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Background and Objective: Chronic interstitial lung disease (ILD) occurs rarely with systemic lupus erythematosus (SLE) as compared with other connective tissue diseases. This multicentric retrospective study of patients with SLE-ILD from the OrphaLung and French SLE networks during 2005-2020 aimed to describe the characteristics of patients with SLE-ILD and analyse factors associated with prognosis., Methods: We analysed data for 89 patients with SLE-ILD (82 women, 92.1%) (median age at SLE diagnosis: 35 years [interquartile range 27-47]). All patients met the 2019 EULAR/ACR criteria for the diagnosis of SLE., Results: Forty two (47.2%) patients were positive for anti-ribonuclear protein antibodies and 45 (50.6%) for anti SSA/Ro antibodies. A total of 58 (65.2%) patients had another connective tissue disease: Sjögren's syndrome (n = 33, 37.1%), systemic sclerosis (n = 14, 15.7%), inflammatory myopathy (n = 6, 6.7%), or rheumatoid arthritis (n = 6, 6.7%). ILD was diagnosed along with SLE in 25 (28.1%) patients and at a median of 6 (0-14) years after the SLE diagnosis. The most frequent CT pattern was suggestive of non-specific interstitial pneumonia (n = 41, 46.0%) with or without superimposed organizing pneumonia. After a median follow-up of 86.5 [39.5-161.2] months, 18 (20.2%) patients had died and 6 (6.7%) underwent lung transplantation. The median 5-year and 10-year transplantation-free survival were 96% (92-100) and 87% (78-97). In total, 44 (49.4%) patients showed ILD progression. Cutaneous manifestations and Raynaud's phenomenon were associated with better survival. Only forced vital capacity was significantly associated with survival and ILD progression., Conclusion: ILD is a rare manifestation of SLE with good overall prognosis but with possible risk of ILD progression. Patients with SLE-ILD frequently have another connective tissue disease., (© 2024 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background and Objective: Variants in surfactant genes SFTPC or ABCA3 are responsible for interstitial lung disease (ILD) in children and adults, with few studies in adults., Methods: We conducted a multicentre retrospective study of all consecutive adult patients diagnosed with ILD associated with variants in SFTPC or ABCA3 in the French rare pulmonary diseases network, OrphaLung. Variants and chest computed tomography (CT) features were centrally reviewed., Results: We included 36 patients (median age: 34 years, 20 males), 22 in the SFTPC group and 14 in the ABCA3 group. Clinical characteristics were similar between groups. Baseline median FVC was 59% ([52-72]) and DLco was 44% ([35-50]). An unclassifiable pattern of fibrosing ILD was the most frequent on chest CT, found in 85% of patients, however with a distinct phenotype with ground-glass opacities and/or cysts. Nonspecific interstitial pneumonia and usual interstitial pneumonia were the most common histological patterns in the ABCA3 group and in the SFTPC group, respectively. Annually, FVC and DL CO declined by 1.87% and 2.43% in the SFTPC group, respectively, and by 0.72% and 0.95% in the ABCA3 group, respectively (FVC, p = 0.014 and DL CO , p = 0.004 for comparison between groups). Median time to death or lung transplantation was 10 years in the SFTPC group and was not reached at the end of follow-up in the ABCA3 group., Conclusion: SFTPC and ABCA3-associated ILD present with a distinct phenotype and prognosis. A radiologic pattern of fibrosing ILD with ground-glass opacities and/or cysts is frequently found in these rare conditions., (© 2024 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Shortened telomere lengths (TLs) can be caused by single nucleotide polymorphisms and loss-of-function mutations in telomere-related genes (TRG), as well as ageing and lifestyle factors such as smoking. Our objective was to determine if shortened TL is associated with interstitial lung disease (ILD) in individuals with rheumatoid arthritis (RA). This is the largest study to demonstrate and replicate that shortened peripheral blood leukocytes-TL is associated with ILD in patients with RA compared with RA without ILD in a multinational cohort, and short PBL-TL was associated with baseline disease severity in RA-ILD as measured by forced vital capacity percent predicted., Competing Interests: Competing interests: TJD reports grant funding and other support from Bristol Myers Squibb, Genentech, and Bayer and personal fees from Boehringer Ingelheim, unrelated to this study. PA-J reports personal fees from Bristol Myers Squibb, Boehringer Ingelheim, Astra-Zeneca and Medac unrelated to this study. MEW reports grant funding from Amgen, Bristol Myers Squibb, Eli Lilly; personal fees from Bristol Myers Squibb, Sanofi, and Eli Lilly, Abbvie, Arena Pharmaceuticals, CorEvitas, GlaxoSmithKline, Horizon Therapeutics, Pfizer, Scipher Medicine, and Setpoint Medical; and other funding from Scipher Medicine, Can-Fite Biopharma, Inmedix, and VersaPharm, unrelated to this study. NAS reports grant funding from Bristol Myers Squibb, Sanofi, Amgen, Crescendo Bioscience, Eli Lilly, and Mallinckrodt Pharmaceuticals and personal fees from Bristol Myers Squibb, unrelated to this study. RG receives grant support from Canon Medical Systems. HH reports grants from Canon Medical Systems, grants from Konica Minolta Inc, personal fees from Mitsubishi Chemical Co, personal fees from Canon Medical Systems Inc. MN reports grants from AstraZeneca, grants from Daiichi Sankyo, grants from Canon Medical Systems, grants from Merck investigator studies program, personal fees from Daiichi Sankyo, and personal fees from AstraZeneca. PFD has been a clinical investigator for Boehringer Ingelheim, Bristol Myers Squibb, and Genentech and currently works on an Advisory Committee for the FDA. JAS has received research support from Bristol Myers Squibb and performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, and Pfizer unrelated to this work. IOR reports grant funding from Genentech, unrelated to this study. KDD has received investigator-initiated grant funding from Janssen Research and Development and Pfizer, unrelated to this study; in addition, KDD reports serving as consultant for Inova Diagnostics, Inc., Bristol Myers Squibb and Exagen Diagnostics, and he has received free research assays from Inova Diagnostics, Inc., not used for this study; KDD has also received investigator-initiated grant from Janssen and Pfizer that are unrelated to this project. MKD has been the recipient of two investigator-initiated grants from Boehringer Ingelheim and Pfizer, unrelated to this research. PJW reports grants from Genentech, grants and personal fees for advisory board work from Boehringer Ingelheim and Sanofi, personal fees for advisory board work from Blade Pharmaceuticals, grants and personal fees for lectures from Pliant, outside the submitted work. JSL reports grants and other support from the NIH, Galapagos, Boehringer Ingelheim, United Therapeutics, Eleven P15, Bonac, Avalyn and the Pulmonary Fibrosis Foundation, outside the submitted work. PD reports grant funding and other support from Boehringer Ingelheim, Bristol Myers Squibb and Pfizer and personal fees from Bristol Myers Squibb, Sanofi, Lilly, Abbvie, Pfizer, Medac, Novartis, UCB Pharma and Boehringer Ingelheim, unrelated to this study. BC reports grant funding from Boehringer Ingelheim, Bristol Myers Squibb and Roche and personal fees from Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, GSK, Novartis, Rochen and Sanofi, unrelated to this study., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The tyrosine kinase inhibitor nintedanib has been recently approved for the treatment of Interstitial Lung Diseases (ILDs) that manifest a progressive fibrosis phenotype other than Idiopathic pulmonary Fibrosis (IPF). Nintedanib reduces the development of lung fibrosis in various animal models resembling features of PF-ILD and in vitro, it inhibits the fibrosing