VEXAS syndrome
Adult-onset autoinflammatory disease from somatic UBA1 mutation.
VEXAS syndrome is a disease that starts in adulthood, mainly affects people assigned male at birth, and results from a somatic mutation in the UBA1 gene within hematopoietic progenitor cells. The acronym VEXAS stands for vacuoles (often seen in bone marrow stem cells), the E1 ubiquitin conjugating enzyme encoded by the mutated UBA1 gene, X-linked inheritance (the recessive mutation is on the X chromosome, so the condition is almost exclusive to individuals with one X chromosome), autoinflammatory (patients experience a broad range of inflammatory conditions), and somatic (the mutations are acquired during life, not inherited, and cannot be passed to offspring).
The condition usually appears after age 50 and involves both autoinflammatory and hematologic symptoms. Common signs include fever and skin rashes, especially those resembling Sweet syndrome. Other possible autoinflammatory issues include periorbital angioedema, uveitis, scleritis, relapsing polychondritis, polyarteritis nodosa, and lung inflammation. Hematologic problems include macrocytic anemia, low platelet counts, and a higher risk of blood cancers, particularly myelodysplastic syndrome. Bone marrow tests often show abnormal vacuoles in myeloid and erythroid precursor cells.
VEXAS syndrome worsens over time and has a high death rate. High-dose corticosteroids can manage symptoms but often cause serious side effects, and symptoms usually return when the dose is lowered. As of 2021, various alternative treatments were being studied. More recent reviews describe VEXAS as a condition at the intersection of clonal hematopoiesis, bone marrow failure, and innate immune dysregulation. The UBA1 mutations impair ubiquitination and protein homeostasis, leading to endoplasmic reticulum stress and activation of inflammatory pathways. Treatment remains difficult: glucocorticoids often control inflammation but are hard to taper, and steroid-sparing options like interleukin-1 blockade, interleukin-6 inhibition, Janus kinase inhibitors, and hypomethylating agents have shown mixed results. Allogeneic hematopoietic stem cell transplantation is seen as the only potentially curative option, though patient selection and transplant risks are major limitations.
The syndrome was identified by a team led by David B. Beck, Peter Grayson, and Daniel L. Kastner.
- Field
- Medicine (rheumatology, hematology, genetics)
- Known for
- Discovery of VEXAS syndrome, an adult-onset autoinflammatory disease linked to somatic UBA1 mutations
- Discovery year
- 2020
- Affected population
- Primarily males over age 50
Lore & Background
VEXAS syndrome arises in late adulthood, typically after age 50, and causes both autoinflammatory and hematologic symptoms. Common signs include fever and skin rashes resembling Sweet syndrome, as well as periorbital angioedema, uveitis, scleritis, relapsing polychondritis, polyarteritis nodosa, and lung inflammation. Hematologic issues include macrocytic anemia, low platelet count, and a predisposition to myelodysplastic syndrome. Bone marrow examination reveals abnormal vacuoles in precursor cells of myeloid and erythroid lineages.
Reader's Guide
VEXAS syndrome represents a significant advance in understanding adult-onset inflammatory diseases. Its discovery in 2020 connected seemingly unrelated inflammatory syndromes through a common somatic mutation in the UBA1 gene, which is located on the X chromosome and causes disease almost exclusively in individuals with a single X chromosome. The syndrome carries a high mortality rate and becomes more severe over time. Treatment remains challenging: high-dose corticosteroids can manage symptoms but cause serious adverse effects and symptoms recur upon tapering. Alternative treatments under investigation include interleukin-1 blockade, interleukin-6 inhibition, Janus kinase inhibitors, and hypomethylating agents, with variable responses. Allogeneic hematopoietic stem cell transplantation is considered the only potentially curative treatment, though patient selection and transplant-related risk are important limitations. The American Society of Hematology deemed the discovery the year's best advancement in hematology-related diagnoses in 2022, and the National Cancer Institute announced a clinical trial to evaluate stem cell transplant as a possible treatment. The discovery builds on findings suggesting that postzygotic somatic mutation may be a more frequent cause of human disease than previously recognized.
Did You Know?
- The name VEXAS is an acronym for vacuoles, E1 ubiquitin conjugating enzyme, X-linked, autoinflammatory, and somatic.
- The initial discovery of the UBA1 mutation was made by Dr. David B. Beck and colleagues at the National Institutes of Health (NIH).
- The American Society of Hematology (ASH) selected the VEXAS discovery as the top advance in hematology for 2021.
More in Autoinflammatory syndromes 1-24
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