MEDICAL ED NG UC UI AT A CONTINUING TIN IO CON N MEDICAL EDUCATION PUBLICATION CME

ISSUE 25 Intermediate : Etiology, Diagnosis, and Treatment

LANA M. RIFKIN, MD Intermediate uveitis can be associated with a variety of infectious causes as well as systemic autoimmune diseases, most commonly and . Treatment is aimed at the cause of the disease, if identi ed, and at the in ammation, with the goal of preventing vision loss and deleterious sequelae. Steroids are the rst-line treatment for non-infectious intermediate uveitis, but patients with recurrent or chronic disease should transition to steroid-sparing therapies as soon as possible. FIGURE 1 Fundus photograph showing snowball opacities and vascular sheathing, indicative of vasculitis in a patient with multiple sclerosis. (Republished from: Ozdal PC, Berker N, Tugal-Tutkun I. Pars Planitis: Epidemiology, Intermediate uveitis (IU) can have severe consequences for clinical characteristics, management and visual prognosis. J Ophthalmic Vis Res. 2015 vision if left untreated and can be associated with life-threat- Oct-Dec;10(4):469-80.) ening conditions. Recognizing and appropriately treating IU is therefore of utmost importace. IU is uveitis in which the major ASSOCIATION OF IU WITH OTHER DISEASES site of infl ammation is the vitreous.1 Th e and More than 50% of IU cases are idiopathic6,9 and only the peripheral may be involved, but anterior segment approximately 4% of cases are associated with an infectious cells and chorioretinal infl ammation are usually minimal or etiology such as syphilis10 (Treponema pallidum), tuberculosis absent.1 Th e term pars plantitis refers to idiopathic IU and is (Mycobacteria tuberculosis) and, less frequently, only used when no infectious or systemic cause can be found.1,2 (Borrelia burgdorferi) or cat scratch fever (Bartonella henselae). Th e prevalence of IU has been reported as 5.9 per 100,000 Viral etiologies of intermediate uveitis include Herpes simplex individuals, with an incidence of 1.4 per 100,000 people per virus, varicella zoster virus, and Epstein-Barr virus. year.1,3 IU constitutes anywhere from 6.1 to 17.6% of all uve- itis cases.4,5 In one study, nearly two-thirds of patients were female,6 but in general, no consistent diff erences in frequency See INSIDE for: between genders have been reported.1,7 Although IU can aff ect Dry AMD Pathobiology: Role for Antiinfl ammatory all ages, it is most frequently diagnosed when patients are in Therapies? by Priyatham S. Mettu, MD their 20s to 40s, with a mean age of approximately 35 years.1,6,8

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Supported byTopics an unrestricted in OCULAR educational ANTIINFLAMMATORIES grant from Shire. 1 Non-infectious IU is more common TOPICS IN OCULAR ANTIINFLAMMATORIES, ISSUE 25 and is oft en associated with systemic au- STATEMENT OF NEED (JavaScript™ and Java™ enabled). For Mac® users: Mac OS® toimmune disease. Approximately 25% of The control of ocular infl ammation is a critical aspect of X 10.4 (Tiger®) or newer; Safari™ 3.0 or newer, Mozilla® medical and surgical ophthalmic practice. Despite their Firefox® 2.0 or newer; (JavaScript™ and Java™ enabled). patients with systemic sarcoidosis and 3% side eff ects, antiinfl ammatory drugs are used to treat a Internet connection required: Cable modem, DSL, or to 27% of patients with multiple sclerosis very wide range of conditions throughout the eye, from better. ocular surface disease and allergic to poste- (MS) may develop IU at some point in rior segment conditions. Use of antiinfl ammatory agents DATE OF ORIGINAL RELEASE December 2018. Ap- their lifetime. Conversely, 2% to 10% of is also critical in ocular surgery, contributing greatly to proved for a period of 12 months. patient comfort and positive outcomes. patients with IU will develop sarcoidosis, ACCREDITATION STATEMENT The ocular antiinfl ammatory landscape is changing as This activity has been planned and implemented in ac- and 8% to 15% of patients with IU will research reveals more about the role of infl ammation in cordance with the accreditation requirements and poli- 1 a range of ocular conditions and as new antiinfl ammatory develop MS. In children younger than 7 cies of the Accreditation Council for Continuing Medical agents enter the market.1,2 Twenty years ago, for example, Education (ACCME) through the joint providership of the years of age, approximately 30% of IU cas- the idea of using a topical to treat dry eye University of Florida College of Medicine and Candeo and/or was viewed with alarm; Clinical/Science Communications, LLC. The University of es are associated with juvenile idiopathic today, it is accepted practice. 10 Florida College of Medicine is accredited by the ACCME arthritis. Other systemic disorders Although and nonsteroidal antiinfl am- to provide continuing medical education for physicians. potentially associated with IU include matory drugs (NSAIDs) have been the mainstays of the ocular anti-infl ammatory armamentarium, a number of CREDIT DESIGNATION STATEMENT tubulointerstitial nephritis uveitis syn- new agents with novel mechanisms of action (and new The University of Florida College of Medicine designates 11 ocular drug delivery systems) have come to market or are this enduring material for a maximum of 1 AMA PRA drome (TINU), Behçet’s disease, Vogt- 3,4 being made ready for market. Category 1 Credit™. Physicians should claim only the Koyanagi-Harada disease, lupus, infl am- As indications expand and change, and as new drugs, credit commensurate with the extent of their participa- matory bowel disease, and HLA-B27 syn- formulations, and delivery systems become available, tion in the activity. 