The Lowdown on High-Tech Iols

EyeNetOCTOBER 2017

International Report The Lowdown on High-Tech IOLs

Unintended Consequences New Cancer Drugs, New Ocular Side Effects

Bioptic Lenses for Driving? Counseling Low Vision Patients

OPINION The Enduring Appeal of Solo Practice OHH, IINTERESTING The ﬁ rst prescription eye drop FDA-approved to treat both the signs and symptoms of Dry Eye Disease

Indication Xiidra® (liﬁ tegrast ophthalmic solution) 5% is indicated for the treatment of signs and symptoms of dry eye disease (DED). Xiidra is a lymphocyte function-associated antigen-1 Important Safety Information In clinical trials, the most common adverse reactions reported in 5-25% (LFA-1) antagonist, the ﬁ rst of patients were instillation site irritation, dysgeusia and reduced visual medication in a new class acuity. Other adverse reactions reported in 1% to 5% of the patients 1 of drugs. were blurred vision, conjunctival hyperemia, eye irritation, headache, increased lacrimation, eye discharge, eye discomfort, eye pruritus Check it out at Xiidra-ECP.com and sinusitis.

Reference: 1. FDA approves new medication for To avoid the potential for eye injury or contamination of the solution, dry eye disease. FDA News Release. July 2016. patients should not touch the tip of the single-use container to their http://www.fda.gov/newsevents/newsroom/ eye or to any surface. pressannouncements/ucm510720.htm. Accessed July 12, 2016. Contact lenses should be removed prior to the administration of Xiidra and may be reinserted 15 minutes following administration. Safety and efﬁ cacy in pediatric patients below the age of 17 years have not been established.

For additional safety information, see accompanying Brief Summary of Safety Information on the adjacent page and Full Prescribing Information on Xiidra-ECP.com.

Marks designated ® and ™ are owned by Shire or an afﬁ liated company. ©2016 Shire US Inc. Lexington, MA 02421 S24432 11/16 Animal Data Lifitegrast administered daily by intravenous (IV) injection to rats, from pre-mating through gestation day 17, caused an increase in mean preimplantation loss and an increased incidence of several minor skeletal anomalies at 30 mg /kg /day, representing 5,400-fold Rx Only the human plasma exposure at the RHOD of Xiidra, based on AUC. No teratogenicity was observed in the rat at BRIEF SUMMARY: Consult the Full Prescribing Information for complete 10 mg /kg /day (460-fold the human plasma exposure at product information. the RHOD, based on AUC ). In the rabbit, an increased incidence of omphalocele was observed at the lowest dose tested, 3 mg /kg /day (400-fold the human INDICATIONS AND USAGE plasma exposure at the RHOD, based on AUC), when ® Xiidra (lifitegrast ophthalmic solution) 5% is indicated administered by IV injection daily from gestation days 7 for the treatment of the signs and symptoms of dry eye through 19. A fetal No Observed Adverse Effect Level disease (DED). (NOAEL) was not identified in the rabbit.

DOSAGE AND ADMINISTRATION Lactation Instill one drop of Xiidra twice daily (approximately 12 There are no data on the presence of lifitegrast in human hours apart) into each eye using a single use container. milk, the effects on the breastfed infant, or the effects on Discard the single use container immediately after using milk production. However, systemic exposure to lifitegrast in each eye. Contact lenses should be removed prior to from ocular administration is low. The developmental and the administration of Xiidra and may be reinserted 15 health benefits of breastfeeding should be considered, minutes following administration. along with the mother’s clinical need for Xiidra and any potential adverse effects on the breastfed child from Xiidra. ADVERSE REACTIONS Clinical Trials Experience Because clinical studies are conducted under widely Pediatric Use Safety and efficacy in pediatric patients below the age of varying conditions, adverse reaction rates observed in 17 years have not been established. clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may Geriatric Use not reflect the rates observed in practice. In five clinical No overall differences in safety or effectiveness have been studies of dry eye disease conducted with lifitegrast observed between elderly and younger adult patients. ophthalmic solution, 1401 patients received at least 1 dose of lifitegrast (1287 of which received lifitegrast 5%). The majority of patients (84%) had ≤3 months of NONCLINICAL TOXICOLOGY treatment exposure. 170 patients were exposed to Carcinogenesis, Mutagenesis, Impairment of Fertility lifitegrast for approximately 12 months. The majority Carcinogenesis: Animal studies have not been conducted of the treated patients were female (77%). The most to determine the carcinogenic potential of lifitegrast. common adverse reactions reported in 5-25 % of patients Mutagenesis: Lifitegrast was not mutagenic in the in vitro were instillation site irritation, dysgeusia and reduced Ames assay. Lifitegrast was not clastogenic in the in vivo visual acuity. Other adverse reactions reported in 1% mouse micronucleus assay. In an in vitro chromosomal to 5% of the patients were blurred vision, conjunctival aberration assay using mammalian cells (Chinese hyperemia, eye irritation, headache, increased hamster ovary cells), lifitegrast was positive at the highest lacrimation, eye discharge, eye discomfort, eye pruritus concentration tested, without metabolic activation. and sinusitis. Impairment of fertility: Lifitegrast administered at intravenous (IV) doses of up to 30 mg/kg/day (5400-fold the human plasma exposure at the USE IN SPECIFIC POPULATIONS recommended human ophthalmic dose (RHOD) of Pregnancy lifitegrast ophthalmic solution, 5%) had no effect on There are no available data on Xiidra use in pregnant fertility and reproductive performance in male and women to inform any drug associated risks. Intravenous female treated rats. (IV) administration of lifitegrast to pregnant rats, from pre-mating through gestation day 17, did not produce teratogenicity at clinically relevant systemic exposures. Intravenous administration of lifitegrast to pregnant Manufactured for: Shire US Inc., 300 Shire Way, Lexington, MA 02421. rabbits during organogenesis produced an increased incidence of omphalocele at the lowest dose tested, For more information, go to www.Xiidra.com or call 1-800-828-2088. 3 mg/kg/day (400-fold the human plasma exposure at Marks designated ® and ™ are owned by Shire the recommended human ophthalmic dose [RHOD], or an affiliated company. based on the area under the curve [AUC] level). Since ©2016 Shire US Inc. human systemic exposure to lifitegrast following US Patents: 8367701; 9353088; 7314938; 7745460; 7790743; ocular administration of Xiidra at the RHOD is low, the 7928122; 9216174; 8168655; 8084047; 8592450; 9085553; 8927574; applicability of animal findings to the risk of Xiidra use in 9447077; 9353088 and pending patent applications. humans during pregnancy is unclear. Last Modified: 12/2016 S26218 Celebrating 1 Years1 of the Malyugin Ring® Years of the Malyugin Ring®

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BAUS3349 BAP Journal Ad Lotemax Gel Eyenet 4/C Live: .5" from trim File Format: PDF/X-1a Carling Communications 6/13/2017 Trim: 8.125" x10.875" Bleed: 8.375"x11.125" CONTENTS OCTOBER 2017 VOLUME 21 • NUMBER 10

FEATURE 44-50 The Lowdown on High-Tech IOLs For curious U.S. ophthalmologists, EyeNet offers an armchair traveler’s look at several lenses available overseas that represent potentially significant advances in IOL technology.

CLINICAL INSIGHTS 19-21 News in Review Immunology Bacterium protects against other microbes on the eye’s surface. Retina Physical activity and AMD risk. Imaging A look at the novel technique known 44 as FLIO. Genetics Home in on diagnosis before order- ing genetic testing.

23-27 Journal Highlights Key findings from Ophthalmology, Ophthalmol- ogy Retina, AJO, JAMA Ophthalmology, and more.

29-35 Clinical Update 19 29 Comprehensive Molecularly targeted cancer drugs are revolutionizing oncology—and raising the risk of new ocular side effects. An overview. 33 37 Low Vision Drivers What ophthalmologists need to know to help low vision patients drive safely.

37-39 Ophthalmic Pearls Dislocated Lenses Risk factors, clinical pre- sentation, and management of a posteriorly dislocated crystalline lens or IOL.

EyeNet® Magazine (ISSN 1097-2986) is published monthly by the American Academy of Ophthalmology, 655 Beach St., San Francisco, CA 94109-1336, as a membership service. Subscription is included in U.S. members’ annual dues. International Member, IMIT, $135 per year. Nonmember in U.S., $150 per year. Nonmember outside U.S., $210 per year. Periodicals Postage Paid at San Francisco, CA, and at additional mailing offices. POSTMASTER: Send address changes toEyeNet , P.O. Box 7424, San Francisco, CA 94120-7424. American Academy of Ophthalmic Executives®, EyeSmart™, EyeWiki®, IRIS® Registry, and ONE® Network are trademarks of the American Academy of Ophthalmology®. All other trademarks are the property of their respective owners.

EYENET MAGAZINE • 7 CLINICAL INSIGHTS 41-42 Morning Rounds The Case of a Second-Look Surprise She said that her painful right eye felt swollen and her vision seemed “greased over.”

IN PRACTICE 58 Savvy Coder Test Your Coding Competency Tackle 9 questions, from bundled codes to foiled surgeries. 61-62 Practice Perfect Enhance Your Website Make it more accessible for those with low vision or no vision. 41

FROM THE AAO 65-67 Academy Notebook Board of Trustees nominees: candidates’ views. l D.C. Report: A push for zero penalties for 2019. 71-72 Destination AAO 2017 Register by Oct. 13 to avoid increased fees. l IRIS lunchtime symposium, named lectures, and hot practice management courses. 72 VIEWPOINTS 12 Letters Gene expression profiling in uveal melanoma.l Bypassing progressive zonular weakness. 14 Opinion Solo practice in ophthalmology: Resisting the tides? 16 Current Perspective Direct-to-consumer advertising in the molecular era.

MYSTERY IMAGE 74 Blink What do you see?

COVER ILLUSTRATION Alfred T. Kamajian xx74

® COPYRIGHT © 2017, American Academy of Ophthalmology, Inc.® All rights reserved. No part of this publication may be reproduced without written permission from the publisher. Letters to the editor and other unsolicited material are assumed intended for publication and EyeNet are subject to editorial review, acceptance, and editing. Disclaimer. The ideas and opinions expressed in EyeNet are those of the authors, and do not necessarily reflect any position of the editors, the publisher, or the American Academy of Ophthalmology. Because this publication provides information on the latest developments in ophthalmology, articles may include information on drug or device applications that are not considered community standard, or that reflect indications not included in approved FDA labeling. Such ideas are provided as information and education only so that practitioners may be aware of alternative methods of the practice of medicine. Information in this publication should not be considered endorsement, promotion, or in any other way encouragement for the use of any particular procedure, technique, device, or product. EyeNet, its editors, the publisher, or the Academy in no event will be liable for any injury and/or damages arising out of any decision made or action taken or not taken in reliance on information contained herein.

