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International audience; IPF is a devastating lung disease with limited therapeutic possibilities. FGF19, an endocrine FGF, was recently shown to decrease liver fibrosis. To ask whether FGF19 had anti-fibrotic properties in the lung and decipher its effects on common features associated with lung fibrogenesis. We assessed, by Elisa, FGF19 levels in plasma and bronchoalveolar lavage fluids (BALF)obtained from controls and IPF patients. In vivo, using an intravenously administered adeno11 associated virus (AAV), we overexpressed FGF19 at the fibrotic phase of two experimental models of murine lung fibrosis and assessed its effect on lung morphology, lung collagen content, fibrosis markers and pro fibrotic mediator expression, at mRNA and protein levels. In vitro, we investigated whether FGF19 could modulate the TGFβ-induced differentiation of primary human lung fibroblast into myofibroblast and the apoptosis of murine alveolar type II cell. While FGF19 was not detected in BALF, FGF19 concentration was decreased in the plasma of IPF patients compared to controls. In vivo, the overexpression of FGF19 was associated with a marked decrease of lung fibrosis and fibrosis markers, with a decrease of pro fibrotic mediator expression and lung collagen content. In vitro, FGF19 decreased alveolar type 2 epithelial cell apoptosis through the decrease of the proapoptotic BIM protein expression and prevented TGF-ß induced myofibroblast differentiation through the inhibition of JNK phosphorylation. Altogether these data identify FGF19 as an anti-fibrotic molecule with a potential therapeutic interest in fibrotic lung disorders.

Matrix remodeling is a salient feature of idiopathic pulmonary fibrosis (IPF). Targeting cells driving matrix production and remodeling could be a promising avenue for IPF treatment. Analysis of public transcriptomic database identified paired-related homeobox protein-1 (PRRX1) as an upregulated mesenchymal transcription factor (TF) in IPF. We confirmed that PRRX1 isoforms were upregulated in IPF lung tissue and strongly expressed by lung fibroblasts. In vitro, PRRX1 expression was up-regulated by cues associated with proliferative and anti-fibrotic properties in lung fibroblasts, while IPF fibroblast-derived matrix increased PRRX1 TFs expression in a PDGFR dependent manner in control ones. Meanwhile, signals promoting myofibroblastic differentiation decreased PRRX1 TF. We demonstrated that PRRX1 inhibition decreased fibroblast proliferation by downregulating the expression of S phase cyclins. PRRX1 inhibition also impacted TGF-{beta} driven myofibroblastic differentiation by inhibiting SMAD2/3 phosphorylation through phosphatase PPM1A upregulation and TGFBR2 downregulation, leading to a TGF-{beta} response global decrease. Finally, targeted inhibition of Prrx1 TFs attenuated fibrotic remodeling both in vivo with intra-tracheal antisense oligonucleotides in the bleomycin mice model of lung fibrosis and ex vivo using mouse and Human precision-cut lung slices stimulated with fibrosis cytokine cocktail. Altogether, our results identified PRRX1 as a mesenchymal transcription factor driving myofibroblastic phenotype and lung fibrogenesis. Brief SummaryInhibition of a single fibroblast-associated transcription factor, namely paired-related homeobox protein 1, is sufficient to dampen lung fibrogenesis.

Idiopathic pulmonary fibrosis (IPF) is characterised by an important remodelling of lung parenchyma. Current evidence indicates that the disease is triggered by alveolar epithelium activation following chronic lung injury, resulting in alveolar epithelial type 2 cell hyperplasia and bronchiolisation of alveoli. Signals are then delivered to fibroblasts that undergo differentiation into myofibroblasts. These changes in lung architecture require the activation of developmental pathways that are important regulators of cell transformation, growth and migration. Among others, aberrant expression of profibrotic Wnt-β-catenin, transforming growth factor-β and Sonic hedgehog pathways in IPF fibroblasts has been assessed. In the present review, we will discuss the transcriptional integration of these different pathways during IPF as compared with lung early ontogeny. We will challenge the hypothesis that aberrant transcriptional integration of these pathways might be under the control of a chaotic dynamic, meaning that a small change in baseline conditions could be sufficient to trigger fibrosis rather than repair in a chronically injured lung. Finally, we will discuss some potential opportunities for treatment, either by suppressing deleterious mechanisms or by enhancing the expression of pathways involved in lung repair. Whether developmental mechanisms are involved in repair processes induced by stem cell therapy will also be discussed.

Patients with interstitial lung disease have been considered at high risk of complications of COVID-19 because of their underlying lung disease and use of immunosuppressive agents.1 However, data on COVID-19 in patients with sarcoidosis are scarce.2–4 Several reasons for an increased risk of severe forms of COVID-19 among sarcoidosis patients have been hypothesised: the involvement of the lung in almost 90% of patients with COVID-19, some of whom have reduced pulmonary function and comorbidities such as diabetes or hypertension, which are largely associated with the use of glucocorticosteroids for treating sarcoidosis; and the use of immunosuppressive agents in a subset of these patients.5 Recently, Gyorfi et al 6 described the case of a patient with sarcoidosis who experienced a symptomatic SARS-CoV-2 infection with spontaneous clinical improvement, and a virological relapse after steroids treatment. This case illustrated the fact that immunosuppression with glucocorticoids may induce relapse of COVID-19 in patients with sarcoidosis. However, we lack data on the outcomes of patients with sarcoidosis affected by COVID-19. We retrospectively collected data for all patients with sarcoidosis and SARS-CoV-2 infection seen among 15 French centres between 1 March and 20 May 2020. The inclusion criteria were a sarcoidosis diagnosis based on the American Thoracic Society/European Respiratory Society/World Association for Sarcoidosis and other granulomatous diseases …

