Sometimes medicine follows predictable patterns. Other times it doesn’t.
Recently I saw a patient whose symptoms did not neatly fit into any familiar diagnosis. He had been unwell for several years, seeing multiple specialists, undergoing many tests, and receiving different treatments — yet no single explanation tied everything together.
This is often how patients with rare autoinflammatory conditions present. One condition that increasingly comes to mind in such cases is VEXAS syndrome, a recently discovered disease that has changed how we think about some unexplained inflammatory disorders.
A Patient With an Unusual Combination of Symptoms
The patient was a man in his early sixties. Over the previous few years he had developed a puzzling constellation of problems.
He experienced:
- recurrent fevers
- severe fatigue
- painful skin lesions
- episodes of joint inflammation
- worsening anaemia
Blood tests repeatedly showed high inflammatory markers and macrocytic anaemia, yet tests for common autoimmune diseases were negative.
At one point he was treated for a presumed autoimmune condition. Steroids helped temporarily, but symptoms returned whenever the dose was reduced.
This pattern — steroid-responsive but treatment-resistant inflammation — is something doctors have started to recognise in patients later diagnosed with VEXAS syndrome.
What Is VEXAS Syndrome?
VEXAS syndrome is a recently described inflammatory condition first identified in 2020.
The name is an acronym that reflects its biological features:
- V — Vacuoles in bone marrow cells
- E — E1 enzyme abnormality
- X — X-linked genetic mutation
- A — Autoinflammatory disease
- S — Somatic mutation
The condition is caused by an acquired mutation in the UBA1 gene, which plays an important role in regulating inflammation within cells.
Unlike inherited diseases, this mutation is acquired during life, usually within bone marrow stem cells. Because of this, VEXAS is classified as a somatic mutation disorder.
The result is abnormal immune activation and widespread inflammation.
Who Gets VEXAS Syndrome?
Most reported patients share similar characteristics.
VEXAS syndrome almost exclusively affects men, typically appearing in later adulthood.
Reported cases generally occur in people:
- aged 45–80 years
- most commonly in their 50s or 60s
This male predominance occurs because the mutation involves a gene located on the X chromosome.
Very rarely, women can develop VEXAS syndrome if they have unusual chromosomal circumstances such as having only one X chromosome.
What Are the Symptoms?
One of the reasons VEXAS syndrome is difficult to recognise is that the symptoms can affect many different organs.
Patients often develop a mixture of inflammatory and blood-related abnormalities.
Common inflammatory symptoms
Many patients experience:
- recurrent fevers
- fatigue
- inflammatory arthritis
- painful skin rashes
Skin manifestations are particularly common and may resemble other inflammatory skin conditions such as Sweet syndrome.
Some patients also develop relapsing polychondritis, an inflammatory condition affecting the ears and nose.
Blood abnormalities
VEXAS syndrome often involves the bone marrow and blood cells.
Typical findings include:
- macrocytic anaemia (large red blood cells)
- low platelet counts
- abnormal bone marrow findings
Some patients may also develop associated blood disorders such as:
- Myelodysplastic syndrome
- Multiple myeloma
- Monoclonal gammopathy of undetermined significance
Why Is VEXAS Syndrome Important?
Although rare, VEXAS syndrome can be serious.
Possible complications include:
- progressive anaemia
- lung inflammation
- blood clots
- multi-organ inflammation
Some patients develop severe complications such as respiratory failure or thrombotic events including Stroke.
Because the condition was only discovered recently, many patients had symptoms for several years before diagnosis.
How Is VEXAS Syndrome Diagnosed?
Diagnosis usually requires a combination of clinical suspicion and specialised testing.
Doctors may investigate patients who have unexplained inflammatory symptoms together with abnormal blood counts.
Typical investigations include:
Blood tests
These often show:
- high inflammatory markers
- macrocytic anaemia
- low platelet counts
Bone marrow examination
A bone marrow biopsy may reveal characteristic vacuoles within blood cell precursors, although this finding is not specific.
Genetic testing
The diagnosis is confirmed by identifying a mutation in the UBA1 gene, usually through targeted genetic sequencing of blood or bone marrow cells.
Treatment Options
Treating VEXAS syndrome can be challenging.
Many conventional treatments for autoimmune disease have limited effectiveness.
High-dose corticosteroids often provide temporary improvement in inflammatory symptoms, but long-term use carries significant side effects.
Other therapies that have been explored include:
- immunosuppressive medications
- biologic drugs targeting inflammatory pathways
- treatments directed at associated blood disorders
Research is ongoing to determine the most effective therapies.
What Is the Prognosis?
VEXAS syndrome is typically a chronic and progressive condition.
Studies have reported significant mortality, largely related to complications of inflammation or associated blood disorders.
However, because the disease was only identified recently, doctors are still learning about its long-term course and optimal treatment.
Early recognition is becoming increasingly important.
Why Awareness Matters
Conditions like VEXAS syndrome highlight how rapidly medicine continues to evolve.
Just a few years ago, many patients with this pattern of symptoms would have been diagnosed with undefined autoimmune disease.
Today, advances in genetic testing are revealing previously hidden causes of illness.
For patients with unexplained inflammation, abnormal blood counts, and symptoms that do not fit typical diagnoses, VEXAS syndrome is increasingly being considered.
And sometimes, identifying the right diagnosis can make all the difference.