Shedding light on developmental drugs for idiopathic pulmonary fibrosis

Introduction: Idiopathic pulmonary fibrosis (IPF) is an age-related disease of unknown cause. The disease is characterized by relentless scarring of the lung parenchyma resulting in respiratory failure and death. Two antifibrotic drugs (pirfenidone and nintedanib) are approved for the treatment of IPF worldwide, but they do not offer a cure and are associated with tolerability issues. Owing to its high unmet medical need, IPF is an area of dynamic research activity. Areas covered: There is a growing portfolio of novel therapies that target different pathways involved in the complex pathogenesis of IPF. In this review, we discuss the mechanisms of action and available data for compounds in the most advanced stages of clinical development. We searched PubMed for articles on this topic published from 1 January 2000, to 6 June 2020. Expert opinion: The approval of pirfenidone and nintedanib has fueled IPF drug discovery and development. New drugs are likely to reach the clinic in the near future. However, numerous challenges remain; the lack of animal models that reproduce the complexity of human disease and the poor translation of preclinical and early-phase positive effects to late stage clinical trials must be tackled. © 2020 Informa UK Limited, trading as Taylor & Francis Group

The Role of Chest Imaging in Patient Management During the COVID-19 Pandemic A Multinational Consensus Statement From the Fleischner Society

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Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)

Interstitial lung diseases (ILDs), which can arise from a broad spectrum of distinct aetiologies, can manifest as a pulmonary complication of an underlying autoimmune and connective tissue disease (CTD-ILD), such as rheumatoid arthritis-ILD and systemic sclerosis (SSc-ILD). Patients with clinically distinct ILDs, whether CTD-related or not, can exhibit a pattern of common clinical disease behaviour (declining lung function, worsening respiratory symptoms and higher mortality), attributable to progressive fibrosis in the lungs. In recent years, the tyrosine kinase inhibitor nintedanib has demonstrated efficacy and safety in idiopathic pulmonary fibrosis (IPF), SSc-ILD and a broad range of other fibrosing ILDs with a progressive phenotype, including those associated with CTDs. Data from phase II studies also suggest that pirfenidone, which has a different -yet largely unknown -mechanism of action, may also have activity in other fibrosing ILDs with a progressive phenotype, in addition to its known efficacy in IPF. Collectively, these studies add weight to the hypothesis that, irrespective of the original clinical diagnosis of ILD, a progressive fibrosing phenotype may arise from common, underlying pathophysiological mechanisms of fibrosis involving pathways associated with the targets of nintedanib and, potentially, pirfenidone. However, despite the early proof of concept provided by these clinical studies, very little is known about the mechanistic commonalities and differences between ILDs with a progressive phenotype. In this review, we explore the biological and genetic mechanisms that drive fibrosis, and identify the missing evidence needed to provide the rationale for further studies that use the progressive phenotype as a target population. © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ

Relative versus absolute change in forced vital capacity in idiopathic pulmonary fibrosis

BACKGROUND: Decline in forced vital capacity (FVC) over time reliably predicts mortality in patients with idiopathic pulmonary fibrosis. The use of this measure in clinical practice is recommended by current evidence-based guidelines. It is unknown if the method of calculating decline in FVC (relative vs. absolute change) impacts its frequency or its ability to predict mortality.METHODS: Patients with idiopathic pulmonary fibrosis from two prospective cohorts were included if they had a baseline and 12-month follow-up FVC. A ?10% decline in FVC from baseline was calculated in two ways: a relative decline of 10% (e.g., from 60% predicted to 54% predicted) and an absolute decline of 10% (e.g., from 60% predicted to 50% predicted). The frequency of a ?10% decline in FVC and its ability to predict 2-year transplant-free survival were compared between these two methods. Declines in FVC of ?5% and ?15% were similarly compared. Analyses were performed unadjusted and adjusted for age, gender, use of oxygen, baseline FVC and baseline diffusion capacity for carbon monoxide.RESULTS: The frequency of any given FVC decline was significantly greater using the relative change in FVC method. For ?10% decline, both methods predicted 2-year transplant-free survival with similar accuracy, and remained significant predictors after adjusting for baseline characteristics. The absolute change method appeared more predictive for ?5% decline.CONCLUSIONS: Using the relative change in FVC maximises the chance of identifying a ?10% decline in FVC without sacrificing prognostic accuracy. This may not hold true for ?5% decline in FVC. These findings have important implications for clinical practice and the design of clinical trials.<br/

The Relationship of Parental Practices and Knowledge to School Adaptation for Immigrant and Nonimmigrant High School Students

