Why Is VEXAS Syndrome Often Fatal? Here’s an Answer

The still-mysterious immunologic syndrome known as VEXAS seems to include heightened risk of infection, said researchers who warned that their findings suggest that the condition may include immunodeficiency.

Among 124 VEXAS patients included in a French national registry, 74 had experienced serious infections — with 133 episodes in all, according to Jerome Hadjadj, MD, PhD, of Saint-Antoine Hospital in Paris, and colleagues.

Many of these patients were taking Janus kinase (JAK)-associated inhibitors for VEXAS syndrome, such that use of these drugs was associated with a nearly fourfold increase in risk for serious infections relative to other targeted therapies (HR 3.84, 95% CI 1.89-7.81, after adjustment for age, chondritis, arthralgia, and genetic factors), the group reported in Annals of the Rheumatic Diseases.

Fifteen of the registry patients died from serious infections after median follow-up of just 4.4 years.

“The high incidence of atypical infections such as legionellosis and invasive fungal infections, especially in patients without immunosuppressive treatment, may indicate an intrinsic immunodeficiency of the disease,” Hadjadj and colleagues wrote.

VEXAS, first reported just 3 years ago, is an acronym delineating the syndrome’s key features: vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, and somatic. Clinical presentations vary — chronic fever, skin lesions, joint pain and chondritis, and venous thrombosis are most common — but the common denominator is mutations in the UBA1 gene. A recent study put the prevalence at about one in 14,000, although that paper also noted that it’s closer to one in 4,000 for men older than 50. (The UBA1 gene is located on the X chromosome but, paradoxically, the mutation is expressed primarily in males.)

In tracking registry patients, Hadjadj and colleagues had noted that 5-year survival was 63% and that infections appeared to be a common cause. Therefore, they sought to perform a rigorous analysis to nail down specifics, including risk factors for serious infections.

To be included, patients had to have a UBA1 mutation as well as confirmation from treating clinicians of the presence or absence of serious infections. Patients with no record of infections and with less than 1 year of follow-up were excluded. (Overall, the registry now includes 267 patients, of which 124 met these criteria.)

All but four of the 124 were men, with median age at symptom onset of 69 (interquartile range 64-76). About three-quarters had no comorbidities such as diabetes or cancer that would convey risk for serious infections.

Among those with serious infections, the lungs were far and away the most common site, seen in 59% of cases. Skin infections were recorded in 10% and urinary tract involvement in 9%. Half of infections with known causes were bacterial, viruses accounted for 30%, and fungal organisms (primarily Pneumocystis jirovecii) were responsible for 15%.

Some 90% of VEXAS patients were taking steroids and 34% were on JAK inhibitors; many were taking synthetic immunosuppressants and/or biologic agents such as tumor necrosis factor inhibitors and interleukin blockers. (Use of multiple drug classes was common; the median number was three.) Patients with serious infections were about twice as likely to be taking JAK inhibitors compared with infection-free patients.

The increased risk with JAK inhibitors may be especially concerning, as a previous study led by Hadjadj (reported last month at the American College of Rheumatology’s annual meeting) had found these drugs to be among the most effective therapies for VEXAS syndrome.

Other risk factors for serious infections included age over 75 (HR 1.81, 95% 1.02-3.24) and presence of a specific UBA1 mutation called p.Met41Val (HR 2.29, 95% CI 1.10-5.10). Other analyses had pointed to this mutation as predicting a less favorable disease course.

Infection risk and mortality appeared to mount steadily after symptom onset. Half of the registry patients had experienced a serious infection by year 4, and mortality at that point was almost 20%.

“Although larger studies are needed, taken together these results suggest that anti-infective prophylaxis, at least anti-pneumocystis, should be considered in VEXAS patients even in the absence of treatment,” Hadjadj and colleagues wrote.

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