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VEXAS syndrome presenting with histological features of histiocytoid sweet syndrome: A case report

Year: 2025

Type: article

Abstract: Dear Editor, Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently identified myeloid-driven autoinflammatory disorder caused by somatic mutations in UBA1. It was first described in 2020[1] and was thought to be a rare disorder. However, its prevalence may be underestimated; a study identified disease-causing UBA1 variants in 1 of 4269 men aged >50 years.[2] This syndrome manifests with cutaneous, inflammatory, and hematologic features, and up to 83% of patients are affected with inflammatory skin lesions, predominantly neutrophilic dermatosis and cutaneous vasculitis.[3] We report a case of VEXAS syndrome in Taiwan, presenting with histological features of histiocytoid Sweet syndrome, and discuss its management. A 70-year-old man presented to our clinic in 2022 with asymptomatic pink-to-erythematous papules on his trunk and extremities for 1 week [Figure 1a and b]. His medical history included rheumatoid arthritis, Sjögren’s syndrome, and suspected myelodysplastic syndrome (MDS). A skin biopsy from the left forearm revealed papillary dermal edema with dense neutrophil and lymphocyte infiltrates sparing the epidermis, in addition to histiocyte-like cells in the dermis and periadnexal areas [Supplementary Figure 1a-d]. Immunohistochemistry demonstrated positive staining for CD68, lysozyme, and myeloperoxidase [Supplementary Figure 1e-g], supporting a diagnosis of histiocytoid Sweet syndrome based on clinicopathologic correlation.Figure 1: (a) Clinical presentation of pink-to-erythematous papules over the anterior chest. (b) Closer view of pink-to-erythematous papules on the left antecubital fossa. (c) Bone marrow biopsy revealed myeloid vacuolization (arrows). (d) Sanger sequencing of UBA1 revealed a c. 121A>C mutation, leading to p.Met41Leu.Supplementary Figure 1: (a and b) Papillary dermal edema with dense infiltrate of neutrophils, lymphocytes, and some histiocyte-like cells in the dermis (H and E, a: ×100, c: ×400). (c and d) Dense infiltrate of neutrophils, lymphocytes, and some histiocyte-like cells in the periadnexal areas (H and E, c: ×100, d: ×400). Immunohistochemical staining showed diffuse and granular staining patterns of (e) CD68 (Pink stain, ×400), (f) lysozyme (×400) and (g) myeloperoxidase (×400).The patient had reported similar skin eruptions since 2020. Previous biopsies indicated neutrophilic dermatosis or leukocytoclastic vasculitis. In 2021, he experienced joint pain, intermittent fever, and a 14% body weight loss within a year. Laboratory findings revealed leukocytopenia (2290/μL), macrocytic anemia (8.7 g/dL), and elevated C-reactive protein (CRP, 8.33 mg/dL). Although a bone marrow biopsy was inconclusive for MDS, he remained transfusion-dependent anemia for one year until receiving prednisolone 20 mg daily. A subsequent bone marrow biopsy review revealed myeloid vacuolization, and Sanger sequencing of UBA1 in late 2022 confirmed a p.Met41Leu mutation [Figure 1c and d], establishing VEXAS syndrome. Treatment transitioned to methotrexate 5 mg weekly. Subsequent laboratory data indicated hemoglobin returning to normal (17 g/dL) and a decreasing CRP level [0.22 mg/dL; Supplementary Figure 2].Supplementary Figure 2: History and laboratory data of the patient (red, hemoglobin; green, C-reactive protein).VEXAS syndrome arises from UBA1 mutations disrupting the ubiquitin–proteasome system, triggering systemic inflammation, bone marrow dysfunction, and varied cutaneous manifestations.[4] Fever is a hallmark of VEXAS syndrome, reported in 64%–100% of patients, along with several extracutaneous features, including respiratory symptoms with ground-glass opacities on imaging, variable-vessel vasculitis, and hematologic abnormalities. Patients may also exhibit polychondritis, polyarthralgia, and periorbital edema. Cutaneous involvement, primarily neutrophilic dermatosis, resembles Sweet syndrome but is distinguished by frequent relapses (>4–6 times/year) and a higher prevalence of cytopenias. Koster et al. recommended that men aged >40 years with neutrophilic dermatosis, cytopenias, and persistent inflammation should be evaluated for VEXAS.[4] Bone marrow examination often reveals a diagnostic clue of vacuoles in myeloid and erythroid precursors. Genetic testing identifies several predominant UBA1 mutations, including p.Met41Thr (49%), p.Met41Val (26%), and p.Met41Leu (19%).[5] These genetic mutations may be associated with corresponding phenotypes. For example, p.Met41Val is associated with vasculitic lesions (55%), and p.Met41Leu is commonly associated with neutrophilic infiltrates resembling histiocytoid Sweet syndrome (82%).[6] No standardized treatment protocol for VEXAS has been developed. Treatment options include glucocorticoids (minimum 15–20 mg/day), disease-modifying antirheumatic drugs (DMARDs), Janus kinase inhibitors (e.g., ruxolitinib), interleukin-6 inhibitors, azacitidine, or hematopoietic stem cell transplantation.[4] The prognosis is dependent on the mutations; p. Met41Leu is associated with the highest 5-year survival rate (100%), followed by p.Met41Thr (83%) and p.Met41Val (77%).[5] For our patient, the clinicopathologic features were interpreted as histiocytoid Sweet syndrome before genetic confirmation. Despite initial transfusion-dependent anemia, overt bone marrow failure was absent, distinguishing this case from severe MDS overlap. Prednisolone provided initial control and was followed by methotrexate, which achieved sustained remission. Although some studies question the steroid-sparing efficacy of traditional DMARDs,[7] De Santis et al. indicated that methotrexate may be effective in patients with mild or no bone marrow failure, as in our case.[8] This case highlights the diagnostic complexity of VEXAS syndrome, which often masquerades as other inflammatory or hematologic disorders. Its clinicopathological presentation as histiocytoid Sweet syndrome, coupled with systemic features, underscores the need for heightened awareness among dermatologists. VEXAS syndrome is a newly defined disease entity, and this case emphasizes the importance of genetic testing in older men with refractory neutrophilic dermatoses and cytopenias. Additional studies are warranted to refine therapeutic strategies and improve recognition of this underdiagnosed syndrome. Ethical approval The study was conducted in accordance with the Declaration of Helsinki and was approved by TMU-Joint Institutional Review Board (approval no.: N202311078; approval date: 2023/11/25). Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. Data availability statement Data sharing is not applicable to this article. Financial support and sponsorship Nil. Conflicts of interest Prof. Woan-Ruoh Lee, an editorial board member at Dermatologica Sinica, had no role in the peer review process of or decision to publish this article. All authors declared no conflicts of interest in writing this paper.

Source: Dermatologica Sinica

DOI: 10.4103/ds.ds-d-25-00096