Showing papers by "Vincent Cottin published in 2023"

The world of rare interstitial lung diseases

Abstract: The world of rare interstitial lung diseases (ILDs) is diverse and complex. Diagnosis and therapy usually pose challenges. This review describes a selection of rare and ultrarare ILDs including pulmonary alveolar proteinosis, pulmonary alveolar microlithiasis and pleuroparenchymal fibroelastosis. In addition, monogenic ILDs or ILDs in congenital syndromes and various multiple cystic lung diseases will be discussed. All these conditions are part of the scope of the European Reference Network on rare respiratory diseases (ERN-LUNG). Epidemiology, pathogenesis, diagnostics and treatment of each disease are presented. Many rare and ultrarare ILDs are underdiagnosed. Increasing insight into pathobiology, genetics and disease behaviour have led to better treatment options. Early consultation with or referral to expert centres (ERN-LUNG) is advised. https://bit.ly/3vwYrib

Study protocol of an international patient-led registry in patients with pulmonary fibrosis using online home monitoring: I-FILE

Abstract: Pulmonary fibrosis (PF) is caused by a heterogeneous group of diseases, with a high inter-individual variability in disease trajectory. Identifying disease progression in patients with PF has impact on clinical management decisions. However, strategies to early identify and predict disease progression for these patients are currently lacking. In this study, we aim to assess long-term FVC change in patients with PF measured with home spirometry, and evaluate the feasibility of a multinational patient-led registry in PF. In addition, we will assess validity of patient-reported outcomes (PROMs) for the different subgroups of patients with PF.In this international, prospective, multicenter, observational study, we aim to include 700 patients across seven European countries. Patients will monitor their disease course for a period of two years using an online home monitoring program (I-FILE), which includes home spirometry, pulse oximetry, and PROMs. Results will be directly sent to the hospital via the online application. Patients will be asked to perform daily home spirometry and pulse oximetry in the first three months, followed by once weekly measurements for a period of two years. PROMs will be completed in the online I-FILE application every six months, including the King's brief Interstitial Lung Disease Health Status, The EuroQol five dimensions five-level, Visual Analogue Scales on cough, dyspnea, fatigue and general complaints, Leicester Cough Questionnaire, Fatigue Assessment Scale, Work Productivity and Activity Impairment Questionnaire, Global Rating of Change Scale, and Living with Pulmonary Fibrosis questionnaire.This study will provide much needed insights in disease trajectories of the different subgroups of patients with PF. Simultaneously, the I-FILE study will yield valuable information on the use and feasibility of home-based data collection. This international patient-led registry will facilitate trans-border collaboration to further optimize care and research for patients with PF.The study was registered on the 12th of March 2020 in the International Clinical Trial Registry, www.gov ; Identifier: NCT04304898.

Inhaled treprostinil for interstitial lung disease-associated pulmonary hypertension: a silver lining on a very dark cloud

Abstract: Pulmonary hypertension (PH) associated with interstitial lung disease (ILD-PH) is classified as group 3 PH, i.e. PH associated with chronic lung disease and/or hypoxia [1]. PH is relatively frequent in patients with ILD, depending on the definition of PH, the diagnostic assessment of PH, and the type of underlying ILD [2]. In patients with idiopathic pulmonary fibrosis (IPF), PH is a frequent complication at an advanced stage of the disease [3], or when emphysema is associated, as in the syndrome of combined pulmonary fibrosis and emphysema [4, 5]. Tweetable abstract Pulmonary hypertension associated with ILD is a very severe condition. The open label extension of the INCREASE trial demonstrates acceptable tolerability of inhaled treprostinil, maintained exercise capacity at week 40, and increase in FVC. https://bit.ly/3qxHvsB

Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis

Abstract: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, characterized by asthma, eosinophilia and granulomatous or vasculitic involvement of several organs. The diagnosis and management of EGPA are often challenging and require an integrated, multidisciplinary approach. Current practice relies on recommendations and guidelines addressing the management of ANCA-associated vasculitis and not specifically developed for EGPA. Here, we present evidence-based, cross-discipline guidelines for the diagnosis and management of EGPA that reflect the substantial advances that have been made in the past few years in understanding the pathogenesis, clinical subphenotypes and differential diagnosis of the disease, as well as the availability of new treatment options. Developed by a panel of European experts on the basis of literature reviews and, where appropriate, expert opinion, the 16 statements and five overarching principles cover the diagnosis and staging, treatment, outcome and follow-up of EGPA. These recommendations are primarily intended to be used by healthcare professionals, pharmaceutical industries and drug regulatory authorities, to guide clinical practice and decision-making in EGPA. These guidelines are not intended to limit access to medications by healthcare agencies, nor to impose a fixed order on medication use.

Changes in the management of chronic thromboembolic pulmonary hypertension over a 10-year period, in a French expert regional competence centre.

