VEXAS Syndrome—Review

Abstract

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined refractory adult-onset autoinflammatory syndrome caused by somatic mutations in the ubiquitin-like modifier-activating enzyme 1 (UBA1) gene in hematopoietic stem and progenitor cells, resulting in a shift in UBA1 isoform expression. Thus, patients develop a spectrum of systemic inflammatory manifestations and hematologic symptoms. To date, patients respond poorly to immune suppressive drugs, except high-dose glucocorticoids, and no treatment guidelines have been established. Given the high mortality rate, VEXAS syndrome needs to be taken seriously by physicians in all specialties. This article aims to describe the key features, pathogenesis, and clinical manifestations of VEXAS syndrome to better understand the targeted treatment and improve the prognosis of VEXAS syndrome.

Keywords

VEXAS syndrome / UBA1 / vacuoles / autoinflammatory / hematological disorders

References

[1] 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

[2] Beck DB, Werner A, Kastner DL, Aksentijevich I. Disorders of ubiquitylation: unchained inflammation. Nat Rev Rheumatol 2022;18(08):435-447

[3] Lacombe V, Prevost M, Bouvier A. et al. Vacuoles in neutrophil precursors in VEXAS syndrome: diagnostic performances and threshold. Br J Haematol 2021;195(02):286-289

[4] 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

[5] Grayson PC, Patel BA, Young NS. VEXAS syndrome. Blood 2021;137(26):3591-3594

[6] Obiorah IE, Patel BA, Groarke EM. et al. Benign and malignant hematologic manifestations in patients with VEXAS syndrome due to somatic mutations in UBA1. Blood Adv 2021;5(16):3203-3215

[7] Patel N, Dulau-Florea A, Calvo KR. Characteristic bone marrow findings in patients with UBA1 somatic mutations and VEXAS syndrome. Semin Hematol 2021;58(04):204-211

[8] 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

[9] Templé M, Duroyon E, Croizier C. et al. Atypical splice-site mutations causing VEXAS syndrome. Rheumatology (Oxford) 2021;60(12):e435-e437

[10] Watanabe R, Kiji M, Hashimoto M. Vasculitis associated with VEXAS syndrome: a literature review. Front Med (Lausanne) 2022;9:983939

[11] Huang H, Zhang W, Cai W. et al. VEXAS syndrome in myelodysplastic syndrome with autoimmune disorder. Exp Hematol Oncol 2021;10(01):23

[12] Heiblig M, Patel BA, Groarke EM, Bourbon E, Sujobert P. Toward a pathophysiology inspired treatment of VEXAS syndrome. Semin Hematol 2021;58(04):239-246

[13] Li P, Venkatachalam S, Ospina Cordona D. et al. A clinical, histopathological, and molecular study of two cases of VEXAS syndrome without a definitive myeloid neoplasm. Blood Adv 2022;6(02):405-409

[14] Oganesyan A, Jachiet V, Chasset F. et al. On behalf MINHEMON. VEXAS syndrome: still expanding the clinical phenotype. Rheumatology (Oxford) 2021;60(09):e321-e323

[15] van Leeuwen-Kerkhoff N, de Witte MA, Heijstek MW, Leavis HL. Case report: up-front allogeneic stem cell transplantation in a patient with the VEXAS syndrome. Br J Haematol 2022;199(03):e12-e15

[16] Gurnari C, Mannion P, Pandit I. et al. UBA1 screening in sweet syndrome with hematological neoplasms reveals a novel association between VEXAS and chronic myelomonocytic leukemia. HemaSphere 2022;6(10):e775

[17] Nune A, Iyengar KP, Barman B, Manzo C. The VEXAS syndrome from rheumatology perspective: genomic DNA sequencing as available blueprint for diagnosing rheumatic diseases with overlapping haematological or dermatological findings. Clin Rheumatol 2022;41(09):2917-2918

[18] Gurnari C, McLornan DP. Update on VEXAS and role of allogeneic bone marrow transplant: considerations on behalf of the Chronic Malignancies Working Party of the EBMT. Bone Marrow Transplant 2022;57(11):1642-1648

[19] Arlet JB, Terrier B, Kosmider O. Mutant UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med 2021;384(22):2163-2165

[20] Barba T, Jamilloux Y, Durel CA. et al. VEXAS syndrome in a woman. Rheumatology (Oxford) 2021;60(11):e402-e403

[21] Stubbins RJ, McGinnis E, Johal B. et al. VEXAS syndrome in a female patient with constitutional 45,X (Turner syndrome). Haematologica 2022;107(04):1011-1013

[22] Guerrero-Bermúdez CA, Cardona-Cardona AF, Ariza-Parra EJ. et al. Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) with prominent supraglottic larynx involvement: a case-based review. Clin Rheumatol 2022;41(11):3565-3572

[23] 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;80(08):1057-1061

[24] van der Made CI, Potjewijd J, Hoogstins A. et al. Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of patients with VEXAS. J Allergy Clin Immunol 2022;149(01)432-439.e4

