Endotype–phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease
Identifieur interne : 000841 ( Main/Exploration ); précédent : 000840; suivant : 000842Endotype–phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease
Auteurs : Anna-Maria Hoffmann-Vold [Norvège] ; S. Samuel Weigt [États-Unis] ; Rajan Saggar [États-Unis] ; Vyacheslav Palchevskiy [États-Unis] ; Elizabeth R. Volkmann [États-Unis] ; Lloyd L. Liang [États-Unis] ; David Ross [États-Unis] ; Abbas Ardehali [États-Unis] ; Joseph P. Lynch [États-Unis] ; John A. Belperio [États-Unis]Source :
- EBioMedicine [ 2352-3964 ] ; 2019.
Abstract
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.
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.
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],
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 (∼45–50%).
Health Grant P01-HL108793 (JAB), South-Eastern Norway Regional Health Authority Grant 2018072 (AMHV).
Url:
DOI: 10.1016/j.ebiom.2019.10.050
PubMed: 31732480
PubMed Central: 6921223
Affiliations:
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Liang</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Ross, David" sort="Ross, David" uniqKey="Ross D" first="David" last="Ross">David Ross</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Ardehali, Abbas" sort="Ardehali, Abbas" uniqKey="Ardehali A" first="Abbas" last="Ardehali">Abbas Ardehali</name><affiliation wicri:level="1"><nlm:aff id="aff0004">Department of Surgery, UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Surgery, UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Lynch, Joseph P" sort="Lynch, Joseph P" uniqKey="Lynch J" first="Joseph P." last="Lynch">Joseph P. Lynch</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Belperio, John A" sort="Belperio, John A" uniqKey="Belperio J" first="John A." last="Belperio">John A. Belperio</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31732480</idno><idno type="pmc">6921223</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6921223</idno><idno type="RBID">PMC:6921223</idno><idno type="doi">10.1016/j.ebiom.2019.10.050</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000505</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000505</idno><idno type="wicri:Area/Pmc/Curation">000505</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000505</idno><idno type="wicri:Area/Pmc/Checkpoint">000782</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000782</idno><idno type="wicri:Area/Ncbi/Merge">000C14</idno><idno type="wicri:Area/Ncbi/Curation">000C14</idno><idno type="wicri:Area/Ncbi/Checkpoint">000C14</idno><idno type="wicri:Area/Main/Merge">000841</idno><idno type="wicri:Area/Main/Curation">000841</idno><idno type="wicri:Area/Main/Exploration">000841</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Endotype–phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease</title><author><name sortKey="Hoffmann Vold, Anna Maria" sort="Hoffmann Vold, Anna Maria" uniqKey="Hoffmann Vold A" first="Anna-Maria" last="Hoffmann-Vold">Anna-Maria Hoffmann-Vold</name><affiliation wicri:level="1"><nlm:aff id="aff0001">Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, 0424 Oslo, Norway</nlm:aff><country xml:lang="fr">Norvège</country><wicri:regionArea>Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, 0424 Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</region></placeName></affiliation><affiliation wicri:level="1"><nlm:aff id="aff0002">Institute of Clinical Medicine, University of Oslo, Rikshospitalet, Pb 4950 Nydalen, 0424 Oslo, Norway</nlm:aff><country xml:lang="fr">Norvège</country><wicri:regionArea>Institute of Clinical Medicine, University of Oslo, Rikshospitalet, Pb 4950 Nydalen, 0424 Oslo</wicri:regionArea><placeName><settlement type="city">Oslo</settlement><region nuts="2">Østlandet</region></placeName></affiliation></author><author><name sortKey="Weigt, S Samuel" sort="Weigt, S Samuel" uniqKey="Weigt