phenotype of human lung fibroblasts (HLFs) isolated from patients with IPF. To get insight on the cellular and molecular mechanisms that drive the clinical efficiency of nintedanib in patients with non-IPF PF-ILD, we investigated its effects on the fibrosing functions of HLFs derived from patients with PF-hypersensitivity pneumonitis (PF-HP, n = 7), PF-sarcoidosis (n = 5) and pleuroparenchymal fibroelastosis (PPFE, n = 4). HLFs were treated with nintedanib (10 nM-1 μM) and then stimulated with PDGF-BB (25-50 ng/ml) or TGF-β1 (1 ng/ml) for 24-72 h to assess proliferation and migration or differentiation. At nanomolar concentrations, nintedanib reduced the levels of PDGF receptor and ERK1/2 phosphorylation, the proliferation and the migration of PF-HP, PF-sarcoidosis and PPFE HLFs stimulated with PDGF-BB. Moreover, nintedanib also attenuates the myofibroblastic differentiation driven by TGF-β1 but only when it is used at 1 μM. The drug reduced the phosphorylation of SMAD2/3 and decreased the induction of collagen, fibronectin and α-smooth muscle actin expression induced by TGF-β1. In conclusion, our results demonstrate that nintedanib counteracts fundamental fibrosing functions of lung fibroblasts derived from patients with PF-HP, PF-sarcoidosis and PPFE, at concentrations previously reported to inhibit control and IPF HLFs. Such effects may contribute to its clinical benefit in patients suffering from these irreversible ILDs., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Laurent Vernhet reports financial support was provided by Boehringer Ingelheim Pharma GmbH & Co KG Biberach., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objectives: Interstitial lung disease (ILD) is a severe extra-articular manifestation of rheumatoid arthritis (RA). The objectives of this study were to estimate mortality rate in patients with RA-ILD and identify factors affecting mortality., Methods: Data from a French national claims database (Système National des Données de Santé) from 2013 to 2018 were analysed. Adults with an RA diagnosis (International Classification of Diseases (ICD)-10 codes M05, M06.0, M06.8 and M06.9) were included. ILD diagnosis was defined with ICD-10 code J84. Mortality rates were compared between patients with RA with and without ILD, using Cox proportional hazards regression, after matching 1:1 for age, sex, age at RA-ILD onset and RA duration., Results: Among 173 132 patients with RA, 4330 (3%) also had ILD (RA-ILD). After matching, RA-ILD was associated with an increased mortality rate (HR 3.4, 95% CI 3.1 to 3.9). The HR for mortality was greater for: patients aged <75 years (HR 4.8, 95% CI 3.9 to 5.9) versus ≥75 years (HR 3.0, 95% CI 2.6 to 3.5); patients with ILD onset occurring before RA onset (HR 8.4, 95% CI 5.5 to 13.0) versus ILD onset occurring after RA onset (HR 2.9, 95% CI 2.6 to 3.3); and men (HR 5.2, 95% CI 4.4 to 6.2) versus women (HR 3.6, 95% CI 3.0 to 4.2)., Conclusion: In this nationwide cohort study, RA-ILD was associated with increased mortality rate (vs in patients with RA without ILD), notably for those aged <75 years, those whose ILD preceded RA onset and men., Competing Interests: Competing interests: PA-J has received grant/research support from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Medac, Novartis, Roche Chugai and Societe Francaise de Rhumatologie; and consultancy fees from Bristol Myers Squibb. LW has received consultancy fees from Boehringer Ingelheim, Bristol Myers Squibb, Roche and Sanofi. SO has received consultancy fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Novartis, Roche-Chugai, SOBI and UCB. GD has received consultancy fees from Bristol Myers Squibb. JZ and VV-M are employees of and shareholders in Bristol Myers Squibb. R-MF has received speakers bureau fees from AbbVie, Bristol Myers Squibb, Eli Lilly, Janssen, Medac, Merck Sharp & Dohme, Novartis, Pfizer and Roche-Chugai; and grant/research support from Amgen, Janssen, Novartis and Pfizer. BC has received consultancy fees from Apellis, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Novartis, Roche and Sanofi; and grant/research support from Boehringer Ingelheim, Bristol Myers Squibb and Roche. PD has received consultancy fees from Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Eli Lilly, Medac, Novartis, Pfizer and Sanofi; and grant/research support from Bristol Myers Squibb, GlaxoSmithKline and Pfizer., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy., Methods: In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety., Findings: Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and -2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41-6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23-0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group., Interpretation: Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection., Competing Interests: Conflict of interest: A. Caille reports grants from French National Research Agency, outside the submitted work. P. Bonniaud reports grants from AstraZeneca, personal fees and non-financial (reimbursement for national and international conferences) support from Roche, Boehringer Ingelheim, AstraZeneca, Novartis, Sanofi and GSK, and non-financial support (reimbursement for national and international conferences) from Chiesi and Stallergene. R. Borie has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from Boehringer, Roche, Sanofi-Genzyme, Savara and Chiesi, outside the submitted work. J. Cadranel reports honoraria for educational events from Boehringer Ingelheim and Roche, outside the submitted work. B. Crestani has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from BMS, Boehringer Ingelheim, Roche, Apellis, Sanofi, Novartis, AstraZeneca and Chiesi, outside the submitted work; and has also received equipment/drugs or other services from Translate Bio. M-P. Debray has received or reimbursement for national and international conferences and educational events over the past 3 years from Boehringer Ingelheim and Roche, outside the submitted work. D. Israel-Biet reports consulting fees from Boehringer Ingelheim, honoraria for educational events from Boehringer Ingelheim and Roche, payments from Galapagos as a member of an adjudication committee, and support for attending meetings and/or travel from Boehringer Ingelheim, outside the submitted work. S. Jouneau has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from AIRB, Bellorophon Therapeutics, Biogen, Boehringer, Chiesi, Fibrogen, Galecto Biotech, Gilead, LVL, Novartis, Olam Pharm, Pfizer, Pliant Therapeutics, Roche, Sanofi-Genzyme and Savara. J-M. Naccache has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from AstraZeneca and Boehringer Ingelheim, outside the submitted work. L. Plantier has received fees, funding or reimbursement for national and international conferences, boards, expert or opinion groups, and research projects over the past 3 years from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Sanofi, Humanair and Arair, outside the submitted work. V. Valentin has received fees, funding or reimbursement for national and international conferences, and boards from Boehringer Ingelheim, outside the submitted work. L. Wémeau-Stervinou reports personal fees and non-financial (reimbursement for national and international conferences) support from Roche, Boehringer Ingelheim, Sanofi and BMS, outside the submitted work. V. Cottin reports grants, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Roche, personal fees from AstraZeneca, Boehringer Ingelheim, Celgene/BMS, MSD, CSL Behring, Galapagos, Galecto, Shionogi, Fibrogen, RedX, PureTech and Promedior, outside the submitted work. S. Marchand-Adam has received fees, funding or reimbursement for national and international conferences, and boards from Boehringer Ingelheim, Roche, BMS, Novartis, AstraZeneca, Pfizer, GSK and Chiesi, outside the submitted work. The remaining authors declare no competing interests., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

