TY - JOUR
T1 - Adult-onset autoinflammation caused by somatic mutations in UBA1
T2 - A Dutch case series of patients with VEXAS
AU - van der Made, Caspar I
AU - Potjewijd, Judith
AU - Hoogstins, Annemiek
AU - Willems, Huub P J
AU - Kwakernaak, A J
AU - de Sevaux, Ruud G L
AU - van Daele, Paul L A
AU - Simons, Annet
AU - Heijstek, Marloes
AU - Beck, David B
AU - Netea, Mihai G
AU - van Paassen, Pieter
AU - Hak, A E
AU - van der Veken, Lars T
AU - van Gijn, Marielle E
AU - Hoischen, Alexander
AU - van der Veerdonk, Frank L
AU - Leavis, Helen L
AU - Rutgers, Abraham
N1 - Funding Information:
Supported by the Solve-RD project of the European Union's Horizon 2020 Research and Innovation Programme (grant 779257 [to A.H.]), an ERC Advanced Grant (no. 833247 [to M.G.N.]), a Spinoza Grant of The Netherlands Organization for Scientific Support (to M.G.N.), a ZonMW Vidi Grant (to F.L.v.d.V.), a Radboud Institute for Molecular Life Sciences PhD grant (to M.N.), and the National Institutes of Health Intramural Research Program (to D.B.).
Funding Information:
Supported by the Solve-RD project of the European Union’s Horizon 2020 Research and Innovation Programme (grant 779257 [to A.H.]), an ERC Advanced Grant (no. 833247 [to M.G.N.]), a Spinoza Grant of The Netherlands Organization for Scientific Support (to M.G.N.), a ZonMW Vidi Grant (to F.L.v.d.V.), a Radboud Institute for Molecular Life Sciences PhD grant (to M.N.), and the National Institutes of Health Intramural Research Program (to D.B.).
Publisher Copyright:
© 2021
PY - 2022/1
Y1 - 2022/1
N2 - BACKGROUND: A novel autoinflammatory syndrome was recently described in male patients who harbored somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenia, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis, and vasculitis, which is abbreviated as VEXAS.OBJECTIVE: This study aimed to (retrospectively) diagnose VEXAS in patients who had previously been registered as having unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease.METHODS: A systematic reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed. When no sequencing data were available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS.RESULTS: A total of 12 male patients who carried mutations in UBA1 were identified. These patients presented with adult-onset (mean age 67 years, range 47-79 years) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory, with a high mortality rate of 50%.CONCLUSION: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures and provide better prognostic information and more suitable treatment options, including stem cell transplantation.
AB - BACKGROUND: A novel autoinflammatory syndrome was recently described in male patients who harbored somatic mutations in the X-chromosomal UBA1 gene. These patients were characterized by adult-onset, treatment-refractory inflammation with fever, cytopenia, dysplastic bone marrow, vacuoles in myeloid and erythroid progenitor cells, cutaneous and pulmonary inflammation, chondritis, and vasculitis, which is abbreviated as VEXAS.OBJECTIVE: This study aimed to (retrospectively) diagnose VEXAS in patients who had previously been registered as having unclassified autoinflammation. We furthermore aimed to describe clinical experiences with this multifaceted, complex disease.METHODS: A systematic reanalysis of whole-exome sequencing data from a cohort of undiagnosed patients with autoinflammation from academic hospitals in The Netherlands was performed. When no sequencing data were available, targeted Sanger sequencing was applied in cases with high clinical suspicion of VEXAS.RESULTS: A total of 12 male patients who carried mutations in UBA1 were identified. These patients presented with adult-onset (mean age 67 years, range 47-79 years) autoinflammation with systemic symptoms, elevated inflammatory parameters, and multiorgan involvement, most typically involving the skin and bone marrow. Novel features of VEXAS included interstitial nephritis, cardiac involvement, stroke, and intestinal perforation related to treatment with tocilizumab. Although many types of treatment were initiated, most patients became treatment-refractory, with a high mortality rate of 50%.CONCLUSION: VEXAS should be considered in the differential diagnosis of males with adult-onset autoinflammation characterized by systemic symptoms and multiorgan involvement. Early diagnosis can prevent unnecessary diagnostic procedures and provide better prognostic information and more suitable treatment options, including stem cell transplantation.
KW - autoinflammation
KW - somatic variants
KW - UBA1
KW - VEXAS
UR - http://www.scopus.com/inward/record.url?scp=85108512225&partnerID=8YFLogxK
U2 - 10.1016/j.jaci.2021.05.014
DO - 10.1016/j.jaci.2021.05.014
M3 - Article
C2 - 34048852
SN - 0091-6749
VL - 149
SP - 432-439.e4
JO - The Journal of Allergy and Clinical Immunology
JF - The Journal of Allergy and Clinical Immunology
IS - 1
ER -