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Introduction to VEXAS syndrome: biology

 

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently discovered autoinflammatory disorder caused by somatic mutations in the UBA1 gene, which encodes the ubiquitin-activating enzyme E1. First described in 2020, VEXAS syndrome predominantly affects older males and is characterized by systemic inflammation, hematological abnormalities, and overlapping features with autoimmune and hematological disorders such as myelodysplastic syndromes (MDS).1,2

Patients with VEXAS syndrome often present with symptoms such as fever, skin lesions, pulmonary infiltrates, and arthritis. Hematological manifestations include cytopenias, bone marrow vacuolization of myeloid precursors, and dysplasia, making it clinically challenging to distinguish from MDS.3 This overlap highlights the need for a deeper understanding of the shared and distinct biological mechanisms underlying these conditions.

Both VEXAS syndrome and MDS involve dysregulated hematopoiesis, but their etiologies differ significantly. In VEXAS syndrome, somatic mutations in UBA1 lead to impaired ubiquitination pathways, resulting in aberrant protein degradation and chronic inflammation.4 In contrast, MDS is a clonal hematopoietic stem cell disorder characterized by ineffective hematopoiesis and a predisposition to acute myeloid leukemia (AML).5

 

While MDS is driven by a variety of genetic mutations, the presence of UBA1 mutations has been identified in a small percentage of patients with MDS, suggesting potential overlap between the two.6 However, not all MDS patients with UBA1 mutations meet the clinical criteria for VEXAS syndrome, underscoring the complexity of these diseases’ interplay.

We recently caught up with Carmelo Gurnari, MD, University of Rome Tor Vergata, Rome, Italy, and Cleveland Clinic, Cleveland, OH, who shared insights into the biology of VEXAS syndrome.

 

Challenges with diagnosing VEXAS syndrome

 

 

Diagnosing VEXAS syndrome remains challenging due to its heterogeneous presentation. A high index of suspicion is required, and a definitive diagnosis relies on identifying somatic mutations through sequencing of the UBA1 gene using peripheral blood leukocytes or bone marrow tissue.7,8 Distinguishing VEXAS syndrome from MDS is further complicated by shared features such as dysplasia and cytopenias. Clinicians must carefully evaluate clinical, laboratory, and histopathological findings to differentiate between the two conditions. Dr Gurnari further discusses the challenges in diagnosing VEXAS syndrome.

Current treatment approaches for VEXAS syndrome

 

VEXAS syndrome remains a challenging disease to treat, with no currently established treatment guidelines.2 Management of VEXAS syndrome focuses on controlling inflammation and addressing hematological complications. Corticosteroids are often used to suppress systemic inflammation; however, long-term use is limited by significant side effects and the potential for steroid dependence.9

For patients with severe cytopenias or refractory disease, allogeneic stem cell transplantation (alloSCT) remains the only curative approach for VEXAS. However, alloSCT carries substantial risks, including infections and graft-versus-host disease (GvHD).9

In addition to corticosteroids and alloSCT, the hypomethylating agent azacitidine has been investigated for VEXAS syndrome due to its ability to modulate cytokine profiles and downregulate proinflammatory cytokines.10 Other agents that have been explored include JAK inhibitors, interleukin-6 (IL-6) inhibitors, and tumor necrosis factor-alpha (TNF-α) inhibitors.9

 

These emerging therapeutic strategies reflect a growing understanding of VEXAS pathophysiology and offer hope for more targeted and effective management approaches in the near future. Hear more from Dr Gurnari on the role of alloSCT in VEXAS syndrome below:

VEXAS syndrome represents a unique intersection of autoinflammation and hematological dysfunction, with notable similarities to MDS. Diagnosing and managing VEXAS syndrome remain challenging due to its heterogeneity and overlap with other disorders. While current treatment strategies primarily focus on controlling inflammatory symptoms, ongoing research is beginning to shed light on the shared and distinct mechanisms underlying VEXAS syndrome and MDS, providing hope for the development of targeted therapies.

References

  1. Ferrada MA, Sikora KA, Luo Y, et al. Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS. Arthritis & Rheumatology. 2021 Oct;73(10):1886-1895.
  2. Kobak S. VEXAS syndrome: Current clinical, diagnostic and treatment approaches. Intractable & Rare Disease Research. 2023 Aug;12(3):170-179.
  3. Koster MJ, Lasho TL, Olteanu H, et al. VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management. American Journal of Hematology. 2024 Feb;99(2):284-299.
  4. Wu Z, Gao S, Gao Q, et al. Early activation of inflammatory pathways in UBA1-mutated hematopoietic stem and progenitor cells in VEXAS. Cell Reports Medicine. 2023 Aug 15;4(8):101160.
  5. Sperling AS, Gibson CJ, Ebert BL. The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nature Reviews Cancer. 2017 Jan;17(1):5-19.
  6. Sirenko M, Bernard E, Creignou M, et al. UBA1 Mutations Identify a Rare but Distinct Subtype of Myelodysplastic Syndromes. Blood. 2023; 142 (Supplement 1): 1862.
  7. Templé M, Kosmider O. VEXAS Syndrome: A Novelty in MDS Landscape. Diagnostics (Basel). 2022 Jun 29;12(7):1590.
  8. Kreutzinger V, Pankow A, Boyadzhieva Z, et al. VEXAS and Myelodysplastic Syndrome: An Interdisciplinary Challenge. Journal of Clinical Medicine. 2024 Feb 12;13(4):1049.
  9. Alqatari S, Alqunais AA, Alali SM, et al. VEXAS Syndrome: A Comprehensive Review of Current Therapeutic Strategies and Emerging Treatments. Journal of Clinical Medicine. 2024 Nov 19;13(22):6970.
  10. Sockel K, Götze K, Ganster C, et al. VEXAS syndrome: complete molecular remission after hypomethylating therapy. Annals of Hematology. 2024 Mar;103(3):993-997.
Written by Anya Dragojlovic Kerkache
Reviewed by Solyana Yohannes
Publishing date: 06/05/2025

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