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The INBUILD trial investigated the efficacy and safety of nintedanib versus placebo in patients with progressive fibrosing interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF). We aimed to establish the effects of nintedanib in subgroups based on ILD diagnosis., info:eu-repo/semantics/published

Interstitial lung diseases (ILDs) can be caused by mutations in theThe consequences of the 11For 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 28This study, which expands the molecular and clinical spectrum of SP-A disorders, shows that pathogenic

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Sarcoidosis is a rare disease of unknown cause with wide heterogeneity in clinical features and outcomes. We aimed to explore sarcoidosis phenotypes and their clinical relevance with particular attention to extrapulmonary subgroups.The Epidemiology of Sarcoidosis (EpiSarc) study is a French retrospective multicentre study. Sarcoidosis patients were identified through national hospitalisation records using appropriate codes from 11 hospital centres between 2013 and 2016 according to a standardised protocol. Medical charts were reviewed. The phenotypes of sarcoidosis were defined using a hierarchical cluster analysis.A total of 1237 patients were included (562 men and 675 women). The mean age at sarcoidosis diagnosis was 43.5±13 years. Hierarchical cluster analysis identified five distinct phenotypes according to organ involvement and disease type and symptoms: 1) erythema nodosum, joint involvement and hilar lymph nodes (n=180); 2) eye, neurological, digestive and kidney involvement (n=137); 3) pulmonary involvement with fibrosis and heart involvement (n=630); 4) lupus pernio and a high percentage of severe involvement (n=41); and 5) hepatosplenic, peripheral lymph node and bone involvement (n=249). Phenotype 1 was associated with being European/Caucasian and female and with non-manual work, phenotype 2 with being European/Caucasian, and phenotypes 3 and 5 with being non-European/Caucasian. The labour worker proportion was significantly lower in phenotype 5 than in the other phenotypes.This multicentre study confirms the existence of distinct phenotypes of sarcoidosis, with a non-random distribution of organ involvement. These phenotypes differ according to sex, geographical origin and socioprofessional category.

Multiple problems may be encountered during the diagnosis of sarcoidosis: at first diagnose sarcoidosis in an appropriate clinical setting, secondly, identify any manifestation to be linked to sarcoidosis at diagnosis work-up and during evolution; thirdly, recognize "danger" in sarcoidosis and parasarcoidosis syndromes, and finally, diagnose sarcoidosis recovery. Diagnosis is often delayed as presentation may be diverse, non-specific, or atypical. Diagnosis of sarcoidosis is based on three criteria: a compatible presentation; evidence of non-caseating granulomas and exclusion of any alternative diagnosis. However, even when all criteria are fulfilled, the probability of sarcoidosis diagnosis varies from definite to only possible depending upon the presence of more or less characteristic radio-clinical and histopathological findings and on the epidemiological context. Bilateral hilar lymphadenopathy and/or diffuse lung micronodules mainly along lymphatics are the most frequent highly suggestive findings. Evidence of granulomas relies on superficial biopsies of clinically suspected lesion when present or most often by bronchial endoscopy. The diagnosis of sarcoidosis may be difficult in absence of thoracic or skin manifestations and may require the benefit of hindsight before being definitive. Differential diagnoses, mainly tuberculosis, must be considered. The diagnosis of events during evolution relies on serial clinical, pulmonary function, radiographic evaluation and on extrapulmonary manifestations work-up, including electrocardiogram and blood biology. Affected organs need to be related to sarcoidosis using an appropriate diagnostic assessment instrument. To declare the recovery of sarcoidosis, all manifestations must have disappeared spontaneously or after 3-5 years post-treatment without relapse.

Sarcoidosis is a systemic granulomatous disease that can reduce life expectancy mainly due to pulmonary fibrosis resulting from granulomatous inflammation The lack of vascularization within pulmonary granulomas suggests that macrophages localized in the center of these structures are hypoxic. Hypoxia signaling pathways are known to be pro-inflammatory and pro-fibrotic in various pathological conditions. Recent data suggest an involvement of the transcription factor hypoxia-inducible factor (HIF) in the pathogenesis of sarcoidosis. This could represent a new research approach for the understanding and therapeutic management of sarcoidosis.

ObjectivesThe predominance of extramuscular manifestations (e.g., skin rash, arthralgia, interstitial lung disease [ILD]) as well as the low frequency of muscle signs in anti–melanoma differentiation-associated gene 5 antibody–positive (anti-MDA5+) dermatomyositis caused us to question the term myositis-specific antibody for the anti-MDA5 antibody, as well as the homogeneity of the disease.MethodsTo characterize the anti-MDA5+ phenotype, an unsupervised analysis was performed on anti-MDA5+ patients (n = 83/121) and compared to a group of patients with myositis without anti-MDA5 antibody (anti-MDA5−; n = 190/201) based on selected variables, collected retrospectively, without any missing data.ResultsWithin anti-MDA5+ patients (n = 83), 3 subgroups were identified. One group (18.1%) corresponded to patients with a rapidly progressive ILD (93.3%; p < 0.0001 across all) and a very high mortality rate. The second subgroup (55.4%) corresponded to patients with pure dermato-rheumatologic symptoms (arthralgia; 82.6%; p < 0.01) and a good prognosis. The third corresponded to patients, mainly male (72.7%; p < 0.0001), with severe skin vasculopathy, frequent signs of myositis (proximal weakness: 68.2%; p < 0.0001), and an intermediate prognosis. Raynaud phenomenon, arthralgia/arthritis, and sex permit the cluster appurtenance (83.3% correct estimation). Nevertheless, an unsupervised analysis confirmed that anti-MDA5 antibody delineates an independent group of patients (e.g., dermatomyositis skin rash, skin ulcers, calcinosis, mechanic's hands, ILD, arthralgia/arthritis, and high mortality rate) distinct from anti-MDA5− patients with myositis.ConclusionAnti-MDA5+ patients have a systemic syndrome distinct from other patients with myositis. Three subgroups with different prognosis exist.

