VEXAS syndrome

VEXAS syndrome, a rare inflammatory condition, was unknown until 2020, which makes it one of rheumatology's newest diagnoses. Each letter stands for one of the features by which it was first defined: Vacuoles, the bubble-like spaces visible in bone-marrow cells under a microscope; the E1 enzyme, the protein that is affected; X-linked, because the gene is on the X chromosome; Autoinflammatory, describing the type of immune overactivity; and Somatic, describing the kind of genetic change responsible.

The gene involved is UBA1. It makes the E1 enzyme, which cells rely on to break down and recycle their own worn-out proteins. When UBA1 fails in certain blood cells, the immune system stays switched on when it should not be, and inflammation breaks out in many parts of the body at once.

The change is acquired, or somatic, rather than inherited. It arises during life, in the blood-forming stem cells of the bone marrow; it is not carried from birth in every cell of the body, it does not come from a parent, and it cannot be handed on to children. That sets it apart from the inherited genetic conditions the word genetic usually brings to mind, and it is a reassuring point to understand.

Almost everyone with VEXAS is a man, and almost every man affected is past 50, most often from his sixties onwards. The sex bias comes from where the gene lives: UBA1 sits on the X chromosome, of which a man has a single copy and a woman two, so a fault in it is likelier to cause disease in a man. Women are affected only very rarely. A condition tied this closely to older men is unusual in rheumatology, and the pairing is itself one of the pointers towards it.

What identifies VEXAS is a pattern so distinctive that, with all its pieces in view at once, little else could explain it. None of the features belongs to VEXAS alone; testing is prompted by their coming together.

The inflammation can involve:

• Fevers that keep coming back, with no infection to explain them
• Inflamed cartilage in the ears and nose, indistinguishable at times from relapsing polychondritis
• Skin lumps that are tender, and rashes: common, and often the first thing noticed
• Joint pain, and at times an inflamed joint
• Inflamed eyes, lungs or blood vessels, the last of these being a form of vasculitis
• Venous clots, commoner than chance would predict

The blood and bone marrow carry a signature of their own alongside those outward features. Macrocytic anaemia, a low blood count in which the red cells run unusually large, is present in most people with VEXAS. Examination of the bone marrow often shows the characteristic vacuoles inside its developing cells, the feature that gives the condition the V in its name. Myelodysplastic syndrome (MDS), a disorder of the bone marrow in which blood cells are made poorly, is associated with VEXAS as well. As MDS belongs to haematology, the specialty concerned with the blood and the bone marrow, this association is one reason why VEXAS is managed jointly with haematologists.

Taken one by one, the features of VEXAS belong to illnesses rheumatologists see all the time, which is why it is so easily mistaken for one of them. Cartilage inflammation points to relapsing polychondritis; inflamed blood vessels point to vasculitis or giant cell arteritis; aching and stiffness across the shoulders and hips can pass for polymyalgia rheumatica; and recurrent fevers with inflammation can be taken for adult-onset Still's disease. Someone can live under one of those labels, and be treated accordingly, for quite a while before the whole picture is seen.

The thought of VEXAS is usually prompted by a pairing: an older man whose inflammation returns each time the steroid dose comes down, and an anaemia with large red cells that has not been explained. If, on top of that, the inflammatory markers refuse to come down with treatment, VEXAS belongs on the list and the specific test is worth requesting. Because it is rare and was unknown until recently, it is often not thought of.

Confirmation comes from a specific genetic test, run on blood or bone marrow, that looks for the acquired change in UBA1. The NHS genomic testing service offers the test, and the specialist who suspects the condition, a rheumatologist included, can request it, though reliable detection depends on particular laboratory techniques, because the change is sometimes present in only a small proportion of cells.

Long before the gene test, routine blood tests usually reveal the two findings that first prompt suspicion: the macrocytic anaemia and the raised inflammatory markers. The assessment can extend to the bone marrow itself, a sample of which shows whether the characteristic vacuoles are present and whether myelodysplastic syndrome is there alongside. It is the genetic result that clinches the diagnosis, accounts for the whole picture and determines who should share in the care from then on.

