Publications
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Gonzalez AT, Maher T, 2016, Predicting mortality in idiopathic pulmonary fibrosis. Which parameters should be used to determine eligibility for treatment? Analysis of a UK prospective cohort, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
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Kreuter M, Wuyts W, Renzoni E, et al., 2016, Anti-acid treatment in patients with IPF: interpret results from post-hoc, subgroup, and exploratory analyses with great caution - Authors' reply, Lancet Respiratory Medicine, Vol: 4, Pages: e48-e48, ISSN: 2213-2619
Maher TM, 2016, Precision Medicine in Idiopathic Pulmonary Fibrosis., QJM, Vol: 109, Pages: 585-587, ISSN: 1460-2725
Kreuter M, Wijsenbeek MS, Vasakova M, et al., 2016, Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis (vol 47, pg 1776, 2016), EUROPEAN RESPIRATORY JOURNAL, Vol: 48, Pages: 593-593, ISSN: 0903-1936
Maher T, 2016, Medicine and Me: a breath of fresh air for IPF, LANCET RESPIRATORY MEDICINE, Vol: 4, Pages: 615-616, ISSN: 2213-2600
Collard HR, Ryerson CJ, Corte TJ, et al., 2016, Acute Exacerbation of Idiopathic Pulmonary Fibrosis: An International Working Group Report, American Journal of Respiratory and Critical Care Medicine, Vol: 194, Pages: 265-275, ISSN: 1535-4970
Acute exacerbation of idiopathic pulmonary fibrosis has been defined as an acute, clinically significant, respiratory deterioration of unidentifiable cause. The objective of this international working group report on acute exacerbation of idiopathic pulmonary fibrosis was to provide a comprehensive update on the topic. A literature review was conducted to identify all relevant English text publications and abstracts. Evidence-based updates on the epidemiology, etiology, risk factors, prognosis, and management of acute exacerbations of idiopathic pulmonary fibrosis are provided. In addition, to better reflect the current state of knowledge and improve the feasibility of future research into its etiology and treatment, the working group proposes a new conceptual framework for acute respiratory deterioration in idiopathic pulmonary fibrosis and a revised definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis.
Fingerlin TE, Zhang W, Yang IV, et al., 2016, Genome-wide imputation study identifies novel HLA locus for pulmonary fibrosis and potential role for auto-immunity in fibrotic idiopathic interstitial pneumonia, BMC Genetics, Vol: 17, ISSN: 1471-2156
BACKGROUND: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci. RESULTS: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)). CONCLUSIONS: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regula
Daccord C, Maher TM, 2016, Recent advances in understanding idiopathic pulmonary fibrosis, F1000 Research, Vol: 5, ISSN: 2046-1402
Despite major research efforts leading to the recent approval of pirfenidone and nintedanib, the dismal prognosis of idiopathic pulmonary fibrosis (IPF) remains unchanged. The elaboration of international diagnostic criteria and disease stratification models based on clinical, physiological, radiological, and histopathological features has improved the accuracy of IPF diagnosis and prediction of mortality risk. Nevertheless, given the marked heterogeneity in clinical phenotype and the considerable overlap of IPF with other fibrotic interstitial lung diseases (ILDs), about 10% of cases of pulmonary fibrosis remain unclassifiable. Moreover, currently available tools fail to detect early IPF, predict the highly variable course of the disease, and assess response to antifibrotic drugs. Recent advances in understanding the multiple interrelated pathogenic pathways underlying IPF have identified various molecular phenotypes resulting from complex interactions among genetic, epigenetic, transcriptional, post-transcriptional, metabolic, and environmental factors. These different disease endotypes appear to confer variable susceptibility to the condition, differing risks of rapid progression, and, possibly, altered responses to therapy. The development and validation of diagnostic and prognostic biomarkers are necessary to enable a more precise and earlier diagnosis of IPF and to improve prediction of future disease behaviour. The availability of approved antifibrotic therapies together with potential new drugs currently under evaluation also highlights the need for biomarkers able to predict and assess treatment responsiveness, thereby allowing individualised treatment based on risk of progression and drug response. This approach of disease stratification and personalised medicine is already used in the routine management of many cancers and provides a potential road map for guiding clinical care in IPF.
