Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension. Compelling preclinical data supports the therapeutic blockade of interleukin-6 signalling.We conducted an open-label phase-II study of intravenous tocilizumab (8 mg·kg-1) over 6 months in group 1 pulmonary arterial hypertension. Co-primary endpoints were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular resistance. Separately, a Mendelian randomisation study was undertaken on 11,744 individuals with European ancestry including 2085 patients with idiopathic/heritable disease for the IL6R variant (rs7529229), known to associate with circulating IL6R levels.Twenty-nine patients (M/F 10/19; mean age 54.9[SD11.4]) were recruited. Nineteen had heritable/idiopathic and ten connective tissue disease associated pulmonary arterial hypertension. Six were withdrawn prior to drug administration. Twenty-three patients received at least one dose of tocilizumab. Tocilizumab was discontinued in 4 patients due to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma interleukin-6 and C-reactive protein levels, both intention-to-treat and modified intention-to-treat analyses demonstrated no change in pulmonary vascular resistance. Inflammatory markers did not predict treatment response. Mendelian randomisation did not support an effect of the lead IL6R variant on risk of pulmonary arterial hypertension (OR 0.99, p=0.88).Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
Date Issued
2021-09-29
Date Acceptance
2021-07-15
Citation
European Respiratory Journal, 2021, 59 (3), pp.1-11
ISSN
0903-1936
Publisher
European Respiratory Society
Start Page
1
End Page
11
Journal / Book Title
European Respiratory Journal
Volume
59
Issue
3
Copyright Statement
©The authors 2021 This version is distributed under the terms of the Creative Commons Attribution Licence 4.0. (https://creativecommons.org/licenses/by/4.0/)
License URL
Sponsor
British Heart Foundation
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/34588193
PII: 13993003.02463-2020
Grant Number
FS/15/59/31839
Subjects
Uniphy Clinical Trials Network
Respiratory System
11 Medical and Health Sciences
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2021-09-29