A role for interleukin-1 receptor antagonism in severe COVID-19?
Authors: Rachel S Tattersall, Dennis McGonagle, Jessica J Manson
Journal: The Lancet Rheumatology (2021)

Early in the COVID-19 pandemic it was noted that a subset of people with severe disease were admitted to hospital with a hyperinflammatory illness.1Mehta P McAuley DF Brown M Sanchez E Tattersall RS Manson JJ COVID 19: consider cytokine storms and immune suppression.Lancet. 2020; 395: 1033-1034Summary Full Text Full Text PDF PubMed Scopus (6851) Google Scholar Subsequently, trials investigating immunomodulation as a treatment for severe COVID-19 resulted in dexamethasone becoming standard of care for people admitted to hospital with severe COVID-19 and the interleukin (IL)-6 receptor inhibitor tocilizumab being recommended for people requiring supplemental oxygen and with evidence of a significant inflammatory response.2Abani O Abbas A Abbas F et al.RECOVERY Collaborative GroupTocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.Lancet. 2021; 397: 1637-1645Summary Full Text Full Text PDF PubMed Scopus (1252) Google Scholar The clinical character, pathophysiology, and phenotype of hyperinflammation in severe COVID-19 is still being elucidated. The hypercytokinaemaia and hyperferritinaemia observed in COVID-19 is modest compared with the prototype cytokine storm syndromes haemophagocytic lymphohistiocytosis and macrophage activation syndrome. Instead, a model of more limited, lung-centric immunothrombogenic inflammatory pathology has been proposed.3McGonagle D Ramanan A Bridgewood C Immune cartography of macrophage activation syndrome in the COVID-19 era.Nat Rev Rheumatol. 2021; 17: 145-157Crossref PubMed Scopus (73) Google Scholar Beyond the established role of corticosteroids and tocilizumab in hyperinflammatory COVID-19, the IL-1 pathway is a target of particular interest. NLRP3 inflammasome activation (with increased IL-18 and IL-1β) has been observed in patients with severe or critical COVID-19 pneumonia,4Rodrigues TS de Sa' KSG Ishimoto AY et al.Inflammasomes are activated in response to SARS-CoV-2 infection and are associated with COVID-19 severity in patients.J Exp Med. 2021; 218e20201707Crossref PubMed Google Scholar and direct mononuclear cell inflammasome activation upon exposure to SARS-CoV-25Ferreira AC Cardoso Soares V de Azevedo-Quintanilha IG et al.SARS-CoV-2 engages inflammasome and pyroptosis in human primary monocytes.Cell Death Discov. 2021; 7: 43Crossref PubMed Scopus (175) Google Scholar has also been reported, supporting the concept that IL-1 pathway antagonism may be a tractable target in severe COVID-19. Anakinra is a recombinant IL-1 receptor antagonist inducing both IL-1α and IL-1β blockade that has a key role in the treatment of hyperinflammatory syndromes and reported benefit in patients with septicaemia.6Shakoory B Carcillo JA Chatham WW et al.Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial.Crit Care Med. 2016; 44: 275-281Crossref PubMed Scopus (622) Google Scholar The recently published negative canakinumab trial in severe COVID-197Caricchio R Abbate A Gordeev I et al.Effect of canakinumab vs placebo on survival without invasive mechanical ventilation in patients hospitalized with severe COVID-19: a randomized clinical trial.JAMA. 2021; 326: 230-239Crossref PubMed Scopus (130) Google Scholar cannot be fully extrapolated to anakinra trials as canakinumab selectively blocks IL-1β and therefore might have a different impact on immunothrombosis. In The Lancet Rheumatology, Evdoxia Kyriazopoulou and colleagues8Kyriazopulou E Huet T Cavalli G et al.Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.Lancet Rheumatol. 2021; (published online Aug 9.)https://doi.org/10.1016/S2665-9913(21)00216-2Summary Full Text Full Text PDF Scopus (122) Google Scholar present the results of a systematic review and meta-analysis of studies assessing the safety and efficacy of anakinra (compared to standard of care or placebo) in treating people admitted to hospital with COVID-19. With a primary outcome of mortality after 28 days, and a secondary outcome of safety, the authors did a meta-analysis of aggregate data from 1185 patients in nine studies and of individual patient-level data from 895 patients in six studies. Mortality was significantly lower in people treated with anakinra (38 [11%] of 342) than in those receiving standard of care or placebo (137 [25%] of 553; adjusted odds ratio 0·32 [95% CI 