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Cited by 314Interstitial Lung Diseases and Idiopathic Pulmonary FibrosisOccupational and environmental lung diseasesChronic Obstructive Pulmonary Disease (COPD) Research

Longitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study

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Jenkins, R Gisli, Simpson, Juliet K, Saini, Gauri, Bentley, Jane H, Russell, Anne-Marie, Braybrooke, Rebecca, Molyneaux, Philip L, McKeever, Tricia M +8 more·2015·The Lancet Respiratory Medicine
DOI 10.1016/s2213-2600(15)00048-x
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Abstract

BACKGROUND: Idiopathic pulmonary fibrosis, a progressive and inevitably fatal disorder, has a highly variable clinical course. Biomarkers that reflect disease activity are urgently needed to inform patient management and for use as biomarkers of therapeutic response (theragnostic biomarkers) in clinical trials. We aimed to determine whether dynamic change in markers of extracellular matrix (ECM) turnover predicts progression of idiopathic pulmonary fibrosis as determined by change in forced vital capacity and death. METHODS: In this ongoing prospective, multicentre, observational cohort study (PROFILE), participants with idiopathic pulmonary fibrosis or idiopathic non-specific interstitial pneumonia diagnosed within the preceding 6 months were recruited from two coordinating centres (Nottingham, UK, and, Royal Brompton Hospital, London, UK). Serum samples were prospectively collected at baseline, 1 month, 3 months, and 6 months and were analysed for a panel of novel matrix metalloprotease (MMP)-degraded ECM proteins, by ELISA-based, neoepitope assay. 11 neoepitopes were tested in a discovery cohort of 55 patients to identify biomarkers of sufficient rigour for more detailed analyses. Eight were then further assessed in a validation cohort of 134 patients with 50 age-matched and sex-matched controls. Changes in biomarker concentrations were related to subsequent progression of idiopathic pulmonary fibrosis (defined as death or decline in forced vital capacity >10% at 12 months after study enrolment) using a repeated measures model. The PROFILE study is registered on ClinicalTrials.gov, numbers NCT01134822 and NCT01110694. FINDINGS: Of 214 eligible participants recruited between Sept 1, 2010, and March 31, 2012, 189 had a confirmed diagnosis of idiopathic pulmonary fibrosis and were included in subsequent analyses. In the discovery cohort, mean concentrations of seven neoepitopes (BGM, p=0·009; C1M, p=0·009; C3M, p=0·046; C6M, p=0·032; CRPM, p=0·008; ELM2, p=0·02; and VICM, p=0·0007) differed significantly between healthy controls and participants with idiopathic pulmonary fibrosis. Baseline concentrations of six neoepitopes (C1M, p=0·012; C3A, p=0·012; C3M, p=0·0005; C6M, p=0·0003; CRPM, p=0·021; and VICM, p=0·046) were significantly higher in patients with progressive idiopathic pulmonary fibrosis (n=32) than in those with stable disease (n=23). In the validation cohort, mean concentrations of C1M (p=0·001), C3M (p=0·044), C6M (p=0·003), and CRPM (p=0·024) at baseline were higher in patients with idiopathic pulmonary fibrosis than in healthy controls. When assessed longitudinally, concentrations of six neoepitopes (BGM, C1M, C3A, C3M, C6M, and CRPM) were significantly higher in patients with progressive idiopathic pulmonary fibrosis (n=71) than in patients with stable idiopathic pulmonary fibrosis (n=60) by 6 months. Baseline concentrations of two neoepitopes were associated with increased mortality (C1M: HR 1·62 [95% CI 1·14-2·31], p=0·0069; C3A: 1·91 [1·06-3·46], p=0·032). The rate of change between baseline and 3 months of six neoepitopes (BGM: HR 1·084 [95% CI 1·03-1·14], p=0·0019; C1M: 1·01 [1·003-1·017], p=0·0039; C3M: 1·106 [1·045-1·170], p=0·0005; C5M: 1·003 [1·001-1·005], p=0·0011; C6M: 1·042 [1·007-1·078], p=0·017; and CRPM: 1·38 [1·16-1·63], p=0·0002) was strongly predictive of overall survival, and the increased risk was proportional to the magnitude of change in neoepitope concentrations. The strongest association with 3-month rate of biomarker change was recorded for CRPM; greater than 0 ng/mL per month conferred a HR of 2·16 (95% CI 1·15-4·07), whereas a rate greater than 1 ng/mL per month resulted in an HR 4·08 (2·14-7·8), and a rate greater than 1·7 ng/mL per month was associated with an HR 6·61 (2·74-15·94). INTERPRETATION: Concentrations of protein fragments generated by MMP activity are increased in the serum of individuals with idiopathic pulmonary fibrosis compared with healthy controls. Increased neoepitope concentrations were associated with disease progression, and the rate of this increase predicted survival. Serial measurements of neoepitopes have potential to be used as theragnostic biomarkers in clinical trials and to guide management of idiopathic pulmonary fibrosis. FUNDING: GlaxoSmithKline R&D and the Medical Research Council.

