VEXAS Syndrome

Complex MONDO:0026777 Pathograph 21 Show in embeddings browser autoinflammatory syndrome rare disease

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). Canonical p.Met41 variants force translation of a catalytically impaired isoform from a downstream start site, whereas pathogenic non-Met41 variants can impair both nuclear and cytoplasmic UBA1 activity. 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 an association with 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.

Ask OpenScientist

Ask a research question about VEXAS Syndrome. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
6
Pathophys.
12
Phenotypes
2
Gaps
21
Pathograph
1
Genes
6
Medical Actions
3
Differentials
3
Datasets
1
Models
4
References
1
Deep Research
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC ONCOLOGY HEMATOLOGY
👪

Inheritance

1
Somatic mosaicism (not inherited) HP:0001442
VEXAS is caused by acquired somatic (post-zygotic, mosaic) UBA1 variants and is not currently known to be a vertically transmitted Mendelian disease. No confirmed vertical transmission or sibling recurrence has been reported. The strong male predominance is consistent with the X-linked location of UBA1, although VEXAS also occurs in women.
Typified by somatic mosaicism
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"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."
GeneReviews confirms the somatic, non-heritable nature of VEXAS with no vertical transmission or sibling recurrence.
?

Discussions and Knowledge Gaps

2
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 hematopoietic dysfunction), or only its molecular/inflammatory arm?
HUMAN MODEL MISMATCH OPEN vexas_model_human_fidelity
Attached to
pathophysiology#Multi-Organ Inflammation
The curated zebrafish knockout reproduces systemic inflammation, and a 2025 base-edited humanized HSPC model recapitulates proteostatic, cytologic, senescence, hematologic, and inflammatory hallmarks. Whether available models reproduce the full relapsing multi-organ clinical syndrome remains unresolved.
Proposed experiments
Humanized hematopoietic-restricted somatic Met41 mouse model
vexas_humanized_met41_mouse
Engineer humanized, hematopoietic-restricted somatic Met41 mouse models with age-dependent clonal acquisition and assess multi-organ phenotype recapitulation including marrow precursor vacuolization and independently classified MDS emergence.
Show evidence (2 references)
PMID:33108101 SUPPORT Model Organism
"Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation."
Establishes the inflammatory phenotype reproduced by the curated zebrafish model.
PMID:40195449 SUPPORT Model Organism
"Humanized models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, recapitulated proteostatic defects, cytological alterations and senescence signatures of patients' cells, as well as hematological and inflammatory disease hallmarks."
Defines the breadth of disease biology reproduced by the newer humanized HSPC model without claiming complete organ-level fidelity.
What are the general-population incidence and validated classification criteria for VEXAS syndrome across diverse populations?
KNOWLEDGE GAP OPEN vexas_population_incidence_criteria
Attached to
disease#VEXAS Syndrome
Prevalence is estimated from a single US regional, predominantly White health-system cohort, so general-population incidence and diverse-ancestry estimates remain sparse. The International VEXAS Working Group has now published the first formal consensus clinical guidance for testing, VEXAS-associated MDS assessment, prognosis, and management; that guidance does not eliminate the need for externally validated classification criteria.
Show evidence (2 references)
PMID:36692560 SUPPORT Human Clinical
"Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum."
The genome-first prevalence study explicitly identifies the need for diverse, population-level replication.
PMID:40787890 SUPPORT Other
"This work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management."
Establishes that formal international clinical guidance now exists, while distinguishing guidance from validated classification criteria.
⚙

