Publications
772 results found
Hoffmann-Vold A-M, Maher TM, Philpot EE, et al., 2021, Assessment of recent evidence for the management of patients with systemic sclerosis-associated interstitial lung disease: a systematic review, ERJ OPEN RESEARCH, Vol: 7
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- Citations: 9
Highland KB, Distler O, Kuwana M, et al., 2021, Efficacy and safety of nintedanib in patients with systemic sclerosis-associated interstitial lung disease treated with mycophenolate: a subgroup analysis of the SENSCIS trial, Publisher: ELSEVIER SCI LTD, Pages: 96-106, ISSN: 2213-2600
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- Citations: 91
Guillotin D, Taylor AR, Plate M, et al., 2021, Transcriptome analysis of IPF fibroblastic foci identifies key pathways involved in fibrogenesis, THORAX, Vol: 76, Pages: 73-82, ISSN: 0040-6376
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- Citations: 16
Wilson AM, Clark AB, Cahn T, et al., 2020, Effect of co-trimoxazole (Trimethoprim-Sulfamethoxazole) vs placebo on death, lung transplant, or hospital admission in patients with moderate and severe idiopathic pulmonary fibrosis the EME-TIPAC randomized clinical trial, JAMA: Journal of the American Medical Association, Vol: 324, Pages: 2282-2291, ISSN: 0098-7484
Importance Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and limited treatment options. Patients with IPF have altered lung microbiota, with bacterial burden within the lungs associated with mortality; previous studies have suggested benefit with co-trimoxazole (trimethoprim-sulfamethoxazole).Objective To determine the efficacy of co-trimoxazole in patients with moderate and severe IPF.Design, Setting, and Participants Double-blind, placebo-controlled, parallel randomized trial of 342 patients with IPF, breathlessness (Medical Research Council dyspnea scale score >1), and impaired lung function (forced vital capacity ≤75% predicted) conducted in 39 UK specialist interstitial lung disease centers between April 2015 (first patient visit) and April 2019 (last patient follow-up).Interventions Study participants were randomized to receive 960 mg of oral co-trimoxazole twice daily (n = 170) or matched placebo (n = 172) for between 12 and 42 months. All patients received 5 mg of folic acid orally once daily.Main Outcomes and Measures The primary outcome was time to death (all causes), lung transplant, or first nonelective hospital admission. There were 15 secondary outcomes, including the individual components of the primary end point respiratory-related events, lung function (forced vital capacity and gas transfer), and patient-reported outcomes (Medical Research Council dyspnea scale, 5-level EuroQol 5-dimension questionnaire, cough severity, Leicester Cough Questionnaire, and King’s Brief Interstitial Lung Disease questionnaire scores).Results Among 342 individuals who were randomized (mean age, 71.3 years; 46 [13%] women), 283 (83%) completed the trial. The median (interquartile range) duration of follow-up was 1.02 (0.35-1.73) years. Events per person-year of follow-up among participants randomized to the co-trimoxazole and placebo groups were 0.45 (84/186) and 0.38 (80/209), respectively, with a hazard ratio of
Jones MG, Hillyar CRT, Nibber A, et al., 2020, Opportunities to diagnose fibrotic lung diseases in routine care: A primary care cohort study, RESPIROLOGY, Vol: 25, Pages: 1274-1282, ISSN: 1323-7799
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- Citations: 5
Paynton ML, Allen RJ, Oldham J, et al., 2020, Human leukocyte antigen-wide association metaanalysis of idiopathic pulmonary fibrosis susceptibility, Publisher: SPRINGERNATURE, Pages: 718-719, ISSN: 1018-4813
Leavy OC, Ma S-F, Molyneaux PL, et al., 2020, Proportion of idiopathic pulmonary fibrosis risk explained by known Common genetic loci in European populations, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 775-778, ISSN: 1073-449X
Genome-wide association studies have identified 14 genetic loci associated with susceptibility to idiopathic pulmonary fibrosis (IPF), a devastating lung disease with poor prognosis. Of these, the variant with the strongest association, rs35705950, is located in the promoter region of the MUC5B gene and has a risk allele (T) frequency of 30-35% in IPF cases. Here we present estimates of the proportion of disease liability explained by each of the 14 IPF risk variants as well as estimates of the proportion of cases that can be attributed to each variant. We estimate that rs35705950 explains 5.9-9.4% of disease liability, which is much lower than previously reported estimates. Of every 100,000 individuals with the rs35705950_GG genotype we estimate 30 will have IPF, whereas for every 100,000 individuals with the rs35705950_GT genotype 152 will have IPF. Quantifying the impact of genetic risk factors on disease liability improves our understanding of the underlying genetic architecture of IPF and provides insight into the impact of genetic factors in risk prediction modelling.
