Background: Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix, which can be measured by collagen synthesis neoepitopes. We hypothesized that the trajectory of neoepitopes following antifibrotics predicts outcomes.

Methods: Two cohorts of 203 IPF patients from two university hospitals were recruited. Serum at baseline and following 3-6 months of nintedanib or pirfenidone were measured for MMP degraded type 3 collagen (C3M), -type 6 collagen (C6M), -C-reactive protein (CRPM) and type 3 collagen (pro-C6) via ELISA. Association of neoepitopes with pulmonary function tests and progression-free-survival (PFS) was analyzed.

Results: Age was 71 years and 20.7% were female with a median follow-up of 1.9 years. 50% received nintedanib, 35% pirfenidone and 15% did not receive antifibrotics. In the pooled cohort, patients with increasing CRPM and pro-C6 levels had worse PFS compared with decreasing levels (adj. HR 1.63, p=0.011 and adj. HR 1.7, p=0.012). In both cohorts, these effects were driven by nintedanib, where increasing levels were associated with poor PFS while not by pirfenidone. We then conducted a competing risk regression analysis with FVC or DLCO decline as the outcome and death or transplant as competing events, demonstrating a strong association between increasing CRPM levels and progression with nintedanib treatment (SHR 11.8; p=0.001) but not with pirfenidone (HR 0.32; p=0.057). Increase of CRPM was also inversely correlated with time to progression (R=-0.32; p=0.033) with nintedanib.

Conclusion: In IPF, increase of CRPM was associated with disease progression with nintedanib but not pirfenidone.