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CATARACT Catherine Green, MBChB PEDIATRIC MAGAZINE Kevin M. Miller, MD, Jeffrey M. Liebmann, MD OPHTHALMOLOGY David W. Parke II, MD Section Editor Steven L. Mansberger, MD, MPH David A. Plager, MD, Section Editor Editor-in-Chief William R. Barlow, MD Ronit Nesher, MD Michael F. Chiang, MD Kenneth L. Cohen, MD Richard K. Parrish II, MD Jane C. Edmond, MD Ruth D. Williams, MD Chief Medical Editor Kendall E. Donaldson, MD Angelo P. Tanna, MD Frank Joseph Martin, MD Warren E. Hill, MD Federico G. Velez, MD Dale E. Fajardo, EdD, MBA LOW VISION Publisher Jason J. Jones, MD Mary Lou Jackson, MD REFRACTIVE SURGERY Boris Malyugin, MD, PhD Lylas G. Mogk, MD George O. Waring IV, MD, Patty Ames Cathleen M. McCabe, MD John D. Shepherd, MD Section Editor Executive Editor Randall J. Olson, MD Damien Gatinel, MD Carey S. Ballard NEURO-OPHTHALMOLOGY Abhay R. Vasavada, MBBS A. John Kanellopoulos, MD Art Director / Leah Levi, MD, Section Editor George D. Kymionis, MD, PhD Production Manager COMPREHENSIVE Kimberly Cockerham, MD, FACS J. Bradley Randleman, MD OPHTHALMOLOGY Helen V. Danesh-Meyer, Chris McDonagh, Jean Shaw Preston H. Blomquist, MD, Karolinne M. Rocha, MD MBCHB, MD Senior Editors Section Editor Marcony R. Santhiago, MD Eric Eggenberger, DO Catherine Morris Sherleen Huang Chen, MD Prem S. Subramanian, MD, PhD RETINA/VITREOUS Advertising Manager / Robert B. Dinn, MD Julia A. Haller, MD, Section Editor Associate Editor OCULOPLASTICS Susan M. MacDonald, MD Neil M. Bressler, MD Evan H. Black, MD, Section Editor Lori Baker-Schena, MBA, EdD; Janet Y. Tsui, MD Kimberly A. Drenser, MD, PhD Elizabeth A. Bradley, MD Leslie Burling-Phillips; Sharon Fekrat, MD Peggy Denny; Miriam Karmel; CORNEA AND EXTERNAL Andrew R. Harrison, MD Mitchell Goff, MD Mike Mott; Linda Roach; DISEASE Don O. Kikkawa, MD Christopher J. Rapuano, MD, Lawrence S. Halperin, MD Lynda Seminara; Annie Stuart Bobby S. Korn, MD, PhD Contributing Writers Section Editor Gregg T. Kokame, MD OPHTHALMIC ONCOLOGY Andreas K. Lauer, MD Kathryn A. Colby, MD, PhD Mark Mrvica, Kelly Miller Zélia M. Corrêa, MD, PhD, Section Jeffrey L. Marx, MD Helena Prior Filipe, MD M.J. Mrvica Associates, Inc. Editor Bennie H. Jeng, MD Prithvi Mruthyunjaya, MD 2 West Taunton Ave., Mark J. Mannis, MD Dan S. Gombos, MD Kyoko Ohno-Matsui, MD Berlin, NJ 08009 Stephen D. McLeod, MD Tatyana Milman, MD Andrew P. Schachat, MD 856-768-9360 Sonal S. Tuli, MD OPHTHALMIC PATHOLOGY Ingrid U. Scott, MD, MPH [email protected] Advertising Sales Deepak Paul Edward, MD Gaurav K. Shah, MD GLAUCOMA David J. Wilson, MD Richard F. Spaide, MD Sanjay G. Asrani, MD, Section Editor Iqbal K. Ahmed, MD OPHTHALMIC UVEITIS Lama Al-Aswad, MD, MPH PHOTOGRAPHY Gary N. Holland, MD, Section Editor Ahmad A. Aref, MD Jason S. Calhoun 655 Beach St. Muge Kesen, MD Anne Louise Coleman, MD, PhD Michael P. Kelly, FOPS San Francisco, CA 94109 Steven J. Gedde, MD H. Nida Sen, MD 866-561-8558, 415-561-8500 Steven Yeh, MD aao.org

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Gene Expression Profiling in Uveal Melanoma of the IOL is necessary for this. But as the many late dislocations of in-the-bag implants indicate, the zonules are not Congratulations to the authors on a nicely written review to be trusted long-term. EyeNet’s “Zonular Weakness and on “Gene Expression Profiling in Uveal Melanoma” (July, Lens Movement” (July, News in Review) notes that 31.4% Ophthalmic Pearls), which points out the necessity for ocu- of all the researchers’ surgical eyes (ages not specified) lar oncologists to be intimately familiar with the molecular showed some “looseness” of the zonules, and that was before genetics of ocular tumors and how this information should the manipulation needed to implant an IOL in the bag. A (and should not) be used in patient care. They note that the recent study1 dealing with late in-the-bag dislocations after uveal melanoma gene expression profile is a prognostic—not uneventful cataract surgery found a burgeoning number diagnostic—test. This is exemplified by 2 case reports in occurring 6 to 9 years postop. Other reports2 show that late which the test was used incorrectly in patients with metastat- dislocations have been occurring since 1993, when in-the-bag ic choroidal tumors misdiagnosed as melanomas.1,2 implants with phacoemulsification became commonplace. We would like to point out a potentially confusing state- In an attempt to avoid zonular weakness altogether, I have ment in this review. The authors claim that “gene expression taken to implanting in the ciliary sulcus all-PMMA implants profile class is only one of many features that may help a cli- that have a 13-mm overall haptic diameter with a 6-mm di- nician assess risk of metastatic disease,” and they list various ameter optic. This allows for a very robust fixation. An intact clinical, pathologic, and chromosomal features. However, posterior capsule helps position the implant; however, even many studies from multiple centers have shown that none large capsular tears still permit precise, secure placement. of these features adds any prognostic information to that Zonular strength becomes nearly irrelevant. The implant of the gene expression profile in uveal melanoma,3 save for stays stable even with major trauma or future vitrectomy. a small modification imparted by basal tumor diameter.4,5 The downside of using a large, solid optic of 6 mm is, of The evolution of the gene expression profile classification course, that a larger corneoscleral wound is required. This does not reflect ongoing additions to the classification but, means a less-precise final refractive error. But again, we are rather, more refined subclassifications.6 None of these im- forgetting lessons from the past, namely that a minimal provements is aided by the inclusion of additional clinical, amount of myopic astigmatism gives pseudoaccommodation. pathologic, or chromosomal data. It is yet to be determined And, yes, this can be very precisely corrected with glasses. whether mutational data may further optimize the accuracy Another benefit of extracapsular ciliary sulcus placement of the gene expression profile classification, and this question using all-PMMA implants is that light toxicity to the macula will be addressed in our multicenter trial, which is sponsored can be drastically minimized. This is because the micro by the National Cancer Institute (http://bit.ly/2u4IdyH). scope can be tilted moderately off-axis so its intense light J. William Harbour, MD, and Manuel Paez-Escamilla, MD falls inferior to the macula. (Less of a red reflex is necessary Miami for visualization with this technique.) Even hazy corneas and Zélia M. Corrêa, MD, PhD other optical issues still permit sufficient visualization. It has Cincinnati been well-established that the operating microscope’s light source can cause photic maculopathy of alarming degrees.3 1 Seider MI et al. Ophthalmic Surg Lasers Imaging Retina. 2014;45(5):441-442. Aiming for precise, in-the-bag positioning requires on-axis 2 Klufas MA et al. JAMA Ophthalmol. 2015;133(9):1073-1076. visualization, which places the intense light source right on 3 Onken MD et al. Ophthalmology. 2012;119(8):1596-1603. the macula. This is particularly true for premium implants. 4 Corréa ZM et al. Am J Ophthalmol. 2016;162:20-27 e1. Phacoemulsification is not required with this approach. 5 Walter SD et al. JAMA Ophthalmol. 2016;134(7):734-740. With the larger wound (to permit the larger solid implant), 6 Field MG et al. Clin Cancer Res. 2016;22(5):1234-1242. the surgeon can gently slide the nucleus out with a nucleus loop, bypassing ultrasonic toxicity to the endothelium. Bypassing Progressive Zonular Weakness Perhaps our obsession with refractive error is causing us to turn a blind eye to the basics. We ophthalmologists seem to have forgotten a critical lesson Joseph L. Calkins, MD from the past: The zonules continue to weaken with age. Lancaster, Pa. In the days of intracapsular/cryo cataract surgery, a simple rocking motion would pull the lens loose easily in patients 1 Kristianslund O et al. Ophthalmology. 2017;124(2):151-159. aged 60 and older. Recently, we have become obsessed with 2 Davison JA. J Cataract Refract Surg. 1993;19(5):582-589. precise refractive error, thinking that in-the-bag placement 3 Michels M et al. Surv Ophthalmol. 1990;34(4):237-252.

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RUTH D. WILLIAMS, MD Solo Practice in Ophthalmology: Resisting the Tides?

ore than 1,000 years ago, Cnut the Great became Solo practice has its stresses, too. Solo docs must shoulder King of England, Denmark, and Norway. A famous alone the cost of implementing an electronic health records Millustration depicts Cnut sitting in his throne on system or purchasing expensive equipment. The recent shift the ocean sands commanding the waves to recede. Scholars of Medicare beneficiaries into Medicare Advantage (MA) suggest that his words were not mad or arrogant ones; rather, plans can limit access to patients, as many MA they were a warning from a wise king to his courtiers that plans contract with larger groups or only man cannot resist larger powers. If Cnut knew about the waves use an existing health system. And of change in today’s health care, would he herald the end of solo practitioners often have less solo practice—or applaud it as a viable and necessary model? leverage when negotiating a con- Overall, solo private practice is declining. A survey of tract with a large payer. more than 17,000 physicians found a decrease in the number Furthermore, the solo of solo practitioners from 24.9% in 2012 to 16.8% in 2016.1 clinician must also be a mini- In contrast, 26% of ophthalmologists responding to a recent expert in marketing, practice Academy membership survey were in solo practice, a number management, human resourc- that declined for the first time in decades. Robert Wiggins Jr., es, MIPS, and contracting. MD, MHA, the Academy’s Senior Secretary for Ophthalmic Ho Sun Choi, MD, started a Practice, reported that younger members, particularly those Google group, SoloEyeDocs, for in training, are less interested in solo practice. Even so, if a solo ophthalmic practitioners to quarter of practicing ophthalmologists are in solo private ask questions, share great advice, and practice, it’s still a viable and robust model. find camaraderie. “Our listserv is an in- Like most young ophthalmologists, cornea specialist valuable resource,” Ho Sun commented. Ruth D. Natasha Herz, MD, never imagined herself as a solo practi- Ophthalmology may be particularly Williams, MD tioner. But when her husband landed his dream job in Wash- well-suited for solo practice. First, as Chief Medical ington, D.C., and she couldn’t find a position, she bought a in rural markets, solo ophthalmologists Editor, EyeNet practice from a retiring ophthalmologist. In Arizona, Dan may be well-positioned to serve smaller Briceland, MD, started his own ophthalmic practice after markets within a larger metropolitan area. These local markets experiencing contract issues with an existing practice. And in may arise from trade barriers—such as congested roadways Colorado, Ron Pelton, MD, started his oculoplastics practice or toll bridges—or a strongly developed community. Second, immediately after fellowship because he was drawn by the solo ophthalmologists can create demand for their services independence. “Solo practice fits my personality,” he said. by providing exceptional care and unique or subspecialty Natasha likes the freedom of setting her own schedule. services. Relationships with referring providers, patients, and “If I want to take next Tuesday afternoon off to go to my the community build loyalty to a solo practitioner. kid’s party—done!” Ron also likes the flexibility. Dan and In an era of health care consolidation, can solo ophthal- Natasha value the close relationship with their staff and mologists survive? Can a young ophthalmologist consider their direct role in setting the tone of the office. Dan related, solo practice? Natasha shared some advice: “The upfront cost “There is no greater joy than to drive to the office with a may be high, but you more than make up for it in benefits smile, and that enthusiasm translates to the office culture.” and compensation down the road. The freedom is incredible, Ron, Dan, and Natasha all appreciate the efficiency of and I love my lifestyle. You can do it!” making decisions without the need to convince a partner or submit to a bureaucracy. Ron runs a lean practice, and while 1 www.physiciansfoundation.org/uploads/default/Biennial_Physician_ he assumes all the financial risk, he enjoys all the profit. Survey_2016.pdf. Accessed Aug. 15, 2017.

