This continuing medical education activity is supported through an unrestricted educational grant from Allergan, Inc.

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1 Based on a CME Symposium sponsored by The New York Eye and Ear Infirmary, held during the AAO/PAAO 29 Joint Meeting. The Current Role of CORTICOSTEROIDS in the Treatment of RETINAL VASCULAR DISEASE Sponsored by The New York Eye and Ear Infirmary Institute for Continuing Medical Education. In Association with Ophthalmology Times This continuing medical education activity is supported through an unrestricted educational grant from Allergan, Inc. Original Release Date: April 15, 21 Last Review Date: March 22, 21 Expiration Date: April 3, 211

2 PROGRAM CHAIR AND MODERATOR David S. Boyer, MD, Chair Clinical Professor Keck School of Medicine University of Southern California Los Angeles, California Senior Partner Retina-Vitreous Associates Medical Group Beverly Hills, California FACULTY Harry W. Flynn, Jr., MD Professor of Ophthalmology The J. Donald M. Gass Distinguished Chair in Ophthalmology Bascom Palmer Eye Institute University of Miami Miller School of Medicine Miami, Florida Julia Haller, MD Professor and Chair Department of Ophthalmology Jefferson Medical College Thomas Jefferson University Thomas Jefferson University Hospital Ophthalmologist-in-Chief Wills Eye Institute Philadelphia, Pennsylvania Baruch D. Kuppermann, MD, PhD Professor of Ophthalmology Chief, Retina Service Gavin Herbert Eye Institute Department of Ophthalmology University of California, Irvine Irvine, California LEARNING METHOD AND MEDIUM This educational activity consists of a supplement and eight (8) study questions. The participant should, in order, read the learning objectives contained at the beginning of this supplement, read the supplement, answer all questions in the post test, and complete the evaluation form. To receive credit for this activity, please follow the instructions provided on the post test and evaluation form. This educational activity should take a maximum of 1 hour to complete. CONTENT SOURCE This continuing medical education (CME) activity is based on a CME symposium held on Sunday, October 25, 29 during the AAO/PAAO 29 Joint Meeting in San Francisco, California. TARGET AUDIENCE This educational activity is intended for comprehensive ophthalmologists. OVERVIEW There remains a great deal of confusion among ophthalmologists regarding the appropriate current use of corticosteroid therapy in patients with retinal vascular conditions. In the absence of up-to-date Guidelines published by a professional organization such as the AAO or ASRS, there remains an urgent need for clarification of available published data and for guidance on appropriate clinical approaches to management of patients with these conditions. At a recent CME symposium held during ARVO, when participants were asked if all steroids are the same in terms of efficacy and side effects in the treatment of retinal vascular disease, over 65% of the respondents answered no, with over 22% indicating that they did now know. In addition, participants were asked if the Diabetic Retinopathy Clinical Research Network (DRCR) Protocol B study had changed their treatment pattern for DME for which respondents were equally divided: one third indicated that the study had indeed changed their treatment pattern; one third indicated that the study had not changed their treatment pattern; and one third weren t sure. Over the course of this past year, participants in an assortment of CME activities have made numerous requests for additional education on treatment strategies for diabetic macular disease and the role of intraocular steroids in the treatment of retinal disorders. Even though intravitreal injections of corticosteroids are an important therapeutic option, in some patients the practical limitations of repeated intravitreal injections make an alternative delivery system desirable. As these various devices come to market, clinicians will need to understand the advantages and disadvantages among the devices and the implant procedures, the differences between the steroids they deliver, their short- and long-term use in DME and RVO, and their adverse-effect profiles and the management of adverse effects. LEARNING OBJECTIVES After successfully completing this activity, learners will have improved their ability to: Describe the pathophysiology of macular edema (ME), from DR, CRVO/BRVO. Summarize the currently available data supporting the use of local corticosteroid therapy to treat ME associated with DR, CRVO/BRVO, as monotherapy or in combination regimens. Describe the practical considerations for local ophthalmic corticosteroid therapy and the currently available data supporting their use to treat ME. ACCREDITATION STATEMENT The New York Eye and Ear Infirmary is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. DESIGNATION STATEMENT The New York Eye and Ear Infirmary designates this educational activity for a maximum of 1. AMA PRA Category 1 Credit. Physicians should only claim credit commensurate with the extent of their participation in the activity. MISSION STATEMENT It is The New York Eye and Ear Infirmary Institute for Continuing Medical Education s stated mission to create medical education activities that will serve to increase the knowledge, skills, professional performance, and relationships that a physician uses to provide services for patients, the public, or the chosen profession. DISCLOSURE POLICY STATEMENT The New York Eye and Ear Infirmary requires that each teacher/ contributor or individual in a position to control the content of a CME activity accredited by The New York Eye and Ear Infirmary disclose the existence of any relevant financial interests or other relationships (eg, paid speaker, employee, paid consultant on a board and/or committee for a commercial company) that would potentially affect the objectivity of activity content. Teachers/Contributors are also asked to make a disclosure that a product is still investigational when an unlabeled use of a commercial product or an investigational use, not yet approved for any purpose, is discussed during an educational activity. The disclosed information in no way presumes to assess the contributor s qualifications or suitability. The intention is to provide full disclosure of any potential conflict of interest, real or apparent, that is related to a specific educational activity. Individuals who neglect to provide information about relevant financial relationships will be disqualified from serving as a planning committee member, teacher, speaker, moderator, or author of the educational activity. In addition, such individuals will