Imperial College London

Professor Toby Maher

Faculty of MedicineNational Heart & Lung Institute

Professor of Interstitial Lung Disease
 
 
 
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Contact

 

+44 (0)20 7594 2151t.maher

 
 
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Assistant

 

Ms Georgina Moss +44 (0)20 7594 2151

 
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Location

 

364Sir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Publication Type
Year
to

766 results found

Montesi SB, Gomez CR, Beers M, Brown R, Chattopadhyay I, Flaherty KR, Garcia CK, Gomperts B, Hariri LP, Hogaboam CM, Jenkins RG, Kaminski N, Kim GHJ, Königshoff M, Kolb M, Kotton DN, Kropski JA, Lasky J, Magin CM, Maher TM, McCormick M, Moore BB, Nickerson-Nutter C, Oldham J, Podolanczuk AJ, Raghu G, Rosas I, Rowe SM, Schmidt WT, Schwartz D, Shore JE, Spino C, Craig JM, Martinez FJet al., 2024, Pulmonary Fibrosis Stakeholder Summit: A Joint NHLBI, Three Lakes Foundation, and Pulmonary Fibrosis Foundation Workshop Report., Am J Respir Crit Care Med, Vol: 209, Pages: 362-373

Despite progress in elucidation of disease mechanisms, identification of risk factors, biomarker discovery, and the approval of two medications to slow lung function decline in idiopathic pulmonary fibrosis and one medication to slow lung function decline in progressive pulmonary fibrosis, pulmonary fibrosis remains a disease with a high morbidity and mortality. In recognition of the need to catalyze ongoing advances and collaboration in the field of pulmonary fibrosis, the NHLBI, the Three Lakes Foundation, and the Pulmonary Fibrosis Foundation hosted the Pulmonary Fibrosis Stakeholder Summit on November 8-9, 2022. This workshop was held virtually and was organized into three topic areas: 1) novel models and research tools to better study pulmonary fibrosis and uncover new therapies, 2) early disease risk factors and methods to improve diagnosis, and 3) innovative approaches toward clinical trial design for pulmonary fibrosis. In this workshop report, we summarize the content of the presentations and discussions, enumerating research opportunities for advancing our understanding of the pathogenesis, treatment, and outcomes of pulmonary fibrosis.

Journal article

Wu Z, Smith DJF, Yazbeck L, Saunders P, Smith JA, Maher TM, Molyneaux PLet al., 2024, Cough Severity Visual Analogue Scale Assesses Cough Burden and Predicts Survival in Idiopathic Pulmonary Fibrosis., Am J Respir Crit Care Med

Journal article

Wijsenbeek M, Swigris JJ, Inoue Y, Kreuter M, Maher TM, Suda T, Baldwin M, Mueller H, Rohr KB, Flaherty KR, INBUILD Trial Investigatorset al., 2024, Effects of nintedanib on symptoms in patients with progressive pulmonary fibrosis., Eur Respir J, Vol: 63

BACKGROUND: Dyspnoea and cough can have a profound impact on the lives of patients with pulmonary fibrosis. We investigated the effects of nintedanib on the symptoms and impact of pulmonary fibrosis in patients with progressive pulmonary fibrosis (PPF) in the INBUILD trial using the Living with Pulmonary Fibrosis (L-PF) questionnaire. METHODS: Patients had a fibrosing interstitial lung disease (ILD) (other than idiopathic pulmonary fibrosis) of >10% extent on high-resolution computed tomography (HRCT) and met criteria for ILD progression within the prior 24 months. Patients were randomised 1:1 to receive nintedanib or placebo. Changes in L-PF questionnaire scores from baseline to week 52 were assessed using mixed models for repeated measures. RESULTS: In total, 663 patients were treated. Compared with placebo, there were significantly smaller increases (worsenings) in adjusted mean L-PF questionnaire total (0.5 versus 5.1), symptoms (1.3 versus 5.3), dyspnoea (4.3 versus 7.8) and fatigue (0.7 versus 4.0) scores in the nintedanib group at week 52. L-PF questionnaire cough score decreased in the nintedanib group and increased in the placebo group (-1.8 versus 4.3). L-PF questionnaire impacts score decreased slightly in the nintedanib group and increased in the placebo group (-0.2 versus 4.6). Similar findings were observed in patients with a usual interstitial pneumonia-like fibrotic pattern on HRCT and in patients with other fibrotic patterns on HRCT. CONCLUSION: Based on changes in L-PF questionnaire scores, nintedanib reduced worsening of dyspnoea, fatigue and cough and the impacts of ILD over 52 weeks in patients with PPF.

