Treatment-Resistant Edematous Annular Plaques and Mild Leukopenia in a Man in His 60s

B. VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, and somatic) syndrome

Subsequent skin biopsy results (Figure 2A) revealed subepidermal clefting; a superficial and deep perivascular, interstitial, and periadnexal infiltrate of lymphocytes; and myeloperoxidase- and CD68-positive immature nonblastic myeloid and histiocytic cells.

Because of the lack of response to therapy, the possibility of myelodysplasia, and diagnostic uncertainty, a bone marrow biopsy specimen was obtained (Figure 2B), which revealed normocellular marrow with cytoplasmic vacuoles in the myeloid and erythroid precursors. Molecular diagnostics revealed a somatic variant in UBA1 (GenBank 7317) p.M41L, diagnostic of VEXAS syndrome.

VEXAS syndrome is an acquired, autoinflammatory disorder caused by a somatic variant of the X-linked UBA1 gene.¹ The UBA1 gene encodes E1, a master enzyme of cellular ubiquination.² The variant occurs at p.Met41, within the translation initiation codon, which leads to loss of the normally active cytoplasmic isoform, UBA1b, and development of an enzymatically impaired, novel isoform, UBA1c.² Impaired cellular ubiquitination activates the unfolded protein response and ultimately upregulates type 1 interferons.³ Three amino acid substitutions have been described: threonine, valine, and leucine.⁴ The amino acid substitution portends disease phenotype and prognosis.^2,5 VEXAS syndrome has predominantly been described in men aged 55 to 65 years, although women with monosomy X have also been reported.^4- 6 A recent observational study suggests VEXAS syndrome prevalence is 1 in 13 591 individuals.⁶ Patients typically present with fever, skin lesions (usually neutrophilic dermatosis), and hematologic abnormalities (eg, macrocytic anemia and thrombocytopenia). Additional signs of inflammation (eg, arthritis, pulmonary infiltrates, venous thrombosis, chondritis, periorbital edema, vasculitis, uveitis, episcleritis, and hearing loss) are frequently reported, as are elevated inflammatory markers.^1,2,4- 7 Biopsy specimens of skin manifestations typically reveal superficial dermal infiltration of immature nonblastic myeloid cells, histiocytes, and lymphocytes.⁷ Bone marrow biopsy reveald hypercellular marrow with cytoplasmic vacuoles in the myeloid and erythroid precursors. Most patients develop myelodysplastic syndrome (MDS), monoclonal gammopathy of unknown significance, or multiple myeloma. Patients with VEXAS syndrome often meet criteria for other autoimmune diseases, specifically Sweet syndrome, polyarteritis nodosa, relapsing polychondritis, and granulomatosis with polyangiitis.¹ Classically, these patients do not respond as expected to standard-of-care therapies and are dependent on systemic corticosteroid therapy. Dapsone, colchicine, hydroxychloroquine, azathioprine, methotrexate, mycophenolate mofetil, tumor necrosis factor inhibitors, anakinra, and Janus kinase inhibitors (with the exception of ruxolitinib in patients with VEXAS syndrome with MDS) have been reported as ineffective therapies.⁴ Tocilizumab may have steroid-sparing effects.⁴ Patients who develop high-risk MDS have been treated with azacitidine and stem cell transplant.⁴ VEXAS syndrome is a highly morbid disease, with mortality of approximately 50% at 5 years.