Joint Bone Spine 91 (2024) 105700

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Review

VEXAS syndrome: An update

Mohamed-Yacine Khitri , Jérôme Hadjadj , Arsène Mekinian , Vincent Jachiet ∗
Service de médecine interne, AP–HP, hôpital Saint-Antoine, Sorbonne université, 184, rue du faubourg, 75012 Paris, France

a r t i c l e i n f o a b s t r a c t

Article history: VEXAS (Vacuoles, E1 Enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a recently described
Accepted 10 January 2024 autoinflammatory syndrome, mostly affecting men older than 50 years, caused by somatic mutation in
Available online 1 February 2024 the UBA1 gene, a X-linked gene involved in the activation of ubiquitin system. Patients present a broad
spectrum of inflammatory manifestations (fever, neutrophilic dermatosis, chondritis, pulmonary infil-
Keywords: trates, ocular inflammation, venous thrombosis) and hematological involvement (macrocytic anemia,
VEXAS syndrome thrombocytopenia, vacuoles in myeloid and erythroid precursor cells, dysplastic bone marrow) that are
UBA1
responsible for a significant morbidity and mortality. The therapeutic management is currently poorly
Autoinflammatory diseases
Myelodysplastic syndrome
codified but is based on two main approaches: controlling inflammatory symptoms (by using corticos-
teroids, JAK inhibitor or tocilizumab) or targeting the UBA1-mutated hematopoietic population (by using
azacitidine or allogeneic hematopoietic stem cell transplantation). Supportive care is also important and
includes red blood cell or platelet transfusions, erythropoiesis stimulating agents, thromboprophylaxis
and anti-infectious prophylaxis. The aim of this review is to provide a current overview of the VEXAS
syndrome, particularly focusing on its pathophysiological, diagnostic and therapeutic aspects.
© 2024 Published by Elsevier Masson SAS on behalf of Société française de rhumatologie.

1. Introduction underdiagnosed, as a recent study involving 163,096 participants

has suggested a prevalence of approximately 1 in 4000 among men
At the end of 2020, Beck and colleagues from the National Insti- over the age of 50 with 100% penetrance [2]. The aim of this review
tute of Health (NIH) described a novel autoinflammatory syndrome is to provide a current overview of the VEXAS syndrome, particu-
in adults named VEXAS, which stands for Vacuoles, E1 enzyme, X- larly focusing on its pathophysiological, diagnostic and therapeutic
linked, Autoinflammatory, and Somatic mutations [1]. In contrast aspects.
to most syndromes which are typically identified based on clinical
phenotypes, the VEXAS syndrome is unique in that it emerged from
a genotypic study. The NIH researchers had the innovative idea of 2. VEXAS pathophysiology: from somatic genetic mutation
examining the exomes and genomes of 1477 patients who pre- to auto-inflammation
sented with undiagnosed recurrent fevers, systemic inflammation,
or both, and 1083 patients with atypical or unclassified disorders. The UBA1 gene is located on the X chromosome. On the exon
Among these 2560 patients without a definitive diagnosis, they 3, codon 41 that is composed of the nucleotides A-T-G is normally
identified three men with a mutation in the UBA1 gene, all occurring translated into a methionine. The mutation responsible for VEXAS
at the same codon 41 which would normally code for a methion- syndrome mainly involves the substitution of one of the three ATG
ine. Therefore, UBA1 mutation screening was conducted in patients nucleotides in exon 3 codon 41 of the UBA1 gene, resulting in a
exhibiting a similar clinical phenotype, leading to the discovery missense mutation that, depending on the substituted nucleotide,
of 15 additional patients from NIH cohorts and 7 from cohorts in leads to the production of a valine (c.121A > G; p.Met41Val variant),
United Kingdom. In total, 25 patients were found to have a mutation threonine (c.122T > C; p.Met41Thr variant) or leucine (c.121A > C;
at codon 41 of the UBA1 gene, thus defining the VEXAS syndrome. p.Met41Leu variant). Beck et al. demonstrated that the mutation
Initially considered as a rare disease, VEXAS syndrome is likely is somatic, restricted to hematopoietic compartment, present not
only in the precursors of myeloid and lymphoid cells but also in
mature myeloid cells such as monocytes, neutrophils, megakary-
ocytes, and erythroblasts, while absent in mature lymphocytes
∗ Corresponding author. [1]. Therefore, patients with a UBA1 mutation exhibit genetic
E-mail address: [email protected] (V. Jachiet). mosaicism, which reaches a frequency of between 30% and 80%

https://doi.org/10.1016/j.jbspin.2024.105700
1297-319X/© 2024 Published by Elsevier Masson SAS on behalf of Société française de rhumatologie.
M.-Y. Khitri, J. Hadjadj, A. Mekinian et al. Joint Bone Spine 91 (2024) 105700

