Innovations in genomics for undiagnosed diseases: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome

Stubbins, Ryan J.; Cherniawsky, Hannah; Chen, Luke Y C; Nevill, Thomas J.

doi:10.1503/cmaj.211770

Cited by 10 publications

(18 citation statements)

References 15 publications

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“…However, the identification of non-steroidal therapies is necessary for long-term management toward reducing the steroid dose and side effects. The steroid-sparing treatments that have been reported to have some success are methotrexate, mycophenolate, azathioprine, cyclophosphamide, and cyclosporine ( 2 – 4 ). Targeted agents, including anti-IL-1 (anakinra and canakinumab), anti-IL-6 (tocilizumab), anti-tumor necrosis factor α (TNF-α) (adalimumab, infliximab, and etanercept), and Janus kinase inhibitors, have been proposed as possible treatments for VEXAS syndrome ( 2 – 4 ).…”

Section: Discussionmentioning

confidence: 99%

“…The steroid-sparing treatments that have been reported to have some success are methotrexate, mycophenolate, azathioprine, cyclophosphamide, and cyclosporine ( 2 – 4 ). Targeted agents, including anti-IL-1 (anakinra and canakinumab), anti-IL-6 (tocilizumab), anti-tumor necrosis factor α (TNF-α) (adalimumab, infliximab, and etanercept), and Janus kinase inhibitors, have been proposed as possible treatments for VEXAS syndrome ( 2 – 4 ). In fact, high serum levels of IL-6 have been observed in patients with VEXAS syndrome ( 1 , 6 ).…”

Section: Discussionmentioning

confidence: 99%

“…VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is the first example of an autoinflammatory disease arising exclusively from somatic mutations and is one of an emerging class of acquired errors of immunity. Although this disorder was only first reported in 2020, hundreds of patients have been identified (1)(2)(3)(4)(5). VEXAS syndrome is caused by pathogenic variants in ubiquitin-like modifier activating enzyme 1 (UBA1), a gene on the X chromosome that encodes UBA1, and these mutations are restricted to myeloid-lineage cells (1).…”

Section: Introductionmentioning

confidence: 99%

“…VEXAS syndrome is caused by pathogenic variants in ubiquitin-like modifier activating enzyme 1 (UBA1), a gene on the X chromosome that encodes UBA1, and these mutations are restricted to myeloid-lineage cells (1). Patients with this syndrome are characterized by adult-onset recurrent fever, neutrophilic dermatoses, leukocytoclastic vasculitis, polyarteritis nodosa, ear and nose chondritis, venous thromboembolism, pulmonary infiltrates, gastrointestinal pain or inflammation, aortitis, hepatosplenomegaly, macrocytic anemia, elevated acutephase reactants, myelodysplastic syndrome (MDS), multiple myeloma, and bone marrow vacuolization restricted to myeloid and erythroid precursor cells (1)(2)(3)(4)(5). The majority of the patients have myeloid lineage-restricted somatic mutations in UBA1, affecting the Met41 residue of the protein.…”

Section: Introductionmentioning

confidence: 99%

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A case of VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) with decreased oxidative stress levels after oral prednisone and tocilizumab treatment

