Dataset Information

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension.

ABSTRACT:

Background

Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling.

Methods

We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg^-1) over 6 months in patients with group 1 PAH. Co-primary end-points 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 IL-6 receptor (IL6R) variant (rs7529229), known to associate with circulating IL-6R levels.

Results

We recruited 29 patients (male/female 10/19; mean±sd age 54.9±11.4 years). Of these, 19 had heritable/idiopathic PAH and 10 had connective tissue disease-associated PAH. Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab. Tocilizumab was discontinued in four patients owing to serious adverse events. There were no deaths. Despite evidence of target engagement in plasma IL-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 PAH (OR 0.99, p=0.88).

Conclusion

Adverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.

SUBMITTER: Toshner M

PROVIDER: S-EPMC8907935 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Publications

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension.

Toshner Mark M Church Colin C Harbaum Lars L Rhodes Christopher C Villar Moreschi Sofia S SS Liley James J Jones Rowena R Arora Amit A Batai Ken K Desai Ankit A AA Coghlan John G JG Gibbs J Simon R JSR Gor Dee D Gräf Stefan S Harlow Louise L Hernandez-Sanchez Jules J Howard Luke S LS Humbert Marc M Karnes Jason J Kiely David G DG Kittles Rick R Knightbridge Emily E Lam Brian B Lutz Katie A KA Nichols William C WC Pauciulo Michael W MW Pepke-Zaba Joanna J Suntharalingam Jay J Soubrier Florent F Trembath Richard C RC Schwantes-An Tae-Hwi L TL Wort S John SJ Wilkins Martin R MR Gaine Sean S Morrell Nicholas W NW Corris Paul A PA

The European respiratory journal 20220310 3

<h4>Background</h4>Inflammation and dysregulated immunity are important in the development of pulmonary arterial hypertension (PAH). Compelling preclinical data supports the therapeutic blockade of interleukin-6 (IL-6) signalling.<h4>Methods</h4>We conducted a phase 2 open-label study of intravenous tocilizumab (8 mg·kg<sup>-1</sup>) over 6 months in patients with group 1 PAH. Co-primary end-points were safety, defined by incidence and severity of adverse events, and change in pulmonary vascular ...[more]

PMID: 34588193

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Dataset Information

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension.

Background

Methods

Results

Conclusion

Publications

Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension.

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