Ophthalmologic Manifestations of Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome

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Article initiated by:
Andrew Go Lee, MD, Blake Colman, MBBS, Eliot Smolyansky, MD, Osama Al Deyabat, MBBS, Saif Aldeen Alryalat, MD
All contributors:
Andrew Go Lee, MD, Eliot Smolyansky, MD, Osama Al Deyabat, MBBS, Saif Aldeen Alryalat, MD, Michael T Yen, MD, Blake Colman, MBBS
Assigned editor:
Shannon S. Joseph, M.D.
Review:
Assigned status Update Pending
 by Michael T Yen, MD on March 12, 2024.


Disease

Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome is a recently described inflammatory monogenic condition defined by somatic mutations in the UBA1 gene on the X chromosome. The condition was first recognized in 2020 in 25 men with late onset, treatment refractory, systemic inflammatory syndromes with hematological abnormalities.[1]

The condition largely affects middle-aged and elderly males. A wide variety of multiorgan presentations may arise yet systemic inflammation and hematologic problems are hallmark components of the disease. Fever and constitutional symptoms, chondritis, hematological abnormalities, arthritis, vasculitis, skin involvement, pulmonary infiltrates, and thrombosis are some of the manifestations that have been described.[2][3] There is a strong association with hematologic malignancies such as myelodysplastic syndrome and plasma cell dyscrasias which contribute to morbidity and mortality rates.[4] Patients typically require high dose corticosteroids to control symptoms and flares, though these are considered temporizing. Steroid sparing agents are required, however effective long-term medical therapies are not yet known.[1][4] Bone marrow transplant has been successfully pursued as a cure in some cases.[4]

Ophthalmologic presentations are diverse. Periorbital edema and recurrent ocular inflammation in the form of episcleritis, conjunctivitis, uveitis, scleritis are the most common presentations observed. Orbital mass, dacryoadenitis, orbital myositis, and optic perineuritis have also been described, alongside other rarer manifestations.

Epidemiology

VEXAS is primarily a disease of middle-aged and elderly males. Males are usually > 50 years at time of diagnosis and the vast majority of cases arise between 40-85 years of age.[4] Instances in females are much less common and occur predominantly through X chromosome monosomy.[4] The overall prevalence of VEXAS has been estimated as 1:13 591. In males and females older than 50 years, prevalence has been estimated as 1:4269 and 1:26 238, respectively.[5]

Pathophysiology

VEXAS is caused by somatic UBA1 gene mutations in hematopoietic progenitor cells. The UBA1 gene is located on the X chromosome (Xp11.23), hence, the vast majority of cases occur in males. The gene codes for a type of E1 enzyme involved in the initial activation stage of ubiquitination – the cellular process of post-translational modification by which proteins are marked for degradation in the proteasome.[1][6][7] Mutations are present in hematopoietic stem cells but are restricted to myeloid-lineage cells in peripheral blood.[1][8] Beck et al. identified 3 somatic missense mutations in UBA1 that account for around 95% of the mutations identified with VEXAS.[4] These mutations lead to 3 single amino acid (AA) substitutions in the UBA1 protein at position 41, namely, p.Met41Thr, p.Met41Val, and p.Met41Leu.[1] Two main isoforms of UBA1 protein exist – UBA1a in the nucleus, and UBA1b in the cytoplasm. The AA sequence of UBA1b begins at p.Met41.[1] Beck et al. demonstrated that p.Met41 AA substitution lead to loss of UBA1b and expression of a catalytically impaired variant, UBA1c. These cellular changes were associated with activation of the innate immune system and unfolded protein response, upregulation of cytokine gene pathways, and elevation in serum inflammatory markers.[1][4][9] Recently, further novel non-Met41 mutations were also identified within UBA1, resulting in a similar typical phenotype.[10]

Ophthalmologic manifestations

Ophthalmologic manifestations in VEXAS are common and may occur early in the disease course.[3][4][11] The predominant presentations include periorbital edema and various ocular inflammatory conditions such as conjunctivitis (with possible chemosis), uveitis, episcleritis, and scleritis (anterior, posterior, and diffuse reported).[11][12][13][14] The prevalence of these conditions vary among study and cohort groups. In the original description of VEXAS, 16% of patients were described with periorbital swelling while 28% experienced ocular inflammation (12% episcleritis, 8% uveitis, 4% scleritis, 4% iritis).[1] A larger French cohort of 116 patients, identified 8.6% patients with periorbital edema and 30.2% with uveitis, scleritis, or episcleritis.[15] In another cohort of 83 patients, 30% had periorbital edema and 24% had an ocular inflammatory presentation,[16] while two smaller cohort studies (11 and 9 patients respectively) found ocular involvement in up to  46% of individuals.[17][18] Ophthalmic manifestations are often recurrent.[11]

