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A New Approach to the Management of COVID-19. Antagonists of IL-6: Siltuximab.

ABSTRACT: Since the beginning of the pandemic, numerous national and international clinical trials have been conducted with a large number of drugs. Many of them are intended for the treatment of other pathologies; however, despite the great effort made, no specific drug is available for the treatment of the symptoms of respiratory disease caused by SARS-CoV-2 infection. The aim of this article is to provide data to justify the use of drugs to tackle the effects produced by IL-6 as the main inflammatory mediator in patients with COVID-19 with severe respiratory complications, considering all clinical evidence linking the poor prognosis of these patients with increased IL-6 levels in the context of cytokine release syndrome. Furthermore, data are provided to justify the proposal of a rational dosing of siltuximab, a monoclonal antibody specifically targeting IL-6, based on RCP levels, considering the limited results published so far on the use of this drug in COVID-19. A literature search was conducted on the clinical trials of siltuximab published to date as well as on the different IL-6 signalling pathways and the effects of its overexpression. Knowledge of the mechanisms of action on these pathways may provide important information for the design of drugs useful in the treatment of these patients. This article describes the characteristics, properties, mechanism of action, therapeutic uses and clinical studies conducted with siltuximab so far. The results confirm that administration of siltuximab downregulates IL-6 levels, thereby reducing the inflammatory process in COVID-19 patients with severe respiratory disease, suggesting that it can be successfully used to prevent cytokine release syndrome and death from this cause.

SUBMITTER: Villaescusa L

PROVIDER: S-EPMC8784859 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceClinical trials assessing the efficacy of IL-6 antagonists in patients hospitalized for COVID-19 have variously reported benefit, no effect, and harm.ObjectiveTo 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 sourcesTrials 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 selectionEligible 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 synthesisIn 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 measuresThe 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.ResultsA 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 relevanceIn 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 registrationPROSPERO Identifier: CRD42021230155.

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A New Approach to the Management of COVID-19. Antagonists of IL-6: Siltuximab.

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