Abstract: Over the last few years, the advent of balloon pulmonary angioplasty (BPA) had led to changes in the management of chronic thromboembolic pulmonary hypertension (CTEPH). We reviewed data from 98 CTEPH patients diagnosed during the last decade in a pulmonary hypertension (PH) expert centre. The management modalities of 2 periods (Period A: 2011-15 and Period B: 2016-20) were compared. Age (period A: 72 [58-80] years; period B: 69 [62-79] years), clinical (New York Heart Association (NYHA) functional class III-IV: 25/41, 61% vs 39/57, 68%), and hemodynamic assessments (pulmonary vascular resistance: 7.5 [6.2-8.7] WU vs 8.0 [6.0-10.2] WU) at baseline were not significantly different. Pulmonary endarterectomy was performed in less than one third of patients (12, 29.3% vs 15, 26.3%). For patients not eligible for surgery, medical therapy was mostly prescribed alone during period A (medical therapy alone, patients diagnosed in period A: 61% vs in period B: 17.5%) while it was associated with BPA during period B (medical therapy + BPA, 12% vs 61.4%). The 5-year survival rate was excellent for patients who underwent surgery (96.3%) or BPA (95.2%), but was only 42.1% for patients under oral medication only (p < 0.0001). Patients diagnosed with CTEPH who cannot be operated should undergo BPA. The survival rate after BPA is as good as after surgery and significantly better than that of oral medication only.

A Narrative Review of Real-World Data on the Safety of Nintedanib in Patients with Idiopathic Pulmonary Fibrosis

Abstract: Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF) and other progressive fibrosing interstitial lung diseases. Placebo-controlled trials showed that the adverse event profile of nintedanib was characterised mainly by gastrointestinal events, particularly diarrhoea. We review the data from all published real-world studies of the safety of nintedanib in patients with IPF. These real-world data were consistent with the safety profile observed in clinical trials and described in the product label. The most common adverse events were diarrhoea, nausea and vomiting, but these infrequently led to permanent treatment discontinuation. Liver enzyme elevations were observed, supporting the recommendation for regular monitoring of liver enzymes, particularly in the first few months of treatment. Bleeding and cardiovascular adverse events were rarely reported. As in clinical trials, in real-world studies, reductions of the nintedanib dose, treatment interruptions and use of anti-diarrhoeal medications were frequently employed to manage adverse events. Few data are available on the use of nintedanib in patients who are elderly or have advanced disease, but there are some data to suggest a greater rate of treatment discontinuation in these patients. Effective management of adverse events associated with nintedanib is important to minimise their impact.

Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials.

Abstract: Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

French recommendations for the diagnosis and management of lymphangioleiomyomatosis.

Abstract: The present article is an English-language version of the French National Diagnostic and Care Protocol, a pragmatic tool to optimize and harmonize the diagnosis, care pathway, management and follow-up of lymphangioleiomyomatosis in France.Practical recommendations were developed in accordance with the method for developing a National Diagnosis and Care Protocol for rare diseases of the Haute Autorité de Santé and following international guidelines and literature on lymphangioleiomyomatosis. It was developed by a multidisciplinary group, with the help of patient representatives and of RespiFIL, the rare disease network on respiratory diseases.Lymphangioleiomyomatosis is a rare lung disease characterised by a proliferation of smooth muscle cells that leads to the formation of multiple lung cysts. It occurs sporadically or as part of a genetic disease called tuberous sclerosis complex (TSC). The document addresses multiple aspects of the disease, to guide the clinicians regarding when to suspect a diagnosis of lymphangioleiomyomatosis, what to do in case of recurrent pneumothorax or angiomyolipomas, what investigations are needed to make the diagnosis of lymphangioleiomyomatosis, what the diagnostic criteria are for lymphangioleiomyomatosis, what the principles of management are, and how follow-up can be organised. Recommendations are made regarding the use of pharmaceutical specialties and treatment other than medications.These recommendations are intended to guide the diagnosis and practical management of pulmonary lymphangioleiomyomatosis.

Rituximab and mycophenolate mofetil combination in patients with interstitial lung disease (EVER-ILD): a double-blind, randomised, placebo-controlled trial

Abstract: Background Standard of care for interstitial lung disease (ILD) with a nonspecific interstitial pneumonia (NSIP) pattern proposes mycophenolate mofetil (MMF) as one of the first-step therapies while rituximab is used as rescue therapy. Methods In a randomised, double-blind, two-parallel group, placebo-controlled trial (NCT02990286), patients with connective tissue disease-associated ILD or idiopathic interstitial pneumonia (with or without autoimmune features) and a NSIP pattern (defined on NSIP pathological pattern or on integration of clinicobiological data and a NSIP-like high-resolution computed tomography pattern) were randomly assigned in a 1:1 ratio to receive rituximab (1000 mg) or placebo on day 1 and day 15 in addition to MMF (2 g daily) for 6 months. The primary end-point was the change in percent predicted forced vital capacity (FVC) from baseline to 6 months analysed by a linear mixed model for repeated measures analysis. Secondary end-points included progression-free survival (PFS) up to 6 months and safety. Findings Between January 2017 and January 2019, 122 randomised patients received at least one dose of rituximab (n=63) or placebo (n=59). The least-squares mean change from baseline to 6 months in FVC (% predicted) was +1.60 (se 1.13) in the rituximab+MMF group and −2.01 (se 1.17) in the placebo+MMF group (between-group difference 3.60, 95% CI 0.41–6.80; p=0.0273). PFS was better in the rituximab+MMF group (crude hazard ratio 0.47, 95% CI 0.23–0.96; p=0.03). Serious adverse events occurred in 26 (41%) patients of the rituximab+MMF group and in 23 (39%) of the placebo+MMF group. Nine infections were reported in the rituximab+MMF group (five bacterial infections, three viral infections, one other) and four bacterial infections in the placebo+MMF group. Interpretation Combination of rituximab and MMF was superior to MMF alone in patients with ILD and a NSIP pattern. The use of this combination must take into consideration the risk of viral infection. Rituximab plus MMF is associated with benefits in lung function and progression-free survival compared with MMF plus placebo after 24 weeks of treatment. The safety profile of rituximab plus MMF was similar to that of MMF plus placebo. http://bit.ly/3zcozku

