VEXAS Syndrome and Hematoinflammatory Disorders

Résumé fourni par la source

VEXAS syndrome has emerged as a paradigm-shifting hematoinflammatory disorder defined by late-onset systemic inflammation, hematologic abnormalities, and characteristic somatic mutations in the UBA1 gene. This lecture will explore the genetic and immunological foundations of VEXAS, highlighting how UBA1 mutations disrupt ubiquitination pathways, alter protein homeostasis, and drive innate immune activation. These molecular insights provide a unifying framework for understanding the syndrome’s striking clinical heterogeneity and its overlap with both rheumatologic and hematologic disease. The talk will review common clinical features—including fever, chondritis, vasculitis, pulmonary involvement, and cytopenias—and discuss typical patterns of disease evolution, emphasizing how the interplay between inflammatory and clonal hematopoietic processes shapes the clinical course. A concise overview of diagnostic strategies will be provided, including characteristic laboratory findings, bone marrow morphology, and the critical role of molecular testing for UBA1 mutations. Current management approaches will be summarized, ranging from glucocorticoids and immunosuppressive therapies to emerging targeted and disease-modifying strategies, with particular attention to the challenges of treating a disorder rooted in somatic hematopoietic mutation. Finally, the lecture will broaden the lens to consider the wider implications of somatic mutations in wider rheumatological disorders. Building on recent discoveries, we will explore how clonal hematopoiesis and acquired genetic variants may contribute to syndromes that mimic or overlap with VEXAS, offering a conceptual framework for “VEXAS-like” conditions. This expanding field underscores the need to integrate genomic insights into the evaluation of unexplained inflammatory presentations. By situating VEXAS within the continuum of hematoinflammatory disease, the lecture aims to provide clinicians and researchers with an up-to-date understanding of this rapidly evolving area and to highlight future directions for diagnosis, mechanistic research, and therapeutic innovation.

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