Hirani N, MacKinnon AC, Nicol L, et al., 2020, Target-inhibition of galectin-3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis., European Respiratory Journal, Vol: 57, Pages: 1-13, ISSN: 0903-1936
Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside-binding lectin that plays a key role in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and IPF exacerbations. TD139 is a novel and potent small molecule inhibitor of Gal-3.A randomised, double-blind, multi-centre, placebo-controlled, phase I/IIa study was conducted to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of inhaled TD139 in 36 healthy subjects and 24 patients with IPF (NCT02257177). Six dose cohorts of six healthy subjects were evaluated (4:2 TD139:placebo ratio) with single doses of TD139 (0.15 mg to 50 mg) and three dose cohorts of eight patients with IPF (5:3 TD139:placebo ratio) with once daily doses of TD139 (0.3 mg to 10 mg) for 14 days.Inhaled TD139 was well tolerated with no significant treatment-related side effects. TD139 was rapidly absorbed, with mean Tmax values ranging from 0.6 h to 3 h and a T½ of 8 h. The concentration of TD139 in the lung was >567-fold higher than in the blood, with systemic exposure predicting exposure in the target compartment. Gal-3 expression on alveolar macrophages was reduced in the 3 mg and 10 mg dose groups compared to placebo, with a concentration-dependent inhibition demonstrated. Inhibition of Gal-3 expression in the lung was associated with reductions in plasma biomarkers centrally relevant to IPF pathobiology (PDGF-BB, PAI-1, Gal-3, CCL18 and YKL-40).TD139 is safe and well tolerated in healthy subjects and IPF patients. It was shown to suppress Gal-3 expression on BAL macrophages and, in a concerted fashion, decrease plasma biomarkers associated with IPF progression.
Miles J, Pinkerton JW, Bonvini SJ, et al., 2020, Modelling IPF-associated chronic cough: role for oxidative stress?, The 2020 ERS International Congress, Publisher: European Respiratory Society, Pages: 1-2, ISSN: 0903-1936
Introduction: Chronic cough is a key symptom that plagues the lives of IPF patients, indeed, it is often the reason the disease is initially diagnosed. The aim of this project was to develop a pre-clinical model of IPF-associated cough and compare the mediator profiles with clinical samples, to aid in the search for effective treatments.Methods: Male guinea pigs (around 325g) were intratracheally dosed with vehicle (saline) or bleomycin (6 USP/kg) and coughs were quantified through manual observation of in-cage video footage, by watching 4.5 hours a day, for 3 weeks. Lung tissue, bronchoalveolar lavage fluid (BALF) and blood was harvested from a parallel group of animals. These were used to assess the extent of fibrosis and measure mediator production (e.g. a marker of oxidative stress: 8-isoprostane). Human BALF was obtained from IPF patients and healthy controls.Results: Spontaneous coughing was recorded in guinea pigs given bleomycin, which was associated with an increase in lung fibrosis and BALF 8-isoprostane (a marker of oxidative stress). We noted similar increases in BALF 8-isoprostane levels in the clinical samples.Conclusions: We have developed a preclinical model to aid in the search for a treatment for IPF-associated coughing. Furthermore, initial data suggests that an increase in oxidative burden (a known trigger of coughing) could be an attractive target.
Ogger PP, Albers GJ, Hewitt RJ, et al., 2020, Itaconate controls the severity of pulmonary fibrosis, Science Immunology, Vol: 5, Pages: 1-13, ISSN: 2470-9468
Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease in which airway macrophages (AMs) play a key role. Itaconate has emerged as a mediator of macrophage function, but its role during fibrosis is unknown. Here, we reveal that itaconate is an endogenous antifibrotic factor in the lung. Itaconate levels are reduced in bronchoalveolar lavage, and itaconate-synthesizing cis-aconitate decarboxylase expression (ACOD1) is reduced in AMs from patients with IPF compared with controls. In the murine bleomycin model of pulmonary fibrosis, Acod1-/- mice develop persistent fibrosis, unlike wild-type (WT) littermates. Profibrotic gene expression is increased in Acod1-/- tissue-resident AMs compared with WT, and adoptive transfer of WT monocyte-recruited AMs rescued mice from disease phenotype. Culture of lung fibroblasts with itaconate decreased proliferation and wound healing capacity, and inhaled itaconate was protective in mice in vivo. Collectively, these data identify itaconate as critical for controlling the severity of lung fibrosis, and targeting this pathway may be a viable therapeutic strategy.
