The IL-6 Inhibitors Tocilizumab and Sarilumab and COVID-19 Treatment: Controversies but Potential Efficacy in Severe Cases

IL-6-Inhibitors

A few recent peer-reviewed or preliminary studies provide conflicting results about the efficacy of the interleukin-6 (IL-6) inhibitors (i.e., IL-6 receptor blockade) Tocilizumab and Sarilumab in COVID-19 treatment. However, some of these studies report encouraging results, particularly in the treatment of severe cases.

These monoclonal antibodies against the interleukin-6 receptor have been used in the treatment of rheumatoid arthritis and systemic juvenile idiopathic arthritis.

Of note, “the NIH guidelines note insufficient data to recommend for or against the use of IL-6 inhibitors, except in a clinical trial. Average wholesale price for 400 mg of Tocilizumab is approximately $2765”.

IL-6 is a pleiotropic, mostly pro-inflammatory cytokine with various hematologic, immune but also hepatic, endocrine and metabolic effects. Recent evidence implicates IL-6 as a major player in the pathogenesis of COVID-19.

High levels of IL-6 are observed in patients with severe or critical disease, including COVID-19, but those  levels are inversely correlated with lymphocyte counts. IL-6 appears to be a predictor of COVID-19 severity as it is significantly elevated in fatal cases.

This cytokine contributes to a severe inflammatory response resembling cytokine release syndrome (CRS). Severe COVID-19 patients exhibit increased IL-6, IL-10, and MCP-1 levels, but “these levels are not as high as those in patients with CRS from other causes ”.

Figure 1. IL-6 Inhibitors and COVID-19

Figure 1. Responses to IL-6 release and their physiological effects. Red indicates negative consequences while green designates positive ones in COVID-19. From: The efficacy of IL-6 inhibitor Tocilizumab in reducing severe COVID-19 mortality: a systematic review, by Avi Gurion Kaye and Robert Siegel, PeerJ. 2020; 8: e10322. Published online 2020 Nov 2. doi: 10.7717/peerj.10322

Importantly, and in apparent contrast, the plasminogen activator inhibitor-1 (PAI-1) levels in COVID-19 patients appear to be as highly elevated as those in patients with bacterial sepsis or ARDS. Thus, IL-6 may increase the rate of fibrotic clot formation and may play a role in the thrombotic complications observed in COVID-19.

  1. The JAMA Internal Medicine Study

The study by S. Gupta et al., published in JAMA Internal Medicine, analyzed whether Tocilizumab can rescue patients with severe respiratory inflammation due to COVID-19.

Selected patients were given a Tocilizumab (n=433) or standard treatment (n=3491) during the first 2 days after ICU admission. From the 433 patients admitted to ICU treated with Tocilizumab, 125 died (28.9%) compared to 1419 deaths (40.6%) from the 3491 patients receiving standard therapy.

In the 30-day mortality follow-up, Tocilizumab reduced mortality to 27.5% when compared to 37.1% from the standard therapy group. Thus, among critically ill patients, the risk of in-hospital mortality in this study was lower in patients treated with Tocilizumab in the first 2 days of ICU admission.

  1. The New England Journal of Medicine Study

In contrast, the study by J.H. Stone et al., recently showed no benefit of IL-6 neutralization therapy on COVID-19 survival. In this study, investigators selected COVID-19 infected patients that presented at least two of the following signs: fever >38°C, pulmonary infiltrates, or the need of oxygen supplementation to maintain saturation >92%. Selected patients then received a single dose (8mg/Kg) of Tocilizumab (n=161) or placebo (n=81).

In this study, Tocilizumab therapy failed to decrease mortality or intubation rate when compared to placebo-treated patients. Thus, it did “not provide support for the concept that early interleukin-6 receptor blockade is an effective treatment strategy in moderately ill patients hospitalized with Covid-19”.

Of note, this study also confirmed that patients with higher serum interleukin-6 concentrations at baseline were more likely to have a poor outcome”.

