Ocular and Orbital Complications of Checkpoint Inhibitors
Introduction to Checkpoint Inhibitors
Mechanism of Action and Pharmacokinetics
Checkpoint inhibitors induce the activation of T-cells against cancer cells. There are several different types of checkpoint inhibitors, classified by the ligand for which it is targeted.
- PD-L1 Inhibitors: Atezolizumab, Avelumab, Durvalumab
- PD-1 Inhibitors: Pembrolizumab, Nivolumab
- CTLA4 Inhibitors: Ipilimumab, Tremelimumab
Indications and Uses
Checkpoint Inhibitors classically have been used to treat metastatic melanoma but have also been employed in colon cancer and lung cancers.
Systemic Adverse Events
Skin disease including psoriasis
Ocular and Orbital Adverse Events
- Myositis secondary to Pembrolizumab use with inflammatory infiltrates on biopsy has been reported. Ophthalmoplegia and ptosis were reported as presenting symptoms.
- Thyroid like orbital inflammation with varied thyroid panel results (one case of normal thryoid levels, another with Graves disease without prior TED) have been reported which resolved with steroids or observation.
- Dry eye is among the most common adverse events.
- Sjogren's like syndrome has been identified with the use of PD1/PD-L1 inhibitors. Lab workup is equivocal although biopsy of the salivary tissue reveals sialadenitis.
- Anterior uveitis is one of the most common side effects.
- VKH-like uveitis has also been reported with use of nivolumab. A case report demonstrated a patient with bilateral anterior chamber reaction and choroidals which resolved after intraocular and systemic steroids.
- Bechet's like syndrome has been reported with Pembrolizumab. The ocular manifestation of the Bechet's like syndrome were corneal erosions while systemically, the patient developed oral and genital ulcers.
- Uveal effusion syndrome has been reported in 3 patients after treatment with PD1/PD-L1 therapy.
- Metastases to the vitreous have been reported in 2 cases despite treatment with ipilimumab.
- Vasculitis has been reported with Ipilimumab. Macular edema as well as vascular leakage were noted on fluorescein angiography. Intravitreal steroids were required for resolution.
- MAR like retinopathy
- Nivolumab has been reported to induce antiretinal antibodies. Optical imaging showed hyperfluorescence with damage to rod/cone function on ERG.
- CNV and chorioretinal atrophy was reported as a complication in one report of MAR-Like retinopathy after ipilimumab/nivolumab combination therapy.
- Choroidal sarcoid granulomas have been noted to be induced with nivolumab therapy.
- Choroidal detachment was reported in one case of a patient on ipilimumab/pembrolizumab combination therapy.
- Subretinal fluid may develop in certain cases
- Ocular myasthenia with anti-acetylcholine receptor antibody production has been described with Pembrolizumab.
- Optic Neuritis has been reported with Pembrolizumab. Early identification led to early treatment with steroids and preservation of vision.
- Nerve Palsies have been reported with Pembrolizumab (abducens) with resolution after drug cessation and treatment with high dose steroids.
Cases are managed on an individual basis with discussion with the oncologist and ophthalmologist. In most cases of uveitis, topical steroids keep the inflammation under control. In certain cases, intraocular steroids can be implanted or retroseptal steroids can be injected. Oral corticosteroids can also be used, if deemed appropriate by the medical oncologist. Rarely, cessation of the immune checkpoint inhibitor is necessary. Plasma exchange therapy has been used in some cases of immune checkpoint-induced myasthenia gravis. Most cases resume to baseline although irreversible adverse events have also been reported.
- Dalvin, LA, et al. Retina. 2018; 36: 1063-1078.
- Antoun, J, et al. Curr Opin Oncol. 2016; 28: 288-294.
- Conrady, CD, et al. Graefes. 2018; 256: 187-191.
- Abdel-Rahman, O, et al. Expert Rev Anticancer There. 2017; 17: 387-394.
- Bitton, K, et al. Am J Ophthal. 2019. Ahead of publication.
- Ayad, N., Al-Shami, K., Yaghan, R. Immunotherapy for HER2-positive breast cancer: recent advances and combination therapeutic approaches. Breast Cancer - Targets and Therapy 2019:11 53–69.
- Reddy, M., Chen, J., Kalevar, A., et al. Immune retinopathy associated with nivolumab administration for metastatic non-small cell lung cancer. Retina Cases Brief Rep. 2020; 14: 120-126.
- Garibaldi, M., Calabro, F., Merlonghi, G., et al. Immune Checkpoint Inhibitors (ICIs)- related Ocular Myositis. Neuromuscular Disorder. 2020; S0960-8966.
- Mihailovic, N., Dyballa, J., Herz, S., et al. Vogt-Koyanagi-Harada-like Uveitis Under Immune Checkpoint Inhibitor Treatment for Metastasized Malignant Melanoma. Ophthalmologe. 2020; 117: 467-471.
- Ung, C., Gragoudas, E. Checkpoint-inhibitor induced sarcoid choroidal Granuloma. Am J Ophthalmology Case Reports. 2020; 18:100652.
- Thomas, S., Bae, C., Joy-Ann, T., et al. Bechet's like syndrome following Pembrolizumab: An Immune Related Adverse Event Associated with Programmed Cell Death receptor-1 Inhibitor Therapy. J Oncol Pharm Pract. 2019.
- Tsui, E., Gonzales, J. Retinal Vasculitis Associated with Ipilimumab. Ocular Immunol Inflamm. 2019; 1-3.
- Ramos-Casals, M., Maria, A., Suarez, M., et al. Sicca/Sjogren's Syndrome Triggered by PD-1/PD-L1 Checkpoint Inhibitors. Data from the International ImmunoCancer Registry (ICIR). Clinic Exp Rheumatol. 2019; 37: 114-122.
- Telfah, M., Whittaker, T., Doolittle, G. Vision Loss with Pembrolizumab Treatment: A report of two cases. J Oncol Pharm Pract. 2019; 25: 1540-1546.
- Sagiv, O., Kandl, T., Thakar, S., et al. Exrtaocular Muscle Enlargement and Thyroid Eye Disease Like Orbital Inflammation Associated with Immune Checkpoint Inhibitor Therapy in Cancer Patients. OPRS. 2019; 35: 50-52.
- Jaben, K., Francis, J., Shoushtari, A., et al. Isolated Abducens Nerve Palsy Following Pembrolizumab. Neurophthalmology. 2019; 44: 182-185.
- Thomas, M., Armenti, S., Ayres, M., et al. Uveal Effusion After Immune Checkpoint Inhibitor Therapy. JAMA Ophthalmology. 136; 553-556.
- Choroidal neovascularization and chorioretinal atrophy in a patient with melanoma-associated retinopathy after ipilimumab/nivolumab combination therapy. Retina Cases Brief Report. 2019.
- O'Bryhim, B., Sychev, Y., Rao, P. Bilateral choroidal detachments secondary to ipilimumab and Pembrolizumab use. Retina Cases Brief Report. 2018.
- Kellermann, N., Maier, M., Feucht, N. Vitreous Metastasis of cutaneous melanoma during treatment with ipilimumab. Ophthalmologe. 2017; 114: 163-166.
- Kanavati, S., Ottensmeier, C., Foria, V., et al. Bilateral metastatic cutaneous melanoma to retina and vitreous after ipilimumab treated with pars plans vitrectomy and radiotherapy. Retina Cases Brief Report. 2018; 12: 184-187.
- Noda, T., Kageyma, H., Miura, M., et al. A Case of myasthenia graves and myositis induced by Pembrolizumab. Rinsho Shinkeigaku. 2019; 59:502-508.