Pathophysiology

6
Somatic Pathogenic UBA1 Mutation in Hematopoietic Stem Cells
The founding lesion of VEXAS is an acquired (post-zygotic, mosaic) somatic pathogenic variant in UBA1 within the hematopoietic stem and progenitor-cell compartment. Variants affecting methionine-41 (p.Met41) predominate, but pathogenic splice-site and selected non-Met41 variants broaden the molecular spectrum. Mutant cells are enriched in the myeloid compartment; in the original cohort, they were not detected in lymphocytes or fibroblasts.
Hematopoietic stem cell CL:0000037 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Hematopoietic stem cell (CL:0000037). CL:0000037 is a cell type from the Cell Ontology.
UBA1 hgnc:12469 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves UBA1 (hgnc:12469). hgnc:12469 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Canonical p.Met41 UBA1b Loss and Reduced Ubiquitylation In the canonical p.Met41 branch, disruption of the UBA1b start codon reduces translation of functional cytoplasmic UBA1b and produces a catalytically impaired downstream isoform.
Emerging Non-Met41 UBA1 Enzymatic Dysfunction Pathogenic variants outside p.Met41 can reduce both nuclear and cytoplasmic UBA1 activity through a mechanism distinct from the canonical UBA1b isoform switch.
Show evidence (3 references)
PMID:33108101 SUPPORT Human Clinical
"We identified 25 men with somatic mutations affecting methionine-41 (p.Met41) in UBA1, the major E1 enzyme that initiates ubiquitylation."
Establishes the defining somatic UBA1 p.Met41 lesion in affected men as the founding genetic event.
PMID:33108101 SUPPORT Human Clinical
"Mutations were found in more than half the hematopoietic stem cells, including peripheral-blood myeloid cells but not lymphocytes or fibroblasts."
Localizes the somatic mutation to hematopoietic stem cells and the myeloid compartment, supporting the HSC origin and diagnostic tissue restriction.
PMID:38552317 SUPPORT Human Clinical
"We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung..."
Demonstrates that a somatic splice-site variant outside the canonical p.Met41 substitutions can produce a VEXAS-compatible phenotype.
Canonical p.Met41 UBA1b Loss and Reduced Ubiquitylation
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 reduction in cytoplasmic ubiquitylation. The level of residual UBA1b translation is genotype-dependent and tracks with disease severity and survival.
Protein ubiquitination GO:0016567 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Protein ubiquitination (GO:0016567). GO:0016567 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Innate Immune Activation Reduced cytoplasmic ubiquitylation triggers cellular stress responses and activates innate immune signaling in mutant myeloid cells.
Myeloid-Skewed Hematopoietic Dysfunction In a canonical p.Met41 model, mutation-engineered HSPCs reproduce cytologic, senescence-like, hematologic, and inflammatory abnormalities.
Show evidence (2 references)
PMID:33108101 SUPPORT In Vitro
"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."
Documents the isoform switch from cytoplasmic UBA1b to a catalytically impaired p.Met67-initiated isoform as the proximal molecular consequence.
PMID:35793467 SUPPORT In Vitro
"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."
Shows that residual cytoplasmic UBA1b translation is genotype-dependent and provides a molecular rationale for the observed survival association.
Emerging Non-Met41 UBA1 Enzymatic Dysfunction
Recurrent, functionally defective non-Met41 UBA1 variants have been reported in hematologic cohorts. Unlike canonical p.Met41 variants, they can reduce the activity of both nuclear and cytoplasmic UBA1 isoforms and are associated with distinct hematologic and biochemical phenotypes. Their relationship to the classic inflammatory VEXAS phenotype is variable and remains under definition.
Protein ubiquitination GO:0016567 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Protein ubiquitination (GO:0016567). GO:0016567 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (3 references)
PMID:41068485 SUPPORT In Vitro
"Canonical pathogenic mutations at UBA1 p.Met41 (M41) lead to the loss of the cytoplasmic isoform (UBA1b), while non-canonical mutations outside of M41 (non-M41) result in reduced activity of both nuclear and cytoplasmic isoforms."
Directly distinguishes the non-Met41 loss of nuclear and cytoplasmic UBA1 activity from the canonical p.Met41 isoform mechanism.
PMID:41068485 SUPPORT In Vitro
"We identified decreased polyubiquitylation in all of the 18 UBA1 variants tested and found differences in H2A/B monoubiquitylation alteration between M41 and non-M41 mutations."
Functional assays support impaired ubiquitylation across the tested non-Met41 variant spectrum.
PMID:41068485 SUPPORT Human Clinical
"In contrast, non-M41 mutations are more likely to appear with co-mutations and are detected in patients with hematologic neoplasms other than MDS."
Supports a hematologic spectrum distinct from the canonical p.Met41 group without implying that every functional non-Met41 variant causes classic inflammatory VEXAS.
Innate Immune Activation
In UBA1-mutant peripheral-blood and myeloid cells, decreased ubiquitylation is associated with activation of innate immune pathways and the systemic autoinflammatory state.
Monocyte CL:0000576 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Monocyte (CL:0000576). CL:0000576 is a cell type from the Cell Ontology.
Inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Multi-Organ Inflammation Innate immune activation drives recurrent multi-organ inflammation; the cited neutrophilic involvement is specific to skin and lung.
Show evidence (2 references)
PMID:33108101 SUPPORT In Vitro
"Mutant peripheral-blood cells showed decreased ubiquitylation and activated innate immune pathways."
Directly links reduced ubiquitylation in mutant cells to activation of innate immune pathways underlying the autoinflammatory phenotype.
PMID:33108101 SUPPORT Model Organism
"Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation."
Zebrafish knockout of the cytoplasmic UBA1 homologue recapitulates systemic inflammation, supporting the causal mechanism in vivo.
Multi-Organ Inflammation
The cytokine-driven inflammatory program produces recurrent, multi-organ inflammation. The cited source specifically describes neutrophilic cutaneous and pulmonary inflammation, alongside chondritis and vasculitis; it does not characterize every involved organ as neutrophilic. This effector phase is the clinical face of the autoinflammatory arm.
Neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
Downstream
Recurrent Fever The systemic inflammatory program manifests clinically with recurrent fever.
Neutrophilic Dermatosis Cutaneous inflammation commonly includes neutrophilic dermatosis.
Cutaneous Leukocytoclastic Vasculitis The cutaneous inflammatory spectrum includes leukocytoclastic vasculitis.
Chondritis Multi-organ inflammation commonly manifests as chondritis.
Pulmonary Infiltrates The multi-organ inflammatory phenotype commonly involves pulmonary infiltrates.
Ocular Inflammation The multi-organ inflammatory phenotype commonly includes pan-ocular inflammation.
Arthritis The multi-organ inflammatory phenotype commonly manifests as arthritis.
Show evidence (1 reference)
PMID:33108101 SUPPORT Human Clinical
"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."
Enumerates the multi-organ inflammatory manifestations driven by the disease. The neutrophilic qualifier applies to the cutaneous and pulmonary involvement; the source lists chondritis and vasculitis without it.
Myeloid-Skewed Hematopoietic Dysfunction
The UBA1-mutant hematopoietic compartment is skewed toward myelopoiesis and shows cytologic and senescence-like abnormalities. Cytoplasmic vacuolization of myeloid and erythroid precursors is characteristic but neither specific nor required. Macrocytic anemia and other cytopenias are common, and a substantial subset of patients also meet criteria for myelodysplastic syndrome; coexistence does not by itself establish linear progression from VEXAS to MDS.
Erythroid lineage cell CL:0000764 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Erythroid lineage cell (CL:0000764). CL:0000764 is a cell type from the Cell Ontology.
Downstream
Macrocytic Anemia Ineffective, myeloid-skewed hematopoiesis is accompanied by macrocytic anemia.
Thrombocytopenia Hematopoietic dysfunction is commonly accompanied by thrombocytopenia.
Show evidence (3 references)
PMID:33108101 SUPPORT Human Clinical
"characteristic vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow"
Documents the precursor vacuolization and dysplastic marrow that define the hematologic arm of VEXAS.
PMID:40195449 SUPPORT Human Clinical
"Hematopoietic stem and progenitor cells (HSPCs) in patients are skewed toward myelopoiesis and acquire senescence-like programs."
Patient HSPCs show the myeloid bias and senescence-like state represented by this node.
PMID:38302223 SUPPORT Other
"The mere observation of vacuolated progenitor cells is not specific to VEXAS syndrome"
Establishes that precursor vacuolization is characteristic but not pathognomonic.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for VEXAS Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Blood 3
Macrocytic Anemia FREQUENT HP:0001972 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Macrocytic anemia (HP:0001972), qualified as course progressive. HP:0001972 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:40787890 SUPPORT Other
"Cytopenia, particularly macrocytic anemia, is a common finding in VEXAS, even in the absence of associated MDS."
The consensus guidance calls macrocytic anemia common, which maps to the FREQUENT band under the qualitative frequency guidance.
PMID:36692560 SUPPORT Human Clinical
"all individuals had anemia (hemoglobin: mean, 7.8 g/dL; median, 7.5 g/dL), which was mostly macrocytic"
A genome-first cohort of 11 variant carriers found anemia in all carriers and macrocytosis in most of them. The cohort is too small to fix a population-level frequency band on its own, so it is retained as a quantitative sub-claim rather than as the basis for the frequency value.
Thrombocytopenia FREQUENT HP:0001873 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thrombocytopenia (HP:0001873). HP:0001873 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40787890 SUPPORT Other
"Macrocytosis is the most common peripheral blood finding in patients with VEXAS, followed by anemia, absolute lymphopenia (80%), moderate thrombocytopenia (30–50%), and monocytopenia (30–50%), whereas neutrophils are often within normal values."
Consensus guidance places moderate thrombocytopenia at 30–50%, supporting the FREQUENT band.
Myelodysplastic Syndrome Myelodysplasia HP:0002863 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myelodysplasia (HP:0002863). HP:0002863 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33108101 SUPPORT Human Clinical
"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."
Documents myelodysplastic syndrome (and multiple myeloma) as hematologic conditions met by patients with VEXAS.
Metabolism 1
Recurrent Fever HP:0001954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent fever (HP:0001954), qualified as temporality recurrent. HP:0001954 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:33108101 SUPPORT Human Clinical
"an often fatal, treatment-refractory inflammatory syndrome develops in late adulthood, with fevers, cytopenias"
Lists fevers among the cardinal features of the late-onset inflammatory syndrome.
Musculoskeletal 1
Arthritis HP:0001369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthritis (HP:0001369). HP:0001369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"recurrent fever, skin lesions, pulmonary infiltrates, recurrent chondritis, arthritis, pan ocular inflammation"
GeneReviews lists arthritis among the common inflammatory findings.
Respiratory 1
Pulmonary Infiltrates HP:0002113 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary infiltrates (HP:0002113). HP:0002113 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"The most common inflammatory findings include recurrent fever, skin lesions, pulmonary infiltrates, recurrent chondritis, arthritis, pan ocular inflammation, and unprovoked venous thrombosis."
GeneReviews explicitly lists pulmonary infiltrates among the most common inflammatory findings.
Other 6
Monoclonal Gammopathy of Undetermined Significance Paraproteinemia HP:0031047 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Paraproteinemia (HP:0031047). HP:0031047 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"Hematologic involvement includes macrocytic anemia, myelodysplastic syndrome (MDS), thrombocytopenia, monoclonal gammopathy of unknown significance, and vacuoles in myeloid and erythroid precursor cells."
GeneReviews explicitly includes monoclonal gammopathy of unknown significance among the hematologic manifestations.
Neutrophilic Dermatosis Neutrophilic infiltration of the skin HP:0031234 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neutrophilic dermatosis, annotated with Neutrophilic infiltration of the skin (HP:0031234). HP:0031234 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38865133 SUPPORT Human Clinical
"skin involvement was common (93 [83%])"
Cohort of 112 patients shows skin involvement in 93/112 (83%). This broad skin-involvement statistic supports the clinical context but is not used as a frequency estimate for neutrophilic dermatosis specifically.
PMID:38865133 SUPPORT Human Clinical
"Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis."
Identifies neutrophilic dermatoses among the cutaneous manifestations that should prompt evaluation for VEXAS, without assigning a patient-level frequency estimate.
Cutaneous Leukocytoclastic Vasculitis HP:0034786 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Leukocytoclastic vasculitis (HP:0034786). HP:0034786 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38865133 SUPPORT Human Clinical
"the p.Met41Val variant was associated with vasculitic lesions"
Documents vasculitic skin lesions associated with the p.Met41Val genotype.
Chondritis HP:0100662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chondritis (HP:0100662), qualified as temporality recurrent. HP:0100662 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:33108101 SUPPORT Human Clinical
"neutrophilic cutaneous and pulmonary inflammation, chondritis, and vasculitis."
Lists chondritis among the characteristic inflammatory manifestations.
Ocular Inflammation Inflammatory abnormality of the eye HP:0100533 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ocular inflammation, annotated with Inflammatory abnormality of the eye (HP:0100533). HP:0100533 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"The most common inflammatory findings include recurrent fever, skin lesions, pulmonary infiltrates, recurrent chondritis, arthritis, pan ocular inflammation, and unprovoked venous thrombosis."
GeneReviews directly lists pan-ocular inflammation among the most common inflammatory findings.
Venous Thrombosis HP:0004936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Venous thrombosis (HP:0004936). HP:0004936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"recurrent chondritis, arthritis, pan ocular inflammation, and unprovoked venous thrombosis."
GeneReviews lists unprovoked venous thrombosis among the most common inflammatory findings.
🧬

Genetic Associations

1
UBA1 (Somatic (post-zygotic, mosaic) mutations in UBA1 (Xp11.23), predominantly at p.Met41 (p.Met41Thr, p.Met41Val, p.Met41Leu), are the defining cause of VEXAS. Pathogenic splice-site and non-Met41 variants expand the genetic and mechanistic spectrum. Among canonical variants, p.Met41Val is associated with less residual UBA1b translation and decreased survival. )
Gene: UBA1 hgnc:12469 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is UBA1 (hgnc:12469). hgnc:12469 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: SOMATIC
Show evidence (3 references)
PMID:35793467 SUPPORT Human Clinical
"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)."
Defines the three canonical p.Met41 somatic genotypes at the cytoplasmic UBA1b start codon.
PMID:35793467 SUPPORT Human Clinical
"ear chondritis was associated with increased survival, whereas transfusion dependence and the p.Met41Val variant were independently associated with decreased survival."
Establishes p.Met41Val as an independent predictor of decreased survival, supporting genotype-phenotype-prognosis correlation.
PMID:38552317 SUPPORT Human Clinical
"Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and provide support for a complete gene evaluation in those patients considered candidates for VEXAS syndrome."
Supports extending diagnostic evaluation beyond the canonical p.Met41 substitutions when the clinical phenotype is strongly suggestive.
💊

