Optic Neuropathy and Immune Checkpoint Inhibitors
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Overview
Immune checkpoint inhibitors (ICI) are a novel treatment against malignancies. ICI work by activating the patient’s immune system to attack cancer cells[1]. Currently, there are three commonly used classes of ICI’s: 1) cytotoxic T-lymphocyte antigen-4 (CTLA-4), 2) programmed death-1 (PD-1), and 3) the PD ligand (PD-L1)[2]. Inhibition of the immune checkpoint however can produce unintended immune-related adverse events (irAEs) and secondary autoimmune disease. We review the epidemiology, pathogenesis, evaluation, management, and prognosis of optic neuropathy as an irAE secondary to ICI.
Epidemiology
The overall incidence of neuro ophthalmic irAE after ICI therapy is low but may occur in up to 0.46% of patients with cutaneous melanoma being the most common ICI treatment indication[1][3]. The frequency of ophthalmic immune-related adverse events (OirAEs) after ICI treatment for melanoma was 341.8/100,000 and 369.6/100,000 in patients with nonmelanoma cancer[4]. Another comparative study of 2,911 patients on ICI for melanoma reported an increased 1-year incidence rate of OirAEs compared to patients with non-melanoma cancer receiving ICI therapy[4]. A 2021 study reported 31 patients receiving one or more ICI including PD-1 inhibitors (e.g., pembrolizumab, nivolumab, or cemiplimab), PD-L1 inhibitors (e.g., atezolizumab, avelumab, or durvalumab), or the CTLA-4 inhibitor ipilimumab[5]. In this study, pembrolizumab was most commonly used ICI followed by combined ipilimumab and nivolumab, and then nivolumab alone[5].
Mechanisms of Action
Cytotoxic T-lymphocyte antigen-4 (CTLA-4) Inhibitors
CTLA-4 molecule is present on T lymphocytes and inhibits T cell activation in response to an antigen[6]. Normally, when presented with an antigen, the major histocompatibility complex (MHC) on dendritic cells interacts with a T cell receptor (TCR) on a T lymphocyte. This receptor interaction serves as an activating signal for an immune response. Another activating signal is initiated when the B7 complex on dendritic cells interacts with the CD28 complex on T cells[6]. With both activating signals, T lymphocytes can be activated to mount an immune response. However, when CTLA-4 binds B7, T lymphocyte activation is inhibited (i.e., immune checkpoint)[6]. Mutations in CTLA-4 genes contribute to the pathogenesis of both autoimmune disease and tumor progression[7]. Thus, CTLA-4 inhibitors block the immune checkpoint and can result in antitumor immunity or an OirAE by potentiating the T lymphocyte response[8].
Programmed death-1 (PD-1) and Programmed death ligand-1 (PDL-1) Inhibitors
The programmed death-1 (PD-1) molecule is an inhibitory receptor present on T lymphocytes that serves as an immune response regulator (i.e., “immune checkpoint”) like CTLA-42[9]. PD-1 on T lymphocytes interacts with programmed death ligand-1 (PDL-1) on hematopoietic and non-hematopoietic cells throughout the body, and this interaction prevents the activation of self-reactive T cells and mediates peripheral immune tolerance[10][11]. However during the development of a tumor, the PD-1 and PDL-1 pathway can be upregulated by malignancies and lead to tumor immune escape by downregulating host immune responses[10]. PD-1 and PDL-1 inhibitors act to disrupt this regulatory mechanism and promote robust host immune responses[10][12].
Lymphocyte activation gene-3 (LAG-3) Inhibitors
The lymphocyte activation gene-3 (LAG-3) molecule is a coinhibitory receptor expressed on activated CD4+ and CD8+ T cells that limits the expansion of activated T cells and the size of the immune memory pool[13]. LAG-3 binds MHC class II on antigen presenting cells, inhibits the activation of its host cell, and promotes a more suppressive immune response[13][14]. Specifically, LAG-3 inhibits cytokine and granzyme production and proliferation and encourages differentiation from cytotoxic T cells to T regulatory cells. LAG-3 inhibitors interfere with another immune regulatory mechanism and are emerging as an important target for immunotherapy in combination with other ICI’s[13].
