A recently discovered inflammatory disease known as VEXAS syndrome is more common, variable and dangerous than previously understood, according to results of a retrospective observational study of a large US healthcare system database.
The findings, published in JAMA Network, found that it struck one in 4 269 men over 50 in a largely white population and caused a variety of symptoms.
“The disease is quite severe,” said study lead author Dr David Beck of the department of medicine at NYU Langone Health. “Patients have a variety of clinical symptoms affecting different parts of the body and are being managed by different medical specialties.”
Beck and colleagues first described VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome in 2020, reports Medscape, linking it to mutations in the UBA1 (ubiquitin-like modifier activating enzyme 1) gene. The enzyme initiates a process that identifies misfolded proteins as targets for degradation.
“VEXAS syndrome is characterised by anaemia and inflammation in the skin, lungs, cartilage and joints,” said Beck, adding that symptoms are frequently mistaken for other rheumatic or hematologic diseases. “However, this syndrome has a different cause, is treated differently, requires additional monitoring, and can be far more severe.”
He said hundreds of people have been diagnosed with the disease in the short time since it was defined. The disease is believed to be fatal in some cases. A previous report found that the median survival was nine years among patients with a certain variant; that was significantly less than patients with two other variants.
For the latest study, researchers searched for UBA1 variants in genetic data from 163 096 subjects (mean age, 52.8 years; 94% white, 61% women) who took part in the Geisinger MyCode Community Health Initiative. The 1996-2022 data are from patients at 10 Pennsylvania hospitals.
Eleven people (nine males, two females) had possible UBA1 variants, and all had anaemia. The cases accounted for one in 13 591 unrelated people (95% confidence interval, 1:7,775-1:23,758), one in 4 269 men older than 50 years (95% CI, 1:2,319-1:7,859), and one in 26 238 women older than 50 (95% CI, 1:7,196-1:147,669).
Other common findings included macrocytosis (91%), skin problems (73%), and pulmonary disease (91%). Ten patients (91%) required transfusions.
Five of the 11 subjects didn’t meet the previously defined criteria for VEXAS syndrome. None had been diagnosed with the condition, which is not surprising considering it hadn’t been discovered and described until recently.
Just more than half of the patients – 55% – had a clinical diagnosis that was previously linked to VEXAS syndrome.
“This means that slightly less than half of the patients with VEXAS syndrome had no clear associated clinical diagnosis,” Beck said. “The lack of associated clinical diagnoses may be due to the variety of non-specific clinical characteristics that span different sub-specialities in VEXAS syndrome. VEXAS syndrome represents an example of a multisystem disease where patients and their symptoms may get lost in the shuffle.”
In the future, “professionals should look out for patients with unexplained inflammation – and some combination of haematologic, rheumatologic, pulmonary, and dermatologic clinical manifestations – that either don’t carry a clinical diagnosis or don’t respond to first-line therapies”, Beck said.
“They will also frequently be anaemic, have low platelet counts, elevated markers of inflammation in the blood, and be dependent on corticosteroids.”
Diagnosis can be made via genetic testing, but the study authors note that it “is not routinely offered on standard workup for myeloid neoplasms or immune dysregulation diagnostic panels”.
As for treatment, Beck said the disease “can be partially controlled by multiple different anticytokine therapies or biologics”.
However, in most cases, patients still need additional steroids and/or disease-modifying antirheumatic agents (DMARDs). In addition, bone marrow transplantation has shown signs of being a highly effective therapy.
The study authors say more research is needed to understand the disease’s prevalence in more diverse populations.
Dr Matthew Koster, a rheumatologist at Mayo Clinic in Rochester, who’s studied the disease but didn’t take part in this research project, said the findings are “highly important”.
“They highlight what many academic and quaternary referral centres were wondering: is VEXAS really more common than we think, with patients hiding in plain sight? The answer is yes,” he said.
“Currently, there are less than 400 cases reported in the literature of VEXAS, but large centres are diagnosing this condition with some frequency. At Mayo Clinic in Rochester, we diagnose on average one new patient with VEXAS every seven-14 days and have diagnosed 60 in the past 18 months. A national collaborative group in France has diagnosed 250 patients over that same time frame when pooling patients nationwide.”
The prevalence is high enough, he said, that “clinicians should consider that some of the patients with diseases not responding to treatment may in fact have VEXAS rather than ‘refractory’ relapsing polychondritis or ‘recalcitrant’ rheumatoid arthritis, etc.”
Study details
Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population
David Beck, Dale Bodian, Vandan Shah, Douglas Stewart, et al.
Published in JAMA Network on 24 January 2023
Abstract
Importance
VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes.
Objective
To determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach.
Design, Setting, and Participants
This retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022.
Main Outcomes and Measures
Outcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays.
Results
In 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harboured likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anaemia (haemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A>T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669).
Conclusions and Relevance
This study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.
Medscape article – VEXAS Syndrome: More Common, Variable, and Severe Than Expected (Open access)
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