Showing papers by "Vincent Cottin published in 2014"

Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis

Abstract: Background Nintedanib (formerly known as BIBF 1120) is an intracellular inhibitor that targets multiple tyrosine kinases. A phase 2 trial suggested that treatment with 150 mg of nintedanib twice daily reduced lung-function decline and acute exacerbations in patients with idiopathic pulmonary fibrosis. Methods We conducted two replicate 52-week, randomized, double-blind, phase 3 trials (INPULSIS-1 and INPULSIS-2) to evaluate the efficacy and safety of 150 mg of nintedanib twice daily as compared with placebo in patients with idiopathic pulmonary fibrosis. The primary end point was the annual rate of decline in forced vital capacity (FVC). Key secondary end points were the time to the first acute exacerbation and the change from baseline in the total score on the St. George’s Respiratory Questionnaire, both assessed over a 52-week period. Results A total of 1066 patients were randomly assigned in a 3:2 ratio to receive nintedanib or placebo. The adjusted annual rate of change in FVC was −114.7 ml with nintedanib versus −239.9 ml with placebo (difference, 125.3 ml; 95% confidence interval [CI], 77.7 to 172.8; P<0.001) in INPULSIS-1 and −113.6 ml with nintedanib versus −207.3 ml with placebo (difference, 93.7 ml; 95% CI, 44.8 to 142.7; P<0.001) in INPULSIS-2. In INPULSIS-1, there was no significant difference between the nintedanib and placebo groups in the time to the first acute exacerbation (hazard ratio with nintedanib, 1.15; 95% CI, 0.54 to 2.42; P = 0.67); in INPULSIS-2, there was a significant benefit with nintedanib versus placebo (hazard ratio, 0.38; 95% CI, 0.19 to 0.77; P = 0.005). The most frequent adverse event in the nintedanib groups was diarrhea, with rates of 61.5% and 18.6% in the nintedanib and placebo groups, respectively, in INPULSIS-1 and 63.2% and 18.3% in the two groups, respectively, in INPULSIS-2. Conclusions In patients with idiopathic pulmonary fibrosis, nintedanib reduced the decline in FVC, which is consistent with a slowing of disease progression; nintedanib was frequently associated with diarrhea, which led to discontinuation of the study medication in less than 5% of patients. (Funded by Boehringer Ingelheim; INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.)

Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study

Abstract: Patients with severe pulmonary arterial hypertension (PAH) in New York Heart Association (NYHA) functional class (FC) III/IV have a poor prognosis, despite survival benefits being demonstrated with intravenous epoprostenol. In this pilot study, the efficacy and safety of a triple combination therapy regimen in patients with severe PAH was investigated. Data from newly diagnosed NYHA FC III/IV PAH patients (n=19) initiated on upfront triple combination therapy (intravenous epoprostenol, bosentan and sildenafil) were collected retrospectively from a prospective registry. Significant improvements in 6-min walk distance and haemodynamics were observed after 4 months' triple combination therapy in 18 patients (p<0.01); 17 patients had improved to NYHA FC I or II. One patient was not included in the month 4 assessment (due to an emergency lung transplant in month 3). At the final evaluation (mean ± sd 32 ± 19 months), all 18 patients had sustained clinical and haemodynamic improvement. Overall survival estimates for the triple combination cohort were 100% at 1, 2 and 3 years. Expected survival calculated from the French equation was 75% (95% CI 68-82%), 60% (95% CI 50-70%) and 49% (95% CI 38-60%) at 1, 2 and 3 years, respectively. This pilot study provides preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH.

Pirfenidone in Idiopathic Pulmonary Fibrosis: Expert Panel Discussion on the Management of Drug-Related Adverse Events

Abstract: Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

Abstract: Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures— conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Pleuroparenchymal fibroelastosis as a late complication of chemotherapy agents.

