Immunotherapy-Associated Uveitis

Abstract

Novel immunotherapies used to treat some cancers, such as checkpoint inhibitors and target therapies of B-RAF protooncogene and mitogen-activated protein kinase (BRAF/MEK), have been strongly associated with adverse events related to immune dysregulation. These effects are known as immune-related adverse events (irAEs). Uveitis is among the known irAEs, and it occurs in approximately 1% of patients using these therapies. The uveitis observed in these patients ranges from anterior, intermediate, to panuveitis. If irAEs are severe, current recommendations are to stop immunotherapy treatment and simultaneously treat the uveitis with steroids (local or systemic). These oncologic immunotherapies have proved to show positive results in cancer treatment. Their use has increased with time, showing ocular side effects that were not reported previously. It is important that ophthalmologists and non-ophthalmologists are aware of these agents and their potential ocular side effects for timely diagnosis and adequate management. This chapter will review different immunotherapies and their potential ocular manifestations and how to diagnose, monitor, and manage these patients.

1. Introduction

Our immune system not only works to fight infections and produce inflammation but also has the ability to adequately recognize self-antigens to prevent autoimmunity. As part of our adaptive immune system, T-cells have a selection process in the thymus in which cells that react too strongly to self-peptides are eliminated to prevent autoreactivity in a process called central tolerance [1]. Only cells with some response to MHC complexes and self-peptides are released into the bloodstream. To prevent autoimmunity, numerous immune checkpoint pathways regulate the activation of T cells at multiple steps during an immune response, in a process called peripheral tolerance [1, 2, 3]. In this process, some of the immune checkpoints involved are cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), which work at different stages of the immune response. Medications aimed at both of these checkpoint inhibitors work by enhancing endogenous antitumor activity. BRAF/MEK inhibitors are another group of immunotherapies used as an anticancer treatment, which works by interfering with B-RAF oncogene mutations, slowing down tumor growth. Checkpoint inhibitors and BRAF/MEK inhibitor medications work very well as anticancer medications but are not without side effects. Side effects caused by these immunotherapies are known as immune-related adverse events (irAEs). An extensive list of organs can be affected in the myriad of these irAEs. Although with checkpoint inhibitors, only approximately 1% involve the eye [4]. For BRAF/MEK therapies, 25–100% of the patient can have ocular side effects [5]. With the ongoing use of these medications, it is essential to recognize these adverse effects early for adequate management and to prevent further complications. Uveitis associated with immunotherapy can present in multiple anatomic locations and with varying degrees of inflammation. The most accepted form of treatment is the use of topical and or systemic corticosteroids. If the inflammation is severe, enough consideration can be taken to discontinue the anticancer medication. This chapter will review the most common medications associated with immunotherapy-associated uveitis and how to diagnose, monitor, and manage these patients.

2. Immune checkpoint inhibitors (ICIs)

T-cell-mediated immunity has multiple steps for selecting specific antigens, trafficking them to different sites, and executing their functions. These steps are regulated by counterbalancing stimulatory and inhibitory signals to maintain balance. Under normal physiologic conditions, the immune system has a series of modulating responses to control the duration and amplitude of response to minimize organ damage. These modulations are regulated by special stop signals called immune checkpoints. On tumor cells, there is an overexpression of inhibitory ligands and receptors. With this overexpression, cancer cells can evade T-cell detection of the host immune system.

The soluble and membrane-bound receptor–ligand immune checkpoints are the most targeted for cancer therapy. Antibodies that block immune checkpoints do not target tumor cells directly. Instead, they target lymphocyte receptors or their ligands in order to enhance endogenous antitumor activity [6]. The two immune checkpoints that have been most actively studied in the context of clinical cancer immunotherapy are cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4, also known as CD152) and programmed cell death protein 1 (PD1, also known as CD279) [6]. Checkpoint inhibitors work by blocking the interaction of tumor cells with these ligands leading to increased antitumor response. Inhibition of the immune checkpoint pathways has led to the United States Food and Drug Administration’s (FDA) approval of seven drugs in the United States [7]. Table 1 shows a list of all seven drugs. There are key similarities and differences in these pathways.