This article discusses a selection of the scientific presentations in the field of interstitial lung diseases (ILDs) that took place at the 2019 European Respiratory Society International Congress in Madrid, Spain. There were sessions from all four groups within Assembly 12: group 12.01 “Idiopathic interstitial pneumonias”, group 12.02 “ILDs/diffuse parenchymal lung diseases (DPLDs) of known origin”, group 12.03 “Sarcoidosis and other granulomatous ILDs/DPLDs” and group 12.04 “Rare ILDs/DPLDs”. The presented studies brought cutting-edge developments on several aspects of these conditions, including pathogenesis, diagnosis and treatment. As many of the ILDs are individually rare, the sharing of experiences and new data that occur during the Congress are very important for physicians interested in ILDs and ILD patients alike., The 2019 #ERSCongress in Madrid provided novel data on interstitial lung diseases https://bit.ly/3iUKMZY

Resume Introduction L’echoendoscopie bronchique (EEB) est une technique peu invasive permettant la realisation de cyto-aspirations transbronchiques guidees d’adenopathies mediastinales. Son utilisation se multiplie et entraine la survenue de complications rares mais graves comme la mediastinite. Observation Une EEB etait realisee chez un homme de 64 ans presentant des adenopathies mediastino-hilaires secondaires a une probable sarcoidose sans preuve histopathologique, avec realisation d’une cytoponction d’une adenopathie sous-carenaire (territoire 7). Dans les heures suivant, la procedure apparaissait une fievre et une toux, puis secondairement un syndrome mediastinal avec dysphonie et dysphagie qui persisterent quatre semaines. Le diagnostic de mediastinite fut finalement evoque sur la conjonction d’un syndrome inflammatoire biologique et d’une collection mediastinale sous-carenaire localisee ponctionnee sous scanner. L’evolution fut rapidement favorable sous antibiotherapie sans recours a une prise en charge chirurgicale. Conclusion La realisation de cyto-aspirations au cours d’une EEB est une cause rare de mediastinite. Les germes habituellement responsables sont des streptocoques commensaux de la cavite buccale, probablement inocules dans le mediastin lors du geste. Un diagnostic precoce et une prise en charge adaptee sont indispensables afin de diminuer l’importante morbi-mortalite associee a ces mediastinites nosocomiales.

Introduction Chronic back pain (CBP) is a frequent complaint in patients with sarcoidosis, which challenges the clinician as multiples causes may potentially underlie this symptom. Interestingly, some reports suggest that the coexistence of sarcoidosis and spondyloarthritis (SpA) may be frequent. This study aimed to determine the prevalence of axial radiographic and non-radiographic SpA in patients with sarcoidosis and CBP and assess the association between patient characteristics and SpA. Methods This cross-sectional study enrolled 64 patients with a diagnosis of sarcoidosis and CBP. Patients describing CBP underwent a full spine MRI and radiography. All patients with inflammatory CBP underwent complementary sacroiliac joint MRI. The diagnosis of axial SpA was based on the Assessment of SpondyloArthritis International Society classification criteria. Results Among the 64 patients (49 women) with sarcoidosis and CBP, 29 had inflammatory pain; 15/64 had a diagnosis of SpA (23.4% [95% CI: 13.7–35.6], 14/29 (48.3% [95% CI: 29.5–67.5] of those with inflammatory back pain). MRI sacroiliitis was found in 13 patients. On both univariate and multivariate analysis, SpA diagnosis was associated with inflammatory CBP (OR=28.5, 95% CI: 1.91–425.4) and sarcoidosis limited to the thorax (OR=6.74, 95% CI: 1.08–42.1). SpA was associated with young age (p = 0.0093) and male sex (p = 0.021) only on univariate analysis. Besides, 12/64 patients (18.8%, 95% CI: 10.1–30.5) had a diagnosis of sarcoidosis spine bone lesions, 7/64 (10.9%, 95% CI: 4.5–21.2) symptomatic vertebral fracture and 30/64 (46.9%, 95% CI: 34.3–59.8) degenerative spine. Conclusions The prevalence of SpA is increased in sarcoidosis patients with inflammatory back pain. The systematic use of spine and sacroiliac MRI in this subgroup is justified. The association between other patient features and SpA needs further confirmation.

Resume La sarcoidose est une granulomatose de cause inconnue avec une atteinte pulmonaire quasi-constante et une evolution difficile a predire. Le diagnostic est retenu dans un triple contexte devant un tableau clinico-radiologique le plus souvent evocateur, la mise en evidence de granulomes typiques sans necrose caseeuse par des biopsies de lesions superficielles, per-endoscopiques bronchiques ou encore ganglionnaires mediastinales sous controle echoendoscopique et l’exclusion des autres causes de granulomatose pouvant donner un meme tableau. La corticotherapie constitue le traitement de premiere ligne en cas d’indication therapeutique, situation rencontree chez la moitie des patients. Les traitements de deuxieme et de troisieme ligne sont respectivement les agents cytotoxiques et les biomedicaments anti-TNF-α. Les formes pulmonaires severes — fibrose sarcoidienne, hypertension pulmonaire, stenoses bronchiques et greffe aspergillaire — sont les premieres causes de morbi-mortalite. Les enjeux dans l’atteinte pulmonaire sont de ne pas meconnaitre un diagnostic alternatif, de savoir quand et comment traiter les patients et de cibler au mieux ceux a risque de developper des formes severes.

