Abstract
Purpose
Immune checkpoint inhibitors (ICIs) are associated with a range of immune-related adverse ophthalmic events. To date, there are scant reports of ocular hypertension coupled with ICI-associated uveitis. However, in instances of ocular hypertension in the context of only mild uveitic reaction and absence of synechiae, trabeculitis is considered. This series describes our observations of presumed trabeculitis in the setting of ICI therapy and investigates the clinical findings, treatment and outcome of these patients.
Observations
Two eyes of 2 patients (both male aged 65 and 43) developed a mild anterior uveitis and elevated intraocular pressure (IOP) with open angles and no evidence of peripheral anterior synechiae in association with ICI treatment for their malignancy; and were considered to have presumed unilateral trabeculitis. The patients underwent 10 cycles (6.53 months) and 2 cycles (3.33 months) respectively of ICI therapy before developing ophthalmic symptoms. Neither patient was on systemic or topical steroid treatment at time of diagnosis and there was no suspicion of a viral etiology for the inflammation. Following management, the anterior uveitis resolved and IOP rapidly returned to normal in both eyes: ICI therapy was discontinued in both patients (and uneventfully re-challenged at a lower dose in one patient) and both eyes were treated with a combination of topical and/or oral glaucoma medications and topical steroids.
Conclusions and Importance
Uveitic ocular hypertension has been described with ICI. However, another immune-related mechanism for ocular hypertension with unique clinical characteristics, includes trabeculitis. We describe two cases of trabeculitis in the setting of ICI-therapy. The intraocular inflammation and elevated intraocular pressure which characterizes trabeculitis often responds rapidly to conservative treatment. In both patients checkpoint inhibitor therapy was discontinued and, in one patient, was re-challenged at a lower dose without recurrence. Immunotherapy is now more widely used for cancer treatment and its potential ocular manifestations should be shared with the ophthalmic community.
1
Introduction
Immune Checkpoint Inhibitors (ICI) are an anti-cancer therapy that are now widely used to treat advanced cancers. There are three main classes of checkpoint inhibitors, which act by potentiating the immune system to attack cancer cells. The classes include cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), programmed cell death (PD-1) and programmed cell death protein 1 (PD-L1) inhibitors. They have been approved by the FDA to treat various types of cancers such as melanoma, non-small-cell lung cancer, renal-cell carcinoma, urothelial carcinoma and Hodgkin’s lymphoma. By unleashing the immune system to attack cancer cells, ICIs can also cause an inflammatory reaction in healthy cells, thereby resulting in immune-related adverse events. The incidence of ocular immune-related adverse events occurs in about 1% of patients and can involve various parts of the eye such as: ocular surface, uveal tract, retina, extraocular muscles, cranial nerves and optic nerve.
ICI-induced inflammation to the uveal tract (anterior, posterior and/or panuveitis) is well documented, but none has been reported about ICI-induced trabeculitis. This study presents two cases of trabeculitis in the setting of ICI therapy and we explore the clinical findings, treatment and outcome of each.
1.1
Findings
Case 1: A 65 year-old male was undergoing treatment with pembrolizumab for metastatic conjunctival melanoma of the right eye, when he developed a presumed unilateral trabeculitis in the left eye 6.53 months (10 cycles) after initiation of immunotherapy. Table 1 outlines patient medical history, ocular symptoms at presentation and ICI treatment regimen. He had no ocular symptoms and the trabeculitis was found incidentally on routine follow-up where he presented with a unilateral non-granulomatous anterior uveitis (graded according to the classifications outlined by the Standardization of Uveitis Nomenclature (SUN) Working Group ) without corneal edema and intraocular pressure (IOP) of 52 mmHg, as measured with Goldmann applanation tonometry in the left eye. There were no cells visible in the anterior vitreous and gonioscopy confirmed that angles were open to ciliary body 360° with no evidence of peripheral anterior synechiae or abnormal pigment distribution. The irises were equal in pigmentation, without iris atrophy or iris nodules. Inflammation of the posterior segment was deemed unlikely based on exam and imaging with fundus photography, autofluoresence and optical coherence tomography. Table 2 outlines pertinent ocular history, clinical features of the ophthalmic findings at presentation and follow-up, as well as visual outcomes. Of note, this patient had a history of steroid response in the past, for which he was taking timolol-dorzolamide ophthalmic solution and brinzolamide ophthalmic solution twice a day in both eyes. He was not being treated with any systemic or topical steroids at the time of the presentation of the trabeculitis. He was treated with topical prednisolone acetate ophthalmic suspension and oral acetazolamide, and the immunotherapy was discontinued. At the time he was re-evaluated (7 days after onset), the anterior uveitis resolved, IOP returned to normal (13 mmHg) and vision returned to 20/20. Optic nerves remained healthy on fundus examination up until his last recorded follow-up.
| Patient | Age (yrs) | Gender | Drug at time of dx | Primary Cancer Diagnosis | No. of CPI cycles prior to ophthalmic dx | Time on drug till symp (mos) | Ocular symptoms | CPI D/C? | Alive | CPI re-started after resolution of trabeculitis? | Time to most recent follow-up (mos) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 65 | M | Pembrolizumab 2 mg/kg, q3 weeks | conjunctival melanoma | 10 | 6.53 | none | Y | Y | N | 19.27 |
| 2 | 43 | M | Ipilimumab 3mg/kg + nivolumab 1mg/kg (once), followed by nivolumab 480mg (once) | cutaneous melanoma | 2 | 3.33 | redness and headache | Y | Y | Y Nivolumab 240mg q2w | 5.70 |
| Pt | Laterality of trabeculitis | Anterior chamber of affected eye(s) at dx | IOP of affected eye(s) at dx (mmHg) | VA of affected eye(s) at dx | Ophthalmic Treatment | Time to resolution of trabeculitis (days) | Anterior chamber of affected eye(s) after treatment | IOP of affected eye(s) at most recent follow-up (mmHg) | VA of affected eye(s) at most recent follow-up | Other intraocular inflammation (Y/N) | Prior h/o elevated IOP? (mmHg) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | Left | gr 2+ cells and diffuse KPs OS | 52 | 20/30 + 1 | Prednisolone acetate 1% q2h and Acetazolamide sequels PO (in addition to current regimen) | 7 | deep and quiet | 13 | 20/20-1 | N | Y OD Tmax:27 OS Tmax: 26 (h/o steroid response, tx with Timolol-dorzolamide and brinzolamide BID OU) |
| 2 | Right | gr 1+ cells/flare and diffuse KPs OU | 33/16 | 20/20 | Prednisolone acetate 1% QID and Timolol-brimonidine BID | 10 | deep and quiet both eyes | 19/19 | 20/20 | N | N |
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