Identification of a conserved sequence of disease progression in idiopathic pulmonary fibrosis

Abstract Rationale Idiopathic pulmonary fibrosis (IPF) begins years before symptoms appear, but the natural history is incompletely understood. Objectives To describe and quantify IPF disease progression using 4 pulmonary function test (PFT) parameters. Methods Two cohorts included 245 adults with subclinical through advanced familial pulmonary fibrosis (FPF) or 347 placebo-treated IPF patients enrolled in 2 randomized controlled trials (RCTs). A Bayesian joint repeated measures model was fit to describe the observed PFT values as a function of the estimated years since onset (EYO). A latent variable estimated the subject-level chronological age at onset. Onset was assumed to occur when the diffusion capacity for carbon monoxide (DLCO) was 70%-predicted. The relationships between EYO and clinical outcomes not included in the model (eg, transplant-free survival) were evaluated, adjusting for age and sex. Measurements and Main Results In FPF, the DLCO declined steadily starting around EYO -10, reaching 86.8%-predicted by EYO -5 and 45.3%-predicted by EYO +5. The forced vital capacity (FVC) declined later, reaching 98.6%-predicted by EYO -5 and 76.2%-predicted by EYO +5. The annualized decline in FVC was 12-fold greater in the year after EYO +5 (6.14%-predicted) than EYO -5 (0.49%-predicted). There was a 31% higher risk of death or transplant (HR, 1.31 [95% CI, 1.25-1.37]) per 1-year increase in EYO. Similar findings were observed in the RCTs. Conclusions We identified a conserved sequential decline in lung function in IPF, which has important implications for the design of clinical trials. The disease progression model provides a powerful framework to investigate the clinical and/or biological processes that initiate and propagate IPF.