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.

Genetic predisposition to pulmonary fibrosis has been confirmed by the discovery of several gene mutations that cause pulmonary fibrosis. Although genetic sequencing of familial pulmonary fibrosis (FPF) cases is embedded in routine clinical practice in several countries, many centres have yet to incorporate genetic sequencing within interstitial lung disease (ILD) services and proper international consensus has not yet been established. An international and multidisciplinary expert Task Force (pulmonologists, geneticists, paediatrician, pathologist, genetic counsellor, patient representative and librarian) reviewed the literature between 1945 and 2022, and reached consensus for all of the following questions: 1) Which patients may benefit from genetic sequencing and clinical counselling? 2) What is known of the natural history of FPF? 3) Which genes are usually tested? 4) What is the evidence for telomere length measurement? 5) What is the role of common genetic variants (polymorphisms) in the diagnostic workup? 6) What are the optimal treatment options for FPF? 7) Which family members are eligible for genetic sequencing? 8) Which clinical screening and follow-up parameters may be considered in family members? Through a robust review of the literature, the Task Force offers a statement on genetic sequencing, clinical management and screening of patients with FPF and their relatives. This proposal may serve as a basis for a prospective evaluation and future international recommendations., Competing Interests: Conflict of interest: R. Borie reports grants from Boehringer Ingelheim, consulting fees from Sanofi, lecture honoraria from Boehringer Ingelheim, Roche and Sanofi, and travel support from Boehringer Ingelheim, outside the submitted work. K. Antoniou reports consulting fees from Boehringer Ingelheim, Roche and GlaxoSmithKline, lecture honoraria from Boehringer Ingelheim, Roche, Chiesi, Menarini, GlaxoSmithKline and AstraZeneca, outside the submitted work. F. Bonella reports lecture honoraria from Boehringer Ingelheim, Fujirebio, Galapagos NV and Roche, travel support from Boehringer Ingelheim and Roche, participation on advisory boards with Boehringer Ingelheim, BMS, Fujirebio, Galapagos NV, GlaxoSmithKline, Roche and Takeda, outside the submitted work. B. Crestani reports grants from BMS, Boehringer Ingelheim and Roche, consulting fees from Apellis, lecture honoraria from Boehringer Ingelheim, BMS, Roche, Sanofi, Novartis, AstraZeneca and Chiesi, and is in receipt of equipment from Translate Bio, outside the submitted work. A. Froidure reports grants and consulting fees from Boehringer Ingelheim, lecture honoraria from Boehringer Ingelheim and GlaxoSmithKline, and travel support from Sanofi, outside the submitted work. L. Galvin reports travel support from the European Lung Foundation, European Respiratory Society and European Pulmonary Fibrosis Federation, leadership roles with the European Pulmonary Fibrosis Federation, Irish Lung Fibrosis Association, European Lung Foundation and European Reference Network On Rare Respiratory Diseases, outside the submitted work. M. Griese reports grants and travel support from Boehringer Ingelheim, outside the submitted work. M. Molina-Molina reports grants from Roche and Boehringer Ingelheim, consulting fees from Esteve-Teijin, Ferrer, Roche and Boehringer Ingelheim, and lecture honoraria from Chiesi, Roche and Boehringer Ingelheim, outside the submitted work. V. Poletti reports lecture honoraria from AMBU, Boehringer Ingelheim, ERBE and Roche, outside the submitted work. E. Renzoni reports grants from Boehringer Ingelheim, and lecture honoraria from Boehringer Ingelheim, Roche and Novartis, outside the submitted work. C.H.M. van Moorsel reports grants from the European Respiratory Society supporting the present manuscript, grants and lecture honoraria from Boehringer Ingelheim, and a leadership role as co-chair of the European Respiratory Society Task Force for genetics in pulmonary fibrosis, outside the submitted work. All other authors have nothing to disclose., (Copyright ©The authors 2023. For reproduction rights and permissions contact permissions@ersnet.org.)

Patients with interstitial lung disease can develop a progressive fibrosing phenotype characterised by an irreversible, progressive decline in lung function despite treatment. Current therapies slow, but do not reverse or stop, disease progression and are associated with side-effects that can cause treatment delay or discontinuation. Most crucially, mortality remains high. There is an unmet need for more efficacious and better-tolerated and -targeted treatments for pulmonary fibrosis. Pan-phosphodiesterase 4 (PDE4) inhibitors have been investigated in respiratory conditions. However, the use of oral inhibitors can be complicated due to class-related systemic adverse events, including diarrhoea and headaches. The PDE4B subtype, which has an important role in inflammation and fibrosis, has been identified in the lungs. Preferentially targeting PDE4B has the potential to drive anti-inflammatory and antifibrotic effects via a subsequent increase in cAMP, but with improved tolerability. Phase I and II trials of a novel PDE4B inhibitor in patients with idiopathic pulmonary fibrosis have shown promising results, stabilising pulmonary function measured by change in forced vital capacity from baseline, while maintaining an acceptable safety profile. Further research into the efficacy and safety of PDE4B inhibitors in larger patient populations and for a longer treatment period is needed., Competing Interests: Conflict of interest: M. Kolb declares research funding for pre-clinical work from Boehringer Ingelheim and Pieris, and research funding for clinical work from Roche; consulting fees from Boehringer Ingelheim, Roche, Horizon, Cipla, AbbVie, Bellerophon, Algernon, CSL Behring, United Therapeutics and LabCorp; payment or honoraria from Roche, Novartis and Boehringer Ingelheim; payment for expert testimony from Roche; participation on a Data Safety Monitoring Board or Advisory Board for United Therapeutics and LabCorp; and received an allowance as the chief editor of the European Respiratory Journal. Conflict of interest: B. Crestani declares grants or contracts from Bristol-Myers Squibb, Boehringer Ingelheim and Roche; personal consulting fees from Apellis; payment or honoraria from Boehringer Ingelheim, Bristol-Myers Squibb, Roche, Sanofi, Novartis, AstraZeneca and Chiesi; and receipt of equipment, materials, drugs or other services from Translate Bio. Conflict of interest: T.M. Maher declares consulting fees from Boehringer Ingelheim, Roche/Genentech, AstraZeneca, Bayer, Blade Therapeutics, Bristol-Myers Squibb, Galapagos, Galecto, GlaxoSmithKline, IQVIA, Pliant, Respivant, Theravance and Veracyte; and payment or honoraria from Boehringer Ingelheim and Roche/Genentech., (Copyright ©The authors 2023.)

Background: Surgical lung biopsy is essential in the diagnostic algorithm of interstitial lung disease (ILD) of unknown cause. Safety concerns have been recently reiterated. This study prospectively assessed 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. VATS-LB was proposed after initial multidisciplinary discussion. 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 the operation, postoperative pulmonary function, quality of life, and pain., Results: A definite diagnosis was reached in 87 patients (84.4%), and 16 remained unclassifiable (15.6%). After VATS-LB, the hypothesized diagnosis changed in 65 patients (63.1%) and treatment changed in 41 patients (39.8%). One patient died of acute exacerbation. In-hospital complications were predicted by a shorter preoperative 6-minute walking test distance and by forced vital capacity lower than 77%. Postoperative quality of life was not modified at 3 months, whereas forced vital capacity decreased slightly. Postoperative neuropathic pain was revealed in 5% of patients at 1 month and in 2% at 3 months., Conclusions: VATS-LB dramatically changed preoperative hypothetical diagnoses and treatment in ILD of unknown cause, with good patient survival in ILD referral centers., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Patients at high risk of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) would benefit from being identified before the onset of respiratory symptoms; this can be done by screening patients with the use of chest high-resolution computed tomography (HRCT). Our objective was to develop and validate a risk score for patients who have subclinical RA-ILD., Methods: Our study included a discovery population and a replication population from 2 prospective RA cohorts (ESPOIR and TRANSLATE2, respectively) without pulmonary symptoms who had received chest HRCT scans. All patients were genotyped for MUC5B rs35705950. After multiple logistic regression, a risk score based on independent risk factors for subclinical RA-ILD was developed in the discovery population and tested for validation in the replication population., Results: The discovery population included 163 patients with RA, and the replication population included 89 patients with RA. The prevalence of subclinical RA-ILD was 19.0% and 16.9%, respectively. In the discovery population, independent risk factors for subclinical RA-ILD were presence of the MUC5B rs35705950 T allele (odds ratio [OR] 3.74 [95% confidence interval (95% CI) 1.37, 10.39]), male sex (OR 3.93 [95% CI 1.40, 11.39]), older age at RA onset (for each year, OR 1.10 [95% CI 1.04, 1.16]), and increased mean Disease Activity Score in 28 joints using the erythrocyte sedimentation rate (for each unit, OR 2.03 [95% CI 1.24, 3.42]). We developed and validated a derived risk score with receiver operating characteristic areas under the curve of 0.82 (95% CI 0.70-0.94) for the discovery population and 0.78 (95% CI 0.65-0.92) for the replication population. Excluding MUC5B rs35705950 from the model provided a lower goodness of fit (likelihood ratio test, P = 0.01)., Conclusion: We developed and validated a risk score that could help identify patients at high risk of subclinical RA-ILD. Our findings support an important contribution of MUC5B rs35705950 to subclinical RA-ILD risk., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background and Objective: 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., Methods: 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., Results: 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., Conclusion: 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., (© 2022 Asian Pacific Society of Respirology.)

