Efficacy of tocilizumab in COVID-19: A review of the current evidence

Abstract

As cases of coronavirus 2019 (COVID-19) keep rising, reported deaths are increasing. Public health measures have been implemented with mixed efficacy. As vaccines are becoming more widely available and accessible globally, treating critically ill COVID-19 patients remains an issue with only dexamethasone found to be therapeutically effective to date. However, trials studying the efficacy of IL-6 inhibitors, namely tocilizumab have been underway with promising results. This paper is a narrative review that aims to review the current evidence provided by randomized clinical trials (RCT) for the use of tocilizumab in COVID-19. Electronic database searches were carried out in Medline, PubMed, Embase, Google Scholar, and ongoing clinical trial registries with the period set from January 1, 2020 to February 20, 2021. Prepublication manuscripts were found using the pre-print repository medRxiv. Keywords included "COVID-19,""coronavirus,""SARS-CoV-2,""sepsis,""pneumonia,""cytokine storm,""cytokine release syndrome,""IL-6 inhibitors," and "tocilizumab," as exact phrases, and a combination of subject headings according to databases syntax. Only trials with a clear and well-defined methodology, at least 100 patients recruited, and which have had results published either after peer review or in pre-print were included. In hospitalized patients with severe COVID-19, who are hypoxic and have a CRP ≥ 75 mg/L, the current evidence favors the use of a combination of tocilizumab and corticosteroids to reduce mortality, among other clinical benefits. There is also overwhelming evidence of the good safety profile of tocilizumab with only few cases of neutropenia reported with a decrease in infection rates. Tocilizumab is currently thought to work through the inhibition of IL-6 receptors (IL-6R), preventing downstream activation of pro-inflammatory reactions and cytokine release syndrome.

Keywords: COVID-19; IL-6 inhibitors; clinical outcomes; mortality; randomized clinical trial; review; tocilizumab.

Figure 1.

Timeline of RCTs evaluating the use of tocilizumab in COVID-19 patients. The dates set refer to the last date at which a patient was recruited, except for June 22, 2020, which refers to the earliest date when results of the RECOVERY Trial concerning Dexamethasone were made public. Whether a study was able to meet its primary endpoint or failed to do so is highlighted by blue and red circles, respectively.

Figure 2.

Fisher Exact Test for clinical failure between tocilizumab and placebo groups in the EMPACTA trial. Calculated using https://www.socscistatistics.com/tests/fisher/default2.aspx. Clinical failure occurred in 12.0% in the tocilizumab group (29/249) versus 19.3% in the placebo group (24/128) with p value set at less than 0.05.

Figure 3.

Fisher Exact Test for mortality difference between tocilizumab and control groups in the REMAP-CAP trial. Calculated using https://www.socscistatistics.com/tests/fisher/default2.aspx.

Figure 4.

Fragility index for hospital mortality results between tocilizumab and control groups in the REMAP-CAP trial. Calculated using https://clincalc.com/Stats/FragilityIndex.aspx.

Figure 5.

Fragility index for death at 15 days results between tocilizumab and control groups in the Veiga et al. RCT. Calculated using https://clincalc.com/Stats/FragilityIndex.aspx.

Figure 6.

Fragility index for hospital mortality benefits results between tocilizumab and control groups in the RECOVERY trial. Calculated using https://clincalc.com/Stats/FragilityIndex.aspx.

Figure 7.

Overview of the IL-6 associated pathways leading to the cytokine release syndrome (CRS) seen in severe COVID-19. gp130: glycoprotein 130; IL: interleukin; JAK/STAT: Janus kinases/signal transducer and activator of transcription; mIL-6R: membrane bound IL-6 receptor; sIL-6R: soluble IL-6 receptor.