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
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673 results found

De Zorzi E, Spagnolo P, Cocconcelli E, Balestro E, Iaccarino L, Gatto M, Benvenuti F, Bernardinello N, Doria A, Maher TM, Zanatta Eet 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.

Journal article

Maher TM, Schiffman C, Kreuter M, Moor CC, Nathan SD, Axmann J, Belloni P, Bengus M, Gilberg F, Kirchgaessler K-U, Wijsenbeek MSet al., 2022, A review of the challenges, learnings and future directions of home handheld spirometry in interstitial lung disease., Respir Res, Vol: 23

BACKGROUND: Patients 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. Rate 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. CONCLUSIONS: Home handheld spirometry in ILD requires further optimisation and research to ensure accurate and reliable FVC measurements before it can be

Journal article

Maher TM, Tudor VA, Saunders P, Gibbons MA, Fletcher SV, Denton CP, Hoyles RK, Parfrey H, Renzoni EA, Kokosi M, Wells AU, Ashby D, Szigeti M, Molyneaux PL, RECITAL Investigatorset al., 2022, Rituximab versus intravenous cyclophosphamide in patients with connective tissue disease-associated interstitial lung disease in the UK (RECITAL): a double-blind, double-dummy, randomised, controlled, phase 2b trial, The Lancet Respiratory Medicine, ISSN: 2213-2600

BACKGROUND: Rituximab is often used as rescue therapy in interstitial lung disease (ILD) associated with connective tissue disease (CTD), but has not been studied in clinical trials. This study aimed to assess whether rituximab is superior to cyclophosphamide as a treatment for severe or progressive CTD associated ILD. METHODS: We conducted a randomised, double-blind, double-dummy, phase 2b trial to assess the superiority of rituximab compared with cyclophosphamide. Patients aged 18-80 years with severe or progressive ILD related to scleroderma, idiopathic inflammatory myositis, or mixed CTD, recruited across 11 specialist ILD or rheumatology centres in the UK, were randomly assigned (1:1) to receive rituximab (1000 mg at weeks 0 and 2 intravenously) or cyclophosphamide (600 mg/m2 body surface area every 4 weeks intravenously for six doses). The primary endpoint was rate of change in forced vital capacity (FVC) at 24 weeks compared with baseline, analysed using a mixed-effects model with random intercepts, adjusted for baseline FVC and CTD type. Prespecified secondary endpoints reported in this Article were change in FVC at 48 weeks versus baseline; changes from baseline in 6 min walk distance, diffusing capacity of the lung for carbon monoxide (DLCO), physician-assessed global disease activity (GDA) score, and quality-of-life scores on the St George's Respiratory Questionnaire (SGRQ), King's Brief Interstitial Lung Disease (KBILD) questionnaire, and European Quality of Life Five-Dimension (EQ-5D) questionnaire at 24 and 48 weeks; overall survival, progression-free survival, and time to treatment failure; and corticosteroid use. All endpoints were analysed in the modified intention-to-treat population, which comprised all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT01862926). FINDINGS: Between Dec 1, 2014, and March 31, 2020, we screened 145 participants, of whom 101 participants were randomly allocated

Journal article

Chung KF, Birring SS, Morice AH, McGarvey LP, Mazzone SB, Maher TM, Dicpinigaitis PVet al., 2022, Tackling the Neuropathic Cough of Idiopathic Pulmonary Fibrosis (IPF): More Needs to be Done, LUNG, ISSN: 0341-2040

Journal article

Strambu IR, Seemayer CA, Fagard LM-CA, Ford PA, Van der Aa TAK, de Haas-Amatsaleh AA, Modgill V, Santermans E, Sondag EN, Helmer EG, Maher TM, Costabel U, Cottin Vet al., 2022, GLPG1205 for idiopathic pulmonary fibrosis: a Phase 2 randomised placebo-controlled trial., Eur Respir J

