New Autoinflammatory Syndrome VEXAS is Likely Underdiagnosed by Rheumatologists

VEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly discovered adult-onset autoinflammatory syndrome due to somatic mutations in the UBA1 gene, recognized as a novel disease and first described in 2020 in the New England Journal of Medicine [1].  Unique to VEXAS is the fact it is an acquired mutation that occurs later in life, unlike other genetic causes of most autoinflammatory syndromes.  Patients with VEXAS can have an overlap of rheumatologic, dermatologic, and hematologic manifestations including relapsing polychondritis, polyarteritis nodosa, giant cell arteritis, Sweet Syndrome, and myelodysplastic syndrome (MDS) or macrocytic anemia [1].

A recent study by Dr. David Beck and colleagues sought to further define the prevalence and phenotypic spectrum of UBA1 variants in VEXAS [2], discovering the clinical spectrum of VEXAS is much more expansive than previously thought.  Because there are no clinical guidelines for what individuals to test for UBA1 variants and there are no diagnostic criteria for VEXAS syndrome, the authors wanted to better describe the phenotypic spectrum of VEXAS.  This condition also demonstrates overlapping laboratory results and clinical features, like many rheumatic diseases, which can make its initial characterization more challenging.

This research evaluated a cohort of around 163,000 individuals seeking health care at a Geisinger facility in Pennsylvania who enrolled in a MyCode Community Initiative, which enabled their samples and data to be linked to the Geisinger electronic health record (EHR).  Relevant clinical data from the EHR was extracted.  Genetic analysis by microarray genotyping and exome sequencing was completed to identify pathogenic or likely pathogenic variants and highly suspicious variants of uncertain significance [2].

Of the 163,000 individuals, the study found 11 individuals (1 in 13,591) had disease-causing or likely pathogenic variants in UBA1, all of whom were over 50 years of age at onset of symptoms.  Of these 11 individuals, 6 (55%) had clinical diagnoses that are associated with VEXAS Syndrome.  Seven individuals (64%) had arthritis and 4 (36%) had rheumatic disease, including psoriasis, polymyalgia rheumatica, dermatomyositis, and sarcoidosis.  All 11 individuals had anemia, 10 (91%) had macrocytosis, 5 (46%) required transfusions for their anemia, and 4 (36%) had MDS.  Associated skin disease was present in 8 individuals (73%) and pulmonary involvement in 10 people (91%).  Six patients underwent bone marrow biopsy as part of standard of care, and 5 (83%) had cytoplasmic vacuoles in myeloid and/or erythroid precursors observed, a characteristic feature often observed in VEXAS syndrome.  Eighty percent had elevated erythrocyte sedimentation rate (ESR).

This study offers novel and interesting findings related to VEXAS phenotype and prevalence.  Ultimately, only 55% of the individuals with UBA1 mutation (VEXAS) had clinical diagnoses that are classically associated with VEXAS syndrome based on initial studies; these results suggest simply using the currently identified clinical phenotypes may not have identified these patients and may miss diagnoses of VEXAS.  Additionally, the frequency of VEXAS syndrome was identified in 1 in 13,591 individuals, which the authors point out is higher frequency than many rheumatic conditions including some that can be seen in VEXAS (for example, granulomatous with polyangiitis is 1/18,000 and polyarteritis nodosa is 1/33,000) [2].  The authors suggest broader UBA1 testing in patients with features that can be seen in VEXAS, such as macrocytic anemia of uncertain etiology and elevated inflammatory markers, may be indicated, even in the absence of the previously defined associated rheumatic diseases.  Limitations of this research include the study based on a single-center cohort with predominantly European ancestry population, which may not be representative of other geographic locations and ancestries.

Dr. David Beck, Assistant Professor in the Department of Medicine at NYU Grossman School of Medicine and lead author on the manuscript, states he was most surprised to discover how common VEXAS is.  “This is a disease that is going to present in most rheumatology practices and is likely being missed in most cases,” Beck said.  “We are really eager for patients to be recognized and tested so that they can receive a diagnosis and start to get more targeted treatments.”

So ultimately, when should rheumatologists be concerned for VEXAS and consider the genetic testing for UBA1?  Dr. Beck says, “if you are seeing an older individual with systemic inflammation, low blood counts, that requires steroids and does not have a clear clinical diagnosis, you should consider genetic testing for UBA1 and VEXAS syndrome.  One of the major findings of our current study is that VEXAS can have a wide variety of clinical manifestations, but inflammation and hematologic involvement are strong clues about who will have the disease,” he said.

And how does one test for VEXAS?  If you have a patient with concern for VEXAS, Dr. Beck notes there are several companies offering VEXAS/UBA1 genetic testing, “ranging from Genomic Testing Cooperative to Invitae.”  He also said he is able to assist rheumatologists with potential research avenues for undiagnosed patients or guidance on how to choose the correct genetic testing.

In rheumatology, we are used to novel discoveries in a constantly evolving field.  VEXAS provides a new entity within the autoinflammatory disease spectrum presenting in older adults, important for rheumatologists to recognize.  Future studies are needed to explore the prevalence and phenotype in unselected and more diverse populations.  The work by Beck et al suggests there is much higher prevalence to VEXAS than initially suspected, the phenotypes seen within VEXAS are likely broader than initially recognized, and that VEXAS is very likely going to be hiding in our clinics and hospitals – waiting for us to recognize and ultimately diagnose it.

References:

[1] Beck DB, Ferrada MA, Sikora KA, et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med (2020); 383 (27):2628-2638.

[2] Beck DB, Bodian DL, Shah V, et al. Estimated prevalence and clinical manifestations

of UBA1 variants associated with VEXAS syndrome in a clinical population. JAMA (2023); 329, 318–324.