Journal article

Wu Z, Spencer LG, Banya W, Westoby J, Tudor VA, Rivera-Ortega P, Chaudhuri N, Jakupovic I, Patel B, Thillai M, West A, Wijsenbeek M, Maher TM, Smith JA, Molyneaux PLet al., 2024, Morphine for treatment of cough in idiopathic pulmonary fibrosis (PACIFY COUGH): a prospective, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial, The Lancet Respiratory Medicine, ISSN: 2213-2600

BackgroundIdiopathic pulmonary fibrosis is a progressive fibrotic lung disease, with most patients reporting cough. Currently, there are no proven treatments. We examined the use of low dose controlled-release morphine compared with placebo as an antitussive therapy in individuals with idiopathic pulmonary fibrosis.MethodsThe PACIFY COUGH study is a phase 2, multicentre, randomised, double-blind, placebo-controlled, two-way crossover trial done in three specialist centres in the UK. Eligible patients aged 40–90 years had a diagnosis of idiopathic pulmonary fibrosis within 5 years, self-reported cough (lasting >8 weeks), and a cough visual analogue scale (VAS) score of 30 mm or higher. Patients were randomly assigned (1:1) to placebo twice daily or controlled-release morphine 5 mg orally twice daily for 14 days followed by crossover after a 7-day washout period. Patients were randomised sequentially to a sequence group defining the order in which morphine and placebo were to be given, according to a computer-generated schedule. Patients, investigators, study nurses, and pharmacy personnel were masked to treatment allocation. The primary endpoint was percentage change in objective awake cough frequency (coughs per h) from baseline as assessed by objective digital cough monitoring at day 14 of treatment in the intention-to-treat population, which included all randomised participants. Safety data were summarised for all patients who took at least one study drug and did not withdraw consent. This study was registered at ClinicalTrials.gov, NCT04429516, and has been completed.FindingsBetween Dec 17, 2020, and March 21, 2023, 47 participants were assessed for eligibility and 44 were enrolled and randomly allocated to treatment. Mean age was 71 (SD 7·4) years, and 31 (70%) of 44 participants were male and 13 (30%) were female. Lung function was moderately impaired; mean forced vital capacity (FVC) was 2·7 L (SD 0·76), mean predicted FVC was 82%

Journal article

Vukmirovic M, Benam KH, Rose JJ, Turner S, Magin CM, Lagares D, Cohen AH, Kaminski N, Hirota JA, Maher TM, Konigshoff M, Mallampalli RK, Sheppard D, Tarran R, Gomer RH, Kenyon NJ, Morris D, Hobbie S, Raju SV, Petrache I, Watkins T, Kumar R, Lam WA, Sherer T, Hecker Let al., 2024, Challenges and Opportunities for Commercializing Technologies in the Pulmonary Arena: An Official American Thoracic Society Report., Ann Am Thorac Soc, Vol: 21, Pages: 1-11

"Translational medicine" has been a buzzword for over two decades. The concept was intended to be lofty, to reflect a new "bench-to-bedside" approach to basic and clinical research that would bridge fields, close gaps, accelerate innovation, and shorten the time and effort it takes to bring novel technologies from basic discovery to clinical application. Has this approach been successful and lived up to its promise? Despite incredible scientific advances and innovations developed within academia, successful clinical translation into real-world solutions has been difficult. This has been particularly challenging within the pulmonary field, because there have been fewer U.S. Food and Drug Administration-approved drugs and higher failure rates for pulmonary therapies than with other common disease areas. The American Thoracic Society convened a working group with the goal of identifying major challenges related to the commercialization of technologies within the pulmonary space and opportunities to enhance this process. A survey was developed and administered to 164 participants within the pulmonary arena. This report provides a summary of these survey results. Importantly, this report identifies a number of poorly recognized challenges that exist in pulmonary academic settings, which likely contribute to diminished efficiency of commercialization efforts, ultimately hindering the rate of successful clinical translation. Because many innovations are initially developed in academic settings, this is a global public health issue that impacts the entire American Thoracic Society community. This report also summarizes key resources and opportunities and provides recommendations to enhance successful commercialization of pulmonary technologies.

Journal article

Guillen-Guio B, Paynton ML, Allen RJ, Chin DPW, Donoghue LJ, Stockwell A, Leavy OC, Hernandez-Beeftink T, Reynolds C, Cullinan P, Martinez F, Booth HL, Fahy WA, Hall IP, Hart SP, Hill MR, Hirani N, Hubbard RB, McAnulty RJ, Millar AB, Navaratnam V, Oballa E, Parfrey H, Saini G, Sayers I, Tobin MD, Whyte MKB, Adegunsoye A, Kaminski N, Ma S-F, Strek ME, Zhang Y, Fingerlin TE, Molina-Molina M, Neighbors M, Sheng XR, Oldham JM, Maher TM, Molyneaux PL, Flores C, Noth I, Schwartz DA, Yaspan BL, Jenkins RG, Wain LV, Hollox EJet al., 2024, Association study of human leukocyte antigen variants and idiopathic pulmonary fibrosis., ERJ Open Res, Vol: 10, ISSN: 2312-0541