Purpose of Review: 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., Recent Findings: 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., Summary: 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., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: 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., Methods: 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., Results: 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., Conclusions: SLB is associated with no serious complication or death and notably changes the diagnosis and treatment of interstitial lung disease., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: Interstitial lung disease associated with systemic sclerosis (SSc-ILD) is a frequent organ manifestation leading to high morbidity and mortality. In 2020, the European management recommendations for SSc-ILD were published. Despite being comprehensive, several questions could not be answered or no consensus was reached., Recent Findings: We highlight recent advances in the screening and early diagnosis, including surveys emphasizing that still 30-40% of all experts do not order baseline HRCTs in their SSc patients. We discuss recent advances in the assessment of disease progression, risk prediction and monitoring of SSc-ILD including novel insights in the disease course of SSc-ILD, clinical predictive factors for disease progression, the role of increasing extent of ILD on serial HRCT and radiomics, PET/CT and home spirometry as sensitive future tools to monitor SSc-ILD patients. We describe recent advances in the treatment of SSc-ILD, including novel data and trials as well as post hoc analyses of clinical trials on mycophenolate, cyclophosmphamide, tocilizumab, rituximab, riociguat and nintedanib. Lastly, we elucidate on peripheral blood cell gene expression profiling as a novel way to identify patients with a better treatment response to mycophenolate., Summary: In this review, we highlight recent advances in the management of SSc-ILD., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background and Objective: Data regarding interstitial lung disease (ILD) in the setting of systemic lupus erythematosus (SLE) are limited. We used a nationwide database to determine the incidence and the prevalence of ILD in SLE., Methods: Characteristics of all SLE inpatients admitted between 2011 and 2012 in France were analysed through the French medico-administrative database. Features associated with the presence of ILD were studied. Cox hazard model was used to measure the impact of ILD on survival from the first stay to 2020. The incidence of ILD in SLE was estimated by analysing the onset of ILD from 2013 to 2020 in SLE patients who had no evidence of ILD in 2013., Results: Between 2011 and 2012, 10,460 SLE patients had at least one hospital stay and could be traced until 2020. Among them, 134 (1.2%) had an ILD diagnosed at baseline. The frequency of ILD in SLE was higher in patients who had an associated autoimmune disease such as Sjögren's syndrome or systemic sclerosis (29.9% vs. 5.9%, p < 0.0001). ILD was associated with an increased risk of death in SLE in the multivariable analysis (hazard ratio [95% CI] 1.992 [1.420-2.794]; p < 0.0001). Among the 31,029 SLE patients with no evidence of ILD at baseline, ILD occurred in 795 (2.6%) between 2013 and 2020. The incidence rate of ILD in SLE was 10.26 for 1000 patient-years [95% CI: 10.24-10.28]., Conclusion: In SLE, ILD is exceedingly rare, often associated with another systemic autoimmune disorder and appears as a major risk factor for death., (© 2022 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Background: This American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Asociación Latinoamericana de Tórax 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.

Background and Objective: 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., Methods: 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., Results: 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., Conclusion: IPF is common among individuals with PARN mutation, but other ILD subtypes may be observed., (© 2022 Asian Pacific Society of Respirology.)

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., (© 2021 S. Karger AG, Basel.)

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)., (© 2021. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

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., Competing Interests: Declaration of Competing Interest PAJ reports personal fees from BMS, outside the submitted work. JSL reports grants from NIH, personal fees from Genentech, personal fees from Celgene outside the submitted work. RB reports grants and personal fees from Roche, grants and personal fees from Boerhinger Ingelheim, outside the submitted work. LWS reports personal fees and non-financial support from Roche, personal fees and non-financial support from Boehringer-Ingelheim, personal fees from Janssen-Cilag, personal fees from Bristol-Myers-Squibb, outside the submitted work. RMF reports grants and personal fees from Roche Chugai, grants and personal fees from Abbvie, personal fees from Bristol-Meyers Squibb, grants and personal fees from Pfizer, outside the submitted work. YU reports personal fees from Roche, personal fees from Bohringer Ingelheim, non-financial support from Oxyvie, outside the submitted work. DV reports personal fees from Roche, personal fees from Bohringer Ingelheim, personal fees from Astra Zenecca, outside the submitted work. PJW reports grants from Genentech, grants from Medimmune, outside the submitted work. DAS reports grants from NIH-NHLBI, grants from NIH-NHLBI, grants from NIH-NHLBI, grants from NIH-NHLBI, grants from DOD Focused Program Grant, during the conduct of the study; other from Eleven P15, Inc., personal fees from NuMedii, Inc., outside the submitted work. In addition, DAS has a patent Compositions and Methods of Treating or Preventing Fibrotic Diseases pending, a patent Biomarkers for the diagnosis and treatment of fibrotic lung disease pending, and a patent Methods and Compositions for Risk Prediction, Diagnosis, Prognosis, and Treatment of Pulmonary Disorders issued. BC reports grants from Apellis, grants and personal fees from Boehringer Ingelheim, personal fees from Astra Zeneca, grants from MedImmune, grants and personal fees from Roche, personal fees from Sanofi, outside the submitted work. PD reports grants from PFIZER, grants and personal fees from ROCHE, grants and personal fees from CHUGAI, grants and personal fees from BMS, personal fees from ABBVIE, personal fees from MSD, outside the submitted work. JS, CvM, RG, FLS, JRS, MIGP, MM, IBR, RFV, EAO, EM, SAP, TK, DB, KMA, PS, AT, JJvdV, AJ, JG, CK, HN, NSK, MCB, CR, TS, TD, MPD, CB and RP have nothing to disclose., (Copyright © 2021. Published by Elsevier Inc.)

Lysosomes are intracellular organelles that are responsible for degrading and recycling macromolecules. Lysosomal storage diseases (LSDs) are a group of inherited diseases caused by mutations affecting genes that encode the function of the lysosomal enzymes. Three LSDs are associated with lung involvement and/or interstitial lung disease (ILD): Gaucher disease (GD); Niemann-Pick disease, also known as acid sphingomyelinase deficiency (ASMD); and Fabry disease (FD). In GD and in ASMD, analysis of bronchoalveolar lavage fluid and lung biopsy can be informative, showing foamy cells. In GD, ILD is rare. Enzyme replacement therapy (ERT) has been available since 1991 and has greatly changed the natural history of GD, with pulmonary failure and death reported before the ERT era. In ASMD, ILD is frequent and is usually associated with spleen enlargement, low platelet cell count and low level of high-density lipoprotein-cholesterol. Results of ERT are promising regarding preliminary results of olipudase alfa in paediatric and adult ASMD populations. The most frequent respiratory manifestation in FD is COPD-like symptoms regardless of smoking habit and dyspnoea due to congestive heart failure. Early diagnosis of these three LSDs is crucial to prevent irreversible organ damage. Early initiation of ERT can, at least in part, prevent organ failure., Competing Interests: Conflict of interest: R. Borie reports grants and personal fees from Roche and Boehringer-Ingelheim, and personal fees from Sanofi-Genzyme and Savara, outside the submitted work. Conflict of interest: B. Crestani reports grants and personal fees from Boehringer-Ingelheim, personal fees from Roche, Sanofi, Apellis and AstraZeneca and grants from Medimmune, outside the submitted work. Conflict of interest: A. Guyart has nothing to disclose. Conflict of interest: O. Lidove reports personal fees from Amicus, Genzyme/Sanofi and Takeda/Shire, outside the submitted work., (Copyright ©The authors 2021.)