Autoantibodies are associated with disease progression in idiopathic pulmonary fibrosis

Abstract: Several reports have highlighted a potential role of autoreactive B-cells and autoantibodies that correlates with increased disease severity in patients with idiopathic pulmonary fibrosis (IPF). Here we show that patients with IPF have an altered B-cell phenotype and that those subjects who have autoantibodies against the intermediate filament protein periplakin (PPL) have a significantly worse outcome in terms of progression-free survival. Using a mouse model of lung fibrosis, we demonstrate that introducing antibodies targeting the endogenous protein PPL (mimicking naturally occurring autoantibodies seen in patients) directly in the lung increases lung injury, inflammation, collagen and fibronectin expression through direct activation of follicular dendritic cells, which in turn activates and drives proliferation of fibroblasts. This fibrocyte population was also observed in fibrotic foci of patients with IPF and was increased in peripheral blood of IPF patients compared to aged-matched controls. This study reiterates the complex and heterogeneous nature of IPF, identifying new pathways that may prove suitable for therapeutic intervention. Antiperiplakin antibodies accelerate the lung fibrotic process https://bit.ly/3ZnZbE8

Pos1283 heart and systemic sclerosis – findings from national cohort study

Abstract: Heart involvement is one of the leading causes of death in systemic sclerosis (SSc). Cardiac manifestations are heterogeneous. In particular, prevalence of SSc-related cardiopathy is poorly known due to a lack of consensus in its definition.Our objective was to investigate the prevalence and prognosis burden of the different heart diseases in a nationwide cohort of patients with SSc.We used data from a national multicentric prospective study using the French SSc national database. We described the characteristics of 3 different types of heart involvement: SSc-related cardiopathy, pulmonary arterial hypertension and ischaemic heart disease. We analyzed overall survival and survival according to the heart disease. Focusing on SSc-related cardiopathy, we aimed to determine its incidence and risk factors.Over the 3528 patients with SSc available for baseline analyses 312 (10.9%) had SSc-related cardiopathy at baseline. They tended to have a diffuse SSc subtype more frequently, had more severe clinical features, and presented more cardiovascular risk factors. From the 1646 patients available for follow-up analysis, SSc-related cardiopathy was associated with an increased risk of death. No significant difference of overall survival was found between SSc-related cardiopathy, ischaemic heart disease or pulmonary arterial hypertension. Concerning survival analysis, 98 patients developed SSc-related cardiopathy at 5 years (5-year event-rate: 11.15% [9.01; 13.23]). Regarding reduced LVEF < 50% and left ventricular diastolic dysfunction, the 5-year event-rate were 2.49% [CI95%: 1.13; 3.83] and 5.84% [CI95%: 4.02; 7.62], respectively. The pericarditis cumulative incidence at 5 years was 3% [CI95%: 1.91; 4.08]). Diffuse SSc subtype was a risk factor of SSc-related cardiopathy and pericarditis (adjusted HR: 1.42 [CI95%: 1.02; 1.97], p = 0.04 and adjusted HR: 1.79 [CI95%: 1.06; 3.02], p = 0.03, respectively). Female sex was associated with less diastolic dysfunction incidence (adjusted HR: 0.39 [CI95%: 0.24; 0.63], p = 0.0001).Our results further describe at a large scale the incidence and prognostic burden of SSc-related cardiopathy, with gender and diffuse SSc subtype as risk factors. Further analyses should assess the potential impact of treatment on these various cardiac outcomes.[1]Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, et al. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis 2017;76:1897–905.https://doi.org/10.1136/annrheumdis-2017-211448.[2]Bulkley BH, Ridolfi RL, Salyer WR, Hutchins GM. Myocardial lesions of progressive systemic sclerosis. A cause of cardiac dysfunction. Circulation 1976;53:483–90.https://doi.org/10.1161/01.cir.53.3.483.[3]Hoogen F van den, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative. Arthritis & Rheumatism 2013;65:2737–47.https://doi.org/10.1002/art.38098.Figure 1.NIL.Alexis F. Guedon: None declared, Fabrice Carrat: None declared, Luc Mouthon: None declared, David Launay: None declared, Benjamin Chaigne: None declared, Gregory Pugnet: None declared, Jean-Christophe Lega: None declared, Arnaud Hot: None declared, Robin Dhote: None declared, Thomas Papo: None declared, Emmanuel Chatelus: None declared, Bernard Bonnotte: None declared, Jean-Emmanuel Kahn: None declared, Elisabeth Diot Speakers bureau: ED received fees as speaker in symposium from Boehringer Ingelheim., Boris Bienvenu: None declared, Nadine Magy-Bertrand: None declared, Viviane Queyrel: None declared, Alain Le Quellec: None declared, Pierre Kieffer: None declared, Zahir Amoura: None declared, Jean-Robert Harlé: None declared, Vincent Cottin: None declared, Jean-Baptiste Gaultier: None declared, Marie-Hélène Balquet: None declared, DENIS WAHL: None declared, Olivier Lidove Grant/research support from: OL received several fees for congress travels and experts’ use from Amicus Therapeutics, Sanofi-Genzyme, and Takeda, Anne-Laure Fauchais: None declared, Yannick Allanore: None declared, Patrick Jégo: None declared, Christian Agard: None declared, olivier fain: None declared, Arsene Mekinian Grant/research support from: AM is investigator of CELGENE, ROCHE, CHUGAI founded trials with APHP and Hopital 15-20 promotion; AM received several fees for congress travels and experts’ use from LFB, SANOFI, SHIRE, and CELGENE, Eric Hachulla: None declared, Sebastien RIVIERE: None declared.

