Current and Emerging Treatment Strategies for VEXAS Syndrome

The talk reviewed current and emerging treatment strategies for VEXAS syndrome, emphasizing that management requires a multidisciplinary approach involving dermatology, hematology, rheumatology, and immunology. Because many patients present first with skin disease, dermatologists can help guide diagnosis and treatment. Therapeutic strategies were framed around three pillars: controlling inflammation, targeting the pathogenic clone to modify disease, and providing supportive care. Steroids remain the initial treatment, but VEXAS is often steroid-dependent and requires very slow tapering; many patients need more than 20 mg/day, so the goal is the lowest effective dose to limit toxicity. Conventional DMARDs and TNF inhibitors have generally performed poorly because the disease is driven more by innate immune pathways than adaptive immunity. Among steroid-sparing options, IL-1 inhibitors have shown limited benefit overall, with canakinumab appearing somewhat better tolerated; IL-6 inhibitors such as tocilizumab and sarilumab offer complete responses in only a minority of patients. JAK inhibitors, especially ruxolitinib, currently appear to be the most promising anti-inflammatory agents, but they carry important risks including cytopenias, infections, and thrombosis. However, these agents do not clearly alter the underlying disease course. True disease modification comes from targeting the clone, especially with azacitidine, which can improve inflammatory symptoms and reduce UBA1 variant allele fraction, even in some patients without overt MDS. Allogeneic stem cell transplantation may be curative and has shown encouraging survival and mutation eradication in reported cases, but patient selection is challenging because many patients are older and frail. Supportive care is critical and includes transfusions, growth factors, thromboprophylaxis, and infection prophylaxis, especially against herpes viruses and Pneumocystis when using immunosuppression. Unexplained skin lesions should prompt biopsy and culture because infections such as nontuberculous mycobacteria can mimic inflammation. Monitoring response relies on symptoms, CRP, blood counts, and mutation burden. The prognosis remains guarded, with poorer outcomes in patients carrying valine mutations and better outcomes in leucine mutations. Updated expert guidance recommends starting with steroids, then considering IL-6 or JAK inhibitors if steroid dependence persists, while azacitidine and stem cell transplantation are the main emerging options for hematologic disease modification. Clinical trials such as those involving pacritinib are underway and offer hope for improved therapies.