1,6,12 clinicians require up-to-date protocols for drug selec- dromes. Malignancies, including lym- tion and use. Such protocols are also needed for routine EDITORIAL BOARD/FACULTY ADVISORS phoma, can also be associated with IU.2 (but nevertheless off -label) uses of corticosteroids and Marguerite B. McDonald, MD, FACS, practices at NSAIDs because important diff erences in effi cacy, safety, Ophthalmic Consultants of Long Island, and is a clinical and tolerability exist between these classes and among professor of at the New York University SIGNS AND SYMPTOMS formulations within each of these classes.5,6 School of Medicine. She is also an adjunct clinical profes- By putting the latest published evidence into the context sor of ophthalmology at Tulane University Health Sciences A patient with IU will commonly of current clinical practice, Topics in Ocular Antiinfl amma- Center. Dr. McDonald is a consultant for Allergan, Alcon, present with gradual onset of blurred vi- tories equips ophthalmologists to maintain competen- Bausch + Lomb, BlephEx, FOCUS Laboratories, Shire, and J&J Vision. 2,13 cies and narrow gaps between their actual and optimal sion and fl oaters, and unlike anterior infl ammation management practices, across the range Victor L. Perez, MD, is a professor of ophthalmology at uveitis, will not typically experience red- of clinical situations in which current and novel ocular the Duke University School of Medicine. He is also the 2 antiinfl ammatories may be used. director of Duke Eye Center’s Ocular Immunology Center ness, pain, or . Young pa- and Ocular Surface Program. Dr. Perez is a consultant for tients with a complaint of fl oaters should REFERENCES Allergan, Shire, EyeGate, and TopiVert. He is also a stock 1. Song JS, Hyon JY, Lee D, et al. Current practice pattern shareholder for EyeGate. be carefully examined for signs of IU. for dry eye patients in South Korea: a multicenter study. Matthew J. Gray, MD, is an assistant professor in the On examination, predominant site Korean Journal of Ophthalmology. 2014;28(2):115-21. Department of Ophthalmology at the University of 2. Ciulla TA, Harris A, McIntyre N, Jonescu-Cuypers C. Treat- Florida College of Medicine. He states that in the past 12 of infl ammation in intermediate uve- ment of diabetic with sustained-release months, he has not had a fi nancial relationship with any itis will be in the vitreous, which will glucocorticoids: intravitreal triamcinolone acetonide, commercial organization that produces, markets, resells, dexamethasone implant, and fl uocinolone acetonide or distributes healthcare goods or services consumed by present with vitritis—characterized by implant. Expert Opin Pharmacother. 2014;15(7):953-9. or used on patients relevant to this manuscript. “snowballs,” which are aggregates of 3. Maya JR, Sadiq MA, Zapata LJ, et al. Emerging therapies Priyatham S. Mettu, MD, is a fellowship-trained medical 2 for noninfectious uveitis: what may be coming to the retina specialist and clinician-scientist and is assistant infl ammatory cells. Exudates on the clinics. J Ophthalmol. 2014;2014:310329. professor of ophthalmology at Duke University School are termed “snowbanks” 4. Sheppard JD, Torkildsen GL, Lonsdale JD, et al, and of Medicine, in Durham, NC. He states that in the past 12 the OPUS-1 Study Group. Lifi tegrast ophthalmic solu- months, he has not had a fi nancial relationship with any and are the hallmark of pars planitis. tion 5.0% for treatment of dry : results commercial organization that produces, markets, resells, Neovascularization and vasculitis may of the OPUS-1 phase 3 study. Ophthalmology. 2014 or distributes healthcare goods or services consumed by Feb;121(2):475-83. 7 or used on patients relevant to this manuscript. also be present (Figure 1). In some cases, 5. Fong R, Leitritz M, Siou-Mermet R, Erb T. Loteprednol Lana M. Rifkin, MD, is a uveitis specialist at Ophthalmic inflammation—usually mild—can etabonate gel 0.5% for postoperative pain and infl am- Consultants of Boston and is the director of uveitis and 2 mation after surgery: results of a multicenter immunology at New England Eye Center and assistant be seen in the anterior segment with trial. Clin Ophthalmol. 2012;6:1113-24. professor of ophthalmology at Tufts University School keratic precipitates on the ,7 an- 6. Singer M, Cid MD, Luth J, et al. Incidence of corneal melt of Medicine. Dr. Rifkin states that she is on the speakers in clinical practice: our experience vs a meta-analysis bureau for AbbVie. terior chamber cell, and possibly have of the literature. Clin Exp Ophthalmol. 2012;S1:003. 14 DISCLAIMER posterior synechiae. OFF-LABEL USE STATEMENT Participants have an implied responsibility to use the new- This work may discuss off -label uses of medications. ly acquired information to enhance patient outcomes and professional development. The information presented in DIFFERENTIAL DIAGNOSIS GENERAL INFORMATION this activity is not meant to serve as a guideline for patient A careful clinical examination and This CME activity is sponsored by the University of Florida care. Procedures, medications, and other courses of diag- thorough patient history are the keys to College of Medicine and is supported by an unrestricted nosis and treatment discussed or suggested in this activity educational grant from Shire. should not be used by clinicians without evaluation of a good diff erential diagnosis of IU. Th e The University of Florida College of Medicine designates their patients’ conditions and possible contraindications underlying systemic cause of IU can of- this activity for a maximum of 1 AMA PRA Category 1 or dangers in use, applicable manufacturer’s product Credit™. There is no fee to participate in this activity. In information, and comparison with recommendations of ten be gleaned from the patient’s history, order to receive CME credit, participants should read other authorities. so it is crucial that the physician inquire the report, and then take the posttest. A score of 80% is required to qualify for CME credit. Estimated time to COMMERCIAL SUPPORTERS about the duration of symptoms, the complete the activity is 60 minutes. On completion, take This activity is supported by an unrestricted educational number of recurrences, and any other the test online at http://cme.ufl .edu/ed/self-study/toai/ grant from Shire. System requirements for this activity are: For PC us- symptoms that the patient is experienc- ers: Windows® 2000, XP, 2003 Server, or Vista; Internet ing—even if they may seem unrelated. Explorer® 6.0 or newer, or Mozilla® Firefox® 2.0 or newer

