Caspar I van der Made1, Judith Potjewijd2, Annemiek Hoogstins3, Huub P J Willems4, Arjan J Kwakernaak5, Ruud G L de Sevaux6, Paul L A van Daele7, Annet Simons8, Marloes Heijstek9, David B Beck10, Mihai G Netea11, Pieter van Paassen2, A Elizabeth Hak5, Lars T van der Veken12, Marielle E van Gijn13, Alexander Hoischen1, Frank L van de Veerdonk11, Helen L Leavis9, Abraham Rutgers14. 1. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 2. Department of Internal Medicine, Maastricht University Medical Center+, Maastricht, The Netherlands. 3. Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 4. Department of Internal Medicine, Maxima Medisch Centrum, Eindhoven, The Netherlands. 5. Department of Internal Medicine and Department of Rheumatology and Clinical Immunology, Amsterdam University Medical Center, location AMC/Meibergdreef, Amsterdam, The Netherlands. 6. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands. 7. Department of Internal Medicine and Department of Immunology, Erasmus Medical Center, Rotterdam, The Netherlands. 8. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 9. Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 10. National Human Genome Research Institute, National Institutes of Health, Bethesda, Md. 11. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 12. Department of Genetics, Division Laboratories, Pharmacy and Biomedical Genetics, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 13. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 14. Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. Electronic address: A.Rutgers@umcg.nl.
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.
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.
Authors: Amrita Goyal; Damodaran Narayanan; Waihay Wong; Alvaro C Laga; Nathan T Connell; Susan Y Ritter; Gabriela Cobos Journal: JAAD Case Rep Date: 2022-03-02