ArticlesLongitudinal change in collagen degradation biomarkers in idiopathic pulmonary fibrosis: an analysis from the prospective, multicentre PROFILE study
Introduction
Idiopathic pulmonary fibrosis is a progressive and inevitably fatal disease with a 5 year survival of only 20%.1 With the advent of specific antifibrotic drugs, there is now hope that disease-modification and improved survival could be realistic therapeutic goals.2, 3 Advances in management of idiopathic pulmonary fibrosis are, however, hampered by heterogeneity of disease progression, absence of validated prognostic measures, and the absence of any markers of treatment response.4 Novel serum biomarkers of fibroproliferation are emerging across a range of non-pulmonary fibrotic diseases, but none have been prospectively validated in carefully phenotyped individuals with idiopathic pulmonary fibrosis.
A cardinal feature of idiopathic pulmonary fibrosis is the accumulation of disordered and architecturally disruptive extracellular matrix (ECM) within the lung tissue. The ECM consists of a dynamic combination of structural proteins, the most abundant of which are collagens. Matrix turnover is determined by several factors including the rate of ECM synthesis by activated myofibroblasts, the extent of collagen cross-linking, and enzymatic matrix degradation.5 Biomarkers that indicate matrix turnover might therefore be indicative of disease activity in fibroproliferative disorders such as idiopathic pulmonary fibrosis.
Most extracellular collagen is degraded by a subset of matrix metalloproteinases (MMPs) including MMP-1, MMP-3, MMP-7, MMP-8, MMP-13, MMP-14, MMP-16, and MMP-18.6 Extracellular collagen fragments generated by these MMPs are then further digested by MMP-2 and MMP-9.6 In idiopathic pulmonary fibrosis, greatly increased rates of ECM protein synthesis are, at least partly, offset by elevated MMP concentrations and activity,7 and MMP-1, MMP-3, and MMP-7 have even been identified as putative prognostic serum biomarkers of the disease.8, 9
During ECM turnover, proteolytically cleaved matrix degradation fragments, or neoepitopes, are released into the systemic circulation.10 Cleavage of each ECM protein by specific MMPs generates a unique neoepitope. These neoepitopes are more accurate diagnostic and prognostic markers for individual fibroproliferative diseases than their protein of origin.10, 11 Previous small point-of-diagnosis studies have suggested that matrix neoepitopes might be elevated in individuals with idiopathic pulmonary fibrosis compared with healthy controls.12, 13, 14
The PROFILE (Prospective Observation of Fibrosis in the Lung Clinical Endpoints) study, the largest prospective study of its type undertaken so far, aimed to determine the prognostic value of longitudinal change in serum concentrations of proteolytically cleaved protein fragments, or neoepitopes. To our knowledge, this study enables, for the first time, sequential temporal assessment of biomarkers in relation to clinical measures of disease activity and progression. Furthermore, the recruitment of incident idiopathic pulmonary fibrosis cases from multiple centres enhances the potential applicability of any findings to real-world clinical practice.
Section snippets
Study design and participants
PROFILE is an ongoing prospective, multicentre, observational cohort study of incident cases (within 6 months of presentation) of idiopathic fibrotic lung disease. Participants with idiopathic pulmonary fibrosis or idiopathic non-specific interstitial pneumonia were identified through two co-ordinating centres: Nottingham, UK, and, Royal Brompton Hospital, London, UK. Only participants with a diagnosis of idiopathic pulmonary fibrosis made in accordance with current internationally accepted
Results
Of 214 eligible participants, recruited between Sept 1, 2010, and March 31, 2012, 189 had a confirmed diagnosis of idiopathic pulmonary fibrosis and were therefore eligible for inclusion in subsequent analyses (figure 1). Participants were predominantly men (79%) with a mean age of 70·1 years (SD 8·3) (table 1). Patients from the Royal Brompton Hospital were significantly younger than patients from Nottingham University Hospitals (p=0·0002), and had slightly, but significantly, worse lung
Discussion
To the best of our knowledge, the PROFILE study is the largest prospective cohort study of incident idiopathic fibrotic lung disease done so far. Patients with incident fibrotic lung disease of all severities were enrolled, through two coordinating centres; because pirfenidone was only approved for reimbursement by the UK National Health Service in August 2013, all participants included in the analysis were naive for antifibrotic therapy. The slightly younger, but more severely affected, cohort
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