French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes

Abstract: Abstract Eosinophilic-related clinical manifestations are protean and the underlying conditions underpinning eosinophilia are highly diverse. The etiological workup of unexplained eosinophilia/hypereosinophilia can be challenging, and can lead sometimes to extensive, inappropriate, costly and/or invasive investigations. To date, guidelines for the etiological workup and management of eosinophilia are mainly issued by hematologists, and thus mostly cover the scope of clonal hypereosinophilic syndromes (HES). Here, thanks to an extensive literature review, and thanks to the joint work of a large panel of experts involving physicians from both adult and pediatric medicine and from various subspecialties (as well as a representative of a patients’ association representative), we provide recommendations for both the step-by step diagnostic workup of eosinophilia (whether unexplained or within specific contexts) as well as the management and follow-up of the full spectrum of eosinophilic disorders (including clonal, reactive, lymphocytic and idiopathic HES, as well as single-organ diseases). Didactic prescription summaries intended to facilitate the prescription of eosinophil-targeted drugs are also provided, as are practical diagnostic and therapeutic algorithms. Lastly, this set of recommendations also includes a summary intended for general practitioners, as well as an overview of the therapeutic patient education program set up by the French reference center for HES. Further updates will be mandatory as new validated information emerges.

Treatable traits: a comprehensive precision medicine in interstitial lung disease.

Abstract: Interstitial lung disease (ILD) is a diverse group of inflammatory and fibrotic lung conditions causing significant morbidity and mortality. A multitude of factors beyond the lungs influence symptoms, health-related quality of life, disease progression, and survival in patients with ILD. Despite an increasing emphasis on multidisciplinary management in ILD, the absence of a framework for assessment and delivery of comprehensive patient care poses challenges in clinical practice. The treatable traits approach is a precision medicine care model that operates on the premise of individualised multidimensional assessment for distinct traits that can be targeted by specific interventions. The potential utility of this approach has been described in airway diseases but has not been adequately considered in ILD. Given the similar disease heterogeneity and complexity between ILD and airway diseases, we explore the concept and potential application of the treatable traits approach in ILD. A framework of aetiological, pulmonary, extra-pulmonary, and behavioural and lifestyle treatable traits relevant to clinical care and outcomes for patients with ILD is proposed. We further describe key research directions to evaluate the application of the treatable traits approach towards advancing patient care and health outcomes in ILD.

Prévalence et incidence de la granulomatose éosinophilique avec polyangéite et description des cas incidents en France

