VEXAS syndrome: little known, but more frequent and serious than expected

A recent study published in JAMA investigated the prevalence and clinical manifestations of VEXAS syndrome, a disease with rheumatological and hematological features caused by somatic variants in the UBA1 gene. This retrospective observational study1 shows that a recently discovered inflammatory disease known as VEXAS syndrome (vacuoles, ubiquitin activating enzyme E1, X-linked, autoinflammatory, somatic) is more frequent, more variable and more dangerous than we thought. Read: Psoriatic arthritis: an encouraging new treatment option The symptoms of VEXAS syndrome (anemia, inflammation of the skin, lungs, cartilage and joints) are often confused with other rheumatic or hematological diseases. However, the cause is different and this syndrome must be treated differently with closer monitoring, given the severity of the disease. The lead author and colleagues first described this disease in 2020 and associated it with mutations in the UBA1 gene, a gene needed to initiate the process of ubiquitination that regulates several aspects of cell biology, including degradation of misfolded proteins.2 The objective of this study was to determine the prevalence of pathogenic UBA1 variants and the associated clinical manifestations, using a genomic verification approach. An assessment of UBA1 variants in exome data from 163,096 participants in the Geisinger MyCode community health initiative was performed. Clinical phenotypes were determined from Geisinger electronic medical record data from Jan. 1, 1996, through Jan. 1, 2022. Patients were from 10 hospitals in Pennsylvania. Read: How weight affects the body's ability to metabolize vitamin D Aspects measured included prevalence of somatic variation in UBA1, presence of rheumatology, hematology, pulmonary, dermatology, as well as other findings in individuals with somatic variation in UBA1 on the electronic medical record review, review of laboratory data, pathological analysis of bone marrow biopsy and in vitro enzyme testing. Of the 163,096 study participants (mean age: 52.8 years; 94% white; 61% female), 11 individuals carried probable somatic variants at known pathogenic positions of UBA1; all with clinical manifestations compatible with VEXAS syndrome (nine men, two women). Although five of the 11 individuals did not meet criteria for the rheumatological and/or hematological diagnoses associated with VEXAS syndrome, all individuals had anemia (hemoglobin, mean: 7.8 g/dl; median: 7.5 g/dl) mainly macrocytic (10/11 individuals, i.e. 91%) with concomitant thrombocytopenia (10/11 individuals). Macrocytosis (91%), skin problems (73%) and lung disease (91%) were the other common findings. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was discovered in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in one in 13,591 unrelated individuals (95% CI: 1:7775 – 1:23,758), one in 4,269 men over the age of 50 ( 95% CI: 1:2319 – 1:7859) and one in 26,238 women aged over 50 (95% CI: 1:7196 – 1:147,669). In conclusion, VEXAS syndrome represents an example of a multisystem disease. Professionals should be alert to patients who present with unexplained inflammation and some combination of hematological, rheumatological, pulmonary and dermatological clinical manifestations. The prevalence of VEXAS syndrome is now high enough that clinicians consider that some patients with diseases that do not respond to treatment may in fact have the syndrome. That said, the authors point out that further studies are needed in unselected and genetically diverse populations to better define the prevalence and phenotypic spectrum in the general population. References: 1. Beck, D.B. et coll. (2023). Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. JAMA329(4), 318-324. 2.Beck, D.B. et coll. (2020). Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med383,2628-2638. This article has been translated from its original French and originally appeared on our sister site Profession Santé.

VEXAS syndrome: little known, but more frequent and serious than expected

Register for free access or login.

Related Topics