Immune Checkpoint Inhibitor-Induced Uveitis

Immune checkpoints are endogenous, inhibitory, receptor-mediated regulators of the immune system known to be central to controlling the duration and extent of normal immune responses, thereby maintaining self-tolerance and preventing autoimmunity. Tumor cells frequently express immune checkpoint activators in an attempt to suppress immune-mediated tumor surveillance and enhance their own survival. Immune checkpoint inhibitors (ICI) belong to a growing class of anti-cancer agents bioengineered to inhibit the ability of tumor cells to suppress the immune system by blocking immune checkpoint activators present on both tumor and white blood cells.^1–3 To date, seven ICIs have been approved for therapeutic use: the CTLA-4 inhibitor ipilimumab (Yervoy®); the programmed cell death protein 1 (PD-1) inhibitors pembrolizumab (Keytruda®), nivolumab (Opdivo®), and cemiplimab (Libtayo®); and the programmed cell death ligand 1 (PD-L1) inhibitors atezolizumab (Tecentriq®), avelumab (Bavencio®), and durvalumab (Imfinzi®). Immune-Related Adverse Events (IRAE) occur in one-third or more of patients receiving ICIs and can be severe – particularly in patients receiving ipilimumab, either alone or in combination with PD-1 or PD-L1 inhibitors. Ocular IRAEs, in contrast, occur in about 1% of patients, tend to be mild, and are often manageable with topical, peri-ocular, or intra-ocular corticosteroids. Non-granulomatous anterior inflammation appears to occur most commonly, although more severe forms of panuveitis with or without granulomatous features, choroidal infiltration and serous retinal detachment, the so-called Vogt-Koyanagi-Harada (VKH)-like response, can also occur. Isolated optic disc and orbital inflammation has also been described, as have associated systemic findings supportive of a diagnosis of drug-induced sarcoidosis.^4–6 Two original articles^7,8 and four letters^9-12 in this issue of Ocular Immunology & Inflammation (OII) address the occurrence of ocular IRAE associated with use of ICIs.

Noble et al.⁷ described the clinical features and management of ocular IRAEs observed in patients on ICIs seen at separate tertiary referral centers in Bethesda, Maryland, Washington DC, and Boston, Massachusetts between 2000 and 2017. Seven male and four female subjects were identified, including nine with intraocular inflammation and one each with dry eye syndrome and severe unilateral optic disc edema associated with an altitudinal defect on Humphrey visual field testing. Among the eleven subjects, four (36.4%) had metastatic melanoma, three (21.4%) had renal cell carcinoma, two (18.2%) had prostate cancer, and one (9.1%) had metastatic choroidal melanoma. Immune checkpoint inhibitor use among subjects included pembrolizumab in three (27.3%), combined nivolumab and ipilimumab in three (27.3%), nivolumab alone in two (18.2%), and ipilimumab alone in one (9.1%). Among those with intraocular inflammation, which was bilateral in five subjects (14 total eyes), findings included non-granulomatous anterior uveitis in eight eyes (57.1%), a VKH-like response in 4 eyes (28.6%), cystoid macular edema (CME) in 2 eyes (14.3%), and one eye each (7.1%) with intermediate and panuveitis. All three subjects (4 eyes) with a VKH-like response had malignant cutaneous or choroidal melanoma. Time from initiation to ICI-induced onset of ocular IRAEs ranged from 1 to 52 weeks, with a median and mean of 13.5 and 15.7 weeks, respectively. While the ocular inflammation was controlled in all cases with local and/or systemic corticosteroid therapy and five patients were able to continue their checkpoint inhibitor therapy, ICI use was discontinued in six subjects, including three as a result of the severity of the ocular IRAEs. The authors reminded us that while ocular IRAEs are uncommon and can be severe, most are mild and can be managed without the need to discontinue ICI therapy.

Parikh et al.⁸ described eight consecutive patients with ocular IRAEs seen following treatment with ICIs and other chemotherapeutic agents at a tertiary referral center in Baltimore, Maryland, between November 2017 and June 2019. The cohort included six women and two men, ranging in age from 45 to 74 years, with a median of 69 years and mean of 65.5 years. Three subjects had non-small cell lung cancer, two had melanoma, and one each had prostate cancer and rectal adenocarcinoma. Four of the eight patients received ICIs, including three cases with nivolumab, one with durvalumab, and one with combined therapy with nivolumab and crizotinib (a protein kinase inhibitor). Two of the four subjects had bilateral anterior uveitis, one had combined bilateral anterior and intermediate uveitis associate with granulomatous keratic precipitates, and the fourth had bilateral optic disc edema. Intraocular inflammation responded to topical 1% prednisolone acetate in each case. The optic disc edema resolved following discontinuation of combined ipilimumab and nivolumab following the development of autoimmune hepatitis. The authors noted that in their small series, intraocular inflammation tended to be mild and could be controlled with topical corticosteroids.