Distal lung diseases, such as pulmonary fibrosis or acute lung injury, are commonly associated with local alveolar hypoxia that may be deleterious through the stimulation of alveolar epithelial cell (AEC) apoptosis. In various murine models of alveolar injury, administration of allogenic human mesenchymal stem cells (hMSCs) exerts an overall protective paracrine effect, limiting lung inflammation and fibrosis. However, the precise mechanisms on lung cells themselves remain poorly understood. Here, we investigated whether hMSC-conditioned medium (hMSC-CM) would protect AECs from hypoxia-induced apoptosis and explored the mechanisms involved in this cytoprotective effect. Exposure of rat primary AECs to hypoxia (1.5% O2for 24 h) resulted in hypoxia-inducible factor (HIF)-1α protein stabilization, partly dependent on reactive oxygen species (ROS) accumulation, and in a twofold increase in AEC apoptosis that was prevented by the HIF inhibitor 3-(5′-hydroxymethyl-2′-furyl)-1-benzyl-indazole and the antioxidant drug N-acetyl cysteine. Incubation of AECs with hMSC-CM significantly reduced hypoxia-induced apoptosis. hMSC-CM decreased HIF-1α protein expression, as well as ROS accumulation through an increase in antioxidant enzyme activities. Expression of Bnip3 and CHOP, two proapoptotic targets of HIF-1α and ROS pathways, respectively, was suppressed by hMSC-CM, while Bcl-2 expression was restored. The paracrine protective effect of hMSC was partly dependent on keratinocyte growth factor and hepatocyte growth factor secretion, preventing ROS and HIF-1α accumulation.

Introduction Les patients atteints d’une infection grave par la COVID-19 sont susceptibles de recevoir une assistance respiratoire par pression positive continue (PPC) ou ventilation non invasive (VNI). L’utilisation de ces traitements est associee a une aerosolisation du virus qui peut mettre en danger le personnel soignant et contre laquelle diverses strategies ont ete proposees par les experts, notamment l’utilisation de masques non ventiles avec ajout d’un filtre bacterien sur les circuits inspiratoire et expiratoire. Methodes Etude sur banc d’essai, nous avons utilise une tete en 3D realiste reliee a un poumon mecanique actif (ASL 5000), sur laquelle un masque naso-buccal non ventile (Quattro FX, ResMed) etait applique. Un ventilateur (Astral 150) etait connecte au masque via 8 configurations de circuits rapportees par les experts de la VNI associees a 2 types de filtre antibacterien (basse pression: Iso-Gard, et echangeur de chaleur et d’humidite: Inter-Therm). Les montages etaient (1) masque, filtre et connecteur a angle droit perce d’un orifice de o4 mm; (2) masque, filtre et valve Whisper Swivel II; (3) masque, connecteur en T et valve Whisper Swivel II; (4) masque, piece imprimee en 3D avec orifice de o4 mm, filtre; (5) masque, circuit double branche avec filtre sur les circuits inspiratoire et expiratoire; (6) masque, valve expiratoire active deportee et filtre; (7) masque, filtre et valve expiratoire active droite; (8) masque Helmet, filtre sur les branches inspiratoire et expiratoire ( Fig. 1 ). Resultats L’ajout d’un filtre etait associe a un travail inspiratoire accru (p = 0,001), une pression inspiratoire delivree diminuee (p Fig. 1 ). Les asynchronismes patient-ventilateur (PVA) ainsi que le travail ventilateur n’etaient pas affectes. Le type de montage impactait l’effort requis pour declencher le ventilateur (p Conclusion Les performances des ventilateurs sont influencees par les differentes configurations de circuits proposees pour minimiser l’aerosolisation des particules virales. L’utilisation d’un adaptateur presentant une fuite intentionnelle sur lequel un filtre bacterien peut etre ajuste semble etre la meilleure approche.

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 Les formes rapidement progressives de PID (RP-PID) sont frequentes au cours des dermatomyosites (DM), en particulier associees a un anticorps (AC) anti-MDA5 (PID-MDA5). Les facteurs predictifs de survenue d’une RP-PID sont mal connus. L’objectif principal etait de determiner les elements facteurs predictifs de survenue des formes RP au cours de PID-MDA5. Methodes Il s’agit d’une etude retrospective multicentrique nationale de patients adultes ayant une PID-MDA5. La RP-PID, a ete definie par une deterioration respiratoire ou Resultats 92 patients ont ete inclus (29 (31 %) hommes, âge median 50,1 ans (38,7–58,6), 57,6 % afro-caribeens, 79,3 % non fumeurs) ( Fig. 1 ). CVF mediane: 68 % (52,2–86,8), DLCO mediane: 47 % (40,5–60,5). Des lesions ulcerations etaient notees chez 42.4 % des patients et 69.6 % etaient amyopathiques. L’extension de la PID etait > 20 % chez 34,8 % des patients. Le pattern initial etait le suivant: PINS (33,7 %), PINS-PO (29,3 %), PID indeterminee (19,6 %) et PIA (7,6 %). Le delai de suivi median etait de 36 mois (7.7-63). Douze patients ont presente un pneumomediastin au cours du suivi. Quarante et un patients (44,5 %) avaient une PID-RP. Les donnees demographiques, le tabac, les signes cutanes et musculaires etaient comparables mais les PID-RP avaient une fievre plus frequente (65.9 vs 29.4 % p = 0,001), et plus de condensations (75.6 vs 49 % p = 0,008). Vingt-neuf patients sont decedes dont 25 dans le groupe PID-RP et 3 ont ete greffes, tous dans le groupe PID-RP. L’extension de la PID, la fievre et la ferritinemie au diagnostic etaient associees a la survenue d’une PID-RP en analyse de regression logistique. La survenue d’une PID-RP etait associee a un pronostic defavorable avec 28 % de survie estimee a 5 ans (p Fig. 1 ). Les patients ayant une forme « limitee » avaient une meilleure survie que ceux ayant une forme « etendue » (p = 0,012). Enfin, en analyse multivariee, l’âge, l’extension de la PID, la ferritinemie etaient des facteurs pronostiques associes a la mortalite. Conclusion Dans cette serie francaise de PID-MDA5, la fievre, la ferritinemie et l’extension de la PID au diagnostic sont associes a la survenue d’une PID-RP.

