VEXAS syndrome represents a revolutionary shift in our understanding of adult-onset autoinflammatory diseases. This condition arises from somatic mutations in the UBA1 gene, which specifically affects innate myeloid cells. Consequently, clinicians often find that VEXAS syndrome neurological symptoms complicate the diagnostic landscape, as they frequently mimic common autoimmune disorders like vasculitis. While the syndrome primarily involves systemic inflammation, it targets the nervous system in approximately 6-10% of cases.

Recognizing VEXAS Syndrome Neurological Symptoms

Neurologists must maintain a high index of suspicion when evaluating refractory inflammatory cases. Specifically, the peripheral nervous system serves as the primary target for this disease, accounting for 70% of all neurological involvements. Most patients present with a severe, refractory axonal polyneuropathy that resists standard immunosuppressive therapy. Furthermore, central nervous system involvement may manifest as neutrophilic meningoencephalitis or aseptic meningitis. Therefore, understanding these patterns is essential for avoiding misdiagnosis in elderly male patients.

In addition to neurological signs, the "hematologic paradox" serves as a critical diagnostic pillar. Traditional vasculitic mimics typically present with thrombocytosis during flares. In contrast, VEXAS syndrome showcases hyperinflammation paired with macrocytic anemia. This unique combination suggests bone marrow dysfunction and should immediately prompt genetic sequencing for UBA1 mutations. Early identification allows for targeted clone suppression therapies rather than broad, ineffective immunosuppression.

The Path to Accurate Diagnosis

Diagnosis begins with recognizing the characteristic triad of fever, skin lesions, and hematologic abnormalities. Because the disease is X-linked, it almost exclusively affects men over the age of 50. If a patient presents with unexplained neuro-inflammation and macrocytosis, clinicians should prioritize bone marrow aspiration. Finding vacuoles in myeloid and erythroid precursor cells provides strong evidence for the syndrome. However, definitive confirmation requires specialized genetic testing to identify somatic variants at the methionine-41 site.

Frequently Asked Questions

How does VEXAS syndrome differ from systemic vasculitis?

VEXAS syndrome typically presents with macrocytic anemia and bone marrow vacuoles, whereas systemic vasculitis often features thrombocytosis and lacks the UBA1 somatic mutation. VEXAS is also notably resistant to conventional steroid-based treatments used for vasculitis.

What are the most common neurological manifestations?

The most frequent manifestation is refractory axonal polyneuropathy. However, some patients may experience central involvement, including encephalopathy, optic perineuritis, or neutrophilic meningoencephalitis.

Is VEXAS syndrome a heritable condition?

No, VEXAS is caused by somatic mutations, meaning the genetic change occurs during the patient\'s lifetime rather than being inherited from parents. It is typically found in hematopoietic stem cells rather than germline cells.

Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice or a professional relationship. Always seek the advice of a qualified healthcare provider regarding any medical condition or treatment. Refer to the latest local and national guidelines for clinical practice.

References

Mitsoudis N et al. A neurologist's guide to VEXAS syndrome: Differentiating somatic autoinflammation from autoimmune mimics. Intractable Rare Dis Res. 2026 May 31. doi: 10.5582/irdr.2026.01013. PMID: 42221042.

Beck DB et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med. 2020;383(27):2628-2638.

Koster MJ et al. 2025 American College of Rheumatology Guidance on Diagnosis and Management of VEXAS. Arthritis Rheumatol. 2025.