**5. Immunotherapy-associated uveitis**

The medical term for intraocular inflammation is uveitis. Uveitis is an inflammation involving uveal tissue, consisting of its three main components: iris, ciliary body, and choroid. The etiology can be of infectious or non-infectious inflammatory origin. This difference is essential to establish when diagnosing patients with intraocular inflammation since the treatments will differ vastly. Immunotherapy-associated uveitis is the term given to patients who develop intraocular inflammation while taking immune-modulating medications. The novel immunotherapies being used to treat cancer have been linked to causing uveitis. The overall reported incidence is 1%, although patients with a combination of ICIs might have a higher incidence [4, 10, 13]. The median onset is 5–9 weeks, depending on various reports [10, 13]. But it can range from 1 to 72 weeks [13]. There is a difference in the onset and severity of uveitis depending on the type of ICI used. Some reports have stated an incident of uveitis in 64% of patients taking the anti-CTLA-4 Ipilimumab [20]. It is important to note that most PD-1 and PD-L1 medications have been approved by the FDA for less time and have fewer indications than Ipilimumab, which could also be a reason for the decreased reported incidence.

A comprehensive literature review of 126 cases of immune checkpoint-associated uveitis in 2020 by E.R Dow et al. showed that 93.5% of patients had bilateral inflammation. The most common anatomic location was anterior with 37.7%, followed by panuveitis at 34.0%, posterior at 25.7%, and intermediate at 0.01% [10]. They also noted that five of their eight unilateral cases were from single case series, suggesting a possible disconnect between the descriptions and interpretations of laterality. Comparing the ICIs, Ipilimumab had the highest anterior uveitis percentage, while atezolizumab had the highest percentage of posterior uveitis. Interestingly the posterior findings of atezolizumab resembled deep capillary ischemic pathologies such as acute macular neuroretinopathy and paracentral acute middle maculopathy with retinal vasculitis or venulitis, while 0% of anterior uveitis. Another common posterior uveitis finding was a Vogt–Koyanagi–Harada (VKH)-like syndrome. This VKH-like presentation gives us more insight into the pathophysiology associated with immuneassociated uveitis, which may represent a spectrum of autoimmune diseases within the eye due to a loss of tolerance in an immune-privileged organ and the subsequent development of T-cell- driven inflammation [8].

Presenting symptoms may include blurred vision, change in color vision, photophobia, visual distortion, scotomas, visual field changes, double vision, tenderness, pain with eye movement, eyelid swelling, proptosis, redness, and dryness [13]. Symptoms may not always correlate with the severity of inflammation. Unfortunately, no standardized controlled trials are available, and there is no information regarding whether the onset is acute or insidious in these immunotherapy-associated uveitis cases. Below we will discuss grading systems used as well as monitor and treatment recommendations.

## **5.1 Grading**

Uveitis grading is based on the terminology proposed by the Standardization of Uveitis Nomenclature for disease classification criteria (SUN Criteria) [21]. It assigns a name based on the predominant anatomical location of active intraocular inflammation. The SUN criteria subdivide the eye into anatomic compartments; anterior, which refers to inflammation in the anterior chamber, intermediate = inflammation located in the vitreous cavity, anterior/intermediate = inflammation equally located in the anterior chamber and vitreous cavity, and posterior = inflammation located in the retina and/or choroid. Panuveitis is termed when all compartments of the eye are equally inflamed. As part of the SUN Criteria classification, they also established a grading system to quantify intraocular inflammation. This consists of grades 0.5+ to 4 + cells. Refer to **Table 3** for grading classification.

The CTCAE is used to grade ocular, and other irAEs secondary to immunotherapies used to treat cancer. The most recent version grades uveitis as follows: grade 1 refers to anterior uveitis with trace cells (0.5+), grade 2 refers to anterior uveitis with 1 to 2+ cells, grade 3 to anterior uveitis with 3+ or greater cells or intermediate/ posterior/panuveitis, and grade 4 to 20/200 vision or worse in the affected eye [22]. Though a helpful guideline, the CTCAE has limitations since it does not consider


## **Table 3.**

*SUN criteria grading for anterior chamber cells.*

prior/baseline ophthalmological conditions that could affect visual acuity. The CTCAE cannot be accurately applied to patients with decreased baseline visual acuity.

## **5.2 Treatment options**

Immunotherapy-associated uveitis is a phenomenon that has been rising with the increased use of ICIs. Currently, no randomized controlled trials are available to provide specific treatment algorithm recommendations since most cases have been reported through case reports and small case series. The most common treatment for immunotherapy-associated uveitis is topical corticosteroids. The main goal is to keep patients on glucocorticoids for as little time as possible and maintain them on their possible life-saving anticancer medication without interruption. General recommendations are to slowly taper the corticosteroids over 4–6 weeks after clinical improvement is confirmed.

In recognition of an increasing need for guidance, The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) partnered to develop guidelines on the management of irAEs, which are resumed in **Table 4** [13, 23, 24]. These guidelines agree in general with the treatment recommendations. For grade 1, both guidelines agree to continue ICI treatment and only use topical corticosteroids. Grade 2 can be treated with topical and/or systemic corticosteroids, but patients can resume ICI therapy once inflammation improves to grade ≤ 1. Grades 3–4 ICI therapy should be permanently discontinued, and treatment should be with highdose systemic steroids. The decision of suspending or discontinuing ICI is a very complex one. There should be good and clear communication between ophthalmologists and oncology specialists for better assessment and decision-making since there are potentially devastating consequences of stopping potentially life-saving treatments.

When and how to reinstate ICI therapy after a uveitis episode is not standardized due to the low amount of data. The NCCN provides the following recommendations: for grade 2, if ICI were stopped, may consider resumption of immunotherapy in consultation with ophthalmologists if inflammation improves to grade ≤ 1. Permanent discontinuation of immunotherapy is warranted in the setting of severe intraocular inflammation (grade 3–4) and episcleritis symptomatic episcleritis with visual acuity worse than 20/40 [24, 25].

## **5.3 Monitoring**

Patients on ICI should undergo prompt ophthalmic evaluation if they develop worsening vision, floaters, or conjunctival injection [8]. Patients with any ocular


## **Table 4.**

*Grading and treatment recommendations of ocular irAEs.*

symptoms should be referred to ophthalmology. Based on the most current cancer association guidelines for grade 1, ophthalmology referral should be within one week of symptoms. For Grades 2–3, an urgent referral is recommended; based on SITC, it should be within two days [24]. For grade 4, an emergent evaluation is recommended.

An initial ophthalmologic evaluation must include visual acuity measurement of each eye separately, color vision assessment, pupil evaluation, eye pressure, slit lamp, and dilated funduscopic evaluation. Current guidelines recommended by cancer associations do not include how to manage or monitor patients with baseline ophthalmologic conditions, making the management and monitoring of this patient population a complex one. Patients with metastatic or unresectable cancers are also in a delicate state of health which predisposes them to a series of infectious pathologies, and therefore if there is suspicion, it is always recommended to rule-out infectious uveitis processes prior to commencing high-dose systemic steroids.

Close follow-up is recommended while inflammation is active and should continue after the inflammation resolves due to the risk of possible reactivation. In the case

series by E.R Dow et al. [10], in most cases, the ICI was stopped, and in more than half of the patients whose ICI was restarted, there was a recurrence of uveitis that was sometimes more severe than the initial episode. We can create more standardized monitoring guidelines as we continue to monitor patients with ICI.
