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VEXAS syndrome

Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic Etiology: - idiopathic Epidemiology: - not rare, ~ 1 in 13,500 people in U.S. may have VEXAS syndrome [2] - predominantly men aged 55-65 years - women with monosomy X hve been reported - UBA1 variants found in 1 of 4,269 men > 50 years & in 1 of 26,238 women > 50 years [3] Pathology: - systemic autoinflammatory disease - involvement of the lungs, skin, blood vessels, & joints - aberrant activation of innate immune-signaling pathways - skin biopsy - subepidermal clefting; lymphocytic infiltrate - myeloperoxidase- & CD68-positive immature myeloid* & histiocytic cells * not myleoblasts (image [5]) - bone marrow biopsy: - normocellular marrow with cytoplasmic vacuoles in myeloid & erythroid precursors (image [5]) Genetics: - X-linked disease - somatic mutation in UBA1 gene Clinical manifestations: - recurrent fevers - skin lesions (usually neutrophilic dermatosis) - erythematous, edematous annular (oval) plaques (image [5]) - systemic inflammation - arthritis, chondritis, vasculitis, uveitis, episcleritis [5] - pulmonary infiltrates, venous thrombosis, periorbital edema, hearing loss [5] - clinical heterogeneity Laboratory: - complete blood count (CBC) - macrocytic anemia, thrombocytopenia [5] - sequencing of UBA1 gene - serum inflammatory markers are increased. - serum tumor necrosis factor - serum interleukin-8 - serum interleukin-6 - serum interferon-inducible protein-10 - serum interferon-gamma, - serum C-reactive protein - erythrocyte sedimentation rate Complications: - high risk of hematologic disease. - macrocytic anemia (96%) - venous thromboembolism (44%) - myelodysplastic syndrome (24%) - multiple myeloma or MUGUS (20%) Differential diagnosis: - patients often meet criteria for other autoimmune diseases [5] - Sweet syndrome - polyarteritis nodosa - relapsing polychondritis - granulomatosis with polyangiitis - response to treatment less successful with Vexas syndrome [5] Management: - generally resistant to treatment - high-dose glucocorticoids - tocilizumab may have steroid-sparing effects [5] - Janus kinase inhibitors are investigational [1] - ruxolitinib may be useful in patients with myelodysplastic syndrome [5] - azacitidine & stem cell transplantation have been used to treat myelodysplastic syndrome [5] - mortality is 50% at 5 years

General

syndrome X-linked disease

References

  1. Guidnot C Have you heard of VEXAS syndrome? MDEdge. Internal Medicine. Dec 12, 2022 https://www.mdedge.com/internalmedicine/article/260055/mens-health/have-you-heard-vexas-syndrome - Medscape. Dec 12, 2022 https://www.medscape.com/viewarticle/985324
  2. Dotinga R VEXAS Syndrome: More Common, Variable, and Severe Than Expected. Medscape. January 25, 2023 https://www.medscape.com/viewarticle/987466 - Beck DB, Bodian DL, Shah V et al Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. JAMA. 2023;329(4):318-324 PMID: 36692560 https://jamanetwork.com/journals/jama/article-abstract/2800661
  3. AMA Morning Rounds. Jan 25, 2023 American Medical Association
  4. Fiore K Inflammatory VEXAS Syndrome May Not Be So Uncommon. Is new disease being missed by physicians? MedPage Today January 24, 2023 https://www.medpagetoday.com/rheumatology/generalrheumatology/102772 - Beck DB et al Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease N Engl J Med 2020; 383:2628-2638 PMID: 33108101 PMCID: PMC7847551 Free PMC article https://www.nejm.org/doi/full/10.1056/NEJMoa2026834
  5. Raess PW, Sendowski M, Fett N Treatment-Resistant Edematous Annular Plaques and Mild Leukopenia in a Man in His 60s. JAMA Dermatol. 2023;159(8):878-879 PMID: 37378991 https://jamanetwork.com/journals/jamadermatology/fullarticle/2806311 https://edhub.ama-assn.org/jn-learning/module/2806311
  6. Gever J Study Confirms: No Great Options for Treating VEXAS. Efficacy versus safety is the inevitable tradeoff, and efficacy isn't that good to begin with. MedPage Today May 24, 2024 https://www.medpagetoday.com/rheumatology/generalrheumatology/110314 - de Valence B, Delaune M, Nguyen Y et al Serious infections in patients with VEXAS syndrome: data from the French VEXAS registry. Ann Rheum Dis. 2024 Feb 15;83(3):372-381. PMID: 38071510