Periorbital oedema may be mistaken for preseptal cellulitis due to pronounced swelling, erythema and systemic signs of fever.[19] Blepharitis may also be seen,[20] while cases of recurrent dacryoadenitis have been reported.[11][13][21] One case of dacryoadenitis in which lacrimal gland was biopsied revealed only non-specific inflammation.[13] In a case of peri and intraorbital swelling and proptosis, biopsy similarly revealed reactive adipose tissue inflammation.[20]

Orbital swelling may be so marked as to cause proptosis.[11][12][20] Ophthalmoplegia[11][22] may result and swelling may require surgical decompression.[22] Cases of orbital myositis have also been reported,[11][12][21][23] as have cases of optic perineuritis.[21][24]

More rarely, a case of bilateral serous retinal detachment developing in concert with ear chondritis has been described.[25] Cases of retinal vasculitis have also been reported.[26]

Diagnosis

There are no current established diagnostic criteria for VEXAS syndrome and due to the heterogenous nature of the condition, VEXAS patients commonly meet diagnostic criteria for a number of other inflammatory and hematologic conditions.[1][2] Diagnosis is dependent on identifying pathogenic UBA1 mutation.[1][5]

One article considered diagnosis established when patients had a UBA1 mutation, characteristic clinical manifestations in 2 organ systems, and cytopenias (anemia and/or thrombocytopenia).[5] In patients with relapsing polychondritis with ear or nose chondritis, a diagnostic algorithm has been devised. It suggests genetic testing should be considered in male patients with MCV >100 fL or platelet count < 200 x 109/L and performed with 100% sensitivity and 96% specificity in identifying VEXAS.[27] Presence of vacuolation in myeloid and erythroid bone marrow precursors is another characteristic feature of VEXAS that is nearly always present.[3] A small study of patients with clinical features suspicious for VEXAS demonstrated that >1 vacuole in ≥ 10% neutrophil bone marrow precursors was associated with VEXAS diagnosis with 100% sensitivity and specificity.[28]

Koster et al. proposed an algorithm to guide clinicians in determining which patients should undergo testing for UBA1 mutations. This algorithm considers features such as male sex (or X monosomy), age, CRP, daily steroid dose, bone marrow vacuolization, and high risk presentation features amongst some of its inputs.[4] This comprehensive approach aims to facilitate more accurate and timely identification of individuals with risk of VEXAS.

Diagnostic procedures

Genetic testing for UBA1 mutations can be performed on bone marrow samples or peripheral blood.[4] In patients with an established VEXAS diagnosis with orbital symptoms, an orbital biopsy would generally not be required.

Differential diagnosis

In the setting of confirmed VEXAS, ophthalmologic manifestations should raise strong suspicion for an underlying VEXAS flare or relapse. A differential of infection is also important to consider for periobital edema and ocular inflammatory presentations. Depending on the presentation, other potential conditions such as orbital inflammatory diseases or neoplastic causes should also be considered.

Management

The mainstay of VEXAS management is immunosuppression, often consisting of steroids and steroid-sparing agents. Patients typically require chronic high-dose steroids and demonstrate intolerance to weaning.[4] Flares are managed by increasing steroid dosages; while intravenous methylprednisolone may be required for severe presentations. Various steroid-sparing agents have been used to control symptoms with varying levels of success in VEXAS. This includes DMARDs, TNF-alpha inhibitors, JAK inhibitors, anti-IL-6 and other interleukin inhibitors. The JAK inhibitor, ruxolitinib, and IL-6-inhibitor, tocilizumab, have shown benefits in controlling symptoms.[4] Azacytidine may be used in cases with prominent cytopenias or in VEXAS with myelodysplasia.[4] It is not uncommon to use multiple therapeutic lines in treatment as over 50% of patients are thought to become therapy refractory over time.[20] In one series, the median number of therapeutic agents trialed was 3.[17]

Allogeneic bone marrow transplant has also been investigated as a way to cure VEXAS with success in some cases.[29][30]

