VEXAS syndrome

Patients with VEXAS syndrome usually have a hypercellular bone marrow with a high M:E ratio (>1:4). At least 5 equally sized vacuoles in granulocytic and erythroid progenitor cells are considered specific signs of VEXAS syndrome (Lacombe et al. 2021, Olteanu et al. 2024), but vacuoles in hematopoietic cells are also observed in e.g. copper deficiency, AML or MDS. Granulocytic hyperplasia with left shift and toxic changes, erythroid hypoplasia with left shift and megakaryocytic hyperplasia with a spectrum of atypical megakaryocytes are typical bone marrow findings. Dysplasia reaching the 10% level is rare, but multinucleation in proerythroblasts (50% of patients) and megakaryocytes with condensed eosinophilic cytoplasm (79%) can be frequently observed. The peripheral blood also shows a left shift leading predominantly to the myelocyte stage of maturation, accompanied by dysgranulopoiesis (Olteanu et al. 2024). It should be noted that in addition to VEXAS syndrome, myeloid and lymphoid neoplasms are also frequently observed (Beck et al. 2020, Obiorah et al. 2021, Beck et al. 2022, Djerbi et al. 2023, Gutierrez-Rodrigues et al. 2023).

Immunophenotyping can also detect the presence of vacuoles, as the SSC reflects the complexity of cells including vacuoles. Thus, VEXAS patients show an increased SSC ratio in neutrophil, monocyte and erythroid progenitor cells in the bone marrow compared to patients without VEXAS syndrome (Ding et al. 2023). Loss of B-cell progenitors (<1% of lymphocytes, 91% of patients) and an inverted CD4:CD8 ratio (73%) are also typical findings, and aberrant CD56 expression in monocytes can also be observed (Obiorah et al. 2021). In addition, VEXAS patients show a reduction in non-classical CD14^loCD16⁺ monocytes and intermediate CD14⁺CD16⁺ monocytes in the peripheral blood (Beck et al. 2020) and the monocytes present show increased dysfunctional immunophenotypes compared to non-VEXAS patients (HLA-DR^lo, CD38⁺, PD-L1^hi)(Kosmider et al. 2024). It should be noted that in addition to VEXAS syndrome, myeloid and lymphoid neoplasms are also frequently observed (Beck et al. 2020, Obiorah et al. 2021, Beck et al. 2022, Djerbi et al. 2023, Gutierrez-Rodrigues et al. 2023).

Patients with VEXAS syndrome have a predisposition to MDS. MDS occurs in 25-55% of patients with VEXAS syndrome, usually shows a normal karyotype and is often classified in the low-risk group according to IPSS-R. If cytopenia is present, chromosome analysis should therefore be sought, possibly supplemented by FISH, to check for the presence of chromosomal aberrations typical of MDS.

VEXAS syndrome is characterized by the presence of somatic UBA1 mutations. UBA1 is an X-linked gene that codes for the E1-activating enzyme. It is required for ubiquitylation. Multiple genetic mutations in proteins involved in ubiquitylation have been described as the cause of monogenic pediatric autoinflammatory syndromes (Beck et al. 2022). In the first description of VEXAS syndrome by Beck et al., three causative variants were identified that altered the start codon (M41) in exon 3 of the UBA1 gene (M41T, M41L, M41V) (Beck et al. 2020). The VAF is often very high in late stages, but a VAF <2% can also be associated with symptoms (Maeda et al. 2023). Therefore, methods with high sensitivity may be required for early diagnosis.

In VEXAS patients, genetic mutations have also been identified at positions other than M41 (Poulter et al. 2021, Faurel et al. 2023, Sakuma et al. 2023), most frequently at position S56, which is also located in exon 3. Patients with S56 variants may have more severe hematologic symptoms and may be co-diagnosed with non-MDS entities, such as CMML (Gurnari et al. 2022, Al-Hakim et al. 2023). Although the functional and clinical significance of variants outside exon 3 has not yet been sufficiently clarified, sequencing of the entire coding region is recommended, especially if an atypical presentation of VEXAS syndrome is observed or if M41 is negative with a strong clinical suspicion of VEXAS syndrome (Sakuma et al. 2023).

The specific mutation p.Met41Val has been shown to be a negative prognostic biomarker for VEXAS syndrome. Patients with this mutation tend to produce less UBA1b protein, and the severity of VEXAS syndrome correlates negatively with the residual amount of this protein isoform (Ferrada et al. 2022).

Other mutations in VEXAS syndrome are more similar to mutations in inflammatory diseases than to those in myeloid neoplasms. DNMT3A and TET2 are among the most frequently mutated genes in VEXAS syndrome (Gutierrez-Rodrigues et al. 2023, Malcovati 2023).