An update on VEXAS syndrome

Expert Review of Clinical Immunology, Journal Year: 2022, Volume and Issue: 19(2), P. 203 - 215

Published: Dec. 20, 2022

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently described, late-onset, acquired autoinflammatory disorder caused by mutations in the UBA1 gene. The various clinical manifestations of broadly divided into inflammatory or haematological. defines new disease category - hematoinflammatory disorders triggered somatic restricted to blood but causing systemic inflammation with multi-organ involvement and associated aberrant bone marrow status. causes significant morbidity reduced life expectancy, optimum standard care remains undefined.This review describes discovery VEXAS, relevant genetic immunopathology disease. A detailed account its mimics provided. Current treatment management options are discussed.New rare variants VEXAS-like negative cases reported. Consensus diagnostic criteria might be required define related disorders. Investigation sporadic, will require application deep sequencing using DNA obtained from cellular tissue locations. Prospective studies needed optimal supportive for patients varying severity prognosis. VEXAS-specific hematopoietic stem cell transplant selection also development.

Language: Английский

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VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management

American Journal of Hematology, Journal Year: 2023, Volume and Issue: 99(2), P. 284 - 299

Published: Nov. 11, 2023

Abstract VEXAS (Vacuoles, E1 enzyme, X‐linked, Autoinflammatory, Somatic) syndrome is a newly identified disease caused by somatic alterations in UBA1 which produce recalcitrant inflammatory state along with hematologic disturbances. Patients can have wide spectrum of clinical symptoms and providers should be familiar the heterogeneity associated features. While parameters may generally non‐specific, peripheral blood features macrocytosis, monocytopenia, and/or thrombocytopenia coupled bone marrow vacuolization erythroid or myeloid precursors raise suspicion for this condition. Due to an increased mortality, prompt recognition accurate diagnosis paramount. Access testing confirmation variants not yet universally available but clinicians understand current options genetic disease. Treatment are limited due lack prospective trials cytokine directed therapies such as interleukin‐6 inhibitors JAK–STAT well hypomethylating agents azacitidine shown evidence partial effect. Though cases limited, allogeneic stem cell transplantation holds promise durable response potential cure. The intent review outline pathophysiology provide practical approach treatment.

Language: Английский

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Skin Manifestations of VEXAS Syndrome and Associated Genotypes

JAMA Dermatology, Journal Year: 2024, Volume and Issue: 160(8), P. 822 - 822

Published: June 12, 2024

Importance VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and marked by systemic inflammation, progressive bone marrow failure, inflammatory cutaneous manifestations. Objective To define the spectrum manifestations association these findings clinical, genetic, histological features. Design, Setting, Participants This observational cohort study included data from 112 patients who were diagnosed VEXAS-defining variants UBA1 between 2019 2023. Data collected medical record review or directly evaluated at National Institutes Health Bethesda, Maryland. Main Outcomes Measures histological, other clinical findings. A secondary outcome was response to treatment VEXAS. Results Among (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement common (93 [83%]), most frequent presenting feature (68 [61%]). Of 64 histopathologic reports available 60 patients, predominant leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), perivascular dermatitis (19 [30%]). Distinct pathogenic associated specific The p.Met41Leu variant frequently dermal infiltrates (14 17 [82%]), often resembling histiocytoid Sweet syndrome. In contrast, p.Met41Val vasculitic lesions (11 20 [55%]) mixed leukocytic infiltrate (17 [85%]). Oral prednisone improved 67 73 (92%). Patients treated anakinra developed severe injection-site reactions (12 16 [75%]), including ulceration (2 12 [17%]) abscess formation (1 [8%]). Conclusions Relevance this show that are early manifestation Genetic evaluation for should be considered male vasculitis, dermatoses, chondritis. Awareness among dermatologists critical facilitate diagnosis.

Language: Английский

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Polyarteritis Nodosa: Old Disease, New Etiologies

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(23), P. 16668 - 16668

Published: Nov. 23, 2023

Polyarteritis nodosa (PAN), also known as panarteritis nodosa, represents a form of necrotizing vasculitis that predominantly affects medium-sized vessels, although it is not restricted to them and can involve smaller vessels. The clinical presentation heterogeneous characterized by significant number patients exhibiting general symptoms, including asthenia, fever, unintended weight loss. Although PAN virtually any organ, preferentially the skin, nervous system, gastrointestinal tract. Orchitis rare but specific manifestation PAN. absence granulomas, glomerulonephritis, anti-neutrophil cytoplasmic antibodies serves distinguish from other types vasculitis. Major complications consist hemorrhagic thrombotic events occurring in mesenteric, cardiac, cerebral, renal systems. Historically, was frequently linked hepatitis B virus (HBV) infection, this association has dramatically changed recent years due declining HBV prevalence. Current epidemiological research often identifies connection between genetic syndromes well neoplasia. This article provides comprehensive review PAN, specifically focusing on progression its manifestations over time.

