Ruxolitinib prevents irreversible autoimmune endocrinopathies in APECED

Abstract

Abstract Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED/APS-1) is a monogenic disorder of failed central tolerance. Interferon-γ-driven inflammation in APECED underlies multiorgan autoimmunity and chronic mucocutaneous candidiasis and is targetable with JAK1/2 inhibition. Whether early cytokine blockade can avert irreversible endocrine failure is currently unknown. Here, we describe two individuals with APECED who developed evolving autoimmune hypoparathyroidism and hypergonadotropic hypogonadism. Treatment with the JAK1/2 inhibitor ruxolitinib halted progression and reversed biochemical and clinical abnormalities, preserving parathyroid and gonadal function. These findings provide clinical evidence that timely JAK-STAT pathway inhibition can intercept evolving endocrine autoimmunity in APECED. More broadly, they advance a disease-interception paradigm in which early, pathway-directed cytokine blockade may alter the natural history of autoimmune endocrinopathies.