Introduction La vaccination antigrippale est recommandee chaque annee chez les patients atteints de fibrose pulmonaire idiopathique (FPI). Les infections virales sont reconnues comme des triggers d’exacerbation aigue (EA). L’objectif de cette etude etait d’etudier l’influence de la vaccination annuelle contre la grippe sur le risque d’EA. Methodes La cohorte prospective longitudinale multicentrique COhorte FIbrose (COFI) comporte 236 FPI et suivi a dure 5 ans. Le statut de vaccinal contre la grippe a ete demande chaque annee. Nous avons defini la couverture vaccinale du 1er septembre au 30 aout de l’annee suivante. 638 visites annuelles etaient disponibles avec un statut vaccinal renseigne. L’etude entre la vaccination grippale et l’incidence des EA a ete realisee par un premier modele de Cox a effets aleatoire puis par un second modele de Cox en divisant les patients en trois groupes: (1) les patients vaccines chaque annee, (2) ceux vaccines pendant au moins la moitie des annees de suivi, (3) ceux vaccines moins de la moitie des annees de suivi. Resultats Le suivi moyen etait de 33,2 ± 23,6 mois. 36 EA sont survenues chez 33 patients. Sur les 33 patients, seuls 27 avaient un statut vaccinal precise l’annee de l’EA. Neuf (33%) des patients ayant presente une EA n’ont pas ete vaccines. Pour 141 (22%) visites annuelles, les patients n’ont pas ete vaccines. 133 patients ont ete vaccines chaque annee de suivi. 35 ont ete vaccines pendant au moins la moitie des annees de suivi, et 36 patients ont ete vaccines pendant moins de la moitie des annees de suivi. Dans le premier modele, la vaccination contre la grippe est associee a une diminution de la frequence des EA, mais l’association est non significative (HR: 0,58 CI95%0,23–1,46, p = 0,25). Dans le second modele, les patients vaccines pendant moins de la moitie des annees de suivi etaient significativement plus exposes au risque d’EA compares aux patients vaccines chaque annee (HR: 2,77 CI95%1.11–6.93, p = 0,03). Conclusion Dans COFI seulement environ la moitie des patients avaient une couverture vaccinale contre la grippe tout au long du suivi. La vaccination annuelle contre la grippe semble reduire le risque d’EA, mais par manque de puissance, cette association n’etait pas significative. Les patients vaccines pendant moins de la moitie des annees de suivi etaient plus exposes au risque d’EA que les patients vaccines chaque annee.

Introduction Le role du statut socio-economique (SSE) dans l’infection au COVID-19 est mal inconnu. En France mars-avril 2020, le taux de surmortalite lie au COVID-19 le plus eleve a touche la Seine-Saint-Denis (SSD), le departement le plus pauvre du Grand Paris. Methodes Objectifs: comparer le SSE des patients entre deux departements du Grand Paris et de determiner si la precarite est un facteur de risque de severite initiale du COVID-19. Etude multicentrique: CHU Avicenne situe en SSD, et CHU Beaujon et Ambroise-Pare situes dans les Hauts-de-Seine (HDS), un departement riche de la region. Les patients hospitalises en unite COVID-19 ont ete interroges le meme jour (20 avril 2020) sur leur SSE, et le score de precarite EPICES a ete utilise. La severite initiale a l’admission a ete definie par: non severe (O2 30/min, ou O2 > 5L/min, ou etendue de lesions > 50% au TDM), Stade III (admission en reanimation). Une regression logistique a ete utilisee pour identifier les facteurs de severite initiale aux COVID-19. Resultats 190 patients ont ete selectionnes, et 78(41%) exclus (45% pour confusion, 21% barriere de la langue, 15% trop severe, 11% tutelle/curatelle, et 8% de refus).112 patients ont ete inclus (59% hommes, âge: 66,7 ± 16,3 ans, 11% Africains ou Afro-Caribeens, et 8% de fumeurs actifs). Le COVID-19 etait severe dans 59,8% des cas. La distribution de la severite initiale etait similaire dans les deux departements, alors que les patients de SSD avaient 10 ans de moins que ceux des HDS (61,8 ± 14,0 contre 71,0 ± 17,1 ans, p = 0,002). Les patients de SSD presentaient plus de surpoids (29,6 ± 6,08 contre 25,2 ± 5,67, p Conclusion La precarite semble etre associee a la gravite initiale du COVID-19 chez les patients hospitalises de moins de 70 ans. Le faible SSE et les comorbidites pourraient expliquer a la surmortalite observee en SSD, le departement le plus pauvre et le plus jeune du Grand Paris.