VEXAS is serious and can put life at risk, so treatment matters; treating it is far from simple, which is why specialist teams take it on. Steroids reliably calm the inflammation, often a great deal, but they rarely hold the disease on their own, and the doses it takes to keep the disease quiet tend to cause trouble of their own over time.

So treatment usually goes beyond steroids to other medicines, with haematology and specialist rheumatology teams deciding jointly. The medicines that come into consideration include those that block particular inflammatory signals, of which tocilizumab, a biologic, is one, and the JAK inhibitors. These medicines damp down the immune system, so infections become likelier while you take them. If myelodysplastic syndrome is present as well, the plan may also draw on treatments for that bone-marrow disorder, azacitidine among them. For selected, fitter patients there is the option of a bone-marrow (stem-cell) transplant, at present the one treatment that can potentially cure VEXAS, and one with significant risks attached.

Which treatment a given person has, and at what point, is decided individually and with care by the teams looking after them. What this page can usefully convey is the outline: steroids help but are seldom enough by themselves, the more definitive treatments are in specialist hands, and a cure is possible only through a transplant.

Suspicion often begins with a rheumatologist, because the inflammatory pattern, the age and sex of the person and the unexplained anaemia tend to converge in a rheumatology clinic. That first step, the pattern spotted, the specific genetic test requested and the right referral under way, decides how soon the right care starts.

Once VEXAS is confirmed, though, its management moves to specialist centres that work hand in hand with haematology, so the inflammatory side of the condition and the bone-marrow side are treated as one problem rather than two. The UK VEXAS Interest Group (VEXNET) has established a national VEXAS multidisciplinary team, a reflection of how new the condition is, and centres can take their complex cases there for shared expert advice on treatment. Other rare and serious conditions work the same way: whoever first suspects it and the teams who then manage it work in step, each taking the part they are best placed to do.

Dr Borukhson practises within a world-renowned tertiary centre, and the consultants in the specialties VEXAS calls on, haematologists among them, are colleagues she can reach directly. If a picture raises the possibility of VEXAS, she can arrange the first tests and involve the right specialist teams promptly, so that a rare and easily missed diagnosis does not slip through.

VEXAS can produce complications that need action straight away, whether the diagnosis is suspected or already confirmed.

Treat any of these as a 999 or A&E emergency: call 999 and do not drive yourself to A&E.

• A high fever that does not settle, in someone who also feels very unwell; uncontrollable shivering; new confusion or drowsiness; breathing very fast; or feeling dramatically worse over hours: any of these can mean serious infection or uncontrolled inflammation
• With a fever or feeling unwell, a rash that does not fade when you press it, a stiff neck with eyes that cannot bear bright light, or skin, lips or tongue turning blue, grey, pale or blotchy, since these can be signs of meningitis or sepsis, and with a fever or feeling unwell a rash of this kind cannot be assumed to be the rash of VEXAS; on black or brown skin the rash and the change of colour may be easier to see on the palms of the hands or the soles of the feet
• Breathlessness that is severe, with gasping, choking or no breath to get words out; coughing up blood; or chest pain that catches as you breathe in, any of which can signal a clot on the lung; clots in the veins are a recognised feature of VEXAS
• Chest pain that is crushing, tight or like a pressure, that spreads to an arm, the jaw, the neck, the stomach or the back, that comes with breathlessness, sweating, feeling sick or feeling light-headed, or that came on suddenly and does not go away
• Palpitations happening now that do not stop, or that come with chest pain, breathlessness, feeling faint or fainting, since a heart whose muscle or rhythm is affected has to be checked at once
• A blackout, which can mean a clot on the lung
• Sudden weakness or numbness on one side, a drooping face or difficulty speaking, a sudden severe headache, sudden confusion or a seizure, or sudden loss of vision, any of which can be a stroke, even if it stops after a short time, and the clots VEXAS is prone to can form in arteries as well as veins
• An eye that suddenly and completely loses its sight
• Vomiting that will not let your tablets stay down, or, during an illness or after an injury, becoming very drowsy or confused, or fainting, after more than a few weeks on steroid tablets, or repeated courses or injections in the past year, since your body may be running short of cortisol and the steroid may need to be given by injection; have your NHS Steroid Emergency Card ready
• Sudden severe pain in the abdomen or back, since the pancreas can react to prednisolone
• Lips, mouth, throat or tongue that suddenly swell, a throat that feels tight, very fast breathing or a struggle to breathe or to swallow, skin, tongue or lips turning blue, grey or pale (on black or brown skin this may be easier to see on the palms of the hands or the soles of the feet), becoming suddenly very confused, drowsy or dizzy, or fainting and not being able to be woken, since this can be a severe allergic reaction, anaphylaxis, which can follow a dose of any medicine
• Vomiting blood, or bleeding from the back passage that is heavy or will not stop, most of all with faintness, confusion or pain in the abdomen, or vomit that is black or dark brown, since a stomach ulcer on prednisolone can bleed
• Serious harm you have already done to yourself, such as an overdose, or a feeling that you may be about to harm yourself, since you need help to keep you safe now

