Circulating CTHRC1 Levels are Associated with IPF Disease Severity and Survival

Objective

Idiopathic pulmonary fibrosis (IPF) is a disease of high morbidity and mortality. We previously identified a novel subset of pathologic fibroblasts, characterized by CTHRC1 expression, uniquely present in fibrotic lung diseases. The aim of this study was to determine the association of serum CTHRC1 with clinical outcomes in IPF to assess its potential as a biologically relevant biomarker.

Methods

A retrospective longitudinal cohort study was performed utilizing two cohorts including a discovery cohort of 352 IPF patients from University of California San Francisco (UCSF) and a validation cohort of 1,152 IPF patients from the Pulmonary Fibrosis Foundation (PFF) as well as 41 healthy controls. Serum CTHRC1 was measured by ELISA and patients were stratified by quartiles of CTHRC1 for analysis. For a subset of patients, serial serum and lung CTHRC1 expression were measured. Associations between CTHRC1 and clinical outcomes, including baseline lung function, lung function trajectory, and transplant-free survival were assessed.

Results

Serum CTHRC1 was elevated in IPF patients compared to healthy controls (UCSF 31661 + 11651 and PFF 33916 + 14547 vs. 24409 + 8630pg/ml, p<0.001). Elevated circulating CTRHC1 was associated with lower FVC% and DLCO% at baseline and a greater decline in FVC over one year. In both cohorts, higher CTHRC1 level was associated with worse transplant-free survival (p<0.03).

Conclusion

Circulating CTHRC1 levels are elevated in patients with IPF and associated with disease severity and overall survival. These findings further support the biological significance of CTHRC1 in IPF as a pathologic marker and potential biomarker reflecting the burden of pathologic fibroblasts in IPF.

Key Messages

What is already known on this topic:

IPF is a progressive fibrotic lung disease driven in part by activation and expansion of pathologic fibroblasts.

CTHRC1+ fibroblasts have been identified in fibrotic lung tissue of IPF and are implicated in fibrogenesis.

While CTHRC1+ expression in lung tissue has been established, its role as a potential circulating biomarker has yet to be studied.

What this study adds:

This study demonstrates serum CTHRC1 levels are significantly elevated in patients with IPF compared to healthy controls.

Elevated serum CTHRC1 levels are associated with decreased baseline lung function, greater disease progression, and reduced 5-year transplant-free survival.

How this study might affect research, practice or policy:

These findings support CTHRC1 as a biologically relevant biomarker for prognostication in IPF.