Das VEXAS-Syndrom

ZUSAMMENFASSUNG

Das VEXAS-Syndrom ist eine neu identifizierte autoinflammatorische Systemerkrankung. Dabei steht das Akronym VEXAS für Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic. Zugrundeliegend für die Erkrankung ist eine somatische Mutation des UBA1-Gens. Dieses kodiert für das E1-Enzym, welches für die Ubiquitinierung von Proteinen verantwortlich ist. Aufgrund der fehlerhaften Ubiquitinierung kommt es zu einer Überregulierung von proinflammatorischen Zytokinen. Da das UBA1-Gen auf dem X-Chromosom liegt, sind von der Erkrankung fast nur Männer betroffen. Interessanterweise tritt das VEXAS-Syndrom erst in der 2. Lebenshälfte auf und die Betroffenen können eine Vielzahl von inflammatorischen klinischen Symptomen aufweisen. Insbesondere das Vorliegen von zytoplasmatischen Vakuolen im Knochenmark ist charakteristisch. Hierbei kommt es in der klinischen Ausprägung häufig zu Überlappungen aus hämatologischen, dermatologischen und rheumatologischen Krankheitsbildern. Der Artikel gibt einen Überblick über die Pathophysiologie, Klinik und Diagnostik des Erkrankungsbildes.

ABSTRACT

VEXAS syndrome is a newly identified autoinflammatory systemic disease. The VEXAS acronym stands for vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic. The disease is caused by a somatic mutation of the UBA1 gene. This gene is responsible for the E1 enzyme, which is involved in the ubiquitination of proteins. Due to abnormal ubiquitination, proinflammatory cytokines are grossly upregulated. Since the UBA1 gene is located on the X chromosome, the disease affects almost only males. Interestingly, VEXAS syndrome does occur in the 2. half of life and affected individuals may present with a variety of inflammatory clinical symptoms. In particular, the presence of cytoplasmic vacuoles in the bone marrow is characteristic. The clinical manifestations often overlap between hematological, dermatological and rheumatological diseases. This article provides an overview of the pathophysiology, clinical manifestations and diagnostic features of the disease.

Schlüsselwörter

Autoinflammation - Hämatoinflammation - X-Chromosom - Vakuolen - myelodypslastisches Syndrom - Polychondritis - Ruxolitinib-Stammzelltransplantation

Keywords

Autoinflammation - hematoinflammation - X-chromosome - vacuoles - myelodysplastic syndrome - polychondritis - ruxolitinib stem cell transplantation

Publication History

Article published online:
07 September 2022

• Literatur

• 1 Poulter JA, Collins JC, Cargo C. et al Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. Blood 2021; 137 (26) 3676-3681
• 2 Bourbon E, Heiblig M, Gerfaud Valentin M. et al Therapeutic options in VEXAS syndrome: insights from a retrospective series. Blood 2021; 137 (26) 3682-3684
• 3 Zakine E, Schell B, Battistella M. et al UBA1 Variations in Neutrophilic Dermatosis Skin Lesions of Patients With VEXAS Syndrome. JAMA Dermatol [Internet] 2021 Sep 8 [cited 2021 Oct 6]; Available from https://jamanetwork.com/journals/jamadermatology/fullarticle/2784048
• 4 Beck DB, Ferrada MA, Sikora KA. et al Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 2020; 383 (27) 2628-2638
• 5 Shaukat F, Hart M, Burns T, Bansal P.. UBA1 and DNMT3A Mutations in VEXAS Syndrome. A Case Report and Literature Review. Modern Rheumatology Case Reports 2021 Sep 4;rxab021
• 6 Dehghan N, Marcon KM, Sedlic T. et al Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: fevers, myalgia, arthralgia, auricular chondritis, and erythema nodosum. The Lancet 2021; 398 10300 621
• 7 Ferrada MA, Sikora KA, Luo Y. et al Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients with VEXAS Syndrome. Arthritis & Rheumatology 2021 Mar 28;art.41743
• 8 Tsuchida N, Kunishita Y, Uchiyama Y. et al Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis. Ann Rheum Dis 2021 Mar 31;annrheumdis-2021–220089
• 9 Muratore F, Marvisi C, Castrignanò P. et al VEXAS syndrome: a case series from a single-center cohort of Italian patients with vasculitis. Arthritis Rheumatol 2021 Oct 5
• 10 Matsumoto H, Asano T, Tsuchida N. et al Behçet’s disease with a somatic UBA1 variant: Expanding spectrum of autoinflammatory phenotypes of VEXAS syndrome. Clinical Immunology 2022; 238: 108996
• 11 Georgin-Lavialle S, Terrier B, Guedon AF. et al Further characterization of clinical and laboratory features occurring in VEXAS syndrome in a large-scale analysis of multicenter case-series of 116 French patients. Br J Dermatol 2021 Oct 10
• 12 Gurnari C, Pagliuca S, Durkin L. et al Vacuolization of hematopoietic precursors: an enigma with multiple etiologies. Blood 2021; 137 (26) 3685-3689
• 13 Zeeck M, Kötter I, Krusche M.. VEXAS-Syndrom. Z Rheumatol [Internet] 2022 Feb 18 [cited 2022 Jul 15]. Available from https://link.springer.com/10.1007/s00393-022-01169-6
• 14 Arlet J-B, Terrier B, Kosmider O. Mutant UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 2021; 384 (22) 2163-2165
• 15 Grey A, Cheong PL, Lee FJ. et al A Case of VEXAS Syndrome Complicated by Hemophagocytic Lymphohistiocytosis. J Clin Immunol 2021; 41 (07) 1648-1651
• 16 Staels F, Betrains A, Woei-A-Jin FJSH. et al Case Report: VEXAS Syndrome: From Mild Symptoms to Life-Threatening Macrophage Activation Syndrome. Front Immunol 2021; 12: 678927
• 17 Euvrard R, Fournier T, Georgescu D. et al VEXAS syndrome-related AA amyloidosis: a case report. Rheumatology 2021 Sep 8;keab683
• 18 Heiblig M, Ferrada MA, Koster MJ. et al Ruxolitinib is more effective than other JAK Inhibitors to treat VEXAS Syndrome: a retrospective multi center study. Blood 2022 May 24;blood.2022016642
• 19 Campochiaro C, Tomelleri A, Cavalli G. et al Successful use of cyclosporin A and interleukin-1 blocker combination therapy in VEXAS syndrome: a single-center case series. Arthritis & Rheumatology 2022; 74 (07) 1302-1303
• 20 Comont T, Heiblig M, Rivière E. et al Azacitidine for patients with Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome (VEXAS) and myelodysplastic syndrome: data from the French VEXAS registry. Br J Haematol 2021 Oct 14
• 21 Diarra A, Duployez N, Terriou L. Mutant UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med 2021; 384 (22) 2163-2164
• 22 Loschi M, Roux C, Sudaka I. et al Allogeneic stem cell transplantation as a curative therapeutic approach for VEXAS syndrome: a case report. Bone Marrow Transplant 2022; 57 (02) 315-318