2 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ A thorough slit lamp and dilated fundus examination is very important to detect snowballs, peripheral infl ammation CORE CONCEPTS and vision-threatening sequelae such as neovascularization. ✦ Most cases of IU are idiopathic, but can be associated Laboratory and ancillary testing are useful to exclude pos- with serious infectious or other systemic causes. sible causes for IU and should include a complete blood count ✦ Diagnosis is based on patient history and clinical and metabolic panel for all patients. To test for sarcoidosis, all examination. patients should be tested for angiotensin-converting enzyme (ACE) and lysozyme.2 However, for patients on ACE inhibitors, ✦ Further testing is useful to identify underlying causes. testing for ACE is not informative and does not exclude this ✦ Treatment is necessary when there is signifi cant vision diagnosis. A chest X-ray should be obtained to help rule out loss or vision-threatening sequelae are present. sarcoidosis and tuberculosis7 and detect possible malignan- ✦ Steroids are eff ective, but it is preferable to transition to cies. To test for TB, blood testing with an interferon-gamma steroid-sparing therapy as soon as possible. release assay such as QuantiFERON Gold is recommended. Alternatively, a purifi ed protein derivative (PPD) skin test can be performed but this necessitates a follow up visit to read the commonly, edema, or are present; PPD and may be falsely positive in patients who have previ- if vision is decreased to 20/40 or less; or if symptoms interfere ously been immunized with BCG vaccine. To exclude syphilis, with the patient’s daily life, then treatment is recommended.2 a specifi c treponemal test such as Treponema pallidum anti- body or FTA-Abs is recommended. TREATMENT Although multiple sclerosis can be associated with IU, Patients with IU should be referred to a uveitis specialist not all patients with IU should be sent for for magnetic if available and may be co-managed with a rheumatologist, resonance imaging (MRI) . Th ose with neurologic symptoms a nephrologist, or a dermatologist. Th e commonly followed, should certainly be referred.15 At each 6-monthly follow-up step-ladder approach proposed by Kaplan in 198414,16 has visit, patients with IU should be asked about new neurologic recommended treatments be tried in the following order: symptoms such as tingling or numbness in the fi ngers or toes, (1) posterior subtenon depot steroid injection; (2) cryopexy any episodes of loss of speech, bowel, or bladder function or (retinal cryotherapy); (3) pars plana vitrectomy; and (4) im- increased clumsiness. If any of these symptoms are present, munosuppressive therapy. Today, steroid-sparing immunosup- an MRI is indicated. pressive is more readily available and better understood and If TINU is suspected, patients may be referred to a ne- thus oft en instituted must earlier than in the past, especially phrologist for a possible kidney biopsy. Testing for infl am- in pediatric patients where the risk of and matory bowel disease should also be considered for patients with steroid use are quite high. with isolated IU, particularly for those with gastrointestinal For unilateral IU, periocular steroids such as triamcino- symptoms. Genetic HLA testing may be helpful, although not lone acetate (20-40 mg) are more eff ective at treating IU than diagnostic. HLA-DR15 has been associated with IU7 but is topical steroids such as acetate and are less prone not specifi c to IU, and clinical experience suggests that it may to side eff ects than systemic steroids.17 Intravitreal steroids not be informative. HLA-B27, however, may be quite helpful, such as intravitreal triamcinolone or dexamethasone implants particularly in a patient with lower back pain, hip pain, and a r e e ff e c t i v ,e 17,18 but carry a high risk of cataract, glaucoma, and back stiff ness suggestive of ankylosing spondylitis. other complications17 so should be used with caution. In some cases, surgical treatment and discussion of medi- Patients with bilateral IU, or with disease that is severe or cal treatment may be necessary, particularly when the patient refractory to treatment, should be treated with systemic steroids is refractory to conventional medical treatment, where vitreous such as oral prednisone. It is advised to transition these patients infl ammation is especially severe, or to exclude malignancy or to steroid-sparing therapy as soon as possible. Th e recommend- infection.1 Retinoblastoma may masquerade as IU and should ed dose varies but should not exceed 1 mg/kg/day, max 60-80 also be excluded, particularly in children.14 mg daily. Patients oft en require this for several weeks with slow taper to prevent quick recurrence. Th e goal is to control WHEN TO TREAT infl ammation with the patient requiring less than 10 mg pred- Infectious causes of IU must be treated with antibiotics, nisone/day,17 and this should be achieved in less than 6 months. antivirals, or antifungals, as appropriate. Non-infectious Steroid-sparing medications include the immune- causes of IU may not require treatment. Patients with no loss suppressing antimetabolites methotrexate, mycophenolate of vision and few fl oaters in the absence of any signs of vision- mofetil, and azathioprine.17,19 Th e calcineurin inhibitor cy- threatening sequelae can be monitored closely with 6-monthly closporine can be used but has a relatively high risk of side follow-up visits. Treatment should be re-evaluated if there is a e ff e c t .s 1,17 More recently developed treatments include tumor change in symptoms or new signs of active disease. necrosis factor (TNF) inhibitors, such as the monoclonal anti- Sequelae of under-treated IU may include cataracts, glauco- bodies infl iximab and adalimumab.17,20 Caution is advised with ma, posterior synechiae, , etc. If sequelae these therapies in intermediate uveitis, since TNF inhibitors that threaten vision, such as cystoid macular edema (CME) most can potentiate demyelinating diseases, including MS, and are

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 3 contraindicated if the patient has a history of demyelinating limited by their side eff ect profi les and include local and sys- disease or a strong family history of MS.20 temic steroids as well as systemic immunosuppressive agents.

