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1. Idiopathic Pulmonary Fibrosis Is Associated with Common Genetic Variants and Limited Rare Variants.

Author: Peljto, Anna L, Blumhagen, Rachel Z, Walts, Avram D, Cardwell, Jonathan, Powers, Julia, Corte, Tamera J, Dickinson, Joanne L, Glaspole, Ian, Moodley, Yuben P, Vasakova, Martina Koziar, Bendstrup, Elisabeth, Davidsen, Jesper R, Borie, Raphael, Crestani, Bruno, Dieude, Philippe, Bonella, Francesco, Costabel, Ulrich, Gudmundsson, Gunnar, Donnelly, Seamas C, Egan, Jim, Henry, Michael T, Keane, Michael P, Kennedy, Marcus P, McCarthy, Cormac, McElroy, Aoife N, Olaniyi, Joshua A, O'Reilly, Katherine MA, Richeldi, Luca, Leone, Paolo M, Poletti, Venerino, Puppo, Francesco, Tomassetti, Sara, Luzzi, Valentina, Kokturk, Nurdan, Mogulkoc, Nesrin, Fiddler, Christine A, Hirani, Nikhil, Jenkins, R Gisli, Maher, Toby M, Molyneaux, Philip L, Parfrey, Helen, Braybrooke, Rebecca, Blackwell, Timothy S, Jackson, Peter D, Nathan, Steven D, Porteous, Mary K, Brown, Kevin K, Christie, Jason D, Collard, Harold R, Eickelberg, Oliver, Foster, Elena E, Gibson, Kevin F, Glassberg, Marilyn, Kass, Daniel J, Kropski, Jonathan A, Lederer, David, Linderholm, Angela L, Loyd, Jim, Mathai, Susan K, Montesi, Sydney B, Noth, Imre, Oldham, Justin M, Palmisciano, Amy J, Reichner, Cristina A, Rojas, Mauricio, Roman, Jesse, Schluger, Neil, Shea, Barry S, Swigris, Jeffrey J, Wolters, Paul J, Zhang, Yingze, Prele, Cecilia MA, Enghelmayer, Juan I, Otaola, Maria, Ryerson, Christopher J, Salinas, Mauricio, Sterclova, Martina, Gebremariam, Tewodros H, Myllärniemi, Marjukka, Carbone, Roberto G, Furusawa, Haruhiko, Hirose, Masaki, Inoue, Yoshikazu, Miyazaki, Yasunari, Ohta, Ken, Ohta, Shin, Okamoto, Tsukasa, Kim, Dong Soon, Pardo, Annie, Selman, Moises, Aranda, Alvaro U, Park, Moo Suk, Park, Jong Sun, Song, Jin Woo, Molina-Molina, Maria, Planas-Cerezales, Lurdes, Westergren-Thorsson, Gunilla, Smith, Albert V, Manichaikul, Ani W, and Kim, John S
Subjects: Biomedical and Clinical Sciences, Cardiovascular Medicine and Haematology, Clinical Sciences, Autoimmune Disease, Lung, Rare Diseases, Genetics, Human Genome, Prevention, Precision Medicine, 2.1 Biological and endogenous factors, Good Health and Well Being, Humans, Idiopathic Pulmonary Fibrosis, Whole Genome Sequencing, Exome, whole-genome sequencing, interstitial lung disease, TOPMed, genetic association studies, telomerase, Medical and Health Sciences, Respiratory System, Cardiovascular medicine and haematology, Clinical sciences
Abstract: Rationale: Idiopathic pulmonary fibrosis (IPF) is a rare, irreversible, and progressive disease of the lungs. Common genetic variants, in addition to nongenetic factors, have been consistently associated with IPF. Rare variants identified by candidate gene, family-based, and exome studies have also been reported to associate with IPF. However, the extent to which rare variants, genome-wide, may contribute to the risk of IPF remains unknown. Objectives: We used whole-genome sequencing to investigate the role of rare variants, genome-wide, on IPF risk. Methods: As part of the Trans-Omics for Precision Medicine Program, we sequenced 2,180 cases of IPF. Association testing focused on the aggregated effect of rare variants (minor allele frequency ⩽0.01) within genes or regions. We also identified individual rare variants that are influential within genes and estimated the heritability of IPF on the basis of rare and common variants. Measurements and Main Results: Rare variants in both TERT and RTEL1 were significantly associated with IPF. A single rare variant in each of the TERT and RTEL1 genes was found to consistently influence the aggregated test statistics. There was no significant evidence of association with other previously reported rare variants. The SNP heritability of IPF was estimated to be 32% (SE = 3%). Conclusions: Rare variants within the TERT and RTEL1 genes and well-established common variants have the largest contribution to IPF risk overall. Efforts in risk profiling or the development of therapies for IPF that focus on TERT, RTEL1, common variants, and environmental risk factors are likely to have the largest impact on this complex disease.
Published: 2023

2. No increased prevalence of autoantibodies neutralizing type I IFNs in idiopathic pulmonary fibrosis patients

Author: Philippot, Quentin, Bastard, Paul, Puel, Anne, Casanova, Jean-Laurent, Cobat, Aurélie, Laouénan, Cédric, Tardivon, Coralie, Crestani, Bruno, and Borie, Raphael
Published: 2023
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3. MUC5B promoter variant rs35705950 and rheumatoid arthritis associated interstitial lung disease survival and progression

Author: Juge, Pierre-Antoine, Solomon, Joshua J, van Moorsel, Coline HM, Garofoli, Romain, Lee, Joyce S, Louis-Sydney, Fabienne, Rojas-Serrano, Jorge, González-Pérez, Montserrat I, Mejia, Mayra, Buendia-Roldán, Ivette, Falfán-Valencia, Ramcés, Ambrocio-Ortiz, Enrique, Manali, Effrosyni, Papiris, Spyros A, Karageorgas, Theofanis, Boumpas, Dimitrios, Antoniou, Katarina M, Sidiropoulos, Prodromos, Trachalaki, Athina, van der Vis, Joanne J, Jamnitski, Anna, Grutters, Jan C, Kannengiesser, Caroline, Borie, Raphaël, Kawano-Dourado, Leticia, Wemeau-Stervinou, Lidwine, Flipo, René-Marc, Nunes, Hilario, Uzunhan, Yurdagul, Valeyre, Dominique, Saidenberg-Kermanac'h, Nathalie, Boissier, Marie-Christophe, Richez, Christophe, Schaeverbeke, Thierry, Doyle, Tracy, Wolters, Paul J, Debray, Marie-Pierre, Boileau, Catherine, Porcher, Raphaël, Schwartz, David A, Crestani, Bruno, and Dieudé, Philippe
Subjects: Biomedical and Clinical Sciences, Clinical Sciences, Clinical Research, Genetics, Lung, Autoimmune Disease, Rare Diseases, Arthritis, Inflammatory and immune system, Respiratory, Aged, Arthritis, Rheumatoid, Female, Humans, Idiopathic Pulmonary Fibrosis, Lung Diseases, Interstitial, Mucin-5B, Promoter Regions, Genetic, Rheumatoid Arthritis, Interstitial Lung Disease, MUC5B, Public Health and Health Services, Arthritis & Rheumatology, Clinical sciences
Abstract: BackgroundThe major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD.MethodsThrough an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline.ResultsOut of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern.ConclusionIn this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.
Published: 2021

4. No increased prevalence of autoantibodies neutralizing type I IFNs in idiopathic pulmonary fibrosis patients

Author: Quentin Philippot, Paul Bastard, Anne Puel, Jean-Laurent Casanova, Aurélie Cobat, Cédric Laouénan, Coralie Tardivon, Bruno Crestani, and Raphael Borie
Subjects: COVID-19, Idiopathic pulmonary fibrosis, Autoimmunity, Diseases of the respiratory system, RC705-779
Abstract: Abstract SARS-CoV2 infection has a poor prognosis in patients affected of idiopathic pulmonary fibrosis (IPF). Autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) are found in the blood of at least 15% of patients with life-threatening COVID-19 pneumonia. Because of the elevated prevalence of some auto-Abs in IPF patients, we hypothesize that the prevalence of auto-Abs neutralizing type I IFNs might be increased in the IPF population and then explained specific poor outcome after COVID-19. We screened the plasma of 247 consecutive IPF patients for the presence of auto-Abs neutralizing type I IFNs. Three patients displayed auto-Abs neutralizing type I IFNs. Among them, the only patient with documented SARS-CoV-2 infection experienced life threatening COVID-19 pneumonia. The prevalence of auto-Abs neutralizing type I IFNs in this cohort of IPF patients was not significantly different from the one of the general population. Overall, this study did not suggest any association between auto-Abs neutralizing type I IFNs and IPF.
Published: 2023
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5. Resequencing Study Confirms That Host Defense and Cell Senescence Gene Variants Contribute to the Risk of Idiopathic Pulmonary Fibrosis

Author: Moore, Camille, Blumhagen, Rachel Z, Yang, Ivana V, Walts, Avram, Powers, Julie, Walker, Tarik, Bishop, Makenna, Russell, Pamela, Vestal, Brian, Cardwell, Jonathan, Markin, Cheryl R, Mathai, Susan K, Schwarz, Marvin I, Steele, Mark P, Lee, Joyce, Brown, Kevin K, Loyd, James E, Crapo, James D, Silverman, Edwin K, Cho, Michael H, James, Judith A, Guthridge, Joel M, Cogan, Joy D, Kropski, Jonathan A, Swigris, Jeffrey J, Bair, Carol, Kim, Dong Soon, Ji, Wonjun, Kim, Hocheol, Song, Jin Woo, Maier, Lisa A, Pacheco, Karin A, Hirani, Nikhil, Poon, Azin S, Li, Feng, Jenkins, R Gisli, Braybrooke, Rebecca, Saini, Gauri, Maher, Toby M, Molyneaux, Philip L, Saunders, Peter, Zhang, Yingze, Gibson, Kevin F, Kass, Daniel J, Rojas, Mauricio, Sembrat, John, Wolters, Paul J, Collard, Harold R, Sundy, John S, O’Riordan, Thomas, Strek, Mary E, Noth, Imre, Ma, Shwu-Fan, Porteous, Mary K, Kreider, Maryl E, Patel, Namrata B, Inoue, Yoshikazu, Hirose, Masaki, Arai, Toru, Akagawa, Shinobu, Eickelberg, Oliver, Fernandez, Isis Enlil, Behr, Jürgen, Mogulkoc, Nesrin, Corte, Tamera J, Glaspole, Ian, Tomassetti, Sara, Ravaglia, Claudia, Poletti, Venerino, Crestani, Bruno, Borie, Raphael, Kannengiesser, Caroline, Parfrey, Helen, Fiddler, Christine, Rassl, Doris, Molina-Molina, Maria, Machahua, Carlos, Worboys, Ana Montes, Gudmundsson, Gunnar, Isaksson, Helgi J, Lederer, David J, Podolanczuk, Anna J, Montesi, Sydney B, Bendstrup, Elisabeth, Danchel, Vivi, Selman, Moises, Pardo, Annie, Henry, Michael T, Keane, Michael P, Doran, Peter, Vašáková, Martina, Sterclova, Martina, Ryerson, Christopher J, Wilcox, Pearce G, Okamoto, Tsukasa, Furusawa, Haruhiko, Miyazaki, Yasunari, Laurent, Geoffrey, Baltic, Svetlana, and Prele, Cecilia
Subjects: Human Genome, Autoimmune Disease, Clinical Research, Lung, Genetics, Rare Diseases, 2.1 Biological and endogenous factors, Aetiology, ATP-Binding Cassette Transporters, Case-Control Studies, Cellular Senescence, DNA Helicases, Exoribonucleases, Female, GTPase-Activating Proteins, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing, Host-Pathogen Interactions, Humans, Idiopathic Pulmonary Fibrosis, Logistic Models, Male, Mucin-5B, Promoter Regions, Genetic, Pulmonary Surfactant-Associated Protein A, Pulmonary Surfactant-Associated Protein C, RNA, Sequence Analysis, DNA, Telomerase, Telomere-Binding Proteins, targeted resequencing, idiopathic pulmonary fibrosis, genetic variants, rare variants, disease risk alleles, Medical and Health Sciences, Respiratory System
Abstract: Rationale: Several common and rare genetic variants have been associated with idiopathic pulmonary fibrosis, a progressive fibrotic condition that is localized to the lung. Objectives: To develop an integrated understanding of the rare and common variants located in multiple loci that have been reported to contribute to the risk of disease. Methods: We performed deep targeted resequencing (3.69 Mb of DNA) in cases (n = 3,624) and control subjects (n = 4,442) across genes and regions previously associated with disease. We tested for associations between disease and 1) individual common variants via logistic regression and 2) groups of rare variants via sequence kernel association tests. Measurements and Main Results: Statistically significant common variant association signals occurred in all 10 of the regions chosen based on genome-wide association studies. The strongest risk variant is the MUC5B promoter variant rs35705950, with an odds ratio of 5.45 (95% confidence interval, 4.91-6.06) for one copy of the risk allele and 18.68 (95% confidence interval, 13.34-26.17) for two copies of the risk allele (P = 9.60 × 10-295). In addition to identifying for the first time that rare variation in FAM13A is associated with disease, we confirmed the role of rare variation in the TERT and RTEL1 gene regions in the risk of IPF, and found that the FAM13A and TERT regions have independent common and rare variant signals. Conclusions: A limited number of common and rare variants contribute to the risk of idiopathic pulmonary fibrosis in each of the resequencing regions, and these genetic variants focus on biological mechanisms of host defense and cell senescence.
Published: 2019