0.20–0·51]; p<0·0001). There was no safety signal associated with anakinra, although the dose and route of administration were not included. Other limitations of the present study include the small numbers of patients recruited in the original studies, a predominantly observational methodology of the included studies, and most studies being done before dexamethasone became standard of care in this setting. Dexamethasone use was not standardised in the studies of anakinra included in this meta-analysis and, based on data from very small numbers of patients, the authors suggest that anakinra was not beneficial above and beyond dexamethasone. By contrast, large trials of tocilizumab and corticosteroids have shown that the addition of IL-6 blockade further improved survival in patients with severe COVID-19.2Abani O Abbas A Abbas F et al.RECOVERY Collaborative GroupTocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.Lancet. 2021; 397: 1637-1645Summary Full Text Full Text PDF PubMed Scopus (1252) Google Scholar If the absence of additional benefit of anakinra in patients treated with dexamethasone was to be prospectively confirmed, what is the role of this costly and limited-availability drug in a global pandemic? It might be that there is a place for anakinra in specific patient groups to enable steroid-minimised treatment regimens, given the worrying reports of increased complications in people with diabetes treated with dexamethasone and the rise of previously rare infections such as mucormycosis.9Singh AK Singh R Joshi SR Misra A Mucormycosis in COVID-19: a systematic review of cases reported worldwide and in India.Diabetes Metab Syndr. 2021; 15102146Crossref PubMed Scopus (564) Google Scholar The observation by Kyriazopoulou and colleagues8Kyriazopulou E Huet T Cavalli G et al.Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysis.Lancet Rheumatol. 2021; (published online Aug 9.)https://doi.org/10.1016/S2665-9913(21)00216-2Summary Full Text Full Text PDF Scopus (122) Google Scholar that the beneficial effect of anakinra was more pronounced in people with evidence of a significant inflammatory response, defined as a C-reactive protein concentration higher than 100 mg/L, is important. We and others have sought to define the hyperinflammatory response in severe COVID-19 infection by use of simple, widely available clinical measures including, but not limited to, C-reactive protein.10Manson JJ Crooks C Naja M et al.COVID-19 associated hyperinflammation and escalation of patient care: a retrospective longitudinal cohort study.Lancet Rheumatol. 2020; 2: e594-e602Summary Full Text Full Text PDF PubMed Scopus (182) Google Scholar Defining the hyperinflammatory phenotype of severe COVID-19 is key in further prospective trials of immunomodulation therapies. Trial designs need to rest on better evidence of the pathophysiology of severe COVID-19 and ensure stratification by phenotype to select patients who have evidence of hyperinflammation and who are therefore more likely to benefit. Equally, such trial designs need to consider where immunosuppression might plausibly cause harm. For example, it has been postulated that in some patients with severe COVID-19, persistence of viral RNA drives the inflammatory responses,11Miki S Sasaki H Horiuchi H et al.On-admission SARS-CoV-2 RNAemia as a single potent predictive marker of critical condition development and mortality in COVID-19.PLoS One. 2021; 16e0254640Crossref PubMed Scopus (17) Google Scholar and the host needs a robust immune system to clear the virus and viral products. The COVID-19 pandemic has shown the importance of multispecialty collaboration. Further prospective trials of IL-1 pathway antagonism are needed, and rheumatologists should be central to the design of such trials to ensure thoughtful stratification of patients to maximise benefit and minimise harm. RST has received personal fees from UCB, AbbVie, and Jansen, outside the submitted work. DM has received personal fees from Sobi, outside the submitted work. JJM declares no competing interests. Effect of anakinra on mortality in patients with COVID-19: a systematic review and patient-level meta-analysisAnakinra could be a safe, anti-inflammatory treatment option to reduce the mortality risk in patients admitted to hospital with moderate to severe COVID-19 pneumonia, especially in the presence of signs of hyperinflammation such as CRP concentrations higher than 100 mg/L. Full-Text PDF