Transfusion dependence, valine gene variant increases mortality risk in VEXAS disease
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Patients with VEXAS syndrome who were blood transfusion dependent or had a variant of the valine gene exhibited a threefold increased risk for mortality, according to data presented at ACR Convergence 2021.
“Patients with VEXAS are older males, mainly males because this is X-linked, and they have an overlap between inflammatory features and hematologic features,” researcher Marcela A. Ferrada, MD, a Lawrence Shulman Scholar at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), said during a press conference. “This is due to somatic mutations in the UBA1 gene and stem cells in the bone marrow. There are three particular mutations that are the most common in this disease: valine, leucine and threonine variants.”
She added that “in terms of clinical features of patients with VEXAS, these patients have a lot of clinical rheumatologic diagnosis, but I wanted to highlight that the most common clinical diagnosis these patients had was relapsing polychondritis.”
To evaluate median survival and predictors of mortality in VEXAS – vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic – syndrome, Ferrada and colleagues examined patients with genetically confirmed VEXAS (n=73) based on disease-associated variants in the UBA1 gene.
All included patients were male, white and ranged in age from 40 years to 85 years, with a median age at disease onset of 66 years; additionally, all patients had been treated with glucocorticoids.
The researchers used Kaplan-Meier to assess median survival rates, and the log rank test to determine difference in survival compared by genotype. Ferrada and colleagues also used Cox proportional hazard regression to identify associations between the patients’ clinical features, including age at disease onset, thromboembolic disease and pulmonary infiltrates, as well as transfusion dependence, genotype and mortality. Additionally, in vitro expression systems were applied to examine associations between genetic variants and UBA1b isoform expression.
According to study results, overall mortality was 27% among patients with VEXAS syndrome, with median survival of 10 years from symptom onset. The researchers determined that mortality was more common for patients with the valine gene variant (50%) vs. patients with leucine (18%) or threonine (22%) variants. Patients with the valine variant demonstrated a median survival of 9 years — “significantly shorter” than patients with other variants (P <0.01).
Through multivariable Cox regression, Ferrada and colleagues established two independent predictors of mortality: Patients with the valine variant exhibited a 3.84 times increased mortality risk (95% CI 1.50-9.81, P = 0.01), while patients who became transfusion dependent exhibited 3.48 times (95% CI 1.28-9.49, P < 0.005) increased risk.
“What we found was that transfusion dependence was associated with increased mortality and that having the valine mutation is also associated with increased mortality, [while] patients that have ear chondritis actually have less mortality,” Ferrada said in the press conference. “These findings are extremely important to help guide the management of these patients. As we know that the mutation is located in the stem cells in the bone marrow, we suspect that doing a bone marrow transplant in these patients is going to be curative, provided that we have the correct patients because bone marrow transplant has a lot of complications.”
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Ferrada M. Abstract 1426. Presented at: ACR Convergence 2021; November 5-9, 2021 (virtual meeting).
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