VEXAS Syndrome: Causes, Symptoms, and Treatment

Introduction:

VEXAS syndrome is an acronym for vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic. The acronym outlines the various characteristic features of the syndrome. The somatic mutation is observed in the UBA1 gene present in the X-chromosome. The condition is found exclusively in the male population. VEXAS syndrome is also known as UBA1 syndrome, named after the responsible gene. VEXAS syndrome has vexed clinicians with its extreme fatality rate.

Who Is Susceptible to VEXAS Syndrome?

VEXAS syndrome is seen in less than one person per 1,000,000 population with an exclusive male affliction. The patients’ age varies within the range of 40 to 80 years suggesting an adult to late age predilection. The median age of onset of symptoms varies between the late 50s to mid-60s. The syndrome was first discovered and described in October 2020, and since then, about 70 to 80 cases of VEXAS have been diagnosed worldwide. To date, just one female VEXAS patient has been identified who incidentally had a single X-chromosome. VEXAS accounts for approximately eight percent of patients with relapsing polychondritis.

What Causes VEXAS Syndrome?

VEXAS syndrome is caused due to mutation in the UBA1 gene. The UBA1 gene is present in the X-chromosome. The syndrome is not hereditary. Hence, it indicates that the aberration is caused due to a mosaic or postzygotic mutation in the gene and not a germline mutation.

The UBA1 gene encodes a protein called ubiquitin-activating enzyme E1.

What Is the Pathophysiology of VEXAS Syndrome?

The Ubiquitin-activating enzyme E1, encoded by the UBA1 gene, is necessary for targeting and degrading nonessential proteins that need to be degraded within the cells. Thereby disrupting protein homeostasis. Ubiquitin is a regulatory protein that is attached to its substrate protein, the process known as ubiquitylation. The mutation results in decreased ubiquitylation, especially in the hematopoietic stem cells, with subsequent activation of the innate immunity. As a result, impaired and nonessential proteins get accumulated instead of being broken down, leading to abnormal activation of immune cells and damage or death of healthy cells.

Old proteins need to be broken down and removed in order to keep the production of new proteins active. Accumulation may also prevent the optimal functioning of normal healthy proteins. When UBA1 gene mutations occur in immune cells or blood cells, they lead to abnormal inflammation, impaired hemopoiesis, and other clinical features of VEXAS syndrome.

What Are the Signs and Symptoms of VEXAS Syndrome?

Cutaneous Manifestations:

• Polychondritis (inflammation of the nose or ear cartilage, sparing the airways and ribs).

• Sweet syndrome-neutrophilic dermatoses or acute febrile neutrophilic dermatosis (painful, reddish-violet, firm, pigmented, or purpuric papules, nodules, and plaques that can be umbilicated)

• Medium-vessel vasculitis (like in livedo racemosa, polyarteritis nodosa, or giant cell arteritis).

• Relapsing polychondritis.

• Neutrophilic dermatosis.

• Leukocytoclastic vasculitis.

Hematological Manifestations:

• Macrocytic anemia (bone marrow produces abnormally large RBCs).

• Thrombocytopenia (low platelet count).

• Pancytopenia (lower RBC and WBC count).

• Myelodysplastic syndrome (the body does not make sufficient healthy RBCs).

• Multiple myeloma (plasma cell neoplasm).

• Monoclonal gammopathy of undetermined significance (monoclonal protein or M protein in circulation).

• Increased CRP (C-reactive protein).

• Increased ESR (erythrocyte sedimentation rate).

Head and Neck Manifestations:

• Inflammatory eye disease.

• Sensorineural hearing loss.

• Periorbital edema.

Cardiopulmonary Manifestations:

• Neutrophilic alveolitis.

• Pleural effusion.

• Myocarditis.

Abdominal Manifestations:

• Hepatosplenomegaly.

• Colitis.

Genital Manifestations:

• Orchitis or epididymitis.

Other Clinical Features:

• Fatigue.

• Recurrent fevers.

• Inflammatory arthritis (inflammation from an overactive immune system).

• Deep vein thrombosis of lower extremities.

How to Diagnose VEXAS Syndrome?

VEXAS syndrome must be suspected in males presenting with complex overlapping inflammatory and hematological manifestations.

• Blood Investigations: The test might reveal raised inflammatory markers, macrocytic anemia, thrombocytopenia, and lymphopenia.

• Bone Marrow Biopsy: The test might demonstrate hypercellular marrow with vacuolization of erythroid and myeloid precursors, which is characteristic but non-specific, and hematopoietic dyspoiesis.

• Skin Biopsy: Biopsy of infiltrated skin lesions demonstrates perivascular mature neutrophils with leukocytoclastic vasculitis, CD163+ myeloid cells with indented nuclei, and lymphoid cells.

• DNA Sequencing: Sequencing of the patient’s genome reveals the UBA1 gene mutation in myeloid cells on skin biopsy, peripheral blood, or bone marrow samples.

How to Treat or Manage VEXAS Syndrome?

VEXAS responds poorly to ant pharmacotherapy with minor success in managing inflammation has been observed with high-dose corticosteroids. DMARDs (disease-modifying antirheumatic drugs ) and immunosuppressive drugs have been widely ineffective, although Colchicine therapy may reduce steroid dependency. The use of Tocilizumab is being studied.

Very selective patients can be treated with hematopoi­e­tic transplant as the treatment has shown mixed results ranging from remission to recurrence and even death after transplant.

What Is the Differential Diagnosis of VEXAS Syndrome?

• Polychondritis.

• Inflammatory arthritis.

• Sweet syndrome.

• Neutrophilic dermatosis.

• Leukocytoclastic vasculitis.

• Multiple myeloma.

What Is the Prognosis of VEXAS Syndrome?

VEXAS syndrome is a rare chronic progressive autoinflammatory syndrome. Patients develop symptoms for four to five years, after which a diagnosis is made. However, the long-term prognosis appears poor due to the lack of definitive treatment therapy. Even the most modern approach that involves stem cell transplant has shown disappointing results. VEXAS has shown 50% mortality in the Netherlands and 56% mortality in the US.

What Are the Complications of VEXAS Syndrome?

• Respiratory failure.

• Progressive anemia.

• Multiorgan failure (including kidney, heart, brain, and bowel).

• Venous thromboembolism.

• Arterial stroke.

• Myeloid cancers.

• Bone marrow failure syndromes.

• Pneumonia.

• Heart failure.

• Permanent blindness.

• Permanent deafness.

• Infertility.

• Liver failure.

Conclusion:

VEXAS syndrome is a relatively new disorder, with the discovery made towards the end of 2022. Several trials and research are underway to better understand the condition and its underlying pathophysiology. The NIH (National Institute of Health, USA), Grossman School of Medicine and NYU Langone Health, and New York University, among others, are actively involved in certain trials and studies. The original discoverer, Dr. Peter Grayson, is vigorously pursuing research on the syndrome at New York University. The NIH is conducting trials with 100 patients with a probable VEXAS diagnosis. French researchers are chasing proposed JAK inhibitors and IL-6 inhibitors drugs as potential treatment options. The current hype and hunt for a VEXAS cure have made the condition gain traction in the entertainment industry as well. The condition requires awareness to bring down the gap between onset and diagnosis. This would also increase the cohort in trials and nurture an effective treatment regimen against, currently extremely fatal, VEXAS syndrome.