Back to Search
Start Over
Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension
- Source :
- 2022, ' Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension ', The European respiratory journal, vol. 59, no. 3, 2002463 . https://doi.org/10.1183/13993003.02463-2020
- Publication Year :
- 2022
-
Abstract
- BackgroundInflammation 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.MethodsWe 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.ResultsWe 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 Six were withdrawn prior to drug administration; 23 patients received at least one dose of tocilizumab.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).ConclusionAdverse events were consistent with the known safety profile of tocilizumab. Tocilizumab did not show any consistent treatment effect.
- Subjects :
- Pulmonary and Respiratory Medicine
Adult
Male
medicine.medical_specialty
Biomedical Research
Disease
chemistry.chemical_compound
Tocilizumab
Internal medicine
medicine
Humans
Familial Primary Pulmonary Hypertension
Adverse effect
Interleukin 6
Associated Pulmonary Arterial Hypertension
Aged
Pulmonary Arterial Hypertension
biology
business.industry
Interleukin-6
Incidence (epidemiology)
Middle Aged
medicine.disease
Connective tissue disease
medicine.anatomical_structure
Treatment Outcome
chemistry
Vascular resistance
biology.protein
Female
business
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- 2022, ' Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension ', The European respiratory journal, vol. 59, no. 3, 2002463 . https://doi.org/10.1183/13993003.02463-2020
- Accession number :
- edsair.doi.dedup.....1669f2f7075fc94c5d8cdd8d56ad4951