This document discusses VEXAS syndrome, a recently discovered autoinflammatory and hematologic condition caused by somatic mutations in the UBA1 gene. It provides details on the clinical manifestations (fevers, inflammatory symptoms affecting skin, joints, lungs, blood vessels), hematological abnormalities (anemia, cytopenias), and challenges in management due to the combined inflammatory and hematological involvement. Diagnosis is confirmed via genetic testing demonstrating UBA1 mutations. Treatment aims to suppress inflammation and eliminate mutant hematopoietic cells, but outcomes remain poor with high mortality.

1. VEXAS Syndrome
A Diagnostic Puzzle
Marwa Abo Elmaaty Besar
Lecturer Of Internal Medicine
(Rheumatology Immunology Unit)
Mansoura school of medicine
Mansoura University

2. • A 62-year-old Asian male presented with fevers, erythema nodosum, inflammatory
arthritis, and periorbital inflammation.
• Labs were significant for persistently elevated inflammatory markers and macrocytic
anemia.
• Over the years his symptoms and inflammatory markers only improved with
glucocorticoids and recurred when prednisone dose was lowered below 15-20 mg
daily.
• He underwent bone marrow biopsy showing non-caseating granulomas and PET scan
showing hilar/mediastinal lymphadenopathy.
• He was initially diagnosed with IgG4-related disease (treated with rituximab) and later
sarcoidosis (treated with infliximab).
• After failing these agents, the possibility of VEXAS was considered and later confirmed
by molecular testing.

3. • Definition
• Pathogenesis
• Diagnosis
• Complication
• Management

5. VEXAS
A novel rheumatologic, hematologic syndrome
that’s making waves

6. Definition
• The recent discovery of Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS)
syndrome demonstrates how molecular diagnostics can reshape disease taxonomy.
• VEXAS is a hemato-inflammatory monogenic disease.
• VEXAS syndrome connects a spectrum of seemingly unrelated systemic inflammatory and
hematologic features into a new disease.
• It is characterized overlap between hematologic disturbances and auto-immunity and/or auto-
inflammatory presentations.
• Characterized by lineage-restricted acquired somatic mutations in hematologic progenitor cells in
the gene UBA1, encoding the master enzyme of cellular ubiquitylation, which resides on the x
chromosome.
Beck db,etal2020

7. History
• First discovered 2020 in 25 men with adult onset inflammatory disease and myeloid
dysplasia.
• As of June 1, 2021, just over 100 confirmed cases of VEXAS have been described, and
therefore the understanding of VEXAS syndrome continues to evolve’’’This was
predominantly a combination of cytopenia and multi-system inflammatory symptoms
in older males’’’.
• This characteristic mix, had been typically managed as either myelodysplastic
syndrome (MDS), discrete inflammatory illnesses or a systemic autoinflammatory
disease (SAID), were found to have the same mutation.
• By contrast, emerges within a new category of autoinflammatory disease in which the
causative mutation is acquired later in life, as a somatic mutation.
• The disease penetrance associated with the known pathogenic mutations in UBA1
EXPERT REVIEW OF CLINICAL IMMUNOLOGY, 2023, VOL. 19, NO.

8. Epidemiology
‘Geisinger Cohort’2022
• Prevalence of 1 in 14,000 from the entire cohort.
• VEXAS had a prevalence similar to Bechet disease (around 1 in 10,000) and MDS (around 1 in 14,000)
which provides a helpful benchmark in the investigation of clinically challenging cases.
• X linked syndrome.
• Occur in male but has been diagnosed in female (monosomy X).
• The disease presents late in life. the mean age was 52.8 years.
• Lower somatic variant frequencies.
The geisinger mycode community health initiative,202

9. Etiology
• The majority of disease-defining mutations are restricted to p.Met41, the translation
initiation codon for UBA1b, leading to a loss of the normally active cytoplasmic isoform
with emergence of an enzymatically impaired, novel isoform (UBA1c). novel isoform,
which has reduced catalytic activity.
• Gene expression profiling in VEXAS samples revealed activation of inflammatory
pathways including tumor necrosis factor (TNF), interleukin-6 and interferon-gamma
(INF-gamma); and correspondingly, serum enzyme-linked immunosorbent assays
(ELISA) revealed increased interleukein-8, interferon-inducible protein 10 (IP –10), and
INF-gamma
Ann Rheum Dis., 80 (8) (2021)

10. Pathogenesis
of
VEXAS

11. https://doi.org/10.1182/blood.202101
Pathogenesis
of
VEXAS

12. Biorender.com (2021
Inflammatory profile within VEXAS syndrome

13. Manifestation of VEXAS:-

14. Clinical description of VEXAS syndrome:-
• Common inflammatory manifestations:-
• Patients often present with intermittent and unexplained fevers, fatigue, myalgia, with a constellation of inflammatory
symptoms affecting the skin, cartilage, joints, lungs and blood vessels.
• Dermatological manifestations:
• Neutrophilic Dermatoses; Vasculitic Rashes;
• Erythème Nodosum; Urticaria;
• Erythematosus Papules,
• Injection-site Reactions.
• Ocular disease:
• Uveitis, Scleritis,
• Episcleritis and Orbital Masses.
• Lung disease:
• Either Pulmonary Infiltrates Or Pleural Effusions. Cartas ao Editor, Acta Med Port 2023 May;36(5):368-380

