Health-related quality of life and symptom burden of patients with vexas: Real-world data from a multicenter observational study

Abstract

Abstract Background VEXAS is a recently discovered rare disease with a broad spectrum of clinical manifestations. Particularly, the disease is associated with a diagnosis of myelodysplastic syndrome/neoplasm (MDS) in up to 30-60% of cases. To date, no guidelines exist for its clinical management nor any treatment has in-label indication for VEXAS. Furthermore, health-related quality of life (HRQoL) data are lacking, thereby hampering our understanding of the real burden of the disease from the patients' perspective. To gain more insight into this, we devised a nationwide study to investigate HRQoL profile of patients with VEXAS, and compare it to matched control patients with MDS. Secondary objectives were to explore HRQoL patterns in VEXAS patients receiving active treatment (yes/no) and to describe symptom prevalence from the patients' perspective. Methods This was a multicenter, cross-sectional observational study conducted by the GIMEMA. Adult patients were eligible for inclusion if they had a confirmed diagnosis of VEXAS, defined by the presence of a pathogenic mutation in the UBA1 gene and a typical clinical picture. Participants completed a battery of validated patient-reported outcome (PRO) measures, including the EORTC QLQ-C30 and an item list from the EORTC Item Library to capture frequently described VEXAS-specific symptoms, such as muscle pain, joint pain, skin problems, hearing problems, and cough. To enable a robust comparison with patients diagnosed with MDS, propensity score matching was conducted using the nearest neighbor method at a 2:1 ratio with a caliper of 0.2. The matching was based on real-world individual baseline data from a previously conducted observational study including 927 newly diagnosed MDS patients. Matching was based on sex, age, and comorbidity. Adjusted mean differences were determined using multiple regression, with the following key HRQoL confounders as covariates: sex, age, comorbidity, and living arrangement. Established criteria guided the determination of the clinical relevance of differences. Group differences were considered statistically significant at an alpha level of 0.05. Patient-reported symptom prevalence was calculated as the proportion of patients reporting the symptom (with any level of concern). Results Overall, 59 patients diagnosed with VEXAS were enrolled from November 2024 to June 2025 across 15 study centers in Italy. Except for one female patient, all patients were male with a median time since diagnosis of 11.7 months (IQR 4.5-25.3). The median age was 74 years (IQR 68.0-77.5) and 54% of patients had also a concomitant MDS. At the time of evaluation, 78% patients were receiving treatment for VEXAS, either as monotherapy or combined with other treatments: steroids (93.5%), biologic Disease-Modifying Anti-Rheumatic Drugs (bDMARDs) (21.7%), and ruxolitinib (19.6%). Compared to patients with MDS, patients with VEXAS reported statistically significant and clinically meaningful worse outcomes in key functional and symptom domains. Patients with VEXAS reported worse physical functioning (Δ=-13.95, CI=-21.25;-6.65,p=<0.001), role functioning (Δ=-10.97,CI=-20.73;-1.22, p=0.028), social functioning (Δ=-10.28,CI=-18.21;-2.35,p=0.011), and higher severity of fatigue (Δ=10.25,CI=2.74;17.75,p=0.008), and pain (Δ=8.85,CI=2.10;15.61,p=0.011). Remarkably, when comparing actively treated patients with VEXAS to those not yet receiving treatment, no significant differences were observed across functional and symptom aspects. According to the EORTC QLQ-C30, the most prevalent general cancer symptoms reported were fatigue (86.4%), dyspnea (64.4%), and pain (62.7%). A distinct VEXAS-specific symptom burden was observed, with a high proportion of patients reporting muscle pain (66.1%), joint pain (62.7%), and skin problems (64.4%). Other commonly reported symptoms included hearing problems (47.5%), swelling of body parts (44.1%), and cough (42.4%). Conclusion: This is the first evidence-based data suggesting that the HRQoL profile of patients with VEXAS is worse than that of their pair-matched peers with MDS. Our results show a high symptom burden of the disease and substantial impairments across several key functional aspects. Current findings lay the groundwork for more targeted supportive care interventions and for the design of future patient-centric trials for patients with this rare condition.