{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T22:10:18Z","timestamp":1781907018980,"version":"3.54.5"},"reference-count":39,"publisher":"European Respiratory Society (ERS)","issue":"1","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Kakihara Foundation."}],"content-domain":{"domain":["publications.ersnet.org"],"crossmark-restriction":true},"short-container-title":["ERJ Open Res"],"accepted":{"date-parts":[[2025,8,6]]},"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Progressive pulmonary fibrosis (PPF) is a chronic interstitial lung disease (ILD) characterised by fibrotic progression and poor prognosis, with effective treatment strategies for previously untreated patients remaining unclear. This study evaluated the efficacy and safety of upfront combination therapy with anti-inflammatory and antifibrotic agents in previously untreated PPF patients.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      This multicentre, single-arm phase 2 study enrolled 34 patients with ILD (including unclassifiable idiopathic interstitial pneumonia, idiopathic nonspecific interstitial pneumonia, fibrotic hypersensitivity pneumonitis and rheumatoid arthritis-associated ILD) all with evidence of PPF. Tacrolimus (0.0375\u2005mg\u00b7kg\n                      <jats:sup>\u22121<\/jats:sup>\n                      twice daily) and prednisolone (10\u2005mg once daily) were initiated on day 1, with nintedanib (150\u2005mg twice daily) added on day 8. The tacrolimus dosage was adjusted to maintain blood trough levels. The primary end-point was the change in the relative decline slope for forced vital capacity % predicted (%FVC) between before and after treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The protocol treatment was associated with a substantial improvement in the relative %FVC decline slope, from \u221220.9% per year before to +11.2% per year after treatment. Subgroup analysis revealed greater improvement in patients with an increased lymphocyte percentage in bronchoalveolar lavage fluid or elevated blood biomarkers. Adverse events, such as diarrhoea (67.6%) and hepatic dysfunction (29.4%), were manageable, with no severe cases or treatment discontinuations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Early combination therapy with tacrolimus, prednisolone and nintedanib was associated with improved pulmonary function and was well tolerated in previously untreated PPF patients. Our findings suggest the potential of this regimen as an initial treatment strategy, but further validation in larger randomised controlled trials is warranted.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1183\/23120541.00697-2025","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T14:45:15Z","timestamp":1758206715000},"page":"00697-2025","update-policy":"https:\/\/doi.org\/10.1183\/ers-crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Upfront combination therapy with nintedanib and anti-inflammatory agents for progressive pulmonary fibrosis: a multicentre, single-arm phase 2 study (TOP-ILD)"],"prefix":"10.1183","volume":"12","author":[{"given":"Kazuya","family":"Tsubouchi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9115-0885","authenticated-orcid":false,"given":"Masayuki","family":"Hirose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reoto","family":"Takei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8809-1781","authenticated-orcid":false,"given":"Tomoyuki","family":"Fujisawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazunori","family":"Tobino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidenori","family":"Ichiyasu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shinyu","family":"Izumi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriho","family":"Sakamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maki","family":"Asami-Noyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osamu","family":"Nishiyama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuko","family":"Waseda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masanori","family":"Nakanishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4294-634X","authenticated-orcid":false,"given":"Tomohisa","family":"Baba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Chiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruhiko","family":"Furusawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiaki","family":"Zaizen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2143-5922","authenticated-orcid":false,"given":"Hiroshi","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaki","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Kondoh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Ogura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuya","family":"Ichikado","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isamu","family":"Okamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"81","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"2026030203000667000_12.1.00697-2025.1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202202-0399ST"},{"key":"2026030203000667000_12.1.00697-2025.2","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201308-1483ST"},{"key":"2026030203000667000_12.1.00697-2025.