Abstract: To the Editor: We identified six patients with clinical, radiographic and physiological features typical of pleuroparenchymal fibroelastosis (PPFE). In the six cases, PPFE may have been causally related to prior alkylating drugs used to treat malignacy, namely cyclophosphamide in five of the cases and carmustine (BCNU (1,3-bis-(2-chloroethyl)-1-nitrosourea)) in one. Based on an extensive review of the literature, we suspect that similar cases may have already been reported in the past 4 decades but have not been recognised either as PPFE or as drug-induced in nature. In 2004, Frankel et al. [1] described a then-new clinicopathologic entity, which they termed “idiopathic PPFE”. The authors identified five patients who had a clinical presentation suggestive of chronic interstitial pneumonitis that did not fit any previously established category of idiopathic interstitial pneumonia. The patients were characterised by significant pleural involvement in the form of pleural thickening, which was more marked in both upper regions. In all five patients, surgical biopsy demonstrated prominent visceral pleural fibrosis with subpleural fibroelastosis and an abrupt transition between the fibrotic area and the near-normal adjoining lung. There was sparing of the underlying lung parenchyma at some depth from the pleural surface, and sparse fibroblast foci were present at the edge of the fibrotic area. Since that seminal report, several cases and small series have been reported that have demonstrated a strikingly similar clinical, radiological and pathological presentation, also characterised by difficult-to-treat pneumothoraces in a sizable fraction of affected patients. In the updated American Thoracic Society/European Respiratory Society classification of idiopathic interstitial pneumonias [2], PPFE is included as a separate but well-defined category of rare entities. Little is known about the aetiology of PPFE and …

Diagnosis and management of idiopathic pulmonary fibrosis: French practical guidelines

Abstract: Idiopathic pulmonary fibrosis (IPF) is the most frequent chronic idiopathic interstitial pneumonia in adults. The management of rare diseases in France has been organised by a national plan for rare diseases, which endorsed a network of expert centres for rare diseases throughout France. This article is an overview of the executive summary of the French guidelines for the management of IPF, an initiative that emanated from the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. This review aims at providing pulmonologists with a document that: 1) combines the current available evidence; 2) reviews practical modalities of diagnosis and management of IPF; and 3) is adapted to everyday medical practice. The French practical guidelines result from the combined efforts of a coordination committee, a writing committee and a multidisciplinary review panel, following recommendations from the Haute Autorite de Sante. All recommendations included in this article received at least 90% agreement by the reviewing panel. Herein, we summarise the main conclusions and practical recommendations of the French guidelines.

Neglected evidence in idiopathic pulmonary fibrosis and the importance of early diagnosis and treatment

Abstract: In idiopathic pulmonary fibrosis (IPF), some facts or concepts based on substantial evidence, whilst implicit for learned subspecialists, have previously been neglected and/or not explicitly formulated or made accessible to a wider audience. IPF is strongly associated with cigarette smoking and is predominantly a disease of ageing. However, its cause(s) remain elusive and, thus, it is one of the most challenging diseases for the development of novel effective and safe therapies. With the approval of pirfenidone for patients with mild-to-moderate IPF, an earlier diagnosis of IPF is a prerequisite for earlier treatment and, potentially, improvement of the long-term clinical outcome of this progressive and ultimately fatal disease. An earlier diagnosis may be achieved in IPF by promoting thin-slice chest high-resolution computed tomography screening of interstitial lung disease as a "by-product" of large-scale lung cancer screening strategies in smokers, but other techniques, which have been neglected in the past, are now available. Lung auscultation and early identification of "velcro" crackles has been proposed as a key component of early diagnosis of IPF. An ongoing study is exploring correlations between lung sounds on auscultation obtained using electronic stethoscopes and high-resolution computed tomography patterns.

Effectiveness of cladribine therapy in patients with pulmonary Langerhans cell histiocytosis.