Fig. 1. The ubiquitin-proteasome system. The ubiquitin-proteasome system operates in two primary steps. The initial step involves the covalent attachment of ubiquitin, a
small protein consisting of 76 amino acids, to a protein substrate, a process called ubiquitination that is orchestrated by a series of enzymes categorized into three groups,
namely E1, E2, and E3. The second step encompasses the recognition and degradation of the tagged substrate by the proteasome. Ub: ubiquitin; E1: enzyme 1; E2: enzyme
2; E3: enzyme 3.

in peripheral blood. Additional non-M41 UBA1 variants have been 3. Clinical and biological presentation: from Beck’s
more recently identified (including splice mutations, p.Ser56Phe, inaugural series to an increasingly diverse phenotype
p.Tyr55His, p.Gly477Ala, p.Ala478Ser, p.Asp506Gly, p. Asp506Asn,
and p.Ser621Cys. . .) and associated with typical or atypical VEXAS All 25 patients in the Beck’s series were male, with a median age
phenotype [3–7]. at disease onset of 64 years. Most of them experienced recurrent
Intracellular proteolysis is a crucial cellular function that facili- episodes of fever (92%), skin involvement (88%, often presenting
tates the degradation of abnormal or excess proteins, controlling as neutrophilic dermatoses and cutaneous vasculitis), pulmonary
processes such as proliferation, differentiation, apoptosis and infiltrate (72%), ear and nose chondritis (64%) and venous throm-
response to extracellular stimuli [8]. It involves a multi-enzymatic boembolism (VTE) (44%). They also exhibited macrocytic anemia
system known as the ubiquitin-proteasome system that is com- (96%), dysmyelopoiesis and vacuoles in bone marrow (BM) progen-
posed of a series of enzymes categorized into three groups, namely itors (100%), primarily affecting myeloid and erythroid precursors.
E1, E2, and E3 (Fig. 1). In humans, there are two E1 enzymes, with Significant increase in acute phase reactants was observed, includ-
UBA1 being predominant, capable of interacting with the majority ing elevated levels of CRP, TNF␣, IL-6 and interferon-␥. Among
of E2 enzymes. UBA1 is expressed as two isoforms differing in trans- the 25 participants, 10 (40%) died from disease-related causes
lation start site: nuclear UBA1a (initiated at Met1) and cytoplasmic or complications associated with treatment. Most of the patients
UBA1b (initiated at Met41) (Fig. 2). In the Met41 variants respon- previously met clinical criteria for another inflammatory disorder
sible for VEXAS syndrome, protein translation does not initiate at (relapsing polychondritis (RP) in 60%, Sweet syndrome in 32%, pol-
Met41 codon as anticipated but instead, it initiates from Met67 yarteritis nodosa, or giant-cell arteritis) or a hematologic condition
codon, giving rise to the synthesis of a pathological isoform UBA1c (myelodysplastic syndrome (MDS) in 24%, multiple myeloma or
presenting a catalytic deficiency. The absence of the cytoplasmic monoclonal gammopathy of unknown significance (MGUS) in 20%).
isoform UBA1b disrupts the protein ubiquitination mechanism, The largest cohort of VEXAS patients reported to date is the
leading to an accumulation of proteins, triggering cellular stress French one with n = 116 patients. The majority were males (96%)
and ultimately resulting in uncontrolled inflammation. with a median age at symptom onset of 67 years and at VEXAS
Kosmider et al. found that VEXAS syndrome involves inflam- diagnosis of 71 years [11]. The main clinical characteristics included
masome pathway activation and monocyte dysfunction in both skin lesions (83%), noninfectious fever (64%), weight loss (62%), lung
blood and tissues [9]. Monocytes in individuals with UBA1 muta- engagement (50%), ocular manifestations (39%), recurrent chondri-
tions are impaired and show exhaustion along with abnormal tis (36%), venous clotting (35%), lymph node abnormalities (34%),
chemokine receptor expression. Pathological skin biopsies from and joint pain (27%). More detailed clinical features are summarized
VEXAS patients indicate an abundance of specific monocytes near in Table 1. MDS was present in 50% (mostly MDS with multilineage
blood vessels and M1 macrophages, potentially contributing to dysplasia) and MGUS in 10% of patients. Somatic UBA1 mutations
local inflammation through STAT3 activation. Peripheral blood in included p.Met41Thr (45%), p.Met41Val (30%), p.Met41Leu (18%)
VEXAS patients has elevated proinflammatory cytokines levels and splice mutations (7%). Screening for somatic mutations asso-
(such as IL-1␤ and IL-18) reflecting inflammasome activation and ciated with myeloid neoplasms using next-generation sequencing
myeloid cell dysregulation. Gene expression analysis reveals upreg- (NGS) was performed in 75 patients, revealing additional muta-
ulation of TNF-␣ and NF␬B signaling pathways, possibly mediating tions in 24% of cases, mostly in DNMT3A (9%) and TET2 (5%). Over
cell death and inflammation. a median follow-up period of 3 years since the onset of VEXAS-
Wu et al. demonstrated that both inflammation and myeloid related symptoms, 18 patients (16%) died, from infectious origin
dominance originate in hematopoietic stem cells in VEXAS (n = 9), MDS progression (n = 3), cardiovascular events (n = 2) or
syndrome [10]. By using transcriptome sequencing of single- another cause (n = 4). The presence of gastrointestinal involvement
bone marrow (BM) hematopoietic cells, they demonstrated that (OR 3.7), lung infiltrates (OR 3.3) and mediastinal lymph node (OR
UBA1-mutated (mtUBA1) myeloid cells upregulate inflammatory 7.7) were the factors associated with mortality, but the presence
pathways compared to wild-type cells, exhibit biased granulo- of MDS did not significantly impact mortality. With an unsuper-
cytic differentiation and increased proliferation, and contribute to vised hierarchical analysis, patients with VEXAS syndrome were
impaired lymphocytopoiesis through apoptosis of mtUBA1 lym- categorized into three distinct clinical phenotypes: cluster 1 (47%;
phoid progenitors. mild-to-moderate disease, fewer clinical and biological inflam-

