VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a severe, late-onset, treatment-refractory systemic autoinflammatory and hematologic disease caused by acquired somatic mutations in UBA1, the X-linked gene encoding the major E1 ubiquitin-activating enzyme. The mutations arise in hematopoietic stem and progenitor cells and predominantly affect methionine-41 (p.Met41), the start codon for the catalytically active cytoplasmic UBA1 isoform (UBA1b); their loss forces translation of a catalytically impaired isoform from a downstream start site, crippling cytoplasmic ubiquitylation. Because UBA1 is X-linked, the disease overwhelmingly affects men (about 96% of patients), with onset typically after age 50. It bridges rheumatology and hematology, combining systemic inflammation (recurrent fever, neutrophilic dermatosis, chondritis, vasculitis, pulmonary infiltrates, ocular inflammation, venous thrombosis) with myeloid-biased hematologic abnormalities (macrocytic anemia, characteristic cytoplasmic vacuoles in myeloid and erythroid precursors, thrombocytopenia, and frequent progression to myelodysplastic syndrome). VEXAS unified several previously idiopathic adult inflammatory presentations (relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, giant-cell arteritis) under a single somatic molecular cause.
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Conditions with similar clinical presentations that must be differentiated from VEXAS Syndrome:
name: VEXAS Syndrome
creation_date: "2026-06-29T00:00:00Z"
category: Complex
disease_term:
preferred_term: VEXAS syndrome
term:
id: MONDO:0026777
label: VEXAS syndrome
parents:
- autoinflammatory syndrome
- rare disease
classifications:
harrisons_chapter:
- classification_value: IMMUNE_RHEUMATOLOGIC
- classification_value: ONCOLOGY_HEMATOLOGY
description: >
VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a
severe, late-onset, treatment-refractory systemic autoinflammatory and
hematologic disease caused by acquired somatic mutations in UBA1, the X-linked
gene encoding the major E1 ubiquitin-activating enzyme. The mutations arise in
hematopoietic stem and progenitor cells and predominantly affect
methionine-41 (p.Met41), the start codon for the catalytically active
cytoplasmic UBA1 isoform (UBA1b); their loss forces translation of a
catalytically impaired isoform from a downstream start site, crippling
cytoplasmic ubiquitylation. Because UBA1 is X-linked, the disease
overwhelmingly affects men (about 96% of patients), with onset typically after
age 50. It bridges rheumatology and hematology, combining systemic
inflammation (recurrent fever, neutrophilic dermatosis, chondritis,
vasculitis, pulmonary infiltrates, ocular inflammation, venous thrombosis)
with myeloid-biased hematologic abnormalities (macrocytic anemia,
characteristic cytoplasmic vacuoles in myeloid and erythroid precursors,
thrombocytopenia, and frequent progression to myelodysplastic syndrome). VEXAS
unified several previously idiopathic adult inflammatory presentations
(relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, giant-cell
arteritis) under a single somatic molecular cause.
synonyms:
- VEXAS
- vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome
- UBA1-related autoinflammatory disease
references:
- reference: PMID:40373178
title: "VEXAS Syndrome."
tags:
- GeneReviews
pathophysiology:
- name: Somatic UBA1 Met41 Mutation in Hematopoietic Stem Cells
description: >
The founding lesion of VEXAS is an acquired (post-zygotic, mosaic) somatic
mutation in UBA1 affecting methionine-41 (p.Met41), arising in hematopoietic
stem and progenitor cells during adult life. Because UBA1 is X-linked, a
single somatic hit in males is sufficient to reach a pathogenic mutant
allele fraction. The mutation is detectable in peripheral-blood myeloid
cells but not in lymphocytes or fibroblasts.
cell_types:
- preferred_term: Hematopoietic stem cell
term:
id: CL:0000037
label: hematopoietic stem cell
evidence:
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation."
explanation: >
Establishes the defining somatic UBA1 p.Met41 lesion in affected men as
the founding genetic event.
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts."
explanation: >
Localizes the somatic mutation to hematopoietic stem cells and the myeloid
compartment, supporting the HSC origin and diagnostic tissue restriction.
downstream:
- target: Loss of Cytoplasmic UBA1 and Reduced Ubiquitylation
causal_link_type: DIRECT
description: >
Loss of the p.Met41 start codon abolishes translation of the cytoplasmic
UBA1b isoform, driving expression of a catalytically impaired isoform and
reduced ubiquitylation.
- name: Loss of Cytoplasmic UBA1 and Reduced Ubiquitylation
description: >
Mutations at p.Met41 abolish initiation of the canonical cytoplasmic UBA1
isoform (UBA1b) and force expression of a novel, catalytically impaired
isoform initiated at a downstream methionine (p.Met67). The net effect is a
global reduction in cytoplasmic ubiquitylation, the obligatory first step of
the ubiquitin-proteasome system. The level of residual UBA1b translation is
genotype-dependent and tracks with disease severity and survival.
biological_processes:
- preferred_term: Protein ubiquitination
term:
id: GO:0016567
label: protein ubiquitination
modifier: DECREASED
evidence:
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mutations affecting p.Met41 resulted in loss of the canonical cytoplasmic isoform of UBA1 and in expression of a novel, catalytically impaired isoform initiated at p.Met67."
explanation: >
Documents the isoform switch from cytoplasmic UBA1b to a catalytically
impaired p.Met67-initiated isoform as the proximal molecular consequence.
- reference: PMID:35793467
reference_title: "Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Using in vitro models and patient-derived cells, we demonstrate that p.Met41Val variant supports less UBA1b translation than either p.Met41Leu or p.Met41Thr, providing a molecular rationale for decreased survival."
explanation: >
Shows that residual cytoplasmic UBA1b translation is genotype-dependent
and mechanistically linked to prognosis.
downstream:
- target: Innate Immune Activation
causal_link_type: DIRECT
description: >
Reduced cytoplasmic ubiquitylation triggers cellular stress responses and
activates innate immune signaling in mutant myeloid cells.
- name: Innate Immune Activation
description: >
In UBA1-mutant peripheral-blood and myeloid cells, decreased ubiquitylation
activates cellular stress responses, including the unfolded protein response,
and engages multiple innate immune pathways (NF-kB, type I interferon, and
inflammasome signaling), producing the cytokine-driven autoinflammatory
state. VEXAS is a prototypic innate-driven (autoinflammatory) disease rather
than a classic adaptive autoimmune disease.
cell_types:
- preferred_term: Monocyte
term:
id: CL:0000576
label: monocyte
biological_processes:
- preferred_term: Inflammatory response
term:
id: GO:0006954
label: inflammatory response
modifier: INCREASED
notes: >
The cited NEJM abstract supports activation of innate immune pathways as an
umbrella. The more specific downstream signals reported in the full text and
later mechanistic work — unfolded protein response (UPR), canonical NF-kB
signaling, type I interferon signature, and inflammasome activation — are
described in the node prose but are not asserted as evidenced GO modifiers
here because the cached abstract does not itemize them; add them with
citable snippets if those specific signals are quoted from a fetched source.
evidence:
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways."
explanation: >
Directly links reduced ubiquitylation in mutant cells to activation of
innate immune pathways underlying the autoinflammatory phenotype.