Abstract: Pulmonary Langerhans cell histiocytosis (PLCH) is a rare disorder characterised by granulomatous proliferation of CD1a-positive histiocytes forming granulomas within lung parenchyma, in strong association with tobacco smoking, and which may result in chronic respiratory failure. Smoking cessation is considered to be critical in management, but has variable effects on outcome. No drug therapy has been validated. Cladribine (chlorodeoxyadenosine, 2-CDA) down-regulates histiocyte proliferation and has been successful in curbing multi-system Langerhans cell histiocytosis and isolated PLCH. We retrospectively studied 5 patients (aged 37–55 years, 3 females) with PLCH who received 3 to 4 courses of cladribine therapy as a single agent (0.1 mg/kg per day for 5 consecutive days at monthly intervals). One patient was treated twice because of relapse at 1 year. Progressive pulmonary disease with obstructive ventilatory pattern despite smoking cessation and/or corticosteroid therapy were indications for treatment. Patients were administered oral trimethoprim/sulfamethoxazole and valaciclovir to prevent opportunistic infections. They gave written consent to receive off-label cladribine in the absence of validated treatment. Functional class dyspnea improved with cladribine therapy in 4 out of 5 cases, and forced expiratory volume in 1 second (FEV1) increased in all cases by a mean of 387 ml (100–920 ml), contrasting with a steady decline prior to treatment. Chest high-resolution computed tomography (HRCT) features improved with cladribine therapy in 4 patients. Hemodynamic improvement was observed in 1 patient with pre-capillary pulmonary hypertension. The results suggested a greater treatment effect in subjects with nodular lung lesions and/or thick-walled cysts on chest HRCT, with diffuse hypermetabolism of lung lesions on positron emission tomography (PET)-scan, and with progressive disease despite smoking cessation. Infectious pneumonia developed in 1 patient, with later grade 4 neutrocytopenia but without infection. Data interpretation was limited by the retrospective, uncontrolled study design and small sample size. Cladribine as a single agent may be effective therapy in patients with progressive PLCH.

TOSCA – first international registry to address knowledge gaps in the natural history and management of tuberous sclerosis complex

Abstract: Background: Tuberous sclerosis complex (TSC) is a rare, multisystem, genetic disorder with an estimated prevalence between 1/6800 and 1/15000. Although recent years have seen huge progress in understanding the pathophysiology and in the management of TSC, several questions remain unanswered. A disease registry could be an effective tool to gain more insights into TSC and thus help in the development of improved management strategies. Methods: TuberOus SClerosis registry to increase disease Awareness (TOSCA) is a multicentre, international disease registry to assess manifestations, interventions, and outcomes in patients with TSC. Patients of any age diagnosed with TSC, having a documented visit for TSC within the preceding 12 months, or newly diagnosed individuals are eligible. Objectives include mapping the course of TSC manifestations and their effects on prognosis, identifying patients with rare symptoms and co-morbidities, recording interventions and their outcomes, contributing to creation of an evidence-base for disease assessment and therapy, informing further research on TSC, and evaluating the quality of life of patients with TSC. The registry includes a ‘core’ section and subsections or ‘petals’. The ‘core’ section is designed to record general information on patients’ background collected at baseline and updated annually. Subsections will be developed over time to record additional data related to specific disease manifestations and will be updated annually. The registry aimed to enrol approximately 2000 patients from about 250 sites in 31 countries. The initial enrolment period was of 24 months. A follow-up observation period of up to 5 years is planned. Results: A pre-planned administrative analysis of ‘core’ data from the first 100 patients was performed to evaluate the feasibility of the registry. Results showed a high degree of accuracy of the data collection procedure. Annual interim analyses are scheduled. Results of first interim analysis will be presented subsequent to data availability in 2014. Implications: The results of TOSCA will assist in filling the gaps in understanding the natural history of TSC and help in planning better management and surveillance strategies. This large-scale international registry to study TSC could serve as a model to encourage planning of similar registries for other rare diseases.

Quantification of Myocardial Extracellular Volume Fraction with Cardiac MR Imaging for Early Detection of Left Ventricle Involvement in Systemic Sclerosis

Abstract: Extracellular volume fraction (ECV) imaging by using cardiac MR imaging can identify ECV changes presumably because of diffuse myocardial fibrosis in systemic sclerosis patients without clinical signs and symptoms of heart disease.