be prohibited from having control of, or the responsibility for, the development, management, presentation, or evaluation of the CME activity. Full disclosure of faculty and commercial relationships, if any, follows. DISCLOSURES David S. Boyer. MD: Dr. Boyer had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board: Alcon, Inc.; Allergan, Inc.; Genentech, Inc.; Novartis Pharmaceuticals Corporation; QLT Inc. and Pfizer Inc. Speakers Bureau: Alcon, Inc. and Genentech, Inc. Harry W. Flynn, Jr., MD: Dr. Flynn had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board: Alcon, Inc.; Allergan, Inc.; Eli Lilly and Company; Genentech, Inc. and Pfizer Inc. Interest: OptiMedica. Julia Haller, MD: Dr. Haller had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board: Allergan, Inc.; Genentech, Inc.; Optherion Inc.; and Regeneron Pharmaceuticals, Inc. Data Safety Monitoring Board (Chair): ThromboGenics. Interest: MacuSight and OptiMedica. Baruch D. Kuppermann, MD, PhD: Dr. Kuppermann had a financial agreement or affiliation during the past year with the following commercial interests in the form of Consultant/Advisory Board: Allergan, Inc.; B. Braun Medical Inc.; CoMentis, Inc.; Fovea Pharmaceuticals; Genentech Inc; Glaukos Corporation; Novartis Pharmaceuticals Corporation; Ophthotech Corporation; Pfizer Inc.; ScyFIX; SurModics; TargeGen, Inc. and Vitreoretinal Technologies, Inc. Contracted Research: Alimera Sciences; Allergan, Inc.; Genentech, Inc.; and Regeneron Pharmaceuticals, Inc. Richard Rosen, MD, Peer Reviewer has not had a financial agreement or affiliation during the past year with any commercial interest. OFF-LABEL DISCUSSION This activity includes off-label discussion of afibercept, bevacizumab, bevasiranib, biodegradable implant, dexamethasone, etanercept, fenofibrate, fluocinolone acetonide intravitreal Implant, hyaluronidase, infliximab, intravitreal triamcinolone acetonide, microplasmin, nepafenac, octreotide pegaptanib, ranibizumab, rosiglitazone, ruboxistaurin, ranibizumab, sirolimus, triamcinolone, and triamcinolone intravitreal implant. EDITORIAL SUPPORT DISCLOSURES Deborah Kaplan and Jack McCain have no relevant commercial relationships to disclose. DISCLOSURE ATTESTATION The contributing physicians listed above have attested to the following: 1. that the relationships/affiliations noted will not bias or otherwise influence their involvement in this activity; 2. that practice recommendations given relevant to the companies with which they have relationships/affiliations will be supported by the best available evidence or, absent evidence, will be consistent with generally accepted medical practice; and 3. that all reasonable clinical alternatives will be discussed when making practice recommendations. GRANTOR STATEMENT This continuing medical education activity is supported through an unrestricted educational grant from Allergan, Inc. TO OBTAIN CME CREDITS To obtain CME credit for this activity, read the material in its entirety and consult referenced sources as necessary. You may access this activity, post test, and evaluation online at Upon successful completion of the post test, your certificate will be issued immediately. Or, you may complete the evaluation form along with the post test answer box within this supplement and return via mail to Kim Corbin, Director, ICME, The New York Eye and Ear Infirmary, 31 East 14th Street, New York, NY 13 or fax to (212) Your certificate will be mailed to the address that you provide on the evaluation form. Please allow 3 weeks for mailed/faxed forms to process. Note: You must score a 7% or higher to receive credit for this activity. The views and opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of The New York Eye and Ear Infirmary, Ophthalmology Times, or Allergan, Inc. Please refer to the official prescribing information for each product for discussion of approved indications, contraindications, and warnings. 21 All rights reserved USA 92143B

3 The Current Role of Corticosteroids in the Treatment of Retinal Vascular Disease Diabetic retinopathy (DR) and retinal vein occlusion (RVO), including central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO), are respectively the first and second most common retinal vascular disorders, and both are associated with macular edema leading to major vision loss. DR is a major cause of blindness and low vision in the United States 1 and diabetic macular edema (DME) is the leading cause of vision loss in persons with diabetes. 2 The Centers for Disease Control and Prevention (CDC) recently increased its estimate of the prevalence of diabetes, reporting that it now affects about 7.8% of the US population some 23.6 million people. 3 This number reflects an increase of 3 million people in 2 years. Another 57 million American adults are thought to have impaired fasting glucose, putting them at increased risk for diabetes. Given the vast number of Americans with or at risk for diabetes, and given that 4% to 45% of patients diagnosed with diabetes have some stage of DR 4 and thus are at risk for DME, ophthalmologists must be informed of the emerging treatment options for these patients in order to preserve or improve visual acuity and reduce the risk of low vision or blindness. Furthermore, there remains a great deal of confusion among ophthalmologists regarding the appropriate current use of corticosteroid therapy in patients with retinal vascular conditions. This supplement provides ophthalmologists with an overview of the pathophysiology of macular edema and summarizes data supporting the use of local corticosteroids and other agents for treating macular edema associated with DR and RVO. References 1. Congdon N, O Colmain B, Klaver CC, et al; Eye Diseases Prevalence Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 24;122(4): Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA. 27;298(8): CDC (Centers for Disease Control and Prevention). National diabetes fact sheet: general information and national estimates on diabetes in the United States, 27. Atlanta, GA: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 28. Available at: 4. NEI (National Eye Institute). Facts about diabetic retinopathy. January 21. Available at: retinopathy.asp. Accessed January 12, 21. Pathophysiology and Clinical Overview of Macular Edema Julia A. Haller, MD Macular edema is a major cause of vision loss in patients with diabetic retinopathy (DR) and other retinal diseases such as retinal vein occlusion, uveitis, and Irvine-Gass syndrome. Diabetes. It is estimated that over 4% of diabetics in the United States have DR, and it threatens the vision of 8% an estimated 9, persons. 