This study assesses the impact of parent practices and knowledge of school on school success for a sample of 240 immigrant and nonimmigrant high school students and their parents. Immigrant parents from the former Soviet Union were less knowledgeable about and had less contact with the school, and allowed less autonomy than U.S.-born parents. Some differences and similarities in the relationship between parental practices and knowledge and school adaptation were found

Supplementary Material for: Metformin Does Not Affect Clinically Relevant Outcomes in Patients with Idiopathic Pulmonary Fibrosis

<b><i>Background:</i></b> Diabetes mellitus is a possible risk factor for the development of idiopathic pulmonary fibrosis (IPF), yet the effect of antidiabetic therapy on the course of IPF is unknown. <b><i>Objectives:</i></b> This post hoc analysis assessed the effect of metformin on clinically relevant outcomes in patients with IPF. <b><i>Methods:</i></b> For the primary analysis, patients randomized to placebo (<i>n</i> = 624) in 3 phase 3, double-blind, controlled trials of pirfenidone (CAPACITY [NCT00287716 and NCT00287729]; ASCEND [NCT01366209]) were categorized by baseline metformin use. The primary outcome was disease progression (forced vital capacity [FVC] decline ≥10%, 6-min walking distance [6MWD] decline ≥50 m, or death). Other outcomes included mortality, hospitalization, FVC decline (≥10 and ≥5%), and 6MWD decline. Outcomes were also assessed in patients with diabetes and/or hyperglycemia (impaired glucose tolerance [IGT] and diabetes population [IGT-diabetes population]) and all patients included in the 3 studies (intention-to-treat [ITT] population). <b><i>Results:</i></b> Overall, 71 (11.4%) patients were metformin users and 553 (88.6%) were nonmetformin users. Baseline data were similar between groups, except for a higher percentage of males (84.5 vs. 73.2%) and a history of diabetes (98.6 vs. 11.6%) in metformin users versus nonmetformin users. The unadjusted 1-year analyses demonstrated no significant differences in disease progression or other outcomes. A higher proportion of metformin users compared with nonmetformin users had a relative FVC decline of ≥5% (63.4 vs. 50.6%, <i>p</i> = 0.043). Results were similar for the IGT-diabetes population and for the ITT population. Multivariable analyses yielded similar results. <b><i>Conclusions:</i></b> Metformin has no effect on clinically relevant outcomes in patients with IPF

Imaging of pulmonary hypertension in adults: a position paper from the Fleischner Society

Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure greater than 20 mm Hg and classified into five different groups sharing similar pathophysiologic mechanisms, hemodynamic characteristics, and therapeutic management. Radiologists play a key role in the multidisciplinary assessment and management of PH. A working group was formed from within the Fleischner Society based on expertise in the imaging and/or management of patients with PH, as well as experience with methodologies of systematic reviews. The working group identified key questions focusing on the utility of CT, MRI, and nuclear medicine in the evaluation of PH: (a) Is noninvasive imaging capable of identifying PH? (b) What is the role of imaging in establishing the cause of PH? (c) How does imaging determine the severity and complications of PH? (d) How should imaging be used to assess chronic thromboembolic PH before treatment? (e) Should imaging be performed after treatment of PH? This systematic review and position paper highlights the key role of imaging in the recognition, work-up, treatment planning, and follow-up of PH

The characterisation of interstitial lung disease multidisciplinary team meetings: A global study

Multidisciplinary team (MDT) diagnosis of interstitial lung disease (ILD) has been proposed as a gold standard, but there are no formal recommendations for MDT process or composition and limited knowledge regarding prevalence in routine practice. We performed a systematic evaluation of ILD diagnostic practice across a range of healthcare settings around the world. Electronic questionnaires were distributed across all global regions via society and collaborators networks. Responses from 457 unique centres across 64 countries were included in the analysis. Of the 350 (76.6%) centres holding formal meetings, the majority held face-to-face MDT meetings (80%), for a minimum of 30 min (93%), and discussed diagnosis (96.9%) and patient management (94.9%) at the meetings. Compared with non-academic and academic non-ILD centres, ILD academic centres reported a higher ILD caseload, held more formal MDT meetings, and were more likely to include histopathology and rheumatology specialists in their diagnostic team. Of the centres holding MDT meetings, 5.5% routinely discussed all new cases at such meetings. An MDT approach to ILD diagnosis is consistently interpreted and widely implemented across a range of routine care settings around the world. This observation will inform future ILD diagnostic agreement studies and diagnostic pathway recommendations. © ERS 2019