Biomarkers of progressive lung fibrosis

Interstitial lung diseases (ILD) encompass a heterogeneous group of immuno-inflammatory and fibrotic diseases of the lung parenchyma. The most common and severe ILD is idiopathic pulmonary fibrosis (IPF), a chronic progressive fibrotic lung disease of unknown aetiology associated with poor prognosis. A substantial proportion of individuals with ILDs other than IPF also develop progressive fibrosis with clinical, radiological, and genetic similarities, suggesting a shared final common pathway across progressive fibrotic ILDs irrespective of aetiology. Study of shared mechanisms of progression has the potential to aid prognostication, enable a precise approach to therapeutic strategies and allow stratification into clinical trials. Biomarkers are objectively measured and reproducible characteristics that enable stratification of disease phenotypes. The aim of this thesis was to examine and characterise the role of clinical biomarkers in fibrotic lung diseases to enable early identification of progressive fibrotic phenotypes. An evidence synthesis of blood biomarkers as prognosticators in IPF highlighted several biomarkers with prognostic potential and identified priorities for future blood biomarker research. The first individual participant data (IPD) meta-analysis in IPF of matrix metalloproteinase-7 demonstrated baseline measurements were independently associated with disease outcomes. To evaluate the role of physiological variables as prognostic biomarkers and as surrogate trial endpoints, the largest analysis of interventional trial placebo arms in IPF was performed using robust IPD methodology. Baseline and three-month change in physiological variables, particularly FVC were independently associated with disease outcomes, supporting their role as prognostic biomarkers. The association between short-term change in FVC and disease outcomes were replicated in individuals receiving anti-fibrotics using pooled analysis of pirfenidone and nintedanib treatment arms. Moreover, a difference in FVC change over three-months between treatment and placebo arms was observed, supporting three-month FVC as a surrogate endpoint in future IPF trials. An ongoing prospective multi-centre observational cohort study (INJUSTIS) to assess longitudinal disease behaviour and the role of biomarkers in other fibrotic lung diseases was established. Interim analysis suggested a significant proportion of individuals with non-IPF fibrotic ILD had progressive phenotypes that were comparable with disease behaviour in IPF. Lung function, particularly FVC change over three-months was independently associated with poorer outcomes. The role of home spirometry in fibrotic ILD was assessed, and though measurements were accurate and reliable when compared with hospital spirometry, daily FVC measurements were unable to predict mortality at earlier timepoints. An exploratory blood biomarker analysis performed in individuals with extremes of IPF offered further support for the role of CA-125 as a prognostic biomarker and identified several biomarkers and biological pathways for more focussed assessment in the complete INJUSTIS cohort. Taken collectively, the data presented in this thesis strongly support an important role for biomarkers in fibrotic ILD to identify progressive fibrotic phenotypes and enable personalised approaches to patient management. Whilst the COVID-19 pandemic was severely disruptive, the work presented forms the basis for further study of biomarkers in progressive pulmonary fibrosis

A systematic review and meta-analysis of Anakinra, Sarilumab, Siltuximab and Tocilizumab for Covid-19

