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 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.

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.