Idiopathic pulmonary fibrosis (IPF) is characterized by the deposition of excessive extracellular matrix and the destruction of lung parenchyma, resulting from an aberrant wound-healing response. Although IPF is often associated with an imbalance in protease activity, the mechanisms underlying the sustained repair mechanisms are not fully understood. Here, we addressed the role of the recently identified, membrane-anchored serine protease human airway trypsin-like protease (HAT). In the present study, we show that both HAT expression and activity were up-regulated in human IPF specimens. Next, adenoviral overexpression of HAT before bleomycin challenge attenuated lung injury as well as extracellular matrix deposition in the bleomycin-induced pulmonary fibrosis model. In vitro, HAT prevented specific fibrosis-associated responses in primary human pulmonary fibroblasts and induced the expression of mediators associated with the prostaglandin E2 pathway. Altogether, our findings suggested that HAT could have a protective role in IPF and other fibrotic lung disorders.-Menou, A., Flajolet, P., Duitmen, J., Justet, A., Moog, S., Jaillet, M., Tabèze, L., Solhonne, B., Garnier, M., Mal, H., Mordant, P., Castier, Y., Cazes, A., Sallenave, J.-M., Mailleux, A. A., Crestani, B. Human airway trypsin-like protease exerts potent, antifibrotic action in pulmonary fibrosis.

CERVOXY CLIN; International audience; We present the cases of two laryngectomised patients who were treated for granulomas of the tracheostomy orifice with a silver nitrate pencil. During tracheostomy care, the tip broke off, was aspirated and fell into the bronchial tree. Necrotising ulcerative injuries of the right bronchial tree with clear delineation were found without lesions in the subsegmental division. To prevent the risk of secondary stenosis of the small airways induced by the spread of silver nitrate, we did not irrigate with saline solution as previously reported. Antibiotherapy and endoscopic monitoring were performed. Complete healing in 4–6 weeks was found without stenosis of the bronchial tree or bleeding.

International audience; Fibroblast growth factor 9 (FGF9) is necessary for fetal lung development and is expressed by epithelium and mesothelium. We evaluated the role of FGF9 overexpression on adenoviral-induced pleural injury in vivo and determined the biological effects of FGF9 on mesothelial cells in vitro. We assessed the expression of FGF9 and FGF receptors by mesothelial cells in both human and mouse lungs. Intrapleural injection of an adenovirus expressing human FGF9 (AdFGF9) or a control adenovirus (AdCont) was performed. Mice were euthanized at days 3, 5, and 14 Expression of FGF9 and markers of inflammation and myofibroblastic differentiation was studied by qPCR and immunohistochemistry. In vitro, rat mesothelial cells were stimulated with FGF9 (20 ng/ml), and we assessed its effect on proliferation, survival, migration, and differentiation. FGF9 was expressed by mesothelial cells in human idiopathic pulmonary fibrosis. FGF receptors, mainly FGFR3, were expressed by mesothelial cells in vivo in humans and mice. AdCont instillation induced diffuse pleural thickening appearing at day 5, maximal at day 14 The altered pleura cells strongly expressed α-smooth muscle actin and collagen. AdFGF9 injection induced maximal FGF9 expression at day 5 that lasted until day 14 FGF9 overexpression prevented pleural thickening, collagen and fibronectin accumulation, and myofibroblastic differentiation of mesothelial cells. In vitro, FGF9 decreased mesothelial cell migration and inhibited the differentiating effect of transforming growth factor-β1. We conclude that FGF9 has a potential antifibrotic effect on mesothelial cells.

Background Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by an unpredictable course. Prognostic markers and disease activity markers are needed. The purpose of this single-center retrospective study was to evaluate the prognostic value of lung fluorodeoxyglucose ([18F]-FDG) uptake assessed by standardized uptake value (SUV), metabolic lung volume (MLV) and total lesion glycolysis (TLG) in patients with IPF. Methods We included 27 IPF patients (IPF group) and 15 patients with a gastrointestinal neuroendocrine tumor without thoracic involvement (control group). We quantified lung SUV mean and SUV max, MLV and TLG and assessed clinical data, high-resolution CT (HRCT) fibrosis and ground-glass score; lung function; gender, age, physiology (GAP) stage at inclusion and during follow-up; and survival. Results Lung SUV mean and SUV max were higher in IPF patients than controls (p

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently discovered coronavirus, is responsible for COVID-19, a newly emerged disease that has become pandemic. SARS-CoV-2 infection leads to direct tissue injury, especially of the lungs, but can also trigger an exaggerated host immune response. Indeed, the pathogeny of proinflammatory cytokine storm is now demonstrated in COVID-19.1 Besides interleukin (IL)-6 blockade,2 we and others1 hypothesised that targeting IL-1 should be a safe and effective approach to avoid mechanic ventilation in patients with moderate to severe COVID-19 pneumonia (P-MSP) hospitalised in a non-intensive care unit (ICU). About one-third of P-MSPs experience acute respiratory distress syndrome and/or ICU admission with a lethality rate of 60.5%.2 3 We observed similar outcomes in our institution and therefore proposed anti-IL-1 blocking by anakinra to nine …

Introduction: IPF is characterized by a reactivation of signaling pathways involved in lung development, such as Fibroblast Growth Factors (FGF). FGFR4 is a FGF receptor activated by endocrine FGF like FGF19. FGFR4 is expressed in the normal and fibrotic lung. Recent evidence indicates that overexpression of FGF19 have antifibrotic properties in experimental liver fibrosis. The aim of this study was to determine the lung anti fibrotic properties of FGF19 in vitro and in vivo Material and Methods: We assessed FGF19 in plasma by Elisa from controls and IPF patients. Human lung fibroblasts from IPF and control patients were stimulated by TGF s (1ng/mL) with or without FGF19 (20 ng/mL) during 30 minutes or 48 hours. Adeno-associated virus-FGF19 (AAV-FGF19) or a control (AAV-GFP) (6x1010 viral genomes) was IV administered in C56/Bl6 male mice at day 0. Intratracheal administration of bleomycine was realized at day 14. ELISA studied mice at day 28. We quantified plasma FGF-19 levels. We assessed inflammation and pro fibrotic markers by qPCR, and western blot. Results: Compared to controls, FGF19 level plasma was significantly decreased in plasma from IPF patients. In vitro, FGF19 prevented the TGFs induced myofibroblast differentiation by decreasing αSMA, Collagen1, fibronectin expression (mRNA and protein levels.) and JNK phosphorylation. In vivo, the AAV-FGF19 group showed significantly less lung fibrosis and a decrease of fibrosis marker at mRNA and protein levels 14 days after bleomycine exposure. Conclusion and Perspective: FGF19 have anti-fibrotic properties in the lung and could be an innovative therapeutic target in IPF. Further studies are needed to determine the implication of FGFR4 in FGF19 anti fibrotic properties.

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.

Introduction Au cours de la fibrose pulmonaire idiopathique (FPI) les voies de signalisation du developpement telles que la voie des Fibroblast Growth Factors (FGF) sont reactivees. Le recepteur FGFR4 a ete suggere comme possible modulateur de la fibrogenese. L’invalidation de Fgfr4 favoriserait le developpement de la fibrose hepatique apres exposition au tetrachloride carbone chez la souris. Nous nous sommes interesses a l’implication de FGFR4 dans la fibrogenese pulmonaire. Methodes L’expression de FGFR4 a ete determinee dans des extraits de poumons totaux de FPI ou de temoins (Western blot, RT-PCR). Le developpement de la fibrose pulmonaire a ete evalue dans un modele murin apres injection intra-tracheale unique de bleomycine (40 μg) chez des souris Fgfr4 -/- et des souris Wild type (WT) littermates, et apres inhibition pharmacologique specifique de FGFR4 par l’inhibiteur Z chez des souris WT par rapport a un groupe controle recevant le solvant seul. L’inhibiteur Z a ete administre par gavage selon un modele preventif de J-1, veille de l’injection de bleomycine, a J14, et selon un modele therapeutique de J7 a J14. La morphologie pulmonaire, le contenu pulmonaire en hydroxyproline et l’expression en RT-PCR et Western blot de marqueurs de fibrose (collagene, fibronectine, l’α-actine du muscle lisse) ont ete evalues. Resultat L’expression de FGFR4 etait diminuee dans des extraits pulmonaires de patients FPI par rapport aux temoins, au niveau proteique et en ARNm. Les souris Fgfr4-/- ne presentaient pas de difference par rapport aux WT concernant le score de fibrose apres injection de bleomycine. Le niveau d’expression proteique du collagene etait diminue chez les souris Fgfr4-/-, cependant le contenu en hydroyproline n’etait pas modifie. Une augmentation de l’α-actine du muscle lisse etait observee au niveau proteique, sans difference significative pour la fibronectine. L’inhibition de FGFR4 par l’inhibiteur Z, n’induisait aucune difference phenotypique par rapport aux souris controles. Conclusion L’expression pulmonaire de FGFR4 etait diminuee au cours de la FPI. Cependant, l’invalidation de Fgfr4 et l’inhibition pharmacologique de FGFR4 ne modifiaient pas le developpement de la fibrose bleomycine-induite chez la souris. Ces donnees ne soutiennent pas l’hypothese d’une implication de FGFR4 dans la physiopathologie de la FPI.

Introduction Les donnees sur l’infection a Sars-Cov-2 chez les patients atteints de sarcoidose sont rares. L’hypothese d’un risque accru de formes severes de Covid-19 dans cette population a ete soulevee, du fait de l’atteinte pulmonaire sous-jacente, des comorbidites associees a l’utilisation de corticoides, et l’utilisation d’immunosuppresseurs. Nous decrivons ici la presentation clinique et le pronostic de l’infection a Sars-Cov-2 chez des patients atteints de sarcoidose a partir d’un registre multicentrique francais. Methodes Nous avons collecte retrospectivement les donnees de tous les patients atteints de sarcoidose et d’infection a Sars-Cov-2 vus dans 15 centres francais, entre le 1er mars et le 1er septembre 2020. Les criteres d’inclusion etaient un diagnostic de sarcoidose selon les criteres ATS/ERS/WASOG, et une infection a Sars-Cov-2 definie par une RT-PCR sur ecouvillon nasopharynge ou tracheal positif ou une serologie positive. Resultats Un total de 36 patients a ete inclus. La majorite des patients (72%) etaient des hommes, avec un âge median a l’infection a Sars-Cov-2 de 54,5 ans (29–100) et une duree mediane d’evolution de la sarcoidose de 10 ans (0–50) au moment de l’infection. Plus de 95% des patients avaient une atteinte ganglionnaire intrathoracique ou une atteinte parenchymateuse pulmonaire, et 33% avaient une fibrose pulmonaire. La presentation clinique de Covid-19 etait classique, et comprenait de la fievre chez la plupart des patients (67%), malgre l’utilisation de corticoides. Vingt-cinq (69%) patients prenaient un traitement par corticoides au long cours au moment de l’infection, avec une dose quotidienne mediane de 7,7 mg (5–50). Les corticoides ont ete arretes chez 1 patient au moment de l’infection. Le methotrexate a ete plus frequemment arrete au moment de l’infection, chez 4/8 (50%) patients. Parmi les 6 patients sous anti-TNF-alpha, le traitement a ete temporairement suspendu chez tous. Cinq patients sont decedes au cours de l’infection a Sars-Cov-2: 4 d’une insuffisance respiratoire aigue et le dernier d’une hypercapnie non controlee dans un contexte d’obesite. Deux de ces patients presentaient une insuffisance renale chronique, une etait sous hemodialyse et l’autre avait presente une insuffisance renale aigue compliquant la maladie renale chronique. Un total de 13 patients (36%) a ete admis en reanimation. Conclusion Ces donnees nationales montrent que la sarcoidose n’est pas associee a un exces de formes severes d’infection a Sars-Cov-2.