et al. 2022

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VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome has recently been described as an autoinflammatory disease associated with severe adult-onset inflammatory manifestations. The various clinical manifestations include recurrent high-grade fever, neutrophilic dermatoses, cutaneous vasculitis, chondritis of the ear and nose, pulmonary infiltrates, cytopenia, uveitis, gastrointestinal pain or inflammation, aortitis, hepatosplenomegaly, and hematological disorders. VEXAS syndrome is caused by somatic mutations of the ubiquitin-like modifier activating enzyme 1 (UBA1) gene in myeloid-lineage cells. It is characterized by vacuolated myeloid and erythroid progenitor cells seen by bone marrow biopsy. We report the case of a 64-year-old Japanese man with VEXAS syndrome. At age 63, he was referred to us with a recurrent erythema on the hands associated with a general fever of 38–40°C that had persisted for 4 or 5 days and had recurred about once a month for a year. The skin rash appeared 2 or 3 days after the onset of each fever episode. Computed tomography (CT) of the chest revealed bilateral hilar lymphadenopathy (BHL), and the mediastinal lymph nodes were swollen. Sarcoidosis was suspected but was ruled out by several tests. Laboratory examinations showed elevated inflammatory markers. Bone marrow examination showed the vacuolization of myeloid precursor cells. A skin biopsy revealed dense dermal, predominantly perivascular, infiltrates. These consisted of mature neutrophils admixed with myeloperoxidase-positive CD163-positive myeloid cells, lymphoid cells and eosinophils. Sequencing analysis identified the somatic UBA1 variant c.122T > C, which results in p.Met41Thr. Treatment with oral prednisone (15 mg/day) and monthly intravenous tocilizumab injections (400 mg) completely resolved the symptoms. Neutrophils are a major source of reactive oxygen species, and the present case demonstrated numerous neutrophilic infiltrates. We hypothesize that the patient might have had elevated derivatives of reactive oxygen metabolites (d-ROMs). d-ROM quantification is a simple method for detecting hydroperoxide levels, and clinical trials have proven it useful for evaluating oxidative stress. In this study, we measured serum d-ROM before and after oral prednisone and tocilizumab treatment. The levels decreased significantly during treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A case of VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) with decreased oxidative stress levels after oral prednisone and tocilizumab treatment

et al. 2022

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“…The most common vasculitis is small-vessel vasculitis, particularly LCV. The reason stems from the fact that skin manifestations, which are observed in 80–90% of patients, often reveal the histopathology of LCV ( 14 , 37 , 60 ). LCV is histologically characterized by angiocentric segmental inflammation, fibrinoid necrosis, and neutrophilic infiltration around the blood vessel walls ( 14 , 61 ).…”

Section: Vasculitis Associated With Vexas Syndromementioning

confidence: 99%

Vasculitis associated with VEXAS syndrome: A literature review

Watanabe¹,

Kiji²,

Hashimoto³

2022

Front. Med.

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Vasculitis is an inflammatory disorder of the blood vessels that causes damage to a wide variety of organs through tissue ischemia. Vasculitis is classified according to the size (large, medium, or small) of the blood vessels. In 2020, VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome, a novel autoinflammatory syndrome, was described. Somatic mutations in methionine-41 of UBA1, the major E1 enzyme that initiates ubiquitylation, are attributed to this disorder. This new disease entity connects seemingly unrelated conditions: inflammatory syndromes (relapsing chondritis, Sweet's syndrome, or neutrophilic dermatosis) and hematologic disorders (myelodysplastic syndrome or multiple myeloma). Notably, such patients sometimes develop vasculitis, such as giant cell arteritis and polyarteritis nodosa, and fulfill the corresponding classification criteria for vasculitis. Thus, vasculitis can be an initial manifestation of VEXAS syndrome. In this research topic exploring the link between autoinflammatory diseases and vasculitis, we first provide an overview of the disease mechanisms and clinical phenotypes of VEXAS syndrome. Then, a literature review using the PubMed database was performed to delineate the clinical characteristics of vasculitis associated with VEXAS syndrome. Finally, the therapeutic options and unmet needs of VEXAS syndrome are discussed.

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Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) with prominent supraglottic larynx involvement: a case-based review

et al. 2022

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Innovations in genomics for undiagnosed diseases: vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome

Cited by 10 publications

References 15 publications

A case of VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) with decreased oxidative stress levels after oral prednisone and tocilizumab treatment

A case of VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) with decreased oxidative stress levels after oral prednisone and tocilizumab treatment

Vasculitis associated with VEXAS syndrome: A literature review

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome (VEXAS syndrome) with prominent supraglottic larynx involvement: a case-based review

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