Question Addressed by the Study: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Fibrotic interstitial lung disease (ILD) is a common complication of RA. Whether MTX exposure increases the risk of ILD in patients with RA is disputed. We aimed to evaluate the association of prior MTX use with development of RA-ILD., Methods: Through a case-control study design with discovery and international replication samples, we examined the association of MTX exposure with ILD in 410 patients with chronic fibrotic ILD associated with RA (RA-ILD) and 673 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques., Results: Analysis of the discovery sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted OR 0.46, 95% CI 0.24-0.90; p=0.022), which was confirmed in the replication samples (pooled adjusted OR 0.39, 95% CI 0.19-0.79; p=0.009). The combined estimate using both the derivation and validation samples revealed an adjusted OR of 0.43 (95% CI 0.26-0.69; p=0.0006). MTX ever-users were less frequent among patients with RA-ILD compared to those without ILD, irrespective of chest high-resolution computed tomography pattern. In patients with RA-ILD, ILD detection was significantly delayed in MTX ever-users compared to never-users (11.4±10.4 years and 4.0±7.4 years, respectively; p<0.001)., Answer to the Question: Our results suggest that MTX use is not associated with an increased risk of RA-ILD in patients with RA, and that ILD was detected later in MTX-treated patients., Competing Interests: Conflict of interest: P-A. Juge has nothing to disclose. Conflict of interest: J.S. Lee reports grants from NIH, personal fees for advisory board work from Genentech and Celgene, outside the submitted work. Conflict of interest: J. Lau has nothing to disclose. Conflict of interest: L. Kawano-Dourado has nothing to disclose. Conflict of interest: J. Rojas-Serrano has nothing to disclose. Conflict of interest: M. Sebastiani has nothing to disclose. Conflict of interest: G. Koduri has nothing to disclose. Conflict of interest: E. Matteson has nothing to disclose. Conflict of interest: K. Bonfiglioli has nothing to disclose. Conflict of interest: M. Sawamura has nothing to disclose. Conflict of interest: R. Kairalla has nothing to disclose. Conflict of interest: L. Cavagna has nothing to disclose. Conflict of interest: E. Bozzalla Cassione has nothing to disclose. Conflict of interest: A. Manfredi has nothing to disclose. Conflict of interest: M. Mejia has nothing to disclose. Conflict of interest: P. Rodríguez-Henriquez has nothing to disclose. Conflict of interest: M.I. González Pérez has nothing to disclose. Conflict of interest: R. Falfán-Valencia has nothing to disclose. Conflict of interest: I. Buendia-Roldán has nothing to disclose. Conflict of interest: G. Pérez-Rubio has nothing to disclose. Conflict of interest: E. Ebstein reports personal fees from Sanofi, outside the submitted work. Conflict of interest: S. Gazal has nothing to disclose. Conflict of interest: R. Borie reports grants and personal fees for lectures from Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: S. Ottaviani has nothing to disclose. Conflict of interest: C. Kannengiesser has nothing to disclose. Conflict of interest: B. Wallaert reports grants and personal fees for advisory board work and meeting attendance from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: Y. Uzunhan reports personal fees from Roche and Boehringer Ingelheim, non-financial support from Oxyvie, outside the submitted work. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: D. Valeyre reports personal fees for advisory board work from Roche and Boehringer Ingelheim, personal fees for lectures from AstraZeneca, outside the submitted work. Conflict of interest: N. Saidenberg-Kermanac'h has nothing to disclose. Conflict of interest: M-C. Boissier has nothing to disclose. Conflict of interest: L. Wemeau-Stervinou reports personal fees for lectures and travel support from Roche, personal fees for lectures and advisory board work, and travel support from Boehringer-Ingelheim, personal fees for lectures from Janssen-Cilag and Bristol-Myers-Squibb, outside the submitted work. Conflict of interest: R.M. Flipo reports grants and personal fees from Roche Chugai, Abbvie and Pfizer, personal fees from Bristol-Meyers Squibb, outside the submitted work. Conflict of interest: S. Marchand-Adam reports fees for research, lectures, meeting attendance, consultancy and advisory board work from Roche, Boehringer Ingelheim and Novartis, outside the submitted work. Conflict of interest: P. Richette reports personal fees from Ipsen/Menarini, AstraZeneca, Savient and Grünenthal, outside the submitted work. Conflict of interest: Y. Allanore reports personal fees from Actelion, Bayer, Bristol-Myers Squibb, Boehringer and Inventiva, grants from Sanofi and Roche, outside the submitted work. Conflict of interest: C. Dromer has nothing to disclose. Conflict of interest: M-E. Truchetet has nothing to disclose. Conflict of interest: C. Richez has nothing to disclose. Conflict of interest: T. Schaeverbeke has nothing to disclose. Conflict of interest: H. Lioté has nothing to disclose. Conflict of interest: G. Thabut reports personal fees from AstraZeneca, outside the submitted work. Conflict of interest: K.D. Deane has nothing to disclose. Conflict of interest: J. Solomon has nothing to disclose. Conflict of interest: T. Doyle has nothing to disclose. Conflict of interest: J.H. Ryu has nothing to disclose. Conflict of interest: I. Rosas reports personal fees for advisory board work from Genentech, Boehringer and Three Lakes Partners, outside the submitted work. Conflict of interest: V.M. Holers reports grants from NIH/NIAID (U01 Grant), during the conduct of the study. Conflict of interest: C. Boileau has nothing to disclose. Conflict of interest: M-P. Debray reports personal fees and non-financial support for travel to meetings from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: R. Porcher has nothing to disclose. Conflict of interest: D.A. Schwartz reports grants from NIH-NHLBI (P01 HL092870, R01 HL097163, R33 HL120770 and UH2 HL123442) and DOD Focused Program (W81XWH-17-1-0597), during the conduct of the study; personal fees for consultancy and advisory board work from NuMedii, Inc., and is an employee of Eleven P15, Inc., outside the submitted work; and has a patent Compositions and Methods of Treating or Preventing Fibrotic Diseases pending, a patent Biomarkers for the Diagnosis and Treatment of Fibrotic Lung Disease pending, and a patent Methods and Compositions for Risk Prediction, Diagnosis, Prognosis, and Treatment of Pulmonary Disorders issued. Conflict of interest: R. Vassallo reports grants from Pfizer, Bristol-Myers-Squibb and SunPharma, outside the submitted work. Conflict of interest: B. Crestani reports grants from Apellis and MedImmune, grants and personal fees for lectures from Boehringer Ingelheim and Roche, personal fees for lectures from AstraZeneca and Sanofi, outside the submitted work. Conflict of interest: P. Dieudé reports fees for consultancy from Pfizer, Abbvie and MSD, grants and personal fees for consultancy and lectures from Roche, Chugai and BMS, outside the submitted work., (Copyright ©ERS 2021.)

