VEXAS syndrome: When inflammation defies treatment and routine tests

First described in 2020, VEXAS syndrome links genetics, inflammation and blood disorders and is forcing doctors to rethink how treatment-resistant inflammation is diagnosed

Unexplained fevers, painful skin rashes, inflamed ears and stubborn anaemia can send patients on a long, frustrating medical journey. For a growing number of older adults, these symptoms are now being traced to VEXAS syndrome, a rare inflammatory disease that originates in the bone marrow and is forcing doctors to rethink how chronic inflammation is diagnosed and treated.

 

First described only in 2020, VEXAS is still widely under-recognised. Yet experts warn that early diagnosis matters, because delayed treatment can lead to serious complications, including bone-marrow failure and life-threatening lung disease.

 

What is VEXAS syndrome?

 

VEXAS is an adult-onset autoimmune disease caused by acquired mutations in the UBA1 gene, which plays a critical role in how cells dispose of damaged proteins. When this system goes wrong, the immune system becomes persistently overactive, triggering widespread inflammation.

 

 

“VEXAS syndrome is a recently identified adult-onset autoinflammatory disease caused by acquired (somatic) mutations in the UBA1 gene, leading to uncontrolled inflammation affecting multiple organ systems,” says Dr Naval Mendiratta, Senior Consultant – Rheumatology, Fortis, Gurgaon.

 

The name itself is an acronym:

 

V – Vacuoles seen in bone-marrow cells

E – E1 enzyme (encoded by UBA1)

X – X-linked

A – Autoinflammatory

S – Somatic (not inherited)

 

The condition commonly affects the blood, skin, joints, cartilage, lungs and immune system, often overlapping with better-known rheumatological and blood disorders.

 

Why is it missed or misdiagnosed?

 

VEXAS is frequently mistaken for other inflammatory and blood disorders because it closely mimics their symptoms.

For instance, vasculitis causes inflamed blood vessels and organ damage, relapsing polychondritis leads to painful inflammation of the ears, nose and airways, Still’s disease triggers high fevers, joint pain and rashes, and myelodysplastic syndromes (MDS) affect the bone marrow and blood counts.

As VEXAS can look like all of these conditions at once, patients are often treated for individual problems rather than the single underlying disease driving them.

 

According to Dr Subodh Kumar, Consultant – Molecular Genomics at Agilus Diagnostics, the problem is also technical. “Routine testing cannot detect VEXAS. The mutations are somatic and confined to bone-marrow or myeloid blood cells. Standard autoimmune panels are negative, and even MDS testing does not include UBA1 unless specifically ordered.”

 

Fragmented care adds to the delay, with patients seeing multiple specialists, each focused on one organ rather than a single unifying diagnosis.

 

Early warning signs doctors should not ignore

 

• Recurrent, unexplained fevers
• Very high inflammatory markers (CRP and ferritin)
• Painful skin rashes
• Inflamed ear or nasal cartilage
• Anaemia, low platelets or low white cells
• Cough and breathlessness
• Blood clots without an obvious cause
• Symptoms that improve with steroids but flare when doses are reduced

 

Who is most at risk?

 

VEXAS predominantly affects men, usually over the age of 50. This is because the UBA1 gene sits on the X chromosome. While extremely rare, it can occur in women if they have certain X-chromosome abnormalities.

 

Experts inform that VEXAS is not inherited. The UBA1 mutation occurs after birth in blood-forming stem cells, meaning there is no family transmission risk, says Dr Mendiratta.

 

How is VEXAS diagnosed?

 

Next-generation sequencing is used to detect somatic UBA1 mutations in bone-marrow samples or blood.

 

Bone-marrow biopsies may reveal tiny empty spaces, called vacuoles, inside developing blood cells. While these findings can raise suspicion of VEXAS, they are not definitive on their own and must be confirmed with genetic testing. “Genetic testing is essential — clinical features alone cannot confirm VEXAS,” Dr Mendiratta stresses.

 

Several studies show that distinctive skin lesions and characteristic microscopic patterns in skin biopsies often appear early in VEXAS, shares Dr Kumar. Recognising these signs can prompt doctors to order genetic testing sooner, allowing dermatologists and pathologists to play a key role in shortening diagnostic delays and enabling earlier, more accurate diagnosis, he explains.

 

Treatment options for VEXAS

 

Most current therapies aim to control inflammation rather than eliminate the disease.

 

• Corticosteroids often work initially, but many patients become steroid-dependent with significant long-term side effects
• Targeted therapies, particularly JAK inhibitors, are emerging as the best options for sustained symptom control They can reduce fevers, inflammation and steroid dependence, but do not remove the underlying mutant clone
• Hypomethylating agents can shrink the abnormal bone-marrow clone and improve blood counts in some patients
• Allogeneic stem-cell transplant (replacement of diseased bone marrow with healthy donor stem cells) remains the only potentially curative treatment. However, it carries a high risk and is suitable only for carefully selected patients

 

Why early diagnosis matters

 

Studies suggest that VEXAS is associated with substantial mortality within a decade of symptom onset, particularly in patients with severe lung disease, thrombosis or progressive bone-marrow failure. This makes early recognition and referral critical, before irreversible organ damage occurs.

 

New research offers hope

 

Awareness of VEXAS is growing rapidly. Expanded genetic testing, international patient registries and clearer testing guidelines are helping shorten diagnostic delays.

Researchers are also mapping the precise inflammatory pathways triggered by the gene mutations in this condition, opening the door to more targeted, disease-modifying treatments.

 

As Dr Kumar puts it, VEXAS is “the first disease where genomics truly determines rheumatology treatment,” a reminder that joining the dots across systems is often key to getting the diagnosis right.   

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This report is for informational purposes only and is not a substitute for professional medical advice.