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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.

Emphysema is a chronic respiratory disorder characterized by destruction of alveoli, usually due to cigarette smoking or exposure to noxious particles or gases. Dysfunction of proteins that are involved in lung development and maintenance, such as alpha-1 antitrypsin, also contributes to emphysema. Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton reorganization. Mutations in the FLNA gene classically lead to abnormal neuronal migration and connective and vascular tissue anomalies. Pulmonary manifestations consist of a wide range of pulmonary disorders that occur during infancy. We report the first familial case of emphysema in non- and very low-smoking adults who carry a loss-of-function mutation of the FLNA gene. The identification of this new risk factor for emphysema encourages (1) screening, prevention and monitoring of pulmonary disorders in patients with FLNA mutation and (2) screening for FLNA mutation in patients with early-onset emphysema that is associated with low-smoking or vascular or connective tissue anomalies.

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.

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.

SARS‐Cov2 outbreak has deeply impacted French lung transplant programs by the decreased number of lung donors, the scarcity of intensive care unit (ICU) beds and most importantly, the assumed worse prognosis of Covid‐19 in recipients during perioperative period. Despite no evidence has been published to suggest that lung transplant recipients were at high‐risk of acquiring the virus or developing severe Covid‐19, immunosuppression may worsen the prognosis of such infection in patient transplanted for end‐staged lung diseases.

Poly(A)-specific ribonuclease (PARN) mutations have been associated with familial pulmonary fibrosis. However, the phenotype of patients with interstitial lung disease (ILD) and PARN mutations is poorly described. We performed a retrospective, observational, non-interventional study. All the patients with an ILD diagnosis and a pathogenic heterozygous PARN mutation, followed in one of the OrphaLung center, were included. We included 30 patients (24 patients from 11 kindreds and 6 sporadic patients with early onset of ILD or extra-pulmonary phenotype). The median age at diagnosis of ILD was 59 years (range 54 - 64). Twenty-three patients (77 %) had a smoking history and/or a fibrogenic exposure. The pulmonary phenotypes were heterogenous but the most frequent diagnosis was idiopathic pulmonary fibrosis (IPF; n=15, 50%). Hematological abnormalities were identified in 3 patients and liver disease in 2 patients. Twenty-one patients received a specific treatment for ILD: steroids (n=13), antifibrotic (n= 11), immunosuppressants (n=5) and N-acetyl cysteine (n=2). The median decline of FVC for the whole population was 292 ml/year (range 146 - 657). After a median follow-up of 2.8 years 8 patients had died and 6 had undergone lung transplantation. The median transplantation-free survival was 4.5 years. PARN mutation carriers were older, and extra-pulmonary manifestations were less frequent as compared to TERT or TERC mutation carriers. PARN mutations are most frequently associated with IPF, but other ILD may be observed. Such phenotypic heterogeneity requires a thorough evaluation of PARN-associated ILD patients in order to define tailored therapeutic strategies.

Emphysema is a chronic respiratory disorder characterized by destruction of alveoli, usually due to cigarette smoking or exposure to noxious particles or gases. Dysfunction of proteins that are involved in lung development and maintenance, such as alpha-1 antitrypsin, also contributes to emphysema. Filamin A (FLNA) is an actin-binding protein involved in cytoskeleton reorganization. Mutations in the FLNA gene classically lead to abnormal neuronal migration and connective and vascular tissue anomalies. Pulmonary manifestations consist of a wide range of pulmonary disorders that occur during infancy. We report the first familial case of emphysema in non- and very low-smoking adults who carry a loss-of-function mutation of the FLNA gene. The identification of this new risk factor for emphysema encourages (1) screening, prevention and monitoring of pulmonary disorders in patients with FLNA mutation and (2) screening for FLNA mutation in patients with early-onset emphysema that is associated with low-smoking or vascular or connective tissue anomalies.

Resume Parmi toutes les formes de pneumopathies interstitielles diffuses, la fibrose pulmonaire idiopathique tient une place a part dans la pratique pneumologique, principalement du fait de la rapidite de son evolution conduisant au deces et de l’absence d’efficacite des traitements jusqu’a peu essayes. La definition de la fibrose pulmonaire idiopathique a ete considerablement remaniee au cours des vingt dernieres annees aboutissant a un diagnostic plus restreint et plus homogene ouvrant la voie a l’elaboration d’essais randomises d’excellente qualite methodologique. La strategie anti-inflammatoire et immunomodulatrice qui avait longtemps ete exploree s’est averee non seulement inefficace, mais parfois meme deletere dans cette maladie. Le developpement et la commercialisation en quelques annees de deux molecules antifibrotiques (la pirfenidone et le nintedanib) qui permettent de ralentir le declin de la fonction respiratoire representent un pas en avant. Certaines pneumopathies interstitielles diffuses associees aux connectivites partagent de nombreux traits communs avec la fibrose pulmonaire idiopathique et certains patients ne repondent pas aux traitements immunosuppresseurs classiquement efficaces. Ces nouvelles voies therapeutiques representent des axes de recherche pertinents pour ces situations.

Introduction La pirfenidone, indiquee dans le traitement de la fibrose pulmonaire idiopathique (FPI), est desormais disponible sous forme de comprimes (nouvelle formulation disponible le 1er avril 2018) ou de gelules. L’objectif de cette etude est de decrire la tolerance, les arrets de traitement et le taux de substitution entre les deux formulations (gelules/comprimes) en France. Methodes Une analyse retrospective de donnees issues de la cohorte RaDiCo-PID (Rare Disease Cohorts — Pneumopathies Interstitielles Diffuses), financee par l’ANR (Agence Nationale de la Recherche) et geree en utilisant l’application REDCap, chez des patients (pts) atteints de FPI ayant recu au moins une dose de pirfenidone (1 juillet 2017–30 juin 2019) a ete realisee. Resultats Parmi les 288 pts traites par la pirfenidone, 162 l’avaient nouvellement initiee sur la periode d’observation. Dans la population des patients traites par la pirfenidone pendant la periode de substitution, apres le 1er avril 2018 (n = 256), les caracteristiques des patients (sexe, âge a l’inclusion/au diagnostic) par type de formulation etaient homogenes. Au total, 44,9 % (IC95 % : 38,8–51,0) des patients sont passes de la gelule au comprime et 4,7 % (IC95 % : 2,10–7,28) du comprime a la gelule. Dans l’ensemble, la duree moyenne du traitement a ete de 21,5 mois (±18,7) et la mediane (Q1 ; Q3) de 16,2 mois [6,3 ; 29,3] avec une dose moyenne de 2106,7 (±460,7) mg/jour. Pres de la moitie des patients (119/256, 46,5 %) ont definitivement arrete le traitement, pour intolerance (81/119 pts, 68,1 %) ou inefficacite (21/119 pts, 10,1 %). Le taux d’arrets de traitement definitifs etait de 36,1 % (IC95 % : 27,5–44,8) dans le groupe « substitution », 45,8 % (IC95 % : 36,9–54,8) dans le groupe « comprimes » et 60,7 % (IC95 % : 51,9–69,5) dans le groupe « gelules uniquement ». Le temps median jusqu’a l’arret de la pirfenidone dans les 3 groupes est presente dans la Fig. 1 . Des evenements indesirables ont ete rapportes chez 112 patients (39 %) dont des evenements indesirables graves (hospitalisations) chez 5 patients (4,9 %). Conclusion Cette etude presente des donnees de vie reelle chez des patients atteints de FPI traites par une seule formulation de la pirfenidone ou ayant eu une substitution entre les deux formulations (gelules ou comprimes). Ces observations suggerent une bonne tolerance de la formulation « comprimes » avec moins d’arrets de traitements et une duree de traitement plus longue par rapport aux gelules.

