{
  "abstract": "Background Idiopathic pulmonary fibrosis (IPF) is characterised by damage to the epithelial layer, closely associated with the alveolar basement membrane (BM). We aimed to investigate how type IV collagen (COL4) in the BM changes with the progression of IPF.Methods COL4 synthesis (PRO-C4) was detected in blood by the nordicPRO-C4 biomarker in patients with IPF from the two prospective, multicentre, observational, longitudinal cohorts, pulmonary fibrosis biomarker (PFBIO) and prospective observation of fibrosis in the lung clinical endpoints (PROFILE). PRO-C4 trajectories over 12 months were compared between progressors and non-progressors by linear mixed effects regression models. Rate of change in PRO-C4 and lung function were compared by Bayesian bivariate longitudinal models. Cox proportional hazards models analysed baseline PRO-C4 and 3 years mortality. COL4 staining in IPF and non-IPF lungs was evaluated by immunohistochemistry.Results In PFBIO and PROFILE, 51/220 (23.2%) and 221/459 (48.1%) patients, respectively, had progressive disease at 12 months. Longitudinal PRO-C4 levels were higher in progressors versus non-progressors (average differences: PFBIO 21.5% (95% CI 3.4% to 42.9%, p=0.0184); PROFILE 10.9% (95% CI 0.8% to 22.1%; p=0.0340). Monthly rate of change in PRO-C4 was steeper in non-survivors versus survivors (mean difference up to 3.12% (95% CI 0.35% to 5.91%)) and was inversely correlated with the change in lung function. High baseline PRO-C4 was associated with increased mortality risk in PFBIO (HR 2.55 (95% CI 1.27 to 5.12), p=0.0083). COL4 staining was higher in IPF versus non-IPF lung but was less obvious in end-stage tissue.Conclusions High and increasing serological PRO-C4 levels were prognostic for progression in two independent IPF cohorts. This study suggests that COL4 synthesis assessed by PRO-C4 is a pathologically relevant biomarker of alveolar BM repair in IPF.",
  "authors": [
    {
      "affiliations": [
        "Nordic Bioscience, Herlev, Denmark"
      ],
      "name": "Jannie M B Sand"
    },
    {
      "affiliations": [
        "Nordic Bioscience, Herlev, Denmark"
      ],
      "name": "Peder Frederiksen"
    },
    {
      "affiliations": [
        "Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "Alison E John"
    },
    {
      "affiliations": [
        "Nordic Bioscience, Herlev, Denmark"
      ],
      "name": "Filipa B Simões"
    },
    {
      "affiliations": [
        "Department of Respiratory Medicine, Herlev and Gentofte University Hospital, Copenhagen, Denmark"
      ],
      "name": "Nils Hoyer"
    },
    {
      "affiliations": [
        "Centre for Rare Lung Diseases, Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark"
      ],
      "name": "Thomas S Prior"
    },
    {
      "affiliations": [
        "Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "Adnan Avdic-Belltheus"
    },
    {
      "affiliations": [
        "Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "Philip L Molyneaux"
    },
    {
      "affiliations": [
        "Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "Iain D Stewart"
    },
    {
      "affiliations": [
        "Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "Hernan P Fainberg"
    },
    {
      "affiliations": [
        "Centre for Respiratory Research, NIHR Biomedical Research Centre and Biodiscovery Institute School of Medicine, University of Nottingham, Nottingham, UK"
      ],
      "name": "Simon R Johnson"
    },
    {
      "affiliations": [
        "Nordic Bioscience, Herlev, Denmark"
      ],
      "name": "Morten A Karsdal"
    },
    {
      "affiliations": [
        "Nordic Bioscience, Herlev, Denmark"
      ],
      "name": "Diana J Leeming"
    },
    {
      "affiliations": [
        "Centre for Rare Lung Diseases, Department of Respiratory Diseases and Allergy, Aarhus University Hospital, Aarhus, Denmark"
      ],
      "name": "Elisabeth Bendstrup"
    },
    {
      "affiliations": [
        "Department of Respiratory Medicine, Herlev and Gentofte University Hospital, Copenhagen, Denmark"
      ],
      "name": "Saher B Shaker"
    },
    {
      "affiliations": [
        "Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, UK",
        "Keck School of Medicine, University of Southern California, Los Angeles, California, USA"
      ],
      "name": "Toby M Maher"
    },
    {
      "affiliations": [
        "Margaret Turner Warwick Centre for Fibrosing Lung Disease, National Heart and Lung Institute, Imperial College London, London, UK"
      ],
      "name": "Gisli Jenkins"
    }
  ],
  "title": "Basement membrane repair response biomarker PRO-C4 predicts progression in idiopathic pulmonary fibrosis: analysis of the PFBIO and PROFILE cohorts",
  "uid": "23eb5e46-9843-554e-a822-a1ab256a7ee4"
}