Name	Target checkpoint
Ipilimumab (Yervoy)	CTLA-4-blocking antibody
Nivolumab (Opdivo)	PD-1-blocking antibody
Pembrolizumab (Keytruda)	PD-1-blocking antibody
Cemiplimab (Libtayo)	PD-1-blocking antibody
Avelumab (Bavencio)	PD-L1-blocking antibody
Durvalumab (Imfinzi)	PD-L1-blocking antibody
Atezolizumab (Tecentriq)	PD-L1-blocking antibody

Table 1.

FDA-approved immune checkpoint inhibitors.

2.1 Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors

CTLA-4 was the first immune checkpoint receptor to be clinically targeted [6]. It is exclusively expressed on T-cells, where it primarily downregulates cellular activation [6, 8, 9]. CTLA-4 is a membrane-bound receptor expressed in the plasma membrane of activated T-cells. During an active immune state, antigen-presenting cells (APCs) bind to CTLA-4 to attenuate T-cell activity, diminishing host organ damage.

2.1.1 Ipilimumab

Currently, only one FDA-approved ICI targets CTLA-4. The generic name is Ipilimumab and the trade name is Yervoy (Bristol-Meyers Squib). It is an intravenous infusion currently approved to treat metastatic or unresectable melanoma and melanoma recurrence. It is also approved for renal cell carcinoma, non-small cell lung cancer, malignant pleural mesothelioma, and esophageal cancer, but only if used as a combination therapy with nivolumab, PD-1 receptor antibody. In a study by Dow ER et al., they found that in patients with immunotherapy-associated uveitis, 96% of all cases with Ipilimumab were associated with metastatic melanoma [10]. This could be due to the restrictive indications the FDA has approved this medication use as monotherapy.

2.2 Programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitor

PD-1 is also an immune receptor involved in downregulating T-cell response. PD-1 regulates T-cell activation by binding to two ligands (PD-L1 and PD-L2). Cancer tumor cells can block antitumor host responses by upregulating PD-1 ligands. PD-1 has similar effects on T-cells as CTLA-4 but differs in its timing of downregulation and the anatomic location of immune inhibition [3]. PD-1 is more expressed on activated T-cells, B-cells, and myeloid cells compared to CTLA-4 [2, 3, 11]. While CTLA-4 functions during the priming phase of T-cell activation, PD-1 functions during the effector phase, predominantly within peripheral tissues [3, 6]. Chronic antigen exposure, as it occurs in cancer, can lead to an excess PD-1 expression on T-cells, leading to a state of “exhaustion” that can be partially reversible by PD-1 pathway blockade [6]. By inhibiting PD-1 pathway with either antibody to the receptor or its ligands, we can increase antitumor activity. There are currently three PD-1 inhibitor medications approved by the FDA (Nivolumab, Pembrolizumab, and Cemiplimab) and three anti-PD-L1 (Avelumab, Durvalumab, and Atezolizumab).

2.2.1 Nivolumab

Trade name Opdivo (Bristol-Meyers Squib) is a PD-1-blocking antibody. It is administered via intravenous infusion, currently approved for metastatic melanoma, non-small-cell lung cancer, metastatic small-cell lung cancer, metastatic squamous cell carcinoma of the head and neck, urothelial cancer, hepatocellular carcinoma, Hodgkin lymphoma, and metastatic colorectal cancer. Nivolumab has numerous approved indications to be used in combination with other therapies, including anti-CTLA-4 Ipilimumab. Nivolumab + Ipilimumab combination is approved for metastatic melanoma and renal cell carcinoma.

2.2.2 Pembrolizumab

Trade name Keytruda (Merck) is a PD-1-blocking antibody. It is administered via intravenous infusion, currently approved for melanoma, non-small cell lung cancer, head and neck squamous cell cancer, classical Hodgkin lymphoma, primary mediastinal B-cell lymphoma, urothelial carcinoma, metastatic colon and rectal cancer, unresectable or metastatic solid tumors with high microsatellite instability, PD-L1 positive cervical cancer, hepatocellular carcinoma, Merkel cell carcinoma, renal cell carcinoma, and advanced endometrial carcinoma. Pembrolizumab is the only approved ICI to demonstrate objective tumor regression [12].

2.2.3 Cemiplimab

Trade name Libtayo (Regeneron/Sanofi Genzyme) is a PD-1-blocking antibody. It is administered via intravenous infusion, currently approved for metastatic or advanced cutaneous squamous cell carcinoma and non-small cell lung cancer.

