Question 1

What is VEXAS syndrome?

Accepted Answer

VEXAS stands for Vacuoles, E1 enzyme, X-linked, Autoinflammatory, and Somatic. VEXAS syndrome is a rare, chronic, serious condition that develops in older adults (>50-year-old, 1 in 4000 men and 1 in 12,000 women) with a broad range of inflammatory and hematologic symptoms, and skin lesions. The syndrome was discovered and published in 2020.

Question 2

What are the symptoms for VEXAS Syndrome patients?

Accepted Answer

The median age for the onset of the VEXAS Syndrome is 64-year-old. The symptoms include:

·       Body: fever, pain and fatigue
·       Skin: painful rashes
·       Breath: short
·       Ears and nose: swelling
·       Blood cell counts: low
·       Blood oxygen: low

Question 3

What has caused the VEXAS Syndrome?

Accepted Answer

As “S” in the name means, VEXAS syndrome has a somatic mutation in the UBA1 gene that codes for ubiquitin E1 enzyme. The enzyme acts like a janitor, cleaning up the damaged or outdated proteins from the cells.

Question 4

What is the prognosis of patients with VEXAS Syndrome patients?

Accepted Answer

The life expectancy of patients with VEXAS Syndrome varies. Up to half of the VEXAS Syndrome patients would die within five years of diagnosis, especially when untreated. The median survival from the onset of the symptoms is 9 years.

Question 5

Can VEXAS Syndrome be treated?

Accepted Answer

Although there is no cure for VEXAS Syndrome, but there are some promising treatments that works better than the common treatments if the VEXAS syndrome is not diagnosed or misdiagnosed. See Part III for more details.

Question 6

Why is it necessary to test for VEXAS syndrome?

Accepted Answer

Here are the main reasons why VEXTAS testing is necessary:

a.     The VEXAS syndromes can be shared by patients with different autoinflammatory and autoimmune diseases and are often misdiagnosed by hematologists, rheumatologists and even dermatologists due to the broad range of symptoms. Without identification of the disease, more efficient treatments towards VEXAS Syndrome will not be applied. This will delay or miss the better treatment. For instance, early diagnosis of VEXAS allows stem cell transplantation before physical deterioration occurs.

b.     The patients with VEXAS have shorter survival/higher mortality rate than other patients with similar symptoms. Early diagnosis benefits patients by extending their lives because better therapy can be applied.

c.      Testing also provides prognosis information. For instance, the Valine mutation at UBA1 codon 41 causes much shorter life expectancy than the Leucine mutation.

Question 7

What types of doctors order the test for VEXAS syndrome?

Accepted Answer

The dermatologists, hematologists, and especially rheumatologists can order the VEXAS test if they suspect their patients with VEXAS syndrome based on their symptoms.

Question 8

Who should be tested for VEXAS Syndrome?

Accepted Answer

VEXAS syndrome has been identified in the following patient population and experts recommend screening these patient groups for UBA1 mutation.

·       Genetic screening for pathogenic UBA1 variants should be considered in patients with vasculitis, autoinflammatory diseases or RP (Relapsed Polychondritis), especially male patients with skin lesions
·       Patients with MDS (myelodysplastic syndromes) and AD (autoimmune disorders) who have characteristic vacuoles in myeloid and erythroid precursor cells 
·       Patients with Sweet Syndrome

Besides these high-risk groups, it is also recommended to screen for the following groups:

·       Recurrent Fevers without an obvious cause
·       Unexplained Inflammation such as elevated CRP and ESR
·       Blood Abnormalities such as anemia, leukopenia, thrombocytopenia, or dysplasia of blood cells
·       Skin Lesions livedo reticularis or vasculitic lesions
·       Male Gender and Older Age with unexplained inflammatory symptoms 
·       Negative Workup for Other Conditions without a clear diagnosis
·       Family members that have experienced unexplained inflammatory symptoms like VEXAS.

Question 9

How VEXAS Syndrome is tested?

Accepted Answer

Traditionally, the following methods are used for VEXAS testing: Sanger sequencing, Next generation sequencing (NGS), and droplet digital PCR (ddPCR or dPCR) are used for testing.