Mercer PF, Woodcock HV, Eley JD, et al., 2016, Exploration of a potent PI3 kinase/mTOR inhibitor as a novel anti-fibrotic agent in IPF, Thorax, Vol: 71, Pages: 701-711, ISSN: 1468-3296
Rationale Idiopathic pulmonary fibrosis (IPF) is themost rapidly progressive and fatal of all fibroticconditions with no curative therapies. Commonpathomechanisms between IPF and cancer areincreasingly recognised, including dysfunctional pan-PI3kinase (PI3K) signalling as a driver of aberrantproliferative responses. GSK2126458 is a novel, potent,PI3K/mammalian target of rapamycin (mTOR) inhibitorwhich has recently completed phase I trials in theoncology setting. Our aim was to establish a scientificand dosing framework for PI3K inhibition with this agentin IPF at a clinically developable dose.Methods We explored evidence for pathway signallingin IPF lung tissue and examined the potency ofGSK2126458 in fibroblast functional assays andprecision-cut IPF lung tissue. We further explored thepotential of IPF patient-derived bronchoalveolar lavage(BAL) cells to serve as pharmacodynamic biosensors tomonitor GSK2126458 target engagement within thelung.Results We provide evidence for PI3K pathwayactivation in fibrotic foci, the cardinal lesions in IPF.GSK2126458 inhibited PI3K signalling and functionalresponses in IPF-derived lung fibroblasts, inhibiting Aktphosphorylation in IPF lung tissue and BAL derived cellswith comparable potency. Integration of these data withGSK2126458 pharmacokinetic data from clinical trials incancer enabled modelling of an optimal dosing regimenfor patients with IPF.Conclusions Our data define PI3K as a promisingtherapeutic target in IPF and provide a scientific anddosing framework for progressing GSK2126458 toclinical testing in this disease setting. A proof-ofmechanismtrial of this agent is currently underway.
Kreuter M, Wijsenbeek MS, Vasakova M, et al., 2016, Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis, European Respiratory Journal, Vol: 47, ISSN: 1399-3003
Russell AM, Adamali H, Molyneaux PL, et al., 2016, Daily home spirometry: an effective tool for detecting progression in idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 194, Pages: 989-997, ISSN: 1535-4970
Rationale: Recent clinical trial successes have created an urgent need for earlier and more sensitive endpoints of disease progression in idiopathic pulmonary fibrosis (IPF). Domiciliary spirometry permits more frequent measurement of FVC than does hospital-based assessment, which therefore affords the opportunity for a more granular insight into changes in IPF progression.Objectives: To determine the feasibility and reliability of measuring daily FVC in individuals with IPF.Methods: Subjects with IPF were given handheld spirometers and instruction on how to self-administer spirometry. Subjects recorded daily FEV1 and FVC for up to 490 days. Clinical assessment and hospital-based spirometry was undertaken at 6 and 12 months, and outcome data were collected for 3 years.Measurements and Main Results: Daily spirometry was recorded by 50 subjects for a median period of 279 days (range, 13–490 d). There were 18 deaths during the active study period. Home spirometry showed excellent correlation with hospital-obtained readings. The rate of decline in FVC was highly predictive of outcome and subsequent mortality when measured at 3 months (hazard ratio [HR], 1.040; 95% confidence interval [CI], 1.021–1.062; P ≤ 0.001), 6 months (HR, 1.024; 95% CI, 1.014–1.033; P < 0.001), and 12 months (HR, 1.012; 95% CI, 1.007–1.016; P = 0.001).Conclusions: Measurement of daily home spirometry in patients with IPF is highly clinically informative and is feasible to perform for most of these patients. The relationship between mortality and rate of change of FVC at 3 months suggests that daily FVC may be of value as a primary endpoint in short proof-of-concept IPF studies.
