Endotype–phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease
Identifieur interne : 000505 ( Pmc/Curation ); précédent : 000504; suivant : 000506Endotype–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
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<author><name sortKey="Palchevskiy, Vyacheslav" sort="Palchevskiy, Vyacheslav" uniqKey="Palchevskiy V" first="Vyacheslav" last="Palchevskiy">Vyacheslav Palchevskiy</name>
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<author><name sortKey="Volkmann, Elizabeth R" sort="Volkmann, Elizabeth R" uniqKey="Volkmann E" first="Elizabeth R." last="Volkmann">Elizabeth R. Volkmann</name>
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<author><name sortKey="Liang, Lloyd L" sort="Liang, Lloyd L" uniqKey="Liang L" first="Lloyd L." last="Liang">Lloyd L. Liang</name>
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<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>
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<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>
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<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>
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<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>
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<author><name sortKey="Belperio, John A" sort="Belperio, John A" uniqKey="Belperio J" first="John A." last="Belperio">John A. Belperio</name>
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<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>
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<series><title level="j">EBioMedicine</title>
<idno type="eISSN">2352-3964</idno>
<imprint><date when="2019">2019</date>
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<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>
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<pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">EBioMedicine</journal-id>
<journal-id journal-id-type="iso-abbrev">EBioMedicine</journal-id>
<journal-title-group><journal-title>EBioMedicine</journal-title>
</journal-title-group>
<issn pub-type="epub">2352-3964</issn>
<publisher><publisher-name>Elsevier</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">31732480</article-id>
<article-id pub-id-type="pmc">6921223</article-id>
<article-id pub-id-type="publisher-id">S2352-3964(19)30725-X</article-id>
<article-id pub-id-type="doi">10.1016/j.ebiom.2019.10.050</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Research paper</subject>
</subj-group>
</article-categories>
<title-group><article-title>Endotype–phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease</article-title>
</title-group>
<contrib-group><contrib contrib-type="author" id="au0001"><name><surname>Hoffmann-Vold</surname>
<given-names>Anna-Maria</given-names>
</name>
<xref rid="aff0001" ref-type="aff">a</xref>
<xref rid="aff0002" ref-type="aff">b</xref>
</contrib>
<contrib contrib-type="author" id="au0002"><name><surname>Weigt</surname>
<given-names>S. Samuel</given-names>
</name>
<xref rid="aff0003" ref-type="aff">c</xref>
</contrib>
<contrib contrib-type="author" id="au0003"><name><surname>Saggar</surname>
<given-names>Rajan</given-names>
</name>
<xref rid="aff0003" ref-type="aff">c</xref>
</contrib>
<contrib contrib-type="author" id="au0004"><name><surname>Palchevskiy</surname>
<given-names>Vyacheslav</given-names>
</name>
<xref rid="aff0003" ref-type="aff">c</xref>
</contrib>
<contrib contrib-type="author" id="au0005"><name><surname>Volkmann</surname>
<given-names>Elizabeth R.</given-names>
</name>
<xref rid="aff0003" ref-type="aff">c</xref>
</contrib>
<contrib contrib-type="author" id="au0006"><name><surname>Liang</surname>
<given-names>Lloyd L.</given-names>
</name>
<xref rid="aff0003" ref-type="aff">c</xref>
</contrib>
<contrib contrib-type="author" id="au0007"><name><surname>Ross</surname>
<given-names>David</given-names>
</name>
<xref rid="aff0003" ref-type="aff">c</xref>
</contrib>
