Identification of a conserved sequence of disease progression in Idiopathic Pulmonary Fibrosis

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 four 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 two 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 (e.g., transplant-free survival) were evaluated, adjusting for age and sex. RESULTS: In FPF, the DLCO declined steadily starting around EYO -10, reaching 86.8%-predicted by EYO -5 and 45.3%-predicted by + 5. The forced vital capacity (FVC) declined later, reaching 98.6%-predicted by EYO -5 and 76.2%-predicted by + 5. The annualized decline in FVC was 12-fold greater in the year after EYO + 5 (6.14%-predicted) than -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 DPM provides a powerful framework to investigate the clinical and/or biological processes that initiate and propagate IPF.