Background There is accumulating evidence for an overly activated immune response in severe Covid-19, with several studies exploring the therapeutic role of immunomodulation. Through systematic review and meta-analysis, we assess the effectiveness of specific interleukin inhibitors for the treatment of Covid-19.Methods Electronic databases were searched on 7th January 2021 to identify studies of immunomodulatory agents (anakinra, sarilumab, siltuximab and tocilizumab) for the treatment of Covid-19. The primary outcomes were severity on an ordinal scale measured at day 15 from intervention and days to hospital discharge. Key secondary endpoints included overall mortality.Results 71 studies totalling 22,058 patients were included, six were randomised trials. Most explored outcomes in patients who received tocilizumab (59/71). In prospective studies, tocilizumab was associated with improved unadjusted survival (RR 0.83 95%CI 0.72;0.96 I2 = 0.0%), but conclusive benefit was not demonstrated for other outcomes. In retrospective studies, tocilizumab was associated with less severe outcomes on an ordinal scale (Generalised odds ratio 1.34 95%CI 1.10;1.64, I2=98%) and adjusted mortality risk (HR 0.52 95%CI 0.41;0.66, I2 =76.6%). The mean difference in duration of hospitalisation was 0.36 days (95%CI -0.07;0.80, I2 =93.8%). There was substantial heterogeneity in retrospective studies, and estimates should be interpreted cautiously. Other immunomodulatory agents showed similar effects to tocilizumab, but insufficient data precluded meta-analysis by agent.Conclusion Tocilizumab was associated with a lower relative risk of mortality in prospective studies, but effects were inconclusive for other outcomes. Current evidence for the efficacy of anakinra, siltuximab or sarilumab in Covid-19 is insufficient, with further studies urgently needed for conclusive findings

The Its Not JUST Idiopathic pulmonary fibrosis Study (INJUSTIS): Description of the protocol for a multicentre prospective observational cohort study identifying biomarkers of progressive fibrotic lung disease

Introduction: The Its Not JUST Idiopathic pulmonary fibrosis Study (INJUSTIS) is a multicentre, prospective, observational cohort study. The aims of this study are to identify genetic, serum and other biomarkers that may identify specific molecular mechanisms, reflecting disease endotypes that are shared among patients with progressive pulmonary fibrosis regardless of aetiology. Furthermore, it is anticipated that these biomarkers will help predict fibrotic activity that may identify patterns of disease behaviour with greater accuracy than current clinical phenotyping.Methods and analysis: 200 participants with the multidisciplinary team confirmed fibrotic lung disease (50 each of rheumatoid-interstitial lung disease (ILD), asbestosis, chronic hypersensitivity pneumonitis and unclassifiable ILD) and 50 idiopathic pulmonary fibrosis participants, recruited as positive controls, will be followed up for 2 years. Participants will have blood samples, lung function tests, quality of life questionnaires and a subgroup will be offered bronchoscopy. Participants will also be given the option of undertaking blinded home handheld spirometry for the first 3 months of the study. The primary end point will be identification of a biomarker that predicts disease progression, defined as 10% relative change in forced vital capacity (FVC) or death at 12 months.Ethics and dissemination: The trial has received ethical approval from the National Research Ethics Committee Nottingham (18/EM/0139). All participants must provide written informed consent. The trial will be overseen by the INJUSTIS steering group that will include a patient representative, and an independent chairperson. The results from this study will be submitted for publication in peer-reviewed journals and disseminated at regional and national conferences.Trial registration number NCT0367057

The diagnosis and management of systemic autoimmune rheumatic disease-related interstitial lung disease: British Society for Rheumatology guideline scope

Interstitial lung disease (ILD) is a significant complication of many systemic autoimmune rheumatic diseases (SARDs), although the clinical presentation, severity and outlook may vary widely between individuals. Despite the prevalence, there are no specific guidelines addressing the issue of screening, diagnosis and management of ILD across this diverse group. Guidelines from the ACR and EULAR are expected, but there is a need for UK-specific guidelines that consider the framework of the UK National Health Service, local licensing and funding strategies. This article outlines the intended scope for the British Society for Rheumatology guideline on the diagnosis and management of SARD-ILD developed by the guideline working group. It specifically identifies the SARDs for consideration, alongside the overarching principles for which systematic review will be conducted. Expert consensus will be produced based on the most up-to-date available evidence for inclusion within the final guideline. Key issues to be addressed include recommendations for screening of ILD, identifying the methodology and frequency of monitoring and pharmacological and non-pharmacological management. The guideline will be developed according to methods and processes outlined in Creating Clinical Guidelines: British Society for Rheumatology Protocol version 5.1.</p

Real-world experience of nintedanib for progressive fibrosing interstitial lung disease in the UK

