Vexas Syndrome: Symptoms, Types, Causes and Treatment

VEXAS syndrome is an adult-onset, life-threatening autoinflammatory disease that has rapidly transformed our understanding of unexplained, refractory inflammatory disorders in older adults. Discovered only in 2020, VEXAS—named for its key features: Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic—unites a spectrum of previously unrelated conditions and is now recognized as a prototype of hematoinflammatory diseases. This article will guide you through what VEXAS syndrome is, the symptoms to look out for, how it is classified, what causes it, and the latest treatment options—all based on up-to-date scientific evidence.

Symptoms of Vexas Syndrome

VEXAS syndrome can manifest in strikingly diverse ways, often making diagnosis challenging. The symptoms typically begin in late adulthood, predominantly affect men, and can involve multiple organ systems. Early recognition is essential for prompt management and improved outcomes.

Symptom	Presentation	Frequency/Severity	Sources
Skin	Rashes, nodules, vasculitis, chondritis	Up to 89% of patients; often first sign	1, 7
Hematologic	Anemia, cytopenias, bone marrow vacuoles	Macrocytic anemia (100%), myelodysplasia common	3, 11
Pulmonary	Cough, dyspnea, lung infiltrates, pleural effusion	40-72% have lung involvement; infiltrates most common	2, 4, 10
Systemic	Fever, fatigue, weight loss, arthritis	Frequent, often severe	10, 12
Thrombotic	Venous/arterial thrombosis, stroke	Thrombosis in ~40%	3, 6

Table 1: Key Symptoms

Skin Manifestations

Skin involvement is the most frequent and often the earliest sign of VEXAS syndrome. Patients may present with:

• Painful, red skin nodules and plaques resembling Sweet syndrome
• Vasculitic rashes, including leukocytoclastic vasculitis
• Periorbital angioedema
• Chondritis, especially of the ears and nose

Histopathology commonly reveals neutrophilic dermatoses or vasculitis. These findings often lead to misdiagnosis as other inflammatory skin diseases until genetic testing confirms VEXAS 1, 7.

Hematologic Features

VEXAS is unique in its overlap with hematological disorders:

• Macrocytic anemia is universal among diagnosed patients
• Other cytopenias (low white cells/platelets) are common
• Bone marrow biopsy reveals characteristic cytoplasmic vacuoles in myeloid and erythroid precursor cells
• Many patients develop myelodysplastic syndrome (MDS) or plasma cell dyscrasias over time 3, 11

Pulmonary Manifestations

Lung involvement is common but underrecognized:

• Symptoms: Cough, shortness of breath, sometimes chest pain
• Radiology: Ground-glass opacities, consolidations, pleural effusions, and interstitial pneumonia
• Lung complications can be severe but often respond to corticosteroids 2, 4, 10

Systemic and Rheumatologic Symptoms

Patients often experience:

• Recurrent fevers
• Profound fatigue and malaise
• Symmetric polyarthritis (joint inflammation)
• Unintentional weight loss

These features can mimic other rheumatologic and autoinflammatory diseases, contributing to diagnostic delays 10, 12.

Thrombotic Complications

VEXAS syndrome is associated with a high risk of blood clots:

• Venous thromboembolism (deep vein thrombosis, pulmonary embolism) is most frequent
• Arterial events, including stroke, also occur
• Thromboses are typically unprovoked, likely due to systemic inflammation 3, 6

Types of Vexas Syndrome

While VEXAS is unified by its genetic cause, the clinical presentation varies significantly among patients. Understanding these types is crucial for prognosis and management.

Type/Variant	Key Features	Associated Phenotypes	Sources
Classic VEXAS	Skin, hematologic, systemic, pulmonary symptoms	Most common; older men	10, 7
Hematologic-dominant	Early MDS, anemia, cytopenias	Overlaps with classic MDS	3, 11
Inflammatory-dominant	Severe autoinflammation, fever, rash	Fewer bone marrow changes	12, 5
Genetic Subtypes	p.Met41Leu, p.Met41Val, p.Met41Thr	Varying survival, symptoms	7, 12

Table 2: VEXAS Syndrome Types and Variants

Classic Presentation

The classic type features the full spectrum:

• Recurrent fevers, skin involvement, anemia, arthritis, pulmonary infiltrates
• Nearly always seen in older males (median age ~67)
• Multisystem involvement is hallmark 7, 10

Hematologic-Dominant Type

Some patients develop or present with:

• Myelodysplastic syndrome (MDS)
• Plasma cell disorders (e.g., multiple myeloma)
• Severe, transfusion-dependent anemia
• Increased risk for progression to hematologic malignancy 3, 11

Inflammatory-Dominant Type

A subset shows:

• Severe systemic inflammation and fevers
• Prominent skin and joint involvement
• Less pronounced bone marrow failure in early disease
• Can mimic autoimmune/autoinflammatory syndromes 12, 5

Genetic Subtypes

Somatic mutations in the UBA1 gene at various positions (especially methionine 41) can influence clinical course:

• p.Met41Leu: More likely to have neutrophilic skin lesions
• p.Met41Val: Associated with vasculitic skin lesions and lower survival rates
• Other variants: May have unique phenotypes and prognoses 7, 12

Causes of Vexas Syndrome

VEXAS syndrome is unique among autoinflammatory diseases because its cause is now well understood at the genetic level.