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation."
explanation: >
Zebrafish knockout of the cytoplasmic UBA1 homologue recapitulates
systemic inflammation, supporting the causal mechanism in vivo.
downstream:
- target: Multi-Organ Neutrophilic Inflammation
causal_link_type: DIRECT
description: >
Innate immune activation drives recurrent neutrophilic inflammation across
skin, cartilage, lung, eye, and vasculature.
- target: Myeloid-Biased Dysplastic Hematopoiesis
causal_link_type: DIRECT
description: >
The UBA1-mutant clone drives myeloid-biased, dysplastic hematopoiesis with
characteristic precursor vacuolization and progression to MDS.
- name: Multi-Organ Neutrophilic Inflammation
description: >
The cytokine-driven inflammatory program produces recurrent, multi-organ
neutrophilic inflammation: neutrophilic and leukocytoclastic cutaneous
lesions, auricular and nasal chondritis, neutrophilic pulmonary
inflammation, scleritis/uveitis, and vasculitis. This effector phase is the
clinical face of the autoinflammatory arm.
cell_types:
- preferred_term: Neutrophil
term:
id: CL:0000775
label: neutrophil
evidence:
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias, characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow, neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis."
explanation: >
Enumerates the multi-organ neutrophilic inflammatory manifestations
driven by the disease.
- name: Myeloid-Biased Dysplastic Hematopoiesis
description: >
The UBA1-mutant clone, originating in hematopoietic stem cells, expands with
a myeloid bias and produces dysplastic hematopoiesis. The pathognomonic
morphologic readout is cytoplasmic vacuolization of myeloid and erythroid
precursor cells in the bone marrow; the hematologic trajectory frequently
progresses to myelodysplastic syndrome and is accompanied by macrocytic
anemia and cytopenias.
cell_types:
- preferred_term: Erythroid lineage cell
term:
id: CL:0000764
label: erythroid lineage cell
evidence:
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow"
explanation: >
Documents the precursor vacuolization and dysplastic marrow that define
the hematologic arm of VEXAS.
phenotypes:
- category: Hematologic
name: Macrocytic Anemia
description: >
Macrocytic anemia is a near-universal hematologic feature of VEXAS and is
often progressive and transfusion-dependent.
phenotype_term:
preferred_term: Macrocytic anemia
term:
id: HP:0001972
label: Macrocytic anemia
clinical_course: PROGRESSIVE
frequency: VERY_FREQUENT
evidence:
- reference: PMID:36692560
reference_title: "Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic (10/11"
explanation: >
Genome-first cohort shows anemia in all carriers, macrocytic in 10/11
(91%), supporting macrocytic anemia as a near-universal (VERY_FREQUENT)
feature.
- category: Hematologic
name: Thrombocytopenia
description: >
Thrombocytopenia frequently accompanies the macrocytic anemia and dysplastic
hematopoiesis.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Thrombocytopenia
term:
id: HP:0001873
label: Thrombocytopenia
evidence:
- reference: PMID:36692560
reference_title: "Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "with concomitant thrombocytopenia (10/11"
explanation: >
Genome-first cohort documents concomitant thrombocytopenia in 10/11 (91%)
of carriers.
- category: Hematologic
name: Myelodysplastic Syndrome
description: >
A substantial fraction of patients develop myelodysplastic syndrome, mostly
lower-risk, reflecting clonal evolution of the UBA1-mutant population.
phenotype_term:
preferred_term: Myelodysplasia
term:
id: HP:0002863
label: Myelodysplasia
evidence:
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most of these 25 patients met clinical criteria for an inflammatory syndrome (relapsing polychondritis, Sweet's syndrome, polyarteritis nodosa, or giant-cell arteritis) or a hematologic condition (myelodysplastic syndrome or multiple myeloma) or both."
explanation: >
Documents myelodysplastic syndrome (and multiple myeloma) as hematologic
conditions met by patients with VEXAS.
- category: Constitutional
name: Recurrent Fever
description: >
Recurrent fevers are a cardinal manifestation of the systemic
autoinflammatory phenotype.
phenotype_term:
preferred_term: Recurrent fever
term:
id: HP:0001954
label: Recurrent fever
temporality: RECURRENT
evidence:
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias"
explanation: >
Lists fevers among the cardinal features of the late-onset inflammatory
syndrome.
- category: Dermatologic
name: Neutrophilic Dermatosis
description: >
Skin involvement is common and is frequently the presenting feature, with
neutrophilic dermal infiltrates (often resembling histiocytoid Sweet
syndrome), leukocytoclastic vasculitis, and perivascular dermatitis.
phenotype_term:
preferred_term: Neutrophilic dermatosis
term:
id: HP:0031234
label: Neutrophilic infiltration of the skin
frequency: VERY_FREQUENT
evidence:
- reference: PMID:38865133
reference_title: "Skin Manifestations of VEXAS Syndrome and Associated Genotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "skin involvement was common (93"
explanation: >
Cohort of 112 patients shows skin involvement in 93/112 (83%) and as the
most frequent presenting feature, supporting VERY_FREQUENT. Note the band
reflects overall skin involvement; neutrophilic dermatosis was the
predominant histopathologic pattern (next evidence item).
- reference: PMID:38865133
reference_title: "Skin Manifestations of VEXAS Syndrome and Associated Genotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "predominant skin histopathologic findings were leukocytoclastic vasculitis"
explanation: >
Documents leukocytoclastic vasculitis and neutrophilic dermatosis as
predominant skin histopathology.
- category: Dermatologic
name: Cutaneous Leukocytoclastic Vasculitis
description: >
Leukocytoclastic vasculitis is a frequent cutaneous histopathologic pattern,
particularly associated with the p.Met41Val genotype.
phenotype_term:
preferred_term: Leukocytoclastic vasculitis
term:
id: HP:0034786
label: Leukocytoclastic vasculitis
evidence:
- reference: PMID:38865133
reference_title: "Skin Manifestations of VEXAS Syndrome and Associated Genotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the p.Met41Val variant was associated with vasculitic lesions"
explanation: >
Documents vasculitic skin lesions associated with the p.Met41Val
genotype.
- category: Musculoskeletal
name: Chondritis
description: >
Relapsing auricular and nasal chondritis is a common manifestation; a large
fraction of older men diagnosed with relapsing polychondritis in fact have
VEXAS.
phenotype_term:
preferred_term: Chondritis
term:
id: HP:0100662
label: Chondritis
temporality: RECURRENT
evidence:
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis."
explanation: >
Lists chondritis among the characteristic inflammatory manifestations.
- category: Respiratory
name: Pulmonary Infiltrates
description: >
Neutrophilic pulmonary inflammation with pulmonary infiltrates (and
organizing pneumonia, pleural effusions) is a frequent organ manifestation.
phenotype_term:
preferred_term: Pulmonary infiltrates
term:
id: HP:0002113
label: Pulmonary infiltrates
evidence:
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis."
explanation: >
Documents neutrophilic pulmonary inflammation as a manifestation.
- category: Ophthalmologic
name: Scleritis
description: >
Ocular inflammation, including scleritis, episcleritis, uveitis, and
periorbital/orbital inflammation, occurs in a substantial minority of
patients.
phenotype_term:
preferred_term: Scleritis
term:
id: HP:0100532
label: Scleritis
evidence:
- reference: PMID:40373178
reference_title: "VEXAS Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The most common inflammatory findings include recurrent fever, skin lesions, pulmonary infiltrates, recurrent chondritis, arthritis, pan ocular inflammation, and unprovoked venous thrombosis."
explanation: >
GeneReviews lists pan ocular inflammation among the most common
inflammatory findings; scleritis is a characteristic ocular manifestation.
- category: Vascular
name: Venous Thromboembolism
description: >
Unprovoked venous thromboembolism (deep venous thrombosis and pulmonary
embolism) is a frequent and clinically important complication.
phenotype_term:
preferred_term: Deep venous thrombosis
term:
id: HP:0002625
label: Deep venous thrombosis
evidence:
- reference: PMID:40373178
reference_title: "VEXAS Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recurrent chondritis, arthritis, pan ocular inflammation, and unprovoked venous thrombosis."
explanation: >
GeneReviews lists unprovoked venous thrombosis among the most common
inflammatory findings.
- category: Musculoskeletal
name: Arthritis
description: >
Inflammatory arthritis and polyarthralgia are common musculoskeletal
manifestations.
phenotype_term:
preferred_term: Arthritis
term:
id: HP:0001369
label: Arthritis
evidence:
- reference: PMID:40373178
reference_title: "VEXAS Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "recurrent fever, skin lesions, pulmonary infiltrates, recurrent chondritis, arthritis, pan ocular inflammation"
explanation: >
GeneReviews lists arthritis among the common inflammatory findings.
biochemical:
- name: Elevated C-reactive protein
biomarker_term:
preferred_term: Elevated circulating C-reactive protein concentration
term:
id: HP:0011227
label: Elevated circulating C-reactive protein concentration
presence: Positive
notes: >
Persistently elevated acute-phase reactants (C-reactive protein, erythrocyte
sedimentation rate) reflect the chronic systemic inflammatory state.
Near-universal in active VEXAS but non-specific; the defining laboratory clue
is macrocytic anemia with elevated acute-phase reactants in an older man.
genetic:
- name: UBA1
gene_term:
preferred_term: UBA1
term:
id: hgnc:12469
label: UBA1
variant_origin: SOMATIC
relationship_type: CAUSATIVE
association: >
Somatic (post-zygotic, mosaic) mutations in UBA1 (Xp11.23), predominantly at
p.Met41 (p.Met41Thr, p.Met41Val, p.Met41Leu) and at splice/non-Met41 sites
that also impair cytoplasmic UBA1b, are the defining cause of VEXAS. The
variants are restricted to the hematopoietic compartment and absent in skin
fibroblasts. Genotype influences phenotype and prognosis: p.Met41Val carries
the worst survival and least residual UBA1b, whereas p.Met41Leu carries the
best.
evidence:
- reference: PMID:35793467
reference_title: "Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We analyzed 83 patients with somatic pathogenic variants in UBA1 at p.Met41 (p.Met41Leu/Thr/Val), the start codon for translation of the cytoplasmic isoform of UBA1 (UBA1b)."
explanation: >
Defines the three canonical p.Met41 somatic genotypes at the cytoplasmic
UBA1b start codon.
- reference: PMID:35793467
reference_title: "Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival."
explanation: >
Establishes p.Met41Val as an independent predictor of decreased survival,
supporting genotype-phenotype-prognosis correlation.
inheritance:
- name: Somatic mosaicism (not inherited)
inheritance_term:
preferred_term: Typified by somatic mosaicism
term:
id: HP:0001442
label: Typified by somatic mosaicism
description: >
VEXAS is caused by acquired somatic (post-zygotic, mosaic) UBA1 variants and
is not a heritable Mendelian disease. There is no germline transmission to
offspring and no recurrence risk in families. The strong male predominance
reflects the X-linked location of UBA1 (single-X dosage in males); affected
females typically require acquired monosomy X, skewed X-inactivation, or a
second somatic event.
evidence:
- reference: PMID:40373178
reference_title: "VEXAS Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, all identified pathogenic variants are acquired (i.e., postzygotic) and lineage restricted in the blood. No confirmed occurrences of vertical transmission or sib recurrence have been reported."
explanation: >
GeneReviews confirms the somatic, non-heritable nature of VEXAS with no
vertical transmission or sibling recurrence.
prevalence:
- population: Men older than 50 years (US regional health system, genome-first ascertainment)
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_5_PER_10000
rate_per_100000: 23.42469
percentage: 1 in 4269
evidence:
- reference: PMID:36692560
reference_title: "Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "1 in 4269 men older than 50 years"
explanation: >
Genome-first Geisinger MyCode study estimates disease-associated UBA1
variant prevalence at 1 in 4269 men older than 50 years.
- population: Women older than 50 years (US regional health system, genome-first ascertainment)
measure_type: POINT_PREVALENCE
prevalence_class: BAND_1_9_PER_100000
rate_per_100000: 3.811266
percentage: 1 in 26238
evidence:
- reference: PMID:36692560
reference_title: "Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "1 in 26 238 women older than 50 years"
explanation: >
Same study estimates a much lower prevalence in women older than 50 years,
consistent with the X-linked male predominance.
diagnosis:
- name: Molecular genetic testing for somatic UBA1 variants
description: >
Diagnosis is established by identifying a somatic UBA1 pathogenic variant by
molecular genetic testing of peripheral blood and/or bone marrow aspirate
(myeloid-enriched fractions increase sensitivity), but not skin fibroblasts.
Because the variant allele fraction is often high, exome sequencing can
misread the somatic variant as hemizygous germline; confirming absence in
non-hematopoietic tissue establishes the somatic (mosaic) state.
diagnosis_term:
preferred_term: molecular genetic testing
term:
id: MAXO:0000533
label: molecular genetic testing
evidence:
- reference: PMID:40373178
reference_title: "VEXAS Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a UBA1 somatic (also known as mosaic or postzygotic) pathogenic variant identified by molecular genetic testing in peripheral blood and/or bone marrow aspirate, but not skin fibroblasts."
explanation: >
GeneReviews specifies the confirmatory molecular test and the diagnostic
tissue restriction (blood/marrow, not fibroblasts).
- reference: PMID:36038944
reference_title: "Exome sequencing can misread high variant allele fraction of somatic variants in UBA1 as hemizygous in VEXAS syndrome: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Sequencing of different tissues should be considered when there is conflict between the UBA1 variant status and the clinical findings."
explanation: >
Highlights the exome misinterpretation pitfall and the need to sequence
multiple tissues to confirm somatic status.
- name: Bone marrow examination for precursor vacuolization
description: >
Bone marrow aspirate classically shows cytoplasmic vacuoles in myeloid and
erythroid precursor cells, a highly suggestive morphologic clue, alongside
myeloid hyperplasia and dysplasia.
diagnosis_term:
preferred_term: bone marrow examination
term:
id: MAXO:0000753
label: bone marrow examination
evidence:
- reference: PMID:40373178
reference_title: "VEXAS Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "vacuoles in myeloid and erythroid precursor cells."
explanation: >
GeneReviews lists the characteristic precursor vacuolization seen on bone
marrow examination.
differential_diagnoses:
- name: Relapsing polychondritis
description: >
A substantial fraction of older men diagnosed with relapsing polychondritis
in fact have VEXAS; the somatic UBA1 mutation, marrow vacuoles, and
macrocytic anemia distinguish VEXAS.
- name: Sweet syndrome
description: >
VEXAS skin lesions frequently resemble (histiocytoid) Sweet syndrome;
accompanying macrocytic anemia and UBA1 testing distinguish VEXAS.
- name: Myelodysplastic syndrome without autoinflammation
description: >
MDS in an older man with prominent systemic inflammation should prompt UBA1
testing for VEXAS.
treatments:
- name: Glucocorticoid Therapy
description: >
Glucocorticoids (e.g., prednisone) are first-line and almost universally
effective for inflammatory manifestations, but VEXAS is typically
steroid-dependent and chronic high-dose exposure drives the need for
steroid-sparing agents.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: prednisone
term:
id: CHEBI:8382
label: prednisone
evidence:
- reference: PMID:38865133
reference_title: "Skin Manifestations of VEXAS Syndrome and Associated Genotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Oral prednisone improved skin manifestations in 67 of 73 patients"
explanation: >
Documents high response of skin manifestations to oral prednisone.
- name: Ruxolitinib (JAK Inhibitor)
description: >
Among JAK inhibitors, the JAK1/2 inhibitor ruxolitinib is the most effective
in VEXAS, with clinical remissions and steroid reduction in the majority of
treated patients.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: ruxolitinib
term:
id: CHEBI:66919
label: ruxolitinib
target_mechanisms:
- target: Innate Immune Activation
treatment_effect: INHIBITS
description: >
JAK1/2 inhibition suppresses the innate immune / cytokine signaling that
drives the autoinflammatory phenotype.
evidence:
- reference: PMID:35609174
reference_title: "Ruxolitinib is more effective than other JAK inhibitors to treat VEXAS syndrome: a retrospective multicenter study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "encouraging evidence supporting the use of the JAK1/2 inhibitor ruxolitinib with clinical remissions and reductions in steroid use seen in the majority of patients."
explanation: >
Retrospective multicenter study supports ruxolitinib efficacy with
remissions and steroid reduction in most patients.
- name: Tocilizumab (IL-6 Inhibition)
description: >
The anti-IL-6 receptor monoclonal antibody tocilizumab is used as a
steroid-sparing agent with partial efficacy.
therapeutic_modality: MONOCLONAL_ANTIBODY
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: Tocilizumab
term:
id: NCIT:C84217
label: Tocilizumab
target_mechanisms:
- target: Innate Immune Activation
treatment_effect: INHIBITS
description: >
IL-6 receptor blockade dampens the cytokine-driven inflammatory program.
evidence:
- reference: PMID:40373178
reference_title: "VEXAS Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and anti-IL-1 therapies."
explanation: >
GeneReviews lists IL-6 inhibitors among second-line steroid-sparing
agents.
- name: Azacitidine (Hypomethylating Agent)
description: >
The hypomethylating agent azacitidine targets the UBA1-mutant hematopoietic
population, used particularly in patients with concurrent MDS, and can
occasionally induce molecular remission of the UBA1 clone.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: chemotherapy
term:
id: MAXO:0000647
label: chemotherapy
therapeutic_agent:
- preferred_term: azacitidine
term:
id: CHEBI:2038
label: 5-azacytidine
target_mechanisms:
- target: Myeloid-Biased Dysplastic Hematopoiesis
treatment_effect: INHIBITS
description: >
Hypomethylating therapy targets the dysplastic, UBA1-mutant myeloid
population.
evidence:
- reference: PMID:40373178
reference_title: "VEXAS Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypomethylating agents like azacitidine are used to treat individuals with VEXAS syndrome with concurrent MDS with varying success."
explanation: >
GeneReviews documents azacitidine use for VEXAS with concurrent MDS.
- name: Allogeneic Hematopoietic Stem Cell Transplantation
description: >
Allogeneic HSCT is currently the only potentially curative therapy; it
eradicates the UBA1-mutant clone but carries considerable transplant-related
morbidity and mortality and is reserved for selected patients.
therapeutic_modality: CELL_THERAPY
treatment_term:
preferred_term: allogeneic hematopoietic stem cell transplantation
term:
id: MAXO:0001479
label: allogeneic hematopoietic stem cell transplantation
target_mechanisms:
- target: Somatic UBA1 Met41 Mutation in Hematopoietic Stem Cells
treatment_effect: INHIBITS
description: >
Replacement of the patient's hematopoietic system eradicates the
UBA1-mutant clone, the founding lesion.
evidence:
- reference: PMID:40373178
reference_title: "VEXAS Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for VEXAS syndrome"
explanation: >
GeneReviews identifies allogeneic HSCT as the only curative therapy.
- name: Anakinra (IL-1 Inhibition)
description: >
Anakinra, a recombinant IL-1 receptor antagonist, is used as an anti-IL-1
steroid-sparing option but has limited efficacy in VEXAS. Importantly, it
frequently causes severe injection-site reactions in VEXAS patients, a
disease-specific safety signal.
therapeutic_modality: PROTEIN_REPLACEMENT
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: anakinra
term:
id: CHEBI:231683
label: Anakinra
target_mechanisms:
- target: Innate Immune Activation
treatment_effect: INHIBITS
description: >
IL-1 receptor antagonism dampens IL-1-driven autoinflammatory signaling.
evidence:
- reference: PMID:40373178
reference_title: "VEXAS Syndrome."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and anti-IL-1 therapies."
explanation: >
GeneReviews lists anti-IL-1 therapies among second-line steroid-sparing
agents.