BACKGROUND: GLPG1205 is a selective functional antagonist of G-protein-coupled receptor 84, which plays an important role in fibrotic processes. This study assessed efficacy, safety, and tolerability of GLPG1205 for treatment of idiopathic pulmonary fibrosis (IPF). METHODS: PINTA (NCT03725852) was a Phase 2, randomised, double-blind, placebo-controlled, proof-of-concept trial. Patients with IPF were randomised 2:1 to once daily oral GLPG1205 100 mg or placebo for 26 weeks and stratified to receive GLPG1205 alone or with local standard of care (nintedanib or pirfenidone). The primary endpoint was change from baseline in forced vital capacity (FVC); other endpoints were safety and tolerability, and lung volumes measured by imaging (high-resolution computed tomography). The study was not powered for statistical significance. RESULTS: In total, 68 patients received study medication. Least squares mean (95% confidence interval) change from baseline in FVC at Week 26 was -33.68 (-112.0, 44.68) mL with GLPG1205 and -76.00 (-170.7, 18.71) mL with placebo (least squares mean difference, 42.33 [-81.84, 166.5] mL; p=0.50). Lung volumes by imaging declined -58.30 versus -262.72 mL (whole lung) and -33.68 versus -135.48 mL (lower lobes) with GLPG1205 versus placebo, respectively. Treatment with GLPG1205 versus placebo resulted in higher proportions of serious and severe treatment-emergent adverse events and treatment-emergent discontinuations, most apparent with nintedanib. CONCLUSION: Treatment with GLPG1205 did not result in a significant difference in FVC decline versus placebo. GLPG1205 demonstrated a poorer safety and tolerability profile than placebo.

Journal article

Fainberg HP, Oldham JM, Molyneau PL, Allen RJ, Kraven LM, Fahy WA, Porte J, Braybrooke R, Saini G, Karsdal MA, Leeming DJ, Sand JMB, Triguero I, Oballa E, Wells AU, Renzoni E, Wain LV, Noth I, Maher TM, Stewart ID, Jenkins RGet al., 2022, Forced vital capacity trajectories in patients with idiopathic pulmonary fibrosis: a secondary analysis of a multicentre, prospective, observational cohort., Lancet Digit Health

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

Journal article

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.

Journal article

Wijsenbeek MS, Moor CC, Johannson KA, Jackson PD, Khor YH, Kondoh Y, Rajan SK, Tabaj GC, Varela BE, van der Wal P, van Zyl-Smit RN, Kreuter M, Maher TMet al., 2022, Home monitoring in interstitial lung diseases, The Lancet Respiratory Medicine, ISSN: 2213-2600

The widespread use of smartphones and the internet has enabled self-monitoring and more hybrid-care models. The COVID-19 pandemic has further accelerated remote monitoring, including in the heterogenous and often vulnerable group of patients with interstitial lung diseases (ILDs). Home monitoring in ILD has the potential to improve access to specialist care, reduce the burden on health-care systems, improve quality of life for patients, identify acute and chronic disease worsening, guide treatment decisions, and simplify clinical trials. Home spirometry has been used in ILD for several years and studies with other devices (such as pulse oximeters, activity trackers, and cough monitors) have emerged. At the same time, challenges have surfaced, including technical, analytical, and implementational issues. In this Series paper, we provide an overview of experiences with home monitoring in ILD, address the challenges and limitations for both care and research, and provide future perspectives. VIDEO ABSTRACT.

Journal article

Maher TM, Schlecker C, Luedtke D, Bossert S, Zoz DF, Schultz Aet 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.

Journal article

Zhang D, 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., 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.

Journal article

Assassi S, Distler O, Allanore Y, Ogura T, Varga J, Vettori S, Crestani B, Voss F, Alves M, Stowasser S, Maher TMet 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.

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., 2022, Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease, RHEUMATOLOGY, ISSN: 1462-0324

Journal article

Denton CP, Goh NS, Humphries SM, Maher TM, Spiera R, Devaraj A, Ho L, Stock C, Erhardt E, Alves M, Wells AU, SENSCIS trial investigatorset al., 2022, Extent of fibrosis and lung function decline in patients with systemic sclerosis and interstitial lung disease: data from the SENSCIS trial, Rheumatology, ISSN: 1462-0324

