The article is available via Open Access. Click on the 'Additional link' above to access the full-text.Published version, accepted version (12 month embargo), submitted versio

Barratt, Shaney L.

Beirne, Paul

Chaudhuri, Nazia

Crawshaw, Anjali

Crowley, Louise E.

Fletcher, Sophie

Gibbons, Michael A.

Hallchurch, Philippa

Horgan, Laura

Jakaityte, Ieva

Lewis, Thomas

McLellan, Tom

Miller, Ryan

Molyneaux, Philip L.

Myall, Katherine J.

Simpson, Thomas

Smith, David J. F.

Stanel, Stefan

Thillai, Muhunthan

Thompson, Fiona

Wallis, Timothy

West, Alex G.

Wu, Zhe

European Respiratory Journal

PubMed

Barratt, Shaney L

Crowley, Louise E

Gibbons, Michael A

Myall, Katherine J

Smith, David J F

Molyneaux, Philip L

West, Alex G

Ulster University's Research Portal

The burden of progressive fibrotic interstitial lung diseaseacross the UKTo the Editor:While idiopathic pulmonary fibrosis (IPF) remains the exemplar progressive fibrotic lung disease, thereremains a cohort of non-IPF fibrotic lung diseases (fILD) which adopt a similar clinical behaviour to IPFdespite therapy [1]. This phenotypically related group of conditions, where progression of disease issimilar to that seen in IPF, have recently been described as progressive fibrotic interstitial lung diseases(PF-ILD) [2]. Historically, treatments for these cases have been limited though given the phenotypicsimilarities many cases may have been given a multidisciplinary working diagnosis of IPF based on theirdisease behaviour [3]. The INBUILD trial broadened the scope of treatable fILD by demonstrating asignificant benefit of Nintedanib in patients with fILD and progressive disease [4]. In response to this theEuropean Commission approved an additional indication for nintedanib in adults for the treatment ofPF-ILD in July 2020.While research interest grows in the progressive phenotype and debates about the optimal diagnosticcriteria continue the incidence of patients with PF-ILD potentially eligible for treatment according to thecriteria laid out in the INBUILD trial remains unclear. Previous attempts to estimate the proportion of fILDwho develop a progressive fibrotic phenotype have either used estimates based on the disease behaviour ofindividual conditions [5], interviews with experts [6] or analysis of insurance claims [7]. This has resultedin estimates ranging from 18 to 40% of all fILD that will develop progressive disease. With the anticipatedapproval of therapeutic interventions for this cohort of patients worldwide, including in the UK, there is anurgent need to refine these estimates in a real-world population to enable appropriate service provision.This retrospective, observational study therefore aimed to estimate the incidence of PF-ILD acrossEngland. Nine centres providing commissioned tertiary referral services for ILD were included. All newreferrals seen for their first outpatient clinic appointment between August 1, 2017, and January 31, 2018,were assessed against the diagnostic criteria for PF-ILD laid out in the INBUILD trial [8] and, inparticular, the criteria for progression: relative decline in forced vital capacity (FVC) % predicted ⩾10%, orFVC decline ⩾5% but <10%, combined with worsening respiratory symptoms, or FVC decline ⩾5% but<10%, combined with radiological progression; or radiological progression with worsening respiratorysymptoms. A full chart and imaging review was undertaken of all the subjects. Continuous variables arepresented as mean±SD, and categorical variables as proportions. Time-to-event curves were calculated usingthe Kaplan–Meier method and compared with the use of the log-rank test.A total of 2368 patients with ILD were assessed across the nine centres. 619 patients were diagnosed andmanaged as IPF and therefore excluded, leaving 1749 patients with fILD who were screened against theINBUILD criteria for progression, to identify cases of PF-ILD either at the first clinical review, or in thesubsequent 2 years of follow up. In the cohort of patients at risk of developing PF-ILD the INBUILDcriteria were met in 14.5% (253 out of 1749) of all new non-IPF fILD referrals despite standard therapy,with a range between these specialist ILD centres from 8.9% to 23.6% of total cases. The average timefrom referral to specialist centre to diagnosis of progressive phenotype was 311±273 days and, at the timeof referral, 20% of patients demonstrated progressive disease (66 out of 253) despite standard therapy.Almost all patients received at least one immunosuppressive agent, with the majority receiving either oralor intravenous corticosteroids (96%). A number of second-line agents were employed with mycophenolateCopyright ©The authors 2021.This version is distributed underthe terms of the CreativeCommons Attribution Licence 4.0.Received: 19 Oct 2020Accepted: 26 Feb 2021Shareable abstract (@ERSpublications)Almost 15% of new referrals with non-IPF fibrotic ILD go on to develop a progressive fibroticphenotype and would benefit from antifibrotic therapy https://bit.ly/3uPhClNCite this article as: Simpson T, Barratt SL, Beirne P, et al. The burden of progressive fibrotic interstitiallung disease across the UK. Eur Respir J 2021; 58: 2100221 [DOI: 10.1183/13993003.00221-2021].https://doi.org/10.1183/13993003.00221-2021 Eur Respir J 2021; 58: 2100221EUROPEAN RESPIRATORY JOURNALRESEARCH LETTERT. SIMPSON ET AL.