6. MUC5B Promoter Variant and Rheumatoid Arthritis with Interstitial Lung Disease

Author: Juge, Pierre-Antoine, Lee, Joyce S, Ebstein, Esther, Furukawa, Hiroshi, Dobrinskikh, Evgenia, Gazal, Steven, Kannengiesser, Caroline, Ottaviani, Sébastien, Oka, Shomi, Tohma, Shigeto, Tsuchiya, Naoyuki, Rojas-Serrano, Jorge, González-Pérez, Montserrat I, Mejía, Mayra, Buendía-Roldán, Ivette, Falfán-Valencia, Ramcés, Ambrocio-Ortiz, Enrique, Manali, Effrosyni, Papiris, Spyros A, Karageorgas, Theofanis, Boumpas, Dimitrios, Antoniou, Katarina, van Moorsel, Coline HM, van der Vis, Joanne, de Man, Yaël A, Grutters, Jan C, Wang, Yaping, Borie, Raphaël, Wemeau-Stervinou, Lidwine, Wallaert, Benoît, Flipo, René-Marc, Nunes, Hilario, Valeyre, Dominique, Saidenberg-Kermanac’h, Nathalie, Boissier, Marie-Christophe, Marchand-Adam, Sylvain, Frazier, Aline, Richette, Pascal, Allanore, Yannick, Sibilia, Jean, Dromer, Claire, Richez, Christophe, Schaeverbeke, Thierry, Lioté, Huguette, Thabut, Gabriel, Nathan, Nadia, Amselem, Serge, Soubrier, Martin, Cottin, Vincent, Clément, Annick, Deane, Kevin, Walts, Avram D, Fingerlin, Tasha, Fischer, Aryeh, Ryu, Jay H, Matteson, Eric L, Niewold, Timothy B, Assayag, Deborah, Gross, Andrew, Wolters, Paul, Schwarz, Marvin I, Holers, Michael, Solomon, Joshua J, Doyle, Tracy, Rosas, Ivan O, Blauwendraat, Cornelis, Nalls, Mike A, Debray, Marie-Pierre, Boileau, Catherine, Crestani, Bruno, Schwartz, David A, and Dieudé, Philippe
Subjects: Epidemiology, Biomedical and Clinical Sciences, Health Sciences, Lung, Rare Diseases, Autoimmune Disease, Genetics, Clinical Research, Arthritis, Rheumatoid Arthritis, 2.1 Biological and endogenous factors, Aetiology, Inflammatory and immune system, Respiratory, Aged, Arthritis, Rheumatoid, Female, Gain of Function Mutation, Genetic Predisposition to Disease, Genotype, Humans, Idiopathic Pulmonary Fibrosis, Lung Diseases, Interstitial, Male, Middle Aged, Mucin-5B, Odds Ratio, Promoter Regions, Genetic, Medical and Health Sciences, General & Internal Medicine, Biomedical and clinical sciences, Health sciences
Abstract: BackgroundGiven the phenotypic similarities between rheumatoid arthritis (RA)-associated interstitial lung disease (ILD) (hereafter, RA-ILD) and idiopathic pulmonary fibrosis, we hypothesized that the strongest risk factor for the development of idiopathic pulmonary fibrosis, the gain-of-function MUC5B promoter variant rs35705950, would also contribute to the risk of ILD among patients with RA.MethodsUsing a discovery population and multiple validation populations, we tested the association of the MUC5B promoter variant rs35705950 in 620 patients with RA-ILD, 614 patients with RA without ILD, and 5448 unaffected controls.ResultsAnalysis of the discovery population revealed an association of the minor allele of the MUC5B promoter variant with RA-ILD when patients with RA-ILD were compared with unaffected controls (adjusted odds ratio, 3.8; 95% confidence interval [CI], 2.8 to 5.2; P=9.7×10-17). The MUC5B promoter variant was also significantly overrepresented among patients with RA-ILD, as compared with unaffected controls, in an analysis of the multiethnic case series (adjusted odds ratio, 5.5; 95% CI, 4.2 to 7.3; P=4.7×10-35) and in a combined analysis of the discovery population and the multiethnic case series (adjusted odds ratio, 4.7; 95% CI, 3.9 to 5.8; P=1.3×10-49). In addition, the MUC5B promoter variant was associated with an increased risk of ILD among patients with RA (adjusted odds ratio in combined analysis, 3.1; 95% CI, 1.8 to 5.4; P=7.4×10-5), particularly among those with evidence of usual interstitial pneumonia on high-resolution computed tomography (adjusted odds ratio in combined analysis, 6.1; 95% CI, 2.9 to 13.1; P=2.5×10-6). However, no significant association with the MUC5B promoter variant was observed for the diagnosis of RA alone.ConclusionsWe found that the MUC5B promoter variant was associated with RA-ILD and more specifically associated with evidence of usual interstitial pneumonia on imaging. (Funded by Société Française de Rhumatologie and others.).
Published: 2018

7. Treatment of Idiopathic Pulmonary Fibrosis with Capsule or Tablet Formulations of Pirfenidone in the Real-Life French RaDiCo-ILD Cohort

Author: Cottin, Vincent, Guéguen, Sonia, Nunes, Hilario, Jouneau, Stéphane, Crestani, Bruno, Bonniaud, Philippe, Wemeau, Lidwine, Israël-Biet, Dominique, Reynaud-Gaubert, Martine, Gondouin, Anne, Cadranel, Jacques, Marchand-Adam, Sylvain, Chevereau, Marie, Dufaure-Garé, Isabelle, Amselem, Serge, and Clément, Annick
Published: 2022
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8. Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study.

Author: Leavy, Olivia C., Dourado, Leticia Kawano, Stewart, Iain D., Quint, Jennifer K., Solomon, Joshua J., Borie, Raphael, Crestani, Bruno, Wain, Louise V., Jenkins, Gisli, Dieudé, Philippe, and Minelli, Cosetta
Subjects: IDIOPATHIC pulmonary fibrosis, RHEUMATOID arthritis, IDIOPATHIC interstitial pneumonias, INTERSTITIAL lung diseases, DISEASE risk factors, HYPERSENSITIVITY pneumonitis, MEDICAL research
Published: 2024
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9. Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective

Author: Spyros A. Papiris, Caroline Kannengiesser, Raphael Borie, Lykourgos Kolilekas, Maria Kallieri, Vasiliki Apollonatou, Ibrahima Ba, Nadia Nathan, Andrew Bush, Matthias Griese, Philippe Dieude, Bruno Crestani, and Effrosyni D. Manali
Subjects: interstitial lung disease, idiopathic pulmonary fibrosis, alveolar epithelial cell, short telomere syndrome, surfactant-related gene mutations, telomere-related-gene mutations, Medicine (General), R5-920
Abstract: Background: Unraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis. Aim: The aim of the present study is to overview the clinical significance of genetics in IPF. Perspective: It is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a “a sporadic entity of the elderly, limited to the lungs” and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and “faces” in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure. Conclusion: By providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing.
Published: 2022
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10. Gender Differences in Idiopathic Pulmonary Fibrosis: Are Men and Women Equal?

Author: Lucile Sesé, Hilario Nunes, Vincent Cottin, Dominique Israel-Biet, Bruno Crestani, Stephanie Guillot-Dudoret, Jacques Cadranel, Benoit Wallaert, Abdellatif Tazi, Bernard Maître, Gregoire Prévot, Sylvain Marchand-Adam, Sandrine Hirschi, Sandra Dury, Violaine Giraud, Anne Gondouin, Philippe Bonniaud, Julie Traclet, Karine Juvin, Raphael Borie, Zohra Carton, Olivia Freynet, Thomas Gille, Carole Planès, Dominique Valeyre, and Yurdagül Uzunhan
Subjects: idiopathic pulmonary fibrosis, gender differences, occupational exposures, lung transplantation, women, Medicine (General), R5-920
Abstract: Background: Idiopathic pulmonary fibrosis (IPF) is characterized by a male predominance. The aim of the study was to explore gender differences in a well-designed French multicentre prospective IPF cohort (COhorte FIbrose, COFI) with a 5-year follow-up.Methods: Between 2007 and 2010, 236 patients with incident IPF were included in COFI. Gender characteristics were compared using a t-test, Chi-squared test and ANOVA, as appropriate. Survival analyses were performed.Results: Fifty-one (22%) females and 185 (78%) males with an average age at diagnosis of 70.1 ± 9.20 and 67.4 ± 10.9 years, respectively, were included in the cohort. Women were significantly less exposed to tobacco smoke [never n = 32 (62.7%) vs. n = 39 (21.1%), p < 0.001] and to occupational exposure [n = 7 (13.7%) vs. n = 63 (34.1%), p = 0.012]. Baseline forced vital capacity, % of predicted (FVC%) was significantly better in women compare to men (83.0% ± 25.0 v. 75.4% ± 18.7 p = 0.046). At presentation honeycombing and emphysema on CT scan were less common in women [n = 40 (78.4%) vs. n = 167 (90.3%) p = 0.041] and [n = 6 (11.8%) vs. n = 48 (25.9%) p = 0.029], respectively. During follow-up fewer women were transplanted compared to men [n = 1 (1.96%) vs. n = 20 (10.8%) p = 0.039]. Medians of survival were comparable by gender [31 months (CI 95%: 28–40) vs. 40 months (CI 95%: 33–72) p = 0.2]. After adjusting for age and FVC at inclusion, being a woman was not associated to a better survival.Conclusions: Women appear to have less advanced disease at diagnosis, maybe due to less exposure history compare to men. Disease progression and overall survival remains comparable regardless gender, but women have less access to lung transplantation.
Published: 2021
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11. Impact of Air Pollution and MUC5B Genotype on Survival in Idiopathic Pulmonary Fibrosis.

Author: Sesé, Lucile, Borie, Raphaël, Kannengiesser, Caroline, Cottin, Vincent, Israel-Biet, Dominique, Crestani, Bruno, Cadranel, Jacques, Chenivesse, Cécile, Boubaya, Marouane, Valeyre, Dominique, Annesi-Maesano, Isabella, and Nunes, Hilario
Subjects: IDIOPATHIC pulmonary fibrosis, AIR pollution, GENETIC risk score, GENOTYPES, INDOOR air pollution
Abstract: The article focuses on the impact of successive Chronic Obstructive Pulmonary Disease (COPD0 hospitalizations on future hospitalizations and death in rural and urban individuals. It examines the association between each successive COPD hospitalization and the risk of future hospitalization and death, considering factors like age, sex, race, distance to the nearest hospital, and comorbidity index and the risk factors associated with future hospitalizations and mortality among COPD patients.
Published: 2024
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12. Short peripheral blood leukocyte telomere length in rheumatoid arthritis- interstitial lung disease.

Author: Doyle, Tracy J., Juge, Pierre- Antoine, Peljto, Anna L., Lee, Seoyeon, Walts, Avram D., Esposito, Anthony Joseph, Poli, Sergio, Gill, Ritu, Hatabu, Hiroto, Nishino, Mizuki, Dellaripa, Paul F., Weinblatt, Michael E., Shadick, Nancy A., Demoruelle, M. Kristen, Sparks, Jeffey A., Rosas, Ivan O., Granger, Benjamin, Deane, Kevin D., Crestani, Bruno, and Wolters, Paul J.
Subjects: INTERSTITIAL lung diseases, TELOMERES, LEUCOCYTES, IDIOPATHIC pulmonary fibrosis
Published: 2024
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13. Study protocol: exploring the efficacy of cyclophosphamide added to corticosteroids for treating acute exacerbation of idiopathic pulmonary fibrosis; a randomized double-blind, placebo-controlled, multi-center phase III trial (EXAFIP)

Author: Jean-Marc Naccache, Melissa Montil, Jacques Cadranel, Marine Cachanado, Vincent Cottin, Bruno Crestani, Dominique Valeyre, Benoit Wallaert, Tabassome Simon, and Hilario Nunes
Subjects: Idiopathic pulmonary fibrosis, Acute exacerbation, Cyclophosphamide, Diseases of the respiratory system, RC705-779
Abstract: Abstract Background Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease, with a median survival of 2–3 years and variable natural history, characterized by gradual and progressive deterioration. Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a severe complication, associated with poor survival and a mortality > 50%. To date, no treatment has proven effective in AE-IPF, with cyclophosphamide (CYC) the only therapy suggested to be effective on survival, primarily based on retrospective series. Considering the high fatality rates of AE-IPF, evaluating the efficacy of immunosuppressive agents in a randomized controlled trial proves crucial, as the results could significantly impact treatment and prognosis of AE-IPF. Methods The EXAFIP study is a French national multicenter double-blind placebo-controlled randomized trial. Its primary objective is to evaluate the efficacy of CYC compared to placebo on early survival in patients treated with corticosteroids. We hypothesize that adding CYC to high-dose corticosteroids would reduce 3-month mortality in AE-IPF patients. The primary outcome is all-cause mortality rate at Month 3; secondary objectives are to evaluate the efficacy of CYC compared to placebo on overall survival at Months 6 and 12, respiratory disease-specific mortality, respiratory morbidity, and chest high-resolution computed tomography features, and to determine prognostic factors in AE-IPF and compare the safety of the two treatment arms during 6 months’ follow-up. Discussion There is an urgent unmet clinical need for effective AE-IPF treatment. The EXAFIP study is the first large Phase III placebo-controlled randomized trial evaluating the efficacy and safety of CYC added to corticosteroids in treating AE-IPF. The results of this study could significantly impact treatment strategy and prognosis of AE-IPF. Trial registration Clinical trials, NCT02460588; Date: June 2, 2015, prospectively; Issue date: 14/11/2017; Protocole Amendment Number: 03.
Published: 2019
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14. Psychometric properties and minimal important differences of SF-36 in Idiopathic Pulmonary Fibrosis

Author: Sabine Witt, Ekaterina Krauss, María Asunción Nieto Barbero, Veronika Müller, Philippe Bonniaud, Carlo Vancheri, Athol U. Wells, Martina Vasakova, Alberto Pesci, Walter Klepetko, Werner Seeger, Bruno Crestani, Reiner Leidl, Rolf Holle, Larissa Schwarzkopf, and Andreas Guenther
Subjects: Idiopathic pulmonary fibrosis, Rare diseases, Quality of life, Patient-reported outcome, Diseases of the respiratory system, RC705-779
Abstract: Abstract Background Idiopathic pulmonary fibrosis (IPF) is a rare disease with a median survival of 3–5 years after diagnosis with limited treatment options. The aim of this study is to assess the psychometric characteristics of the Short Form 36 Health Status Questionnaire (SF-36) in IPF and to provide disease specific minimally important differences (MID). Methods Data source was the European IPF Registry (eurIPFreg). The psychometric properties of the SF-36 version 2 were evaluated based on objective clinical measures as well as subjective perception. We analysed acceptance, feasibility, discrimination ability, construct and criterion validity, responsiveness and test-retest-reliability. MIDs were estimated via distribution and anchor-based approaches. Results The study population included 258 individuals (73.3% male; mean age 67.3 years, SD 10.7). Of them 75.2% (194 individuals) had no missing item. The distribution of several items was skewed, although floor effect was acceptable. Physical component score (PCS) correlated significantly and moderately with several anchors, whereas the correlations of mental component score (MCS) and anchors were only small. The tests showed mainly significant lower HRQL in individuals with long-term oxygen therapy. Analyses in stable individuals did not show significant changes of HRQL except for one dimension and anchor. Individuals with relevant changes of the health status based on the anchors had significant changes in all SF-36 dimensions and summary scales except for the dimension PAIN. PCS and MCS had mean MIDs of five and six, respectively. Mean MIDs of the dimensions ranged from seven to 21. Conclusion It seems that the SF-36 is a valid instrument to measure HRQL in IPF and so can be used in RCTs or individual monitoring of disease. Nevertheless, the additional evaluation of longitudinal aspects and MIDs can be recommended to further analyse these factors. Our findings have a great potential impact on the evaluation of IPF patients. Trial registration The eurIPFreg and eurIPFbank are listed in https://clinicaltrials.gov (NCT02951416).
Published: 2019
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15. Interleukin-8 release by endothelial colony-forming cells isolated from idiopathic pulmonary fibrosis patients might contribute to their pathogenicity

