Publications
772 results found
Podolanczuk AJ, Kim JS, Cooper CB, et al., 2022, Design and rationale for the prospective treatment efficacy in IPF using genotype for NAC selection (PRECISIONS) clinical trial, BMC Pulmonary Medicine, Vol: 22, ISSN: 1471-2466
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with few treatment options. N-acetylcysteine (NAC) is a well-tolerated, inexpensive treatment with antioxidant and anti-fibrotic properties. The National Heart, Lung, and Blood Institute (NHLBI)-sponsored PANTHER (Prednisone Azathioprine and NAC therapy in IPF) trial confirmed the harmful effects of immunosuppression in IPF, and did not show a benefit to treatment with NAC. However, a post hoc analysis revealed a potential beneficial effect of NAC in a subgroup of individuals carrying a specific genetic variant, TOLLIP rs3750920 TT genotype, present in about 25% of patients with IPF. Here, we present the design and rationale for the Phase III, multi-center, randomized, double-blind, placebo-controlled Prospective Treatment Efficacy in IPF Using Genotype for NAC Selection (PRECISIONS) clinical trial. METHODS: The PRECISIONS trial will randomize 200 patients with IPF and the TOLLIP rs3750920 TT genotype 1:1 to oral N-acetylcysteine (600 mg tablets taken three times a day) or placebo for a 24-month duration. The primary endpoint is the composite of time to 10% relative decline in forced vital capacity (FVC), first respiratory hospitalization, lung transplantation, or death from any cause. Secondary endpoints include change in patient-reported outcome scores and proportion of participants with treatment-emergent adverse events. Biospecimens, including blood, buccal, and fecal will be collected longitudinally for future research purposes. Study participants will be offered enrollment in a home spirometry substudy, which explores time to 10% relative FVC decline measured at home, and its comparison with study visit FVC. DISCUSSION: The sentinel observation of a potential pharmacogenetic interaction between NAC and TOLLIP polymorphism highlights the urgent, unmet need for better, molecularly focused, and precise therapeutic strategies in IPF. The PRECISIONS clinical trial is the first study
Fainberg HP, Oldham JM, Molyneau PL, et al., 2022, Forced vital capacity trajectories in patients with idiopathic pulmonary fibrosis: a secondary analysis of a multicentre, prospective, observational cohort, The Lancet Digital Health, Vol: 4, Pages: e862-e872, ISSN: 2589-7500
BACKGROUND: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease with a variable clinical trajectory. Decline in forced vital capacity (FVC) is the main indicator of progression; however, missingness prevents long-term analysis of patterns in lung function. We aimed to identify distinct clusters of lung function trajectory among patients with idiopathic pulmonary fibrosis using machine learning techniques. METHODS: We did a secondary analysis of longitudinal data on FVC collected from a cohort of patients with idiopathic pulmonary fibrosis from the PROFILE study; a multicentre, prospective, observational cohort study. We evaluated the imputation performance of conventional and machine learning techniques to impute missing data and then analysed the fully imputed dataset by unsupervised clustering using self-organising maps. We compared anthropometric features, genomic associations, serum biomarkers, and clinical outcomes between clusters. We also performed a replication of the analysis on data from a cohort of patients with idiopathic pulmonary fibrosis from an independent dataset, obtained from the Chicago Consortium. FINDINGS: 415 (71%) of 581 participants recruited into the PROFILE study were eligible for further analysis. An unsupervised machine learning algorithm had the lowest imputation error among tested methods, and self-organising maps identified four distinct clusters (1-4), which was confirmed by sensitivity analysis. Cluster 1 comprised 140 (34%) participants and was associated with a disease trajectory showing a linear decline in FVC over 3 years. Cluster 2 comprised 100 (24%) participants and was associated with a trajectory showing an initial improvement in FVC before subsequently decreasing. Cluster 3 comprised 113 (27%) participants and was associated with a trajectory showing an initial decline in FVC before subsequent stabilisation. Cluster 4 comprised 62 (15%) participants and was associated with a trajectory showing stable lung
De Zorzi E, Spagnolo P, Cocconcelli E, et al., 2022, Thoracic involvement in systemic autoimmune rheumatic diseases: pathogenesis and management, Clinical Reviews in Allergy and Immunology, Vol: 63, Pages: 472-489, ISSN: 1080-0549
