7 Key Symptoms of VEXAS Syndrome You Should Know

VEXAS syndrome is a rare autoinflammatory disease that was first identified in recent years. The acronym VEXAS stands for Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic syndrome. This condition primarily affects adult men and is caused by mutations in the UBA1 gene, which plays a crucial role in cellular protein regulation. Understanding the symptoms of VEXAS syndrome is essential for early detection and proper medical management.

The condition is characterized by chronic inflammation affecting multiple organ systems, leading to a wide range of symptoms that can significantly impact quality of life. Because VEXAS syndrome is relatively newly discovered, many patients may have been previously misdiagnosed with other inflammatory or hematologic conditions. Recognition of the characteristic symptom pattern can help healthcare providers make an accurate diagnosis and provide appropriate care.

1. Recurrent Fever Episodes

One of the hallmark symptoms of VEXAS syndrome is recurrent fever that occurs without an obvious infectious cause. These fever episodes are typically persistent and can last for extended periods, often accompanied by a general feeling of being unwell.

The fever pattern in VEXAS syndrome differs from typical infections:

• Temperatures often exceed 38°C (100.4°F)
• Fever may occur in cycles or be continuously present
• Standard antibiotics do not resolve the fever
• Fever is often accompanied by chills and night sweats
• The inflammatory nature of the fever distinguishes it from infectious causes

These fever episodes reflect the underlying autoinflammatory nature of the disease, where the immune system is chronically activated without an external trigger. Patients often describe feeling exhausted and debilitated during these episodes, which can interfere with daily activities and work.

2. Skin Manifestations and Rashes

Dermatological symptoms are extremely common in VEXAS syndrome, with the majority of patients experiencing various types of skin problems. These skin manifestations can be one of the first noticeable signs of the condition and may vary in appearance and severity.

Common skin symptoms include:

• Neutrophilic dermatosis: Painful, raised red or purple lesions that may resemble Sweet’s syndrome
• Cutaneous vasculitis: Inflammation of blood vessels in the skin causing purplish patches
• Nodules: Firm bumps under the skin surface
• Ulcerations: Open sores that may be slow to heal
• Erythematous patches: Red, inflamed areas of skin

These skin lesions can appear on various parts of the body, including the trunk, arms, legs, and face. They may be itchy, painful, or tender to touch. Some patients develop photosensitivity, meaning their skin symptoms worsen with sun exposure. The skin manifestations often correlate with disease activity and may flare up during periods of increased inflammation.

3. Severe Anemia and Blood Abnormalities

Hematologic problems are a defining feature of VEXAS syndrome, with anemia being particularly prominent and often severe. The blood-related symptoms can be among the most debilitating aspects of the disease and may be what initially brings patients to medical attention.

Blood-related symptoms and findings include:

• Macrocytic anemia: Low red blood cell count with abnormally large red blood cells
• Severe fatigue: Overwhelming tiredness due to insufficient oxygen delivery to tissues
• Pallor: Pale skin and mucous membranes
• Shortness of breath: Difficulty breathing, especially with exertion
• Rapid heartbeat: Tachycardia as the heart tries to compensate for low oxygen
• Dizziness: Lightheadedness, especially when standing

The anemia in VEXAS syndrome is typically refractory, meaning it does not respond well to standard treatments like iron supplementation or vitamin B12. Some patients may require blood transfusions to manage severe anemia. Bone marrow examination often reveals characteristic vacuoles (empty spaces) in blood cell precursors, which is one of the diagnostic features of the syndrome.

4. Ear and Nose Cartilage Inflammation (Chondritis)

Inflammation of cartilage, particularly in the ears and nose, is a distinctive and often painful symptom of VEXAS syndrome. This condition, known as polychondritis or chondritis, can cause significant discomfort and potentially lead to structural changes if left unmanaged.

Chondritis manifestations include:

• Auricular chondritis: Painful, red, swollen ears that are tender to touch
• Nasal chondritis: Inflammation of the nasal cartilage causing nasal pain and swelling
• Saddle nose deformity: Collapse of the nasal bridge in severe cases
• Cauliflower ear: Deformation of the ear structure from repeated inflammation
• Hearing problems: Inflammation can affect the auditory canal and middle ear
• Respiratory symptoms: If tracheal cartilage is involved, breathing difficulties may occur

The cartilage inflammation in VEXAS syndrome can resemble relapsing polychondritis, another autoimmune condition, which sometimes leads to initial misdiagnosis. The ear involvement is particularly characteristic – patients often describe their ears as feeling hot, swollen, and extremely tender. The earlobe, which contains no cartilage, is typically spared, helping to distinguish this from other causes of ear inflammation.