(46%) the most commonly used. Five of the subjects with PF-ILD received antifibrotic therapy oncompassionate grounds.The most common diagnoses associated with a PF-ILD phenotype were chronic hypersensitivitypneumonitis (84 (33.2%) out of 253), unclassifiable ILD (44 (17.3%) out of 253), connective tissuedisease-associated ILDs including rheumatoid arthritis-associated ILD (42 (16.6%) out of 253) andnon-specific interstitial pneumonitis (36 (14.2%) out of 253). In the PF-ILD cases, the mean age was68±12.4 years and, interestingly, 53.4% of the cohort was female, compared with the well-recognised malepredominance seen in IPF. This is likely driven by the significant female predominance in both chronichypersensitivity pneumonitis and connective tissue disease which make up almost half of the PF-ILD cases.Patients with progressive disease had a significantly higher mortality compared to those withnon-progressive fILD (hazard ratio, 3.32; 95% confidence interval, 2.53–4.37; p=<2×10−16). Indeed, thesurvival of patients with PF-ILD was no different to the subjects with IPF (hazard ratio, 1.06; 95% CI0.84–1.35; p=0.6) (figure 1).Of the progression events, the majority were driven by a measured drop in FVC, with more than half ofpatients (52.2%) experiencing a drop of ⩾10%. A further quarter of patients (24.1%) were diagnosed withprogressive disease on the basis of radiological and symptomatic progression alone without a spirometricdeterioration. The remainder experienced a decline of FVC between 5 and 10% with either radiological(15.8%) or symptomatic (7.9%) progression.The variations between centres and clinicians in diagnostic pathways, approaches to follow-up anddefinitions of progression has previously made it difficult to define and assess this cohort of patients. Oneof the strengths of our approach was the central collation and uniform application of the INBUILDinclusion criteria. However, this was done retrospectively and this is the main limitation of our study.While the INBUILD trial criteria are mostly objectively measurable phenomena, the definition ofprogressive symptoms may allow some biasing towards inclusion in those cases where spirometricprogression was either not evidenced or not available, thus increasing the numbers of cases. Over a quarterof referrals received a final multidisciplinary team diagnosis of IPF, and this is often pragmatic and basedon their clinical disease behaviour, to allow access to antifibrotic therapy. However, a patient’s initialclinical and radiological features may have had more in keeping with a different ILD but with a PF-ILDphenotype. While all of the cases underwent local ILD multidisciplinary assessment, we did not undertakeany central reassessment and therefore some cases of non-IPF PF-ILD may have been missed. Progressionwas only assessed at presentation and over a period of 2 years, as per the INBUILD screening criteria;however, we do know that progression may occur later during follow-up [9] and therefore some late0.751.000.500.250.00Survival probabilityTime days0 100p<0.0001Non PF-ILDPF-ILDIPFStrata400300200 500 600 700 800 900 1000FIGURE 1 Kaplan–Meier curves comparing survival between patients with idiopathic pulmonary fibrosis (IPF),progressive fibrotic interstitial lung diseases (PF-ILD) and non-progressive non-IPF fibrotic lung diseases (nonPF-ILD). Log-rank p test value is reported.https://doi.org/10.1183/13993003.00221-2021 2EUROPEAN RESPIRATORY JOURNAL RESEARCH LETTER | T. SIMPSON ET AL.progressors would not have been captured in this analysis. Our estimates therefore may be if anything anunderestimate but importantly they reflect current clinical practice, which we aimed to capture.This study represents a fair and balanced approach to assessing the incidence of objectively measurableand treatable PF-ILDs in the UK. A rate of 14.5% of new referrals with non-IPF ILD is less than thatreported in previous studies however our methodology is likely to give a more accurate result thanestimates based on extrapolation from general disease statistics, from physician-reported estimates prone tosignificant biases, or insurance claim processes also substantially prone to bias. This information hasimplication for workforce planning and the funding of anti-fibrotic therapy in the UK and beyond.Thomas Simpson1, Shaney L. Barratt 2,3, Paul Beirne4, Nazia Chaudhuri5, Anjali Crawshaw6,Louise E. Crowley6, Sophie Fletcher7, Michael A. Gibbons8, Philippa Hallchurch2, Laura Horgan4,Ieva