Prognosis

Median time of survival from symptoms onset is about 10 years and probability of 5-year survival is approximately 80%.[4][15][16] Development of transfusion dependence and the p.Met41Val mutation in UBA1 have been associated with worse prognosis, while p.Met41Leu[15] and history of ear chondritis confers better prognosis.[16] One study categorized patients into 3 clusters: cluster 1 (mild-moderate phenotype), cluster 2 (MDS phenotype), cluster 3 (constitutional/inflammatory phenotype).[15] Cluster 1 had 5-year probability of survival 84.2%, cluster 2 50.5%, and cluster 3 89.6%.[15]

Conclusion

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome) is caused by somatic mutations in the UBA1 gene on the X chromosome. VEXAS should be suspected in any late onset, treatment refractory, systemic inflammatory syndromes with hematological abnormalities[1] and recurrent ocular/orbital inflammation. Clinicians should consider VEXAS in males with recurrent ocular inflammation (e.g., episcleritis, conjunctivitis, uveitis, scleritis) as well as in the differential diagnosis for orbital mass, dacryoadenitis, orbital myositis, or optic perineuritis.

References

  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 Beck DB, Ferrada MA, Sikora KA, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med. 2020;383(27):2628-2638. doi:10.1056/NEJMoa2026834
  2. ↑ 2.0 2.1 Al-Hakim A, Savic S. An update on VEXAS syndrome. Expert Rev Clin Immunol. 2023;19(2):203-215. doi:10.1080/1744666X.2023.2157262
  3. ↑ 3.0 3.1 3.2 Zhang Y, Dong X, Wang H. VEXAS Syndrome-Review. Glob Med Genet. 2023;10(3):133-143. doi:10.1055/s-0043-1770958
  4. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 Koster MJ, Lasho TL, Olteanu H, et al. VEXAS syndrome: Clinical, hematologic features and a practical approach to diagnosis and management. Am J Hematol. 2024;99(2):284-299. doi:10.1002/ajh.27156
  5. ↑ 5.0 5.1 5.2 Beck DB, Bodian DL, Shah V, et al. Estimated Prevalence and Clinical Manifestations of UBA1 Variants Associated With VEXAS Syndrome in a Clinical Population. JAMA. 2023;329(4):318-324. doi:10.1001/jama.2022.24836
  6. ↑ Schulman BA, Wade Harper J. Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways. Nat Rev Mol Cell Biol. 2009;10(5):319-331. doi:10.1038/nrm2673
  7. ↑ Groen EJN, Gillingwater TH. UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration. Trends Mol Med. 2015;21(10):622-632. doi:10.1016/j.molmed.2015.08.003
  8. ↑ Poulter JA, Collins JC, Cargo C, et al. Novel somatic mutations in UBA1 as a cause of VEXAS syndrome. Blood. 2021;137(26):3676-3681. doi:10.1182/blood.2020010286
  9. ↑ Poulter JA, Savic S. Genetics of somatic auto-inflammatory disorders. Semin Hematol. 2021;58(4):212-217. doi:10.1053/j.seminhematol.2021.10.001
  10. ↑ Sakuma M, Blombery P, Meggendorfer M, et al. Novel causative variants of VEXAS in UBA1 detected through whole genome transcriptome sequencing in a large cohort of hematological malignancies. Leukemia. 2023;37(5):1080-1091. doi:10.1038/s41375-023-01857-5
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 Myint K, Patrao N, Vonica O, Vahdani K. Recurrent superior orbital fissure syndrome associated with VEXAS syndrome. J Ophthalmic Inflamm Infect. 2023;13(1):39. doi:10.1186/s12348-023-00362-1
  12. ↑ 12.0 12.1 12.2 Martín-Nares E, Vargas-Serafín C, Delgado-de la Mora J, et al. Orbital and periorbital inflammation in VEXAS syndrome. Scand J Rheumatol. 2022;51(4):338-341. doi:10.1080/03009742.2022.2045791
  13. ↑ 13.0 13.1 13.2 Beecher MB, Tong JY, Halliday LA, Hissaria P, Selva D. Recurrent orbital inflammation associated with VEXAS syndrome. Orbit Amst Neth. Published online September 27, 2022:1-4. doi:10.1080/01676830.2022.2126501