OBJECTIVE: To assess associations between the extent of fibrotic interstitial lung disease (ILD) and forced vital capacity (FVC) at baseline and change in FVC over 52 weeks in patients with systemic sclerosis-associated ILD (SSc-ILD) in the SENSCIS trial. METHODS: We used generalised additive models, which involve few assumptions and allow for interaction between non-linear effects, to assess associations between the extent of fibrotic ILD on high-resolution computed tomography (HRCT), and the interplay of extent of fibrotic ILD on HRCT and FVC % predicted, at baseline and FVC decline over 52 weeks. RESULTS: In the placebo group (n = 288), there was weak evidence of a modest association between a greater extent of fibrotic ILD at baseline and a greater decline in FVC % predicted at week 52 (r: -0.09 [95% CI -0.2, 0.03]). Higher values of both the extent of fibrotic ILD and FVC % predicted at baseline tended to be associated with greater decline in FVC % predicted at week 52. In the nintedanib group (n = 288), there was no evidence of an association between the extent of fibrotic ILD at baseline and decline in FVC % predicted at week 52 (r: 0.01 [95% CI: -0.11, 0.12]) or between the interplay of extent of fibrotic ILD and FVC % predicted at baseline and decline in FVC % predicted at week 52. CONCLUSION: Data from the SENSCIS trial suggest that patients with SSc-ILD are at risk of ILD progression and benefit from nintedanib largely irrespective of their extent of fibrotic ILD at baseline. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02597933.

Journal article

Maher TM, 2022, A clinical short-cut to identifying short telomeres in idiopathic pulmonary fibrosis?, RESPIROLOGY, Vol: 27, Pages: 916-917, ISSN: 1323-7799

Journal article

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

Journal article

Allen RJ, Oldham JM, Jenkins DA, Leavy OC, Guillen-Guio B, Melbourne CA, Ma S-F, Jou J, Kim JS, CleanUP-IPF Investigators of the Pulmonary Trials Cooperative, Fahy WA, Oballa E, Hubbard RB, Navaratnam V, Braybrooke R, Saini G, Roach KM, Tobin MD, Hirani N, Whyte MKB, Kaminski N, Zhang Y, Martinez FJ, Linderholm AL, Adegunsoye A, Strek ME, Maher TM, Molyneaux PL, Flores C, Noth I, Gisli Jenkins R, Wain LVet al., 2022, Longitudinal lung function and gas transfer in individuals with idiopathic pulmonary fibrosis: a genome-wide association study, The Lancet Respiratory Medicine, ISSN: 2213-2600

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an incurable lung disease characterised by progressive scarring leading to alveolar stiffness, reduced lung capacity, and impeded gas transfer. We aimed to identify genetic variants associated with declining lung capacity or declining gas transfer after diagnosis of IPF. METHODS: We did a genome-wide meta-analysis of longitudinal measures of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO) in individuals diagnosed with IPF. Individuals were recruited to three studies between June, 1996, and August, 2017, from across centres in the US, UK, and Spain. Suggestively significant variants were investigated further in an additional independent study (CleanUP-IPF). All four studies diagnosed cases following American Thoracic Society/European Respiratory Society guidelines. Variants were defined as significantly associated if they had a meta-analysis p<5 × 10-8 when meta-analysing across all discovery and follow-up studies, had consistent direction of effects across all four studies, and were nominally significant (p<0·05) in each study. FINDINGS: 1329 individuals with a total of 5216 measures were included in the FVC analysis. 975 individuals with a total of 3361 measures were included in the DLCO analysis. For the discovery genome-wide analyses, 7 611 174 genetic variants were included in the FVC analysis and 7 536 843 in the DLCO analysis. One variant (rs115982800) located in an antisense RNA gene for protein kinase N2 (PKN2) showed a genome-wide significant association with FVC decline (-140 mL/year per risk allele [95% CI -180 to -100]; p=9·14 × 10-12). INTERPRETATION: Our analysis identifies a genetic variant associated with disease progression, which might highlight a new biological mechanism for IPF. We found that PKN2, a Rho and Rac effector protein, is the most likely gene of interest fro

Journal article

Maher TM, 2022, Biomarkers for Interstitial Lung Abnormalities: A Stepping-stone Toward Idiopathic Pulmonary Fibrosis Prevention?, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 206, Pages: 244-246, ISSN: 1073-449X