Jakaityte8, Thomas Lewis2, Tom McLellan9, Katherine J. Myall1, Ryan Miller8,David J.F. Smith10, Stefan Stanel5, Muhunthan Thillai 9, Fiona Thompson7, Timothy Wallis7,Zhe Wu 10,11, Philip L. Molyneaux 10,11,12 and Alex G. West 1,121Dept of Respiratory Medicine, Guy’s and St Thomas’ NHS Foundation Trust, London, UK. 2BristolInterstitial Lung Disease Service, North Bristol NHS trust, Southmead Hospital, Bristol, UK. 3AcademicRespiratory Unit, University of Bristol, Bristol, UK. 4Leeds Interstitial Lung Disease Service, St James’sUniversity Hospital, Leeds, UK. 5North West Lung Centre, Wythenshawe Hospital, Manchester, UK.6Birmingham Interstitial Lung Disease Unit, Queen Elizabeth Hospital Birmingham, UniversityHospitals Birmingham NHS Foundation Trust, Birmingham, UK. 7University Hospitals SouthamptonNHS Foundation Trust, Southampton, UK. 8South West Peninsula ILD Network, Royal Devon andExeter Foundation NHS Trust, Exeter, UK. 9Dept of Interstitial Lung Disease, Royal Papworth HospitalNHS Foundation Trust, Cambridge, UK. 10Royal Brompton Hospital, London, UK. 11National Heart andLung Institute, Imperial College London, London, UK. 12Contributed equally as last authors.Corresponding author: Philip L. Molyneaux (p.molyneaux@imperial.ac.uk)Conflict of interest: T. Simpson reports non-financial support (educational support/leadership course) fromBoehringer Ingelheim, outside the submitted work. S.L. Barratt reports grants, personal fees and non-financialsupport for meeting attendance from Boehringer Ingelheim, outside the submitted work. P. Beirne reportspersonal fees for consultancy and non-financial support for meeting attendance from Boehringer IngelheimPharmaceuticals, outside the submitted work. N. Chaudhuri reports grants and personal fees for consultancy fromBoehringer Ingelheim, personal fees for consultancy from Roche, outside the submitted work. A. Crawshaw hasreceived honoraria from Boehringer Ingelheim for educational meetings (chair/talks) and grants for virtualattendance at international conferences. L.E. Crowley has nothing to disclose. S. Fletcher has nothing to disclose.M.A. Gibbons has served on advisory boards and received support to attend conferences from Roche andBoehringer Ingelheim. P. Hallchurch has nothing to disclose. L. Horgan has nothing to disclose. I. Jakaityte hasnothing to disclose. T. Lewis has nothing to disclose. T. McLellan reports unrestricted educational grants fromBoehringer Ingelheim, outside the submitted work. K.J. Myall has nothing to disclose. R. Miller has nothing todisclose. D.J.F. Smith has nothing to disclose. S. Stanel has nothing to disclose. M. Thillai has nothing to disclose.F. Thompson has nothing to disclose. T. Wallis has nothing to disclose. Z. Wu has nothing to disclose.P.L. Molyneaux, via his institution, received industry–academic funding from AstraZeneca and has received speakerand consultancy fees from Boehringer Ingelheim and Hoffman-La Roche, outside the submitted work. A.G. Westhas nothing to disclose.Support statement: P.L. Molyneaux is supported by an Action for Pulmonary Fibrosis Mike Bray fellowship.References1 Brown KK, Martinez FJ, Walsh SLF, et al. The natural history of progressive fibrosing interstitial lung diseases.Eur Respir J 2020; 55: 2000085.2 Cottin V, Hirani NA, Hotchkin DL, et al. Presentation, diagnosis and clinical course of the spectrum ofprogressive-fibrosing interstitial lung diseases. Eur Respir Rev 2018; 27: 180076.3 Cottin V. Treatment of progressive fibrosing interstitial lung diseases: a milestone in the management ofinterstitial lung diseases. Eur Respir Rev 2019; 28: 190109.4 Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in progressive fibrosing interstitial lung diseases. N Engl JMed 2019; 381: 1718–1727.https://doi.org/10.1183/13993003.00221-2021 3EUROPEAN RESPIRATORY JOURNAL RESEARCH LETTER | T. SIMPSON ET AL.5 Olson AL, Gifford AH, Inase N, et al. The epidemiology of idiopathic pulmonary fibrosis and interstitial lungdiseases at risk of a progressive-fibrosing phenotype. Eur Respir Rev 2018; 27: 180077.6 Wijsenbeek M, Kreuter M, Olson A, et al. Progressive fibrosing interstitial lung diseases: current practice indiagnosis and management. Curr Med Res Opin 2019; 35: 2015–2024.7 Olson AL, Maher TM, Acciai V, et al. Healthcare resources utilization and costs of patients with Non-IPFprogressive fibrosing interstitial lung disease based on insurance claims in the USA. Adv Ther 2020; 37:3292–3298.8 Flaherty KR, Brown KK, Wells AU, et al. Design of the PF-ILD trial: a double-blind, randomised,placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease.BMJ Open Respir Res 2017; 4: e000212.9 Nasser M, Larrieu S, Si-Mohamed S, et al. Progressive fibrosing interstitial lung disease: a clinical cohort (thePROGRESS® study). Eur Respir J 2020; 57: 2002718.https://doi.org/10.1183/13993003.00221-2021 4EUROPEAN RESPIRATORY JOURNAL RESEARCH LETTER | T. SIMPSON ET AL.