Lung and heart-lung transplantation for systemic sclerosis patients. A monocentric experience of 13 patients, review of the literature and position paper of a multidisciplinary Working Group.

Abstract: Systemic sclerosis per se should not be considered as an a priori contraindication for a pre-transplantation assessment in patients with advanced interstitial lung disease and/or pulmonary hypertension. For lung or heart-lung transplantation, a multidisciplinary approach, adapting the pre-transplant assessment to systemic sclerosis and optimizing systemic sclerosis patient management before, during and after surgery should improved the short- and long-term prognosis. Indications and contraindications for transplantation have to be adapted to the specificities of systemic sclerosis. A special focus on the digestive tract involvement and its thorough evaluation are mandatory before transplantation in systemic sclerosis. As the esophagus is almost always involved, isolated gastro-oesophageal reflux disease, pH metry and/or manometry abnormalities should not be a systematic per se contraindication for pre-transplantation assessment. Corticosteroids may be harmful in systemic sclerosis as they are associated with acute renal crisis. A low dose corticosteroids protocol for immunosuppression is therefore advisable in systemic sclerosis.

Current approaches to the diagnosis and treatment of idiopathic pulmonary fibrosis in Europe: the AIR survey

Abstract: This review presents the results of the 2013 Advancing IPF Research (AIR) survey, which assessed current approaches to the diagnosis and treatment of idiopathic pulmonary fibrosis (IPF) by experienced physicians. A total of 149 physicians, predominantly from European countries, replied to the 28-question survey. The results of the AIR survey were compared with a similar survey of 509 French pulmonologists conducted by the French National Reference Centre and the Network of Regional Competence Centres for Rare Lung Diseases. A number of positive findings emerged from the AIR survey, including the high level of multidisciplinary team involvement in both diagnosis and management. This survey, when taken together with the French survey, suggests that there is still a need to improve earlier diagnosis of IPF.

S11 Pirfenidone Post-authorisation Safety Registry (passport)–interim Analysis Of Ipf Treatment

Abstract: Introduction Pirfenidone (Esbriet ® ) is approved for mild/moderate idiopathic pulmonary fibrosis (IPF). PASSPORT is a post-authorisation safety registry required by the European Medicine Agency. Objective To present interim data from PASSPORT. Method Up to 140 EU sites will enrol 1000 patients. Safety data are recorded at routine clinic visits for 2 years. Adverse drug reactions (ADR: a noxious, unintended drug response at therapeutic doses) and serious ADRs (SADR: ADRs that are life-threatening; cause death, disability, congenital anomaly; require hospitalisation or an intervention to prevent permanent impairment) are collected. Results Data from 530 patients enrolled by 68 sites in 7 countries are included. Age was 69 ± 8.8 years (mean ± SD); IPF diagnosis duration was 1.8 ± 3.51 years; 81% were men. Median time in study was 5.5 months; total exposure was 284 person-years. Of 311 patients with ADRs, 85 discontinued due to ADR and 41 discontinued for other reasons. Approximately 1/3 of patients with ADRs had their dose adjusted. For patients who experienced an ADR: 55% of patients without a dose adjustment were able to continue treatment, while 69% of those with a dose adjustment were able to continue treatment. 20% discontinued due to the ADR after having a dose adjustment, but 31% discontinued due to the ADR without a dose adjustment. When ADRs were managed by dose adjustment, dose adjustment was associated with continuing treatment. Conclusion PASSPORT ADRs are comparable to those in clinical trials of pirfenidone in IPF. No new safety issues emerged. Dose adjustment may influence long-term tolerability of pirfenidone.