Medical Actions

6
Glucocorticoid Therapy
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: prednisone CHEBI:8382 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses prednisone (CHEBI:8382). CHEBI:8382 is a therapeutic agent from Chemical Entities of Biological Interest.
Glucocorticoids (e.g., prednisone) are generally used first-line and inflammatory manifestations are typically sensitive, but high-level corticosteroid dependence commonly drives the need for steroid-sparing treatment.
Show evidence (2 references)
PMID:40373178 SUPPORT Other
"Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and..."
GeneReviews supports glucocorticoid sensitivity while explicitly noting clinically important corticosteroid dependence.
PMID:38865133 SUPPORT Human Clinical
"Oral prednisone improved skin manifestations in 67 of 73 patients"
Documents high response of skin manifestations to oral prednisone.
Ruxolitinib (JAK Inhibitor)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ruxolitinib CHEBI:66919 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ruxolitinib (CHEBI:66919). CHEBI:66919 is a therapeutic agent from Chemical Entities of Biological Interest.
A retrospective multicenter study reported encouraging evidence for the JAK1/2 inhibitor ruxolitinib, with clinical remissions and steroid reduction in the majority of treated patients.
Mechanism Target:
INHIBITS Innate Immune Activation — JAK inhibition is used as an inflammation-targeting strategy; this edge does not identify a more specific cytokine pathway than the cited source.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and..."
GeneReviews lists JAK inhibitors as steroid-sparing treatment for inflammatory manifestations without establishing a more specific node.
Show evidence (1 reference)
PMID:35609174 SUPPORT Human Clinical
"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."
Retrospective multicenter study supports ruxolitinib efficacy with remissions and steroid reduction in most patients.
Tocilizumab (IL-6 Inhibition)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: Tocilizumab NCIT:C84217 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses Tocilizumab (NCIT:C84217). NCIT:C84217 is a therapeutic agent from the NCI Thesaurus.
The anti-IL-6 receptor monoclonal antibody tocilizumab is used as a second-line steroid-sparing agent, with variable clinical success reported.
Mechanism Target:
INHIBITS Innate Immune Activation — IL-6 inhibition is used as an inflammation-targeting strategy; the edge is kept at the broad innate-activation node supported by the synthesis.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and..."
GeneReviews lists IL-6 inhibitors as steroid-sparing treatment for inflammatory manifestations.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and..."
GeneReviews lists IL-6 inhibitors among second-line steroid-sparing agents.
Azacitidine (Hypomethylating Agent)
Action: chemotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is chemotherapy (NCIT:C15632). NCIT:C15632 is a clinical intervention from the NCI Thesaurus. Ontology label: Chemotherapy NCIT:C15632
Agent: azacitidine CHEBI:2038 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses azacitidine, annotated with 5-azacytidine (CHEBI:2038). CHEBI:2038 is a therapeutic agent from Chemical Entities of Biological Interest.
The hypomethylating agent azacitidine is used particularly in patients with concurrent MDS, with variable clinical success.
Mechanism Target:
MODULATES Myeloid-Skewed Hematopoietic Dysfunction — In concurrent MDS, azacitidine is categorized as a strategy directed at the UBA1-mutated hematopoietic population. Variable clinical success does not establish clone eradication or molecular remission.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"Targeting the UBA1-mutated hematopoietic population: Similar to classic MDS without VEXAS syndrome, hypomethylating agents like azacitidine are used to treat individuals with VEXAS syndrome with concurrent MDS with varying success."
GeneReviews places azacitidine under hematopoietic-population targeting but describes variable success, supporting a conservative modulation edge.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"hypomethylating agents like azacitidine are used to treat individuals with VEXAS syndrome with concurrent MDS with varying success."
GeneReviews documents azacitidine use for VEXAS with concurrent MDS.
Allogeneic Hematopoietic Stem Cell Transplantation
Action: allogeneic hematopoietic stem cell transplantationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is allogeneic hematopoietic stem cell transplantation (NCIT:C46089). NCIT:C46089 is a clinical intervention from the NCI Thesaurus. Ontology label: Allogeneic Hematopoietic Stem Cell Transplantation NCIT:C46089
Allogeneic HSCT is currently the only curative therapy identified in the cited clinical guidance, but it carries considerable transplant-related morbidity and mortality and is reserved for selected patients.
Mechanism Target:
MODULATES Myeloid-Skewed Hematopoietic Dysfunction — Allogeneic HSCT is categorized as targeting the UBA1-mutated hematopoietic population and is clinically curative in selected patients; this edge does not independently assert molecular clonal clearance.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for VEXAS syndrome; however, it is sometimes associated with considerable morbidity and even mortality and should be only be considered in selected individuals after discussion with..."
GeneReviews identifies allogeneic HSCT as the only curative treatment, supporting conservative linkage to hematopoietic dysfunction without directly measuring clonal clearance.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for VEXAS syndrome; however, it is sometimes associated with considerable morbidity and even mortality and should be only be considered in selected individuals after discussion with..."
GeneReviews identifies allogeneic HSCT as the only curative therapy.
Anakinra (IL-1 Inhibition)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: anakinra CHEBI:231683 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses anakinra (CHEBI:231683). CHEBI:231683 is a therapeutic agent from Chemical Entities of Biological Interest.
Anakinra, a recombinant IL-1 receptor antagonist, is used as an anti-IL-1 steroid-sparing option with variable clinical success. It frequently causes severe injection-site reactions in VEXAS patients, a disease-specific safety signal.
Mechanism Target:
INHIBITS Innate Immune Activation — Anti-IL-1 therapy is used as an inflammation-targeting strategy; the edge is kept at the broad innate-activation node supported by the synthesis.
Show evidence (1 reference)
PMID:40373178 SUPPORT Other
"Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and..."
GeneReviews lists anti-IL-1 therapy as steroid-sparing treatment for inflammatory manifestations.
Show evidence (2 references)
PMID:40373178 SUPPORT Other
"Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and..."
GeneReviews lists anti-IL-1 therapies among second-line steroid-sparing agents.
PMID:38865133 SUPPORT Human Clinical
"Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions"
Documents the disease-specific anakinra injection-site reaction safety signal in VEXAS patients.
🔬

Biochemical Markers

3
Elevated C-reactive protein (Positive)
Show evidence (2 references)
PMID:40787890 SUPPORT Other
"Erythrocyte sedimentation rate (ESR), ferritin, and C‐reactive protein (CRP) are increased in most untreated patients and can trend with acute episodes of inflammation."
Consensus guidance supports elevated CRP in most untreated patients and scopes it as a marker that can track acute inflammatory episodes.
PMID:35868738 SUPPORT Human Clinical
"with higher median C-reactive protein levels (64 mg/L vs 10 mg/L, p<0.001)."
In a French relapsing-polychondritis cohort, patients with VEXAS-RP had a substantially higher median CRP than patients with idiopathic RP.
Elevated erythrocyte sedimentation rate (Positive)
Show evidence (1 reference)
PMID:40787890 SUPPORT Other
"Erythrocyte sedimentation rate (ESR), ferritin, and C‐reactive protein (CRP) are increased in most untreated patients and can trend with acute episodes of inflammation."
Consensus guidance supports elevated ESR in most untreated patients and scopes it to inflammatory activity.
Increased circulating ferritin concentration (Positive)
Show evidence (1 reference)
PMID:40787890 SUPPORT Other
"Erythrocyte sedimentation rate (ESR), ferritin, and C‐reactive protein (CRP) are increased in most untreated patients and can trend with acute episodes of inflammation."
Consensus guidance supports increased ferritin in most untreated patients and scopes it to inflammatory activity.
🔬

Diagnosis

2
Molecular genetic testing for somatic UBA1 variants
Diagnosis is established by identifying a somatic UBA1 pathogenic variant by molecular genetic testing of peripheral blood and/or bone marrow aspirate 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.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:40373178 SUPPORT Other
"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."
GeneReviews specifies the confirmatory molecular test and the diagnostic tissue restriction (blood/marrow, not fibroblasts).
PMID:36038944 SUPPORT Human Clinical
"Sequencing of different tissues should be considered when there is conflict between the UBA1 variant status and the clinical findings."
Highlights the exome misinterpretation pitfall and the need to sequence multiple tissues to confirm somatic status.
Bone marrow examination for precursor vacuolization
Bone marrow aspirate may show cytoplasmic vacuoles in myeloid and erythroid precursor cells. This is a characteristic clue but is neither required nor specific, so diagnosis still requires identification of a pathogenic somatic UBA1 variant in the appropriate clinical context.
bone marrow examination NCIT:C92958 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:40373178 SUPPORT Other
"vacuoles in myeloid and erythroid precursor cells."
GeneReviews lists the characteristic precursor vacuolization seen on bone marrow examination.
PMID:38302223 SUPPORT Other
"The mere observation of vacuolated progenitor cells is not specific to VEXAS syndrome"
A focused hematopathology review explains that precursor vacuoles have a differential diagnosis beyond VEXAS.
PMID:38302223 SUPPORT Other
"However, the absence or a low proportion of vacuolated cells should not prevent UBA1 gene sequencing."
Supports treating vacuoles as a clue rather than a required diagnostic feature.
📊

