Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS - 05/01/22

Doi : 10.1016/j.jaci.2021.05.014

Caspar I. van der Made, MD ^a,^b, Judith Potjewijd, MD ^c, Annemiek Hoogstins, MD ^d, Huub P.J. Willems, MD ^e, Arjan J. Kwakernaak, MD, PhD ^f, Ruud G.L. de Sevaux, MD, PhD ^a,^g, Paul L.A. van Daele, MD, PhD ^h, Annet Simons, PhD ^b, Marloes Heijstek, MD, PhD ⁱ, David B. Beck, MD, PhD ^j, Mihai G. Netea, MD, PhD ^a, Pieter van Paassen, MD, PhD ^c, A. Elizabeth Hak, MD, PhD ^f, Lars T. van der Veken, PhD ^k, Marielle E. van Gijn, PhD ^l, Alexander Hoischen, PhD ^a,^b, Frank L. van de Veerdonk, MD, PhD ^a, Helen L. Leavis, MD, PhD ^i,^{^{∗
These authors contributed equally to this work.}}, Abraham Rutgers, MD, PhD ^d,^⁎^{^{∗
These authors contributed equally to this work.}}
^a Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
^b Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
^c Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands
^d Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
^e Department of Internal Medicine, Maxima Medisch Centrum, Eindhoven, The Netherlands
^f Department of Internal Medicine and Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Center, location AMC/Meibergdreef, Amsterdam, The Netherlands
^g Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands
^h Department of Internal Medicine and Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands
ⁱ Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
^j National Human Genome Research Institute, National Institutes of Health, Bethesda, Md
^k Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands
^l Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

^∗Corresponding author: Abraham Rutgers, MD, PhD, Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen 9700RB, The Netherlands.Department of Rheumatology and Clinical ImmunologyUniversity Medical Center GroningenUniversity of GroningenGroningenThe Netherlands9700RB

Abstract

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.

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Key words : UBA1, VEXAS, autoinflammation, somatic variants

Abbreviations used : CT, IEI, IQR, MDS, PET, VAF, VEXAS

Plan

Introduction

Results and discussion

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.).

Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.

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Vol 149 - N° 1

P. 432 - janvier 2022 Retour au numéro

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Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS - 05/01/22

Abstract

Background

Objective

Methods

Results

Conclusion

Plan

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