Interferons are glycoproteins that have antiviral, antiproliferative, and immunomodulatory functions. They are used widely for the treatment of many conditions like Hepatitis C, cancers, and immune-mediated disorders like multiple sclerosis. Interferon was discovered by Issacs and Lindenmann in 1957 while studying the phenomenon of virus interference. The FDA approved the use of interferon-alpha-2a and alpha-2b for the treatment of hairy cell leukemia in 1986. As time progressed, the use of interferons (IFN) has expanded to include a broad spectrum of conditions. However, their use correlates with numerous adverse effects like fatigue, influenza-like syndrome, toxicities related to the central nervous system, the gastrointestinal tract, endocrine system, and cardiovascular, renal, and musculoskeletal systems. Ikebe and associates made the first report of ocular toxicity of IFN therapy in 1990 in a 39-year-old patient who developed retinal hemorrhages and cotton wool spots after receiving intravenous IFN.
Interferons are a family of proteins released by a variety of cells in response to infections caused by viruses. There are several classes of IFN, including IFN alpha, beta, and gamma. IFN alpha has been used for the management of hairy cell leukemia, malignant melanoma, follicular lymphoma, condylomata acuminata, AIDS-related Kaposi sarcoma, and chronic hepatitis B and C. IFN beta has been used for multiple sclerosis, and IFN gamma has been used for chronic granulomatous disease and malignant osteopetrosis. In ophthalmology, IFN has been used to manage subretinal neovascularization of age-related macular degeneration, glaucoma filtering surgery, and ocular cicatricial pemphigoid. The ophthalmic complications of IFN are mainly limited to the optic disc and retina, and the characteristic finding is vascular retinopathy.
The reported incidence of IFN-associated retinopathy ranges from 18% to 86%, according to various studies. Higher incidences occur in some parts of Japan, where values of more than 50% are common. Increased rates of retinopathy correlated with older age and in patients with systemic conditions like hypertension and diabetes mellitus and are probably related to the dose of IFN as well. IFN retinopathy can occur at any time between four to 28 weeks of initial treatment, and various studies report the average time of presentation at around 20 weeks. Another peculiar phenomenon reported in some studies is that nonresponsiveness to IFN therapy was more prevalent in those developing retinopathy.
The exact pathogenesis of the development of IFN retinopathy is not clear. Some authors suggest ischemia as the cause of the vascular changes. Others implicate immune complex deposits in the blood vessel walls, which can cause a reduction in retinal capillary perfusion and formation of cotton wool spots. There are also suggestions that inflammatory cytokine deposition in the blood vessel wall may be the underlying causative factor for this condition. Some studies have found an association between IFN retinopathy and elevated serum vascular endothelial growth factor (VEGF) levels. Vascular endothelial growth factor is associated with neovascularization, but the correlation between IFN retinopathy and high serum vascular endothelial growth factor levels is not clear. Studies were conducted by Abe and associates about the long-term effect of IFN on mice. They discovered that there was occlusion of the retinal vascular bed in mice pretreated with urethane and not in those without pretreatment. They concluded that a diseased retina predisposed to the development of IFN retinopathy.
Different authors have suggested that certain risk factors predispose the patient to the development of IFN retinopathy. They include systemic hypertension, diabetes mellitus, the age of the patient, and the dose of interferon. Concomitant administration of drugs like ribavirin may predispose patients to the development of retinopathy. Arterial sclerosis, erythrocyte count, leukocyte count, platelet count, serum glutamic-pyruvic transaminase (SGPT) levels, serum glutamic-oxaloacetic transaminase (SGOT) levels, hemoglobin, triglycerides, and total cholesterol have been examined as risk factors, but so far, the results are inconclusive.
The classical presenting complaint in the typical IFN retinopathy is a defective vision, but many patients may be asymptomatic. Characteristic ocular findings include cotton wool spots, and retinal hemorrhages in the posterior pole, particularly around the optic disc.
Atypical ocular side effects have presented in some patients. These include central retinal artery occlusion, central retinal vein occlusion, anterior ischemic optic neuropathy, optic disc edema, neovascular glaucoma, vitreous hemorrhage, Vogt-Koyanagi-Harada-like disease, retinal detachment, subconjunctival hemorrhage, optic disc edema, and panophthalmitis. Common to these conditions are severe and permanent visual impairment, which persists despite discontinuation of IFN therapy and instituting appropriate ophthalmological management. Some authors believe that IFN may not be entirely responsible for these complications but could be related to pre-existing ocular pathology in these patients.
Most authors claim that there is no difference in the clinical features of patients receiving different types of IFN.
Any patient complaining of any ocular symptoms while receiving IFN treatment requires a thorough examination. One should especially be vigilant in older patients, those receiving higher doses of IFN or combination with other medicines, and patients with preexisting morbidities like hypertension and diabetes mellitus. Visual acuity testing, pupil examination, and dilated fundus examination are mandatory. Fluorescein angiography may reveal areas of capillary dropout, hemorrhages, and cotton wool spots that may cause blocked fluorescence. Optical coherence tomography may help to diagnose macular edema, especially in subtle cases.
