VEXAS is a newly define adult-onset inflammatory syndrome manifested with treatment-refractory fevers, arthritis, chondritis, vasculitis, cytopenias, typical vacuoles in hematopoietic precursor cells, neutrophilic cutaneous and pulmonary inflammation.
What does VEXAS Syndrome Stand for?
The letters in VEXAS syndrome’s name are an acronym for how healthcare providers can identify and diagnose it:
• Vacuoles: Vacuoles are rounded, empty spaces that form in abnormal cells. People with VEXAS syndrome usually have vacuoles in their bone marrow cells.
• E1 enzyme: The ineffective E1 enzyme your cells make when you have a mutated UBA1 gene.
• X-linked: Two chromosomes determine your biological sex. People assigned female at birth have XX chromosomes and people assigned male at birth have XY chromosomes. The mutated UBA1 gene that causes VEXAS syndrome is located on the X chromosome.
• Autoinflammation: Autoinflammation is the medical term for the inflammation your immune system causes when it attacks your body.
• Somatic: The mutation that causes VEXAS syndrome is somatic. That means it happens randomly and isn’t passed from biological parents to their children (it’s not hereditary).
Genetics of VEXAS Syndrome
VEXAS syndrome is caused by somatic mutations in the UBA1 gene, which is located on the X chromosome. These mutations are acquired rather than inherited, meaning they arise during an individual’s lifetime and are not passed down to offspring.
UBA1 Gene encodes ubiquitin-activating enzyme 1, a critical enzyme in the ubiquitin-proteasome system, which regulates protein degradation, DNA repair, and immune signaling. The somatic mutations typically occur at the Met41 codon in the UBA1 gene.
VEXAS syndrome predominantly affects males due to its location on the X chromosome, as they lack a second X chromosome to compensate. Rare cases in females are linked to skewed X-inactivation. Since it is not germline, it cannot be passed to offspring.
Mechanism
The defective ubiquitin-activating enzyme in VEXAS syndrome disrupts the ubiquitin-proteasome system, impairing protein degradation, DNA repair, and immune regulation. The resulting cellular stress triggers inflammation and immune dysregulation. Mutations in hematopoietic stem cells cause clonal expansion, leading to systemic inflammatory symptoms and hematologic abnormalities, such as vacuoles in myeloid cells, anemia, and bone marrow dysplasia.
Immunological Aspect
The immunological aspect of VEXAS syndrome is marked by dysregulated inflammation and immune dysfunction caused by mutations in the UBA1 gene. These mutations impair the ubiquitin-proteasome system, leading to abnormal protein turnover and heightened activation of inflammatory pathways. This results in systemic autoinflammation, characterized by recurrent fevers, skin rashes, and inflammatory conditions such as chondritis and vasculitis.
Hematopoietic clonal expansion of mutated cells contributes to an imbalance in immune cell populations, further exacerbating inflammation.
VEXAS syndrome is characterized by the abnormal production of pro-inflammatory cytokines, which play a central role in the development of inflammation and tissue damage. These cytokines, such as TNF-alpha, IL-1, and IL-6, are typically released by immune cells in response to infection or injury. However, in VEXAS syndrome, mutations in the UBA1 gene lead to defective protein function, resulting in the continuous activation of the immune system. This persistent inflammation can cause severe symptoms, including fever, skin rashes, and damage to organs such as the lungs and kidneys. The overproduction of these cytokines contributes to the chronic inflammatory state seen in patients with VEXAS. Targeting these cytokines has become a potential therapeutic strategy for managing the condition.
Symptoms
VEXAS syndrome presents with a wide range of symptoms, often involving systemic inflammation and multi-organ damage. Common symptoms include recurrent fever, skin rashes, and painful joints, which are signs of the underlying inflammation. Patients may also experience lung problems, such as difficulty breathing or pulmonary infiltrates, along with kidney dysfunction and vasculitis. Additionally, some individuals with VEXAS syndrome develop hematologic abnormalities, including anemia and elevated white blood cell counts. Neurological symptoms, such as headaches or cognitive impairment, can also occur. The severity of symptoms varies, but the condition tends to worsen over time without proper treatment.
Risk Factors
Studies have found that men or people assigned male at birth are much more likely to experience VEXAS syndrome. It’s also more common among people older than 50.
Complications
Complications of VEXAS syndrome can be severe and life-threatening due to the chronic inflammation and organ damage associated with the condition. Persistent inflammation can lead to progressive tissue damage in vital organs, including the lungs, kidneys, and heart. Pulmonary complications such as interstitial lung disease or respiratory failure are common, and renal involvement may lead to kidney failure.
The syndrome also increases the risk of developing vasculitis, which can damage blood vessels and impair circulation. Hematologic complications, including anemia and thrombocytosis, are frequent and can further contribute to the severity of the disease. In some cases, the syndrome can lead to a higher risk of infections due to the dysregulated immune response. As the disease progresses, these complications can significantly impact the patient's quality of life and survival.
Treatment
The treatment of VEXAS syndrome primarily focuses on managing inflammation and preventing complications, as there is no definitive cure for the condition. Corticosteroids are commonly used to reduce inflammation and control symptoms, although their effectiveness may vary over time. Other immunosuppressive drugs, such as methotrexate or azathioprine, may be prescribed to further suppress the overactive immune response.
In some cases, biologic therapies targeting specific pro-inflammatory cytokines like TNF-alpha, IL-1, or IL-6 have shown promise in reducing symptoms.
For patients with severe or refractory disease, stem cell or bone marrow transplantation may be considered as a potential treatment option.
Supportive care, including management of organ-specific complications, is crucial in improving the patient’s quality of life and preventing further damage. Close monitoring by healthcare providers is essential to adjust treatment strategies based on the evolving course of the syndrome
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