More than two years have passed since the beginning of the coronavirus disease 2019 (COVID-19) pandemic. Extensive efforts have been invested into better understanding the pathogenesis of this disease and developing the ideal pharmacological approach [
[1]
]. However, severe COVID-19 still remains a therapeutic challenge. Since the very beginning of the pandemic, a detrimental inflammatory response was implicated as the major driver of the significant morbidity and mortality that characterizes patients with critical COVID-19 [[2]
]. As targeted anti-viral medications were lacking, different anti-inflammatory strategies were studied to stop the progression of tissue damage and respiratory failure [[3]
,[4]
. In light of their remarkable anti-inflammatory properties, monoclonal antibodies targeting interleukin (IL)-6 [[5]
] intuitively posed as agents of choice in these difficult-to-treat patients, also because this cytokine was found to be elevated in patients with severe COVID-19 [[1]
,[6]
. However, the first studies on monoclonal antibodies blocking the IL-6 pathway, many of which were also published in this Journal, showed mixed results [[2]
,7
, 8
, 9
. Later, the first randomized studies that were designed to address this issue paradoxically contributed to uncertainty: three studies did not find that IL-16 was associated to a significant clinical benefit in patients with variable degrees of disease severity [10
, 11
, 12
]. Intriguingly, one study even hinted at a possible ominous effect in terms of survival in patients treated with tocilizumab [[13]
]. On the other hand, the larger RECOVERY trial showed that tocilizumab was able to decrease both mortality and the need for mechanical ventilation in severely ill patients with COVID-19 [[14]
]. As a result of this latter observation, IL-6 blocking agents were approved for the treatment of patients with severe COVID-19 []. Differences in study samples, disease severity, and duration of follow-up have been regarded as possibly responsible for such discrepant results. Also, the timing of those treatments with regards to the different clinical phases of COVID-19 might have contributed to make the potential beneficial effects of IL-6 blockade less evident [16
, 17
, 18
, 19
]. Once these issues were made clear, the need for accurate and comprehensive re-analysis of the generated data became glaring. Indeed, one meta-analysis of randomized clinical trials did show that IL-6 inhibition had, in fact, a beneficial effect on survival in patients with severe COVID-19 [[20]
]. However, this study analyzed aggregate data from each study without considering individual patient information. On the contrary, meta-analyses of raw individual patient data from each analyzed study are more reliable, since different durations of follow-up, sample sizes, and outcomes can be evaluated separately. Hence, more definitive conclusions may be drawn from such studies.In their work published in this issue of the Journal [
[21]
], Tasoudis and colleagues present the first meta-analysis on IL-6 inhibition in COVID-19 based on individual patient data. Tasoudis et al retrieved and analyzed data about more than 7,000 individual patients with COVID-19 from nine different randomized clinical trials. The Authors then confirmed the remarkable therapeutic potential of IL-6 inhibition, which was associated with a reduction of mortality that has been estimated to be up to 25%. A 26% reduction of the likelihood of need for mechanical ventilation and a 28% increase in the probability of discharge from hospital were also found in patients treated with monoclonal antibodies targeting IL-6. Furthermore, the Authors found that the beneficial effect of IL-6 inhibition was even more pronounced in those studies in which a greater proportion of patients received corticosteroids as a concomitant medication. Finally, there was a tendency to a greater improvement associated with IL-6 inhibition in older patients with severe COVID-19.In summary, Tasoudis and colleagues were able to identify by means of their analysis a beneficial impact of pharmacological blockade of IL-6 in patients with COVID-19. Very importantly, this study gives new insights about the apparent discrepancies between the findings of previous clinical trials, as the overall therapeutic effect of IL-6 inhibition is – as highlighted by the elegant design of their meta-analysis – clear-cut.
More than two years since the beginning of the pandemic, the role of IL-6 inhibition in severe COVID-19 finally seems to be clearer. The initial findings suggesting this approach as an effective treatment for severe cases of COVID-19 have been – at last – confirmed, and pharmacological blockade of IL-6 now represents a significant therapeutic option in this scenario.
References
- Repurposing of Biologic and Targeted Synthetic Anti-Rheumatic Drugs in COVID-19 and Hyper-Inflammation: A Comprehensive Review of Available and Emerging Evidence at the Peak of the Pandemic.Front Pharmacol. 2020; 11598308
- Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study.Eur J Intern Med. 2020; 76: 43-49
- COVID-19: Pharmacology and kinetics of viral clearance.Pharmacol Res. 2020; 161105114
- Targeting IL-1, IL-6 or GM-CSF in COVID-19. Response to: “More evidences on which biologic and which pathway is key in severe-critical COVID-19 pneumonia” by Ferraccioli.Ann Rheum Dis. 2020; (annrheumdis-2020-218612)
- Tocilizumab for the treatment of immune-related adverse events: a systematic literature review and a multicentre case series.Eur J Intern Med. 2021; 93: 87-94
- Detectable Serum Severe Acute Respiratory Syndrome Coronavirus 2 Viral Load (RNAemia) Is Closely Correlated With Drastically Elevated Interleukin 6 Level in Critically Ill Patients With Coronavirus Disease 2019.Clin Infect Dis. 2020; 71: 1937-1942
- Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy.Eur J Intern Med. 2020; 76: 36-42
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- Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19.Eur J Intern Med. 2021; 83: 34-38
- Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia.N Engl J Med. 2021; 384: 1503-1516
- Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.N Engl J Med. 2020; 383: 2333-2344
- Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.JAMA Intern Med. 2021; 181: 24-31
- Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.BMJ. 2021; : 372
- Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.Lancet. 2021; 397: 1637-1645
- Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Respir Med. 2021; 9: 522-532
- The right place for IL-1 inhibition in COVID-19.Lancet Respir Med. 2021; 9: 223-224
- Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study.Lancet Rheumatol. 2021; 3: e253-e261
- Respiratory Impairment Predicts Response to IL-1 and IL-6 Blockade in COVID-19 Patients With Severe Pneumonia and Hyper-Inflammation.Front Immunol. 2021; : 12
- Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.JAMA. 2021; 326: 499-518
- Interleukin-6 inhibitors reduce mortality in coronavirus disease- 2019: An individual patient data meta-analysis from randomized controlled trials.Eur J Intern Med. 2022; 101: 40-47https://doi.org/10.1016/j.ejim.2022.04.004
Article info
Publication history
Published online: April 24, 2022
Accepted:
April 21,
2022
Received:
April 15,
2022
Footnotes
CoI Statement: Dr. Dagna reports personal fees from Sanofi Genzyme, personal fees from Roche, outside the submitted work; Dr. Farina has no conflicts of interest to disclose.
Identification
Copyright
© 2022 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
