{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T03:43:40Z","timestamp":1780544620514,"version":"3.54.1"},"reference-count":59,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,25]],"date-time":"2023-04-25T00:00:00Z","timestamp":1682380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pirfenidone and nintedanib are antifibrotic medications approved for idiopathic pulmonary fibrosis treatment by regulatory agencies and available for clinical use worldwide. These drugs have been shown to reduce the rate of decline in forced vital capacity and the risk of acute exacerbation among patients with idiopathic pulmonary fibrosis. Recent data suggest that different interstitial lung diseases with a progressive pulmonary fibrosis phenotype can share similar pathogenetic and biological pathways and could be amenable to antifibrotic therapies. Indeed, historical management strategies in interstitial lung disease have failed to identify potential treatments once progression has occurred despite available drugs. In this systematic review, we summarized data on the efficacy of pirfenidone and nintedanib in interstitial lung diseases other than idiopathic pulmonary fibrosis as well as ongoing and upcoming clinical trials. We identify two well-designed trials regarding nintedanib demonstrating the efficacy of this drug in slowing disease progression in patients with interstitial lung diseases other than idiopathic pulmonary fibrosis. On the other hand, results on the use of pirfenidone in interstitial lung diseases other than idiopathic pulmonary fibrosis should be interpreted with more caution on the basis of trial limitations. Several randomized control trials are underway to improve the quality of evidence in the interstitial lung disease field.<\/jats:p>","DOI":"10.3390\/ijms24097849","type":"journal-article","created":{"date-parts":[[2023,4,26]],"date-time":"2023-04-26T02:30:52Z","timestamp":1682476252000},"page":"7849","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":57,"title":["Efficacy of Pirfenidone and Nintedanib in Interstitial Lung Diseases Other than Idiopathic Pulmonary Fibrosis: A Systematic Review"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8248-7785","authenticated-orcid":false,"given":"Francesco","family":"Amati","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy"},{"name":"Respiratory Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8875-2252","authenticated-orcid":false,"given":"Anna","family":"Stainer","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy"},{"name":"Respiratory Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronica","family":"Polelli","sequence":"additional","affiliation":[{"name":"Respiratory Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Mantero","sequence":"additional","affiliation":[{"name":"Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2315-5737","authenticated-orcid":false,"given":"Andrea","family":"Gramegna","sequence":"additional","affiliation":[{"name":"Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2285-9970","authenticated-orcid":false,"given":"Francesco","family":"Blasi","sequence":"additional","affiliation":[{"name":"Respiratory Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy"},{"name":"Department of Pathophysiology and Transplantation, Universit\u00e0 degli Studi di Milano, 20122 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Aliberti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, Pieve Emanuele, 20072 Milan, Italy"},{"name":"Respiratory Unit, IRCCS Humanitas Research Hospital, Via Manzoni 56, Rozzano, 20089 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1164\/rccm.201308-1483ST","article-title":"An official American Thoracic Society\/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias","volume":"188","author":"Travis","year":"2013","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1056\/NEJMra1705751","article-title":"Idiopathic Pulmonary Fibrosis","volume":"378","author":"Lederer","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e3","DOI":"10.1164\/rccm.201506-1063ST","article-title":"An Official ATS\/ERS\/JRS\/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline","volume":"192","author":"Raghu","year":"2015","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2071","DOI":"10.1056\/NEJMoa1402584","article-title":"Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis","volume":"370","author":"Richeldi","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1016\/j.chest.2021.06.049","article-title":"Impact of Antifibrotic Therapy on Mortality and Acute Exacerbation in Idiopathic Pulmonary Fibrosis: A Systematic Review and Meta-Analysis","volume":"160","author":"Petnak","year":"2021","journal-title":"Chest"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e18","DOI":"10.1164\/rccm.202202-0399ST","article-title":"Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS\/ERS\/JRS\/ALAT Clinical Practice Guideline","volume":"205","author":"Raghu","year":"2022","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Amati, F., Spagnolo, P., Oldham, J.M., Ryerson, C.J., Stainer, A., Gramegna, A., Mantero, M., Lacedonia, D., Sverzellati, N., and Richeldi, L. (2023). Treatable traits in interstitial lung diseases: A call to action. Lancet Respir. Med., ahead of print.","DOI":"10.1016\/S2213-2600(23)00002-4"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ebiom.2019.10.050","article-title":"Endotype-phenotyping