A systematic review of blood biomarkers with individual participant data meta-analysis of matrix metalloproteinase-7 in idiopathic pulmonary fibrosis

Abstract

Background: Blood-derived biomarkers have been described extensively as potential prognostic markers in idiopathic pulmonary fibrosis (IPF), but studies have been limited by analyses using data-dependent thresholds, inconsistent adjustment for confounders and an array of end-points, thus often yielding ungeneralisable results. Meta-analysis of individual participant data (IPD) is a powerful tool to overcome these limitations. Through systematic review of blood-derived biomarkers, sufficient studies with measurements of matrix metalloproteinase (MMP)-7 were identified to facilitate standardised analyses of the prognostic potential of this biomarker in IPF.

Methods: Electronic databases were searched on 12 November 2020 to identify prospective studies reporting outcomes in patients with untreated IPF, stratified according to at least one pre-specified biomarker, measured at either baseline, or change over 3 months. IPD were sought for studies investigating MMP-7 as a prognostic factor. The primary outcome was overall mortality according to standardised MMP-7 z-scores, with a secondary outcome of disease progression in 12 months, all adjusted for age, gender, smoking and baseline forced vital capacity.

Results: IPD was available for nine studies out of 12 identified, reporting outcomes from 1664 participants. Baseline MMP-7 levels were associated with increased mortality risk (adjusted hazard ratio 1.23, 95% CI 1.03-1.48; I²=64.3%) and disease progression (adjusted OR 1.27, 95% CI 1.11-1.46; I²=5.9%). In limited studies, 3-month change in MMP-7 was not associated with outcomes.

Conclusion: IPD meta-analysis demonstrated that greater baseline MMP-7 levels were independently associated with an increased risk of poor outcomes in patients with untreated IPF, while short-term changes did not reflect disease progression.

FIGURE 1

Flow diagram illustrating systematic search and screening strategy, including numbers of studies meeting eligibility criteria and numbers excluded. MMP: matrix metalloproteinase; IPD: individual participant data; IIP: idiopathic interstitial pneumonia; IPF: idiopathic pulmonary fibrosis; BAL: bronchoalveolar lavage.

FIGURE 2

Risk of bias assessment for a) matrix metalloproteinase (MMP)-7 studies only; b) all included studies. The risk of bias across studies was rated as low, moderate or high in six categories using the Quality in Prognostic Studies tool.

FIGURE 3

Mortality forest plot. a) Overall mortality; b) mortality at 12 months. Adjusted effect sizes with 95% confidence intervals per standard deviation increase in baseline matrix metalloproteinase-7. aHR: adjusted hazard ratio; aOR: adjusted odds ratio. All estimates were adjusted for age, sex, smoking status and baseline forced vital capacity. Weights are from random-effects model.

FIGURE 4

Summary of study results. Each dot represents a study (or individual cohort in studies with more than one cohort). FVC: forced vital capacity; SP: surfactant protein; KL: Krebs von den Lungen; CA-125: cancer antigen 125; CA19-9: carbohydrate antigen 19-9; LOXL: lysyl oxidase-like; CCL: C-C motif chemokine ligand; CXCL: chemokine ligand; IL: interleukin; YKL40: chitinase-3-like protein 1; ICAM: intracellular adhesion molecule; IGFBP: insulin-like growth factor binding protein.

FIGURE 5

Disease progression forest plot. Pooled adjusted odds ratios (aOR) with 95% confidence intervals for risk of disease progression, per standard deviation increase in baseline matrix metalloproteinase-7. All estimates were adjusted for age, sex, smoking status and baseline forced vital capacity. Weights are from random-effects model.

FIGURE 6

Relative change in percentage predicted forced vital capacity (FVC) forest plot. Pooled effect size with 95% confidence intervals for FVC % pred relative change at 12 months, per standard deviation increase in baseline matrix metalloproteinase-7. All estimates were adjusted for age, sex, smoking status and baseline FVC. Weights are from random-effects model.