Interstitial lung diseases (ILDs), which can arise from a broad spectrum of distinct aetiologies, can manifest as a pulmonary complication of an underlying autoimmune and connective tissue disease (CTD-ILD), such as rheumatoid arthritis-ILD and systemic sclerosis (SSc-ILD). Patients with clinically distinct ILDs, whether CTD-related or not, can exhibit a pattern of common clinical disease behaviour (declining lung function, worsening respiratory symptoms and higher mortality), attributable to progressive fibrosis in the lungs. In recent years, the tyrosine kinase inhibitor nintedanib has demonstrated efficacy and safety in idiopathic pulmonary fibrosis (IPF), SSc-ILD and a broad range of other fibrosing ILDs with a progressive phenotype, including those associated with CTDs. Data from phase II studies also suggest that pirfenidone, which has a different-yet largely unknown-mechanism of action, may also have activity in other fibrosing ILDs with a progressive phenotype, in addition to its known efficacy in IPF. Collectively, these studies add weight to the hypothesis that, irrespective of the original clinical diagnosis of ILD, a progressive fibrosing phenotype may arise from common, underlying pathophysiological mechanisms of fibrosis involving pathways associated with the targets of nintedanib and, potentially, pirfenidone. However, despite the early proof of concept provided by these clinical studies, very little is known about the mechanistic commonalities and differences between ILDs with a progressive phenotype. In this review, we explore the biological and genetic mechanisms that drive fibrosis, and identify the missing evidence needed to provide the rationale for further studies that use the progressive phenotype as a target population., Competing Interests: Competing interests: PS reports grants, personal fees, non-financial support and other from Boehringer Ingelheim, during the conduct of the study; grants, personal fees and non-financial support from Roche and PPM Services; and personal fees from Red X Pharma, Galapagos and Chiesi outside the submitted work. His wife is an employee of Novartis. OD reports personal fees from Boehringer Ingelheim, during the conduct of the study; grants and personal fees from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi; personal fees and non-financial support from Pfizer; and personal fees from Abbvie, Acceleron Pharma, Anamar, Amgen, Catenion, CSL Behring, ChemomAb, Ergonex, GSK, Inventiva, Italfarmaco, iQone, iQvia, Medac, Medscape, Menarini, Mepha, MSD, Lilly, Novartis, Roche, Sanofi, Target BioScience, UCB, Baecon Discovery, Blade Therapeutics, Curzion Pharmaceuticals and Glenmark Pharmaceuticals, outside the submitted work. In addition, OD has a patent US8247389, EP2331143 issued. CJR reports grants and personal fees from Boehringer Ingelheim and Hoffmann-La Roche, outside the submitted work. AT reports grants, personal fees, non-financial support and other from BI Hellas, during the conduct of the study; and other from Roche, outside the submitted work. In addition, AT has a patent for inhaled or aerosolised delivery of thyroid hormone to the lung as a novel therapeutic agent in fibrotic lung diseases issued. JSL reports grants from NIH and Boehringer Ingelheim, and personal fees from Boehringer Ingelheim, Galapagos, Celgene and Genentech, outside the submitted work. FB reports grants, personal fees and non-financial support from Boehringer Ingelheim, during the conduct of the study; grants, personal fees and non-financial support from Boehringer Ingelheim; personal fees and non-financial support from Savara, Bristol Myers Squibb and Roche; and personal fees from Galapagos, outside the submitted work. DB reports grants, personal fees, non-financial support and other from BI Hellas and other from Roche, outside the submitted work. A-MH-V reports personal fees, grants, non-financial support and other from Boehringer Ingelheim, personal fees and non-financial support from Actelion, personal fees from Bayer and Roche, outside the submitted work. BC reports personal fees and non-financial support from AstraZeneca, Sanofi and BMS; grants, personal fees and non-financial support from Boehringer Ingelheim and Roche; and personal fees from Genzyme, outside the submitted work. ELM reports personal fees from Boehringer Ingelheim, outside the submitted work., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Interstitial lung diseases (ILDs) can be caused by mutations in the SFTPA1 and SFTPA2 genes, which encode the surfactant protein (SP) complex SP-A. Only 11 SFTPA1 or SFTPA2 mutations have so far been reported worldwide, of which five have been functionally assessed. In the framework of ILD molecular diagnosis, we identified 14 independent patients with pathogenic SFTPA1 or SFTPA2 mutations. The present study aimed to functionally assess the 11 different mutations identified and to accurately describe the disease phenotype of the patients and their affected relatives., Methods: The consequences of the 11 SFTPA1 or SFTPA2 mutations were analysed both in vitro , by studying the production and secretion of the corresponding mutated proteins and ex vivo , by analysing SP-A expression in lung tissue samples. The associated disease phenotypes were documented., Results: For the 11 identified mutations, protein production was preserved but secretion was abolished. The expression pattern of lung SP-A available in six patients was altered and the family history reported ILD and/or lung adenocarcinoma in 13 out of 14 families (93%). Among the 28 SFTPA1 or SFTPA2 mutation carriers, the mean age at ILD onset was 45 years (range 0.6-65 years) and 48% underwent lung transplantation (mean age 51 years). Seven carriers were asymptomatic., Discussion: This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic SFTPA1 or SFTPA2 mutations share similar consequences for SP-A secretion in cell models and in lung tissue immunostaining, whereas they are associated with a highly variable phenotypic expression of disease, ranging from severe forms requiring lung transplantation to incomplete penetrance., Competing Interests: Conflict of interest: M. Legendre has nothing to disclose. Conflict of interest: A. Butt has nothing to disclose. Conflict of interest: R. Borie reports grants and personal fees from Boehringer Ingelheim and Roche, and personal fees from Savapharma, outside the submitted work. Conflict of interest: M-P. Debray has nothing to disclose. Conflict of interest: D. Bouvry has nothing to disclose. Conflict of interest: E. Filhol-Blin has nothing to disclose. Conflict of interest: T. Desroziers has nothing to disclose. Conflict of interest: V. Nau has nothing to disclose. Conflict of interest: B. Copin has nothing to disclose. Conflict of interest: F. Dastot Le Moal has nothing to disclose. Conflict of interest: M. Héry has nothing to disclose. Conflict of interest: P. Duquesnoy has nothing to disclose. Conflict of interest: N. Allou has nothing to disclose. Conflict of interest: A. Bergeron has nothing to disclose. Conflict of interest: J. Bermudez has nothing to disclose. Conflict of interest: A. Cazes has been invited to national and international meetings, and/or has received grants and/or personal fees for various activities from Boehringer Ingelheim and Roche, outside the submitted work. Conflict of interest: A-L. Chene has nothing to disclose. Conflict of interest: V. Cottin reports personal fees for lectures and advisory board work and non-financial support for meeting attendance from Actelion; grants, personal fees for lectures and advisory board work, and non-financial support for meeting attendance from Boehringer Ingelheim; personal fees for advisory board and data monitoring committee work from Bayer/MSD and Galapagos; personal fees for lectures and advisory board work from Novartis; personal fees for lectures, consultancy, data monitoring committee and steering committee work, and non-financial support for meeting attendance from Roche/Promedior; personal fees for lectures from Sanofi and AstraZeneca; personal fees for data monitoring committee work from Celgene and Galecto; and personal fees for advisory board work from Shionogi, outside the submitted work. Conflict of interest: B. Crestani has nothing to disclose. Conflict of interest: J-C. Dalphin has nothing to disclose. Conflict of interest: C. Dombret has nothing to disclose. Conflict of interest: B. Doray has nothing to disclose. Conflict of interest: C. Dupin reports personal fees for lectures and advisory board work, and non-financial support and meeting invitations from AstraZeneca; personal fees for lectures, non-financial support and meeting invitations from Boehringer and Novartis; personal fees for research and lectures, and non-financial support and meeting invitations from GSK; personal fees for lectures and meeting invitations from Chiesi; personal fees for lectures and advisory board work, and non-financial support from Sanofi; and personal fees, non-financial support and meeting invitations from Roche, outside the submitted work. Conflict of interest: V. Giraud has nothing to disclose. Conflict of interest: A. Gondouin has nothing to disclose. Conflict of interest: L. Gouya has nothing to disclose. Conflict of interest: D. Israël-Biet has nothing to disclose. Conflict of interest: C. Kannengiesser has nothing to disclose. Conflict of interest: A. Le Borgne has nothing to disclose. Conflict of interest: S. Leroy has nothing to disclose. Conflict of interest: E. Longchampt has nothing to disclose. Conflict of interest: G. Lorillon has nothing to disclose. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: C. Picard has nothing to disclose. Conflict of interest: M. Reynaud-Gaubert has nothing to disclose. Conflict of interest: J. Traclet has nothing to disclose. Conflict of interest: P. de Vuyst has nothing to disclose. Conflict of interest: A. Coulomb L'Hermine has nothing to disclose. Conflict of interest: A. Clement has nothing to disclose. Conflict of interest: S. Amselem has nothing to disclose. Conflict of interest: N. Nathan reports a 2018 AstraZeneca Mobility Grant from Société de pneumologie pédiatrique et d'allergologie (France), outside the submitted work., (Copyright ©ERS 2020.)