CONCLUSION Lana M. Rifkin, MD, is a uveitis specialist at Ophthalmic Consultants of Boston The definition of successful treatment of IU can be and is the director of uveitis and immunology at New England Eye Center and considered as achieving control of infl ammation and dis- assistant professor of ophthalmology at Tufts University School of Medicine. ease with vision preserved and without vision-threatening Dr. Rifkin states that she is on the speakers bureau for AbbVie. Medical writer sequelae. In most cases, infl ammation can be completely David Loebel, PhD, of Markey Medical Consulting Pty Ltd, assisted in the controlled, but clinical experience suggests that it requires preparation of this manuscript. long-term treatment. Patients who are treated with systemic immunosuppression should expect treatment to last 1.5 to 2.5 years, or possibly longer. Treatment modalities are RIFKIN REFERENCES continue on page 9

Dry AMD Pathobiology: Role for Antiin ammatory Therapies? PRIYATHAM S. METTU, MD In ammation, in particular complement and macrophages, may FIGURE 1 Clinical color fundus contribute to a number of pathogenic mechanisms in photograph (CFP) and optical AMD. With no treatments available for dry AMD and coherence tomography (OCT) of fovea-involving geographic current treatment options con ned to anti-VEGF drugs atrophy (GA), the advanced for wet AMD, drugs targeting speci c in ammatory stage of dry age-related macular pathways may represent an untapped resource for the degeneration (AMD), which causes signifi cant central development of new AMD therapies. vision loss. On CFP, the area of is delimited Age-related (AMD) is a progressive between green arrows, which corresponds to area of outer degenerative disease of the retina and the leading cause of vi- retinal thinning on OCT, delimited 1,2 sion loss in the elderly. Clinically, AMD can be categorized between red arrows. (Images as either “dry” or “wet” (ie, neovascular, also referred to as courtesy of Dr. Mettu.) exudative). AMD is characterized by an accumulation of lipid- and protein-rich deposits, called drusen that are subjacent neovascular lesion. Neovascular AMD can manifest as plasma to the retinal pigment epithelium (RPE), and by progressive leakage, hemorrhage, and fi brosis, all of which can contribute damage to RPE and photoreceptor cells. In the early stages of to severe and frequently rapidly progressive vision loss.1,2 dry AMD, patients may be asymptomatic, but many patients Risk factors for the development of AMD include ad- complain of diffi culty seeing in low-light conditions, poor vanced age, cigarette smoking, and a high-fat, high-cholesterol vision when transitioning from light to dark environments, diet.2 Th ere is some evidence to suggest that female gender, or other visual defi cits aff ecting activities of daily life. Geo- Caucasian race, obesity, history of cardiovascular disease, graphic atrophy (GA), the advanced stage of dry AMD, is hypertension, and hyperlipidemia may also be associated characterized by multiple foci of RPE loss and photoreceptor with increased AMD risk.1,2 Genetic association studies have cell death that may grow in size and become confl uent (hence, revealed multiple genetic loci associated with development of the term “geographic” or resembling a map). Patients with AMD, especially genes linked to regulation of complement GA experience more pronounced visual defi cits; and as GA activity. Th ese studies have identifi ed increased frequency progresses to involve the fovea, they can suff er from advanced of certain gene alleles among AMD patients as compared to and signifi cant vision loss (Figure 1). controls, highlighting genetic factors that modulate disease Neovascular AMD may develop at any point along the susceptibility and suggesting potential pathways that may play course of AMD disease and is typically characterized by the a role in disease pathogenesis.3 formation of aberrant choroidal new vessels (choroidal neovas- Nonetheless, the pathogenesis of dry AMD is complex cularization) subjacent to the RPE and retina. In a minority of and multifactorial, and involves the interplay of mechanisms cases, neovascular AMD disease can manifest as intraretinal in multiple tissue compartments: neurosensory retina, RPE, neovascularization (retinal angiomatous proliferation) or as Bruch’s membrane, and choriocapillaris. Th e specifi c mecha- a choroidal exudative disease in the absence of a discernible nisms that mediate disease onset, progression, and associated

4 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ vision loss are largely unknown; thus, there is a dearth of viable targets for development of eff ective treatments. Th ere have CORE CONCEPTS been several disease paradigms put forth as frameworks to un- ✦ AMD pathogenesis involves: derstand disease, which off er opportunities to develop critical ✦ primary retinal disease involving RPE and new knowledge about AMD pathobiology. In this monograph, photoreceptors we will highlight specifi c pathogenic paradigms, understand- ing how infl ammatory mechanisms may contribute to each, ✦ lipid and protein deposition within retinal, subretinal and we will discuss eff orts “in the pipeline” to develop novel and choroidal tissues anti-infl ammatories for dry AMD. ✦ oxidative stress and ROS-related damage ✦ infl ammation with non-cellular (complement cascade) POSSIBLE MECHANISMS OF DRY AMD PATHOGENESIS and cellular (ocular phagocytes) components Abnormal Barrier Hypothesis ✦ Novel therapies directed against complement and Th e barrier hypothesis postulates that subRPE deposit macrophages are currently under development and drusen formation occurs as a result of an acquired defect in Bruch’s membrane permeability, which creates a barrier to the normal fl ow of nutrients and oxygen from the into reactive