Idiopathic pulmonary fibrosis (IPF) is a deadly disease with a median survival of approximately three years in historical cohorts. Despite increased knowledge of disease pathophysiology and selection of more targeted therapy, main clinical trials yielded negative results. However, two agents, pirfenidone and nintedanib, were recently shown to be effective in IPF and received marketing authorization worldwide. Both drugs significantly reduce functional decline and disease progression with an acceptable safety profile. Yet, none of these drugs actually improves or even stabilizes the disease or the symptoms perceived by the patient. Several other treatments and combinations are currently tested, and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF.

Introduction: Centers dedicated to severe asthma (SA) patients have demonstrated benefits on asthma control in the UK. Our center offers a systematic assessment of SA patients, which includes an outpatient visit with an asthma specialist, followed by a one-day in hospital evaluation, including evaluation of asthma diagnosis, and educational and environmental assessment by a multidisciplinary team. This is a retrospective evaluation of the patients selected for the one-day visit between 2014 and 2016. Results: During this period, 201 patients were referred for the one-day evaluation. After the visit, the diagnosis of asthma was refuted in 36 (18%) of the patients. Poor adherence to treatment was found in 31 (15%) patients. Finally 102 (51%) of the patients were considered to have SA. 88% of the patients were referred by a pulmonologist. Median asthma duration before the visit was 24 yrs (1-74). One third of the patients received daily oral steroids and 20% previously failed to improve after an omalizumab trial. Pulmonary rehabilitation was proposed to 6 among the SA patients and nocturnal ventilation for obstructive sleep apnea to 4. Fourteen patients were included in a therapeutic trial and excluded from final analysis. Omalizumab was prescribed to 25 patients, daily course of steroids to 4 and thermoplasty to 9. During the 12months-follow-up, we observed a significant improvement in asthma control (mean ACT score changed from 13±5 to 16±5.3, p Conclusion: A multidisciplinary approach in a specialized center improves SA outcomes.

IPF is characterized by a reactivation of signaling pathways involved in lung development, such as Fibroblast Growth Factors (FGF). FGFR4 is a FGF receptor activated by endocrine FGFs, such as FGF19, in the presence of the co-receptor s klotho. Recent evidence indicates that complete deletion of FGFR4 and Fgf15 (murine orthologue of FGF19) leads to increased liver fibrosis suggesting that the FGFR4/FGF19 axis has some antifibrotic properties. The aim of this work was to study the regulation of FGFR4 expression and to assess the effect of its activation/inibition on the lung fibroblast phenotype. Material and Methods: We assessed FGFR4, s klotho and FGF19 expression by immunohistochemistry RT-PCR in lung tissue from controls and IPF patients. Human lung fibroblasts from IPF and control patients were stimulated in vitro with pro- or anti-fibrotic factors with or without FGF19 (20 ng/mL) during 48 hours. We studied the expression of FGFR4 at mRNA level and assessed the effect of FGF19 on fibroblast differentiation, proliferation and migration. Results: FGFR4 and s klotho were expressed by alveolar epithelial cells and by lung fibroblast in IPF lung, while FGF19 was not detected. FGFR4 mRNA expression by control and IPF fibroblasts was downregulated by pro fibrotic factors (TGFβ, CTGF, ET-1) and up-regulated by HGF. FGF9 prevented the TGFs- induced myofibroblast differentiation by significantly decreasing αSMA, Collagen1 , fibronectin, PAI-1 and CTGF at mRNA and protein levels. FGF19 increased fibroblast migration but didn9t influence proliferation. Conclusion: FGF19 inhibits TGFβ-induced differentiation in vitro. FGF19 may have anti-fibrotic properties in the lung which need to be documented in vivo.