Journal article

Cottin V, Tomassetti S, Valenzuela C, Walsh SLF, Antoniou KM, Bonella F, Brown KK, Collard HR, Corte TJ, Flaherty KR, Johannson KA, Kolb M, Kreuter M, Inoue Y, Jenkins RG, Lee JS, Lynch DA, Maher TM, Martinez FJ, Molina-Molina M, Myers JL, Nathan SD, Poletti V, Quadrelli S, Raghu G, Rajan SK, Ravaglia C, Remy-Jardin M, Renzoni E, Richeldi LK, Spagnolo P, Troy L, Wijsenbeek M, Wilson KC, Wuyts W, Wells AU, Ryerson CJet al., 2022, Integrating Clinical Probability into the Diagnostic Approach to Idiopathic Pulmonary Fibrosis An International Working Group Perspective, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 206, Pages: 247-259, ISSN: 1073-449X

Journal article

Maher TM, Bourdin A, Volkmann ER, Vettori S, Distler JHW, Alves M, Stock C, Distler Oet al., 2022, Decline in forced vital capacity in subjects with systemic sclerosis-associated interstitial lung disease in the SENSCIS trial compared with healthy reference subjects, Respiratory Research, Vol: 23, ISSN: 1465-9921

BACKGROUND: The forced vital capacity (FVC) of healthy individuals depends on their age, sex, ethnicity and height. Systemic sclerosis-associated interstitial lung disease (SSc-ILD) is characterised by loss of FVC. We compared FVC values in the subjects with SSc-ILD in the SENSCIS trial of nintedanib versus placebo with values from hypothetical matched healthy references. METHODS: The SENSCIS trial enrolled subjects with SSc with first non-Raynaud symptom in the prior ≤ 7 years, extent of fibrotic ILD on HRCT ≥ 10%, and FVC ≥ 40% predicted. FVC at baseline and decline in FVC over 52 weeks were compared with FVC values in hypothetical healthy reference subjects matched 1:1 to the subjects in the trial for age, sex, ethnicity and height, determined using equations published by the European Respiratory Society Global Lung Function Initiative. RESULTS: At baseline, mean (SD) FVC was 2460 (737) mL in the nintedanib group (n = 287) compared with 3403 (787) mL in the hypothetical matched healthy references. Mean (SD) FVC was 2544 (817) mL in the placebo group (n = 286) compared with 3516 (887) mL in the hypothetical matched healthy references. Mean (SE) changes in FVC at week 52, i.e., age-related loss of lung function, in the hypothetical healthy references matched to the nintedanib and placebo groups, respectively, were - 26.3 (0.5) mL and - 25.8 (0.5) mL. The difference in the change in FVC at week 52 between the nintedanib group and the hypothetical healthy references was 26.6 mL (95% CI: 1.2, 52.0; p = 0.04). The difference in the change in FVC at week 52 between the placebo group and the hypothetical healthy references was 77.5 mL (95% CI: 51.4, 103.7; p < 0.0001). CONCLUSIONS: Subjects with SSc-ILD in the SENSCIS trial had impaired lung function at baseline and experienced further deterioration over 52 wee

Journal article

Zhang D, Povysil G, Kobeissy PH, Li Q, Wang B, Amelotte M, Jaouadi H, Newton CA, Maher TM, Molyneaux PL, Noth I, Martinez FJ, Raghu G, Todd JL, Palmer SM, Haefliger C, Platt A, Petrovski S, Garcia JA, Goldstein DB, Garcia CKet al., 2022, Rare and common variants in KIF15 contribute to genetic risk of idiopathic pulmonary fibrosis, American Journal of Respiratory and Critical Care Medicine, Vol: 206, ISSN: 1073-449X

RATIONALE: Genetic studies of Idiopathic Pulmonary Fibrosis (IPF) have improved our understanding of this disease, but not all causal loci have been identified. OBJECTIVE: To identify genes enriched with rare deleterious variants in IPF and familial pulmonary fibrosis. METHODS: We performed gene burden analysis of whole exome data, tested single variants for disease association, conducted KIF15 functional studies, and examined human lung single cell RNA sequencing data. MEASUREMENT AND MAIN RESULTS: Gene burden analysis of 1,725 cases and 23,509 controls identified heterozygous rare deleterious variants in KIF15, a kinesin involved in spindle separation during mitosis, and three telomere-related genes (TERT, RTEL1, PARN). KIF15 was implicated in autosomal dominant models of rare deleterious variants (OR 4.9 [95%CI 2.7, 8.8] P=2.55x10-7) and rare protein-truncating variants (OR 7.6 [3.3, 17.1], P=8.12x10-7). Meta-analysis of the discovery and replication cohorts, including 2,966 cases and 29,817 controls, confirm the involvement of KIF15, plus the three telomere-related genes. A common variant within a KIF15 intron (rs74341405, OR 1.6 [1.4, 1.9], P=5.63x10-10) is associated with IPF risk, confirming a prior report. Lymphoblastoid cells from individuals heterozygous for the common variant have decreased KIF15 and reduced rates of cell growth. Cell proliferation is dependent on KIF15 in the presence of an inhibitor of Eg5/KIF11, which has partially redundant function. KIF15 is expressed specifically in replicating human lung cells, and shows diminished expression in replicating epithelial cells of IPF patients. CONCLUSIONS: Both rare deleterious variants and common variants in KIF15 link a non-telomerase pathway of cell proliferation with IPF susceptibility.

