Orbital Inflammation: Important Associations

Nora was a middle-aged woman booked directly into my orbital clinic after a few episodes of what was diagnosed as conjunctivitis. The symptoms had not improved with drops, and at her eye casualty visit, diplopia had been elicited.

“I see you don’t have any medical problems?” I said—a quick, essential question as well as an attempt to assure Nora that I had read her notes. I had seen the “medical history: nil” entry, but I still needed to satisfy myself that any known systemic associations for her eye complaints did not exist. Best to search for low-hanging fruit first.

“No, nothing.”

“Any joint pains, rash, feeling unwell?”

“Not particularly.”

“Right, we’re going to need to send some tests, then.”

For the most part, our clinics are filled with patients who have neat problems, like cataracts or glaucoma. Usually there is not an undiagnosed systemic disorder (other than ageing) with which we need to concern ourselves. Treating our patients well involves correctly identifying the cause of their vision complaint and treating that well.

This is one of the main attractions of ophthalmology—we can improve our patients’ quality of life by improving or maintaining their vision with a suite of highly targeted, highly evolved interventions. We can make adjustments when there is a relevant co-pathology; for example, we might add topical NSAIDs for our cataract patients with type 2 diabetes or check a 24-hour blood pressure monitor for our normal tension glaucoma patients. So far, so straightforward.

But this is not always the case. We need to be vigilant and slow down when we have a patient who falls outside this picture. A uveitis patient may harbour an associated systemic vasculitis, for instance, or a child whose amblyopia does not respond to occlusion may have something else going on. Our orbital patients should also give us pause.

Orbital inflammation is wide-ranging, and each case of orbital inflammation is unique. In treating these patients (which is not necessarily straightforward), we need to actively pursue a range of potential associations, some commonplace and a few rare and serious. A good starting point arises from that frequent exam question for ophthalmology residents: what is the most common cause of orbital inflammation, outside of infectious orbital cellulitis?

The answer, of course, is thyroid eye disease, and the top association to be screened for is dysthyroidism. Once a clinical suspicion is raised, the relevant blood components to check include thyroid-stimulating hormone (TSH), thyroid hormone levels, and TSH-receptor antibodies (TRrab). Thyroid eye disease is most often associated with hyperthyroidism, although hypothyroidism is also associated. Confusingly, a thyroid eye disease phenotype can also be seen in euthyroidism, where there is no evidence of thyroid hormone levels being off. Testing TRab levels can be helpful in these cases, as a raised TRrab level may be the only biochemical abnormality detected.

Investigating these patients involves more than thyroid bloods, of course. We need to obtain orbital imaging, along with other bloods and targeted investigations, depending on the history and exam. Investigation and treatment are nuanced. Starting immunosuppression if the diagnosis is uncertain can be problematic, as this can have a detrimental effect on the yield of an orbital biopsy, resulting in delay and uncertainty about the eventual diagnosis.

Outside of thyroid eye disease, orbital inflammation has a long list of associations, including potentially fatal conditions. One well-established association is granulomatosis with polyangiitis (GPA), a vasculitis that typically involves the upper and lower respiratory tract and the kidneys. Useful tests include serum ANCA levels, inflammatory markers, and urinalysis for casts, although biopsy of an affected site is confirmative. Another potentially fatal association, VEXAS, has been described as recently as 2020.

VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome is a somatic, non-germline genetic disorder that develops in adulthood. In VEXAS, a clonal expansion of abnormal haematopoietic stem cells occurs, leading to systemic inflammation and bone marrow failure along with eye conditions, including orbital inflammation, orbital myositis, and uveitis. There is a wide range of ocular features associated with VEXAS that were published in a meta-analysis in the American Journal of Ophthalmology in August 2025.

VEXAS occurs due to a mutation in UBA1 at codon p.Met41, located on the X chromosome. This results in a specific demographic pattern of pathology: males, or individuals with one X chromosome, are overwhelmingly affected. Females can be affected in rare instances—when they have congenital monosomy X, known as Turner syndrome, or acquired mosaic monosomy X. As the disease has only recently been described, the epidemiology of VEXAS is not well known yet, but it appears to have an estimated prevalence of one in 4,000 men older than age 50.

Upon diagnosis, VEXAS has a significant mortality rate of 30–50% within 5 years. Multisystem inflammation and susceptibility to infection via disease-mediated and treatment-related mechanisms likely contribute to this. The inflammation associated with VEXAS responds to systemic glucocorticoids and is otherwise difficult to control.

Nora’s “conjunctivitis” turned out to be orbital myositis and dacryoadenitis, with an orbital biopsy showing nonspecific inflammation in keeping with idiopathic orbital inflammatory disease. She responded to a slow taper of oral steroids, resulting in an easy orbit.

This article is part of a series of columns on eyelid conditions. Previous columns are available on the EuroTimes website.

Clare Quigley MD is a Consultant Eye Surgeon in private practice in Progressive Vision, and in public practice in the Royal Victoria Eye and Ear Hospital and St James’s Hospital, Dublin, Ireland.