Sanger sequencing is simple, but mutant alleles must be over 15 to 20%. Therefore, it is not good for detection of patients at early stage when the frequency of somatic UBA1 mutations is still low.

NGS is the most modern and more sensitive technique for low-frequency mutation detection as well as high-frequency mutation detection. Some testing facilities add the UBA1 mutations to the existing immunology panel to test VEXAS. Although this made the panel more comprehensive, it is costly when only VEXAS test order is necessary.

ddPCR only targets the UBA1 mutation with high sensitivity but limited with the throughput for the number of mutations. It is very likely that newer UBA1 or other mutations are added when new research on the new VEXAS Syndrome continues.

Question 10

How does DiaCarta’s VEXAS Test work?

Accepted Answer

DiaCarta took a different approach to identify the UBA1 mutations by combining our Proprietary XNA technology and Luminex’s xMAP technology. The XNA technology enriches low-frequent somatic mutations, allowing identification of mutations missed by Sanger sequencing. Meanwhile, xMAP can detect up to 100 mutations within a working day rather than 2 weeks for NGS. In addition, the cost is significantly reduced compared to NGS as well. In summary, our test can detect UBA1 mutation earlier in development if necessary and has a quick turnaround with a fraction of the cost of NGS.

Question 11

What are treatments before testing of VEXAS Syndrome?

Accepted Answer

Relapsing polychondritis (RP) is a systemic immune-mediated inflammatory disease that is like VEXAS, but without the UBA1 mutation. Before identification of UBA1 mutations in RP, VEXAS is likely to be treated like RP patients. It is estimated that half of the RP patients are VEXAS patients.

Although there is no standardization of treatment of RP, the common treatment depends on the severity of the clinical manifestations. Here are some of the treatment methods for RP published:

·       Mild patients with joint pain and inflammation of the cartilage at the level of the external ear and nose:
o   Use nonsteroidal anti-inflammatory drugs (NSAIDs) in possible combination with dapsone or colchicine

·       Severe forms of RP with ocular, cardiac, laryngotracheal, vasculitic or neurological damage: 
o   Use medium to high doses of corticosteroids (CSs)

·       Serious but non-responsive patients:
o   Use synthetic DMARDs (DMARDs) such as methotrexate (MTX), azathioprine (AZA), cyclosporine A or cyclophosphamide (CYC)

·       Patients with insufficient or absent response:
o   Use anti-cytokinic biological agents such as TNFα inhibitors (Infliximab, Adalimumab or Etanercept) and IL-1 (anakinra) and IL-6 (tocilizumab) blockers, or abatacept, an inhibitor of T-lymphocyte costimulation

Question 12

How to efficiently treat patients with VEXAS Syndrome?

Accepted Answer

Due to the recent discovery of the disease, there is no standardization for treatment.  Because of the complex pathogenicity and poor response to many treatments, VEXAS patients have high mortality. Currently, there is no cure for the disease. The common immunosuppressive drugs are not efficient in VEXAS patients.

• Preventive, supportive interventions therapy:
o   Use anticoagulant treatment and erythrocyte or platelet transfusions 
o   Use infectious prophylaxis carried out through vaccination and antibiotic or antiviral therapy

• Significant systemic inflammation:

o   Requires the administration of high doses of corticosteroids

• Hematological manifestations:
o   Use DNA methyltransferase inhibitors (azacytidine and decitabine)
o   Use erythropoiesis-stimulating agents
o   Use a thrombopoietin receptor agonist—eltrombopag
o   Or use targeted synthetic molecules—Janus kinase inhibitors (JAKis—especially ruxolitinib)

• Severe, non-responsive cases
o   Use bone marrow transplantation

• The only definitive treatment:
o   allogeneic hematopoietic stem cell transplantation (HSCT)

• Suppression of UBA1 clone
o   Use azacytidine

Question 13

What are the future therapy strategies?

Accepted Answer

Future therapies may include target therapy based on the UBA1 mutation and gene therapy to correct the mutated gene using CRISPR technology.

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