Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19
Authors: Jonas Bovijn, Cecilia M Lindgren, Michael V Holmes
Journal: The Lancet Rheumatology (2020)

Few effective therapeutic options are available for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. IL-6 receptor blockade has been proposed as one potential therapeutic strategy, and more than 40 clinical trials of anti-IL-6 receptor antibodies (including tocilizumab and sarilumab) in the setting of SARS-CoV-2 infection are underway (appendix p 2). Early evidence from observational studies and open-label, uncontrolled trials has suggested that IL-6 receptor blockers might confer benefit, particularly in patients with severe COVID-19.1Biran N Ip A Ahn J et al.Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational study.Lancet Rheumatol. 2020; (published online Aug 14.)https://doi.org/10.1016/S2665-9913(20)30277-0Summary Full Text Full Text PDF PubMed Scopus (216) Google Scholar Human genetics enables the investigation of potential opportunities for drug repurposing. We leveraged large-scale human genetic data to investigate whether IL-6 receptor blockade might confer therapeutic benefit in COVID-19. A genetic instrument consisting of seven genetic variants in or close to IL6R (pairwise r2≤0·1; appendix pp 8–9) was recently shown to be associated with altered concentrations of C-reactive protein, fibrinogen, circulating IL-6, and soluble IL-6 receptor, concordant with known effects of pharmacological IL-6 receptor blockade (appendix p 4).2Georgakis MK Malik R Gill D et al.Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes: a mendelian randomization study.Circ Genom Precis Med. 2020; 13e002872Crossref PubMed Scopus (76) Google Scholar We investigated the effect of these IL6R variants on risk of hospitalisation for COVID-19 and other SARS-CoV-2-related outcomes using data from the COVID-19 Host Genetics Initiative (appendix pp 2–3, 10).3COVID-19 Host Genetics InitiativeThe COVID-19 Host Genetics Initiative, a global initiative to elucidate the role of host genetic factors in susceptibility and severity of the SARS-CoV-2 virus pandemic.Eur J Hum Genet. 2020; 28: 715-718Crossref PubMed Scopus (478) Google Scholar Based on data from UK Biobank, the IL6R variants were confirmed to be associated with lower serum C-reactive protein concentrations (appendix pp 5–6). Meta-analysis of scaled estimates identified a lower risk of rheumatoid arthritis (odds ratio 0·93 per 0·1 SD lower C-reactive protein; 95% CI 0·90–0·96, p<0·0001; appendix pp 5–6), supporting this established indication for IL-6 receptor inhibitors (eg, tocilizumab and sarilumab), as well as a lower risk of coronary heart disease (0·96; 0·95–0·98, p<0·0001), which has previously been linked to genetic variation in IL6R.4Swerdlow DI Holmes MV et al.Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) ConsortiumThe interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis.Lancet. 2012; 379: 1214-1224Summary Full Text Full Text PDF PubMed Scopus (802) Google Scholar The IL6R instrument was also associated with a lower risk of hospitalisation for COVID-19 (0·88; 0·78–0·99, p=0·03; appendix pp 5–6). We found a consistent association when using a population-based control group (ie, all non-cases; 0·91; 0·87–0·96, p=0·0005; appendix pp 5–6). On evaluation of further SARS-CoV-2-related outcomes, we detected an association of the IL6R instrument with risk of SARS-CoV-2 infection (0·92; 0·89–0·95, p<0·0001 using a population-based control group; appendix pp 5–6), but no evidence of association with death or need for respiratory support. The results of the main analysis were robust to various sensitivity analyses (appendix p 7). Our findings show that IL6R variants mimicking therapeutic inhibition of IL-6 receptor are associated with a lower risk of hospitalisation for COVID-19, a phenotype that is associated with disease severity (eg, requiring supplemental oxygen is a typical reason for hospitalisation). This result suggests that pharmacological blockade of IL-6 receptor might be expected to lead to reduced COVID-19 severity. We also found an association with lower risk of SARS-CoV-2 infection; although this finding might suggest that IL-6 receptor blockade lowers susceptibility to SARS-CoV-2 infection, these phenotypes could be biased by symptom severity (ie, individuals with more severe symptoms might be more likely to present for testing, to be offered testing, or to have a positive test). The lack of association with