PURPOSE
To identify and analyze ocular features seen in Vacuoles, E1-ligase, X-linked Auto-inflammatory, Somatic (VEXAS) syndrome.
DESIGN
A systematic literature review was performed following PRISMA guidelines (PROSPERO registration number: ID 566167).
METHODS
Article inclusion criteria comprised genetic confirmation VEXAS syndrome that included eye involvement. Exclusion criteria included lack of genetic testing, or ocular feature reporting. A systematic search of the PubMed/MEDLINE, Embase, and CENTRAL databases was performed from January 2020 to September 2024. Data were collected and risk of bias assessed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. For the meta-analysis, specific UBA1 mutation and systemic feature data were also included. An association between severity of ocular features, presence of specific ophthalmic or systemic features, with age or causative mutation was investigated using Kruskal-Wallis rank sum testing and Fisher exact test, respectively, using R.
RESULTS
Fifty-two articles were included, amounting to 204 individuals (1 female). Mean age of VEXAS symptom onset was 67 ± 5 years (range: 46-87). Orbital inflammation was the most common ocular manifestation, comprising periorbital edema (n = 83, 40.7%), orbital myositis (n = 14, 6.9%), dacryoadenitis (n = 6, 2.9%), and orbital compartment syndrome (n = 1, 0.5%). Other features included episcleritis (n = 28, 13.7%), scleritis (n = 28, 13.7%), uveitis (n = 25, 12.3%), and retinal vasculitis (n = 2, 1%), among others. Visual acuity reporting was limited (n = 4, 2%). Meta-analysis was conducted on 32 articles (n = 48) with genotype and ocular feature data. The most commonly reported UBA1 mutation was the missense mutation p.Met41Thr (n = 24, 50%), followed by p.Met41Val (n = 17, 35%), p.Met41Leu (n = 4, 8%), and splice site mutations or deletions (n = 3, 6%). There was an association for more severe ophthalmic features in the splice site mutation group vs methionine 41 missense mutations ( P = .04). The most commonly associated systemic features included dermatologic manifestations (n = 41, 85%), recurrent fever (n = 38, 79%), and pulmonary involvement (n = 30, 63).
CONCLUSION
There is notable variation in the ophthalmic features of VEXAS. Ophthalmic review is advised for VEXAS patients who develop eye symptoms, given the risk of sight-threatening disease.
V acuoles, E1-ligase, X-linked Auto- inflammatory, Somatic (VEXAS) syndrome, first described in 2020, is an auto-inflammatory disorder associated with myeloid dysplasia that may show ophthalmic features. The syndrome is caused by somatic mutations of UBA1 , an X chromosome gene encoding the ubiquitin-activating enzyme 1 (UBA1). UBA1 is necessary for initiation of ubiquitylation, a posttranslational protein modification that regulates diverse cellular processes including protein degradation through the autophagy-lysosome system. Acquired inactivating UBA1 mutations expand clonally in genetic mosaicism and result in decreased ubiquitylation. This causes systemic inflammation, a broad spectrum of autoinflammatory disease, and progressive bone marrow failure that typically presents in late adulthood in males.
VEXAS may be caused by missense mutations at codon 41 (p.Met41) of UBA1 , or splice site mutations that affect UBA1 function. , Systemic features of VEXAS show overlap with inflammatory syndromes including relapsing polychondritis, Sweet syndrome, and polyarteritis nodosa. There is a strong association between VEXAS and hematologic malignancy including myelodysplastic syndrome (MDS) and multiple myeloma. , Vacuolation of myeloid and erythroid precursors on bone marrow biopsy is a key pathologic sign of VEXAS. Estimated prevalence of disease-causing UBA1 variants is as high as 1 in 4269 in men aged >50 years.
