When to Consider UBA1 Testing in VEXAS Syndrome: Clinical, Serologic, and Pathologic Clues

Conclusions

• VEXAS syndrome should be suspected primarily in older men, but women can also be affected, especially in contexts such as X-chromosome loss or other clonal hematologic disease.
• The strongest clinical triggers for UBA1 testing are recurrent inflammatory features such as fever, chondritis, neutrophilic skin disease, vasculitis, pulmonary involvement, and steroid dependence.
• Concurrent or evolving multi-morphology disease, especially combinations of chondritis, vasculitis, and neutrophilic dermatosis, greatly increases suspicion for VEXAS.
• Hematologic abnormalities are major clues, particularly macrocytic anemia, cytopenias, monocytopenia, thrombocytopenia, and coexisting myelodysplastic syndrome or plasma cell disorders.
• Elevated inflammatory markers, especially CRP, support the diagnosis, while ESR is less specific in the setting of hematologic abnormalities.
• Bone marrow vacuolization is a classic supportive finding but is neither fully sensitive nor specific, so a negative marrow does not exclude VEXAS.
• Dermatopathology can be highly suggestive when it shows neutrophilic dermatosis, histiocytoid Sweet syndrome, leukocytoclasia, vasculitic changes, or lupus-like/mucinous patterns in the right clinical setting.
• Treatment resistance to typical steroid-sparing agents is a major practical clue, because many VEXAS patients remain corticosteroid dependent despite standard therapies.
• Thrombosis, especially unprovoked venous thrombosis in the setting of autoinflammation or dysplasia, should heighten suspicion for VEXAS.
• Genetic confirmation is usually sought with UBA1 testing from peripheral blood or bone marrow, with higher-sensitivity methods preferred when clone size is small.
• Negative first-line testing does not fully exclude the diagnosis, and broader sequencing should be pursued when clinical suspicion remains high.
• Some patients who look like VEXAS but are UBA1-negative may instead have other clonal myeloid disorders, such as IDH-mutated neoplasms, that produce a VEXAS-like inflammatory syndrome.
• Overall, the presentation argues for a low threshold to test selected patients with adult-onset, multisystem, steroid-refractory inflammation and hematologic abnormalities, especially older men.