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M.-Y. Khitri, J. Hadjadj, A. Mekinian et al. Joint Bone Spine 91 (2024) 105700

Fig. 2. Isoforms of UBA1. M1: methionine 1; M41: methionine 41; M67: methionine 67; UTR: untranslated transcribed region.

Table 1 ear chondritis was associated with increased survival, while trans-
Clinical characteristics and laboratory data of VEXAS syndrome.
fusion dependence and the p.Met41Val variant were independently
n = 116 associated with mortality. In addition, this cohort also provides
Clinical characteristics novel insights into pathogenesis of VEXAS: by using in vitro mod-
Skin lesions 84% els and patient-derived cells, Ferrada et al. demonstrated that
Neutrophilic dermatosis 40% p.Met41Val variant supports less UBA1b translation than either
Cutaneous vasculitis 26% p.Met41Leu or p.Met41Thr, providing a molecular rationale for
Erythematosus papules 22%
decreased survival.
Injection-site reactions 8%
Fever 65% Of note, in a Spanish cohort, analysis of mosaicism distri-
Weight loss 55% bution revealed the presence of postzygotic UBA1 variants in
Myelodysplastic syndrome 50% non-hematopoietic tissue (nails, a non-blood contaminated tissue),
Lung involvement 49%
leading the authors to question the previous notion of myeloid-
Pulmonary infiltrates 41%
Pleural effusion 10% restricted mosaicism in VEXAS and to suggest that the mutational
Ocular inflammation 41% event causing VEXAS could possibly occur during embryonic devel-
Episcleritis 12% opment [13]. Indeed, a Mexican team recently reported a diagnosis
Uveitis 10% of VEXAS syndrome in a young man aged 23 when the symptoms
Scleritis 9%
started [14].
Periorbital oedema 3%
Chondritis 36% Finally, VEXAS syndrome has also been documented in around
Unprovoked thrombosis 35% ten women, with the majority of them exhibiting X-acquired mono-
Lymph node enlargement 35% somy or Turner syndrome [2,15–19]. Their clinical presentation is
Arthralgias 28%
comparable to that seen in men.
Peripheral nervous system involvement 15%
Gastrointestinal involvement 14%
Abdominal pain 9%
Chronic diarrhea 7% 4. A focus on a few key inflammatory manifestations
Laboratory data
Hemoglobin (g/dL) 10.1 [9,11.5] Skin involvement seems to be one of the most common symp-
Mean corpuscular volume (fL) 101 [94,107]
Platelets (G/L) 204 [138,260]
toms, and may be the first manifestation of VEXAS syndrome. In
Leucocytes (G/L) 4.4 [3,6.2] a case series study of 8 men by Zakine et al., all patients had neu-
Neutrophils (G/L) 2.6 [1.6, 4.2] trophilic dermatosis skin lesions, including tender red or violaceous
C-reactive protein (mg/L) 61 [30,128] papules, sometimes edematous, recurrence of pathergy, inflam-
Data from the French VEXAS cohort [11]. matory edematous papules on the neck and trunk (sometimes
umbilicated), and firm erythematous purpuric or pigmented infil-
trated plaques and nodules; 3 patients had livedo racemosa [20].
mation, fewer treatment, significant association with the UBA1 Histologic findings identified that infiltrates were perivascular and
p.Met41Leu); cluster 2 (16%; higher prevalence of relapsing chon- consisted of mature neutrophils with leukocytoclasia, which were
dritis, gastrointestinal, lung and cardiac involvement, infections, admixed with myeloperoxidase-positive CD163-positive myeloid
with more frequent MGUS and MDS, and higher mortality rates); cells with indented nuclei and lymphoid cells in all cases. A
and cluster 3 (37%; constitutional manifestations, higher CRP levels sequencing analysis of paired BM samples and skin lesion biopsies
and less frequent chondritis). Analysis of overall survival based on identified the same loss-of-function UBA1 variation in both sam-
these three clusters showed an increased mortality rate in cluster 2 ples for all patients, suggesting that the dermal infiltrates seen in
with a 5-year survival probability of 63% compared to 87% in cluster VEXAS skin lesions are derived from the pathological myeloid clone.
1 and 93% in cluster 3. In another centralized review of photographs and biopsies from
The USA/UK cohort is the second largest cohort with 83 VEXAS 59 VEXAS patients in the French cohort, Zakine et al. emphasized
patients (all male, median age 66 at symptom onset) with the 3 the heterogeneous nature of skin lesions, their initial occurrence in
canonical VEXAS variants and also emphasizes the high mortality two-thirds of patients and the presence of arcuate-shaped lesions
rate and substantial clinical heterogeneity [12]. The clinical pre- in a third of patients [21]. Regarding pathology, they noted that the
sentation closely resembled that observed in the French cohort, characteristic infiltrates typically consisted of superficial perivas-
except for the reported occurrence of hearing loss in 29% of cular and periadnexal lymphohistiocytic infiltrates with immature
patients. 97% of patients had macrocytic anemia, 83% had throm- myeloid cells and signs of dysplasia in most cases, along with fre-
bocytopenia and 31% a diagnosis of MDS. Patients with the quent reports of vasculitis (25–70%), although it is likely that this
p.Met41Val genotype were most likely to have an undifferenti- rate was overestimated due to the absence of vasculitis in central-
ated inflammatory syndrome. Multivariate analysis showed that ized review despite a high prevalence of leukocytoclasia.

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M.-Y. Khitri, J. Hadjadj, A. Mekinian et al. Joint Bone Spine 91 (2024) 105700

Fig. 3. Main differences between VEXAS-RP and Idiopathic-RP [26].

