VEXAS syndrome is a rare autoinflammatory disorder that is acquired in adulthood and caused by mutations in the UBA1 gene. It is triggered by acquired somatic mutations in the blood tissues, resulting in hematoinflammatory manifestations [1, 18]. In this paper, we present ocular manifestations in eight patients diagnosed with VEXAS and review the myriad of ocular features reported in the literature.

The clinical spectrum of orbital involvement in VEXAS syndrome continues to be defined as more cases are confirmed and described. A literature review carried out by Koster et al. concluded that 15% of VEXAS patients experienced orbital and/or periorbital inflammation [19]. Beecher and colleagues reported a similar rate of 13.9% [11]. The reported prevalence of ocular symptoms in patients with VEXAS is between 16–39% [1, 20, 21]. Periorbital oedema was the most frequently described ocular manifestation. Georgin et al. found that 10 out of 116 patients (8.6%) presented with periorbital oedema [21]. Ferrada and colleagues reported a higher rate of 30% in a case series of 83 patients [20]. We identified 7 out of 8 (87.5%) patients with periorbital oedema. We assume that patients with periorbital oedema might be underdiagnosed since the symptoms could be mild and sometimes are managed by general physicians or outpatient ophthalmologists. Moreover, most studies reported in the literature were conducted by internal medicine specialists, specifically rheumatologists, immunologists, dermatologists, and haematologists. To our knowledge, this case series is the first reported by ophthalmologists, focusing on ocular and orbital manifestations.

In our study, we found that four patients (50%) presented with orbital inflammatory syndrome (OIS), including dacryoadenitis, posterior scleritis, and EOM orbital myositis. Other reported orbital presentations include cellulitis [12, 13], optic perineuritis [4, 6], polycranial neuritis causing ophthalmoplegia [14], peri/intraorbital panniculitis [15], and ocular palsy [9]. Reviewing the cases of VEXAS patients reported in the literature, we found that only a small subset of patients underwent orbital imaging. This may serve as an explanation for the underdiagnosis of orbital involvement.

Georgin et al. reported that 9.5% of VEXAS patients presented with uveitis [21]. Anterior uveitis was present in two patients (25%) in our series. One patient (12.5%) presented with episcleritis. Similarly, the same rate was reported in Georgin’s paper (12.1%). Other reported intraocular manifestations included optic neuritis [7] and retinal vasculitis [16].

Orbital biopsy was performed only in case number 2. The histopathology of the lacrimal gland showed a patchy T and B lymphocytic infiltrate and negative IgG4 staining. Beecher reported lacrimal gland biopsy demonstrating weak IgG4 granular staining in mast cells and very few IgG positive plasma cells [11]. Histopathologic evaluation reported by Van der made showed adipose tissue with reactive changes and panniculitis [15]. All reported biopsies were inconclusive and showed nonspecific inflammation. Therefore, based on the literature and our series, the value of orbital biopsy is limited and does not contribute to VEXAS diagnosis.

Almost all of the known pathogenic mutations leading to VEXAS syndrome involve substitutions of Methionine-41 (p.Met41). Around half of all published cases of VEXAS have the c.122T>C, p.Met41Thr substitution, while another fifth are made up of the c.121A>G, Met41Val and c.121A>C, Met41Leu substitution [4, 12, 17]. In our series, out of six patients who underwent genetic testing, four patients (66%) were diagnosed with Met41Val mutation. This mutation was also reported in VEXAS patients with ocular involvement [5,6,7, 11, 22]. The fact that Met41Val mutation is not the most common one and that it is highly diagnosed in our case series and in other ocular manifestations could warrant the speculation that this mutation may be related to ocular involvement in VEXAS syndrome. Further studies are needed to confirm this hypothesis.

Two patients (case 1 & 2) demonstrated elevated thyroglobulin antibody, and one (case 2) also showed a high titre of thyroid peroxidase antibody. Both patients had euthyroid function without clinical features of hyper or hypothyroidism. Both patients did not show typical EOM enlargement on CT scan compatible with thyroid ophthalmopathy. Thyroid antibodies were not undertaken in the rest of the patients. Huang reported a rate of 16.5% among VEXAS patients who had autoimmune disorders [23]. The most common was rheumatoid arthritis followed by psoriasis, hypothyroidism, and Behcet syndrome. Reviewing the literature, there was no reported data showing the correlation between thyroid antibodies and VEXAS syndrome.

All patients in this series had a good ocular prognosis. Patients with orbital involvement showed a rapid and good response to corticosteroids. Prednisone 20–40 mg/day seems to be the most effective treatment for VEXAS-related inflammation flares, including ophthalmological manifestations [9, 19, 24]. However, Beecher reported a case of recurrent dacryoadenitis refractory to methotrexate, which was controlled upon the treatment of the JAK inhibitor tofacitinib [10].

Early diagnosis of VEXAS is of high clinical importance. The detection of multisystem life-threatening syndromes such as VEXAS can prevent unnecessary immunological, histopathological, and radiological evaluations. Administration of appropriate systemic treatment in the early stages may prevent developing systemic inflammatory manifestations. In our paper, ocular manifestation was the presenting symptom in two patients (25%). Case 1 was diagnosed in the early stages and avoided needless investigations. Case 2 presented first before VEXAS was reported. He underwent extensive laboratory and imaging investigations. Since the diagnosis of VEXAS was performed, ocular and systemic manifestations were well controlled under tocilizumab and steroids. We suggest that in older male patients with haematological cytopenia (mainly MDS and macrocytic anaemia), presenting with ocular symptoms and high inflammatory markers, a genetic test to diagnose VEXAS syndrome should be undertaken.

The limitations of this study stem from its retrospective design and small sample size. In addition, the diagnosis in two patients was based on clinical and bone marrow aspiration features without genetic testing for a UBA1 mutation.

In conclusion, we have reported the largest series to date of VEXAS patients with ocular and orbital manifestations, including orbital inflammation, dacryoadenitis, myositis, uveitis, scleritis, episcleritis, and periorbital oedema. Ophthalmologists should be aware of this entity and refer suspected patients for genetic testing, which may save unnecessary testing and long wait times until a precise diagnosis is made. Due to the recent discovery of VEXAS and the heterogeneity of clinical manifestations, larger clinical series with longer follow-up periods are required to further investigate the ocular and orbital manifestations of this new clinical entity.