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DAVID W. PARKE II, MD Direct-to-Consumer Advertising in the Molecular Era

n late August, I received an email from 23andMe an- and hear, “Doctor, I sent my spit to company X to see if I was nouncing “exciting news.” It read, “The Food and Drug at risk for disease Y, and the results show I may get glaucoma IAdministration allows marketing of first direct-to-con- (or age-related macular degeneration or some other ophthal- sumer tests that provide genetic risk information for certain mic disease). What do you think? I’m worried.” conditions.” The email went on with lengthy and carefully How many of us would know if the right gene is tested, if written disclaimers. One of these stated, “23andMe does not the testing is clinically meaningful, if the laboratory is high provide medical advice.” It encourages consumers to talk quality, etc.? (Just last month, one laboratory had to retest with a physician or genetic counselor about the results. 50,000 samples for incorrect reporting about a serious in- Remember Super Bowl XXXVIII? It is famous not only herited disease.) It’s a consumer purchase, and we are being for the Janet Jackson wardrobe malfunction but also for the asked to validate and explain its significance—perhaps a first direct-to-consumer (DTC) marketing of an erectile 1-hour process for a certified genetic counselor. dysfunction drug. Considering that the average Super Bowl You might say that this is an argument ad that year was about $2.3 million, going DTC was not an for enhanced training in ophthalmic inconsequential decision! genetics, one of the most fascinating, DTC marketing took another leap on Nov. 22, 2007, when complex, and increasingly clinically viewers of the Dallas Cowboys–New York Jets game witnessed relevant disciplines in our field. Is a commercial for a drug-eluting stent to be used with cor testing rendering ophthalmolo- onary angioplasty. As I watched, I thought, “Really? In the gists diagnostically less relevant? midst of a heart attack someone’s going to say, ‘Excuse me. Absolutely not. Ed Stone and I want the stent advertised during the Jets game.’ Come on!” colleagues recently commented: DTC advertising of medical devices, sophisticated niche “As genetic tests have become pharmaceuticals, and diagnostic testing services seem to larger in scope and sensitivity, the be everywhere—but only in a few countries. In the United need for exceptionally detailed and States, growth in DTC marketing has far outstripped growth accurate clinical information also in pharmaceutical research and development. In 2015, U.S. has increased.”1 Anthony Moore, in an pharmaceutical companies are estimated to have spent nearly accompanying editorial, stated explicitly, $5 billion on DTC television advertising. A study showed re- “…testing should be directed by clinical David W. turns up to $2.50 for every $1.00 invested in DTC advertising. findings, and equally important, molec- Parke II, MD No doubt there is a positive side to DTC drug and device ular genetic findings need to be carefully Academy CEO marketing—disease awareness, public education, and in- evaluated in the context of the clinical creased medication adherence. On the negative side, we have phenotype to avoid errors in molecular diagnosis.” stimulated unnecessary demand, consumer confusion, and The genie is out of the bottle. Consumers are becoming economic costs. Notably, drugs and devices generally require more engaged in their own disease management. Mailing physician prescription for use. bottled spit is easy and not dangerous. But accurately and Consumer-initiated genetic testing heralds a new era: appropriately dealing with the results will be difficult and Physician involvement is not at the front end of the care may have dangerous consequences. As physicians, we must process, deciding based on patient phenotype (family history, realize that no matter how many detailed educational re- symptoms, signs, and diagnostic data) whether genotyping sources the testing companies put on their websites, patients is indicated. It is at the back end. The patient has ordered the will ask, “Doctor, am I going to get this disease?” test and now is trying to make sense of the results. How would you respond if you walk in your exam room 1 Stone EM et al. Ophthalmology. 2017;124(9):1314-1331.

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out onto the surface of the Bacterium Protects eye and patrol the eye for Against Other pathogens,” she said. “What we were able to find is that Microbes the bacterium that we have identified actually lives on THE MUCOSAL SURFACE OF A HEAL the ocular surface for the thy eye is awash in a stew of antimicro long term.” bial molecules and immune cells. But, Persistence on surface. under homeostatic conditions, the In mice, the NEI researchers bacterial species Corynebacterium found, C. mast is transmitted mastitidis (C. mast) can thrive there from mother to pup, but it harmlessly while also boosting the eye’s is not passed between adult immunological defenses against other animals. This supports the infections, researchers have discovered. notion that C. mast actively In a series of mouse experiments, colonizes the tissue and is a team of scientists at the National not continually reinoculated Eye Institute (NEI) found that C. mast from the skin, said Anthony IMMUNE RESPONSE. C. mast, found on the murine induced T-cells in the ocular mucosa St. Leger, PhD, lead author ocular surface and fluorescently labeled in this to produce interleukin-17 (IL-17), of the study. image, stimulates a beneficial immune response which controls the local production of “The C. mast colonizes in the ocular mucosa—and is not eradicated from antimicrobial molecules. In turn, this the eye very early in life, the eye. prevented invasive surface infections before the immune system of Candida albicans and Pseudomonas has a chance to mature. Despite the at the point of finding that taking this aeruginosa.1 bacterium stimulating an immune bacterium away leaves the eye open to Ocular microbiome. There has been response, somehow it has evolved a way pathogenic infections,” Dr. Caspi said. increasing recognition in recent years to avoid being eradicated from the eye,” “We have not gone beyond that to try that commensal bacteria—the “micro he said. to see if we leave these mice alone now biome”—play important roles in local Next steps. In addition to deter if this bacterium is going to come back, ized immune processes of the skin, gut, mining how the bacteria persist, the and maybe even become antibiotic- and other organ systems, said coauthor researchers plan to investigate the resistant.” Rachel R. Caspi, PhD. But there was impacts of antibiotic medications on From mice to people. It is too early some doubt that commensal bacteria the commensal system. “We treated the to know if C. mast or another microbe could survive on the ocular surface, she mice with antibiotics and it effectively might also function as a commensal in said. killed the bug, but it suppressed that the human eye. However, it is likely, as “There was really no consensus that immune response as well. So I think Corynebacterium species are routinely anything could live there, because the our study highlights the need to better found in conjunctival swabs of hu surface of the eye is highly antibac understand how topical and systemic mans, said coauthor H. Nida Sen, MD, terial. We have lysozyme in tears. We antibiotics manipulate the ocular mi MHSc. have antibacterial peptides and other crobiome,” Dr. St. Leger said. “I think the relevance to the human

National Eye Institute Eye National substances. And neutrophils come “For the moment, we’ve just stopped ocular surface has to be established

EYENET MAGAZINE • 19 first,” Dr. Sen said. “But conceptually, RETINA were selected for analysis. Because of as a [research] group, we are interested the higher prevalence of AMD among in what this might mean for human Physical Activity whites and the role of genetics on inflammatory diseases or ocular surface and AMD Risk disease development, studies with non diseases in general. Manipulation of the white populations were excluded. microbiome has the potential to shift IN A REMINDER OF THE IMPACT OF Positive effect. To account for study the paradigm in treatment and preven lifestyle factors on disease development, variations in physical assessment, tion of disease.” researchers conducted a meta-analy participants were broadly classified as For instance, perhaps contact lens– sis of studies on physical activity and either sedentary or active. related infections could eventually be age-related macular degeneration Even a modest amount of exercise treated with commensal eyedrops that (AMD). They found that a more active —3 hours per week of low-to-moderate boost the localized immune system, Dr. lifestyle was independently associated activity—conferred benefits, the re Caspi said. “We probably don’t want with lower odds of both the early and searchers found. The greatest reduction to be instilling live bacteria into the late forms of the disease.1 in the odds of having AMD was seen eye. So we would want to test prepara Much of the literature published to with the late form of the disease; active tions—either an attenuatation or, more date on AMD and exercise has either participants were 41% less likely than simply, an extract from the bacterium produced conflicting results or has were their sedentary counterparts to —for their ability to replace the whole found “only small effects with unclear have late AMD. With respect to early entire bug. The goal would be to mimic overall significance,” said Robert P. AMD, the benefit was much more a commensal bacterium, but it would Finger, MBBS, PhD, at the University of modest: Active participants were 8% be under our control,” she said. Bonn in Bonn, Germany. “We have now less likely to have early AMD compared —Linda Roach demonstrated that there is a clear asso to their sedentary counterparts. ciation and [confirmed] that it might Limitations and nuances. “The stud 1 St Leger AJ et al. Immunity. 2017;47(1):148-158. be worthwhile to assess physical activity ies we pooled were cross-sectional; we e5. in longitudinal studies of AMD.” still lack good longitudinal data on this Relevant financial disclosures—Drs. Caspi, Sen, Findings. The authors identified 620 research question,” Dr. Finger said. and St. Leger: None. eligible published studies, 9 of which Moreover, he said, the studies mea

IMAGING FLIO Images Earliest Retinal Changes

FLUORESCENCE LIFETIME IMAGING Heidelberg Spectralis platform, ophthalmoscopy (FLIO), a novel im- which is not yet a standard prod- aging modality that reveals specific uct.) In contrast, unlike FAF, FLIO patterns in almost any fundus disor- can provide quantitative analysis by der, may one day serve as a tool for measuring the fluorescence lifetime visualizing early retinal changes in of fluorophores. myriad retinal disorders. In other words, FLIO is a tool While the role of FLIO is still that tells how long any given retinal evolving, researchers expect FLIO fluorophore glows after excitation to be “a cornerstone for retinal with a laser pulse. This span of time imaging in the future,” said Martin S. is known as fluorescence lifetimes. Zinkernagel, MD, PhD, at University Pilot studies. Comparisons of Hospital Bern in Bern, Switzerland, mean lifetimes of diseased eyes

and coauthor of a review of FLIO.1 to healthy controls have revealed Research in Retinal and Eye Progress In proof-of-concept studies, he said, FLIO’s potential for monitoring © 2017 © 2017 “We and other groups have provid- disease progression and therapeu- ed [evidence] that FLIO can provide tic outcomes, Dr. Zinkernagel said. FLUORESCENT LIFETIMES. Macular unique information to complement He added that FLIO has provided hole, before surgery (A) and 3 months that [which is] obtained through information on potential markers for after successful closure of the hole (B). other imaging modalities.” disease progression in retinal hered- What is FLIO? Like convention- itary disorders and macular degen- In addition, earlier this year, al fundus autofluorescence (FAF), eration, suggesting it may be used researchers reported using FLIO to FLIO is mainly a qualitative imaging in clinical trials on gene therapy for better understand the pathogenesis procedure. (It relies on a modified these diseases. of drusen in AMD. They found that

20 • OCTOBER 2017 sured physical activity using question GENETICS naires. “We now have a much more precise way to measure physical activity Genetic Testing: using accelerometers. Data from the What to Order NHANES (National Health and Nutri tion Examination Survey) have demon SOMETIMES YOU CAN HAVE TOO strated that these can be successfully much information, as a molecular used in large-scale studies and that the investigation of families with inher magnitude of the association between ited retinal disease demonstrates.1 amount of physical activity and AMD This retrospective analysis identified might be stronger than what we found disease-causing genotypes in 760 of in our meta-analysis.” the 1,000 consecutive families treated Ongoing research. Dr. Finger’s team by a single clinician, a sensitivity well will continue to follow this avenue of beyond the 5% chance of a molecular RETINITIS PIGMENTOSA. A 64-year-old study, he said. “We are building up a diagnosis when the field was young. male with USH2A-associated RP. Note cohort of patients with early and inter Advances in genome sequencing pose the characteristic lacy black intraretinal mediate AMD, in which we will assess a new set of challenges to clinicians, pigment, narrowed arterioles, and activity via accelerometers.” In addi said Edwin M. Stone, MD, PhD, at the slightly pale optic disc. tion, he said, the Rheinland Study—a University of Iowa Stephen A. Wynn prospective cohort study based in Bonn Institute for Vision Research in Iowa much lower false genotype rate (FGR). that is examining aging of the brain City. There’s a common misconception “All clinical tests have some false and the eye—is including assessments that as diagnostic modalities evolve, the positives, and molecular tests are no of physical activity. —Jean Shaw need for good clinical skills diminishes, exception,” said Dr. Stone. The study he said. In fact, the opposite is true. showed the likelihood of observing a 1 McGuiness MB et al. Am J Ophthalmol. 2017; “Good clinical skills are more plausible disease-causing “result” purely 180:29-38. important than ever for arriving at a by chance to be 128%, if one tested 300

