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Biomarkers of collagen turnover are related to annual change in FEV1 in patients with chronic obstructive pulmonary disease within the ECLIPSE study.

ABSTRACT: Change in forced expiratory volume in one second (FEV1) is important for defining severity of chronic obstructive pulmonary disease (COPD). Serological neoepitope markers of collagen turnover may predict rate of change in FEV1.One thousand COPD subjects from the observational, multicentre, three-year ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study (NCT00292552, trial registration in February 2006) were included. Matrix metalloproteinase (MMP)-generated fragments of collagen type I, and type VI (C1M and C6M) were assessed in month six serum samples. A random-coefficient model with both a random intercept and a random slope was used to test the ability of the markers to predict post-dose bronchodilator FEV1 (PD-FEV1) change over two years adjusting for sex, age, BMI, smoking, bronchodilator reversibility, prior exacerbations, emphysema and chronic bronchitis status at baseline.Annual change of PD-FEV1 was estimated from a linear model for the two-year study period. Serum C1M and C6M were independent predictors of lung function change (p?=?0.007/0.005). Smoking, bronchodilator reversibility, plasma hsCRP and emphysema were also significant predictors. The effect estimate between annual change in PD-FEV1 per one standard deviation (1SD) increase of C1M and C6M was +10.4 mL/yr. and +8.6 mL/yr. C1M, and C6M, had a significant association with baseline FEV1.We demonstrated that markers of tissue turnover were significantly associated with lung function change. These markers may function as prognostic biomarkers and possibly as efficacy biomarkers in clinical trials focusing on lung function change in COPD.NCT00292552 , Retrospectively registered, trial registration in February 2006.

SUBMITTER: Leeming DJ

PROVIDER: S-EPMC5716018 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Biomarkers of collagen turnover are related to annual change in FEV<sub>1</sub> in patients with chronic obstructive pulmonary disease within the ECLIPSE study.

Leeming Diana J DJ Byrjalsen Inger I Sand Jannie M B JMB Bihlet Asger R AR Lange Peter P Thal-Singer Ruth R Miller Bruce E BE Karsdal Morten A MA Vestbo Jørgen J

BMC pulmonary medicine 20171204 1

<h4>Background</h4>Change in forced expiratory volume in one second (FEV<sub>1</sub>) is important for defining severity of chronic obstructive pulmonary disease (COPD). Serological neoepitope markers of collagen turnover may predict rate of change in FEV<sub>1</sub>.<h4>Methods</h4>One thousand COPD subjects from the observational, multicentre, three-year ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints) study (NCT00292552, trial registration in February 200 ...[more]

PMID: 29202744

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Project description:BackgroundIdentifying subjects with chronic obstructive pulmonary disease (COPD) at high risk of exacerbation and mortality is key to aid individual management of COPD. The only FDA approved blood-based drug development biomarker for patients at high risk of mortality, is plasma fibrinogen. In this study, we benchmarked two biomarkers of basement membrane remodeling, a characteristic of COPD, against plasma fibrinogen alone and as a combination. The biomarkers of basement membrane remodeling are two neoepitopes from of the alpha 3 chain of type IV collagen (COL4A3).Materials and methodsCOL4A3 degradation was assessed by the biomarkers C4Ma3 and tumstatin (TUM) in year 1 plasma samples in 984 COPD subjects, 95 non-smoking controls and 95 smoking controls from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) cohort. They were measured by competitive ELISA using monoclonal antibodies recognizing two specific MMP-generated cleavage site within COL4A3. The level of fibrinogen was previously assessed in year 1 plasma.ResultsIn COPD subjects, plasma C4Ma3 levels were significantly correlated with plasma fibrinogen levels (0.389 (P < 0.0001)). Cox proportional-hazards regression adjusted for relevant confounders showed that high levels of plasma C4Ma3, but not TUM, were related to a higher risk of mortality (hazard ratio 5.12 (95% CI 2.28-11.50), P < 0.0001). High levels of plasma fibrinogen were not associated with all-cause mortality in this subpopulation, contradictory to published results. Whereas plasma C4Ma3 multiplied by fibrinogen showed to be related to a higher risk of mortality (hazard ratio 5.74 (95% CI 2.65-12.41), P < 0.0001). Plasma C4Ma3 levels were related to the number of hospitalizations due to COPD exacerbations in the year before study start (P = 0.0375). Fibrinogen levels were related to hospitalized exacerbations prior to study start (P = 0.0058) and were also related to future exacerbations (P < 0.0001).ConclusionWe compared herein fibrinogen, C4Ma3 and TUM as biomarkers for COPD prognosis. Fibrinogen was related to future exacerbation, whereas C4Ma3 and the combination of C4Ma3 with fibrinogen were superior to fibrinogen alone in predicting mortality. This pilot study suggests that the assessment of plasma C4Ma3 could be important for identifying COPD patients with a poor prognosis.Trial registrationNCT00292552 , GSK Study No. SCO104960.

Dataset Information

Biomarkers of collagen turnover are related to annual change in FEV1 in patients with chronic obstructive pulmonary disease within the ECLIPSE study.

Publications

Biomarkers of collagen turnover are related to annual change in FEV<sub>1</sub> in patients with chronic obstructive pulmonary disease within the ECLIPSE study.

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