Background:Autoantibodies permit to classify and subgroup connective tissue diseases (CTD) in homogeneous groups of patients in terms of phenotype and prognosis. Anti PM-Scl antibodies have been associated with different CTD categories such as: idiopathic inflammatory myositis (IIM), systemic sclerosis (SSc), Sjögren’s syndrome (SjS), systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD) or undifferentiated connective tissue disease (UCTD).Objectives:To determine clinical spectrum of anti-PM-Scl associated disease and if it an homogenous condition.Methods:This multicentric (four hospitals) observational and retrospective study included all consecutive patients with positive testing for anti PM-Scl antibodies on immunoblot assay and connective tissue disease (2011 -2020). Epidemiological, biological, clinical and radiological data were collected in standard form as well as patient’s outcome.Results:One hundred twenty height patients (female n=96;75%) were included. Median [quartiles] age at diagnosis was 50 [18;84] (IQR) and follow-up duration of 7 [3.75-12] years. Seventy-six (59.3%) patients were simple anti-Pm-Scl positive, and 40.7% were associated with other antibodies: anti-SSA/Ro52 (n=13; 10.92%), SSc associated antibodies (n=21; 16.4%), anti-dsDNA for (n=9; 7%), anti-RNP (n=6; 4.7%) and anti-CCP antibodies (n=6; 4.7%). Most patients had cutaneous involvement (n=106; 83%) with skin thickening (n=47; 36%), mechanics hands (n= 28; 22%), calcinosis (n=26; 20.3%) and subcutaneous edema (n=20; 15.62%). Vascular involvement was frequent with Raynaud phenomenon (n= 89; 69%), telangiectasia (n=36; 28%), skin ulcers (n=27; 21%), pulmonary hypertension (n=8/120; 6.7%) and scleroderma renal crisis (n=2; 1.5%). A majority of patients also displayed an interstitial lung disease (ILD) (n=83; 65.8%); nonspecific interstitial pneumonia (92.7%) and/or organizing pneumonia (25.3%). ILD was characterized by a subacute onset in 37/81 (45.7%); median [quartiles] forced vital capacity (FVC) and total lung capacity (TLC) at diagnosis of 88% [73-105] and 79.5% [68.5-101] respectively. Sixty patients (47%) had muscular sign including myalgia (47%), elevated CPK (n=51; 40%) and muscular weakness (Medical Research Council score Conclusion:Conducted on the largest cohort of Anti-PM-Scl patients, this study highlights two main phenotypes that determine different outcome and prognosis. One was associated with muscular disease and subacute onset ILD with more frequent relapses. The second with a vascular phenotype associated with chronic ILD, digestive involvement, chronic evolution and increased incidence of death. This could lead to a reclassification of PM-Scl associated auto immune diseases.Disclosure of Interests:None declared

Context Idiopathic pulmonary fibrosis (IPF) is a severe chronic disease during which anxiety and depression are frequent comorbidities. Better knowledge of patients’ expectations is needed to inform an action plan to improve medical care. Aim To describe feelings and expectations of patients suffering from IPF and of their carers about antifibrotic therapy and compare them to what is perceived by their pulmonologist. Methods National prospective study on practices and perceptions. Specific questionnaires were e-mailed to all 3276 pulmonologists in France who, in turn, invited patients and carers to participate in a survey. Results 147 pulmonologists, 161 patients and 144 carers participated in the survey. The role of the carer was evaluated as “important” or “very important” by more than 90% of participants, i.e. pulmonologists, patients or carers. Inconsistencies between how patients felt and how pulmonologists perceived them were identified: 88% of patients responded that they understood quite well what IPF is (vs. 75% of patients according to pulmonologists); 85.5% of patients said they were determined to fight the disease (vs. 68.0%); 61.7% of patients wanted to be kept informed of potential complications before they occurred (vs. 69.6%) and 81.2% wanted to be involved in therapeutic decisions (vs. 43.1%). Globally, patients had a more positive view of antifibrotic therapies than expected by pulmonologists: 41.5% evaluated their advantages superior to what they had expected (vs. 29.1% of patients according to pulmonologists) and 76.5% had a positive image of the benefits/disadvantages ratio (vs. 62.4%). Although pulmonologists had the impression that they were keeping their patients well-informed about exacerbations, hospital stays and the possible negative evolution of the disease despite antifibrotic therapies, 34.0%, 42.0% and 22.0% of patients respectively declared not being aware of these aspects. Conclusion The feelings of patients suffering from IPF regarding their disease and treatment globally proved more positive compared with how pulmonologists perceived them. Taking into account the expectations and needs of patients may allow healthcare professionals to better address their needs and priorities.

Most cases of sarcoidosis are mild and self-limited, with a spontaneous cure. However, in some patients, this disease may also be life-threatening, particularly when severe manifestations induce vital organ dysfunction. Sarcoidosis may also severely impair the quality of life through diverse, persistent disabling symptoms. To date, there is no curative treatment for sarcoidosis, but only anti-inflammatory drugs limiting the pathologic impact of sarcoidosis in reducing enhanced immunity reactions, granulomatous formation, and their consequences. Current anti-inflammatory treatments for sarcoidosis include corticosteroids as the first-line treatment; disease-modifying antisarcoid drugs, mainly immunosuppressive and immunomodulatory drugs, as second-line treatment; and finally tumor necrosis factor (TNF) inhibitors, as third-line treatment. Corticosteroids are most effective; they give rapid results, sometimes with serious, incremental adverse effects. A second-line treatment, mainly low-dose methotrexate and azathioprine, is indicated in case of corticosteroid resistance, intolerance, or contraindication or more often as a corticosteroid-sparing agent when a prolonged treatment of more than 10 mg/d equivalent prednisone is expected. TNF inhibitors are considered in severe refractory sarcoidosis. Infliximab has been proven effective. Usually, treatment for sarcoidosis lasts up to 1 year or longer. The usual drug regimen is made of an induction and then a maintenance protocol before a step-by-step decrease and eventual withdrawal. Contraindications may exist. Each therapeutic decision must follow a rigorous diagnostic evaluation to determine the disease impact, its outcome (progression or not), and its response to treatment in the long run. Pharmacogenetics is still in its infancy, but could help develop a more personalized therapy. Non anti-inflammatory treatments, such as implantable cardiac devices, are also useful, particularly for some organs. In the end, persistent disabling symptoms are very frequent and call for an accurate diagnosis, which may be difficult to treat.

Sarcoidosis is a granulomatous disorder of unknown cause characterized by non-caseating granuloma in young adults. Cardiac involvement is rare and range from 2 to 75% depending on diagnostic criteria. Cardiac involvement in sarcoidosis may be asymptomatic or may manifest as rhythm/conduction troubles or congestive heart failure. The diagnosis and treatment of cardiac sarcoidosis may be challenging. However, advances have come in recent years from the use of cardiac MRI and 18FDG-TEP scanner, as well as from the stratification of the risk of ventricular tachycardia/fibrillation. Due to the rarity of the disease, there is no reliable prospective large study to guide therapeutic strategy for cardiac sarcoidosis. Corticosteroids are probably efficacious, in particular in case of atrio-ventricular block or moderate heart failure. Immunosuppressive drugs have not been largely studied but methotrexate could be helpful. In refractory forms, TNF-α antagonists have been used with success.

