Circulating lung biomarkers in idiopathic lung fibrosis and interstitial lung diseases associated with connective tissue diseases: Where do we stand?

•ctd-ild and ipf share common biomarkers suggesting common pathways.•KL-6, SP-D and MMP7 are sensitive but not specific to diagnose lung fibrosis in IPF.•KL-6, SP-D and CCL18 are sensitive but not specific for SSc-ILD diagnosis.•KL-6 is the most sensitive circulating biomarker for diagnosis.•KL-6 and CCL18 can predict lung involvement worsening in IPF and SSc-ILD. Interstitial lung diseases (ILDs) are complex diseases with various courses where personalized medicine is highly expected. Biomarkers are indicators of physiological, pathological processes or of pharmacological response to therapeutic interventions. They can be used for diagnosis, risk-stratification, prediction and monitoring of treatment response. To better delineate the input and pitfalls of biomarkers in ILDs, we performed a systematic review and meta-analysis of literature in MEDLINE and Embase databases from January 1960 to February 2019. We focused on circulating biomarkers as having the highest generalizability. Overall, 70 studies were included in the review and 20 studies could be included in the meta-analysis. This review highlights that ILD associated with connective tissue diseases (CTD-ILD) and idiopathic pulmonary fibrosis (IPF) share common biomarkers, suggesting common pathophysiological pathways. KL-6 and SP-D, could diagnose lung fibrosis in both IPF and CTD-ILD, with KL-6 having the strongest value (OR: 520.95[110.07–2465.58], p