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF, and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Owing to the important role that the human leukocyte antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. METHODS: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising 5159 cases and 27 459 controls, including a prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold of p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. RESULTS: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. CONCLUSION: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Journal article

Suen AO, Iyer AS, Cenzer I, Farrand E, White DB, Singer J, Sudore R, Kotwal Aet al., 2023, National Prevalence of Social Isolation and Loneliness in Adults with Chronic Obstructive Pulmonary Disease., Ann Am Thorac Soc, Vol: 20, Pages: 1709-1717

Rationale: Social isolation and loneliness are gaining recognition for their role in health outcomes, yet they have not been defined in people with chronic obstructive pulmonary disease (COPD). Objective: To determine the national prevalence of and characteristics associated with social isolation and loneliness in people with COPD. Methods: This is a cross-sectional study of community-dwelling adults aged ⩾50 years in the nationally representative HRS (Health and Retirement Study) (2016-2018). Participants self-reported COPD and supplemental oxygen use and were categorized into three groups: 1) no COPD; 2) COPD; and 3) COPD on oxygen. Social isolation was defined using a nine-item scale indicating minimal household contacts, social network interaction, and community engagement. Loneliness was measured using the 3-Item UCLA Loneliness Scale. Multivariable logistic regression defined prevalence and associated characteristics for both. Results: Participants (n = 10,384) were on average 68 years old (standard deviation, ±10.5), 54% female, 10% Black, 11% self-reported COPD, and 2% self-reported supplemental oxygen. Overall, 12% were socially isolated, 12% lonely, and 3% both socially isolated and lonely. People with COPD had a higher adjusted prevalence of social isolation (no COPD: 11%; COPD: 16%; COPD on oxygen: 20%; P < 0.05) and loneliness (no COPD: 11%; COPD: 18%; COPD on oxygen: 22%; P < 0.001). In those with COPD, characteristics associated with social isolation (P < 0.05) included sex (men: 22%; women: 13%), non-Hispanic White ethnicity (White: 19%; Black: 7%), low net worth (<$6,000: 32%; $81,001-$239,000: 10%), depression (depression: 24%; no depression: 14%), having difficulty with one or more activities of daily living (one or more difficulty: 22%; no difficulty: 14%), and current cigarette use (current: 24%; never: 13%). Characteristics associated with loneliness (P&thi

Journal article

Barnett JL, Maher TM, Quint JK, Adamson A, Wu Z, Smith DJF, Rawal B, Nair A, Walsh SLF, Desai SR, George PM, Kokosi M, Jenkins G, Kouranos V, Renzoni EA, Rice A, Nicholson AG, Chua F, Wells AU, Molyneaux PL, Devaraj Aet al., 2023, Combination of BAL and computed tomography differentiates progressive and non-progressive fibrotic lung diseases, American Journal of Respiratory and Critical Care Medicine, Vol: 208, Pages: 975-982, ISSN: 1073-449X

Rationale: Identifying patients with pulmonary fibrosis (PF) at risk of progression can guide management. Objectives: To explore the utility of combining baseline BAL and computed tomography (CT) in differentiating progressive and nonprogressive PF. Methods: The derivation cohort consisted of incident cases of PF for which BAL was performed as part of a diagnostic workup. A validation cohort was prospectively recruited with identical inclusion criteria. Baseline thoracic CT scans were scored for the extent of fibrosis and usual interstitial pneumonia (UIP) pattern. The BAL lymphocyte proportion was recorded. Annualized FVC decrease of >10% or death within 1 year was used to define disease progression. Multivariable logistic regression identified the determinants of the outcome. The optimum binary thresholds (maximal Wilcoxon rank statistic) at which the extent of fibrosis on CT and the BAL lymphocyte proportion could distinguish disease progression were identified. Measurements and Main Results: BAL lymphocyte proportion, UIP pattern, and fibrosis extent were significantly and independently associated with disease progression in the derivation cohort (n = 240). Binary thresholds for increased BAL lymphocyte proportion and extensive fibrosis were identified as 25% and 20%, respectively. An increased BAL lymphocyte proportion was rare in patients with a UIP pattern (8 of 135; 5.9%) or with extensive fibrosis (7 of 144; 4.9%). In the validation cohort (n = 290), an increased BAL lymphocyte proportion was associated with a significantly lower probability of disease progression in patients with nonextensive fibrosis or a non-UIP pattern. Conclusions: BAL lymphocytosis is rare in patients with extensive fibrosis or a UIP pattern on CT. In patients without a UIP pattern or with limited fibrosis, a BAL lymphocyte proportion of ⩾25% was associated with a lower likelihood of progression.

