Vexas syndrome in Germany: Insights from a prospective registry on clinical presentation, management and outcomes

Abstract

Abstract Background VEXAS syndrome (vacuoles, E1 enzyme, x-linked, autoinflammatory, somatic) is an acquired hematoinflammatory disorder caused by somatic UBA1 mutations. Since its identification in 2020, treatment has remained largely empirical lacking standardized guidelines. The German VEXAS Registry was established to prospectively collect clinical, therapeutic and outcome data in a national real-world cohort. This report provides initial cohort characterization and outlines current treatment practices in Germany. Methods The German VEXAS Registry was initiated in May 2024. Centers provide standardized data on patient characteristics, treatment, response, complications, and patient-reported outcomes (PRO) at set intervals. Retrospective inclusion is allowed if data are sufficient. Therapeutic response is assessed longitudinally per investigator judgment, including both clinical (major: full control of inflammatory symptoms and daily steroid dose <10 mg; minor: symptom improvement not meeting criteria for major response) and hematologic response (per hematologic disease, e.g., IWG 2023 criteria for myelodysplastic neoplasm [MDS]). By July 2025, 81 pts were enrolled from 12 German centers, both hematologic and rheumatologic. Median follow-up from diagnosis was 17 (range 1–75) months (mo). Results All but one pt were male; median age at diagnosis was 70 (range: 54–91) years. UBA1 mutations predominantly affected codon 41 (75%); others included splice-site and exon 15 variants. Additional mutations were found in 49%, mainly in MDS-associated genes (e.g., DNMT3A, TET2, ASXL1, SRSF2). Cytogenetics were normal in 80%; aberrations included -Y and single cases of +8, del(9q), del(20q), -X (female pt), and complex karyotype. Most frequent inflammatory symptoms were fever (47%), skin lesions (68%), arthritis/arthralgia (70%), polychondritis (32%) and ocular inflammation (30%). Hematologic findings included MDS diagnosed in 66% (82% MDS with low blasts); others had isolated cytopenia or monoclonal gammopathy of undetermined significance. General symptoms, e.g. fatigue (44%), night sweats (31%), and weight loss (46.5%) were also common. As previously reported, clinical manifestations differed by UBA1 mutation type, with p.41Val variants tending to show more fever and pulmonary involvement, splice site mutations presenting with fewer inflammatory and predominant hematologic features, and significantly more cutaneous inflammation observed in p.41Leu pts (p = .007). Median time from first symptoms to diagnosis was 9 mo, with retrospective confirmation up to 10 years after symptom onset. PRO indicated substantial impairment, with 48% reporting moderate to severe limitations on EQ-5D and a median EQ-VAS score of 60. Steroid-sparing therapies included azacytidine (AZA), JAK inhibitors, conventional immunomodulators and cytokine blockers (TNFα, IL-1, IL-6). AZA was used in 34% of pts, all with low-risk MDS; 72% of those treated ≥3 mo showed partial or complete clinical and hematologic responses. Four pts discontinued AZA in remission; one relapsed after 23 mo and resumed therapy. JAK inhibitors (ruxolitinib, upadacitinib, tofacitinib, baricitinib) were given in 27%; 53% were switched due to lack of efficacy after a median duration of 4 mo. Sustained responses ≥3 mo occurred in 21%, all on ruxolitinib. Immunomodulators and/or cytokine blockers were used in 36% (median 2 agents, range 1–4); 40% had at least a minor clinical response, most commonly with methotrexate or anti-IL-1 agents, although all anti-IL-1 treatments were eventually discontinued due to intolerance. Three pts underwent allogeneic hematopoietic stem cell transplantation for refractory autoinflammation after 3–7 prior therapies (immunomodulators, cytokine blockers and JAK inhibitors); all achieved clinical remission by day +100 post-transplant. To date, four deaths have been reported during follow-up, mostly due to severe infections. Conclusion This early analysis of the German VEXAS Registry provides detailed real-world insights into the clinical spectrum and treatment patterns of VEXAS syndrome in a national cohort. Our data confirm the considerable heterogeneity of both disease manifestations and therapeutic responses, highlighting the need to strengthen interdisciplinary collaboration and improve treatment standards. Even though a proportion of patients had a disease onset even before VEXAS was described, time to diagnosis underscores the importance of raising disease awareness.