Bone marrow vacuolization to curative strategies: Evolving paradigms in VEXAS syndrome management

VEXAS syndrome (vacuoles, E1 enzyme, X-linked alongside autoinflammatory and somatic) is a severe aggressive inflammation disorder arising in adults that results from acquired changes to the UBA1 gene. These genetic alterations lead to widespread chronic systemic inflammation, prominent features of clonal hematopoiesis, and worsening cytopenic decays alongside hematological malignancies. The grim prognosis includes survival-seeking patients facing life-threatening infections, bone marrow failure or thrombotic complications with only 76 % three-year survival rate. It mainly occurs in older men but rare cases in women stem from atypical patterns of X-chromosome inactivation. This syndrome shares characteristics with autoimmune disorders like relapsing polychondritis and blood disorders predominantly myelodysplastic syndromes. Diagnosis requires UBA1 genetic analysis and bone marrow examination which shows characteristic vacuolization in myeloid and erythroid progenitors. Current therapeutic approaches concentrate on fighting inflammation alongside supportive therapy. This includes infection control, transfusion administration, hypomethylating agents such as azacitidine, which provide the dual benefit of reducing mutant clones alongside inflammation, as well as immunosuppressive drugs, steroids, and Janus Kinase (JAK) inhibitors. Even though allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole option for a cure, its extensive toxicity limits widespread application. Some investigational therapies targeting specific pathways show promise, particularly nucleotide-binding domain, Leucine-rich Repeat-containing family, pyrin domain containing 3 (NLRP3) inflammasome blockers (IL-1β/IL-6 inhibitors) and proteasome inhibitors like bortezomib (Bortezomib), which exploit the proteostasis defects in UBA1-mutated cells. Core obstacles still lie in the absence of a standardized treatment paradigm due to gaps in genotype-phenotype expression and variability, alongside insufficient biomarkers able to guide therapy selection and directed personalized therapeutic interventions. This review highlights the curative strategies, therapeutic challenges, and advancements in VEXAS syndrome, underscoring the urgent need for targeted strategies to improve the patient outcomes.