VEXAS syndrome

VEXAS syndrome is a rare inflammatory condition that was first described only in 2020, which makes it one of the most recently recognised diseases in rheumatology. Its name is an acronym for the features that first defined it: Vacuoles (bubble-like spaces seen inside bone-marrow cells under the microscope), the E1 enzyme (the protein affected), X-linked (the gene lies on the X chromosome), Autoinflammatory (the type of immune overactivity involved) and Somatic (the kind of genetic change behind it).

The change happens in a gene called UBA1, which carries the instructions for that E1 enzyme, a protein cells use to recycle and dispose of their own worn-out proteins. When UBA1 stops working properly in certain blood cells, the immune system becomes persistently and inappropriately overactive, driving inflammation in many parts of the body at once.

The genetic change in VEXAS is acquired and somatic. In plain terms, that means it appears during a person's life in the blood-forming stem cells of the bone marrow, rather than being present from birth in every cell of the body. It is not inherited from a parent, and it cannot be passed on to children. This is quite different from the inherited genetic conditions many people picture when they hear the word genetic, and it is an important point to understand and to be reassured about.

VEXAS overwhelmingly affects men, and almost always those over the age of 50, most often around their sixties. The reason lies in where the UBA1 gene sits: on the X chromosome. Men have a single X chromosome, so a change affecting it is more likely to cause disease. Women, who have two X chromosomes, are only very rarely affected. This makes VEXAS an unusual example of a condition tied closely both to being male and to older age, and that combination is itself one of the pointers towards it.

The heart of recognising VEXAS is a distinctive pattern that, once the pieces are seen together, is hard to explain any other way. No single feature is unique to it, but the combination is what prompts testing.

The inflammation of VEXAS can involve:

• Recurrent, unexplained fevers that come and go without an infection being found
• Inflammation of the cartilage of the ears and nose, which can look just like relapsing polychondritis
• Tender skin lumps and rashes, which are common and are often one of the first clues
• Inflammation of the eyes, the lungs and the blood vessels (a form of vasculitis)
• Blood clots in the veins, which occur more often than would otherwise be expected

Alongside these outward features is a distinctive signature in the blood and bone marrow. Most people with VEXAS have a low blood count with unusually large red cells, a pattern called macrocytic anaemia. When the bone marrow is examined, its developing cells often contain the characteristic vacuoles that give the condition the letter V in its name. There is also a recognised link with myelodysplastic syndrome (MDS), a bone-marrow disorder in which blood cells are not made properly. There is no separate guide on MDS on this site, but it is one of the reasons VEXAS is looked after jointly with haematology, the specialty that deals with disorders of the blood and bone marrow.

VEXAS is easily mistaken for other conditions because, taken one at a time, its features belong to illnesses that rheumatologists see regularly. Cartilage inflammation suggests relapsing polychondritis; inflammation of the blood vessels suggests vasculitis or giant cell arteritis; aching and stiffness across the shoulders and hips can look like polymyalgia rheumatica; and recurrent fevers with inflammation can resemble adult-onset Still's disease. Any of these may be diagnosed and treated for a time before the fuller picture emerges.

The clue that most often brings VEXAS to mind is a particular combination: an older man with inflammation that keeps coming back and depends on steroids to stay controlled, together with an unexplained macrocytic anaemia. When those two things sit side by side, and especially when the inflammatory markers stay stubbornly high despite treatment, VEXAS is worth considering and specific testing is worth arranging. Thinking of it at all is often the hardest part, precisely because it is rare and was unknown until recently.

VEXAS is confirmed by a specific genetic test that looks for the acquired change in the UBA1 gene. This is carried out on a sample of blood or bone marrow, and is usually arranged through a specialist centre, because it needs particular laboratory techniques to detect the change reliably, sometimes when it is present in only a small proportion of cells.

Before that point, routine blood tests usually show the macrocytic anaemia and the raised inflammatory markers that first raise suspicion. A bone-marrow sample may be examined as part of the assessment, both to look for the characteristic vacuoles and to check for an associated myelodysplastic syndrome. The diagnosis is then secured by the genetic result, which also explains the whole picture and guides who should be involved in ongoing care.

VEXAS is a serious condition that can be life-threatening, so treatment matters, but it is complex and it belongs with specialist teams. Steroids reliably calm the inflammation and often help a great deal, but the disease is difficult to control with steroids alone, and the doses needed to keep it quiet tend to bring their own problems over time.