oxygen species (ROS) generation that eventually the RPE, and waste products from RPE into the choroid. Th is overwhelms tissues’ capacity for clearance and repair. Indeed, abnormal barrier could arise as a result of abnormal deposition the macula is subject to enormous photooxidative stress from of plasma-derived lipids and proteins in the inner collagenous light exposure, and all AMD risk factors have been implicated layer of Bruch’s membrane—as a result of aging and/or oxida- in ROS generation.4 Further, there is histologic evidence of tive injury from smoking, diet, or other factors.4,5 Alternatively, advanced lipid peroxidation end-products in lipofuscin (as well the abnormal barrier may arise as a result of abnormal produc- as Bruch’s membrane and in drusen) of patients with AMD.2 tion and secretion of lipids and proteins by the RPE, and AMD then develops as a response-to-retention of sub-RPE lipopro- Choroidal Hypoperfusion Hypothesis teins, analogous to a model of atherosclerotic disease. In either Th e choriocapillaris supplies oxygen and provides meta- case, the development of abnormal barrier promotes worsening bolic support to the RPE and photoreceptors. In patients with of membrane thickening, worsening selective impermeability, dry AMD, decreased choroidal blood fl ow may occur either and continued accumulation of lipids and proteins in the form through decreased density or diameter of choriocapillaris of subRPE deposits. Th e accumulation of abnormal lipids and or through increased resistance to choroidal blood fl ow (eg, proteins may also trigger infl ammatory response—complement secondary to vascular sclerosis or increased scleral rigidity). deposition, macrophage recruitment and retention—which While diminished choroidal blood fl ow has been observed in may contribute to tissue injury and disease progression. AMD eyes, it remains unclear whether this alteration is a pri- mary cause of disease or a phenomenon occurring secondary Lipofuscin/Lysosomal Failure Hypothesis to drusen and subRPE deposit formation, barrier formation, Lipofuscin is a retinal cell metabolic byproduct that ac- or more generalized RPE dysfunction.2 cumulates in RPE cells due to an age-related failure in RPE lysosomal enzymatic degradation of phagocytosed lipid mem- Genetic Hypotheses branes and RPE-derived proteins; it contributes to RPE autofl u- Genetic and epigenetic (ie, environmental factors that orescence, enabling visualization of certain macular disorders, modulate gene expression) mechanisms potentially underlie including dry AMD, on fundus autofl uorescence imaging.4 a number of pathogenic pathways related to the onset and Possible mechanisms for impaired lysosomal function include progression of AMD. With rare exception, there is little damaged or downregulated lysosomal enzymes, or loss of ac- evidence to suggest that dry AMD is mediated specifi cally by cess to lysosomal pathways due to oxidant-mediated modifi ca- inherited primary causative mutations in proteins specifi c to tion of RPE proteins or genetically altered RPE proteins leading retinal or RPE function, as with hereditary (eg, to misfolding. Accumulation of lipofuscin may lead to further Stargardt’s, Best disease) or retinal degenerations (eg, phagolysosome failure as it interrupts cellular catabolism and pigmentosa). However, there is compelling evidence that poly- clearance of photoreceptor-derived lipids that have undergone morphisms in general metabolic pathways that interact with oxidative degeneration. Th is may occur via direct damage to outer retinal function may serve as susceptibility cofactors lysosomal pathways or indirectly by serving as a robust pro- in AMD. Th is has been particularly true for multiple genetic oxidant substrate.2 Impaired and congested phagolysosomes loci related to the complement cascade, especially comple- within RPE cells may promote oxidant-driven mechanisms ment factor H (CFH). Genetic studies have also identifi ed of subRPE formation or may contribute to AMD disease pro- polymorphisms in other infl ammatory molecules—unrelated gression via activation of RPE cell death pathways (ie, apop- or indirectly related to complement—indicating polygenic tosis, necroptosis) and triggering of infl ammatory response. modulation of AMD pathogenesis and disease risk. Th ese Th is hypothesis is consistent with the more general “free include variants of genes encoding TLR3 and TLR4 (pathogen radical theory,” which asserts that diseases of aging stem from receptors found on macrophages and other innate immune

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 5 cells); C-reactive protein (a biomarker of acute-phase infl am- in mouse models. Since that time, additional polymorphisms mation); age-related susceptibility 2 (ARMS2); in complement factor I, complement factor B, and C3 have and high temperature requirement factor A of serine peptidase been identifi ed in association with dry AMD. However, the 1 (HTRA1, a proteolytic enzyme).2 mechanism(s) by which the complement cascade might infl u- ence development or progression of AMD remains unknown. Mitochondrial Dysfunction Hypothesis One possibility is that activation of the alternative pathway Mitochondria have long been known as the intracellular of the complement system triggers formation of the membrane organelle responsible for energy production in the form of attack complex (MAC), a conglomeration of complement ATP. However, mitochondria also have other vital cellular components assembled into a transmembrane channel, caus- functions, including regulation of cellular response to injury ing osmotic lysis of the target cell. Aberrant MAC formation and initiation of apoptosis (eg, via cytochrome C release), in the setting of AMD may inappropriately target RPE cells modulation of protein modifi cation and cellular