VEXAS syndrome is a newly recognized autoinflammatory disorder affecting adults, typically presenting in the late 50s or 60s. The condition is characterized by profound systemic inflammation combined with abnormalities in the blood cell production system. Because its symptoms mimic conditions like relapsing polychondritis, Sweet syndrome, or myelodysplastic syndrome, VEXAS syndrome is often difficult to diagnose. The disorder carries a high mortality rate, making early recognition and management urgent for affected individuals.
The Genetic and Molecular Basis
The root cause of VEXAS syndrome is a somatic mutation in the \(UBA1\) gene, which is located on the X chromosome. A somatic mutation means the genetic change is acquired during a person’s lifetime and is present only in certain cells, such as those that produce blood cells. The X-linked nature of the gene explains why the syndrome is seen almost exclusively in males.
The \(UBA1\) gene provides instructions for making the E1 enzyme, which initiates ubiquitylation—a system that tags damaged proteins for recycling within the cell. When the \(UBA1\) gene is mutated, the E1 enzyme does not function correctly, leading to a breakdown in the cell’s waste cleanup system. This failure triggers a continuous, abnormal activation of the innate immune system.
The name VEXAS is an acronym describing this mechanism and its features: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, and Somatic. The disorder’s first defining feature was the presence of vacuoles in blood-forming cells. The most common mutation converts the methionine-41 codon (p.Met41) of the gene, which primarily affects the cytoplasmic form of the E1 enzyme.
The Spectrum of Clinical Manifestations
The hallmark symptoms of VEXAS syndrome are an overlap of systemic inflammation and blood-related issues that often resist conventional treatments. The disease is characterized by chronic, unexplained inflammation affecting multiple organ systems throughout the body.
Systemic Autoinflammation
Recurrent, persistent fevers are one of the most common constitutional symptoms, occurring in a majority of patients. These fevers are typically unexplained by infection and are often accompanied by fatigue, unintended weight loss, and generalized body pain. This pain includes joint pain (arthralgia) and muscle aches (myalgia). The systemic inflammation can also lead to complications such as inflammation in the lungs (pulmonary infiltrates) and blood clots (venous thrombosis).
Dermatologic Features
Skin manifestations are frequent, providing a visible clue to the underlying inflammatory process. Patients often develop neutrophilic dermatoses, which are skin conditions characterized by an accumulation of neutrophils. These rashes can resemble Sweet syndrome, presenting as tender, red-violaceous plaques or nodules.
Inflammation of the cartilage, known as chondritis, is another distinguishing feature, often mimicking relapsing polychondritis. This typically involves the cartilage of the ears and nose, which may become swollen and painful. Some individuals also experience vasculitis, an inflammation of the blood vessels, which may manifest as conditions similar to polyarteritis nodosa or giant cell arteritis.
Hematologic Abnormalities
The somatic mutation originates in hematopoietic stem cells, the precursors for all blood cell types, leading to a range of hematologic issues. Many patients present with macrocytic anemia, a condition where red blood cells are abnormally large. A shortage of platelets (thrombocytopenia) and other blood cell deficiencies (cytopenia) are also common findings.
The most specific finding in the bone marrow is the presence of cytoplasmic vacuoles—empty, rounded spaces observed within the precursor cells of the myeloid and erythroid lines. This finding, which gives the “V” in VEXAS, is characteristic but not unique to the syndrome. The condition frequently progresses to myelodysplastic syndrome (MDS), a type of bone marrow failure that can increase the risk of developing leukemia.
Confirming the Diagnosis
Diagnosing VEXAS syndrome requires integrating clinical suspicion with specific laboratory and genetic testing. The syndrome should be considered in any male over the age of 50 with unexplained, treatment-resistant systemic inflammation and concurrent hematologic abnormalities.
The first step often involves a bone marrow biopsy to look for the characteristic vacuoles in the myeloid and erythroid precursor cells. While the presence of these vacuoles suggests VEXAS, this finding alone is not definitive, as it can occur in other conditions.
The definitive diagnosis relies on genetic confirmation, specifically the detection of the somatic \(UBA1\) mutation. Genetic testing, such as targeted sequencing, is performed on samples like peripheral blood or bone marrow aspirate to identify the acquired pathogenic variant. Identifying the \(UBA1\) mutation in the blood-forming cells is the final confirmation required to establish the diagnosis.
Treatment and Disease Management
The primary goal of managing VEXAS syndrome is to control the chronic inflammation, which is challenging due to the disease’s underlying genetic mechanism. Glucocorticoids, particularly high-dose prednisone, are generally the first-line treatment because they are effective at quickly reducing inflammatory symptoms. However, many patients become dependent on these steroids to maintain control, which can lead to significant side effects over time.
Immunosuppressive agents and other biologic drugs are often used to find a durable, steroid-sparing treatment regimen. These include drugs like Janus kinase (JAK) inhibitors or IL-6 inhibitors, which help suppress the overactive immune system response. The response to these conventional treatments is variable among patients.
For patients with refractory disease or rapidly progressing hematologic issues like high-risk MDS, allogeneic hematopoietic stem cell transplantation (bone marrow transplant) is considered. This procedure aims to replace the mutated blood-forming cells with healthy donor cells, offering the potential for a cure by eliminating the source of the faulty \(UBA1\) gene. Despite treatment, the prognosis remains poor for many patients, with high mortality rates often due to refractory inflammation, infections, or complications arising from hematologic malignancies.