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POS0363 CHALLENGES IN RECOGNIZING VEXAS SYNDROME: DELAYED DIAGNOSIS, MISDIAGNOSIS, AND SPECIFIC GENE MUTATIONS ASSOCIATIONS

2024; BMJ; Linguagem: Inglês

10.1136/annrheumdis-2024-eular.3990

1468-2060

Paloma García, Marta Gómez, M. Maraver, Alexis Dorta, B. P. Magallares López, F. J. Toyos Sáenz de Miera, D. Dios Santos, Íñigo Rúa‐Figueroa, J. A. Hernandez Beriain, Beatriz Frade‐Sosa, Paloma Vela, María Dolores Ibáñez, Josep Font, Elena Riera Alonso, E P Trallero, Meritxell Sallés, C. Merino Argumánez, I. Monjo-Henry, I. Vázquez-Gómez, C. Sieiro Santos, E. Diez Alvarez, M. Rodríguez Laguna, Eleuterio Merayo, J. A. Miranda Fillloy, R. González, C. García Belando, G. Boselli Oporto, Juan Otaño, A. V. Orenes Vera, C. De Miguel Sánchez, Z. Ortiz de Zárate Caballero, Jaime Calvo Alén,

Ubiquitin and proteasome pathways

Background: VEXAS syndrome is characterized by heterogeneous rheumatologic and hematologic manifestations driven by somatic UBA1 gene mutations. It, however, requires a more precise clinical definition. Objectives: This study aims to highlight some issues in the diagnosis process of this entity. Methods: A nationwide survey across 126 rheumatologic units within Spanish public hospitals identified 38 VP based on clinical compatibility, characteristic bone marrow biopsy (BMB) findings, and/or confirmed UBA1 gene mutations. Demographic, clinical, laboratory, and outcome data were retrospectively collected from medical records in a standardized form. Results: Thirty-eight VP were identified. Mean age at onset of symptoms was 67.67 (±SD 10.18/range 40-92) years of age, while mean age at final diagnostic was 73.18 (±SD 9.08/range 46.5-93) years of age. Median diagnostic delay was 5.51 (±SD 5.06) years and median time from first symptom appearance to Rheumatology referral was 35.19 (±SD 34.55) months. Alternative diagnoses prior to final identification of VEXAS syndrome are summarized in Table 1. Thirty-two (84.21%) patients underwent bone marrow biopsy; presence of at least 1 cytoplasmic vacuole was described in 30 cases. Genetic tests were performed in 34 (89.47) patients. Within our cohort, among the three primary causative variants, 13 patients exhibited a M41L mutation, 12 patients had a M41T mutation, and 5 patients presented a M41V mutation. One patient presented a new variation affecting c.209T>A, causing a leucine to histidine change; this alteration has not been previously described in other studies to our knowledge at the time of this publication. Finally, data regarding specific mutation was missed in 3 cases. The M41L mutation was preferentially associated with a phenotype more limited to the skin and joints, while the threonine one showed a broader repertoire of clinical manifestations. Valine mutation was also linked with fever and skin lesions. However, most of these associations were numerical rather than statistically significant due to sample size limitations (Table 2). Finally, 5 (13.16%) patients died due to VEXAS syndrome (n= 2 M41T, n=2 M41L, n=1 M41V mutations). Conclusion: VEXAS syndrome presents a significant delay probably due to frequent misdiagnosis with other multisystemic entities. Type of mutation may influence in the clinical picture of the syndrome with leucine mutation more associated with cutaneous and articular involvement, threonine mutation with chondritis and a multi-organ clinical picture, and valine mutation mainly with fever and skin lesions. These associations need further clarification through larger cohorts, which should also investigate the role of the new mutation (c.209T >A: p.L70H) identified in this particular cohort. REFERENCES: [1] Beck DB, Ferrada MA, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med. 2020 Dec 31;383(27):2628-2638. doi: 10.1056/NEJMoa2026834. Epub 2020 Oct 27. PMID: 33108101; PMCID: PMC7847551. Acknowledgements: NIL. Disclosure of Interests: None declared.