Molecular endotypes predict differential response to immunosuppressant therapy in non–idiopathic pulmonary fibrosis interstitial lung disease
Year: 2026
Type: article
Study design: Observational Study
Abstract: RATIONALE: Interstitial lung diseases (ILDs) are a clinically and biologically diverse group of disorders characterized by varying inflammation and fibrosis of the lung parenchyma. Immunosuppressant therapy is commonly used to treat non-idiopathic pulmonary fibrosis (non-IPF) ILD, but treatment response is variable and difficult to predict. OBJECTIVE: Identify and validate molecular endotypes of non-IPF ILD. METHODS: Twenty plasma proteins associated with inflammation were used to perform latent class analysis in 2 observational non-IPF ILD cohorts (discovery n = 676; validation n = 585). Proteins were measured using a semi-quantitative Olink Explore 3072 platform. The primary outcome was 3-year transplant-free survival. Weighted Cox regression was used to assess differential response to mycophenolate or azathioprine in each cohort according to molecular endotype classification. RESULTS: A 2-class model best fit both cohorts (P <0.01), with Class 2 comprising ∼30% of patients. Compared to Class 1, Class 2 was associated with significantly lower 3-year transplant-free survival in both discovery (78% vs 36%, P <0.001) and validation (83% vs 46%, P <0.001) cohorts. Significant interaction between molecular endotype and immunosuppressant exposure was observed in both cohorts (discovery Pinteraction = 0.022; validation Pinteraction = 0.019), with survival benefit seen only in Class 2. In pooled analysis, similar trends were observed irrespective of ILD subtype. Pathway analysis supported enrichment of inflammatory signatures in Class 2. CONCLUSION: In this multicenter observational cohort study, we identified and validated 2 distinct molecular endotypes of non-IPF ILD with divergent outcomes and response to immunosuppressant therapy. These endotypes could inform precision medicine strategies and clinical trial design in ILD.
Authors: Manoj V Maddali, Janelle V Pugashetti, Shaun M Pienkos, Andrew R Moore, Samuel B Konkol, John S Kim, Shwu-Fan Ma, Chad A Newton, Christine K Garcia, Ayodeji Adegunsoye, Mary E Strek, Ching-Hsien Chen, Angela L Linderholm, Rachel L Zemans, Bethany B Moore, Paul J Wolters, Rishi Raj, Jonathan H Chen, Fernando J Martinez, Imre Noth, Angela J Rogers, Justin M Oldham
Institutions: Stanford University, University of Michigan, Michigan Medicine, University of Virginia, The University of Texas Southwestern Medical Center, Columbia University, University of Chicago, University of California, Davis, University of California, San Francisco, Stanford Medicine, University of Massachusetts Chan Medical School
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Pulmonary Fibrosis and Telomerase Dysfunction, Improving Pulmonary Fibrosis Classification with Genomics Informed Phenotypic Clusters, Molecular Markers of Idiopathic Pulmonary Fibrosis Progression, Prognostic Biomarker Development in Progressive Fibrosing Interstitial Lung Disease, 1/2 Prospective tReatment EffiCacy in IPF uSlng genOtype for Nac Selection (PRECISIONS) trial and Molecular Endophenotyping in Idiopathic Pulmonary Fibrosis and Interstitial Lung Diseases study, Biomedical Informatics Training Program at Stanford, A Multi-Dimensional Signature to Predict Treatment Failure in Patients with Connective Tissue Disease-Associated Interstitial Lung Disease, Proteomic Profiling of Idiopathic Pulmonary Fibrosis Progression Trajectory, Immune crosstalk in lung injury and fibrosis, Role of polyunsaturated fatty acids in pulmonary fibrosis, Multidisciplinary Training Program in Lung Disease, Lung Remodeling Mediated by Telomere Dysfunction in Alveolar Type II Cells, The Prognostic and Predictive Impact of Telomere Length in Fibrotic Interstitial Lung Disease
OpenAlex ID: W7126369291