- reference: PMID:38865133
reference_title: "Skin Manifestations of VEXAS Syndrome and Associated Genotypes."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions"
explanation: >
Documents the disease-specific anakinra injection-site reaction safety
signal in VEXAS patients.
animal_models:
- species: Danio rerio (zebrafish)
genotype: Cytoplasmic UBA1 isoform homologue knockout (CRISPR-Cas9)
description: >
CRISPR-Cas9 knockout of the cytoplasmic UBA1 isoform homologue in zebrafish
causes systemic inflammation, providing in vivo support for the proximal
ubiquitylation-loss mechanism driving autoinflammation.
evidence:
- reference: PMID:33108101
reference_title: "Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation."
explanation: >
Zebrafish model recapitulates systemic inflammation downstream of
cytoplasmic UBA1 loss.
discussions:
- discussion_id: vexas_model_human_fidelity
kind: HUMAN_MODEL_MISMATCH
status: OPEN
attaches_to:
- pathophysiology#Multi-Organ Neutrophilic Inflammation
prompt: >
Do existing zebrafish and mouse Uba1-perturbation models faithfully
reproduce the full multi-organ, relapsing human VEXAS syndrome (chondritis,
neutrophilic skin disease, vacuolated marrow precursors, and clonal
evolution to MDS), or only its molecular/inflammatory arm?
rationale: >
Animal and cellular models reproduce the proximal ubiquitylation defect,
UPR/innate-immune activation, and myeloid bias well, but no single model
reproduces the age-dependent somatic-clonal acquisition or the human-specific
UBA1b cytoplasmic-isoform start-codon architecture at Met41 that underlies
the human multi-organ syndrome. Translational fidelity to the human clinical
phenotype therefore remains open.
proposed_experiments:
- experiment_id: vexas_humanized_met41_mouse
name: Humanized hematopoietic-restricted somatic Met41 mouse model
description: >
Engineer humanized, hematopoietic-restricted somatic Met41 mouse models
with age-dependent clonal acquisition and assess multi-organ phenotype
recapitulation including marrow precursor vacuolization and MDS evolution.
- discussion_id: vexas_population_incidence_criteria
kind: KNOWLEDGE_GAP
status: OPEN
attaches_to:
- disease#VEXAS Syndrome
prompt: >
What are the general-population incidence and finalized formal diagnostic
criteria for VEXAS syndrome?
rationale: >
Prevalence is estimated from a single US regional, predominantly White
health-system cohort; general-population incidence and validated consensus
diagnostic criteria are not yet established, and diverse-ancestry data are
sparse.
notes: >
VEXAS is a clonal-hematopoietic autoinflammatory disorder bridging
rheumatology and hematology, defined by somatic UBA1 p.Met41 mutations. No
existing dismech mechanism module maps cleanly to its somatic-clonal /
type-I-interferon-adjacent innate-immune-dysregulation pattern, so no
conforms_to edge is asserted; a future clonal-hematopoiesis or
interferonopathy module would be the natural conformance target. The repo's
Relapsing_Polychondritis entry already models the VEXAS overlap from the RP
side. Some clinical details (precise organ-specific frequencies, plasma-cell
dyscrasia, aseptic meningitis, orchitis) are documented in the literature but
were not added as separate phenotype nodes where a verified exact-substring
snippet for the specific claim was not available.
Overview. VEXAS syndrome is a severe, adult-onset, treatment-refractory autoinflammatory disease driven by acquired (somatic) loss-of-function mutations in the X-linked gene UBA1, the apex enzyme of the ubiquitylation cascade. The mutation arises in hematopoietic stem and progenitor cells (HSPCs), so it sits at the crossroads of autoinflammation and clonal hematologic disease (myelodysplastic syndrome, plasma-cell dyscrasias). The name is an acronym coined in the discovery paper:
Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic — Beck DB et al., NEJM 2020 (PMID:33108101).
It is best understood as a clonal hematopoietic disorder masquerading as, and overlapping with, a host of rheumatologic syndromes (relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, giant cell arteritis, undifferentiated systemic inflammation). It unified many previously "idiopathic" adult inflammatory presentations under a single molecular cause.
Key identifiers. - MONDO: MONDO:0026777 - OMIM: #301054 (VEXAS SYNDROME) - Orphanet: ORPHA:596753 - GARD: 15001 - MeSH: indexed under "VEXAS syndrome" (introduced ~2022) - ICD-10/ICD-11: No dedicated code yet; typically coded under autoinflammatory/myelodysplastic categories (ICD-10 D89.9 / D46.x). ICD-11 has no specific stem code as of this writing — (data gap).
Synonyms / alternative names. "UBA1-related autoinflammatory disease"; "Somatic UBA1-mutation–associated autoinflammatory syndrome"; historically subsumed under "relapsing polychondritis with myelodysplasia," "Sweet syndrome with MDS," and "idiopathic adult-onset autoinflammatory disease."
Data derivation. Knowledge is a mix: deep-phenotyped disease-level cohorts (NIH/NHGRI, French GFEV, multicenter registries) plus a landmark genome-first / EHR-linked population study (Geisinger MyCode, PMID:36692560) that ascertained patients from sequencing rather than clinic — an unusual and valuable "reverse" ascertainment for a rare disease.
Sources: NEJM 2020 (PMID:33108101) · GeneReviews NBK614471 · OMIM 301054
Primary cause (genetic, somatic). VEXAS is caused by somatic (post-zygotic, mosaic) mutations in UBA1 acquired in hematopoietic stem cells during adult life — it is not inherited and not a germline disease. The canonical mutations hit codon 41 (p.Met41), which is the alternative translation-initiation start codon for the cytoplasmic UBA1b isoform. Loss of Met41 abolishes cytoplasmic UBA1b initiation; cells instead make a catalytically impaired, mislocalized isoform (UBA1c) from a downstream start site, crippling cytoplasmic ubiquitylation.
"We identified 25 men who had somatic mutations in UBA1... The mutations were found in peripheral-blood cells... the somatic mutations affected methionine-41 (p.Met41)." — Beck DB et al., NEJM 2020 (PMID:33108101). (HUMAN_CLINICAL)
Risk factors. - Age: Strongest determinant. Disease is essentially adult-only, median onset mid-60s; risk rises with age (consistent with age-related clonal hematopoiesis as the soil for acquiring the UBA1 mutation). - Sex (male): Because UBA1 is X-linked, males (one X) need only a single somatic hit to reach a pathogenic mutant allele fraction. Males ≈96% of cases. - Clonal hematopoiesis: VEXAS is mechanistically a form of clonal hematopoiesis; co-occurring DNMT3A and TET2 mutations are common and may precede or accompany the UBA1 clone. - Genetic risk in females: Females generally require an additional event — acquired monosomy X (loss of the wild-type X), X-inactivation skewing, or a second somatic hit — to manifest, which explains their rarity. (PMID:33108101; GeneReviews NBK614471).
Protective factors. No established environmental protective factors. The closest "protective" genetic concept is the mutation-type gradient: p.Met41Leu (which preserves more residual UBA1b translation) carries markedly better survival than p.Met41Val. Higher residual wild-type/UBA1b activity is protective at the cellular level (PMID:35793465, Ferrada/Beck Blood 2022, IN_VITRO + HUMAN_CLINICAL).
Gene–environment interactions. No proven exogenous trigger. The dominant "environment" is endogenous aging hematopoiesis providing the clonal substrate. Infection/inflammation can precipitate flares but is not a documented cause. (Largely a data gap for true GxE.)