Introduction La fibrose pulmonaire idiopathique (FPI) a pour principaux symptomes la dyspnee et la toux qui alterent la qualite de vie. Les traitements anti-fibrotiques permettent de ralentir l’evolution de la maladie mais leurs effets sur la symptomatologie n’ont pas ete evalues. L’objectif de cette etude exploratoire etait de decrire l’evolution de la dyspnee, de la toux et de la qualite de vie a 3 et 6 mois de l’introduction d’un traitement anti-fibrotique. Methodes Nous avons mene une etude prospective au centre hospitalier universitaire de Lille chez des patients presentant une FPI de diagnostic recent avec instauration d’un traitement anti-fibrotique. Nous avons mesure, a l’aide de questionnaires, la dyspnee (EVA, Borg, Multidimensional Dyspnea Profile MDP, mMRC, BDI/TDI), la toux (EVA, Leicester Cough Questionnaire [LCQ]) et la qualite de vie (HAD, K-BILD) a l’introduction du traitement, a 3 mois et a 6 mois. Resultats Douze patients ont ete inclus. La dyspnee de repos (EVA) et d’effort (Borg au test de marche de 6 minutes) etaient des symptomes frequents a l’etat de base (33 % et 75 %) et semblaient stables apres 3 et 6 mois de traitement. L’intensite de la dyspnee etait notable au cours des efforts de la vie quotidienne et se majorait a 3 mois (MDP-QS : +3 points, DIQ [0–4], p = 0,055). L’impact de la dyspnee qui etait majeur sur l’activite physique (mMRC ≥ 2 chez 42 % des patients et BDI a 6) et sur la qualite de vie (K-BILD a 64,5 % dont dimension dyspnee et activite a 58,3 %) persistait a 3 et a 6 mois. La toux etait frequente (67 %) avec un impact leger sur la qualite de vie (LCQ a 15,3, DIQ [13,2–19,3]) et n’evoluait pas a 3 et 6 mois. La symptomatologie depressive (HAD-D) semblait s’aggraver a 3 mois (+1,5 points ; DIQ [0–4] ; p = 0,047) et persistait a 6 mois. Les effets indesirables des traitements anti-fibrotiques etaient frequents (50 % a 3 mois et 71 % a 6 mois) avec notamment un amaigrissement significatif a 6 mois (−4 kg ; DIQ [−4 a −3] ; p = 0,016). Conclusion Ces donnees exploratoires suggerent l’absence d’amelioration de la dyspnee et de la toux dans la FPI sous traitement anti-fibrotique et donc l’interet d’une prise en charge specifique symptomatique precoce. Par ailleurs, elles mettent en evidence l’interet du questionnaire MDP par rapport aux questionnaires existants pour juger de l’evolution de la dyspnee au cours de la FPI.

Introduction RaDiCo est un programme national du Plan d’investissement d’Avenir, developpe a l’Inserm U933, soutenu par l’ANR, et dedie a la construction et a l’analyse de cohortes de patients atteints de maladies rares [1] . Depuis 2015, en partenariat avec les centres de competences, de References et les filieres dediees aux pathologies hebergees, RaDiCo construit, enrichit et analyse des collections de donnees en vie reelle. Parmi les 13 cohortes RaDiCo longitudinales, RaDiCo-PID concerne les pneumopathies interstitielles diffuses (PID) de l’enfant et de l’adulte. Elle est active depuis 2017 avec entre autres objectifs, ameliorer le diagnostic et la prise en charge des patients. Niches dans cette cohorte, plusieurs projets de recherches specifiques relatifs a la fibrose pulmonaire idiopathique (FPI) (la plus frequente des PID) sont en cours. Cette affection est irreversible avec un envahissement fibreux du tissu pulmonaire apres 60 ans. Deux molecules anti-fibrosantes recommandees en ralentissent la progression [2] . Methode Criteres d’inclusion : patients âges de plus de 18 ans avec une FPI confirmee, depuis moins de trois ans avant l’inclusion (criteres internationaux ATS/ERS 2011 [3] ). Collecte des donnees anonymisees sur la plateforme Inserm RaDiCo, RGPD compatible, via REDcap, application web securisee avec une interface intuitive et controle qualite du circuit des donnees. Resultats Apres 2 ans d’inclusion, 1259 patients PID ont ete inclus dans 18 centres francais ( Fig. 1 ), 66 % sont des FPI ; 666 patients repondaient aux criteres d’inclusion dont 54 % de cas incidents (diagnostic Fig. 2 ) avec 82 % d’hommes, citadins (63 %), de 72 ± 9 ans. A l’inclusion, l’IMC moyen etait de 27 ± 4 kg/m2 ( Tableau 1 ), la CVF moyenne predite etait de 80 ± 19 % et la DLCO moyenne predite de 47 ± 17 % ( Tableau 2 ). A l’inclusion, 205 patients (31 %) ont ete traites par du nintedanib, 189 patients (29 %) par de la pirfenidone, 235 patients (35 %) n’etaient pas sous anti-fibrosant ( Tableau 3 ). Conclusion La cohorte RaDiCo-PID est tres active avec un grand nombre de patients inclus au debut de leur maladie ce qui va permettre de suivre leur progression. Les effectifs actuels permettent d’envisager des analyses plus approfondies sur des questions specifiques et non specifiques encore peu abordees.

Introduction Des mutations de Poly(A)-specific ribonuclease (PARN) ont ete associees a des cas familiaux de fibrose pulmonaire. Le phenotype des patients presentant une pneumopathie interstitielle diffuse (PID) et une mutation de PARN est cependant mal decrit. Methodes Nous avons realise une etude retrospective, observationnelle, non interventionnelle. Tous les patients avec une PID et une mutation de PARN, suivis dans les centres du reseau OrphaLung, ont ete inclus. Resultats Vingt patients, issus de 12 familles, ont ete inclus. L’âge median lors du diagnostic de PID etait de 58,8 ans (ecart interquartile [IQR] de 52,8 a 64,5 ans). Les diagnostics les plus frequents etaient : fibrose pulmonaire idiopathique (FPI ; n = 8 ; 40 %) et fibrose inclassable (n = 5 ; 12,5 %). L’hemogramme, disponible pour 17 patients, et le bilan hepatique, disponible pour 16 patients, etaient normaux. Treize patients ont recu un traitement specifique pour leur PID comme suit : corticoides (n = 8), anti-fibrosant (n = 6), immunosuppresseur (n = 2) et N-acetyl-cysteine (n = 1). Sept patients n’ont pas recu de traitement specifique. Aucun patient n’a presente une amelioration respiratoire (objectivee par des epreuves fonctionnelles respiratoires ou une diminution des besoins en oxygene). Le declin median de capacite vitale forcee, pour l’ensemble de la population, etait de 219 mL par an (IQR de −73 a −511). Apres un suivi median de 2,9 ans (IQR de 0,93 a 7,1), sept patients sont decedes et cinq patients ont ete transplantes. Conclusion Cette etude objective que les mutations de PARN sont le plus souvent associees avec une FPI, d’autres phenotypes peuvent neanmoins etre observes. Une telle heterogeneite phenotypique implique une evaluation complete des PID associees aux mutations de PARN afin de definir une strategie therapeutique adaptee.