Ocular features in VEXAS were first described by Beck and associates in their seminal study. Ocular involvement was present in 12 patients (48%) and included periorbital edema, episcleritis, scleritis, uveitis, and giant cell arteritis (GCA). Subsequent reports have described other ophthalmic features including dacryoadenitis and myositis. Ocular symptoms can be the presenting feature in VEXAS syndrome, as was the case in 25% of patients in the series (n = 8) reported by Abumanhal and associates.
Although early diagnosis of VEXAS facilitates multidisciplinary management in these complex cases, there is a lack of evidence-based treatment strategies. Broadly, treatment may be directed at eradicating the UBA1-mutated myeloid clone, via allogenic stem cell transplant or DNA hypomethylating agents, or at mediating systemic inflammation. , ,
This systematic review aims to identify the range, frequency, and severity of ocular manifestations in VEXAS syndrome, and to describe demographic characteristics in these cases. We conducted a meta-analysis to identify the relative frequency of different pathogenic UBA1 mutations in VEXAS patients who have ophthalmic features, and to investigate whether age of symptom onset or specific UBA1 mutations are associated with severity of ocular features.
METHODS
ELIGIBILITY CRITERIA FOR CONSIDERING STUDIES FOR THIS REVIEW
Primary studies published in English that included a description of ocular features, defined as eye, eyelid, or orbital pathology, in genetically confirmed VEXAS syndrome were included. Additionally, an accessible full-text version was required. Studies were excluded if patients did not have a diagnosis of VEXAS syndrome, if the study was a review or abstract without a description of an original case, or if an English language version was not available.
SEARCH METHODS FOR IDENTIFYING STUDIES
This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines (Appendix 1). The review was registered on PROSPERO, ID 566167. A search of the databases PubMed/MEDLINE, Embase, and CENTRAL was performed from 2020 (year of first description of VEXAS) to September 25, 2024, by 2 reviewers working independently (C.Q. and J.P.). Clinical trial registries were also searched. Search diversification was enhanced using Boolean operators AND/OR (Appendix 2). Manual searching was also performed. Risk of bias was assessed by 2 reviewers, who were unblinded, using the Critical Appraisal Skills Programme (CASP) Checklist for cohort studies.
DATA COLLECTION
Extracted data included patient demographics, age of onset of VEXAS, genetic confirmation of VEXAS and UBA1 mutation, the associated ocular and systemic feature(s), laterality of ocular involvement, and whether this was the presenting complaint. Extraction of systemic features was not exhaustive and was performed for the 10 most common systemic features, including mortality due to VEXAS. Studies were included in the meta-analysis if specific UBA1 mutation data were available and specific ophthalmic features of an original case were described. Meta-analysis included descriptive statistics of demographic features and UBA1 mutation and also analysis for association of severity of ophthalmic features, and death associated with VEXAS, with age of onset or UBA1 mutation.
Mild involvement comprised blepharitis and episcleritis, moderate involvement included orbital inflammation (periorbital edema, dacryoadenitis, myositis) or uveitis (excluding retinal vasculitis), and severe involvement was classified as the presence of scleritis, retinal vasculitis, or GCA. Statistical analysis was performed using R, version 5.12.10. For nonparametric data the median and range are described, and for parametric data mean ± SD are described. Kruskal-Wallis rank sum tests and Fisher exact tests were used to analyze continuous and categorical variables, respectively.
RESULTS
SYSTEMATIC REVIEW
Articles included
In total 52 articles fulfilled inclusion criteria ( Figure 1 , Table 1 ). , , , , , , No study had a high risk of bias. The oldest included study was published in 2020. Some overlapping patient cohorts were reported in multiple studies, including a cohort in France , , , , , , and Japan. , , The largest most recently described cohorts from these studies , were analyzed to inform the reported totals and describe demographic characteristics. There was risk of potential overlap among other studies, and each were included in the systematic review but not the meta-analysis. , , There was significant variation in the precision of ophthalmic findings among studies.