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 sarcoidose (SA) est une affection qui peut reduire l’esperance de vie principalement en raison d’une fibrose pulmonaire induite par le granulome epithelioide, lesion histologique cardinale. Du fait du manque de vascularisation des granulomes, les macrophages constitutifs de ces structures se trouvent en hypoxie (Hx). Le but de notre etude etait de determiner les consequences de l’Hx sur les macrophages dans la perennisation de l’inflammation et le developpement de la fibrose. Methodes Quarante patients atteints de SA pulmonaire (active et inactive) et 31 temoins sains apparies (âge, sexe) ont ete inclus. Leurs monocytes sanguins ont ete cultives 10 jours pour induire leur maturation en macrophages, puis places 24 h en normoxie ou Hx (1,5 % O2). Les macrophages ont ete etudies au niveau des ARNm, de la production cytokinique, des marqueurs de surface et de l’expression et l’activite transactivatrice de HIF1α. L’effet du surnageant des macrophages sur la migration, la proliferation (Ki67) et la differenciation (αSMA) de fibroblastes pulmonaires humains (NHLF) a ete etudie. Resultats L’Hx induit la transcription et de la production de cytokines pro-inflammatoires, profibrosantes et pro-angiogeniques. Cette augmentation est plus marquee dans les formes actives de SA, notamment pour des cytokines induisant une activation des lymphocytes Th1 (TNFα, IL1b, IL18) et pour les cytokines profibrosantes PAI-1, TGFβ1, VEGF-A. L’activite transactivatrice de HIF1α induite par l’Hx est exacerbee dans les SA actives. L’Hx diminue l’expression des marqueurs de polarisation M1 (CD80, CD86) dans les 2 groupes et augmente le marqueur M2 CD163 uniquement pour les SA. La phagocytose et l’expression du recepteur scavenger CD36 sont diminuees chez les temoins en Hx, mais maintenues chez les SA. Le surnageant des macrophages exposes a l’Hx ralentit la migration des NHLF particulierement pour les SA actives, sans modifier leur proliferation. L’inhibition de la migration est inversement correlee au taux de PAI-1 et s’accompagne d’un marquage αSMA des NHLF. Conclusion L’hypoxie via HIF1α pourrait favoriser le maintien du granulome dans la sarcoidose par un effet pro-inflammatoire et l’evolution vers la fibrose par sequestration et differenciation des fibroblastes en myofibroblastes en peripherie du granulome. Travail soutenu par le Fonds de Recherche en sante respiratoire, appel d’offres 2017 emis en commun avec la Fondation du Souffle.

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.

Objective: To compare the efficacy of methotrexate (MTX) and mycophenolate mofetil (MMF) in the prevention of relapses in neurosarcoidosis. Methods: We conducted a retrospective multicenter study including patients who received MTX or MMF for the treatment of histologically proven neurosarcoidosis. The efficacy of the immunosuppressive drug was assessed by determining the time to relapse. Results: Forty patients with a diagnosis of neurosarcoidosis (24 men, 16 women, median age at diagnosis 43.5 years) who received at least 3 months of MTX (n = 32) or MMF (n = 14) were included. The immunosuppressive drug was always associated with steroids. The rate of relapse was 47% in the MTX group (0.2 relapses per year of exposure) and 79% in the MMF group (0.6 relapses per year of exposure) (p = 0.058). The median time to relapse was significantly shorter in the MMF group (11 months) compared with the MTX group (28 months) (p = 0.049). Adverse events occurred in 11 patients during MTX therapy and in 1 patient during MMF therapy (p = 0.12). Conclusions: Relapses of neurosarcoidosis occur frequently, despite the use of an immunosuppressive drug in addition to corticosteroids. MTX significantly increases the survival time without relapse compared to MMF and should be preferred over MMF for the treatment of neurosarcoidosis. This study provides Class IV evidence that for patients with neurosarcoidosis taking steroids, MTX is superior to MMF in reducing the risk of relapse.

Interstitial lung disease (ILD) is a common form of extramuscular involvement in patients with polymyositis/dermatomyositis and is associated with poor prognosis. This study was designed to describe the long-term outcome of myositis-associated ILD. This retrospective observational study was conducted in 48 consecutive patients. Two groups defined according to outcome were compared to determine prognostic factors: a “severe” group (vital capacity [VC]

Introduction La cryptococcose est une mycose cosmopolite due a des levures encapsulees du complexe d’especes Cryptococcus neoformans/Cryptococcus gattii touchant principalement le patient immunodeprime. L’atteinte osteoarticulaire de la cryptococcose est rare. Elle est classee en deux types : la cryptococcose osteoarticulaire associee a une cryptococcose disseminee et la cryptococcose osteoarticulaire primaire, ne touchant pas d’autres tissus. Chez les patients atteints de sarcoidose, la cryptococcose represente jusqu’a 50 % des infections opportunistes. Chez les sujets non-VIH, la sarcoidose est un facteur de risque de cryptococcose independant de la corticotherapie. Or, en cas de cryptococcose associee a une sarcoidose, la prevalence de l’atteinte osteoarticulaire est de 25 % chez les sujets non VIH contre 5 – 10 % chez les sujets VIH. Observation Afin de mieux comprendre l’association forte entre sarcoidose et cryptococcose osteoarticulaire, nous rapportons 3 cas et realisons une analyse systematique des cas publies entre 1960 et aujourd’hui (caracteristiques clinicobiologiques, therapeutiques et pronostiques des sarcoidoses et cryptococcoses), a l’aide des bases de donnees PubMed, Web of Science et Embase. Au total, 36 cas de cryptococcose osteoarticulaire compliquant une sarcoidose ont ete rapportes. L’âge median etait de 37 ± 12 ans avec un ratio H :F de 1. La moyenne de suivi etait de 18 ± 12 mois avec un pronostic favorable dans 87 % des cas. Tous les stades de la sarcoidose etaient representes, stade I (n = 9), II (n = 7), III (n = 3), IV (n = 1) avec 11 atteintes autres que pulmonaire. Vingt patients etaient sous corticoides, 32 presentaient une osteomyelite et 7 une arthrite. Vingt-neuf etaient des cryptococcoses osteoarticulaires primaires. Discussion La sarcoidose est un facteur de risque de cryptococcose osteoarticulaire independamment de l’atteinte, du stade et du traitement. Le ratio H :F de 1 est concordant avec celui de la sarcoidose. L’âge des patients developpant une cryptococcose osteoarticulaire ainsi que la prevalence des corticoides ne sont pas statistiquement differents de celui des patients ayant une autre localisation de la cryptococcose. Conclusion Cette revue systematique de la litterature nous permet de faire une photographie de cette sous-population pour comprendre la forte association entre sarcoidose et cryptococcose osteoarticulaire.