[25] Wilke MVMB, Morava-Kozicz E, Koster MJ. et al. Exome sequencing can misread high variant allele fraction of somatic variants in UBA1 as hemizygous in VEXAS syndrome: a case report. BMC Rheumatol 2022;6(01):54

[26] Georgin-Lavialle S, Terrier B, Guedon AF. et al. French VEXAS group, GFEV, GFM, CEREMAIA, MINHEMON. Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients. Br J Dermatol 2022;186(03):564-574

[27] Ferrada MA, Savic S, Cardona DO. et al. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. Blood 2022;140(13):1496-1506

[28] Templé M, Kosmider O. VEXAS syndrome: a novelty in MDS landscape. Diagnostics (Basel) 2022;12(07):1590

[29] Stubbins RJ. Lost in translation: cytoplasmic UBA1 and VEXAS syndrome. Blood 2022;140(13):1455-1457

[30] Hage-Sleiman M, Lalevée S, Guermouche H. et al. Dominance of an UBA1 mutant clone over a CALR mutant clone: from essential thrombocytemia to VEXAS. Haematologica 2021;106(12):3245-3248

[31] Hormaechea-Agulla D, Matatall KA, Le DT. et al. Chronic infection drives Dnmt3a-loss-of-function clonal hematopoiesis via IFNγ signaling. Cell Stem Cell 2021;28(08)1428-1442.e6

[32] Raaijmakers MHGP, Hermans M, Aalbers A. et al. Azacytidine treatment for VEXAS syndrome. HemaSphere 2021;5(12):e661

[33] Manzoni M, Bosi A, Fabris S. et al. Clinical, morphological and clonal progression of VEXAS syndrome in the context of myelodysplasia treated with azacytidine. Clin Hematol Int 2022;4(1-2):52-55

[34] Shimizu T, Ide H, Tsuji Y, Koga T, Kawakami A. VEXAS syndrome complicated with severe infection. Rheumatology (Oxford) 2022;61(12):e374-e376

[35] Zakine E, Schell B, Battistella M. et al. UBA1 variations in neutrophilic dermatosis skin lesions of patients with VEXAS syndrome. JAMA Dermatol 2021;157(11):1349-1354

[36] Sterling D, Duncan ME, Philippidou M, Salisbury JR, Kulasekararaj AG, Basu TN. VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) for the dermatologist. J Am Acad Dermatol 2022: S0190-9622(22)00181-5

[37] Lacombe V, Beucher A, Urbanski G. et al. Distinction between clonal and paraclonal cutaneous involvements in VEXAS syndrome. Exp Hematol Oncol 2022;11(01):6

[38] Khitri MY, Guedon AF, Georgin-Lavialle S. et al. French VEXAS group and MINHEMON. Comparison between idiopathic and VEXAS-relapsing polychondritis: analysis of a French case series of 95 patients. RMD Open 2022;8(02):e002255

[39] Ferrada MA, Sikora KA, Luo Y. et al. Somatic mutations in UBA1 define a distinct subset of relapsing polychondritis patients with VEXAS. Arthritis Rheumatol 2021;73(10):1886-1895

[40] Itagane M, Teruya H, Kato T. et al. Clinical images: VEXAS syndrome presenting as treatment-refractory polyarteritis nodosa. Arthritis Rheumatol 2022;74(11):1863-1864

[41] Patel BA, Young NS. Towards treatments for VEXAS. Br J Haematol 2022;196(04):804-805

[42] Shaukat F, Hart M, Burns T, Bansal P. UBA1 and DNMT3A mutations in VEXAS syndrome. A case report and literature review. Mod Rheumatol Case Rep 2022;6(01):134-139

[43] Patel BA, Ferrada MA, Grayson PC, Beck DB. VEXAS syndrome: an inflammatory and hematologic disease. Semin Hematol 2021;58(04):201-203

[44] Lötscher F, Seitz L, Simeunovic H. et al. Case report: genetic double strike: VEXAS and TET2-positive myelodysplastic syndrome in a patient with long-standing refractory autoinflammatory disease. Front Immunol 2022;12:800149

[45] Oo TM, Koay JTJ, Lee SF, Lee SMS, Lim XR, Fan BE. Thrombosis in VEXAS syndrome. J Thromb Thrombolysis 2022;53(04):965-970

[46] Khider L, Templé M, Bally C. et al. Systematic search for the UBA1 mutation in men after a first episode of venous thromboembolism: a monocentric study. J Thromb Haemost 2022;20(11):2697-2699

[47] 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

[48] Bert-Marcaz C, Briantais A, Faucher B. et al. Expanding the spectrum of VEXAS syndrome: association with acute-onset CIDP. J Neurol Neurosurg Psychiatry 2022;93(07):797-798

[49] Sikora KA, Wells KV, Bolek EC, Jones AI, Grayson PC. Somatic mutations in rheumatological diseases: VEXAS syndrome and beyond. Rheumatology (Oxford) 2022;61(08):3149-3160