| Reference | Study ID | Design | Sample Size | Demographics | ||||
|---|---|---|---|---|---|---|---|---|
| Overall | VEXAS | VEXAS-Oph | Sex | Age, y, Mean (Range) | ||||
| n | n | n (%) | VEXAS-Oph | VEXAS-Oph | VEXAS | |||
| Abumanhal et al, 2024 | 1 | CS | 8 | 6 | 6 | 6 (M) | 74.5 (69-87) | – |
| Agwan et al, 2024 | 2 | C | 1 | 1 | 1 | 1 (M) | 73 | – |
| Al-Hakim et al, 2022 | 3 | C | 4 | 4 | 1 (25) | 1 (M) | 64 | 59 (49-64) |
| Ang et al, 2024 | 4 | C | 1 | 1 | 1 | 1 (M) | 78 | – |
| Barba et al, 2021 | 5 | C | 1 | 1 | 1 | 1 (F) | 51 | – |
| Beck et al, 2020 a | 6 | CS | 25 | 25 | 12 (48) | 12 (M) | NR | NR |
| Beecher et al, 2022 | 7 | C | 1 | 1 | 1 | 1 (M) | 68 | – |
| Belicard et al, 2023 | 8 | C | 1 | 1 | 1 | 1 (M) | 70 | – |
| Bourbon et al, 2021 (Fr) | 9 | CS | 19 | 11 | 5 (45) | 5 (M) | 63 (53-66) | 66 (47-83) |
| Campochiaro et al, 2022 | 10 | CS | 1 | 3 | 1 (33) | 1 (M) | 68 | 69 (68-70) |
| Ciferska et al, 2022 | 11 | CS | 3 | 3 | 2 (66) | 2 (M) | 72 (68-76) | 74 (68-76) |
| Ciprian et al, 2022 | 12 | C | 1 | 1 | 1 | 1 (M) | 56 | – |
| Delplanque et al, 2021 (Fr) | 13 | CS | 26 | 6 | 1 (17) | 1 (M) | 64.5 | 64.3 (63.6-68.2) |
| Diprose et al, 2022 | 14 | C | 1 | 1 | 1 | 1 (M) | 68 | – |
| Fanlo et al, 2022 | 15 | C | 1 | 1 | 1 | 1 (M) | 77 | – |
| Ferrada et al, 2021 | 16 | CS | 98 | 13 | 4 (31) | 4 (M) | NR | 56 (45-70) |
| Ferrada et al, 2022 b | 17 | CS | 83 | 83 | 45 (54) | 45 (M) | NR | 66 (41-80) |
| Fukuda et al, 2024 | 18 | C | 1 | 1 | 1 | 1 (M) | 67 | – |
| Georgin-Lavialle et al, 2022 (Fr) | 19 | CS | 116 | 116 | 47 (41) | 47 (NR) | NR | 71 (66, 76) c |
| Goyal et al, 2022 | 20 | C | 1 | 1 | 1 | 1 (M) | 64 | – |
| Guerrero-Bermúdez et al, 2022 | 21 | C | 1 | 1 | 1 | 1 (M) | 72 | – |
| Gupta et al, 2024 | 22 | C | 1 | 1 | 1 | 1 (M) | 63 | – |
| Hines et al, 2023 | 23 | CS | 25 | 25 | 16 (64) | 16 (M) | NR | 66 (59-70) c |
| Holmes et al, 2024 | 24 | C | 1 | 1 | 1 | 1 (M) | 70 | – |
| Islam et al, 2022 | 25 | CS | 3 | 3 | 3 | 3 (M) | 68 (67-69) | – |
| Khitri et al, 2022 (Fr) | 26 | CS | 95 | 55 | 30 (57) | NR | NR | 66 (61-72) c |
| Kirino et al, 2021 (J) | 27 | CS | 3 | 3 | 2 (66) | 2 (M) | 66.5 (66-67) | 66.6 (66.3-73.5) |
| Kunishita et al, 2022 (J) | 28 | CS | 3 | 3 | 2 (66) | 2 (M) | 66.5 (66-67) | 66.6 (66.3-73.5) |
