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Interleukin 6 inhibition in severe COVID-19: Another piece of the puzzle

  • Nicola Farina
    Affiliations
    Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy

    Vita-Salute San Raffaele University, Milan, Italy
    Search for articles by this author
  • Lorenzo Dagna
    Correspondence
    Corresponding author at: Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Via Olgettina, 60, I-20132 Milano, Italy.
    Affiliations
    Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Hospital, Milan, Italy

    Vita-Salute San Raffaele University, Milan, Italy
    Search for articles by this author
Published:April 24, 2022DOI:https://doi.org/10.1016/j.ejim.2022.04.018
      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 [
      • Cavalli G
      • Farina N
      • Campochiaro C
      • et al.
      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.
      ]. 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 [
      • Campochiaro C
      • Della-Torre E
      • Cavalli G
      • et al.
      Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study.
      ]. As targeted anti-viral medications were lacking, different anti-inflammatory strategies were studied to stop the progression of tissue damage and respiratory failure [
      • Farina N
      • Ramirez GA
      • de Lorenzo R
      • et al.
      COVID-19: Pharmacology and kinetics of viral clearance.
      ,
      • Della-Torre E
      • Campochiaro C
      • Cavalli G
      • et al.
      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.
      . In light of their remarkable anti-inflammatory properties, monoclonal antibodies targeting interleukin (IL)-6 [
      • Campochiaro C
      • Farina N
      • Tomelleri A
      • et al.
      Tocilizumab for the treatment of immune-related adverse events: a systematic literature review and a multicentre case series.
      ] 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 [
      • Cavalli G
      • Farina N
      • Campochiaro C
      • et al.
      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.
      ,
      • Chen X
      • Zhao B
      • Qu Y
      • et al.
      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.
      . However, the first studies on monoclonal antibodies blocking the IL-6 pathway, many of which were also published in this Journal, showed mixed results [
      • Campochiaro C
      • Della-Torre E
      • Cavalli G
      • et al.
      Efficacy and safety of tocilizumab in severe COVID-19 patients: a single-centre retrospective cohort study.
      ,
      • Morena V
      • Milazzo L
      • Oreni L
      • et al.
      Off-label use of tocilizumab for the treatment of SARS-CoV-2 pneumonia in Milan, Italy.
      ,
      • Capra R
      • de Rossi N
      • Mattioli F
      • et al.
      Impact of low dose tocilizumab on mortality rate in patients with COVID-19 related pneumonia.
      ,
      • di Nisio M
      • Potere N
      • Candeloro M
      • et al.
      Interleukin-6 receptor blockade with subcutaneous tocilizumab improves coagulation activity in patients with COVID-19.
      . 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 [
      • Rosas IO
      • Bräu N
      • Waters M
      • et al.
      Tocilizumab in Hospitalized Patients with Severe Covid-19 Pneumonia.
      ,
      • Stone JH
      • Frigault MJ
      • Serling-Boyd NJ
      • et al.
      Efficacy of Tocilizumab in Patients Hospitalized with Covid-19.
      ,
      • Salvarani C
      • Dolci G
      • Massari M
      • et al.
      Effect of Tocilizumab vs Standard Care on Clinical Worsening in Patients Hospitalized With COVID-19 Pneumonia: A Randomized Clinical Trial.
      ]. Intriguingly, one study even hinted at a possible ominous effect in terms of survival in patients treated with tocilizumab [
      • Veiga VC
      • Prats JAGG
      • Farias DLC
      • et al.
      Effect of tocilizumab on clinical outcomes at 15 days in patients with severe or critical coronavirus disease 2019: randomised controlled trial.
      ]. 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 [
      • Abani O
      • Abbas A
      • Abbas F
      • et al.
      Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.
      ]. 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 [
      • Lescure FX
      • Honda H
      • Fowler RA
      • et al.
      Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial.
      ,
      • Cavalli G
      • Dagna L.
      The right place for IL-1 inhibition in COVID-19.
      ,
      • Cavalli G
      • Larcher A
      • Tomelleri A
      • et al.
      Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study.
      ,
      • Della-Torre E
      • Lanzillotta M
      • Campochiaro C
      • et al.
      Respiratory Impairment Predicts Response to IL-1 and IL-6 Blockade in COVID-19 Patients With Severe Pneumonia and Hyper-Inflammation.
      ]. 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 [
      • Shankar-Hari M
      • Vale CL
      • Godolphin PJ
      • et al.
      Association Between Administration of IL-6 Antagonists and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis.
      ]. 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 [
      • Tasoudis P
      • Arvaniti C
      • Adamou A
      • et al.
      Interleukin-6 inhibitors reduce mortality in coronavirus disease- 2019: An individual patient data meta-analysis from randomized controlled trials.
      ], 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.

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