medwireNews: Azacitidine and tocilizumab are more effective than other targeted therapies for the treatment of VEXAS syndrome, a real-world UK study finds.
Azacitidine, in particular, demonstrated “high response rates and a possible disease-modifying role beyond symptom control supported by sustained haematological improvements, potential for reaching transfusion independence, and robust glucocorticoid sparing effect,” say Sinisa Savic, from Leeds Institute for Rheumatic and Musculoskeletal Medicine, and colleagues, in The Lancet Rheumatology.
VEXUS – vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic – syndrome is a recently described autoinflammatory disorder, treated with prednisolone as a first-line therapy, as well as therapies targeted to manage refractory inflammation and improve hematological function.
However, say the researchers, “the retrospective nature of current evidence, heterogeneous response definitions, and paucity of head-to-head comparisons limit definitive conclusions about optimal therapeutic strategies.”
To address this, the researchers analyzed the outcomes of a possible 71 targeted therapies in 59 patients with genetically confirmed VEXAS syndrome from the UK VEXAS registry. They had a mean age of 71 years and all but one were men.
The five main categories of therapy were tocilizumab based on weight or as a weekly 162 mg subcutaneous injection (n=19), subcutaneous anakinra 100 mg (n=13), subcutaneous azacitidine (n=13), oral baricitinib 4 mg/day (n=11), and prednisolone only (n=10).
Clinical and biochemical data were recorded at diagnosis, initiation of treatment, and at 3-, 6-, and 12-month follow-ups. Complete response was defined as clinical remission, C-reactive protein (CRP) 10 mg/L or less, and prednisolone doses of 10 mg/day or lower, and partial response as clinical remission with at least 50% reduction in both CRP and glucocorticoid dose from baseline.
Myelodysplastic syndrome was present in 46% of patients overall and predominantly among those receiving azacitidine, at a rate of 77%, while 45% of the total patients had thrombocytopenia.
At 6 months, 30 patients continued to take therapy, among whom the rate of complete or partial response was 91% in 11 patients receiving azacitidine, 64% in 11 patients receiving tocilizumab, 100% in three patients receiving anakinra, and 40% in five patients receiving baricitinib. The corresponding rates of complete response were 27%, 36%, 33%, and 0%. The likelihood of any response was greatest for azacitidine, with a significant risk ratio of 2.47 compared with all the other therapies combined.
“These findings highlight important differences in both the initial response rates and long-term durability of different therapeutic approaches,” the researchers comment.
They acknowledge that while there was a 100% response rate among patients taking anakinra, the discontinuation rate with this therapy at 12 months was high, at 62%, primarily due to serious injection-site infections. This compared with an overall discontinuation rate of 39%, ranging from 26% with tocilizumab to 45% with baricitinib.
Treatments were discontinued mainly due to serious adverse events (AEs), occurring in 17% of patients overall, death (13%), or insufficient disease control or treatment switching (11%). Infections were the most common AE, particularly in patients receiving azacitidine or tocilizumab, at rates of 62% and 47%, compared with 18% among those receiving baricitinib.
Almost all the patients were taking glucocorticoids prior to targeted therapy, and these were reduced or minimized to the greatest extent at 12 months among patients in the azacitidine and anakinra groups, with daily prednisolone doses reduced to 5 mg or less in 60% and 50% of patients, respectively. By comparison, respective rates of 25% and 15% were seen for those in the baricitinib and tocilizumab groups.
Six-month reductions in CRP were greatest with tocilizumab (from median 30 mg/L to 4 mg/L) and anakinra (18 mg/L to 2 mg/L). This compared with an increase from 9 mg/L to 16 mg/L among those given azacitidine.
However, hemoglobin responses were more pronounced among the azacitidine group, improving from a mean at baseline of 104 g/L to 120 g/L at 6 months, which was maintained at 12 months.
There was also evidence that azacitidine, a hypomethylating agent, might help to eliminate mutated stem cells. Alongside clinical improvement, two patients receiving azacitidine showed “substantial reductions in UBA1 variant allele frequency,” from 71% to 33% in one patient and from 81% to 7% in the other, the researchers report.
“This improvement was not observed in a patient receiving tocilizumab,” they note.
Matthew Koster, of the Mayo Clinic in Rochester, Minnesota, USA, says in an accompanying comment that this finding warrants “evaluation in prospective studies of hypomethylating agents to evaluate efficacy in patients with VEXAS syndrome with or without myelodysplastic syndrome,” given that this benefit was also reported by the French VEXAS study group.
The study authors comment that the practical implications of their findings include considering “early use of azacitidine in patients with clinically significant cytopenias or co-existing myelodysplastic syndrome,” while tocilizumab “offers a balanced efficacy–safety profile as an alternative first-line therapy,” and anakinra “could be considered for patients with severe flares who require admission to hospital as it can be delivered intravenously and has a short half-life.”
Koster also points out that the research illustrates the need to “evaluate clinical, biochemical, and haematological domains and mutational burden, individually and in aggregate,” to best determine treatment response.
“Although such a definition might seem too stringent, for patients with VEXAS syndrome, anything less would be considered incomplete,” he argues.
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Lancet Rheumatol 2025; doi:10.1016/S2665-9913(25)00034-7
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