Patient Reported Outcomes in Vexas Syndrome
Authors: Patel Bhavisha A. , Groarke Emma M. , Shalhoub Ruba , Rodrigues Fernanda , Fike Alice , Quinn Kaitlin , Darden Ivana , Liu Shanni , Goodspeed Wendy , Miao Rui , Wu Colin O. , Young Neal S. , Grayson Peter C 
Published: December 2024

Introduction: VEXAS, caused by somatic mutations in UBA1, is an adult-onset clonal myeloid disease which presents as autoinflammation and progressive marrow failure. Glucocorticoids are highly effective, but dependency is common. Many studies have reported the increased mortality risk in VEXAS, but data are lacking regarding patient reported outcomes (PRO) in this highly morbid disease. We aimed to study the quality of life and symptom burden in VEXAS patients seen at National Institutes of Health and correlate results with disease phenotype and outcomes.
Methods: All VEXAS patients enrolled in natural history study, NCT02257866, were offered the Medical Outcomes Survey Short Form (SF)-36 questionnaire from 2018-2024 at first and follow-up visits. SF-36v2 responses were scored and grouped to scale in 8 domains. Demographics, UBA1 genotype and mutation burden, disease phenotype, blood counts, treatment, and survival data were collected and correlated with the PRO.
Results: Forty-seven patients were included; all male, median age 66 years (range 41-86), and 96% white. Canonical UBA1 variants were confirmed in 46 patients (18 M41T, 17 M41V, 9 M41L, 2 splice acceptor) and one had Gly477Ala, a disease causing non-canonical variant. At first visit, general health (mean 32; IQR 15,50), vitality (mean 36; IQR 25, 47), physical functioning (mean 51; IQR 35, 68), and role-physical (mean 38; IQR 22-56) had the lowest average scores out of 100. In comparison, social functioning (SF - mean 56; IQR 60-76), role-emotional (RE - mean 75; IQR 50-100), bodily pain (BP - mean 59; IQR 45-80), and mental health (MH - mean 56; IQR 60,76) were less impacted.
UBA1 M41V has been associated with poorer survival, while M41L with a more indolent disease course; however, neither UBA1 genotype nor mutational burden was associated with PROs in any domain. Interestingly, younger patients had significantly more impact on their mental health than older individuals (R=0.36, p=0.013). In the absence of validated disease severity index, inflammation was graded based on number of systems involved since disease onset; 26/47 (55%) patients had 5 or less systems affected and 21/47 (45%) had &gt;5 (range 6-9). All domains that were severely impacted (general health, vitality, functioning, and role-physical) negatively correlated with higher inflammation; higher CRP also associated with decrease functionality. No associations were found with other disease phenotypes including myelodysplastic syndrome, thromboembolism, or plasma cell disorder, but expectedly, there was a trend towards worse mental health in those with red cell transfusion dependence (p=0.08). Of the other blood counts, WBC negatively correlated with vitality (R=-0.29, p=0.04), and pain (R=-0.29, p=0.05), and higher platelet counts were associated with better scores on role-physical domain (R=0.3, p=0.04).
Ninety-six percent (n=45) of patients were glucocorticoid dependent; mean prednisone dose was 20mg (range 0-50). Other adjunctive therapies included JAK inhibitors (n=7), hypomethylating agents (n=3), anti-IL-1 or IL-6 (n=12), or other biologics (n=8). No correlation was found between PROs and prednisone dose or other therapies. Twelve patients (25%) had died at median 488 days (range 1 - 2550 days) after the PRO survey. Of the 8 domains, PF was lower in those who ultimately died but did not reach significance (mean 36 vs 55; p=0.06).
Conclusion: VEXAS is a chronic and progressive disease requiring toxic therapies that result in significant physical and psychological burden on patients. Quality of life assessment focusing on general health, vitality, and physical functioning should be incorporated in future prospective clinical trial endpoints in VEXAS, as in PNH and myeloproliferative neoplasms, which are similar clonal hematologic diseases with a high symptom burden. PROs may be helpful in identifying risks and benefits of glucocorticoid sparing therapies; however, our study was limited by small sample size in assessing this.