1 In patients with DR, diabetic macular edema (DME) is the main cause of mild to moderate vision loss. Over a 1-year period, DME will develop in 14% of patients with diabetes. 2 The incidence of DME increases as DR severity increases, from 3% in mild nonproliferative DR to 38% in moderate/severe nonproliferative DR and 71% in proliferative DR. Within 2 years of diagnosis, approximately 5% of patients with DME lose 2 lines of visual acuity. 3 The classic ETDRS study (1985) defined clinically significant macular edema as any of the following: thickening of the retina at or within 5 µm of the center of the macula; hard exudates at or within 5 µm of the center of the macula, if associated with thickening of adjacent retina; or a zone or zones of retinal thickening 1 disc area or larger, any part of which is within 1 disc diameter of the center of the macula. 4,5 Since the advent of Optical Coherence Tomography, however, this definition has largely disappeared from clinical and research usage, and has been supplanted by the objective measurement of thickening of the central macula. For many studies, retinal thickening greater than 25 microns in the central subfield qualifies as DME. Another classification distinction used historically and still persisting in the literature is that of focal vs. diffuse leakage. This was determined by whether there were single or localized clusters of leakage sites owing to microaneurysms, as opposed to a more diffuse pattern of leakage reflecting generalized breakdown of the blood-retinal barrier with leakage from vessels throughout the posterior pole of the eye as well as from the RPE. Today, most clinicians no longer make such a distinction because investigations have shown that it is not only difficult to differentiate between focal and diffuse DME angiographically, but that such a distinction does not appear to have prognostic or therapeutic value. Retinal Vein Occlusions (RVO). RVO is second only to DR as a cause of visual loss due to retinal vascular disease. Retinal vein occlusion is classified according to the vein in which the occluding thrombus has formed. In central RVO (CRVO), which accounts for about 2% of RVO cases, the central retinal vein is occluded, while in branch RVO (BRVO), which accounts for about 8% of RVO cases, a branch retinal vein is occluded. Any type of RVO may be ischemic or nonischemic. Either BRVO or CRVO can lead to persistent macular edema. RVO is associated with systemic hypertension, diabetes, and glaucoma. 6 The prevalence of RVO increases with age, 7 making it of growing importance in the aging US population. RVO is a significant cause of vision loss in middle-aged as well as elderly patients. The Current Role of Corticosteroids in the Treatment of Retinal Vascular Disease 3

4 The prognosis for patients with BRVO is generally favorable, as about half of untreated patients will recover visual acuity of 2/4 or better after 1 year. 8 The prognosis is worse in patients who develop retinal neovascularization or macular edema, however. About 6% of BRVO patients will develop macular edema, and it will become chronic in about 65% of this group. About 85% of patients with chronic or persistent macular edema will develop visual loss due to macular edema of 2/5 or worse. 8 Uveitis. Cystoid macular edema (CME) is the most common reason for vision loss associated with uveitis (intraocular inflammation). 9 The cause of uveitis often is idiopathic, but it has been associated with autoimmune disorders, infection, exposure to toxins, and intraocular surgery. Also known as postsurgical cystoid macular edema, Irvine-Gass syndrome is the most common cause of decreased vision after cataract surgery. 1 It occurs after about 5% of intracapsular cataract extractions, 2% of extracapsular cataract extractions, and 1% of phacoemulsification procedures. Pathophysiology of macular edema. Macular edema occurs when fluid and toxic protein deposits accumulate in the macula after retinal tissue has been stressed in some fashion, such as by hypoxia, altered blood flow, ischemia, toxicity, or surgery. At the beginning of the disease process, the stress to the retinal tissue initiates inflammatory processes in the retinal vasculature, beginning with the recruitment of leukocytes. The luminal surface of vascular endothelial cells expresses several inflammatory adhesion molecules, including intracellular adhesion molecule-1 (ICAM-1), that support leukocyte rolling and adhesion. After adhesion, several chemotactic molecules, such as monocyte chemoattractive protein 1 (MCP-1), are secreted by the vascular lumen. These molecules promote leukocyte transmigration into retinal tissue where they secrete a variety of inflammatory mediators including interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and vascular epithelial growth factor (VEGF), all of which increase vascular permeability. The presence of inflammatory mediators stimulates the production of more of these molecules and leads to amplification of the inflammatory response. As vascular abnormalities progress, the tight junctions between adjacent endothelial cells that constitute the blood-retinal barrier begin to break down. Vascular permeability increases and extravasation of lipoproteins and other macromolecules occurs. These vascular changes lead to accumulation of intraretinal fluid and thickening of the macular region, resulting in decreased visual acuity. If macular edema persists, irreversible dysfunction can result in permanent vision loss. The complexity of the inflammatory response suggests that therapies that target more than one part of the pathophysiologic process could be of the greatest clinical benefit. Therapies that target only one inflammatory mediator may not break the cycle of disease progression. In particular, corticosteroids appear to have beneficial effects on numerous pathological processes involved in macular edema. In conclusion, macular edema is a major cause of vision loss in numerous retinal vascular disorders. Inflammatory processes and vascular abnormalities are intertwined in a pathobiological cycle whose final common pathway results in macular edema. If the cycle is not interrupted, irreversible vision loss can occur. References 1. Kempen JH, O Colmain BJ, Leske MC, et al; Eye Diseases Prevalence Research Group. The prevalence of diabetic retinopathy among adults in the United States. Arch Ophthalmol. 24;122(4): Klein R, Klein BE, Moss SE, Cruickshanks KJ. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XV. The long-term incidence of macular edema. Ophthalmology. 1995;12(1): Ferris FL 3rd, Patz A. Macular edema. A complication of diabetic retinopathy. Surv Ophthalmol. 1984;28(suppl): Early Treatment Diabetic Retinopathy Study research group. Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study report number 1. Arch Ophthalmol. 1985;13(12): Pelzek C, Lim JI. Diabetic macular edema: review and update. Ophthalmol Clin North Am. 22;15(4): Sperduto RD, Hiller R, Chew E, et al. Risk factors for hemiretinal vein occlusion: comparison with risk factors for central and branch retinal vein occlusion: the eye disease case-control study. Ophthalmology. 1998;15(5): Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia. The Blue Mountains Eye Study. Arch Ophthalmol. 1996;114(1): Gutman FA. Macular edema in branch retinal vein occlusion: prognosis and management. Trans Sect Ophthalmol Am Acad Ophthalmol Otolaryngol. 1977;83(3 Pt 1): Couch SM, Bakri SJ. Intravitreal triamcinolone for intraocular inflammation and associated macular edema. Clin Ophthalmol. 29;3: Rossetti L, Autelitano A. Cystoid macular edema following cataract surgery. Curr Opin Ophthalmol. 2;11(1): Latest Management Strategies for Macular Edema from RVO David S. Boyer, MD In recent months, data from several new studies have been published with the potential to alter management strategies for macular edema secondary to retinal vein occlusion (RVO). For 25 years, our thinking about treatment of macular edema associated with branch RVO (BRVO) has been influenced by the Branch Vein Occlusion Study, in which patients with BRVO and macular edema with reduced vision to 2/4 or worse (139 eyes) were randomly assigned to treatment with argon laser photocoagulation or an untreated control group. 1 After 3 years of follow-up, treated patients (n=48) had gained a mean of 1.33 lines compared with.23 lines in the control group (n=35; P <.1). Visual acuity of 2/4 or better was attained by 6% of the treated patients vs 34% of the control group (P=.2). In contrast, the Central Vein Occlusion Study showed no benefit from macular grid photocoagulation in patients with macular edema due to CRVO and best-corrected visual acuity of 2/5 or poorer (N=155). 2 In this study, eyes were randomly assigned to macular grid photocoagulation (n=77 eyes) or no treatment (n=78 eyes) and followed for 3 years. Initial visual acuity was 2/16 and 2/125 in treated and untreated eyes, respectively. Although treatment reduced angiographic evidence of macular edema, there was no difference in visual acuity between treated and untreated eyes at any point; final visual acuity was 2/2 and 2/16 in treated and untreated eyes, respectively. In patients with CRVO, laser photocoagulation is reserved for management of rubeosis, being employed after the first appearance of iris neovascularization. Intravitreal triamcinolone. A different treatment approach to macular edema secondary to CRVO was taken in the recently published SCORE (Standard Care vs Corticosteroid for Retinal Vein Occlusion) study, preservative-free intravitreal triamcinolone (IVTA). 3 Patients were randomly assigned to IVTA 1 mg (n=92), 4 mg (n=91), or observation (n=88), which at the time constituted standard care for CRVO. At 12 months, 27% and 26% of patients in the IVTA 1 mg and 4 mg groups achieved the primary outcome, a gain of 15 letters 4 A Certified CME Supplement to Ophthalmology Times: April 21

5 ( 3 lines), compared with 7% of the observation group (P=.4). Patients in either IVTA group were 5 times more likely to achieve the primary outcome compared with the observation group. Although there was no difference in efficacy between the 1 mg and 4 mg groups, rates of elevated intraocular pressure and cataract were higher in the 4 mg group compared with the 1 mg and observation groups (Table 1). The improvements in visual acuity appear to have been sustained through 2 years of follow-up (Figure 1). IVTA also was evaluated by the SCORE Study Research Group in 411 patients with macular edema secondary to BRVO. 4 In this study, standard care constituted grid photocoagulation, whose efficacy was demonstrated Participants With Gain in Visual Acuity Letter Score of 15. % TABLE 1. SCORE: SAFETY RESULTS: CRVO Characteristic Events Through 12 Months Elevated IOP/glaucoma Initiation of IOP-lowering medication,* IOP>35 mm Hg IOP>1 mm Hg above baseline Laser peripheral iridotomy Trabeculectomy Tube shunt Cataract FIGURE 1. SCORE: PRIMARY OUTCOME: ME DUE TO CRVO mg 4mg in the Branch Vein Occlusion Study, as previously discussed. Patients were randomly assigned to grid laser (n=137), IVTA 1 mg (n=136), or IVTA 4 mg (n=138). The primary outcome was the same as in the SCORE CRVO study percent of patients who gain visual acuity of 15 letters at 12 months. The primary outcome was reached by 29%, 26%, and 27% of the laser, 1 mg, and 4 mg groups, respectively; there were no statistically significant differences among these groups. As in the CRVO study, rates of IOP elevation were similar in the standard care and IVTA 1 mg groups but higher in the 4 mg group. At 3 years, standard care continued to be as good as or better than either dose of triamcinolone as measured by the percentage of patients gaining 15 letters. Observation 1 mg 4 mg mg 4mg Observation (n=88) 1mg 4mg 7(8) 1 2 Baseline phakic eyes Lens opacity onset or progression Cataract surgery 66 12(18) 77 2(26) * P=.2 for observation vs 1-mg; P <.1, observation vs 4 mg; P=.2, 1 mg vs 4 mg. Time, mo. 1mg 4mg No. (%) 1 mg (n=92) 18(2) mg 4mg 4 mg (n=91) 32(35) (33) 4 SCORE Study Research Group. Arch Ophthalmol. 29;127(9): mg 4mg SCORE Study Research Group. Arch Ophthalmol. 29;127(9): In summary, the results of the SCORE studies suggest that IVTA 1 mg would be a reasonable therapy for patients with macular edema secondary to CRVO, but laser grid photocoagulation appears to remain preferable to IVTA for patients with macular edema secondary to BRVO. In CRVO, the available data suggest moderate short-term efficacy (about 5 letters in improved visual acuity and reduced retinal thickness). The duration of the treatment effect typically is <6 months, so many patients will require retreatment. IVTA also is associated with a high risk of elevated IOP and cataract formation, particularly with repeated treatment. Intravitreal dexamethasone implants. In June 29, the FDA approved a biodegradable intravitreal implant containing dexamethasone.7 mg for treatment of macular edema secondary to BRVO or CRVO. The implant is injected directly into the vitreous with a single-use, pre-loaded applicator, producing a self-sealing wound. In 2 studies enrolling patients with macular edema following BRVO or CRVO, the onset of improvement by 15 letters in visual acuity occurred within the first 2 months after implantation in 2-3% of patients (Table 2). 