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2005230"},{"key":"2026030203000667000_12.1.00697-2025.4","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1016\/j.resinv.2021.04.011","article-title":"2020 guide for the diagnosis and treatment of interstitial lung disease associated with connective tissue disease","volume":"59","author":"Kondoh","year":"2021","journal-title":"Respir Investig"},{"key":"2026030203000667000_12.1.00697-2025.5","doi-asserted-by":"publisher","DOI":"10.1183\/16000617.0169-2021"},{"key":"2026030203000667000_12.1.00697-2025.6","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00174914"},{"key":"2026030203000667000_12.1.00697-2025.7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1402584"},{"key":"2026030203000667000_12.1.00697-2025.8","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1908681"},{"key":"2026030203000667000_12.1.00697-2025.9","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00752-2023"},{"key":"2026030203000667000_12.1.00697-2025.10","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00529-2023"},{"key":"2026030203000667000_12.1.00697-2025.11","first-page":"200","article-title":"The role of nintedanib in the treatment of progressive pulmonary fibrosis of autoimmune-related interstitial lung disease","volume":"3","author":"Ardan","year":"2023","journal-title":"J Respir"},{"key":"2026030203000667000_12.1.00697-2025.12","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1186\/s12931-022-01974-2","article-title":"Safety and tolerability of nintedanib in patients with progressive fibrosing interstitial lung diseases: data from the randomized controlled INBUILD trial","volume":"23","author":"Cottin","year":"2022","journal-title":"Respir Res"},{"key":"2026030203000667000_12.1.00697-2025.13","doi-asserted-by":"crossref","first-page":"5536","DOI":"10.1007\/s12325-023-02668-x","article-title":"Effect of nintedanib in patients with progressive pulmonary fibrosis in subgroups with differing baseline characteristics","volume":"40","author":"Kolb","year":"2023","journal-title":"Adv Ther"},{"key":"2026030203000667000_12.1.00697-2025.14","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.04587-2020"},{"key":"2026030203000667000_12.1.00697-2025.15","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.210322"},{"key":"2026030203000667000_12.1.00697-2025.16","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1093\/rheumatology\/kez394","article-title":"Impact of adding tacrolimus to initial treatment of interstitial pneumonitis in polymyositis\/dermatomyositis: a single-arm clinical trial","volume":"59","author":"Takada","year":"2020","journal-title":"Rheumatology (Oxford)"},{"key":"2026030203000667000_12.1.00697-2025.17","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200703-463PP"},{"key":"2026030203000667000_12.1.00697-2025.18","doi-asserted-by":"crossref","first-page":"E36","DOI":"10.1164\/rccm.202005-2032ST","article-title":"Diagnosis of hypersensitivity pneumonitis in adults: an official ATS\/JRS\/ALAT clinical practice guideline","volume":"202","author":"Raghu","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"2026030203000667000_12.1.00697-2025.19","doi-asserted-by":"publisher","DOI":"10.1002\/art.27584"},{"key":"2026030203000667000_12.1.00697-2025.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.chest.2016.10.029"},{"key":"2026030203000667000_12.1.00697-2025.21","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1111\/crj.13086","article-title":"Use of mycophenolate mofetil and azathioprine for the treatment of chronic hypersensitivity pneumonitis: a single-centre experience","volume":"13","author":"Fiddler","year":"2019","journal-title":"Clin Respir J"},{"key":"2026030203000667000_12.1.00697-2025.22","doi-asserted-by":"crossref","first-page":"101878","DOI":"10.1016\/j.pupt.2019.101878","article-title":"Impact of azathioprine use in chronic hypersensitivity pneumonitis patients","volume":"60","author":"Terras Alexandre","year":"2020","journal-title":"Pulm Pharmacol Ther"},{"key":"2026030203000667000_12.1.00697-2025.23","doi-asserted-by":"crossref","first-page":"14","DOI":"10.3390\/jcm8010014","article-title":"Effects