  14. ↑ Vitale A, Caggiano V, Bimonte A, et al. VEXAS syndrome: a new paradigm for adult-onset monogenic autoinflammatory diseases. Intern Emerg Med. 2023;18(3):711-722. doi:10.1007/s11739-023-03193-z
  15. ↑ 15.0 15.1 15.2 15.3 15.4 Georgin-Lavialle S, Terrier B, Guedon A f., et al. Further characterization of clinical and laboratory features in VEXAS syndrome: large-scale analysis of a multicentre case series of 116 French patients*. Br J Dermatol. 2022;186(3):564-574. doi:10.1111/bjd.20805
  16. ↑ 16.0 16.1 16.2 Ferrada MA, Savic S, Cardona DO, et al. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. Blood. 2022;140(13):1496-1506. doi:10.1182/blood.2022016985
  17. ↑ 17.0 17.1 Bourbon E, Heiblig M, Gerfaud Valentin M, et al. Therapeutic options in VEXAS syndrome: insights from a retrospective series. Blood. 2021;137(26):3682-3684. doi:10.1182/blood.2020010177
  18. ↑ Koster MJ, Kourelis T, Reichard KK, et al. Clinical Heterogeneity of the VEXAS Syndrome: A Case Series. Mayo Clin Proc. 2021;96(10):2653-2659. doi:10.1016/j.mayocp.2021.06.006
  19. ↑ Koster MJ, Warrington KJ. VEXAS within the spectrum of rheumatologic disease. Semin Hematol. 2021;58(4):218-225. doi:10.1053/j.seminhematol.2021.10.002
  20. ↑ 20.0 20.1 20.2 20.3 Made CI van der, Potjewijd J, Hoogstins A, et al. Adult-onset autoinflammation caused by somatic mutations in UBA1: A Dutch case series of patients with VEXAS. J Allergy Clin Immunol. 2022;149(1):432-439.e4. doi:10.1016/j.jaci.2021.05.014
  21. ↑ 21.0 21.1 21.2 Ang T, Tong JY, Selva D. Orbital Inflammatory Disease Due to VEXAS Syndrome: An Entity to Consider. Ophthal Plast Reconstr Surg. 2024;40(1):116-117. doi:10.1097/IOP.0000000000002570
  22. ↑ 22.0 22.1 Islam S, Cullen T, Sumpton D, et al. VEXAS syndrome: lessons learnt from an early Australian case series. Intern Med J. 2022;52(4):658-662. doi:10.1111/imj.15742
  23. ↑ Lokhande A, Jarmale S, Vaishnav YJ, Schaefer J. An Orbital Manifestation of VEXAS Syndrome. Ophthal Plast Reconstr Surg. 2023;39(6):e194-e197. doi:10.1097/IOP.0000000000002450
  24. ↑ Takahashi N, Takeichi T, Nishida T, et al. Extensive Multiple Organ Involvement in VEXAS Syndrome. Arthritis Rheumatol. 2021;73(10):1896-1897. doi:10.1002/art.41775
  25. ↑ Neupane K, Jayarangaiah A, Zhang Y, Kumar A. VEXAS syndrome with progression of MDS to MDS/MPN overlap syndrome. BMJ Case Rep. 2022;15(12):e251089. doi:10.1136/bcr-2022-251089
  26. ↑ Khitri MY, Guedon AF, Georgin-Lavialle S, et al. Comparison between idiopathic and VEXAS-relapsing polychondritis: analysis of a French case series of 95 patients. RMD Open. 2022;8(2):e002255. doi:10.1136/rmdopen-2022-002255
  27. ↑ Ferrada MA, Sikora KA, Luo Y, et al. Somatic Mutations in UBA1 Define a Distinct Subset of Relapsing Polychondritis Patients With VEXAS. Arthritis Rheumatol. 2021;73(10):1886-1895. doi:10.1002/art.41743
  28. ↑ Lacombe V, Prevost M, Bouvier A, et al. Vacuoles in neutrophil precursors in VEXAS syndrome: diagnostic performances and threshold. Br J Haematol. 2021;195(2):286-289. doi:10.1111/bjh.17679
  29. ↑ Mangaonkar AA, Langer KJ, Lasho TL, et al. Reduced intensity conditioning allogeneic hematopoietic stem cell transplantation in VEXAS syndrome: Data from a prospective series of patients. Am J Hematol. 2023;98(2):E28-E31. doi:10.1002/ajh.26786
  30. ↑ Gurnari C, Koster L, Baaij LGA, et al. Allogeneic Hematopoietic Cell Transplantation for VEXAS Syndrome: Results of a Multicenter Study of the EBMT. Blood Adv. Published online February 8, 2024:bloodadvances.2023012478. doi:10.1182/bloodadvances.2023012478
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