VEXAS syndrome, a late-onset, acquired autoinflammatory disorder caused by mutations in the UBA1 gene, was recently described in the literature. 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 [21]. Beecher and colleagues, reported the same rate of 13.9% [11]. The reported prevalence of ocular symptoms in patients with VEXAS is 16–39% [1, 19, 20]. Periorbital edema was the most frequently described ocular manifestation. Georgin et al found that 10 of 116 patients (8.6%) presented with periorbital edema [20]. Ferrada and colleagues reported a higher rate of 30% in a case series of 83 patients [19]. We identified 7 out of 8 (87.5%) patients with periorbital edema. We assume that patients with periorbital edema 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 hematologists. To our knowledge, this case series is the first reported by ophthalmologists, focusing on ocular and orbital manifestations.
In our paper, four patients (50%) presented with orbital inflammatory syndrome (OIS) such as: 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 orbital involvement underdiagnosis.
Georgin et al reported that 9.5% of VEXAS patients presented with uveitis [20]. 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 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. So, the value of orbital biopsy, based on the literature and our series, is limited and does not contribute for 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.122 T > C, p.Met41Thr substitution, while another fifth are made up of the c.121A > G, Met41Val and c.121A > C, Met41Leu substitution [12, 23, 24]. In our series, out of six patient 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, 25]. 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.
Tow patients (case 1 & 2) demonstrated elevated thyroglobulin antibody, and one (case 2) also showed high titer 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 anti-bodies were not undertaken in the rest of the patients. Huang reported a rate of 16.5% among VEXAS patients who had autoimmune disorders [26]. The most common was rheumatoid arthritis followed by psoriasis, hypothyroidism and behcet syndrome. Reviewing the literature, there was no reported data shows the correlation between thyroid anti-bodies and VEXAS syndrome.
All patients, in this series, had ocular good prognosis. Patients with orbital involvement showed rapid and good response to corticosteroids. Prednisone 20-40mg/day seems to be the most effective treatment for VEXAS related inflammation flares, including ophthalmological manifestations [9, 21, 27]. 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 has high clinical importance. The detection of multisystem life-threatening syndrome, such VEXAS, can withhold unnecessary immunological, histopathological and radiological evaluations, and administration of appropriate systemic treatment in the early stages may prevent developing systemic inflammatory manifestations. In our paper, the ocular manifestation was the presenting symptoms in two patients (25%). Case 1 was diagnosed in 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 hematological cytopenia (mainly MDS and macrocytic anemia), 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 the 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 reported the largest series to date of VEXAS patients with ocular and orbital manifestations including orbital inflammation, dacryoadenitis, myositis, uveitis, scleritis, episcleritis and periorbital edema. Ophthalmologists should be aware of this entity and refer suspected patients for genetic testing, which may save unnecessary testing and long time until precise diagnosis. Due to the recent discovery of VEXAS and heterogeneity of clinical manifestations, larger clinical series with longer follow-up period are required to further investigate the ocular and orbital manifestations of this new clinical entity.