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

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Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension. / Toshner, Mark; Church, Colin; Harbaum, Lars; Rhodes, Christopher; Villar Moreschi, Sofia S; Liley, James; Jones, Rowena; Arora, Amit; Batai, Ken; Desai, Ankit A; Coghlan, John G; Gibbs, J Simon R; Gor, Dee; Gräf, Stefan; Harlow, Louise; Hernandez-Sanchez, Jules; Howard, Luke S; Humbert, Marc; Karnes, Jason; Kiely, David G; Kittles, Rick; Knightbridge, Emily; Lam, Brian; Lutz, Katie A; Nichols, William C; Pauciulo, Michael W; Pepke-Zaba, Joanna; Suntharalingam, Jay; Soubrier, Florent; Trembath, Richard C; Schwantes-An, Tae-Hwi L; Wort, S John; Wilkins, Martin; Gaine, Sean; Morrell, Nicholas W; Corris, Paul A.

In: EUR RESPIR J, Vol. 59, No. 3, 03.2022.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Toshner, M, Church, C, Harbaum, L, Rhodes, C, Villar Moreschi, SS, Liley, J, Jones, R, Arora, A, Batai, K, Desai, AA, Coghlan, JG, Gibbs, JSR, Gor, D, Gräf, S, Harlow, L, Hernandez-Sanchez, J, Howard, LS, Humbert, M, Karnes, J, Kiely, DG, Kittles, R, Knightbridge, E, Lam, B, Lutz, KA, Nichols, WC, Pauciulo, MW, Pepke-Zaba, J, Suntharalingam, J, Soubrier, F, Trembath, RC, Schwantes-An, T-HL, Wort, SJ, Wilkins, M, Gaine, S, Morrell, NW & Corris, PA 2022, 'Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension', EUR RESPIR J, vol. 59, no. 3. https://doi.org/10.1183/13993003.02463-2020

APA

Toshner, M., Church, C., Harbaum, L., Rhodes, C., Villar Moreschi, S. S., Liley, J., Jones, R., Arora, A., Batai, K., Desai, A. A., Coghlan, J. G., Gibbs, J. S. R., Gor, D., Gräf, S., Harlow, L., Hernandez-Sanchez, J., Howard, L. S., Humbert, M., Karnes, J., ... Corris, P. A. (2022). Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension. EUR RESPIR J, 59(3). https://doi.org/10.1183/13993003.02463-2020

Vancouver

Toshner M, Church C, Harbaum L, Rhodes C, Villar Moreschi SS, Liley J et al. Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension. EUR RESPIR J. 2022 Mar;59(3). https://doi.org/10.1183/13993003.02463-2020

Bibtex

@article{e9d1ed8d84154a0bb6b3bb5b84581c1d,
title = "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.",
author = "Mark Toshner and Colin Church and Lars Harbaum and Christopher Rhodes and {Villar Moreschi}, {Sofia S} and James Liley and Rowena Jones and Amit Arora and Ken Batai and Desai, {Ankit A} and Coghlan, {John G} and Gibbs, {J Simon R} and Dee Gor and Stefan Gr{\"a}f and Louise Harlow and Jules Hernandez-Sanchez and Howard, {Luke S} and Marc Humbert and Jason Karnes and Kiely, {David G} and Rick Kittles and Emily Knightbridge and Brian Lam and Lutz, {Katie A} and Nichols, {William C} and Pauciulo, {Michael W} and Joanna Pepke-Zaba and Jay Suntharalingam and Florent Soubrier and Trembath, {Richard C} and Schwantes-An, {Tae-Hwi L} and Wort, {S John} and Martin Wilkins and Sean Gaine and Morrell, {Nicholas W} and Corris, {Paul A}",
note = "Copyright {\textcopyright}The authors 2021.",
year = "2022",
month = mar,
doi = "10.1183/13993003.02463-2020",
language = "English",
volume = "59",
journal = "EUR RESPIR J",
issn = "0903-1936",
publisher = "European Respiratory Society",
number = "3",

}

RIS

TY - JOUR

T1 - Mendelian randomisation and experimental medicine approaches to interleukin-6 as a drug target in pulmonary arterial hypertension

AU - Toshner, Mark

AU - Church, Colin

AU - Harbaum, Lars

AU - Rhodes, Christopher

AU - Villar Moreschi, Sofia S

AU - Liley, James

AU - Jones, Rowena

AU - Arora, Amit

AU - Batai, Ken

AU - Desai, Ankit A

AU - Coghlan, John G

AU - Gibbs, J Simon R

AU - Gor, Dee

AU - Gräf, Stefan

AU - Harlow, Louise

AU - Hernandez-Sanchez, Jules

AU - Howard, Luke S

AU - Humbert, Marc

AU - Karnes, Jason

AU - Kiely, David G

AU - Kittles, Rick

AU - Knightbridge, Emily

AU - Lam, Brian

AU - Lutz, Katie A

AU - Nichols, William C

AU - Pauciulo, Michael W

AU - Pepke-Zaba, Joanna

AU - Suntharalingam, Jay

AU - Soubrier, Florent

AU - Trembath, Richard C

AU - Schwantes-An, Tae-Hwi L

AU - Wort, S John

AU - Wilkins, Martin

AU - Gaine, Sean

AU - Morrell, Nicholas W

AU - Corris, Paul A

N1 - Copyright ©The authors 2021.

PY - 2022/3

Y1 - 2022/3

N2 - 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.

AB - 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.

U2 - 10.1183/13993003.02463-2020

DO - 10.1183/13993003.02463-2020

M3 - SCORING: Journal article

C2 - 34588193

VL - 59

JO - EUR RESPIR J

JF - EUR RESPIR J

SN - 0903-1936

IS - 3

ER -