.33) in patients not receiving corticosteroids at randomization and was 0.77 (95% CI, 0.68-0.87) in patients receiving corticosteroids at randomization.”
    Quote in the paperSubstantial claim
  • Findingown data

    By 28 days after randomization, 1407 deaths occurred among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo.

    “By 28 days after randomization, there were 1407 deaths among 6449 patients randomized to IL-6 antagonists and 1158 deaths among 4481 patients randomized to usual care or placebo.”
    Quote in the paperSubstantial claim
  • Findingown data

    In 19 trials, tocilizumab compared with usual care or placebo was associated with lower 28-day all-cause mortality (summary OR 0.83, 95% CI 0.74-0.92; P<.001).

    “In 19 trials that randomized 4299 patients to tocilizumab (960 deaths) and 3749 patients to usual care or placebo (1023 deaths), the summary OR was 0.83 (95% CI, 0.74-0.92;P < .001).”
    Quote in the paperSubstantial claim
  • May combine two claims. 31
  • The quote only partly states this claim. 1
  • Classified as probably not a substantial claim. 23

  • May combine two claims.

    Findingown data

    There was no clear association between administration of IL-6 antagonists and all-cause mortality at 90 days or in the duration of invasive mechanical ventilation among patients who required invasive mechanical ventilation at randomization; however, the data were limited.

    “There was no clear association between administration of IL-6 antagonists and all-cause mortality at 90 days or in the duration of IMV among patients who required IMV at randomization; however, the data were limited.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After excluding the RECOVERY trial, the ORs comparing tocilizumab with usual care or placebo were 0.82 (95% CI 0.68-0.98) for 28-day all-cause mortality and 0.71 (95% CI 0.59-0.84) for progression to invasive mechanical ventilation or death within 28 days, consistent with primary analyses.

    “After excluding the large RECOVERY trial, the ORs comparing tocili- zumab with usual care or placebo were 0.82 (95% CI, 0.68- 0.98) for 28-day all-cause mortality and 0.71 (95% CI, 0.59- 0.84) for progression to IMV or death within 28 days (consistent with the primary analyses).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The OR for all-cause mortality at 90 days was 0.85 (95% CI 0.69-1.05) for tocilizumab and 0.92 (95% CI 0.74-1.16) for sarilumab.

    “The corresponding ORs were 0.85 (95% CI, 0.69-1.05)for tocilizumab and 0.92 (95% CI, 0.74-1.16)for sarilumab.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Among 22 trials reporting 28-day infection outcomes, the fixed-effect summary OR for infection comparing IL-6 antagonists with usual care or placebo was 0.99 (95% CI 0.85-1.16), with little inconsistency (I2=0%, P=.49).

    “The fixed-effect summary OR was 0.99 (95% CI, 0.85-1.16)and there was little inconsistency between the trial results (I 2 = 0%, P = .49for heterogeneity; Figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Larger trials were mainly conducted in high-income settings; 65.9% of tocilizumab data came from RECOVERY and 71.0% of sarilumab data came from the Regeneron trial.

    “Fifth, larger trials were mainly conducted in highincome settings; 65.9% of the tocilizumab data were provided by participants in the RECOVERY trial 9 and 71.0% of the sarilumab data were provided by participants in the Regeneron trial (NCT04315298).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [9] Abani, 2021, Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial., Lancet source

      Not checked in the free run.

    • cites NCT04315298

      Not checked in the free run.

  • May combine two claims.

    Findingreasoning

    The majority of patients in trials of sarilumab were not receiving corticosteroids at randomization, whereas the majority of patients in trials of tocilizumab were receiving corticosteroids at randomization.

    “The majority of patients in trials of sarilumab were not receiving corticosteroids at randomization, whereas the majority of patients in trials of tocilizumab were receiving corticosteroids at randomization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The association of IL-6 antagonists with lower 28-day all-cause mortality was more marked among patients who did not require invasive mechanical ventilation at randomization, consistent with the inverse association of progression to invasive mechanical ventilation or death among these patients.

    “The association of IL-6 antagonists with lower 28-day all-cause mortality was more marked among patients who did not require IMV at randomization, consistent with the inverse association of progression to IMV or death among these patients.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The ORs restricted to trials published in peer-reviewed journals were consistent with overall ORs for tocilizumab but imprecisely estimated for sarilumab because of exclusion of the largest trial.

