VEXAS Syndrome: An Unusual Dermatological Presentation With Histiocytic Infiltration

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Abstract

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a late-onset autoinflammatory disorder that results from mutations in the UBA1 gene, which encodes the X-linked, ubiquitin-activating enzyme E1 [1]. It typically affects male patients older than 60 years old and the most common manifestations include fever and constitutional symptoms, along with cutaneous, hematological, and rheumatological manifestations [2]. Cutaneous findings are one of the most common features in up to 88% of patients [1]. Neutrophilic dermatoses represent the most prevalent skin finding, with other presentations including vasculitis and chondritis [2]. We report an unusual case of mucocutaneous lesions with histiocytic infiltrate, leading to a diagnosis of VEXAS syndrome in association with myelodysplastic syndrome. To our knowledge, this is the second case described as having an extensive cutaneous histiocytic reaction in the setting of VEXAS [3]. A 73-year-old male presented with a 1-year evolution of evanescent erythematous nonpruritic papules on the trunk. He reported constitutional symptoms and denied a recent history of medication use. The initial diagnostic considerations included Sweet syndrome, urticarial vasculitis, and cutaneous lymphoma. The diagnostic workup revealed macrocytic anemia, and serological, autoimmune, and oncological screening were negative. The skin biopsy revealed neutrophilic dermatitis without vasculitis (Figure 1A,B). A diagnosis of Sweet syndrome was assumed, and he was treated with systemic corticosteroids with a good clinical response. Three years later, he was observed again for nonpruriginous erythematous papules, affecting the trunk and upper limbs (Figure 2A), as well as annular brown-pink plaques and papules on the back (Figure 2B) and lower lip (Figure 2C). Punch biopsies were performed from the trunk and lip lesions and demonstrated a diffuse infiltrate of histiocytes in the dermis with abundant foamy macrophages, karyorrhexis, and collagen necrobiosis (Figure 1C,D). CD68 staining highlighted a diffuse infiltrate of histiocytes, whereas S-100 protein was negative (Figure 1E,F). At this time, he was being observed by hematology and internal medicine for a progressive constitutional syndrome, polyarthralgia, macrocytic anemia, and thrombocytopenia in association with optic neuritis. The diagnostic workup included a thoracoabdominal and pelvic computed tomography that revealed no pertinent clinical alterations; a positron emission tomography that demonstrated diffuse bone marrow uptake and increased uptake in scattered thickened skin areas; a bone marrow biopsy with findings that suggest myelodysplastic syndrome. Considering the clinical and laboratory findings, the patient's age, and gender, the possibility of VEXAS was considered. Peripheral blood genetic testing identified a somatic variant c.121A>C on the UBA1 gene, confirming the diagnosis of VEXAS syndrome. The patient was subsequently started on tocilizumab in association with prednisolone. Although neutrophilic dermatitis is the most common finding, we describe a patient with xanthomatous lesions whose histology revealed an extensive histiocytic infiltrate, probably reactive in the setting of VEXAS, a few years after the onset of dermatological manifestations. Cutaneous manifestations are part of the initial presentation in 63% of patients [4]. Therefore, dermatologists play an important role in the diagnostic process of this disease, given that skin manifestations can serve as indicators of potential systemic complications. Our patient also had associated myelodysplastic syndrome, which is present in over 75% of patients, as well as arthralgias and ocular manifestations that are also common in this disease [2]. There is no standard treatment for VEXAS. Patients often require glucocorticoids for disease control. [2] Some of the drugs that showed benefit include ruxolitinib (a Janus kinase inhibitor), azacitidine (a DNA methyltransferase inhibitor), and tocilizumab (an anti-interleukin-6 therapy) [5]. A few patients may benefit from stem cell transplants [2]. There are no recognized clinical diagnostic criteria, so VEXAS syndrome should be contemplated in adult men with systemic symptoms, cutaneous manifestations, and hematological abnormalities. In those cases, genetic testing is critical to confirm the diagnosis [1]. The authors declare no conflicts of interest.

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