Sarcoïdose et aspergillome

PARIS6-Bibl. St Antoine CHU (751122104) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Association sarcoïdose et maladies auto-immunes (étude rétrospective cas-témoins de 33 patients)

Nous rapportons une étude rétrospective mono-centrique comparative cas-témoins réalisée au sein du service de Pneumologie de l hôpital Avicenne. Trente trois patients présentant une ou plusieurs maladies auto-immunes associées à une sarcoïdose, sont comparés à 33 témoins ayant une sarcoïdose isolée et appariés selon l âge, le sexe et la date de prise en charge. Résultats : Les maladies auto-immunes étaient : un syndrome de Gougerot-Sjögren primaire (n=8), une thyroïdite d Hashimoto (n=9), une maladie de Basedow (n=5), une cirrhose biliaire primitive (n=5), un SGS secondaire (n=3), un syndrome des anti-phospholipides (n=2), une polyarthrite rhumatoïde (n=2), un lupus érythémateux disséminé (n=3), et une sclérodermie systémique (n=2). Cette population comportait une majorité de femmes (88%). L âge médian était respectivement de 43,5 ans et 47,5 ans au diagnostic de la sarcoïdose et de la maladie auto-immune. La sarcoïdose était le plus souvent la maladie préexistante (52% des cas). La maladie auto immune était alors décrite à distance du diagnostic de la sarcoïdose (8,5 ans en moyenne). En cas de maladie auto-immune première (27% des cas), la sarcoïdose était décelée dans un délai plus court (10 mois en moyenne). Enfin, pour 7 patients (21%), le diagnostic des deux affections était simultané. Bien que comparable au groupe témoin sur la sévérité, le phénotype clinique des patients était marqué par une prévalence plus importante des arthralgies au diagnostic de la sarcoïdose (p=0,015). Sur le plan biologique, outre la présence plus fréquente d anticorps anti-nucléaires (64% vs 43% chez les témoins), on note que l enzyme de conversion de l angiotensine était le plus souvent normale au diagnostic de la sarcoïdose chez les patients ayant une maladie auto-immune (p=0,008) et que le taux de gammaglobulines était en revanche plus élevé (p=0,04). Enfin, la cellularité du lavage broncho alvéolaire était plus forte (p=0,004). Conclusion : L association d une sarcoïdose avec une voire plusieurs maladies auto-immunes ne semble pas conférer un phénotype plus grave aux patients bien qu il y ait des arguments biologiques pour un environnement cytokinique plus riche.PARIS13-BU Serge Lebovici (930082101) / SudocSudocFranceF

Immunopathogenesis of the Anti-Synthetase Syndrome

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ER Stress is Involved in Epithelial-To-Mesenchymal Transition of Alveolar Epithelial Cells Exposed to a Hypoxic Microenvironment

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal interstitial lung disease of unknown origin. Alveolar epithelial cells (AECs) play an important role in the fibrotic process as they undergo sustained endoplasmic reticulum (ER) stress, and may acquire a mesenchymal phenotype through epithelial-to-mesenchymal transition (EMT), two phenomena that could be induced by localized alveolar hypoxia. Here we investigated the potential links between hypoxia, ER stress and EMT in AECs. Methods: ER stress and EMT markers were assessed by immunohistochemistry, western blot and qPCR analysis, both in vivo in rat lungs exposed to normoxia or hypoxia (equivalent to 8% O2) for 48 h, and in vitro in primary rat AECs exposed to normoxia or hypoxia (1.5% O2) for 2–6 days. Results: Hypoxia induced expression of mesenchymal markers, pro-EMT transcription factors, and the activation of ER stress markers both in vivo in rat lungs, and in vitro in AECs. In vitro, pharmacological inhibition of ER stress by 4-PBA limited hypoxia-induced EMT. Calcium chelation or hypoxia-inducible factor (HIF) inhibition also prevented EMT induction under hypoxic condition. Conclusions: Hypoxia and intracellular calcium are both involved in EMT induction of AECs, mainly through the activation of ER stress and HIF signaling pathways

How to Tackle the Diagnosis and Treatment in the Diverse Scenarios of Extrapulmonary Sarcoidosis

International audienceExtrapulmonary sarcoidosis occurs in 30-50% of cases of sarcoidosis, most often in association with pulmonary involvement, and virtually any organ can be involved. Its incidence depends according to the organs considered, clinical phenotype, and history of sarcoidosis, but also on epidemiological factors like age, sex, geographic ancestry, and socio-professional factors. The presentation, symptomatology, organ dysfunction, severity, and lethal risk vary from and to patient even at the level of the same organ. The presentation may be specific or not, and its occurrence is at variable times in the history of sarcoidosis from initial to delayed. There ar

Extracorporeal life support allows lung transplant in anti-MDA5+ rapidly progressive interstitial lung disease.

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Rituximab and Cyclophosphamide in Antisynthetase Syndrome–related Interstitial Lung Disease: An Observational Retrospective Study

International audienceObjective Antisynthetase syndrome (AS)-related interstitial lung disease (ILD) has a poor prognosis. Intravenous cyclophosphamide (IV CYC) and rituximab (RTX) are the main treatments currently used for moderate to severe ILD. Here, we compare the efficacy of CYC followed by standard immunosuppressive treatment (IST) versus RTX in AS-related ILD. Methods This observational retrospective study was conducted between 2003 and 2016 in 3 tertiary care centers. All patients with AS-related ILD and treated with CYC or RTX with at least 6 months of follow-up were included. Pulmonary progression-free survival (PFS), defined according to the American Thoracic Society guidelines, was assessed at 6 months and 2 years. All severe adverse events (AE) were recorded. Results Sixty-two patients were included. Thirty-four patients received 2–12 monthly IV CYC pulses, followed by standard IST in 30 cases (88%). The RTX group included 28 patients. Following the initial Day 1 to Day 15 infusions, RTX was repeated every 6 months in 26 cases (93%) and 15 patients (54%) concomitantly received another IST. The median steroid dose was similar between both groups. Although RTX and CYC demonstrated similar PFS at 6 months (92% vs 85%, respectively), RTX was superior at 2 years (HR 0.263, 95% CI 0.094–0.732, P = 0.011). Interestingly, lower diffusing lung capacity for carbon monoxide (DLCO) at baseline was independently predictive of poor 2-year PFS [0.965 (0.936–0.995), P = 0.023]. Forced vital capacity and DLCO improved in both groups without significant differences. Serious AE were similar in both groups. Conclusion Despite similar PFS at 6 months, RTX was associated with a better 2-year PFS compared to CYC in patients with AS-related ILD

Mesenchymal stem cells reduce hypoxia-induced apoptosis in alveolar epithelial cells by modulating HIF and ROS hypoxic signaling

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% O 2 for 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