| Lacombe et al, 2021 (Fr) | 29 | CS | 6 | 6 | 2 (33) | 2 (M) | NR | 74 (70-78) c |
| Lee et al, 2021 | 30 | C | 1 | 1 | 1 | 1 (M) | 69 | – |
| Lohaus et al, 2023 | 31 | C | 1 | 1 | 1 | 1 (M) | 77 | – |
| Lokhande et al, 2023 | 32 | C | 1 | 1 | 1 | 1 (M) | 57 | – |
| Lotscher et al, 2022 | 33 | C | 1 | 1 | 1 | 1 (M) | 68 | – |
| Martín-Nares et al, 2022 | 34 | C | 1 | 1 | 1 | 1 (M) | 77 | – |
| Matsumoto et al, 2022 | 35 | C | 1 | 1 | 1 | 1 (M) | 60 | – |
| Midtvedt et al, 2022 | 36 | C | 1 | 1 | 1 | 1 (M) | late 60s | – |
| Muratore et al, 2022 | 37 | CS | 7 | 3 | 1 (33) | 1 (M) | 64 | – |
| Myint et al, 2023 | 38 | C | 1 | 1 | 1 | 1 (M) | 76 | – |
| Neupane et al, 2022 | 39 | C | 1 | 1 | 1 | 1 (M) | early 60s | – |
| Raaijmakers et al, 2021 | 40 | CS | 3 | 3 | 3 | 3 (M) | 67 (61-77) | – |
| Riescher et al, 2024 (Fr) | 41 | CS | 20 | 2 | 1 (50) | 1 (M) | 64 | 63 (62-64) |
| Rivera et al, 2022 | 42 | C | 1 | 1 | 1 | 1 (M) | 75 | – |
| Staels et al, 2021 (Fr) | 43 | CS | 2 | 2 | 2 | 2 (M) | 72 (69-75) | – |
| Strasser et al, 2024 | 44 | C | 1 | 1 | 1 | 1 (M) | 46 | – |
| Takahashi et al, 2021 | 45 | C | 1 | 1 | 1 | 1 (M) | 55 | – |
| Templé et al, 2021 (Fr) | 46 | CS | 2 | 2 | 1 (50) | 1 (M) | 74 | 72.5 (71-74) |
| Topilow et al, 2022 | 47 | C | 1 | 1 | 1 | 1 (M) | 57 | – |
| Tsuchida et al, 2021 (J) | 48 | CS | 14 | 8 | 3 (37.5) | 3 (M) | 66.6 (66.3-68.7) | 72.4 (66.3-81.1) |
| van der Made et al, 2022 | 49 | CS | 12 | 12 | 5 (42) | 5 (M) | 69 (47-79) | 67 (47-79) |
| Vitale et al, 2024 | 40 | CS | 59 | 59 | 27 (46) | 27 (M) | 65.2 ± 11.75 d | 65.4 ± 10.6 d |
| Vu et al, 2023 | 51 | C | 1 | 1 | 1 | 1 (M) | 62 | – |
| Zewar et al, 2024 | 52 | C | 1 | 1 | 1 | 1 (M) | 67 | – |
a Beck and associates reported the presence of ocular findings in 7 patients (episcleritis = 3, uveitis = 2, scleritis = 1, iritis = 1) and also separately periorbital edema (n = 4) and 1 case of giant cell arteritis.
b Ferrada and associates reported the presence of periorbital edema (n = 25) and ocular inflammation (n = 20) within a cohort of 83 patients with VEXAS. There is lack of information on potential overlap of patients with these reported features, or with overlap with other case series.
