ICPIs are classified according to the immune ligand targeted. Ipilimumab is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen-4 (CRLA-4) and nivolumab targets programmed cell death protein 1 (PD-1) [1]. A 2022 randomised clinical trial comparing ipilimumab and nivolumab combination therapy versus monotherapy in untreated unresectable stage III or stage IV melanoma reported the longest median overall survival (OS) reported to date: 57% OS at 6.5 years with BRAF-mutant tumours and 46% OS at 6.5 years in BRAF-wild type tumours [2]. While these treatments have been proven highly successful in treating cancers such as metastatic melanoma, lung and colon cancer, they characteristically induce side-effects known as IRAEs which can affect the eye [3, 4]. A recent large meta-analyses reported diarrhoea, colitis, rash, pruritis, hypophysitis, hypothyroidism, hyperthyroidism and pneumonitis as the most frequent IRAEs, with each ICPI and cancer type associated with a different toxicity profile [3]. The incidence of all-grade uveitis was 2.0% with ipilimumab and nivolumab combination therapy compared to < 1% for ipilimumab, nivolumab and pembrolizumab monotherapies [3].
In addition to uveitis, potential ophthalmic IRAEs reported include orbital inflammation/ocular myositis [3, 5, 6], peripheral ulcerative keratitis [3], retinal vasculitis [7], melanoma associated retinopathy (MAR) like retinopathy [8], Vogt-Koyanagi Harada like posterior uveitis [9, 10], cranial neuropathies [6, 11], optic neuritis [6] and ocular myasthenia [6, 12]. Nivolumab is associated with the highest rate of ocular IRAEs overall whilst ipilimumab has the strongest association with uveitis [12]. Cases are managed on an individual basis with a multidisciplinary team (MDT) approach. Intraocular or oral corticosteroids can be initiated to reduce inflammation and occasionally therapeutic plasma exchange has been utilised in refractory cases [13]. Temporary or permanent ICPI cessation may be necessary [6, 13].
In this case, the patient presented with reduced vision and photophobia following completion of her third round of ICPIs for malignant vaginal melanoma. The diagnostic challenge in this case was to identify the primary aetiology for the uveitis which compromised of a bilateral non-granulomatous anterior uveitis, right eye chorioretinal changes and an active left eye CNVM with scattered choroidal lesions. The clinical appearance of her right fundus was suggestive of a quiescent/inactive SLC. The left eye had multiple choroidal lesions evident on ICGA imaging with a secondary inflammatory CNVM. This raised the index of suspicion for a TB related uveitis, potentially caused by ICPI induced reactivation of latent TB, which has been reported [14]. SLC is an immune-mediated inflammation of the choriocapillaris caused by Mycobacterium tuberculosis (Mtb) growth within the retinal pigment epithelium (RPE) [15]. There is no consensus on the proper management of SLC. It can be difficult to manage due to poor RPE penetration with ATT and the requirement for prolonged immunosuppression to dampen the associated inflammatory response [15]. Fundal findings and FFA imaging did not show activity in this lesion which was likely treated a number of years prior to this presentation with prolonged systemic medication.
ICPI-induced enhancement of effector T cells with associated excessive tumour necrosis factor-alpha (TNF- α) secretion is hypothesised to cause destruction of granuloma extracellular matrix in latent TB with enhancement of Mtb growth and spread [14]. Lung histology showed a granulomatous lymphadenitis with TB confirmed on PCR testing. ICGA revealed multiple round hypofluorescent dark dots which have been reported in up to 100% of eyes with presumed intraocular TB [16]. Treatment was centred around temporary discontinuation of ICPIs, systemic ATT and systemic steroids. Anti-VEGF therapy was employed successfully to treat the active inflammatory CNVM secondary to choroiditis in the left eye and BCVA was excellent post treatment. Following this, ICPIs cycle four was recommenced but unfortunately due to the advanced stage of disease, treatment was unsuccessful and the patient passed away. This case highlights the importance of the multiple ways in which ICPIs can cause ocular complications and the importance of an MDT approach to complex medical cases.