PO:22:033 | Unraveling VEXAS syndrome: when skin manifestations and monoclonal gammopathy precede hematological myeloid alterations

Laura Di Centa¹, Simone Longhino¹, Valeria Manfrè¹, Stefania Sacco¹, Luca Quartuccio¹ | ¹ASST Papa Giovanni XXIII, Bergamo, Italy

Background. VEXAS (Vacuoles, Enzyme E1, X-linked, Autoinflammatory, Somatic) syndrome is a rare adult disease caused by somatic mutations in the UBA1 gene within hematopoietic stem cells (1). These mutations compromise the ubiquitin-activating E1 enzyme and lead to a heterogeneous clinical presentation that includes autoinflammatory signs—such as fever and skin involvement in 80% of cases, primarily manifesting as neutrophilic dermatosis, chondritis, and serositis—as well as hematological alterations in myeloid lineage cells, including macrocytic anemia, myelodysplastic syndrome, and stem cell vacuolization in the bone marrow (1, 2).

Case report: P.L., is a 80 years old man who developed fever, weight loss, fatigue, and urticarioid rash in the lower limbs and dorsum: exams showed an increase of inflammation markers (CRP 250 mg/L, ferritin 2,500 ng/mL) and a newly discovered seric IgG-lambda monoclonal component (MC), while complete blood count, LDH, autoimmunity, and liver and kidney function were within the normal range; the first skin biopsy suggested eczema. Steroid therapy was started, with a temporary benefit that was lost during tapering. Three months later the patient developed pericarditis and started colchicine. Total-body CT and PET scans ruled out possible occult malignancies. Given the need of prolonged steroid therapy to control the symptoms and the new MC, a bone marrow biopsy (BMB) was performed (no signs of disease) alongside a new skin biopsy, positive for neutrophilic dermatosis. The patient started dapsone, but there was no improvement. After a rheumatologic consult, according to Strasburg criteria (chronic urticaria, MC, high inflammation markers) (4), the patient was diagnosed with Schnitzler syndrome (SchS) and started anakinra. Eventually, given the lack of improvement and the development of injection-site reactions, therapy switched to canakinumab with partial improvement. The patient then developed macrocytic anemia. Considering the failure of IL1 block, the atypical MC (IgG instead of IgM), pericarditis, and the recent onset of anemia, suspecting VEXAS syndrome, the UBA1 gene was analyzed, showing a p.Met41Thr mutation. VEXAS was confirmed.

Conclusions. This case highlights how VEXAS syndrome must be taken into consideration in elder male patients with unexplained inflammatory and cutaneous manifestations, even when no typical vacuolization in the bone marrow(1-3), nor myeloid anomalies at the complete blood count (a characteristic feature described in almost every case report) can be seen and are, instead, preceded by clonal lymphoid anomalies (MC). VEXAS, therefore, can be considered a monoclonal gammopathy of clinical significace, even though it has not been officially included among them yet. Early recognition of UBA1 mutation is pivotal in order to timely diagnose and properly manage the disease. Lastly, the inefficacy of anakinra and the developement of injection-site reactions may give a diagnostic clue towards VEXAS. (2,3).