Prevalence

2
Men older than 50 years (US regional health system, genome-first ascertainment)
Point Prevalence 23.42469 per 100,000 1–9 per 10,000
Show evidence (1 reference)
PMID:36692560 SUPPORT Human Clinical
"1 in 4269 men older than 50 years"
Genome-first Geisinger MyCode study estimates disease-associated UBA1 variant prevalence at 1 in 4269 men older than 50 years.
Women older than 50 years (US regional health system, genome-first ascertainment)
Point Prevalence 3.811266 per 100,000 1–9 per 100,000
Show evidence (1 reference)
PMID:36692560 SUPPORT Human Clinical
"1 in 26 238 women older than 50 years"
Same study estimates a much lower prevalence in women older than 50 years, consistent with the X-linked male predominance.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from VEXAS Syndrome:

Relapsing polychondritis
Overlapping Features VEXAS can present with a relapsing-polychondritis phenotype; somatic UBA1 testing distinguishes VEXAS from idiopathic relapsing polychondritis.
Sweet syndrome
Overlapping Features VEXAS skin lesions frequently resemble (histiocytoid) Sweet syndrome; accompanying macrocytic anemia and UBA1 testing distinguish VEXAS.
Myelodysplastic syndrome without autoinflammation
Overlapping Features MDS in an older man with prominent systemic inflammation should prompt UBA1 testing for VEXAS.
📊

Related Datasets

3
Single-cell RNA sequencing of blood cells from patients with VEXAS syndrome. geo:GSE249131
We performed single cell RNA sequencing, and VDJ sequencing of TCR and BCR of peripheral blood samples (Peripheral Blood Mononuclear Cells[PBMCs]) from 9 patients with VEXAS to understand disease pathogenesis.
human SINGLE CELL RNA SEQ n=66
PMID:40394087
Identified by GEO DataSets index search for VEXAS Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
Single-cell profiling of hematopoietic cells in VEXAS syndrome geo:GSE196052
Background and methods: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has been recently recognized as an adult-onset autoinflammatory syndrome due to somatic mutations affecting Ubiquitin Like Modifier Activating Enzyme 1 (UBA1) gene. Following-up studies have been mostly limited to case reports; transcriptome of especially hematopoiesis in VEXAS syndrome has not been well characterized. Results: We performed whole transcriptome sequencing of single bone marrow cells (BMMNCs) and enriched Lineage-CD34+ hematopoietic stem and progenitor cells (HSPCs) from nine patients included in the original VEXAS cohort.
human SINGLE CELL RNA SEQ n=56
PMID:37586319
Identified by GEO DataSets index search for VEXAS Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
POISONING OF HEALTHY HEMATOPOIESIS IS AN UNANTICIPATED MECHANISM DRIVING CLONAL DOMINANCE IN VEXAS SYNDROME [scRNA-seq] geo:GSE272816
Clonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common non-malignant disorders. VEXAS syndrome is a recently discovered adult-onset autoinflammatory disease burdened by a high mortality rate and caused by dominant hematopoietic clones bearing somatic mutations in the UBA1 gene. However, pathogenic mechanisms fueling clonal dominance are unknown. Moreover, the lack of disease models hampers the development of disease-modifying therapies. Here, we performed immunophenotypic dissection of hematopoiesis and single-cell transcriptomics in a VEXAS patient cohort revealing pervasive inflammation across all lineages.
human SINGLE CELL RNA SEQ n=14
PMID:40195449
Identified by GEO DataSets index search for VEXAS Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
🐁

Animal Models

1
Cytoplasmic UBA1 homologue knockout zebrafish
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.
Species
Danio rerio (zebrafish)
Genotype
Cytoplasmic UBA1 isoform homologue knockout (CRISPR-Cas9)
Show evidence (1 reference)
PMID:33108101 SUPPORT Model Organism
"Knockout of the cytoplasmic UBA1 isoform homologue in zebrafish caused systemic inflammation."
Zebrafish model recapitulates systemic inflammation downstream of cytoplasmic UBA1 loss.
{ }