Journal article

Molina-Molina M, Shull JG, Vicens-Zygmunt V, Rivera-Ortega P, Antoniou K, Bonella F, Renzoni E, Russell A-M, Maher TM, Vancheri A, Bachs A, Avilés V, Palma J, Bermudo G, Suarez-Cuartin G, Tebé C, Rigo-Bonnin R, Montes-Worboys A, Wijsenbeek M, Vancheri Cet al., 2023, Gastrointestinal pirfenidone adverse events in idiopathic pulmonary fibrosis depending on diet: the MADIET clinical trial., Eur Respir J, Vol: 62

Individuals with IPF who follow a MUFA diet report a lower incidence of pirfenidone gastrointestinal adverse events than those that follow a SFA diet, which could explain the different prevalence in GI pirfenidone AEs reported by countries in IPF cohorts https://bit.ly/3LuzAUJ

Journal article

Hewitt R, Puttur F, Gaboriau D, Fercoq F, Fresquet M, Traves W, Yates LL, Walker S, Molyneaux P, Kemp S, Nicholson A, Rice A, Roberts E, Lennon R, Carlin L, Byrne A, Maher T, Lloyd Cet al., 2023, Lung extracellular matrix modulates KRT5+ basal cell activity in pulmonary fibrosis, Nature Communications, Vol: 14, ISSN: 2041-1723

Aberrant expansion of KRT5+ basal cells in the distal lung accompanies progressive alveolar epithelial cell loss and tissue remodelling during fibrogenesis in idiopathic pulmonary fibrosis (IPF). The mechanisms determining activity of KRT5+ cells in IPF have not been delineated. Here, we reveal a potential mechanism by which KRT5+ cells migrate within the fibrotic lung, navigating regional differences in collagen topography. In vitro, KRT5+ cell migratory characteristics and expression of remodelling genes are modulated by extracellular matrix (ECM) composition and organisation. Mass spectrometry- based proteomics revealed compositional differences in ECM components secreted by primary human lung fibroblasts (HLF) from IPF patients compared to controls. Over-expression of ECM glycoprotein, Secreted Protein Acidic and Cysteine Rich (SPARC) in the IPF HLF matrix restricts KRT5+ cell migration in vitro. Together, our findings demonstrate how changes to the ECM in IPF directly influence KRT5+ cell behaviour and function contributing to remodelling events in the fibrotic niche.

Journal article

Maher TM, Ford P, Wijsenbeek MS, 2023, Ziritaxestat and Lung Function in Idiopathic Pulmonary Fibrosis-Reply., JAMA, Vol: 330, Pages: 973-974

Journal article

Maher TM, Assassi S, Azuma A, Cottin V, Hoffmann-Vold A-M, Kreuter M, Oldham JM, Richeldi L, Valenzuela C, Wijsenbeek MS, Coeck C, Schlecker C, Voss F, Wachtlin D, Martinez FJet al., 2023, Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with progressive pulmonary fibrosis (FIBRONEER-ILD)., BMJ Open Respir Res, Vol: 10

INTRODUCTION: Progressive pulmonary fibrosis (PPF) includes any diagnosis of progressive fibrotic interstitial lung disease (ILD) other than idiopathic pulmonary fibrosis (IPF). However, disease progression appears comparable between PPF and IPF, suggesting a similar underlying pathology relating to pulmonary fibrosis. Following positive results in a phase II study in IPF, this phase III study will investigate the efficacy and safety of BI 1015550 in patients with PPF (FIBRONEER-ILD). METHODS AND ANALYSIS: In this phase III, double-blind, placebo-controlled trial, patients are being randomised 1:1:1 to receive BI 1015550 (9 mg or 18 mg) or placebo twice daily over at least 52 weeks, stratified by background nintedanib use. Patients must be diagnosed with pulmonary fibrosis other than IPF that is progressive, based on predefined criteria. Patients must have forced vital capacity (FVC) ≥45% predicted and haemoglobin-corrected diffusing capacity of the lung for carbon monoxide ≥25% predicted. Patients must be receiving nintedanib for at least 12 weeks, or not receiving nintedanib for at least 8 weeks, prior to screening. Patients on stable treatment with permitted immunosuppressives (eg, methotrexate, azathioprine) may continue their treatment throughout the trial. Patients with clinically significant airway obstruction or other pulmonary abnormalities, and those using immunosuppressives that may confound FVC results (cyclophosphamide, tocilizumab, mycophenolate, rituximab) or high-dose steroids will be excluded. The primary endpoint is absolute change from baseline in FVC (mL) at week 52. The key secondary endpoint is time to the first occurrence of any acute ILD exacerbation, hospitalisation for respiratory cause or death, over the duration of the trial. ETHICS AND DISSEMINATION: The trial is being carried out in accordance with the ethical principles of the Declaration of Helsinki, the International Council on Harmonisation Guideline for Good Clinical P

Journal article

Saunders P, Wu Z, Fahy WA, Stewart ID, Saini G, Smith DJF, Braybrooke R, Stock C, Renzoni EA, Johnson SR, Jenkins RG, Belvisi MG, Smith JA, Maher TM, Molyneaux PLet al., 2023, The burden and impact of cough in patients with idiopathic pulmonary fibrosis: an analysis of the prospective observational PROFILE study, Annals of the American Thoracic Society, Vol: 20, Pages: 1267-1273, ISSN: 1546-3222