Author: Blandinières, Adeline, Gendron, Nicolas, Bacha, Nour, Bièche, Ivan, Chocron, Richard, Nunes, Hilario, Nevo, Nathalie, Rossi, Elisa, Crestani, Bruno, Lecourt, Séverine, Chevret, Sylvie, Lokajczyk, Anna, Mignon, Virginie, Kisaoglu, Alexandre, Juvin, Karine, Bertil, Sebastien, Valeyre, Dominique, Cras, Audrey, Gaussem, Pascale, Israël-Biet, Dominique, and Smadja, David M.
Published: 2019
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16. Lung Fibroblasts from Idiopathic Pulmonary Fibrosis Patients Harbor Short and Unstable Telomeres Leading to Chromosomal Instability

Author: Radhia M’Kacher, Madeleine Jaillet, Bruno Colicchio, Eirini Vasarmidi, Arnaud Mailleux, Alain Dieterlen, Caroline Kannengiesser, Claire Borie, Noufissa Oudrhiri, Steffen Junker, Philippe Voisin, Eric Jeandidier, Patrice Carde, Michael Fenech, Annelise Bennaceur-Griscelli, Bruno Crestani, and Raphael Borie
Subjects: idiopathic pulmonary fibrosis, telomere dysfunction, dicentric chromosome, anaphase bridges, micronuclei, TERT, Biology (General), QH301-705.5
Abstract: Idiopathic pulmonary fibrosis (IPF) is associated with several hallmarks of aging including telomere shortening, which can result from germline mutations in telomere related genes (TRGs). Here, we assessed the length and stability of telomeres as well as the integrity of chromosomes in primary lung fibroblasts from 13 IPF patients (including seven patients with pathogenic variants in TRGs) and seven controls. Automatized high-throughput detection of telomeric FISH signals highlighted lower signal intensity in lung fibroblasts from IPF patients, suggesting a telomere length defect in these cells. The increased detection of telomere loss and terminal deletion in IPF cells, particularly in TRG-mutated cells (IPF-TRG), supports the notion that these cells have unstable telomeres. Furthermore, fibroblasts from IPF patients with TRGs mutations exhibited dicentric chromosomes and anaphase bridges. Collectively, our study indicates that fibroblasts from IPF patients exhibit telomere and chromosome instability that likely contribute to the physiopathology.
Published: 2022
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17. Morphologic and molecular study of lung cancers associated with idiopathic pulmonary fibrosis and other pulmonary fibroses

Author: Alice Guyard, Claire Danel, Nathalie Théou-Anton, Marie-Pierre Debray, Laure Gibault, Pierre Mordant, Yves Castier, Bruno Crestani, Gérard Zalcman, Hélène Blons, and Aurélie Cazes
Subjects: Idiopathic pulmonary fibrosis, Fibrosis-associated lung cancer, Next-generation sequencing, Diseases of the respiratory system, RC705-779
Abstract: Abstract Background Primitive lung cancers developed on lung fibroses are both diagnostic and therapeutic challenges. Their incidence may increase with new more efficient lung fibrosis treatments. Our aim was to describe a cohort of lung cancers associated with idiopathic pulmonary fibrosis (IPF) and other lung fibrotic disorders (non-IPF), and to characterize their molecular alterations using immunohistochemistry and next-generation sequencing (NGS). Methods Thirty-one cancer samples were collected from 2001 to 2016 in two French reference centers for pulmonary fibrosis - 18 for IPF group and 13 for non-IPF group. NGS was performed using an ampliseq panel to analyze hotspots and targeted regions in 22 cancer-associated genes. ALK, ROS1 and PD-L1 expressions were assessed by immunohistochemistry. Results Squamous cell carcinoma was the most frequent histologic subtype in the IPF group (44%), adenocarcinoma was the most frequent subtype in the non-IPF group (62%). Forty-one mutations in 13 genes and one EGFR amplification were identified in 25 samples. Two samples had no mutation in the selected panel. Mutations were identified in TP53 (n = 20), MET (n = 4), BRAF (n = 3), FGFR3, PIK3CA, PTEN, STK11 (n = 2), SMAD4, CTNNB1, DDR2, ERBB4, FBXW7 and KRAS (n = 1) genes. No ALK and ROS1 expressions were identified. PD-L1 was expressed in 10 cases (62%) with only one (6%) case >50%. Conclusions This extensive characterization of lung fibrosis-associated cancers evidenced molecular alterations which could represent either potential therapeutic targets either clues to the pathophysiology of these particular tumors. These findings support the relevance of large molecular characterization of every lung fibrosis-associated cancer.
Published: 2017
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18. Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults

Author: Ganesh Raghu, Martine Remy-Jardin, Luca Richeldi, Carey C. Thomson, Yoshikazu Inoue, Takeshi Johkoh, Michael Kreuter, David A. Lynch, Toby M. Maher, Fernando J. Martinez, Maria Molina-Molina, Jeffrey L. Myers, Andrew G. Nicholson, Christopher J. Ryerson, Mary E. Strek, Lauren K. Troy, Marlies Wijsenbeek, Manoj J. Mammen, Tanzib Hossain, Brittany D. Bissell, Derrick D. Herman, Stephanie M. Hon, Fayez Kheir, Yet H. Khor, Madalina Macrea, Katerina M. Antoniou, Demosthenes Bouros, Ivette Buendia-Roldan, Fabian Caro, Bruno Crestani, Lawrence Ho, Julie Morisset, Amy L. Olson, Anna Podolanczuk, Venerino Poletti, Moisés Selman, Thomas Ewing, Stephen Jones, Shandra L. Knight, Marya Ghazipura, Kevin C. Wilson, and Pulmonary Medicine
Subjects: progressive pulmonary fibrosis, Pulmonary and Respiratory Medicine, histopathology, Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO, respiratory system, idiopathic pulmonary fibrosis, Critical Care and Intensive Care Medicine, radiology, respiratory tract diseases
Abstract: Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociacion Latinoamericana de Torax guideline updates prior idiopathic pulmonary fibrosis (IPF) guidelines and addresses the progression of pulmonary fibrosis in patients with interstitial lung diseases (ILDs) other than IPF. Methods: A committee was composed of multidisciplinary experts in ILD, methodologists, and patient representatives. 1) Update of IPF: Radiological and histopathological criteria for IPF were updated by consensus. Questions about transbronchial lung cryobiopsy, genomic classifier testing, antacid medication, and antireflux surgery were informed by systematic reviews and answered with evidence-based recommendations using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. 2) Progressive pulmonary fibrosis (PPF): PPF was defined, and then radiological and physiological criteria for PPF were determined by consensus. Questions about pirfenidone and nintedanib were informed by systematic reviews and answered with evidence-based recommendations using the GRADE approach. Results: 1) Update of IPF: A conditional recommendation was made to regard transbronchial lung cryobiopsy as an acceptable alternative to surgical lung biopsy in centers with appropriate expertise. No recommendation was made for or against genomic classifier testing. Conditional recommendations were made against antacid medication and antireflux surgery for the treatment of IPF. 2) PPF: PPF was defined as at least two of three criteria (worsening symptoms, radiological progression, and physiological progression) occurring within the past year with no alternative explanation in a patient with an ILD other than IPF. A conditional recommendation was made for nintedanib, and additional research into pirfenidone was recommended. Conclusions: The conditional recommendations in this guideline are intended to provide the basis for rational, informed decisions by clinicians.
Published: 2022

19. Study protocol: exploring the efficacy of cyclophosphamide added to corticosteroids for treating acute exacerbation of idiopathic pulmonary fibrosis; a randomized double-blind, placebo-controlled, multi-center phase III trial (EXAFIP)

Author: Naccache, Jean-Marc, Montil, Melissa, Cadranel, Jacques, Cachanado, Marine, Cottin, Vincent, Crestani, Bruno, Valeyre, Dominique, Wallaert, Benoit, Simon, Tabassome, and Nunes, Hilario
Published: 2019
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20. Psychometric properties and minimal important differences of SF-36 in Idiopathic Pulmonary Fibrosis

Author: Witt, Sabine, Krauss, Ekaterina, Barbero, María Asunción Nieto, Müller, Veronika, Bonniaud, Philippe, Vancheri, Carlo, Wells, Athol U., Vasakova, Martina, Pesci, Alberto, Klepetko, Walter, Seeger, Werner, Crestani, Bruno, Leidl, Reiner, Holle, Rolf, Schwarzkopf, Larissa, and Guenther, Andreas
Published: 2019
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21. SRC and TKS5 mediated podosome formation in fibroblasts promotes extracellular matrix invasion and pulmonary fibrosis.

Author: Barbayianni, Ilianna, Kanellopoulou, Paraskevi, Fanidis, Dionysios, Nastos, Dimitris, Ntouskou, Eleftheria-Dimitra, Galaris, Apostolos, Harokopos, Vaggelis, Hatzis, Pantelis, Tsitoura, Eliza, Homer, Robert, Kaminski, Naftali, Antoniou, Katerina M., Crestani, Bruno, Tzouvelekis, Argyrios, and Aidinis, Vassilis
Subjects: PULMONARY fibrosis, EXTRACELLULAR matrix, IDIOPATHIC pulmonary fibrosis, FIBROBLASTS, SCAFFOLD proteins
Abstract: The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components, is a pathogenic hallmark of Idiopathic Pulmonary Fibrosis, a lethal and incurable disease. In this report, increased expression of TKS5, a scaffold protein essential for the formation of podosomes, was detected in the lung tissue of Idiopathic Pulmonary Fibrosis patients and bleomycin-treated mice. Τhe profibrotic milieu is found to induce TKS5 expression and the formation of prominent podosome rosettes in lung fibroblasts, that are retained ex vivo, culminating in increased extracellular matrix invasion. Tks5+/- mice are found resistant to bleomycin-induced pulmonary fibrosis, largely attributed to diminished podosome formation in fibroblasts and decreased extracellular matrix invasion. As computationally predicted, inhibition of src kinase is shown to potently attenuate podosome formation in lung fibroblasts and extracellular matrix invasion, and bleomycin-induced pulmonary fibrosis, suggesting pharmacological targeting of podosomes as a very promising therapeutic option in pulmonary fibrosis. The activation and accumulation of lung fibroblasts resulting in aberrant deposition of extracellular matrix components is a pathogenic hallmark of idiopathic pulmonary fibrosis. Here, the authors show that the formation of podosomes in lung fibroblasts stimulates extracellular matrix invasion in a mouse model of the disease, suggesting that pharmacological targeting of podosome formation or organization might be a therapeutic option. [ABSTRACT FROM AUTHOR]
Published: 2023
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22. Macrophage Implication in IPF: Updates on Immune, Epigenetic, and Metabolic Pathways.

Author: Pokhreal, Deepak, Crestani, Bruno, and Helou, Doumet Georges
Subjects: *IDIOPATHIC pulmonary fibrosis, *INTERSTITIAL lung diseases, *PULMONARY fibrosis, *MACROPHAGES, *GROWTH factors, *CYTOKINE receptors
Abstract: Idiopathic pulmonary fibrosis (IPF) is a lethal interstitial lung disease of unknown etiology with a poor prognosis. It is a chronic and progressive disease that has a distinct radiological and pathological pattern from common interstitial pneumonia. The use of immunosuppressive medication was shown to be completely ineffective in clinical trials, resulting in years of neglect of the immune component. However, recent developments in fundamental and translational science demonstrate that immune cells play a significant regulatory role in IPF, and macrophages appear to be among the most crucial. These highly plastic cells generate multiple growth factors and mediators that highly affect the initiation and progression of IPF. In this review, we will provide an update on the role of macrophages in IPF through a systemic discussion of various regulatory mechanisms involving immune receptors, cytokines, metabolism, and epigenetics. [ABSTRACT FROM AUTHOR]
Published: 2023
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23. Cyclophosphamide added to glucocorticoids in acute exacerbation of idiopathic pulmonary fibrosis (EXAFIP): a randomised, double-blind, placebo-controlled, phase 3 trial