Source YAML

click to show 
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). Canonical p.Met41 variants force translation
  of a catalytically impaired isoform from a downstream start site, whereas
  pathogenic non-Met41 variants can impair both nuclear and cytoplasmic UBA1
  activity. 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 an association with 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
- reference: PMID:40787890
  title: American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
- reference: PMID:40195449
  title: Mechanisms of hematopoietic clonal dominance in VEXAS syndrome.
- reference: PMID:41068485
  title: Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations.
pathophysiology:
- name: Somatic Pathogenic UBA1 Mutation in Hematopoietic Stem Cells
  description: >
    The founding lesion of VEXAS is an acquired (post-zygotic, mosaic) somatic
    pathogenic variant in UBA1 within the hematopoietic stem and progenitor-cell
    compartment. Variants affecting methionine-41 (p.Met41) predominate, but
    pathogenic splice-site and selected non-Met41 variants broaden the molecular
    spectrum.
    Mutant cells are enriched in the myeloid compartment; in the original
    cohort, they were not detected in lymphocytes or fibroblasts.
  cell_types:
  - preferred_term: Hematopoietic stem cell
    term:
      id: CL:0000037
      label: hematopoietic stem cell
  genes:
  - preferred_term: UBA1
    term:
      id: hgnc:12469
      label: UBA1
  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.
  - reference: PMID:38552317
    reference_title: Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a novel, somatic variant in a canonical splice site of the UBA1 gene (c.346-2A>G), which was identified in two unrelated adult male patients with late-onset, unexplained inflammatory manifestations including recurrent fever, Sweet syndrome-like neutrophilic dermatosis, and lung inflammation responsive only to glucocorticoids."
    explanation: >
      Demonstrates that a somatic splice-site variant outside the canonical
      p.Met41 substitutions can produce a VEXAS-compatible phenotype.
  downstream:
  - target: Canonical p.Met41 UBA1b Loss and Reduced Ubiquitylation
    causal_link_type: DIRECT
    description: >
      In the canonical p.Met41 branch, disruption of the UBA1b start codon
      reduces translation of functional cytoplasmic UBA1b and produces a
      catalytically impaired downstream isoform.
  - target: Emerging Non-Met41 UBA1 Enzymatic Dysfunction
    causal_link_type: DIRECT
    description: >
      Pathogenic variants outside p.Met41 can reduce both nuclear and
      cytoplasmic UBA1 activity through a mechanism distinct from the canonical
      UBA1b isoform switch.
- name: Canonical p.Met41 UBA1b Loss 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
    reduction in cytoplasmic ubiquitylation. 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: IN_VITRO
    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 provides a molecular rationale for the observed survival association.
  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.
  - target: Myeloid-Skewed Hematopoietic Dysfunction
    causal_link_type: DIRECT
    description: >
      In a canonical p.Met41 model, mutation-engineered HSPCs reproduce
      cytologic, senescence-like, hematologic, and inflammatory abnormalities.
    evidence:
    - reference: PMID:40195449
      reference_title: Mechanisms of hematopoietic clonal dominance in VEXAS syndrome.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Humanized models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, recapitulated proteostatic defects, cytological alterations and senescence signatures of patients' cells, as well as hematological and inflammatory disease hallmarks."
      explanation: >
        Mutation-engineered human HSPCs in a humanized model reproduce the
        hematopoietic abnormalities, supporting the canonical branch's causal
        link to hematopoietic dysfunction.
- name: Emerging Non-Met41 UBA1 Enzymatic Dysfunction
  mechanism_confidence: PROVISIONAL
  description: >
    Recurrent, functionally defective non-Met41 UBA1 variants have been reported
    in hematologic cohorts. Unlike canonical p.Met41 variants, they can reduce
    the activity of both nuclear and cytoplasmic UBA1 isoforms and are associated
    with distinct hematologic and biochemical phenotypes. Their relationship to
    the classic inflammatory VEXAS phenotype is variable and remains under
    definition.
  biological_processes:
  - preferred_term: Protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: DECREASED
  evidence:
  - reference: PMID:41068485
    reference_title: Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Canonical pathogenic mutations at UBA1 p.Met41 (M41) lead to the loss of the cytoplasmic isoform (UBA1b), while non-canonical mutations outside of M41 (non-M41) result in reduced activity of both nuclear and cytoplasmic isoforms."
    explanation: >
      Directly distinguishes the non-Met41 loss of nuclear and cytoplasmic UBA1
      activity from the canonical p.Met41 isoform mechanism.
  - reference: PMID:41068485
    reference_title: Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identified decreased polyubiquitylation in all of the 18 UBA1 variants tested and found differences in H2A/B monoubiquitylation alteration between M41 and non-M41 mutations."
    explanation: >
      Functional assays support impaired ubiquitylation across the tested
      non-Met41 variant spectrum.
  - reference: PMID:41068485
    reference_title: Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast, non-M41 mutations are more likely to appear with co-mutations and are detected in patients with hematologic neoplasms other than MDS."
    explanation: >
      Supports a hematologic spectrum distinct from the canonical p.Met41 group
      without implying that every functional non-Met41 variant causes classic
      inflammatory VEXAS.
  notes: >
    This provisional branch intentionally has no downstream inflammatory edge:
    the cited study establishes enzymatic dysfunction and a distinct hematologic
    spectrum but does not show that every functional non-Met41 variant converges
    on classic VEXAS inflammation.
- name: Innate Immune Activation
  description: >
    In UBA1-mutant peripheral-blood and myeloid cells, decreased ubiquitylation
    is associated with activation of innate immune pathways and the systemic
    autoinflammatory state.
  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. More specific candidate signals reported elsewhere are not asserted
    here because the cited abstract does not itemize them.
  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 Inflammation
    causal_link_type: DIRECT
    description: >
      Innate immune activation drives recurrent multi-organ inflammation; the
      cited neutrophilic involvement is specific to skin and lung.
- name: Multi-Organ Inflammation
  description: >
    The cytokine-driven inflammatory program produces recurrent, multi-organ
    inflammation. The cited source specifically describes neutrophilic
    cutaneous and pulmonary inflammation, alongside chondritis and vasculitis;
    it does not characterize every involved organ as neutrophilic. 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 inflammatory manifestations driven by the
      disease. The neutrophilic qualifier applies to the cutaneous and
      pulmonary involvement; the source lists chondritis and vasculitis
      without it.
  downstream:
  - target: Recurrent Fever
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The systemic inflammatory program manifests clinically with recurrent
      fever.
    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: >
        Directly associates fever with the late-onset inflammatory syndrome.
  - target: Neutrophilic Dermatosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Cutaneous inflammation commonly includes neutrophilic dermatosis.
    evidence:
    - reference: PMID:38865133
      reference_title: "Skin Manifestations of VEXAS Syndrome and Associated Genotypes."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis."
      explanation: >
        Identifies neutrophilic dermatoses among the cutaneous manifestations
        that should prompt evaluation for VEXAS.
  - target: Cutaneous Leukocytoclastic Vasculitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The cutaneous inflammatory spectrum includes leukocytoclastic vasculitis.
    evidence:
    - 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: >
        Identifies leukocytoclastic vasculitis as a predominant skin
        histopathologic finding.
  - target: Chondritis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Multi-organ inflammation commonly manifests as chondritis.
    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: >
        The defining cohort lists chondritis in the inflammatory phenotype.
  - target: Pulmonary Infiltrates
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The multi-organ inflammatory phenotype commonly involves pulmonary
      infiltrates.
    evidence:
    - reference: PMID:40373178
      reference_title: "VEXAS Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      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 includes pulmonary infiltrates among the common inflammatory
        findings.
  - target: Ocular Inflammation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The multi-organ inflammatory phenotype commonly includes pan-ocular
      inflammation.
    evidence:
    - reference: PMID:40373178
      reference_title: "VEXAS Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      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 includes pan-ocular inflammation among the common
        inflammatory findings.
  - target: Arthritis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      The multi-organ inflammatory phenotype commonly manifests as arthritis.
    evidence:
    - reference: PMID:40373178
      reference_title: "VEXAS Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "recurrent fever, skin lesions, pulmonary infiltrates, recurrent chondritis, arthritis, pan ocular inflammation"
      explanation: >
        GeneReviews includes arthritis among the common inflammatory findings.
- name: Myeloid-Skewed Hematopoietic Dysfunction
  description: >
    The UBA1-mutant hematopoietic compartment is skewed toward myelopoiesis and
    shows cytologic and senescence-like abnormalities. Cytoplasmic vacuolization
    of myeloid and erythroid precursors is characteristic but neither specific
    nor required. Macrocytic anemia and other cytopenias are common, and a
    substantial subset of patients also meet criteria for myelodysplastic
    syndrome; coexistence does not by itself establish linear progression from
    VEXAS to MDS.
  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.
  - reference: PMID:40195449
    reference_title: Mechanisms of hematopoietic clonal dominance in VEXAS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hematopoietic stem and progenitor cells (HSPCs) in patients are skewed toward myelopoiesis and acquire senescence-like programs."
    explanation: >
      Patient HSPCs show the myeloid bias and senescence-like state represented
      by this node.
  - reference: PMID:38302223
    reference_title: "Vacuoles in bone marrow progenitors: VEXAS syndrome and beyond."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mere observation of vacuolated progenitor cells is not specific to VEXAS syndrome"
    explanation: >
      Establishes that precursor vacuolization is characteristic but not
      pathognomonic.
  downstream:
  - target: Macrocytic Anemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Ineffective, myeloid-skewed hematopoiesis is accompanied by macrocytic
      anemia.
    evidence:
    - reference: PMID:40787890
      reference_title: American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Cytopenia, particularly macrocytic anemia, is a common finding in VEXAS, even in the absence of associated MDS."
      explanation: >
        Consensus guidance identifies macrocytic anemia as a common cytopenic
        manifestation of VEXAS.
  - target: Thrombocytopenia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Hematopoietic dysfunction is commonly accompanied by thrombocytopenia.
    evidence:
    - reference: PMID:40787890
      reference_title: American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Macrocytosis is the most common peripheral blood finding in patients with VEXAS, followed by anemia, absolute lymphopenia (80%), moderate thrombocytopenia (30–50%), and monocytopenia (30–50%), whereas neutrophils are often within normal values."
      explanation: >
        The consensus guidance identifies moderate thrombocytopenia as a common
        peripheral-blood finding in VEXAS.
phenotypes:
- category: Hematologic
  name: Macrocytic Anemia
  description: >
    Macrocytic anemia is a common hematologic feature of VEXAS and can be
    progressive and transfusion-dependent.
  phenotype_term:
    preferred_term: Macrocytic anemia
    term:
      id: HP:0001972
      label: Macrocytic anemia
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:40787890
    reference_title: American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Cytopenia, particularly macrocytic anemia, is a common finding in VEXAS, even in the absence of associated MDS."
    explanation: >
      The consensus guidance calls macrocytic anemia common, which maps to the
      FREQUENT band under the qualitative frequency guidance.
  - 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"
    explanation: >
      A genome-first cohort of 11 variant carriers found anemia in all carriers
      and macrocytosis in most of them. The cohort is too small to fix a
      population-level frequency band on its own, so it is retained as a
      quantitative sub-claim rather than as the basis for the frequency value.
- category: Hematologic
  name: Thrombocytopenia
  description: >
    Thrombocytopenia frequently accompanies the macrocytic anemia and dysplastic
    hematopoiesis.
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Thrombocytopenia
    term:
      id: HP:0001873
      label: Thrombocytopenia
  evidence:
  - reference: PMID:40787890
    reference_title: American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Macrocytosis is the most common peripheral blood finding in patients with VEXAS, followed by anemia, absolute lymphopenia (80%), moderate thrombocytopenia (30–50%), and monocytopenia (30–50%), whereas neutrophils are often within normal values."
    explanation: >
      Consensus guidance places moderate thrombocytopenia at 30–50%, supporting
      the FREQUENT band.
- category: Hematologic
  name: Myelodysplastic Syndrome
  description: >
    Myelodysplastic syndrome is a recognized hematologic comorbidity in VEXAS.
    Its presence should be assessed using MDS-specific criteria rather than
    assumed from cytopenias, dysplasia, or vacuolization alone.
  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: Hematologic
  name: Monoclonal Gammopathy of Undetermined Significance
  description: >
    Monoclonal gammopathy of undetermined significance is a recognized
    hematologic manifestation of VEXAS.
  phenotype_term:
    preferred_term: Paraproteinemia
    term:
      id: HP:0031047
      label: Paraproteinemia
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Hematologic involvement includes macrocytic anemia, myelodysplastic syndrome (MDS), thrombocytopenia, monoclonal gammopathy of unknown significance, and vacuoles in myeloid and erythroid precursor cells."
    explanation: >
      GeneReviews explicitly includes monoclonal gammopathy of unknown
      significance among the hematologic manifestations.
- 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
  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 [83%])"
    explanation: >
      Cohort of 112 patients shows skin involvement in 93/112 (83%). This broad
      skin-involvement statistic supports the clinical context but is not used
      as a frequency estimate for neutrophilic dermatosis specifically.
  - reference: PMID:38865133
    reference_title: "Skin Manifestations of VEXAS Syndrome and Associated Genotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis."
    explanation: >
      Identifies neutrophilic dermatoses among the cutaneous manifestations
      that should prompt evaluation for VEXAS, without assigning a
      patient-level frequency estimate.
- category: Dermatologic
  name: Cutaneous Leukocytoclastic Vasculitis
  description: >
    Leukocytoclastic vasculitis is a recognized cutaneous histopathologic pattern
    and is associated with the p.Met41Val genotype in a skin-focused cohort.
  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.
  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: >
    Pulmonary infiltrates are a common inflammatory manifestation.
  phenotype_term:
    preferred_term: Pulmonary infiltrates
    term:
      id: HP:0002113
      label: Pulmonary infiltrates
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    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 explicitly lists pulmonary infiltrates among the most common
      inflammatory findings.
- category: Ophthalmologic
  name: Ocular Inflammation
  description: >
    Pan-ocular inflammation is a common inflammatory manifestation; reported
    presentations span several ocular and orbital compartments.
  phenotype_term:
    preferred_term: Ocular inflammation
    term:
      id: HP:0100533
      label: Inflammatory abnormality of the eye
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    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 directly lists pan-ocular inflammation among the most common
      inflammatory findings.
- category: Vascular
  name: Venous Thrombosis
  description: >
    Unprovoked venous thrombosis is a common and clinically important
    manifestation. This phenotype is intentionally not assigned an inbound
    pathograph edge because the cited clinical synthesis establishes its
    association with VEXAS but not a causal direction or thrombo-inflammatory
    mechanism.
  phenotype_term:
    preferred_term: Venous thrombosis
    term:
      id: HP:0004936
      label: Venous thrombosis
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    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: OTHER