RATIONALE: Cough is a commonly reported symptom in idiopathic pulmonary fibrosis (IPF) that negatively impacts patient-reported quality of life. However, both the burden of cough at diagnosis and the behaviour of cough over time have not been systematically described in patients with IPF. OBJECTIVES: By utilising data prospectively collected as part of the PROFILE study we sought to assess cough burden and the impact that this has on quality of life within a cohort of patients with newly diagnosed IPF. We also re-examined the previously described relationship between cough and mortality and the association of cough with the MUC5B promoter polymorphism. METHODS: The PROFILE study is a multicentre, prospective, observational, longitudinal cohort study of incident IPF. Leicester cough questionnaire (LCQ) scores were recorded at baseline in 632 subjects and then repeated 6 monthly in a subset (n=216) of the cohort. RESULTS: The median LCQ at diagnosis was 16.1 (inter-quartile range 6.5). LCQ scores remained stable over the subsequent year in the majority of patients. There was a weak association between LCQ score and baseline lung function with worse cough related quality of life associating with more severe physiological impairment. Cough scores were not associated with subsequent mortality after correcting for baseline lung function. Furthermore, there was no relationship between LCQ score and MUC5B promotor polymorphism status. CONCLUSION: The burden of cough in IPF is high. Although cough is weakly associated with disease severity at baseline, cough-specific QoL as measured by the LCQ, confers no prognostic value. Cough-specific QoL burden remains relatively stable over time and does not associate with MUC5B promotor polymorphism.

Journal article

Maher TM, Stowasser S, Voss F, Bendstrup E, Kreuter M, Martinez FJ, Sime PJ, Stock Cet al., 2023, Decline in forced vital capacity as a surrogate for mortality in patients with pulmonary fibrosis, RESPIROLOGY, ISSN: 1323-7799

Journal article

Richeldi L, Azuma A, Cottin V, Kreuter M, Maher TM, Martinez FJ, Oldham JM, Valenzuela C, Gordat M, Liu Y, Stowasser S, Zoz DF, Wijsenbeek MSet al., 2023, Design of a phase III, double-blind, randomised, placebo-controlled trial of BI 1015550 in patients with idiopathic pulmonary fibrosis (FIBRONEER-IPF), BMJ OPEN RESPIRATORY RESEARCH, Vol: 10

Journal article

Maher TM, Sciascia T, Bortey E, Molyneaux PL, Wijsenbeek M, Smith Jet al., 2023, Nalbuphine Extended Release Treatment Achieved Rapid and Sustained Reduction in Reported Cough Frequency in Patients with Idiopathic Pulmonary Fibrosis, Publisher: SPRINGER, Pages: 4-4, ISSN: 0341-2040

Conference paper

Maher TM, Avram C, Bortey E, Hart SP, Hirani N, Molyneux PL, Porter JC, Smith JA, Sciascia Tet al., 2023, Nalbuphine Tablets for Cough in Patients with Idiopathic Pulmonary Fibrosis., NEJM Evid, Vol: 2

Nalbuphine for Cough with Idiopathic Pulmonary FibrosisIn patients with idiopathic pulmonary fibrosis, cough may have a negative impact on daily life. In a randomized, 22-day treatment period, placebo-controlled, crossover trial, extended-release nalbuphine (NAL ER), an opioid agonist-antagonist, was compared to placebo for cough control and adverse effects. During active treatment there was a 75.1% reduction in daytime objective cough frequency compared with 22.6% in the placebo treatment period. Nausea, fatigue, constipation, and dizziness were more common with NAL ER than with placebo.

Journal article

Guillen-Guio B, Paynton ML, Allen RJ, Chin DPW, Donoghue LJ, Stockwell A, Leavy OC, Hernandez-Beeftink T, Reynolds C, Cullinan P, Martinez F, CleanUP-IPF Investigators of the Pulmonary Trials Cooperative, Booth HL, Fahy WA, Hall IP, Hart SP, Hill MR, Hirani N, Hubbard RB, McAnulty RJ, Millar AB, Navaratnam V, Oballa E, Parfrey H, Saini G, Sayers I, Tobin MD, Whyte MKB, Adegunsoye A, Kaminski N, Shwu-Fan M, Strek ME, Zhang Y, Fingerlin TE, Molina-Molina M, Neighbors M, Sheng XR, Oldham JM, Maher TM, Molyneaux PL, Flores C, Noth I, Schwartz DA, Yaspan BL, Jenkins RG, Wain LV, Hollox EJet al., 2023, Association study of human leukocyte antigen (HLA) variants and idiopathic pulmonary fibrosis., medRxiv

