VEXAS syndrome initially presenting as relapsing polychondritis and progressing into neutrophilic dermatosis with systemic symptoms over a 5‐year period

Dear Editor,

Vacuoles, E1 enzyme, X‐linked, autoinflammatory, somatic (VEXAS) syndrome is a newly established adult‐onset autoinflammatory disorder driven by somatic variants in UBA1. ¹ Herein, we present a Japanese patient with VEXAS syndrome who initially presented with relapsing polychondritis (RP) in the bilateral earlobes and progressed to neutrophilic dermatosis with periodic fever over a 5‐year clinical course. ²

A 75‐year‐old Japanese man was referred to our department with a swollen left earlobe of 2 weeks' duration (Figure 1a). Two months after his visit, the right earlobe became reddish and swollen. Laboratory tests revealed an elevated serum C‐reactive protein (CRP) level of 21.60 mg/dL and macrocytic anemia with a hemoglobin level of 10.4 g/dL and a mean corpuscular volume of 100.3 fL. Myeloperoxidase‐ and proteinase 3‐antineutrophil cytoplasmic antibodies were negative.

Figure 1.

(a) Reddish and swollen left earlobe. (b) Histopathological examination of the earlobe biopsy specimen shows auricular chondritis with neutrophilic infiltration into the auricular cartilage (hematoxylin and eosin staining, original magnification ×400). (c) Genomic DNA sequencing from peripheral blood mononuclear cells confirms a somatic UBA1 variant (NM_003334.3: c.121A>C, p. Met41Leu).

Histopathological examination of an earlobe biopsy specimen revealed auricular chondritis with neutrophilic infiltration of the auricular cartilage (Figure 1b). Nasal and laryngotracheobronchial involvement was not observed; iritis developed 10 months later. Based on the bilateral auricular chondritis, ocular manifestations, and histopathological findings of the earlobe, the patient was diagnosed with RP and treated with oral prednisone 5–20 mg daily. Three years after the initial visit, the patient developed periodic fever with elevated serum CRP levels (8.63–30.16 mg/dL). The patient was treated intensively with oral prednisone (30 mg/day). Four and a half years after the initial visit, infiltrated red or violaceous papules and plaques were observed on the nape. Skin biopsy revealed dense dermal neutrophilic infiltration with leukocytoclasia.

Genomic sequencing of DNA from peripheral blood mononuclear cells confirmed a somatic UBA1 variant (NM_003334.3:c.121A>C, p. Met41Leu) (Figure 1c). Bone marrow examination revealed myelodysplastic syndrome with vacuoles in the erythroid and myeloid precursor cells (Figure 2a). Finally, the patient was diagnosed with VEXAS syndrome. He had a recalcitrant clinical course with periodic fever and exanthema. Five years after the initial visit, computed tomography showed diffuse bilateral lung opacities. The patient died in the same year, soon after the skin lesions suddenly worsened (Figure 2b), involving histopathologically more intense neutrophil infiltration and leukocytoclastic vasculitis (Figure 2c,d), suggesting the rapid progression of VEXAS. No exacerbation of the auricular chondritis or lung opacities was observed.

Figure 2.

(a) Bone marrow examination shows myelodysplastic syndrome with vacuoles in the erythroid and myeloid precursor cells. (b) Multiple infiltrated red papules and plaques on the entire back. (c, d) Histopathological examination of the back showing severe changes compared to the preceding biopsy. Red circle: leukocytoclastic vasculitis (hematoxylin and eosin stain, original magnification ×100 and ×400).

VEXAS syndrome was first reported in 2020. ¹ Myeloid‐restricted somatic variants have been identified around Met41 of UBA1 at Xp11.3, which encodes the enzyme that initiates ubiquitination. Previously reported UBA1 variants include c.122T>C, c.121A>C, c.121A>G, and c.118‐1G>C. ² Ubiquitination plays a crucial role in the immune system. Dysregulated ubiquitination can lead to systemic inflammatory responses in the skin, lungs, blood vessels, and cartilage, often resulting in RP. ¹ Auricular chondritis is a common clinical feature of VEXAS syndrome. Twenty of 40 (50%) Japanese patients with VEXAS syndrome had auricular chondritis. ² Cutaneous lesions are common, ¹ , ² characterized by Sweet syndrome‐like multiple red or violaceous papules affecting the trunk, limbs, and neck. Some of them mimic livedo racemose. ³ Leukocytoclastic vasculitis is the most common type of small‐vessel vasculitis in patients with VEXAS syndrome. ⁴ Histopathological findings show leukocytoclastic vasculitis caused by dermal neutrophilic infiltration arising from the myeloid clone with the UBA1 variant. ³ The median time from the onset of relevant symptoms to cutaneous involvement is 17.5 days. ⁵ However, the skin lesions developed 4.5 years after the onset of auricular chondritis in this patient.

In conclusion, we report a case of VEXAS syndrome that initially presented as RP, and later progressed to a critical stage of neutrophilic dermatosis and leukocytoclastic vasculitis. RP of the earlobes, periodic fever, macrocytic anemia, and neutrophilic dermatosis with leukocytoclasia may provide clues for diagnosing VEXAS syndrome. Furthermore, skin manifestations of leukocytoclastic vasculitis are associated with mortality.

Patient consent

Written informed consent was obtained from the patient for the publication of his clinical case details.