Author: Abdellatif Tazi, Aurélie Le Borgne-Krams, Marine Cachanado, Tabassome Simon, Sylvain Marchand-Adam, Morgane Didier, Lidwine Wemeau-Stervinou, Sandrine Hirschi, Frédéric Rivière, Arnaud Bourdin, François Lebargy, Stéphane Dominique, Aude Gibelin, Alexandre Chabrol, Tristan Dégot, Jacques Cadranel, Martine Reynaud-Gaubert, Marie-Pierre Debray, Sylvie Leroy, Frédéric Gagnadoux, Emmanuel Bergot, François-Xavier Blanc, Alexandra Rousseau, Raphael Borie, Pierre Yves Brillet, Guillaume Beltramo, Mallorie Kerjouan, Hilario Nunes, Olivia Freynet, Julie Traclet, Bruno Crestani, Anne-Sophie Gamez, Grégoire Prévot, Jean Pastré, Dominique Israel-Biet, Marie-Christine Dombret, Laurent Plantier, Cécile Chenivesse, Laurence Berard, Ana Nieves, Emmanuel Gomez, Dominique Valeyre, Stéphane Jouneau, Anne Gondouin, Elodie Blanchard, C. Launois, Nathalie Bautin, Jean-Marc Naccache, Vincent Cottin, Antoine Parrot, Philippe Bonniaud, Centre de référence maladies rares des maladies pulmonaires rares de l’adulte (CHU Dijon) (CRMR des maladies pulmonaires rares de l’adulte), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Sorbonne Université (SU), Centre hospitalier Saint-Joseph [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Foch [Suresnes], CHU Pontchaillou [Rennes], École des Hautes Études en Santé Publique [EHESP] (EHESP), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Hôpital Avicenne [AP-HP], Laboratoire d'Excellence INFLAMEX [Paris], Université Sorbonne Paris Cité (USPC), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), AP-HP - Hôpital Bichat - Claude Bernard [Paris], CHU Saint-Antoine [AP-HP], Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre régional de pharmacovigilance de Marseille Provence Corse [CHU de Marseille] (CRPV-Marseille), Assistance Publique - Hôpitaux de Marseille (APHM)-CHU Marseille, CHU Dijon, Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Les Hôpitaux Universitaires de Strasbourg (HUS), Nouvel Hôpital Civil de Strasbourg, Centre Hospitalier Universitaire de Reims (CHU Reims), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), CHU Lille, Hôpital Albert Calmette, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Référence des Maladies Pulmonaires Rares [Hôpital Louis Pradel - HCL], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Hospices Civils de Lyon (HCL), Université de Lyon, CIC CHU Lyon (inserm), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Nice (CHU Nice), Université d'Angers (UA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Hôpital d'instruction des Armées Percy, Service de Santé des Armées, Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Hôpital JeanMinjoz, CHU Bordeaux [Bordeaux], Hôpital Haut-Lévêque [CHU Bordeaux], unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Rouen, Normandie Université (NU), CHU Tenon [AP-HP], Immunologie humaine, physiopathologie & immunothérapie (HIPI (UMR_S_976 / U976)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université Paris Cité (UPCité), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), CHU Montpellier, Université de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Roche, Ministere de la Sante et des Solidarites, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), CHU Marseille-Assistance Publique-Hôpitaux de Marseille (AP-HM), Hôpital Larrey [Toulouse], CHU Toulouse [Toulouse], Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, education.field_of_study, Exacerbation, Cyclophosphamide, business.industry, [SDV]Life Sciences [q-bio], Population, medicine.disease, Placebo, 3. Good health, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, 030228 respiratory system, Methylprednisolone, Internal medicine, Clinical endpoint, Medicine, 030212 general & internal medicine, business, education, Adverse effect, ComputingMilieux_MISCELLANEOUS, medicine.drug
Abstract: Summary Background The use of cyclophosphamide in patients with acute exacerbation of idiopathic pulmonary fibrosis (IPF) is unknown. Our study was designed to evaluate the efficacy and safety of four cyclophosphamide pulses in addition to high-dose methylprednisolone in this population. Methods In this double-blind, placebo-controlled trial done in 35 departments across 31 hospitals in France, adult patients (≥18 years) with acute exacerbation of IPF and those with suspected acute exacerbation of IPF were randomly assigned in a 1:1 ratio using a web-based system to receive either intravenous pulses of cyclophosphamide (600 mg/m2) plus uromitexan as haemorrhagic cystitis prophylaxis (200 mg/m2) at the time of cyclophosphamide administration and then again, 4 h later, or placebo at days 0, 15, 30, and 60. Random assignment was stratified according to the severity of IPF and was block-balanced with variable block sizes of four or six patients. Patients receiving mechanical ventilation, with active infection, with active cancer, or who were registered on the lung transplant waiting list were excluded. All patients received standardised high-dose glucocorticoids. The investigators, patients, and the sponsor were masked to the treatment assignments. The primary endpoint was 3-month all-cause mortality, analysed by a χ2 test adhering to an intention-to-treat principle. The trial is now complete and registered with ClinicalTrials.gov , NCT02460588 . Findings Between Jan 22, 2016, and July 19, 2018, 183 patients were assessed for eligibility, of whom 120 patients were randomly assigned and 119 patients (62 [52%] with severe IPF) received at least one dose of cyclophosphamide (n=60) or placebo (n=59), all of whom were included in the intention-to-treat analysis. The 3-month all-cause mortality was 45% (27/60) in patients given cyclophosphamide compared with 31% (18/59) in the placebo group (difference 14·5% [95% CI −3·1 to 31·6]; p=0·10). Similar results were found after adjustment by IPF severity (odds ratio [OR] 1·89 [95% CI 0·89–4·04]). The risk of death at 3 months, independent of the treatment received, was higher with severe than non-severe IPF (OR 2·62 [1·12–6·12]) and was lower with the use of antifibrotic therapy (OR 0·33 [0·13–0·82]). Adverse events were similar between groups by 6 months (25 [42%] in the cyclophosphamide group vs 30 [51%] in the placebo group) and their proportion, including infections, did not differ. Overall infection was the main adverse event and occurred in 20 (33%) of 60 patients in the cyclophosphamide group versus 21 (36%) of 59 patients in the placebo group. Interpretation In patients with acute exacerbation of IPF, adding intravenous cyclophosphamide pulses to glucocorticoids increased 3-month mortality. These findings provide evidence against the use of intravenous cyclophosphamide in such patients. Funding Programme Hospitalier de Recherche Clinique of the French Ministry of Health (PHRC 2014–502), Roche Pharmaceuticals.
Published: 2022

24. Identification of Paired-related Homeobox Protein 1 as a key mesenchymal transcription factor in pulmonary fibrosis

Author: Marchal-Duval, Emmeline, Homps-Legrand, Méline, Froidure, Antoine, Jaillet, Madeleine, Ghanem, Mada, Lou, Deneuville, Justet, Aurélien, Maurac, Arnaud, Vadel, Aurelie, Fortas, Emilie, Cazes, Aurelie, Joannes, Audrey, Giersh, Laura, Mal, Herve, Mordant, Pierre, Piolot, Tristan, Truchin, Marin, Mounier, Carine, Schirduan, Ksenija, Korfei, Martina, Gunther, Andreas, Mari, Bernard, Jaschinski, Frank, Crestani, Bruno, Mailleux, Arnaud, UCL - SSS/IREC/PNEU - Pôle de Pneumologie, ORL et Dermatologie, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Equipe de recherche sur les relations matrice extracellulaire-cellules (ERRMECe), Fédération INSTITUT DES MATÉRIAUX DE CERGY-PONTOISE (I-MAT), CY Cergy Paris Université (CY)-CY Cergy Paris Université (CY), Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), and Justus-Liebig-Universität Gießen = Justus Liebig University (JLU)
Subjects: MESH: Idiopathic Pulmonary Fibrosis, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, lung, Mice, Transforming Growth Factor beta, MESH: Cell Proliferation, fibroblasts, transcription factors, MESH: Homeodomain Proteins, cell biology, Animals, Humans, MESH: Animals, human, MESH: Mice, MESH: Transforming Growth Factor beta, mouse, Cell Proliferation, Homeodomain Proteins, MESH: Humans, fibrosis, MESH: Transcription Factors, TGF beta pathway, Idiopathic Pulmonary Fibrosis, Protein Phosphatase 2C, MESH: Protein Phosphatase 2C
Abstract: Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix remodeling could be a promising avenue for IPF treatment. Analysis of transcriptomic database identified the mesenchymal transcription factor PRRX1 as upregulated in IPF. PRRX1, strongly expressed by lung fibroblasts, was regulated by a TGF-β/PGE2 balance in vitro in control and IPF human lung fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 expression in a PDGFR-dependent manner in control ones. PRRX1 inhibition decreased human lung fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-β driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to TGF-β response global decrease. Finally, targeted inhibition of Prrx1 attenuated fibrotic remodeling in vivo with intra-tracheal antisense oligonucleotides in bleomycin mouse model of lung fibrosis and ex vivo using human and mouse precision-cut lung slices. Our results identified PRRX1 as a key mesenchymal transcription factor during lung fibrogenesis.
Published: 2023

25. Inhibition of the Arp2/3 complex represses human lung myofibroblast differentiation and attenuates bleomycin‐induced pulmonary fibrosis

Author: Laurent Plantier, Victor Tiroille, Damien Sizaret, Mélia Magnien, Sylvain Marchand-Adam, Madeleine Jaillet, Bruno Crestani, Coralie Mergault, Woodys Lenga Mabonda, Christelle Parent, and Fanny Lisée
Subjects: Arp2/3 complex, macromolecular substances, Bleomycin, Actin-Related Protein 2-3 Complex, Transforming Growth Factor beta1, Mice, chemistry.chemical_compound, Idiopathic pulmonary fibrosis, In vivo, Fibrosis, Pulmonary fibrosis, medicine, Animals, Humans, Myofibroblasts, Lung, Pharmacology, biology, Chemistry, Cell Differentiation, Fibroblasts, respiratory system, medicine.disease, Actin cytoskeleton, Idiopathic Pulmonary Fibrosis, Mice, Inbred C57BL, biology.protein, Cancer research, Myofibroblast
Abstract: BACKGROUND AND PURPOSE The Arp2/3 multiprotein complex regulates branched polymerisation of the actin cytoskeleton and may contribute to collagen synthesis and fibrogenesis in the lung. EXPERIMENTAL APPROACH Expression of Arp2/3 components was assessed in human lung fibroblasts and in the bleomycin-induced pulmonary fibrosis model in mice. The Arp2/3 complex was repressed with the allosteric inhibitor CK666 and with interfering RNAs targeting the ARP2, ARP3 and ARPC2 subunits (siARP2, siARP3 and siARPC2) in CCD-16Lu human lung fibroblasts in vitro. Mice received daily intraperitoneal injections of CK666 from the 7th to the 14th day after tracheal bleomycin instillation. KEY RESULTS Expression of Arp2/3 complex subunits mRNAs was increased in fibroblasts treated with TGF-β1 and in the lungs of bleomycin-treated mice compared with controls. In vitro, CK666 and siARPC2 inhibited cell growth and TGF-β1-induced α-smooth muscle actin (ACTA2) and collagen-1 (COL1) expression. CK666 also decreased ACTA2 and COL1 expression in unstimulated cells. CK666 reduced Akt phosphorylation and repressed phospho-GSK3β, β-catenin and MRTF-A levels in unstimulated fibroblasts. In vivo, CK666 reduced levels of both procollagen-1 and insoluble collagen in bleomycin-treated mice. CONCLUSION AND IMPLICATIONS Expression of the Arp2/3 complex was increased in profibrotic environments in vitro and in vivo. Inhibition of the Arp2/3 complex repressed ACTA2 and COL1 expression and repressed an Akt/phospho-GSK3β/β-catenin/MRTF-A pathway in lung fibroblasts. CK666 exerted antifibrotic properties in the lung in vivo. Inhibition of the Arp2/3 complex could represent an interesting new therapy for idiopathic pulmonary fibrosis and other fibrotic interstitial lung diseases.
Published: 2021

26. Interstitial lung disease following coronavirus disease 2019

Author: Eirini Vasarmidi, Mada Ghanem, and Bruno Crestani
Subjects: Pulmonary and Respiratory Medicine, COVID-19, Humans, Lung Diseases, Interstitial, Lung, Idiopathic Pulmonary Fibrosis, Respiratory Function Tests
Abstract: The aim of this review was to summarize the recent data concerning interstitial lung disease after COVID-19, a field where knowledge is evolving very quickly.It has been found that a proportion of patients displayed fibrotic-like pattern on chest computed tomography shortly after COVID-19 pneumonia. Those lesions can potentially represent precursors of fibrosis, although most of them will resolve until 1 year postinfection. There was a wide range of the prevalence of post-COVID-19 interstitial lung disease detected in the literature, which can be attributed to the heterogeneous definition of lung abnormalities and the discrepancy of study design. The severity of acute COVID-19 disease has been linked to increased risk of residual imaging and functional abnormalities, while reduced DLco was the most common functional abnormality in long-term survivors. Studies indicated that pathophysiology of post-COVID interstitial lung disease shares common mechanisms with idiopathic pulmonary fibrosis. Regarding therapeutic strategies of post-COVID-19 interstitial lung disease, the role of immunosuppressive and antifibrotic treatment is currently under investigation.We still need to learn about the natural history of COVID-19 disease, allowing for a better targeting of therapeutic interventions through a multidisciplinary approach.
Published: 2022

27. Origins of pathological myofibroblasts in lung fibrosis: insights from lineage tracing mouse models in the single-cell RNA sequencing era.

Author: Homps-Legrand, Méline, Crestani, Bruno, and Mailleux, Arnaud A.
Subjects: *LUNGS, *PULMONARY fibrosis, *RNA sequencing, *MYOFIBROBLASTS, *IDIOPATHIC pulmonary fibrosis, *LABORATORY mice
Abstract: Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease with a poor prognosis. Chronic microinjuries, mainly caused by environmental factors to an aging alveolar epithelium, would lead to the aberrant differentiation and accumulation of aberrant mesenchymal cells with a contractile phenotype, known as fibrosis-associated myofibroblasts, which trigger abnormal extracellular matrix accumulation and fibrosis. The origin of those pathological myofibroblasts in pulmonary fibrosis is not fully understood to date. Lineage tracing methods using mouse models have opened new avenues for studying cell fate in a pathological context. This review aims to present a nonexhaustive list of different potential sources of those harmful myofibroblasts during lung fibrosis, based on these in vivo approaches, and considering the normal and fibrotic lung cellular atlas recently established by single-cell RNA sequencing. [ABSTRACT FROM AUTHOR]
Published: 2023
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28. MUC5B rs35705950 minor allele associates with older age and better survival in idiopathic pulmonary fibrosis.

Author: van der Vis, Joanne J., Prasse, Antje, Renzoni, Elisabetta A., Stock, Carmel J. W., Caliskan, Canay, Maher, Toby M., Bonella, Francesco, Borie, Raphael, Crestani, Bruno, Petrek, Martin, Wuyts, Wim A., Wind, Anne E., Molyneaux, Philip L., Grutters, Jan C., and van Moorsel, Coline H. M.
Subjects: ALLELES, PROPORTIONAL hazards models, PULMONARY function tests, IDIOPATHIC pulmonary fibrosis
Abstract: Background and Objective: The minor T‐allele of the MUC5B promoter polymorphism rs35705950 is strongly associated with idiopathic pulmonary fibrosis (IPF). However, conflicting results have been reported on the relationship between the MUC5B minor allele and survival and it is unknown whether a specific subgroup of IPF patients might benefit from MUC5B minor allele carriage. We investigated the association between MUC5B rs35705950, survival and patient characteristics in a real‐world population of European IPF patients. Methods: In this retrospective study, 1751 patients with IPF from 8 European centres were included. MUC5B rs35705950 genotype, demographics, clinical characteristics at diagnosis and survival data were analysed. Results: In a multi‐variate Cox proportional hazard model the MUC5B minor allele was a significant independent predictor of survival when adjusted for age, sex, high resolution computed tomography pattern, smoking behaviour and pulmonary function tests in IPF. MUC5B minor allele carriers were significantly older at diagnosis (p = 0.001). The percentage of MUC5B minor allele carriers increased significantly with age from 44% in patients aged <56 year, to 63% in patients aged >75. In IPF patients aged <56, the MUC5B minor allele was not associated with survival. In IPF patients aged ≥56, survival was significantly better for MUC5B minor allele carriers (45 months [CI: 42–49]) compared to non‐carriers (29 months [CI: 26–33]; p = 4 × 10−12). Conclusion: MUC5B minor allele carriage associates with a better median transplant‐free survival of 16 months in the European IPF population aged over 56 years. MUC5B genotype status might aid disease prognostication in clinical management of IPF patients. In idiopathic pulmonary fibrosis (IPF), the proportion of MUC5B rs35705950 minor allele carriers increases significantly with age. In IPF patients diagnosed at ≥56 years, transplant free survival is significantly better for MUC5B minor allele carriers compared to non‐carriers. These findings support implementation of MUC5B genotyping for clinical prognostication in IPF. [ABSTRACT FROM AUTHOR]
Published: 2023
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29. Genotype-Phenotype Relationships in Inheritable Idiopathic Pulmonary Fibrosis: A Greek National Cohort Study