transport, and and photoreceptors (and possibly choroidal endothelial cells), retrograde mitochondrial DNA (mtDNA) signaling to nuclear leading to cell death and progressive disease.11 transcription. Th us, mitochondria function goes beyond cel- Another possibility is that C3a and C5a—cleavage prod- lular bioenergetics and can contribute to the regulation of ucts of complement—may act as anaphylatoxins, increasing numerous functions, including regulation of complement, vascular permeability and recruiting infl ammatory cells such innate immunity, and angiogenesis.6 as leukocytes and macrophages to the site of disease, which Mitochondrial dysfunction at the RPE and neurosensory then promote progression of dry AMD and/or conversion to retina can be triggered by a host of endogenous factors, in- neovascular AMD.11 cluding macrophage-derived oxidants, complement, immune complexes, and cytokines, and external exposures, including MACROPHAGES cigarette smoke, environmental toxicants, and blue light. Th is Macrophages, cells of the innate immune system, may leads not only to diminished ATP production but also “electron modulate the severity of AMD disease depending on their leak” and generation of superoxide, singlet oxygen, and other activation state. Blood-derived macrophages are recruited from oxidants that become injury stimuli, promoting lipid and protein the systemic circulation as monocytes and directed to Bruch’s peroxidation and damage within mitochondria and at other cel- membrane, RPE, and the retina by infl ammatory cytokines lular organelles. Th is vicious cycle of oxidant injury triggered and at the site of disease. On the one hand, macrophages that are perpetuated by mitochondrial dysfunction activates cellular re- primed for reparative function (as well as microglia, the resident sponse to injury signaling mechanisms and processes, including immune cells of the retina) may act as scavengers to remove cortical actin cytoskeleton disassembly, cell membrane blebbing, cellular debris, remove infl ammatory stimuli, promote drusen and increased turnover of the extracellular matrix, all of which clearance, and healthy tissue repair, thereby limiting progres- serve as biochemical mediators of subRPE deposit formation. sion of disease. On the other hand, macrophages may be pro-in- In healthy cells, damaged mitochondria and other oxidative fl ammatory, producing cytokines and eff ector molecules (TNF- stress-induced cellular debris would be removed via a process a, IL-6, IL-1b) that promote nonlethal or lethal injury to RPE of RPE autophagy (or “self-eating”); however, in a setting of au- cells and photoreceptors, promoting disease progression.12,13 tophagy dysregulation and increased oxidative stress associated Evident within the neurosensory retina, subretinal space, and with AMD, it is postulated that damaged mitochondria that re- subRPE space in various stages of dry AMD by histopathol- main uncleared may contribute to local infl ammatory processes ogy, macrophages may also cause vision impairment through in the retina.6,7 Histopathology studies have demonstrated dam- deleterious eff ects on retinal circuitry. Possibilities include aged and fragmented mitochondria in association with drusen interruption of the normal visual cycle between RPE and photo- in eyes from AMD patients, and severity of AMD disease has receptors in the subretinal space; secretion of eff ector molecules been correlated with the extent of damaged RPE mtDNA. that disrupt synaptic transmission between photoreceptors and bipolar cells; or compromise to Muller cell processes that pro- COMPLEMENT vide perisynaptic support within the inner and middle retina. Th e complement cascade is vital for host defense against Macrophages also contribute to neovascular AMD, particu- pathogens and for turnover and clearance of damaged cells. In larly the subset of disease that is resistant to anti-VEGF thera- 2005, a series of high-profi le, genome-wide association studies pies. Treatment-resistant disease occurs most frequently among revealed a link between polymorphisms in complement factor eyes with CNV lesions with branching arterialization and H (CFH) and increased susceptibility to dry AMD.8-10 As CFH perivascular fi brosis, which animal studies show is mediated by serves to regulate complement activation, this raised the hy- nonclassical or reparative macrophages that secrete fi brogenic pothesis that increased complement activation may play a role factors (TGF-b, IGF-1, FGF, others). Glucocorticoids do not in dry AMD pathogenesis. Previous to that, histopathologic diminish the biologic activity of the macrophage subset (and studies revealed deposition of complement components within in fact, may upregulate their activity), which perhaps explains the choroid, Bruch’s membrane, and the subretinal space of why adjunctive corticosteroids have not been shown to be eff ec- eyes with AMD, and these were subsequently corroborated by tive for patients with anti-VEGF resistant neovascular AMD.14 fi ndings of complement in association with subretinal deposits Novel macrophage-targeting therapies—several of which