2.2.4 Avelumab

Trade name Bavencio (EMD Serono & Pfizer) is a PD-L1-blocking antibody. It is administered via intravenous infusion and is currently approved for urothelial and renal cell carcinoma.

2.2.5 Durvalumab

Trade name Imfinzi (AstraZeneca) is a PD-L1-blocking antibody. It is administered via intravenous infusion and approved for the treatment of unresectable stage III non-small cell lung cancer, extensive-stage small cell lung cancer and for bile duct and gallbladder cancer.

2.2.6 Atezolizumab

Trade name Tecentriq (Genentech) is a PD-L1-blocking antibody. It is administered via intravenous infusion. It is approved for the treatment of non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, and melanoma.

3. Immune-related adverse events (irAEs)

With the increasing use of ICIs as novel therapies for cancer treatment, it is expected to observe more side effects and adverse events secondary to these medications. The use of ICIs is rising exponentially, with approximately 40% of patients with cancer in the United States in 2019 eligible for treatment [13]. ICIs are not the only medication class to cause adverse effects, as other types of immunotherapies can cause this. With more immunotherapies currently being investigated, the number of available treatments could exponentially increase over time. Despite the observed clinical advantages these medications demonstrate, they produce a myriad of side effects that can involve several body systems. These side effects are called irAEs. The incidence and onset of irAEs vary depending on the class and dose of ICIs, the type of cancer, and factors related to patients [13]. More than two-thirds of reported cases of cancer immunotherapy-related irAEs are related to ICIs, and three drugs (Ipilimumab, Nivolumab, and Pembrolizumab) are responsible for almost 60% of reported cases [14]. It is believed that CTLA-4 might be more closely related to causing irAEs since its mechanism of action is less specific compared to PD-1/PD-L1 medications [10]. The onset of irAEs has been described as occurring as early as within a few days of ICI initiation and ≥ 1 year after completion of therapy. The median onset is within 2–16 weeks from the commencement of therapy [14, 15, 16]. Patients treated with combined therapy, anti-PD-1/PD-L1 + anti-CTLA-4 have an increased incidence, severity, and earlier onset of irAEs [13, 14].

The exact mechanism as to why irAEs occur due to ICIs is not entirely understood. It is important to note that there are differences in the clinical presentation and frequency of specific irAEs and the organs most commonly involved [17]. The most frequent irAEs include gastrointestinal, endocrine, and dermatological [18]. Table 2 shows a full list of all reported irAEs. Uveitis only accounts for approximately 1% of patients with irAEs. However, it is of utmost importance to be aware of it since delay in diagnosis and treatment could lead to detrimental irreversible visual consequences.