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial pneumonia marked by progressive lung fibrosis and a poor prognosis. Recent studies have highlighted the potential role of infection in the pathogenesis of IPF and a prior association of the HLA-DQB1 gene with idiopathic fibrotic interstitial pneumonia (including IPF) has been reported. Due to the important role that the Human Leukocyte Antigen (HLA) region plays in the immune response, here we evaluated if HLA genetic variation was associated specifically with IPF risk. METHODS: We performed a meta-analysis of associations of the HLA region with IPF risk in individuals of European ancestry from seven independent case-control studies of IPF (comprising a total of 5,159 cases and 27,459 controls, including the prior study of fibrotic interstitial pneumonia). Single nucleotide polymorphisms, classical HLA alleles and amino acids were analysed and signals meeting a region-wide association threshold p<4.5×10-4 and a posterior probability of replication >90% were considered significant. We sought to replicate the previously reported HLA-DQB1 association in the subset of studies independent of the original report. RESULTS: The meta-analysis of all seven studies identified four significant independent single nucleotide polymorphisms associated with IPF risk. However, none met the posterior probability for replication criterion. The HLA-DQB1 association was not replicated in the independent IPF studies. CONCLUSION: Variation in the HLA region was not consistently associated with risk in studies of IPF. However, this does not preclude the possibility that other genomic regions linked to the immune response may be involved in the aetiology of IPF.

Journal article

Oldham JM, Johnson KW, Albers GJ, Calamita E, Mah J, Ghai P, Hewitt RJ, Maher TM, Molyneaux PL, Huang M, Byrne AJet al., 2023, Airway soluble CSF1R predicts progression in patients with idiopathic pulmonary fibrosis, ERJ OPEN RESEARCH, Vol: 9

Journal article

Nolan CM, Schofield SJ, Maddocks M, Patel S, Barker RE, Walsh JA, Polgar O, George PM, Molyneaux PL, Maher TM, Cullinan P, Man WD-Cet al., 2023, Change in gait speed and adverse outcomes in patients with idiopathic pulmonary fibrosis: a prospective cohort study, Respirology, Vol: 28, Pages: 649-658, ISSN: 1323-7799

BACKGROUND AND OBJECTIVE: Gait speed is associated with survival in individuals with idiopathic pulmonary fibrosis (IPF). The extent to which four-metre gait speed (4MGS) decline predicts adverse outcome in IPF remains unclear. We aimed to examine longitudinal 4MGS change and identify a cut-point associated with adverse outcome. METHODS: In a prospective cohort study, we recruited 132 individuals newly diagnosed with IPF and measured 4MGS change over 6 months. Death/first hospitalization at 6 months were composite outcome events. Complete data (paired 4MGS plus index event) were available in 85 participants; missing 4MGS data were addressed using multiple imputation. Receiver-Operating Curve plots identified a 4MGS change cut-point. Cox proportional-hazard regression assessed the relationship between 4MGS change and time to event. RESULTS: 4MGS declined over 6 months (mean [95% CI] change: -0.05 [-0.09 to -0.01] m/s; p = 0.02). A decline of 0.07 m/s or more in 4MGS over 6 months had better discrimination for the index event than change in 6-minute walk distance, forced vital capacity, Composite Physiologic Index or Gender Age Physiology index. Kaplan-Meier curves demonstrated a significant difference in time to event between 4MGS groups (substantial decline: >-0.07 m/s versus minor decline/improvers: ≤-0.07 m/s; p = 0.007). Those with substantial decline had an increased risk of hospitalization/death (adjusted hazard ratio [95% CI] 4.61 [1.23-15.83]). Similar results were observed in multiple imputation analysis. CONCLUSION: In newly diagnosed IPF, a substantial 4MGS decline over 6 months is associated with shorter time to hospitalization/death at 6 months. 4MGS change has potential as a surrogate endpoint for interventions aimed at modifying hospitalization/death.

Journal article

Oldham JM, Allen RJ, Lorenzo-Salazar JM, Molyneaux PL, Ma S-F, Joseph C, Kim JS, Guillen-Guio B, Hernández-Beeftink T, Kropski JA, Huang Y, Lee CT, Adegunsoye A, Pugashetti JV, Linderholm AL, Vo V, Strek ME, Jou J, Muñoz-Barrera A, Rubio-Rodriguez LA, Hubbard R, Hirani N, Whyte MKB, Hart S, Nicholson AG, Lancaster L, Parfrey H, Rassl D, Wallace W, Valenzi E, Zhang Y, Mychaleckyj J, Stockwell A, Kaminski N, Wolters PJ, Molina-Molina M, Banovich NE, Fahy WA, Martinez FJ, Hall IP, Tobin MD, Maher TM, Blackwell TS, Yaspan BL, Jenkins RG, Flores C, Wain LV, Noth Iet al., 2023, PCSK6 and survival in idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 207, Pages: 1515-1524, ISSN: 1073-449X

