Clinical Clues, Testing, and Diagnosis of VEXAS Syndrome

Conclusions

• VEXAS testing should be strongly considered in older adults, especially men over 50, who present with systemic inflammation, cytopenias, and steroid-responsive but relapsing disease.
• The combination of recurrent fevers, elevated CRP/ESR, macrocytic anemia or other cytopenias, and neutrophilic skin disease or chondritis is particularly suggestive of VEXAS.
• Concurrent or sequential overlap of morphologies such as Sweet-like neutrophilic dermatosis, vasculitis, and chondritis increases suspicion for a clonal autoinflammatory syndrome.
• Treatment resistance to conventional steroid-sparing agents is a major clue, because many VEXAS patients remain corticosteroid dependent despite multiple therapies.
• Thrombosis, especially unprovoked venous thromboembolism in a patient with inflammatory or marrow abnormalities, should prompt consideration of UBA1 testing.
• Pulmonary, musculoskeletal, and ocular involvement are common enough to support the diagnosis when they occur alongside the core hematologic and inflammatory features.
• Bone marrow vacuolization is a classic pathologic clue, but its absence does not exclude VEXAS and its presence is not fully specific.
• Skin biopsies can provide useful clues, including neutrophilic dermatitis, histiocytoid Sweet syndrome, leukocytoclasia, perieccrine inflammation, and sometimes mucinous or lupus-like patterns.
• The pretest probability of VEXAS rises substantially when demographic risk, inflammatory markers, cytopenias, and compatible clinical morphology are present together.
• Although VEXAS is X-linked and enriched in men, women can also carry UBA1 variants and may develop disease in settings such as monosomy X or other loss of X-function states.
• Population data suggest incomplete penetrance of VEXAS-defining UBA1 variants, meaning that carrying the mutation does not always produce clinically evident disease.
• Standard tests may miss low-level or non-exon 3 variants, so negative Sanger or targeted exon 3 assays should be followed by more sensitive or broader sequencing when suspicion remains high.
• Next-generation sequencing of peripheral blood, bone marrow, or affected tissue is often the most practical approach, with digital droplet PCR useful for low variant allele fractions.
• VEXAS-like inflammatory syndromes can also arise from other clonal myeloid mutations, such as IDH-mutated neoplasms, so broader clonal evaluation may be warranted when UBA1 testing is negative.