may predict a treatment response in progressive fibrosing interstitial lung disease","volume":"50","author":"Weigt","year":"2019","journal-title":"Ebiomedicine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1718","DOI":"10.1056\/NEJMoa1908681","article-title":"Nintedanib in progressive Fibrosing interstitial lung diseases","volume":"381","author":"Flaherty","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2518","DOI":"10.1056\/NEJMoa1903076","article-title":"Nintedanib for systemic sclerosis-associated interstitial lung disease","volume":"380","author":"Distler","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"264","DOI":"10.7326\/0003-4819-151-4-200908180-00135","article-title":"Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement","volume":"151","author":"Moher","year":"2009","journal-title":"Ann. Intern. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1111\/j.1398-9995.2009.01973.x","article-title":"Grading quality of evidence and strength of recommendations in clinical practice guidelines. Part 1 of 3. An overview of the GRADE approach and grading quality of evidence about interventions","volume":"64","author":"Brozek","year":"2009","journal-title":"Allergy"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Solomon, J.J., Danoff, S.K., Woodhead, F.A., Hurwitz, S., Maurer, R., Glaspole, I., Dellaripa, P.F., Gooptu, B., Vassallo, R., and Cox, P.G. (2022). Safety, tolerability, and efficacy of pirfenidone in patients with rheumatoid arthritis-associated interstitial lung disease: A randomised, double-blind, placebo-controlled, phase 2 study. Lancet Respir. Med., ahead of print.","DOI":"10.1101\/2022.04.01.22273270"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"871861","DOI":"10.3389\/fmed.2022.871861","article-title":"The Efficacy and Safety of Pirfenidone Combined with Immunosuppressant Therapy in Connective Tissue Disease-Associated Interstitial Lung Disease: A 24-Week Prospective Controlled Cohort Study","volume":"9","author":"Wang","year":"2022","journal-title":"Front. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1016\/S2213-2600(20)30554-3","article-title":"Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): A double-blind, randomised, placebo-controlled, phase 2b trial","volume":"9","author":"Behr","year":"2021","journal-title":"Lancet Respir. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/S2213-2600(19)30341-8","article-title":"Pirfenidone in patients with unclassifiable progressive fibrosing interstitial lung disease: A double-blind, randomised, placebo-controlled, phase 2 trial","volume":"8","author":"Maher","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1007\/s00296-020-04565-w","article-title":"Efficacy and safety of pirfenidone in systemic sclerosis-related interstitial lung disease-a randomised controlled trial","volume":"40","author":"Acharya","year":"2020","journal-title":"Rheumatol. Int."},{"key":"ref_18","first-page":"163","article-title":"An Open-label Study with Pirfenidone on Chronic Hypersensitivity Pneumonitis","volume":"56","author":"Estrada","year":"2020","journal-title":"Arch. Bronconeumol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.ymgme.2011.02.003","article-title":"Pirfenidone for the treatment of Hermansky-Pudlak syndrome pulmonary fibrosis","volume":"103","author":"Troendle","year":"2011","journal-title":"Mol. Genet. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/S1096-7192(02)00044-6","article-title":"Effect of pirfenidone on the pulmonary fibrosis of Hermansky-Pudlak syndrome","volume":"76","author":"Gahl","year":"2002","journal-title":"Mol. Genet. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1186\/s12931-021-01668-1","article-title":"Nintedanib and immunomodulatory therapies in progressive fibrosing interstitial lung diseases","volume":"22","author":"Cottin","year":"2021","journal-title":"Respir. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S2213-2600(20)30036-9","article-title":"Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: A randomised, double-blind, placebo-controlled, parallel-group trial","volume":"8","author":"Wells","year":"2020","journal-title":"Lancet Respir. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1007\/s12325-021-02009-w","article-title":"Pirfenidone in Unclassifiable Interstitial Lung Disease: A Subgroup Analysis by Concomitant Mycophenolate Mofetil and\/or Previous Corticosteroid Use","volume":"39","author":"Kreuter","year":"2022","journal-title":"Adv. Ther."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"897102","DOI":"10.3389\/fmed.2022.897102","article-title":"Efficacy of Pirfenidone vs. Placebo in Unclassifiable Interstitial Lung Disease, by Surgical Lung Biopsy Status: Data From a post-hoc Analysis","volume":"9","author":"Kreuter","year":"2022","journal-title":"Front. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"644671","DOI":"10.3389\/fphar.2021.644671","article-title":"Hermansky-Pudlak Syndrome and Lung Disease: Pathogenesis and Therapeutics","volume":"12","author":"Nakajima","year":"2021","journal-title":"Front. Pharmacol."},{"key":"ref_26","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT05065190, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05065190."},{"key":"ref_27","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT05067517, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05067517."