VEXAS Syndrome

Excerpt

Clinical characteristics: VEXAS syndrome is an autoinflammatory syndrome caused by a somatic UBA1 (i.e., mosaic or postzygotic) pathogenic variant in hematopoietic stem cells. Because UBA1 is an X-linked gene, VEXAS syndrome mostly affects males; however, females account for about 4% of affected individuals. VEXAS syndrome, characterized by inflammatory and hematologic findings, typically affects males older than age 50 years. The most common inflammatory findings include recurrent fever, skin lesions, pulmonary infiltrates, recurrent chondritis, arthritis, pan ocular inflammation, and unprovoked venous thrombosis. Hematologic involvement includes macrocytic anemia, myelodysplastic syndrome (MDS), thrombocytopenia, monoclonal gammopathy of unknown significance, and vacuoles in myeloid and erythroid precursor cells.

Diagnosis/testing: The diagnosis of VEXAS syndrome is established in an individual with suggestive findings and a UBA1 somatic (also known as mosaic or postzygotic) pathogenic variant identified by molecular genetic testing in peripheral blood and/or bone marrow aspirate, but not skin fibroblasts. Pathogenic variants, although somatic, are typically present at a high variant allele fraction and can be detected in whole peripheral blood.

Management: Treatment of manifestations: Because large prospective trials are lacking, the therapeutic management of individuals with VEXAS syndrome is currently poorly standardized and is based on retrospective studies and expert opinion. The two main approaches to treatment are targeting inflammation and targeting the UBA1-mutated hematopoietic population. Targeting inflammation: Because conventional disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, azathioprine, cyclosporine, or cyclophosphamide have no or minimal anecdotal efficacy, glucocorticoids are generally used as a first-line treatment. Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and anti-IL-1 therapies. Targeting the UBA1-mutated hematopoietic population: Similar to classic MDS without VEXAS syndrome, hypomethylating agents like azacitidine are used to treat individuals with VEXAS syndrome with concurrent MDS with varying success. Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for VEXAS syndrome; however, it is sometimes associated with considerable morbidity and even mortality and should be only be considered in selected individuals after discussion with multidisciplinary care providers.

Surveillance: Monitoring existing manifestations, the individual's response to treatment of manifestations, and the emergence of new manifestations requires routinely scheduled follow up with the treating physicians.

Genetic counseling: VEXAS syndrome is an X-linked disorder caused by somatic pathogenic variants in UBA1. To date, all identified pathogenic variants are acquired (i.e., postzygotic) and lineage restricted in the blood. No confirmed occurrences of vertical transmission or sib recurrence have been reported.