Tsui and Gonzales⁹ described a 47-year-old Caucasian man receiving ipilimumab for chronic myeloid leukemia who developed unilateral anterior uveitis that was managed successfully with topical corticosteroids. The patients developed systemic IRAEs that necessitated discontinuation of his ipilimumab, but 5 months later developed diffuse retinal vascular leakage and CME in the fellow eye, which was managed successfully with systemic corticosteroids and a dexamethasone intraocular implant. The authors cited previous reports of the occurrence of retinal vasculitis following treatment with nivolumab and pembrolimzumab,^13–15 and reminded us that ocular IRAEs can occur even following discontinuation of ICIs.

Lee et al.¹⁰ described a 77-year-old Korean man with a history of sympathetic ophthalmia (SO) that was controlled with systemic corticosteroids and cyclosporine who developed a recurrence of his uveitis following three infusions of pembrolizumab to treat small-cell lung cancer. The recurrence was characterized as a panuveitis associated with large (“mutton-fat”) keratic precipitates and “annular choroidal detachment” accompanied by choroidal thickening and overlying serous retinal detachment – all consistent with recurrent SO. The pembrolizumab was discontinued and the uveitis was controlled with systemic corticosteroids. The authors suggested that those with a history of uveitis who then receive an ICIs may be at increased risk of recurrence.

Ahmad et al.¹¹ described a 61-year-old woman who developed bilateral anterior uveitis that was controlled promptly with topical and systemic corticosteroids. Testing at presentation failed to identify a cause for the uveitis, but revealed inoperable non-small cell lung cancer that was treated with biweekly infusions of durvalumab. Two months after initiation of treatment, the patient developed recurrent, bilateral anterior uveitis, which responded promptly to topical corticosteroids. The authors cited a previously reported case of recurrent anterior uveitis following pembrolizumab treatment,¹⁶ along with a review by Abdel-Wahab et al.¹⁷ that noted that half of all patients with autoimmune disease who are treated with ICIs experience exacerbations in their underlying inflammatory disease.

Yoshida et al.¹² described a 61-year-old man undergoing treatment of metastatic renal cell carcinoma with nivolumab who developed severe, bilateral anterior uveitis, worse in the left eye, which also had the VKH-like findings of vitritis and diffuse choroidal thickening with overlying serous retinal detachment. A vitrectomy was performed on the left, followed by cytokine analysis performed on the vitreous, which showed high levels of interleukin-6, granulocyte-colony stimulating factor, and interferon-inducible protein-10 as compared to a control patient who underwent vitrectomy for macular hole repair. The uveitis was controlled following discontinuation of the nivolumab and treatment with topical, periocular and systemic corticosteroids. The patient experienced a recurrence of his uveitis following re-initiation of nivolumab.

Together, these reports highlight both the occurrence and spectrum of ocular IRAEs associated with ICI use, including a VKH-like response characterized by choroidal involvement with serous retinal detachment; a systemic, sarcoid-like inflammation that may also involve the eye; and exacerbation or reactivation of preexisting, unrelated ocular inflammatory disease. Patients administered an ICI may also develop ocular inflammation completely unrelated to ICI use. We recommend, therefore, that the workup of patients who develop uveitis while taking an ICI include imaging of the mediastinum to rule out granulomatous disease, syphilis serologies, an interferon-gamma releasing assay, and focused testing to address other etiologies supported by history and physical examination. While ICI-induced intraocular inflammation tends to be mild, anterior, and readily managed with regional corticosteroids,¹⁸ patients with more severe or multi-organ inflammation may require systemic corticosteroids with or without discontinuation of their ICI. Given the very real potential for ICIs to both prolong and improve the quality of life for those with advanced cancer, the decision of whether or not to discontinue ICIs in the setting of ocular IRAEs should be made in close collaboration with both the patient and their oncologist.

Acknowledgments

The authors received no financial support for this editorial.

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Funding

ETC and RSM have no relevant financial conflicts. MZ is a consultant to AbbVie, Alimera, Santen and Gilead.