Background/Aims
We report a patient presenting with an inflammatory illness consistent with relapsing polychondritis (RP) and a pancytopaenia. Testing of his bone marrow revealed confirmation of the somatic mutation for the newly recognised condition VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. VEXAS is an acquired, adult-onset autoinflammatory syndrome which is progressive and frequently fatal. First reported in October 2020 by Beck et al, it results from somatic mutations at methionine-41 (p.Met41) of UBA1 gene, the major E1 enzyme that initiates ubiquitylation. Clinical features of VEXAS include periodic fevers, neutrophilic dermatoses, pulmonary infiltrates, chondritis and venous thromboembolic events. Bone marrow biopsy (BMB) shows vacuoles in myeloid precursor cells, and these cause hematologic abnormalities like myelodysplastic syndrome, multiple myeloma, or monoclonal gammopathy of unknown significance.
Methods
Clinical details were collected retrospectively. UBA1 sequencing: UBA1 exon 3 (NM_153280) was amplified from using High-Fidelity Phusion Polymerase (Life Tech) and primers UBA1-3F and UBA1-3R. PCR products were sequenced using the BigDye v3.1 terminator sequencing kit on an ABI3130xl (Life Tech). Electropherograms were analysed using 4Peaks software.
Results
A previously fit 63-year-old gentleman presented with a three-month history of recurrent fevers, night sweats and intermittent cough. At presentation he also had left testicular pain. Bloods showed neutropenia (1.9x10^9/L), normocytic anaemia (128g/L) and raised CRP (98mg/L). However, his symptoms progressed with headaches, myalgia, conjunctivitis, nasal chondritis and sinusitis. His CRP rose to 149mg/L and ferritin was 886ng/mL. He had a negative PET scan, autoimmune screen, myeloma screen and normal levels of complement, CK and ACE. Furthermore, multiple blood cultures and infectious disease screening tests were negative. He subsequently developed a left auricular chondritis. Within a week of commencing prednisolone 40mg and methotrexate 15mg his symptoms improved by 80% and his CRP was 10mg/L. At 15mg of prednisolone his CRP rose (134mg/L) and his fevers, night sweats and arthralgia returned. His prednisolone was then increased to 20mg. Over the next nine months his disease progressed despite prednisolone and methotrexate. He developed worsening cytopenias (Hb86/L, plts105x109/L, MCV117fL), bilateral sclerouveitis, inflammatory joint pains, vasculitic rash, chest pain and dyspnoea on exertion. CTPA and HRCT showed no significant abnormalities. VEXAS syndrome was diagnosed after BMB testing identified the UBA1 mutation c.122T>c, p.Met41Thr. His treatment now encompasses prednisolone and Tocilizumab. His cytopenias are transfusion dependent, he has been under review to consider BMT although is currently stable clinically.
Conclusion
VEXAS syndrome should be considered in men over 50 with treatment-refractory giant cell arteritis, RP, polyarteritis nodosa and Sweet’s syndrome. VEXAS has a significant mortality and developing effective treatments is a priority. Given there is an available confirmatory test early recognition and subsequent testing for the UBA1 mutation will help physicians to identify appropriate treatment options and avoid unnecessary investigations.
Disclosure
S. Sajawal: None. M. Green: None. S. Savic: Consultancies; Novartis, SOBI, TAKEDA. Member of speakers’ bureau; Novartis, SOBI. Grants/research support; SOBI.