Abstract: La granulomatose éosinophilique avec polyangéite (GEPA) est une vascularite appartenant au groupe des vascularites nécrosantes associées aux anticorps anti-cytoplasme des polynucléaires neutrophiles (ANCA). Il n’y a pas de données épidémiologiques de la GEPA en France portant sur l’ensemble des patients affiliés au régime général. Nous avons donc voulu estimer la prévalence et l’incidence de la GEPA à partir des données issues du Système National des Données de Santé (SNDS). Les patients atteints de GEPA identifiés entre le 01/01/2013 et le 31/12/2019 dans le SNDS ont été inclus, afin de définir les cas prévalents et les cas incidents. L’historique des patients a été analysé depuis le 01/01/2010 afin de définir les cas prévalents et les cas incidents. Les patients inclus devaient être affiliés au régime général et avoir soit une ALD M30 stricte ou M301 soit une hospitalisation avec un code M301 (périartérite avec atteinte pulmonaire [Churg–Strauss]), représentant la population d’analyse principale. Une analyse de sensibilité a été faite dans une population limitée aux patients ayant eu au moins 3 dispensations de glucocorticoïdes oraux dans l’année suivant le diagnostic. Les cas prévalents atteints de GEPA représentaient 7238 individus, tandis que les cas incidents représentaient 1650 individus dans l’analyse principale. Dans l’analyse de sensibilité, les cas prévalents et incidents étaient de 3328 et 1035 individus, respectivement. La prévalence et l’incidence de la GEPA dans l’analyse principale étaient de 85,3 et 3,5 cas par million, respectivement, tandis qu’elles étaient de 38,4 et 2,1 cas par million, respectivement, dans l’analyse de sensibilité. Il n’y avait pas de différence saisonnière dans les diagnostics de GEPA. Dans la population de cas incidents, l’âge moyen à l’inclusion était de 61,7 ± 17,4 ans dans l’analyse principale et 62,4 ± 15,9 ans dans l’analyse de sensibilité, avec une légère prédominance féminine, les femmes représentant 57,1 % et 54,0 % dans les analyses principale et de sensibilité, respectivement. Dans les 2 ans précédant le diagnostic de GEPA, 76,7 % des patients avaient eu au moins une dispensation de glucocorticoïdes oraux et 53,9 % des corticoïdes inhalés dans l’analyse principale, et 89,5 % et 68,4 % dans l’analyse de sensibilité, respectivement. Des événements ORL étaient signalés dans les 2 ans précédant le diagnostic de GEPA chez 62,7 % et 71,8 % des patients dans les analyses principale et de sensibilité. Cette étude épidémiologique sur la GEPA en France permet d’estimer la prévalence et l’incidence de la maladie à partir des données issues du SNDS. La prévalence est plus élevée que dans les études antérieures, posant la question soit d’un sur-diagnostic de la GEPA en particulier en cas d’asthme éosinophilique, soit d’une augmentation de la prévalence ces dernières années. Elle apporte également des informations sur la démographie de la maladie et les comorbidités et traitements reçus avant le diagnostic de GEPA (cette recherche a été menée avec le soutien d’AstraZeneca).

Op0304 benralizumab for eosinophilic granulomatosis with polyangiitis (egpa): results from a european multicenter study on 121 patients

Abstract: Eosinophilic granulomatosis with polyangiitis (EGPA) is an ANCA-associated vasculitis characterized by asthma, ear-nose-throat (ENT) manifestations, peripheral hypereosinophilia and systemic vasculitic involvement [1]. Increased serum levels of interleukin 5 (IL-5) have been observed in eosinophilic disorders, including EGPA, and a genome-wide association study identified the IL-5 region as a major EGPA-associated loci [2]. On these bases, an increasing interest is focusing on benralizumab (an IL-5 receptor antagonist approved for severe eosinophilic asthma at the dosage of 30mg every 4 weeks for 3 administrations, then every 8 weeks) as a new potential therapy for EGPA.Following the promising results of a pilot study on 10 patients [3], a randomized double-blind trial is ongoing to assess the efficacy and safety of benralizumab at a higher dosage (30mg/4 weeks), as compared to mepolizumab (another IL-5 inhibitor approved for EGPA) in patients with EGPA (NCT04157348). In the meanwhile, isolated cases of patients with refractory EGPA, successfully treated with benralizumab, have been described in the literature [4,5].This study aimed to assess the efficacy and safety of benralizumab in a multicenter European cohort of patients with EGPA.The study included patients with EGPA treated with benralizumab at 28 centers belonging to the European EGPA Study Group. Efficacy and safety outcomes were assessed after 3, 6 and 12 months of treatment. Complete response (CR) was defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] = 0) and a daily prednisone equivalent dose ≤4 mg. Respiratory outcomes included asthma, ENT manifestations and lung function.A cohort of 121 patients with EGPA was included. All were treated with benralizumab at the dosage approved for eosinophilic asthma (30mg every 4 weeks for 3 administrations, then every 8 weeks). The proportion of patients meeting the criteria for CR was 16% at 3 months, 26% at 6 months and 46% at 12 months of follow-up (Table 1). During follow-up, a drop in BVAS was recorded, from a median score of 3 (IQR 2-8) at baseline to 0 (0-2) at month 3 and 6 and to 0 (0-1) at month 12 (p<0.001 at all timepoints). Regarding respiratory outcomes, the proportion of patients reporting active asthmatic decreased from 94% at baseline to 39% at 3 months (p<0.001), and that of patients with active ENT manifestations decreased from 70% at baseline to 49% at 3 months (p<0.001), with concomitant improvements in lung function. 19 patients experienced adverse events, three requiring hospitalization.The results from this large European real-world study suggest that benralizumab, at the dosage approved for severe eosinophilic asthma, could be effective and safe to control respiratory EGPA manifestations and overall disease activity.[1]Trivioli, Rheumatol 2020[2]Lyon, Nat Commun 2019[3]Guntur, JACI Pract 2021[4]Bormioli, JIACI 2021[5]Menzella, Multidisciplinary Respir Med 2021Table 1.Efficacy outcomesBenralizumab beginning (t0)3 monthsp-value (t3 vs t0)6 monthsp-value (t6 vs t0)12 monthsp-value (t12 vs t0)N patients12112110185Complete response-15/96 (15.6%)23/87 (26.4%)32/69 (46.4%)BVAS, median (IQR)3 (2-8)0 (0-2)[n=96]<0.001*0 (0-2)[n=87]<0.001*0 (0-1)[n=69]<0.001*Respiratory involvementPulmonary114 (94.2)43/111 (38.7)<0.001*36 (35.6)<0.001*33 (38.8)<0.001*ENT85 (70.3)54/111 (48.6)<0.001*46 (45.5)<0.001*40 (47.1)<0.001*BVAS= Birmingham Vasculitis Activity Score; ENT= ear-nose-throat; IQR= interquartile range.We acknowledge drs./profs. Francesco Cinetto, Marco Caminati, Pavel Novikov, Alvise Berti, Paolo Cameli, Pascal Cathébras, Angelo Coppola, Cécile-Audrey Durel, Marco Folci, Alberto Lo Gullo, Carlo Lombardi, Sara Monti, Paola Parronchi, Carlos Martinez Rivera, Roser Solans, Angelo Vacca, Maria Cinta Cid, and Domenico Prisco, who contributed to this study.Alessandra Bettiol: None declared, Irene Mattioli: None declared, Maria Letizia Urban: None declared, Federica Bello: None declared, Roberto Padoan Consultant of: GSK, Matthieu Groh: None declared, Giuseppe Lopalco: None declared, Allyson Egan: None declared, Vincent Cottin Consultant of: Astra Zeneca and GSK., Paolo Fraticelli: None declared, Claudia Crimi Speakers bureau: Honoraria for lectures from GSK, Sanofi, Astra Zeneca, Novartis, Resmed, Fisher & Paykel., Stefano Del Giacco: None declared, Jan Schroeder: None declared, Laura Moi: None declared, David Jayne Consultant of: Astra-Zeneca, Aurinia, BMS, Boehringer-Ingelheim, Chemocentryx, Chugai, CSL, GSK, Infla-RX, Janssen, Novartis, Roche/Genentech, Takeda and Vifor, Augusto Vaglio Consultant of: GSK, Giacomo Emmi Consultant of: GSK.

