An ACR expert panel urges multidisciplinary care for patients with the life-threatening autoinflammatory syndrome.
Patients with vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome should be managed within multidisciplinary teams, with referral to an expert centre or consultation with clinicians experienced in the disease whenever possible, according to new expert guidance.
VEXAS is a newly recognised, clonal autoinflammatory disease driven by somatic mutations in UBA1 that produces systemic inflammation, bone marrow failure and multisystem organ involvement.
The disease is both complex and potentially life-threatening, with a median survival of approximately 10 years from symptom onset.
The American College of Rheumatology this month issued the world’s first Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel, and published in Arthritis & Rheumatology.
Dr Hugh Caterson, rheumatology staff specialist at Sydney’s Prince of Wales Hospital, welcomed the release of the guidance.
“Broadly, VEXAS is a newly discovered condition. It’s very difficult to treat,” he told Rheumatology Republic.
“There will certainly be patients out in Australia who are going undiagnosed due to under recognition. As they say in the paper, there’s likely, based upon studies of prevalence, possibly a million patients in the world with VEXAS, up to one in 15,000 individuals over the age of 50.
“So it’s something that we should as rheumatologists be thinking about. It’s very good that this is the first ever guidelines. It’s about five years now of research, not clinical trials, but there’s been an accumulation of case studies and cohorts, which is now getting enough evidence that we can put together this first ever guideline.
“So it’s very useful that there is a document out there for us to refer to.”
Australians have been involved in the guidance development, including Sydney rheumatologist Associate Professor Anthony Sammel, and haematologist Dr Annemarie Bosco.
Dr Caterson said he and other Australian specialists were also continuing to work with the International VEXAS Working Group.
“The big thing from this paper is they have a very nice framework of who to consider testing,” he told RR.
“It’s mainly males, but you can’t totally forget females older than 50, and they should have elevated inflammatory markers.
“And we should be thinking about it in the in that sort of demographics, people who have these otherwise unexplained skin inflammation, cartilage inflammation, periorbital oedema and venous thromboembolism are some of the main things, and if they have haematological conditions that are associated with it.
“These are people who we should be testing if they get getting any sort of these combination of these features.”
Defining disease activity in VEXAS is critical to both clinical care and research. Activity is determined by the presence of systemic inflammation or worsening marrow failure, and flares are marked by recurrence of clinical or laboratory features such as fever, rash, cytopenias, or rising inflammatory markers, the guidance author said.
CRP may be a more reliable biomarker than ESR, as hematologic abnormalities themselves can raise ESR in the absence of active inflammation. Bone marrow failure frequently manifested as macrocytic anaemia, thrombocytopenia or lymphopenia, with some patients progressing to transfusion dependence, a factor associated with increased mortality risk.
Haematologic and inflammatory features often tracked together but may worsen independently, underscoring the need for ongoing multidisciplinary monitoring.
The goals of treatment extended beyond inflammation control, the authors wrote.
Haematologists played a central role in evaluating clonal disease, guiding transfusion strategies, and managing the sequelae of bone marrow failure, while rheumatologists, immunologists and internists were positioned to address the inflammatory aspects of the condition and balance the toxicities of immunosuppression.
Dermatologists, pulmonologists, cardiologists, infectious disease specialists and other subspecialists were frequently required to address organ-specific or treatment-related complications, reflecting the systemic burden of this syndrome.
Glucocorticoids remain the mainstay of treatment, with most patients requiring moderate to high daily doses to suppress inflammation. Attempts to taper steroids often result in relapse, and steroid-free remission is rare, even with the use of concomitant steroid-sparing agents.
Caution was advised during tapering, as small reductions in dose can precipitate flares.
“The goal of steroid therapy is to find the minimal glucocorticoid dose required to control disease activity while minimising the complications of long-term therapy,” the authors wrote.
“Medications that target inflammatory pathways (e.g., JAK inhibitors, interleukin-6 [IL-6] inhibitors) are more effective than conventional disease-modifying antirheumatic drugs (DMARDs) (e.g., methotrexate, azathioprine) or B cell–directed therapies (e.g., rituximab).”
The researchers noted that VEXAS was not a heritable disease, and that to date, all reported cases had been attributed to somatic or acquired mutations in UBA1, with no evidence of heritable VEXAS.
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“There has yet to be a documented case of a UBA1 mutation being transmitted to offspring or inherited, consistent with the mutation being restricted to the blood lineage,” they wrote.
“However, no standardised assessment of children has been performed, and there are reports of pathogenic UBA1 mutations being found outside of the blood, in both skin and nail samples.
“In both of these nonhematologic tissues, the UBA1 mutation may be present due to peripheral blood contamination because the culturing of patient fibroblasts did not reveal any pathogenic mutations.”
The authors noted that clinical trials were needed to identify the best treatment for patients with VEXAS.
“Several recent reports have detailed clinical response to various treatments for VEXAS. Most of these studies provide case report– or case series–level data,” they said.
“Data from prospective observational cohort studies are lacking, and randomised controlled trials have not been performed to date. The quality of data to support treatment considerations in VEXAS is therefore low primarily due to selection bias, insufficient follow-up time and precision in the diagnosis of associated MDS, and a lack of standardised definitions of treatment response.
“Efficacy of any medication beyond glucocorticoids has not been definitively established. Furthermore, because VEXAS is typically a progressive clonal disease of the bone marrow, the timing of therapy initiation, in addition to the specific therapeutic strategy, may have an important impact on clinical response and will need to be considered in future therapeutic trials.”
Dr Caterson told RR that even though it was early days for this disease, the release of the guidance was a big step forward, especially in raising awareness of the existence of VEXAS.
He said he treated a number of VEXAS patients in his clinic and there was no doubt it was a complex and debilitating disease.
“I think it [awareness] is creeping out there into the rheumatology community and that’s a good thing,” he said.