VEXAS demographics and ocular features
We identified 204 individual reported cases of genetically confirmed VEXAS with ophthalmic features (including 1 female with monosomy X; Table 2 ). The mean age of symptom onset was 66.6 ± 5.1 years (range 46-87). Orbital inflammation was the most common ocular manifestation, comprising periorbital edema (n = 83, 40.7%), orbital myositis (n = 14, 6.9%), dacryoadenitis (n = 6, 2.9%), and orbital compartment syndrome (n = 1, 0.5%). Other ophthalmic features included episcleritis (n = 28, 13.7%), scleritis (n = 28, 13.7%), uveitis (n = 25, 12.3%), retinal vasculitis (n = 2, 1%), ocular inflammation (n = 20, 9.8%), blepharitis (n = 5, 2.5%), conjunctivitis (n = 6, 2.9%), optic peri-neuritis (n = 2, 1%), red eye (n = 1, 0.5%), GCA (n = 1, 0.5%), and ocular involvement not otherwise specified (n = 16, 7.8%).
| Reference | Sample Size | Age, y | Periorbital Edema | Myositis | Dacryoadenitis | Episcleritis | Scleritis | Uveitis | Retinal Vasculitis | Ocular Inflammation | Blepharitis | Conjunctivitis | Optic Perineuritis | Red Eye | Giant Cell Arteritis | Orbital Compartment Syndrome | Involvement Not Otherwise Specified |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Abumanhal et al, 2024 | 6 | 74.5 (69-87) | 5 | 1 | 2 | 1 | 2 | 1 | – | – | – | – | – | – | – | – | – |
| Agwan et al, 2024 | 1 | 73 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Al-Hakim et al, 2022 | 1 | 64 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Ang et al, 2024 | 1 | 78 | 1 | 1 | 1 | – | – | – | – | – | – | – | 1 | – | – | – | – |
| Barba et al, 2021 | 1 | 51 | – | – | – | 1 | – | – | – | – | – | – | – | – | – | – | – |
| Beck et al, 2020 | 12 a | NR | 4 | – | – | 3 | – | 3 | – | – | – | – | – | – | 1 | – | – |
| Beecher et al, 2022 | 1 | 68 | 1 | – | 1 | – | – | – | – | – | – | – | – | – | – | – | – |
| Belicard et al, 2023 | 1 | 70 | 1 | – | – | 1 | – | – | – | – | – | – | – | – | – | – | – |
| Campochiaro et al, 2022 | 1 | 68 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Ciferska et al, 2022 | 2 | 72 (68-76) | – | – | – | 1 | – | 1 | – | – | – | – | – | – | – | – | – |
| Ciprian et al, 2022 | 1 | 56 | 1 | 1 | – | – | 1 | – | – | – | – | – | – | – | – | – | – |
| Diprose et al, 2022 | 1 | 68 | 1 | – | – | 1 | – | – | – | – | – | 1 | – | – | – | – | – |
| Fanlo et al, 2022 | 1 | 77 | 1 | – | – | 1 | – | – | – | – | – | – | – | – | – | – | – |
| Ferrada et al, 2021 | 4 | NR | 4 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Ferrada et al, 2022 b | 45 | NR | 25 | – | – | – | – | – | – | 20 | – | – | – | – | – | – | |
| Fukuda et al, 2024 | 1 | 67 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Georgin-Lavialle et al, 2022 (Fr) | 47 | NR | 14 c | – | – | 14 | 10 | 11 | – | – | – | – | – | – | – | – | – |
| Goyal et al, 2022 | 1 | 64 | 1 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Guerrero-Bermúdez et al, 2022 | 1 | 72 | – | – | – | – | – | – | – | – | – | – | – | 1 | – | – | – |
| Gupta et al, 2024 | 1 | 63 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | 1 | – |
| Hines et al, 2023 d | 16 | 66 [59-70] | – | – | – | – | – | – | – | – | – | – | – | – | – | – | 16 |
| Holmes et al, 2024 | 1 | 70 | 1 | – | – | – | – | 1 | – | – | – | – | – | – | – | – | – |