Clinical Phenotype and Outcomes of Pulmonary Hypertension Associated with Myeloproliferative Neoplasms: A Population-based Study.

Abstract: RATIONALE Precapillary pulmonary hypertension (PH) is a rare and largely unrecognized complication of myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (MF). OBJECTIVES To describe characteristics and outcomes of MPN-associated PH. METHODS We report clinical, functional, and hemodynamic characteristics, classification and outcomes of patients with PV, ET or primary MF in the French PH registry. MEASUREMENTS AND MAIN RESULTS Ninety MPN patients (42 PV, 35 ET; 13 primary MF) presented with precapillary PH with severe hemodynamic impairment, with a median mPAP and PVR of 42 mmHg and 6.7 WU, respectively, and impaired clinical conditions, with 71% in NYHA functional classes III/IV and having a median 6-minute walk distance of 310 m. Half of patients were diagnosed with CTEPH; the other half were considered to have group 5 PH. MF was preferentially associated with group 5 PH, whereas PV and ET in the absence of MF were generally related to CTEPH. Proximal lesions were diagnosed in half of CTEPH patients. Thromboendarterectomy was performed in 18 selected patients with high risk of complications (5 early deaths). Overall survival at 1, 3, and 5 years was 67%, 50% and 34% in group 5 PH and 81%, 66% and 42% in CTEPH, respectively. CONCLUSION Precapillary PH is a life-threatening condition potentially occurring in MPN, with causes equally distributed between CTEPH and group 5 PH. Physicians should be aware that PH affects the burden of MPN patients, especially in group 5 PH, with unknown pathophysiological mechanisms.

Interstitial lung disease-associated pulmonary hypertension - what the future holds.

Abstract: PURPOSE OF REVIEW Pulmonary hypertension associated with interstitial lung disease (ILD-PH) is associated with significant alteration of quality of life, exercise capacity, and survival. Over the past 2 years, there were changes in the guideline definition and classification of ILD-PH, and positive randomized controlled trials were published. RECENT FINDINGS Pulmonary hypertension associated with chronic lung disease is now hemodynamically defined as a mean pulmonary artery pressure more than 20 mmHg, with pulmonary artery wedge pressure 15 mmHg or less, and pulmonary vascular resistance (PVR) at least 2 Wood units. Severe ILD-PH is defined by PVR more than 5 Wood units. In the INCREASE trial, patients receiving inhaled treprostinil had favorable significant changes in 6-min walk distance, NT-proBNP level, clinical worsening events, and forced vital capacity, which were maintained in the open label extension study. Promising results were obtained in a placebo-controlled pilot trial using escalated doses of inhaled nitric oxide. According to European guidelines, patients with ILD-PH should be referred to pulmonary hypertension centers, where inhaled treprostinil may be considered; phosphodiesterase type-5 inhibitors may also be considered in patients with severe ILD-PH. SUMMARY Recent changes in the definitions and a new therapeutic option have an impact on the diagnosis and management of ILD-PH.

