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VEXAS Syndrome

What Is It, Causes, Treatment, and More

Author: Ashley Mauldin, MSN, ARPN, FNP-BC, CNE

Editors: Alyssa Haag, Lily Guo, Kelsey LaFayette, DNP

Illustrator: Jessica Reynolds, MS

Copyeditor: David G. Walker


What is VEXAS syndrome?

VEXAS syndrome, identified by the National Institutes of Health in 2020, is a rare, severe, progressive, X-linked autoimmune condition that causes systemic inflammation due to mutations in the UBA1 gene. The skin, lungs, blood vessels, and cartilage are most commonly affected. VEXAS syndrome can be difficult to diagnose as it has similar characteristics with other more common autoimmune conditions, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

VEXAS is an acronym that stands for the characteristics of the condition. “V” stands for vacuoles, which refers to the abnormal spaces within cells that develop; “E” stands for E1 enzyme, which is the enzyme that is malfunctioning due to mutations in the UBA1 gene; “X” stands for X chromosome, which is the location of the mutated UBA1 gene; “A” stands for autoinflammatory; and somatic, represented by the “S”, means acquired sometime in life.

What causes VEXAS syndrome?

VEXAS syndrome is caused by mutations in the UBA1 gene, with the variants responsible for the disorder present in hematopoietic stem and progenitor cells in the bone marrow. The UBA1 gene normally codes for ubiquitin-activating enzymes, also known as E1 enzymes. E1 enzymes activate ubiquitin-like proteins (UBLs), which are a group of proteins that help to regulate multiple cellular processes like nuclear transport, proteolysis, and autophagy, among others. Mutations in the UBA1 gene lead to dysfunctional E1 enzyme activity, which causes an autoimmune reaction whereby the innate immune system mistakenly damages healthy cells, causing systemic inflammation. However, the exact mechanisms underlying the inflammatory symptoms in VEXAS remain poorly understood.

Risk factors for VEXAS syndrome include being assigned male at birth and those aged 50 years and older.

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What are the signs and symptoms of VEXAS syndrome?

Signs and symptoms of VEXAS syndrome are related to systemic inflammation caused by the condition and affect a variety of body systems. Skin manifestations can include painful rashes; respiratory manifestations can include cough and shortness of breath; blood vessel involvement can cause vasculitis, which can predispose to thromboembolic disease (i.e., blood clots); and if cartilage is involved, symptoms can include swelling, usually of the ears and nose. 

Individuals typically also present with constitutional symptoms like fever, fatigue, and joint pain. Additionally, individuals can present with deficiencies in red blood cells (i.e., anemia); thrombocytopenia (i.e. low platelets); and progressive bone marrow failure, which can evolve to hematologic malignancy including myelodysplastic syndrome and multiple myeloma

How is VEXAS syndrome diagnosed?

Diagnosis of VEXAS syndrome begins with a thorough history and physical examination and may require other more common autoimmune disorders, like SLE and RA, to be ruled out first. Blood work may be done and typically shows increased inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Bone marrow biopsies can be completed to visualize the presence of vacuoles in bone marrow cells, which are specific to VEXAS syndrome. Diagnosis is confirmed through genetic testing to identify mutations in the UBA1 gene. 

How is VEXAS syndrome treated?

Currently, there is no specific treatment for VEXAS syndrome, and most individuals will require a multidisciplinary team of healthcare providers, including hematologists, rheumatologists, and dermatologists. Medical management is aimed at treating the underlying systemic inflammation through the use of steroids, like prednisone, and other immunosuppressants, like azacitidine.  Some individuals may undergo bone marrow transplantation to replace bone marrow. Currently, researchers are studying the potential for stem cell transplantation as a possible treatment. 

What are the most important facts to know about VEXAS syndrome?

VEXAS syndrome is a severe progressive autoimmune condition that causes systemic inflammation. It is caused by mutations in the UBA1 gene on the X chromosome, which encodes for ubiquitin-activating enzymes or E1 enzymes. Typical signs and symptoms of VEXAS syndrome include fever, fatigue, rashes, cough, shortness of breath, joint swelling, and swelling of cartilage. VEXAS syndrome is diagnosed through genetic testing to identify mutations in the UBA1 gene. There is no current treatment for VEXAS syndrome and medical management is aimed at treating the underlying systemic inflammation through the use of steroids and other immunosuppressants

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Related links

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Resources for research and reference

VEXAS. About VEXAS. Published 2022. Accessed August 1, 2023. Available from: https://vexas.org

Beck DB, Bodian DL, Shah V, et al. Estimated prevalence and clinical manifestations of UBA1 variants associated with VEXAS syndrome in a clinical population. JAMA. 2023;329(4):318. doi:10.1001/jama.2022.24836

Grayson PC, Patel BA, Young NS. VEXAS syndrome. Blood. 2021;137(26):3591-3594. doi:10.1182/blood.2021011455

Stiburkova B, Pavelcova K, Belickova M, et al. Novel somatic UBA1 variant in a patient with VEXAS syndrome. Arthritis Rheumatol. 2023;75(7):1285-1290. doi:10.1002/art.42471

Shimizu T, Ide H, Tsuji Y, Koga T, Kawakami A. VEXAS syndrome complicated with severe infection. Rheumatology. 2022;61(12):e374-e376. doi:10.1093/rheumatology/keac364

UBA1 Gene. MedlinePlus. Published June 16, 2022. Accessed August 1, 2023. Available from: https://medlineplus.gov/genetics/gene/uba1/#conditions

National Institute of Arthritis and Musculoskeletal and Skin Diseases. What is VEXAS Syndrome? Published January 18, 2022. Available from: https://www.niams.nih.gov/labs/grayson-lab/vexa