15. Clinical description of VEXAS syndrome:-
• Haematological manifestations:-
• Macrocytic Anaemia 100%, Lymphopenia (80%), Thrombocytopenia (50%) And Monocytopenia (50%).
• Haematological malignancies and plasma cell dyscrasias.
• Transfusion-dependent and the worsening anaemia despite erythropoietin- stimulating agents
• Thrombosis in VEXAS:
• Very early, with 44% risk.
• VTEs are the most common thrombotic manifestation of VEXAS, unprovoked, 2 years of onset inflammatory
symptoms.
• Including deep vein thrombosis’ (DVT); pulmonary embolisms (PE); arterial thromboses; cardiovascular
accidents (CVA) and myocardial infarctions (MI).
• The underlying pathogenesis remains unclear; Chronic inflammation, vascuilitis.
Cartas ao Editor, Acta Med Port 2023 May;36(5):368-380

16. VEXAS syndrome and hematologic
malignancies
• VEXAS and MDS:-
• Cytopenia, and progression to MDS, are common features of VEXAS syndrome.
• MDS was diagnosed in 31–50% of VEXAS.
• It suggests the inflammatory component of VEXAS may be playing a key role in the resultant hematologic
phenotype.
• Bone marrow morphology:-
The typical marrow findings
• Moderate hypercellularity with occasional cytoplasmic vacuoles in the myeloid precursor cells.
• Hypercellular marrow with granulocytic hyperplasia; minimal dyspoiesis without evidence of overt dysplasia;
a normal karyotype; and no increase in blasts in the absence of associated MDS.
Huang et al. Exp Hematol Oncol (2021) 10:23

17. Mortality
• Geisinger Cohort’2022
High mortality in patients with VEXAS syndrome
Gastrointestinal involvement (OR 3.7),
Lung infiltrates (OR 3.3)
Mediastinal lymphadenopathy (OR 7.73)
• USA/UK cohort (2021,2022);
The median survival time from symptom onset was 10 years.
There was greater risk of dying in those with the VAL variant,

18. The VEXAS syndrome:
Another great mimicker
• Relapsing Polychondritis (Rp), Sweet’s syndrome (SWS),
• IGg4-related disease.
• Vasculitis(giant Cell Arteritis, Polyarteritis Nodosa, ANCA-associated Vasculitis, Behçet’s Syndrome)
• Syphilis.
• Myositis, Lupus-like disease,
• Tubulointerstitial nephritis
• Undifferentiated inflammatory bowel disease (IBD),
• Spondylarthropathies and
• Haemophagocytic lymphohystiocytosis.
• Macrophage activation syndrome (MAS)

19. When to consider the VEXAS syndrome?
• Bruno A,2023;
Clinicians should consider the VEXAS syndrome in every male older than 50 years of age who
presents with systemic inflammation, multiorgan involvement and cytopenia.
However, this condition may represent a ‘late stage’.
• Whether broad genetic testing of cohorts (possibly selected by artificial intelligence approaches based
on patient charts and laboratory results) will translate into daily practice remains of great interest.
• The relatively specific features of the VEXAS syndrome may allow a sufficient selection of individuals.
• However, the diagnosis of the VEXAS syndrome also relies on the clinician’s suspicion in daily
practice, We must challenge diagnoses such as ‘refractory giant cell arteritis’ or ‘atypical polyarteritis’ in
light of the recent discovery.
• Does giant cell arteritis really present with a rash? Is the lung actually a classic target of polyarteritis?
Ruffer N, Krusche M. RMD Open 2023;9:e003332. doi:10.1136/rmdopen-2023-003332

20. Screening:
• With a bone marrow (BM) biopsy; vacuoles
• Genetic testing for UBA1 screening in men with sweet’s syndrome and
haematological abnormalities, especially those with vacuoles
Patient presenting with cytopenia and systemic inflammatory symptoms
should be considered for genetic testing.
Despite mimicking many rheumatological conditions, the uniqueness of VEXAS
syndrome warranted introduction of a specific disease category –hemato-
inflammatory diseases, to reflect its particular immunopathogenesis.
Cases are not science’ but neither are they fiction

21. Management

22. Management
• The coexistence of inflammatory and haematological dysfunction presents a unique
challenge in the management, often requires a multipronged approach, involving
different specialist teams.
• Currently, there are no standardised treatment models for VEXAS and
recommendations are based on a limited number of retrospective studies and best clinical
reasoning.
• Two main approach;
To target and eradicate the UBA1-mutated hematopoietic population,
To inhibit the inflammatory underpinnings of the disease
• Symptoms are typically refractory to treatment.

