Azacitidine in VEXAS: Up-Front Multidisciplinary Treatment or a Last Resort?

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently characterised adult-onset autoinflammatory disorder driven by acquired mutations in UBA1. We present the diagnostic and therapeutic journey of a 64-year-old man whose multisystem disease illustrates the complexity—and promise—of managing VEXAS through a multidisciplinary lens. Initially labelled as post-viral fatigue, the patient developed escalating systemic features in late 2023, including rash, migratory polyarthritis, lymphadenopathy, non-specific intestinal inflammation, pulmonary infiltrates, thrombocytopoenia, and transfusion-dependent macrocytic anaemia. Skin and bone histopathology revealed small-vessel vasculitis and hyperplastic marrow, respectively. A peripheral blood UBA1 pathogenic variant c.122T>C p.(Met41Thr) was detected (variant allele frequency—also known as VAF—74%) in December 2023, securing the diagnosis. Corticosteroids induced partial remission but could not be weaned without flare. In September 2024, azacitidine was initiated as a disease-modifying agent. Over nine cycles, inflammatory markers normalised, haemoglobin improved from 83 g/L to 144 g/L, and UBA1 VAF fell to 46%. Corticosteroid tapering was achieved down to prednisolone 2.5 mg daily without clinical relapse. Multidisciplinary coordination between haematology, immunology, and rheumatology was pivotal. Input was required to coordinate azatadine infusions, interpret a co-existent DNMT3A pathogenic variant detected on marrow next-generation sequencing (VAF 44%), monitor clinical and molecular remission, and navigate complications, including atrial fibrillation and HSV-1 reactivation. The patient continues on azacitidine with plans for repeat molecular assessment at cycle 12. Conclusion This case highlights the diagnostic delay, heterogeneous presentation, and steroid dependency characteristic of VEXAS. It supports the emerging role of azacitidine as an early disease-modifying therapy capable of inducing measurable clinical and molecular responses. The patient’s trajectory reinforces the value of cross-specialty collaboration and contributes to the growing real-world evidence base for azacitidine in the management of VEXAS syndrome.