Kreuter M, Wuyts W, Renzoni E, et al., 2016, Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis, The Lancet Respiratory Medicine, Vol: 4, Pages: 381-389, ISSN: 2213-2600
Byrne AJ, Maher TM, Lloyd CM, 2016, Pulmonary macrophages: a new therapeutic pathway in fibrosing lung disease?, Trends in Molecular Medicine, Vol: 22, Pages: 303-316, ISSN: 1471-4914
Pulmonary fibrosis (PF) is a growing clinical problem which can result in breathlessness or respiratory failure and has an average life expectancy of 3 years from diagnosis. Therapeutic options for PF are limited and there is therefore a significant unmet clinical need. The recent resurgent interest in macrophage biology has led to a new understanding of lung macrophage origins, biology, and phenotypes. In this review we discuss fibrotic mechanisms and focus on the role of macrophages during fibrotic lung disease. Data from both human and murine studies are reviewed, highlighting novel macrophage-orientated biomarkers for disease diagnosis and potential targets for future anti-fibrotic therapies.
Evans IC, Barnes JL, Garner IM, et al., 2016, Epigenetic regulation of cyclooxygenase-2 by methylation of c8orf4 in pulmonary fibrosis, Clinical Science, Vol: 130, Pages: 575-586, ISSN: 1470-8736
Fibroblasts derived from the lungs of patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (SSc) produce low levels of prostaglandin (PG) E2, due to a limited capacity to up-regulate cyclooxygenase-2 (COX-2). This deficiency contributes functionally to the fibroproliferative state, however the mechanisms responsible are incompletely understood. In the present study, we examined whether the reduced level of COX-2 mRNA expression observed in fibrotic lung fibroblasts is regulated epigenetically. The DNA methylation inhibitor, 5-aza-2'-deoxycytidine (5AZA) restored COX-2 mRNA expression by fibrotic lung fibroblasts dose dependently. Functionally, this resulted in normalization of fibroblast phenotype in terms of PGE2 production, collagen mRNA expression and sensitivity to apoptosis. COX-2 methylation assessed by bisulfite sequencing and methylation microarrays was not different in fibrotic fibroblasts compared with controls. However, further analysis of the methylation array data identified a transcriptional regulator, chromosome 8 open reading frame 4 (thyroid cancer protein 1, TC-1) (c8orf4), which is hypermethylated and down-regulated in fibrotic fibroblasts compared with controls. siRNA knockdown of c8orf4 in control fibroblasts down-regulated COX-2 and PGE2 production generating a phenotype similar to that observed in fibrotic lung fibroblasts. Chromatin immunoprecipitation demonstrated that c8orf4 regulates COX-2 expression in lung fibroblasts through binding of the proximal promoter. We conclude that the decreased capacity of fibrotic lung fibroblasts to up-regulate COX-2 expression and COX-2-derived PGE2 synthesis is due to an indirect epigenetic mechanism involving hypermethylation of the transcriptional regulator, c8orf4.
Maher TM, Spagnolo P, 2016, Perspectives for the future, ERS Monograph, Vol: 2016, Pages: 260-274, ISSN: 2312-508X
The recent establishment of two effective therapies for IPF is a remarkable achievement for patients and clinicians alike. However, the unmet medical need for patients with IPF remains substantial, and a number of issues need to be urgently addressed if we are to move IPF research forward. One such priority is the establishment of well-characterised cohorts of patients with standardised, comprehensive and longitudinally collected clinical and biological data. Equally important are the establishment of centralised open-access biorepositories of samples from patients (and appropriate controls), the validation of an IPF-specific patient-reported outcome tool, and the development and validation of biomarkers to facilitate the design and efficiency of future therapeutic trials. Several pharmacological agents with high potential are currently being tested in trials and many more are ready to be evaluated in the near future. However, only through a continued, concerted partnership between all stakeholders will the ultimate goal of curing patients with this terrible disease be achieved.