Introduction La fibrose pulmonaire idiopathique (FPI) est une affection rare et peu de donnees epidemiologiques sont disponibles en France. Ce projet vise a decrire les caracteristiques en vie reelle des patients atteints de FPI recevant un traitement anti-fibrosant, ainsi que leurs comorbidites et la mortalite. Methodes RaDiCo-PID est une cohorte longitudinale a long terme incluant des patients enfants et adultes atteints de pneumopathies interstitielles diffuses (PID) idiopathiques suivis dans des centres de reference et de competence de la filiere Respifil et des reseaux OrphaLung et Respirare. RaDiCo-PID comporte un sous-groupe de patients atteints de FPI. Nous presentons ici les caracteristiques de base des patients atteints de FPI apres 2 ans d’inclusion. Resultats Entre le 15 juin 2017 et le 4 septembre 2019, 1246 patients atteints de pneumopathie interstitielle diffuse ont ete inclus dans le registre Radico-PID dans 18 centres, dont 847 atteints de FPI (68 %). Les patients atteints de FPI etaient en majorite des hommes (82,7 %), avec un âge moyen de 72,5 ± 9 ans a l’inclusion et un index de masse corporelle moyen de 26,8 ± 4,3. Parmi les patients avec FPI, 44,6 % etaient des cas incidents avec une duree mediane entre le diagnostic et l’inclusion de 8,9 mois (Q1 = 0,9 et Q3 = 26,4) ; 25,3 % de ces patients avaient eu une biopsie. La capacite vitale forcee moyenne au diagnostic etait de 73,4 ± 25,0 % de la valeur theorique (n = 561), et la capacite de transfert du monoxyde de carbone moyenne au diagnostic etait de 39,6 ± 18,2 % (n = 498). Selon les donnees disponibles sur les traitements anti-fibrosants (n = 661), 347 patients ont ete traites, au moins une fois, par du nintedanib et 312 patients par de la pirfenidone ; 113 patients ont recu sequentiellement ces 2 molecules. Conclusion La cohorte Radico-PID fournit des donnees concretes precieuses sur les caracteristiques demographiques des patients, notamment au moment du diagnostic de FPI. Les effectifs actuels permettent d’envisager des analyses plus approfondies.

International audience; Carriers of telomerase related genes (TRG) mutation seem to present a worst prognosis with more common hematological complications after lung transplantation (LT) for pulmonary fibrosis. The aim of this study was to describe the outcomes after LT and identify pre-LT prognosis factors in a multicenter cohort of lung transplant recipients with TRG mutation.We retrospectively reviewed all identified patients with pathogenic TRG mutation (n=38; TERT, n=22, TERC, n=10, RTEL1, n=6) who received LT in France, Switzerland and Belgium between 2009 and 2018. The median age at LT was 54 years (46-59), 70% were male, and 60% had idiopathic pulmonary fibrosis (IPF). At diagnosis of pulmonary fibrosis, 84% had a hematological disease, including 8 with myelodysplasia, and 45% had a liver disease. After a median follow up of 2.2 years (1,2-3,7), 16 received a single LT, 22 a double LT and 2 a combined liver-LT.The overall post-LT median survival was 3.75 years (1.8-NA). Patients with myelodysplasia before LT had an increased risk of death after LT (HR= 4.12 (1.47-11.53) p=0.007). After LT, all patients showed anemia, 70% thrombocytopenia, and 60% neutropenia. Four patients showed severe liver disease: portal hypertension, cirrhosis. Sixteen patients (42%) experienced acute renal failure and 18 (47%) developed chronic renal insufficiency during follow up. Four developed chronic lung allograft dysfunction.Overall survival after LT supports LT in TRG mutation carriers. Careful evaluation at diagnosis, might limit LT indication for patients with established myelodysplasia.

Introduction Pulmonary rehabilitation (PR) is known to improve exercise tolerance, mood, and quality of life in patients with chronic respiratory diseases. The aim of this work was to determine whether PR provides long-term benefits in increasing daily life physical activity in patients with chronic sarcoidosis. Methods This randomized prospective study (registered ClinicalTrials.gov NCT02044939 ) of 38 patients with stage IV chronic sarcoidosis was performed between 2012 and 2016. Patients were assigned to participate in a 2-month PR program (n = 20) or receive counseling (n = 18). Assessments were performed at baseline, 2 months (end of the PR program), 6 months, and 12 months, and included daily life physical activity parameters (measured for 5 consecutive days), exercise tolerance, dyspnea, anxiety, depression, fatigue, and quality of life. The primary outcome was the 12-month change in time spent in activities above an estimated energy expenditure of 2.5 metabolic equivalents (METs). Secondary daily life physical activity outcomes included number of steps per day, total daily energy expenditure, and total energy expenditure above 2.5 METs. Results The primary outcome did not differ between the two groups; mean between-group differences were −13.2 min (95% confidence interval [CI]: −76.3 to 49.8) at 6 months and −18.1 min (95% CI: −55.7 to 19.4) at 12 months. Although PR had no effect on secondary daily life physical activity outcomes, it did significantly increase exercise tolerance at 6 and 12 months and decrease the dyspnea score at 6 months and the fatigue score at 12 months. Conclusion This trial failed to demonstrate a beneficial effect of PR on daily life physical activity in sarcoidosis patients, suggesting that long-term behavioral programs may be necessary to complement PR.

International audience; No abstract available

Background: Methotrexate (MTX) is a key anchor drug for rheumatoid arthritis (RA) management. Its use has been associated with hypersensitivity pneumonitis and diffuse lung disease. Whether MTX exposure increases the risk of interstitial lung disease (ILD) in patients with RA is disputed. Objectives: We aimed to evaluate the association of antecedent MTX use with development of RA-ILD. Methods: Through a case-control study design with derivation and international validation samples, we examined the association of MTX exposure with ILD in 482 patients with RA-ILD and 741 patients with RA without ILD. Estimates were pooled over the different samples using meta-analysis techniques. Results: Analysis of the derivation sample revealed an inverse relationship between MTX exposure and RA-ILD (adjusted odds ratio [OR], 0.48; 95% confidence interval [CI], 0.25 to 0.92; P=0.028), which was confirmed in the validation samples (pooled adjusted OR, 0.39; 95% CI, 0.23 to 0.68; P Conclusion: Our results suggest that MTX is not a risk factor for RA-ILD and support a possible disease modifying effect of MTX on development of RA-ILD. Disclosure of Interests: Pierre-Antoine Juge: None declared, Joyce S. Lee Consultant of: Celgene, Genentech, Boehringer Ingelheim, Jessica Lau: None declared, Leticia Kawano: None declared, Jorge Rojas-Serrano: None declared, Marco Sebastiani: None declared, Gouri Koduri: None declared, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Karina Bonfiglioli Consultant of: Roche, Abbvie, Pfizer, Janssen and BMS, Marcio Sawamura: None declared, Ronaldo Kairalla: None declared, Lorenzo Cavagna: None declared, Emanuele Bozzalla Cassione: None declared, Andreina Manfredi: None declared, Mayra Mejia: None declared, Pedro Rodriguez Henriquez: None declared, Montserrat I. Gonzalez-Perez: None declared, Ramces Falfan-Valencia: None declared, Ivette Buendia-Roldan: None declared, Glora Perez-Rubio: None declared, Esther Ebstein Consultant of: BMS, Employee of: BMS, Steven Gazal: None declared, Raphael Borie Consultant of: Roche, Boehringer Ingelheim, Sebastien Ottaviani: None declared, Caroline Kannengiesser: None declared, Benoit Wallaert Consultant of: Roche, Boehringer Ingelheim, Yurdagul Uzunhan Consultant of: Roche, Boehringer Ingelheim,, Hilario Nunes: None declared, Dominique Valeyre Consultant of: Astra Zeneca, Roche, Boehringer Ingelheim, Nathalie Saidenberg Kermanac’h: None declared, marie-Christophe Boissier: None declared, Lidwine Wemeau Stervinou Consultant of: Roche, Janssen, BMS, Boehringer Ingelheim, Rene-Marc Flipo Speakers bureau: Novartis, Janssen, Lilly, Sylvain Marchand-Adam Consultant of: Roche, Novartis, Boehringer Ingelheim, Pascal Richette: None declared, Yannick Allanore Shareholder of: Sanofi, Roche, Consultant of: Actelion, Bayer, BMS, Boehringer Ingelheim, Inventiva, Sanofi, Claire Dromer: None declared, Marie-Elise Truchetet: None declared, Christophe Richez Consultant of: Abbvie, Amgen, Mylan, Pfizer, Sandoz and UCB., Thierry Schaeverbeke: None declared, Huguette Liote: None declared, Gabriel Thabut Employee of: Astra Zeneca, Kevin Deane Grant/research support from: Janssen, Consultant of: Inova, ThermoFisher, Janseen, BMS and Microdrop, Joshua Solomon: None declared, Tracy Doyle: None declared, Jay H. Ryu: None declared, Ivan O. Rosas Consultant of: Boehringer Ingelheim, Gerentech, Three Lakes Partners, V. Michael Holers Grant/research support from: Janssen, Celgene, and BMS, Catherine Boileau: None declared, Marie-Pierre Debray: None declared, Raphael Porcher: None declared, David A. Schwartz Consultant of: NuMedii, Robert Vassallo Shareholder of: Pfizer, BMS, SunPharma, Bruno Crestani Shareholder of: Apellis, Boehringer Inghelheim, Medillune, Roche, Consultant of: Boehringer Ingelhiem, Astra Zeneca, Roche, Sanofi, Philippe Dieude: None declared

