Allogeneic haematopoietic stem cell transplantation for <scp>VEXAS</scp> syndrome: <scp>UK</scp> experience

Al‐Hakim, Adam; Poulter, James A.; Mahmoud, Dina G.; Rose, Ailsa M. S.; Elcombe, Suzanne; Lachmann, Helen; Cargo, Catherine; Duncan, Christopher; Bishton, Mark; Bigley, Venetia; Khan, Anjum; Savic, Sinisa

doi:10.1111/bjh.18488

Cited by 34 publications

(15 citation statements)

References 6 publications

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“…Establishing the clinical spectrum of UBA1 variants using biobanks is a necessary step to better define disease criteria and testing recommendations. Identification of UBA1 pathogenic variants defines VEXAS syndrome and can alter treatment, prognosis, and screening plans . Therefore, broad UBA1 testing in patients with features indicative of VEXAS, including those with nonspecific differential diagnoses, such as macrocytic anemia of uncertain etiology in association with elevated inflammatory markers, may be indicated.…”

Section: Discussionmentioning

confidence: 99%

Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population

Beck

Bodian

Shah

et al. 2023

JAMA

106

100

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ImportanceVEXAS (vacuoles, E1-ubiquitin-activating enzyme, X-linked, autoinflammatory, somatic) syndrome is a disease with rheumatologic and hematologic features caused by somatic variants in UBA1. Pathogenic variants are associated with a broad spectrum of clinical manifestations. Knowledge of prevalence, penetrance, and clinical characteristics of this disease have been limited by ascertainment biases based on known phenotypes.ObjectiveTo determine the prevalence of pathogenic variants in UBA1 and associated clinical manifestations in an unselected population using a genomic ascertainment approach.Design, Setting, and ParticipantsThis retrospective observational study evaluated UBA1 variants in exome data from 163 096 participants within the Geisinger MyCode Community Health Initiative. Clinical phenotypes were determined from Geisinger electronic health record data from January 1, 1996, to January 1, 2022.ExposuresExome sequencing was performed.Main Outcomes and MeasuresOutcome measures included prevalence of somatic UBA1 variation; presence of rheumatologic, hematologic, pulmonary, dermatologic, and other findings in individuals with somatic UBA1 variation on review of the electronic health record; review of laboratory data; bone marrow biopsy pathology analysis; and in vitro enzymatic assays.ResultsIn 163 096 participants (mean age, 52.8 years; 94% White; 61% women), 11 individuals harbored likely somatic variants at known pathogenic UBA1 positions, with 11 of 11 (100%) having clinical manifestations consistent with VEXAS syndrome (9 male, 2 female). A total of 5 of 11 individuals (45%) did not meet criteria for rheumatologic and/or hematologic diagnoses previously associated with VEXAS syndrome; however, all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11 [91%]) with concomitant thrombocytopenia (10/11 [91%]). Among the 11 patients identified, there was a pathogenic variant in 1 male participant prior to onset of VEXAS-related signs or symptoms and 2 female participants had disease with heterozygous variants. A previously unreported UBA1 variant (c.1861A&gt;T; p.Ser621Cys) was found in a symptomatic patient, with in vitro data supporting a catalytic defect and pathogenicity. Together, disease-causing UBA1 variants were found in 1 in 13 591 unrelated individuals (95% CI, 1:7775-1:23 758), 1 in 4269 men older than 50 years (95% CI, 1:2319-1:7859), and 1 in 26 238 women older than 50 years (95% CI, 1:7196-1:147 669).Conclusions and RelevanceThis study provides an estimate of the prevalence and a description of the clinical manifestations of UBA1 variants associated with VEXAS syndrome within a single regional health system in the US. Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum.

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Section: Discussionmentioning

confidence: 99%

Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population

Beck

Bodian

Shah

et al. 2023

JAMA

106

100

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“…Hierfür liegen ebenfalls erste Fallberichte vor [ 29 ]. Eine kritische Patient*innenauswahl im Hinblick auf Erkrankungsalter und Komorbiditäten ist dabei essenziell [ 30 ].…”

Section: Monogenetische Fiebersyndromeunclassified

Autoinflammatory syndromes

Bonnekoh

Krusche

Feist³

et al. 2023

Innere Medizin

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Das Konzept der Autoinflammation umfasst eine heterogene Gruppe monogenetischer und polygener Erkrankungen. Kennzeichnend ist eine übermäßige Aktivierung des angeborenen Immunsystems ohne antigenspezifische T‑Zellen oder Autoantikörperbildung. Periodische Fieberschübe und erhöhte serologische Entzündungszeichen sind charakteristisch. Zu den monogenetischen Erkrankungen zählen unter anderem das familiäre Mittelmeerfieber sowie das neu beschriebene VEXAS-Syndrom ( VEXAS „vacuoles, E1 enzyme, X‑linked, autoinflammatory, somatic“). Zu den heterogenen Erkrankungen zählen unter anderem das Still-Syndrom und das seltene Schnitzler-Syndrom. Die Therapie zielt auf die Verhinderung der überschießenden Entzündungsreaktion ab, um langfristige Schäden, wie das Auftreten einer Amyloid-A(AA)-Amyloidose, zu vermeiden.

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“…Given the effects of UBA1 dysfunction in VEXAS pathogenesis it is rationale to use more general chemotherapies, such as the hypomethylating agent azacytidine 25,26 . In severe cases with multi‐systemic and hematological involvement, bone marrow transplantation may be a curative therapeutic option 27,28 …”

Section: Recurrent Fevermentioning

confidence: 99%

What the genes tell us in the VEXAS syndrome? A rheumatologist's perspective

Kobak

2023

Int J of Rheum Dis

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Allogeneic haematopoietic stem cell transplantation for VEXAS syndrome: UK experience

Cited by 34 publications

References 6 publications

Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population

Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population

Autoinflammatory syndromes

What the genes tell us in the VEXAS syndrome? A rheumatologist's perspective

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