    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: >
    C-reactive protein is a nonspecific marker of inflammatory activity. The
    64-versus-10 mg/L median comparison applies specifically to the
    VEXAS-relapsing-polychondritis subgroup; it is not a universal VEXAS
    threshold.
  evidence:
  - reference: PMID:40787890
    reference_title: American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Erythrocyte sedimentation rate (ESR), ferritin, and C‐reactive protein (CRP) are increased in most untreated patients and can trend with acute episodes of inflammation."
    explanation: >
      Consensus guidance supports elevated CRP in most untreated patients and
      scopes it as a marker that can track acute inflammatory episodes.
  - reference: PMID:35868738
    reference_title: "Comparison between idiopathic and VEXAS-relapsing polychondritis: analysis of a French case series of 95 patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with higher median C-reactive protein levels (64 mg/L vs 10 mg/L, p<0.001)."
    explanation: >
      In a French relapsing-polychondritis cohort, patients with VEXAS-RP had a
      substantially higher median CRP than patients with idiopathic RP.
- name: Elevated erythrocyte sedimentation rate
  biomarker_term:
    preferred_term: Elevated erythrocyte sedimentation rate
    term:
      id: HP:0003565
      label: Elevated erythrocyte sedimentation rate
  presence: Positive
  notes: >
    ESR is increased in most untreated patients and can trend with acute
    inflammatory episodes; this does not assert a universal value or diagnostic
    threshold.
  evidence:
  - reference: PMID:40787890
    reference_title: American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Erythrocyte sedimentation rate (ESR), ferritin, and C‐reactive protein (CRP) are increased in most untreated patients and can trend with acute episodes of inflammation."
    explanation: >
      Consensus guidance supports elevated ESR in most untreated patients and
      scopes it to inflammatory activity.
- name: Increased circulating ferritin concentration
  biomarker_term:
    preferred_term: Increased circulating ferritin concentration
    term:
      id: HP:0003281
      label: Increased circulating ferritin concentration
  presence: Positive
  notes: >
    Ferritin is increased in most untreated patients and can trend with acute
    inflammatory episodes; this does not assert a universal value or diagnostic
    threshold.
  evidence:
  - reference: PMID:40787890
    reference_title: American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Erythrocyte sedimentation rate (ESR), ferritin, and C‐reactive protein (CRP) are increased in most untreated patients and can trend with acute episodes of inflammation."
    explanation: >
      Consensus guidance supports increased ferritin in most untreated patients
      and scopes it to inflammatory activity.
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), are the defining cause of
    VEXAS. Pathogenic splice-site and non-Met41 variants expand the genetic and
    mechanistic spectrum. Among canonical variants, p.Met41Val is associated
    with less residual UBA1b translation and decreased survival.
  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.
  - reference: PMID:38552317
    reference_title: Description of a novel splice site variant in UBA1 gene causing VEXAS syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Overall, these results further demonstrate the expanding spectrum of variants in UBA1 leading to pathology and provide support for a complete gene evaluation in those patients considered candidates for VEXAS syndrome."
    explanation: >
      Supports extending diagnostic evaluation beyond the canonical p.Met41
      substitutions when the clinical phenotype is strongly suggestive.
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 currently known to be a vertically transmitted Mendelian disease. No
    confirmed vertical transmission or sibling recurrence has been reported.
    The strong male predominance is consistent with the X-linked location of
    UBA1, although VEXAS also occurs in women.
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    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
    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: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    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 may show cytoplasmic vacuoles in myeloid and erythroid
    precursor cells. This is a characteristic clue but is neither required nor
    specific, so diagnosis still requires identification of a pathogenic somatic
    UBA1 variant in the appropriate clinical context.
  diagnosis_term:
    preferred_term: bone marrow examination
    term:
      id: NCIT:C92958
      label: Bone Marrow Aspiration and Biopsy
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "vacuoles in myeloid and erythroid precursor cells."
    explanation: >
      GeneReviews lists the characteristic precursor vacuolization seen on bone
      marrow examination.
  - reference: PMID:38302223
    reference_title: "Vacuoles in bone marrow progenitors: VEXAS syndrome and beyond."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mere observation of vacuolated progenitor cells is not specific to VEXAS syndrome"
    explanation: >
      A focused hematopathology review explains that precursor vacuoles have a
      differential diagnosis beyond VEXAS.
  - reference: PMID:38302223
    reference_title: "Vacuoles in bone marrow progenitors: VEXAS syndrome and beyond."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "However, the absence or a low proportion of vacuolated cells should not prevent UBA1 gene sequencing."
    explanation: >
      Supports treating vacuoles as a clue rather than a required diagnostic
      feature.
differential_diagnoses:
- name: Relapsing polychondritis
  description: >
    VEXAS can present with a relapsing-polychondritis phenotype; somatic UBA1
    testing distinguishes VEXAS from idiopathic relapsing polychondritis.
- 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 generally used first-line and
    inflammatory manifestations are typically sensitive, but high-level
    corticosteroid dependence commonly drives the need for steroid-sparing
    treatment.
  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:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and anti-IL-1 therapies."
    explanation: >
      GeneReviews supports glucocorticoid sensitivity while explicitly noting
      clinically important corticosteroid dependence.
  - 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: >
    A retrospective multicenter study reported encouraging evidence for the
    JAK1/2 inhibitor ruxolitinib, 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: >
      JAK inhibition is used as an inflammation-targeting strategy; this edge
      does not identify a more specific cytokine pathway than the cited source.
    evidence:
    - reference: PMID:40373178
      reference_title: "VEXAS Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of second-line steroid-sparing agents including interleukin (IL)-6 inhibitors, Janus kinase inhibitors (JAKi), and anti-IL-1 therapies."
      explanation: >
        GeneReviews lists JAK inhibitors as steroid-sparing treatment for
        inflammatory manifestations without establishing a more specific node.
  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
    second-line steroid-sparing agent, with variable clinical success reported.
  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 inhibition is used as an inflammation-targeting strategy; the edge is
      kept at the broad innate-activation node supported by the synthesis.
    evidence:
    - reference: PMID:40373178
      reference_title: "VEXAS Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of 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 as steroid-sparing treatment for
        inflammatory manifestations.
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of 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 is used particularly in patients with
    concurrent MDS, with variable clinical success.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: chemotherapy
    term:
      id: NCIT:C15632
      label: Chemotherapy
    therapeutic_agent:
    - preferred_term: azacitidine
      term:
        id: CHEBI:2038
        label: 5-azacytidine
  target_mechanisms:
  - target: Myeloid-Skewed Hematopoietic Dysfunction
    treatment_effect: MODULATES
    description: >
      In concurrent MDS, azacitidine is categorized as a strategy directed at
      the UBA1-mutated hematopoietic population. Variable clinical success does
      not establish clone eradication or molecular remission.
    evidence:
    - reference: PMID:40373178
      reference_title: "VEXAS Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Targeting the UBA1-mutated hematopoietic population: Similar to classic MDS without VEXAS syndrome, hypomethylating agents like azacitidine are used to treat individuals with VEXAS syndrome with concurrent MDS with varying success."
      explanation: >
        GeneReviews places azacitidine under hematopoietic-population targeting
        but describes variable success, supporting a conservative modulation
        edge.
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    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 curative therapy identified in the
    cited clinical guidance, but it 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: NCIT:C46089
      label: Allogeneic Hematopoietic Stem Cell Transplantation
  target_mechanisms:
  - target: Myeloid-Skewed Hematopoietic Dysfunction
    treatment_effect: MODULATES
    description: >
      Allogeneic HSCT is categorized as targeting the UBA1-mutated
      hematopoietic population and is clinically curative in selected patients;
      this edge does not independently assert molecular clonal clearance.
    evidence:
    - reference: PMID:40373178
      reference_title: "VEXAS Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for VEXAS syndrome; however, it is sometimes associated with considerable morbidity and even mortality and should be only be considered in selected individuals after discussion with multidisciplinary care providers."
      explanation: >
        GeneReviews identifies allogeneic HSCT as the only curative treatment,
        supporting conservative linkage to hematopoietic dysfunction without
        directly measuring clonal clearance.
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Allogeneic hematopoietic stem cell transplantation (HSCT) is currently the only curative treatment for VEXAS syndrome; however, it is sometimes associated with considerable morbidity and even mortality and should be only be considered in selected individuals after discussion with multidisciplinary care providers."
    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 with variable clinical success. It frequently causes
    severe injection-site reactions in VEXAS patients, a disease-specific safety
    signal.
  therapeutic_modality: OTHER
  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: >
      Anti-IL-1 therapy is used as an inflammation-targeting strategy; the edge
      is kept at the broad innate-activation node supported by the synthesis.
    evidence:
    - reference: PMID:40373178
      reference_title: "VEXAS Syndrome."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of 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 therapy as steroid-sparing treatment for
        inflammatory manifestations.
  evidence:
  - reference: PMID:40373178
    reference_title: "VEXAS Syndrome."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Although inflammatory manifestations are typically glucocorticoid sensitive, the complications of high-level corticosteroid dependence often require use – with varying success – of 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:
- name: Cytoplasmic UBA1 homologue knockout zebrafish
  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 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 hematopoietic
    dysfunction), or only its molecular/inflammatory arm?
  rationale: >
    The curated zebrafish knockout reproduces systemic inflammation, and a 2025
    base-edited humanized HSPC model recapitulates proteostatic, cytologic,
    senescence, hematologic, and inflammatory hallmarks. Whether available
    models reproduce the full relapsing multi-organ clinical syndrome remains
    unresolved.
  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: >
      Establishes the inflammatory phenotype reproduced by the curated
      zebrafish model.
  - reference: PMID:40195449
    reference_title: Mechanisms of hematopoietic clonal dominance in VEXAS syndrome.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Humanized models of VEXAS syndrome, generated by inserting the causative mutation in healthy HSPCs through base editing, recapitulated proteostatic defects, cytological alterations and senescence signatures of patients' cells, as well as hematological and inflammatory disease hallmarks."
    explanation: >
      Defines the breadth of disease biology reproduced by the newer humanized
      HSPC model without claiming complete organ-level fidelity.
  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 independently
      classified MDS emergence.
- discussion_id: vexas_population_incidence_criteria
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - disease#VEXAS Syndrome
  prompt: >
    What are the general-population incidence and validated classification
    criteria for VEXAS syndrome across diverse populations?
  rationale: >
    Prevalence is estimated from a single US regional, predominantly White
    health-system cohort, so general-population incidence and diverse-ancestry
    estimates remain sparse. The International VEXAS Working Group has now
    published the first formal consensus clinical guidance for testing,
    VEXAS-associated MDS assessment, prognosis, and management; that guidance
    does not eliminate the need for externally validated classification criteria.
  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: "Additional studies are needed in unselected and genetically diverse populations to better define general population prevalence and phenotypic spectrum."
    explanation: >
      The genome-first prevalence study explicitly identifies the need for
      diverse, population-level replication.
  - reference: PMID:40787890
    reference_title: American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This work marks the first formal international consensus guidance for VEXAS and is intended to be used as a resource for clinicians seeking to understand the disease and its management."
    explanation: >
      Establishes that formal international clinical guidance now exists, while
      distinguishing guidance from validated classification criteria.
notes: >
  VEXAS is a clonal-hematopoietic autoinflammatory disorder bridging
  rheumatology and hematology, defined by somatic pathogenic UBA1 variants. No
  existing dismech mechanism module maps cleanly to its somatic-clonal
  innate-immune-dysregulation pattern, so no conforms_to edge is asserted; a
  future clonal-hematopoiesis module would be the natural conformance target.
  The repo's Relapsing_Polychondritis entry already models the VEXAS overlap
  from the RP side. Consensus organ-specific frequency ranges such as 75–100%,
  55–95%, 14–64%, and 20–50% straddle two FrequencyEnum bands, so frequency is
  omitted on those phenotypes rather than guessed. Aseptic meningitis and
  orchitis are reported as less common VEXAS manifestations but are not
  modeled as separate phenotype nodes, because no reference cached for this
  entry carries a claim-specific quotable snippet for them.
datasets:
- accession: geo:GSE249131
  title: Single-cell RNA sequencing of blood cells from patients with VEXAS syndrome.
  description: We performed single cell RNA sequencing, and VDJ sequencing of TCR and BCR of peripheral blood samples (Peripheral Blood Mononuclear Cells[PBMCs]) from 9 patients with VEXAS to understand disease pathogenesis.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 66
  publication: PMID:40394087
  notes: Identified by GEO DataSets index search for VEXAS Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE196052
  title: Single-cell profiling of hematopoietic cells in VEXAS syndrome
  description: 'Background and methods: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has been recently recognized as an adult-onset autoinflammatory syndrome due to somatic mutations affecting Ubiquitin Like Modifier Activating Enzyme 1 (UBA1) gene. Following-up studies have been mostly limited to case reports; transcriptome of especially hematopoiesis in VEXAS syndrome has not been well characterized. Results: We performed whole transcriptome sequencing of single bone marrow cells (BMMNCs) and enriched Lineage-CD34+ hematopoietic stem and progenitor cells (HSPCs) from nine patients included in the original VEXAS cohort.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 56
  publication: PMID:37586319
  notes: Identified by GEO DataSets index search for VEXAS Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
- accession: geo:GSE272816
  title: POISONING OF HEALTHY HEMATOPOIESIS IS AN UNANTICIPATED MECHANISM DRIVING CLONAL DOMINANCE IN VEXAS SYNDROME [scRNA-seq]
  description: Clonal dominance characterizes hematopoiesis during aging and increases susceptibility to blood cancers and common non-malignant disorders. VEXAS syndrome is a recently discovered adult-onset autoinflammatory disease burdened by a high mortality rate and caused by dominant hematopoietic clones bearing somatic mutations in the UBA1 gene. However, pathogenic mechanisms fueling clonal dominance are unknown. Moreover, the lack of disease models hampers the development of disease-modifying therapies. Here, we performed immunophenotypic dissection of hematopoiesis and single-cell transcriptomics in a VEXAS patient cohort revealing pervasive inflammation across all lineages.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  data_type: SINGLE_CELL_RNA_SEQ
  sample_count: 14
  publication: PMID:40195449
  notes: Identified by GEO DataSets index search for VEXAS Syndrome (scripts/discover_datasets.py); accession and metadata verified against NCBI E-utilities on 2026-08-01. Title, sample count, and organism are GEO's own values.
📚