S" first="S. Samuel" last="Weigt">S. Samuel Weigt</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Saggar, Rajan" sort="Saggar, Rajan" uniqKey="Saggar R" first="Rajan" last="Saggar">Rajan Saggar</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Palchevskiy, Vyacheslav" sort="Palchevskiy, Vyacheslav" uniqKey="Palchevskiy V" first="Vyacheslav" last="Palchevskiy">Vyacheslav Palchevskiy</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Volkmann, Elizabeth R" sort="Volkmann, Elizabeth R" uniqKey="Volkmann E" first="Elizabeth R." last="Volkmann">Elizabeth R. Volkmann</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Liang, Lloyd L" sort="Liang, Lloyd L" uniqKey="Liang L" first="Lloyd L." last="Liang">Lloyd L. Liang</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Ross, David" sort="Ross, David" uniqKey="Ross D" first="David" last="Ross">David Ross</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Ardehali, Abbas" sort="Ardehali, Abbas" uniqKey="Ardehali A" first="Abbas" last="Ardehali">Abbas Ardehali</name><affiliation wicri:level="1"><nlm:aff id="aff0004">Department of Surgery, UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Surgery, UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Lynch, Joseph P" sort="Lynch, Joseph P" uniqKey="Lynch J" first="Joseph P." last="Lynch">Joseph P. Lynch</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author><author><name sortKey="Belperio, John A" sort="Belperio, John A" uniqKey="Belperio J" first="John A." last="Belperio">John A. Belperio</name><affiliation wicri:level="1"><nlm:aff id="aff0003">Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095</wicri:regionArea><wicri:noRegion>CA 90095</wicri:noRegion></affiliation></author></analytic><series><title level="j">EBioMedicine</title><idno type="eISSN">2352-3964</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Findings</title><p>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], <italic>p</italic> < 0·001; PDGF-BB 102·5 pg/ml [±78·8] vs. 61·9 pg/ml [±47·0], <italic>p</italic> < 0·001; FGF-2 1442·4 pg/ml [±426·6] vs. 1201·7 pg/ml [±535·2], <italic>p</italic> = 0·009; VEGF 40·6 pg/ml [±20·1] vs. 24·9 pg/ml [±29·5], <italic>p</italic> < 0·001; and M-CSF 25526 pg/ml [±24,799] vs. 6120 pg/ml [±7245], <italic>p</italic> < 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.</p></sec><sec><title>Interpretation</title><p>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 (∼45–50%).</p></sec><sec><title>Funding</title><p>Health Grant P01-HL108793 (JAB), South-Eastern Norway Regional Health Authority Grant 2018072 (AMHV).</p></sec></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Travis, W D" uniqKey="Travis W">W.D. 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Samuel Weigt</name></noRegion><name sortKey="Ardehali, Abbas" sort="Ardehali, Abbas" uniqKey="Ardehali A" first="Abbas" last="Ardehali">Abbas Ardehali</name><name sortKey="Belperio, John A" sort="Belperio, John A" uniqKey="Belperio J" first="John A." last="Belperio">John A. Belperio</name><name sortKey="Liang, Lloyd L" sort="Liang, Lloyd L" uniqKey="Liang L" first="Lloyd L." last="Liang">Lloyd L. Liang</name><name sortKey="Lynch, Joseph P" sort="Lynch, Joseph P" uniqKey="Lynch J" first="Joseph P." last="Lynch">Joseph P. Lynch</name><name sortKey="Palchevskiy, Vyacheslav" sort="Palchevskiy, Vyacheslav" uniqKey="Palchevskiy V" first="Vyacheslav" last="Palchevskiy">Vyacheslav Palchevskiy</name><name sortKey="Ross, David" sort="Ross, David" uniqKey="Ross D" first="David" last="Ross">David Ross</name><name sortKey="Saggar, Rajan" sort="Saggar, Rajan" uniqKey="Saggar R" first="Rajan" last="Saggar">Rajan Saggar</name><name sortKey="Volkmann, Elizabeth R" sort="Volkmann, Elizabeth R" uniqKey="Volkmann E" first="Elizabeth R." last="Volkmann">Elizabeth R. Volkmann</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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