Clinical FeaturesRheumatology

VEXAS: a Genotype-First Approach to Novel Disease Discovery

Written by Dr John Stack, Consultant Rheumatologist, Mater Misericordiae University Hospital

Introduction: VEXAS: a Genotype-First Approach to Novel Disease Discovery

VEXAS (Vacuoles, E-1 enzyme, X-linked, Auto-inflammatory, Somatic) is a newly discovered haemato-immune disease that was first described in 2020. It results from an acquired, somatic mutation of the UBA1 gene resulting in impaired ubiquitylation with resultant fever, cytopenia, neutrophilic dermatosis, pulmonary infiltrates, chondritis and vasculitis. It occurs almost exclusively in men with a median age of onset of 64. Presence of vacuoles in myeloid precursor cells is a universal finding on bone marrow aspiration. Severe cases will progress to develop myelodysplastic syndrome (MDS). The disease is associated with a high mortality and treatment pathways have yet to be fully defined.

In this article I will describe a recent case encountered at the Mater Misericordiae University Hospital. I describe how genomics was used to discover VEXAS and how this discovery will have important implications for disease discovery in general. Finally I will outline the various ways in which VEXAS can present and discuss potential treatment options.


A 69 year old male presented to the emergency department with diplopia and a painful, tender and erythematous right ear. He also reported pain and swelling in his right calf and a patchy erythematous rash on his trunk and arms. He had a complex past medical history which included: frequent admissions for investigation of pyrexia of unknown origin, lingular pneumonia, neutrophilic dermatosis, pancytopenia and macrocytic anaemia. He had seen a heamatologist 6 months previously who had performed a bone marrow aspirate- the results were described as reactive. On examination he was febrile. His left eye showed signs of hypertopia and proptosis. Extraocular movements were painful. He had a papular erythematous rash on his trunk and arms.

Investigations revealed elevated ESR, CRP, Ferritin and D-dimer. Longstanding macrocytic anaemia was evident along with neutropenia, lymphopenia and monocytaemia. Ultrasound of right lower limb was positive for superficial vein thrombosis. MRI brain confirmed presence of chondrits of the right ear and showed high signal intensity in the left orbital apex suggestive of an inflammatory process. [Figure 1] Histopathology from punch biopsy of the diffuse papular rash was consistent with a leucocytoclastic vasculitis.

Retrospective review of the bone marrow aspirate performed 6 months prior confirmed vacuolation of the myeloid precursor cells. [Figure 2 on page 72] Genetic testing showed presence of mutation in the UBA1 gene confirming the diagnosis of VEXAS.

The patient was pulsed with IV methylprednisone 500mg x3 over consecutive days with complete resolution of diplopia by day 5. His fever and inflammatory rash also resolved. He was then switched to prednisone 40mg reducing slowly but unfortunately relapsed when the dose was reduced to 20mg daily. He was then started on a Janus Kinase inhibitor, tofacitinib 11mg daily and remains well presently.

VEXAS disease discovery- from genotype to phenotype

Diseases are usually discovered by first identifying individuals with the same phenotypic features. The genetic basis of disease is then determined by identifying loci of genetic variation (e.g. polymorphisms and mutations) within the same group of phenotypically similar patients. The group of researchers who discovered VEXAS inverted this process by using a genotype-first approach. 1 They examined a group of seemingly disparate group of individuals with varying phenotypic features who had consented to participate in the ‘Undiagnosed Diseases Programme’ (patients who had been screened for periodic fever syndromes with no underlying genetic cause found). The exome sequence of 2560 persons was examined. They focussed on 841 genes associated with protein ubiquitylation, an important cell-signalling mechanism which the authors hypothesised if impaired would give rise to auto-inflammation. They identified 3 individuals, all of whom were men in their fifth to seventh decades, who were heterozygous for a mutation affecting the methionine-41 codon (p.Met41) of the X-linked UBA1 gene. The fact that these men were heterozygous for an X-linked gene raised the possibility of sequencing error. Men have only one X-chromosome so how could they possess two copies of a gene which is X-linked? The answer was that this mutation is somatic i.e. acquired in adulthood and expressed in some cell types but not in others.

