Introduction:

• It is a adult onset auto-inflammatory syndrome characterized by presence of vacuoles in cells of bone marrow
• VEXAS stands for Vacuoles, E1 enzyme, X-Linked, autoinflammatory, somatic.

Epidemiology:

• Usually seen in adults in 5^th decade of life
• Only men are affected as women are protected by unmutated allele
• Exact number of cases are still not known due to lack of awareness about this disorder.

Etiology:

• Somatic mutations in UBA1 gene in hematopoietic progenitor cells
• UBA1 gene is X linked gene that escapes X inactivation
• As it is not a germline mutation, family members are not affected.

Pathogenesis:

Mutations in UBA1 gene located on the X chromosome (Xp.11.23) 

(Most common mutation- p.Met41Thr)

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Decreased E1 enzyme

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Defective cellular ubiquitylation (ubiquitin-proteosome system is responsible for nonlysosomal proteolysis of intracellular proteins)

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Formation of vacuoles +Increased cellular stress + stimulation of aberrant

cytokine production + activation the innate immune pathway

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Autoinflammation

Clinical features: May vary depending on mutations in UBA1 gene

• Systemic autoimmune manifestations
  • Fever
  • Sweet syndrome
  • Relapsing polychrondritis (Auricular/Nasal)
  • Polyarteritic nodosa
  • Giant cell arteritis
  • Neutrophilic alveolitis
  • Inflammatory arthritis
  • Orchitis
  • Eye involvement: Episcleritis, iritis, uveitis, orbit/peri-orbital edema
  • Interstitial nephritis
  • Pulmonary: Dyspnea, cough, HRCT-Ground-glass opacities in lung, consolidation, reticulation, pleural effusions and septal lines
• Hematological problems
  • Anemia
  • Thromboembolic disease(Venous and arterial)
  • Progressive BM failure
  • MGUS

Complications:

• Development of AML or MDS
• Development of myeloma

Investigations:

• ESR/ CRP: Elevated
• Hemogram:
  • Macrocytic anemia
  • Monocytopenia
  • Thrombocytopenia
  • Neutrophilia with shift to left and toxic granulation
  • Rarely lymphopenia and neutropenia
• Bone marrow: 
  • Hypercellular
  • Vacuoles in myeloid and erythroid progenitor cells- vacuoles are evenly sized and number at least 5 per individual cell
  • Myeloid:Erythroid >4:1
  • Multinucleated pronormoblasts
  • Megakaryocyte hyperplasia
  • Erythroid hypoplasia
• Cytogenetics: Normal in 80% cases
• Myeloid mutation panel: Additional somatic mutations are seen in 50% cases
• UBA1 gene sequencing study

Differential diagnosis: Vacuoles in erythroid and myeloid precursors are also seen in

• Copper deficiency
• AML
• Menke’s disease
• Transcobalamine II deficiency
• MDS
• Alcohol intoxication

Prognosis:

• Associated with high risk of morbidity and mortality
• Depends on mutations in UBA1 gene

Treatment: No effective treatment is available. Options include:

• High dose steroids: 
  • Risk of relapse is very high
  • May have to give a maintenance dose of Prednisolone (15 mg/day or more)
• Interleukin 6 inhibitors- Tocilizumab- 162 mg/0.9 mL subcutaneous every other week or 4 mg/kg intravenous every 4 weeks
• Azacytidine
• JAK 2 inhibitors
• HSCT: Only option of cure. Usual indications include:
  • Severe, glucocorticoid refractory, recurrent inflammatory symptoms 
  • Persistent (≥3 months) cytopenias, including the need for packed red blood cell transfusion and/or platelet transfusions
  • Coexistent myeloid malignancy (MDS-EB or AML) or clonal abnormalities predictive of myeloid transformation

Recent advances:

Allogeneic haematopoietic stem cell transplantation for VEXAS syndrome

VEXAS syndrome is caused by myeloid-restricted somatic mutations in ubiquitin-like modifier-activating enzyme 1 (UBA1), the gene that encodes E1 ubiquitin ligase. Current treatment options are limited to symptomatic control, with corticosteroids being universally effective and Janus kinase (JAK) inhibitors showing promising results. Present study describes four additional cases of VEXAS in whom HSCT was performed. Outcomes following HSCT were variable. Patient 1 died from sepsis and multiorgan failure in the early post-transplant period (day +11). Patient 2 survived the transplant with good engraftment and full donor chimerism, but recovery was complicated by haemophagocytic lymphohistiocytosis, aseptic encephalitis and Epstein–Barr Virus reactivation within 2 months of transplant, and subsequent extensive chronic graft-versus-host disease requiring systemic treatment, and recurrent bacterial infections. Patient 3 achieved disease control with no molecular evidence of VEXAS; however, developed severe post-transplant myelitis resulting in paraplegia, urinary and faecal incontinence, and passed away 11 months post-transplant from infectious complications. Patient 4 is the only one who at the time of writing (40 months post-transplant) remains alive and in good health. 

https://doi.org/10.1111/bjh.18488

Allogeneic hematopoietic cell transplantation in VEXAS syndrome

VEXAS syndrome is a late-onset X-linked inflammatory and myeloid disorder often progressing to require allo-HCT due to limited response to initial therapies. This systematic review and meta-analysis included four studies (39 patients) and found that allo-HCT achieved a 56% event-free survival (EFS) and 86% overall survival (OS) with a non-relapse mortality (NRM) rate of 14%. Rates of acute and chronic GVHD were 42% and 13%, respectively. These results highlight allo-HCT as a promising treatment for VEXAS syndrome and emphasize the need for further awareness and diagnosis of this rare condition.

https://doi.org/10.1038/s41409-024-02375-3