Journal article

Molina-Molina M, Kreuter M, Cottin V, Corte TJ, Gilberg F, Kirchgaessler K-U, Axmann J, Maher TMet al., 2022, Efficacy of pirfenidone vs. placebo in unclassifiable interstitial lung disease, by surgical lung biopsy status: data from a post-hoc analysis, Frontiers in Medicine, Vol: 9, ISSN: 2296-858X

Approximately 12-13% of patients with interstitial lung disease (ILD) are diagnosed with unclassifiable ILD (uILD), often despite thorough evaluation. A recent Phase 2 study (NCT03099187) described a significant effect of pirfenidone vs. placebo on forced vital capacity (FVC) measured by site spirometry in patients with progressive fibrosing uILD (hereafter referred to as the pirfenidone in uILD study). Here, we present the results from a post-hoc analysis of this study to assess patient baseline characteristics and the efficacy of pirfenidone vs. placebo analyzed by surgical lung biopsy (SLB) status. Mean FVC (mL) change over 24 weeks was included as a post-hoc efficacy outcome. Of 253 randomized patients, 88 (34.8%) had a SLB and 165 (65.2%) did not. Baseline characteristics were generally similar between SLB subgroups; however, patients who had a SLB were slightly younger and had a higher 6-min walk distance than those without a SLB. Mean FVC change over 24 weeks for pirfenidone vs. placebo was -90.9 vs. -146.3 mL, respectively, in patients who had a SLB, and 8.2 vs. -85.3 mL, respectively, in patients without a SLB. Overall, the results from the post-hoc analysis identified that pirfenidone may be an effective treatment in progressive fibrosing uILD over 24 weeks, irrespective of SLB status; however, caution should be taken when interpreting these data due to several limitations. There are differences in the treatment effect of pirfenidone between the subgroups that require further pathological and radiological investigation. In this manuscript, we also descriptively compared baseline characteristics from the overall pirfenidone in uILD study population with other uILD populations reported in the literature, with the aim of understanding if there are any similarities or differences within these cohorts. Most baseline characteristics for patients in the pirfenidone in uILD study were within the ranges reported in the literature; however, ranges were wide, highlig

Journal article

Molyneaux PL, Fahy WA, Byrne AJ, Braybrooke R, Saunders P, Toshner R, Albers G, Chua F, Renzoni EA, Wells AU, Karkera Y, Oballa E, Saini G, Nicholson AG, Jenkins G, Maher TMet al., 2022, CYFRA 21-1 predicts progression in IPF: a prospective longitudinal analysis of the PROFILE cohort, American Journal of Respiratory and Critical Care Medicine, Vol: 205, Pages: 1440-1448, ISSN: 1073-449X

