Abstract Rationale Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease that leads to respiratory failure and death. Pre-clinical studies have implicated the complement pathway, a key component of innate immunity, in the pathogenesis of IPF. A systematic evaluation of circulating markers of complement activation in patients with IPF may help identify targets for therapeutic intervention. Methods The cohort included 624 participants with IPF enrolled in the US multi-center IPF-PRO Registry. Plasma concentrations of complement proteins at the time of enrollment were evaluated in duplicate using a bead-based multiplex assay. We used the Milliplex Map Human Complement Panel 1 to simultaneously quantify the following analytes: C4b, C5, C5a, mannose-binding lectin (MBL), Factor I, and C9. We used the Milliplex Map Human Complement Panel 2 to simultaneously quantify C3b/iC3b and C3. Cox proportional hazards models were fit to evaluate associations between log2-transformed concentrations of complement proteins and the risk of IPF progression, defined as ≥ 10% decline in FVC % predicted, death, or lung transplant. Models were adjusted for age, sex, body mass index, supplemental oxygen use, FVC % predicted, DLco % predicted, antifibrotic therapy, and oral steroid use at enrollment. The interaction between antifibrotic use at enrollment and each complement protein was evaluated. Results The cohort was predominantly male (74.4%) and white (91.1%), with a median (Q1,Q3) age of 70 (65, 75) years. Median FVC % predicted and DLCO % predicted were 71.4% (60.3, 83.5) and 42.6% (33.0, 51.4), respectively. Over a median follow-up of 37.2 (17.3, 59.1) months, higher circulating levels of C5a were significantly associated with an increased risk of IPF progression (HR 1.12 per 1-unit higher log2-transformed C5a; 95% CI 1.03 - 1.22; p = 0.007, Figure). Higher circulating levels of C9 were associated with an increased risk of progression (HR 1.08 per 1-unit higher log2-transformed C9; 95% CI 1.02 - 1.15; p = 0.006, Figure). The associations remained significant after adjustment for clinical covariates and did not vary by antifibrotic therapy use. Other complement proteins, including C3, C3b/iC3b, C4b, MBL, and Factor I did not have a significant association with progression. Conclusions Elevated plasma levels of C5a and C9 are independently associated with an increased risk of progression in patients with IPF. Our findings support the role of complement activation in progression of IPF and highlight C5a and C9 as potential biomarkers for future investigation. This abstract is funded by: The IPF-PRO/ILD-PRO Registry is supported by Boehringer Ingelheim Pharmaceuticals, Inc and run in collaboration with the Duke Clinical Research Institute and enrolling centers.
Swaminathan et al. (Fri,) studied this question.