English

The burden of progressive fibrotic interstitial lung disease across the UK

Simpson, T

Barratt, SL

Beirne, P

Chaudhuri, N

Crawshaw, A

Crowley, LE

Fletcher, S

Gibbons, MA

Hallchurch, P

Horgan, L

Jakaityte, I

Lewis, T

McLellan, T

Myall, KJ

Miller, R

Smith, DJF

Stanel, S

Thillai, M

Thompson, F

Wallis, T

Wu, Z

Molyneaux, PL

West, AG

Spiral - Imperial College Digital Repository

Early View Research letter The burden of Progressive Fibrotic Interstitial lung disease across the UK Thomas Simpson, Shaney L. Barratt, Paul Beirne, Nazia Chaudhuri, Anjali Crawshaw, Louise E. Crowley, Sophie Fletcher, Michael A. Gibbons, Philippa Hallchurch, Laura Horgan, Ieva Jakaityte, Thomas Lewis, Tom McLellan, Katherine J. Myall, Ryan Miller, David J. F. Smith, Stefan Stanel, Muhunthan Thillai, Fiona Thompson, Timothy Wallis, Zhe Wu, Philip L. Molyneaux, Alex G. West Please cite this article as: Simpson T, Barratt SL, Beirne P, et al. The burden of Progressive Fibrotic Interstitial lung disease across the UK. Eur Respir J 2021; in press (https://doi.org/10.1183/13993003.00221-2021). This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Copyright ©The authors 2021. This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.The burden of Progressive Fibrotic Interstitial lung disease across the UK Thomas Simpson1, Shaney L Barratt2&3, Paul Beirne4, Nazia Chaudhuri5, Anjali Crawshaw6, Louise E Crowley6, Sophie Fletcher7, Michael A Gibbons8, Philippa Hallchurch2, Laura Horgan4, Ieva Jakaityte8, Thomas Lewis2, Tom McLellan9, Katherine J Myall1, Ryan Miller8, David JF Smith11, Stefan Stanel5, Muhunthan Thillai9, Fiona Thompson7, Timothy Wallis7, Zhe Wu10&11, Philip L Molyneaux10&11* and Alex G West1* *Contributed equally as last authors Corresponding author: Dr Philip L. Molyneaux, National Heart and Lung Institute, Imperial College London, UK. E-mail: p.molyneaux@imperial.ac.uk  Affiliations: 1 Department of Respiratory Medicine, Guy’s and St Thomas‘ NHS Foundation Trust, Great Maze Pond, London SE1 9RT 2 Bristol Interstitial Lung Disease Service, North Bristol NHS trust, Southmead Hospital, Bristol UK 3 Academic Respiratory Unit, University of Bristol, Bristol, UK 4 Leeds interstitial Lung Disease Service, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK 5 North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK 6 Birmingham Interstitial Lung Disease Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 7 University Hospitals Southampton NHS Foundation Trust, Southampton, UK 8 South West Peninsula ILD Network, Royal Devon & Exeter Foundation NHS Trust, Barrack Road, Exeter EX2 5DW, UK 9 Department of Interstitial Lung Disease, Royal Papworth Hospital NHS Foundation Trust, Cambridge UK 10 National Heart and Lung Institute, Imperial College London, UK 11 Royal Brompton Hospital, UK.  Funding: PLM is supported by an Action for Pulmonary Fibrosis Mike Bray fellowship.    To the Editor. While Idiopathic pulmonary fibrosis (IPF) remains the exemplar progressive fibrotic lung disease, there remains a cohort of non-IPF fibrotic lung diseases (fILD) which adopt a similar clinical behaviour to IPF despite therapy [1]. This phenotypically related group of conditions, where progression of disease is similar to that seen in IPF, have recently been described as Progressive Fibrotic Interstitial Lung diseases (PF-ILD) [2]. Historically treatments for these cases have been limited though given the phenotypic similarities many cases may have been given a multidisciplinary working diagnosis of IPF based on their disease behaviour [3]. The INBUILD trial broadened the scope of treatable fILD by demonstrating a significant benefit of Nintedanib in patients with fILD and progressive disease [4]. In response to this the European Commission (EC) approved an additional indication for Nintedanib in adults for the treatment of PF-ILD in July 2020. While research interest grows in the progressive phenotype and debates about the optimal diagnostic criteria continue the incidence of patients with PF-ILD potentially eligible for treatment according to the criteria laid out in the INBUILD trial remains unclear. Previous attempts to estimate the proportion of fILD who develop a progressive fibrotic phenotype have either used estimates based on the disease behaviour of individual conditions [5], interviews with experts [6] or analysis of insurance claims [7].  This has resulted in estimates ranging from 18 to 40% of all fILD that will develop progressive disease. With the anticipated approval of therapeutic interventions for this cohort of patients worldwide, including in the UK, there is an urgent need to refine these estimates in a real-world population to enable appropriate service provision. This retrospective, observational study therefore aimed to estimate the incidence of PF-ILD across England. Nine centres providing commissioned tertiary referral services for ILD were included. All new referrals seen for their first outpatient clinic appointment between 1st August 2017 and 31st January 2018 were assessed against the diagnostic criteria for PF-ILD laid out in the INBUILD trial [8] and in particular, the criteria for progression: relative decline in FVC % predicted ≥10%, or FVC decline ≥5% but <10%, combined with worsening respiratory symptoms, or FVC decline ≥5% but <10%, combined with radiological progression; or radiological progression with worsening respiratory symptoms. A full chart and imaging review was undertaken of all the subjects. Continuous variables are presented as means (± Standard Deviation [SD]), and categorical variables as proportions. Time-to-event curves were calculated using the Kaplan–Meier method and compared with the use of the log-rank test. A total of 2368 patients with ILD were assessed across the 9 centres. Six hundred and nineteen patients were diagnosed and managed as IPF and therefore excluded, leaving 1749 patients with fILD who were screened against the INBUILD criteria for progression, to identify cases of PF-ILD either at the first clinical review, or in the subsequent 2 years of follow up (Table 1). In the cohort of patients at risk of developing PF-ILD the INBUILD criteria were met in 14.5% (253/1749) of all new non-IPF fILD referrals despite standard therapy, with a range between these specialist ILD centres from 8.9% to 23.6% of total cases. The average time from referral to specialist centre to diagnosis of progressive phenotype was 311(±273) days and at the time of referral 20% of patients demonstrated