Pulmonary manifestations are prevalent in VEXAS syndrome, follow-up of 37 months, whereas no deaths occurred in I-RP group
although they are not the main clinical problem. Borie et al. docu- over a median follow-up of 92 months.
mented pleuro-pulmonary involvement in 45 VEXAS patients, with Ocular involvement is common in VEXAS syndrome, observed
44% reporting dyspnea, 40% reporting cough, but only 7% requir- in 40 to 57% in key studies. The most frequent manifestations
ing oxygen [22]. All patients displayed lung opacities on chest CT include episcleritis, scleritis, and uveitis, while orbital and peri-
scans, including ground-glass opacities (87%), consolidations (49%), orbital inflammation is less frequent. Periorbital edema is the
reticulations (38%), and septal lines (51%). Furthermore, pleural predominant ocular adnexal finding, with additional manifesta-
effusion was observed in 53% and mediastinal adenomegaly in 58% tions such as orbital inflammation or cellulitis, orbital myositis,
of the patients. Importantly, the initial prognosis with prednisone dacryoadenitis, optic perineuritis, or oculomotor nerve paresis
treatment appeared to be favorable, and there was no evolution to [27–29]. Notably, the p.Met41Thr mutation is consistently asso-
pulmonary fibrosis. ciated with ocular involvement in a majority of patients.
Thrombotic events were reported in 35 to 45% in the main series, Serious infections are frequently associated with VEXAS syn-
encompassing both deep and superficial thromboses, recurrent drome. In a French retrospective study including 74 patients with
thromboses and even recurrences occurring despite anticoagula- 133 serious infections, the most common sites of infections were
tion. A literature review showed a higher incidence of VTE (36.4%) lung (59%), skin (10%), and urinary tract (9%). Microbiological
than arterial thrombosis (1.6%), with deep vein thrombosis (DVT) confirmation was obtained in 76%: 52% bacterial, 30% viral, 15%
being more common than pulmonary embolism [23]. Khider et al. fungal and 3% mycobacterial. The high incidence of atypical infec-
screened UBA1 mutations in 97 men over 50 years old with a first tions such as legionellosis and invasive fungal infections, occurring
VTE (50.5% of unprovoked VTE), and no mutations were detected despite anti-infective prophylaxis or in patients without immuno-
[24]. Consequently, there is currently no evidence supporting sys- suppressive treatment may indicate an intrinsic immunodeficiency
tematic screening for UBA1 mutations in men aged over 50 years of the disease. In multivariate analysis, risk factors identified were
with a first unprovoked VTE in the absence of other manifestations age > 75 years at VEXAS onset, arthralgia, p.Met41Val mutation and
of VEXAS syndrome. use of JAK inhibitor [30].
Ferrada et al. demonstrated in a cohort of 92 RP patients that
somatic mutations in UBA1 were present in 7.6% of cases [25]. 5. A focus on a few key hematologic manifestations
Patients with VEXAS-RP (n = 13) were all male, ≥ 45 years at disease
onset, and commonly had fever, ear chondritis, skin involvement, Obiorah et al. reported 16 VEXAS patients with benign and
deep vein thrombosis, and pulmonary infiltrates. No patient with malignant hematologic manifestations including MDS (6/16),
VEXAS-RP had chondritis of the airways or costochondritis. Mor- multiple myeloma (2/16), MGUS (2/16), and monoclonal B-cell
tality was greater in VEXAS-RP than in Idiopathic-RP (I-RP) (27 vs. lymphocytosis (MBL) (2/16), and a few of them with 2 co-existing
2%), a finding confirmed by a Japanese study [19]. We reported clonal processes [31].
the largest VEXAS-RP cohort (n = 55), and compared them to 40 The presence of vacuoles in myeloid and erythroid progenitor
patients with I-RP [26] : the key distinctions between VEXAS-RP cells in BM aspirates is a key feature of VEXAS syndrome. They
and I-RP are illustrated in Fig. 3. VEXAS-RP patients demonstrated are found in over 80% of cases but lack specificity to VEXAS, as
a lower likelihood of remission and a higher risk of relapse. Fur- they can also be observed in conditions such as copper deficiency,
thermore, VEXAS-RP was associated with an increased mortality, zinc toxicity, liver disease/alcoholism, acute myeloid leukemia,
with 6 patients (11%) died in the VEXAS-RP group during a median lymphoproliferative disorders, multiple myeloma, myeloprolifer-