In this retrospective study, a beneficial effect of pirfenidone on lung function decline could not be demonstrated in patients carrying TERT/TERC mutation

Background Autoantibodies against lung epithelial antigens are often detected in patients with Idiopathic Pulmonary Fibrosis (IPF). Anti-Parietal Cell Antibodies (APCA) target the H+/K+ATPase (proton pump). APCA prevalence and lung H+/K+ATPase expression was never studied in IPF patients. Methods We retrospectively collected clinical, lung function and imaging data from APCA positive patients (APCA+IPF) and compared them with APCA negative IPF patients matched on the date of diagnostic assessment. H+/K+ATPase expression was assessed with immunohistochemistry and PCR. Results Among 138 IPF patients diagnosed between 2007 and 2014 and tested for APCA, 19 (13.7%) APCA+ patients were identified. APCA+IPF patients were 16 men and 3 women, mean age 71 years. The median titer of APCA was 1:160. A pernicious anemia was present in 5 patients and preceded the fibrosis in 3 cases. With a mean follow up of 31 months, 2 patients had an exacerbation and 7 patients died. As compared with 19 APCA- IPF patients, APCA+IPF patients had a less severe disease with better DLCO (57% vs 43% predicted), preserved PaO2 (85 ± 8 mmHg vs 74 ± 11 mmHg), a lower rate of honeycombing on HRCT (58% vs 89%), but they experienced an accelerated decline of FVC (difference 61.4 ml/year; p = .0002). The H+/K+ATPase was strongly expressed by hyperplastic alveolar epithelial cells in the fibrotic lung. Conclusion Anti-parietal cell autoimmunity is detected in some IPF patients and is associated with an accelerated decline of lung function. Anti-parietal cell autoimmunity may promote lung fibrosis progression.

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

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

Introduction Une eosinophilie sanguine autour de 500/mm3 est banale chez un asthmatique, liee a l’inflammation T2. Lorsqu’elle depasse 1500/mm3, decrite chez 0,3 % des asthmatiques [1] , elle doit faire rechercher d’autres causes, comme une aspergillose bronchopulmonaire allergique, une vascularite mais aussi des parasitoses ou des hemopathies lymphoides ou myeloides. Methodes Tous les patients asthmatiques severes ayant une hypereosinophilie sanguine (> 1500/mm3) suivis dans notre centre beneficient d’une recherche systematique d’anomalie clonale (mutation V617F de Janus Kinase 2, JAK2 ; translocation FIP1L1-PDGFRalpha, PDGFRbeta, FGFR1, recherche d’un clone T circulant). Nous rapportons ici les cas de 3 patients asthmatiques hypereosinophiles porteurs d’une mutation de JAK2. Resultats Les 3 patients (2 femmes, 1 homme) avaient un asthme atopique debute a l’adolescence pour 1 et dans l’enfance pour les 2 autres, s’aggravant a l’âge adulte a 30, 40 et 58 ans, respectivement. La recrudescence des symptomes s’accompagnait d’une hypereosinophile sanguine jusqu’a 2000/mm3 pour 2 malades et 4500 pour le 3e, avec presence d’infiltrats pulmonaires chez les 3 patients. A cette occasion, une mutation V617F de JAK2 a ete decouverte chez les 3 patients. Un patient avait un antecedent de thrombose veineuse profonde et une patiente un antecedent de thrombose arterielle radiale, justifiant un traitement anticoagulant au long cours. Une patiente presentait au moment du diagnostic une thrombocytemie autour de 600 000/mm3 et un syndrome myeloproliferatif confirme sur la biopsie osteomedullaire traite par hydrea associe a une corticotherapie orale a 10 mg/j. Chez une patiente, les taux de tryptase et de vitamine B12 etaient eleves, evocateurs de syndrome myeloproliferatif, mais sans autre anomalie de la formule sanguine ou medullaire. Chez le dernier patient, aucun syndrome myeloproliferatif n’a ete retrouve a ce jour, l’asthme est controle avec une corticotherapie orale Conclusion Chez les patients asthmatiques, lorsque l’eosinophilie est superieure a 1500/mm3 et persistante, il convient d’en rechercher d’autres causes, dont une mutation de JAK2, dont la presence peut faire proposer une prise en charge specifique.

In a large subset of patients with asthma, blood eosinophilia is common, as a marker of T helper 2 cell (Th2) inflammation. Hypereosinophilia (HE), defined by blood eosinophil count >1500/mm3, is rare, observed in 0.3% of asthmatic patients [1]. Classically, in the context of uncontrolled asthma and HE, allergic bronchopulmonary aspergillosis, vasculitis or parasitic infection must be investigated [2]. Asthma is also a feature of HE related to various haematological disorders, although respiratory manifestations are rarely isolated in this setting [2]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Tabeze has nothing to disclose. Conflict of interest: Dr. Marchand-Adam has nothing to disclose. Conflict of interest: Dr. BORIE reports grants and personal fees from Boerhinger ingelheim, grants and personal fees from Roche, outside the submitted work. Conflict of interest: Dr. JUSTET has nothing to disclose. Conflict of interest: Dr. DOMBRET has nothing to disclose. Conflict of interest: Dr. CRESTANI reports grants and personal fees from Boerhinger ingelheim, grants and personal fees from Roche, grants from Apellis, personal fees from Astra Zeneca, grants from Medimmune, personal fees from Sanofi, outside the submitted work. Conflict of interest: Dr. TAILLE reports personal fees and other from Astra Zeneca, personal fees and other from Boeringher, personal fees from Chiesi, grants, personal fees and other from GSK, personal fees and other from Novartis, personal fees from Teva, personal fees and other from ALK, other from Sanofi, outside the submitted work. Conflict of interest: Dr. Dupin has nothing to disclose.

