Vexas syndrome: what dermatologists should know

Prof Cédric Lenormand, one of the presenters during the first plenary session of EADV, discussed VEXAS syndrome with Prof Jan Gutermuth, highlighting key insights for dermatologists. Vexas syndrome is a recently described autoinflammatory disorder first identified in 2020 by colleagues at the National Institutes of Health (NIH, USA). It results from a somatic mutation in the UBA1 gene located on the X chromosome, specifically in myeloid progenitor cells. As a consequence, the disease affects almost exclusively men over 50 years of age, with the exception of women with Turner syndrome. Epidemiological studies suggest that approximately one in 4,000 men above this age harbours the mutation, indicating that the syndrome is not exceedingly rare.

The disorder is systemic and can manifest with inflammatory involvement of nearly all organs. Cutaneous symptoms are particularly prevalent, affecting around 80% of patients. The most characteristic dermatological presentation is a neutrophilic dermatosis, which may appear as papules, plaques, or arcuate lesions with central scaling and residual bluish discoloration. Relapsing polychondritis, with inflammation of auricular or nasal cartilage, is another frequent clinical feature. Other organ involvement includes arthritis, ocular inflammation (e.g., uveitis), and pulmonary disease. Haematologic findings are often present, particularly macrocytic anaemia, which serves as a useful diagnostic clue.

Diagnosis is established by genetic testing for UBA1 mutations in peripheral blood, which is available in most university or tertiary referral hospitals. Routine laboratory work-up should include complete blood counts and evaluation of cytopenias, given the frequent association with myelodysplastic syndromes.

Therapeutic options remain limited. Corticosteroids are effective but require sustained high doses, rendering them unsuitable for long-term management. Conventional disease-modifying agents, such as methotrexate or azathioprine, are ineffective and poorly tolerated. Targeted therapies, including IL-6 inhibitors (e.g., tocilizumab) and JAK inhibitors, provide clinical benefit in only a minority of cases (approximately 30%). The most promising therapeutic approach to date is azacitidine, a hypomethylating agent used in myelodysplastic syndromes. Clinical studies report response rates of up to 60%, with durable remissions in the majority of responders, making it the current best treatment option.

In summary, VEXAS syndrome represents a paradigm of rapidly advancing medical knowledge, with over 500 scientific publications since its first description. Dermatologists and clinicians should consider the diagnosis in men over 50 years presenting with unexplained systemic inflammation, skin lesions, and macrocytic anaemia. Increased awareness is essential, as early recognition and haematology referral can significantly improve patient outcomes.