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. 2025 Jun;30(6):504-514.
doi: 10.1111/resp.14894. Epub 2025 Feb 7.

Pre-Treatment MMP7 Predicts Progressive Idiopathic Pulmonary Fibrosis in Antifibrotic Treated Patients

Roger M Li  1   2   3 , Dino B A Tan  1   2   3 , Chantalia Tedja  1   2 , Wendy A Cooper  4   5   6 , Helen E Jo  3   4   5 , Christopher Grainge  3   7   8 , Ian N Glaspole  3   9   10 , Nicole Goh  3   9   11 , Samantha Ellis  9 , Peter M A Hopkins  12   13 , Christopher Zappala  12 , Gregory J Keir  12 , Paul N Reynolds  3   14   15 , Sally Chapman  15 , E Haydn Walters  16   17 , Darryl Knight  18 , Svetlana Baltic  2 , HuiJun Chih  19 , Tamera J Corte  3   4   5 , Yuben P Moodley  1   2   3   20
Affiliations

Pre-Treatment MMP7 Predicts Progressive Idiopathic Pulmonary Fibrosis in Antifibrotic Treated Patients

Roger M Li et al. Respirology. 2025 Jun.

Abstract

Background and objective: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with a poor prognosis. Antifibrotics slow the decline of pulmonary function after 12-months, but limited studies have examined the role of circulatory biomarkers in antifibrotic treated IPF patients.

Methods: Serum from 98 IPF participants, from the Australian Idiopathic Pulmonary Fibrosis Registry were collected at four time-points over 1 year post-antifibrotic treatment and analysed as two separate cohorts. Patients were stratified as progressive, if they experienced ≥ 10% decline in FVC or ≥ 15% decline in DLCO or were deceased within 1 year of treatment initiation: or otherwise as stable. Ten molecules of interest were measured by ELISAs in patient serum.

Results: Baseline MMP7 levels were higher in progressive than stable patients in Cohort 1 (p = 0.02) and Cohort 2 (p = 0.0002). Baseline MMP7 levels also best differentiated progressive from stable patients (Cohort 1, AUC = 0.74, p = 0.02; Cohort 2, AUC = 0.81, p = 0.0003). Regression analysis of the combined cohort showed that elevated MMP7 levels predicted 12-month progression (OR = 1.530, p = 0.010) and increased risk of overall mortality (HR = 1.268, p = 0.002). LASSO regression identified a multi-biomarker panel (MMP7, ICAM-1, CHI3L1, CA125) that differentiated progression more accurately than MMP7 alone. Furthermore, GAP combined with MMP7, ICAM-1, CCL18 and SP-D was more predictive of 3-year mortality than GAP alone.

Conclusion: MMP7 along with a multi-biomarker and GAP panel can predict IPF progression and mortality, with the potential for optimising management.

Keywords: biomarker; disease progression; idiopathic pulmonary fibrosis.

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Conflict of interest statement

During the peer review process, Paul N. Reynolds is Co‐Editor‐in‐Chief of the journal and co‐author of this article. He was excluded from the peer‐review process and all editorial decisions related to the acceptance and publication of this article. Peer‐review was handled independently by past Co‐Editor in Chief Philip G. Bardin and present Co‐Editor in Chief Toshiaki Kikuchi to minimise bias. In addition, Christopher Grainge, Darryl Knight, Tamera J Corte and Yuben P Moodley and were Editorial Board members of Respirology and co‐authors of this article. They were excluded from all editorial decision‐making related to the acceptance of this article for publication.

R. M. Li, D. B. A. Tan, C. Tedja, W. A. Cooper, S. Ellis, P. M. A. Hopkins, C. Zappala, G. J. Keir, P. N. Reynolds, E.H. Walters, H. J. Chih, D. Knight and S. Baltic has nothing to disclose. Y. P. Moodley, C. Grainge, I. N. Glaspole and S. Chapman reports personal fees for advisory board work from Boehringer Ingelheim and Roche, outside the submitted work. H. E. Jo reports other (travel support and lecture fees) from Boehringer Ingelheim and Roche, outside the submitted work. N. S. Goh reports grants from the National Health Medical Research Council (NHMRC) (APP1066128, APP114776) and the Centre of Research Excellence in Pulmonary Fibrosis (CRE‐PF), Australia (NHMRC GNT116371; 2017–2021), during the conduct of the study. T. J. Corte reports grants, personal fees and nonfinancial support from Boehringer Ingelheim, grants and personal fees from Roche, grants from Galapagos, Actelion and Bayer, outside the submitted work.

Figures

FIGURE 1
FIGURE 1
Progressive IPF patients is characterised by elevated levels of MMP7. Serum MMP7 levels in progressive (red) and stable (blue) at 0, 3, 6 and 12 months post‐antifibrotic treatment in the (a) Cohort 1, (b) Cohort 2 and (c) Combined cohort. Baseline AUC analysis of MMP7 for progression in the (d) Cohort 1, (e) Cohort 2 and (f) Combined cohort. Box represents interquartile range with median and whiskers represent range. *p < 0.05, **p < 0.01, ***p < 0.001, ****p < 0.0001.
FIGURE 2
FIGURE 2
IPF stables showed decrease in CA125 and POSTN levels 3 months post‐antifibrotic treatment. Serum CA125 and POSTN levels in progressive (red) and stable (blue) at 0, 3, 6 and 12 months post‐antifibrotic treatment in the (a and d) Cohort 1, (b and e) Cohort 2 and (c and f) Combined cohort. Box represents interquartile range with median and whiskers represent range. *p < 0.05, **p < 0.01, ***p < 0.001.
FIGURE 3
FIGURE 3
AUC analysis of GAP score in addition to biomarkers selected by least absolute shrinkage and selection operator (LASSO) regression models of progression and 3‐year mortality. The sensitivity and specificity were assessed via AUC of ROC analysis by comparing the predicted progression/mortality vs. actual progression/mortality using (a, b) GAP score only, (c, d) biomarkers only or (e, f) combined GAP and biomarkers. LASSO was applied to (c, d) biomarkers only and (e, f) combined GAP and biomarkers. (e) LASSO for combined GAP and biomarkers for progression did not include GAP as a predictor. Imputation was performed using classification and regression trees. **p < 0.01, ****p < 0.0001.
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