| Islam et al, 2022 | 3 | 68 (67-69) | 2 | – | – | – | 1 | – | – | – | – | – | – | – | – | – | – |
| Kunishita et al, 2022 (J) | 2 | 66.5 (66-67) | – | – | – | – | 2 | – | – | – | – | – | – | – | – | – | – |
| Lee et al, 2021 | 1 | 69 | – | – | – | – | 1 | – | – | – | – | 1 | – | – | – | – | – |
| Lohaus et al, 2023 | 1 | 77 | – | – | – | – | – | 1 | – | – | – | – | – | – | – | – | – |
| Lokhande et al, 2023 | 1 | 57 | 1 | 1 | – | – | 1 | – | – | – | – | – | – | – | – | – | – |
| Lotscher et al, 2022 | 1 | 68 | – | – | – | – | 1 | – | – | – | – | – | – | – | – | – | – |
| Martín-Nares et al, 2022 | 1 | 77 | 1 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Matsumoto et al, 2022 | 1 | 60 | – | – | – | – | – | – | 1 | – | – | – | – | – | – | – | – |
| Midtvedt et al, 2022 | 1 | 67 e | – | – | – | – | – | 1 | – | – | – | – | – | – | – | – | – |
| Muratore et al, 2022 | 1 | 64 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Myint et al, 2023 | 1 | 76 | 1 | 1 | 1 | – | – | – | – | – | – | – | – | – | – | – | – |
| Neupane et al, 2022 | 1 | 63 f | – | – | – | – | 1 | – | 1 | – | – | – | – | – | – | – | – |
| Poulter et al, 2021 | 1 | NR | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Raaijmakers et al, 2021 | 3 | 67 | 1 | – | – | – | 2 | – | – | – | – | – | – | – | – | – | – |
| Rivera et al, 2022 | 1 | 75 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Strasser et al, 2024 | 1 | 46 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Takahashi et al, 2021 | 1 | 51 | 1 | 2 | – | – | 1 | – | – | – | – | – | 1 | – | – | – | – |
| Topilow et al, 2022 | 1 | 57 | – | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – |
| van der Made et al, 2022 | 5 | 69 (47-79) | 1 | 1 | 1 | – | – | 2 | – | – | 2 | – | – | – | – | – | – |
| Vitale et al, 2024 | 27 | 65.2 ± 11.75 | 8 | 2 | – | 5 | 5 | 4 | – | – | 3 | 4 | – | – | – | – | – |
| Vu et al, 2023 | 1 | 62 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Zewar et al, 2024 | 1 | 67 | 1 | 1 | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Total (%) | 204 (100) | 66.6± 5.1 years | 83 (40.7) | 14 (6.9) | 6 (2.9) | 28 (13.7) | 28 (13.7) | 25 (12.3) | 2 (1) | 20 (9.8) | 5 (2.5) | 6 (2.9) | 2 (1) | 1 (0.5) | 1 (0.5) | 1 (0.5) | 16 (7.8) |
a Beck and associates report ophthalmic manifestations in 7 patients, and separately report GCA (n = 1) and periorbital edema (n = 4).
b Ferrada and associates reported the presence of periorbital edema (n = 25) and ocular inflammation (n = 20) within a cohort of 83 patients with VEXAS. There is lack of information on the potential overlap between these features.
c Georgin-Lavialle and associates reported periorbital edema in 10 patients and also “orbital mass” in 4 patients.
d Hines reported ocular inflammation in 16 patients and had a separate reporting of facial swelling (including periorbital) in 6 patients.
e Age reported as late 60s (67).
Visual acuity was not included in most reports, and when reported, there was predominantly a mild reduction in visual acuity (n = 4, 2%), , , , with severe visual loss (RVA 6/120) reported in VEXAS-associated orbital compartment syndrome that improved to 6/15 within 3 days of emergency lateral canthotomy and cantholysis. Magnetic resonance imaging may demonstrate typical findings in dacryoadenitis and scleritis ( Figure 2 ).