Currently approved immune checkpoint inhibitors (ICI)[1]
| Drug Class | Drug | Year First Approved |
|---|---|---|
| CTLA-4 Inhibitors | Ipilimumab | 2011[15] |
| Tremelimumab | 2022[16] | |
| PD-1 Inhibitors | Pembrolizumab | 2014[17] |
| Nivolumab | 2014[18] | |
| Cemiplimab | 2018[19] | |
| PD-L1 Inhibitors | Atezolizumab | 2016[20] |
| Avelumab | 2017[21] | |
| Durvalumab | 2017[22] | |
| LAG-3 Inhibitors | Relatlimab | 2022[23] |
Immune check point inhibitors associated Optic Neuropathy
An autoimmune optic neuropathy can occur as an OirAE from ICI. The clinical findings of an optic neuropathy include loss of visual acuity, visual field, and color vision, an ipsilateral relative afferent pupillary defect (RAPD) in unilateral or bilateral but asymmetric, and a swollen, pale, or normal (retrobulbar) optic nerve. A complete eye examination including testing of visual acuity and optic nerve functions is recommended for all patients suspected of having an optic neuropathy.
In a previous systematic review, there were 11 articles out of 331 that identified optic neuropathy due to OirAE from ICI therapy[24]. Four (57%) were men and 3 (43%) were female. The average patient age was 60 years old with a standard deviation of 17.4 years. Of the 7 patients, 2 were treated for malignant melanoma; the other five were treated for metastatic nonsmall cell lung cancer, hodgkin’s lymphoma, metastatic renal cell carcinoma, metastatic prostate cancer, and squamous cell carcinoma of the head and neck . The most common indication for ICI was malignant melanoma[1][3][25]. Of 7 patients, 5 had optic disc edema and not enough information was provided for the other 2 cases. Magnetic resonance imaging (MRI) of the head and orbit with and without contrast was performed in 4 patients, of which 2 had optic nerve enhancement. All patients were treated with corticosteroids. The final visual acuity in affected patients was improved in all 7 patients. Of 7 patients, 4 had complete discontinuation of the ICI, 1 had treatment momentarily halted, and 2 had no change in their ICI treatment despite the development of optic neuropathy.
Case Series for Different ICI-associated Optic Neuropathy
| Drug Name | Patient Info | Indication for ICI Therapy | Chief Complaint | Physical Exam | Neuroimaging | Treatment |
|---|---|---|---|---|---|---|
| Atezolizumab | 82 yr old M | Metastatic non-
small cell lung cancer |
- sudden-onset
painless vision loss |
- fundoscopic
exam: R eye pale macula with a cherry-red spot, cotton wool spots, and a pale and swollen optic nerve head with obscuration of vessels - visual acuity: no light perception in the R eye |
- MRI: not
performed |
- IV methylprednisolone followed
by oral prednisolone |
| Pembrolizumab | 67 yr old F | Hodgkin’s
Lymphoma |
- blurred vision
- visual field impairment - altered color perception |
Initial:
- fundoscopic exam: R eye papilledema in the temporal optic disc, - visual acuity: 0.05 in R eye - Visual field testing: horizontal visual field loss
- fundoscopic exam: L eye sectorial papilledema- visual acuity: 0.4 in L eye - Visual field testing: horizontal visual field loss |
Initial:
- MRI: no abnormalities
- MRI: increased CSF signal along L optic nerve |
Initial:
- IV methylprednisolone followed by oral prednisone taper over four months
- IV methylprednisolone, plasmapheresis, immunoglobulin treatment, retrobulbar injection of steroids and mycophenolate mofetil followed by six month long steroid taper |
| Ipilimumab | 67 yr old M | Metastatic
melanoma |
- bilateral blurred
vision - bilateral photopsias of temporal visual fields |
- fundoscopic
exam: mild bilateral optic disc edema - Slit lamp examination:1+ anterior chamber cell and posterior synechia bilaterally - Visual acuity: 20/20 |
- MRI: small
vessel ischemic changes |
- topical
prednisolone every 2 hours and atropine drops |
| 27 yr old F | Metastatic renal
cell carcinoma |
- bilateral vision
loss |
- fundoscopic
exam: severe bilateral optic disc swelling - visual acuity: 20/80 - visual field testing: bilateral large paracentral scotoma |
- MRI: bilateral T2
hyperintensity of optic discs and nerves and 1 small enhancing periventricular lesion |
- IV methylprednisolone followed
by oral steroid taper - plasma exchange | |
| Durvalumab | 65 yr old M | Metastatic
prostate cancer |
-L inferior
scotoma and discomfort with extraocular movements |
-fundoscopic
exam: 4+ disc edema in L eye - visual field testing: near complete central sparing inferior defect in L eye |
- MRI: no
abnormalities |
- IV high dose
corticosteroids |
| Nivolumab | 64 yr old M | Malignant
melanoma |
-visual field
impairment |
- intermediate
uveitis with bilateral papillitis and acute anterior ischemic optic neuropathy of L eye |
-information not
included in review |
- no treatment
administered |
| Cemiplimab | 50 yr old F | Squamous cell
carcinoma of the head and neck |
-visual impairment | -visual field
testing: OD: 20/30 OS: 20/100 |
-information not
included in review |
- Methylprednisolon e and prednisone |
Atezolizumab-associated arteritic anterior ischemic optic neuropathy (AION)
An 82 year old male with metastatic non-small cell lung cancer was treated with the PD-L1 agent, atezolizumab and developed an optic neuropathy consistent with arteritic AION[26]. The patient initially presented to the emergency department with a 1-week history of sudden-onset painless vision loss associated with frontal headaches and jaw claudication[26]. On exam, there was a diffusely swollen optic disc in the right eye (OD), and RAPD OD, and delayed choroidal and retinal arterial filling on fundus fluorescein angiography OD.