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by limited treatment options and high mortality. A better understanding of the molecular drivers of IPF progression is needed. OBJECTIVE: To identify and validate molecular determinants of IPF survival. METHODS: A staged genome-wide association study (GWAS) was performed using paired genomic and survival data. Stage I cases were drawn from centers across the US and Europe and stage II cases from Vanderbilt University. Cox proportional hazards regression was used to identify gene variants associated with differential transplant-free survival (TFS). Stage I variants with nominal significance (p<5x10-5) were advanced for stage II testing and meta-analyzed to identify those reaching genome-wide significance (p<5x10-8). Downstream analyses were performed for genes and proteins associated with variants reaching genome-wide significance. MAIN RESULTS: After quality controls, 1481 stage I cases and 397 stage II cases were included in the analysis. After filtering, 9,075,629 variants were tested in stage I, with 158 meeting advancement criteria. Four variants associated with TFS with consistent effect direction were identified in stage II, including one in an intron of proprotein convertase subtilisin/kexin type 6 (PCSK6) reaching genome-wide significance (HR 4.11; 95%CI 2.54-6.67; p=9.45x10-9). PCSK6 protein was highly expressed in IPF lung parenchyma. PCSK6 lung staining intensity, peripheral blood gene expression and plasma concentration were associated with reduced transplant-free survival. CONCLUSIONS: We identified four novel variants associated with IPF survival, including one in PCSK6 that reached genome-wide significance. Downstream analyses suggested that PCSK6 protein plays a potentially important role in IPF progression. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/lic

Journal article

Chua F, Low S, Chai GT, Inoue Y, Ong V, Wongkarnjana A, Kawkitinarong K, Song JW, Hamid ZA, Aziz AA, Campomanes M, Maher TM, Molyneaux PL, Syakirin Set al., 2023, Knowledge gaps in fibrotic interstitial lung disease in pan-Asian populations: data not missing at random?, The Lancet Respiratory Medicine, Vol: 11, Pages: 502-504, ISSN: 2213-2600

Journal article

Zhang D, Li Q, Povysil G, Newton CA, Maher TM, Molyneaux PL, Noth I, Martinez FJ, Raghu G, Todd JL, Palmer SM, Platt A, Petrovski S, Goldstein DB, Garcia CKet al., 2023, Genome-wide Enrichment of TERT Rare Variants in Idiopathic Pulmonary Fibrosis Patients of Latino Ancestry (vol 10, 1411, 2023), AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 207, Pages: 1411-1411, ISSN: 1073-449X

Journal article

Myall KJ, West AG, Martinovic JL, Lam JL, Roque D, Wu Z, Maher TM, Molyneaux PL, Suh E-S, Kent BDet al., 2023, Nocturnal hypoxemia associates with symptom progression and mortality in patients with progressive fibrotic interstitial lung disease., Chest, Pages: 1-34, ISSN: 0012-3692

BACKGROUND: Obstructive sleep apnea (OSA) and nocturnal hypoxemia (NH) are common in patients with fibrotic interstitial lung disease (F-ILD), but their relationship with disease outcomes remains unclear. RESEARCH QUESTIONS: What is the relationship between NH and OSA and clinical outcomes in patients with F-ILD? STUDY DESIGN AND METHODS: Prospective observational cohort study of patients with F-ILD and without daytime hypoxemia. Subjects underwent home sleep study at baseline and were followed up for at least one year or until death. NH was defined as ≥ 10% of sleep with SpO2 <90%. OSA was defined as an apnea-hypopnea index of ≥ 15/hour. RESULTS: Among 102 (male 74.5%; age 73.0 ± 8.7 years; FVC 2.74 ± 0.78L; 91.1% idiopathic pulmonary fibrosis) participants, 20 (19.6%) demonstrated prolonged nocturnal hypoxemia (NH), and 32 (31.4%) had obstructive sleep apnea (OSA). There were no significant differences between those with and without NH or OSA at baseline. Despite this, nocturnal hypoxemia was associated with a more rapid decline in both quality of life as measured by the King's Brief Interstitial Lung Disease questionnaire (change -11.3 ± 5.3 points in the NH group vs -6.7 ± 6.5 in those without NH, p=0.005) and higher all-cause mortality at one year (HR 8.21; 95% CI 2.40-28.1, p<0.001). No statistically significant difference was seen between the groups in annualised change in measures of pulmonary function testing. INTERPRETATION: Prolonged NH but not OSA is associated with worsening disease-related quality of life and increased mortality in patients with F-ILD.