Author: Manali, Effrosyni, Kannengiesser, Caroline, Borie, Raphael, Ba, Ibrahima, Bouros, Demosthenes, Markopoulou, Aikaterini, Antoniou, Katerina, Kolilekas, Lykourgos, Papaioannou, Andriana, Tzilas, Vasileios, Tzouvelekis, Argyrios, Daniil, Zoe, Fouka, Evangelia, Papakosta, Despoina, Xyfteri, Areti, Karakatsani, Anna, Loukides, Stylianos, Korbila, Ioanna, Tomos, Ioannis, Konstantinidis, Athanasios, Gogali, Athina, Steiropoulos, Paschalis, Papanikolaou, Ilias, Bazaka, Chrysa, Haritou, Aggeliki, Vassilakopoulos, Theodoros, Maniati, Maria, Kagouridis, Konstantinos, Markozannes, Evangelos, Bouros, Evangelos, Rampiadou, Christina, Kounti, Georgia, Trachalaki, Athina, Dimeas, Ilias, Karampitsakos, Theodoros, Lyberopoulos, Panagiotis, Malamadakis, Nikolaos, Spyropoulou, Sofia, Revy, Patrick, Lainey, Elodie, Dieudé, Philippe, Rebah, Khedidja, Ménard, Christelle, Oudin, Claire, Masson, Cécile, Plessier, Aurélie, Legendre, Marie, Nathan, Nadia, Coulomb-L’hermine, Aurore, Clement, Annick, Amselem, Serge, Boileau, Catherine, Crestani, Bruno, Papiris, Spyros, National and Kapodistrian University of Athens (NKUA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre de Référence des Maladies Pulmonaires Rares [AP-HP Hôpital Bichat], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Iatriko Medical Center [Athens], General Hospital of Thessaloniki George Papanikolaou, University of Crete [Heraklion] (UOC), 'Sotiria' General Hospital [Athens], University of Patras, University of Thessaly [Larissa], Aristotle University of Thessaloniki, Private Clinic, Messini, University of Ioannina, Democritus University of Thrace (DUTH), Corfu General Hospital [Corfu], Private Clinic, Agrinio, Private Clinic, Ioannina, Private Clinic, Chalkis, Genome dynamics in the immune system (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Paris Cité (UPCité), Hôpital Beaujon [AP-HP], Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Service de Pneumologie pédiatrique [CHU Trousseau], Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Greek Group of ILD Investigators, and Couvet, Sandrine
Subjects: Pulmonary and Respiratory Medicine, Genotype, Greece, [SDV]Life Sciences [q-bio], Inheritable pulmonary fibrosis, MUC5B rs35705950 T risk allele, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Prognosis, Surfactant protein-related genes, Idiopathic Pulmonary Fibrosis, Cohort Studies, [SDV] Life Sciences [q-bio], Phenotype, Telomere-related genes, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Humans, Pathogenic variations, Genetic Predisposition to Disease
Abstract: Background: Monogenic and polygenic inheritances are evidenced for idiopathic pulmonary fibrosis (IPF). Pathogenic variations in surfactant protein-related genes, telomere-related genes (TRGs), and a single-nucleotide polymorphism in the promoter of MUC5B gene encoding mucin 5B (rs35705950 T risk allele) are reported. This French-Greek collaborative study, Gen-Phen-Re-GreekS in inheritable IPF (iIPF), aimed to investigate genetic components and patients’ characteristics in the Greek national IPF cohort with suspected heritability. Patients and Methods: 150 patients with familial PF, personal-family extrapulmonary disease suggesting short telomere syndrome, and/or young age IPF were analyzed. Results: MUC5B rs35705950 T risk allele was detected in 103 patients (90 heterozygous, 13 homozygous, allelic frequency of 39%), monoallelic TRG pathogenic variations in 19 patients (8 TERT, 5 TERC, 2 RTEL1, 2 PARN, 1 NOP10, and 1 NHP2), and biallelic ABCA3 pathogenic variations in 3. Overlapping MUC5B rs35705950 T risk allele and TRG pathogenic variations were shown in 11 patients (5 TERT, 3 TERC, 1 PARN, 1 NOP10, and 1 NHP2), MUC5B rs35705950 T risk allele, and biallelic ABCA3 pathogenic variations in 2. In 38 patients, neither MUC5B rs35705950 T risk allele nor TRG pathogenic variations were detectable. Kaplan-Meier curves showed differences in time-to-death (p = 0.025) where patients with MUC5B rs35705950 T risk allele alone or in combination with TRG pathogenic variations presented better prognosis. Conclusion: The Gen-Phen-Re-GreekS in iIPF identified multiple and overlapping genetic components including the rarest, underlying disease’s genetic “richesse,” complexity and heterogeneity. Time-to-death differences may relate to diverse IPF pathogenetic mechanisms implicating “personalized” medical care driven by genotypes in the near future.
Published: 2022

30. FGF19 is Downregulated in Idiopathic Pulmonary Fibrosis and Inhibits Lung Fibrosis in Mice

Author: Aurélien Justet, Mada Ghanem, Tiara Boghanim, Mouna Hachem, Eirini Vasarmidi, Madeleine Jaillet, Aurélie Vadel, Audrey Joannes, Pierre Mordant, Philippe Bonniaud, Martin Kolb, Lei Ling, Aurélie Cazes, Hervé Mal, Arnaud Mailleux, Bruno Crestani, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), and McMaster University [Hamilton, Ontario]
Subjects: Pulmonary and Respiratory Medicine, [SDV]Life Sciences [q-bio], Clinical Biochemistry, Cell Biology, Fibroblasts, respiratory system, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Fibroblast Growth Factors, Bleomycin, Mice, Transforming Growth Factor beta, Animals, Humans, Collagen, Myofibroblasts, Molecular Biology, Lung
Abstract: International audience; IPF is a devastating lung disease with limited therapeutic possibilities. FGF19, an endocrine FGF, was recently shown to decrease liver fibrosis. To ask whether FGF19 had anti-fibrotic properties in the lung and decipher its effects on common features associated with lung fibrogenesis. We assessed, by Elisa, FGF19 levels in plasma and bronchoalveolar lavage fluids (BALF)obtained from controls and IPF patients. In vivo, using an intravenously administered adeno11 associated virus (AAV), we overexpressed FGF19 at the fibrotic phase of two experimental models of murine lung fibrosis and assessed its effect on lung morphology, lung collagen content, fibrosis markers and pro fibrotic mediator expression, at mRNA and protein levels. In vitro, we investigated whether FGF19 could modulate the TGFβ-induced differentiation of primary human lung fibroblast into myofibroblast and the apoptosis of murine alveolar type II cell. While FGF19 was not detected in BALF, FGF19 concentration was decreased in the plasma of IPF patients compared to controls. In vivo, the overexpression of FGF19 was associated with a marked decrease of lung fibrosis and fibrosis markers, with a decrease of pro fibrotic mediator expression and lung collagen content. In vitro, FGF19 decreased alveolar type 2 epithelial cell apoptosis through the decrease of the proapoptotic BIM protein expression and prevented TGF-ß induced myofibroblast differentiation through the inhibition of JNK phosphorylation. Altogether these data identify FGF19 as an anti-fibrotic molecule with a potential therapeutic interest in fibrotic lung disorders.
Published: 2022

31. Immune checkpoint blockade for patients with lung cancer and idiopathic pulmonary fibrosis

Author: Boris Duchemann, Bruno Crestani, Gérard Zalcman, Hilario Nunes, and Johan Pluvy
Subjects: Oncology, Cancer Research, medicine.medical_specialty, business.industry, medicine.disease, Immune checkpoint, Blockade, Idiopathic pulmonary fibrosis, Text mining, Internal medicine, medicine, business, Lung cancer
Published: 2021

32. [Idiopathic pulmonary fibrosis: Update of French practical guidelines]

Author: Cottin, V, Bonniaud, P, Cadranel, J, Jouneau, S, Marchand-Adam, S, Nunes, H, Wémeau-Stervinou, L, Crestani, B, Centre national de référence des maladies pulmonaires rares [Lyon] (CRMPM), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut Coeur Poumon [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Centre Constitutif de Référence des Maladies Pulmonaires Rares [AP-HP Tenon], Centre national de référence des maladies pulmonaires rares [Lyon] (CRMPM)-Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université d'Angers (UA)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )
Subjects: [SDV]Life Sciences [q-bio], Pulmonary Medicine, Humans, Tomography, X-Ray Computed, Idiopathic Pulmonary Fibrosis, ComputingMilieux_MISCELLANEOUS
Abstract: National audience
Published: 2022

33. Weight loss and outcomes in subjects with progressive pulmonary fibrosis: data from the INBUILD trial.

Author: Kreuter, Michael, Bendstrup, Elisabeth, Jouneau, Stéphane, Maher, Toby M., Inoue, Yoshikazu, Miede, Corinna, Lievens, Dirk, and Crestani, Bruno
Subjects: PULMONARY fibrosis, WEIGHT loss, IDIOPATHIC pulmonary fibrosis, BODY mass index, DISEASE exacerbation
Abstract: Background: Lower body mass index (BMI) and weight loss have been associated with worse outcomes in some studies in patients with pulmonary fibrosis. We analyzed outcomes in subgroups by BMI at baseline and associations between weight change and outcomes in subjects with progressive pulmonary fibrosis (PPF) in the INBUILD trial. Methods: Subjects with PPF other than idiopathic pulmonary fibrosis were randomized to receive nintedanib or placebo. In subgroups by BMI at baseline (< 25, ≥ 25 to < 30, ≥ 30 kg/m2), we analyzed the rate of decline in FVC (mL/year) over 52 weeks and time-to-event endpoints indicating disease progression over the whole trial. We used a joint modelling approach to assess associations between change in weight and the time-to-event endpoints. Results: Among 662 subjects, 28.4%, 36.6% and 35.0% had BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m2, respectively. The rate of decline in FVC over 52 weeks was numerically greater in subjects with baseline BMI < 25 than ≥ 25 to < 30 or ≥ 30 kg/m2 (nintedanib: − 123.4, − 83.3, − 46.9 mL/year, respectively; placebo: − 229.5; − 176.9; − 171.2 mL/year, respectively). No heterogeneity was detected in the effect of nintedanib on reducing the rate of FVC decline among these subgroups (interaction p = 0.83). In the placebo group, in subjects with baseline BMI < 25, ≥ 25 to < 30 and ≥ 30 kg/m2, respectively, 24.5%, 21.4% and 14.0% of subjects had an acute exacerbation or died, and 60.2%, 54.5% and 50.4% of subjects had ILD progression (absolute decline in FVC % predicted ≥ 10%) or died over the whole trial. The proportions of subjects with these events were similar or lower in subjects who received nintedanib versus placebo across the subgroups. Based on a joint modelling approach, over the whole trial, a 4 kg weight decrease corresponded to a 1.38-fold (95% CI 1.13, 1.68) increase in the risk of acute exacerbation or death. No association was detected between weight loss and the risk of ILD progression or the risk of ILD progression or death. Conclusions: In patients with PPF, lower BMI at baseline and weight loss may be associated with worse outcomes and measures to prevent weight loss may be required. Trial registration:https://clinicaltrials.gov/ct2/show/NCT02999178. Plain language summary: Patients with worsening fibrosis (scarring) of the lungs may lose weight. This study suggests that the course of disease may be worse in patients who lose weight. Measures to prevent weight loss may be needed in these patients. [ABSTRACT FROM AUTHOR]
Published: 2023
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34. No association between human herpesvirus or herpesvirus saimiri and idiopathic pulmonary fibrosis

Author: Quentin Le Hingrat, Benoit Visseaux, Gilles Collin, Mada Ghanem, Bruno Crestani, Diane Descamps, Charlotte Charpentier, and Aurélie Cazes
Subjects: Pulmonary and Respiratory Medicine, Herpesvirus saimiri, Lung, business.industry, viruses, Original Research Letters, lcsh:R, lcsh:Medicine, respiratory system, medicine.disease, Virology, respiratory tract diseases, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, medicine.anatomical_structure, 030228 respiratory system, medicine, 030212 general & internal medicine, business, Viral load, Human herpesvirus
Abstract: Idiopathic pulmonary fibrosis (IPF) is a rare, progressive and irreversible lung disease leading to death within 3 to 5 years of diagnosis [1]. The current hypothesis concerning pathophysiology is that chronic alveolar epithelial cell injury leads to an aberrant reparative response resulting in chronic architecture remodelling of the lung. By inducing alveolar cell injury, viral infection or reactivation has been proposed to play a role in the pathogenesis of IPF and could act as a trigger for acute exacerbation [2]. Herpesviruses are particular suspects since a higher prevalence of Epstein–Barr virus (EBV) and human herpesvirus 8 (HHV-8) has been identified in lung samples from IPF patients [2–7]. However, many of these studies were performed in a period where steroids and immunosuppressive drugs were the standard of care for IPF patients. Mouse models have also suggested the involvement of human herpesviruses as an enhancer of the fibrotic response in lung, by inducing pro-fibrotic factors [8]. Herpesvirus saimiri (HVS), a nonpathogenic gamma herpesvirus infecting squirrel monkeys, has been associated with IPF in one study [9]. This finding has not been confirmed yet. The role of torque teno virus (TTV) has been previously suspected in acute exacerbation of IPF [10]., There is a high prevalence of human herpesviruses in lung samples of IPF patients but this does not differ from controls, neither regarding prevalence, viral load levels nor co-infection rates. Herpesvirus saimiri DNA is not detected in any lung samples. https://bit.ly/2ZrKiDJ
Published: 2020

35. Impact of Gender on the Characteristics of Patients with Idiopathic Pulmonary Fibrosis Included in the RaDiCo-ILD Cohort