Pembrolizumab-associated optic neuropathy
A patient with Hodgkin lymphoma was treated with pembrolizumab and developed a unilateral optic neuropathy OD 19 weeks after initiation of treatment[27]. Despite cessation of pembrolizumab contralateral involvement occurred in the left eye (OS), 7 months later[27].
Ipilimumab-associated optic neuropathy
There are multiple reported cases of ipilimumab-associated optic neuropathy[25]. A 67-year-old man with stage III metastatic melanoma treated with ipilimumab monotherapy developed bilateral optic disc edema after his third ICI infusion[28]. Another case reported a 27-year-old woman treated with ipilimumab for metastatic renal cell carcinoma who also developed bilateral optic neuropathy 5 weeks after her last infusionu[29].
Durvalumab-associated optic neuropathy
A 65-year-old male with metastatic prostate cancer was treated with durvalumab and developed unilateral optic neuropathy of his left eye[30]. He developed acute scotoma in the left eye with grade 4 optic nerve edema and near complete inferior altitudinal defect seen on visual field testing[30].
Nivolumab-associated optic neuropathy
A 64-year-old male was treated with nivolumab for metastatic melanoma and consequently developed intermediate uveitis with bilateral papillitis and acute anterior ischemic optic neuropathy of his left eye[31]. He also had concurrent hypertensive meningitis, another irAE[31].
Cemiplimab-associated optic neuropathy
A 50-year-old female diagnosed with squamous cell carcinoma of the head and neck was treated with cemiplimab[5]. She subsequently developed bilateral optic neuropathy with visual field deficits[5].
Diagnosis & Management
The Common Terminology Criteria for Adverse Events (CTCAE) Version 5, published by the US Department of Health and Human Services has four grades for patients with ocular toxicity from medications[1][9]. There are currently no formal treatment recommendations for neuro-ophthalmic or OirAE associated with ICIs. The Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group has suggested general guidelines for management of immune related adverse events by grade[1][32].
Although corticosteroids are the mainstay of presumed OirAE after ICI[25][29][30][33][34] the decision for discontinuation or dose reduction of the ICI treatment should be decided on a case by case basis in a multidisciplinary team approach to weigh the risks and benefits of ICI treatment[30].
Diagnosis and Management Guidelines[1]
| Grade | Description | Management |
|---|---|---|
| Grade 1 | Mild toxicity (patients may be asymptomatic,
but have clinically detectable findings) |
Typically, do not require corticosteroid
administration or cessation of ICI |
| Grade 2 | Moderately symptomatic, which may interfere
with ADL’s and with visual acuity of 20/40 or better (or loss of 3 lines or fewer from baseline) |
Might consider temporary suspension of ICI
and initiation of systemic corticosteroids (either intravenous or oral). Consider resuming ICI once symptoms have improved to grade 1 |
| Grade 3 | Decrease in vision (worse than 20/40, or more
than 3 lines decreased from baseline, but better than 20/200), limiting activities of daily living, severe pain, and visual field defects |
Warrant consideration of suspension of ICI
and cessation if symptoms haven’t resolved within 4 – 6 weeks, as well as systemic steroids |
| Grade 4 | Visual acuity equivalent to or worse than
20/200 |
Typically discontinue ICI and give systemic
steroids |
Rituximab
Rituximab is a chimeric CD-20 monoclonal antibody classically used for relapsed or chemorefractory low-grade or follicular non-Hodgkin's lymphoma[35]. Rituximab direct mechanisms of action include complement-mediated cytotoxicity and antibody-dependent cell-mediated cytotoxicity[35]. Indirectly, rituximab can induce apoptosis and sensitize cancer cells to chemotherapy[35]. As a monoclonal antibody, Rituximab has also shown significant improvement in the management of ICI related cutaneous, musculocutaneous, neurological, and hematologic adverse events[35][36][37].
