Molecular endotypes predict differential response to immunosuppressant therapy in non–idiopathic pulmonary fibrosis interstitial lung disease

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