Genetic testing is proposed for suspected cases of pulmonary fibrosis of genetics origin but clinicians and patients need advice about the related diagnostic and management issues. Because multidisciplinary team (MDT) has been shown to improve accuracy of ILD diagnosis, we evaluated the feasibility of an MDT dedicated to the indication and interpretation of genetic testing. The MDT met monthly, included pneumologists experts in ILD in adults, children, geneticists, radiologist. Hematologists, rheumatologists, dermatologists, hepatologists, and pathologists were also invited to attend. Since 2016, 70 patients (37 males, 33 females) were discussed, from 31 different centers (7 countries). Mean age was 46.4 years [0-71] including 3 patients The MDT therapeutic proposals were: antifibrotic drugs (n=23), best supportive care (n=4), surgical lung biopsy (n=2), steroids (n=7), lung transplantation (n=16), or watch and wait (n=9). Our experience shows that a dedicated MDT with genetic analysis is feasible including patients of all ages and provides a unique opportunity to improve knowledge and to adapt patient management and therapy.

Background Rheumatoid arthritis–associated interstitial lung disease (RA-ILD) and idiopathic pulmonary fibrosis (IPF) share phenotypic similarities. The gain-of-function MUC5B promoter variant rs35705950 is the strongest risk factor for development of IPF Objectives We hypothesised that rs35705950 would also contribute to the risk of ILD in RA patients. Methods Using a French discovery population and multi-ethnic validation populations from 6 different countries, we tested the association of the MUC5B promoter variant in RA-ILD (n=620), RA without ILD (n=614), and unaffected controls (n=5448). Results The discovery population revealed an association of the MUC5B promoter variant with RA-ILD when compared to unaffected controls (ORadj=3.8 95% CI: 2.8 to 5.2; p=9.7x10–17) (figure 1A). Similar to the discovery cohort, the MUC5B promoter variant was significantly over-represented among the cases of RA-ILD in the multi-ethnic study cohorts when compared to unaffected controls (ORadj=5.5 95% CI: 4.2 to 7.2; p=4.7x10–35) (figure 1A), and when the discovery population and the multi-ethnic cohorts were combined (ORcombined=4.7 95% CI: 3.9 to 5.8; p=1.3x10–49) (figure 1A). Additionally, the MUC5B promoter variant was found to increase the risk of ILD among patients with RA (ORcombined=3.1 95% CI: 1.8 to 5.4; p=7.4x10–5), however, no statistical association with the MUC5B promoter variant was observed for RA without ILD (figure 1B). The association of the MUC5B promoter variant with RA-ILD increased significantly when restricted to the usual interstitial pneumonia (UIP) by high-resolution computed tomography (ORcombined=6.1 95% CI: 2.9 to 13.1; p=2.5x10–6) (figure 1C). Immunohistochemical and in-situ hybridization analysis of RA-ILD lung tissue demonstrated expression of MUC5B by type 2 alveolar epithelial cells undergoing endoplasmic reticulum stress. Conclusions Our findings demonstrate that MUC5B promoter variant rs35705950 is a risk factor for RA-ILD specifically associated with radiologic evidence of UIP. Disclosure of Interest None declared

Regulator of telomere length 1 (

Introduction Les patients atteints d’une pneumopathie interstitielle diffuse associee a une mutation d’un gene regulateur du complexe telomerase (TRG) semblent presenter une moins bonne survie et des complications hematologiques plus frequentes apres transplantation pulmonaire (TxP). L’objectif de cette etude etait de determiner l’evolution apres TxP de ces patients dans une cohorte francaise. Methodes Tous les patients porteurs d’une mutation d’un TRG ayant eu une TxP en France entre 2009 et 2017 ont ete identifies par les centres de transplantation et le reseau francais OrphaLung. Resultats Vingt-sept patients ont ete inclus, dont 67 % etaient des hommes, avec des mutations de TERT (n = 17), TERC (n = 6), et RTEL1 (n = 4). Avant la greffe, 19 (70 %) presentaient une atteinte hematologique, dont 6 un syndrome myelodysplasique et 14 une hepatopathie. L’âge median lors de la TxP etait de 54 (± 9) ans. Apres la TxP, tous les patients presentaient une anemie, 74 % une thrombopenie, et 54 % une neutropenie. Quatre patients ont presente des complications hepatiques severes : une hemochromatose post transfusionnelle, une fibrose hepatique et deux patients une hypertension portale. 26 % ont presente une dysfonction chronique du greffon dans un delai median de 2,1 (± 1,3) ans. Quinze receveurs sont decedes (56 %) au cours du suivi. La mediane de survie apres la TP etait de 4,4 ans. La presence d’une myelodysplasie avant la TxP etait associee a une diminution de la survie (p Conclusion La survie apres TxP des patients porteurs d’une mutation d’un TRG est comparable a celle des patients sans mutation. Une TxP est possible apres un bilan exhaustif des comorbidites extra-respiratoires et une prise en charge post-greffe adaptee. La presence d’un syndrome myelodysplasique avant la greffe doit faire rediscuter le projet de greffe.

The purpose of the study was to evaluate the prevalence of compressive lymphadenopathy on pulmonary veins (PV) and left atrium (LA) in patients with sarcoidosis.A total of 101 consecutive patients underwent a chest computed tomography angiographic examination with specific analysis of: (a) 3 nodal stations (ie, 7, 8, and 9 stations) for detection of LA compression; (b) 2 nodal stations (ie, 10 and 11 right and left stations) for detection of PV compression.Lymphadenopathy was present in 64 patients (64/101; 63.4%) with computed tomography features of venoatrial compression in 17 patients (17/101; 16.8%). This subgroup included 10 patients with LA compression alone (10/64; 15.6%), 6 patients with PV compression alone (6/64; 9.4%), and 1 patient with both (1/64; 1.5%). The mean diameter of enlarged lymph nodes compressing the LA and PVs was 3.18 ± 0.73 cm (range: 2.1 to 4.4 cm) and 1.9 ± 0.45 cm (range: 1 to 2.9 cm), respectively. PV compression was depicted in a total of 7 patients (7/101; 6.9%), observed as a unilateral (n = 5) or bilateral (n = 2) finding, with a mean number of 3.0 PVs compressed per patient (range: 1 to 7). A total of 10 venous sections showed features of compression, at the level of a lobar confluence (n = 6) or individual segmental veins (V6; n = 4), with a mean reduction in the venous cross-sectional area of 51.09% ± 12.85% (median: 50.06%). Nonfibrotic lung infiltration associated with sarcoidosis was observed in 88.2% of patients with compressive lymphadenopathy (15/17).The prevalence of venoatrial compression in sarcoidosis is 16.8% in the studied population.