Cutaneous adverse effects presenting in patients treated with ICI therapy bullous dermatoses like bullous pemphigoid, other autoimmune bullous dermatoses or bullous drug reaction[35][36]. One study showed that in seven patients with corticosteroid-refractory immune related cutaneous adverse events (ircAEs), rituximab lead to significant improvement of ircAEs[38]. Another study showed that rituximab was associated with ircAE improvement of ≥2 grades in every patient treated[36]. Additionally, rituximab can provide significant relief for musculoskeletal irAEs like primary myositis, however treatment must be carefully monitored due to rituximab’s long duration of action[35]. Furthermore, for treatment refractory neurologic irAEs including autoimmune encephalopathy and myasthenia gravis, rituximab may be considered alongside plasmapharesis[35]. Finally, many dangerous hematologic irAEs including CNS hemorrhage, thrombosis/embolism, or renal failure may be treated with rituximab if there is no improvement or worsening while on corticosteroids[35].
Atezolizumab-associated Arteritic anterior ischemic optic neuropathy
For this specific case study, after the initial diagnosis of AAION was made, high-dose corticosteroid therapy was initiated (intravenous methylprednisolone followed by oral prednisolone[26] and atezolizumab was discontinued.
Pembrolizumab-associated optic neuropathy
In this report, when the right eye was affected, pembrolizumab treatment was halted and high-dose steroid treatment was initiated (intravenous methylprednisolone for five days), followed by a prednisone taper over four months[27]. 7 months later when the left eye was affected, high-dose steroids (intravenous methylprednisolone), plasmapheresis, immunoglobulin treatment, retrobulbar injection of steroids and mycophenolate mofetil helped treat symptoms[27]. All of these treatment modalities were then followed with a six month long steroid taper[27].
Ipilimumab-associated bilateral optic neuropathy
For the 67-year-old patient, initial symptoms were treated with topical prednisolone and atropine drops in both eyes, and treatment with ipilimumab was continued[28]. Further exacerbations in optic neuropathy were treated with topical prednisolone every 2 hours in both eyes. Systemic corticosteroids were considered but administered due to patient preference[28]. Another 27-year-old woman with metastatic renal cell carcinoma was given intravenous methylprednisolone (1g per day for 3 days), followed by an oral steroid taper (1mg per kg per day) and plasma exchange (10 sessions)[29]. Ipilimumab treatment was halted for six months and resumed with addition of nivolumab.
Durvalumab-associated optic neuropathy
After the diagnosis of ICI related optic neuropathy was made, the patient was treated with IV high dose corticosteroids and durvalumab treatments were not terminated[30]. The patient endorsed significant improvement of his visual deficits after steroid treatment[30].
Nivolumab-associated optic neuropathy
After the patient was diagnosed with unilateral uveitis and optic neuropathy, nivolumab treatment was discontinued, and no other treatments were administered[31]. The patients had transient worsening of symptoms with eventual partial remission[31].
Cemiplimab-associated optic neuropathy
Once the patient was diagnosed with bilateral optic neuropathy, cemiplimab was held and high dose IV methylprednisolone at up to 1 gm/day for 1–7 days was administered followed by oral tapering over a period of several months[5]. Significant improvement of visual symptoms was noted[5].
Prognosis
Since OirAEs have a relatively low frequency, long term complications and prognosis are still unknown[1][39]. However, sources agree that most OirAEs can be well controlled or resolved with topical or systemic corticosteroids[33][40].
Conclusion
Clinicians should be aware that optic neuropathy can occur unilaterally or bilaterally in patients treated with ICI as an OirAE. Neuroimaging studies are recommended to exclude alternative etiologies for the optic neuropathy including metastatic, radiation induced, or paraneoplastic etiologies. Unfortunately, there is no current biomarker for OirAE and the condition is a diagnosis of exclusion. Discontinuation or dose reduction of the ICI should be decided via a multidisciplinary approach including ophthalmology and oncology. Treatment with corticosteroids is recommended but the dose, route, and duration remain ill defined. The use of rituximab or other B-cell depletion strategy as an immune countermeasure to OirAE due to ICI likewise remains controversial. Further research is needed to determine the precise treatment and prognosis for these patients.