5. Pulmonary Complications and Breathing Problems

Lung involvement is a serious and potentially life-threatening complication of VEXAS syndrome. Respiratory symptoms can range from mild to severe and may progressively worsen over time if inflammation is not adequately controlled.

Pulmonary manifestations include:

• Interstitial lung disease: Scarring and inflammation of lung tissue
• Pleural effusion: Fluid accumulation around the lungs
• Chronic cough: Persistent coughing that may be dry or productive
• Dyspnea: Shortness of breath, even at rest in severe cases
• Chest pain: Discomfort or tightness in the chest
• Reduced exercise tolerance: Inability to perform physical activities due to breathing difficulties
• Low oxygen saturation: Decreased oxygen levels in the blood

Imaging studies such as chest X-rays or CT scans may reveal infiltrates, nodules, or other abnormalities in the lungs. Some patients develop pulmonary vasculitis, where blood vessels in the lungs become inflamed. Pulmonary function tests typically show restrictive patterns with reduced lung capacity. Early recognition and monitoring of pulmonary symptoms is crucial, as lung involvement is associated with increased morbidity and mortality in VEXAS syndrome.

6. Joint Pain and Inflammatory Arthritis

Musculoskeletal symptoms are very common in VEXAS syndrome, with many patients experiencing joint pain and inflammation similar to rheumatoid arthritis or other inflammatory arthropathies. These symptoms can significantly affect mobility and quality of life.

Joint-related symptoms include:

• Polyarthritis: Inflammation affecting multiple joints simultaneously
• Morning stiffness: Joint stiffness that is worse upon waking and improves with movement
• Symmetrical involvement: Both sides of the body are often affected equally
• Swelling: Visible joint swelling and warmth
• Pain: Aching or sharp pain in affected joints
• Reduced range of motion: Difficulty moving joints through their full range
• Myalgia: Muscle pain and tenderness

The arthritis in VEXAS syndrome commonly affects the hands, wrists, knees, and ankles, though any joint can be involved. Unlike some forms of inflammatory arthritis, the joint inflammation in VEXAS syndrome is typically non-erosive, meaning it does not cause permanent joint damage visible on X-rays. However, chronic inflammation can still lead to functional limitations. Some patients also experience tendonitis or enthesitis (inflammation where tendons attach to bone).

7. Blood Clots and Vascular Complications

Thrombotic events, or blood clot formation, represent a serious and potentially dangerous complication of VEXAS syndrome. The chronic inflammation associated with this condition increases the risk of abnormal blood clotting in both veins and arteries.

Vascular complications may include:

• Deep vein thrombosis (DVT): Blood clots in the deep veins, usually in the legs, causing pain, swelling, and warmth
• Pulmonary embolism (PE): Blood clots that travel to the lungs, causing sudden shortness of breath, chest pain, and potentially life-threatening complications
• Vasculitis: Inflammation of blood vessels that can affect multiple organs
• Superficial thrombophlebitis: Inflammation and clotting in superficial veins
• Arterial thrombosis: Clots in arteries, potentially leading to stroke or heart attack
• Leg pain and swelling: Symptoms resulting from venous insufficiency

The risk of thrombotic events in VEXAS syndrome is thought to be related to the chronic inflammatory state, which activates the clotting cascade and makes blood more prone to clotting. Patients may notice leg swelling, pain, redness, or warmth, which should prompt immediate medical evaluation. Some patients with VEXAS syndrome may require anticoagulation therapy to prevent further clotting events, though this decision must be carefully balanced against bleeding risks, especially in patients with low platelet counts.

Main Causes of VEXAS Syndrome

VEXAS syndrome has a specific genetic cause that distinguishes it from other autoinflammatory conditions. Understanding the underlying cause helps explain why certain populations are affected and why the disease behaves as it does.

UBA1 Gene Mutation: The primary cause of VEXAS syndrome is a somatic mutation in the UBA1 gene located on the X chromosome. The UBA1 gene provides instructions for making an enzyme called ubiquitin-activating enzyme E1, which plays a critical role in tagging proteins for degradation. When this gene is mutated, the normal process of protein regulation is disrupted, leading to cellular dysfunction and inflammation.

