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- Title
Molecular Endotypes of Idiopathic Pulmonary Fibrosis: A Latent Class Analysis of Two Multicenter Observational Cohorts.
- Authors
Maddali, Manoj V.; Moore, Andrew R.; Sinha, Pratik; Newton, Chad A.; Kim, John S.; Adegunsoye, Ayodeji; Ma, Shwu-Fan; Strek, Mary E.; Chen, Ching-Hsien; Linderholm, Angela L.; Zemans, Rachel L.; Moore, Bethany B.; Wolters, Paul J.; Martinez, Fernando J.; Rogers, Angela J.; Raj, Rishi; Noth, Imre; Oldham, Justin M.
- Abstract
Rationale: Idiopathic pulmonary fibrosis (IPF) causes irreversible fibrosis of the lung parenchyma. Although antifibrotic therapy can slow IPF progression, treatment response is variable. There exists a critical need to develop a precision medicine approach to IPF. Objectives: To identify and validate biologically driven molecular endotypes of IPF. Methods: Latent class analysis (LCA) was independently performed in prospectively recruited discovery (n = 875) and validation (n = 347) cohorts. Twenty-five plasma biomarkers associated with fibrogenesis served as class-defining variables. The association between molecular endotype and 4-year transplant-free survival was tested using multivariable Cox regression adjusted for baseline confounders. Endotype-dependent differential treatment response to future antifibrotic exposure was then assessed in a pooled cohort of patients naive to antifibrotic therapy at the time of biomarker measurement (n = 555). Measurements and Main Results: LCA independently identified two latent classes in both cohorts (P < 0.0001). WFDC2 (WAP four-disulfide core domain protein 2) was the most important determinant of class membership across cohorts. Membership in class 2 was characterized by higher biomarker concentrations and a higher risk of death or transplant (discovery, hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.64–2.48; P < 0.001; validation, HR, 1.95; 95% CI, 1.34–2.82; P < 0.001). In pooled analysis, significant heterogeneity in treatment effect was observed between endotypes (P = 0.030 for interaction), with a favorable antifibrotic response in class 2 (HR, 0.64; 95% CI, 0.45–0.93; P = 0.018) but not in class 1 (HR, 1.19; 95% CI, 0.77–1.84; P = 0.422). Conclusions: In this multicohort study, we identified two novel molecular endotypes of IPF with divergent clinical outcomes and responses to antifibrotic therapy. Pending further validation, these endotypes could enable a precision medicine approach for future IPF clinical trials.
- Subjects
IDIOPATHIC pulmonary fibrosis; TREATMENT effect heterogeneity; PULMONARY fibrosis; INDIVIDUALIZED medicine; PROTEIN domains
- Publication
American Journal of Respiratory & Critical Care Medicine, 2024, Vol 210, Issue 4, p455
- ISSN
1073-449X
- Publication type
Article
- DOI
10.1164/rccm.202402-0339OC