Author: Sandrine Hirschi, Sonia Gueguen, M. Chevereau, Serge Amselem, Anne-Sophie Gamez, Martine Reynaud-Gaubert, Philippe Bonniaud, Dominique Israel-Biet, Annick Clement, I. Dufaure-Garé, Sylvain Marchand-Adam, Lidwine Wemeau-Stervinou, David Montani, Vincent Cottin, Jacques Cadranel, Hilario Nunes, Sébastien Quétant, Bruno Crestani, Stéphane Jouneau, Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Hospices Civils de Lyon (HCL), Maladies génétiques d'expression pédiatrique (U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Hypoxie et Poumon : pneumopathologies fibrosantes, modulations ventilatoires et circulatoires (H&P), UFR SMBH-Université Sorbonne Paris Nord, Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Hôpital Claude Huriez [Lille], CHU Lille, Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Microbes évolution phylogénie et infections (MEPHI), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Pathologies Respiratoires : Protéolyse et Aérosolthérapie, Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle Thorax et Vaisseaux [CHU Grenoble], Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Strasbourg, Hypertension pulmonaire : physiopathologie et innovation thérapeutique (HPPIT), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Hôpital Lapeyronie [Montpellier] (CHU), CHU Trousseau [APHP], French National Research Agency under the 'cohorts' programme of the Investissements d'Avenir (Investments for the Future) French National Research Agency (ANR) [ANR-10-COHO-0003], ANR-10-COHO-0003,RADICO,Cohorte nationale maladies rares(2010), École pratique des hautes études (EPHE), Physiopathologie des maladies génétiques d'expression pédiatrique (UMRS_933), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre Constitutif de Référence des Maladies Pulmonaires Rares [AP-HP Tenon], Centre national de référence des maladies pulmonaires rares [Lyon] (CRMPM)-Service de Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Centre national de référence des maladies pulmonaires rares [Lyon] (CRMPM)-Service de Pneumologie = Pneumologie - Oncologie Thoracique - Maladies Pulmonaires Rares [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Tenon [AP-HP], UF de Génétique moléculaire [CHU Trousseau], Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], Service de Pneumologie pédiatrique [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], Chard-Hutchinson, Xavier, and Cohortes - Cohorte nationale maladies rares - - RADICO2010 - ANR-10-COHO-0003 - COHO - VALID
Subjects: Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, Vital capacity, Registry, [SDV]Life Sciences [q-bio], Idiopathic pulmonary fibrosis, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Pulmonary function testing, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Rare Diseases, Internal medicine, medicine, Humans, 030212 general & internal medicine, Honeycombing, Idiopathic interstitial pneumonia, 10. No inequality, Emphysema, Patient characteristics, business.industry, Interstitial lung disease, Gender, respiratory system, medicine.disease, Confidence interval, 3. Good health, respiratory tract diseases, [SDV] Life Sciences [q-bio], 030228 respiratory system, Cohort, Quality of Life, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Female, France, business, Lung Diseases, Interstitial
Abstract: Background: There is growing evidence of gender-specific phenotypic differences among patients with idiopathic pulmonary fibrosis (IPF), which may affect patient outcomes. Objectives: We present the characteristics of patients with IPF at inclusion in the French Rare Disease Cohort – Interstitial Lung Disease (RaDiCo-ILD) with the aim of characterizing gender-specific phenotypic differences. Methods: Patients with IPF who were enrolled in the national, multicentre RaDiCo-ILD cohort were included. Demographic characteristics, comorbidities, health-related quality of life (HRQoL) scores, pulmonary function, chest imaging, and IPF treatment were collected at inclusion and described by gender. Results: The cohort included 724 patients with IPF (54% of RaDiCo-ILD cohort), of whom 82.9% were male. The proportion of male and female patients with a prior history of smoking was 75.0% and 26.8%, respectively. Emphysema was present in 17.0% (95% confidence interval [CI]: 10.0, 24.0) of men and 5.4% (95% CI: 1.2, 9.6) of women. At inclusion, females had poorer HRQoL than males based on St. George’s Respiratory Questionnaire scores (48.5 [95% CI: 43.9, 53.0] and 41.5 [39.4, 43.6], respectively). The mean forced vital capacity per cent predicted was 77.7% (95% CI: 76.2, 79.3) and 87.4% (83.4, 91.4) for males and females, respectively. Honeycombing on high-resolution computed tomography (HRCT) was present in 70.8% (95% CI: 61.0, 80.6) of males and 45.8% (95% CI: 35.1, 56.5) of females. Conclusions: This analysis of patients with IPF at inclusion in the RaDiCo-ILD cohort provides evidence that comorbid emphysema, lung volume reduction, and honeycombing on HRCT are more common characteristics of males than females.
Published: 2022

36. Genetic testing in interstitial lung disease : An international survey

Author: Terwiel, Michelle, Borie, Raphael, Crestani, Bruno, Galvin, Liam, Bonella, Francesco, Fabre, Aurelie, Froidure, Antoine, Griese, Matthias, Grutters, Jan C., Johannson, Kerri, Kannengiesser, Caroline, Kawano-Dourado, Leticia, Molina-Molina, Maria, Prasse, Antje, Renzoni, Elisabetta A., van der Smagt, Jasper, Poletti, Venerino, Antoniou, Katerina, van Moorsel, Coline H. M., Smagt, Jasper, Moorsel, Coline H. M., and UCL - (SLuc) Service de pneumologie
Subjects: interstitial lung disease, Pulmonary and Respiratory Medicine, familial ILD, familial pulmonary fibrosis, Medizin, Idiopathic Pulmonary Fibrosis, genetic testing, relative, perceptions, experience, Pulmonologists, Surveys and Questionnaires, international survey, Humans, patient, Genetic Testing, pulmonologist, Lung Diseases, Interstitial, needs
Abstract: Genetic analysis is emerging for interstitial lung diseases (ILDs); however, ILD practices are not yet standardized. We surveyed patients', relatives' and pulmonologists' experiences and needs on genetic testing in ILD to evaluate the current situation and identify future needs. A clinical epidemiologist (MT) together with members of the ERS taskforce and representatives of the European Idiopathic Pulmonary Fibrosis and related disorders Federation (EU-IPFF) patient organisation developed a survey for patients, relatives and pulmonologists. Online surveys consisted of questions on five main topics: awareness of hereditary ILD, the provision of information, genetic testing, screening of asymptomatic relatives and clinical impact of genetic analysis in ILD. Survey respondents consisted of 458 patients with ILD, 181 patients' relatives and 352 pulmonologists. Most respondents think genetic testing can be useful, particularly for explaining the cause of disease, predicting its course, determining risk for developing disease and the need to test relatives. Informing patients and relatives on genetic analysis is primarily performed by the pulmonologist, but 88% (218) of pulmonologists identify a need for more information and 96% (240) ask for guidelines on genetic testing in ILD. A third of the pulmonologists who would offer genetic testing currently do not offer a genetic test, primarily because they have limited access to genetic tests. Following genetic testing, 72% (171) of pulmonologists may change the diagnostic work-up and 57% (137) may change the therapeutic approach. This survey shows that there is wide support for implementation of genetic testing in ILD and a high need for information, guidelines and access to testing among patients, their relatives and pulmonologists.
Published: 2022

37. Treatment of Idiopathic Pulmonary Fibrosis with Capsule or Tablet Formulations of Pirfenidone in the Real-Life French RaDiCo-ILD Cohort

Author: Cottin, Vincent, Guéguen, Sonia, Nunes, Hilario, Jouneau, Stéphane, Crestani, Bruno, Bonniaud, Philippe, Wemeau, Lidwine, Israël-Biet, Dominique, Reynaud-Gaubert, Martine, Gondouin, Anne, Cadranel, Jacques, Marchand-Adam, Sylvain, Chevereau, Marie, Dufaure-Garé, Isabelle, Amselem, Serge, Clément, Annick, Bergot, Emmanuel, Bourdin, Arnaud, Chenivesse, Cécile, Dalphin, Jean-Charles, Dromer, Claire, Gomez, Emmanuel, Hirschi, Sandrine, Montani, David, Prévot, Grégoire, Quetant, Sébastien, Valeyre, Dominique, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Maladies génétiques d'expression pédiatrique [CHU Trousseau] (Inserm U933), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Avicenne [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Pontchaillou [Rennes], AP-HP - Hôpital Bichat - Claude Bernard [Paris], CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), CHU Lille, Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), CHU Marseille, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), UF de Génétique moléculaire [CHU Trousseau], CHU Trousseau [APHP], Service de Pneumologie pédiatrique [CHU Trousseau], Centre de référence national pour les maladies respiratoires rares de l’enfant RespiRare [CHU Trousseau], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Trousseau [APHP], and the RaDiCo team: Emmanuel Bergot, Philippe Bonniaud, Arnaud Bourdin, Jacques Cadranel, Cécile Chenivesse, Vincent Cottin, Bruno Crestani, Jean-Charles Dalphin, Claire Dromer, Emmanuel Gomez, Sandrine Hirschi, Dominique Israël-Biet, Stéphane Jouneau, Sylvain Marchand-Adam, David Montani, Hilario Nunes, Grégoire Prévot, Sébastien Quetant, Martine Reynaud-Gaubert, Dominique Valeyre, Lidwine Wemeau, and MORNET, Dominique
Subjects: medicine.medical_specialty, Pyridones, [SDV]Life Sciences [q-bio], Population, Interstitial lung disease, Pirfenidone, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Cohort Studies, 03 medical and health sciences, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Internal medicine, medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, Adverse effect, education, Capsule, ComputingMilieux_MISCELLANEOUS, education.field_of_study, business.industry, General Medicine, medicine.disease, Rash, Idiopathic Pulmonary Fibrosis, 3. Good health, Clinical trial, Treatment Outcome, 030228 respiratory system, Cohort, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, France, Antifibrotic, medicine.symptom, Tablet, Lung Diseases, Interstitial, business, Tablets, Cohort study, medicine.drug
Abstract: Auteur groupe collaboratif RaDiCo team; International audience; Introduction: Pirfenidone, an antifibrotic medication for idiopathic pulmonary fibrosis (IPF), is now available in France in two formulations: tablets since April 2018, and the initial capsules form. We conducted a cohort study to describe tolerance and acceptability of capsules and/or tablets of pirfenidone in patients with IPF.Methods: This study was nested within the French, non-randomized, multicenter RaDiCo-ILD (Rare Disease Cohort-Interstitial Lung Diseases). Included patients with IPF received at least one dose of pirfenidone tablets or capsules from July 2017 to June 2019 in three populations: the inclusion population (patients treated at least once with pirfenidone during the study period, n = 288); the potential switch population (patients treated with pirfenidone during the switch period starting April 2018, n = 256); the newly treated population (patients who initiated pirfenidone during the study period, n = 162). Each of those last two populations included three subgroups (tablets, capsules, and substitution).Results: In 288 patients treated, 162 newly initiated pirfenidone during the study period: there were no meaningful differences in the baseline characteristics with the 256 patients treated during the potential switch period. In the newly treated population, 30.3% started pirfenidone treatment with tablet formulation. In the potential switch population, 44.9% of patients shifted from capsule to tablet. Half of the patients shifted to tablet formulation within the first 10 months. The mean treatment duration was 21.5 months with a mean dose of 2106.7 mg/day; 46.5% of patients discontinued treatment, mainly because of adverse events. There were fewer discontinuations in the tablets and substitution subgroups than in the capsules-only subgroup. The most reported adverse event was skin rash (11.5%). No new adverse event was identified.Conclusions: This real-life cohort assessing the characteristics of the prescription of pirfenidone tablets and capsules suggests a good acceptability of the tablet formulation by patients with IPF.Trial registration: Clinical trial registered with www.clinicaltrials.gov (NCT04238871).
Published: 2021

38. Interstitial lung diseases associated with mutations of poly(A)-specific ribonuclease: A multicentre retrospective study

Author: Quentin, Philippot, Caroline, Kannengiesser, Marie Pierre, Debray, Clément, Gauvain, Ibrahima, Ba, Margherita, Vieri, Anne, Gondouin, Jean-Marc, Naccache, Martine, Reynaud-Gaubert, Yurdagul, Uzunhan, Benjamin, Bondue, Dominique, Israël-Biet, Philippe, Dieudé, Cécile, Fourrage, Elodie, Lainey, Effrosyne, Manali, Spyros, Papiris, Lidwine, Wemeau, Sandrine, Hirschi, Hervé, Mal, Hilario, Nunes, Frédéric, Schlemmer, Elodie, Blanchard, Fabian, Beier, Vincent, Cottin, Bruno, Crestani, and Raphaël, Borie
Subjects: Pulmonary and Respiratory Medicine, Exoribonucleases, Mutation, Humans, Lung Diseases, Interstitial, Idiopathic Pulmonary Fibrosis, Retrospective Studies
Abstract: Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. This study aims to describe the phenotype of patients with interstitial lung disease (ILD) and heterozygous PARN mutations.We performed a retrospective, observational, non-interventional study of patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation followed up in a centre of the OrphaLung network.We included 31 patients (29 from 16 kindreds and two sporadic patients). The median age at ILD diagnosis was 59 years (range 54 to 63). In total, 23 (74%) patients had a smoking history and/or fibrogenic exposure. The pulmonary phenotypes were heterogenous, but the most frequent diagnosis was idiopathic pulmonary fibrosis (n = 12, 39%). Haematological abnormalities were identified in three patients and liver disease in two. In total, 21 patients received a specific treatment for ILD: steroids (n = 13), antifibrotic agents (n = 11), immunosuppressants (n = 5) and N-acetyl cysteine (n = 2). The median forced vital capacity decline for the whole sample was 256 ml/year (range -363 to -148). After a median follow-up of 32 months (range 18 to 66), 10 patients had died and six had undergone lung transplantation. The median transplantation-free survival was 54 months (95% CI 29 to ∞). Extra-pulmonary features were less frequent with PARN mutation than telomerase reverse transcriptase (TERT) or telomerase RNA component (TERC) mutation.IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed.
Published: 2021

39. Post hoc Analysis of Clinical Outcomes in Placebo-and Pirfenidone-treated Patients with IPF Stratified by BMI and Weight Loss

Author: Ronan Thibault, Ming Yang, Bruno Crestani, Mathieu Lederlin, Laurent Vernhet, Stéphane Jouneau, Vincent Cottin, Elizabeth Morgenthien, Klaus-Uwe Kirchgaessler, CHU Pontchaillou [Rennes], Institut de recherche en santé, environnement et travail (Irset), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Physiopathologie et Epidémiologie des Maladies Respiratoires (PHERE (UMR_S_1152 / U1152)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département de Radiologie [Rennes], Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Laboratoire Traitement du Signal et de l'Image (LTSI), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Genentech, Inc. [San Francisco], F. Hoffmann-La Roche [Basel], Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Infections Virales et Pathologie Comparée - UMR 754 (IVPC), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), This analysis was sponsored by Genentech, Inc. and F. Hoffmann-La Roche, Ltd, Jonchère, Laurent, Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Rennes (UR), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), and École Pratique des Hautes Études (EPHE)
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Pyridones, [SDV]Life Sciences [q-bio], Vital Capacity, Interstitial lung disease, Idiopathic pulmonary fibrosis, Placebo, Body composition, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, 03 medical and health sciences, FEV1/FVC ratio, 0302 clinical medicine, Weight loss, Internal medicine, Post-hoc analysis, Weight Loss, medicine, Humans, 030212 general & internal medicine, Adverse effect, Body mass index, 2. Zero hunger, business.industry, Anti-Inflammatory Agents, Non-Steroidal, Percent Predicted Forced Vital Capacity, 3. Good health, [SDV] Life Sciences [q-bio], Treatment Outcome, 030228 respiratory system, Cohort, [SDV.MHEP.PSR] Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, medicine.symptom, business
Abstract: Background: Weight loss is frequently reported in patients with idiopathic pulmonary fibrosis (IPF) and may be associated with worse outcomes in these patients. Objective: The aim of this study was to investigate the relationships between body mass index (BMI) and weight loss, and outcomes over 1 year in patients with IPF. Methods: Data were included from placebo patients enrolled in ASCEND (NCT01366209) and CAPACITY (NCT00287716 and NCT00287729), and all patients in INSPIRE (NCT00075998) and RIFF Cohort A (NCT01872689). An additional analysis included data from pirfenidone-treated patients. Outcomes (annualized change in percent predicted forced vital capacity [%FVC], percent predicted carbon monoxide diffusing capacity, 6-min walk distance, St. George’s Respiratory Questionnaire total score, hospitalization, mortality, and serious adverse events) were analyzed by baseline BMI (2, 25 kg/m2–2, or ≥30 kg/m2) and annualized percent change in body weight (no loss, >0–Results: Placebo-treated patients with a baseline BMI 2 or annualized weight loss may experience worse outcomes versus those with a baseline BMI ≥25 kg/m2 or no weight loss. The proportion of placebo-treated patients who experienced a relative decline of ≥10% in %FVC or death up to 1 year post-randomization was highest in patients with a baseline BMI 2. Pirfenidone-treated patients with an annualized weight loss ≥5% may also experience worse outcomes versus those with no weight loss. Conclusions: Patients with a baseline BMI 2 or annualized weight loss of >0–2 or no weight loss.
Published: 2021