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a progressive and inevitably fatal condition for which there are a lack of effective biomarkers to guide therapeutic decision making. RATIONALE: To determine the relationship between serum levels of the cytokeratin fragment CYFRA 21-1 and disease progression and mortality in individuals with IPF enrolled in the PROFILE study. METHODS: CYFRA 21-1 was identified by immunohistochemistry in samples of human lung. Concentrations of CYFRA 21-1 were measured using an Elisa-based assay in serum, collected at baseline, 1- and 3-months, from 491 individuals with an incident diagnosis of IPF enrolled in the PROFILE study and from 100 control subjects. Study subjects were followed for a minimum of 3 years. MEASUREMENTS AND MAIN RESULTS: CYFRA 21-1 localises to hyperplastic epithelium in IPF lung. CYFRA 21-1 levels were significantly higher in IPF subjects compared to healthy controls in both discovery (n=132) (control 0.96±0.81 ng/mL versus IPF; 2.34±2.15 ng/mL, p < 0.0001) and validation (n=359) (control; 2.21±1.54 ng/mL and IPF; 4.13±2.77 ng/mL, p<0.0001) cohorts. Baseline levels of CYFRA 21-1 distinguished individuals at risk of 12-month disease progression (C-statistic 0.70 (95% CI 0.61-0.79), p < 0.0001) and were predictive of overall-mortality (HR 1.12 (1.06-1.19) per 1 ng/mL increase in CYFRA 21-1, p=0.0001). Furthermore, 3-month change in levels of CYFRA 21-1 separately predicted 12-month and overall survival in both the discovery and validation cohorts. CONCLUSIONS: CYFRA 21-1, a marker of epithelial damage and turnover, has the potential to be an important prognostic and therapeutic biomarker in individuals with IPF.

Journal article

Allen RJ, Stockwell A, Oldham JM, Guillen-Guio B, Schwartz DA, Maher TM, Flores C, Noth I, Yaspan BL, Jenkins RG, Wain Let al., 2022, Genome-wide association study across five cohorts identifies five novel loci associated with idiopathic pulmonary fibrosis, THORAX, Vol: 77, Pages: 829-833, ISSN: 0040-6376

Journal article

Kreuter M, Hoffmann-Vold A-M, Matucci-Cerinic M, Saketkoo LA, Highland KB, Wilson H, Alves M, Erhardt E, Schoof N, Maher TMet al., 2022, Impact of lung function and baseline clinical characteristics on patient-reported outcome measures in systemic sclerosis-associated interstitial lung disease, Rheumatology, ISSN: 1462-0324

OBJECTIVE: The SENSCIS® trial demonstrated a significant reduction of lung function decline in patients with systemic sclerosis (SSc)-associated interstitial lung disease (SSc-ILD) treated with nintedanib, but no significant effect on health-related quality of life (HRQoL). To assess whether SSc/SSc-ILD severity and large changes in lung function correlate with HRQoL, a post-hoc analysis of SENSCIS®, aggregating treatment arms, was undertaken. METHODS: Patient-reported outcome (PRO) measures (St. George's Respiratory Questionnaire [SGRQ], Functional Assessment of Chronic Illness Therapy [FACIT]-Dyspnoea, and Health Assessment Questionnaire-Disability Index [HAQ-DI], incorporating the Scleroderma Health Assessment Questionnaire visual analogue scale [SHAQ VAS]) at baseline and week 52 were assessed for associations to SSc-ILD severity. RESULTS: At baseline and at week 52, forced vital capacity (FVC) <70% predicted was associated with worse PRO measure scores compared with FVC ≥70% predicted (week 52: SGRQ 45.1 vs 34.0 [p< 0.0001]; FACIT-Dyspnoea 48.9 vs 44.5 [p< 0.0001]; HAQ-DI 0.7 vs 0.6 [p< 0.0228]; SHAQ VAS breathing problems 3.6 vs 2.6 [p< 0.0001]). Patients with diffuse cutaneous SSc and other characteristics associated with SSc-ILD severity had worse PRO measure scores. Patients requiring oxygen or with >30% fibrosis on high-resolution computed tomography at baseline demonstrated worse PRO measure scores at week 52. After 1 year, patients with a major (>10%) improvement/worsening in FVC demonstrated corresponding improvement/worsening in SGRQ and other PRO measures, significant for the SGRQ symptom domain (p< 0.001). CONCLUSION: Severe SSc-ILD and major deteriorations in lung function have important impacts on HRQoL. Treatments that slow lung function decline and prevent severe SSc-ILD are important to preserve HRQoL. TRIAL REGISTRATION: clinicaltrials.gov, www.clinicaltrials.gov, NCT02597933.