Purpose of Review: To provide an overview of recent studies that could be helpful in a better understanding of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and to facilitate the clinical management of this severe complication of RA., Recent Findings: The advances in deciphering the genetic architecture of RA-ILD support the hypothesis of RA-ILD as a complex disease with a complex phenotype encompassing at least the usual interstitial pneumonia (UIP) high-resolution CT pattern and non-UIP. Genetics studies have provided evidence for a shared genetic background in idiopathic pulmonary fibrosis (IPF) and RA-ILD, and more specifically RA-UIP, a disease with high morbidity and mortality. These findings support the rationale for common pathogenic pathways opening new avenues for future intervention in RA-ILD, notably with - drugs that proved active in IPF. In agreement, a recent controlled trial suggests efficacy of nintedanib, an antifibrotic drug, in patients with progressive lung fibrosis, including RA-ILD. However, there is a substantial gap in RA-ILD treatment, notably evaluating the effect of the RA treatments on the ILD course because of no controlled trial yet., Summary: The phenotypical, environmental, and genetic similarities between IPF and RA-ILD have led to a better understanding of the underlying pathogenesis of RA-ILD. Despite the identification of several biomarkers and useful screening tools, several questions remain unanswered regarding the identification of patients with RA at increased risk of ILD and risk of progression. Other substantial gaps are the lack of recommendations for how high-risk patients should be screened and which specific therapeutic strategy should be initiated. International collaborative efforts are needed to address these issues and develop specific recommendations for RA-ILD.

At least 10% of patients with pulmonary fibrosis, whether idiopathic or secondary, present heritable pulmonary fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 30% of those patients have an identified mutation mostly in telomere related genes (TRG) more rarely in surfactant homeostasis or other genes. TRG mutation may be associated with hematological and hepatic diseases that may worsen after lung transplantation requiring a specific care and adapted immunosuppression. Surfactant genes mutations are usually associated with ground-glass opacities and cysts on CT scan and may improve with steroids, hydroxychloroquine or azithromycin. Moreover relatives should benefit from a genetic analysis associated with a clinical evaluation according to the gene involved. Genetics of pulmonary fibrosis raise specific problems from diagnosis, therapy or genetic counseling varying from one gene to another., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Background: Progressive fibrosing interstitial lung disease (ILD) is rarely associated with antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). This study focused on the outcomes of ILD patients with associated AAV (AAV-ILD)., Methods: AAV-ILD (cases: microscopic polyangiitis (MPA) or granulomatosis with polyangiitis (GPA) with ILD) were compared to AAV patients without ILD (controls). ILD was defined as a usual interstitial pneumonia (UIP) or non-specific interstitial pneumonia (NSIP) pattern. Two controls were matched to each case for age (>or ≤65 years), ANCA status (PR3-or MPO-positive) and creatininemia (≥or <150 μmol/L)., Results: Sixty-two cases (89% MPO-ANCA+) were included. Median age at AAV diagnosis was 66 years. ILD (63% UIP), was diagnosed before (52%) or simultaneously (39%) with AAV. Cases versus 124 controls less frequently had systemic vasculitis symptoms. One-, 3- and 5-year overall survival rates, respectively, were: 96.7%, 80% and 66% for cases versus 93.5%, 89.6% and 83.8% for controls (p = 0.008). Multivariate analyses retained age >65 years (hazard ratio (HR) 4.54; p < 0.001), alveolar haemorrhage (HR 2.25; p = 0.019) and UIP (HR 2.73; p = 0.002), but not immunosuppressant use, as factors independently associated with shorter survival., Conclusion: For AAV-ILD patients, only UIP was associated with poorer prognosis. Immunosuppressants did not improve the AAV-ILD prognosis. But in analogy to idiopathic pulmonary fibrosis, anti-fibrosing agents might be useful and should be assessed in AAV-ILD patients with a UIP pattern., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Interstitial lung diseases (ILDs) are a set of heterogeneous lung diseases characterised by inflammation and, in some cases, fibrosis. These lung conditions lead to dyspnoea, cough, abnormalities in gas exchange, restrictive physiology (characterised by decreased lung volumes), hypoxaemia and, if progressive, respiratory failure. In some cases, ILDs can be caused by systemic diseases or environmental exposures. The ability to treat or cure these ILDs varies based on the subtype and in many cases lung transplantation remains the only curative therapy. There is a growing body of evidence that both common and rare genetic variants contribute to the development and clinical manifestation of many of the ILDs. Here, we review the current understanding of genetic risk and ILD., Competing Interests: Conflict of interest: R. Borie reports personal fees and non-financial support from Roche, and Boehringer Ingelheim, outside the submitted work. Conflict of interest: P. Le Guen has nothing to disclose. Conflict of interest: M. Ghanem has nothing to disclose. Conflict of interest: C. Taillé has received personal fees and other funding from AstraZeneca and Roche, personal fees from Teva and Genzyme, grants, personal fees and other from GlaxoSmithKline, Novartis and Sanofi, and other funding from Boehringer Ingelheim. Conflict of interest: C. Dupin reports personal fees, non-financial support and other from AstraZeneca, Boehringer, GlaxoSmithKline and Novartis, personal fees and other from Chiesi, personal fees from Sanofi, and non-financial support and other from Roche, outside the submitted work. Conflict of interest: P. Dieudé has nothing to disclose. Conflict of interest: C. Kannengiesser has nothing to disclose. Conflict of interest: B. Crestani reports personal fees from AstraZeneca, grants, personal fees and non-financial support from Boehringer Ingelheim and Roche, personal fees and non-financial support from Sanofi, and grants from Novartis, outside the submitted work., (Copyright ©ERS 2019.)

