J.-F. Cordier

Interstitial lung disease in amyopathic dermatomyositis, dermatomyositis and polymyositis

This study investigated interstitial pneumonia associated with amyopathic dermatomyositis, dermatomyositis and polymyositis, paying particular attention to muscular and/or cutaneous manifestations and their chronology relative to lung involvement. Patients included four males and 13 females, aged 51.7±10.8 yrs, who had surgical lung biopsy. Diagnoses included dermatomyositis (10 patients), polymyositis (four patients) and amyopathic dermatomyositis (three patients). Solitary respiratory manifestations preceded the onset of any skin or muscle disease in four cases (24%). Reticular and ground glass opacities were the most frequent computed tomography (CT) findings. Pathological review showed nonspecific interstitial pneumonia (eleven, 65%; cellular, two; cellular and fibrotic, five; fibrotic, four), usual interstitial pneumonia (two), organising pneumonia (two), lymphocytic interstitial pneumonia (one), and unclassifiable interstitial pneumonia (one). Nonspecific interstitial pneumonia was the most common histological pattern of interstitial pneumonia in patients with amyopathic dermatomyositis (three of three) and in patients with respiratory symptoms as the initial clinical manifestation of the connective tissue disease (three of four). Survival at 5 yrs was 50%. This study shows the clinician should remain alert to potential muscular or cutaneous manifestations whenever a pathological diagnosis of nonspecific interstitial pneumonia is made.

Eosinophilic granulomatosis with polyangiitis (Churg–Strauss) (EGPA) Consensus Task Force recommendations for evaluation and management

OBJECTIVE To develop disease-specific recommendations for the diagnosis and management of eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome) (EGPA). METHODS The EGPA Consensus Task Force experts comprised 8 pulmonologists, 6 internists, 4 rheumatologists, 3 nephrologists, 1 pathologist and 1 allergist from 5 European countries and the USA. Using a modified Delphi process, a list of 40 questions was elaborated by 2 members and sent to all participants prior to the meeting. Concurrently, an extensive literature search was undertaken with publications assigned with a level of evidence according to accepted criteria. Drafts of the recommendations were circulated for review to all members until final consensus was reached. RESULTS Twenty-two recommendations concerning the diagnosis, initial evaluation, treatment and monitoring of EGPA patients were established. The relevant published information on EGPA, antineutrophil-cytoplasm antibody-associated vasculitides, hypereosinophilic syndromes and eosinophilic asthma supporting these recommendations was also reviewed. DISCUSSION These recommendations aim to give physicians tools for effective and individual management of EGPA patients, and to provide guidance for further targeted research.

Heterozygous RTEL1 mutations are associated with familial pulmonary fibrosis

Pulmonary fibrosis is a fatal disease with progressive loss of respiratory function. Defective telomere maintenance leading to telomere shortening is a cause of pulmonary fibrosis, as mutations in the telomerase component genes TERT (reverse transcriptase) and TERC (RNA component) are found in 15% of familial pulmonary fibrosis (FPF) cases. However, so far, about 85% of FPF remain genetically uncharacterised. Here, in order to identify new genetic causes of FPF, we performed whole-exome sequencing, with a candidate-gene approach, of 47 affected subjects from 35 families with FPF without TERT and TERC mutations. We identified heterozygous mutations in regulator of telomere elongation helicase 1 (RTEL1) in four families. RTEL1 is a DNA helicase with roles in DNA replication, genome stability, DNA repair and telomere maintenance. The heterozygous RTEL1 mutations segregated as an autosomal dominant trait in FPF, and were predicted by structural analyses to severely affect the function and/or stability of RTEL1. In agreement with this, RTEL1-mutated patients exhibited short telomeres in comparison with age-matched controls. Our results provide evidence that heterozygous RTEL1 mutations are responsible for FPF and, thereby, extend the clinical spectrum of RTEL1 deficiency. Thus, RTEL1 enlarges the number of telomere-associated genes implicated in FPF. Whole-exome sequencing reveals heterozygous RTEL1 mutations in familial pulmonary fibrosis with short telomeres http://ow.ly/LHvor

Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management

BACKGROUND Lymphangioleiomyomatosis (LAM) is a rare cystic lung disease that primarily affects women. The purpose of these guidelines is to provide recommendations for the diagnosis and treatment of LAM. METHODS Systematic reviews were performed to summarize evidence pertinent to our questions. The evidence was summarized and discussed by a multidisciplinary panel. Evidence-based recommendations were then formulated, written, and graded using the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS After considering the panels confidence in the estimated effects, the balance of desirable (i.e., benefits) and undesirable (i.e., harms and burdens) consequences of treatment, patient values and preferences, cost, and feasibility, recommendations were formulated for or against specific interventions. These included recommendations for sirolimus treatment and vascular endothelial growth factor D testing and recommendations against doxycycline and hormonal therapy. CONCLUSIONS Evidence-based recommendations for the diagnosis and treatment of patients with LAM are provided. Frequent reassessment and updating will be needed.

Recommandations pratiques pour le diagnostic et la prise en charge de la fibrose pulmonaire idiopathique. Élaborées par le centre national de référence et les centres de compétence pour les maladies pulmonaires rares sous l’égide de la Société de pneumologie de langue française

a Inra, UMR754, IFR 128, centre national de reference des maladies pulmonaires rares, centre de competences de l’hypertension pulmonaire, service de pneumologie, universite de Lyon, universite Claude-Bernard Lyon 1, hospices civils de Lyon, hopital Louis-Pradel, 28, rue du Doyen-Lepine, 69000 Lyon, France b CHU Bichat, centre de competences pour les maladies pulmonaires rares, 46, rue Henri-Huchard, 75877 Paris cedex 18, France

French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis – 2017 update. Short-length version

V. Cottina,∗,1, B. Crestanib, J. Cadranelc, J.-F. Cordiera, S. Marchand-Adamd, G. Prévote, B. Wallaert f, E. Bergotg, P. Camush, J.-C. Dalphin i, C. Dromerj, E. Gomezk, D. Israel-Biet l, S. Jouneaum, R. Kesslern, C.-H. Marquetteo, M. Reynaud-Gaubertp, B. Aguilaniuq, D. Bonnetr, P. Carrés, C. Danel t, J.-B. Faivreu, G. Ferretti v, N. Justw, F. Lebargyx, B. Philippey, P. Terriouxz, F. Thivolet-Béjuiaa, B. Trumbicab, D. Valeyreac

[Pulmonary lymphangioleiomyomatosis: From pathogenesis to management].

INTRODUCTION Pulmonary lymphangioleiomyomatosis (LAM) is a rare disease affecting mainly young women. BACKGROUND The respiratory manifestations are characterized by a progressive cystic destruction of the lung parenchyma. Extrapulmonary involvement includes benign renal tumours called angiomyolipomas and abdominal lymphatic masses called lymphangioleiomyomas. At the pathological level, the cellular proliferation found in LAM is in part due to the presence of mutations in the tumour suppressor genes TSC1 and TSC2 (Tuberous Sclerosis Complex). These mutations lead to the activation of the mTOR pathway, which is currently the main therapeutic target. mTOR inhibitors such as sirolimus or everolimus have shown a beneficial effect on the decline in pulmonary function and a reduction of angiomyolipoma size, but are necessary in only some patients. PERSPECTIVES LAM cells have migratory properties mediated by the formation of new lymphatic vessels. They are also able to secrete metalloproteases, which enhance their invasiveness. Moreover, the expression of estrogen and progesterone receptors by LAM cells suggests a possible role for sex hormones in the pathogenesis of the disease. CONCLUSION A better understanding of mTOR-independent mechanisms would allow the development of novel therapeutic approaches.