23. Management
• Severe, treatment-refractory systemic inflammation coupled with progressive bone marrow
failure makes VEXAS syndrome an often-fatal disease.
• Bone marrow transplant has been proposed as curative; however, selection of appropriate
candidates for transplant is challenging due to the heterogeneity of the disease, older age at disease
onset, associated comorbidities, and risks of transplant.
• Allogenic haemopoietic stem cell transplant (AHSCT) becomes the only viable option,
though this of course carries its own significant risk.
• As the only treatment with curative intent, it is increasingly likely that AHSCT will become the
mainstay of early intervention upon diagnosis, though there will always be a subset of patients
unable to have the treatment due to the high morbidity and mortality in older and frailer patients.

24. Management
• High-dose systemic corticosteroids, are highly effective at controlling the inflammatory symptoms,
• Steroid-sparing agents; may depend on whether they are manifesting primarily inflammatory or
haematological disease.
• In patients manifesting mostly inflammatory and rheumatological disease,
 Anti-interleukin (IL)1 (anakinra & canakinumab), anti-IL6 (tocilizumab)
 JAK inhibitors (e.g Baricititinib & Ruxolitinib).
• In patients with haematological manifestations;
 the JAKI is viable option on cell counts and transfusion dependence.
 The DNA methyltransferase inhibitors (DNMTI) e.g Azacitidine and decitabine, which are commonly used in
MDS for pre-treatment prior to HSCT and have shown efficacy in MDS-associated inflammation.
 Erythropoietin stimulating agents (ESA) and the thrombopoietin receptor agonist Eltrombopag, 70%
effective if used when serum erythropoietin levels are <100 U/L.

25. Management
• Supportive preventive:-
In lymphopenia patients, vaccinations could be considered,
Prophylactic antibiotic/antivirals may be indicated in the context of recurrent infections.
To reduce the risk of thrombotic complications, typically unprovoked VTES, long-term
anticoagulation, though this needs to be balanced against the risk of bleeding.
If patients are developing worsening anaemia they should be referred to haematology for
consideration of appropriate supportive treatments

26. VEXAS-proposed treatment algorithm and outstanding questions to
address.
https://doi.org/10.1080/1744666X.2023.2157262

27. VAXES Other autoinflammatory
syndrome
age 6th to 7th decade
45 to 83 years old
Early childhood or adolescence
Gender Male
Monosomy X female
Male= female
Clinical feature
Laboratory Neutropenia
Leukopenia
Microcytic anemia
Neutrophilia
Leukocytosis
Treatment Glucocorticoids (20-60mg)*
Bone Marrow transplant
IL-1 inhibitors
IL-6 inhibitors
TNF-inhibitors
Response Sever reaction to Anakinra
injection.
Good response to cytokine blocker
M.J. Koster and K.J. Warrington / Seminars in Hematology 58 (2021) 218–225
Autoinflammatory
syndrome
&
VEXAS

29. 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.
E bourbon, M heiblig, M gerfaud valentin, et al. Therapeutic options in VEXAS syndrome: insights from a retrospective series blood., 137 (26) (2021), pp. 3682-3684.
N Tsuchida, Y Kunishita, Y Uchiyama, et al. Pathogenic UBA1 variants associated with VEXAS syndrome in Japanese patients with relapsing polychondritis Ann Rheum
Dis., 80 (8) (2021), pp. 1057-1061
Miles LA , Bowman RL , Merlinsky TR , et al. Single-cell mutation analysis of clonal evolution in myeloid malignancies. Nature 2020;587(7834):477 .
Patel BA, Ferrada MA, Grayson PC, et al. VEXAS syndrome: an inflammatory and hematologic disease. Semin Hematol. 2021;58 (4):201–203.
Temple M, Kosmider O, Syndrome: VEXAS. A Novelty in MDS Landscape. Diagnostics (Basel). 2022;12:1590.
Ferrada MA, Savic S, Cardona DO, et al. Translation of cytoplasmic UBA1 contributes to VEXAS syndrome pathogenesis. Blood. 2022;140(13):1496–1506.
van der Made CI , Potjewijd J , Hoogstins A , et al. Adult-onset autoinflammation caused by somatic mutations in UBA1: a Dutch case series of VEXAS patients. J Allergy
Clin Immunol 2021 May 25:S0 091-6749(21)0 0819-8 .
Beck DB, Bodian DL, Shah V, et al. Genomic ascertainment for UBA1 variants and VEXAS syndrome: a population-based study. medRxiv. 2022.
Horton RK, Zheng G. A case of VEXAS syndrome with subtle morphologic findings. Blood. 2021;138(15):1378.
Patel N, Dulau-Florea A, Calvo KR. Characteristic bone marrow findings in patients with UBA1 somatic mutations and VEXAS syndrome. Semin Hematol. 2021;58(4):204–
211.
Georgin-Lavialle S, Terrier B, Guedon AF, 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.