40. RCT Abstract - Cyclophosphamide added to glucocorticoids in acute exacerbation of idiopathic pulmonary fibrosis (EXAFIP): a randomized, double-blind, placebo-controlled, phase 3 trial

Author: Jean-Marc Naccache, Morgane Didier, Hilario Nunes, Julie Traclet, Olivia Freynet, Dominique Israel-Biet, Alexandre Chabrol, Arnaud Bourdin, Nathalie Bautin, Emmanuel Bergot, Grégoire Prévot, Jean Pastré, Sylvie Leroy, Philippe Bonniaud, Tristan Dégot, Frédéric Rivière, Raphael Borie, Cécile Chenivesse, Vincent Cottin, Lidwine Wemeau-Stervinou, Bruno Crestani, Martine Reynaud-Gaubert, Antoine Parrot, Dominique Valeyre, Marie-Christine Dombret, Malorie Kerjouan, Abdellatif Tazi, Anne Gondouin, Stéphane Jouneau, Elodie Blanchard, Sylvain Marchand-Adam, Sandrine Hirschi, C. Launois, Ana Nieves, Stéphane Dominique, François-Xavier Blanc, Jacques Cadranel, Marie-Pierre Debray, Anne-Sophie Gamez, Frédéric Gagnadoux, Marine Cachanado, Laurence Berard, Guillaume Beltramo, Tabassome Simon, Pierre-Yves Brillet, A. Gibelin, Emmanuel Gomez, Aurélie Le Borgne-Krams, François Lebargy, Alexandra Rousseau, and Laurent Plantier
Subjects: medicine.medical_specialty, Cyclophosphamide, Exacerbation, business.industry, medicine.disease, Placebo, Gastroenterology, law.invention, Double blind, Idiopathic pulmonary fibrosis, Randomized controlled trial, law, Internal medicine, Medicine, business, medicine.drug
Published: 2021

41. New insights into methylome alterations and consequences during myofibroblastic differentiation in pulmonary fibrosis

Author: Arnaud A. Mailleux and Bruno Crestani
Subjects: Pulmonary and Respiratory Medicine, Epigenome, Humans, Cell Differentiation, Fibroblasts, Myofibroblasts, Idiopathic Pulmonary Fibrosis
Published: 2022

42. Genetics in Idiopathic Pulmonary Fibrosis: A Clinical Perspective.

Author: Papiris, Spyros A., Kannengiesser, Caroline, Borie, Raphael, Kolilekas, Lykourgos, Kallieri, Maria, Apollonatou, Vasiliki, Ba, Ibrahima, Nathan, Nadia, Bush, Andrew, Griese, Matthias, Dieude, Philippe, Crestani, Bruno, and Manali, Effrosyni D.
Subjects: IDIOPATHIC pulmonary fibrosis, GENETICS, PULMONARY alveolar proteinosis, MEDICAL genetics, GENETIC variation, PULMONARY fibrosis
Abstract: Background: Unraveling the genetic background in a significant proportion of patients with both sporadic and familial IPF provided new insights into the pathogenic pathways of pulmonary fibrosis. Aim: The aim of the present study is to overview the clinical significance of genetics in IPF. Perspective: It is fascinating to realize the so-far underestimated but dynamically increasing impact that genetics has on aspects related to the pathophysiology, accurate and early diagnosis, and treatment and prevention of this devastating disease. Genetics in IPF have contributed as no other in unchaining the disease from the dogma of a "a sporadic entity of the elderly, limited to the lungs" and allowed all scientists, but mostly clinicians, all over the world to consider its many aspects and "faces" in all age groups, including its co-existence with several extra pulmonary conditions from cutaneous albinism to bone-marrow and liver failure. Conclusion: By providing additional evidence for unsuspected characteristics such as immunodeficiency, impaired mucus, and surfactant and telomere maintenance that very often co-exist through the interaction of common and rare genetic variants in the same patient, genetics have created a generous and pluralistic yet unifying platform that could lead to the understanding of the injurious and pro-fibrotic effects of many seemingly unrelated extrinsic and intrinsic offending factors. The same platform constantly instructs us about our limitations as well as about the heritability, the knowledge and the wisdom that is still missing. [ABSTRACT FROM AUTHOR]
Published: 2022
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43. 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

Author: Rainer Georg Goeldner, S. Abe, Dirk Skowasch, Romain Kessler, S. Izumi, A. Barczyk, E. Belloli, J. S. Park, H. Takaya, C. Marquette, Neil Ettinger, Krishna Thavarajah, Nina Patel, Manuel Quaresma, Yasuhiko Nishioka, D Koschel, Silvia Quadrelli, M. A. Bergna, J. Sauleda, M. Salinas Fénero, J. Kang, G. Giessel, Oksana A. Shlobin, Kevin K. Brown, T. Kawamura, Ketan P. Buch, W. Randerath, O. Acosta, A. Silva Orellana, L. Wemeau, N. Sakamoto, Bruno Crestani, Sonye K. Danoff, Shane Shapera, S. Stieglitz, M. Reynaud-Gaubert, Tejaswini Kulkarni, P. Elias, Leslie Tolle, Lake Morrison, C. Glazer, Yoshikazu Inoue, Rozsa Schlenker-Herceg, Yolanda Mageto, Anand Devaraj, Zeenat Safdar, H. Hayashi, Y. Kim, Nik Hirani, Srihari Veeraraghavan, Sylvain Marchand-Adam, S. Cerri, J. Golden, D. Hotchkin, Rebecca Bascom, K. Ichikado, Martin Kolb, Nazia Chaudhuri, H. Cai, B. Crestani, J. W. Song, V. Yakusevich, Anoop M. Nambiar, Sergey Moiseev, Y. Kondoh, F. Lebargy, Wim A. Wuyts, Maria Padilla, A. Gamez-Dubuis, Sergey Avdeev, A. León Jiménez, R. Martinez, Luca Richeldi, J. Dematte D'Amico, Teng Moua, E. Bergot, J. Falk, Benjamin Bondue, K. Kishi, Danielle Antin-Ozerkis, L. Gómez Carrera, Francesco Bonella, Vincent Cottin, T. Moua, A. Villar, Stéphane Jouneau, Z. Xu, R. Hallowell, Mary E. Strek, H. Takahashi, Antje Prasse, A. Cantin, M. Okamoto, G. Criner, M. Rossman, M. Schwartz, R. Refini, Myriam Aburto, S. Makino, Y. Inoue, L. Jones, J. Burk, L. Morrow, Shelley L. Schmidt, S. Chaaban, M. Ilkovich, J. A. Rodríguez Portal, Athol U. Wells, S. Blaas, C. Andrews, D. M. Castillo Villegas, Caroline Dahlqvist, Q. Luo, H. Yamauchi, Justin M. Oldham, Julien Guiot, M. Kolb, Nitin Y. Bhatt, Y. Yamada, Maria Otaola, Alberto Pesci, E. Britt, W. Wuyts, E. Jassem, Daniel F. Dilling, Kevin R. Flaherty, H. Kitamura, H. Poonyagariyagorn, Y. Miyazaki, Robert J. Kaner, L. Pitts, Toby M. Maher, Marilyn K. Glassberg, G. Arce, J. Kus, S. Weigt, E. R. Fernández Pérez, Ivan O. Rosas, Michael Kreuter, Claudia Valenzuela, S. Tomassetti, Susanne Stowasser, K. Tomii, C. Kono, Ben Hope-Gill, D. Ziora, B. Sigal, E. Bazdyrev, R. Maturana Rozas, Paul Beirne, T. Saito, F. Varone, T. Suda, M. Arias, A. Cazaux, J. Hetzel, Helen Stone, Maria Molina-Molina, F. Riviere, L. Homik, Mary Beth Scholand, A. Gifford, W. Piotrowski, Carlo Vancheri, T. Takeuchi, H. Sugiura, M. Martínez, and Hilario Nunes
Subjects: Diarrhea, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Indoles, Vital Capacity, Population, nintedanib, idiopathic pulmonary fibrosis, Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO, behavioral disciplines and activities, law.invention, 03 medical and health sciences, chemistry.chemical_compound, Idiopathic pulmonary fibrosis, FEV1/FVC ratio, 0302 clinical medicine, Double-Blind Method, Randomized controlled trial, law, Internal medicine, nintedanib, medicine, Humans, 030212 general & internal medicine, education, Protein Kinase Inhibitors, Idiopathic interstitial pneumonia, Aged, education.field_of_study, business.industry, Interstitial lung disease, Nausea, Middle Aged, respiratory system, Sciences bio-médicales et agricoles, medicine.disease, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, body regions, 030228 respiratory system, chemistry, Disease Progression, Female, Nintedanib, business, Hypersensitivity pneumonitis
Abstract: The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis., info:eu-repo/semantics/published
Published: 2020

44. Outcomes following decline in forced vital capacity in patients with idiopathic pulmonary fibrosis: Results from the INPULSIS and INPULSIS-ON trials of nintedanib

Author: Moisés Selman, Luca Richeldi, Vincent Cottin, Bruno Crestani, Susanne Stowasser, Martin Kolb, Manuel Quaresma, Arata Azuma, and Wibke Stansen
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Vital capacity, Indoles, Vital Capacity, Interstitial lung disease, Settore MED/10 - MALATTIE DELL'APPARATO RESPIRATORIO, 03 medical and health sciences, chemistry.chemical_compound, FEV1/FVC ratio, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Internal medicine, medicine, Humans, In patient, 030212 general & internal medicine, business.industry, respiratory system, medicine.disease, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Treatment Outcome, 030228 respiratory system, chemistry, Cardiology, Nintedanib, business, circulatory and respiratory physiology
Abstract: We explored the impact of FVC decline on subsequent FVC decline and mortality in the INPULSIS trials of nintedanib in patients with IPF and their open-label extension, INPULSIS-ON.Changes in FVC and mortality between weeks 24 and 52 of the INPULSIS trials were assessed in patients with an increase/no decline in FVC % predicted and with declines in FVC10% and ≥10% predicted from baseline to week 24. Changes in FVC and mortality in the first year of INPULSIS-ON were assessed in patients treated with nintedanib in the preceding INPULSIS trial who did and did not have a decline in FVC ≥10% predicted at week 52.The proportion of placebo-treated patients with decline in FVC ≥10% predicted between weeks 24 and 52 of INPULSIS was similar in patients with increase/no decline in FVC and with decline in FVC ≥10% predicted between baseline and week 24 (20.5% and 18.9%, respectively). Mortality between weeks 24 and 52 of INPULSIS was higher in patients with FVC decline ≥10% predicted than10% predicted between baseline and week 24 (13.2% vs 3.8%). Among nintedanib-treated patients in INPULSIS who had decline in FVC ≥10% versus10% predicted at week 52, 34.0% versus 21.4%, respectively, had decline in FVC ≥10% predicted in the first year of INPULSIS-ON. Mortality in the first year of INPULSIS-ON was 21.3% vs 5.7% in these groups, respectively.Decline in FVC did not predict FVC decline but was associated with mortality in patients with IPF.
Published: 2019

45. Long‐term treatment with nintedanib in Asian patients with idiopathic pulmonary fibrosis: Results from INPULSIS®‐ON

Author: Takashi Ogura, Yoshikazu Inoue, Susanne Stowasser, Wibke Stansen, Bruno Crestani, Manuel Quaresma, Jin Woo Song, and Zuojun Xu
Subjects: Diarrhea, Male, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Vital capacity, Indoles, Time Factors, Vital Capacity, Placebo, Interstitial Lung Disease, 03 medical and health sciences, FEV1/FVC ratio, chemistry.chemical_compound, Idiopathic pulmonary fibrosis, 0302 clinical medicine, Asian People, Internal medicine, nintedanib, medicine, Humans, 030212 general & internal medicine, Protein Kinase Inhibitors, Aged, clinical trials, business.industry, lung fibrosis, Interstitial lung disease, Middle Aged, medicine.disease, Idiopathic Pulmonary Fibrosis, Clinical trial, Treatment Outcome, 030228 respiratory system, Tolerability, chemistry, Disease Progression, Original Article, Female, Nintedanib, ORIGINAL ARTICLES, business
Abstract: Background and objective The efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis (IPF) were investigated in the placebo‐controlled INPULSIS® trials. All patients who completed an INPULSIS® trial could receive open‐label nintedanib in the extension trial INPULSIS®‐ON. Methods We assessed the long‐term efficacy and safety of nintedanib in patients of Asian race who were treated in INPULSIS®‐ON. Analyses were descriptive. Results A total of 215 Asian patients were treated in INPULSIS®‐ON, of whom 121 continued nintedanib in INPULSIS®‐ON and 94 initiated nintedanib in INPULSIS®‐ON having received placebo in an INPULSIS® trial. At baseline of INPULSIS®‐ON, the mean (SD) age of Asian patients was 66.3 (7.5) years, 80.5% were males and mean (SD) forced vital capacity (FVC) was 78.9 (19.3) % predicted. Median total exposure to nintedanib in both INPULSIS® and INPULSIS®‐ON was 42.2 months; maximum exposure was 64.1 months. In INPULSIS®, the annual rate (SE) of decline in FVC over 52 weeks in Asian patients was −124 (20) mL/year in the nintedanib group and −218 (24) mL/year in the placebo group. In INPULSIS®‐ON, the annual rate (SE) of decline in FVC over 192 weeks in Asian patients was −127 (11) mL/year. Diarrhoea was reported in Asian patients at event rates of 58.8 and 82.5 events per 100 patient exposure–years in patients who continued and initiated nintedanib in INPULSIS®‐ON, respectively. Conclusion The effect of nintedanib on slowing disease progression in Asian patients with IPF is sustained over the long term. Long‐term treatment with nintedanib has an acceptable safety and tolerability profile., In a subgroup analysis of data from the open‐label extension of the INPULSIS® trials, INPULSIS®‐ON, the effect of nintedanib on slowing disease progression in Asian patients with idiopathic pulmonary fibrosis was sustained over the long term. Long‐term treatment with nintedanib had an acceptable safety and tolerability profile.
Published: 2019