Pirfenidone post-authorization safety registry (PASSPORT) – Interim analysis of IPF treatment

Abstract: Introduction Pirfenidone (Esbriet®) is approved for mild/mod idiopathic pulmonary fibrosis (IPF). PASSPORT is a post-authorization safety registry required by the European Medicine Agency. Objective Present interim data from PASSPORT Method Up to 140 EU sites will enroll 1000 patients. Safety data are recorded at routine clinic visits for 2 years. Adverse drug reactions (ADR: a noxious, unintended drug response at therapeutic doses) and serious ADRs (SADR: ADRs that are life-threatening; cause death, disability, congenital anomaly; require hospitalization or an intervention to prevent permanent impairment) are collected. Results Data from 530 patients enrolled by 68 sites in 7 countries are included. Age was 69 ± 8.8 years (mean ± SD); IPF diagnosis duration (1.8 ± 3.51 years); 81% were men. Median time in study was 5.5 months; total exposure was 284 person-years. View this table: Of 311 patients with ADRs, 85 discontinued due to ADR and 41 for other reasons. Dosing of patients discontinuing due to ADR compared to those continuing pirfenidone showed a significant association between dose adjustment (reduction or brief interruption) and remaining on therapy. When ADRs were managed by dose adjustment, patients were less likely to discontinue (24.7% vs 75.3%; chi2=5.210, df=1, p=0.02). Conclusion PASSPORT ADRs are comparable to those in clinical trials of pirfenidone in IPF. No new safety issues emerged. Dose adjustment may influence long-term tolerability of pirfenidone.

[Interstitial lung disease-associated with amyopathic dermatomyositis and anti-MDA5 autoantibodies].

Abstract: Resume Introduction Les dermatomyosites cliniquement amyopathiques associees aux auto-anticorps anti-MDA5 sont rares et de description tres recente. Observation Une femme de 58 ans a consulte pour dyspnee subaigue de classe IV NYHA, toux, myalgies, arthrites des poignets et scapulalgies, associees a des episodes febriles. L’examen a revele des lesions cutanees de dermatomyosite avec rash, papules de Gottron, « mains de mecanicien » et des râles crepitants a l’auscultation des bases pulmonaires. L’hypoxemie (61 mmHg) etait associee a un trouble ventilatoire restrictif et une diminution de la DLCO. Le scanner thoracique etait compatible avec une pneumopathie organisee. Le lavage broncho-alveolaire montrait 22 % de polynucleaires neutrophiles. La concentration serique de creatine kinase et l’electromyogramme etaient normaux ; la ferritinemie etait elevee. Les auto-anticorps antinucleaires etaient positifs et des auto-anticorps anti-MDA5 ont ete identifies. L’evolution a ete favorable avec la corticotherapie, secondairement associee au mycophenolate mofetil. Conclusion Les dermatomyosites amyopathiques associees aux auto-anticorps anti-MDA5 ont des caracteristiques communes avec celles des dermatomyosites associees aux auto-anticorps anti-synthetases. L’atteinte musculaire est souvent discrete. Le pronostic pourrait etre ameliore par un diagnostic et un traitement plus precoces.

Effect of baseline emphysema on reduction in FVC decline with nintedanib in the INPULSIS™ trials

Abstract: Background: The INPULSIS™ trials were two replicaterandomized, placebo-controlled, 52-week Phase III trials that assessed the efficacy and safety of nintedanib 150 mg twice daily in patients with IPF. Inboth trials, nintedanib slowed disease progression by significantly reducingthe annual rate of decline in forced vital capacity (FVC), the primaryendpoint, compared with placebo. Methods: A post-hoc subgroup analysis of the effect of nintedanib on the primary endpoint in patients with or without emphysema at baseline,as assessed on qualitative central assessment of chest high-resolution computed tomography (HRCT) scans, was undertaken using pooled data from both trials. Results: In total, 420 patients (nintedanib 254, placebo166) had emphysema at baseline and 641 patients (nintedanib 384, placebo 257) did not. Baseline characteristics for patients with versus without emphysema were as follows: mean age 65.8 versus 67.4 years, 89.0% versus 72.9% were male, meanFVC % predicted was 82.5% versus 77.7%. There was no statistically significant treatment by subgroup interaction for the primary endpoint (p=0.5199): theadjusted annual rate of decline in FVC was -105.1 mL/year with nintedanib and-207.2 mL/year with placebo (difference: 102.0 mL/year [95% CI: 43.2, 160.9]) for patients with emphysema versus -118.8 mL/year with nintedanib and -234.2mL/year with placebo (difference: 115.4 mL/year [95% CI: 73.8, 157.1]) for patients without emphysema at baseline. Conclusion: A post-hoc subgroup analysis of pooled data from the INPULSIS™ trials demonstrated that nintedanib slowed disease progression by reducing the annual rate of FVC decline independent of thepresence of emphysema at baseline.

