Could It be Vexas? Considering This Rare Disease Based on Hematological Findings

Introduction

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome), a recently characterized disease, is caused by somatic mutations in the UBA1 gene and usually presents with hematological anomalies, including predisposition to develop myelodysplastic syndromes (MDS). Our objective was to describe the hematological characteristics, which are currently under-reported in scientific literature, in patients with VEXAS.

Methods

This single-center retrospective cohort study included patients aged ≥18 years with VEXAS, in whom we described hematological characteristics in laboratory studies, bone marrow aspirates (BMA), and bone biopsies. Screening was conducted in patients who, between 2001 and 2024, were diagnosed with (1) Sweet syndrome, (2) relapsing polychondritis, and (3) MDS with autoinflammatory manifestations. The UBA1 mutation was identified through Sanger sequencing of exons 3, 14, and 16, leading to a diagnosis of VEXAS in affected individuals. Bone marrow aspirates and biopsies from all VEXAS patients were meticulously reviewed by two independent observers to ensure accuracy and consistency. We performed a descriptive analysis of clinical and hematological characteristics, and for comparison between patients with and without VEXAS, we used the chi-square test.

Results

Of 50 suspected cases, 13 were positive for the UBA1 mutation, with a median age of 60 years, 69.2% male. The most common UBA1 mutation was c.122T>C (p.Met41Thr, 66%). Clinically, presence of skin lesions was noted in 12 patients (92.3%), fever in 8 (61.5%), splenomegaly in 5 (38.5%), and lymphadenopathy in 3 (27.3%). All patients presented with some hematological manifestation, and 4 thrombotic events were documented.

The main hematological manifestations we observed were macrocytosis (n=10, 90.9%) with median mean corpuscular volume (MCV) of 99.9 fL (IQR; 96-108.9), anemia (n=8, 72.7%) with median hemoglobin of 10.7 g/dl (IQR; 9.3-11.75), and lymphopenia (n=6, 54.5%) with median total lymphocyte count of 810/μl (IQR; 598-1852). Seven patients (54%) met the WHO 2022 diagnostic criteria for MDS, 5 of them (62.5%) with MDS karyotype alterations, and 4 patients (57.1%) of low risk according to the IPSS- R. One case of multiple myeloma was documented.

We had BMA data from 10 patients with VEXAS. Median cellularity was 80% (range 50-100%), megakaryocytes 3/field (range; 1-7), blasts 0.5/field (range 0-6), vacuolated precursors 2.5/field (range; 0-12), and 2 vacuoles per precursor (range; 0-8). Erythroid dysplasia ≥10% was present in 6 (60%), granulocyte dysplasia ≥10% in 9 (90%); of these, hypogranularity in 8 (88.9%), presence of Pelger-Huet anomaly in 6 (66.7%), vacuoles in promyelocytes, myelocytes, and metamyelocytes in 7 (77.8%), and only in one case, mature neutrophils. Megakaryocyte dysplasia ≥10% was found in 9 (90%), characterized by hypolobulated nuclei and micromegakaryocytes. Only 4 patients had bone biopsies. All of them showed dysplasia of the three cell lines, presence of inflammatory cells, erythroid hypoplasia, and megakaryocyte hyperplasia. Granulocytic hyperplasia was found in 3 (75.0%) and fibrosis in 2 (50.0%). No blasts were found in bone biopsies.

Comparing VEXAS patients with those screened without the mutation, anemia (OR; 6.9; 95% CI 1.2-37.2) and macrocytosis (OR 12.5, 95% CI 1.3-119.3) were associated with higher likelihood of having the UBA1 mutation. The best MCV cutoff point to predict the UBA1 mutation was 97.4 fL (sensitivity 77.7%, specificity 81.5%, AUC 0.799).

Conclusions

Hematological manifestations in VEXAS are very frequent, to the extent that their presence suggests this condition in patients with autoimmune or autoinflammatory conditions. The high frequency of dysplasia, even in patients without MDS, is notable. This suggests that these patients may develop clonal dysplasia of uncertain significance, a premalignant entity that can evolve into MDS. Therefore, UBA1 could be a driver mutation in myeloid neoplasms and might even be considered for inclusion in the myeloid panel.

Apodaca Chavez:AbbVie: Speakers Bureau; Bristol: Speakers Bureau; Novartis: Speakers Bureau; Astrazeneca: Speakers Bureau.