Interleukin-6 Receptor Antagonists in Critically Ill Patients with Covid-19

To the Editor: The variable efficacy of the interleukin-6 receptor antagonist tocilizumab against Covid-19, as shown most recently in the results of REMAP-CAP reported by Gordon et al. 1 and the results of the COVACTA trial reported by Rosas et al. 2 (April 22 issue), may reflect the fact that interleukin-6 has a dual role.Interleukin-6 stimulates desirable antibody production by immune cells that express membranous interleukin-6 receptors and also stimulates undesirable proinflammatory effects by cells that lack interleukin-6 receptors.Interleukin-6 trans-signaling to cells that lack interleukin-6 receptors requires dimerization of shed soluble interleukin-6 receptors with another membrane protein, glycoprotein 130 (gp130). 3 Since tocilizumab blocks both desirable and undesirable actions of interleukin-6, selective blockade of the undesirable actions by soluble recombinant gp130 could provide a greater net benefit than tocilizumab. 3,4 A related explanation for the variable efficacy of tocilizumab between trials -and indeed variable susceptibility to Covid-19 in generalis suggested by two variants of IL6ST (the gene encoding gp130) that are predicted to be deleterious: p.Ile454Thr (rs2228046) and p.Gly148Arg (rs2228044).The minor-allele frequencies of these variants are 30 to 40% higher in the African genome than in other genomes.According to data from UK Biobank, the minor (risk) alleles of both variants are associated with a higher mortality from Covid-19 in Black patients than the major (reference) alleles (Table 1); the proportion of Black patients in REMAP-CAP was 4.0% and in the COVACTA trial 15.1%.The minor allele of rs2228046 has previously been associated with an antibody response to measles vaccine that is 3 times as high as the response in its absence. 5