Background Despite its high prevalence and mortality, little is known about the pathogenesis of RA–associated interstitial lung disease (RA-ILD). Given that familial pulmonary fibrosis (FPF) and RA–ILD frequently share the usual interstitial pneumonia pattern and common environmental risk factors, we hypothesized that the two diseases may share additional risk factors including FPF-linked genes. Objectives Our aim was to identify coding mutations of FPF-risk genes associated with RA-ILD. Methods 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. Results Among the 101 RA–ILD patients included, 12 (11.9%) had 13 WESidentified 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 for RA–ILD patients (p=9.45’10-4, odds ratio [OR] 3.17 95% CI 1.53 – 6.12). Telomeres were shorter for RA-ILD patients with a TERT, RTEL1 or PARN mutation than controls (p=2.87x10-2). Conclusions Our results support the contribution of FPF-linked genes to RA–ILD susceptibility. Disclosure of Interest None declared

Idiopathic pulmonary fibrosis has been associated with the reactivation of developmental pathways, notably the Hedgehog-Glioma-associated oncogene homolog (GLI) pathway. In this study, we determined whether the Hedgehog pathway was activated in bleomycin-induced lung injury in mice, and whether targeting the Hedgehog-Gli pathway could decrease bleomycin-induced lung fibrosis. After intratracheal injection of bleomycin on Day 0, C57Bl6 mice received GDC-0449 (an inhibitor of Smoothened, the transducer of the pathway), or 2,2'-[[Dihydro-2-(4-pyridinyl)-1,3(2H,4H)-pyrimidinediyl]bis(methylene)]bis[N,N dimethylbenzenamine (GANT61; an inhibitor of GLI transcription factors in the nucleus), from Day 7 to Day 13. At Day 14, whole-lung homogenates were obtained for morphological analysis, assessment of cell apoptosis and proliferation, collagen quantification, and evaluation of profibrotic (transforming growth factor-β, connective tissue growth factor, plasminogen activator inhibitor 1, vascular endothelial growth factor-A) and proinflammatory mediators (IL-1β) expression. We showed that the Hedgehog pathway was activated in bleomycin-induced lung fibrosis on Day 14 after injury, with an increased lung expression of the ligand, Sonic Hedgehog, and with increased messenger RNA expression and nuclear localization of GLI1 and GLI2. Inhibition of Smoothened with GDC-0449 did not influence the development of bleomycin-induced lung fibrosis. By contrast, the inhibition of GLI activity with GANT61 decreased lung fibrosis and lung collagen accumulation, and promoted an antifibrotic and anti-inflammatory environment. Our results identify the hedgehog-Gli pathway as a profibrotic pathway in experimental fibrosis. Inhibition of the Hedgehog-Gli pathway at the level of GLI transcriptional activity could be a therapeutic option in fibrotic lung diseases.

Background and objectives Little is known about the consequences of chronic sarcoidosis on daily life physical activity (DLPA). The aim of this prospective study was to measure DLPA in patients with chronic sarcoidosis and to determine its relationship to clinical and functional parameters. Methods Fifty‐three patients with chronic sarcoidosis and 28 healthy control subjects were enrolled in this multicenter prospective study. Two markers of DLPA (number of steps walked per day [SPD]) and total daily energy expenditure (TEE) were assessed for five consecutive days with a physical activity monitor. Pulmonary function, aerobic capacity (maximal oxygen uptake [VO2max]), exercise capacity (6‐min walk test [6MWT]), and quality of life (self‐reported questionnaires) were also evaluated. Comparisons of DLPA parameters between the two groups were performed using an analysis of covariance adjusted for age, sex, and body mass index (BMI). Relationships between DLPA parameters and patient characteristics were assessed in multivariable linear regression models. Results Patients with sarcoidosis walked significantly fewer SPD than did the control subjects (6395 ± 4119 and 11 817 ± 3600, respectively; P

Introduction La fibrose pulmonaire idiopathique (FPI) et le syndrome emphyseme fibrose (SEF) sont associes a un risque accru d’hypertension pulmonaire (HTP). Peu de donnees sont disponibles sur la relation entre hemodynamique et physiologie respiratoire, et l’effet du traitement de l’HTP. Les objectifs de notre etude etaient d’evaluer les caracteristiques respiratoires et hemodynamiques des patients atteints de FPI ou SEF et d’HTP ; de rechercher des correlations entre elles ; et d’evaluer et de comparer la reponse au traitement de l’HTP et le pronostic. Methodes Parmi 220 patients avec HTP pre-capillaire inclus dans l’etude observationnelle multicentrique prospective HYPID (NCT01443598), 61 patients avec FPI et 75 avec SEF ont ete inclus dans l’analyse. Resultats Le 89 % des patients etaient hommes avec un âge moyen de 70 ± 8,5 ans. La CVF moyenne au diagnostic d’HTP etait de 76 ± 24,5 % et la DLco de 24,7 ± 10,9 %. La classe NYHA etait I-II (18 %), III (58 %), IV (24 %). La distance parcourue en 6 min (DM6) etait de 276 ± 145,4 m. La PAPm etait 37 ± 9 mmHg, l’index cardiaque (IC) 2,6 ± 0,6 l/min/m2 et les resistances vasculaires pulmonaires (RVP) 6,6 ± 2,9 UW. Le KCO etait plus bas chez les SEF que chez les FPI (35 % vs 49 % ; p = 0,0005), ainsi que la SpO2 (93 % vs 94,6 %, p = 0,006). La DLco etait significativement correlee avec la PAPm (r = −0,55, p = 0,0002) et les RVP (r = −0,53, p = 0,005) chez les FPI mais pas chez les SEF. La SpO2 etait significativement correlee avec tous les parametres hemodynamiques dans le groupe SEF, mais avec aucun d’entre eux chez les FPI. L’HTP etait severe chez 73,3 % des patients SEF contre 78,7 % des FPI (p = 0,47). Le traitement de l’HTP a entraine une diminution significative de la PAPm et des RVP et une augmentation de l’IC chez les patients SEF, mais pas chez les FPI. En considerant la totalite des patients traites, un traitement combine avec un antagoniste des recepteurs de l’endotheline et un inhibiteur de la phosphodiesterase − 5 a montre une amelioration significative des RVP (p = 0,05). La survie mediane etait de 20,2 mois, sans difference significative de survie entre les deux groupes. La DM6 etait le seul facteur predictif independant de la survie globale (HR 0,997, IC 0,995–0,998, p Conclusion L’hemodynamique de l’HTP est comparable au cours de FPI et SEF, mais la relation avec la fonction pulmonaire et la reponse au traitement different, suggerant des differences physiopathologiques. La distance parcourue au test de marche est le seul facteur independant de la survie.

Introduction L’omalizumab est un traitement de l’asthme severe allergique non controle. Son efficacite dans l’asthme severe allergique associe a une bronchopneumopathie chronique obstructive (ACO) n’est pas connue. L’objectif de cette etude etait de decrire les caracteristiques et l’evolution des patients ACO traites par omalizumab. Methodes Etude retrospective d’une cohorte d’asthmatiques severes allergiques traites par omalizumab au CHU de Lille entre 2005 et 2017. Les criteres d’ACO etaient : âge > 40 ans, tabagisme > 10 paquets-annees (PA), VEMS/CVF 400 mL apres bronchodilatateurs et atopie documentee. Nous avons evalue la dyspnee (mMRC), le score de controle des symptomes de l’asthme (ACT), le nombre d’exacerbations et le VEMS a l’initiation puis a 3 mois et 12 mois de traitement. Les resultats sont exprimes en mediane [25e–75e percentile]. Resultats Parmi les 159 asthmatiques severes traites par omalizumab, 19 patients avaient des criteres d’ACO (prevalence = 12 %). Ils avaient les caracteristiques suivantes : 68 % d’hommes, âges de 57 ans [52–66,5], tabagisme a 25 PA [20–38] dont 5 actifs, 2 sensibilisations aux pneumallergenes [1–4,5], taux d’IgE a 462 kU/L [238–741,5], mMRC a 2 [1–3,5], ACT a 12 [8,5–16], 7 exacerbations dans l’annee precedente [2,5–11] et VEMS de 60 % [37,5–73,5]. A 3 mois de traitement, on observait une amelioration de l’ACT de 12 [8,5–16] a 21 [13,5–22,5] (p Conclusion Dans l’ACO, le traitement par omalizumab est associe a une amelioration du controle des symptomes d’asthme, une amelioration de la dyspnee d’effort, une diminution de la frequence des exacerbations sans modification du VEMS.

