When to suspect VEXAS syndrome
Consider the possibility of VEXAS in middle-aged or older men in a rheumatology clinic with characteristics suggestive of treatment-refractory relapsing polychondritis, giant cell arteritis, polyarteritis nodosa, or Sweet syndrome. In the original series of 25 men, 15 were diagnosed with relapsing polychondritis, 8 with Sweet syndrome, 3 with polyarteritis nodosa, and 1 with giant cell arteritis.
Men with VEXAS often have periodic fevers, pulmonary infiltrates, a history of unprovoked venous thromboembolic events, neutrophilic dermatoses, and/or hematologic abnormalities such as myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown origin.
Dr. Katherine R. Calvo, M.D., Ph.D., NIH Clinical Center
A bone marrow aspirate specimen shows characteristic vacuoles present in myeloid precursor cells of VEXAS patients.
Bone marrow biopsy will show vacuoles in myeloid and erythroid precursor cells. Inflammatory marker levels are very high: In the NIH series, the median C-reactive protein was 73 mg/L and median erythrocyte sedimentation rate was 97 mm/hr. The diagnosis of VEXAS can be confirmed by genetic testing performed by Dr. Beck and his NIH coworkers (david.beck@nih.gov).
In interviews, Dr. Beck and Dr. Ferrada emphasized that management of VEXAS requires a multidisciplinary team of clinicians including rheumatologists, hematologists, and dermatologists.
Dr. Ferrada said that rheumatologists could suspect VEXAS in patients who have very high inflammatory markers and do not have a clear diagnosis or do not meet all criteria for other rheumatologic diseases, particularly in older men, but it’s possible in younger men as well. Hematologists could also consider VEXAS in patients with macrocytic anemia or macrocytosis without an explanation and inflammatory features, she said.
Dr. Ferrada, Dr. Beck, and colleagues also published a study in Arthritis & Rheumatology that presents a useful clinical algorithm for deciding whether to order genetic screening for VEXAS in patients with relapsing polychondritis.
First off, Dr. Ferrada and colleagues performed whole-exome sequencing and testing for UBA1 variants in an observational cohort of 92 relapsing polychondritis patients to determine the prevalence of VEXAS, which turned out to be 8%. They added an additional 6 patients with relapsing polychondritis and VEXAS from other cohorts, for a total of 13. The investigators determined that patients with VEXAS were older at disease onset, and more likely to have fever, ear chondritis, DVT, pulmonary infiltrates, skin involvement, and periorbital edema. In contrast, the RP cohort had a significantly higher prevalence of airway chondritis, joint involvement, and vestibular symptoms.
Courtesy Dr. Marcela Ferrada
Auricular chondritis in a man with VEXAS.
Dr. Ferrada’s algorithm for picking out VEXAS in patients who meet diagnostic criteria for relapsing polychondritis is based upon a few simple factors readily apparent in screening patient charts: male sex; age at onset older than 50 years; macrocytic anemia; and thrombocytopenia. Those four variables, when present, identify VEXAS within an RP cohort with 100% sensitivity and 96% specificity. “As we learn more about [VEXAS] and how it presents earlier, I think we are going to be able to find different manifestations or laboratory data that are going to allow us to diagnose these patients earlier,” she said. “The whole role of that algorithm was to guide clinicians who see patients with relapsing polychondritis to test these patients for the mutation, but I think over time that is going to evolve.”
Researchers are taking similar approaches for other clinical diagnoses to see which should be referred for UBA1 testing, Dr. Beck said.