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

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; I(2)=64.3%) and disease progression (adjusted OR 1.27, 95% CI 1.11–1.46; I(2)=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.