Differential Effects of Antifibrotic Treatment on Outcome Prediction via Serial Matrix Metalloproteinase-Degraded C-Reactive Protein Neoepitope Levels in Idiopathic Pulmonary Fibrosis

Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is characterized by an increase in proteolytic enzymes, including matrix metalloproteinases that degrade the extracellular matrix and markers of localized inflammation. Protein fragments (neoepitopes) are detectable in the circulation.

Research question: Can short-term trajectories of neoepitopes after initiation of antifibrotic treatment predict therapy-related outcomes, including mortality, in patients with IPF?

Study design and methods: Two hundred and three treatment-naive patients with IPF from two German tertiary centers were prospectively recruited. At baseline and within 6 months of nintedanib or pirfenidone treatment, serum concentrations of matrix metalloproteinase-degraded C-reactive protein (CRPM), collagen III, and collagen 6 fragments, as well as procollagen 6, were measured. Association of neoepitopes and their longitudinal kinetics (positive/increasing or negative/declining slope) with mortality and progression- and transplant-free survival (PTFS) was analyzed. Modes of action of anti-fibrotic therapy on neoepitope kinetics were further investigated by cell culture experiments.

Results: Patient mean age was 71 years, and 20.7% were female. After baseline measurements, 50% received nintedanib, 35% received pirfenidone, and 15% received no antifibrotic treatment. Patients with a positive CRPM slope, treated with nintedanib, showed increased 5-year mortality (adjusted hazard ratio, 2.27; P = .020). In contrast, PTFS was significantly reduced with positive slopes of all tested neoepitopes. The association between positive CRPM slopes and impaired PTFS was confirmed by means of propensity score matching. In both cohorts, effects on PTFS were driven by the nintedanib-treated subcohort. Intercohort validation of the association between CRPM slopes and PTFS was evident. In cell-culture experiments, nintedanib exclusively modulated CRPM kinetics in human umbilical vein-derived endothelial cells, but not IPF-derived fibroblasts. This suggests that the observed nintedanib/CRPM related effect is partly mediated by endothelial cells.

Interpretation: Our results show that positive/increasing CRPM serum levels (slopes) were associated with worse 5-year survival in patients with IPF treated with nintedanib, but not pirfenidone. Nintedanib, but not pirfenidone, reduced endothelial CRPM formation in vitro.

German clinical trials registration: Nos.: DRKS00000017 and DRKS00000620; URL: https://drks.de/search/en/trial/.

Keywords: antifibrotic; biomarker; collagen; idiopathic pulmonary fibrosis; neoepitopes; progressive pulmonary fibrosis.