Introduction La dyspnee est le symptome majeur des patients souffrant de pneumopathie interstitielle diffuse (PID). Les determinants de l’intensite de la dyspnee sont mal connus avec une association faible avec les parametres des explorations fonctionnelles respiratoires (EFR). Ceci pourrait etre lie en partie aux outils unidimensionnels habituellement utilises pour mesurer la dyspnee. L’objectif de cette etude est de caracteriser les dimensions sensorielle et affective de la dyspnee et d’evaluer leurs associations avec les EFR dans un groupe de patients atteints de PID. Methodes Nous avons mene une etude prospective monocentrique chez 49 patients dyspneiques atteints de PID (55 % hommes, âge 65 ans, IMC 28 kg/m2, dont 12 FPI, 11 PINS et 8 sarcoidoses). La dyspnee etait evaluee par le Multidimensional Dyspnea Profile (MDP), l’anxiete et la depression par le questionnaire Hospital Anxiety and Depression (HAD). Les EFR comportaient une spirometrie, une D LCO et un test de marche (TM6). Des analyses univariee et multivariee ont teste l’association entre les dimensions sensorielle (QS) et affective (A2) de la dyspnee et les EFR. Les resultats sont exprimes en medianes (intervalle inter-tertile). Resultats La validite interne du MDP etait excellente avec un coefficient alpha de Cronbach a 0,89. Les 2 meilleurs descripteurs de la dyspnee etaient une sensation de respiration forte (64 %) et de manque d’air (47 %). L’intensite de la dyspnee etait moderee avec un score sensoriel QS median a 12/50 et un score affectif A2 median a 9/50, 55 % des patients presentaient un score mMRC ≥ 2. Les scores QS et A2 etaient correles a l’HAD anxiete (r = 0,5 et 0,7, p Conclusion Nos resultats montrent que dans une population de PID de severite EFR moderee, la dyspnee est peu intense dans ses dimensions sensorielle et affective et essentiellement correlee a l’anxiete et au declin de la CVF sur les 3 derniers mois.

Introduction Les mutations du complexe telomerase sont retrouvees chez environ 15 % des patients atteints de fibrose pulmonaire familiale et sont associees a des manifestations hepatiques, cutanees et hematologiques. La pirfenidone et le nintedanib permettent de ralentir le declin de la CVF et d’augmenter la survie des patients atteints de Fibrose Pulmonaire Idiopathique. Peu de donnees existent concernant l’efficacite et l’innocuite de ces traitements chez les patients porteurs d’une mutation du complexe telomerase. Methodes L’objectif de cette etude multicentrique retrospective, realisee dans le cadre du reseau OrphaLung des maladies pulmonaires rares, etait d’evaluer l’efficacite et la tolerance des traitements anti fibrosants chez des patients atteints de fibrose pulmonaire et porteurs d’une mutation du complexe telomerase. Resultats Nous avons identifie 109 patients dans 5 pays (Belgique, Espagne, France, Grece et Hollande) porteurs d’une mutation TERT (n = 82), TERC (n = 14), RTEL1 (n = 10) ou PARN (n = 3), Un diagnostic de FPI a ete pose chez 100 patients, 5 patients etaient atteints d’une PINS et 4 d’une Fibroelastose Pleuropulmonaire (PPFE). 44 patients ont recu du nintedanib, 39 de la pirfenidone et 26 ont recu les deux traitements de facon consecutive. L’âge moyen au diagnostic etait de 57,6 ± 13,6 ans. A l’initiation du traitement, la CVF moyenne etait de 80,8 % ± 20,2 % et la DLCO etait de 44,0 ± 13,7 %. La duree mediane de traitement etait de 354 jours [186,8–469,0]. Le traitement anti-fibrosant a ete arrete chez 18 patients pour progression de la maladie et chez 14 patients pour la survenue d’effets secondaires, principalement digestifs (nintedanib, n = 4 ; pirfenidone, n = 10). Le declin median de la CVF avant l’initiation du traitement etait de 24,0 mL[4,4–57,3] par mois. Apres initiation du traitement, le declin de la la CVF etait de 16,0 mL [4,4–48,7] par mois chez les patients traites par nintedanib et de 17,0 mL/mois [6,05 ; 39,7] chez les patients traites par pirfenidone. Conclusion Ces donnees retrospectives suggerent que les traitements anti-fibrosants sont bien toleres et ralentissent le declin de la CVF chez les patients atteints de fibrose pulmonaire et porteurs d’une mutation du complexe telomerase.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease of unknown cause. Key signaling developmental pathways are aberrantly expressed in IPF. The hedgehog pathway plays a key role during fetal lung development and may be involved in lung fibrogenesis. We determined the expression pattern of several Sonic hedgehog (SHH) pathway members in normal and IPF human lung biopsies and primary fibroblasts. The effect of hedgehog pathway inhibition was assayed by lung fibroblast proliferation and differentiation with and without transforming growth factor (TGF)-β1. We showed that the hedgehog pathway was reactivated in the IPF lung. Importantly, we deciphered the cross talk between the hedgehog and TGF-β pathway in human lung fibroblasts. TGF-β1 modulated the expression of key components of the hedgehog pathway independent of Smoothened, the obligatory signal transducer of the pathway. Smoothened was required for TGF-β1–induced myofibroblastic differentiation of control fibroblasts, but differentiation of IPF fibroblasts was partially resistant to Smoothened inhibition. Furthermore, functional hedgehog pathway machinery from the primary cilium, as well as GLI-dependent transcription in the nucleus, was required for the TGF-β1 effects on normal and IPF fibroblasts during myofibroblastic differentiation. These data identify the GLI transcription factors as potential therapeutic targets in lung fibrosis.

We report on 11 cases of specific polysaccharide antibody deficiency (SPAD) revealed in adulthood by severe infections with encapsulated bacteria. Given that immunoglobulin replacement therapy can effectively prevent the recurrence of bacterial infections in this context, SPAD should be considered once other antibody deficiencies have been ruled out.

Background Mutations within TERT and TERC are found in 15% of familial pulmonary fibrosis and are associated with hematologic, liver and dermatological disorders. Pirfenidone has been shown to limit FVC decline and to decrease 12 months mortality rate in idiopathic pulmonary fibrosis (IPF). To our knowledge, pirfenidone has not been specifically evaluated in carriers of TERT / TERC mutations. Objectives The aim of this multicenter retrospective French study was to evaluate the safety and efficacy of pirfenidone in carriers of TERT mutations. Results We identified 18 patients (11 men) with a TERT mutation who received pirfenidone: 16 IPF, 1 pneumoconiosis and 1 rheumatoid arthritis-associated ILD. At diagnosis, mean age was 59 ± 6 years, mean FVC was 78.0% ± 16.4 % and mean DLCO was 52.4± 10.2%. The median duration of treatment was 304 days [14 -791]. Gastro intestinal intolerance was observed in 6 patients (33%). One patient showed a transient thrombocytopenia. Pirfenidone was discontinued in 10 patients (55%) due to disease progression (n=5, 28%), exacerbation (n=2, 11%), increased liver enzymes (n=2, 11%) or gastro intestinal intolerance (n=1, 5%). The median FVC decline was 32.6 mL [0-165] per month before pirfenidone initiation versus 35.7 mL [5-166] per month after treatment initiation; 7 patients showed an FVC decline >10% during treatment. Conclusion These preliminary data suggest that pirfenidone is safe in patients with TERT mutation. Disease progression is frequent in this population and does not seem to be influenced by pirfenidone.

