Key points: ● Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a monogenic disease of adulthood characterised by treatment-refractory systemic inflammation and progressive bone marrow failure. ● VEXAS syndrome is caused by acquired mutations in the UBA1 gene that are restricted to haematopoietic cells. ● Men aged 50 years or older are particularly susceptible to VEXAS syndrome, with prevalence estimates of approximately one in 4000 men. ● The inflammatory manifestations of VEXAS syndrome are multisystemic, and the classic phenotype includes constitutional, cutaneous, cartilaginous, musculoskeletal, pulmonary, and ophthalmologic symptoms that fluctuate (See Figures 1 and 2 in original paper). ○ Histological examination generally shows neutrophilic dermatosis, septal panniculitis, and leukocytoclastic vasculitis. An association between UBA1 genotype and cutaneous phenotype was reported showing p.Met41Leu with more frequent neutrophilic dermatosis and p.Met41Val with more frequent purpuric and petechial manifestations. ● Haematological manifestations of VEXAS are broad and include bone marrow failure with consequent progressive cytopenia, increased risk of haematological malignancies (including myeloid neoplasia and plasma cell dyscrasia), and high thrombotic risk. ○ Macrocytic anaemia is almost ubiquitous, occurring in more than 95% of patients with VEXAS syndrome. ○ Bone marrow morphology typically shows hypercellularity for age with left shifted granulopoiesis and vacuolisation of myeloid and erythroid precursors. ○ Mild dyspoiesis is a common but non-specific finding, particularly evident in the megakaryocyte lineage. ○ Although myeloid and erythroid precursor vacuolisation is common and characteristic, it is not disease-specific, and its absence does not preclude a diagnosis of VEXAS syndrome. ○ More severe haematological phenotype has been associated with specific UBA1mut genotypes, and M41L has been associated with increased rates of myelodysplastic syndrome. ■ The incidence of reported myelodysplastic syndrome has been widely varied within described VEXAS syndrome cohorts, from 20% to 55%, likely due to intervariability of myelodysplastic syndrome diagnosis. ■ Most patients have normal chromosomal karyotype and the somatic mutation profile is predominated by DNMT3A and TET2 gene mutations, more associated with age-related clonal haematopoiesis or inflammation than with leukaemia. ■ High-risk myelodysplastic syndrome with increased blasts and acute myeloid leukaemia are uncommon, representing less than 10% of confirmed myeloid neoplasms in patients with VEXAS syndrome. ● Perturbation of UBA1, the master enzyme of cellular ubiquitination, promotes myeloid-driven inflammation that is difficult to control with medications other than glucocorticoids (eg, prednisone 15–35 mg daily). Cytokine-directed therapies (ie, IL-6 and JAK inhibitors) might temporise symptoms and allow glucocorticoid reduction. See Figure 3 in original paper. ○ No randomised controlled trials in VEXAS syndrome have been completed, and data regarding available therapies are mainly based on case series and cohort studies. Additionally, there remain no standardised definitions of treatment response. ○ Hypomethylating agents (ie, azacytidine) can induce clinical and molecular remission in some patients, but are associated with substantial toxicities. ● Haematopoietic cell transplant (HCT) might be an effective treatment in patients who are suitable candidates. The primary indication for HCT is clinically significant and persistent cytopenia nonresponsive to medical therapy, although some patients with refractory-inflammatory disease have undergone successful transplantation. |