Thoracic involvement is one of the main determinants of morbidity and mortality in patients with autoimmune rheumatic diseases (ARDs), with different prevalence and manifestations according to the underlying disease. Interstitial lung disease (ILD) is the most common pulmonary complication, particularly in patients with systemic sclerosis (SSc), idiopathic inflammatory myopathies (IIMs) and rheumatoid arthritis (RA). Other thoracic manifestations include pulmonary arterial hypertension (PAH), mostly in patients with SSc, airway disease, mainly in RA, and pleural involvement, which is common in systemic lupus erythematosus and RA, but rare in other ARDs.In this review, we summarize and critically discuss the current knowledge on thoracic involvement in ARDs, with emphasis on disease pathogenesis and management. Immunosuppression is the mainstay of therapy, particularly for ARDs-ILD, but it should be reserved to patients with clinically significant disease or at risk of progressive disease. Therefore, a thorough, multidisciplinary assessment to determine disease activity and degree of impairment is required to optimize patient management. Nevertheless, the management of thoracic involvement-particularly ILD-is challenging due to the heterogeneity of disease pathogenesis, the variety of patterns of interstitial pneumonia and the paucity of randomized controlled clinical trials of pharmacological intervention. Further studies are needed to better understand the pathogenesis of these conditions, which in turn is instrumental to the development of more efficacious therapies.
Maher TM, Schiffman C, Kreuter M, et al., 2022, A review of the challenges, learnings and future directions of home handheld spirometry in interstitial lung disease, Respiratory Research, Vol: 23, ISSN: 1465-9921
BackgroundPatients with interstitial lung disease (ILD) require regular physician visits and referral to specialist ILD clinics. Difficulties or delays in accessing care can limit opportunities to monitor disease trajectory and response to treatment, and the COVID-19 pandemic has added to these challenges. Therefore, home monitoring technologies, such as home handheld spirometry, have gained increased attention as they may help to improve access to care for patients with ILD. However, while several studies have shown that home handheld spirometry in ILD is acceptable for most patients, data from clinical trials are not sufficiently robust to support its use as a primary endpoint. This review discusses the challenges that were encountered with handheld spirometry across three recent ILD studies, which included home spirometry as a primary endpoint, and highlights where further optimisation and research into home handheld spirometry in ILD is required.Abstract bodyRate of decline in forced vital capacity (FVC) as measured by daily home handheld spirometry versus site spirometry was of primary interest in three recently completed studies: STARLINER (NCT03261037), STARMAP and a Phase II study of pirfenidone in progressive fibrosing unclassifiable ILD (NCT03099187). Unanticipated practical and technical issues led to problems with estimating FVC decline. In all three studies, cross-sectional correlations for home handheld versus site spirometry were strong/moderate at baseline and later timepoints, but longitudinal correlations were weak. Other issues observed with the home handheld spirometry data included: high within-patient variability in home handheld FVC measurements; implausible longitudinal patterns in the home handheld spirometry data that were not reflected in site spirometry; and extreme estimated rates of FVC change.ConclusionsHome handheld spirometry in ILD requires further optimisation and research to ensure accurate and reliable FVC measurements before it
Chung KF, Birring SS, Morice AH, et al., 2022, Tackling the neuropathic cough of idiopathic pulmonary fibrosis (IPF): more needs to be done, Lung: an international journal on lungs, airways and breathing, Vol: 200, Pages: 673-675, ISSN: 0341-2040
Up to 80% of patients with idiopathic pulmonary fibrosis (IPF) suffer from a chronic cough, which may be the first symptom of the disease. Cough has been reported to be an independent predictor of disease progression [1] and is associated with reduced quality of life (QoL), because from the patients’ point of view, it causes physical and emotional distress with chest pain, hoarse voice, incontinence, and sleep disturbance [2, 3]. In addition, cough QoL scores have been independently associated with a higher risk of hospitalisation, lung transplantation and death at 1 year [4]. Therefore, control of cough in IPF remains an important priority.