Journal article

Molyneaux PL, Maher TM, authors of CYFRA 21-1 predicts progression in IPF; a prospective longitudinal analysis of the PROFILE cohort, 2022, Reply to: the need for a CYFRA 21-1 cut-off value to predict clinical progression of IPF in clinical practice., American Journal of Respiratory and Critical Care Medicine, Vol: 206, Pages: 649-650, ISSN: 1073-449X

Journal article

Richeldi L, Azuma A, Cottin V, Hesslinger C, Stowasser S, Valenzuela C, Wijsenbeek MS, Zoz DF, Voss F, Maher TM, 1305-0013 Trial Investigatorset al., 2022, Trial of a preferential phosphodiesterase 4B inhibitor for idiopathic pulmonary fibrosis., New England Journal of Medicine, Vol: 386, Pages: 2178-2187, ISSN: 0028-4793

BACKGROUND: Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis. METHODS: In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent. RESULTS: A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups. CONCLUSIONS: In this placebo-controlled trial, treatment with BI 1015550, either alone or with ba

Journal article

Bonella F, Cottin V, Valenzuela C, Wijsenbeek M, Voss F, Rohr KB, Stowasser S, Maher TMet al., 2022, Meta-analysis of effect of nintedanib on reducing FVC decline across interstitial lung diseases, Advances in Therapy, Vol: 14/5/22, Pages: 3392-3402, ISSN: 0741-238X

INTRODUCTION: The effect of nintedanib on slowing the rate of decline in forced vital capacity (FVC) has been investigated in randomized placebo-controlled trials in subjects with idiopathic pulmonary fibrosis (IPF), other progressive fibrosing interstitial lung diseases (ILDs), and ILD associated with systemic sclerosis (SSc-ILD). We assessed the consistency of the effect of nintedanib on the rate of decline in FVC over 52 weeks across four placebo-controlled phase III trials. METHODS: We used data on FVC decline from the INPULSIS-1 and INPULSIS-2 trials in subjects with IPF, the INBUILD trial in subjects with progressing fibrosing ILDs other than IPF, and the SENSCIS trial in subjects with SSc-ILD. In each trial, the primary endpoint was the annual rate of decline in FVC (mL/year) assessed over 52 weeks. We performed fixed effect and random effects meta-analyses based on the relative treatment effect of nintedanib versus placebo on the rate of decline in FVC (mL/year) over 52 weeks. Heterogeneity of the relative treatment effect of nintedanib across populations was assessed using the I2 statistic, τ2 and corresponding p value from a Q test for heterogeneity. RESULTS: The combined analysis comprised 1257 subjects treated with nintedanib and 1042 subjects who received placebo. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 51.0% (95% CI 39.1, 63.0) compared with placebo. The relative effect (95% CI) was the same using the fixed effect and random effects models. There was no evidence of heterogeneity in the relative treatment effect of nintedanib across the populations studied (I2 = 0%, τ2 = 0, p = 0.93). CONCLUSIONS: A meta-analysis of data from four placebo-controlled trials demonstrated that nintedanib approximately halved the rate of decline in FVC over 52 weeks across subjects with different forms of pulmonary fibrosis, with no evidence of het

Journal article

Kraven LM, Taylor AR, Molyneaux PL, Maher T, McDonough J, Mura M, Yang I, Schwartz DA, Huang Y, Noth I, Ma SF, Yeo AJ, Fahy WA, Jenkins G, Wain Let al., 2022, Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis, Thorax, ISSN: 0040-6376

Background Considerable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes.Methods We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).Findings We identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10−5).Interpretation We have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

Journal article

Maher TM, Jenkins RG, Bonella F, Assassi S, Diefenbach C, Ittrich C, Rohr KB, Kolb Met al., 2022, Effects of Nintedanib on Circulating Biomarkers in Subjects with Progressive Fibrosing Interstitial Lung Diseases (ILDs), International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X

Conference paper

Raghu G, Remy-Jardin M, Richeldi L, Thomson CC, Inoue Y, Johkoh T, Kreuter M, Lynch DA, Maher TM, Martinez FJ, Molina-Molina M, Myers JL, Nicholson AG, Ryerson CJ, Strek ME, Troy LK, Wijsenbeek M, Mammen MJ, Hossain T, Bissell BD, Herman DD, Hon SM, Kheir F, Khor YH, Macrea M, Antoniou KM, Bouros D, Buendia-Roldan I, Caro F, Crestani B, Ho L, Morisset J, Olson AL, Podolanczuk A, Poletti V, Selman M, Ewing T, Jones S, Knight SL, Ghazipura M, Wilson KCet al., 2022, Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 205, Pages: E18-E47, ISSN: 1073-449X

Journal article

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