© The University of Iowa University © The Relevant financial disclosures—Dr. Finger: None. correct molecular diagnosis,” Dr. Stone genes at a time, as current retinal dis said. “Because of the large amount of ease sequencing panels can do. Using a noise in each person’s genome, one tiered approach, the FGR fell below 5%. soft drusen associated with AMD needs a quite focused clinical hypothe Cost. The study also found that a progression showed longer flu- sis to obtain a statistically significant tiered approach was 17.7% less expen orescence decays than did hard result from a broad genetic test like sive than whole exome sequencing. drusen. Thus, they hypothesized, whole exome sequencing.” The latter cost $1,200 per patient. In FLIO might give information Study specifics.While more than contrast, customized testing based on about the individual risk for the 300 genes are currently known to cause clinical findings cost $990 on average. development of late AMD.2 inherited retinal disorders, only 104 However, cost is not the reason Looking forward. Although Dr. genes were observed in this study popu Dr. Stone advocates a refined testing Zinkernagel predicted that FLIO lation. Of those, 13 genes were respon strategy. “The main value of the pretest will become an important diag- sible for nearly half of disease in all hypothesis is to reduce the number of nostic technology, its precise use families (497 families). false positives and thereby increase the is yet to be revealed. “Whether The researchers compared 2 testing statistical significance of the results.” it will be used in an academic strategies: 1) Whole exome sequencing, Should you order testing? Retina setting or by ophthalmologists a single test that can examine hun specialists could use the classification in practice is difficult to predict dreds of retinal disease–causing genes system reported in this study directly, based on the current knowledge.” at once; and 2) tiered testing, which said Dr. Stone. Other clinicians will —Miriam Karmel relies on a good clinical diagnosis to have to customize it a bit for their direct the molecular testing. The latter practices. All physicians should try to 1 Dysli C et al. Prog Retin Eye Res. approach narrows the number of genes establish the narrowest possible clinical Published online June 30, 2017. under consideration, thereby increasing diagnosis before performing a molecu 2 Sauer L et al. Time-resolved fundus the statistical significance of the results. lar test, he said. —Miriam Karmel autofluorescence in dry AMD. Present- Accuracy. The results showed that ed at: ARVO; May 9, 2017; Baltimore. the tiered testing strategy was 6.1% 1 Stone EM et al. Ophthalmology. 2017;124(9): Relevant financial disclosures:Dr. more sensitive than whole exome 1314-1331. Zinkernagel—National Cancer Insti- sequencing alone. It also resulted in a Relevant financial disclosures—Dr. Stone: None. tute/National Institutes of Health: S; Swiss National Science Foundation: S. See the financial disclosure key,page 10. For full disclosures, including category descriptions, view this News in Review at aao.org/eyenet.

EYENET MAGAZINE • 21 20% DIVIDEND AND CONTINUED LOW RATES IN 2017

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A Risk Retention Group

DIVIDEND 2016 EYENET ad REV 10-18-16.indd 1 10/18/16 3:53 PM Journal Highlights NEW FINDINGS FROM THE PEER-REVIEWED LITERATURE

Ophthalmology odds of white Medicaid members having surgeries in the United States. Com- Selected by Stephen D. McLeod, MD no glaucoma test were found to be 198% prehensive ophthalmic exams were greater than for whites with commer- performed pre- and postoperatively for Insurance Coverage and cial health insurance. Black both procedures. Volume 124 | Number 10 pp. XXXX–XXXX Disparities in Glaucoma Care Medicaid members were Volume 124 | Number 10 | October 2017 Best-corrected Elsevier | ISSN 0161-6420 October 2017 even less likely to be tested; visual acuity the odds of no testing were (BCVA) was Elam et al. compared the receipt of 291% higher among those measured and glaucoma care between patients with with Medicaid. patients complet- Medicaid and those with commercial The findings emphasize ed the National health insurance. They found that, the profound impact of race Eye Institute regardless of race or ethnicity, patients and type of health plan on OPHTHALMOLOGY Visual Function- INSERT ADVERT with commercial plans received sub- the care of patients with ing Questionnaire stantially more monitoring. OAG, the authors said, and (NEI-VFQ) 30-90 For this longitudinal study, records they concluded that con- days pre- and were reviewed for 18,372 commercial siderable efforts are needed October 2017 postoperatively. plan (managed care) members and to improve the quality and NEI-VFQ scores 3,394 Medicaid members with newly timelinessOPHTHA_v124_i10_COVER.indd 1 of glaucoma care 17-06-2017 01:51:38 were calculated diagnosed open-angle glaucoma (OAG). for Medicaid recipients, especially those using a traditional subscale scoring The proportion of patients who received who are black and/or are members algorithm and the Rasch-refined the following exams within 15 months of other minority groups. (See related approach, each yielding separate data of diagnosis was documented: visual commentary by Eve J. Higginbotham, for socioemotional impact (QOL) field (VF) testing, fundus photography SM, MD, in the same issue.) and visual function. Primary outcome (FP), and other ocular imaging (OOI). measures were postoperative NEI-VFQ Odds ratios (OR) were calculated, and Second-Eye Cataract Surgery, scores and the differences between multivariable logistic regression was Vision, and Quality of Life these scores for the 2 procedures. applied to determine the extent to which October 2017 Relative to the second eyes, first eyes race/ethnicity and type of health insur had poorer mean preoperative BCVA ance affected the odds of having a glau Second-eye cataract surgery is common (0.55 vs. 0.36 logMAR), greater im- coma monitoring test. in developed countries and is expected provement in mean BCVA after surgery The proportions of patients with to grow in popularity, despite reports (–0.50 vs. –0.32 logMAR), and slightly commercial plans who underwent VF indicating that its benefits may be worse postoperative BCVA (0.06 vs. testing, FP, and OOI were 63%, 22%, inferior to those of first-eye surgery. 0.03 logMAR). Second-eye surgery and 54%, respectively. In comparison, Shekhawat et al. determined that visual resulted in higher postoperative NEI- those percentages for Medicaid mem- function and quality of life (QOL) VFQ scores for nearly all traditional bers were 35%, 19%, and 30%. Patients improve substantially after surgery on subscales and for the visual function with Medicaid were 234% more likely the second eye. and socioemotional subscales (visual to not receive any glaucoma-related test For this multicenter study, the function, –3.85 vs. –2.91 logits; socio- within 15 months of diagnosis. researchers included 328 patients economic, –2.63 vs. –2.10 logits). With regard to race and ethnicity, (mean age, 70.4 years) who underwent The authors concluded that, in after adjusting for confounders, the separate first- and second-eye cataract general, second-eye cataract surgery

EYENET MAGAZINE • 23 appears more beneficial than first- The authors concluded that CXL visit, in 148 of 200 eyes (74%). In eyes eye surgery, especially with respect to treatment effectively and safely halts treated with ocriplasmin alone, those QOL. They recommend that, during the progression of keratoconus, find- results were 85 of 190 eyes (45%) at consultation for potential surgery on ings supported by several international 4 weeks, 83 of 191 eyes (43%) at 12 the second eye, patients be asked about studies. The benefits include reduced weeks, and 90 of 200 eyes (45%) at the their current level of satisfaction with corneal steepness, better visual acuity, final visit. visual function and QOL. and improved subjective functioning. For eyes with a macular hole at —Summaries by Lynda Seminara baseline, closure was achieved with U.S. Multicenter Trial of CXL for ocriplasmin alone in 35 of 64 eyes Keratoconus Ophthalmology Retina (55%) by the first week, 42 of 73 (58%) September 2017 Selected by Andrew P. Schachat, MD by 4 weeks, and in 30 of 75 (40%) by the last visit. With regard to VA, it had Hersh et al. studied data from 2 Ocriplasmin for Symptomatic improved by ≥ 2 lines at the final visit multicenter trials of corneal collagen Vitreomacular Adhesion in 69 eyes (35%) and by ≥ 3 lines in 54 cross-linking (CXL) for keratoconus September/October 2017 eyes (27%)—but had decreased by ≥ 2 and noted beneficial effects on disease lines in 35 eyes (18%) and by ≥ 3 lines progression. Lim et al. evaluated the anatomic in 27 eyes (14%). In the concurrent studies, 205 pa- and visual outcomes in patients with Complications included photop- tients with keratoconus (mean age, symptomatic vitreomacular adhesion sias (15%), dimness of vision (14%), 33 years) were assigned randomly to (VMA) who were treated with ocri- decreased color vision (10%), and either standard ultraviolet A–riboflavin plasmin. They found that VMA had macular hole development (5%). 0.1% CXL treatment (n = 102 eyes) resolved with ocriplasmin alone in 83 —Summary by Jean Shaw or sham treatment (riboflavin 0.1% of 191 eyes (43%) by week 12 and in with dextran, no epithelial removal 148 of 200 eyes (74%) by the last visit, American Journal of or irradiation; n = 103 eyes). The including eyes that underwent pars Ophthalmology primary efficacy endpoint was the plana vitrectomy (PPV). Selected by Richard K. Parrish II, MD between-group difference in maxi- For this retrospective chart review, mum keratometry change over 1 year. the authors surveyed members of the Pediatric Nystagmus: Incidence Secondary endpoints were corrected Macula Society online. Participating and Types and uncorrected distance visual acu- clinicians provided information for October 2017 ity (CDVA and UDVA, respectively), each eligible patient in their practice, manifest refraction spherical equivalent data collection was open for 6 months, Estimates of the incidence of pediatric (MRSE), endothelial cell count, and and no limit was placed on the length nystagmus, including its subtypes, are adverse events. of follow-up. Information was collected limited. Nash et al. addressed this by Ninety CXL eyes and 76 control eyes on demographics, visual acuity (VA), compiling information from a large were followed for 12 months. The mean extent of VMA, presence or absence of epidemiologic database. They found decrease in maximum keratometry macular hole, and spectral-domain op- that developmental delays are common value in the CXL group was 1.6 ± 4.2 tical coherence tomography (SD-OCT) among young patients with nystagmus, D during the 1-year period; a decrease findings before and after treatment. as are associations with retinal and of ≥ 2.0 D occurred in 28 eyes (31.5%) All told, 31 investigators participated, optic nerve pathology, and that malig- and an increase of ≥ 2 D occurred in contributing data on 208 patients (208 nancy of the central nervous system 5 eyes (5.6%). In contrast, the control eyes). Of these, 52 (25%) had diabetes, appears to be rare. group had a mean increase of 1.0 ± 143 (69%) were female, and 175 (84%) For this study, the authors reviewed 5.1 D. The difference in maximum were non-Hispanic whites. At baseline, medical records for all children younger keratometry change between the study all patients had symptomatic VMA, than 19 years of age in Olmsted County, groups was 2.6 D. CDVA in the CXL 75 (36%) had a full-thickness macular Minnesota, who were diagnosed as group improved by 5.7 logMAR letters, hole, and 41 (20%) had a lamellar hole. having nystagmus during a 30-year with 23 of 83 eyes (27.7%) gaining and Mean VA at baseline was 20/63. The period. Of particular interest were data 5 eyes (6%) losing ≥ 10 letters. UDVA median follow-up was 166 days (range, from the exam in which nystagmus was improved by 4.4 logMAR letters in the 21-704 days). first observed and from the most recent CXL group. Corneal haze was the most Release of VMA—regardless of follow-up evaluation. common adverse effect of CXL. The whether the eye underwent subse- The incidence of nystagmus among endothelial cell count did not change quent PPV—was observed as follows: the study population was 6.72 per significantly during the year following 1) by the first week, in 70 of 161 eyes 100,000 (N = 71). The median age at treatment, and the between-group (44%); 2) by week 4, in 94 of 190 eyes diagnosis was 12.7 months (range, differences in MRSE changes were not (49%); 3) by week 12, in 111 of 191 0-18.6 years), and 42 (59.2%) were significant. eyes (58%); and 4) by the patient’s final male. Sixty-two (87.3%) of the 71 chil-