Regulator of telomere length 1 ( RTEL1 ) mutations have been evidenced in 5-9% of familial pulmonary fibrosis; however, the phenotype of patients with interstitial lung disease (ILD) and RTEL1 mutations is poorly understood.Whole exome sequencing was performed in 252 probands with ILD and we included all patients with ILD and RTEL1 mutation. RTEL1 expression was evaluated by immunochemistry in the lungs of controls, as well as in RTEL1 and telomerase reverse transcriptase ( TERT ) mutation carriers.We identified 35 subjects from 17 families. Median age at diagnosis of ILD was 53.1 years (range 28.0-80.6). The most frequent pulmonary diagnoses were idiopathic pulmonary fibrosis (n=20, 57%), secondary ILD (n=7, 20%) and unclassifiable fibrosis or interstitial pneumonia with autoimmune features (n=7, 20%). The median transplant-free and overall survival periods were 39.2 months and 45.3 months, respectively. Forced vital capacity at diagnosis was the only factor associated with decreased transplant-free survival. Extra-pulmonary manifestations were less frequent as compared to other telomere-related gene mutation carriers. A systematic analysis of the literature identified 110 patients with ILD and RTEL1 mutations (including this series) and confirmed the heterogeneity of the pulmonary phenotype, the prevalence of non-idiopathic diseases and the low prevalence of extra-pulmonary manifestations.Immunohistochemistry showed that RTEL1 was expressed by bronchial and alveolar epithelial cells, as well as by alveolar macrophages and lymphocytes, but not by fibroblasts., Competing Interests: Conflict of interest: R. Borie reports grants and personal fees from Roche, personal fees from Boerhinger Ingelheim and Savapharma, outside the submitted work. Conflict of interest: D. Bouvry has nothing to disclose. Conflict of interest: V. Cottin reports personal fees for consultancy, lecturing and travel to medical meetings from Actelion and Roche, personal fees for development of educational presentations, consultancy, lecturing and travel to medical meetings from Boehringer Ingelheim, personal fees for consultancy from Bayer and GSK, personal fees for adjudication committee work from Gilead, personal fees for consultancy and travel to medical meetings from MSD, personal fees for consultancy and lecturing from Novartis and Sanofi, institutional grants from Boehringer Ingelheim and Roche, personal fees for data and safety monitoring board work from Promedior and Celgene, personal fees for consultancy and data and safety monitoring board work from Galapagos, outside the submitted work. Conflict of interest: C. Gauvain has nothing to disclose. Conflict of interest: A. Cazes has nothing to disclose. Conflict of interest: M-P. Debray reports personal fees from Boehringer-Ingelheim, and reimbursement for travel and accommodation for medical meeting for Guerbet and Roche, outside the submitted work. Conflict of interest: J. Cadranel has nothing to disclose. Conflict of interest: P. Dieude has nothing to disclose. Conflict of interest: T. Degot reports personal fees for expert testimony in ILD and travel reimbursement for the Congress CPLF 2018 in Lyon from Boerhinger Ingelheim France, and personal fees for expert testimony in ILD from Roche France, outside the submitted work. Conflict of interest: S. Dominique reports personal fees from Roche and Boehringer Ingelheim, outside the submitted work. Conflict of interest: A.S. Gamez has nothing to disclose. Conflict of interest: M. Jaillet has nothing to disclose. Conflict of interest: P-A. Juge has nothing to disclose. Conflict of interest: A. Londono-Vallejo has nothing to disclose. Conflict of interest: A. Mailleux has nothing to disclose. Conflict of interest: H. Mal has nothing to disclose. Conflict of interest: C. Boileau has nothing to disclose. Conflict of interest: C. Menard has nothing to disclose. Conflict of interest: H. Nunes has nothing to disclose. Conflict of interest: G. Prevot has nothing to disclose. Conflict of interest: S. Quetant has nothing to disclose. Conflict of interest: P. Revy has nothing to disclose. Conflict of interest: J. Traclet has nothing to disclose. Conflict of interest: L. Wemeau-Stervinou reports personal fees and non-financial support from Boehringer-Ingelheim and Roche, personal fees from Bristol-Myers-Squibb and Jansen-Cilag, outside the submitted work. Conflict of interest: M. Wislez has nothing to disclose. Conflict of interest: C. Kannengiesser has nothing to disclose. Conflict of interest: B. Crestani reports grants for research and personal fees for development of educational presentations, consultancy, lecturing and travel to medical meetings from Boehringer Ingelheim, grants for research and personal fees for consultancy, lecturing and travel to medical meetings from Roche, personal fees for consultancy and lecturing from Sanofi and Apellis, personal fees for consultancy, lecturing and travel to medical meetings from AstraZeneca, and research grants from MedImmune, outside the submitted work., (Copyright ©ERS 2019.)

Background: Given 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., Methods: Using 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., Results: Analysis 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., Conclusions: We 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.).

We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Despite its high prevalence and mortality, little is known about the pathogenesis of rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA-ILD frequently share the usual pattern of interstitial pneumonia and common environmental risk factors, we hypothesised that the two diseases might share additional risk factors, including FPF-linked genes. Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD.We used whole exome sequencing (WES), followed by restricted analysis of a discrete number of FPF-linked genes and performed a burden test to assess the excess number of mutations in RA-ILD patients compared to controls.Among the 101 RA-ILD patients included, 12 (11.9%) had 13 WES-identified heterozygous mutations in the TERT , RTEL1 , PARN or SFTPC coding regions . The burden test, based on 81 RA-ILD patients and 1010 controls of European ancestry, revealed an excess of TERT , RTEL1 , PARN or SFTPC mutations in RA-ILD patients (OR 3.17, 95% CI 1.53-6.12; p=9.45×10 -4 ). Telomeres were shorter in RA-ILD patients with a TERT , RTEL1 or PARN mutation than in controls (p=2.87×10 -2 ).Our results support the contribution of FPF-linked genes to RA-ILD susceptibility., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at erj.ersjournals.com, (Copyright ©ERS 2017.)

At least 10% of patients with interstitial lung disease present monogenic lung fibrosis suspected on familial aggregation of pulmonary fibrosis, specific syndromes or early age of diagnosis. Approximately 25% of families have an identified mutation in genes mostly involved in telomere homeostasis, and more rarely in surfactant homeostasis.Beyond pathophysiological knowledge, detection of these mutations has practical consequence for patients. For instance, mutations involved in telomere homeostasis are associated with haematological complications after lung transplantation and may require adapted immunosuppression. Moreover, relatives may benefit from a clinical and genetic evaluation that should be specifically managed.The field of genetics of pulmonary fibrosis has made great progress in the last 10 years, raising specific problems that should be addressed by a specialised team., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at err.ersjournals.com, (Copyright ©ERS 2017.)

Purpose of Review: Familial pulmonary fibrosis has long been recognized and suggests that pulmonary fibrosis may have a genetic origin in some cases with an autosomal dominant transmission., Recent Findings: Mutations in the telomerase complex and in the surfactant pathways have been discovered in the last decade. Almost 20% of the cases of familial pulmonary fibrosis are related to known functional mutations in one of these systems. A polymorphism in the promoter of the MUC5B gene has been associated with both sporadic and familial forms of idiopathic pulmonary fibrosis; however, the impact of this association remains to be determined., Summary: These genes point to alveolar epithelium injury and repair as a major component of the fibrotic process.

Objectives: Consensus is lacking on the immunological tests to perform for diagnosis of interstitial lung diseases (ILDs). In particular, the value of detecting anti-SSA antibody in this context is unknown. We aimed to determine whether the detection of anti-SSA antibody in patients with ILD can identify a subgroup of patients with CTD., Methods: We compared the characteristics of patients with newly diagnosed apparently idiopathic ILD with anti-SSA antibody [anti-SSA(+) group] and without anti-SSA antibody (control group). RESULTS; Anti-SSA(+) patients (n = 15) more often had extra-respiratory signs (xerostomia and ocular dryness), auto-immune features, a CT scan pattern of non-specific interstitial pneumonia and more severe lung function alteration than controls (n = 30). Of patients who were anti-SSA(+), 2 met the criteria for SS and 13 (86%) of 15 met the criteria for the diagnosis of undifferentiated CTD., Conclusions: Our results suggest that identification of anti-SSA antibody in patients with early ILD can reveal a specific subgroup of patients with more ground glass opacity and more severe lung function impairment than those without anti-SSA antibody.