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Crossref · 10.1016/s2213-2600(15)00048-x

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  • The rate of change between baseline and 3 months of BGM, C1M, C3M, C5M, C6M and CRPM was strongly predictive of overall survival, with the strongest association being with CRPM.

    “The rate of change between baseline and 3 months of BGM, C1M, C3M, C5M, C6M and CRPM was strongly predictive of overall survival, and the increased risk was proportional to the magnitude of change in neoepitope concentrations, with strongest association being with CRPM (Jenkins et al., 2015).”

    From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Jenkins et al., 2015

  • Several ECM neoepitopes (BGM, C1M, C3M, C3A, C6M, ELM2, VICM) and CRPM were able to distinguish IPF patients from healthy controls; six neoepitopes at baseline were higher in progressive IPF than stable disease; and longitudinally six neoepitopes were higher in progressive versus stable IPF by 6 months.

    “Biomarkers representing abnormal lung synthesis and remodelling, based on the detection of ECM neoepitopes were investigated in the PROFILE study and revealed that several neoepitopes (BGM, C1M, C3M, C3A, C6M, ELM2, VICM) in addition to C-reactive protein degraded by MMP-1/8 (CRPM) were able to distinguish IPF patients from healthy controls. Six neoepitopes (C1M, C3A, C3M, C”

    From Pulmonary fibrosis: Emerging diagnostic and therapeutic strategies (2023) · cites this paper as Jenkins et al., 2015

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Authors
Jenkins, R. G., Simpson, J. K., Saini, G., Bentley, J. H., Russell, A.-M., Braybrooke, R., Molyneaux, P. L., McKeever, T. M., Wells, A. U., Flynn, A., Hubbard, R. B., Leeming, D. J., Marshall, R. P., Karsdal, M. A., Lukey, P. T., & Maher, T. M.
Affiliations
  • GlaxoSmithKline (United Kingdom) (GB)
  • University of Nottingham (GB)
  • National Institute for Health and Care Research (GB)
  • Imperial College London (GB)
  • Nordic Bioscience (Denmark) (DK)
Corresponding author
Maher, Toby M
ORCID
Venue
The Lancet Respiratory Medicine
Publisher
Elsevier BV
Published
2015-06
Volume
3
Issue
6
Pages
462-472
ISSN
2213-2600 (ISSN-L)
DOI
10.1016/s2213-2600(15)00048-x
OpenAlex
W2002587076
Cited by
314
References
34
Citations by year
2026: 14 · 2025: 15 · 2024: 28 · 2023: 22 · 2022: 22 · 2021: 25 · 2020: 32 · 2019: 37 · 2018: 39 · 2017: 35 · 2016: 29 · 2015: 16
FWCI
31.42
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Respiratory Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Repository@Nottingham (University of Nottingham) (acceptedVersion, other-oa)
  • UCL Discovery (University College London) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by-nc-nd)
Funders
NIHR Clinician Scientist Fellowship (NIHR Ref: CS-2013-13-017)
Topics
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Occupational and environmental lung diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
Keywords
idiopathic pulmonary fibrosis, extracellular matrix turnover, neoantigens, disease progression, forced vital capacity decline, mortality, longitudinal biomarker dynamics, C1M, C3M
MeSH terms
Aged, Collagen, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, Humans, Longitudinal Studies, Male, Prospective Studies, Cohort Studies, Biomarkers, Matrix Metalloproteinases, Idiopathic Pulmonary Fibrosis

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