Cardiac	◦ Autoimmune hepatitis	◦ Panuveitis
• Myocarditis^a	◦ Eosinophilic hepatitis	◦ Posterior uveitis
◦ Autoimmune myocarditis	• Lymphocytic gastritis	• Vogt–Koyanagi–Harada syndrome
◦ Myocardial fibrosis	• Pancreatitis	Pulmonary
• Pericarditis	Hematological	• Interstitial lung disease^a
◦ Autoimmune pericarditis	• Aplastic anemia/pure red cell aplasia	◦ Alveolitis
◦ Pericardial effusion	• Autoimmune hemolytic anemia	◦ Organizing pneumonitis
◦ Pericardial tamponade	• Autoimmune neutropenia	◦ Pneumonitis
Dermatological	• Hemophagocytic lymphohistiocytosis	◦ Pulmonary fibrosis
• Alopecia areata/universalis	• Immune thrombocytopenic purpura	◦ Pulmonary hemorrhage
• Dermatitis herpetiformis	Muscular	Renal
• Erythema multiforme	• Myalgias^a	• Acute tubulointerstitial nephritis/renal tubular acidosis
• Granuloma annulare	• Myositis^a	• Glomerulonephritis
• Lichen planopilaris/planus/lichenoid dermatitis	◦ Anti-synthetase syndrome	Skeletal
• Panniculitis/erythema nodosum	◦ Bulbar myopathy	• Arthralgia^a/polyarthralgia
• Pemphigoid/pemphigus	◦ Dermatomyositis	• Arthritis^a
• Psoriasis	◦ Diaphragmatic lymphocytic polymyositis	◦ Monoarthritis
• Pyoderma gangrenosum	◦ Necrotizing myopathy	◦ Oligoarthritis
• Sweet syndrome	◦ Orbital myositis	◦ Polyarthritis
• Vitiligo^a	Neurological	• Enthesitis
Endocrine	• Aseptic meningitis	• Fasciitis/eosinophilic fasciitis
• Adrenitis^a	• Encephalitis	• Jaccoud arthropathy
◦ Adrenal insufficiency	• Cranial nerve involvement	• Polymyalgia rheumatica
◦ Cortisol deficiency	◦ Bilateral hearing loss	• Psoriatic arthritis
◦ Hypercortisolism	◦ Facial palsy	• Rheumatoid arthritis
◦ Hypoadrenalism	◦ Oculomotor paresis	• Spondyloarthropathy
◦ Isolated adrenocorticotropic hormone deficiency	• Motor neuropathy	• Tenosynovitis
• Autoimmune diabetes mellitus	◦ Acute generalized motor neuropathy	Systemic
• Hyperparathyroidism	◦ Multifocal motor block neuropathy	• Antiphospholipid syndrome
• Hypogonadism	• Myasthenia gravis	• Lupus
• Hypophysitis^a	• Neuromyelitis optica spectrum disorders	◦ Lupus nephropathy
◦ Autoimmune hypophysitis	◦ Optic neuritis	◦ Subacute cutaneous lupus erythematosus
◦ Hypopituitarism	◦ Transverse myelitis	◦ Systemic lupus erythematosus
◦ Pan-hypopituitarism	• Polyneuropathies^a	• Sarcoidosis
• Thyroiditis^a	◦ Axonal sensory-motor polyneuropathy	◦ Cutaneous sarcoidosis
◦ Autoimmune thyroiditis	◦ Multiplex mononeuritis	◦ Pulmonary sarcoidosis
◦ Hyperthyroidism	◦ Peripheral sensory neuropathy	◦ Renal sarcoidosis
◦ Hypothyroidism	• Polyradiculopathies	• Sicca syndrome^a/Sjögren syndrome
◦ Graves’ disease	◦ Chronic inflammatory demyelinating polyneuropathy	• Systemic sclerosis
◦ Thyrotoxicosis	◦ Guillain–Barré syndrome	• Vasculitis^a
Gastrointestinal	Ocular	◦ Cerebral vasculitis
• Enterocolitis^a	• Conjunctivitis	◦ Cryoglobulinaemia
◦ Ileitis	• Episcleritis/scleritis	◦ Cutaneous vasculitis
◦ Ileocolitis	• Orbital inflammation	◦ Eosinophilic granulomatosis with polyangiitis
◦ Ischemic colitis	• Uveitis^a	◦ Giant cell arteritis
◦ Microscopic colitis	◦ Anterior uveitis	◦ Pulmonary vasculitis
◦ Ulcerative colitis	◦ Chorioretinopathy	◦ Henoch–Schönlein purpura
• Hepatitis^a	◦ Iridocyclitis/iritis	^aMore than 100 cases reported.

Table 2.

Organ-based reported irAEs.

Obtained from Ramos-Casals M, Brahmer JR, Callahan MK, et al. Immune-related adverse events of checkpoint inhibitors. Nat Rev. Dis Prim. 2020;6 (1). doi:10.1038/s41572-020-0160-6.

Treatment depends on the organ system affected and the grade of toxicity according to the Common Terminology Criteria for Adverse Events (CTCAE) classification. Specific treatments for irAEs beyond uveitis are out of the scope of this chapter. However, some of the treatments used are glucocorticoids, hormone replacement, immunosuppressive agents, IV immunoglobulin, plasma exchange, and monoclonal antibodies.

4. Target therapies of proto-oncogene B-RAF and mitogen-activated protein kinase BRAF/MEK

ICIs are not the only immunomodulatory medication associated with uveitis. Approximately 25–100% of patients treated with BRAF/MEK inhibitors develop ocular adverse effects [5]. These medications are primarily used in the treatment of melanoma. Nearly 50% of the patients with advanced melanoma have BRAF (V600E) mutations [19]. The MEK gene is closely connected to the BRAF gene, so drugs that target MEK also help with BRAF mutation melanomas. BRAF inhibitor drugs as monotherapy have shown high rapid response rates not previously seen in melanoma patients. However, the duration of responses is limited in most patients. The same occurs in MEK monotherapy. The combination of BRAF/MEK inhibitors has shown significant improvement in response rates [19]. BRAF inhibitors include vemurafenib (Zelboraf), dabrafenib (Tafinlar), and encorafenib (Braftovi). MEK inhibitors approved are trametinib (Mekinist), cobimetinib (Cotellic), and binimetinib (Mektovi).