Maher TM, 2022, A clinical short-cut to identifying short telomeres in idiopathic pulmonary fibrosis?, RESPIROLOGY, Vol: 27, Pages: 916-917, ISSN: 1323-7799
Myall KJ, West AG, Martinovic JL, et al., 2022, NOCTURNAL HYPOXAEMIA RATHER THAN OBSTRUCTIVE SLEEP APNOEA IS ASSOCIATED WITH PROGRESSIVE DETERIORATION IN QUALITY OF LIFE IN PATIENTS WITH FIBROTIC INTERSTITIAL LUNG DISEASE, Winter Meeting of the British-Thoracic-Society (BTS), Publisher: BMJ PUBLISHING GROUP, Pages: A5-A6, ISSN: 0040-6376
Allen RJ, Oldham JM, Jenkins DA, et al., 2022, GENOME-WIDE ANALYSIS OF LONGITUDINAL LUNG FUNCTION AND GAS TRANSFER IN INDIVIDUALS WITH IDIOPATHIC PULMONARY FIBROSIS, Winter Meeting of the British-Thoracic-Society (BTS), Publisher: BMJ PUBLISHING GROUP, Pages: A67-A68, ISSN: 0040-6376
Wu Z, Saunders P, Smith D, et al., 2022, CHARACTERISING COUGH BURDEN IN HYPERSENSITIVITY PNEUMONITIS, Winter Meeting of the British-Thoracic-Society (BTS), Publisher: BMJ PUBLISHING GROUP, Pages: A6-A6, ISSN: 0040-6376
Molyneaux PL, Forbes W, Bortey E, et al., 2022, EFFICACY OF ORAL NALBUPHINE EXTENDED RELEASE FOR THE TREATMENT OF CHRONIC COUGH IN IDIOPATHIC PULMONARY FIBROSIS: ANALYSIS OF A PHASE 2 STUDY, British Thoracic Society Winter Conference, Publisher: BMJ PUBLISHING GROUP, Pages: A13-A14, ISSN: 0040-6376
Zhang D, Povysil G, Newton CA, et al., 2022, Genome-wide enrichment of TERT rare variants in Idiopathic Pulmonary Fibrosis patients of Latino ancestry, American Journal of Respiratory and Critical Care Medicine, Vol: 206, Pages: 903-905, ISSN: 1073-449X
Genome-wide rare variant studies of IPF patients of non-European ancestry have been understudied. Here, we evaluate the enrichment of rare genetic variants of 241 unrelated non-European cases, representing individuals of Latino, African, South Asian, East Asian, and Other Admixed ancestry. Gene burden analysis of deleterious rare (protein-truncating and missense) variants demonstrate an excess of TERT rare damaging variants (OR 67.1, 95% CI [23.1, 195.0], P = 9.4 x 10-14) in non-European subjects. Analysis by ancestry demonstrated an excess of rare, damaging TERT variants in the Latino subgroup (OR 80.9, 95% CI [17.3, 383.8], P = 2.6 x 10-8). Although the non-European group did not show enrichment of PARN, RTEL1, and KIF15 rare deleterious variants, these groups all showed a trend in the same direction as the European ancestry group. For TERT and KIF15, the inclusion of IPF patients of non-European ancestry led to a higher odds ratios and increased evidence in favor of rare deleterious variant contributions, thus demonstrating the increased power of multi-ethnic studies over single-ethnicity studies. To our knowledge, this is the first study that confirms the involvement of rare deleterious TERT variants for IPF patients of Latino and non-European ancestry. To better understand the genetic underpinnings of IPF patients of all ancestries, additional work will be needed to broaden patient recruitment to normalize imbalances.
