Tocilizumab improves oxidative stress and endothelial glycocalyx: A mechanism that may explain the effects of biological treatment on COVID-19

Ignatios Ikonomidis, George Pavlidis, Pelagia Katsimbri, Vaia Lambadiari, John Parissis, Ioanna Andreadou, Maria Tsoumani, Dimitrios Boumpas, Dimitrios Kouretas, Efstathios Iliodromitis, Ignatios Ikonomidis, George Pavlidis, Pelagia Katsimbri, Vaia Lambadiari, John Parissis, Ioanna Andreadou, Maria Tsoumani, Dimitrios Boumpas, Dimitrios Kouretas, Efstathios Iliodromitis

Abstract

We investigated the effects of tocilizumab on endothelial glycocalyx, a determinant of vascular permeability, and myocardial function in rheumatoid arthritis (RA). Eighty RA patients were randomized to tocilizumab (n = 40) or conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and glucocorticoids (GC) (n = 40) for 3 months. Forty healthy subjects with similar age and sex served as controls. We measured: (a)perfused boundary region (PBR) of the sublingual arterial microvessels (increased PBR indicates reduced glycocalyx thickness), (b)pulse wave velocity (PWV), (c)global LV longitudinal strain (GLS), (d)global work index (GWI) using speckle tracking echocardiography and e)C-reactive protein (CRP), malondialdehyde (MDA) and protein carbonyls (PCs) as oxidative stress markers at baseline and post-treatment. Compared to controls, RA patients had impaired glycocalyx and myocardial deformation markers (P < 0.05). Compared with baseline, tocilizumab reduced PBR(2.14 ± 0.2 versus 1.97 ± 0.2 μm; P < 0.05) while no significant differences were observed post-csDMARDs + GC(P > 0.05). Compared with csDMARDs + GC, tocilizumab achieved a greater increase of GLS, GWI and reduction of MDA, PCs and CRP(P < 0.05). The percent improvement of glycocalyx thickness (PBR) was associated with the percent decrease of PWV, MDA, PCs and the percent improvement of GLS and GWI(P < 0.05). Tocilizumab improves endothelial function leading to a greater increase of effective myocardial work than csDMARDs + GC through a profound reduction of inflammatory burden and oxidative stress. This mechanism may explain the effects of tocilizumab on COVID-19. CLINICAL TRIAL REGISTRATION: url: https://www.clinicaltrials.gov. Unique identifier: NCT03288584.

Keywords: COVID-19; Endothelial glycocalyx; Interleukin 6; Myocardial deformation; Rheumatoid arthritis; Tocilizumab.

Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Copyright © 2020. Published by Elsevier Ltd.

Figures

Fig. 1
Fig. 1
(A) Perfused boundary region (PBR, μm), (B) global work index (GWI, mmHg%), (C) global constructive work (GCW, mmHg%), and (D) global wasted work (GWW, mmHg%) in the two study groups pre- and post-treatment. The Τ lines on bars of the figures indicate standard deviation of the mean value.

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