Systemic sclerosis associated interstitial lung disease: a survey of current practices in France

Abstract: Background: Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc). Objective: We performed an overview of the diagnostic approaches, follow-up and treatment strategies used in France for the management of SSc-associated ILD (SSc-ILD). Design: Structured nationwide online survey.Methods: A structured nationwide online survey was submitted to participants via the French Medical Societies for Internal Medicine and Pneumology, and research groups on SSc-ILD from May 2018 to June 2020. The 79 multiple-choice and 9 open-ended questions covered the screening of ILD at baseline, monitoring of patients with established SSc-ILD and its management. Fourteen optional vignettes exploring different clinical phenotypes of SSc-ILD were submitted to evaluate therapeutic decisions. Results: All of the 93 participants screened SSc patients for ILD at baseline with 83 (89%) participants relying on a systematic chest computed tomography (CT) scan. Pulmonary function tests (PFT) were prescribed by 87 (94%) participants at baseline and during follow-up. Treatment was started based on abnormal PFT (95%), chest CT scan characteristics (89%), worsening dyspnoea (72%) and drop in SpO2 during 6-min walk tests (66%). First-line therapy was cyclophosphamide (CYC) (89%), mycophenolate mofetil (MMF) (83%) and prednisone (73%). Rituximab as second-line immunosuppressive therapy (41%) was preferred to antifibrotic agents (18%), and a median daily prednisone dose of 10 mg (interquartile range, 10–15) was prescribed by 73% participants. Extensive SSc-ILD with worsening PFT (95%), regardless of diffusing capacity for carbon monoxide values and skin extension, were more likely to be treated, and CYC was favoured over MMF (p < 0.01). Extensive SSc-ILD with disease duration of less than 5 years was also a criterium for treatment initiation. Conclusion: This overview of practices in diagnosis, follow-up and treatment of SSc-ILD in France describes real-life management of patients. It highlights heterogeneity in this management and gaps in current strategies that should be addressed to improve and harmonize clinical practices in SSc-ILD.

In-depth characterization of pulmonary arterial hypertension in mixed connective tissue disease: a French national multicenter study.

Abstract: OBJECTIVE pulmonary arterial hypertension (PAH) is a leading cause of death in mixed connective tissue disease (MCTD). We aimed to describe PAH in well-characterized MCTD patients. METHODS MCTD patients enrolled in the French Pulmonary Hypertension Registry with a PAH diagnosis confirmed by right heart catheterization were included in the study and compared with matched controls: MCTD patients without PAH, systemic lupus erythematous (SLE) patients with PAH, and systemic sclerosis (SSc) patients with PAH. Survival rates were estimated by the Kaplan-Meier method and risk factors for PAH in MCTD patients and risk factors for mortality in MCTD-PAH were sought using multivariate analyses. RESULTS thirty-six patients with MCTD-PAH were included in the study. Comparison with MCTD patients without PAH and multivariate analysis revealed that pericarditis, polyarthritis, thrombocytopenia, interstitial lung disease (ILD), and anti-Sm antibodies were independent predictive factors of PAH/PH in MCTD. Estimated survival rates at 1 year, 5 years, and 10 years, following PAH diagnosis were 83%, 67%, and 56%, respectively. MCTD-PAH presentation and survival did not differ from SLE-PAH and SSc-PAH. Multivariate analysis revealed that tobacco exposure was an independent factor predictive of mortality in MCTD-PAH. CONCLUSION PAH is a rare and severe complication of MCTD, associated with a 56% 10-year survival. We identified ILD, pericarditis, thrombocytopenia, and anti-Sm antibodies as risk factors for PAH in MCTD and tobacco exposure as predictor of mortality in MCTD-PAH.

Mouth opening in systemic sclerosis: A longitudinal analysis from the French National Cohort Study.

Abstract: BACKGROUND Few studies have evaluated mouth opening (MO) in systemic sclerosis (SSc). None have studied MO trajectories. OBJECTIVE To study MO trajectories in SSc. METHODS This multicentre study included patients enrolled in the French national SSc cohort with at least one MO assessment, described patients based on MO baseline measure, modeled MO trajectories, and associated MO measures with SSc prognosis. RESULTS We included 1101 patients. Baseline MO was associated with disease severity. On Kaplan-Meier analysis, MO < 30 mm was associated with worse 30-year-survival (p<0.01) and risk of pulmonary arterial hypertension (p<0.05). Individual MO trajectories were heterogenous among patients. The best model of MO trajectories according to latent-process mixed modeling showed that 88.8% patients had a stable MO trajectory and clustered patients into 3 groups that predicted SSc survival (p<0.05) and interstitial lung disease (ILD) occurrence (p<0.05). The model highlighted a cluster of 9.5% patients with diffuse cutaneous SSc (dcSSc) (p<0.05) and high but decreasing MO over 1 year (p<0.0001) who were at increased risk of poor survival and ILD. CONCLUSION MO, which is a simple and reliable measure, could be used to predict disease severity and survival in SSc. Although MO remained stable in most SSc patients, dcSSc patients with high but decreasing MO were at risk of poor survival and ILD. This article is protected by copyright. All rights reserved.