Any of these needs an assessment that is urgent, on the same day, from your GP, your rheumatology or haematology team, or NHS 111:

• A fever, or feeling generally unwell, on immunosuppressant, biologic or steroid treatment, since an infection has to be treated early
• A joint that is hot and swollen, with a fever or feeling unwell, since an infected joint has to be ruled out at once, at A&E or through NHS 111
• A joint that has become hot and very swollen suddenly, or is worsening quickly, even without a fever, since an infected joint does not always announce itself with one; a joint that will take no weight at all, or that cannot be moved, is a 999 or A&E emergency, whether or not there is a fever
• New chest pain, new palpitations, or breathlessness that is new or getting worse, since either a heart problem or a falling blood count can be behind them; palpitations happening now that do not stop, or that come with chest pain, breathlessness, feeling faint or fainting, belong to the first list
• A persistent dry cough with a fever, with new breathlessness, or that is worsening over hours to days
• A new red, painful eye, or sight that has blurred, dimmed or changed, which needs an eye casualty or urgent eye clinic the same day, as does an eye that light hurts
• A calf that is swollen, hot or painful, or a limb that is painful, swollen or discoloured, which can mean a clot; with breathlessness, chest pain, palpitations or feeling faint, this is a 999 or A&E emergency: call 999 and do not drive yourself to A&E
• Thoughts of ending your life or of hurting yourself, or harm you have done to yourself that is not serious, short of the line in the first list, which steroids can bring on: ask your GP to see you that day or call NHS 111, and Samaritans answer at any hour on 116 123
• A marked change in mood or behaviour, confusion, or seeing or hearing things that are not there, on steroid treatment, since prednisolone can do this, the more so the higher the dose; confusion that is new or comes on suddenly is a 999 or A&E emergency, as the first list says, and so, after more than a few weeks on steroid tablets, or repeated courses or injections in the past year, is becoming very drowsy or confused during an illness or after an injury
• Unusual thirst or hunger, or passing urine more often, on steroids, or swelling of the arms or legs, bruising or bleeding that is not normal, black or dark red stools, severe stomach pain, severe back pain, a severe upset stomach, being sick, or very bad dizziness, since each can be a steroid effect that needs checking without delay; pain in the abdomen or back that comes on suddenly and severely is a 999 or A&E emergency, as the first list says, and so, after more than a few weeks on steroid tablets, or repeated courses or injections in the past year, is vomiting that will not let your tablets stay down, or, during an illness or after an injury, becoming very drowsy or confused, or fainting
• Contact with measles, chickenpox or shingles, since these infections can be severe on steroids and a medicine to protect you may be needed
• Being near someone with measles, chickenpox or shingles, while you take a medicine that weakens the immune system, since measles and chickenpox can be dangerous when the immune system is weakened, and you can catch chickenpox from someone with shingles if you have never had chickenpox; NHS 111 can tell you what to do that day

