American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel

Abstract

Objective: Vacuoles E1 enzyme X-linked autoinflammatory somatic syndrome (VEXAS) is a recently identified rare genetic disorder associated with somatic mutations in the UBA1 gene. VEXAS presents with a combination of inflammatory and hematologic manifestations, leading to increased morbidity and mortality.

Methods: Given the variability in disease presentation and the limited number of studies to date, no clinical documents currently exist to provide guidance to health care providers about the management of VEXAS. To address this gap, we formed an international multidisciplinary panel of VEXAS experts.

Results: Through formalized meetings and a voting process, the group developed consensus clinical guidance considerations for the management of VEXAS. These considerations offer practical advice on several key topics: (1) clinical features of VEXAS, (2) UBA1 screening methods, (3) the diagnosis of myelodysplastic syndromes (MDSs) in patients with VEXAS, and (4) prognosis and management. The aim is to provide expert guidance on which patients to test, how to test for VEXAS, how to approach MDS in the context of VEXAS, and considerations for management.

Conclusion: This work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management.

Figure 1

When to consider testing for VEXAS. A list of typical and less common disease features of VEXAS are presented to help guide clinicians regarding when to consider testing for acquired mutations in UBA1. Bx, biopsy confirmation required; CRP, C‐reactive protein; ESR, erythrocyte sedimentation rate; LCV, leukocytoclastic vasculitis; MCV, mean corpuscular volume; MDS, myelodysplastic syndrome; SOC, standard of care; VEXAS, vacuoles E1 enzyme X‐linked autoinflammatory somatic syndrome.

Figure 2

Genetic testing strategies for VEXAS. A practical approach to genetic testing is shown. Testing can be performed on bone marrow aspirate or peripheral blood. In rare instances when a bone marrow or peripheral blood sample is not available, testing could be performed on affected tissue. Different genetic testing strategies have different sensitivities to detect mutational burden of disease. Choice of genetic testing may be guided by access to resources. HTS, high throughout sequencing; PCR, polymerase chain reaction; VEXAS, vacuoles E1 enzyme X‐linked autoinflammatory somatic syndrome.

Figure 3

Approach to hematological diagnoses in VEXAS. A flow diagram is provided regarding a practical approach to hematologic evaluation of patients with a genetically confirmed diagnosis of VEXAS. ICC, International Consensus Classification; MDS, myelodysplastic syndrome; M:E, myeloid‐to‐erythroid; MGUS, Monoclonal Gammopathy of Undetermined Significancy; MM, multiple Myeloma; WHO, World Health Organization; VEXAS, vacuoles E1 enzyme X‐linked autoinflammatory somatic syndrome.

Figure 4

Treatment of VEXAS. A practical treatment algorithm is provided for clinical management of VEXAS syndrome based on current available evidence. Treatment decisions should be customized to each individual patient. CS, corticosteroid; DEXA, dual‐energy x‐ray absorptiometry; GC, glucocorticoid; HSCT, hematopoietic stem cell transplantation; HSV, Virus Herpes Simplex; IL‐1, interleukin‐1; IV, intravenous; JAKi, JAK inhibitor; NTM, nontuberculous mycobacteria; PJP, Pneumocystis jiroveci pneumonia; VEXAS, vacuoles E1 enzyme X‐linked autoinflammatory somatic syndrome; VZV, varicella‐zoster virus. Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.43287/abstract.