Maher TM, Schlecker C, Luedtke D, et al., 2022, Phase I studies of BI 1015550, a preferential phosphodiesterase 4B inhibitor, in healthy males and patients with idiopathic pulmonary fibrosis, ERJ Open Research, Vol: 8, ISSN: 2312-0541
Introduction: BI 1015550 is a phosphodiesterase 4 (PDE4) inhibitor that has antifibrotic properties. Phase I and Ic studies were conducted to investigate the safety, tolerability and pharmacokinetics of BI 1015550 in healthy male subjects and patients with idiopathic pulmonary fibrosis (IPF).Methods: In the phase I study, 42 subjects were partially randomised to receive placebo or BI 1015550 in single rising doses of 36 mg and 48 mg, or multiple rising doses of 6 mg and 12 mg twice daily over 14 days. In the phase Ic study, 15 patients with IPF were randomised to receive 18 mg BI 1015550 or placebo twice daily for up to 12 weeks. For both studies, the primary endpoint was the number of subjects with drug-related adverse events (AEs).Results: In the Phase I study, drug-related AEs were reported for 50.0% of healthy male subjects treated with a single dose of BI 1015550, compared with 16.7% receiving placebo. For those receiving multiple doses, drug-related AEs were reported for 37.5% of those treated with BI 1015550 and 12.5% receiving placebo. The most frequently reported AEs by organ class were nervous system disorders, which were largely driven by headache. In the Phase Ic study, drug-related AEs were reported in 90.0% of patients treated with BI 1015550, compared with 60.0% of those receiving placebo. The most frequent AEs by organ class were gastrointestinal AEs.Conclusions: BI 1015550 had an acceptable safety profile in healthy male subjects and male and female patients with IPF, supporting further development in larger trials.
Assassi S, Distler O, Allanore Y, et al., 2022, Effect of nintedanib on progression of systemic sclerosis-associated interstitial lung disease over 100 weeks: data from a randomized controlled trial, ACR Open Rheumatology, Vol: 10, Pages: 837-844, ISSN: 2578-5745
ObjectiveIn the SENSCIS trial, participants with systemic sclerosis-associated interstitial lung disease (SSc-ILD) were randomized to receive nintedanib or placebo until the last participant reached week 52 but for 100 weeks or less. Nintedanib reduced the rate of decline in forced vital capacity (FVC) (ml/year) over 52 weeks by 44% (41 ml [95% confidence interval (95% CI): 2.9-79.0]) versus placebo. We investigated the effect of nintedanib over the whole SENSCIS trial.MethodsThe annual rate of decline in FVC (ml/year) over the whole trial was assessed descriptively using 1) on-treatment data plus off-treatment data from participants who prematurely discontinued treatment (intent-to-treat analysis) and 2) only on-treatment data to assess the effect of nintedanib in participants who remained on treatment.ResultsIn the intent-to-treat analysis, the adjusted mean (SE) annual rate of decline in FVC over 100 weeks was −54.9 (11.1) and −88.8 (10.9) ml/year in the nintedanib (n = 287) and placebo (n = 288) groups, respectively (difference 34.0 ml/year [95% CI: 3.4-64.5]). In the on-treatment analysis, the adjusted mean (SE) annual rate of decline in FVC over 100 weeks was −55.1 (12.3) and −94.0 (11.7) ml/year in the nintedanib (n = 286) and placebo (n = 288) groups, respectively (difference 38.9 ml/year [95% CI: 5.6-72.1]). The adverse event profile of nintedanib over 100 weeks was consistent with that observed over 52 weeks.ConclusionNintedanib provides a sustained benefit on slowing the progression of SSc-ILD over 100 weeks, with adverse events that are manageable for most patients.