Journal article

Maher TM, Ford P, Brown KK, Costabel U, Cottin V, Danoff SK, Groenveld I, Helmer E, Jenkins RG, Milner J, Molenberghs G, Penninckx B, Randall MJ, Van Den Blink B, Fieuw A, Vandenrijn C, Rocak S, Seghers I, Shao L, Taneja A, Jentsch G, Watkins TR, Wuyts WA, Kreuter M, Verbruggen N, Prasad N, Wijsenbeek MS, Chambers D, Chia M, Corte T, Glaspole I, Goh N, Holmes M, Malouf M, Thien F, Veitch E, Bondue B, Dahlqvist C, Froidure A, Slabbynck H, Wuyts W, Cartagena Salinas C, Feijoó Seoane R, Martínez V, Maturana R, Pavie Gallegos J, Rosenblut A, Silva R, Undurraga Pereira A, Doubkova M, Pauk N, Plackova M, Sterclova M, Bendstrup E, Shaker SB, Titlestad I, Budweiser S, Grohé C, Koschel D, Kreuter M, Prasse A, Weber M, Wirtz H, Antoniou K, Daniil Z, Gaga M, Papakosta D, Izumi S, Okamoto M, Guerreros Benavides A, Iberico Barrera C, Peña Villalobos AM, Campo Ezquibela A, Cifrian Martinez JM, Fernandez Fabrellas E, Leiro V, Molina-Molina M, Nieto Barbero A, Sellares Torres J, Valenzuela C, Cheng S-L, Kuo P-H, Lee K-Y, Sheu C-C, Gunen H, Mogulkoc Bishop N, Nayci S, Adamali H, Bianchi S, Chaudhuri N, Gibbons M, Hart S, Molyneaux P, Parfrey H, Saini G, Spencer LG, Wiscombe S, Antin-Ozerkis D, Bascom R, Belperio J, Britt E, Fitzgerald J, Gomez Manjarres D, Gotfried M, Gupta N, Hotchkin D, Kaye M, Kreider M, Kureishy S, Lacamera P, Lancaster L, Lasky J, Lorch D, Mannem H, Morrow L, Moua T, Nambiar A, Raghu G, Raj R, Ramaswamy M, Reddy R, Russell T, Scholand MB, Shea B, Suliman S, Swigris J, Thavarajah K, Tolle L, Tomic R, Warshoff N, Wesselius L, Yung G, Bergna M, De Salvo M, Fernandez Acquier M, Rodriguez A, Saez Scherbovsky P, Assayag D, Dhar A, Khalil N, Morisset J, Provencher S, Ryerson C, Shapera S, Bourdin A, Crestani B, Lebargy F, Reynaud-Gaubert M, Bonella FT, Claussen M, Hammerl P, Karagiannidis C, Keller C, Randerath W, Stubbe B, Csánky E, Medgyasszay B, Muller V, Adir Y, Bar-Shai A, Berkman N, Fink G, Kramer M, Shitrit D, Bargagli E, Gasparini S, Harari S, Ravaglia C, Richet al., 2023, Ziritaxestat, a novel autotaxin inhibitor, and lung function in idiopathic pulmonary fibrosis, JAMA: Journal of the American Medical Association, Vol: 329, Pages: 1567-1578, ISSN: 0098-7484

Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2.Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life).Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL

Journal article

Roofeh D, Brown KK, Kazerooni EA, Tashkin D, Assassi S, Martinez F, Wells AU, Raghu G, Denton CP, Chung L, Hoffmann-Vold A-M, Distler O, Johannson KA, Allanore Y, Matteson EL, Kawano-Dourado L, Pauling JD, Seibold JR, Volkmann ER, Walsh SLF, Oddis C, White ES, Barratt SL, Bernstein EJ, Domsic RT, Dellaripa PF, Conway R, Rosas I, Bhatt N, Hsu V, Ingegnoli F, Kahaleh B, Garcha P, Gupta N, Khanna S, Korsten P, Lin C, Mathai SC, Strand V, Doyle TJ, Steen V, Zoz DF, Ovalles-Bonilla J, Rodriguez-Pinto I, Shenoy PD, Lewandoski A, Belloli E, Lescoat A, Nagaraja V, Ye W, Huang S, Maher T, Khanna Det al., 2023, Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease, RHEUMATOLOGY, Vol: 62, Pages: 1877-1886, ISSN: 1462-0324

Journal article

Jones S, Flewett M, Flewett R, Lee S, Vick B, Thompson M, Pinnetti S, Zoz DF, Hoffmann-Vold A-M, Kreuter M, Maher TMet al., 2023, Clinical trial simulations in pulmonary fibrosis: patient-focused insights and adaptations, ERJ OPEN RESEARCH, Vol: 9

Journal article

Huang Y, Oldham J, Ma S, Adegunsoye AO, Lee CT, Murray S, Kim J, Bonham C, Paul T, Mannem H, Linderholm A, Maher TM, Molyneaux PL, Strek ME, Martinez FJ, Noth Iet al., 2023, Machine Learning of Plasma Proteomics for Differential Diagnosis of Interstitial Lung Disease, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Maher TM, Brown KK, Cunningham S, Deboer EM, Deterding R, Fiorino EK, Griese M, Schwerk N, Warburton D, Young LR, Gahlemann M, Voss F, Stock Cet al., 2023, Estimating the Effect of Nintedanib on Forced Vital Capacity in Children and Adolescents With Fibrosing Interstitial Lung Disease: Extrapolation Using a Bayesian Borrowing Approach, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

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