  1. Preliminary, non- peer-reviewed study published online on the medRxiv website

This study, by Anthony C. Gordon et al., published online, January 9, 2021, on www.medrxiv.org
evaluated the effects of Tocilizumab and Sarilumab in patients with Covid-19, within 24 hours of commencing organ support in an ICU, receiving either Tocilizumab (8mg/kg) or Sarilumab (400mg) or standard care (control).

Roche Products Ltd and Sanofi supported the trial through provision of Tocilizumab and Sarilumab in the United Kingdom.

Hospital mortality was 28.0% (98/350) for Tocilizumab, 22.2% (10/45) for Sarilumab and 35.8% (142/397) for control. The overall data, from nearly 800 severely ill COVID-19 patients involved in this international study, showed that the two drugs reduced mortality rates from 35.8% in a control group to 27.3% among patients receiving either Tocilizumab or Sarilumab.

That would mean that for every 12 patients treated with one of the two drugs, an extra life would be saved, said Anthony Gordon, an Imperial College London professor of anesthesia and critical care who co-led the study.”

In conclusion, as per this study, in critically ill patients with Covid-19 the IL-6 inhibitors Tocilizumab and Sarilumab, are both effective treatments compared with current standard of care, which included corticosteroids in the majority of patients (>80%).

The actual controversy of the IL-6 inhibitors’ efficacy between these studies can be explained, at least in part, to patient selection related to primary outcomes, such as ICU admission, intubation, timing of treatment, ICU follow-up or patients ethnic background, etc.

Many previously reported trials, included less severely ill patients, thus, it is possible that the maximum benefit from IL-6 inhibition is seen in the most severely ill patients.

In fact, as per Anthony Gordon’s results, previous studies had found no clear benefit, but those trials had included less severely ill patients and started treatment at different stages in the disease course. “A crucial difference may be that in our study, critically ill patients were enrolled within 24 hours of starting organ support,” he said.

“This highlights a potential early window for treatment where the sickest patients may gain the most benefit from immune modulation treatment.”

  1. High PAI-1 levels in COVID-19 – inhibition of IL-6 signaling decreases PAI-1 production and alleviates clinical manifestations

Recently, a study by Sujin Kang et al. from the Osaka University, Japan, published in the Proceedings of the National Academy of Sciences of the United States of America (PNAS) identified IL-6 signalling as a major player in the endothelial cell dysfunction in CRS.

The study indicated the following:

– COVID-19 patients have a relatively lower elevation in the serum levels of inflammatory cytokines, such as IL-6, IL-10, and MCP-1 when compared to those with sepsis, ARDS, or burns.

– The serum IL-6 level is positively correlated with the serum levels of PAI-1 in patients with CRS

– However, COVID-19 patients have a similar elevation of PAI-1 serum levels, as in the case of sepsis, ARDS, or burns.

The inhibition of IL-6 signaling by Tocilizumab treatment decreases the PAI-1 production and alleviates clinical manifestations in severe COVID-19 patients.

  1. The Efficacy of IL-6 Inhibitor Tocilizumab – a Recent Systematic Review

In a recent systemic review conducted by Avi Kaye and Robert Siegel, at Stanford University, their aim was to evaluate the efficacy of Tocilizumab in reducing COVID-19 mortality. PubMed and SearchWorks databases were searched for sixteen case-control studies comparing mortality between Tocilizumab and standard of care and identified for quantitative synthesis.

Importantly, the results from this systematic analysis “provide positive evidence for the potential efficacy of Tocilizumab to treat severe COVID-19”.

As per the authors of this systematic review, taking into account some methodological limitations in the studies analysed, including the potential for an inadequate evaluation due to unpublished data, the “use of Tocilizumab in outside the clinical trial context is discouraged until results from these clinical trials are released”.

Gabriel Bassi, PhD
Assistant Editor, BrainImmune
Ilia Elenkov, MD, PhD
Editor, BrainImmune

Cover Image Credit: Left panel, IL-6 and thrombus formation via PAI-1. Effect of Tocilizumab. Credit: Osaka University, cf. https://www.europeanpharmaceuticalreview.com/news/127168/il-6-signalling-blockade-alleviates-severe-covid-19-symptoms/

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