Endotype-phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease

Background: Some interstitial lung disease (ILD) patients develop a progressive fibrosing-ILD phenotype (PF-ILD), with similar persistent lung function decline suggesting common molecular pathways involved. Nintedanib, a tyrosine kinase inhibitor targeting the PDGF, FGF, VEGF and M-CSF pathways, has shown comparable efficacy in idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD). We hypothesize that Nintedanib targeted molecular pathways will be augmented to a similar degree across PF-ILD regardless of aetiology. Methods: We collected explanted lung tissue at the time of lung transplantation from 130 PF-ILD patients (99 (76%) IPF, 14 (11%) SSc-ILD, 17 (13%) other PF-ILD), and wedge biopsies from 200 donor lungs and measured PDGF, FGF, VEGF and M-CSF concentrations by Luminex. Findings: The concentrations of PDGF-AA, PDGF-BB, FGF-2, VEGF and M-CSF were significantly increased in PF-ILD lungs compared to donor lungs (PDGF-AA 93.0 pg/ml [+/- 97.2] vs. 37.5 pg/ml [+/- 35.4], p<0.001; PDGF-BB 102.5 pg/ml [+/- 78.8] vs. 61.9 pg/ml [+/- 47.0], p<0.001; FGF-2 1442.4 pg/ml [+/- 426.6] vs. 1201.7 pg/ml [+/- 535.2], p=0009; VEGF 40.6 pg/ml [+/- 20.1] vs. 24.9 pg/ml [+/- 29.5], p<0.001; and M-CSF 25526 pg/ml [+/- 24,799] vs. 6120 pg/ml [+/- 7245], p<0.001). There were no significant differences in these growth factor/angiogenic molecules/cytokine concentrations when segregated by IPF, SSc-ILD and other PF-ILDs. Interpretation: Nintedanib specific targeted molecular pathways are augmented to a similar magnitude in all PF-ILD lung tissue as compared to controls, suggesting that Nintedanib treatment may be efficacious in PF-ILD regardless of aetiology. We speculate that clinical trials using Nintedanib for PF-ILD with or without IPF or SSc-ILD should show a similar relative reduction in FVC decline as seen in IPF and SSc-ILD (similar to 45-50%). (C) 2019 The Authors. Published by Elsevier B.V.