    “The ORs restricted to trials published in peer-reviewed journals were consistent with the overall ORs for tocilizumab but were imprecisely estimated for sarilumab because of exclusion of the largest trial.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The OR for discharge alive by 28 days was 1.30 (95% CI 1.18-1.43) for tocilizumab and 0.95 (95% CI 0.79-1.15) for sarilumab.

    “The corresponding ORs were 1.30 (95% CI, 1.18-1.43)for tocilizumab and 0.95 (95% CI, 0.79-1.15)for sarilumab.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The OR for 28-day infection was 0.95 (95% CI 0.77-1.16) for tocilizumab and 1.03 (95% CI 0.80-1.32) for sarilumab.

    “The ORs were 0.95 (95% CI, 0.77-1.16)for tocilizumab and 1.03 (95% CI, 0.80-1.32)for sarilumab”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The ORs were similar for open-label and placebo-controlled trials; however, the association of sarilumab compared with usual care for secondary infections appeared more marked in open-label trials (1.97, 95% CI 0.89-4.34) than in placebo-controlled trials (0.96, 95% CI 0.74-1.24).

    “The ORs were similar for open-label and placebo-controlled trials; however, the association of sarilumab compared with usual care for sec- ondary infections appeared more marked in open-label trials (1.97 [95% CI, 0.89-4.34]) than in placebo-controlled trials (0.96 [95% CI, 0.74-1.24]).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The absolute risk of progression to invasive mechanical ventilation or death among patients not on invasive mechanical ventilation at randomization was 28% for all IL-6 antagonists, 27% for tocilizumab, and 33% for sarilumab, compared with an assumed 33% for usual care or placebo.

    “The corresponding absolute risks of progression to IMV or death were 28% for all IL-6 antagonists, 27% for tocilizumab, and 33% for sarilumab compared with an assumed risk of 33% for usual care or placebo.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The assumed risk of progression to invasive mechanical ventilation or death in the usual care or placebo group is 33%.

  • The quote only partly states this claim.

    Findingown data

    The summary OR for all-cause mortality at 90 days (or 60 days in 4 trials) comparing IL-6 antagonists with usual care or placebo was 0.89 (95% CI 0.76-1.04).

    “The summary OR comparing IL-6 antagonists with usual care or placebo was 0.89 (95% CI, 0.76-1.04).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For tocilizumab, the summary ORs for progression to invasive mechanical ventilation or death were 0.95 (95% CI 0.76-1.20) in patients not receiving corticosteroids and 0.69 (95% CI 0.61-0.78) in those receiving corticosteroids.

    “The corresponding summary ORs for tocilizumab (17 trials, 6608 patients, and 2104 progressed) were 0.95 (95% CI, 0.76-1.20)and 0.69 (95% CI, 0.61-0.78),respectively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For sarilumab, the summary ORs for progression to invasive mechanical ventilation or death were 0.98 (95% CI 0.67-1.44) in patients not receiving corticosteroids and 1.08 (95% CI 0.67-1.75) in those receiving corticosteroids.

    “The corresponding summary ORs for sarilumab (7 trials, 1362 patients, and 298 progressed) were 0.98 (95% CI, 0.67-1.44)and 1.08 (95% CI, 0.67-1.75),respectively”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    One trial was judged high risk, comprising 0.65% of the weight, because usual procedures to ensure allocation sequence concealment were not in place, though there was no reason to suspect concealed allocation was not implemented as intended.

    “In 1 trial judged as high risk, comprising 0.65% of the weight, the usual procedures were not in place to ensure that the allocation sequence was concealed; however, there was no reason to suspect that the concealed allocation was not implemented as intended.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Risk of bias was assessed with Cochrane Risk of Bias version 2, independently by three investigators, with disagreements resolved through discussion.

    “For each trial, the risk of bias (low risk, some concerns, or high risk) was assessed using version 2 of the Cochrane Risk of Bias Assessment Tool.15”
    • Also stated in: § Risk of Bias Assessment · plain
      “Risk of bias assessments were done independently by 3 of the investigators (J.P.T.H., F.S., J.S.) with disagreements resolved through discussion.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Sterne, 2019, RoB 2: a revised tool for assessing risk of bias in randomised trials., BMJ source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    The PICO framework, outcome definitions, and subgroups of interest were agreed before outcome data were collected.