<contrib contrib-type="author" id="au0008"><name><surname>Ardehali</surname>
<given-names>Abbas</given-names>
</name>
<xref rid="aff0004" ref-type="aff">d</xref>
</contrib>
<contrib contrib-type="author" id="au0009"><name><surname>Lynch</surname>
<given-names>Joseph P.</given-names>
<suffix>III</suffix>
</name>
<xref rid="aff0003" ref-type="aff">c</xref>
</contrib>
<contrib contrib-type="author" id="au0010"><name><surname>Belperio</surname>
<given-names>John A.</given-names>
</name>
<email>JBelperio@mednet.ucla.edu</email>
<xref rid="aff0003" ref-type="aff">c</xref>
<xref rid="cor0001" ref-type="corresp">⁎</xref>
</contrib>
</contrib-group>
<aff id="aff0001"><label>a</label>
Department of Rheumatology, Oslo University Hospital, Rikshospitalet, Pb 4950 Nydalen, 0424 Oslo, Norway</aff>
<aff id="aff0002"><label>b</label>
Institute of Clinical Medicine, University of Oslo, Rikshospitalet, Pb 4950 Nydalen, 0424 Oslo, Norway</aff>
<aff id="aff0003"><label>c</label>
Department of Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</aff>
<aff id="aff0004"><label>d</label>
Department of Surgery, UCLA, 10833 Le Conte Ave, Los Angeles, CA 90095, USA</aff>
<author-notes><corresp id="cor0001"><label>⁎</label>
Corresponding author. <email>JBelperio@mednet.ucla.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="pmc-release"><day>12</day>
<month>11</month>
<year>2019</year>
</pub-date>
<pmc-comment> PMC Release delay is 0 months and 0 days and was based on .</pmc-comment>
<pub-date pub-type="collection"><month>12</month>
<year>2019</year>
</pub-date>
<pub-date pub-type="epub"><day>12</day>
<month>11</month>
<year>2019</year>
</pub-date>
<volume>50</volume>
<fpage>379</fpage>
<lpage>386</lpage>
<history><date date-type="received"><day>9</day>
<month>9</month>
<year>2019</year>
</date>
<date date-type="rev-recd"><day>25</day>
<month>10</month>
<year>2019</year>
</date>
<date date-type="accepted"><day>28</day>
<month>10</month>
<year>2019</year>
</date>
</history>
<permissions><copyright-statement>© 2019 The Authors</copyright-statement>
<copyright-year>2019</copyright-year>
<license license-type="CC BY" xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).</license-p>
</license>
</permissions>
<abstract id="abs0001"><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>
</abstract>
<kwd-group id="keys0001"><title>Keywords</title>
<kwd>Interstitial lung disease</kwd>
<kwd>Idiopathic pulmonary fibrosis</kwd>
<kwd>Connective tissue disease</kwd>
<kwd>Proteins</kwd>
<kwd>Outcome</kwd>
</kwd-group>
<kwd-group id="keys0002"><title>Abbreviations</title>
<kwd>ANOVA, analysis of variance</kwd>
<kwd>CSF1R, colony stimulating factor 1 receptor</kwd>
<kwd>CTD, connective tissue disease</kwd>
<kwd>DLCO, diffusing capacity for carbon monoxide</kwd>
<kwd>FDA, Food and Drug Administration</kwd>
<kwd>FGF, fibroblast growth factor</kwd>
<kwd>FGFR, fibroblast growth factor receptor</kwd>
<kwd>FVC, forced vital capacity</kwd>
<kwd>GAP, Global Alignment and Proportion</kwd>
<kwd>HP, hypersensitivity pneumonitis</kwd>
<kwd>HRCT, high resolution computed tomography</kwd>
<kwd>ILD, interstitial lung disease</kwd>
<kwd>IPF, idiopathic pulmonary fibrosis</kwd>
<kwd>Lck, lymphocyte-specific tyrosine protein kinase</kwd>
<kwd>M-CSF1R, M-colony stimulating factor</kwd>
<kwd>PDGF, Platelet derived growth factor</kwd>
<kwd>PDGFRα, Platelet derived growth factor receptor-alpha</kwd>
<kwd>PDGFRβ, Platelet derived growth factor receptor-beta</kwd>
<kwd>PF-ILD, progressive fibrosing-ILD</kwd>
<kwd>RA, rheumatoid arthritis</kwd>
<kwd>SD, Standard deviation</kwd>
<kwd>6MWD, six minute walking distance</kwd>
<kwd>SSc, systemic sclerosis</kwd>
<kwd>Tfh, T follicular helper cells</kwd>
<kwd>TGF-β, transforming growth factor beta</kwd>
<kwd>Th2, T2 helper cells</kwd>
<kwd>UCLA, University of California Los Angeles</kwd>
<kwd>VEGF, Vascular Endothelial Growth Factor</kwd>
<kwd>VEGFR, Vascular Endothelial Growth Factor Receptor</kwd>
</kwd-group>
</article-meta>
</front>
</pmc>
</record>
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