Pulmonary hypertension-specific therapy in patients with chronic respiratory insufficiency

Abstract: To the Editor: We read with much interest the article by Held et al. [1] regarding pulmonary hypertension (PH) due to hypoventilation. In this retrospective study, the authors reported 18 patients with alveolar hypoventilation (due to obesity or chronic obstructive pulmonary disease (COPD)) and daytime PH associated with reduced exercise capacity. They showed that noninvasive positive-pressure ventilation (NIPPV) was followed by significant improvement in haemodynamics and exercise capacity; thus, strongly supporting the use of NIPPV in patients with hypoventilation and PH, and suggesting a major role for hypoxia and hypercapnia in PH [2]. As it is unknown whether PH-specific therapy targeting vasculopathy and remodelling of the pulmonary arteries may also have an impact in this setting, we retrospectively studied patients with chronic respiratory insufficiency and hypoventilation treated with long-term NIPPV who received off-label specific therapy for severe PH. We extracted from the French registry, in which all consecutive adult patients with PH are prospectively included with written consent [3], incident cases from our centre …

Treatment of lymphangioleiomyomatosis: building evidence in orphan diseases.

Abstract: Lymphangioleiomyomatosis (LAM) is a rare (orphan) lung disease, in which the lung parenchyma is progressively replaced by cysts associated with a proliferation of immature smooth muscle cells and perivascular epithelioid cells (so-called LAM cells) around lymphatic vessels [1, 2]. LAM can be sporadic, almost exclusively affecting females, or can be associated with tuberous sclerosis complex (TSC) where it affects 30–50% of adult females, and less frequently males [3–6]. Patients with LAM most commonly present with relapsing pneumothorax and dyspnoea on exertion, and may have angiomyolipomas (benign tumours) of the kidneys and, occasionally, chylothorax or chylous ascites. Computed tomography of the chest shows characteristic multiple, round thin-walled cysts evenly distributed throughout the lung parenchyma [7], possibly associated with pneumothorax, pleural effusion, lymphadenopathies or lymphangiomas. Over time the disease may progress to chronic obstructive respiratory failure that may require lung transplantation. Pulmonary hypertension is very rare [8]. Diagnostic criteria and management guidelines have been proposed by a task force of the European Respiratory Society. Furthermore, the serum level of vascular endothelial growth factor (VEGF)-D, a major growth factor for lymphatic vessels, may further contribute to the noninvasive diagnosis of LAM if elevated [9]. For many years, treatment of LAM has been mostly supportive, including bronchodilators, supplemental oxygen (if needed), management of complications (especially pneumothorax) and lung transplantation. With a high variability of disease progression [10], many patients with LAM do not need a treatment intervention, whereas a minority of patients do progress to respiratory failure. In 2000, a major breakthrough in the understanding of the pathophysiology of the disease led to a novel treatment approach 10 years later [11]. Based on the observation that pulmonary LAM is present in patients with TSC [4], …