A persistent dry cough on its own is something to tell your team promptly, without waiting for a routine slot, and so is breathlessness that has drifted slowly, over weeks or months, which in VEXAS can also mean a falling blood count. Arrange a prompt review with your GP or specialist team if the inflammation keeps returning as the steroid dose is reduced, as rashes, tender skin lumps, aching joints, or ear or nose pain, or if, over weeks, you grow more tired and paler, which can reflect a falling blood count. A fever while you are on treatment, or a joint that is hot and swollen, is a same-day matter, as the second list says, unless it comes with the signs the first list gives a fever, which make it a 999 or A&E emergency; a joint that will take no weight at all, or that cannot be moved, is a 999 or A&E emergency, as the second list also says; before treatment has begun, a fever that keeps coming back belongs with the other returning signs, at the same prompt review with your GP or specialist team. Symptoms that are steady, and questions about your medicines, can wait for the planned appointment. If you take a steroid, a biologic or a JAK inhibitor, the warning signs that belong to each are set out in our guides to steroids and biologics and JAK inhibitors. If you cannot tell how urgent something is, asking is never a mistake.

Rare, and only lately named, VEXAS went under other diagnoses before 2020 in the people who had it, and even now it typically takes more than a year to be recognised. A diagnosis gives the inflammation a cause and the blood count that never recovered an explanation, and there are treatments, and teams who know how to use them, for a condition that can be serious. The treatment itself is not delivered in a rheumatology clinic, and confirmed VEXAS is cared for elsewhere, but the clinic is where the suspicion starts, the test is requested and the right centre is found, and that first step counts for a great deal. Where an older man has inflammation that returns again and again, stays quiet only on steroids and comes with an anaemia that has no explanation, VEXAS is worth raising as a possibility.

Where does the name VEXAS come from, and can it run in families?

The name is a string of initials, and each one stands for something seen in the first patients described: Vacuoles, found in the cells of the bone marrow; the E1 enzyme, which is the protein affected; X-linked, since the gene is carried on the X chromosome; Autoinflammatory, for the sort of immune overactivity at work; and Somatic, for the kind of genetic change involved. Somatic means acquired: the change turns up during life, in the bone marrow's blood-forming cells, and was never there from birth in the body's cells at large. Nobody receives it from a parent or gives it to a child, which sets it well apart from the inherited conditions that the word genetic tends to suggest.

Which people does VEXAS syndrome affect?

Men, overwhelmingly, and almost always men past 50; the sixties and seventies are the commonest decades. The reason is the X chromosome, where UBA1 sits: men have a single copy of it, so a change there more readily produces disease. A woman has two X chromosomes, and in women the condition is only very rarely seen. Being so bound up with men and with later life is, in itself, one of the things that set VEXAS apart from other inflammatory conditions.

When does VEXAS come into a doctor's mind?

When a pattern forms, rather than on the strength of one symptom. The classic picture is an older man whose inflammation keeps returning and needs steroids to stay controlled, together with an unexplained low blood count with large red cells (macrocytic anaemia). Other features may cluster around that core: a tendency to clots; inflammation in the eyes, the lungs or the blood vessels; tender lumps or rashes on the skin; cartilage inflamed in the ears or nose; and fevers that recur. Add inflammatory markers that will not come down, and there is a case for the specific genetic test.

What confirms VEXAS, and what is done about it?

A gene test settles it: a blood or bone-marrow sample is checked for the acquired change in UBA1. It is available through the NHS genomic testing service, and a rheumatologist or any other specialist involved can ask for it. Treatment is another matter: it is complex and led by specialists. Steroids quieten the inflammation and are often a great help, but on their own they rarely hold the disease, so haematology and specialist rheumatology teams usually guide further medicines. Only a bone-marrow (stem-cell) transplant holds out the possibility of a cure, and its significant risks mean it is considered solely for selected, fitter patients.

Who looks after VEXAS, and what part does a rheumatologist play?

Often it is a rheumatologist who first thinks of VEXAS, since the inflammation and the blood changes tend to land in the same rheumatology clinic. The rheumatologist's part is to notice the pattern, ask for the right genetic test and start the referral. After confirmation the care passes to specialist centres, with haematology as a partner, so that the inflammatory and the bone-marrow aspects are managed as a single problem. So new is VEXAS that the UK VEXAS Interest Group (VEXNET) has set up a national multidisciplinary team for it, and centres take their complex cases there for shared expert advice.