Introduction Une atteinte des petites voies aeriennes serait particulierement frequente au cours du syndrome de Gougerot-Sjogren (SGS) primitif. Les objectifs de cette etude etaient de decrire la presentation clinicoradiologique et le profil evolutif de patients atteints d’un SGS primitif et presentant une atteinte bronchiolaire predominante. Methodes Nous avons identifie tous les patients de notre centre qui presentaient un SGS primitif defini selon les criteres de 2016 et une atteinte des petites voies aeriennes definie par le scanner et/ou l’histologie. Nous avons exclu les patients qui presentaient une autre connectivite, une autre cause de maladie bronchiolaire ou une atteinte interstitielle predominante sur l’imagerie. Resultats Parmi 172 patients atteints de SGS dans la base de donnees, nous avons identifie 25 patients, dont 23 femmes (92 %) avec une predominance de non-fumeurs (75 %), d’âge moyen 62 ans (32–85 ans). Tous presentaient des symptomes respiratoires chroniques. Le delai entre le diagnostic de SGS et le diagnostic de l’atteinte respiratoire etait de 48 mois (0–150 mois). L’atteinte respiratoire etait revelatrice chez 5 patients. Les EFR montraient un trouble ventilatoire obstructif chez 8 patients (VEMS 55 %, 35–105 %), et un trouble ventilatoire restrictif chez 2 patients, parmi les 15 patients avec une EFR sans trouble ventilatoire, le DEM 25–75 etait diminue chez 10 d’entre eux. Le scanner montrait un aspect de perfusion en mosaique avec trappage aerique (86 %), des bronchectasies (67 %) et des micronodules centrolobulaires avec aspect d’arbre en bourgeon (33 %), des kystes (30 %) et des anomalies interstitielles (30 %). L’examen microbiologique detectait une colonisation bacterienne chez 2 patients (S. aureus, P. aeruginosa). Le suivi moyen etait de 5,9 annees (1 a 12 ans). 6 patients (24 %) ont recu des macrolides, 10 (40 %) une corticotherapie inhalee, 12 (48 %) une corticotherapie par voie systemique et 7 (28 %) un traitement immunosuppresseur. Au cours du suivi, le VEMS (n = 21) etait stable chez 13 patients (62 %), ameliorees chez 4 patients (19 %) et degradees chez 4 patients (19 %). Un patient a evolue vers une insuffisance respiratoire chronique. Aucun patient n’est decede ou n’a necessite de transplantation pulmonaire. Un scanner de suivi (n = 11) montrait une regression partielle des micronodules, et une stabilite des autres lesions. Conclusion Cette serie retrospective suggere que l’atteinte bronchiolaire au cours du SGS est generalement peu severe fonctionnellement et peu evolutive.

Introduction La Fibrose Pulmonaire Idiopathique (FPI) se caracterise par une reactivation des voies de signalisation impliquees dans le developpement pulmonaire, telles que les facteurs de croissance des fibroblastes (FGF). FGFR4 est un recepteur du FGF active par les FGF endocriniens, tels que le FGF19, en presence du co-recepteur s klotho. Ce recepteur est seul FGFR qui n’est pas cible par le nintedanib, un traitement anti-fibrosant qui a demontre son efficacite dans la FPI. Des donnees recentes indiquent que la deletion complete de FGFR4 et Fgf15 (orthologue murin du FGF19) entraine une augmentation de la fibrose hepatique, ce qui suggere que l’axe FGFR4/FGF19 possede certaines proprietes anti-fibrotiques. Le but de cette etude etait d’etudier la regulation de l’expression de FGFR4 et d’evaluer l’effet de son activation/inhibition sur le phenotype des fibroblastes du poumon. Methodes Nous avons evalue l’expression de FGFR4, s klotho et FGF19 par immunohistochimie RT-PCR dans le tissu pulmonaire de temoins et de patients atteints de FPI. Les fibroblastes du poumon humain provenant de la FPI et des patients temoins ont ete stimules in vitro avec des facteurs pro- ou anti-fibrotiques avec ou sans FGF19 (20 ng/mL) pendant 48 heures. Nous avons etudie l’effet de l’activation de FGFR4 par le FGF19 sur la differenciation, la proliferation et la migration des fibroblastes pulmonaires temoins ou FPI. Resultats FGFR4 et s klotho sont exprimes par les cellules epitheliales alveolaires et par les fibroblastes pulmonaire dans le poumon normal et fibreux. Le FGF19 n’est pas detecte au niveau pulmonaire, en revanche la concentration plasmatique du FGF19 est significativement diminuee chez les patients atteints de FPI par rapport aux controles. La stimulation des fibroblastes pulmonaires par des facteurs profibrotiques (TGFβ, CTGF, ET-1) induit une diminution du contenu en ARNM du FGFR4 alors qu’une stimulation de ces cellules induit une augmentation du contenu en ARN messager de FGFR4. Le FGF19 previent la differenciation des myofibroblastes induite par le TGFs en diminuant significativement contenus proteiques et en ARNm d’αSMA, de collagene 1, de fibronectine, de PAI-1 et de CTGF aux niveaux de l’ARNm et des proteines. Le FGF19 augmente la migration des fibroblastes mais n’influence pas la proliferation. Conclusion L’axe FGFR4/FGF19 a des proprietes anti-fibrotiques in vitro qui doivent etre confirmees in vivo. Cet axe pourrait constituer dans le futur une cible therapeutique innovante dans la FPI.

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.

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.