Lung Dual-Energy CT Perfusion Blood Volume as a Marker of Severity in Chronic Thromboembolic Pulmonary Hypertension

Abstract: In chronic thromboembolic pulmonary hypertension (CTEPH), assessment of severity requires right heart catheterization (RHC) through cardiac index (CI). Previous studies have shown that dual-energy CT allows a quantitative assessment of the lung perfusion blood volume (PBV). Therefore, the objective was to evaluate the quantitative PBV as a marker of severity in CTEPH. In the present study, thirty-three patients with CTEPH (22 women, 68.2 ± 14.8 years) were included from May 2017 to September 2021. Mean quantitative PBV was 7.6% ± 3.1 and correlated with CI (r = 0.519, p = 0.002). Mean qualitative PBV was 41.1 ± 13.4 and did not correlate with CI. Quantitative PBV AUC values were 0.795 (95% CI: 0.637–0.953, p = 0.013) for a CI ≥ 2 L/min/m2 and 0.752 (95% CI: 0.575–0.929, p = 0.020) for a CI ≥ 2.5 L/min/m2. In conclusion, quantitative lung PBV outperformed qualitative PBV for its correlation with the cardiac index and may be used as a non-invasive marker of severity in CTPEH patients.

Pos1265 real-life multicentric national observational study of the use of nintedanib in systemic sclerosis-associated interstitial lung disease

Abstract: Interstitial Lung Disease related to Systemic Sclerosis (ILD-SSc) is the first cause of mortality rate in this disease [1]. Significative functional decline in Forced vital capacity is one of the major pronostic factor in ILD-SSc and evaluation of the FCV is a key part of the follow-up of patient [2]. Nintedanib is a tyrosine kinase inhibitor that has been shown to be effective in ILD-SSc by significantly slowing decline in CVF [3]. To this day, no real-life data are available in ILD-SSc.Evaluation of efficacity and tolerance profile of Nintedanib in ILD-SSc patients in real life in France.Multicentric data collection on call for observations through the GFRS, SNFMI and Orphalung. The data were obtained in an ambispective way with collection of epidemiological, clinical and paraclinical parameters including in particular CT scan, functional and cardiac data.105 patients were included in 11 centers. 76 (74%) were female, mean age of patients was 58±11 years. 51 (48%) had diffuse SSc, 58 (60%) had anti-topoisomerase 1 antibodies. Median time from 1st non-Raynaud’s sign to introduction of nintedanib was 6 years (1; 41). ILD-SSc was extensive (>20% of the lung) in 60% of cases, and CT pattern was PINS in 85% of cases. Mean FVC at nintedanib introduction was 1.96±0.47L (64±15%). Mean DLCO was 36 ±11%. Data were available at 6 months after introduction of nintedanib in 60 patients. Seven patients (12%) had discontinued treatment because of digestive intolerance (diarrhea in 5 cases, 1 significant weight loss) and including 1 death (cardiac decompensation). In the 53 remaining patients, the mean loss of FVC was 10 ± 120 mL at 6 months of nintedanib treatment versus 165 ± 225 mL in the year before the introduction of treatment. Two patients had severe infections (1 SARS CoV2 infection; 1 Clostridium difficile infection). 22 (40%) patients experienced adverse events, including 17 diarrhea, 6 abdominal pain, 4 nausea or vomiting, and 7 weight loss >5 kg.ILD-SSc population in this real-life study of nintedanib has similar epidemiological characteristics to SENSCIS [3]. However, the FVC and DLCO of these patients are lower than those of the SENSCIS population (1.96± 0.47 L vs 2.46± 0.74 L and 36±11% vs 53±15%, respectively). At 6 months, there was a smaller decline in FVC in patients on nintedanib than the decline in the year before starting treatment. The current results at 6 months show a tolerance profile similar to that observed in idiopathic pulmonary fibrosis. These initial results in real-life study in a more severe ILD-SSc population than the pivotal trial suggest that nintedanib limits functional decline in FVC at 6 months. A significant number of side effects were observed, particularly related to the digestive tract, which reinforces need for better management of these side effects. Further data from this ongoing study will provide additional data at 6, 12 and 24 months.[1]Elhai M, Meune C, Boubaya M, Avouac J, Hachulla E, Balbir-Gurman A, et al. Mapping and predicting mortality from systemic sclerosis. Ann Rheum Dis. 2017 Nov;76(11):1897–905.[2]Cottin V, Brown KK. Interstitial lung disease associated with systemic sclerosis (SSc-ILD). Respir Res. 2019;20:13.[3]Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al. Nintedanib for Systemic Sclerosis-Associated Interstitial Lung Disease. N Engl J Med. 2019 Jun 27;380(26):2518–28.NIL.None Declared.