5 After onset, the treatment effect persisted approximately 1 to 3 months. However, 21% of BRVO patients and 17% of CRVO patients required only 1 treatment to achieve 2/2 vision and CRT <25 µm after 12 months of follow-up. 6 Of the patients receiving dexamethasone, 25% experienced increased IOP, with.7% (3/421) requiring laser or surgical procedures for its management. 5 A long-acting intravitreal fluocinolone acetonide sustained drug delivery implant, an FDA-approved treatment for noninfectious uveitis, recently was evaluated in a noncomparative small case series enrolling patients with refractory macular edema secondary to chronic CRVO (N=14; 14 eyes). 7 At 2 months, median visual acuity had improved from 2/126 at baseline to 2/6; at 12 months visual acuity was 2/8. At 12 months, mean and median central retinal thickness (CRT) had decreased from 622 and 6 µm, respectively, at baseline to 37 and 199 µm (P=.8). By month 12, 13 of 14 eyes required medical or surgical intervention to lower IOP, and all 5 phakic patients had developed cataract. Two other trials of this implant are in progress, one enrolling patients with macular edema secondary to CRVO (NCT952614) and one enrolling patients with macular edema owing to RVO (NCT636493). Both are scheduled to end in January 211; Glenn J. Jaffe, MD, is the principal investigator of each. The Current Role of Corticosteroids in the Treatment of Retinal Vascular Disease 5

6 In addition, a phase 2 study of a different long-lasting fluocinolone acetonide intravitreal insert is in progress in patients with macular edema secondary to RVO (NCT7777) and is scheduled for completion in November 21. Anti-VEGF therapies. Various anti-vegf therapies on the market have been investigated for treatment of macular edema secondary to RVO, including pegaptanib, bevacizumab, and ranibizumab. Bevacizumab is a full-length humanized monoclonal antibody that binds to and inhibits VEGF-A; ranibizumab is a monoclonal antibody fragment that acts similarly. In a 3-week phase 2 trial enrolling 98 patients with CRVO of <6 months duration, patients received pegaptanib.3 mg, 1 mg, or sham every 6 weeks. Although the differences in the primary endpoint (the percentage of patients gaining 15 letters in visual acuity at week 3) failed to reach statistical significance, some differences in secondary endpoints were statistically significant (Table 3). Numerous small trials and case reports have suggested that bevacizumab and ranibizumab may be beneficial for treating patients with macular edema secondary to CRVO or BRVO. For example, in a 12-month prospective study of 29 eyes (BRVO, 21 eyes; CRVO, 8 eyes) patients initially received bevacizumab 1 mg at monthly intervals, with retreatment determined by CRT. 9 At 12 months, patients had gained 16 letters from baseline (5 letters; P<.1) and CRT decreased by 249 µm from baseline (558 µm). However, patients required frequent reinjection, as they received a mean 8 of 13 possible injections. TABLE 2. PERCENT OF PATIENTS WITH 15 LETTERS IMPROVEMENT FROM BASELINE IN BEST-CORRECTED VISUAL ACUITY 5 STUDY 1 STUDY 2 Dex.7 mg Sham P-value* Dex.7 Sham P-value* (n=21) (n=22) mg (n=226) (n=224) Study day Day 3 2% 7% <.1 23% 8% <.1 Day 6 29% 1% <.1 3% 12% <.1 Day 9 22% 12% <.1 21% 14%.39 Day 18 19% 18%.78 24% 17%.87* P=.2 * P-values were based on the Pearson s chi-square test TABLE 3. PRIMARY AND SELECTED SECONDARY ENDPOINTS IN PHASE 2 TRIAL OF PEGAPTANIB IN CRVO 8 Endpoint 15 letters gained (primary endpoint) Number of letters gained or lost, mean Loss of 15 letters Reduction in CRT from baseline at week 1 References 1. Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group. Am J Ophthalmol. 1984;98(3): Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;12(1): Ip MS, Scott IU, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol. 29;127(9): Scott IU, Ip MS, VanVeldhuisen PC, et al; SCORE Study Research Group. A randomized trial comparing the efficacy and safety of PEGAPTANIB.3 mg (n=33) P-value vs sham 36% % µm <.1 PEGAPTANIB 1 mg (n=33) P-value vs sham 39% %.1 21 µm <.1 SHAM (n=32) 38% % 5 µm intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol. 29;127(9): Ozurdex [package insert]. Irvine, CA: Allergan, Inc; June Haller J. 6-month randomized controlled clinical trial of an intravitreal dexamethasone implant in macular edema associated with retinal vein occlusion. Presented at: Retina Congress 29; October 4, 29: New York, NY. 7. Ramchandran RS, Fekrat S, Stinnett SS, Jaffe GJ. Fluocinolone acetonide sustained drug delivery device for chronic central retinal vein occlusion: 12-month results. Am J Ophthalmol. 28;146(2): Wroblewski JJ, Wells JA 3rd, Adamis AP, et al; Pegaptanib in Central Retinal Vein Occlusion Study Group. Pegaptanib sodium for macular Results from 2 phase 3 studies of ranibizumab in BRVO and CRVO, BRAVO and CRUISE, respectively, recently were announced. The safety of ranibizumab in both trials was the same as has been reported in the Phase 3 trials for age related macular degeneration. In CRUISE, patients with CRVO (N=392) were randomly assigned to treatment with ranibizumab.3 mg (n=132), ranibizumab.5 mg (n=13), or sham (n=13). 1 At 6 months, 17% of the sham group had gained 15 letters from baseline, compared with 46% and 48% of the ranibizumab.3 and.5 mg groups, respectively. In BRAVO, patients with BRVO (N=397) likewise were randomly assigned to treatment with ranibizumab.3 mg (n=134), ranibizumab.5 mg (n=131), or sham (n=132). 11 At 6 months, the mean gain from baseline was 17 and 18 letters in the.3 and.5 mg groups, respectively, vs 7 letters in the sham group. Twenty-nine percent of the sham group gained 15 letters at 6 months vs 55% and 66% of the.3 and.5 mg groups, respectively. In conclusion, a biodegradable implant that delivers dexamethasone recently received FDA approval for treatment of macular edema secondary to RVO. Various anti-vegf therapies may emerge as alternative treatments, but their use may be hindered by the need for frequent injections. edema secondary to central retinal vein occlusion. Arch Ophthalmol. 29;127(4): Prager F, Michels S, Kriechbaum K, et al. Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a prospective clinical trial. Br J Ophthalmol. 29;93(4): Brown D. Safety and efficacy of intravitreal ranibizumab (Lucentis ) in patients with macular edema secondary to central retinal vein occlusion: CRUISE. Presented at: Retina Congress 29; October 4, 29: New York, NY. 11. Campochiaro PA, Gray S, Yee W, et al Safety and efficacy of intravitreal ranibizumab (Lucentis ) in patients with macular edema secondary to branch retinal vein ccclusion: the BRAVO study. Presented at Retina Congress 29. October 4, 29: New York, NY. 6 A Certified CME Supplement to Ophthalmology Times: April 21