    “The PICO (patient problem or population, intervention, comparison or control, and outcome) framework, definitions of outcomes, and subgroups of interest were agreed upon prior to collection of outcome data.6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Tierney, 2021, A framework for prospective, adaptive meta-analysis (FAME) of aggregate data from randomised trials., PLoS Med source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The GRADE approach was used to assess the certainty of the evidence.

    “The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Outcome data were supplied for 10,930 patients, representing 95.4% of all patients randomized in eligible trials.

    “Outcome data were supplied for 10 930 patients, representing 95.4% of all patients randomized in eligible trials (eFigure 1 in Supplement 1).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The primary outcome was missing for 183 patients (1.6%).

    “The primary outcome was missing for 183 patients (1.6%).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Six trials were judged to have some concerns, mainly because small numbers of patients were excluded for not receiving their assigned intervention.

    “Six trials were judged to have some concerns, mainly due to small numbers of patients being excluded from the data set because they did not receive their assigned intervention.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    The prospective meta-analysis protocol was registered on PROSPERO on January 14, 2021, and updated, with the final version registered before analyses began on March 29, 2021.

    “The prospective meta-analysis protocol was registered on the PROSPERO database on January 14, 2021, and regularly updated.”
    • Also stated in: § Development of Prospective Meta-analysis Protocol · plain
      “The final version of the prospective meta-analysis protocol was registered before analyses started on March 29, 2021.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    For secondary infections, open-label trials were judged to have some concerns over bias in determining whether infections occurred because the decision was subjective.

    “For secondary infections, results from open-label trials were judged to have some concerns over bias in determining whether such infections had occurred due to the subjective nature of the decision (eFigure 2 and eTable 4 in Supplement 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Concurrent treatments at randomization varied substantially among the trials.

    “Concurrent treatments at randomization varied substantially among the trials.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The prospective meta-analysis protocol specified that no threshold for statistical significance would be used.

    “the prospective metaanalysis protocol specified that a threshold for statistical significance would not be used.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Because of diversity in race/ethnicity classification among trials, subgroup analyses according to race/ethnicity are not reported.

    “Because of the diversity of classification of race/ethnicity among different trials, the subgroup analyses according to race/ethnicity are not reported.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All trials had secured institutional review board approval, but approval was not required for secondary analyses.

    “All trials had secured institutional review board approval, but approval was not required for secondary analyses.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    A greater proportion of patients in sarilumab trials received invasive mechanical ventilation compared with tocilizumab trials, and a smaller proportion received corticosteroids.

    “A greater proportion of patients in the sarilumab trials received IMV (31% [873/3136 patients]) compared with patients in the tocilizumab trials (15% [1211/8134 patients]) and a smaller proportion received corticosteroids (35% [890/3136 patients] vs 66% [5317/8134 patients], respectively; Table 1).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    Concurrent administration of IL-6 antagonists and corticosteroids, which both have anti-inflammatory effects, may provide greater improvement than either type of drug given individually.

    “Concurrent administration of IL-6 antagonists 5 and corticosteroids, 26 which both have anti-inflammatory effects, may provide greater improvement than either type of drug given individually.8,9”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [8] Gordon, 2021, Interleukin-6 receptor antagonists in critically ill patients with Covid-19., N Engl J Med source

      Not checked in the free run.

    • cites [9] Abani, 2021, Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial., Lancet source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Trial investigators completed baseline and outcome data collection forms that were subsequently verified by trial teams.

    “Trial investigators were asked to complete baseline and outcome data collection forms that were subsequently verified by trial teams.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Data on respiratory support at randomization were available in 21 trials (9835 patients and 2493 deaths).

    “Data on respiratory support at randomization were available in 21 trials (9835 patients and 2493 deaths).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Both drugs were IL-6 receptor antagonists, but there may be differences between tocilizumab and sarilumab in receptor binding or lung concentrations.

    “Both drugs were IL-6 receptor antagonists, but there may be differences between tocilizumab and sarilumab in receptor binding or lung concentrations.25”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Xu, 2021, Differential binding of sarilumab and tocilizumab to IL-6Ra and effects of receptor occupancy on clinical parameters., J Clin Pharmacol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Queries regarding eligibility for inclusion were resolved by consensus.

    “Queries regarding eligibility for inclusion were resolved by consensus.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In general, associations with improved outcomes were more marked for tocilizumab than for sarilumab, although comparisons between tocilizumab and sarilumab were indirect (made between trials).

