VEXAS syndrome, a rare and severe inflammatory condition, has been identified as primarily affecting men over the age of 50. The disease, which stands for vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic, is caused by a specific gene mutation and presents with a range of symptoms that were previously thought to be separate illnesses.
“There is one specific gene mutation that causes VEXAS, but this syndrome doesn’t cause the same symptoms for every patient,” said Jose Pablo Garcia, M.D., rheumatologist at the University of Miami Health System.
Recent research suggests that among individuals showing some symptoms of VEXAS, approximately one in 13,591 people carries the gene mutation. Medical records from the U.S. National Institutes of Health indicate that about one in every 4,269 men older than 50 has been diagnosed with VEXAS.
Symptoms associated with VEXAS include anemia, fever, headaches, joint pain, low blood oxygen levels, night sweats, persistent cough, red eye, shortness of breath, skin rash, swelling and swollen testicles. Dr. Garcia explained: “Usually, the patient’s experience starts with a constellation of odd inflammatory symptoms. It’s not uncommon that we see a VEXAS patient — typically a male older than 50 — with recurrent fevers with no known cause. These patients find it very hard to taper off of the steroids that we’re using to control their inflammatory symptoms (such as fever, rash or joint swelling/joint pain). Patients with VEXAS usually require high doses of prednisone (above 20 mg). This is a unique feature.”
As inflammation progresses in some patients with VEXAS syndrome, there is an increased risk for additional health problems such as arthritis or bone marrow failure. Other complications can include chondritis (swollen cartilage), colitis and deep vein thrombosis. Dr. Garcia noted: “As VEXAS advances, some patients develop chondritis (specifically relapsing polychondritis which is inflammation of the cartilage of the nose outer ear and/or trachea). We now know that relapsing chondritis and stridorous breathing (high-pitched sounds caused by a partially blocked airway) with sore throat are often key indicators of VEXAS.”
VEXAS was officially recognized as an autoimmune disorder in 2020. Dr. Garcia stated: “We have found that it is a somatic mutation that happens randomly in the bone marrow… We know it’s a mutation of the UBA1 gene on the X chromosome.” Because males have only one X chromosome while females have two copies—requiring two simultaneous mutations—the condition rarely affects women.
“Unfortunately we don’t know why these myeloid cells undergo a mutation,” he added. “We don’t know yet if this gene mutation is inherited or if it’s triggered by say environmental or lifestyle conditions. That is still being investigated.”
Diagnosis relies on genetic testing for mutations in the UBA1 gene using either blood or bone marrow samples depending on whether there are signs consistent with myelodysplastic syndrome (MDS), such as macrocytosis—enlarged red blood cells—or other related blood disorders.
“One feature that is unique to VEXAS is its association with a group of blood disorders called myelodysplastic syndrome (MDS), including macrocytosis (enlarged red blood cells),” Dr. Garcia said. If severe macrocytosis without clear cause exists alongside steroid dependence for symptom management patients should be tested for this genetic change.
“For patients with MDS the gold standard for genetic testing is a bone marrow biopsy,” he said. “If we don’t suspect the patient has MDS then we can conduct genetic testing with a blood sample.”
Treatment begins primarily with high-dose steroids due to limited effectiveness from most other immunosuppressant drugs commonly used in rheumatology practice.
“It usually requires a very high dose of steroids to control the symptoms,” Dr. Garcia said.“All of the other immunosuppressants that we usually use in rheumatology haven’t proved to be successful in treating VEXAS unfortunately.”
Some cases report marginal benefits from certain immunosuppressants though none have achieved remission or allowed reduction below high steroid doses thus far.
Other treatments may depend on individual presentations; JAK inhibitors like Ruxolitinib can assist those who also have MDS while biologics targeting IL-6 inhibitors show promise according to ongoing studies.“The other treatments that are being explored are biologics specifically IL-6 inhibitors (which block activity of an inflammation-triggering protein). This class has had some good results,” he noted.
Doctors may try methotrexate—a drug used against cancer and various autoimmune diseases—for patients whose arthritis mimics rheumatoid arthritis but further research continues into optimal therapies for this newly recognized disorder.
“There are also case reports of doctors and their patients with VEXAS trying different treatments to control inflammatory arthritis symptoms and those that mimic rheumatoid arthritis.Patients…may try methotrexate.” Research efforts remain focused on understanding what triggers these mutations improving diagnostic strategies and finding effective anti-inflammatory medications.
