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Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal disorder with a variable disease trajectory. The aim of this study was to assess potential biomarkers to predict outcomes for people with IPF., Methods: PROFILE is a large prospective longitudinal cohort of treatment-naive patients with IPF. We adopted a two-stage discovery and validation design using patients from the PROFILE cohort. For the discovery analysis, we examined 106 patients and 50 age and sex matched healthy controls from Nottingham University Hospitals NHS Trust and the Royal Brompton Hospital. We did an unbiased, multiplex immunoassay assessment of 123 biomarkers. We further investigated promising novel markers by immunohistochemical assessment of IPF lung tissue. In the validation analysis, we examined samples from 206 people with IPF from among the remaining 212 patients recruited to PROFILE Central England. We used the samples to attempt to replicate the biomarkers identified from the discovery analysis by use of independent immunoassays for each biomarker. We investigated the predictive power of the selected biomarkers to identify individuals with IPF who were at risk of progression or death. The PROFILE studies are registered on ClinicalTrials.gov, numbers NCT01134822 (PROFILE Central England) and NCT01110694 (PROFILE Royal Brompton Hospital)., Findings: In the discovery analysis, we identified four serum biomarkers (surfactant protein D, matrix metalloproteinase 7, CA19-9, and CA-125) that were suitable for replication. Histological assessment of CA19-9 and CA-125 suggested that these proteins were markers of epithelial damage. Replication analysis showed that baseline values of surfactant protein D (46·6 ng/mL vs 34·6 ng/mL, p=0·0018) and CA19-9 (53·7 U/mL vs 22·2 U/mL; p<0·0001) were significantly higher in patients with progressive disease than in patients with stable disease, and rising concentrations of CA-125 over 3 months were associated with increased risk of mortality (HR 2·542, 95% CI 1·493-4·328, p=0·00059)., Interpretation: We have identified serum proteins secreted from metaplastic epithelium that can be used to predict disease progression and death in IPF., Funding: GlaxoSmithKline R&D and the UK Medical Research Council., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)