Differential effects of antifibrotic treatment on outcome prediction via serial CRPM levels in IPF.
Abstract
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is characterized by an increase in proteolytic enzymes, including matrix metalloproteinases (MMPs) that degrade the extracellular matrix (ECM) and markers of localized inflammation. Protein fragments (neoepitopes) are detectable in the circulation.
RESEARCH QUESTION
Can short-term trajectories of neoepitopes following initiation of antifibrotic treatment predict therapy-related outcomes including mortality in IPF patients?
STUDY DESIGN AND METHODS
203 treatment-naïve IPF patients from two German tertiary centres were prospectively recruited. At baseline and within 6 months of nintedanib or pirfenidone treatment, serum concentrations of MMP degraded C-reactive protein (CRPM), collagen III (C3M) and collagen 6 (C6M) fragments, as well as procollagen 6 (PRO-C6) 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 analysed. 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% pirfenidone and 15% no antifibrotic treatment. Patients with a positive CRPM slope treated with nintedanib showed increased 5-year mortality (adj.HR 2.27, P=0.020). 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 sub-cohort. Inter-cohort validation of the association between CRPM slopes and PTFS was evident. In cell-culture experiments, nintedanib exclusively modulated CRPM kinetics in human umbilical cord derived endothelial cells, but not IPF-derived fibroblasts. This suggests the observed nintedanib/CRPM related effect is partly mediated by endothelial cells.
INTERPRETATION
Positive/increasing CRPM serum levels (slopes) were associated with worse 5-year survival in IPF patients treated with nintedanib, but not pirfenidone. Nintedanib, but not pirfenidone reduced endothelial CRPM formation in-vitro.