progressive disease (66/253) despite standard therapy. All most all patients received at least one immunosuppressive agent, with the majority receiving either oral or intravenous corticosteroids (96%). A number of second line agents were employed with Mycophenolate (46%) the most commonly used. Five of the subjects with PF-ILD received antifibrotic therapy on compassionate grounds. The most common diagnoses associated with a PF-ILD phenotype were chronic hypersensitivity pneumonitis (84/253, 33.2%), unclassifiable ILD (44/253, 17.3%), connective tissue disease-associated ILDs including rheumatoid arthritis-associated ILD (42/253, 16.6%) and non-specific Interstitial pneumonitis (36/253, 14.2%). In the PF-ILD cases, the mean age was 68 ±12.4 years and interestingly 53.4% of the cohort was female, as compared to the well-recognised male predominance seen in IPF. This is likely driven by the significant female predominance in both CHP and CTD which make up almost half of the PF-ILD cases.   Patients with progressive disease had a significantly higher mortality compared to those with non-progressive fILD (hazard ratio, 3.32; 95% confidence interval, 2.53–4.37; P=<2e-16). Indeed, the survival of patients with PF-ILD was no different to the subjects with IPF (hazard ratio, 1.06; 95% confidence interval, 0.84–1.35; P=0.6) (Figure 1).  Figure 1. Kaplan-Meier curves comparing survival between patients with IPF, PF-ILD and non-progressive fILD. Log-rank P test value is reported. Of the progression events the majority were driven by a measured drop in FVC, with more than half of patients (52.2%) experiencing a drop of ≥10%. A further quarter of patients (24.1%) were diagnosed with progressive disease on the basis of radiological and symptomatic progression alone without a spirometric deterioration. The remainder experienced a decline of FVC between 5 and 10% with either radiological (15.8%) or symptomatic (7.9%) progression.  The variations between centres and clinicians in diagnostic pathways, approaches to follow-up and definitions of progression has previously made it difficult to define and assess this cohort of patients. One of the strengths of our approach was the central collation and uniform application of the INBUILD inclusion criteria. However, this was done retrospectively and this is the main limitation of our study. While the INBUILD trial criteria are mostly objectively measurable phenomena, the definition of progressive symptoms may allow some biasing towards inclusion in those cases where spirometric progression was either not evidenced or not available, thus increasing the numbers of cases. Over a quarter of referrals received a final multidisciplinary team (MDT) diagnosis of IPF, and this is often pragmatic and based on their clinical disease behaviour, to allow access to antifibrotic therapy. However, a patient’s initial clinical and radiological features may have had more in keeping with a different ILD but with a PF-ILD phenotype. While all of the cases underwent local ILD multidisciplinary assessment, we did not undertake any central reassessment and therefore some cases of non-IPF PF-ILD may have been missed. Progression was only assessed at presentation and over a period of two years, as per the INBUILD screening criteria, however, we do know that progression may occur later during follow-up [9] and therefore some late progressors would not have been captured in this analysis. Our estimates therefore maybe if anything an underestimate but importantly they reflect current clinical practice, which we aimed to capture. This study represents a fair and balanced approach to assessing the incidence of objectively measurable and treatable PF-ILDs in the UK. A rate of 14.5% of new referrals with non-IPF ILD is less than that reported in previous studies however our methodology is likely to give a more accurate result than estimates based on extrapolation from general disease statistics, from physician-reported estimates prone to significant biases, or insurance claim processes also substantially prone to bias. This information has implication for workforce planning and the funding of anti-fibrotic therapy in the UK and beyond. Refrences: 1.  Brown KK, Martinez FJ, Walsh SLF, Thannickal VJ, Prasse A, Schlenker-Herceg R, Goeldner R-G, Clerisme-Beaty E, Tetzlaff K, Cottin V, Wells AU. The natural history of progressive fibrosing interstitial lung diseases. Eur. Respir. J. 2020; 55: 1168–1170. 2.  Cottin V, Hirani NA, Hotchkin DL, Nambiar AM, Ogura T, Otaola M, Skowasch D, Park JS, Poonyagariyagorn HK, Wuyts W, Wells AU. Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur. Respir. Rev. 2018; 27: 180076. 3.  Cottin V. Treatment of progressive fibrosing interstitial lung diseases: a milestone in the management of interstitial lung diseases. Eur. Respir. Rev. 2019; 28: 190109. 4.  Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, Richeldi L, Kolb M, Tetzlaff K, Stowasser S, Coeck C, Clerisme-Beaty E, Rosenstock B, Quaresma M, Haeufel T, Goeldner R-G, Schlenker-Herceg R, Brown KK, INBUILD Trial Investigators. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N. Engl. J. Med. 2019; 381: 1718–1727. 5.  Olson AL, Gifford AH, Inase N, Fernández Pérez ER, Suda T. The epidemiology of idiopathic pulmonary fibrosis and interstitial lung diseases at risk of a progressive-fibrosing phenotype. Eur. Respir. Rev. 2018; 27: 180077. 6.  Wijsenbeek M, Kreuter M, Olson A, Fischer A, Bendstrup E, Wells CD, Denton CP, Mounir B, Zouad-Lejour L, Quaresma M, Cottin V. Progressive fibrosing interstitial lung diseases: current practice in diagnosis and management. Curr. Med. Res. Opin. 2019; 35: 2015–2024. 7.  Olson AL, Maher TM, Acciai V, Mounir B, Quaresma M, Zouad-Lejour L, Wells CD, De Loureiro L. Healthcare Resources Utilization and Costs of Patients with Non-IPF Progressive Fibrosing Interstitial Lung Disease Based on Insurance Claims in the USA. Adv. Ther. 2020; 37: 3292–3298. 8.  Flaherty KR, Brown KK, Wells AU, Clerisme-Beaty E, Collard HR, Cottin V, Devaraj A, Inoue Y, Le Maulf F, Richeldi L, Schmidt H, Walsh S, Mezzanotte W, Schlenker-Herceg R. Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ open Respir. Res. 2017; 4: e000212. 9.  Nasser M, Larrieu S, Si-Mohamed S, Ahmad K, Boussel L, Brevet M, Chalabreysse L, Fabre C, Marque S, Revel D, Thivolet-Bejui F, Traclet J, Zeghmar S, Maucort-Boulch D, Cottin V. Progressive fibrosing interstitial lung disease: a clinical cohort (the PROGRESS® study). Eur. Respir. J. 2020; : 2002718.  