},{"key":"ref_28","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT05335278, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05335278."},{"key":"ref_29","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT04856111, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04856111."},{"key":"ref_30","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT04619680, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04619680."},{"key":"ref_31","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT04541680, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04541680."},{"key":"ref_32","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT04338802, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04338802."},{"key":"ref_33","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT04161014, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04161014."},{"key":"ref_34","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT03805477, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03805477."},{"key":"ref_35","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT03283007, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03283007."},{"key":"ref_36","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT03062943, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03062943."},{"key":"ref_37","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT02496585, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02496585."},{"key":"ref_38","first-page":"79","article-title":"Therapeutic options targeting angiogenesis in nonsmall cell lung cancer","volume":"23","author":"Metro","year":"2014","journal-title":"Eur. Respir. Rev. Off. J. Eur. Respir. Soc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1124\/jpet.113.208223","article-title":"Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis","volume":"349","author":"Wollin","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"805535","DOI":"10.3389\/fphar.2021.805535","article-title":"The Interaction Between Pulmonary Fibrosis and COVID-19 and the Application of Related Anti-Fibrotic Drugs","volume":"12","author":"Shen","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_41","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT05505409, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05505409."},{"key":"ref_42","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT05288179, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05288179."},{"key":"ref_43","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT05133453, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05133453."},{"key":"ref_44","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT05118256, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05118256."},{"key":"ref_45","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT05075161, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT05075161."},{"key":"ref_46","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT04928586, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04928586."},{"key":"ref_47","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT04675619, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04675619."},{"key":"ref_48","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT04607928, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04607928."},{"key":"ref_49","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT04461587, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04461587."},{"key":"ref_50","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT04193592, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT04193592."},{"key":"ref_51","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT03902509, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03902509."},{"key":"ref_52","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT03857854, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03857854."},{"key":"ref_53","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT03856853, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03856853."},{"key":"ref_54","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT03385668, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03385668."},{"key":"ref_55","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT03315741, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03315741."},{"key":"ref_56","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT03221257, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03221257."},{"key":"ref_57","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT02958917, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02958917."},{"key":"ref_58","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT02496182, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02496182."},{"key":"ref_59","unstructured":"ClinicalTrials.gov (2022, December 22). Identifier: NCT02262299, Available online: https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02262299."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/7849\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:23:33Z","timestamp":1760124213000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/7849"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,25]]},"references-count":59,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24097849"],"URL":"https:\/\/doi.org\/10.3390\/ijms24097849","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,25]]}}}