7 Latest Management Strategies for Diabetic Macular Edema Harry W. Flynn, Jr, MD retinal thickening and exudates that were involving or threatening the fovea. Eyes with certain of those characteristics were designated clinically significant macular edema (CSME). In 1985, the Early Treatment Diabetic Retinopathy Study (ETDRS) established treatment with laser photocoagulation as a beneficial therapy in patients with CSME. 1 Because some patients with diabetic macular edema (DME) continue to lose vision despite photocoagulation, various pharmacologic therapies have been investigated. Pharmacotherapies for DME include local (ocular) therapies and systemic therapies (Table 1). At this time, no intravitreal medication has received FDA approval for the treatment of DME, although several of these agents are currently being used in an off-label capacity. intravitreal preservative-free triamcinolone, 1 mg, and 4 mg, with focal/grid photocoagulation in patients with DME (84 eyes, 693 patients). 2 At 4 months, median visual acuity was better in patients receiving triamcinolone 4 mg than it was in laser-treated patients, but from month 12 through month 24 visual acuity was better in the laser-treated eyes (Figure 1). Similarly, reduction in median central subfield thickness was initially greater in eyes treated with triamcinolone 4 mg, but at month 24 central subfield thickness was less in laser-treated eyes (Figure 2). At 12 months, rates of cataract surgery were similar in the 3 treatment groups, but by month 36 the cumulative probability of cataract surgery was 83% in the triamcinolone 4 mg group vs 46% in the 1 mg group and 31% in the laser group. 3 In the early 198s, ophthalmologists used clinical examination and stereo photography to map zones of Corticosteroids. The Diabetic Retinopathy Clinical Research Network (DRCR) compared 2 doses of FIGURE 1. MEDIAN VISUAL ACUITY IN LASER AND 4 MG IVTA TREATED EYES In general, these results appear to argue for laser treatment over triamcinolone. However, subgroup analysis suggests that patients with DME whose visual acuity is very poor may benefit from triamcinolone 4 mg (Table 2). In this subgroup analysis, the number of patients with visual acuity worse than 2/2 was too small for these results to be statistically significant, but the trend nevertheless points to triamcinolone as an important option for patients with DME and very poor vision. For many DME patients, however, intravitreal triamcinolone may not be the best choice if corticosteroids are being considered. See the next article in this supplement for a discussion of devices that are already available or in development to deliver various corticosteroids locally. Anti-VEGF agents. Many small trials and case series have explored the use of anti-vegf agents in DME, including bevacizumab and ranibizumab. FIGURE 2. MEDIAN CENTRAL SUBFIELD THICKNESS IN LASER AND IVTA TREATED EYES An important randomized clinical trial of an anti-vegf agent to treat DME is READ-2, in which 126 patients were randomized to treatment with ranibizumab.5 mg at baseline and months 1, 3, and 5; focal/grid laser photocoagulation at baseline and month 3 if necessary; or the combination of laser photocoagulation and ranibizumab.5 mg at baseline and month 3. 4 At month 6, patients in the ranibizumab group had gained 7.24 letters compared with a gain of 3.8 letters in the group receiving combination therapy (P=.1) and a loss of.43 letters in the laser group. Similar results were reported in another recently published trial in which 129 patients with DME were randomized to treatment with intravitreal bevacizumab 1.25 mg, intravitreal bevacizumab plus intravitreal triamcinolone, or laser photocoagulation. At 24 weeks, patients treated with bevacizumab monotherapy had more favorable The Current Role of Corticosteroids in the Treatment of Retinal Vascular Disease 7

8 TABLE 1. LOCAL (OCULAR) AND SYSTEMIC THERAPIES FOR DIABETIC RETINOPATHY Agent LOCAL (OCULAR) THERAPIES Corticosteroids Intravitreal triamcinolone acetonide Triamcinolone intravitreal implant (I-vation TM ) Fluocinolone acetonide intravitreal implant (Retisert ) Fluocinolone acetonide intravitreal implant (Iluvein ) Dexamethasone 7 µg biodegradable implant (Ozurdex TM ) Anti-VEGF agents Bevacizumab (Avastin ) Ranibizumab (Lucentis ) Pegaptanib (Macugen ) Afibercept (VEGF Trap) Sirolimus/rapamycin Bevasiranib Vitreolytic agents Hyaluronidase Microplasmin Anti-inflammatory agents Nepafenac (Nevanac ) Etanercept (Enbrel ) Infliximab (Remicade ) SYSTEMIC THERAPIES Fenofibrate Infliximab (Remicade ) Octreotide Rosiglitazone (Avandia ) Ruboxistaurin Current DME status Published RCTs Ongoing RCTs Completed phase 3 RCT Phase 3 results of FAME expected Feb 21 Completed phase 3 RCT Published RCTs Ongoing phase 3 RCTs Ongoing RCTs Published phase 1 RCT Ongoing phase 2 RCT Completed phase 2 RCT Published RCTs Ongoing phase 3 RCT Published case series Published pilot study Ongoing RCT Published RCT Published pilot series Published RCT Published case series Published phase 3 RCTs Comments Device is helical coil with drug-eluting polymer coating FDA approval in April 25 for chronic noninfectious posterior uveitis; Must be implanted in OR; Remains in eye unless removed; High risk of IOP, cataract May be injected in office with 25-gauge needle Remains permanently in eye, floats in vitreous FDA approval in June 29 for treatment of ME secondary to CRVO or BRVO FDA approval Feb 24 as treatment of metastatic colorectal cancer FDA approval June 26 as treatment of wet AMD FDA approval Dec 24 as treatment of wet AMD FDA approval Sept 1999 as antifungal Small interfering RNA (sirna) FDA approval March 195 as spreading agent FDA approval Aug 25 as NSAID Agent is TNF antagonist FDA approval Nov 1998 as treatment of rheumatoid arthritis Agent is TNF antagonist Initial FDA approval Aug 1998 as treatment of Crohn s disease FDA approval Oct 1988 as treatment of various tumors FDA approval May 1999 as treatment of diabetes mellitus outcomes than patients treated with photocoagulation. 5 Other anti-vegf agents which have been investigated as treatments for DME include pegaptanib, 6,7 VEGF Trap, 8 rapamycin, and bevasiranib. 9 Anti-inflammatory agents. Anecdotal brief reports and case series suggest that anti-inflammatory agents such as the NSAID nepafenac 1,11 and the TNF inhibitors etanercept and infliximab 12,13 may be effective in treating certain patients with DME. Intravitreal infliximab may be associated with substantial toxicity and is generally only used in the context of a formal clinical trial. Systemic therapies. A variety of systemic agents have been investigated as potential treatments of DME, including ruboxistaurin, fenofibrate, and candesartan. In general, intravitreal agents appear to offer greater effectiveness at this time. 8 A Certified CME Supplement to Ophthalmology Times: April 21

