Pneumologie 2020; 74(S 01): 104
DOI: 10.1055/s-0039-3403294
Posterbegehung (PO20) – Sektion Klinische Pneumologie
Fortschritte bei Lungenfibrosen 2020
Georg Thieme Verlag KG Stuttgart · New York

Blood biomarkers predicting disease progression in patients with IPF: data from the INMARK trial*

A Prasse
1   Department of Respiratory Medicine, MHH Hannover Medical School
,
TM Maher
2   National Heart and Lung Institute, Imperial College London, UK; National Institute for Health Research Clinical Research Facility, Royal Brompton Hospital, London, UK
,
RG Jenkins
3   National Institute for Health Research Respiratory Biomedical Research Centre, City Campus, Nottingham University Hospital, Nottingham, UK
,
V Cottin
4   Respiratory Diseases Department, National Reference Center for Rare Pulmonary Diseases, Respiratory Diseases Department, Louis Pradel Hospital, Claude Bernard Lyon 1 University, Lyon, France
,
Y Nishioka
5   Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan
,
I Noth
6   Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, Virginia, USA
,
M Selman
7   Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
,
JW Song
8   Department of Pulmonary and Critical Care Medicine, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, South Korea
,
C Ittrich
9   Boehringer Ingelheim Pharma GmbH & Co. Kg, Biberach an der Riss, Germany
,
C Diefenbach
9   Boehringer Ingelheim Pharma GmbH & Co. Kg, Biberach an der Riss, Germany
,
KB Rohr
10   Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
,
S Stowasser
10   Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
,
ES White
11   University of Michigan, Division of Pulmonary and Critical Care Medicine, Ann Arbor, Michigan, USA
› Author Affiliations
Further Information

Publication History

Publication Date:
28 February 2020 (online)

Also available at
 

Introduction: The INMARK trial investigated biomarkers as predictors of disease progression in patients with IPF and preserved lung volume.

Aim: To assess the association between baseline values of biomarkers of extracellular matrix turnover, inflammation and epithelial dysfunction and disease progression in the INMARK trial.

Methods: Subjects with IPF and FVC ≥ 80% predicted were randomised 1 : 2 to receive nintedanib 150 mg bid or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. The association between baseline levels of biomarkers and the proportion of subjects with disease progression (absolute decline in FVC ≥ 10% predicted or death) over 52 weeks was assessed in the placebo group using a logistic regression analysis with the baseline value of the biomarker as a linear covariate.

Results: A total of 230 subjects (mean [SD] baseline FVC 98.0 [12.6] % predicted) received placebo for 12 weeks followed by open-label nintedanib for 40 weeks, of whom 70 (30.4%) had disease progression over 52 weeks. Baseline C-reactive protein degraded by MMP-1/8 (CRPM), collagen 3 degraded by MMP-9 (C3M), C-reactive protein (CRP), Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D) were significantly associated with disease progression over 52 weeks ([Table 1]).

Table 1 Association between baseline levels of biomarkers and the proportion of patients with disease progression (absolute decline in FVC ≥ 10% predicted or death) over 52 weeks in patients randomised to receive placebo for 12 weeks followed by open-label nintedanib for 40 weeks.

Biomarker

Odds ratio (95% CI)

Analyses in subjects who were randomised to placebo and received ≥ 1 dose of study drug. Data were log10 transformed (or negative reciprocal root transformed for C1M) before analysis. Odds ratios relate to the effect of a ten-fold increase in the variable (except C1M). ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; MMP: matrix metalloproteinase. *p < 0.05.

Collagen 1 degraded by MMP-2/9/13 (C1M) (ng/mL)

18.19 (0.09, 5943.18)

Collagen 3 degraded by MMP-9 (C3M) (ng/mL)

10.62 (1.27, 102.51)*

C-reactive protein degraded by MMP-1/8 (CRPM) (ng/mL)

7.6 (1.26, 56.83)*

Intercellular adhesion molecule 1 (ICAM-1) (ng/mL)

4.13 (0.37, 48.42)

Surfactant protein D (SP-D) (ng/mL)

3.36 (1.25, 9.58)*

Krebs von den Lungen-6 (KL-6) (U/mL)

3.27 (1.19, 9.3)*

C-reactive protein (CRP) (mg/L)

1.89 (1.05, 3.46)*

Biglycan degraded by MMP (BGM) (ng/mL)

1.86 (0.67, 5.58)

Collagen 3 degraded by ADAMTS-1/4/8 (C3A) (ng/mL)

1.85 (0.38, 15.64)

Collagen 6 degraded by MMP-2/9 (C6M) (ng/mL)

1.48 (0.47, 4.76)

Lysyl oxidase-like 2 (LXOL2) (ng/mL)

1.41 (0.49, 4.22)

N-terminal propeptide of type III collagen (Pro-C3) (ng/mL)

1.17 (0.19, 7.1)

N-terminal propeptide of type VI collagen (Pro-C6)

0.58 (0.13, 2.48)

Neutrophil-specific elastin fragments (NE-EL) (ng/mL)

0.68 (0.29, 1.58)

Collagen 5 degraded by MMP-2/9 (C5M) (ng/mL)

0.68 (0.17, 2.97)

Citrullinated vimentin degraded by MMP-2/8 (VICM)

0.94 (0.42, 2.05)

Conclusions: Levels of CRPM, C3M, CRP, KL-6 and SP-D may be predictors of disease progression in patients with IPF and limited FVC impairment.

* presented at ERS 2019, ‡ presenting on behalf of the authors