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.

International audience; Background: The syndrome of combined pulmonary fibrosis and emphysema (CPFE) primarily due to tobacco smoking has been reported in connective tissue disease, but little is known about its characteristics in systemic sclerosis (SSc).Methods: In this retrospective multi-center case-control study, we identified 36 SSc patients with CPFE, and compared them with 72 SSc controls with interstitial lung disease (ILD) without emphysema.Results: Rate of CPFE in SSc patients with CT scan was 3.6%, and 7.6% among SSc patients with ILD. CPFE-SSc patients were more likely to be male (75 % vs 18%, p < 0.0001), smokers (83 % vs 33%, p < 0.0001), and to have limited cutaneous SSc (53 % vs 24% p < 0.01) than ILD-SSc controls. No specific autoantibody was significantly associated with CPFE. At diagnosis, CPFE-SSc patients had a greater decrease in carbon monoxide diffusing capacity (DLCO 39 +/- 13 % vs 51 +/- 12% of predicted value, p < 0.0001) when compared to SSc-ILD controls, whereas lung volumes (total lung capacity and forced vital capacity) were similar. During follow-up, CPFE-SSc patients more frequently developed precapillary pulmonary hypertension (PH) (44 % vs 11%, p < 10-4), experienced more frequent unscheduled hospitalizations (50 % vs 25%, p < 0.01), and had decreased survival (p < 0.02 by Kaplan Meier survival analysis) as compared to ILD-SSc controls.Conclusions: The CPFE syndrome is a distinct pulmonary manifestation in SSc, with higher morbidity and mortality. Early diagnosis of CPFE by chest CF in SSc patients (especially smokers) may result in earlier smoking cessation, screening for PH, and appropriate management.

Telomeres are nucleoprotein structures at the end of chromosomes. The telomerase complex, constituted of the catalytic subunit TERT, the RNA matrix hTR and several cofactors, including the H/ACA box ribonucleoproteins Dyskerin, NOP10, GAR1, NAF1 and NHP2, regulates telomere length. In humans, inherited defects in telomere length maintenance are responsible for a wide spectrum of clinical premature aging manifestations including pulmonary fibrosis (PF), dyskeratosis congenita (DC), bone marrow failure and predisposition to cancer. NHP2 mutations have been so far reported only in two patients with DC. Here, we report the first case of Høyeraal–Hreidarsson syndrome, the severe form of DC, caused by biallelic missense mutations in NHP2. Additionally, we identified three unrelated patients with PF carrying NHP2 heterozygous mutations. Strikingly, one of these patients acquired a somatic mutation in the promoter of TERT that likely conferred a selective advantage in a subset of blood cells. Finally, we demonstrate that a functional deficit of human NHP2 affects ribosomal RNA biogenesis. Together, our results broaden the functional consequences and clinical spectrum of NHP2 deficiency.

Rationale: The level of diagnostic likelihood at which physicians prescribe antifibrotic therapy without requesting surgical lung biopsy (SLB) in patients suspected of idiopathic pulmonary fibrosis (IPF) is unknown. Objectives: To determine how often physicians advocate SLB in patient subgroups defined by IPF likelihood and risk associated with SLB, and to identify the level of diagnostic likelihood at which physicians prescribe antifibrotic therapy with requesting SLB. Methods: An international cohort of respiratory physicians evaluated 60 cases of interstitial lung disease, giving: 1) differential diagnoses with diagnostic likelihood; 2) a decision on the need for SLB; and 3) initial management. Diagnoses were stratified according to diagnostic likelihood bands described by Ryerson and colleagues. Measurements and Main Results: A total of 404 physicians evaluated the 60 cases (24,240 physician-patient evaluations). IPF was part of the differential diagnosis in 9,958/24,240 (41.1%) of all physician-patient evaluations. SLB was requested in 8.1%, 29.6%, and 48.4% of definite, provisional high-confidence and provisional low-confidence diagnoses of IPF, respectively. In 63.0% of provisional high-confidence IPF diagnoses, antifibrotic therapy was prescribed without requesting SLB. No significant mortality difference was observed between cases given a definite diagnosis of IPF (90-100% diagnostic likelihood) and cases given a provisional high-confidence IPF diagnosis (hazard ratio, 0.97; P = 0.65; 95% confidence interval, 0.90-1.04). Conclusions: Most respiratory physicians prescribe antifibrotic therapy without requesting an SLB if a provisional high-confidence diagnosis or "working diagnosis" of IPF can be made (likelihood>70%). SLB is recommended in only a minority of patients with suspected, but not definite, IPF.

