Toward a pathophysiology inspired treatment of VEXAS syndrome

VEXAS syndrome has an unmet need for therapeutic interventions. Even if few data exist regarding the treatment of this newly described syndrome, different options can be proposed given the unique pathophysiological consequences of the clonal dominance of UBA1 mutated hematopoietic stem cells. To date, allogeneic transplantation is the only curative option, but many questions remain regarding the selection of eligible patients, the conditioning regimen or management of toxicities that may be unique to VEXAS patients. Alternatively, drugs used in myelodysplastic syndrome such as hypomethylating agents or lenalidomide are interesting candidates, which could theoretically have also an effect on the clone. Another strategy is to target the inflammatory cascade, by inhibiting proinflammatory cytokines (such as TNFα, IL1, IL6) or effector cells, for example with JAK inhibitors. Whatever the choice of treatment for VEXAS patients, supportive care is always needed to be considered to manage frequent complications such as cytopenia, thrombosis and infections. Finally, we discuss the challenges of the design of clinical trials for VEXAS patients, from inclusion criteria to clinical and biological endpoints of activity.