Seibold JR, Maher TM, Highland KB, et al., 2020, Safety and tolerability of nintedanib in patients with systemic sclerosis-associated interstitial lung disease: data from the SENSCIS trial, Annals of the Rheumatic Diseases, Vol: 79, Pages: 1478-1484, ISSN: 0003-4967
OBJECTIVES: To characterise the safety and tolerability of nintedanib and the dose adjustments used to manage adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: In the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib 150 mg two times per day or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg two times per day. We assessed adverse events and dose adjustments over 52 weeks. RESULTS: A total of 576 patients received nintedanib (n=288) or placebo (n=288). The most common adverse event was diarrhoea, reported in 75.7% of patients in the nintedanib group and 31.6% in the placebo group; diarrhoea led to permanent treatment discontinuation in 6.9% and 0.3% of patients in the nintedanib and placebo groups, respectively. In the nintedanib and placebo groups, respectively, 48.3% and 12.2% of patients had ≥1 dose reduction and/or treatment interruption, and adverse events led to permanent discontinuation of the trial drug in 16.0% and 8.7% of patients. The adverse events associated with nintedanib were similar across subgroups defined by age, sex, race and weight. The rate of decline in forced vital capacity in patients treated with nintedanib was similar irrespective of dose adjustments. CONCLUSIONS: The adverse event profile of nintedanib in patients with SSc-ILD is consistent with its established safety and tolerability profile in patients with idiopathic pulmonary fibrosis. Dose adjustment is important to minimise the impact of adverse events and help patients remain on therapy.
John AE, Graves RH, Pun KT, et al., 2020, Translational pharmacology of an inhaled small molecule alpha v beta 6 integrin inhibitor for idiopathic pulmonary fibrosis, Nature Communications, Vol: 11, ISSN: 2041-1723
The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and disease-related end points. Here, we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy.
Stock CJ, Conti C, Montero-Fernandez Á, et al., 2020, Interaction between the promoter MUC5B polymorphism and mucin expression: is there a difference according to ILD subtype?, Thorax, Vol: 75, Pages: 901-903, ISSN: 0040-6376
The MUC5B promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in MUC5B rs35705950 T-carriers is specific to IPF.
Woodcock HV, Eley JD, Guillotin D, et al., 2020, The mTORC1/4E-BP1 axis represents a critical signaling node during fibrogenesis (vol 10, 6, 2019), NATURE COMMUNICATIONS, Vol: 11, ISSN: 2041-1723
White E, Cottin V, Kolb M, et al., 2020, Changes in biomarkers with nintedanib plus sildenafil in subjects with IPF by presence of emphysema in the INSTAGE trial, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
White E, Behr J, Kolb M, et al., 2020, Changes in biomarkers with nintedanib and sildenafil in subjects with IPF in the INSTAGE trial: subgroup analysis by right heart dysfunction (RHD), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Cottin V, Corte TJ, Kreuter M, et al., 2020, Pirfenidone in unclassifiable ILD (uILD): subgroup analysis of patients with/without a surgical lung biopsy (SLB), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Bonella F, Maher TM, Cottin V, et al., 2020, Consistent effect of nintedanib on reducing FVC decline across interstitial lung diseases (ILDs), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Price LC, Kouranos V, Dimopoulos K, et al., 2020, Sarcoidosis-associated Pulmonary Hypertension: A London Cohort, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Kokosi M, Trachalaki A, Stock C, et al., 2020, Serum KL-6 identifies ILD patients with a progressive fibrosing phenotype, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Stock C, Molyneaux P, Saunders P, et al., 2020, MUC2MUC5B and TOLLIP variants: no association with disease progression and survival in an IPF cohort, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 2
Bonifazi M, Sverzellati N, Negri E, et al., 2020, Pleuroparenchymal fibroelastosis in systemic sclerosis: prevalence and prognostic impact, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Trachalaki A, Tsitoura E, Invernizzi R, et al., 2020, Inflammasome activation in airway macrophages and the lung microbiome in IPF, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Jenkins G, Noth I, Selman M, et al., 2020, Effects of nintedanib on markers of epithelial damage in subjects with IPF: data from the INMARK trial, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 3
Chaudhuri N, Cottin V, Cerri S, et al., 2020, Does nintedanib have the same effect on FVC decline in patients with progressive fibrosing ILDs treated with DMARDs or glucocorticoids?, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Valenzuela C, Maher TM, Bonella F, et al., 2020, Effects of nintedanib in patients with progressive fibrosing ILDs and differing baseline FVC: further analyses of the INBUILD trial, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 2
Nolan CM, Maddocks M, Maher TM, et al., 2020, Sarcopenia in idiopathic pulmonary fibrosis ( IPF): Prevalence and response to pulmonary rehabilitation (PR), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Tzouvelekis A, Maher TM, Goh N, et al., 2020, Monocyte count and decline in forced vital capacity (FVC) in patients with IPF, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Wuyts WA, Azuma A, Distler JHW, et al., 2020, Effects of nintedanib in patients with SSc-ILD and preserved and highly impaired lung function, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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- Citations: 1
Molyneaux PL, Smith JJ, Saunders P, et al., 2020, Bronchoalveolar lavage is safe and well tolerated in individuals with idiopathic pulmonary fibrosis: an analysis of the PROFILE study, American Journal of Respiratory and Critical Care Medicine, Vol: 203, Pages: 136-139, ISSN: 1073-449X
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