To evaluate the tolerance and level of enhancement achievable after inhalation of stable krypton.This study was approved by the institutional review board and the local ethics committee. Written informed consent was obtained from all subjects. The study was planned as a Fleming two-stage design, enabling one to assess the effectiveness of a newer treatment or technique on a small number of patients. At the end of each stage, the results are computed, and the trial can be stopped if the effectiveness is less than a minimum success rate or greater than an expected success rate. After informed consent was obtained, a total of 32 patients (ie, two successive series of 16 patients each) with severe emphysema underwent a dual-source, dual-energy chest computed tomographic (CT) examination after inhalation of a mixture of stable krypton (80%) and oxygen (20%), with reconstruction of diagnostic and ventilation images. For each patient, two regions of interest were selected on a diagnostic image, one in a region of severe emphysema (presumed to be poorly ventilated or not ventilated) and a second one in a region devoid of structural abnormalities (presumed to be normally ventilated), with measurements of attenuation values on the corresponding ventilation image.All examinations were successfully performed, without adverse effects. Differences in attenuation between normal lung and emphysematous areas were found in 28 patients (88%; 95% confidence interval: 71%, 96.5%). The maximal level of attenuation within normal lung was 18.5 HU. Krypton attenuation difference between normal and emphysematous lung was significant, with a median value of 51.8% (P.001).The level of enhancement after inhalation of krypton and its excellent clinical tolerance makes this gas eligible for ventilation CT examinations.

Background: Patients with sarcoidosis frequently exhibit exertional dyspnea. Although the functional limitation might be related to ventilatory problems, some patients exhibited exertional dyspnea without significant abnormalities of pulmonary function tests (PFT). Therefore, the mechanisms responsible for exercise intolerance remain unclear. Objectives: The aim of this retrospective study was to determine the mechanisms responsible for exercise intolerance. Methods: Cardiopulmonary exercise testing (CPET) was performed in 157 dyspneic sarcoid patients (stage I: 29; stage II–III: 95; stage IV: 33) and VO2 peak was correlated with radiological stage and resting PFT. Results: VO2 peak was decreased in 73% patients, did not differ according to radiological stage and was correlated with VC, FVC, FEV1, TLC and DLCO. FVC was the major significant predictor of VO2 peak explaining 17% of VO2 variation. Among CPET variables, peak heart rate and VE/VO2 at ventilatory threshold explained 22% of VO2 alteration in stage I and stage II–III, and 9% in stage IV. In stage IV, VD/VT peak explained 41% of VO2 alteration. Conclusion: In conclusion, in the lower stages circulatory impairment and impaired heart rate response to exercise are involved in the exercise capacity limitation, whereas in stage IV the ventilatory and gas exchange impairment may be more important. CPET must be performed to accurately characterize the mechanisms responsible for exercise limitation and help the clinician in the management of the disease.

Introduction Une enquete aupres de patients atteints de fibrose pulmonaire, idiopathique (FPI) ou avec une origine connue (non FPI) a ete menee a l’initiative des centres de reference et de competences pour les maladies pulmonaires rares. Methodes Au total, 265 patients ont repondu par courrier a un questionnaire auto-administre, dont 172 FPI (65 %) et 93 non FPI (35 %). Resultats Dans les memes proportions : 43 % des patients souhaitaient une reduction des delais de confirmation du diagnostic, 30 % eprouvaient des difficultes tres importantes lors d’une activite physique jusqu’a necessiter une aide y compris pour se rendre a l’hopital, et 18 % exprimaient le besoin d’une aide autour des soins palliatifs et la prise en charge de la douleur. Quelle que soit l’etiologie de la fibrose, 42 % des patients souhaitaient avoir un role plus actif dans le suivi de leur maladie, 67 % estimaient qu’une association de patients etait utile ; seuls 9 % adheraient a une association de patients principalement dans la FPI (7 %) grâce au pneumologue qui les avait informes de son existence. Cinquante pour cent auraient envie d’adherer a une association de patients et 38 % aimeraient se rendre disponibles pour aider les autres. Soixante-dix pour cent des patients interroges utilisaient internet a partir d’un ordinateur, peu utilise pour rechercher des informations complementaires sur la maladie (37 %), et rarement pour correspondre avec d’autres patients (5 %). Conclusion Cette enquete nationale originale a montre : de nombreuses similitudes entre les 2 sous populations de patients atteints de fibrose au niveau du vecu et des attentes, le meme souhait d’implication dans la prise en charge, et des opportunites de collaboration entre pneumologues et representants de patients.

Introduction La pneumopathie interstitielle diffuse (PID) est l’une des causes majeure de mortalite chez les patients atteints de polyarthrite rhumatoide (PR). Malgre une prevalence et une mortalite importante, la physiopathologie de la PID associee a la PR (PR-PID) reste meconnue. La PR-PID partage plusieurs caracteristiques phenotypiques avec la fibrose pulmonaire idiopathique (FPI) telles que l’aspect de pneumopathie interstitielle commune sur le scanner et un pronostic tres severe. Enfin, les similitudes entre PR-PID et FPI concernent egalement les facteurs environnementaux (tabac,…) suggerant que ces deux pathologies pourraient egalement partager des facteurs de risques genetiques tels que ceux predisposant a la FPI familiale (FPF). Methodes Nous avons utilise des donnees d’exome obtenue par whole-exome sequencing (WES) de patients atteints de PR-PID provenant de differents centres de rhumatologie et de pneumologie francais. L’ensemble des patients PR-PID+ repondaient aux criteres ACR/EULAR 2010. Le diagnostic de PID etait realise apres analyse de scanner thoracique de haute resolution. Apres une analyse restrictive de 9 genes rapportes comme etant associes aux FPF, nous avons compare le nombre de mutations retrouvees parmi les patients PR-PID au nombre de mutations retrouvees chez des individus temoins. Un burden test a ete effectue pour definir l’exces de mutations chez les patients PR-PID au sein de ces 9 genes d’interet. Resultats Parmi les 101 patients PR-PID inclus, 12 (11,9 %) presentaient des mutations au sein des regions codantes des genes TERT, RTEL1, PARN et SFTPC. Le burden test comparant 81 patients PR-PID a 1010 individus temoins caucasiens europeens a confirme un exces de mutations parmi ces genes chez les patients PR-PID (P = 9,45 × 10−4 ; OR = 3,17 ; IC 95 % 1,53–6,12). Chez les patients PR-PID porteurs de mutations des genes TERT, RTEL1 et PARN, appartenant au complexe telomerase, la taille des telomeres etait significativement plus petite que celle observees chez les temoins (P = 2,87 × 10−2). Conclusion Ces resultats sont en faveur d’un fond genetique commun entre FPI et PR-PID, suggerant une physiopathologie commune entre ces deux pathologies. En cas de confirmation de ces resultats, les avancees therapeutiques realisees dans la prise en charge des FPI pourraient alors beneficier aux patients atteints de PR-PID.

