Clinicians should consider using azacitidine early in the treatment of VEXAS syndrome patients who have clinically significant cytopenias or co-existing myelodysplastic syndrome, researchers say.
The advice follows the first comprehensive analysis of the real-world treatment of UK patients with VEXAS [vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic] syndrome [link here].
With little therapeutic evidence and no agreed treatment recommendations for this recently described autoinflammatory disorder, UK researchers set out to retrospectively compare treatment outcomes of targeted therapies versus prednisolone alone in the largest UK cohort of patients with VEXAS syndrome to date.
Their study examined 71 targeted therapies in 59 patients with genetically confirmed VEXAS syndrome (pathogenic UBA1 mutation) at six tertiary referral centres across the UK between July 2014 and October 2024.
About a third of patients (n=19) received tocilizumab, whereas the rest received anakinra (n=13), azacitidine (n=13), baricitinib (n=11), or prednisolone only (n=10), according to their findings, published in The Lancet Rheumatology (link here).
Azacitidine had the highest rates of overall response and complete response at six months (risk ratio 2.47, 95% CI 1.18–5.20; p=0.018), with an overall response in 10 (91%) of 11 patients and a complete response in three (36%). At 12 months, five (100%) of five patients who were still taking the drug had an overall response, with a complete response in three (60%).
Anakinra also showed promising efficacy at three months, but by six months its high drop-out rate – eight of 13 recipients – had taken the shine off its good response rates.
Meanwhile, the effectiveness of tocilizumab was maintained in just over three-quarters (77%) of the 13 patients who were still on the drug at 12 months, with 10 responding, two (15%) of them completely.
However, the lower therapeutic benefit of baricitinib persisted, with a partial response in one (25%) of the four patients continuing to receive the drug at 12 months and no complete responses.
Looking at baseline factors, the researchers found that an absence of fever or thromboembolism at diagnosis was associated with better outcomes at 12 months, with a complete response being 80% less likely with unexplained fevers (RR 0.21) and any response nearly 90% less likely with venous thromboembolism (RR 0.12).
“In this UK cohort of patients with VEXAS syndrome, azacitidine and tocilizumab showed superior effectiveness compared with anakinra, baricitinib, and prednisolone only,” concluded the UK team of researchers led by Dr Adam Al-Hakim from Leeds Institute for Rheumatic and Musculoskeletal medicine.
“Treatment algorithms should consider early use of azacitidine in patients with clinically significant cytopenias or co-existing myelodysplastic syndrome, whereas tocilizumab offers a balanced efficacy–safety profile as an alternative first-line therapy.
“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,” they added.
Azacitidine steroid-sparing, improves blood counts
Patients receiving azacitidine were also more likely to have reduced doses of prednisone ≤5 mg daily by 12 months compared to other agents. Furthermore, the research team also found that azacitidine was the only agent associated with reducing the UBA1 variant allele frequency.
Patients taking azacitidine also showed the greatest increase in haemoglobin at six months (from mean concentration 104 g/L [SD 17·5] to 120 g/L [14·4]), while the most consistent improvements in median CRP concentrations were seen in tocilizumab (from 30 mg/L [IQR 13–45] to 4 mg/L [3–37]) and anakinra recipients (from 18 mg/L [11–52] to 2 mg/L [1–28]), the researchers said.
“Azacitidine showed promising effectiveness, improved blood counts, and favourable steroid-sparing effects in patients, suggesting a potential disease-modifying role beyond symptom control,” the researchers noted.
“The study confirms the effectiveness of tocilizumab in selected patients and reports use of baricitinib, with this drug showing lower effectiveness than other JAK inhibitors for patients with VEXAS syndrome – important, given that baricitinib might be the only available agent in some countries.”
A call for an international consensus
Writing in an accompanying editorial [link here], US-based rheumatologist Dr Matthew Koster from the Mayo Clinic, Rochester, stressed the need for consistency in definitions of VEXAS in order for studies to be more broadly compared. “As investigators, we need to consider if the current response definitions are appropriate or sufficient. VEXAS syndrome spans the disciplines of haematology and rheumatology, and language and response definitions are not universal between these fields”, he wrote.
He added that international consensus guidelines on the definition of response and remission were also imperative to guide well-designed prospective clinical trials.