9 Combination therapies. The DRCR network is studying combination therapies, and results from several randomized clinical trials are anticipated soon. In Protocol I (NCT4446), patients with visual acuity of 2/32 or worse and OCT central subfield 25 µm were randomized to 4 treatment groups:1) sham injection plus photocoagulation, 2) ranibizumab plus immediate photocoagulation, 3) ranibizumab plus deferred photocoagulation, and 4) photocoagulation plus intravitreal triamcinolone. In conclusion, laser remains the first-line therapy for most patients with DME, but several agents being used off-label show great promise. New medications and delivery systems may provide a means to achieving a longer duration therapeutic effect with fewer intravitreal injections. TABLE 2. CHANGE IN VISUAL ACUITY AT YEAR 2 IN DME PATIENTS TREATED WITH TRIAMCINOLONE OR LASER Baseline VA 1-letter worsening 1-letter improvement 2/32 2/63 2/63 2/2 2/2 2/32 Laser (189 eyes) 23% Laser (129 eyes) 12% Laser (12 eyes) 17% IVTA 1 mg (149 eyes) 28% IVTA 1 mg (94 eyes) 24% IVTA 1 mg (13 eyes) 15% IVTA 4 mg (149 eyes) 33% IVTA 4 mg (92 eyes) 26% IVTA 4 mg (13 eyes) % Laser (189 eyes) 23% Laser (129 eyes 43% Laser (12 eyes) 42% IVTA 1 mg (149 eyes) 17% IVTA 1 mg (94 eyes) 33% IVTA 1 mg (13 eyes) 46% IVTA 4 mg (149 eyes) 16% IVTA 4 mg (92 eyes) 39% IVTA 4 mg (13 eyes) 77% References 1. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985;13(12): Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 28;115(9): Diabetic Retinopathy Clinical Research Network (DRCR.net), Beck RW, Edwards AR, et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch Ophthalmol. 29;127(3): Nguyen QD, Shah SM, Heier JS, et al; READ-2 Study Group. Primary end point (six months) results of the Ranibizumab for Edema of the Macula in Diabetes (READ-2) study. Ophthalmology. 29;116(11): Soheilian M, Ramezani A, Obudi A, et al. Randomized trial of intravitreal bevacizumab alone or combined with triamcinolone versus macular photocoagulation in diabetic macular edema. Ophthalmology. 29;116(6): Cunningham ET Jr, Adamis AP, Altaweel M, et al; Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelial growth factor aptamer, for diabetic macular edema. Ophthalmology. 25;112(1): Querques G, Bux AV, Martinelli D, Iaculli C, Noci ND. Intravitreal pegaptanib sodium (Macugen) for diabetic macular oedema. Acta Ophthalmol. 29;87(6): Do DV, Nguyen QD, Shah SM, et al. An exploratory study of the safety, tolerability and bioactivity of a single intravitreal injection of vascular endothelial growth factor Trap-Eye in patients with diabetic macular oedema. Br J Ophthalmol. 29;93(2): Tremolada G, Lattanzio R, Mazzolari G, Zerbini G. The therapeutic potential of VEGF inhibition in diabetic microvascular complications. Am J Cardiovasc Drugs. 27;7(6): Callanan D, Williams P. Topical nepafenac in the treatment of diabetic macular edema. Clin Ophthalmol. 28;2(4): Hariprasad SM, Callanan D, Gainey S, He YG, Warren K. Cystoid and diabetic macular edema treated with nepafenac.1%. J Ocul Pharmacol Ther. 27;23(6): Sfikakis PP, Markomichelakis N, Theodossiadis GP, et al. Regression of sight-threatening macular edema in type 2 diabetes following treatment with the anti-tumor necrosis factor monoclonal antibody infliximab. Diabetes Care. 25;28(2): Theodossiadis PG, Markomichelakis NN, Sfikakis PP. Tumor necrosis factor antagonists: preliminary evidence for an emerging approach in the treatment of ocular inflammation. Retina. 27;27(4): Are All Steroids Created Equal? Baruch D. Kuppermann, MD, PhD Corticosteroids are positioned to interrupt the pathophysiologic cascade of events that leads to macular edema, regardless of whether it is mediated by vascular endothelial growth factor or inflammation. All steroids are not created equal, however. For example, they differ in their relative potency. In comparison with cortisol, an equal weight of triamcinolone has 5 times the potency, and an equal amount of dexamethasone, betamathasone, or fluocinolone acetonide has 25 times the potency. The superior potency of the synthetic corticosteroids is due to fluorination at the 9-α position, which increases the receptor binding affinity. We have studied the toxicity of corticosteroids on retinal pigment epithelial (ARPE-19) and retinal neurosensory (R28) cells grown in tissue culture. After exposure to triamcinolone at doses normally used in clinical practice, cell viability was greatly reduced. 1 In contrast, cytotoxicity was much less when these cell cultures are exposed to dexamethasone. 2 To see any signs of toxicity, the cells had to be subjected to dexamethasone doses that were 1 times the doses used clinically. 2,3 Further, the limited toxicity seen with dexamethasone actually was due to the benzyl alcohol preservative, not the dexamethasone itself. 3 Compared with dexamethasone, triamcinolone also was more toxic to lens epithelial cells in vitro 4 and human trabecular mesh network cells. 5 These in vitro findings do not translate into clinical practice, but they suggest that the benefit seen with the use of triamcinolone may mask a toxic component of the therapy, and that the treatment benefit could be improved if a steroid lacks a toxic component. Although dexamethasone may be appealing on the basis of its toxicity profile, it has a very short half-life and is not suitable for use as a free agent for anything other than an acute event, eg, to mitigate the inflammatory effects of PDT without incurring the risk of cataract and glaucoma. New drug delivery systems may offer a solution to that problem. Fluocinolone acetonide intravitreal implant (Retistert ). The fluocinolone acetonide.59 mg implant was the first corticosteroid implant to receive FDA approval, in 25, for treatment of chronic noninfectious posterior uveitis. Implanted through a 3.5 mm pars plana incision and sutured to the eye wall, it provides a low level of the drug for about 3 years. The dimensions of the disc-shaped device are The Current Role of Corticosteroids in the Treatment of Retinal Vascular Disease 9