References & Deep Research

References

4
PMID:40373178
VEXAS Syndrome.
No top-level findings curated for this source.
PMID:40787890
American College of Rheumatology Guidance Statement for Diagnosis and Management of VEXAS Developed by the International VEXAS Working Group Expert Panel.
No top-level findings curated for this source.
PMID:40195449
Mechanisms of hematopoietic clonal dominance in VEXAS syndrome.
No top-level findings curated for this source.
PMID:41068485
Distinct characteristics of VEXAS-causative UBA1 M41 and recurrent functional non-M41 mutations.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
1. Disease Information
claude-haiku-4-5-20251001, claude-opus-4-8[1m] 10 citations 2026-06-29T11:09:58.072764

1. Disease Information

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

2. Etiology

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.)

3. Phenotypes

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).

4. Genetic / Molecular Information

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.

5. Environmental Information

  • Environmental/toxic factors: None established as causal. (Data gap.)
  • Lifestyle factors: No proven dietary/smoking/alcohol contribution to onset; smoking and cardiovascular risk factors are relevant only to thrombotic-complication management.
  • Infectious agents: No infectious cause. Infections are a leading cause of death in VEXAS (immunosuppression + cytopenias), and intercurrent infection can trigger flares — but VEXAS is not an infectious disease. NCBI Taxonomy: not applicable.

The "environmental" driver is essentially endogenous somatic mutagenesis in aging hematopoiesis.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

  1. Somatic UBA1 p.Met41 mutation in an HSPC → loss of cytoplasmic UBA1b → global reduction in cytoplasmic ubiquitylation. (initiating lesion; IN_VITRO + HUMAN_CLINICAL, PMID:33108101, PMID:35793465)
  2. Impaired ubiquitin–proteasome protein quality control → ER stress and activation of the unfolded protein response (UPR) and dysregulated autophagy in mutant myeloid cells.
  3. Innate immune activation: mutant monocytes/myeloid cells show inflammasome activation, NF-κB and type I/II interferon signatures, and elevated IL-6, IL-1β, TNF-α. Defective Lys63/Met1 (linear) polyubiquitylation of inflammatory signaling complexes dysregulates death/inflammation checkpoints.