24 • OCTOBER 2017 dren had infantile nystagmus, defined as onset by 6 months of age; this represents a birth prevalence of 1 in 821. Nystagmus occurred bilaterally in 64 cases (90.1%), in only the right eye in 2 cases (2.8%), and in just the left eye in 3 cases (4.2%). The most common type of nystagmus was that associated with retinal/optic nerve disease (n = 23; 32.4%), followed by idiopathic or congenital motor nystagmus (n = 22; 31.0%) and latent forms of nystagmus (n = 17; 24.0%). Less common were associations with Chiari malformation, medication use, or a tumor of the central nervous system (n = 2.8 each). Thirty-one children (43.7%) had a developmental delay, 25 (35.2%) had strabismus, and 10 (14.1%) had ambly- opia. Of the 60 patients (84.4%) whose visual acuity was assessed at presenta- tion, 48 (80.0%) had 20/40 vision or better in at least 1 eye. INCREASING SEVERITY. In this group of male patients, changes similar to mild Sleep Apnea and Retinopathy hypertensive retinopathy became more apparent with increasing OSA severity. October 2017 (Top left) No OSA; the patient’s apnea-hyponea index (AHI) was 3.0 per hour. (Top right) This patient had mild OSA and an AHI of 14.4/hr. (Bottom left) An example of Obstructive sleep apnea (OSA) is linked moderate OSA; the patient’s AHI was 21.4/hr. (Bottom right) An example of severe to ocular conditions caused by vascular OSA; the patient’s AHI was 40.6/hr. dysregulation, including optic disc edema and nonarteritic anterior ischemic in 35, and mild in 25; the remaining ated with retinal arteriolar narrowing optic neuropathy. Advances in retinal 14 patients served as controls. and attenuated vascular pulsation am- imaging have enabled noninvasive ac- Static retinal vascular caliber was plitude. Retinal vasculature is easily im- curate detection of retinal microvascu- calculated as the average diameter aged and may be a surrogate biomarker lar pathology, which may long precede of retinal arterioles and venules and of cerebral and systemic vascular risk in clinical evidence of disease. Tong et al. summarized as the arteriovenous ratio patients with OSA requiring extensive examined the quantitative relationship (AVR). Dynamic retinal vascular caliber evaluation. between both static and dynamic retinal was defined as the average pulsation —Summaries by Lynda Seminara vascular caliber and the severity of OSA amplitude of retinal arterioles and and found an independent association venules. Groups were compared using JAMA Ophthalmology between retinal arteriolar narrowing multivariate linear regression analysis. Selected by Neil M. Bressler, MD, and and attenuated vascular pulsation Results were adjusted for age, body Deputy Editors amplitude. mass index, and arterial pressure. For this prospective cross-section- Increasing AHI was significantly Maternal Preeclampsia, Risk of al study, the researchers performed a associated with decreasing AVR and Premature Birth, and ROP quantitative analysis of retinal vascular decreasing central retinal arteriolar September 2017 caliber among patients with OSA, who equivalent. Also significant was the were recruited from adult patients who relationship between increasing AHI Studies of the effect of preeclampsia planned to undergo diagnostic poly- and attenuated retinal vascular pulsa- on premature birth and retinopathy somnography at a private tertiary sleep tion amplitude. Qualitative grading of of prematurity (ROP) have produced unit in Australia. OSA severity was fundus photographs demonstrated that conflicting results. In research aimed at defined by the apnea-hypopnea index retinal vascular changes resembling clarifying this relationship and explain- (AHI), as follows: ≥ 30 = severe; ≥ 15 mild hypertensive retinopathy were ing the discrepancies, Shulman et al. to < 30 = moderate; ≥ 5 to < 15 = mild; more common in patients with moder- found that preeclampsia was associated and < 5 = control. Of the 115 final ate and severe OSA than in controls. with elevated risk of ROP in an unre- American Journal of Ophthalmology American Journal of participants (mean age, 58 years; 73 The investigators concluded that stricted cohort, but it reduced the risk

EYENET MAGAZINE • 25 For this study, the researchers Outcomes were evaluated 6 months graft becoming undetectable increas- reviewed records of 290,992 live births postoperatively and included subjective es substantially each year after ADD that occurred during a 10-year period change measured on a 10-point visual surgery, and their use does not ensure (January 2001–December 2010). They disturbance scale, a 5-level qualitative long-term tube coverage. used generalized estimating equations scale, and the National Eye Institute This cross-sectional study involved for logistic regression, with covariate Visual Functioning Questionnaire 25 107 patients (120 eyes) who underwent adjustment, to determine the relation (NEI VFQ-25). Secondary outcomes ADD surgery with a GISC patch graft ship between ROP and maternal pre- included objective change assessed by at Wilmer Eye Institute in Baltimore eclampsia among 2 cohorts: the entire masked grading of color fundus photo- between July 2010 and October 2016. study population and the preterm sub- graphs and by measuring visual acuity. Of these, 49 were male, and 43 were group with very low birth weight born At the 6-month follow-up exam, African American. The patients’ mean before 31 weeks’ gestation (n = 2,015). self-reported improvement in floater- age was 64 years (range, 24-96 years), Infants in the latter group weighed related visual disturbance was greater and the mean time since surgery was < 1,500 g. in the treatment group (54% vs. 9%). 1.7 years (range, 1 day to 6 years). In the full (unrestricted) cohort, Improvement in the 10-point visual Primary outcomes were graft thickness preeclampsia was associated with an in- disturbance score also was superior for over time and risk factors for unde- creased risk of all ROP, severe ROP, in- the treatment group (3.2 vs. 0.1). On tectable grafts. Measurements were fant death, and having a premature/low the 5-level qualitative scale, 19 (53%) obtained by anterior segment optical birth weight baby. In the premature/ of the 36 patients treated actively coherence tomography (AS-OCT) low birth weight cohort, preeclampsia and none (0%) of the sham controls during follow-up exams. was inversely associated with all ROP, reported substantial or complete im- The linear regression model used severe ROP, and infant death. provement in symptoms. NEI VFQ-25 to evaluate time after ADD surgery In conclusion, these findings suggest responses showed that laser treatment (with graft thickness as the outcome) an overall adverse effect of preeclamp- yielded better general and peripheral demonstrated that thinner grafts were sia on ROP and are consistent with vision, fewer role difficulties, and observed as time passed (β regression evidence of a protective effect of pre- less dependency. Grading of masked coefficient, −60 µm per year since sur- eclampsia on infants born prematurely. wide-angle photographs demonstrated gery). Moreover, in 16.6% of eyes, no However, it is unclear whether the latter that 34 (94%) of the 36 patients with GISC patch graft could be discerned. denotes a true direct protective effect, active treatment experienced significant Each year after ADD surgery, the odds collider bias, and/or another form of or complete resolution of floaters, com- ratio of the graft being undetectable by uncontrolled confounding. pared with none (0%) of the patients in AS-OCT increased by 2.1. No correla- the sham group. No clinically relevant tion was found between graft presence/ Laser Vitreolysis for adverse events were noted. absence and age, sex, race, type of ADD, Symptomatic Floaters The authors concluded that Nd:YAG position of ADD, previous conjunctival September 2017 laser vitreolysis produces moderate surgery, or diagnosis of uveitis or dry improvement in floater symptoms. eye syndrome. Vitreous floaters, which become more However, they cautioned that larger —Summaries by Lynda Seminara common with age, often are bother- studies are needed to confirm long- some and can hamper visual quality. term stability of outcomes and to fully OTHER JOURNALS Shah and Heier performed a trial of capture adverse events. Selected by Deepak P. Edward, MD Nd:YAG laser vitreolysis, a potential but understudied treatment for Weiss ring Course of Gamma-Irradiated Screening for Congenital Zika floaters, and found that it produced Corneal Patch Grafts After Virus Infection subjective improvement in symptoms Drainage Device Placement JAMA Pediatrics and objective improvement in appear- September 2017 Published online July 17, 2017 ance. The single-center, randomized Although surgically implanted aque- According to current guidelines, clinical trial involved 52 patients (35 ous drainage devices (ADDs) lower screening eye exams are recommend- females) with symptomatic Weiss ring intraocular pressure in patients with ed for infants with microcephaly or floaters secondary to posterior vitreous glaucoma, the devices often become laboratory-confirmed infection with detachment. Participants were assigned exposed through the conjunctiva over the Zika virus (ZIKV) but not for all randomly (2:1) to receive either uni- time. de Luna et al. hypothesized that infants potentially exposed to the virus lateral treatment with Nd:YAG laser the thinning of gamma-irradiated in utero. To assess the adequacy of this vitreolysis (n = 36; mean age, 61.4 sterile cornea (GISC) patch grafts com- recommendation, Zin et al. examined years) or sham laser treatment (n = 16; monly used to cover the tube of ADDs ophthalmic findings of infants whose mean age, 61.1 years). All procedures contributes to this exposure. They mothers were infected with ZIKV were performed by the same physician. found that the risk of a GISC patch during pregnancy. They found that eye