The burden of Progressive Fibrotic Interstitial lung disease across the UK.

Wijsenbeek

Olson

Nasser

Crossref

Explore Bristol Research

                          Simpson, T., Barratt, S. L., Beirne, P., Chaudhuri, N., Crawshaw, A.,Crowley, L. E., Fletcher, S., Gibbons, M. A., Hallchurch, P., Horgan,L., Jakaityte, I., Lewis, T., McLellan, T., Myall, K. J., Miller, R., Smith,D. J. F., Stanel, S., Thillai, M., Thompson, F., ... West, A. G. (2021).The burden of Progressive Fibrotic Interstitial lung disease across theUK. The European respiratory journal, 58(1), [2100221].https://doi.org/10.1183/13993003.00221-2021Peer reviewed versionLicense (if available):CC BYLink to published version (if available):10.1183/13993003.00221-2021Link to publication record in Explore Bristol ResearchPDF-documentThis is the author accepted manuscript (AAM). The final published version (version of record) is available onlinevia European Respiratory Society at https://erj.ersjournals.com/content/early/2021/03/02/13993003.00221-2021. Please refer to any applicable terms of use of the publisher.University of Bristol - Explore Bristol ResearchGeneral rightsThis document is made available in accordance with publisher policies. Please cite only thepublished version using the reference above. Full terms of use are available:http://www.bristol.ac.uk/red/research-policy/pure/user-guides/ebr-terms/Early View Research letter The burden of Progressive Fibrotic Interstitial lung disease across the UK Thomas Simpson, Shaney L. Barratt, Paul Beirne, Nazia Chaudhuri, Anjali Crawshaw, Louise E. Crowley, Sophie Fletcher, Michael A. Gibbons, Philippa Hallchurch, Laura Horgan, Ieva Jakaityte, Thomas Lewis, Tom McLellan, Katherine J. Myall, Ryan Miller, David J. F. Smith, Stefan Stanel, Muhunthan Thillai, Fiona Thompson, Timothy Wallis, Zhe Wu, Philip L. Molyneaux, Alex G. West Please cite this article as: Simpson T, Barratt SL, Beirne P, et al. The burden of Progressive Fibrotic Interstitial lung disease across the UK. Eur Respir J 2021; in press (https://doi.org/10.1183/13993003.00221-2021). This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Copyright ©The authors 2021. This version is distributed under the terms of the Creative Commons Attribution Licence 4.0.The burden of Progressive Fibrotic Interstitial lung disease across the UK Thomas Simpson1, Shaney L Barratt2&3, Paul Beirne4, Nazia Chaudhuri5, Anjali Crawshaw6, Louise E Crowley6, Sophie Fletcher7, Michael A Gibbons8, Philippa Hallchurch2, Laura Horgan4, Ieva Jakaityte8, Thomas Lewis2, Tom McLellan9, Katherine J Myall1, Ryan Miller8, David JF Smith11, Stefan Stanel5, Muhunthan Thillai9, Fiona Thompson7, Timothy Wallis7, Zhe Wu10&11, Philip L Molyneaux10&11* and Alex G West1* *Contributed equally as last authors Corresponding author: Dr Philip L. Molyneaux, National Heart and Lung Institute, Imperial College London, UK. E-mail: p.molyneaux@imperial.ac.uk  Affiliations: 1 Department of Respiratory Medicine, Guy’s and St Thomas‘ NHS Foundation Trust, Great Maze Pond, London SE1 9RT 2 Bristol Interstitial Lung Disease Service, North Bristol NHS trust, Southmead Hospital, Bristol UK 3 Academic Respiratory Unit, University of Bristol, Bristol, UK 4 Leeds interstitial Lung Disease Service, St James's University Hospital, Beckett Street, Leeds LS9 7TF, UK 5 North West Lung Centre, Wythenshawe Hospital, Manchester M23 9LT, UK 6 Birmingham Interstitial Lung Disease Unit, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK 7 University Hospitals Southampton NHS Foundation Trust, Southampton, UK 8 South West Peninsula ILD Network, Royal Devon & Exeter Foundation NHS Trust, Barrack Road, Exeter EX2 5DW, UK 9 Department of Interstitial Lung Disease, Royal Papworth Hospital NHS Foundation Trust, Cambridge UK 10 National Heart and Lung Institute, Imperial College London, UK 11 Royal Brompton Hospital, UK.  Funding: PLM is supported by an Action for Pulmonary Fibrosis Mike Bray fellowship.    To the Editor. While Idiopathic pulmonary fibrosis (IPF) remains the exemplar progressive fibrotic lung disease, there remains a cohort of non-IPF fibrotic lung diseases (fILD) which adopt a similar clinical behaviour to IPF despite therapy [1]. This phenotypically related group of conditions, where progression of disease is similar to that seen in IPF, have recently been described as Progressive Fibrotic Interstitial Lung diseases (PF-ILD) [2]. Historically treatments for these cases have been limited though given the phenotypic similarities many cases may have been given a multidisciplinary working diagnosis of IPF based on their disease behaviour [3]. The INBUILD trial broadened the scope of treatable fILD by demonstrating a significant benefit of Nintedanib in patients with fILD and progressive disease [4]. In response to this the European Commission (EC) approved an additional indication for Nintedanib in adults for the treatment of PF-ILD in July 2020. While research interest grows in the progressive phenotype and debates about the optimal diagnostic criteria continue the incidence of patients with PF-ILD potentially eligible for treatment according to the criteria laid out in the INBUILD trial remains unclear. Previous attempts to estimate the proportion of fILD who develop a progressive fibrotic phenotype have either used estimates based on the disease behaviour of individual conditions [5], interviews with experts [6] or analysis of insurance claims [7].  This has resulted in estimates ranging from 18 to 40% of all fILD that will develop progressive disease. With the anticipated approval of therapeutic interventions for this cohort of patients worldwide, including in the UK, there is an urgent need to refine these estimates in a real-world population to enable appropriate service provision. This retrospective, observational study therefore aimed to estimate the incidence of PF-ILD across England. Nine centres providing commissioned tertiary referral services for ILD were included. All new referrals seen for their first outpatient clinic appointment between 1st August 2017 and 31st January 2018 were assessed against the diagnostic criteria for PF-ILD laid out in the INBUILD trial [8] and in particular, the criteria for progression: relative decline in FVC % predicted ≥10%, or FVC decline ≥5% but <10%, combined with worsening respiratory symptoms, or FVC decline ≥5% but <10%, combined with radiological progression; or radiological progression with worsening respiratory symptoms. A full chart and imaging review was undertaken of all the subjects. Continuous variables are presented as means (± Standard Deviation [SD]), and categorical variables as proportions. Time-to-event curves were calculated using the Kaplan–Meier method and compared with the use of the log-rank test. A total of 2368 patients with ILD were assessed across the 9 centres. Six hundred and nineteen patients were diagnosed and managed as IPF and therefore excluded, leaving 1749 patients with fILD who were screened against the INBUILD criteria for progression, to identify cases of PF-ILD either at the first clinical review, or in the subsequent 2 years of follow up (Table 1). In the cohort of patients at risk of developing PF-ILD the INBUILD criteria were met in 14.5% (253/1749) of all new non-IPF fILD referrals despite standard therapy, with a range between these specialist ILD centres from 8.9% to 23.6% of total cases. The average time from referral to specialist centre to diagnosis of progressive phenotype was 311(±273) days and at the time of referral 20% of patients demonstrated progressive disease (66/253) despite standard therapy. All most all patients received at least one immunosuppressive agent, with the majority receiving either oral or intravenous corticosteroids (96%). A number of second line agents were employed with Mycophenolate (46%) the most commonly used. Five of the subjects with PF-ILD received antifibrotic therapy on compassionate grounds. The most common diagnoses associated with a PF-ILD phenotype were chronic hypersensitivity pneumonitis (84/253, 33.2%), unclassifiable ILD (44/253, 17.3%), connective tissue disease-associated ILDs including rheumatoid arthritis-associated ILD (42/253, 16.6%) and non-specific Interstitial pneumonitis (36/253, 14.2%). In the PF-ILD cases, the mean age was 68 ±12.4 years and interestingly 53.4% of the cohort was female, as compared to the well-recognised male predominance seen in IPF. This is likely driven by the significant female predominance in both CHP and CTD which make up almost half of the PF-ILD cases.   Patients with progressive disease had a significantly higher mortality compared to those with non-progressive fILD (hazard ratio, 3.32; 95% confidence interval, 2.53–4.37; P=<2e-16). Indeed, the survival of patients with PF-ILD was no different to the subjects with IPF (hazard ratio, 1.06; 95% confidence interval, 0.84–1.35; P=0.6) (Figure 1).  Figure 1. Kaplan-Meier curves comparing survival between patients with IPF, PF-ILD and non-progressive fILD. Log-rank P test value is reported. Of the progression events the majority were driven by a measured drop in FVC, with more than half of patients (52.2%) experiencing a drop of ≥10%. A further quarter of patients (24.1%) were diagnosed with progressive disease on the basis of radiological and symptomatic progression alone without a spirometric deterioration. The remainder experienced a decline of FVC between 5 and 10% with either radiological (15.8%) or symptomatic (7.9%) progression.  The variations between centres and clinicians in diagnostic pathways, approaches to follow-up and definitions of progression has previously made it difficult to define and assess this cohort of patients. One of the strengths of our approach was the central collation and uniform application of the INBUILD inclusion criteria. However, this was done retrospectively and this is the main limitation of our study. While the INBUILD trial criteria are mostly objectively measurable phenomena, the definition of progressive symptoms may allow some biasing towards inclusion in those cases where spirometric progression was either not evidenced or not available, thus increasing the numbers of cases. Over a quarter of referrals received a final multidisciplinary team (MDT) diagnosis of IPF, and this is often pragmatic and based on their clinical disease behaviour, to allow access to antifibrotic therapy. However, a patient’s initial clinical and radiological features may have had more in keeping with a different ILD but with a PF-ILD phenotype. While all of the cases underwent local ILD multidisciplinary assessment, we did not undertake any central reassessment and therefore some cases of non-IPF PF-ILD may have been missed. Progression was only assessed at presentation and over a period of two years, as per the INBUILD screening criteria, however, we do know that progression may occur later during follow-up [9] and therefore some late progressors would not have been captured in this analysis. Our estimates therefore maybe if anything an underestimate but importantly they reflect current clinical practice, which we aimed to capture. This study represents a fair and balanced approach to assessing the incidence of objectively measurable and treatable PF-ILDs in the UK. A rate of 14.5% of new referrals with non-IPF ILD is less than that reported in previous studies however our methodology is likely to give a more accurate result than estimates based on extrapolation from general disease statistics, from physician-reported estimates prone to significant biases, or insurance claim processes also substantially prone to bias. This information has implication for workforce planning and the funding of anti-fibrotic therapy in the UK and beyond. Refrences: 1.  Brown KK, Martinez FJ, Walsh SLF, Thannickal VJ, Prasse A, Schlenker-Herceg R, Goeldner R-G, Clerisme-Beaty E, Tetzlaff K, Cottin V, Wells AU. The natural history of progressive fibrosing interstitial lung diseases. Eur. Respir. J. 2020; 55: 1168–1170. 2.  Cottin V, Hirani NA, Hotchkin DL, Nambiar AM, Ogura T, Otaola M, Skowasch D, Park JS, Poonyagariyagorn HK, Wuyts W, Wells AU. Presentation, diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases. Eur. Respir. Rev. 2018; 27: 180076. 3.  Cottin V. Treatment of progressive fibrosing interstitial lung diseases: a milestone in the management of interstitial lung diseases. Eur. Respir. Rev. 2019; 28: 190109. 4.  Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, Richeldi L, Kolb M, Tetzlaff K, Stowasser S, Coeck C, Clerisme-Beaty E, Rosenstock B, Quaresma M, Haeufel T, Goeldner R-G, Schlenker-Herceg R, Brown KK, INBUILD Trial Investigators. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N. Engl. J. Med. 2019; 381: 1718–1727. 5.  Olson AL, Gifford AH, Inase N, Fernández Pérez ER, Suda T. The epidemiology of idiopathic pulmonary fibrosis and interstitial lung diseases at risk of a progressive-fibrosing phenotype. Eur. Respir. Rev. 2018; 27: 180077. 6.  Wijsenbeek M, Kreuter M, Olson A, Fischer A, Bendstrup E, Wells CD, Denton CP, Mounir B, Zouad-Lejour L, Quaresma M, Cottin V. Progressive fibrosing interstitial lung diseases: current practice in diagnosis and management. Curr. Med. Res. Opin. 2019; 35: 2015–2024. 7.  Olson AL, Maher TM, Acciai V, Mounir B, Quaresma M, Zouad-Lejour L, Wells CD, De Loureiro L. Healthcare Resources Utilization and Costs of Patients with Non-IPF Progressive Fibrosing Interstitial Lung Disease Based on Insurance Claims in the USA. Adv. Ther. 2020; 37: 3292–3298. 8.  Flaherty KR, Brown KK, Wells AU, Clerisme-Beaty E, Collard HR, Cottin V, Devaraj A, Inoue Y, Le Maulf F, Richeldi L, Schmidt H, Walsh S, Mezzanotte W, Schlenker-Herceg R. Design of the PF-ILD trial: a double-blind, randomised, placebo-controlled phase III trial of nintedanib in patients with progressive fibrosing interstitial lung disease. BMJ open Respir. Res. 2017; 4: e000212. 9.  Nasser M, Larrieu S, Si-Mohamed S, Ahmad K, Boussel L, Brevet M, Chalabreysse L, Fabre C, Marque S, Revel D, Thivolet-Bejui F, Traclet J, Zeghmar S, Maucort-Boulch D, Cottin V. Progressive fibrosing interstitial lung disease: a clinical cohort (the PROGRESS® study). Eur. Respir. J. 2020; : 2002718.  

