Background/Purpose: VEXAS is a multisystem autoinflammatory disorder due to somatic mutations in UBA1. The disease is characterized by ineffective hematopoiesis with increased risk of transfusion dependence, infections, and early mortality. Cytoplasmic deficiency of UBA1b is variable between the canonical variants that define VEXAS, either severe (p.M41V or c.118-1) or partial (p.M41T/L). Our goal was to identify variance in transplant free survival, hematologic, and inflammatory parameters in patients with canonical UBA1 mutations.

Methods: Retrospective review of consecutively evaluated VEXAS patients with canonical variants (n = 74) complete blood counts, acute phase reactants, and daily glucocorticoid dose along with prospective clinical data from onsite visits were aggregated. Generalized additive mixture models were used to estimate means and confidence intervals of each parameter as function of time by patient random slopes with each group (severe vs. partial) reported as population average of each time point. Time to death or hematopoietic stem cell transplant (HSCT) was assessed in the overall population and by variant status using a Cox-proportional hazard model, adjusting for age at disease onset.

Results: p.M41T/L variants (72%) were more common than p.M41V or c.118-1 variants (28%) in the cohort. There were similar rates of exposure to JAK inhibitors (39.8% vs. 33.3%) and IL-6 inhibitors (69.8% vs. 57.1%) between the variant groups. Daily equivalent prednisone dose was similar between groups, and most patients received moderate to high doses of glucocorticoids for several years after symptoms onset (Figure 1). Acute phase response including, serum CRP and IL-6, was highest within the first years after symptoms onset and reduced over time in both groups.

Cytopenias (Figure 2), dysplasia, and transplant-free survival were more frequent in patients with severe UBA1b deficiency. Anemia and thrombocytopenia were more prevalent over time in patients with partial UBA1b deficiency but were observed earlier in the severe group. Monocytopenia was most pronounced in severe UBA1b deficiency. Myelodysplasia was more frequently recognized on bone marrow biopsy in patients with severe UBA1b deficiency, 38.1% vs. 11.3%, p-value < 0.01. Numerically increased hazard of HSCT or death was observed in patients with severe UBA1b deficiency adjusting for level of comorbidity, adjusted HR [95%CI] 1.98 [0.87-4.51], p-value = 0.10.

Conclusion: These findings serve as a reference standard for disease progression and glucocorticoid use in VEXAS. The degree of UBA1b deficiency explains some of the heterogeneity of bone marrow failure in VEXAS patients. Further understanding the cellular implications of varying degrees of UBA1b deficiency may enable improved hematologic disease monitoring and discovery of novel therapeutic targets.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/bone-marrow-failure-in-vexas-is-associated-with-the-degree-of-uba1b-deficiency/