Introduction La fibrose pulmonaire familiale est definie par au moins 2 membres de la meme famille atteints de pneumopathie interstitielle idiopathique. Les mutations les plus frequentes impliquent les genes du complexe telomerase tels que TERT , TERC , RTEL1 ou PARN . Les mutations du gene TERT et TERC touchent entre 15 et 20 % des patients atteints de fibrose pulmonaire familiale et sont associees a des anomalies hematologiques, hepatiques et cutanees. La pirfenidone est un traitement valide de la fibrose pulmonaire idiopathique (FPI). Plusieurs essais ont demontre qu’elle permettait un ralentissement du declin de la CVF et une augmentation de la survie sans progression. Elle est egalement associee a la survenue d’effets secondaires digestifs, hepatiques et cutanes. L’objectif de ce travail est d’evaluer l’efficacite et la tolerance de la pirfenidone chez les patients atteints de fibrose pulmonaire et porteurs de mutation du complexe telomerase. Methodes Nous avons realise une etude retrospective multicentrique et internationale en Grece, en Espagne et en France. Nous avons inclus tout patient atteint d’une fibrose pulmonaire, porteur d’une mutation du complexe telomerase et ayant recu au moins une dose de pirfenidone. Les donnees demographiques, cliniques, paracliniques, l’adherence et la tolerance au traitement ainsi que les epreuves fonctionnelles respiratoires etaient collectees lors du diagnostic, a l’initiation du traitement et a chaque visite lors du suivi. Resultats Trente patients ont ete inclus dans cette etude, 28 porteurs d’une mutation TERT et 2 porteurs d’une mutation TERC. La mediane de survie sans progression et sans transplantation etait de 6 ans (0,25–8,12), 8 patients sont morts durant le suivi. A 12 mois de suivi, 60 % des patients avaient arrete le traitement, la moitie du fait d’une progression de la maladie l’autre moitie du fait de la survenue d’effet secondaire. En terme d’efficacite, la pirfenidone n’a pas permis de ralentir le declin moyen annuel de la CVF (estime a 375,9 mL/an avant initiation versus 426,9 apres initiation, p = 0,19) dans un modele lineaire a effet mixte. La tolerance etait similaire a celle decrite dans la population de FPI sporadique. Conclusion Dans cette premiere etude retrospective, multicentrique et internationale, la pirfenidone n’influence pas le declin de la CVF. Des etudes prospectives sont necessaires pour evaluer l’efficacite et la tolerance des traitements anti-fibrosants chez les patients porteur d’une mutation du complexe telomerase.

The 6-min walk test (6MWT) is commonly used to assess exercise capacity in patients with fibrotic idiopathic interstitial pneumonia (f-IIP). However, it is not known whether patients with f-IIP have reduced levels of physical activity in daily life (DLPA) or whether pulmonary function tests and the 6MWT correlate with their DLPA.The aim of this study was to measure DLPA in patients with f-IIP and to determine the relationships between DLPA and the 6MWT, pulmonary functional parameters, and anxiety and depression scores. Fifty patients with f-IIP and 25 sex- and age-matched healthy control subjects were enrolled. Markers of DLPA were assessed with a physical activity monitor for 4 consecutive days. Hospital Anxiety and Depression Scale (HADS) scores were evaluated.DLPA parameters were significantly reduced in patients with f-IIP compared with control subjects (all P.001). The mean number of steps per day correlated strongly with diffusing capacity of the lung for carbon monoxide (Dlco), FVC, the 6MWT distance, and the 6MWT lowest oxygen saturation as measured by pulse oximetry (Spo₂). DLPA was unrelated to HADS scores. Multivariate analysis showed that Dlco and 6MWT distance explained only 31% of the variance in the number of steps per day. Dlco, 6MWT distance, 6MWT lowest Spo₂, and DLPA were significant predictors of mortality, but only Dlco and 6MWT distance were independent predictors.Quantitation of DLPA is a novel patient-centered approach to assess function in f-IIP and may be a useful tool for clinical care and assessing response to therapy.

Background Rheumatoid arthritis (RA) is a systemic autoimmune disease, the most severe manifestation being interstitial lung disease (ILD). Therapeutic options are undefined and ILD is one of the leading causes of mortality for RA patients. A better characterization of RA-ILD–associated factors may improve the risk stratification of RA patients. Objectives To identify variables associated with ILD occurrence in RA. Methods RA-ILD patients (RA-ILD+) in a French multicentric cohort were compared to monocentric RA cases without ILD (RA-ILD-). All patients fulfilled 2010 ACR/EULAR criteria for RA and had a HRCT chest scan for suspected ILD or during a pre-biologic assessment. ILD was defined by HRCT results. Because ILD occurrence increases with RA duration, RA-ILD+ and RA-ILD- patients were matched by disease duration (1:1). Demographic data, clinical features of RA and treatment modalities before the ILD diagnosis were collected. Results significant on univariate analysis (P Results Among 253 consecutive RA patients, 81 were male (32.02%), 112 (48.07%) were smokers, mean age at RA onset was 48.11 ± 16.33 years, and mean RA duration 11.69 ± 10.10 years; 199 patients (85.78%) were ACPA-positive and 171 (71.85%) had erosive status; 134 (60.63%) received MTX and 63 (28.25%) a TNF inhibitor. Among the 253 patients, 138 (54.55%) had ILD. Among the RA-ILD+ patients, 72 (74.23%) had UIP and 25 (25.77%) NSIP. On univariate analysis, ILD was associated with older age at RA onset (52.69 ± 15.00 vs 42.86 ± 16.26 years, P=0.0001), male sex (40.68% vs 21.74%, P=0.001), ACPA rate ≥60 N (20.63% vs 6.41%, P=0.012), less use of anti-TNF agents and MTX (14.55% vs 41.59%, P=0.001, and 50.94% vs 69.57, P=0.005, respectively) and lower MTX dosage (15.26 ± 4.44 vs 16.83 ± 4.31 mg/week, P=0.046). There was no difference for erosive status. On multivariate analysis, ILD was independently associated with older age at RA onset ( P P =0.0006), less use of MTX ( P =0.015) with lower dosage ( P =0.005) and less use of anti-TNF agents ( P =0.004). Conclusions As previously reported, ILD was independently associated with male sex as well as older age at RA onset and, of interest, less use of MTX and anti-TNF biologics before ILD diagnosis, even though patients did not differ in erosive status. Larger prospective studies are required to further elucidate the role of DMARDs and anti-TNF biologics in ILD occurrence and progression in RA patients. Disclosure of Interest None declared

Introduction La lipoproteinose alveolaire (LPA) auto-immune est caracterisee par une accumulation alveolaire de surfactant secondaire a la presence d’anticorps anti-GMCSF. Le traitement de reference est le lavage pulmonaire therapeutique. Dans une etude prospective le rituximab, un anticorps monoclonal anti-CD20, ameliorait l’atteinte pulmonaire chez 8 des 9 patients traites [1] . Methodes Nous avons analyse retrospectivement l’efficacite et la tolerance du rituximab chez 12 patients francais atteints de LPA auto-immune. Resultats Huit hommes et 4 femmes ont ete inclus, âge moyen 46 ans [30–59], 8 fumeurs ou avec une exposition toxique environnementale. Le diagnostic avait ete realise en moyenne depuis 26,6 mois ; 10 patients avaient beneficie de lavages therapeutiques, 4 avaient recu du GMCSF sous-cutane, et 1 du GMCSF inhale. Onze patients ont beneficie de 2 cures de rituximab (1 g) a 14 jours d’intervalle, et 3 patients ont eu une reinjection a M6. Un patient a ete perdu de vue apres la 1re injection. Durant le suivi, un patient s’est aggrave et a requis une transplantation pulmonaire a M1. A M6, un patient presentait une augmentation de la DLCO > 10 %, aucun n’avait d’amelioration de la CV > 10 % ou de la PaO2 > 10 mmHg. A M12, 3/9 patients amelioraient la DLCO et la PaO2, 3 autres etaient stables, alors que 3 autres s’aggravaient. Enfin, 1/9 patient ameliorait la CV > 10 %, 1/9 diminuait la CV > 10 %, les autres etaient stables. Aucun des 3 patients repondeurs n’a recu d’autre traitement concomitant de la LPA. L’analyse des scanners est en cours. Le taux d’anticorps anti-GMCSF a significativement diminue chez 4/6 patients. Aucun effet indesirable severe n’a ete observe. Conclusion Le pourcentage de repondeurs au rituximab dans cette serie est beaucoup plus faible que ce qui a ete rapporte par Kavuru et al. [1] . La place du rituximab dans le traitement de la LPA auto-immune reste a definir.