A cohort study by F. Dimitriou et al., published in 2021, investigated if the occurrence of uveitis under treatment with BRAF/MEK and ICI is more frequent than in a general population of patients without treatment for cutaneous melanoma and found that patients treated with BRAF/MEK inhibitors had a two-fold higher hazard of developing uveitis. Clinical findings were similar in patients treated with ICI and BRAF/MEK inhibitors. They do not specify treatments but state that the course was complicated in four of eleven patients requiring systemic steroids. No patients had to discontinue their cancer treatment due to the uveitis. There are minimal reports of BRAF/MEK clinical trials, which could account for an underreporting of rare adverse events, such as uveitis [5]. But as we gather more data, more information can be gathered, and more accurate treatment and diagnostic recommendations can be made.

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 immune-associated 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.

0	<1
1+	1–5
2+	6–15
3+	16–25
4+	26–50
5+	>50

Table 3.

SUN criteria grading for anterior chamber cells.

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 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 high-dose 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.

Grade	Definition CTCAE	ASCO	SITC
1	Anterior uveitis with trace cells	Continue ICI Refer to ophthalmology within 1 week Artificial tears	Continue ICI Refer to ophthalmology within 1 week Artificial tears
2	Anterior uveitis with 1+ or 2+ cells	Hold ICI temporarily until after ophthalmology consult. Topical (e.g., 1% prednisolone) and systemic steroids Resume ICI treatment once off systemic corticosteroids or once corticosteroids for other concurrent systemic irAEs are reduced to 10 mg; continued topical corticosteroids are permitted when resuming therapy to manage and minimize local toxicity.	Hold ICI Ophthalmology referral within 2 days, prior to initiating uveitis treatment Topical corticosteroids, and/or systemic corticosteroids
3	Anterior uveitis with 3+ or greater cells; intermediate posterior or panuveitis	Permanently discontinue ICI Systemic corticosteroids and intravitreal or periocular/ or topical corticosteroids. Methotrexate may be used in patients who respond poorly to systemic corticosteroids or those with severe sight-threatening inflammation.	Permanently discontinue ICI Systemic corticosteroids in addition to intravitreal/periocular corticosteroids/topical corticosteroid.
4	Best corrected visual acuity of 20/200 or worse in the affected eye	Permanently discontinue ICI. Systemic corticosteroids—prednisone 1–2 mg/kg/day or methylprednisolone 0.8–1.6 mg/kg/day Intravitreal or periocular or topical corticosteroids	◦ Permanently discontinue ICI; ◦ Same as grade 3

Table 4.

Grading and treatment recommendations of ocular irAEs.

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 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.

6. Conclusion

Immunotherapy-associated uveitis is an increasing occurrence that has become more apparent with the increased use of immunologic cancer treatments. Both ICI and BRAF/MEK therapies help improve survival in cancer patients by improving the patient’s ability to attack cancer cells. Due to the positive effects these medications provide to metastatic and unresectable cancer patients, we hypothesize that more patients would continue to benefit from their use. With ongoing approvals and combinations of new medications, we may continue to foresee new information about ocular irAEs. Generally, most patients can be treated successfully with topical or systemic steroids without needing to hold or completely discontinue their cancer treatment. The way we treat and monitor these uveitis patients is based on limited literature, for which more controlled and standardized studies are needed to help have better treatment and monitoring algorithms. It remains unclear when to stop or discontinue cancer immunotherapies in patients with immunotherapy-associated uveitis. However, it is of utmost importance for oncologists, ophthalmologists, and all physicians involved in the care of cancer patients to be aware of the complications of these medications for prompt diagnosis and referral to improve patient care. Although relatively rare, the most crucial aspect of immunotherapy-associated uveitis is that it requires prompt recognition and treatment to avoid irreversible ocular damage. Any decision to hold or permanently discontinue these potentially lifesaving cancer medications should be thoroughly evaluated and discussed between the oncologists and ophthalmologists.

Conflict of interest

Erick Rivera-Grana has no conflict of interests to disclose. Stephanie M. Llop has no conflict of interests to disclose.