26 • OCTOBER 2017 abnormalities may occur in the absence replacement with the AAV2 vector was For this study, the researchers of microcephaly and may be the sole safe and effective. created an anonymous online survey initial sign of congenital ZIKV infection. For this open-label, randomized and distributed it via email to AGS For this descriptive case series, the phase 3 trial, the researchers enrolled members who subscribe to the AGS-net. researchers examined 112 mothers and 31 patients who were ≥ 3 years of age Participants were asked about their their infants at a facility for high-risk at 2 sites in the United States. Partici- practice location and date of glaucoma pregnancies in Brazil. During gesta- pants had a best-corrected visual acuity fellowship training; in addition, they tion, the mothers were confirmed to (BCVA) of 20/60 or worse in each eye were asked to report on their preferred be infected with the virus by real-time and/or a visual field < 20 degrees in any approach for a set of common clinical polymerase chain reaction (PCR) test- meridian as well as a confirmed genetic scenarios. The data were then compared ing. The infants were evaluated from diagnosis of biallelic RPE65 mutations. with the results from previous surveys birth to 1 year of age by a multidisci- All participants were required to have (conducted in 1996, 2002, and 2008). plinary team. Median age at the first eye sufficient viable retinal cells and to All told, 252 (23%) of the 1,091 sub- exam was 31 days (range, 0-305 days). perform a standardized multiluminance scribers to the AGS-net participated in Eye abnormalities were documented, mobility test (MLMT) within the lumi- this survey. A majority (59%) reported and their relationship to microcephaly, nance range evaluated. that they are in private practice, while central nervous system (CNS) findings, Of the 31 patients, 21 were random- the remainder practice in an academ- and the timing of maternal infection ly assigned to the intervention arm; ic setting. Most had completed their was explored. the remaining 10 were assigned to the fellowship training either ≥ 20 years ago Ocular defects were observed in control arm. Treatment consisted of (33%) or ≤ 5 years ago (29%). 24 (21.4%) of the 112 infants born to bilateral subretinal injection (1.5 × 10¹¹ When the results were analyzed by ZIKV-infected mothers, with abnor- vector genomes of voretigene nepar- practice setting, no significant differ- malities of the retina and optic nerve vovec in 0.3 mL total volume). The pri- ences emerged between surgeons in the most common findings. Of these mary efficacy outcome was the 1-year private and academic settings regarding 24 infants, 10 (41.7%) did not have mi- change in MLMT performance, with any given surgical technique in any crocephaly, and 8 (33.3%) had normal functional vision measured at specified clinical scenario. However, differences CNS findings. light levels. did emerge when years of surgical expe- With regard to the timing of mater- The mean bilateral change in MLMT rience were factored in: Older surgeons nal infection, 14 of the 24 infants with score from baseline to one year was 1.8 were more likely to use trabeculectomy an eye abnormality (58.3%) were born light levels in the intervention group with mitomycin-C (MMC) in several to mothers who contracted ZIKV in and 0.2 light levels in the control group. clinical scenarios, while their younger their first trimester, 8 (33.3%) to those Thirteen (65%) of the 20 intervention counterparts preferred GDDs. infected during the second trimester, participants and none of the controls Overall, the respondents preferred to and 2 (8.3%) to those infected in the passed the MLMT at 1 lux, demonstrat- use GDDs in 7 of the 8 clinical scenar- third trimester. ing that maximum possible improve- ios presented. This represents nearly a As eye abnormalities may be the ment was achieved in those 13 patients. complete reversal from the results of only initial indicator of congenital No serious adverse events related to the the 1996 survey, in which trabeculec- ZIKV infection, the authors recom- study treatment occurred, and there tomy was selected most frequently mended that screening eye exams be were no deleterious immune responses. to manage glaucoma in all clinical given to all infants potentially exposed Most adverse ocular events were mild. scenarios presented, the authors noted. to the virus at any point during ges- —Summaries by Lynda Seminara The results also indicate that GDDs are tation, regardless of CNS findings or being used more frequently in eyes at laboratory confirmation of infection. Assessing Practice Preferences low risk for filtration failure. in Glaucoma Surgery A new question—on combined Gene Replacement for RPE65- Journal of Glaucoma cataract/glaucoma surgery and min- Mediated Inherited Retinal 2017;26(8):687-693 imally invasive glaucoma surgery Dystrophy (MIGS)—was added to this iteration Lancet How have practice patterns changed of the survey. When given the scenario Published online July 13, 2017 among glaucoma surgeons during of a patient with cataract and primary the past 20 years? Vinod et al. set out open-angle glaucoma, 44% of the re- Building on evidence of the potential to assess glaucoma surgical trends, as spondents reported that they would use benefit of gene replacement for RPE65- reported by members of the American phacoemulsification alone, 24% would mediated inherited retinal dystrophy, Glaucoma Society (AGS). The results combine phaco with trabeculectomy/ Russell et al. evaluated voretigene confirm that the trend away from MMC, 22% would perform phaco with neparvovec in patients whose retinal trabeculectomy and toward the use of MIGS, and 9% would perform phaco dystrophy would cause complete blind- glaucoma drainage devices (GDDs) and implant a GDD. ness if untreated. They found that gene continues in most clinical settings. —Summary by Jean Shaw

EYENET MAGAZINE • 27 EyeNet Corporate Breakfasts EyeNet® Magazine helps you make the most of your time at AAO 2017 by bringing you free corporate educational program breakfasts* onsite at the Ernest N. Morial Convention Center.

Room R02-04, 2nd Floor Check-in and Breakfast Pickup Program Ernest N. Morial 6:45-7:00 a.m. Breakfast is provided 7:00-8:00 a.m. Convention Center on a first-come basis.

Programs Saturday, Nov. 11 The Impact of UWF Imaging on Quality of Care and Practice Efficiency: Leading Anterior and Posterior Segment Specialists Review the Evidence Speakers: David M. Brown, MD, Jeffrey S. Heier, MD, Warren E. Hill, MD Presented by Optos

Sunday, Nov. 12 Ligneous Conjunctivitis and Plasminogen-Related Disease: Can We Finally Treat Them? Speakers: Edward J. Holland, MD, Shira L. Robbins, MD Presented by Prometic Life Sciences

Check aao.org/eyenet/corporate-events for updated program information.

* These programs are non-CME and are developed independently by industry. They are not affiliated with the official program of AAO 2017 or Subspecialty Day. By attending a breakfast, you may be subject to reporting under the Physician Payment Sunshine Act. COMPREHENSIVE CLINICAL UPDATE

Molecularly Targeted Cancer Drugs and Ocular Toxicity

hen medical oncologist April K.S. Salama, MD, Wlaunched her practice in 2010, her patients with malignant melanoma had 2 treatment options. And while both drugs were FDA-approved, neither had demonstrated an overall survival benefit. In most instances, the best she could offer her patients with advanced melanoma was supportive care and hospice. One short year later, the outlook for many of her patients changed dramatically with the introduction of ipilimumab, the first FDA-approved entry in a class of immunotherapy drugs known as immune checkpoint inhibitors. “This was the first agent that had ANTIBODY TX. This illustration shows the use of antibodies in active and passive ever demonstrated a survival benefit in immunotherapy of cancer. (A) Checkpoint blockade by anti-CTLA4. CD80 and malignant melanoma patients, some of CD86 bind to the costimulatory molecule CD28 to help activate T-cell prolifera- whom are now long-term survivors,” tion and then to the checkpoint inhibitor CTLA4 to attenuate T-cell proliferation. said Dr. Salama, at Duke University in The antibody ipilimumab blocks the interaction of CTLA4 with its ligands, thereby Durham, North Carolina. releasing the checkpoint inhibitor and favoring T-cell proliferation. (B) Checkpoint blockade and inhibiting immune suppression by anti–PD-1 or anti–PD-L1. Generally, New Benefits, New Risks inhibition of both PD-L1 and PD-L2 (e.g., by anti–PD-1) is required to block negative As Dr. Salama put it, “Recent advances regulation by dendritic cells, whereas only PD-L1 inhibition (by anti–PD-1 or anti–PD-L1) in genetics and immunotherapy have should relieve immunosuppression (immune rheostat) activity in the tumor bed. Note . led to more drugs and drug combina- that, for clarity, only the primary interactions of PD-1, PD-L1, and PD-L2 are illustrated. tion approaches, revolutionizing the treatment landscape.” on the neuro-ophthalmic side effects of ophthalmologists do not necessarily aao.org/eyenet Yet these advances are not without molecularly targeted cancer drugs.2 need to memorize the nuances of each their risks, including ocular toxicity “Despite the notion that increased of these new cancer drugs, they do linked to the drugs’ mechanism of tumor cell specificity results in decreased need to be aware of the recent advance- action. These risks caught the attention complications, toxicity remains a major ments and their possible effect on their of M. Tariq Bhatti, MD, also at Duke,1 hurdle in the development and imple- patients.” and Drs. Bhatti and Salama subse- mentation of many of the targeted an- quently conducted an extensive review ticancer drugs,” Dr. Bhatti said. “While A Developing Story

. For full credit, see this article at full credit, . For Molecularly targeted therapies can be grouped into 4 broad categories: mono- Science BY LORI BAKER-SCHENA, MBA, EDD, INTERVIEWING M. TARIQ BHATTI, MD, clonal antibodies (mAbs), immune

EYENET MAGAZINE • 29 kinase inhibitors, and third-generation aromatase inhibitors. A Look at the Timeline While these drugs hold great promise in terms of efficacy and tolerability, In the past 2 decades, improved understanding of the cellular, molecular, and many potentially toxic side effects, in- genetic processes involved in human pathology has led to advances in molec- cluding those related to the eye, remain ularly targeted therapy. unknown. “Many of the molecularly In this more personalized treatment approach in the fight against cancer, targeted cancer drugs have unique ad- specific cellular molecules (overexpressed, mutationally activated, or selec- verse effect (AE) profiles based on their tively expressed proteins) are manipulated to decrease the transformation, underlying mechanism of action,” Dr. proliferation, and/or survival of selected cells, Dr. Bhatti said. Bhatti said. “The FDA approval of rituximab ushered in a new era of targeted therapy Unanticipated downstream effects. for cancer,” said Dr. Bhatti. “And the approval of ipilimumab in 2011 was the As science pushes the envelope of first of several next-generation drugs that signaled a resurgence in immuno- immunotherapy and immunomodula- therapy options for cancer.” tion, “we are opening ourselves to the unknown,” Dr. Bhatti noted. “Even if [a researcher has] a specific molecular target in mind, we often do not have a true appreciation or understanding of the downstream effects.” The PML example. He referenced the mAb natalizumab, which demonstrated great efficacy when used to LANDMARK EVENTS. A revolution in the making, starting with approval of the treat multiple sclerosis. “But what chimeric mAb rituximab for B-cell non-Hodgkin lymphoma in 1997. was completely unanticipated was the development of progressive multifocal leukoencephalopathy (PML), a of anticancer drugs. is significantly less—approximately 1%. rare infectious disorder of the central Monoclonal antibodies. Currently, Example: Ipilimumab. Ocular AEs nervous system that occurs secondary 14 FDA-approved mAbs are available. noted with this drug include bleph- to the John Cunningham virus,” Dr. Their mechanism of action includes aritis, choroidal neovascularization, Bhatti said. apoptosis, activation or inhibition of a conjunctivitis, keratitis, episcleritis, Natalizumab was approved by the surface cell receptor, antibody-depen- scleritis, and uveitis. In addition, there FDA in 2004 and withdrawn from the dent cellular cytotoxicity, and comple- have been reports of neuroretinitis, market a year later after 3 cases of PML ment-dependent cytotoxicity. Addi- myasthenia gravis, and optic neuritis. were identified in clinical trials. It was tionally, mAbs can target tumor cells, Small molecule kinase inhibitors. reintroduced to the market in 2006, immune cells, or vascular/stromal cells. These drugs affect the intracellular sig- with subsequent reports of PML in “In general terms, the ocular toxicity nal pathways that are dysfunctional in patients taking the drug. “No one could profile of mAbs is good,” Dr. Bhatti said. cancer cells. FDA approval of the first have predicted this AE,” Dr. Bhatti said. Example: Ado-trastuzumab emtan- small molecule kinase inhibitor, imati- (Natalizumab isn’t the only mAb to be sine. This drug has been reported to nib, occurred 15 years ago; as of 2016, associated with the risk of PML; others cause dry eye, blurred vision, cataract 30 of these drugs were on the market. include alemtuzumab, bevacizumab, formation, conjunctivitis, photophobia, Example: Crizotinib. In 2 open- brentuximab vedotin, cetuximab, ibri- and lacrimal duct edema. label, randomized trials reported in the tumomab tiuxetan, and rituximab.) Immune checkpoint inhibitors. These package insert for crizotinib, 60%-70% Missing puzzle pieces. The reporting drugs activate the immune system by of patients experienced a “vision disor- of AEs can be “inconsistent and diffi- blocking the immune inhibitory path der” further defined as blurred vision, cult to interpret,”3 Dr. Bhatti cautioned, ways activated by cancer cells. Four diplopia, photophobia, photopsia, re- and information can be missing from drugs in this class are on the market. duced visual acuity, visual impairment, package inserts4 once a drug is on the “Immune checkpoint inhibitors and vitreous floaters. market. have a unique safety profile because the Third-generation aromatase inhibi- immune system is activated, resulting tors. Three FDA-approved third- Selected Toxicity Profiles in immune-related AEs, which are generation aromatase inhibitors (AIs) While molecularly targeted drugs common,” Dr. Bhatti said. This subset are used to treat breast cancer in post- are too numerous to mention in this of AEs occurs in 70% to 90% of patients menopausal patients. Unlike the breast article, the following overview provides and can affect multiple organ systems, cancer drug tamoxifen—which blocks a few examples of ocular toxicity he said. Fortunately, the incidence of estrogen from binding to the estrogen

associated with this new generation ocular AEs associated with these drugs receptor—the third-generation AIs MD Bhatti, M. Tariq