Language: Английский

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The link between rheumatic disorders and inborn errors of immunity

EBioMedicine, Journal Year: 2023, Volume and Issue: 90, P. 104501 - 104501

Published: March 2, 2023

Language: Английский

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VEXAS Syndrome—Review

Global Medical Genetics, Journal Year: 2023, Volume and Issue: 10(03), P. 133 - 143

Published: July 10, 2023

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

Language: Английский

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VEXAS syndrome: Current clinical, diagnostic and treatment approaches

Intractable & Rare Diseases Research, Journal Year: 2023, Volume and Issue: 12(3), P. 170 - 179

Published: Aug. 17, 2023

VEXAS syndrome, is a hemato-inflammatory chronic disease characterized with predominantly rheumatic and hematologic systemic involvement. It was first described in 2020 by group of researchers the United States. syndrome rare condition that primarily affects adult males caused mutation UBA1 gene located on X chromosome. Its pathogenesis related to somatic affecting methionine-41 (p.Met41) UBA1, major E1 enzyme initiates ubiquitylation. Mutant lead decreased ubiquitination activated innate immune pathways inflammation occur. The specific mechanism which leads clinical features not yet fully understood. newly define adult-onset inflammatory manifested treatment-refractory fevers, arthritis, chondritis, vasculitis, cytopenias, typical vacuoles hematopetic precursor cells, neutrophilic cutaneous pulmonary inflammation. Diagnosing can be challenging due its rarity overlap symptoms other conditions. Genetic testing identify essential for definitive diagnosis. Currently, there no known cure treatment mainly focuses managing symptoms. This may involve use anti-inflammatory medications, immunosuppressive drugs, supportive therapies tailored individual patient's needs. Due recent discovery ongoing research being conducted better understand pathogenesis, features, potential options. In this review article, clinical, diagnostic approaches were evaluated light latest literature data.

Language: Английский

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VEXAS Syndrome and Thrombosis: Findings of Inflammation, Hypercoagulability, and Endothelial Dysfunction

Seminars in Thrombosis and Hemostasis, Journal Year: 2024, Volume and Issue: 50(06), P. 897 - 901

Published: Jan. 5, 2024

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a novel autoinflammatory due to ubiquitin like modifier activating enzyme 1 (UBA1) somatic mutation, recently discovered in 2020.[1] This mutation affects the major that initiates conjugation of cellular proteins meant for degradation by proteasomes, where decreased ubiquitination causes accumulation prominent intracellular vacuoles seen myeloid and erythroid precursors bone marrow.[2] disease has significant hematologic malignancy thrombotic burden, with an increased incidence venous thromboembolism (VTE) (36.4%), deep vein thrombosis (DVT) more common than pulmonary embolism (PE), lower arterial (1.6%).[3] However, limited information available on potential mechanisms patients syndrome. We describe two male diagnosed Singapore performed biomarkers evaluating hemostatic, inflammatory, endothelial function.

Language: Английский

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Unveiling the clinical spectrum of relapsing polychondritis: insights into its pathogenesis, novel monogenic causes, and therapeutic strategies

Advances in Rheumatology, Journal Year: 2024, Volume and Issue: 64(1)

Published: April 16, 2024

Abstract Relapsing polychondritis is a rare multisystem disease involving cartilaginous and proteoglycan-rich structures. The diagnosis of this mainly suggested by the presence flares inflammation cartilage, particularly in ears, nose or respiratory tract, more rarely, other manifestations. spectrum clinical presentations may vary from intermittent episodes painful often disfiguring auricular nasal chondritis to an occasional organ even life-threatening manifestations such as lower airway collapse. There lack awareness about due its rarity. In 2020, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, novel autoinflammatory was described. syndrome attributed somatic mutations methionine-41 UBA1 , major enzyme that initiates ubiquitylation. This new entity connects seemingly unrelated conditions: systemic inflammatory syndromes (relapsing chondritis, Sweet’s neutrophilic dermatosis) hematologic disorders (myelodysplastic multiple myeloma). Therefore, article reviews current literature on both entities.

Language: Английский

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Ubiquitin-like modifier-activating enzyme 1 interacts with Zika virus NS5 and promotes viral replication in the infected cell

Journal of General Virology, Journal Year: 2025, Volume and Issue: 106(1)

Published: Jan. 8, 2025

Translation errors, impaired folding or environmental stressors (e.g. infection) can all lead to an increase in the presence of misfolded proteins. These activate cellular responses their removal, including intracellular protein degradation activities. Protein ubiquitylation is involved two major pathways, ubiquitin-proteasome system and selective autophagy. In humans, ubiquitin-like modifier-activating enzyme 1 (UBA1) primary E1 ubiquitin conjugation cascade. Viruses have evolved exploit pathways complete infection cycles. Zika virus (ZIKV) emerging orthoflavivirus causing serious neurologic disorders neonates (congenital microcephaly) adults (Guillain–Barré syndrome). Non-structural 5 (NS5), largest most conserved orthoflaviviruses, catalyses synthesis capping new viral genomes. addition RNA replication cytoplasm, ZIKV NS5 translocated into nucleus interfere with host antiviral responses. Here, we demonstrate that co-immunoprecipitates UBA1. Immunofluorescence assays suggest this interaction takes place primarily infected cell, although colocalization both proteins also detected cytosol. interference-mediated depletion UBA1 leads reduced titres cells, while transient overexpression favours faster kinetics, higher levels detected. Moreover, UBA1-targeting drugs cause significant drops infectivity. results support a proviral role for during encourage potential use inhibitors against its NS5-interacting epitopes as therapeutic targets.

Language: Английский

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