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M.-Y. Khitri, J. Hadjadj, A. Mekinian et al. Joint Bone Spine 91 (2024) 105700

Table 2 and is based on small retrospective studies and expert opin-

Differential diagnosis of VEXAS syndrome.
ion. The treatment is based on two main approaches: targeting
Sweet syndrome and other neutrophilic dermatoses immune and inflammatory pathways or targeting the UBA1-
Relapsing polychondritis mutated hematopoietic population.
Polyarteritis nodosa
Giant-cell arteritis
ANCA-associated vasculitides
7.1. Targeting immune and inflammatory pathways
MDS associated inflammatory diseases
Behçet’s syndrome Glucocorticoids are generally used as a first line treatment.
Inflammatory bowel disease The inflammatory manifestations are typically glucocorticoid-
Inflammatory arthritis
sensitive, but often at the cost of high-level corticosteroid-
Macrophage activation syndrome
dependence requiring second-line steroid-sparing agents.
ANCA: antineutrophil cytoplasmic autoantibody; MDS: myelodysplastic syndrome.
Conventional disease-modifying anti-rheumatic drugs
(DMARDs) such as methotrexate, azathioprine, cyclosporine
ative neoplasm (MPN), MDS, MDS/MPN overlap, or as an artifact of or cyclophosphamide, have been used with no or anecdotal
sample preparation [32]. Bone marrow hypercellularity is a com- efficacy. Biological DMARDs can be beneficial for patients primar-
mon feature in VEXAS syndrome, although both normocellular and ily experiencing inflammatory and rheumatological conditions.
hypocellular marrows can also be seen [33]. Tocilizumab, an anti-IL-6 receptor, has been tested in 7 Japanese
MDS is frequently reported in VEXAS syndrome, with rates rang- patients and showed promising results [37–39]. Moreover, it has
ing from 25% to 55%, depending on the series [34,35]. In contrast to shown efficacy in the four patients of the Dutch series (three
classical MDS, VEXAS-MDS is characterized by moderate dysplasia partial response and one good response) [40], some cases reports
with little or no blast excess, a normal karyotype in approximately [41], and a good but transient efficacy in 4/4 patients from a French
80% of cases, a mostly favorable prognosis according to the R- case series of 11 patients [42]. Anakinra, an anti-interleukin(IL)1R
IPSS score, and the absence of transformation into acute myeloid was used in seven patients from the Dutch case series, two had
leukemia (except for a single reported case to date [36]). a good response, one had a disease recurrence and four were
Gutierrez-Rodrigues et al. explored the mutational landscape of discontinued due to injection-site reactions; three of them were
VEXAS syndrome in 80 patients, including 95% with UBA1 muta- switched to canakinumab with one having a good response and
tion at hot spot p.M41 (median variant allele frequency (VAF) of one having disease recurrence [40].
75%) [34]. Typical clonal hematopoiesis (CH) was observed in 60% of A French case series of 11 patients by Bourbon et al. of raised the
patients, characterized by dominant DNMT3A and TET2 mutations potential benefit of Janus kinase inhibitors (JAKi) in 3 patients [42].
with disparate VAF in peripheral blood (25% and 1%, respectively). A further international retrospective analysis involving 30 patients
Based on integrated bulk and single-cell DNA analyses in periph- treated with various JAKi (including ruxolitinib (n = 12), tofacitinib
eral blood, they identified two major patterns likely caused by the (n = 11), baricitinib (n = 4) and upadacitinib (n = 3)) reported clin-