    “In general, associations with improved outcomes were more marked for tocilizumab than for sarilumab, although comparisons between tocilizumab and sarilumab were indirect (made between trials).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Due to limited data, associations for siltuximab within predefined subgroups were not estimated.

    “Due to limited data (including outcome events), associations for siltuximab within predefined subgroups were not estimated.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Definitions and reporting of serious adverse events were not consistent across trials, so a meta-analysis for this secondary end point was not conducted.

    “Fourth, the definitions and reporting of serious adverse events were not consistent across the trials and therefore a meta-analysis for this secondary end point was not conducted.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    Of 72 potentially eligible trials, 27 met the study selection criteria and were included.

    “Among 72 potentially eligible trials, 27 (37.5%)met study selection criteria.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Searches were not restricted by trial status, publication status, or language.

    “Searches were not restricted by trial status (ongoing or completed), publication status, or language.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    For tocilizumab, the results from other trials were similar to those from the large RECOVERY trial, supporting generalizability of the findings across settings.

    “For tocilizumab, the results from other trials were similar to those from the large RECOVERY trial, supporting generalizability of the findings across settings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The tendency for stronger inverse associations among patients receiving corticosteroids appeared broadly consistent across respiratory support subgroups, though the associations were not estimated precisely.

    “The tendency for more marked inverse associations among patients receiving corticosteroids appeared broadly consistent across respiratory support subgroups; however, the associations were not estimated precisely.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    Because data were shared based on standardized definitions of outcomes and subgroups agreed upon in advance, these aggregate data meta-analyses had many of the advantages of individual-patient data meta-analyses while avoiding the need to establish formal data sharing agreements.

    “Because data were shared based on standardized definitions of outcomes and subgroups agreed upon in advance, these aggregate data meta-analyses had many of the advantages of individual-patient data meta-analyses while avoiding the need to establish formal data sharing agreements.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The trials of sarilumab were generally done earlier in the pandemic than those of tocilizumab and before corticosteroids became the standard of care.

    “However, the trials of sarilumab were generally done earlier in the pandemic than those of tocilizumab and before corticosteroids became the standard of care.7”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Sterne, 2020, Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis., JAMA source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Differences between subgroups may have arisen due to sampling variation.

    “However, these differences between subgroups may have arisen due to sampling variation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    This limitation was addressed in sensitivity analyses and the results were consistent with the primary analyses.

    “This limitation was addressed in the sensitivity analyses and the results were consistent with the primary analyses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Because outcome data were generally complete or nearly complete across trials, analyses were restricted to trial participants with recorded outcomes.

    “Because outcome data were generally complete or nearly complete across trials, we restricted the analyses to trial participants with outcomes recorded.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Interpretationnone given

    It is possible that lack of participation or participation by some ongoing trials may be based on knowledge of their interim results.

    “It is possible that lack of participation or participation by some of the ongoing trials may be based on knowledge of their interim results.”
    Quote in the paperNot a substantial claim
47 of 47

  • The authors state this as an assumption.

    The assumed risk of progression to invasive mechanical ventilation or death in the usual care or placebo group is 33%.

    “compared with an assumed risk of 33% for usual care or placebo”
    “compared with an assumed risk of 33% for progression to IMV or death for usual care or placebo”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Sarilumab death count differs between text and figure

    Minor

    The results text reports 473 deaths in the sarilumab group, while the mortality figure reports 437 deaths among the same 2073 patients.

  • Sarilumab corticosteroid percentage does not match its fraction

    Minor

    The stated fraction is 28.38%, not 35%.

    Reported 35 · recomputed 28.380102

  • Sarilumab ventilation percentage uses an inconsistent denominator

    Minor

    The stated fraction is 27.84%, not 31%.

    Reported 31 · recomputed 27.83801

  • Control-group infection percentage is understated

    Minor

    There were 330 infections among 1787 control patients, which is 18.47%, not 17.6%.

    Reported 17.6 · recomputed 18.466704

  • Risk-of-bias trial counts exceed the number of included trials

    Minor

    The risk-of-bias categories describe 22 low-risk, 6 some-concerns, and 1 high-risk trials, totaling 29, although the paper says 27 trials were included.

5 of 5

Cites

Flagged first, then by citations

2 of the 31 references couldn’t be matched to a known paper.