Using sanger sequencing the authors were able to demonstrate that the UBA1 mutation was only expressed in specific haemopoetic cell lineages – myeloid cells , but not lymphocytes or fibroblasts. The findings were subsequently corroborated in a cohort of 141,600 patients, in which 25 patients with the UBA1 mutation were identified. All of the cases were men with a median age of 64 years. Vacuoles in the myeloid precursor cells were present on bone marrow in 100% of cases. The name VEXAS therefore refers to the genetic basis of this disease and the biological pathway affected by this mutation.

Clinical features of VEXAS

Patients with VEXAS can present with a variety of autoinflammatory and haematological abnormalities. Within the original cohort, the majority (96%) had a history of recurrent fever and macrocytic anaemia (96%). Inflammatory skin disease was also common as was chondritis, venous thromboembolism and lung inflammation. Interestingly 60% of patients had previously been classified as having relapsing polychondritis , 32% with Sweets syndrome, 24% with myelodysplastic syndrome, 20% with multiple myeloma, 12% with polyarteritis nodosa and 4% with giant cell arteritis. More recently described clinical features include: inflammatory eye disease (as in case above), sensorineural hearing loss, myocarditis, colitis, hepatosplenomegaly, lymphadenopathy, arthritis mimicking rheumatoid arthritis and orchitis/epididymitis. 2 The list of clinical features is likely to expand as more patients with VEXAS are identified.

VEXAS- treatment options and prognosis

Patients with VEXAS appear to respond (at least initially) to corticosteroids -albeit requiring very high doses. Biological drugs used in the treatment of other auto-inflammatory disease have been described with varying success in treating VEXAS. A cases series of 19 patients highlighted the potential efficacy of a variety of immunomodulatory drugs in the treatment of VEXAS by comparing time to next treatment. 3 Median time to next treatment was 8 months for Tocilizumab (anti-IL6 receptor), 3.4 months for adalimumab, 3.9 months for corticosteroids, 12.7 months for cyclosporine and 21.9 months for azacytidine. Patients treated with Janus kinase (JAK) inhibitors such as tofacitinib and ruxolitinib remained on treatment at the time of reporting and therefore time to next treatment could not be determined, but it does suggest promising efficacy for JAK inhibitors. Randomised clinical trials have yet to be performed.

VEXAS appears to be associated with a high mortality. 10 out of 25 patients (40%) included in the original NEJM paper died from complications of their disease. A more recent retrospective case series of 116 French patients reported 5 year survival rates according to 3 different clusters. 2 Clusters 1 and 3 were characterised as mild to moderate disease with 5-year survival probability of 84.2% and 89.6% respectively. Patients in cluster 2 were characterised by higher prevalence of chondritis and MDS and a 5-year survival probability of 50.5%. Presence of MDS in particular appears to be a poor prognostic indicator and autologous stem cell transplantation should be considered for such patients.

Future implications

The discovery of VEXAS is an important milestone for rheumatology as it is the first inflammatory disease identified which results from a somatic mutation acquired in adulthood. Whilst somatic mutations are well recognised causes of cancer, the discovery of VEXAS implies that somatic mutations may play a causative role in a much wider range of disease than was previously thought. The genotype to phenotype approach described above highlights the power of modern genomics not just in diagnosing disease but also discovering new diseases and is likely to be replicated in other disease domains. Although formal epidemiological studies have yet to be performed, the estimated disease prevalence of VEXAS is thought to lie between 1 in 20,000 and 1 in 30,000 persons- so not as rare as one might assume. This fact along with its protean manifestations mean that many specialists are likely to encounter VEXAS at some point over the coming years.


In summary VEXAS is a novel haemato-immune disease caused by a somatic mutation in the X-linked UBA1 gene. The diagnosis should be considered in men in their fifth to seventh decades presenting with unexplained systemic inflammation and cytopenias who are found to have vacuoles in the myeloid precursor cells on bone marrow aspirate.

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