of corticosteroid treatment and antigen avoidance in a large hypersensitivity pneumonitis cohort: a single-centre cohort study","volume":"8","author":"De Sadeleer","year":"2018","journal-title":"J Clin Med"},{"key":"2026030203000667000_12.1.00697-2025.24","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.01983-2019"},{"key":"2026030203000667000_12.1.00697-2025.25","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/145.1.3"},{"key":"2026030203000667000_12.1.00697-2025.26","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00441-2023"},{"key":"2026030203000667000_12.1.00697-2025.27","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1016\/j.chest.2023.12.019","article-title":"Impact of antigen exposure on outcomes and treatment response in fibrotic hypersensitivity pneumonitis","volume":"165","author":"Mullin","year":"2024","journal-title":"Chest"},{"key":"2026030203000667000_12.1.00697-2025.28","doi-asserted-by":"publisher","DOI":"10.1183\/23120541.00016-2017"},{"key":"2026030203000667000_12.1.00697-2025.29","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.resinv.2023.01.007","article-title":"Interstitial pneumonia with autoimmune features and histologic usual interstitial pneumonia treated with anti-fibrotic versus immunosuppressive therapy","volume":"61","author":"Yamano","year":"2023","journal-title":"Respir Investig"},{"key":"2026030203000667000_12.1.00697-2025.30","doi-asserted-by":"publisher","DOI":"10.1136\/thorax-2024-222367"},{"key":"2026030203000667000_12.1.00697-2025.31","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1113354"},{"key":"2026030203000667000_12.1.00697-2025.32","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.838449"},{"key":"2026030203000667000_12.1.00697-2025.33","doi-asserted-by":"crossref","first-page":"1474","DOI":"10.1007\/s12325-022-02411-y","article-title":"Real-world safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: interim report of a post-marketing surveillance in Japan","volume":"40","author":"Ogura","year":"2023","journal-title":"Adv Ther Adis"},{"key":"2026030203000667000_12.1.00697-2025.34","doi-asserted-by":"crossref","first-page":"107603","DOI":"10.1016\/j.rmed.2024.107603","article-title":"Predictive factors for dose reduction and discontinuation of nintedanib in fibrotic interstitial lung diseases: real life data","volume":"225","author":"Costa","year":"2024","journal-title":"Respir Med"},{"key":"2026030203000667000_12.1.00697-2025.35","doi-asserted-by":"crossref","first-page":"10811","DOI":"10.1038\/s41598-017-11321-x","article-title":"Low body surface area predicts hepatotoxicity of nintedanib in patients with idiopathic pulmonary fibrosis","volume":"7","author":"Ikeda","year":"2017","journal-title":"Sci Rep"},{"key":"2026030203000667000_12.1.00697-2025.36","doi-asserted-by":"crossref","first-page":"4581","DOI":"10.1007\/s12325-024-03023-4","article-title":"Safety and tolerability of nintedanib in patients with fibrosing interstitial lung diseases: post-marketing data","volume":"41","author":"Chaudhuri","year":"2024","journal-title":"Adv Ther"},{"key":"2026030203000667000_12.1.00697-2025.37","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-48593-4"},{"key":"2026030203000667000_12.1.00697-2025.38","doi-asserted-by":"crossref","first-page":"100832","DOI":"10.1016\/j.conctc.2021.100832","article-title":"Design of phase 2 study of TAS-115, a novel oral multi-kinase inhibitor, in patients with idiopathic pulmonary fibrosis","volume":"23","author":"Nishioka","year":"2021","journal-title":"Contemp Clin Trials Commun"},{"key":"2026030203000667000_12.1.00697-2025.39","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/j.resinv.2023.04.008","article-title":"Exploratory phase 2 study of the novel oral multi-kinase inhibitor TAS-115 in patients with idiopathic pulmonary fibrosis","volume":"61","author":"Nishioka","year":"2023","journal-title":"Respir Investig"}],"container-title":["ERJ Open Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1183\/23120541.00697-2025","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T11:00:23Z","timestamp":1772449223000},"score":1,"resource":{"primary":{"URL":"https:\/\/publications.ersnet.org\/lookup\/doi\/10.1183\/23120541.00697-2025"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,18]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,2,16]]},"published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1183\/23120541.00697-2025"],"URL":"https:\/\/doi.org\/10.1183\/23120541.00697-2025","relation":{},"ISSN":["2312-0541"],"issn-type":[{"value":"2312-0541","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,18]]}}}