Lower-respiratory-tract (LRT) amyloidosis has rarely been investigated. Our study presents characteristics, outcomes and survival of LRT amyloidosis. This multicenter retrospective study, from 1995 to 2017, included 73 patients with amyloidosis and LRT involvement. Respiratory patterns were: tracheobronchial (n = 17), nodular (n = 10), interstitial (n = 14) or composite (several respiratory involvements, n = 32). Interstitial and composite patterns were associated with multi-organ amyloidosis (n = 37, 80%) while tracheobronchial and nodular patterns were associated with organ-limited amyloidosis (n = 21, 78%). Amyloid light chain (AL) amyloidosis was diagnosed in 43 patients (59%), mainly of lambda type (n = 33, 77%). Smokers' proportion was higher in tracheobronchial (71%) and nodular (90%) patterns than in interstitial (14%) and composite (34%) patterns. The B-cell neoplasms involved 15 patients (21%), solid neoplasms 8 (11%), connective tissue diseases 8 (11%) and multiple myeloma 6 (8%). The B-cell and solid neoplasms were most prevalent in nodular pattern. Median follow-up was 4.4 years (2.2-8.9). Twenty-four patients died, mostly from respiratory infection. Survival at 1, 5, 10 years was respectively 88%, 70% and 54% for multi-organ amyloidosis, 96%, 89% and 69% for organ-limited amyloidosis (P = .125). Tracheobronchial and nodular patterns survival was better than in other respiratory patterns (P = .039). Death risk factors (multivariate analysis) were: cardiac localization (hazard-ratio [HR] 4.3 [95% confidence interval 1.6-11.5]; P = .004), age (HR 2.1 [1.2-3.7]; P = .008) and dyspnea at diagnosis (HR 4.0 [1.3-12.3]; P = .014). Various LRT amyloidosis patterns depend on smoking habits, organ-limited or multi-organ extension and comorbidities. They are associated with a different survival, which is also predicted by age, cardiac localization and dyspnea at presentation.

Anti-PD1 immunotherapies have become an essential treatment for bronchial cancer. According to published studies, PD1 and PD-L1 inhibitors have a better toxicity profile than chemotherapy. Nevertheless, some immune related toxicities can be potentially severe, such as induced interstitial lung disease (ILD). Currently, ILD patients are excluded from clinical trials using immunotherapy in lung cancer. IPF is the most frequent and severe form of ILD. Lung cancer represents a major complication of this disease and to date few data exist on the safety of immunotherapy in this context. We report 3 cases of IPF with lung cancer treated by nivolumab. All had a clinically mild to moderate IPF. The patients had received at least one line of chemotherapy before nivolumab and had progressive, metastatic lung cancer. Two patients experienced rapid cancer progression without immune toxicities. The third had a partial response but developed grade III immune colitis that led to discontinuation of the treatment. None developed lung toxicity or worsening of IPF on CT during follow-up, and death was always related to progression of the cancer. In our series of three patients with IPF, nivolumab was well tolerated with regard to their pulmonary condition. As inflammation and autoimmunity are probably marginal mechanisms in the pathogenesis of IPF, we do not believe that the presence of IPF should definitely disqualify potential candidates for treatment with nivolumab. Decisions should be taken, case-by-case, in selected patients without severe IPF and with no evidence of autoimmunity. In view of the epidemiology of lung cancer in IPF and the critical role of immunotherapy in the management of lung cancer, studies of prospective cohorts are urgently needed in this population.

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.

This article reviews a selection of the scientific presentations on interstitial lung disease (ILD)/diffuse parenchymal lung disease (DPLD) that were made at the 2018 European Respiratory Society (ERS) International Congress in Paris. A number of advances in the epidemiology, pathogenesis, diagnosis and treatment of these disorders were presented and discussed by clinicians and researchers. The research topics span over all four groups of ERS Assembly 12: Interstitial Lung Diseases (Group 12.01: Idiopathic interstitial pneumonias; Group 12.02: ILD/DPLD of known origin; Group 12.03: Sarcoidosis and other granulomatous ILD/DPLD; Group 12.04: Rare ILD/DPLD)., A selection of the scientific presentations on interstitial lung disease from the 2018 #ERSCongress in Paris http://ow.ly/LAbD30nmsFs

Telomere related gene (TRG) mutations are found in approximately 20% of patients with familial pulmonary fibrosis and are associated with hepatic, cutaneous and hematologic manifestations. Pirfenidone and nintedanib have been shown to slow the decline of FVC of patients with idiopathic pulmonary fibrosis (IPF). There is limited evidence of efficacy and safety of these treatments in IPF patients carrying a TRG mutation. The objective of this retrospective multicenter study was to analyze the efficacy and safety of antifibrotic drugs in IPF patients carrying a TRG mutation. We identified 103 IPF patients carrying a mutation in TERT (n=74), TERC (n=17), RTEL1 (n=10) or PARN (n=3). from 6 countries (France, Netherlands, Belgium, Spain, Greece and Switzerland) Forty-four patients received nintedanib, 59 received pirfenidone. The mean age at diagnosis was 57.9 ± 13.6 years and the median delay between diagnosis and treatment initiation was 6.0 months [3.0-15.1]. At initiation of treatment, the FVC was 80.8% ± 20.2% and the DLCO was 44.0% ± 13.7%. The median duration of treatment was 10.8 months [6.5-18.1]. Antifibrotic treatment was terminated in 18 patients because of progression of the disease and in 15 patients due to intolerable side effects, mainly digestive (nintedanib, n = 9, pirfenidone, n = 6). The median decline in FVC prior to initiation of treatment was 24.5 mL [10.5-30.1] per month. After initiation of treatment, the median decline in FVC was 18.0 mL [9.0-27.0] per month in patients treated with nintedanib and 25.4 mL per month [14.7-36.7] in patients treated with pirfenidone. This retrospective series shows that antifibrotic therapies are well tolerated in IPF patients with TRG mutations. Further analyses are needed to evaluate the efficacy.