References
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- ↑ Lentz RW, Colton MD, Mitra SS, Messersmith WA. Innate Immune Checkpoint Inhibitors: The Next Breakthrough in Medical Oncology?. Mol Cancer Ther. 2021;20(6):961-974. doi:10.1158/1535-7163.MCT-21-0041
- ↑ 3.0 3.1 Yu CW, Yau M, Mezey N, Joarder I, Micieli JA. Neuro-ophthalmic Complications of Immune Checkpoint Inhibitors: A Systematic Review. Eye Brain. 2020;12:139-167. Published 2020 Nov 3. doi:10.2147/EB.S277760
- ↑ 4.0 4.1 Braun D, Getahun D, Chiu VY, et al. Population-Based Frequency of Ophthalmic Adverse Events in Melanoma, Other Cancers, and After Immune Checkpoint Inhibitor Treatment. Am J Ophthalmol. 2021;224:282-291. doi:10.1016/j.ajo.2020.12.013
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- ↑ 9.0 9.1 Common Terminology Criteria for Adverse Events (CTCAE). Version 5.; 2017
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- ↑ Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nat Rev Immunol. 2018;18(3):153-167. doi:10.1038/nri.2017.108
- ↑ Zhang N, Tu J, Wang X, Chu Q. Programmed cell death-1/programmed cell death ligand-1 checkpoint inhibitors: differences in mechanism of action. Immunotherapy. 2019;11(5):429-441. doi:10.2217/imt-2018-0110
- ↑ 13.0 13.1 13.2 Sauer N, Szlasa W, Jonderko L, et al. LAG-3 as a Potent Target for Novel Anticancer Therapies of a Wide Range of Tumors. Int J Mol Sci. 2022;23(17):9958. Published 2022 Sep 1. doi:10.3390/ijms23179958
- ↑ Li Y, Ju M, Miao Y, Zhao L, Xing L, Wei M. Advancement of anti-LAG-3 in cancer therapy. FASEB J. 2023;37(11):e23236. doi:10.1096/fj.202301018R
- ↑ Yervoy (Ipilimumab) [Package Insert]. Bristol Myers Squibb; 2020
- ↑ IMJUDO® (tremelimumab-actl) [Prescribing Information]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2023
- ↑ Keytruda (pembrolizumab) [package insert]. Merck Sharp Dohme; 2021
- ↑ Opdivo (nivolumab) [package insert]. Bristol Myers Squibb; 2015
- ↑ Libtayo (cemiplimab) [package insert]. Regeneron Pharmaceuticals; 2021
- ↑ Tecentriq (atezolizumab) [package insert]. Genentech Inc; 2016
- ↑ Bavencio (avelumab) [package insert]. EMD Serono Inc; 2017
- ↑ Imfinzi (durvalumab) [package insert]. Astrazeneca UK Ltd; 2021
- ↑ Opdualag [package insert]. Princeton, NJ: Bristol-Myers Squibb Company; 2022
- ↑ Pietris, J., Santhosh, S., Ferdinando Cirocco, G., Lam, A., Bacchi, S., Tan, Y., Gupta, A. K., Kovoor, J. G., & Chan, W. (2023). Immune Checkpoint Inhibitors and Optic Neuropathy: A Systematic Review. Seminars in ophthalmology, 38(6), 547–558. https://doi.org/10.1080/08820538.2023.2168494
- ↑ 25.0 25.1 25.2 Dalvin LA, Shields CL, Orloff M, Sato T, Shields JA. CHECKPOINT INHIBITOR IMMUNE THERAPY: Systemic Indications and Ophthalmic Side Effects. Retina. 2018;38(6):1063-1078. doi:10.1097/IAE.0000000000002181
- ↑ 26.0 26.1 26.2 Berry EC, Mullany S, Quinlivan A, et al. Eosinophilic Vasculitis and Arteritic Anterior Ischemic Optic Neuropathy Associated With Anti-PD-L1 Therapy. J Immunother. 2022;45(1):51-55. doi:10.1097/CJI.0000000000000394
- ↑ 27.0 27.1 27.2 27.3 27.4 Daetwyler E, Zippelius A, Meyer P, Läubli H. Pembrolizumab-induced optic neuropathy - a case report. Front Immunol. 2023;14:1171981. Published 2023 May 9. doi:10.3389/fimmu.2023.1171981