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible, and lethal lung disease of unknown etiology. IPF begins in the subpleural region and extends centrally. Pleural mesothelial cells may contribute to pleural fibrosis. Key developmental lung signalling pathways such as FGFs are reactivated in IPF. During lung development, FGF9 is expressed in mesothelium and is implicated in the control of epithelial branching and mesenchymal proliferation. We observed that FGF9 is reactivated in pleural cells in IPF patients compared to controls. In this study, we investigated the effects of FGF9 on rat mesothelial cells proliferation, differentiation, and migration in vitro . In basal condition, mesothelial cells mostly expressed receptors with a high affinity for FGF9 (FGFR3IIIc>FGFR2IIIc>FGFR1IIIc). TGFβ1 (5ng/ml) decreased the expression of FGFR3IIIc while FGFR4 expression was increased. In basal condition, FGF9 (20ng/ml) activated p-Erk, did not influence mesothelial cell proliferation, decreased Collagen-1 production, decreased α-smooth muscle actin (α-SMA) and Wilms tumor (WT1) expression and decreased mesothelial cells migratory abilities. FGF9 also partially prevented TGFβ1-induced mesothelial cell differentiation (collagen-1 expression) and migration upregulation. These results suggest that FGF9 modulates mesothelial cells plasticity to maintain an undifferentiated and anti-migratory phenotype and could have an antifibrogenic role in the early phase of IPF.

Introduction: Lung fibrosis is associated with the reactivation of molecular pathways involved in lung development. Mesothelial cells are involved in the fibrotic lung process but their exact role is debated. Fibroblast Growth Factor-9 (FGF-9) is expressed by epithelial cells and visceral pleura during embryonic lung development. Mice homozygous for a targeted disruption of FGF-9 exhibit lung hypoplasia with reduced mesenchyme and early postnatal death. The aim of this study was to evaluate the role of FGF-9 expression by mesothelial cells in the adult lung. We used adenovirus-mediated (FGF-9) gene transfer in mesothelial cells in vivo. Material and Methods: AdFGF9 or a control adenovirus (AdCont) (108pfu/mL) was administered in 100 μl of 0.9% NaCl by pleural injection of C56/Bl6 male mice. Mice were studied at day 3, day 5, and day 14.We quantified FGF-9 in pleural fluid by ELISA. The expression of FGF-9, inflammation and pro fibrotic markers were assessed by qPCR, and immunochemistry. Results: Intrapleural injection of AdCont led to pleural inflammation and pleural remodeling beginning at day 5 and maximal at day 14, with pleural thickening, and accumulation of α-SMA+ cells and collagen. AdCont induced murine FGF-9 expression in the pleura. AdFGF-9 led to human FGF-9 overexpression in the pleural fluid and in the lung at day 5. AdFGF-9 completely inhibited the development of pleural remodeling, with a significant decrease of Collagen I, III, fibronectin, PAI-1, CTGF mRNA expression. Conclusion: Intrapleural injection of adenovirus induces pleural fibrosis. It is prevented by pleural overexpression of human FGF-9 suggesting that mesothelial FGF-9 has anti fibrotic properties.

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.

Introduction La fibrose pulmonaire idiopathique (FPI) est caracterisee par une degradation progressive de la fonction respiratoire. Les facteurs predictifs de l’evolution de la FPI font defaut. L’objectif de cette etude retrospective monocentrique est d’evaluer l’interet pronostique du Total Lesion Glycolysis (TLG), rapport du volume hypermetabolique et du SUV moyen, mesure sur le TEP/FDG dans la FPI. Methodes Vingt-six patients atteints de FPI et non traites ont ete inclus dans cette etude et ont realise un TEP scanner. Nous avons mesure le TLG dans le poumon total et l’avons compare aux donnees cliniques et paracliniques et enfin a la survie. Resultats Le TLG moyen etait de 1426 ± 1030. Le TLG etait correle avec la severite de l’atteinte pulmonaire mesuree par la CVF, la DLCO et le score GAP. En revanche, il n’existait pas de correlation avec l’atteinte tomodensitometrique appreciee par les scores de fibrose et de verre depoli. Le TLG etait associe a la survie sans progression, hazard ratio (IC 95 % : 1,04–1,19 ; p = 0,002). Dans deux analyses multivariees incluant le TLG avec l’âge, la CVF, la DLCO puis avec le score GAP, le TLG restait associe a la survie sans progression (HR = 1,12 ; IC 95 % : 1,03–1,22 ; p = 0.) et (HR = 1,13 ; IC 95 % : 1,0–1,2 ; p = 0,005), respectivement. Conclusion Ces resultats identifient le TLG comme un facteur pronostique independant de la survie sans progression dans la FPI. Ces resultats devront etre confirmes dans de futures etudes prospectives.

