P020 Clinical characteristics, disease trajectories and management of Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome: a systematic review
Authors: Kouranloo Koushan , Dey Mrinalini , Almutawa Jude , Myall Nikki , Nune Arvind 
Published: April 2024

Background/Aims

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is an autoinflammatory condition, characterised by somatic mutation of UBA1 gene. To date, no systematic literature review (SLR) has been undertaken to summarise the clinical manifestations, genotypes and treatment of VEXAS. We undertook a SLR to evaluate the multisystem characteristics and genotypes associated with VEXAS syndrome.

Methods

Articles discussing VEXAS syndrome, published 1946 until May 2023, were included. The protocol was registered in the PROSPERO database of systematic reviews (CRD42023407547). Medline, Embase and Cochrane Databases were searched.

The research questions were: 1) What are the clinical characteristics of patients diagnosed with VEXAS? 2) What are the genotypes associated with VEXAS? 3) What are the effective treatments for VEXAS?

Articles meeting inclusion criteria were examined by two authors at abstract and full paper stage. Information was extracted on: demographics, type and prevalence of clinical manifestations, genetic mutations, and treatment. Meta-analysis using a random effects model was used to determine pooled estimates of serum markers.

Results

From 214 articles, 64 were included, comprising 273 patients with VEXAS. 96.3% were male, with a mean age of 67.2 years (SD 6.8) at disease onset. Study cohorts were from: Europe (n = 25); North America (n = 18); South America (n = 1); Asia (n = 16); Australasia (n = 4).

The most frequent diagnoses made prior to VEXAS were: relapsing polychondritis (n = 48); Sweet’s syndrome (n = 24); polyarteritis nodosa (n = 11); myelodysplastic syndrome (n = 10). Fever was reported in 195 cases (71.4%) and weight loss in 69 (25.3%). Most patients had pulmonary (n = 231; 84.6%), haematological (n = 228; 83.5%) dermatological (n = 217; 79.5%) and musculoskeletal (n = 138; 50.5%) involvement, although other organ manifestations of varying prevalence were also recorded.

Pooled estimates of serological investigations were: ESR 101.3 mm/hr (SE 4.8; n = 246); CRP 144.2 mg/L (SE 14.1; n = 258); Hb 91.0 g/L (SE 3.2; n = 265); MCV 107.3 fL (SE 2.3; n = 265).

The most commonly reported mutations were “c.122T&gt;C pMET41Thr” (n = 71), “c.121A&gt;G pMET41Val” (n = 35) and “c.121A&gt;C pMet41Leu” (n = 33).

Most patients received glucocorticoids (n = 133, 48.7%) followed by methotrexate (n = 55, 20.1%) and IL-6 inhibitors (n = 47, 17.2%). One patient underwent splenectomy; six received bone marrow transplants.

Regarding mortality, 44 patients were reported to have died due to manifestations of VEXAS syndrome.

Conclusion

This is the first SLR to capture clinical manifestations, genetics and treatment of cases of VEXAS reported to date. Diagnosis remains clinically challenging, as evidenced by the multiple prior diagnoses ascribed to patients, most commonly relapsing polychondritis and Sweet’s syndrome. Most patients present with haematological disorders, fever, pulmonary and dermatological involvement. Reported mortality was consistent with genetic variants strongly associated with reduced survival rates. Genetics and treatment of VEXAS continue to be an active area of research. Future studies are needed to better understand these as well as optimize treatment for people with this rare condition.

Disclosure

K. Kouranloo: None. M. Dey: None. J. Almutawa: None. N. Myall: None. A. Nune: None.