Skin Manifestations of VEXAS Syndrome and Associated Genotypes

Abstract

Importance: VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a newly defined genetic disease with an estimated prevalence of 1 in 4269 men older than 50 years and is marked by systemic inflammation, progressive bone marrow failure, and inflammatory cutaneous manifestations.

Objective: To define the spectrum of cutaneous manifestations in VEXAS syndrome and the association of these findings with clinical, genetic, and histological features.

Design, setting, and participants: This observational cohort study included data from 112 patients who were diagnosed with VEXAS-defining genetic variants in UBA1 between 2019 and 2023. Data were collected from medical record review or from patients with VEXAS directly evaluated at the National Institutes of Health in Bethesda, Maryland.

Main outcomes and measures: To define the spectrum of cutaneous manifestations in VEXAS in association with genetic, histological, and other clinical findings. A secondary outcome was cutaneous response to treatment in VEXAS.

Results: Among the 112 patients (median [range] age, 69 [39-79] years; 111 [99%] male), skin involvement was common (93 [83%]), and the most frequent presenting feature of disease (68 [61%]). Of 64 histopathologic reports available from 60 patients, predominant skin histopathologic findings were leukocytoclastic vasculitis (23 [36%]), neutrophilic dermatosis (22 [34%]), and perivascular dermatitis (19 [30%]). Distinct pathogenic genetic variants were associated with specific cutaneous manifestations. The p.Met41Leu variant was most frequently associated with neutrophilic dermal infiltrates (14 of 17 patients [82%]), often resembling histiocytoid Sweet syndrome. In contrast, the p.Met41Val variant was associated with vasculitic lesions (11 of 20 patients [55%]) with a mixed leukocytic infiltrate (17 of 20 patients [85%]). Oral prednisone improved skin manifestations in 67 of 73 patients (92%). Patients with VEXAS treated with anakinra frequently developed severe injection-site reactions (12 of 16 [75%]), including ulceration (2 of 12 [17%]) and abscess formation (1 of 12 [8%]).

Conclusions and relevance: Results of this cohort study show that skin manifestations are a common and early manifestation of VEXAS syndrome. Genetic evaluation for VEXAS should be considered in older male patients with cutaneous vasculitis, neutrophilic dermatoses, or chondritis. Awareness of VEXAS among dermatologists is critical to facilitate early diagnosis.

Figure 1.. Cutaneous Signs of VEXAS Syndrome

The most common cutaneous features of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome are graphically depicted. Nondestructive inflammation of ear and nose cartilage can lead to a clinical diagnosis of relapsing polychondritis. Periorbital edema with inflammation is relatively specific for VEXAS syndrome. Urticarialike lesions and neutrophilic dermatosis can invoke a diagnosis of urticarial vasculitis or Sweet syndrome, respectively. Livedo reticularis and nodular skin lesions with associated medium-vessel vasculitis can lead to a clinical diagnosis of polyarteritis nodosa. Purpuric lesions with leukocytoclastic vasculitis or leukocytoclasia without overt vasculitis have been described.

Figure 2.. Spectrum of Clinical Findings of VEXAS Syndrome

Cutaneous features of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome include infiltrated red papules and plaques on the chest (A) and neck (B), arcuate plaques (C), urticarialike small papules on the lateral torso (D) and larger plaques on the forearm (E), and nummular thin plaques on the abdomen (F).

Figure 3.. Association of Genotype With Clinical and Histopathologic Findings

^aStatistically significant comparison (P < .05).

Figure 4.. Spectrum of Histopathologic Findings of VEXAS Syndrome

A, Dermal leukocytoclasia (hematoxylin-eosin; original magnification ×200). B, Medium-sized artery in subcutis with intravascular fibrin and lymphocytes in vessel wall with inflammatory debris in lumen (hematoxylin-eosin; original magnification ×100). C, Perieccrine lymphocytic and neutrophilic infiltrate with leukocytoclasia (hematoxylin-eosin; original magnification ×100). D, Colloidal iron stain marking mucinous perieccrine stroma (original magnification ×100). VEXAS indicates vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic.