Inflammatory Signatures in VEXAS Syndrome, Myelodysplasia Cutis, and Sweet Syndrome.

Abstract

Importance: VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a monogenic disease caused by UBA1 somatic variants in hematopoietic progenitor cells, mostly involving adult men. It is associated with inflammatory-related symptoms, frequently involving the skin and hematological disorders. Recently described myelodysplasia cutis (MDS-cutis) is a cutaneous manifestation of myelodysplasia in which clonal myelodysplastic cells infiltrate the skin. In both cases, skin lesions are driven by the infiltration of clonal mutated myeloid cells and may clinically and histologically mimic Sweet syndrome (SS), a neutrophilic skin disease.

Objective: To decipher the underlying mechanisms driving these 3 myeloid-related skin diseases (ie, VEXAS, MDS-cutis, and SS) compared with leukemia cutis (LC), a neoplastic blastic myeloid-related skin condition, and healthy control skin samples.

Design, setting, and participants: This multicenter translational study on formaldehyde-fixed paraffin-embedded lesional skin samples of VEXAS syndrome, MDS-cutis, idiopathic SS, LC, and healthy controls using bulk RNA sequencing analyses was conducted in France. Patients included had cutaneous lesions of VEXAS syndrome, MDS-cutis, idiopathic SS, or LC. The data were analyzed from June 2023 to March 2024.

Main outcomes and measures: Differentially expressed genes between conditions were studied. These genes were used to characterize the enrichment in activated inflammatory pathways in each condition using Gene Set Enrichment Analysis and Ingenuity Pathway Analysis.

Results: Twenty patients with skin conditions (median [range] age, 67 [43-88] years; 10 [50%] men) were included. Six had cutaneous lesions of VEXAS syndrome, 4 had MDS-cutis, 5 had idiopathic SS, and 5 had LC. They were compared with 5 healthy control skin samples. Bulk RNA sequencing analysis reveals that MDS-cutis and VEXAS syndrome lesions display closely related transcriptomic profiles, highly imprinted by cytokine responses, interferon signatures, and activation of the apoptosis pathway. A shared inflammatory environment between MDS-cutis, VEXAS syndrome, and idiopathic SS was observed, mostly relying on a type 1 immune response led by type 1 and 2 interferons, along with the activation of tumor necrosis factor and interleukin (IL)-1β pathways. Conversely, LC showed an isolated transcriptomic profile mainly enriched in cell cycle pathways.

Conclusions and relevance: The findings of this translational study highlight a common inflammatory pattern shared between VEXAS syndrome, MDS-cutis, and refractory idiopathic SS skin samples. This suggests the potential therapeutic targeting of interferon pathways in patients affected with refractory nonblastic myeloid-related skin diseases.