Further characterization of clinical and laboratory features in VEXAS syndrome: large‐scale analysis of a multicentre case series of 116 French patients*

TLDR

A recently identified autoinflammatory disorder caused by somatic UBA1 mutations, termed VEXAS syndrome, presents with a broad spectrum of organ involvement and variable prognostic profiles. The study aimed to delineate the clinical, laboratory, and outcome characteristics of VEXAS and to evaluate the prognostic impact of specific UBA1 mutations. Among 116 French patients, skin lesions (83 %), fever (64 %), weight loss (62 %), and lung involvement (50 %) were most common, 50 % had hematologic disease (primarily MDS), and a 15.5 % mortality rate was observed over a median 3‑year follow‑up; unsupervised clustering revealed three phenotypic groups with 5‑year survival rates of 84 %, 51 %, and 90 % respectively, and the p.Met41Leu mutation was associated with a more favorable prognosis.

Abstract

A new autoinflammatory syndrome related to somatic mutations of UBA1 was recently described and called VEXAS syndrome ('Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic syndrome').To describe clinical characteristics, laboratory findings and outcomes of VEXAS syndrome.One hundred and sixteen patients with VEXAS syndrome were referred to a French multicentre registry between November 2020 and May 2021. The frequency and median of parameters and vital status, from diagnosis to the end of the follow-up, were recorded.The main clinical features of VEXAS syndrome were found to be skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung involvement (50%), ocular symptoms (39%), relapsing chondritis (36%), venous thrombosis (35%), lymph nodes (34%) and arthralgia (27%). Haematological disease was present in 58 cases (50%): myelodysplastic syndrome (MDS; n = 58) and monoclonal gammopathy of unknown significance (n = 12; all patients with MGUS also have a MDS). UBA1 mutations included p.M41T (45%), p.M41V (30%), p.M41L (18%) and splice mutations (7%). After a median follow-up of 3 years, 18 patients died (15·5%; nine of infection and three due to MDS progression). Unsupervised analysis identified three clusters: cluster 1 (47%; mild-to-moderate disease); cluster 2 (16%; underlying MDS and higher mortality rates); and cluster 3 (37%; constitutional manifestations, higher C-reactive protein levels and less frequent chondritis). The 5-year probability of survival was 84·2% in cluster 1, 50·5% in cluster 2 and 89·6% in cluster 3. The UBA1 p.Met41Leu mutation was associated with a better prognosis.VEXAS syndrome has a large spectrum of organ manifestations and shows different clinical and prognostic profiles. It also raises a potential impact of the identified UBA1 mutation.