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Mendelian randomisation and experimental medicine approaches to IL-6 as a drug target in PAH.

Mark R ToshnerColin ChurchLars HarbaumChristopher RhodesSofia S Villar MoreschiJames LileyRowena JonesAmit AroraKen BataiAnkit A DesaiJohn G CoghlanJ Simon R GibbsDee GorStefan GräfLouise HarlowJules Hernandez-SanchezLuke S HowardMarc HumbertJason KarnesDavid G KielyRick KittlesEmily KnightbridgeBrian LamKatie A LutzWilliam C NicholsMichael W PauciuloJoanna Pepke-ZabaJay SuntharalingamFlorent SoubrierRichard C TrembathTae-Hwi L Schwantes-AnS John WortMartin R WilkinsSean GaineNicholas W MorrellPaul A Corris
Published in: The European respiratory journal (2021)
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 Six were withdrawn prior to drug administration.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.
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