30 • OCTOBER 2017 inactivate the cytochrome P450 enzyme be aware that the long-term prognosis aromatase, thereby reducing production for many patients has dramatically im- Coming in the next of estrogen from androgens. (Note: proved: “While some of these patients ® Tamoxifen is known to cause ocular once had weeks or months to survive, side effects, including cataracts, macu- many are now long-term survivors, lar edema, and retinal deposits.) and proper and timely management Example: Anastrozole. One study of these ocular side effects contributes documented an 11.4% frequency of greatly to the quality of their lives.” Feature retinal hemorrhage in patients taking Dr. Bhatti agreed, and he cited an is- Artificial Intelligence anastrozole.5 All affected patients had sue that needs to be handled with great The AI revolution in health a single hemorrhage. “The authors hy- sensitivity: “These patients often have care is here. A look at how pothesized that a decrease in estrogen all their hopes tied to their medication,” it is beginning to affect level either compromised the vascular he said. “Therefore, stopping treatment ophthalmology. system or resulted in vitreoretinal trac- is a difficult decision, and it cannot be Smartphone tion,” Dr. Bhatti noted. made without the input of the patient Photography and the oncologist.” Fortunately, he How to take great slit-lamp Keeping Current added, “in some cases, the drug can As more cancer drugs are introduced, be successfully continued if a specific photos with your phone. ophthalmologists will be challenged to management plan is instituted.” keep up with their potential ocular AEs. Detailed history. Dr. Bhatti also Clinical Update National registry. Stay informed suggested conducting a detailed history Glaucoma Lancet study through the National Registry of Drug- of patients to discover whether they are results may change standard Induced Ocular Side Effects (www. taking one of the molecularly targeted of care for some primary eyedrugregistry.com), founded in 1976 cancer therapies. “As ophthalmologists, angle-closure glaucoma and supported by the Academy and the we do need to be aware that the field of cases. Casey Eye Institute at Oregon Health & cancer treatment has advanced signifi- Pediatrics Three experts Science University in Portland, Oregon. cantly,” he said. discuss their use of OCT Frederick W. Fraunfelder, MD, MBA, 1 Bhatti MT. Neuro-ophthalmic side effects of for pediatric imaging. at the University of Missouri School of new cancer drugs. Presented at: 43rd Annual Medicine in Columbia, Missouri, and Meeting of the North American Neuro-Ophthal- Savvy Coder director of the Registry, noted that while mology Society; April 6, 2017; Washington, D.C. MIPS the introduction of drugs in some classes 2 Bhatti MT, Salama AKS. Eye (Lond). 2017; in How to avoid the MIPS (such as antibiotics) has slowed down, press. penalty. anticancer drugs have “really exploded” 3 Scharf O, Colevas AD. J Clin Oncol. 2006; onto the market. And given that they 24(24):3933-3938. have different mechanisms of action Practice Perfect 4 Seruga B et al. J Clin Oncol. 2011;29(2):174-185. that can affect the eyes, “there are some Physician Well-Being 5 Eisner A et al. Optom Vis Sci. 2008;85(5):301-308. hidden side effects we are just starting For a long career, develop to uncover,” he said. Dr. Bhatti is chief of the neuro-ophthalmology habits that mitigate stress. Published studies. “It is incumbent division and professor in the departments of upon ophthalmologists to stay current ophthalmology, neurology, and neurosurgery at Blink with high-impact literature, which Duke Eye Center and Duke University Medical Take a guess at the next includes the journals in our profession Center in Durham, N.C. Relevant financial disclo- issue’s mystery image. that affect our patients,” Dr. Fraunfelder sures: Novartis: L; Receptos: C. said. “It is impossible to know every Dr. Fraunfelder is chairman and Roy E. Mason ocular AE of every drug, but we need to and Elizabeth Patee Mason Distinguished For Your Convenience stay current on the big issues.” Professor of Ophthalmology at the University of These stories also will be Missouri School of Medicine in Columbia, Mo. available online at Implications for Practice Relevant financial disclosures: None. aao.org/eyenet. Dr. Salama noted that she has seen Dr. Salama is assistant professor of medicine and patients with uveitis in her medical a member of the Duke Cancer Institute at Duke FOR ADVERTISING INFORMATION oncology practice. University Medical Center in Durham, N.C. Rel- Mark Mrvica or Kelly Miller Collaboration. “It is important that evant financial disclosures: Bristol-Meyers Squibb: ophthalmologists work closely with a C,L,S; Genentech: C,S; Merck: S. Note: All grant M. J. Mrvica Associates Inc. patient’s oncologist should ocular side support paid to Dr. Salama’s institution. 856-768-9360 effects arise,” Dr. Salama said. In addi- See the disclosure key, page 10. For full disclo- [email protected] tion, she said, ophthalmologists should sures, view this article at aao.org/eyenet.

EYENET MAGAZINE • 31 Celebrate the Fun of Mardi Gras Laissez Les Bon Temps Rouler in Support of Academy Programs

2017 Orbital Gala Sunday, Nov. 12 | Mardi Gras World | New Orleans Let the good times roll! Join the American Academy of Ophthalmology Foundation for an evening of fun and fantasy in the heart of the Big Easy. This 14th annual fundraiser will be the premier social event of AAO 2017. Dine, dance, enjoy live entertainment, get great silent auction deals and see Mardi Gras floats up close. Proceeds will support the Academy’s educational, quality of care and service programs.

2017 Honoree: H. Dunbar Hoskins Jr., MD Join us in honoring Dr. Hoskins for his years of service to the Academy and Tickets on sale our profession. Make a tribute gift and May 15 at aao.org/foundation. place a message in his commemorative tribute book.

Foundation LOW VISION CLINICAL UPDATE

Low Vision Drivers: The Ophthalmologist’s Role and Responsibility

ecades ago, acquiring or retain ing a driver’s license would have 1 Dbeen a significant challenge or improbability for individuals with mild to moderate vision loss. Today, thanks to expanded vision standards for driv ing in licensing jurisdictions across the United States, many candidates with low vision can now qualify and apply for (at least restrictive) driving privi leges. The decision to commence—or con tinue—driving must be made based on a discussion between the individual, an ophthalmologist, a driver rehabilitation specialist or driving instructor, and the BIOPTIC LENS. A binocular-mounted dual-lens system is used for visual assistance in state licensing authority. “Although it driving. The driver is using the telescopic unit for short-term vertical spotting to re- may be tempting to tell some patients solve distant detail, color, or movement of objects or forms in her dynamic driving that they cannot drive, this decision environment. must be considered carefully because driving privileges should not be with take appropriate action. Many individ a small telescopic unit mounted onto a held without clear justification,” said uals with mild to moderate visual acuity pair of eyeglasses (carrier lens), slightly John D. Shepherd MD, at the University (VA) loss are capable of recognizing above an individual’s natural sightline of Nebraska Medical Center in Omaha. these cues; however, due to reduced (Fig. 1). The driver looks through the Ophthalmologists have multiple central VA, identifying or interpreting carrier lens about 95% of the total responsibilities to low vision patients them may be a challenge. “With the aid driving time. The telescope is used who are seeking licensure, including of a bioptic lens and specialized driver intermittently and for brief fractions assessment, education, and referrals— training, many of these individuals can of a second for glimpsing detail, color, and, in some cases, discussion about learn to drive safely,” said driver reha or activity in the field of view and the use of a bioptic lens system. bilitation specialist Charles P. Huss for spotting road signs, traffic lights, COMS, who estimated that there are pedestrians, or motor vehicles that The Bioptic Lens System approximately 8,000 to 10,000 persons are 20 feet distant or farther. Viewing Why a bioptic lens? In order to safely in the United States who are currently through the telescope is only undertaken operate a vehicle, drivers must be able licensed bioptic drivers. when the car is on straight sections of to identify cues within their visual field, How the lens works. A bioptic lens a roadway and when other cars are at a accurately assess this information, and is a dual-optic lens system consisting of safe distance. Using the telescopic lens is not as easy as putting on a pair of glasses BY LESLIE BURLING-PHILLIPS, INTERVIEWING RHONDA DALYAI, MA, TVI, and shifting the car into drive, how CDI, CHARLES P. HUSS, COMS, CYNTHIA OWSLEY, PHD, MSPH, AND JOHN ever. Viewing through the miniature

Susan A. Patterson, COMS Susan A. Patterson, D. SHEPHERD, MD. magnifying unit, even though briefly,

EYENET MAGAZINE • 33 can present 2 problems to new users, ple, key differences include the mini ogists must assess and guide these according to Dr. Shepherd: It can cause mum level of VA allowed; the degree patients as well. a pericentral scotoma, and it causes of horizontal visual field required; the Identify patients who do not meet apparent motion. The latter, he said, maximum amount of telescopic mag the visual requirements for driving. “is exacerbated by a moving vehicle nification permitted; whether or not When you recognize that a patient may and can be quite disturbing to a novice night driving and interstate driving are not qualify for state licensure, “discuss user. It is therefore imperative to train permitted; and the type and extent of the legality of driving and issues that individuals in both stationary and adaptive driver’s training that is need may compromise safety for driving, moving environments to ensure that ed. “Ophthalmologists should know which will make a difference in terms they can benefit from the bioptic lens the visual requirements for licensing of whether an individual should be for driving.” in their state and be able to educate licensed or not. All recommendations Using the lens. The driver training their patients about bioptic driving should be documented in the medical requirements for bioptic lenses vary, when relevant. The requirements can record,” said Dr. Shepherd. but most states require extensive train be found online at your state’s licensing Recognize the distinction between ing and a rigorous assessment upon bureau,” said Cynthia Owsley, PhD, legal and safe. Even if an individual completion. For example, West Virgin MSPH, at the University of Alabama at passes the tests needed to drive, this ia’s program is a 6-week course that Birmingham. does not necessarily mean that they are involves 90 hours of training evenly Inform viable candidates about safe to drive. Much more is involved divided between classroom instruction, bioptic driving. Bioptic driving can be than maintaining the legal VA and VF. passenger-in-car related instruction, prescribed for a range of diseases and Driving also requires the sensory ability and on-road driving instruction. Prior conditions, but most suitable candidates to perceive changes in a rapidly chang to graduation, students must pass a have mild to moderate central vision ing environment, the mental ability to standardized 40-mile, 80-minute on- loss with a VA of 20/50 to 20/200 and a judge this information in a timely fash road driving assessment on a variety of stable ocular condition. Additional ion and to make appropriate decisions, roadways and under several conditions factors that make an individual a good and the motor ability to execute those (e.g. bright sun, overcast, rain, light to candidate for the bioptic system include: decisions. All are important factors heavy traffic). • Full or relatively full visual fields (VFs) when assessing who is safe to drive. Rhonda Dalyai, MA, TVI, CDI, a • Acuity that can be improved with a 4X While someone might meet the visual West Virginia driving instructor to those telescope or less (varies by state) requirements, a prolonged reaction with low vision, said, “We help clients • Not light sensitive time or impaired motor ability (e.g., with a wide variety of visual issues and • Good contrast sensitivity arthritis) could make it inadvisable to diagnoses. Based on their needs, we try • Good glare recovery skills issue a driver’s license because it could to accommodate and assist them with • Good color vision potentially be unsafe. what will work best for them in the • Normal head, neck, and eye movement Look for red flags.Some patients dynamic driving environment.” • Normal bilateral hearing may meet the visual requirements The research shows that, once trained • Average or above-average intelligence for driving, but they may have other and licensed, bioptic drivers find the • Free of visual attention deficits (i.e., visual problems or physical or cog device helpful;1 they have personal reduced speed of visual processing, nitive impairments that could affect insight about any driving deficiencies reduced ability to divide attention, and their driving. According to Mr. Huss, they may have;2 and they are no more reduced selective attention) ophthalmologists should be alert to the likely than their nonbioptic counter • Highly motivated, dedicated, goal warning signs and recommend driving parts to receive a traffic offence or be oriented cessation or refer the patient for further involved in collisions.3,4 (Mr. Huss • Able to accept objective criticism evaluation if there is evidence of slow suggests finding a driver rehabilitation • Emotionally stable reaction rates, cognitive decline, signif specialist at www.aded.net.) • Prior driving experience, or a realistic icant VA or VF loss, contrast sensitivity Know your state’s visual require- grasp on the concept of driving and its loss, reduced glare recovery, or poor ments for driving. “As many as 23 responsibilities night vision, or if driving tasks are states now license people down to, and • Has participated in sports or recre becoming challenging. including, the 20/200 level, which is a ational activities that require forward Dr. Shepherd noted that it is import dramatic shift in what was thought fea scanning (i.e., looking ahead to where ant to remember that the final respon sible 50 years ago,” said Mr. Huss, who your body will be in the next few sec sibility of issuing a driver’s license rests is based in West Virginia. While many onds), lateral head and eye scanning, with the state driver licensing authority. states offer some type of bioptic driving and object avoidance. If there is any question about a patient’s licensure, Connecticut and Utah do not ability, he said, “it is the prerogative of allow it in any form. When a Lens May Not Work the ophthalmologist to appeal to the Among the states that do permit the Not all low vision patients will qualify licensing authority for a behind-the- device, the laws vary widely. For exam for a bioptic lens, and ophthalmol wheel evaluation for the patient.”