VEXAS is multisystem. Frequencies below are pooled from GeneReviews and major cohorts (NEJM 2020, JAMA 2023, French cohort). Mark these as HUMAN_CLINICAL.
Constitutional / inflammatory - Recurrent fevers — 65–90%. HPO: HP:0001954 (Recurrent fever) / HP:0011947. Episodic, often weekly; adult onset; recurrent. - Weight loss / cachexia, fatigue, malaise — very frequent. HP:0001824 (Weight loss).
Skin (≈80%, often the presenting feature) - Neutrophilic dermatosis / Sweet-syndrome–like lesions — dominant pattern. HPO: HP:0200035 (Neutrophilic dermatosis) / HP:0000962 (Hyperkeratosis – not apt); best: HP:0200035. - Cutaneous vasculitis, leukocytoclastic vasculitis — HP:0011008 / HP:0025476 (Cutaneous small vessel vasculitis). - Skin biopsy classically shows a leukocytoclastic and neutrophilic/histiocytoid infiltrate with myeloid precursors carrying the UBA1 mutation.
Cartilage / musculoskeletal - Relapsing chondritis (auricular and nasal) — 36–54%. HPO: HP:0002770 (Chondritis) / HP:0100786 (auricular). A large fraction of "relapsing polychondritis" in older men is actually VEXAS. - Inflammatory arthritis / polyarthralgia — 28–58%. HP:0001369 (Arthritis).
Eye (30–46%) - Periorbital edema, scleritis, episcleritis, uveitis, orbital inflammation — HPO: HP:0100534 (Scleritis), HP:0000554 (Uveitis), HP:0100539 (Periorbital edema).
Lung (35–55%) - Pulmonary infiltrates, organizing pneumonia, pleural effusions, neutrophilic alveolitis — HPO: HP:0006530 (Abnormal pulmonary interstitial morphology) / HP:0002113 (Pulmonary infiltrates) / HP:0002202 (Pleural effusion).
Vascular / thrombotic (23–41%) - Venous thromboembolism (DVT/PE) predominant; some arterial. HPO: HP:0002625 (Deep venous thrombosis), HP:0002204 (Pulmonary embolism), HP:0001907 (Thromboembolism). Episodic/recurrent.
Hematologic (near-universal) - Macrocytic anemia — ~97%. HPO: HP:0001972 (Macrocytic anemia) / HP:0001903 (Anemia). Progressive, transfusion-dependent in many. - Cytoplasmic vacuoles in myeloid and erythroid precursors (bone marrow) — the pathognomonic morphologic clue. HPO: closest is HP:0011273 (Abnormal myeloid cell morphology) — (no precise "vacuolated precursor" HP term; data gap). - Thrombocytopenia — 10–48%. HP:0001873. - Myelodysplastic syndrome (MDS) — 31–53% (mostly low/very-low risk). HP:0002863 (Myelodysplasia). - Plasma-cell dyscrasia (MGUS / multiple myeloma) — 10–25%. HP:0012184 (Abnormal circulating immunoglobulin) / monoclonal gammopathy. - Markedly elevated CRP/ESR — near-universal. HP:0011227 (Elevated C-reactive protein level), HP:0003565 (Elevated erythrocyte sedimentation rate).
Other - Orchitis/epididymitis, aseptic meningitis, gastrointestinal inflammation, hearing loss reported less commonly.
Onset / severity / progression / QoL. Onset adult (median ~66 y). Course is chronic, relapsing-remitting with progressive cumulative organ damage; severity moderate-to-severe and frequently glucocorticoid-dependent. QoL impact is high: chronic high-dose steroid exposure, transfusion dependence, recurrent hospitalization, and substantial fatigue/pain burden. Formal EQ-5D/SF-36 data are sparse — (QoL instrument data gap).
Causal gene. UBA1 (ubiquitin-like modifier-activating enzyme 1; E1 enzyme). HGNC: HGNC:12469 (dismech CURIE form hgnc:12469); NCBI Gene 7317; Xp11.23; OMIM gene 314370. Encodes the sole or principal E1 that charges ubiquitin with ATP and hands it to E2 conjugating enzymes — the obligatory first step of essentially all cellular ubiquitylation.
Pathogenic variants (somatic, X-linked). - Canonical codon-41 variants (≈80–90% of cases): - p.Met41Thr — c.122T>C — most common; associated with more ocular inflammation; ~83% 5-yr survival. - p.Met41Val — c.121A>G — most aggressive; less chondritis, more undifferentiated systemic inflammation, worst survival (~60–77% 5-yr); lowest residual UBA1b. - p.Met41Leu — c.121A>C — frequent skin/Sweet phenotype; best survival (~100% 5-yr). - Splice and non-Met41 variants: e.g., c.118-1G>C, c.118-2A>C (splice-site), p.Ser56Phe, p.Gly477Ala, and others that also impair cytoplasmic UBA1b — these broaden the variant spectrum and are recognized in later cohorts (Poulter JA et al., Blood 2021, PMID:33690795; and subsequent series). (HUMAN_CLINICAL / IN_VITRO)
Classification. Pathogenic / likely pathogenic per functional + segregation-with-disease evidence; these are somatic mosaic calls, so ACMG germline rules apply imperfectly — interpretation hinges on variant allele fraction (VAF) and functional data.
Variant origin & allele fraction. Somatic, not germline. Restricted to the hematopoietic compartment (blood/marrow), absent in skin fibroblasts — a key diagnostic discriminator. VAF ranges ~4–95%, typically high in peripheral myeloid cells; the mutation enriches in myeloid lineage over time.
Population frequency. Not present in germline population databases (gnomAD) as a constitutional variant — it is an acquired somatic event, so "allele frequency" is age- and tissue-dependent rather than a fixed population number.
Functional consequence. Loss of cytoplasmic UBA1b → global reduction in cytoplasmic ubiquitylation (a partial loss-of-function with downstream gain-of-inflammatory-function at the cellular level). Met41 is the AUG start for the catalytically active cytoplasmic isoform; its loss forces use of a downstream Met67 start producing the dysfunctional UBA1c.
"Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis... patients with p.Met41Val have... lower residual translation of the normal cytoplasmic UBA1 isoform UBA1b." — Ferrada/Beck et al., Blood 2022 (PMID:35793465). (IN_VITRO + HUMAN_CLINICAL)
Modifier genes. Co-occurring clonal mutations — DNMT3A, TET2 (clonal hematopoiesis), and MDS-associated genes — modify hematologic trajectory and malignant risk.
Epigenetics. No primary epigenetic cause; however, the therapeutic efficacy of hypomethylating agents (azacitidine) implies DNA-methylation–sensitive clonal biology. Direct methylome studies are limited — (data gap).
Chromosomal abnormalities. Acquired monosomy X / loss of wild-type X is an important mechanism enabling disease in females and can accompany clonal evolution in males.
The "environmental" driver is essentially endogenous somatic mutagenesis in aging hematopoiesis.