[50] Obiorah IE, Beck DB, Wang W. et al. Myelodysplasia and bone marrow manifestations of somatic UBA1 mutated autoinflammatory disease. Blood 2020;136(Suppl. 01):20-21

[51] Himmelmann A, Brücker R. The VEXAS syndrome: uncontrolled inflammation and macrocytic anaemia in a 77-year-old male patient. Eur J Case Rep Intern Med 2021;8(04):002484

[52] Koster MJ, Kourelis T, Reichard KK. et al. Clinical heterogeneity of the VEXAS syndrome: a case series. Mayo Clin Proc 2021;96(10):2653-2659

[53] Costantini B, Kordasti SY, Kulasekararaj AG. et al. The effects of 5-azacytidine on the function and number of regulatory T cells and T-effectors in myelodysplastic syndrome. Haematologica 2013;98(08):1196-1205

[54] Comont T, Heiblig M, Rivière E. et al. French VEXAS study group, Groupe Francophone des Myélodysplasies (GFM) and MedecineINterne, HEmato et ONco (MINHEMON) group. 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 2022;196(04):969-974

[55] Mekinian A, Zhao LP, Chevret S. et al. A Phase II prospective trial of azacitidine in steroid-dependent or refractory systemic autoimmune/inflammatory disorders and VEXAS syndrome associated with MDS and CMML. Leukemia 2022;36(11):2739-2742

[56] Komrokji R, Swern AS, Grinblatt D. et al. Azacitidine in lower-risk myelodysplastic syndromes: a meta-analysis of data from prospective studies. Oncologist 2018;23(02):159-170

[57] Diarra A, Duployez N, Fournier E. et al. Successful allogeneic hematopoietic stem cell transplantation in patients with VEXAS syndrome: a 2-center experience. Blood Adv 2022;6(03):998-1003

[58] 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

[59] National Cancer Institute (NCI). A Phase II Study of Allogeneic Hematopoietic Stem Cell Transplant for Subjects with VEXAS (Vacuoles, E1 Enzyme, X-Linked, Autoinflammatory, Somatic) Syndrome. clinicaltrials.gov; 2022. Accessed November 3, 2022 at: https://clinicaltrials.gov/ct2/show/NCT05027945

[60] Takahashi N, Takeichi T, Nishida T. et al. Extensive multiple organ involvement in VEXAS syndrome. Arthritis Rheumatol 2021;73(10):1896-1897

[61] Alhomida F, Beck DB, George TI. et al. Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome-clinical presentation of a newly described somatic, autoinflammatory syndrome. JAAD Case Rep 2021;14:111-113

[62] Heiblig M, Ferrada MA, Gerfaud-Valentin M. et al. Clinical efficacy of JAK inhibitors in patients with VEXAS syndrome: a multicenter retrospective study. Blood 2021;138(Suppl. 01):2608-2608

[63] Heiblig M, Ferrada MA, Koster MJ. et al. Ruxolitinib is more effective than other JAK inhibitors to treat VEXAS syndrome: a retrospective multicenter study. Blood 2022;140(08):927-931

[64] Guilpain P. JAK inhibitors in autoinflammatory syndromes? The long road from drug development to daily clinical use. Rheumatology (Oxford) 2023;62(04):1368-1369

[65] Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ. JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 2017;16(12):843-862

[66] Goyal A, Narayanan D, Wong W. et al. Tocilizumab for treatment of cutaneous and systemic manifestations of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome without myelodysplastic syndrome. JAAD Case Rep 2022;23:15-19

[67] Kirino Y, Takase-Minegishi K, Tsuchida N. et al. Tocilizumab in VEXAS relapsing polychondritis: a single-center pilot study in Japan. Ann Rheum Dis 2021;80(11):1501-1502

[68] Balmain A. The critical roles of somatic mutations and environmental tumor-promoting agents in cancer risk. Nat Genet 2020;52(11):1139-1143

[69] Magnol M, Couvaras L, Degboé Y. et al. VEXAS syndrome in a patient with previous spondyloarthritis with a favourable response to intravenous immunoglobulin and anti-IL17 therapy. Rheumatology (Oxford) 2021;60(09):e314-e315

[70] Islam S, Cullen T, Sumpton D. et al. VEXAS syndrome: lessons learnt from an early Australian case series. Intern Med J 2022;52(04):658-662

[71] 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 Rheumatol 2022;74(07):1302-1303

[72] Verduga MZ, Tavera MAU, Pereira DA, Madrigal-Burgaleta R, Berges-Gimeno P, Alvarez-Cuesta E. Desensitization to anakinra case report. J Allergy Clin Immunol 2014;133(02)AB274

[73] Ciprian G. Adverse reaction to COVID-19 mRNA vaccination in a patient with VEXAS syndrome. Cureus 2022;14(03):e23456

[74] Dufrost V, Risse J, Zuily S, Wahl D. Direct oral anticoagulants use in antiphospholipid syndrome: are these drugs an effective and safe alternative to warfarin? A systematic review of the literature. Curr Rheumatol Rep 2016;18(12):74

RIGHTS & PERMISSIONS

2023 Global Medical Genetics