46. Clinical Impact of Surgical Lung Biopsy for Interstitial Lung Disease in a Reference Center

Author: Clairelyne Dupin, Raphael Borie, Pierre Mordant, Jules Iquille, Pierre Le Guen, Alice Guyard, Arnaud Roussel, Mada Ghanem, Aurélie Cazes, Antoine Khalil, Bruno Crestani, Camille Taillé, Yves Castier, Marie-Pierre Debray, and M.C. Dombret
Subjects: Pulmonary and Respiratory Medicine, Male, medicine.medical_specialty, Non-specific interstitial pneumonia, Biopsy, Lung biopsy, FEV1/FVC ratio, Idiopathic pulmonary fibrosis, Usual interstitial pneumonia, medicine, Humans, Lung, Aged, Retrospective Studies, business.industry, Interstitial lung disease, medicine.disease, Idiopathic Pulmonary Fibrosis, Surgery, Pneumothorax, Female, Cardiology and Cardiovascular Medicine, business, Lung Diseases, Interstitial, Hypersensitivity pneumonitis
Abstract: Diagnosis of interstitial lung disease is based on the analysis of clinical, biological, radiological, and pathological findings during a multidisciplinary discussion (MDD). When a definitive diagnosis is not possible, guidelines recommend obtaining lung samples through surgical lung biopsy (SLB). We sought to determine morbidity, mortality, diagnostic yield, and therapeutic impact of SLB in the management of patients with interstitial lung disease.We retrospectively analyzed morbidity, mortality, diagnostic yield, and therapeutic changes after SLB for interstitial lung disease performed electively from January 2015 to May 2019 in a reference center. Each case was reviewed during 2 MDDs, first without and then with the result of the SLB.The study group included 73 patients (56% male, age 66 [interquartile range (IQR), 57-70] years, forced vital capacity 79% [IQR, 69%-91%], diffusing capacity of the lungs for carbon monoxide 52% [IQR, 46%-63%]). Median postoperative hospital length of stay was 2 (IQR, 0-11) days. Thirteen (17%) patients experienced at least 1 complication, including pain at 1 month (n = 8) and residual pneumothorax (n = 6). No serious complication or postoperative death was noticed. After the first retrospective MDD, the working diagnosis was idiopathic nonspecific interstitial pneumonia in 20 (27%), idiopathic pulmonary fibrosis in 18 (25%), fibrotic hypersensitivity pneumonitis in 15 (21%), unclassifiable interstitial lung disease in 5 (7%), and other diagnosis in 15 (21%) patients. After SLB and second retrospective MDD, the final diagnosis was modified in 35 (48%) patients and led to therapeutic changes in 33 (45%) patients.SLB is associated with no serious complication or death and notably changes the diagnosis and treatment of interstitial lung disease.
Published: 2021

47. Patient-reported outcomes and patient-reported outcome measures in interstitial lung disease: where to go from here?

Author: Kalluri, M., Luppi, F., Vancheri, A., Vancheri, C., Balestro, E., Varone, F., Mogulkoc, N., Cacopardo, G., Bargagli, E., Renzoni, E., Torrisi, S., Calvello, M., Libra, A., Pavone, M., Bonella, F., Cottin, V., Valenzuela, C., Wijsenbeek, M., Bendstrup, E., 3rd International Summit for ILD (ISILD), Erice collaborators listed below: Carlo Albera, Goksel, Altinisik, Kjetil, Ask, Elisabetta, Balestro, Elena, Bargagli, Elisabeth, Bendstrup, Marialuisa, Bocchino, Francesco, Bonella, Martina, Bonifazi, Giulia, Cacopardo, Maria, Calvello, Diego, M Castillo, Nazia, Chaudhuri, Ulrich, Costabel, Vincent, Cottin, Bruno, Crestani, Manuela, Funke-Chambour, Jack, Gauldie, Peter, M George, Johannes, C Grutters, Sergio, Harari, Richard, G Jenkins, Kerri, A Johannson, Mark, G Jones, Meena, Kalluri, Michael, P Keane, Maria, A Kokosi, Michael, Kreuter, Donato, Lacedonia, Brett, Ley, Alessandro, Libra, Fabrizio, Luppi, Toby, M Maher, George, A Margaritopoulos, Fernando, J Martinez, Jelle, Miedema, Nesrin, Mogulkoc, Maria, Molina-Molina, Philip, L Molyneaux, Julie, Morisset, Stefano, Palmucci, Mauro, Pavone, Ganesh, R Raghu, Elisabetta, A Renzoni, Luca, Richeldi, Gianluca, Sambataro, Alfredo, Sebastiani, Paolo, Spagnolo, Giulia Maria Stella, Martina, Sterclova, Irina, Strambu, Tomassetti, Sara, Sebastiano, Torrisi, Jacopo, Simonetti, Haluk, Turktas, Argyrios, Tzouvelekis, Claudia, Valenzuela, Ada, Vancheri, Carlo, Vancheri, Francesco, Varone, Patrizio, Vitulo, Athol, U Wells, Marlies, S Wijsenbeek, Wim, A Wuyts, Kalluri, M, Luppi, F, Vancheri, A, Vancheri, C, Balestro, E, Varone, F, Mogulkoc, N, Cacopardo, G, Bargagli, E, Renzoni, E, Torrisi, S, Calvello, M, Libra, A, Pavone, M, Bonella, F, Cottin, V, Valenzuela, C, Wijsenbeek, M, Bendstrup, E, Kalluri, M., Luppi, F., Vancheri, A., Vancheri, C., Balestro, E., Varone, F., Mogulkoc, N., Cacopardo, G., Bargagli, E., Renzoni, E., Torrisi, S., Calvello, M., Libra, A., Pavone, M., Bonella, F., Cottin, V., Valenzuela, C., Wijsenbeek, M., Bendstrup, E., and Bocchino, M.
Subjects: Pulmonary and Respiratory Medicine, medicine.medical_specialty, Concordance, Health Status, interstitial lung dieseases, MEDLINE, Medizin, Prom, 03 medical and health sciences, 0302 clinical medicine, Medicine, Humans, 030212 general & internal medicine, Patient Reported Outcome Measures, Intensive care medicine, business.industry, Minimal clinically important difference, Interstitial lung disease, respiratory system, medicine.disease, Idiopathic Pulmonary Fibrosis, female genital diseases and pregnancy complications, respiratory tract diseases, Clinical trial, patient reported outcomes, patient reported outcome measures, idiopathic pulmonary fibrosi, 030228 respiratory system, Patient-reported outcome, Computerized adaptive testing, Patient Participation, business, Lung Diseases, Interstitial
Abstract: Patient-reported outcome measures (PROMs), tools to assess patient self-report of health status, are now increasingly used in research, care and policymaking. While there are two well-developed disease-specific PROMs for interstitial lung diseases (ILD) and idiopathic pulmonary fibrosis (IPF), many unmet and urgent needs remain. In December 2019, 64 international ILD experts convened in Erice, Italy to deliberate on many topics, including PROMs in ILD. This review summarises the history of PROMs in ILD, shortcomings of the existing tools, challenges of development, validation and implementation of their use in clinical trials, and the discussion held during the meeting. Development of disease-specific PROMs for ILD including IPF with robust methodology and validation in concordance with guidance from regulatory authorities have increased user confidence in PROMs. Minimal clinically important difference for bidirectional changes may need to be developed. Cross-cultural validation and linguistic adaptations are necessary in addition to robust psychometric properties for effective PROM use in multinational clinical trials. PROM burden of use should be reduced through appropriate use of digital technologies and computerised adaptive testing. Active patient engagement in all stages from development, testing, choosing and implementation of PROMs can help improve probability of success and further growth.
Published: 2021

48. MUC5B promoter variant rs35705950 and rheumatoid arthritis associated interstitial lung disease survival and progression

Author: David A. Schwartz, Joanne J. van der Vis, Bruno Crestani, Marie-Christophe Boissier, Jan C. Grutters, Athina Trachalaki, Raphaël Porcher, Pierre-Antoine Juge, Thierry Schaeverbeke, Spyros Papiris, Nathalie Saidenberg-Kermanac’h, Catherine Boileau, Christophe Richez, Raphael Borie, Jorge Rojas-Serrano, Yurdagul Uzunhan, Theofanis Karageorgas, Montserrat I González-Pérez, Caroline Kannengiesser, Philippe Dieudé, Anna Jamnitski, Tracy J. Doyle, Leticia Kawano-Dourado, René-Marc Flipo, Dimitrios T. Boumpas, Enrique Ambrocio-Ortiz, Dominique Valeyre, Ramcés Falfán-Valencia, Ivette Buendía-Roldán, Joyce S. Lee, Joshua J. Solomon, Coline H.M. van Moorsel, Marie-Pierre Debray, Romain Garofoli, Paul J. Wolters, Lidwine Wemeau-Stervinou, Fabienne Louis-Sydney, Mayra Mejía, Katarina M. Antoniou, Effrosyni D. Manali, Prodromos Sidiropoulos, and Hilario Nunes
Subjects: Lung Diseases, Vital capacity, medicine.medical_specialty, Clinical Sciences, Rheumatoid Arthritis, Gastroenterology, Interstitial Lung Disease, MUC5B, Autoimmune Disease, Pulmonary function testing, Promoter Regions, Arthritis, Rheumatoid, Idiopathic pulmonary fibrosis, Rare Diseases, Rheumatology, Genetic, Interquartile range, Clinical Research, Internal medicine, Rheumatoid, medicine, Genetics, Humans, Risk factor, Promoter Regions, Genetic, Lung, Aged, Proportional hazards model, business.industry, Mortality rate, Arthritis, Inflammatory and immune system, Interstitial lung disease, respiratory system, medicine.disease, Mucin-5B, Idiopathic Pulmonary Fibrosis, respiratory tract diseases, Arthritis & Rheumatology, Anesthesiology and Pain Medicine, Respiratory, Public Health and Health Services, Female, business, Interstitial, Lung Diseases, Interstitial
Abstract: Background The major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD. Methods Through an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline. Results Out of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern. Conclusion In this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.
Published: 2021

49. [Telomeres and lung]

Author: C, Guérin, B, Crestani, C, Dupin, L, Kawano-Dourado, I, Ba, C, Kannengiesser, and R, Borie
Subjects: Vital Capacity, Humans, Nuclear Proteins, Cell Cycle Proteins, Telomere, Lung Diseases, Interstitial, Lung, Idiopathic Pulmonary Fibrosis
Abstract: Genetic studies of familial forms of interstitial lung disease (ILD) have led to the discovery of telomere-related gene (TRG) mutations (TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1, NOP10, NHP2, ACD, ZCCH8) in approximately 30% of familial ILD forms. ILD patients with TRG mutation are also subject to extra-pulmonary (immune-hematological, hepatic and/or mucosal-cutaneous) manifestations. TRG mutations may be associated not only with idiopathic pulmonary fibrosis (IPF), but also with non-IPF ILDs, including idiopathic and secondary ILDs, such as hypersensitivity pneumonitis (HP). The presence of TRG mutation may also be associated with an accelerated decline of forced vital capacity (FVC) or poorer prognosis after lung transplantation, notwithstanding which, usual ILD treatments may be proposed. Lastly, patients and their relatives are called upon to reduce their exposure to environmental lung toxicity, and are likely to derive benefit from specific genetic counseling and pre-symptomatic genetic testing.
Published: 2021

50. Diagnosis Yield and Safety of Surgical Biopsy in Interstitial Lung Diseases: A Prospective Study

Author: Anne Charpentier, Denis Debrosse, Pierre Mordant, Olivia Freynet, Hilario Nunes, Yves Castier, Emmanuel Martinod, Jean Pierre L'Huillier, Marie-Pierre Debray, Françoise Le Pimpec-Barthes, Martine Antoine, Karine Juvin, Dana M. Radu, Pierre-Yves Brillet, Jean-Marc Naccache, Vincent Lévy, Sebastian Tavolaro, Mohammad Zaahid Noorah, Patrice Guiraudet, Dominique Valeyre, Sadek Beloucif, Clairelyne Dupin, Aurélie Cazes, Dominique Israël-Biet, Yurdagul Uzunhan, Marianne Kambouchner, I. Honoré, Marouane Boubaya, Jalal Assouad, Laure Gibault, Marco Alifano, Bruno Crestani, and Pauline Pradère
Subjects: Pulmonary and Respiratory Medicine, High-resolution computed tomography, medicine.medical_specialty, Vital capacity, medicine.diagnostic_test, business.industry, Thoracic Surgery, Video-Assisted, Biopsy, Interstitial lung disease, Lung biopsy, medicine.disease, Surgery, Pulmonary function testing, Idiopathic pulmonary fibrosis, FEV1/FVC ratio, medicine, Humans, Prospective Studies, Cardiology and Cardiovascular Medicine, Prospective cohort study, business, Lung Diseases, Interstitial, Lung, Retrospective Studies
Abstract: Background Surgical lung biopsy is essential in the diagnostic algorithm of interstitial lung disease (ILD) of unknown cause. Safety concerns have been recently reiterated. The aim of this study was to prospectively assess the yield of diagnosis and safety of video-assisted thoracoscopic surgical lung biopsy (VATS-LB) for ILD diagnosis. Methods This prospective study, conducted in 6 ILD-referral Paris hospitals, included 103 patients with ILD. After initial multidisciplinary discussion, VATS-LB was proposed. A final diagnosis was made after the procedure, during a second multidisciplinary discussion. The main outcome was to determine the final diagnoses and their proportion after VATS-LB. Other outcomes were the percentage of change in diagnosis and treatment propositions after VATS-LB and adverse events during 3 months after surgery, postoperative pulmonary function, quality of life and pain. Results A definite diagnosis was reached in 87 cases (84.4%), while 16 remained unclassifiable (15.6%). Hypothesized diagnosis and treatment changed after VATS-LB in 65 (63.1%) and in 41 patients (39.8%), respectively. There was one death due to acute exacerbation. In-hospital complications were predicted by a lower preoperative distance at 6-minute walking test and by forced vital capacity lower than 77%. Postoperative quality of life was not modified at 3 months while forced vital capacity decreased slightly. Postoperative neuropathic pain was revealed in 5% and 2% patients at 1 and 3 months, respectively. Conclusions VATS-LB dramatically changed preoperative hypothetical diagnoses and treatment in ILD of unknown cause with good patient survival in ILD-referral centers.
Published: 2021

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