META-ANALYSIS
VEXAS demographics and genetics
Meta-analysis included 33 studies (n = 48, mean age 67.9 ± 8.5 years; Supplementary Table). , , , , , , , , , , , , , , , , , , , , , , , The most commonly reported UBA1 mutation was the missense mutation p.Met41Thr (c.122T>C, n = 24, 50%), followed by p.Met41Val (c.121A>G, n = 17, 35%), p.Met41Leu (c.121A>C, n = 4, 8.3%) and splice site mutations or deletions (various, including c.118-1G>C, c.118-9_118-2del, n = 3, 6.3%, Figure 3 ).
VEXAS ocular features
Presentation of VEXAS was with ocular symptoms in a minority (n = 5, 10%). , , , Of these cases the time from presentation to VEXAS diagnosis was reported for 4 patients, at median 10 months (range 1-48). , , Laterality of ophthalmic involvement was reported for a subset of cases (n = 20) and was bilateral in most (n = 13, 65%). Age of symptom onset was not associated with severity of ophthalmic manifestation ( P = .6), older age was associated with dacryoadenitis ( P = .03), and there was a trend toward older age being associated with periorbital edema ( P = .07). UBA1 splice site mutation was associated with presence of retinal vasculitis ( P = .01). There was a significant association for more severe ophthalmic manifestations with UBA1 splice site mutations or deletions, vs methionine 41 missense mutations ( P = .05, Table 3 ). UBA1 mutation was not associated with initial VEXAS presentation being ocular.
| Age, y, Median (Range) | UBA1 Mutation | Systemic Features | Total Case no. per Feature / Severity / Presentation / Laterality/ Overall | |||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| thr | val | leu | Splice | Myelodysplasia | Macrocytic Anemia | Chondritis | Recurrent Fever | Weight Loss | Pulmonary | Venous Thrombosis | Dermatologic | Arthritis | Mortality Due to VEXAS | |||
| Ophthalmic features | ||||||||||||||||
| Blepharitis | 58 (47-69) | 2 (100) | – | – | – | 1 (50) | 1 (50) | 2 (100) | 1 (50) | – | 1 (50) | – | 2 (100) | 1 (50) | – | 2 |
| Episcleritis | 70 (51-77) | 3 (60) | 1 (20) | 1 (20) | – | 3 (60) | 2 (40) | 4 (80) | 5 (100) | 1 (20) | 3 (60) | 1 (20) | 5 (100) | 2 (40) | – | 5 |
| Periorbital edema | 70 (46-87) | 10 (40) | 13 (52) | 1 (4) | 1 (4) | 15 (60) | 9 (36) | 11 (44) | 20 (80) | 5 (20) | 19 (76) | 12 (48) | 20 (80) | 12 (48) | 2 (8) | 25 |
| Dacryoadenitis | 77 (68-87) | 1 (33) | 2 (66) | – | 1 (33) | 2 (66) | 1 (33) | – | 1 (33) | 1 (33) | 2 (66) | 2 (66) | 3 (100) | – | 1 (33) | 3 |
| Myositis | 70 (56-78) | 2 (33) | 2 (33) | 1 (17) | 1 (17) | 4 (66) | 3 (50) | 3 (50) | 4 (66) | 2 (33) | 5 (83) | 3 (50) | 5 (83) | 4 (66) | 1 (17) | 6 |