Reduction in disease progression with nintedanib in the INPULSIS™ trials

Abstract: Background: Nintedanib, an intracellular inhibitor of tyrosine kinases, is in development for the treatment of idiopathic pulmonary fibrosis (IPF). The INPULSIS™ trials were two replicate 52-week, randomized, double-blind, placebo-controlled Phase III trials that investigated the efficacy and safety of nintedanib 150 mg twice daily in 1066 patients with IPF. Declines in forced vital capacity (FVC) % predicted of >5% and >10% in patients with IPF have been proposed as indicators of disease progression and have been associated with reduced survival. Aim: To determine the effect of nintedanib on changes in FVC % predicted in the INPULSIS™ trials. Methods: The proportions of patients with absolute and relative declines in FVC % predicted of >5% and >10% at week 52 in each INPULSIS™ trial were determined in a post-hoc analysis. Results: In each trial, a significantly greater proportion of patients in the placebo group had an absolute decline in FVC % predicted of >5% compared with the nintedanib group. In INPULSIS™-1, a significantly greater proportion of patients in the placebo group had an absolute decline in FVC % predicted of >10% compared with the nintedanib group; the difference between groups in INPULSIS™-2 was numerically in favour of nintedanib but did not reach statistical significance. In each trial, significantly greater proportions of patients in the placebo group had relative declines in FVC % predicted of >5% and >10% compared with the nintedanib group. Conclusion: In the INPULSIS™ trials, nintedanib reduced the proportion of patients with IPF who experienced disease progression as measured by categorical FVC decline.

Hypertension pulmonaire au cours des maladies respiratoires chroniques

Abstract: Points essentiels L’hypertension pulmonaire est frequente a un stade avance des maladies respiratoires chroniques, avec au stade de la transplantation pulmonaire une prevalence estimee a 30 a 50 % au cours de la fibrose pulmonaire idiopathique, 30 a 50 % au cours de la bronchopneumopathie chronique obstructive, 50 % au cours du syndrome d’emphyseme et fibrose pulmonaire combines, 75 % au cours de la sarcoidose, et plus de 75 % des cas au cours de la granulomatose pulmonaire a cellules de Langerhans. Les lesions histologiques comportent a des degres variables un remodelage arteriel pulmonaire (predominant), une rarefaction vasculaire (emphyseme), une fibrose ou des lesions specifiques des arteres pulmonaires (fibrose pulmonaire idiopathique, sarcoidose, lymphangioleiomyomatose, granulomatose a cellules de Langerhans), des lesions de thrombose in situ, et une frequente atteinte veineuse pulmonaire associee (sarcoidose, fibrose pulmonaire idiopathique). L’hypertension pulmonaire est detectee le plus souvent par l’echographie cardiaque avec Doppler, mais c’est le catheterisme cardiaque droit qui permet de l’affirmer (pression arterielle pulmonaire ≥ 25 mmHg) et d’etablir son caractere precapillaire (pression arterielle pulmonaire d’occlusion ≤ 15 mmHg). Elle est associee a une moindre capacite fonctionnelle a l’effort et un pronostic plus defavorable. Elle est presque toujours multifactorielle ; l’hypoxie participe a son mecanisme, mais l’oxygenotherapie la corrige rarement. Sa prise en charge repose avant tout sur le traitement de la maladie sous-jacente. Les donnees disponibles ne sont pas en faveur d’un benefice des traitements specifiques de l’hypertension pulmonaire au cours des maladies respiratoires chroniques, mais tres peu d’essais ont ete conduits specifiquement dans cette indication.

Spontaneous pneumomediastinum associated with pneumorachis.

Abstract: An 18-year-old woman with a history of childhood allergic asthma was admitted for acute swelling of the face, neck, and upper chest 5 days after the onset of acute bronchitis. Further examination revealed wheezes on lung auscultation and rhinolalia. Blood pressure and oxygenation were normal. Computed tomography of the chest showed extensive pneumomediastinum with subcutaneous emphysema and pneumorachis (Figure 1, arrows) extending throughout the entire cervical and dorsal spine. Neurologic examination was normal. Management included rest, bronchodilators, and corticosteroids. The patient was discharged on Day 7 with complete recovery. Pneumorachis is defined by the presence of air in the spinal canal (1–3). It may result from trauma, but most cases are unrelated to trauma; it is present in about 10% of cases of spontaneous pneumomediastinum (3, 4). Clinicians should be aware of this complication in the setting of acute bronchitis or asthma exacerbation. Generally asymptomatic, pneumorachis can occasionally cause spinal cord compression, especially in cases of trauma. Supplemental nasal oxygen might accelerate air resorption. Outcomes are favorable most of the time (3). n