10 3 x 2 x 5 mm. It is intended to deliver a nominal initial rate of fluocinolone.6 µg/d, decreasing over the first month to a steady state between.3.4 µg/d over approximately 3 months. Although the implant was studied in a phase 3 trial in DME, an indication for DME has not been sought, owing to high rates of cataract and glaucoma. After 36 months, 28% of patients treated with the fluocinolone.59 mg implant had gained 3 lines in visual acuity compared with 15% of the standard of care group (P<.5), but a high percentage of eyes required surgery to treat glaucoma, and cataracts were ubiquitous. 6 A benefit of this implant is that it frees uveitis patients from debilitating systemic therapy, but the tradeoff between risks and benefits seems inappropriate for patients with DME. Fluocinolone acetonide intravitreal implant (Iluvien ). This fluocinolone implant (formerly known as Medidur) is being investigated in high- and low-dose versions. The high-dose device (.45 µg/d) delivers approximately the same dose as the fluocinolone acetonide.59 mg implant but for 18 months, while the low-dose implant (.23 µg/d) releases about half the daily dose for up to 36 months. The rod-shaped device measures 3.5 mm by.37 mm. It is injected into the eye with a 25-gauge needle. Instead of being sutured to the eye wall, it floats freely until it is trapped by the vitreous base. It rests further from the trabecular mesh network and the lens and closer to the macula. Two-year results of the main Iluvien DME phase 3 study (N=956), FAME (NCT344968) were released in December 29 7 and showed the following: Efficacy Trial A: 26.8% of patients in the low-dose group and 26.% in the high-dose group had 3-line improvement in BCVA at 2 years. Trial B: 3.6% and 31.2% increase in BCVA low/high dose respectively. Safety The percentage of eyes with IOP greater than 3 mmhg at any time point was 16.3% in the low-dose group and 21.6% in high dose groups. Surgical trabeculectomy was performed in 2.1% of low-dose patients and 5.1% of high-dose patients by 24 months. The company states that it will file for the low-dose version by second quarter 21. Triamcinolone intravitreal implant (I-vation TM ). This sustained drug delivery system is a proprietary helical coil covered with a drug-eluting polymer. Implanted with a pars plana needlestick <.5 mm in diameter, the coil is screwed into the eye, residing under the conjunctival membrane. The coating is compatible with a variety of drugs and has been studied in a phase 1 trial (N=31) in which it delivered triamcinolone 925 µg at the rate of about 1 µg/d (slow-release) or 3 µg/d (fast-release) in patients with DME. 8 At 24 months, mean macular thickness decreased in the slow group from 529 µm at baseline to 328 µm, and in the fast group from 376 µm at baseline to 268 µm. Lenticular opacity was the most commonly reported medication-related adverse event, with 17 of 18 phakic eyes having had cataract extractions by 24 months. As this drug delivery system advances through the approval process, it will be important to monitor incidence of retinal tears, endophthalmitis, and retinal detachment. Dexamethasone biodegradable implant (Ozurdex TM ). Approved by the FDA in June 29 for treatment of macular edema secondary to retinal vein occlusion (RVO) (see the preceding article by David Boyer for clinical trial results), this intravitreal implant gradually delivers dexamethasone 7 µg over the course of about 1 month via a biodegradable solid copolymer, poly [lactic-glycolic] PLGA polymer matrix. These polymers also have been used to make absorbable sutures. The copolymer hydrolyzes to lactic and glycolic acids; the lactic acid is metabolized to H 2 and CO 2, while the glycolic acid is either excreted or enzymatically converted to other metabolized species. In a phase 2 trial, patients with macular edema from mixed causes that had not responded well to treatment (N=315) were randomly assigned to observation or treatment with dexamethasone 35 µg or 7 µg via this drug delivery system. 9 At 6 months, 18% and 15% of the 35 µg and 7 µg treatment groups had gained 15 letters from baseline, compared to 8% of the observation group. There were no differences between groups in the incidence of retinal detachment or cataract. Increased IOP was seen in 17% and 12% of the 35 µg and 7 µg groups, respectively, compared with % of the observation group (P<.1). Vitreous hemorrhage was mostly mild and likely related to the surgical procedure than to the study medication. There were no treatment-related cases of endophthalmitis. Recruitment has been completed for 3 phase 3 trials of dexamethasone biodegradable implant in DME. A trial that compares the combination of dexamethasone biodegradable implant and laser photocoagulation vs laser alone is scheduled for completion in May 21 (NCT464685). The other 2 trials compare dexamethasone.35 and.7 mg with a sham comparator (NCT168389, NCT168337). Both studies are expected to be completed by June 214. In conclusion, steroids are uniquely positioned to interrupt the cascade of events leading to macular edema. Steroids vary in their potency and toxicity profile. Through steroid differentiation as well as drug delivery differentiation, it should be possible to provide steroid treatment with a lower rate of cataract and glaucoma than has been seen with triamcinolone. References 1. Narayanan R, Mungcal JK, Kenney MC, Seigel GM, Kuppermann BD. Toxicity of triamcinolone acetonide on retinal neurosensory and pigment epithelial cells. Invest Ophthalmol Vis Sci. 26;47(2): Luthra S, Narayanan R, Marques LE, et al. Toxicity of dexamethasone on neurosensory retinal cells. Invest Ophthalmol Vis Sci : E-Abstract Zacharias LC, Luthra S, Dong J, et al., Effect of dexamethasone on mitochondrial function and cell viability in human retinal pigment epithelial and rat neurosensory retinal cells in vitro. Invest Ophthalmol Vis Sci. 27;48:e-abstract Pirouzmanesh A, Sharma A, Audley UP, Kenny MC, Kuppermann BD. Evaluation of in vitro effects of triamcinolone acetonide and dexamethasone on human lens epithelial cells. Invest Ophthalmol Vis Sci. 28;49:e-Abstract Jayaprakash Patil A, Sharma A, Mansoor S, Estrago-Franco M-F, Raymond V, Kenney MC, Kuppermann BD. Effects of dexamethasone on human trabecular meshwork cells in vitro. Invest Ophthalmol Vis Sci. 6. Pearson P, Levy B, Comstock T; Fluocinolone Acetonide Implant Study Group Fluocinolone acetonide intravitreal implant to treat diabetic macular edema: 3 year results of a multi center clinical trial. Invest Ophthalmol Vis Sci. 26;47:e-abstract Alimera announces positive results from the two phase 3 FAME trials of Iluvien in patients with diabetic macular edema. Bioresearche Online. December 28, Dugel PU, Eliott D, Cantrill HL, Mahmoud T, Avery R, Erickson SR. I-vation TA: 24-month clinical results of the phase I safety and preliminary efficacy study. Invest Ophthalmol Vis Sci. 29;5:e-abstract Kuppermann BD, Blumenkranz MS, Haller JA, et al; Dexamethasone DDS Phase II Study Group. Randomized controlled study of an intravitreous dexamethasone drug delivery system in patients with persistent macular edema. Arch Ophthalmol. 27;125(3): A Certified CME Supplement to Ophthalmology Times: April 21