| Uveitis | 74 (67-79) | 1 (33) | 2 (66) | – | – | 2 (66) | 2 (66) | 2 (66) | 2 (66) | 2 (66) | 2 (66) | – | 3 (100) | 1 (33) | 2 (66) | 3 |
| Scleritis | 67 (51-76) | 8 (62) | 2 (15) | 2 (15) | 1 (8) | 8 (62) | 8 (62) | 10 (77) | 11 (85) | 2 (15) | 5 (38) | 3 (23) | 12 (92) | 4 (31) | 3 (23) | 13 |
| Retinal vasculitis | 63 (60-71) | 1 (33) | – | – | 2 (66) | 3 (100) | 1 (33) | 2 (66) | 1 (33) | – | 3 (100) | 1 (33) | 3 (100) | – | – | 3 |
| Giant cell arteritis | 77 | – | 1 (100) | – | – | 1 (100) | – | – | 1 (100) | – | 1 (100) | – | – | – | 1 (100) | 1 |
| Age, y, median (range) | – | 67 (46-78) | 73 (51-87) | 67 (57-72) | 71 (60-75) | 69 (46-79) | 68 (51-87) | 67 (46-77) | 68 (46-79) | 74 (57-79) | 69 (46-79) | 69 (56-77) | 68 (46-79) | 68 (51-77) | 72 (67-79) | |
| UBA1 mutation | ||||||||||||||||
| thr | 67 (46-78) | – | – | – | – | 10 (42) | 15 (63) | 19 (79) | 19 (79) | 3 (13) | 12 (50) | 4 (17) | 21 (88) | 13 (54) | 1 (4) | 24 |
| val | 73 (51-87) | – | – | – | – | 12 (71) | 7 (41) | 6 (35) | 13 (76) | 4 (24) | 13 (76) | 7 (41) | 13 (76) | 5 (29) | 4 (24) | 17 |
| leu | 67 (57-72) | – | – | – | – | 3 (75) | 2 (50) | 3 (75) | 4 (100) | 1 (25) | 2 (50) | 2 (50) | 4 (100) | 2 (50) | – | 4 |
| Splice | 71 (60-75) | – | – | – | – | 3 (100) | – | 1 (33) | 2 (66) | 1 (33) | 3 (100) | 2 (66) | 3 (100) | – | 1 (33) | 3 |
| Severity | ||||||||||||||||
| Mild | 69 (47-77) | 5 (71) | 1 (14) | 1 (14) | – | 4 (57) | 3 (43) | 6 (86) | 6 (86) | 1 (14) | 4 (57) | 1 (14) | 7 (100) | 3 (43) | – | 7 |
| Moderate | 70 (46-87) | 12 (46) | 12 (46) | 2 (8) | – | 13 (50) | 13 (50) | 12 (46) | 19 (73) | 6 (23) | 18 (69) | 10 (38) | 20 (77) | 13 (50) | 2 (8) | 25 |
| Severe | 67 (51-77) | 8 (50) | 3 (19) | 2 (13) | 3 (19) | 11 (69) | 8 (50) | 11 (69) | 13 (50) | 2 (13) | 8 (50) | 4 (25) | 14 (88) | 4 (25) | 4 (25) | 16 |
| Initial presentation: ophthalmic | 75 (57-87) | 1 (20) | 2 (40) | 1 (20) | 1 (20) | 3 (60) | 3 (60) | 2 (40) | 3 (60) | 2 (40) | 2 (40) | 1 (20) | 4 (80) | 2 (40) | 2 (40) | 5 |
| Laterality a | ||||||||||||||||
| Unilateral | 69 (57-75) | 3 (43) | 2 (29) | 2 (29) | – | 5 (71) | 4 (57) | 4 (57) | 6 (86) | 1 (14) | 6 (86) | 0 | 7 (100) | 4 (57) | 1 (14) | 7 |
| Bilateral | 75 (56-87) | 4 (31) | 8 (62) | – | 1 (8) | 9 (69) | 4 (31) | 4 (31) | 8 (62) | 4 (31) | 11 (85) | 7 (54) | 10 (77) | 3 (23) | 2 (15) | 13 |
| Overall | 68.4 (46-87) | 24 (50) | 17 (35) | 4 (8) | 3 (6) | 28 (58) | 24 (50) | 29 (60) | 38 (79) | 9 (19) | 30 (63) | 15 (31) | 41 (85) | 20 (41) | 6 (13) | 48 (100) |
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