The recommendation is that all patients receiving IFN therapy should have a thorough ophthalmological examination before starting treatment. Any preexisting retinopathy should be ruled out. Monthly monitoring of patients should be in place while receiving therapy if there is preexisting retinopathy and every three months in asymptomatic patients unless they complain of defective vision.
If a patient presents with an ophthalmological complication while receiving IFN therapy, the general recommendation is to stop IFN treatment. However, some authors suggest discontinuing treatment only in those with severe retinopathy or those with preexisting diseases like diabetes mellitus. A good outcome occurs in many cases after stopping IFN.
IFN retinopathy is a relatively new entity, but it requires attention since a large number of patients, especially those suffering from hepatitis C receive IFN as a part of their treatment. All patients should undergo a comprehensive ocular examination before starting treatment, and regular follow up is important, especially in the first six months when most complications arise.
The internist, infectious disease expert, oncologist, and hematologist may administer interferon to their patients for a variety of reasons. However, these professionals need to be aware of interferon-induced retinopathy. A baseline eye exam by an ophthalmology nurse is recommended. If the patient has any change in vision or ocular complaints, a consult with an ophthalmologist is necessary. If a patient presents with an ophthalmological complication while receiving IFN therapy, the general recommendation is to stop IFN treatment. However, some authors suggest discontinuing treatment only in those with severe retinopathy or those with preexisting diseases like diabetes mellitus. A good outcome results in many cases after stopping IFN.
|||Ophthalmological side effects of interferon therapy of chronic hepatitis C., Medhat E,Esmat G,Hamza E,Abdel Aziz A,Fouad Fathalah W,Darweesh SK,Zakaria Z,Mostafa S,, Hepatobiliary surgery and nutrition, 2016 Jun [PubMed PMID: 27275462]|
|||Retinopathy associated with interferon therapy in patients with hepatitis C virus., Abd El-Badie Mohamed M,Abd-El Azeem Eed K,, Clinical ophthalmology (Auckland, N.Z.), 2012 [PubMed PMID: 22969278]|
|||Rentiya ZS,Wells M,Bae J,Chen KJ,Chao AN,Turgeon N,Shah SM,Hanout M, Interferon-α-induced retinopathy in chronic hepatitis C treatment: summary, considerations, and recommendations. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie. 2019 Mar; [PubMed PMID: 30547319]|
|||Kashif M,Saleem MK,Farooka IK,Husnain A,Siddiqui AM, Incidence of retinopathy in chronic hepatitis C patients treated with pegylated interferon alpha 2a and ribavirin combination therapy. Pakistan journal of medical sciences. 2015 Jan-Feb [PubMed PMID: 25878638]|
|||Heath G,Airody A,Gale RP, The Ocular Manifestations of Drugs Used to Treat Multiple Sclerosis. Drugs. 2017 Mar; [PubMed PMID: 28181178]|
|||Literature systematic review on the ophthalmological side effects of interferons., Fragoso YD,Paggiaro MS,Mastromauro R,Jacondino Gda S,Wilson HM,, Arquivos brasileiros de oftalmologia, 2011 Jul-Aug [PubMed PMID: 22068863]|
|||Hayasaka S,Nagaki Y,Matsumoto M,Sato S, Interferon associated retinopathy. The British journal of ophthalmology. 1998 Mar [PubMed PMID: 9602634]|
|||Fouad YM,Khalaf H,Ibraheem H,Rady H,Helmy AK, Incidence and risk factors of retinopathy in Egyptian patients with chronic hepatitis C virus treated with pegylated interferon plus ribavirin. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2012 Jan [PubMed PMID: 22115957]|
|||Bajaire BJ,Paipilla DF,Arrieta CE,Oudovitchenko E, Mixed vascular occlusion in a patient with interferon-associated retinopathy. Case reports in ophthalmology. 2011 Jan 11 [PubMed PMID: 21326840]|
|||Bourgeois N,Chavant F,Lafay-Chebassier C,Leveziel N,Pérault-Pochat MC, [Drugs and retinal disorders: A case/non-case study in the French pharmacovigilance database]. Therapie. 2016 Sep; [PubMed PMID: 27203167]|
|||Lückoff A,Caramoy A,Scholz R,Prinz M,Kalinke U,Langmann T, Interferon-beta signaling in retinal mononuclear phagocytes attenuates pathological neovascularization. EMBO molecular medicine. 2016 Jun; [PubMed PMID: 27137488]|
|||Zarbin MA,Jampol LM,Jager RD,Reder AT,Francis G,Collins W,Tang D,Zhang X, Ophthalmic evaluations in clinical studies of fingolimod (FTY720) in multiple sclerosis. Ophthalmology. 2013 Jul; [PubMed PMID: 23531349]|