Genetic IL-6R variants and therapeutic inhibition of IL-6 receptor signalling in COVID-19 – Authors' reply
Authors: Jonas Bovijn, Cecilia M Lindgren, Michael V Holmes
Journal: The Lancet Rheumatology (2020)

We thank Christoph Garbers and Stefan Rose-John for their interest in our Correspondence1Bovijn J Lindgren CM Holmes MV Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19.Lancet Rheumatol. 2020; 2: e658-e659Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar 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. The precise mechanism by which a drug modulates a therapeutic target, and by which a genetic variant influences the same target, might not be identical. However, this does not necessarily obviate the use of such genetic instruments to make deductions about the probable efficacy of modifying a therapeutic target, especially if a drug and genetic variant exhibit similar associations with target-associated molecular pathways. The concordant effects of IL6R genetic variants and pharmacological IL-6 receptor inhibition on multiple biomarkers (eg, fibrinogen, C-reactive protein, IL-6, and soluble IL-6R2Georgakis MK Malik R Gill D et al.Interleukin-6 signaling effects on ischemic stroke and other cardiovascular outcomes.Circ Genom Precis. 2020; 13e002872Crossref PubMed Scopus (76) Google Scholar) and disease (eg, rheumatoid arthritis) argue for phenotypic consistency between the genetic instrument and therapeutic effect. Furthermore, the rs2228145 missense variant has been shown to impede membrane-bound IL-6 receptor signalling,3Ferreira RC Freitag DF Cutler AJ et al.Functional IL6R 358Ala allele impairs classical IL-6 receptor signaling and influences risk of diverse inflammatory diseases.PLoS Genet. 2013; 9e1003444Crossref PubMed Scopus (200) Google Scholar and the effect on disease outcomes (including potentially COVID-19) might therefore be mediated via this mechanism (in addition to, or in lieu of, the IL-6 buffering mechanism proposed by Garbers and Rose-John). Mendelian randomisation studies of drug targets are subject to various caveats (including the mechanistic considerations highlighted in the foregoing text), and results from such studies should not be interpreted as representing definitive evidence of drug efficacy or safety. Rather, such genetic investigations provide evidence for (or against) therapeutic hypotheses, in which the acid test ultimately remains evidence of efficacy derived from well-designed randomised, controlled trials. As we noted in our original Correspondence,1Bovijn J Lindgren CM Holmes MV Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19.Lancet Rheumatol. 2020; 2: e658-e659Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar our results provide evidence for the potential efficacy of IL-6 receptor inhibition (and possibly the role of IL-6 signalling more broadly) in COVID-19, which should be further evaluated in adequately powered randomised, controlled trials. A further dimension must be considered in the context of drug-target Mendelian randomisation applied to an emerging infectious disease such as COVID-19. In contrast to coronary heart disease, for example, where data from large-scale genome-wide association study consortia are already established, the same is not the case for COVID-19. Effect estimates might therefore not be stable to the addition of newer data that become available. To this end, following our original publication,1Bovijn J Lindgren CM Holmes MV Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19.Lancet Rheumatol. 2020; 2: e658-e659Summary Full Text Full Text PDF PubMed Scopus (39) Google Scholar the COVID-19 Host Genetics Initiative released an updated dataset including a larger number of cases and controls. We updated our analyses using these newly released data and found that our results remained largely unchanged (appendix p 1). Notably, we found that the association of the IL-6 receptor genetic instrument with the most severe COVID-19 phenotype (COVID-19 requiring respiratory support or leading to death) was strengthened with an increased number of cases from 536 to 4336 (OR 0·94 scaled to a 0·1 SD lower C-reactive protein, [95% CI, 0·90–0·98], p=0·005, by use of the updated data, vs 0·98, [95% CI, 0·88–1·10], p=0·78 by use of the original data). Findings from randomised, controlled trials of tocilizumab have shown conflicting results,4Furlow B COVACTA trial raises questions about tocilizumab's benefit in COVID-19.Lancet Rheumatol. 2020; 2: e592Summary Full Text Full Text PDF PubMed Google Scholar which might suggest that IL-6 receptor inhibition does not provide therapeutic benefit in all patients with COVID-19. Ongoing randomised, controlled trials, such as the RECOVERY trial,5Parr JB Time to reassess tocilizumab's role in COVID-19 pneumonia.JAMA Intern Med. 2020; (published online Oct 20.)https://doi.org/10.1001/jamainternmed.2020.6557Crossref PubMed Scopus (59) Google Scholar will be crucial in providing further evidence. JB reports grants from the Rhodes Trust and the Clarendon Fund and personal fees from the Bill & Melinda Gates Foundation. CML reports grants from the Li Ka Shing Foundation, the 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, and did not accept any personal honoraria or other payments. Download .pdf (.75 MB) Help with pdf files Supplementary appendix Genetic variants mimicking therapeutic inhibition of IL-6 receptor signaling and risk of COVID-19Few 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. 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