very severe COVID-19 requiring respiratory support or leading to death might be relevant in the context of the announced failure of sarilumab in a phase 3 randomised controlled trial in patients with COVID-19 requiring mechanical ventilation.5RegeneronRegeneron and Sanofi provide update on Kevzara (sarilumab) phase 3 U.S. trial in COVID-19 patients.https://investor.regeneron.com/news-releases/news-release-details/regeneron-and-sanofi-provide-update-kevzarar-sarilumab-phase-3Date: July 2, 2020Date accessed: July 8, 2020Google Scholar However, the genetic analysis with very severe COVID-19 was based on relatively few cases (n=536), limiting robust inference, and the EMPACTA randomised controlled trial reported a lower risk of progressing to mechanical ventilation or death in patients with COVID-19 pneumonia who received tocilizumab compared with patients who received placebo (hazard ratio 0·56; 95% CI 0·32–0·97, p=0·035).6Business WireGenentech's phase III EMPACTA study showed actemra reduced the likelihood of needing mechanical ventilation in hospitalized patients with COVID-19 associated pneumonia.https://www.businesswire.com/news/home/20200917006062/en/Genentech%E2%80%99s-Phase-III-EMPACTA-Study-Showed-Actemra-Reduced-the-Likelihood-of-Needing-Mechanical-Ventilation-in-Hospitalized-Patients-With-COVID-19-Associated-PneumoniaDate: Sept 18, 2020Date accessed: September 18, 2020Google Scholar Our results serve as genetic evidence for the potential efficacy of IL-6 receptor blockade in COVID-19 and support the study of IL-6 receptor inhibitors in randomised controlled trials. On their own, these data should not be used to influence clinical care. Ongoing, large-scale randomised controlled trials of IL-6 receptor inhibitors will be instrumental in identifying the potential settings, including stage of disease and potential pharmacogenetic subgroups, in which these agents might be effective. JB reports grants from Rhodes Trust and Clarendon Fund and personal fees from the Bill & Melinda Gates Foundation. CML reports grants from Li Ka Shing Foundation National Institute for Health Research Oxford Biomedical Research Centre, Novo Nordisk, and Bayer and personal fees from Pfizer. CML's spouse is an employee of Vertex. MVH reports grants from the British Heart Foundation (Intermediate Clinical Research Fellowship; FS/18/23/33512) and the National Institute for Health Research Oxford Biomedical Research Centre. MVH has collaborated with Boehringer Ingelheim in research, and in adherence with staff policy of the Clinical Trial Service Unit and Epidemiological Studies Unit of the University of Oxford, did not accept any personal honoraria or other payments. CML and MVH contributed equally to this work. Download .pdf (.89 MB) Help with pdf files Supplementary appendix Tocilizumab among patients with COVID-19 in the intensive care unit: a multicentre observational studyIn this observational study, patients with COVID-19 requiring ICU support who received tocilizumab had reduced mortality. Results of ongoing randomised controlled trials are awaited. Full-Text PDF Genetic IL-6R variants and therapeutic inhibition of IL-6 receptor signalling in COVID-19The COVID-19 pandemic, caused by infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major challenge for treating physicians as long as neither a vaccine nor an available therapy is generally effective. Patients with SARS-CoV-2 often display hyperinflammation, and several small studies reported a benefit when patients were treated with tocilizumab, a monoclonal antibody targeting the interleukin (IL)-6 receptor (IL-6R).1,2 However, the phase 3 COVACTA trial did not show an improvement in clinical status in patients with COVID-19-associated pneumonia nor a reduction in patient mortality with tocilizumab, suggesting that IL-6 blockade might not be beneficial in all COVID-19 patients. Full-Text PDF Genetic IL-6R variants and therapeutic inhibition of IL-6 receptor signalling in COVID-19 – Authors' replyWe thank Christoph Garbers and Stefan Rose-John for their interest in our Correspondence1 on genetic variants in the gene encoding the interleukin (IL)-6 receptor (IL6R) mimicking pharmacological IL-6 receptor inhibition. Garbers and Rose-John propose an interpretation of our genetic findings that posits that the genetic instrument acts as a buffer for IL-6. We see this as a complementary interpretation to that in which the genetic instrument mimics therapeutic inhibition of the IL-6 receptor. Full-Text PDF