6 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ are in early stages of development—would off er an attractive transmembrane channel. HMR59 (Hemera Biosciences) is an alternative or adjunct to anti-VEGF therapies for poorly re- adeno-associated virus vector (AAV2) expressing a soluble sponsive wet AMD patients. form of CD59 (sCD59), delivered via single intravitreal injec- tion. A Phase 1 study is underway to assess safety of HMR59 NLRP3 INFLAMMASOME in patients with dry AMD and GA. Th e NLRP3 infl ammasome is a multimeric complex of Development has ceased for intravitreal anti-complement cellular proteins that assembles in response to specifi c danger factor D lampalizumab (Roche/Genentech, San Francisco CA) signals (eg, dsRNA, cytoplasmic DNA), integrating cellular and intravenous anti-C5 eculizumab (Alexion Pharma, New Ha- responses to various injury stimuli (eg, oxidants) and inducing ven CT), following failure to meet clinical endpoints during re- an infl ammatory response in the form of cytokine (eg, IL-18, spective phase 3 and phase 2 clinical trials for treatment of GA.22,23 IL-1b) production and secretion. Previously described in my- eloid cells including macrophages and microglia, the NLRP3 Therapies Against Macrophages and Infl ammasome infl ammasome has recently been described and characterized TMi-018 (Translatum Medicus Inc., Toronto CA) is a in RPE cells. Several studies, including from Ambati and col- transcriptional modulator of macrophage activation state, leagues have demonstrated that NLRP3 activation in RPE, currently in pre-clinical development (short-acting and slow- particularly by accumulation of Alu RNA, is associated with release formulations) for dry AMD and GA.24 pyroptosis and lethal injury of RPE cells and photoreceptor Nucleoside reverse transcriptase inhibitors (NRTIs) have loss in mouse models of dry AMD, with corroborative features been shown to prevent atrophic disease in mouse models of present in histopathology of human dry AMD.15,16 On the other AMD via downregulation of NLRP3 infl ammasome activity in hand, other investigators have suggested that activation of several studies by Ambati and colleagues.25 Work is underway NLRP3, particularly in macrophages, may ameliorate AMD to develop optimized NRTI derivatives for the treatment of disease severity.17 Further study is needed to characterize the dry AMD (Infl ammasome Th erapeutics).26 specifi c roles of NLRP3 infl ammasome in various stages of AMD disease, but modulation of NLPR3 infl ammasome activ- Other Immunomodulatory Therapies ity could represent a therapeutic target in dry AMD. Immunosuppressive agent sirolimus, which inhibits T and B cells and may also have anti-macrophage activity, failed its phase NEW AND IN-DEVELOPMENT INTERVENTIONS 2 trial of intravitreal treatment of GA.27 Studies of sirolimus in the While a comprehensive review of drugs in development treatment of noninfectious uveitis have been more successful and for the treatment of AMD is beyond the scope of this article, are ongoing. Research has also halted development of topical ocu- several novel drugs “in the pipeline” targeting complement or lar antiangiogenic and anti-infl ammatory molecule squalamine macrophages are highlighted below. (Ohr Pharmaceuticals, New York, NY) aft er failing to meet its primary endpoint in a phase 3 trial when administered adjunc- Complement Inhibitors tively with anti-VEGF therapy in the treatment of wet AMD.28 Complement factor C3 is a central component of the complement cascade that may contribute to GA, so there is CONCLUSION strong rationale for inhibition of C3 for the prevention or Th e lack of available effi cacious therapies for dry AMD reduction of RPE and photoreceptor cell death in AMD.18 highlights the importance of new knowledge about specifi c Two phase 3 trials (DERBY and OAKS) are underway for C3 disease-mediating mechanisms. An increasingly appreciated inhibitor APL-2 (Apellis Pharmaceuticals, Crestwood, KY), role for infl ammation in AMD pathogenesis, in particular a pegylated cyclic peptide administered once- or bi-monthly complement-, macrophage-, and infl ammasome-mediated by intravitreal injection, to reduce progression of GA.19 A pathways, may reveal new targets for drug development. phase 2 trial (FILLY) showed that APL-2 given monthly or Clinical trials for novel anti-infl ammatory drugs targeting bi-monthly reduced disease progression by 29% (P = 0.008) complement and macrophages, if successful, will validate and 20% (P = 0.067) respectively at 12 months compared with specifi c targets and provide additional insights into AMD control (sham injections), with more pronounced eff ect in pathobiology for future drug development initiatives. the second 6 months of treatment. A higher rate of activated exudative AMD was observed in patients receiving APL-2; Priyatham S. Mettu, MD, is a fellowship-trained medical retina specialist and however, overall visual outcomes were unaff ected.20 APL-2 is clinician-scientist and is assistant professor of ophthalmology at Duke University also in phase 2 trials for the treatment of neovascular AMD. School of Medicine, in Durham, NC. He states that in the past 12 months, he Avacincaptad pegol (Zimura; Ophthotech, Princeton NJ), has not had a fi nancial relationship with any commercial organization that an inhibitor of complement factor C5, is currently in phase 2 produces, markets, resells, or distributes healthcare goods or services consumed clinical trials for the treatment of GA. An open-label phase 2a by or used on patients relevant to this manuscript. Medical writer Noelle Lake, trial is also underway for avacincaptad pegol as an adjunct to MD, assisted in the preparation of this manuscript. anti-VEGF therapy for the treatment to neovascular AMD.21 CD59, also known as MAC inhibitory protein (MAC-IP) is a membrane-bound protein that inhibits formation of MAC METTU REFERENCES continue on page 9

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 7 EXAMINATION QUESTIONS TOPICS IN OCULAR ANTIINFLAMMATORIES | ISSUE 25 This CME activity is sponsored by the University of Florida College of Medicine and is supported by an unrestricted educational grant from Shire. Participants must score at least 80% on this exam in order to receive credit. The University of Florida College of Medicine designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. To take this exam and obtain credit, please take the test online at http://cme.ufl.edu/ed/self-study/toai/. Expires: November 30, 2019.

