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. 2023 Mar 23;61(3):2201232.
doi: 10.1183/13993003.01232-2022. Print 2023 Mar.

Cytokines as prognostic biomarkers in pulmonary arterial hypertension

Athénaïs Boucly  1   2   3 , Ly Tu  1   2 , Christophe Guignabert  1   2 , Christopher Rhodes  4 , Pascal De Groote  5 , Grégoire Prévot  6 , Emmanuel Bergot  7 , Arnaud Bourdin  8 , Antoine Beurnier  1   2   3 , Anne Roche  1   2   3 , Mitja Jevnikar  1   2   3 , Xavier Jaïs  1   2   3 , David Montani  1   2   3 , Martin R Wilkins  4 , Marc Humbert  1   2   3 , Olivier Sitbon  1   2   3   9 , Laurent Savale  10   2   3   9
Affiliations
Free article

Cytokines as prognostic biomarkers in pulmonary arterial hypertension

Athénaïs Boucly et al. Eur Respir J. .
Free article

Abstract

Background: Risk stratification and assessment of disease progression in patients with pulmonary arterial hypertension (PAH) are challenged by the lack of accurate disease-specific and prognostic biomarkers. To date, brain natriuretic peptide (BNP) and/or its N-terminal fragment (NT-proBNP) are the only markers for right ventricular dysfunction used in clinical practice, in association with echocardiographic and invasive haemodynamic variables to predict outcome in patients with PAH.

Methods: This study was designed to identify an easily measurable biomarker panel in the serum of 80 well-phenotyped PAH patients with idiopathic, heritable or drug-induced PAH at baseline and at first follow-up. The prognostic value of identified cytokines of interest was secondly analysed in an external validation cohort of 125 PAH patients.

Results: Among the 20 biomarkers studied with the multiplex Ella platform, we identified a three-biomarker panel composed of β-NGF, CXCL9 and TRAIL that were independently associated with prognosis both at the time of PAH diagnosis and at the first follow-up after initiation of PAH therapy. β-NGF and CXCL9 were predictors of death or transplantation, whereas high levels of TRAIL were associated with a better prognosis. Furthermore, the prognostic value of the three cytokines was more powerful for predicting survival than usual non-invasive variables (New York Heart Association Functional Class, 6-min walk distance and BNP/NT-proBNP). The results were validated in a fully independent external validation cohort.

Conclusion: The monitoring of β-NGF, CXCL9 and TRAIL levels in serum should be considered in the management and treatment of patients with PAH to objectively guide therapeutic options.

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Conflict of interest statement

Conflict of interest: A. Boucly reports grants from Acceleron, Janssen and MSD, lecture honoraria from Janssen and Merck, and travel support from Janssen, outside the submitted work. C. Guignabert reports grants from Acceleron, Janssen, Merck and ShouTi, and lecture honoraria from Merck, outside the submitted work. C. Rhodes reports support for the present manuscript from BHF fellowship (FS/15/59/31839), Academy of Medical Sciences Springboard fellowship (SBF004\1095); consulting fees from United Therapeutics and Janssen, travel support from United Therapeutics, a patent submitted for prognostic protein model from Imperial Innovations, and advisory board participation with United Therapeutics and Janssen, outside the submitted work. P. De Groote reports consulting fees and lecture honoraria from Janssen, outside the submitted work. G. Prévot reports lecture honoraria from Boehringer Ingelheim, Sanofi and Jansen, and travel support from Boehringer Ingelheim, outside the submitted work. E. Bergot reports lecture honoraria and travel support from Janssen, Actelion and GSK, outside the submitted work. A. Bourdin reports grants from AstraZeneca and Boehringer Ingelheim, consulting fees, lecture honoraria and travel support from AstraZeneca, GSK, Novartis, Sanofi Regeneron, Boehringer Ingelheim and Chiesi, and advisory board participation with AB Science; outside the submitted work. A. Beurnier reports lecture honoraria and travel support from Sanofi, outside the submitted work. X. Jaïs reports grants from Acceleron, Janssen and MSD, lecture honoraria from Janssen and MSD, and travel support from Janssen, outside the submitted work. D. Montani reports grants from Acceleron, Janssen and Merck, consulting fees from Acceleron, and lecture honoraria from Bayer, Janssen and Merck, outside the submitted work. M.R. Wilkins reports support for the current manuscript from the British Heart Foundation and National Institute for Health Research; outside the submitted work, consulting fees from MorphogenIX, Actelion and Novartis, a patent under consideration on “Biomarker panel for pulmonary hypertension based on blood biomarkers”, and participation on advisory boards with Acceleron and GSK. M. Humbert reports support for the current manuscript from Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC EFORT) and ANR-15-RHUS-0002 (RHU BIOART-LUNG 2020); outside the submitted work, grants and consulting fees from Acceleron, Janssen and Merck, lecture honoraria from Janssen and Merck, and advisory board participation for Acceleron, Janssen, Merck and United Therapeutics. O. Sitbon reports grants from Acceleron, Janssen, GSK and MSD, consulting fees from Gossamer Bio, Janssen and MSD, lecture honoraria from AOP Orphan, Janssen, Ferrer and MSD, and advisory board participation for Acceleron, Janssen, MSD and Ferrer, outside the submitted work. L. Savale reports grants from Acceleron, Janssen and Merck, and lecture honoraria from GSK and Janssen, outside the submitted work. All other authors have nothing to disclose.

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