Khanna D, Distler O, Cottin V, et al., 2022, Diagnosis and monitoring of systemic sclerosis-associated interstitial lung disease using high-resolution computed tomography, JOURNAL OF SCLERODERMA AND RELATED DISORDERS, Vol: 7, Pages: 168-178, ISSN: 2397-1983
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Kreuter M, Bendstrup E, Maher TM, et al., 2022, Impact of weight loss on outcomes in patients with progressive fibrosing interstitial lung diseases (ILDs), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Richeldi L, Azuma A, Cottin V, et al., 2022, Additive effect of BI 1015550 and nintedanib in patients with IPF, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Maher T, Ganslandt C, Batta R, et al., 2022, Interim results from AIR, an open-label, single arm, 36-week ph 2 trial of C21 in subjects with idiopathic pulmonary fibrosis, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Maher T, Wijsenbeek M, Hirani N, et al., 2022, GALACTIC-1: Galectin-3 inhibition in idiopathic pulmonary fibrosis (IPF) - rationale, objectives and design of a 52-week, Phase IIb study of GB0139, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Ford P, Cottin V, Flaherty K, et al., 2022, A phase 2b randomized trial to evaluate LYT-100 in patients with idiopathic pulmonary fibrosis (IPF), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Myall K, West A, Martinovic J, et al., 2022, Limited utility of STOP-BANG in identification of obstructive sleep apnoea in fibrotic interstitial lung disease, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Patel S, Sylvester K, Wu Z, et al., 2022, Validity and symptom burden of impulse oscillometry (iOS) in idiopathic pulmonary fibrosis (IPF), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Myall K, Martinovic J, Wu Z, et al., 2022, Nocturnal hypoxaemia is associated with mortality in patients with fibrotic interstitial lung disease, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Kreuter M, Denton CP, Ho LA, et al., 2022, Progression of systemic sclerosis-associated ILD (SSc-ILD) and effect of nintedanib in subgroups by monocyte and neutrophil counts, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Maher TM, Forbes W, Bortey E, et al., 2022, An interim analysis of a phase 2 trial evaluating oral nalbuphine extended release for treating chronic cough in idiopathic pulmonary fibrosis, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Wiqvist K, Ingelsten M, Jevnikar Z, et al., 2022, A transcriptomic, metabolic and phenotypic study of the anti-fibrotic effects of PGE2 in IPF lung fibroblasts and macrophages, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Kreuter M, Lee JS, Tzouvelekis A, et al., 2022, A modified blood cell GAP (cGAP) to prognosticate outcomes in IPF, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
van der Vis J, Prasse A, Renzoni E, et al., 2022, Association of mUC5B rs35705950 minor allele with age and survival in European patients with Idiopathic Pulmonary Fibrosis, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Maher TM, Nambiar AM, Wells AU, 2022, The role of precision medicine in interstitial lung disease, European Respiratory Journal, Vol: 60, ISSN: 0903-1936
The management of interstitial lung disease (ILD) may benefit from a conceptual shift. Increased understanding of this complex and heterogeneous group of disorders over the past 20 years has highlighted the need for individualised treatment strategies that encompass diagnostic classification and disease behaviour. Biomarker-based approaches to precision medicine hold the greatest promise. Robust, large-scale biomarker-based technologies supporting ILD diagnosis have been developed, and future applications relating to staging, prognosis and assessment of treatment response are emerging. Artificial intelligence may redefine our ability to base prognostic evaluation on both diagnosis and underlying disease processes, sharpening individualised treatment algorithms to a level not previously achieved. Compared with therapeutic areas such as oncology, precision medicine in ILD is still in its infancy. However, the heterogeneous nature of ILD suggests that many relevant molecular, environmental and behavioural targets may serve as useful biomarkers if we are willing to invest in their identification and validation.
Maher T, Tudor V, Saunders P, et al., 2022, Rituximab versus Cyclophosphamide for the Treatment of Connective Tissue Disease Associated Interstitial Lung Disease (RECITAL): A Sub-group Analysis of a Multi-centre Randomised Controlled Trial, Publisher: WILEY, Pages: 5-7, ISSN: 2326-5191
Richeldi L, Stowasser S, Maher TM, 2022, Trial of a phosphodiesterase 4 inhibitor for idiopathic pulmonary fibrosis. reply., New England Journal of Medicine, Vol: 387, Pages: 762-762, ISSN: 0028-4793
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