From diagnostic uncertainty to targeted therapy: a case-based review of VEXAS syndrome

VEXAS syndrome (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) is a recently identified autoinflammatory disorder caused by somatic UBA1 mutations. It presents with intractable systemic inflammation and hematologic abnormalities. Diagnostic delay and limited therapeutic consensus pose challenges in clinical practice.

To illustrate the phenotypic heterogeneity and therapeutic response in two patients with genetically confirmed VEXAS syndrome, and to conduct a targeted narrative review of the literature focused on treatment outcomes.

Two adult male patients presenting with multisystem inflammatory features and cytopenias were diagnosed with VEXAS syndrome via detection of somatic UBA1 mutations on next-generation sequencing. To contextualize these cases, we performed a narrative literature review using PubMed, Scopus, Web of Science and, Directory of Open Access Journals (DOAJ) for studies published up to October 2024. Search terms included "Autoinflammatory Diseases," "Mutation, Somatic," "Ubiquitin-Activating Enzymes," "Glucocorticoids," "Biologic Therapy," and "Stem Cell Transplantation." Only peer-reviewed, English-language studies involving adult human patients with clinically characterized VEXAS syndrome were included. Pediatric cases and reports limited to genomic analysis without clinical correlation were excluded.

Both patients exhibited classic features of VEXAS, including multisystem inflammation and cytopenias. Genetic sequencing confirmed UBA1 mutations. Treatment with corticosteroids combined with biologic agents such as tocilizumab in one patient and canakinumab in the other achieved clinical stabilization while allowing for reduction of corticosteroid doses. Literature review indicates that while glucocorticoids remain first-line therapy, IL-1 and IL-6 inhibitors demonstrate promising steroid-sparing efficacy in selected patients. Data on long-term outcomes and standardization of care remain limited.

These cases reflect the diagnostic and therapeutic complexities of VEXAS syndrome. A high index of suspicion, followed by genetic testing, is essential for timely diagnosis. Biologic therapies targeting IL-1 and IL-6 pathways may offer effective steroid-sparing options in refractory cases. Further prospective studies are needed to define optimal treatment strategies.