Cited by

Sorted by citations

Related

Authors
The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group, Domingo, P., Mur, I., Mateo, G. M., Gutierrez, M. D. M., Pomar, V., de Benito, N., Corbacho, N., Herrera, S., Millan, L., Muñoz, J., Malouf, J., Molas, M. E., Asensi, V., Horcajada, J. P., Estrada, V., Gutierrez, F., Torres, F., Perez-Molina, J. A., Fortun, J., Villar, L. M., Hohenthal, U., Marttila, H., Vuorinen, T., Nordberg, M., Valtonen, M., Frigault, M. J., Mansour, M. K., Patel, N. J., Fernandes, A., Harvey, L., Foulkes, A. S., Healy, B. C., Shah, R., Bensaci, A. M., Woolley, A. E., Nikiforow, S., Lin, N., Sagar, M., Shrager, H., Huckins, D. S., Axelrod, M., Pincus, M. D., Fleisher, J., Lampa, J., Nowak, P., Vesterbacka, J. C., Rasmuson, J., Skorup, P., Janols, H., Niward, K. F., Chatzidionysiou, K., Asgeirsson, H., Parke, Å., Blennow, O., Svensson, A.-K., Aleman, S., Sönnerborg, A., Henter, J.-I., Horne, A. C., Al-Beidh, F., Angus, D., Annane, D., Arabi, Y., Beane, A., Berry, S., Bhimani, Z., Bonten, M., Bradbury, C., Brunkhorst, F., Buxton, M., Cheng, A., Cove, M., De Jong, M., Derde, L., Estcourt, L., Goossens, H., Gordon, A., Green, C., Haniffa, R., Ichihara, N., Lamontagne, F., Lawler, P., Litton, E., Marshall, J., McArthur, C., McAuley, D., McGuinness, S., McVerry, B., Montgommery, S., Mouncey, P., Murthy, S., Nichol, A., Parke, R., Parker, J., Reyes, F., Rowan, K., Saito, H., Santos, M., Seymour, C., Shankar-Hari, M., Turgeon, A., Turner, A., van Bentum-Puijk, W., van de Veerdonk, F., Webb, S., Zarychanski, R., Baillie, J. K., Beasley, R., Cooper, N., Fowler, R., Galea, J., Hills, T., King, A., Morpeth, S., Netea, M., Ogungbenro, K., Pettila, V., Tong, S., Uyeki, T., Youngstein, T., Higgins, A., Lorenzi, E., Berry, L., Salama, C., Rosas, I. O., Ruiz-Antorán, B., Muñez Rubio, E., Ramos Martínez, A., Campos Esteban, J., Avendaño Solá, C., Pizov, R., Sanz Sanz, J., Abad-Santos, F., Bautista-Hernández, A., García-Fraile, L., Barrios, A., Gutiérrez Liarte, Á., Alonso Pérez, T., Rodríguez-García, S. C., Mejía-Abril, G., Prieto, J. C., Leon, R., VEIGA, V. C., SCHEINBERG, P., FARIAS, D. L. C., PRATS, J. G., CAVALCANTI, A. B., MACHADO, F. R., ROSA, R. G., BERWANGER, O., AZEVEDO, L. C. P., LOPES, R. D., DOURADO, L. K., CASTRO, C. G., ZAMPIERI, F. G., AVEZUM, A., LISBOA, T. C., ROJAS, S. S. O., COELHO, J. C., LEITE, R. T., CARVALHO, J. C., ANDRADE, L. E. C., SANDES, A. R., PINTÃO, M. C. T., SANTOS, S. V., ALMEIDA, T. M. L., COSTA, A. N., GEBARA, O. C. E., FREITAS, F. G. R., PACHECO, E. S., MACHADO, D. J. B., MARTIN, J., CONCEIÇÃO, F. G., SIQUEIRA, S. R. R., DAMIANI, L. P., ISHIHARA, L. M., SCHNEIDER, D., DE SOUZA, D., Hermine, O., Mariette, X., Tharaux, P. L., Resche Rigon, M., Porcher, R., Ravaud, P., Azoulay, E., Cadranel, J., Emmerich, J., Fartoukh, M., Guidet, B., Humbert, M., Lacombe, K., Mahevas, M., Pene, F., Pourchet-Martinez, V., Schlemmer, F., Tibi, A., Yazdanpanah, Y., Dougados, M., Bureau, S., Horby, P. W., Landray, M. J., Baillie, K. J., Buch, M. H., Chappell, L. C., Day, J. N., Faust, S. N., Haynes, R., Jaki, T., Jeffery, K., Juszczak, E., Lim, W. S., Mafham, M., Montgomery, A., Mumford, A., Thwaites, G., Kamarulzaman, A., Syed Omar, S. F., Ponnampalavanar, S., Raja Azwa, R. I. S., Wong, P. L., Kukreja, A., Ong, H. C., Sulaiman, H., Basri, S., Ng, R. X., Megat Johari, B., Rajasuriar, R., Chong, M. L., Neelamegam, M., Syed