Toshner RJ, Allden SJ, Byrne AJ, et al., 2016, The Il-33/st2 Axis Is Upregulated In Fibrotic Lung Disease, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Allden SJ, Toshner RJ, Byrne AJ, et al., 2016, Expression Of Cd71 On Alveolar Macrophages Reveals Distinct Cell Populations In Human Bronchoalveolar Lavage From Patients With Interstitial Lung Disease, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Stock C, Bonini M, Kingston S, et al., 2016, Muc5b And Tollip Variants: Association With Disease Progression And Survival In An Ipf Cohort, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Saunders P, Stock C, Kingston S, et al., 2016, Muc5b Genotype Does Not Affect Cough Severity In Fibrotic Lung Diseases, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Kokosi MA, Keir G, Corte T, et al., 2016, Rituximab In Progressive, Refractory To Conventional Treatment, Interstitial Lung Disease, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Raghu G, Inoue Y, Behr J, et al., 2016, Effect Of Nintedanib On Disease Progression In The Inpulsis® Trials In Patients With Idiopathic Pulmonary Fibrosis (ipf), International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Maher TM, Flaherty KR, Azuma A, et al., 2016, Effect Of Nintedanib On Decline In Forced Vital Capacity (FVC) Over Time In The Inpulsis® Trials In Patients With Idiopathic Pulmonary Fibrosis, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Peix L, Evans IC, Pearce DR, et al., 2016, Potential Role Of Altered Clusterin Expression And Localization In Ipf To Limit Fibroproliferation, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Woodcock H, Eley J, Peace S, et al., 2016, Rapamycin Insensitive Mtor Signalling Promotes Tgf-β Induced Pro-Fibrotic Gene Expression In Human Lung Fibroblasts, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Kreuter M, Bonella F, Maher TM, et al., 2016, Impact Of Statins On Lung Function Decline In Idiopathic Pulmonary Fibrosis (ipf), International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Herazo-Maya J, Sun J, Duncan SR, et al., 2016, A 52-Gene Signature In Peripheral Blood Identifies An Ipf Subphenotype With Rapid Disease Progression And Poor Disease Outcomes, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Kreuter M, Spagnolo P, Wuyts W, et al., 2016, Antiacid Therapy And Disease Progression In Patients With Idiopathic Pulmonary Fibrosis (ipf) Under Pirfenidone Treatment, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Spagnolo P, Bonella F, Vasakova M, et al., 2015, Current and Future Therapies for Idiopathic Pulmonary Fibrosis, Pulmonary Therapy, Vol: 1, ISSN: 2364-1754
Idiopathic pulmonary fibrosis (IPF) is the most common form of fibrosing idiopathic interstitial pneumonia. The disease, which primarily occurs in older adults, is inexorably progressive with a 5-year survival of approximately 20%. Improved understanding of disease pathobiology has affected the approach to treatment. Indeed, originally thought to be a chronic inflammatory disorder, IPF is now considered the result of persistent alveolar epithelial micro-injury followed by an aberrant repair response. This paradigm shift along with significant improvement in disease definition and patient stratification has led to an exponential increase in the number of high-quality clinical trials, most of which, however, have produced negative results, probably due to the multitude of cell types, growth factors and signaling pathways involved in the fibrotic process. Therefore, until recently IPF has lacked effective therapies. Finally, in 2014, pirfenidone, a compound with broad antifibrotic, anti-inflammatory and antioxidant properties and nintedanib, an orally available, small-molecule tyrosine kinase inhibitor with selectivity for vascular endothelial growth factor, platelet-derived growth factor and fibroblast growth factor receptors, have shown to significantly slow functional decline and IPF disease progression with an acceptable safety profile. This is a major step forward. However, neither pirfenidone nor nintedanib is a cure for IPF; neither drug improves lung function and the disease continues to progress in most patients despite treatment. A number of agents with high potential are currently being tested and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing this devastating disease.
Russell AM, Doyle AM, Ross D, et al., 2015, PATIENT AND CARER CO-INVESTIGATORS: SHARED EXPERIENCES OF A RESEARCH STEERING GROUP FROM THE IDIOPATHIC PULMONARY FIBROSIS PATIENT REPORTED OUTCOME MEASURE (IPF-PROM) STUDY, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A76-A77, ISSN: 0040-6376
George PM, Richardson L, Renzoni EA, et al., 2015, EFFECT OF PIRFENIDONE ON GAS TRANSFER IN PATIENTS WITH IDIOPATHIC PULMONARY FIBROSIS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A79-A79, ISSN: 0040-6376
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