VEXAS syndrome

VEXAS syndrome is a rare genetic condition characterised by the key clinical features for which it is named: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic. It is caused by somatic (acquired) variants in the UBA1 gene, and typically presents in adults with a spectrum of systemic inflammatory manifestations and hematologic symptoms.

VEXAS syndrome may present with a wide range of multisystem clinical manifestations, which can make diagnosis challenging. It typically affects adults, particularly males aged over 50 years. Symptoms may present as relapsing and remitting episodes of inflammation, but the disease can progress with life-threatening complications over time. Clinical features include the below.

Haematological features:

• anaemia;
• thrombocytopaenia;
• characteristic vacuoles present in myeloid and erythroid precursor cells (this is a hallmark feature but not definitive for diagnosis); and
• myelodysplastic syndrome.

Dermatological features:

• vasculitis;
• neutrophilic dermatosis, with some cases presenting with acute febrile episodes (Sweet syndrome); and
• ulcers.

Rheumatological features:

• polychondritis, particularly affecting cartilage around ears and nose; and
• medium- and large-joint arthritis.

Pulmonary features:

• interstitial lung disease; and
• pleural effusions.

Inflammatory features:

• recurrent fevers;
• lymphadenopathy;
• splenomegaly;
• night sweats; and
• scleritis.

VEXAS syndrome is caused by somatic (acquired, non-inherited) pathogenic variants in the UBA1 gene, which codes for ubiquitin-activating E1 enzyme on the X chromosome. The variants occur in hematopoietic stem and progenitor cells.

Patients are typically males, though a small number of female patients have been identified as a result of acquired monosomy, structural rearrangement of the X chromosome or skewed X-inactivation.

Missense variants in codon 41 (methionine) of the E1 enzyme (exon 3) have been identified in almost all patients to date.

Pathogenic variants have a loss-of-function mechanism by reducing the production of the UBA1 isoform most commonly seen in the cytoplasm. This typically reduces overall cellular activity, rather than completely abolishing it.

Genomic testing should be undertaken on blood or haematopoietic cells from bone marrow. Mosaicism may occur – that is, some cells carry the pathogenic variant and others remain unaffected. The proportion of cells affected, also termed the variant allele frequency, correlates with disease severity.

A clinical diagnosis may be suspected in an individual presenting with suggestive features as listed above. Characteristic vacuolation of myeloid and erythroid precursors on bone marrow specimens can be found in almost all patients with VEXAS syndrome.

Definitive VEXAS diagnosis requires detection of a pathogenic variant in the UBA1 gene in peripheral blood- or bone marrow-derived DNA in patients with suggestive clinical features.

• Massively parallel sequencing (sometimes called next-generation sequencing) for UBA1 variants is preferred for its ability to detect low-level mosaicism in peripheral tissues.
• High-depth Sanger sequencing or droplet digital polymerase chain reaction (ddPCR) of exon 3 may be utilised if it is available.
• Variant burden may be reduced with concurrent use of hypomethylating agents such as azacytidine, which may complicate the results of sequencing.

See the recent American College of Rheumatology guidelines for further information about the diagnosis and management of VEXAS syndrome.

For information about testing, see ‘Child with a suspected autoinflammatory condition‘.

VEXAS syndrome may be identified before any symptoms appear; for example, through the Generation Study. Confirmation of the diagnosis will require referral to an autoinflammatory or specialist rheumatology service where available. Please refer to the local pathway for your region for this condition.

• VEXAS syndrome is a very rare acquired condition caused by somatic pathogenic variants in the UBA1 gene in hematopoietic stem and progenitor cells.
• Somatic variants are changes to DNA in body cells that happen after conception. They are not inherited from a parent and may only be transmitted from an affected individual to their offspring if present in the egg or sperm cells (germline mosaicism).
• As UBA1 variants arise in hematopoietic stem and progenitor cells (non-germline), there is no familial transmission of the condition and no increased risk of the condition for future generations.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

VEXAS syndrome is a rare, complex condition and is best managed by a multidisciplinary autoinflammatory and/or specialist rheumatology service. Treatment is aimed at controlling inflammation and preventing life-threatening complications, such as bone marrow failure.

Inflammatory symptoms are often initially treated with corticosteroids, with the dose tapered to the minimal required to control symptoms. If flares continue, targeted modulators of inflammations are preferred as steroid-sparing agents, such as anti-IL-6, anti-IL-1 and JAK-inhibitors. Patients with myelodysplastic syndrome may benefit from azacytidine, which can control both inflammatory and haematological features.

Allogeneic haematopoietic stem cell transplantation (HSCT) is a potentially curative treatment with successful disease remission occurring. However, HSCT carries significant risks, such as graft-versus-host disease, infections and transplant-related mortality.

VEXAS syndrome may be identified before any symptoms appear; for example, through the Generation Study. Management of these individuals may differ from those presenting symptomatically.

For clinicians

• GeneReviews: VEXAS syndrome
• OMIM: 301054 VEXAS syndrome

References:

• Kaul A, Al-Hakim A, Lachmann H and others. ‘VEXAS syndrome and immune-mediated rheumatic diseases: Overlaps in clinical features and mechanisms‘. The Lancet Rheumatology 2025: volume 7, issue 10, pages e719–e733. DOI: 10.1016/S2665-9913(25)00197-3
• Mekinian AM, Georgin-Lavaille S, Ferrada MA, et al. American College of Rheumatology guidance statement for diagnosis and management of VEXAS developed by the international VEXAS working group expert panel. Arthritis & Rheumatology 2025. DOI: 10.1002/art.43287

For patients

• AiArthritis: VEXAS syndrome
• Royal Free London NHS Foundation Trust: Fever syndromes