Background Nintedanib slows progression of lung function decline in patients with progressive fibrosing (PF) interstitial lung disease (ILD) and was recommended for this indication within the United Kingdom (UK) National Health Service in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date, there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting.Methods 26 UK centres were invited to take part in a national service evaluation between 17 November 2021 and 30 September 2022. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability were collected via electronic survey.Results 24 UK prescribing centres responded to the service evaluation invitation. Between 17 November 2021 and 30 September 2022, 1120 patients received a multidisciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298 out of 1120, 26.6%), connective tissue disease associated ILD (197 out of 1120, 17.6%), rheumatoid arthritis associated ILD (180 out of 1120, 16.0%), idiopathic nonspecific interstitial pneumonia (125 out of 1120, 11.1%) and unclassifiable ILD (100 out of 1120, 8.9%). Of these, 54.4% (609 out of 1120) were receiving concomitant corticosteroids, 355 (31.7%) out of 1120 were receiving concomitant mycophenolate mofetil and 340 (30.3%) out of 1120 were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD.Conclusion We have demonstrated the use of nintedanib for the treatment of PF-ILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD has demonstrated acceptable tolerability in a real-world setting

Understanding the burden of interstitial lung disease post-COVID-19: the UK Interstitial Lung Disease-Long COVID Study (UKILD-Long COVID)

Introduction The COVID-19 pandemic has led to over 100 million cases worldwide. The UK has had over 4 million cases, 400 000 hospital admissions and 100 000 deaths. Many patients with COVID-19 suffer long-term symptoms, predominantly breathlessness and fatigue whether hospitalised or not. Early data suggest potentially severe long-term consequence of COVID-19 is development of long COVID-19-related interstitial lung disease (LC-ILD). Methods and analysis The UK Interstitial Lung Disease Consortium (UKILD) will undertake longitudinal observational studies of patients with suspected ILD following COVID-19. The primary objective is to determine ILD prevalence at 12 months following infection and whether clinically severe infection correlates with severity of ILD. Secondary objectives will determine the clinical, genetic, epigenetic and biochemical factors that determine the trajectory of recovery or progression of ILD. Data will be obtained through linkage to the Post-Hospitalisation COVID platform study and community studies. Additional substudies will conduct deep phenotyping. The Xenon MRI investigation of Alveolar dysfunction Substudy will conduct longitudinal xenon alveolar gas transfer and proton perfusion MRI. The POST COVID-19 interstitial lung DiseasE substudy will conduct clinically indicated bronchoalveolar lavage with matched whole blood sampling. Assessments include exploratory single cell RNA and lung microbiomics analysis, gene expression and epigenetic assessment. Ethics and dissemination All contributing studies have been granted appropriate ethical approvals. Results from this study will be disseminated through peer-reviewed journals. Conclusion This study will ensure the extent and consequences of LC-ILD are established and enable strategies to mitigate progression of LC-ILD

