Changes in serum metabolomics in idiopathic pulmonary fibrosis and effect of approved antifibrotic medication

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with significant mortality and morbidity. Approval of antifibrotic therapy has ameliorated disease progression, but therapy response is heterogeneous and to date, adequate biomarkers predicting therapy response are lacking. In recent years metabolomic technology has improved and is broadly applied in cancer research thus enabling its use in other fields. Recently both aberrant metabolic and lipidomic pathways have been described to influence profibrotic responses. We thus aimed to characterize the metabolomic and lipidomic changes between IPF and healthy volunteers (HV) and analyze metabolomic changes following treatment with nintedanib and pirfenidone. We collected serial serum samples from two IPF cohorts from Germany (n = 122) and Spain (n = 21) and additionally age-matched healthy volunteers (n = 16). Metabolomic analysis of 630 metabolites covering 14 small molecule and 12 different lipid classes was carried out using flow injection analysis tandem mass spectrometry for lipids and liquid chromatography tandem mass spectrometry for small molecules. Levels were correlated with survival and disease severity. We identified 109 deregulated analytes in IPF compared to HV in cohort 1 and 112 deregulated analytes in cohort 2. Metabolites which were up-regulated in both cohorts were mainly triglycerides while the main class of down-regulated metabolites were phosphatidylcholines. Only a minority of de-regulated analytes were small molecules. Triglyceride subclasses were inversely correlated with baseline disease severity (GAP-score) and a clinical compound endpoint of lung function decline or death. No changes in the metabolic profiles were observed following treatment with pirfenidone. Nintedanib treatment induced up-regulation of triglycerides and phosphatidylcholines. Patients in whom an increase in these metabolites was observed showed a trend towards better survival using the 2-years composite endpoint (HR 2.46, p = 0.06). In conclusion, we report major changes in metabolites in two independent cohorts testing a large number of patients. Specific lipidic metabolite signatures may serve as biomarkers for disease progression or favorable treatment response to nintedanib.