UBA1 Variations in Neutrophilic Dermatosis Skin Lesions of Patients With VEXAS Syndrome

Abstract

IMPORTANCE VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is a recently described severe adult-onset autoinflammatory disease that is associated with myeloid lineage-restricted ubiquitin-activating enzyme 1 (UBA1) somatic variations that primarily affect the skin (Sweet syndrome), cartilage, and bone marrow. Skin symptoms have been poorly described.OBJECTIVE To better describe clinical and pathological skin manifestations and their pathophysiology in VEXAS syndrome. DESIGN, SETTING, AND PARTICIPANTSThis multicenter retrospective case series study of clinical and histological features of 8 patients with VEXAS syndrome and skin involvement was conducted in France from December 2007 to March 2021, with molecular data obtained from March to April 2022. Any UBA1 variations were detected by Sanger or next-generation sequencing that was performed on bone marrow and formalin-fixed paraffin-embedded tissue sections of skin lesion biopsies.RESULTS All 8 patients were men, and the median age at symptom onset was 65.5 years (interquartile range, 54-76 years). All patients had neutrophilic dermatosis skin lesions, including tender red or violaceous papules, sometimes edematous, without fever, arthralgia, recurrence or pathergy, inflammatory edematous papules on the neck and trunk (sometimes umbilicated), and firm erythematous purpuric or pigmented infiltrated plaques and nodules. Three patients had livedo racemosa. The infiltrates were perivascular and consisted of mature neutrophils with leukocytoclasia, which were admixed with myeloperoxidase-positive CD163-positive myeloid cells with indented nuclei and lymphoid cells in all cases. A sequencing analysis of paired bone marrow samples and skin lesion biopsies identified the same loss-of-function UBA1 variation in both samples for all patients.CONCLUSIONS AND RELEVANCE This case series study describes the different clinical presentations of skin lesions found in VEXAS syndrome, which is characterized histologically by neutrophilic dermatosis. The findings suggested that the dermal infiltrates seen in VEXAS skin lesions are derived from the pathological myeloid clone. This suggests that using therapies that target the pathological clone may be effective in the long-term management of the disease.

SARS-CoV-2/COVID-19 and its relationship with NOD2 and ubiquitination

“…Patients can have purpuric macules, dermal, urticarial or eczematous papules or plaques, subcutaneous nodules, morbilliform exanthem, and erythema multiforme-like eruption [ 33 ]. These recurrent skin lesions are neutrophilic dermatosis mostly and small to medium-vessel vasculitis occasionally [ 34 ]. Another clinical feature is chondritis involving the nose and ears.…”

Tocilizumab for treatment of cutaneous and systemic manifestations of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome without myelodysplastic syndrome

“…There is evidence that the dermal infiltrates in the VEXAS cutaneous lesions are derived from the pathologic myeloid clone, suggesting that therapies targeting the pathologic clone may be critical for the long-term management of cutaneous involvement. 3 …”

“… 1 , 2 Nearly all patients with VEXAS present with cutaneous manifestations of the disease, most commonly a robust neutrophilic dermatosis. 3 …”

Neutrophilic Dermatoses: a Clinical Update

“…More recently, peripheral blood exome sequencing identified a mutation in UBA1 , a gene encoding the ubiquitin-activating enzyme 1, in a severe adult-onset inflammatory disorder coined VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. This disorder is characterized by recurrent fevers, pulmonary symptoms, and dermatologic manifestations, including neutrophilic dermatoses [ 19 •, 20 ].…”