Biomarkers of progressive lung fibrosis

Interstitial lung diseases (ILD) encompass a heterogeneous group of immuno-inflammatory and fibrotic diseases of the lung parenchyma. The most common and severe ILD is idiopathic pulmonary fibrosis (IPF), a chronic progressive fibrotic lung disease of unknown aetiology associated with poor prognosis. A substantial proportion of individuals with ILDs other than IPF also develop progressive fibrosis with clinical, radiological, and genetic similarities, suggesting a shared final common pathway across progressive fibrotic ILDs irrespective of aetiology. Study of shared mechanisms of progression has the potential to aid prognostication, enable a precise approach to therapeutic strategies and allow stratification into clinical trials. Biomarkers are objectively measured and reproducible characteristics that enable stratification of disease phenotypes. The aim of this thesis was to examine and characterise the role of clinical biomarkers in fibrotic lung diseases to enable early identification of progressive fibrotic phenotypes. An evidence synthesis of blood biomarkers as prognosticators in IPF highlighted several biomarkers with prognostic potential and identified priorities for future blood biomarker research. The first individual participant data (IPD) meta-analysis in IPF of matrix metalloproteinase-7 demonstrated baseline measurements were independently associated with disease outcomes. To evaluate the role of physiological variables as prognostic biomarkers and as surrogate trial endpoints, the largest analysis of interventional trial placebo arms in IPF was performed using robust IPD methodology. Baseline and three-month change in physiological variables, particularly FVC were independently associated with disease outcomes, supporting their role as prognostic biomarkers. The association between short-term change in FVC and disease outcomes were replicated in individuals receiving anti-fibrotics using pooled analysis of pirfenidone and nintedanib treatment arms. Moreover, a difference in FVC change over three-months between treatment and placebo arms was observed, supporting three-month FVC as a surrogate endpoint in future IPF trials. An ongoing prospective multi-centre observational cohort study (INJUSTIS) to assess longitudinal disease behaviour and the role of biomarkers in other fibrotic lung diseases was established. Interim analysis suggested a significant proportion of individuals with non-IPF fibrotic ILD had progressive phenotypes that were comparable with disease behaviour in IPF. Lung function, particularly FVC change over three-months was independently associated with poorer outcomes. The role of home spirometry in fibrotic ILD was assessed, and though measurements were accurate and reliable when compared with hospital spirometry, daily FVC measurements were unable to predict mortality at earlier timepoints. An exploratory blood biomarker analysis performed in individuals with extremes of IPF offered further support for the role of CA-125 as a prognostic biomarker and identified several biomarkers and biological pathways for more focussed assessment in the complete INJUSTIS cohort. Taken collectively, the data presented in this thesis strongly support an important role for biomarkers in fibrotic ILD to identify progressive fibrotic phenotypes and enable personalised approaches to patient management. Whilst the COVID-19 pandemic was severely disruptive, the work presented forms the basis for further study of biomarkers in progressive pulmonary fibrosis

Real world experience of nintedanib for progressive fibrosing interstitial lung disease in the UK

Background Nintedanib slows progression of lung function decline in patients with progressive fibrosing interstitial lung disease (PF-ILD) and was recommended for this indication within the NHS in Scotland in June 2021 and in England, Wales and Northern Ireland in November 2021. To date there has been no national evaluation of the use of nintedanib for PF-ILD in a real-world setting. Methods Twenty-six UK centres were invited to take part in a national service evaluation between 17/11/21 and 30/09/22. Summary data regarding underlying diagnosis, pulmonary function tests, diagnostic criteria, radiological appearance, concurrent immunosuppressive therapy and drug tolerability was collected via electronic survey. Results Twenty-four UK prescribing centres responded to the service evaluation invitation. Between 17/11/2021 and 30/09/2022, 1120 patients received a multi-disciplinary team recommendation to commence nintedanib for PF-ILD. The most common underlying diagnoses were hypersensitivity pneumonitis (298/1120,26.6%), connective tissue disease associated interstitial lung disease (197/1120,17.6%), rheumatoid arthritis associated ILD (180/1120,16.0%), idiopathic non-specific interstitial pneumonia (125/1120,11.1%) and unclassifiable ILD (100/1120,8.9%). Of these, 54.4% (609/1120) were receiving concomitant corticosteroids, 355/1120 (31.7%) were receiving concomitant mycophenolate mofetil and 340/1120 (30.3%) were receiving another immunosuppressive/modulatory therapy. Radiological progression of ILD combined with worsening respiratory symptoms was the most common reason for the diagnosis of PF-ILD. Conclusion We have demonstrated the use of nintedanib for the treatment of PFILD across a broad range of underlying conditions. Nintedanib is frequently co-prescribed alongside immunosuppressive and immunomodulatory therapy. The use of nintedanib for the treatment of PF-ILD has demonstrated acceptable tolerability in a real-world setting