Mansor, S. M., Zulhaimi, N. S., Lee, C. S., Altice, F., Price, C., Malinis, M., Hasan, M. S., Wong, C. K., Chidambaram, S., Misnan, N. A., Mohd Thabit, A. A., Sim, B., Bidin, F. N., Mohd Abd Rahim, M. A. H., Saravanamuttu, S., Tuang, W. X., Mohamed Gani, Y., Thangavelu, S., Tay, K. H., Ibrahim, N. M., Halid, L. A., Tan, K. T., Mukri, M. N. A., Arip, M., Koh, H. M., Syed Badaruddin, S. N. A., Raja Sureja, L., Chun, G. Y., TORRE-CISNEROS, J., MERCHANTE, N., LEON, R., CARCEL, S., GARRIDO, J. C., Galun, E., Soriano, A., Martínez, J. A., Castán, C., Paredes, R., Dalmau, D., Carbonell, C., Espinosa, G., Castro, P., Muñóz, J., Almuedo, A., Prieto, S., Pacheco, I., Ratain, M., Pisano, J., Strek, M., Adegunsoye, A., Karrison, T., Jozefien, D., Karel F.A., V. D., Elisabeth, D. L., Cedric, B., Bastiaan, M., Shankar-Hari, M., Vale, C. L., Godolphin, P. J., Fisher, D., Higgins, J. P. T., Spiga, F., Savovic, J., Tierney, J., Baron, G., Benbenishty, J. S., Berry, L. R., Broman, N., Cavalcanti, A. B., Colman, R., De Buyser, S. L., Derde, L. P. G., Domingo, P., Omar, S. F., Fernandez-Cruz, A., Feuth, T., Garcia, F., Garcia-Vicuna, R., Gonzalez-Alvaro, I., Gordon, A. C., Haynes, R., Hermine, O., Horby, P. W., Horick, N. K., Kumar, K., Lambrecht, B. N., Landray, M. J., Leal, L., Lederer, D. J., Lorenzi, E., Mariette, X., Merchante, N., Misnan, N. A., Mohan, S. V., Nivens, M. C., Oksi, J., Perez-Molina, J. A., Pizov, R., Porcher, R., Postma, S., Rajasuriar, R., Ramanan, A. V., Ravaud, P., Reid, P. D., Rutgers, A., Sancho-Lopez, A., Seto, T. B., Sivapalasingam, S., Soin, A. S., Staplin, N., Stone, J. H., Strohbehn, G. W., Sunden-Cullberg, J., Torre-Cisneros, J., Tsai, L. W., van Hoogstraten, H., van Meerten, T., Veiga, V. C., Westerweel, P. E., Murthy, S., Diaz, J. V., Marshall, J. C., & Sterne, J. A. C.
Affiliations
  • The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group
  • St. Michael's Hospital (CA)
  • MRC Clinical Trials Unit at UCL (GB)
  • University of Bristol (GB)
  • Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, England
  • Inserm (FR)
  • Hadassah Medical Center (IL)
  • Berry Consultants, Austin, Texas
  • Turku University Hospital (FI)
  • BP-A Beneficência Portuguesa de São Paulo, Rua Maestro Cardim, São Paulo, Brazil
  • Ghent University (BE)
  • Department of Public Health and Primary Care, Ghent University, Ghent, Belgium
  • Department of Intensive Care Medicine, University Medical Center Utrecht, Utrecht, the Netherlands
  • Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta de Hierro-Majadahonda, Madrid, Spain
  • Infectious Diseases Department, Hospital Clinic Barcelona-IDIBAPS, Barcelona, Spain
  • Rheumatology, Hospital Universitario La Princesa IIS-IP, Madrid, Spain
  • Division of Anaesthetics, Pain Medicine and Intensive Care, Imperial College London, London, England
  • Medanta The Medicity (IN)
  • Regeneron (United States) (US)
  • Genentech, South San Francisco, California
  • University Medical Center Groningen (NL)
  • Department of Clinical Pharmacology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
  • University of Oxford (GB)
  • Massachusetts General Hospital (US)
  • Karolinska University Hospital (SE)
  • Department of Infectious Diseases, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
  • Genentech (US)
  • Global Medical Affairs, Sanofi-Genzyme, Bridgewater, New Jersey
  • Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands
  • University of British Columbia (CA)
Corresponding author
Seymour, Chris
ORCID
Venue
JAMA
Publisher
American Medical Association (AMA)
Published
2021-08-10
Volume
326
Issue
6
Pages
499
ISSN
  • 0002-9955 (ISSN-L)
  • 0098-7484
DOI
10.1001/jama.2021.11330
PMC
PMC8261689
OpenAlex
W3181530483
Semantic Scholar
eb99d2480fe8ca5efe5a708d37ca25946541e1e2
Cited by
678
References
31
Citations by year
2026: 25 · 2025: 43 · 2024: 105 · 2023: 147 · 2022: 263 · 2021: 92 · 2020: 2
FWCI
48.65
Type
journal article
Language
en
Open access
Locations
  • JAMA (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Ghent University Academic Bibliography (Ghent University) (submittedVersion, other-oa)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
  • HAL (submittedVersion)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
  • Bristol Research (University of Bristol) (submittedVersion)
Funders
  • Bristol-Myers Squibb
  • Eli Lilly and Company
  • Pfizer
  • GlaxoSmithKline
  • Sanofi
  • World Health Organization (COVID-19)
  • Massachusetts General Hospital
  • Gilead Sciences (COVID-19)
  • Biogen
  • Alexion Pharmaceuticals
  • Celgene
  • University of Chicago
  • Regeneron Pharmaceuticals
  • ViiV Healthcare
  • Innovative Medicines Canada
  • UK Research and Innovation
  • Argenx
  • Roche España
  • Cancer Research UK (16896)
  • National Institute for Health and Care Research (NIHR201409, NIHR202424, COVID-19, NF-SI-0617-10145, RP-2015-06-018, COVID-19-RECPLAS)
  • European Commission (COVID-19)
  • University of Bristol
  • Institut National de la Santé et de la Recherche Médicale (UMR1153, UMR1184)
  • Hebrew University of Jerusalem
  • University of Toronto
  • Karolinska Institutet
  • Vetenskapsrådet
  • Universiteit Gent
  • Universiti Malaya
  • Ministerio de Ciencia e Innovación
  • Universitair Medisch Centrum Groningen
  • Shionogi
  • Institut National de la Recherche Agronomique
  • Université Paris-Saclay (UMR1184)
  • Universidad de Córdoba
  • Assistance publique-Hôpitaux de Paris
  • Swedish Orphan Biovitrum
  • PharmaMar
  • European Society of Intensive Care Medicine
  • Aspen
  • National Institutes of Health (2kl2tr002387-06)
  • Genentech
  • Biomedical Advanced Research and Development Authority
  • Sanofi Genzyme
  • Canadian Institutes of Health Research (COVID-19)
  • Medical Research Council (MC_UU_00004/06, MC_PC_20062)
  • Instituto de Salud Carlos III
  • European Regional Development Fund
  • Center for Innovative Medicine
  • Belgian Health Care Knowledge Centre
  • National Institute of Allergy and Infectious Diseases (UM1AI144295)
  • National Center for Advancing Translational Sciences (KL2‐TR002387)
  • Institute of Infection and Immunity
  • Cilag
  • Health Data Research UK
Topics
  • Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Keywords
IL-6 inhibitors, COVID-19 pandemic, tocilizumab, sarilumab, 28-day all-cause mortality, hospitalized patients, immunomodulatory therapy, secondary infection, invasive mechanical ventilation, corticosteroids, risk of bias
MeSH terms
COVID-19, Interleukin-6 Inhibitors, COVID-19 Drug Treatment, Aged, Cause of Death, Drug Therapy, Combination, Female, Glucocorticoids, Hospitalization, Humans, Male, Middle Aged, Prospective Studies, Respiration, Artificial, Randomized Controlled Trials as Topic, Disease Progression, Coinfection, Antibodies, Monoclonal, Humanized

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review