key: cord-1052931-nqrapz4h
authors: Garbers, Christoph; Rose-John, Stefan
title: Genetic IL-6R variants and therapeutic inhibition of IL-6 receptor signalling in COVID-19
date: 2020-12-15
journal: Lancet Rheumatol
DOI: 10.1016/s2665-9913(20)30416-1
sha: cb80815de1d78d703eca772d1eeef2fe144e01a3
doc_id: 1052931
cord_uid: nqrapz4h

nan

The COVID-19 pandemic, caused by infections with severe acute respira tory 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.

In their Correspondence in The Lancet Rheumatology, 3 Jonas Bovijn and colleagues analysed seven genetic IL-6R variants in the context of COVID-19. Of these, only one single nucleo tide polymorphism, rs2228145, which encodes the non-synonymous IL-6R variant Asp358Ala, has been functionally analysed, 4 whereas data for the other, mostly intronic, variants are lacking. These variants have previously been shown to be associated with reduced serum concentrations of C-reactive protein and fibrinogen and increased serum concentrations of IL-6 and soluble IL-6R (sIL-6R).

Because these clinical features are also present in patients undergoing anti-IL-6R therapy, Bojvin and colleagues conclude that the genetic IL-6R variants mimic therapeutic inhibition of IL-6R signalling. 3 Their analysis convincingly shows that the IL-6R variants are associated with a lower risk of rheumatoid arthritis and coronary heart disease, and interestingly also with a lower risk of hospitalisation for COVID-19 and risk of SARS-CoV-2 infection. 3 Although we do not question the validity of the results presented by Bovijn and colleagues, we think that the molecular nature of all variants should be discussed and related to the complex biology of IL-6. Specifically, we disagree with their notion that genetic IL-6R variants mimic therapeutic inhibition of IL-6R signalling. For example, the variant rs2228145 increases sIL-6R serum concentrations in individuals who are heterozygous or homozygous for this allele, owing to enhanced proteolytic cleavage of IL-6R and consequently reduced membrane bound IL-6R. 4 Importantly, all IL-6R variants retain their biological activity and can bind IL-6. This is a completely different scenario in patients treated with tocilizumab, in which IL-6 signalling via both membrane-bound and soluble IL-6R variants is blocked. In our opinion, the more probable explanation is that increased sIL-6R in combination with endogenous soluble gp130 acts as a buffer that neutralises IL-6 5 and that this mechanism accounts for the reduced risks of hospitalis ation for COVID-19 and other inflammatory diseases.

CG has received a research grant from Corvidia Therapeutics and has acted as a consultant for AbbVie. SRJ has acted as a consultant and speaker for AbbVie, Chugai, Roche, Regeneron, Genentech Roche, Pfizer, and Sanofi. He also declares that he is an inventor on patents owned by CONARIS Research Institute, which develops the sgp130Fc protein Olamkicept and he has stock ownership in CONARIS. Funding work in the groups of the authors is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation)-Projektnummer 125440785-SFB 877 (projects A1, A10, and A14).

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