La fibrose pulmonaire idiopathique (FPI) est une pathologie incurable et mortelle. Elle debute et predomine dans les regions sous-pleurales. Elle serait la consequence d’une reactivation des voies impliquees dans le developpement pulmonaire et d’une anomalie de communication entre les differentes cellules pulmonaires. Le fibroblast growth factor-9 (FGF-9) est necessaire pour le developpement pulmonaire fœtal. Au cours de la FPI, le FGF-9 est reexprime par les cellules mesotheliales pleurales. L’objectif de ce travail est de determiner l’effet de la surexpression de FGF-9 par les cellules mesotheliales de la plevre au cours du processus fibrosant pulmonaire. Materiel et methodes De souris mâles C56/Bl6 ont recu une injection intrapleurale unique d’un volume de 100 microlitres contenant du serum physiologique (groupe Phy) ou un adenovirus recombine exprimant le FGF-9 humain (groupe AdFGF-9) ou un adenovirus controle (groupe Adcont), a la concentration de 1 × 10 8 pfu/mL. Les souris ont ete sacrifiees a j3, j5, j14 et j25. Le FGF-9 a ete quantifie dans le liquide pleural et le LBA par ELISA. La morphologie pulmonaire et pleurale a ete analysee sur coupe paraffine. L’expression du FGF-9 et des marqueurs d’inflammation et de transformation myofibroblastique a ete etudiee par qPCR et immuno-histochimie. Resultats L’injection d’Adcont entraine un epaississement pleural diffus qui apparait des j5. Il est maximal a j14 et disparait progressivement a j25. Les cellules qui s’accumulent dans la plevre remaniee expriment fortement l’alpha-actine du muscle lisse et le collagene. L’injection d’AdFGF-9 induit une expression de FGF-9 dans le poumon et la cavite pleurale qui est maximale a j5. Dans ce groupe, l’epaississement pleural est minime a j5, et disparait a j14. L’expression de l’ARNm du collagene I et III, de la fibronectine, du PAI-1 et du CTGF sont significativement diminues dans le groupe AdFGF-9. Conclusion L’injection d’un adenovirus dans la cavite pleurale murine induit une fibrose pleurale reversible. Ce phenomene est prevenu par la surexpression pleurale de FGF-9. Ces resultats demontrent que le FGF-9 possede des proprietes anti-fibrosantes.

Introduction Des auto-anticorps diriges contre des antigenes epitheliaux sont souvent detectes chez les patients atteints de fibrose pulmonaire idiopathique (FPI) et posent la question du role d’une auto-immunite muqueuse dans la maladie. Nous decrivons un sous-groupe de patients atteints de pneumopathie interstitielle diffuse idiopathique (PIDI) qui presentent des Ac anti-cellules parietales gastriques (anti-CPG). Methodes Les patients atteints de PIDI vus entre 04/2007 et 12/2014 presentant des anti-CPG positifs sur le bilan diagnostique et sans connectivite definie ont ete identifies. Nous avons recueilli retrospectivement leurs caracteristiques cliniques, biologiques, EFR, tomodensitometriques et evolutives. Resultats Dix-neuf patients ont ete identifies (16 hommes, âge moyen 75 ans, 53 % anciens fumeurs). Le titre median des anti-CPG etait au 1/320e (max > 1280e, min 80e). Douze patients (63 %) presentaient d’autres auto-anticorps a des titres faibles (11 AAN (mediane au 1/80e), 1 p-ANCA anti-MPO, 1 anti-thyroide). Une maladie de Biermer etait presente dans 38 % des cas, et preexistait au diagnostic de fibrose dans 60 % des cas. Lors de l’endoscopie gastrique, 36 % etaient porteurs d’Helicobacter pylori, 85 % presentaient une gastrite atrophique. L’aspect tomodensitometrique etait celui de pneumopathie interstitielle commune certaine (11, 58 %) ou possible (4, 21 %) ou etait inclassable (4, 21 %). Le diagnostic final etait FPI certaine dans 14 cas (73 %) et fibrose inclassable dans 5 cas qui n’avaient pas beneficie de biopsie pulmonaire. Le LBA retrouvait une lymphocytose > 15 % dans 38 % des cas. Avec un suivi moyen de 22 mois, 11 % ont presente une exacerbation et 7 (37 %) sont decedes. Conclusion Nous avons identifie un sous-groupe de patients avec une PIDI (essentiellement FPI) presentant une auto-immunite muqueuse anti-cellules parietales gastriques. La fibrose pulmonaire pourrait favoriser la genese de ces auto-anticorps etant donne l’origine embryologique commune aux voies digestives et respiratoires.

Lung involvement in primary Sjögren syndrome occurs in approximately 10-20% of patients. Tocilizumab, an anti-interleukin-6 receptor antibody, has demonstrated efficacy and safety in small series of systemic sclerosis, and systemic lupus erythematosus, but its effect on interstitial lung manifestations of connective tissue diseases is not well known. We report the use of tocilizumab in a refractory organising pneumonia associated with Sjögren's disease. Our observation suggests that tocilizumab could be an alternative therapeutic in refractory organising pneumonia.

La fibrose pulmonaire idiopathique (FPI) est une pathologie incurable, mortelle, d’incidence croissante et d’evolution imprevisible. Des marqueurs pronostiques et de l’activite de la maladie font defaut. L’objectif de cette etude retrospective monocentrique est d’evaluer l’interet pronostique de la tomographie par emission de positons avec injection de 18F-fluorodesoxyglucose couplee a un scanner thoracique (TEP-scanner). Vingt-sept patients atteints de FPI (groupe FPI), 11 patients atteints de fibrose pulmonaire non idiopathique (groupe PID) et 15 patients suivis pour une tumeur neuroendocrine sans localisation thoracique (groupe temoin) ont realise un TEP scanner. Nous avons mesure le SUV moyen et le SUV maximum pulmonaire et l’avons compare aux donnees cliniques et paracliniques et a la survie. Le SUV moyen ( p p 2 , la CVF et la DLCO, mais pas avec l’atteinte tomodensitometrique appreciee par les scores de fibrose et de verre depoli. Dans le groupe FPI, un SUV moyen superieur a la mediane etait associe a une survie plus courte (Chi 2 = 2,5, p = 0,05). Dans un modele de Cox univarie, l’augmentation du SUV moyen etait associee a un risque de deces plus eleve (Hazard ratio = 1,26, p = 0,058). Cependant, en analyse multivariee, le SUV moyen n’est plus associe a la survie. Nous concluons que l’intensite de fixation pulmonaire du FDG est correlee a la severite de la FPI mais ne constitue pas un facteur pronostique independant de survie.