Causal chain (upstream → downstream):
"Mutant cells showed decreased ubiquitylation [activating] cellular stress responses that lead to upregulation of the unfolded-protein response... and a shared gene expression signature consistent with the activation of multiple innate immune pathways." — Beck DB et al., NEJM 2020 (PMID:33108101). (IN_VITRO)
Molecular pathways / GO suggestions: - GO:0016567 protein ubiquitination (DECREASED) — the core lesion - GO:0000209 protein polyubiquitination - GO:0030968 endoplasmic reticulum unfolded protein response (INCREASED) - GO:0006914 autophagy (dysregulated) - GO:0032606 type I interferon production / GO:0034340 response to type I interferon (INCREASED) - GO:0070423 nucleotide-binding oligomerization domain containing signaling / GO:0140447 cytokine precursor processing (inflammasome) (INCREASED) - GO:0043123 positive regulation of canonical NF-κB signaling (INCREASED) - GO:0097190 apoptotic signaling / RIPK1-dependent necroptosis (INCREASED)
Cell types (CL suggestions): - CL:0000576 monocyte (key dysregulated effector) - CL:0000775 neutrophil (neutrophilic dermatosis, alveolitis) - CL:0000037 hematopoietic stem cell (clonal origin) - CL:0000839 myeloid lineage restricted progenitor cell - CL:0000764 erythroid lineage cell (vacuolated precursors) / CL:0000557 granulocyte monocyte progenitor cell - CL:0000786 plasma cell (associated dyscrasia)
Subcellular (GO cellular component): GO:0005783 endoplasmic reticulum; GO:0005829 cytosol (site of lost UBA1b activity); GO:0000502 proteasome complex.
Immune involvement: Prototypic autoinflammatory (innate-driven) disease, not classic autoimmunity — though autoantibody/overlap features occur. Cytokine drivers: IL-6, IL-1β, TNF-α, type I/II IFN.
Molecular profiling: Transcriptomics of patient marrow/blood shows interferon + inflammatory signatures arising early in primitive HSPCs and the myeloid lineage (Cell Reports Med / iScience 2023; PMC12092610, S2666379123003130). Single-cell genotype–phenotype mapping links the mutant clone directly to the inflammatory program and suggests therapeutic vulnerabilities (biorxiv 2024.05.19.594376). (IN_VITRO / COMPUTATIONAL)
Primary site: Bone marrow / hematopoietic system — the origin and engine. UBERON: UBERON:0002371 (bone marrow), UBERON:0000178 (blood).
Multi-organ secondary involvement (UBERON): - Skin — UBERON:0002097 (skin of body) / UBERON:0000014 (zone of skin) - Cartilage — auricular UBERON:0001691 (external ear) / nasal cartilage UBERON:0001737 (laryngeal cartilage—approx.); cartilage tissue UBERON:0002418 - Eye — UBERON:0000970 (eye); sclera UBERON:0001773; orbit UBERON:0001697 - Lung — UBERON:0002048 (lung); pleura UBERON:0000175 - Blood vessels (veins) — UBERON:0001638 (vein); vasculature UBERON:0002049 - Joints — UBERON:0000465 (material anatomical entity—joint) / UBERON:0001485 (synovial joint approx.)
Body systems: hematopoietic/immune, integumentary, respiratory, cardiovascular (venous), musculoskeletal, ocular/visual, occasionally nervous (aseptic meningitis) and reproductive (orchitis).
Tissue/cell level: myeloid and erythroid bone-marrow precursors (vacuolated); circulating monocytes and neutrophils; dermal neutrophilic/histiocytoid infiltrates; cartilage perichondrial inflammation.
Subcellular: ER (UPR), cytosol (ubiquitylation failure), proteasome; characteristic cytoplasmic vacuoles.
Localization/laterality: Generally systemic and bilateral (e.g., bilateral auricular chondritis, periorbital edema), though skin and pulmonary lesions can be patchy/asymmetric.
Epidemiology. - Prevalence (landmark genome-first study, Geisinger MyCode, 163,096 unselected adults): ~1 in 4,269 men >50 y and ~1 in 26,238 women >50 y; ~1 in 13,591 unrelated individuals >50 y overall.
"...estimated prevalence of disease-associated UBA1 variants... 1 in 4269 men and 1 in 26,238 women older than 50 years." — Beck DB et al., JAMA 2023;329(4):318-324 (PMID:36692560). (HUMAN_CLINICAL)
Genetics of transmission. - Inheritance pattern: Not inherited — somatic/acquired. Functionally X-linked in the sense that the male single-X dosage explains the strong sex skew, but there is no germline transmission to offspring and no recurrence risk in families. - Penetrance: Among carriers identified genome-first, penetrance of the combined inflammatory+hematologic phenotype was reported as high (approaching ~100% in symptomatic ascertainment), though milder/oligosymptomatic carriers are increasingly recognized. - Expressivity: Highly variable (chondritis-predominant vs skin-predominant vs MDS-predominant), partly by genotype. - Anticipation / germline mosaicism / founder effects / consanguinity / carrier frequency: Not applicable (somatic disease).
Demographics. - Sex ratio: Strongly male; ~96% male / ~4% female (females usually require monosomy X or skewed XCI). - Age distribution: Overwhelmingly >50 y; peak 6th–8th decades. - Ethnic/geographic distribution: Reported worldwide across ancestries; no strong ethnic predilection established (the major cohorts are US and European). No endemic geography (not environmental/infectious).
Definitive test — molecular. - UBA1 somatic mutation detection in peripheral blood and/or bone marrow (myeloid-enriched fractions increase sensitivity). Methods: targeted Sanger (high-VAF), NGS panels, ddPCR, or WGS/WES (caution: high-VAF somatic UBA1 can be misread as hemizygous germline on exome — PMID:36038944). Confirm somatic status by absence in skin fibroblasts/non-hematopoietic tissue.
Morphologic clue. - Bone marrow aspirate: cytoplasmic vacuoles in myeloid and erythroid precursor cells — the original "V." Highly suggestive but not 100% specific/sensitive.
Laboratory. - Persistently elevated CRP/ESR; macrocytic anemia (high MCV), variable thrombocytopenia/leukopenia/monocytopenia; ferritin often high. LOINC: CRP (LOINC:1988-5), ESR (LOINC:4537-7), MCV (LOINC:787-2), Hemoglobin (LOINC:718-7). - SPEP/immunofixation for monoclonal protein (plasma-cell dyscrasia screen).
Imaging. CT chest for pulmonary infiltrates/effusions; vascular imaging for VTE; cross-sectional imaging for large-vessel vasculitis when GCA/large-vessel overlap suspected.
Histopathology. Skin/marrow biopsy: neutrophilic/leukocytoclastic infiltrates, perichondrial inflammation; marrow shows myeloid hyperplasia ± dysplasia and vacuolated precursors.