Somatic vs. Germline Mutation: Importantly, the mutation in VEXAS syndrome is somatic rather than inherited. This means the genetic change occurs in blood stem cells during a person’s lifetime rather than being passed down from parents. The mutation arises spontaneously in hematopoietic stem cells (blood-forming cells) in the bone marrow.

X-Linked Pattern: Because the UBA1 gene is located on the X chromosome, VEXAS syndrome predominantly affects males. Men have only one X chromosome, so a mutation in UBA1 affects all the proteins produced from that gene. Women have two X chromosomes, which typically provides protection, though rare cases in females have been reported.

Clonal Hematopoiesis: The mutated blood stem cells gain a selective advantage and expand over time, a process called clonal hematopoiesis. This results in an increasing proportion of blood cells carrying the mutation, which correlates with disease severity and symptom onset.

Age-Related Occurrence: VEXAS syndrome typically manifests in older adults, usually after age 50. This is consistent with the concept of age-related clonal hematopoiesis, where acquired mutations in blood stem cells become more common with advancing age.

Inflammatory Cascade: The UBA1 mutation leads to activation of multiple inflammatory pathways, including the innate immune system. This results in excessive production of inflammatory cytokines, causing the widespread inflammation that characterizes the syndrome.

Frequently Asked Questions

What is VEXAS syndrome?

VEXAS syndrome is a rare autoinflammatory disease caused by somatic mutations in the UBA1 gene. It primarily affects older men and causes chronic inflammation affecting multiple organ systems, including the skin, blood, lungs, and joints.

Who is most likely to develop VEXAS syndrome?

VEXAS syndrome predominantly affects men over the age of 50. Due to the X-linked nature of the genetic mutation, males are much more commonly affected than females. The condition is considered rare, though increased awareness may lead to more frequent diagnosis.

How is VEXAS syndrome diagnosed?

Diagnosis involves genetic testing to identify mutations in the UBA1 gene. Bone marrow examination showing characteristic vacuoles in blood cell precursors, along with clinical symptoms and blood abnormalities, support the diagnosis. A combination of hematologic, rheumatologic, and dermatologic findings typically raises suspicion for VEXAS syndrome.

Is VEXAS syndrome hereditary?

No, VEXAS syndrome is not inherited from parents. The mutation is somatic, meaning it occurs spontaneously in blood stem cells during a person’s lifetime. It is not passed down to children through germline cells.

Can VEXAS syndrome be cured?

Currently, there is no cure for VEXAS syndrome. Management focuses on controlling inflammation and symptoms. Some patients may be candidates for stem cell transplantation, which could potentially be curative, but this decision requires careful evaluation by specialists and consideration of risks and benefits.

What is the prognosis for people with VEXAS syndrome?

The prognosis varies depending on disease severity and organ involvement. VEXAS syndrome can be a serious condition with potential life-threatening complications, including severe anemia, pulmonary disease, and blood clots. Early diagnosis and appropriate management are important for improving outcomes. Patients should work closely with a multidisciplinary medical team.

What specialists should treat VEXAS syndrome?

Because VEXAS syndrome affects multiple organ systems, care typically involves a multidisciplinary team including rheumatologists (for inflammatory symptoms), hematologists (for blood abnormalities), dermatologists (for skin manifestations), pulmonologists (for lung involvement), and other specialists as needed based on individual symptoms.

Can VEXAS syndrome symptoms come and go?

Yes, VEXAS syndrome can have a relapsing and remitting course, with periods of increased disease activity (flares) alternating with periods of relative quiescence. However, many patients experience chronic, persistent symptoms. The pattern varies among individuals.

Are there any lifestyle modifications that can help with VEXAS syndrome?

While lifestyle modifications cannot cure VEXAS syndrome, maintaining overall health is important. This includes avoiding smoking, eating a balanced diet, staying as active as symptoms allow, getting adequate rest, and avoiding triggers that may worsen inflammation. Patients should consult with their healthcare providers about specific recommendations.

References:

• New England Journal of Medicine – VEXAS Syndrome
• National Organization for Rare Disorders (NORD) – VEXAS Syndrome
• Mayo Clinic – Autoinflammatory Diseases
• Johns Hopkins Medicine – Rheumatology
• National Institutes of Health – Genetic and Rare Diseases Information Center