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AB0180 Biomarkers of extracellular matrix remodeling are associated with acute exacerbations of idiopathic interstitial pneumonia
  1. J Sand1,
  2. P Juhl1,
  3. Y Tanino2,
  4. T Nikaido2,
  5. K Misa2,
  6. Y Sato2,
  7. R Togawa2,
  8. X Wang2,
  9. M Karsdal1,
  10. A-C Bay-Jensen1,
  11. D Leeming1,
  12. AS Siebuhr1,
  13. M Munakata2
  1. 1Nordic Bioscience, Herlev, Denmark
  2. 2Department of Pulmonary Medicine, Fukushima Medical University School of Medicine, Fukushima, Japan

Abstract

Background Idiopathic interstitial pneumonia (IIP) is characterized by an increased rate of extracellular matrix (ECM) turnover resulting in fibrosis. The pathogenic remodeling includes increased levels of protein synthesis and degradation mediated by proteases such as matrix metalloproteinases (MMPs). Acute exacerbations of IIP (AE-IIP) represent periods of increased disease activity. Pulmonary involvement, especially pulmonary fibrosis, is common in patients suffering from systemic sclerosis (SSc) and ankylosing spondylitis (AS)

Objectives The objective was to investigate if ECM remodeling was altered during AE-IIP by serological neo-epitope biomarkers.

Methods Serum samples were collected from patients with IIP at clinically stable disease (S-IIP, n=29) and at AE-IIP (n=68). Of these, 11 and 28 patients, respectively, had idiopathic pulmonary fibrosis (IPF). 28 IIP patients had paired samples. Biomarkers released from MMP-mediated degradation of collagen type I (C1M), III (C3M), IV (C4M), and VI (C6M), elastin (ELM7), versican (VCANM), biglycan (BGM), and C-reactive protein (CRPM) were assessed in serum by competitive ELISAs utilizing neo-epitope specific monoclonal antibodies. Data were analysed using Mann-Whitney test, Wilcoxon test, Spearman's rank correlation, and Kaplan-Meier curves as appropriate.

Results Mean age of patients was 71 (range 54–86) at AE-IIP and 69 (range 55–83) at S-IIP. Mean forced vital capacity in percentage of predicted value (%FVC) was 55.6% (SD 19.5) at AE-IIP and 79.0% (SD 26.5) at S-IIP. Serum levels of C4M, C6M, and CRPM at AE-IIP were positively correlated with %FVC (r=0.37, p=0.008; r=0.36, p=0.011; r=0.33, p=0.020; respectively). Serum levels of C4M (p=0.002) and C6M (p=0.024) were increased while ELM7 (p=0.024) and VCANM (p<0.0001) were decreased at AE-IIP as compared with S-IIP when analyzing all patients. IPF patients had lower levels of VCANM at AE-IPF (p=0.0001). Patients with paired samples showed significantly elevated serum levels of C4M (p=0.004) and decreased levels of ELM7 and VCANM (p=0.036 and p=0.0001, respectively) at AE-IIP. C1M and C6M levels at AE-IIP were borderline related to mortality outcome for IPF patients (both p=0.059) with levels above median associated with a higher risk of mortality. Analyses of all or paired patients showed no associations with mortality.

Conclusions Serological levels of neo-epitope biomarkers of ECM degradation were associated with AE-IIP and weakly with mortality outcome. These results indicate that the rate of ECM remodeling in the lungs of patients with IIP is significantly altered during periods of high disease activity such as an acute exacerbation. The difference in degradation profile for the proteins studied is intriguing and indicate activation of different processes contributing to AE-IIP.

Neo-epitope biomarkers of the ECM might be useful in identifying patients diagnosed with rheumatic disease as SSc and AS with pulmonary involvement.

Acknowledgements The Danish Research Foundation

Disclosure of Interest None declared

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