order of clonal events in relation to UBA1 mutation: with either ical response rates of 50% at 1 month and approximately 30% at
typical CH preceding UBA1 mutation selection in a clone (pattern 6 months, with ruxolitinib demonstrating a superior response at
1, associated with DNMT3A mutations) or occurring as an UBA1 6 months compared to other JAKi [43]. However, the side effects
mutation subclone or in independent clones (pattern 2, associated of JAKi should be considered, especially serious infections and
with TET2 mutations). Hematologic manifestations did not differ thrombotic events in this elderly population with comorbidities.
between patients with or without typical CH mutations. However, A multicenter retrospective study conducted within the French
transfusion-dependent anemia, moderate thrombocytopenia, and national VEXAS study registry including 110 patients receiving 194
typical CH mutations (DNMT3A or TET2) were correlated with an targeted therapies confirmed the benefit of JAKi and anti-IL-6 with
increased mortality risk. similar response rates (30%), whereas the other targeted therapies
(mainly anti-IL-1 and anti-TNF-alpha) appeared to have lower effi-
cacy [44]. Moreover, survival without treatment withdrawal was
6. Diagnosis significantly longer with JAKi than with the other targeted thera-
pies.
Genetic testing of UBA1 gene should be considered for patients
with a compatible clinical phenotype. The diagnosis of VEXAS syn- 7.2. Targeting the UBA1-mutant clone
drome relies on identifying a M41 or splice-site mutation in the
UBA1 gene, from different biological samples, mostly blood and Similar to classical MDS without VEXAS, hypomethylating
BM. Several techniques can be used to screen for UBA1 muta- agents like azacitidine (AZA) were used to treat VEXAS patients
tions. Sanger sequencing targeting hotspot mutations is a fast and with concomitant MDS. Comont et al. found that AZA led to a clini-
cost-effective method with a sensitivity of VAF 15-20%). Next- cal response in 46% of 11 VEXAS patients with concurrent MDS, and
generation sequencing gene panel is more time-consuming and allowed a significant decrease in steroids with response durations
expensive but has sensitivity of VAF 2%, and enables simultane- ranging from 6 to over 27 months [45]. In the prospective GFM-AZA-
ous analysis of other myeloid genes. For patients with RP, VEXAS SAID trial assessing AZA for patients with steroid-dependent or
syndrome can be predicted, according to Ferrada et al., with 100% refractory inflammatory disorders associated with MDS and CMML,
sensitivity and 96% specificity if the following 3 criteria are present: 30 patients were included, including 12 with VEXAS syndrome [46].
male gender, MCV > 100 fl, and platelet counts < 200 G/L [25]. Since After six treatment cycles, 66% of patients achieved an inflamma-
the symptomatology of VEXAS syndrome is complex and polymor- tory response, and 59% attained a hematological response, with
phic, many differential diagnoses must be discussed particularly similar response rates observed in both UBA1-positive and non-
other inflammatory diseases (Table 2). mutated cases. Raaijmakers et al. reported the efficacy of AZA in
two patients with concomitant DNMT3A mutation but not in the
7. Therapeutic options in VEXAS third patient who had concomitant TET2 mutation, potentially sug-
gesting a particular effectiveness of AZA in cases associated with
Because large prospective trials are lacking, the therapeu- DNMT3A mutation [47]. More recently, Comont et al. confirmed
tic management of VEXAS patients is currently poorly codified the efficacy of AZA in a cohort of 51 VEXAS patients with 77% of

