Clinical and histological features of histiocytoid Sweet syndrome associated with VEXAS syndrome.

ABSTRACT

BACKGROUND: "Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic" (VEXAS) syndrome is caused by acquired somatic mutations in the ubiquitin-activating enzyme 1 (UBA1) gene. Sweet-syndrome-like skin disorders (and especially histiocytoid Sweet syndrome (HSS)) may be associated with VEXAS syndrome. OBJECTIVE: To characterize the clinical and histopathological features of HSS in patients with VEXAS syndrome. METHODS: The skin biopsies with a histological diagnosis of HSS had been collected at Rennes University Medical Center (Rennes, France) between October 2011 and January 2022. Sanger sequencing and digital PCR were used to screen skin, blood, and bone marrow samples for UBA1 variants, and thus classify patients as having VEXAS syndrome or not. We evaluated the clinical, histological, and molecular (UBA1) characteristics of patients with or without VEXAS syndrome. RESULTS: We compared 15 skin biopsies from seven patients found to have VEXAS syndrome and 19 skin biopsies from 15 patients without VEXAS syndrome. Persistent inflammatory syndrome, macrocytosis, anemia, and hematological malignancies were more prevalent in patients with VEXAS syndrome (86%, 86%, 100%, and 86%, respectively) than in patients without (36%, 40%, 53%, and 53%, respectively). These features sometimes appeared after the first skin manifestations, and a UBA1 mutation was found in the skin of five patients with VEXAS syndrome. Dermal infiltration by myeloperoxidase-positive, CD163-positive, reniform histiocytoid cells and a periadnexal distribution were more frequently observed in VEXAS syndrome biopsies (100% and 20% respectively, vs. 58% and 0% in non-VEXAS syndrome biopsies, respectively). CONCLUSION: Our findings might help the pathologist to consider a diagnosis of VEXAS syndrome and to initiate early genetic testing.