VEXAS ( vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome )

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ACR Releases International Consensus Guidance on Managing VEXAS Syndrome

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The American College of Rheumatology (ACR) recently issued the first formal international consensus guidance statement on diagnosing and managing vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome (VEXAS), which appeared in Arthritis & Rheumatology.

A multidisciplinary panel of 57 experts from 18 countries — representing rheumatology, hematology, dermatology, genetics, immunology, internal medicine, infectious disease, pathology, and critical care — developed the consensus guidance. The process included structured virtual meetings, subgroup literature reviews of PubMed and Medline for articles published from January 2020 to August 2024, and a 2-day international workshop in Paris in May 2024.

Draft statements were refined through iterative discussions and finalized through electronic voting, with at least 80% agreement required. Evidence quality was assessed using the Grading of Recommendations Assessment, Development and Evaluation methodology, but most recommendations remain conditional due to limited prospective data and a lack of randomized controlled trials.

Clinical Features

Vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome is a hematoinflammatory disease caused by somatic mutations in the UBA1 gene. It primarily affects men aged at least 50 years, though rare cases have been reported among women with monosomy X and younger patients.

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VEXAS is a newly recognized disease, and these clinical guidance statements are intended to help clinicians better manage this condition.

Clinical features are heterogeneous, with persistent systemic inflammation and overlapping rheumatologic, dermatologic, and hematologic manifestations. Common findings include recurrent fevers (75%-100%), skin involvement such as erythema nodosum, panniculitis, and urticarial lesions (85%), lung disease with interstitial infiltrates or pleuropericarditis (55%-95%), auricular and nasal chondritis (14%-64%), ocular inflammation (20%-50%), and venous thrombosis (~50%). The guideline authors emphasized the importance of clinicians and other health care providers being familiar with these common features.

Hematologic abnormalities are frequent, with macrocytic anemia the most common, though lymphopenia, thrombocytopenia, and monocytopenia often emerge as the disease progresses. Vacuoles in bone marrow precursor cells are suggestive but not diagnostic, and UBA1 genetic testing is required for confirmation; VEXAS is not heritable, as all reported cases arise from acquired mutations. Persistent elevation of inflammatory markers accompanied by skin, ocular, lung, or cartilage involvement and/or cytopenia should raise suspicion for VEXAS.

Genetic Testing and Diagnosis

Most patients have missense or splice site mutations in exon 3 of UBA1. Sequencing methods vary based on resources, with next-generation sequencing offering the highest sensitivity for low-level variants, while targeted Sanger sequencing of exon 3 provides a cost-effective initial approach.

Bone marrow testing should be considered when peripheral blood testing is negative despite high clinical suspicion. Because cytopenias are common, bone marrow examination is recommended among patients with confirmed VEXAS to exclude associated hematologic neoplasms, particularly myelodysplastic syndrome (MDS). Interpretation can be challenging due to frequent dysplasia in VEXAS, which can mimic MDS, and therefore, cytogenetics and molecular testing are advised.

Mutational profiles often include DNMT3A and TET2, reflecting overlap with clonal hematopoiesis. Most MDS cases in VEXAS are lower risk, with limited progression to acute myeloid leukemia.

Management and Outcomes

Management of VEXAS requires a multidisciplinary team, ideally with referral to expert centers. Treatment goals include controlling inflammation, preventing bone marrow failure, minimizing treatment-related complications, and improving quality of life.

Glucocorticoids remain the cornerstone of therapy, often requiring moderate to high daily doses, but tapering should be attempted to reduce long-term toxicity. Steroid-sparing therapies targeting innate immune pathways — such as Janus kinase inhibitors and interleukin-6 inhibitors — have shown greater benefit than conventional disease-modifying anti-rheumatic drugs or B cell-directed therapies. Azacitidine may reduce clonal burden in some patients, while allogeneic stem cell transplantation offers a potential cure but is limited to carefully selected patients with severe or refractory disease due to high procedural risks.

Supportive measures are essential, including prophylaxis against opportunistic infections, thromboprophylaxis for patients at risk for thromboembolic disease, and active management of glucocorticoid-related complications such as bone loss and cardiovascular risks. Despite these approaches, the median survival from symptom onset is approximately 10 years.

Conclusion

This consensus guidance highlights the need for early recognition of VEXAS, genetic confirmation of UBA1 mutations, and integrated management addressing both inflammatory and hematologic disease.

The guideline authors concluded, "VEXAS is a newly recognized disease, and these clinical guidance statements are intended to help clinicians better manage this condition."

This article originally appeared on Rheumatology Advisor