- ↑ 28.0 28.1 28.2 Yeh OL, Francis CE. Ipilimumab-associated bilateral optic neuropathy. J Neuroophthalmol. 2015;35(2):144-147. doi:10.1097/WNO.0000000000000217
- ↑ 29.0 29.1 29.2 Boisseau W, Touat M, Berzero G, et al. Safety of treatment with nivolumab after ipilimumab-related meningoradiculitis and bilateral optic neuropathy. Eur J Cancer. 2017;83:28-31. doi:10.1016/j.ejca.2017.05.036
- ↑ 30.0 30.1 30.2 30.3 30.4 30.5 Noble CW, Gangaputra SS, Thompson IA, et al. Ocular Adverse Events following Use of Immune Checkpoint Inhibitors for Metastatic Malignancies. Ocul Immunol Inflamm. 2020;28(6):854-859. doi:10.1080/09273948.2019.1583347
- ↑ 31.0 31.1 31.2 31.3 Chaudot F, Sève P, Rousseau A, et al. Ocular Inflammation Induced by Immune Checkpoint Inhibitors. J Clin Med. 2022;11(17):4993. Published 2022 Aug 25. doi:10.3390/jcm11174993
- ↑ Puzanov I, Diab A, Abdallah K, et al. Managing toxicities associated with immune checkpoint inhibitors: Consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group. Journal for ImmunoTherapy of Cancer. 2017;5(1). doi:10.1186/s40425-017-0300-z
- ↑ 33.0 33.1 Fortes BH, Liou H, Dalvin LA. Ophthalmic adverse effects of immune checkpoint inhibitors: the Mayo Clinic experience. Br J Ophthalmol. 2021;105(9):1263-1271. doi:10.1136/bjophthalmol-2020-316970
- ↑ Wladis EJ, Kambam ML. Ophthalmic complications of immune checkpoint inhibitors. Orbit. 2022;41(1):28-33. doi:10.1080/01676830.2020.1867192
- ↑ 35.0 35.1 35.2 35.3 35.4 35.5 35.6 35.7 Cerny, T., Borisch, B., Introna, M., Johnson, P., & Rose, A. L. (2002). Mechanism of action of rituximab. Anti-cancer drugs, 13 Suppl 2, S3–S10. https://doi.org/10.1097/00001813-200211002-00002
- ↑ 36.0 36.1 36.2 Mital, R., Otto, T. S., Savu, A., Baumrin, E., Cardones, A. R., Carlesimo, M., Caro, G., Freites-Martinez, A., Hirner, J. P., Markova, A., McLellan, B. N., Rossi, A., Sauder, M. B., Seminario-Vidal, L., Sibaud, V., Owen, D. H., Dulmage, B. O., Chen, S. T., & Kaffenberger, B. H. (2023). Detection of novel therapies using a multi-national, multi-institutional registry of cutaneous immune-related adverse events and management. International journal of dermatology, 62(8), 1020–1025. https://doi.org/10.1111/ijd.16714
- ↑ Perdigoto, A. L., Kluger, H., & Herold, K. C. (2021). Adverse events induced by immune checkpoint inhibitors. Current opinion in immunology, 69, 29–38. https://doi.org/10.1016/j.coi.2021.02.002
- ↑ Phillips, G. S., Wu, J., Hellmann, M. D., Postow, M. A., Rizvi, N. A., Freites-Martinez, A., Chan, D., Dusza, S., Motzer, R. J., Rosenberg, J. E., Callahan, M. K., Chapman, P. B., Geskin, L., Lopez, A. T., Reed, V. A., Fabbrocini, G., Annunziata, M. C., Kukoyi, O., Pabani, A., Yang, C. H., … Lacouture, M. E. (2019). Treatment Outcomes of Immune-Related Cutaneous Adverse Events. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 37(30), 2746–2758. https://doi.org/10.1200/JCO.18.02141
- ↑ Vishnevskia-Dai V, Rozner L, Berger R, et al. Ocular side effects of novel anti-cancer biological therapies. Sci Rep. 2021;11(1):787. Published 2021 Jan 12. doi:10.1038/s41598-020-80898-7
- ↑ Mazharuddin AA, Whyte AT, Gombos DS, et al. Highlights on Ocular Toxicity of Immune Checkpoint Inhibitors at a US Tertiary Cancer Center. J Immunother Precis Oncol. 2022;5(4):98-104. Published 2022 Nov 30. doi:10.36401/JIPO-22-14