Diagnostic criteria. No validated formal criteria yet. Working approach (GeneReviews; Koster/Mayo and others): adult male with relapsing multisystem inflammation (chondritis/skin/eye/lung) + macrocytic anemia/cytopenias ± marrow vacuoles + steroid dependence → test UBA1. Proposed clinical screening scores exist (e.g., to prioritize who to sequence) but are not consensus-finalized — (data gap / evolving).
Differential diagnosis (to distinguish): relapsing polychondritis, Sweet syndrome, polyarteritis nodosa, giant cell arteritis/large-vessel vasculitis, adult-onset Still disease, MDS without autoinflammation, IgG4-related disease, Behçet disease. The unifying discriminator is the somatic UBA1 mutation + marrow vacuoles + macrocytic anemia in an older man.
Screening. No population newborn/carrier screening (somatic disease). Emerging concept: opportunistic UBA1 testing in older men presenting with otherwise-unexplained relapsing inflammation plus macrocytosis.
"Of the 25 patients, 10 died during the study period." — Beck DB et al., NEJM 2020 (PMID:33108101). (HUMAN_CLINICAL)
No regulatory-approved therapy and no consensus guideline exist; management is empirical, drawn from cohorts/case series. Two strategic arms: (A) suppress inflammation and (B) target/eradicate the UBA1-mutant clone.
A. Anti-inflammatory / immunosuppressive - Glucocorticoids — first-line, almost universally effective but disease is steroid-dependent; chronic toxicity drives the need for steroid-sparing agents. MAXO: MAXO:0000058 (pharmacotherapy) / corticosteroid; CHEBI:50858 (corticosteroid) / CHEBI:8378 (prednisone). - JAK inhibitors — ruxolitinib is the most effective JAK inhibitor (superior to tofacitinib/baricitinib/upadacitinib), with meaningful clinical response in roughly half of treated patients.
"Ruxolitinib is more effective than other JAK inhibitors to treat VEXAS syndrome." — Heiblig M et al., Blood 2022 (PMID:35609174). (HUMAN_CLINICAL) CHEBI:75045 (ruxolitinib); modality SMALL_MOLECULE; target JAK1/JAK2. - IL-6 inhibition (tocilizumab) — partial benefit (~26% response). CHEBI/NCIT tocilizumab; modality MONOCLONAL_ANTIBODY. - IL-1 inhibition (anakinra, canakinumab) — limited efficacy (<10%); anakinra can cause severe injection-site reactions in VEXAS. - Conventional DMARDs (methotrexate, azathioprine), TNF inhibitors — generally poorly/inconsistently effective.
B. Clone-directed (hematologic) - Hypomethylating agents — azacitidine — clinical responses (~5/11 with concurrent MDS in GeneReviews summary) and, importantly, occasional deep/complete molecular remission of the UBA1 clone, sometimes permitting therapy de-escalation.
"Two patients achieved complete molecular remission of the underlying UBA1 mutant clone... receiving treatment with the hypomethylating agent azacitidine." — Blood / Annals of Hematology 2023–2025 reports. (HUMAN_CLINICAL) CHEBI:2038 (azacitidine); MAXO chemotherapy/pharmacotherapy. - Allogeneic hematopoietic stem cell transplantation (allo-HSCT) — the only curative therapy; eradicates the mutant clone. Systematic review/meta-analysis supports efficacy in selected, fit patients, balanced against transplant-related mortality (Nature BMT 2024, s41409-024-02375-3). MAXO: MAXO:0001175/MAXO:0010039 (hematopoietic/organ transplantation); modality CELL_THERAPY.
Emerging / experimental. UBA1-targeted and clone-selective strategies, optimized HMA + JAKi combinations, and refined transplant conditioning are under active study. Recent retrospective treatment-outcome cohorts (Lancet Rheumatology 2025, PIIS2665-9913(25)00034-7) are defining comparative effectiveness. Relevant trial registries: search ClinicalTrials.gov for "VEXAS" (e.g., natural-history/genetics protocol NCT06004349; several interventional JAKi/HMA studies). (Add specific NCT IDs at curation time.)
Supportive care. Transfusion support, infection prophylaxis (especially under steroids/JAKi/HMA — PJP prophylaxis), anticoagulation for VTE, bone protection, vaccination. MAXO:0000950 (supportive care).
Pharmacogenomics. No VEXAS-specific PGx; standard JAKi/azacitidine considerations apply.
| Claim | Reference | PMID | Evidence type |
|---|---|---|---|
| Discovery; UBA1 p.Met41 somatic mutation; vacuoles; 25 men; 10 deaths | Beck DB et al. NEJM 2020;383:2628-2638 | 33108101 | HUMAN_CLINICAL + IN_VITRO |
| Population prevalence (1/4269 men >50) | Beck DB et al. JAMA 2023;329:318-324 | 36692560 | HUMAN_CLINICAL |
| Cytoplasmic UBA1b translation; genotype–survival (Val worst) | Ferrada/Beck et al. Blood 2022;140:1496-1506 | 35793465 | IN_VITRO + HUMAN_CLINICAL |
| Novel/expanded UBA1 variant spectrum (splice, non-Met41) | Poulter JA et al. Blood 2021;137:3676-3681 | 33690795 | HUMAN_CLINICAL |
| Ruxolitinib superior among JAK inhibitors | Heiblig M et al. Blood 2022 | 35609174 | HUMAN_CLINICAL |
| Exome can misread high-VAF somatic UBA1 as hemizygous | (case report) | 36038944 | HUMAN_CLINICAL |
| Comprehensive clinical/genetic synthesis | GeneReviews: VEXAS Syndrome (Beck DB) | Bookshelf NBK614471 | Review |
| Mechanism: inflammation vs myeloid bias independent | Nature 2025 (s41586-025-09815-0) | (PMID pending) | MODEL_ORGANISM |
Sources (web): - Beck et al. NEJM 2020 — PMID:33108101 - Beck et al. JAMA 2023 — PMID:36692560 - GeneReviews: VEXAS Syndrome — NBK614471 - OMIM #301054 - Ferrada/Beck Blood 2022 — Translation of cytoplasmic UBA1 (PMC9523373) - Heiblig et al. Blood 2022 — Ruxolitinib (PMID:35609174) - Nature 2025 — Independent mechanisms of inflammation and myeloid bias - NCI/DCEG genome-first prevalence summary - Bone Marrow Transplantation 2024 — allo-HSCT meta-analysis - Lancet Rheumatology 2025 — treatment outcomes cohort
kb/disorders/VEXAS_Syndrome.yaml)hgnc:12469 (UBA1) · note somatic origin in the genetic block (GENO somatic mutation, not germline inheritance).just fetch-reference'd and every snippet: verified as an exact substring of the real abstract (the quotes here are paraphrase-adjacent search excerpts and must be replaced with verified verbatim text). Run just validate, just validate-references, and just validate-terms-file on the file.discussions with kind: KNOWLEDGE_GAP for these, and kind: HUMAN_MODEL_MISMATCH for the model-organism translational gap.