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M.-Y. Khitri, J. Hadjadj, A. Mekinian et al. Joint Bone Spine 91 (2024) 105700

Fig. 4. VEXAS-proposed treatment algorithm. alloHSCT: allogeneic hematopoietic stem cell transplant; AZA: azacitidine; DAC: decitabine; DNMTI: DNA methyltransferase
inhibitors; ESA: erytrhopoietin stimulating agents; JAKi: Janus kinase inhibitors; MDS: myelodysplastic syndrome; PLT: platelet; RBC: red blood cell.

response, even in those with no demonstrated underlying MDS, will notably help define therapeutic goals and propose response
albeit with a significant infectious risk [48]. criteria across various components of the disease (inflammatory,
Allogeneic haematopoietic stem cell transplantation (AHSCT) is hematological, and molecular) to facilitate the implementation of
currently the only curative treatment for VEXAS, sometimes with large-scale clinical trials.
considerable morbidity and mortality. Only small case reports [49]
and series of AHSCT in VEXAS are available. In a French case series
Disclosure of interest
of six patients who underwent AHSCT for severe inflammatory
syndrome (n = 4) or MDS (n = 2), three were in durable complete
The authors declare that they have no competing interest.
remission 32, 38, and 37 months after AHSCT, two others were
in complete remission after 3 and 5 months and one patient died
post-AHSCT [50]. In a UK case series of four patients, two were References
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