The burden of Progressive Fibrotic Interstitial lung disease across the UK

Southampton (e-Prints Soton)

While Idiopathic pulmonary fibrosis (IPF) remains the exemplar progressive fibrotic lung disease, there remains a cohort of non-IPF fibrotic lung diseases (fILD) which adopt a similar clinical behaviour to IPF despite therap. This phenotypically related group of conditions, where progression of disease is similar to that seen in IPF, have recently been described as Progressive Fibrotic Interstitial Lung diseases (PF-ILD). Previous estimates suggest that between 18 to 40% of all fILD will develop progressive disease, however, the exact burden remains unknown. This retrospective, observational study therefore aimed to estimate the incidence of PF-ILD across England.All new referrals seen across nine UK centres for their first outpatient clinic appointment between 1st August 2017 and 31st January 2018 were assessed against the diagnostic criteria for PF-ILD laid out in the INBUILD trial. A total of 1749 patients with fILD were assessed. In this cohort of patients at risk of developing PF-ILD the INBUILD criteria were met in 14.5% (253/1749) of all new non-IPF fILD referrals. The average time from referral to specialist centre to diagnosis of progressive phenotype was 311 days. Of the progression events the majority were driven by a measured drop in FVC, with more than half of patients experiencing a drop of 10%. Almost one quarter of patients (24.1%) were diagnosed with progressive disease on the basis of radiological and symptomatic progression alone without a spirometric deterioration.This study represents a fair and balanced approach to assessing the incidence of objectively measurable and treatable PF-ILDs in the UK. A rate of 14.5% of new referrals with non-IPF ILD is less than that reported in previous studies however our methodology is likely to give a more accurate result than estimates based on extrapolation from general disease statistics, from physician-reported estimates prone to significant biases, or insurance claim processes also substantially prone to bias. This information has implication for workforce planning and the funding of anti-fibrotic therapy in the UK and beyond

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The burden of Progressive Fibrotic Interstitial lung disease across the UK

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