Cause	Description	Clinical Impact	Sources
UBA1 Mutation	Somatic mutations in UBA1 gene (X chromosome)	Drives disease; not inherited	12, 9, 10
Clonal Hematopoiesis	UBA1-mutated stem cell clones dominate	Leads to inflammation, cytopenias	11, 3
Secondary Mutations	Co-mutations in DNMT3A, TET2 etc.	May affect prognosis	11
Inflammatory Cascade	Uncontrolled cytokine release	Drives systemic symptoms	14, 12

Table 3: Causes of VEXAS Syndrome

Somatic UBA1 Mutations

• VEXAS is caused by acquired (somatic) mutations in the UBA1 gene, located on the X chromosome
• These mutations arise in hematopoietic (blood-forming) stem cells after birth, not inherited from parents
• The most common mutations affect the methionine 41 codon (p.Met41) 12, 9, 10

Clonal Hematopoiesis

• The mutated UBA1 stem cells expand, creating a dominant blood cell clone
• This leads to a unique overlap of autoinflammation and bone marrow failure
• Clonal dominance drives the persistent inflammation and cytopenias seen in VEXAS 11, 3

Additional Gene Mutations

• Many patients have co-existing mutations in genes like DNMT3A and TET2, commonly found in age-related clonal hematopoiesis
• These may influence disease severity and survival, but UBA1 mutation is required for diagnosis 11

Inflammatory Pathways

• The UBA1 mutation impairs protein ubiquitylation, a process vital for cellular housekeeping
• This defect leads to uncontrolled activation of inflammatory pathways and cytokine storms, producing the multisystem symptoms of VEXAS 14, 12

Treatment of Vexas Syndrome

Treating VEXAS syndrome remains challenging, as conventional immunosuppressive drugs often fail to control symptoms or prevent disease progression. However, recent research has highlighted promising therapies and a path toward a cure.

Treatment Modality	Effectiveness/Notes	Adverse Events/Risks	Sources
Glucocorticoids	Rapid symptom control, not curative	Long-term toxicity, infections	13, 7
JAK Inhibitors	24-33% response rate, best for inflammation	Thrombotic risk, infections	13, 17
IL-6 Inhibitors	20-32% response rate, often used	Infections, partial efficacy	13, 17
IL-1 Inhibitors	Less effective (9% response)	Injection site reactions	17, 7
Azacitidine (Hypomethylating agent)	25% CR, 39% PR; molecular remission in some	Cytopenias, infections	13, 15
Allogeneic Stem Cell Transplant	Only curative option; 86% OS in selected patients	Graft-vs-host disease, mortality	13, 14, 16
Supportive Care	Essential for anemia, infection, thrombosis	Standard risks	14

Table 4: Treatment Strategies for VEXAS Syndrome

Glucocorticoids

• Mainstay for acute symptom control
• Most patients require high-dose steroids, but long-term use is associated with significant side effects: osteoporosis, diabetes, infections
• Not curative; symptoms often recur when dose is tapered 13, 7

Targeted Immunosuppressive Therapies

JAK Inhibitors

• Target the overactive inflammatory signaling seen in VEXAS
• Response rates range from 24-33%
• Some risk of blood clots and infections; careful monitoring required 13, 17

IL-6 Inhibitors

• Drugs like tocilizumab can help control inflammation
• Response rates around 20-32%
• May reduce steroid requirements but not always sufficient as monotherapy 13, 17

IL-1 Inhibitors

• Canakinumab, anakinra: generally less effective, and injection site reactions are frequent 17, 7

Disease-Modifying Agents

Azacitidine and Other Hypomethylating Agents

• Used in myelodysplastic syndrome, now showing promising results in VEXAS
• Some patients achieve molecular remission and can discontinue therapy
• Risks include cytopenias and infection; not all patients respond 13, 15

Allogeneic Hematopoietic Stem Cell Transplantation (allo-HCT)

• Currently the only curative treatment
• 86% overall survival in selected patients, but risk of non-relapse mortality (14%) and graft-vs-host disease 16
• Best for younger patients or those with severe, refractory disease 14, 16

Supportive Care

• Management of anemia, infection prevention, and thrombosis prophylaxis are vital for all patients 14

Ongoing Challenges

• Many patients become refractory to treatment
• High rates of severe infection and blood clots complicate management
• Clinical trials are urgently needed to optimize therapy 13, 17, 14

Conclusion

VEXAS syndrome is a recently discovered, complex disease that bridges rheumatology, hematology, and dermatology. Its recognition has unified multiple unexplained autoinflammatory conditions under a single genetic cause, transforming diagnosis and management for many patients.

Key Points:

• VEXAS syndrome is caused by somatic mutations in the UBA1 gene, leading to clonal hematopoiesis and systemic inflammation 10, 12.
• Symptoms are diverse and multisystemic, most commonly involving the skin, blood, lungs, and joints 1, 7, 10.
• There are several clinical types and genetic subtypes, with varying prognoses and manifestations 7, 12.
• Treatment is evolving: steroids, JAK inhibitors, IL-6 inhibitors, and azacitidine offer control for many, but allogeneic stem cell transplant is currently the only cure 13, 16.
• Early diagnosis, genetic confirmation, and individualized therapy are essential for improving outcomes in this life-altering syndrome.

VEXAS syndrome highlights the importance of integrating clinical suspicion, molecular diagnostics, and multidisciplinary care to identify and effectively manage complex autoinflammatory diseases.