Because of this, treatment usually involves additional medicines, and these decisions are led by haematology and specialist rheumatology teams working together. Options that may be considered include medicines that block specific inflammatory signals, such as tocilizumab, and the group of medicines known as JAK inhibitors. Where there is an associated myelodysplastic syndrome, treatments used for that bone-marrow disorder, such as azacitidine, may also form part of the plan. In selected, fitter patients, a bone-marrow (stem-cell) transplant may be considered, and this is currently the only treatment with the potential to cure VEXAS, although it carries significant risks of its own.

The detail of who receives which treatment, and when, is individual and carefully weighed by the teams involved. What matters on this page is the shape of it: steroids help but are rarely enough on their own, the more definitive options are specialist-led, and a transplant is the only potential cure.

A rheumatologist is often the first doctor to suspect VEXAS, because the pattern of inflammation, the older man affected, and the unexplained anaemia tend to come together in a rheumatology clinic. Recognising that pattern, arranging or requesting the specific genetic test, and setting the right referral in motion can be the single most valuable step in the whole journey.

Confirmed VEXAS, though, is managed at specialist centres. In the UK these work as a network sometimes called VEXNET, alongside haematology, so that the inflammatory side of the condition and the bone-marrow side are treated together rather than in isolation. This is the same principle that applies to other rare and serious conditions: the person who first suspects it and the teams who go on to manage it work in a coordinated way, each doing the part they are best placed to do.

Dr Borukhson practises within a world-renowned tertiary centre, with ready access to consultant colleagues across the specialties that VEXAS involves, including haematology. Where a picture raises the possibility of VEXAS, she can arrange the right initial tests and involve the appropriate specialist teams promptly, so that a rare and easily missed diagnosis is not left to drift.

VEXAS is rare, it is recent, and for years the people who had it were told they had something else. Recognising it changes things. It gives a name to inflammation that had seemed to make no sense, it explains why the blood count and the inflammation would not settle, and it opens the door to treatments and to teams equipped to manage a condition that can be serious. A rheumatologist cannot cure VEXAS in the clinic, and confirmed cases are looked after elsewhere, but suspecting it early, arranging the right test, and connecting someone with the right centre is exactly the kind of step that makes a difference. If you are an older man with inflammation that keeps returning, depends on steroids and comes with an unexplained anaemia, it is a possibility worth raising.

What does VEXAS stand for, and is it inherited?

VEXAS is an acronym for the features that first defined the condition: Vacuoles seen in bone-marrow cells, the E1 enzyme that is affected, X-linked because the gene sits on the X chromosome, Autoinflammatory for the type of immune overactivity, and Somatic for the kind of genetic change involved. That change is acquired, meaning it appears during a person's life in the blood-forming cells of the bone marrow rather than being present from birth in every cell. It is not inherited from a parent and cannot be passed on to children, which sets it apart from the inherited conditions many people picture when they hear the word genetic.

Who gets VEXAS syndrome?

VEXAS overwhelmingly affects men, and almost always those over the age of 50, most often around their sixties. This is because the UBA1 gene lies on the X chromosome, of which men have only one copy, so a change affecting it is more likely to cause disease. Women, who have two X chromosomes, are only very rarely affected. This strong link to being male and to older age is one of the features that helps distinguish VEXAS from other inflammatory conditions.

What makes a doctor suspect VEXAS?

The clue is a pattern rather than any single symptom. The one that most often brings VEXAS to mind is an older man with inflammation that keeps returning and depends on steroids to stay controlled, together with an unexplained low blood count with large red cells (macrocytic anaemia). Around that may be recurrent fevers, inflammation of the cartilage of the ears or nose, tender skin lumps or rashes, inflammation of the eyes, lungs or blood vessels, and a tendency to blood clots. When these sit alongside stubbornly raised inflammatory markers, specific genetic testing is worth arranging.

How is VEXAS diagnosed and treated?

The diagnosis is confirmed by a specific genetic test that looks for the acquired change in the UBA1 gene, carried out on a blood or bone-marrow sample and usually arranged through a specialist centre. Treatment is complex and specialist-led. Steroids calm the inflammation and often help a great deal, but the disease is hard to control with steroids alone, so additional medicines guided by haematology and specialist rheumatology teams are usually needed. A bone-marrow (stem-cell) transplant is the only treatment with the potential to cure VEXAS, and it is considered only in selected, fitter patients because it carries significant risks.

Where is VEXAS cared for, and what is the rheumatologist's role?

A rheumatologist is often the first doctor to suspect VEXAS, because its pattern of inflammation and its blood changes come together in a rheumatology clinic. Recognising that pattern, arranging or requesting the right genetic test, and setting the referral in motion can be the most valuable step. Confirmed VEXAS is then managed at specialist centres, which in the UK work as a network sometimes called VEXNET, alongside haematology, so that the inflammatory and the bone-marrow sides of the condition are treated together.