"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)

  1. Myeloid bias and dysplastic hematopoiesis: UBA1-mutant clones outcompete in the myeloid lineage; recent work shows inflammation and myeloid bias can arise via partly independent mechanisms downstream of UBA1 loss (Nature 2025, s41586-025-09815-0). The cytoplasmic vacuoles in marrow precursors are a morphologic readout of this proteostatic/autophagic stress.
  2. Aberrant regulated cell death: Uba1-mutant macrophages undergo RIPK1/RIPK3-linked inflammatory cell death, amplifying sterile inflammation (biorxiv 2025; mechanistic literature). (MODEL_ORGANISM / IN_VITRO)
  3. Clinical output: chronic, relapsing multi-organ neutrophilic/cytokine-driven inflammation plus progressive bone-marrow failure and clonal evolution to MDS/plasma-cell disease.

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)

7. Anatomical Structures Affected

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.

8. Temporal Development

  • Onset: Adult/late-onset. Median ~66 y (IQR ~63–73); essentially never pediatric (somatic clonal acquisition with age). HPO onset: HP:0003581 (Adult onset) → HP:0003596 (Middle age onset)/late onset. Pattern usually insidious/subacute with episodic flares.
  • Progression / stages: No formal staging. Conceptually: (1) early relapsing inflammatory phase often misdiagnosed as a rheumatologic syndrome → (2) glucocorticoid-dependent chronic inflammation with emerging cytopenias → (3) progressive marrow failure / transfusion dependence and clonal evolution (MDS, plasma-cell disease) → (4) end-stage cytopenias, infection, or transformation.
  • Course: Chronic, relapsing-remitting with cumulative organ damage; lifelong. Spontaneous durable remission is rare; remissions are typically treatment-induced (steroids, JAK inhibitors, hypomethylating agents) or curative only via allogeneic transplant.
  • Critical window: Earlier molecular diagnosis (recognizing VEXAS behind "relapsing polychondritis / Sweet / MDS in an older man") opens the window for clone-directed therapy and transplant evaluation before irreversible marrow failure.

9. Inheritance and Population

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)

  • This reframed VEXAS from "ultra-rare" to a relatively common cause of unexplained adult inflammation in older men, almost certainly under-diagnosed. Incidence figures are not yet firmly established — (data gap).

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).

10. Diagnostics

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.

11. Outcome / Prognosis

  • Mortality / survival: High. Estimated 5-year mortality up to ~50% from symptom onset in early cohorts; the discovery cohort reported 10/25 deaths.

"Of the 25 patients, 10 died during the study period." — Beck DB et al., NEJM 2020 (PMID:33108101). (HUMAN_CLINICAL)

  • Genotype-stratified 5-yr survival: p.Met41Leu ~100% > p.Met41Thr ~83% > p.Met41Val ~60–77% (Ferrada/Beck, Blood 2022, PMID:35793465).
  • Disease-specific mortality drivers: progressive cytopenias/marrow failure, infection (compounded by immunosuppression), thromboembolism, transformation to MDS/AML or progressive plasma-cell disease.
  • Prognostic factors: p.Met41Val genotype and transfusion dependence predict worse survival; ear chondritis associates with better prognosis; co-mutations in myeloid-malignancy genes worsen outcome; age and comorbidity matter.
  • Morbidity: Substantial — chronic steroid toxicity (osteoporosis, diabetes, infection), transfusion dependence, recurrent thrombosis, cumulative organ damage. Most patients fail to achieve durable drug-free remission.
  • Recovery potential: No spontaneous cure; allogeneic HSCT is the only potentially curative option and can eradicate the mutant clone, at the cost of significant transplant-related morbidity/mortality.

12. Treatment

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.

13. Prevention

  • Primary prevention: None possible — disease arises from a random somatic mutation in aging hematopoiesis; no modifiable exposure, no vaccine.
  • Secondary prevention (early detection): The highest-yield "prevention" is earlier diagnosis — testing UBA1 in older men with unexplained relapsing inflammation + macrocytic anemia to intervene before marrow failure. Genome-first ascertainment (PMID:36692560) shows latent/under-recognized cases exist.
  • Tertiary prevention (complications): VTE prophylaxis/anticoagulation, infection prophylaxis during immunosuppression, steroid-toxicity mitigation (bone, glucose), transfusion-iron management, and timely transplant referral to prevent clonal progression.
  • Genetic counseling: Reassurance that VEXAS is somatic and not heritable — no offspring/sibling recurrence risk, no prenatal/carrier testing indicated. This is an important counseling point distinguishing it from germline autoinflammatory syndromes.
  • Public-health/environmental interventions: Not applicable.

14. Other Species / Natural Disease

  • Taxonomy: Human disease (NCBITaxon:9606). No naturally occurring animal counterpart described.
  • Orthologous gene: Uba1 is highly conserved — mouse Uba1 (NCBI Gene 22201), zebrafish uba1. Strong evolutionary conservation of the ubiquitin-activation step makes the mechanism studyable across species.
  • Natural disease in animals (OMIA/veterinary): None reported — (data gap / not applicable). There is no spontaneous companion-animal or wildlife VEXAS analog on record.
  • Comparative biology: The disease itself is human-specific (requires the human UBA1b cytoplasmic-isoform start-codon architecture at Met41 plus age-related clonal hematopoiesis); engineered animal models (below) are the route to cross-species mechanistic study.
  • Transmission/zoonosis: Not applicable (non-communicable, somatic).

15. Model Organisms

  • Zebrafish (Danio rerio): uba1-perturbation models recapitulate IRF3 accumulation, excessive type I interferon, and inflammation, supporting the proximal-ubiquitylation→IFN mechanism. (MODEL_ORGANISM) — useful for innate-immune readouts and drug screening. ZFIN resource.
  • Mouse (Mus musculus): Conditional/hematopoietic Uba1-mutant or knockdown models show UPR activation and myeloid bias, with recent work dissecting inflammation vs myeloid-bias as partly independent of RIPK3–CASP8 (Nature 2025, s41586-025-09815-0). (MODEL_ORGANISM) MGI resource; IMPC for Uba1 alleles.
  • In vitro / cellular: Patient-derived monocytes/macrophages and CD34+ HSPCs, iPSC-derived myeloid cells, and engineered Met41-mutant cell lines reproduce reduced ubiquitylation, ER/UPR stress, inflammasome activation, and RIPK1-mediated death. (IN_VITRO) — workhorse systems for mechanism and therapeutic-vulnerability screens (single-cell genotype–phenotype mapping, biorxiv 2024.05.19.594376).
  • Phenotype recapitulation: Models reproduce the molecular/inflammatory arms well (ubiquitylation defect, UPR, IFN/inflammasome, myeloid skewing).
  • Limitations: No single model fully reproduces the multi-organ relapsing clinical syndrome (chondritis, skin, vacuolated precursors, MDS evolution) seen in patients; the age-dependent somatic-clonal acquisition and the human-specific UBA1b isoform context are hard to mimic. Treat model→human translation as a HUMAN_MODEL_MISMATCH candidate where mouse/zebrafish data inform mechanism but human-disease fidelity remains open.
  • Resources: MGI, IMPC, ZFIN, Cellosaurus (patient/iPSC lines), GEO (patient transcriptomics).

Key Citations (PMID-anchored)

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

Curation notes for the dismech entry (kb/disorders/VEXAS_Syndrome.yaml)

  • Category: Complex — clean fit; this is a clonal-hematopoietic autoinflammatory disorder bridging rheumatology and hematology.
  • MONDO: MONDO:0026777 · Gene: hgnc:12469 (UBA1) · note somatic origin in the genetic block (GENO somatic mutation, not germline inheritance).
  • Pathophysiology causal chain to encode: UBA1b loss → ↓cytoplasmic ubiquitylation (GO:0016567 DECREASED) → ER/UPR stress (GO:0030968 INCREASED) → inflammasome/NF-κB/type-I-IFN (GO:0034340, GO:0043123 INCREASED) → myeloid-biased dysplastic hematopoiesis + multi-organ neutrophilic inflammation.
  • Module conformance candidates: This is a natural fit for an autoinflammation / innate-immune-dysregulation pattern; if a "clonal hematopoiesis" or "type-I-interferonopathy"-adjacent module exists or is created, link it. (No exact existing module from the CLAUDE.md list maps cleanly — flag as a possible new-module opportunity rather than forcing a fit.)
  • Before committing evidence: every PMID above must be 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.
  • Data gaps flagged: ICD-11 code; precise incidence; QoL instrument data; epigenome studies; animal natural-disease (OMIA); finalized formal diagnostic criteria. Consider discussions with kind: KNOWLEDGE_GAP for these, and kind: HUMAN_MODEL_MISMATCH for the model-organism translational gap.