1. TMi-018, in development for 4. Non-infectious IU is most often 7. Failure of phagolysosomal function treatment of dry AMD, targets associated with: is a central mechanism in which which of the following? A. Sarcoidosis paradigm of AMD pathogenesis? A. Complement B. Multiple sclerosis A. Barrier hypothesis B. Macrophages C. Lupus B. Choroidal hypoperfusion C. Inflammasome D. A and B C. Lipofuscin hypothesis D. None of the above D. Mitochondria hypothesis 5. Studies have uncovered a genetic 2. The most common cause of vision link to AMD for which of the 8. Effective steroid sparing loss in IU is: following immune/inflammatory medications include: A. Cystoid macular edema components? A. Mycophenolate mofetil B. Retinal vasculitis A. Complement factor H B. TNF inhibitors C. Cataract B. C-reactive protein C. Methotrexate D. Glaucoma C. ARMS2 D. A, B, and C D. All of the above 3. Among the following choices, the 9. MRI is indicated: most likely diagnosis in a 65-year- 6. Which of the following is NOT a A. For all patients with IU old patient who has normal visual risk factor for AMD? B. For patients with IU and acuity (ie, 20/20) but complains of A. Mediterranean diet neurologic symptoms difficulty reading in low light is: B. Smoking C. For patients with IU and A. Exudative AMD C. Age suspected sarcoidosis B. Geographic atrophy D. Genetic predisposition D. Never C. Early dry AMD D. Lysosomal storage disease 10. A hallmark of IU is: A. Photophobia B. Ocular pain C. Snowballs in the vitreous D. Redness

8 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ RIFKIN REFERENCES from page 4 1. Babu BM, Rathinam SR. Intermediate uveitis. diate uveitis in a Canadian referral centre. Can J planitis: epidemiology, clinical characteristics, Indian J Ophthalmol. 2010;58:21-7. Ophthalmol. 2010;45:144-8. management and visual prognosis. J Ophthalmic 2. Lai FH, Liu DT, Lam DS. Review of inter- 9. Shoughy SS, Kozak I, Tabbara KF. Associations Vis Res. 2015;10:469-80. mediate uveitis. Asia Pac J Ophthalmol (Phila). of systemic diseases with intermediate uveitis. 15. Petrushkin H, Kidd D, Pavesio C. Intermediate 2013;2:375-87. Ophthalmic Epidemiol. 2016;23:27-31. uveitis and multiple sclerosis: to scan or not to 3. Vadot E. Epidemiology of intermediate uveitis: 10. Barisani-Asenbauer T, Maca SM, Mejdoubi L, scan. Br J Ophthalmol. 2015;99:1591-3. a prospective study in Savoy. Dev Ophthalmol. Emminger W, Machold K, Auer H. Uveitis–a 16. Kaplan HJ. Intermediate uveitis (pars planitis, 1992;23:33-4. rare disease often associated with systemic chronic cyclitis)–A four step approach to treat- 4. Chams H, Rostami M, Mohammadi S, Ohno S. diseases and infections—a systematic review of ment. Experta Medica. 1984. p. 169‑72. Epidemiology and prevalence of uveitis: review 2619 patients. Orphanet J Rare Dis. 2012;7:57. 17. Leung TG, Thorne JE. Emerging drugs for the of literature. Iranian Journal of Ophthalmology. 11. Habib GS, Kushnir D, Hyams M, Frajewicki treatment of uveitis. Expert Opin Emerg Drugs. 2009;21:4-16. V. Tubulointerstitial nephritis and uveitis syn- 2013;18:513-21. 5. Llorenç V, Mesquida M, Sainz de la Maza M, drome: a diagnosis that should be considered by 18. Palla S, Biswas J, Nagesha CK. Efficacy of et al. Epidemiology of uveitis in a Western rheumatologists. Ann Rheum Dis. 2003;62:281-2. Ozurdex implant in treatment of noninfec- urban multiethnic population. The challenge of 12. Amaratunge BC, Camuglia JE, Hall AJ. Syphi- tious intermediate uveitis. Indian J Ophthalmol. globalization. Acta Ophthalmol. 2015;93:561-7. litic uveitis: a review of clinical manifestations 2015;63:767-70. 6. Ness T, Boehringer D, Heinzelmann S. Interme- and treatment outcomes of syphilitic uveitis 19. Hersh AO, Cope S, Bohnsack JF, Shakoor A, diate uveitis: pattern of etiology, complications, in human immunodeficiency virus-positive Vitale AT. Use of immunosuppressive medica- treatment, and outcome in a tertiary academic and negative patients. Clin Exp Ophthalmol. tions for treatment of pediatric intermediate center. Orphanet J Rare Dis. 2017;12:81. 2010;38:68-74. uveitis. Ocul Immunol Inflamm. 2018;26:642-50. 7. Bonfioli AA, Damico FM, Curi AL, Or- 13. Jain R, Ferrante P, Reddy GT, Lightman S. 20. Hoy SM. Adalimumab: A Review in non- efice F. Intermediate uveitis.Semin Ophthalmol. Clinical features and visual outcome of interme- Infectious non-anterior uveitis. BioDrugs. 2005;20:147-54. diate uveitis in children. Clin Exp Ophthalmol. 2017;31:135-42. 8. Chan SM, Gan KD, Weis E. Characteristics and 2005;33:22-5. predictors of recurrence of anterior and interme- 14. Ozdal PC, Berker N, Tugal-Tutkun I. Pars

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To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 9