Clinical phenotypes and survival of pre-capillary pulmonary hypertension in systemic sclerosis

Pre-capillary pulmonary hypertension (PH) in systemic sclerosis (SSc) is a heterogeneous condition with an overall bad prognosis. The objective of this study was to identify and characterize homogeneous phenotypes by a cluster analysis in SSc patients with PH. Patients were identified from two prospective cohorts from the US and France. Clinical, pulmonary function, high-resolution chest tomography, hemodynamic and survival data were extracted. We performed cluster analysis using the k-means method and compared survival between clusters using Cox regression analysis. Cluster analysis of 200 patients identified four homogenous phenotypes. Cluster C1 included patients with mild to moderate risk pulmonary arterial hypertension (PAH) with limited or no interstitial lung disease (ILD) and low DLCO with a 3-year survival of 81.5% (95% CI: 71.4–88.2). C2 had pre-capillary PH due to extensive ILD and worse 3-year survival compared to C1 (adjusted hazard ratio [HR] 3.14; 95% CI 1.66–5.94; p = 0.0004). C3 had severe PAH and a trend towards worse survival (HR 2.53; 95% CI 0.99–6.49; p = 0.052). Cluster C4 and C1 were similar with no difference in survival (HR 0.65; 95% CI 0.19–2.27, p = 0.507) but with a higher DLCO in C4. PH in SSc can be characterized into distinct clusters that differ in prognosis.

French practical guidelines for the diagnosis and management of idiopathic pulmonary fibrosis: 2017 update. Summary.

V. Cottina,∗,1, B. Crestanib, J. Cadranelc, J.-F. Cordiera, S. Marchand-Adamd, G. Prévote, B. Wallaert f, E. Bergotg, P. Camush, J.-C. Dalphin i, C. Dromerj, E. Gomezk, D. Israel-Biet l, S. Jouneaum, R. Kesslern, C.-H. Marquetteo, M. Reynaud-Gaubertp, B. Aguilaniuq, D. Bonnetr, P. Carrés, C. Danel t, J.-B. Faivreu, G. Ferretti v, N. Justw, F. Lebargyx, B. Philippey, P. Terriouxz, F. Thivolet-Béjuiaa, B. Trumbicab, D. Valeyreac

Maladies pulmonaires rares : de l’adoption des maladies orphelines à la structuration de la filière de soins

C g d t a c c fi d d l t t i s fi s m c c cient pas d’une attention suffisante de la part de la société, et pour lesquelles il n’y a souvent pas de traitement [1]. Ces maladies n’ont pas constitué une priorité de la recherche par les firmes pharmaceutiques pour des raisons de rentabilité financière. Les personnes atteintes perçoivent un accès inéquitable au diagnostic et aux soins. Même si, à l’échelle mondiale, les maladies orphelines sont dans leur majorité d’origine infectieuse parasitaire (maladies tropicales négligées), affectant au moins un milliard de personnes dans le monde, en France les maladies orphelines sont rares. Les maladies rares sont définies par une prévalence inférieure à une personne sur 2000 en Europe (ce qui représente environ 30 000 personnes atteintes en France) ou moins de 200 000 personnes atteintes aux États-Unis [1]. Cette définition fondée sur des éléments commerciaux correspond à la prévalence en dessous de laquelle le développement d’une innovation diagnostique ou thérapeutique n’était pas jugé rentable. Compte tenu de leur nombre, les maladies rares représentent collectivement un enjeu de santé publique. Ainsi, dans le seul domaine respiratoire (Tableau 1), les maladies pulmonaires rares concerneraient 1,5 à 3 millions d’Européens, et 1,2 à 2,5 millions de Nord-Américains [1]. Les maladies rares sont caractérisées par une attente considérable de la part des personnes atteintes, qui se sentent encore trop souvent abandonnées par le système de santé, et qui attendent de leur médecin qu’il fasse le maximum pour leur prise en charge. Cependant, les médecins ne peuvent pas connaître chacune des 6 à 8000 maladies orphelines ou rares, et chacun en a le plus souvent une expérience [ i p m