TY - JOUR
T1 - Molecular Endotypes of Idiopathic Pulmonary Fibrosis A Latent Class Analysis of Two Multicenter Observational Cohorts
AU - Maddali, Manoj V.
AU - Moore, Andrew R.
AU - Sinha, Pratik
AU - Newton, Chad A.
AU - Kim, John S.
AU - Adegunsoye, Ayodeji
AU - Ma, Shwu Fan
AU - Strek, Mary E.
AU - Chen, Ching Hsien
AU - Linderholm, Angela L.
AU - Zemans, Rachel L.
AU - Moore, Bethany B.
AU - Wolters, Paul J.
AU - Martinez, Fernando J.
AU - Rogers, Angela J.
AU - Raj, Rishi
AU - Noth, Imre
AU - Oldham, Justin M.
N1 - Publisher Copyright:
© 2024 by the American Thoracic Society.
PY - 2024/8/15
Y1 - 2024/8/15
N2 - 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.
AB - 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.
KW - antifibrotic
KW - endotype
KW - idiopathic pulmonary fibrosis
KW - latent class analysis
UR - http://www.scopus.com/inward/record.url?scp=85201436473&partnerID=8YFLogxK
U2 - 10.1164/rccm.202402-0339OC
DO - 10.1164/rccm.202402-0339OC
M3 - Article
C2 - 38913573
AN - SCOPUS:85201436473
SN - 1073-449X
VL - 210
SP - 455
EP - 464
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 4
ER -