34 • OCTOBER 2017 Suggest alternative transportation. It is important to remain sensitive when discussing driving cessation with a patient. Suggesting alternative trans portation should be part of the discus sion with those who do not qualify for a driver’s license. For example: getting rides with family and friends, taxi ser vices, Uber or Lyft, shuttle buses, and public transportation are all common choices. “Local agencies on aging and rehabilitation are usually great resourc es for transportation options that exist in a community. Encourage the visually impaired individual and their family members to tap these resources as well,” High-quality said Dr. Owsley. research from the “If a patient comes to me with the expectation that a bioptic lens will help world’s leading them to drive and they are not a good candidate, I have found that putting the ophthalmic journal costs into perspective helps. In addition to the costs of the bioptic telescope and driver’s training, there are the costs of owning and operating a motor vehicle, including auto insurance, car mainte nance and repairs, licensing and title, and gasoline. In reality, the amount of money saved can provide a lot of alternative transportation,” said Dr. Shepherd.

1 Bowers AR et al. Invest Ophthalmol Vis Sci. 2005;46(1):66-74. 2 Owsley C et al. Invest Ophthalmol Vis Sci. 2014; The Academy’s newest scientific 55:330-336. publication, Ophthalmology® 3 Wood JM et al. Invest Ophthalmol Vis Sci. 2013; 54:3790-3797. Retina, focuses on advances in 4 Vincent C et al. Assistive Technology. 2012;24(3): medical drug treatment, surgery 184-195. and technology for retina-related Ms. Dalyai is a certified teacher of the visually disesases and conditions. impaired and certified driving instructor at the West Virginia Division of Rehabilitation Services, Nitro, W.V. Relevant financial disclosures: None. Subscribe at aao.org/store. Mr. Huss is a driver rehabilitation specialist at the West Virginia Division of Rehabilitation, Nitro, W.V. Relevant financial disclosures: None. Dr. Owsley is professor and vice chair for research administration in the department of ophthalmology at the University of Alabama at Birmingham. Relevant financial disclosures: None. Dr. Shepherd is director of the Weigel Williamson Center for Visual Rehabilitation and assistant professor of ophthalmology at the University of Nebraska Medical Center in Omaha. Relevant financial disclosures: None.

EYENET MAGAZINE • 35 Join William L. Rich III, MD, FACS in Supporting Academy Programs

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Foundation LENS AND CATARACT OPHTHALMIC PEARLS

Diagnosis and Management of Posteriorly Dislocated Lenses

he crystalline lens is normally Risk Factors held in a stable intraocular Risk factors may be divided broadly Tposition by zonular fibers that into congenital or acquired categories. connect to the ciliary body and attach In systemic disorders, dislocation is circumferentially to the equatorial usually bilateral. region of the lens capsule. Similarly, Congenital. Systemic. Marfan syn- placement of an intraocular lens (IOL) drome, which is a systemic connective into the capsule after cataract removal tissue disorder, is the most common provides anatomical support to the congenital cause of crystalline lens IOL. However, damage to the zonular- dislocation. A mutation in the FBN1 capsular complex from trauma or gene renders the zonules weak and lax, disease can lead to structural weakness leading to lens subluxation or disloca- and loss of lens stability. Severity may tion, classically in the superotemporal range from mild phacodonesis or direction. DISPLACED IOL. Fundus photograph pseudophacodonesis to partial sub Homocystinuria, the second most shows a posteriorly dislocated intraoc- luxation and even complete lens dis common congenital cause, is associated ular lens with the capsular bag in the location, into either the anterior with brittle zonules, which can result vitreous. or posterior segment. in inferonasal lens subluxation or An anteriorly dislocated crystalline dislocation. injury, trauma may be associated with lens or IOL is often considered to be an Other important congenital etiolo- multiple other complex injuries such as ocular emergency because of the risk of gies include Weill-Marchesani syndrome, retinal detachment, intraocular foreign lens-induced angle-closure glaucoma sulfite oxidase deficiency, hyperlysin- bodies, and corneoscleral laceration, and corneal damage. emia, and congenital ectopia lentis et leading to difficulties in surgical repair In contrast, posterior dislocation pupillae. and visual rehabilitation. usually involves comanagement with Ocular. Pseudoexfoliation syn- Even if frank phacodonesis is not a vitreoretinal surgeon for consider- drome, associated with a mutation apparent immediately after the trauma, ation of vitrectomy and removal of the in the LOXL1 gene, can cause repet- such patients are at higher risk of sub- dislocated lens or IOL through a pars itive chafing of the midperipheral sequently developing progressive zonu- plana approach. If the posteriorly dislo- iris against lens zonules, leading to lar dehiscence. cated crystalline lens is intact, it may be phacodonesis and increased risks of Myopia. Pathologic axial myopia is observed in some cases. Some eyes with iatrogenic zonulysis during phacoemul- another important underlying etiology posteriorly dislocated lens or IOL may sification. associated with acquired lens dislo- be left aphakic. Acquired. Trauma. Ocular trauma cation. It is especially relevant in the In this article, we focus on the diag- is a common cause of acquired poste- context of an East Asian population, nosis and management of posteriorly rior lens dislocation. Whether it occurs owing to the prevalence of high myopia dislocated crystalline lenses and IOLs. in the form of closed- or open-globe in this group. Axial myopia inherently predisposes to zonular instability; in addition, BY YU QIANG SOH, MD, DANIEL S.W. TING, MD, PHD, AND EDMUND Y.M. myopia increases the risk of retinal WONG, FRCS(ED). EDITED BY SHARON FEKRAT, MD, AND INGRID U. SCOTT, detachment, and reparative vitreo

Kasi Sandhanam and Joseph Ho, Singapore National Eye Centre Eye National Singapore Sandhanam and Joseph Ho, Kasi MD, PHD. retinal surgery may further weaken

EYENET MAGAZINE • 37 the zonular-capsular complex. the-bag dislocations suggest zonular a dislocated crystalline lens, a frag- Inflammation.Persistent intraocular weakness, whether primary or second- matome is inserted via a pars plana inflammation secondary to chronic ary, while out-of-the-bag dislocations incision. The cataract or clear lens is uveitic conditions may similarly result are often associated with posterior cap- emulsified in the midvitreous cavity in weakening of lens zonules. sular rupture during cataract surgery or using ultrasound. other trauma. Removal of the IOL. In the case of Clinical Presentations Systemic evaluation. A thorough a posteriorly dislocated IOL, levitation The patient may experience posture- systemic examination is helpful in iden- of the IOL into the anterior chamber dependent visual fluctuation, ocular tifying characteristic features suggestive can be performed using end-gripping pain, or headache from intermittent of connective tissue diseases, for exam- intraocular vitrectomy forceps. angle closure or intraocular inflam- ple, the tall, lean habitus, hyperflexible Flexible IOLs can be cut with an mation preceding the occurrence of joints, and cardiovascular anomalies IOL cutter in the anterior chamber lenticular dislocation into the vitreous associated with Marfan syndrome. under dispersive viscoelastic cover and cavity. removed via a corneal or sclerocorneal After posterior lens dislocation, Conservative Management incision. Care must be taken to avoid visual changes may range from a In the absence of sight-threatening trauma to the cornea, iris, and angles. sudden decrease in visual acuity (VA) complications such as elevated IOP or Rigid IOLs are usually removed due to the loss of lenticular refractive corneal decompensation, conservative through a larger scleral tunnel or power to a sudden improvement in VA management may be an appropriate sclerocorneal incision. secondary to a significant reduction choice, especially for patients who have Secondary IOL implantation. In in refractive error in a phakic myopic good vision in the fellow eye or are the absence of capsular support, the patient. medically unfit for surgery. Such pa- secondary IOL can be inserted into There may also be complaints of a tients may be fitted with a contact lens either the anterior or posterior cham- “floater,” often in the superior visual for visual rehabilitation. ber. The choice of techniques is highly field, corresponding to the dislocated Follow-up needed. However, the dependent on patient, ocular, and sur- crystalline lens or IOL settling in a ophthalmologist should perform reg geon factors. Corneal, scleral, and iris dependent position within the vitreous ular clinical follow-up and remain conditions (e.g., atrophy or traumatic cavity. vigilant for possible sequelae that might aniridia) must be considered carefully When assessing such symptoms, indicate a need for surgical interven- to determine the appropriate method. especially in the presence of the risk tion. These include increased intraocu- Anterior chamber placement. Im- factors mentioned above, the ophthal- lar pressure (IOP), bullous keratopathy, plantation of an anterior chamber IOL mologist should maintain a high index cystoid macular edema, retinal break, (ACIOL), with fixation in the angle, of suspicion for lenticular dislocation and retinal detachment. Patients who is relatively quick, very stable, and and investigate further to ascertain the have high IOP should be referred to a less technically demanding than the diagnosis. glaucoma specialist. other techniques. However, even with Endothelial cell count and central modern open-loop ACIOL models, Evaluation cornea thickness measurement are use- angle-supported IOLs are associated In a patient with posterior lens disloca- ful for monitoring corneal health. with potential long-term risks such as tion, clinical evaluation and investiga- corneal endothelial decompensation, tion should be directed at identifying Surgery glaucoma, and persistent intraocular the underlying etiology, evaluating In patients who have complications inflammation.1 the need for surgical intervention, and or bothersome symptoms, the typical Posterior chamber placement. Many planning for surgical or optical rehabil- approach involves pars plana vitrecto- of the complications associated with itation. my (PPV) and removal of the dislo- ACIOLs can be avoided with use of Clinical exam. Detailed examina- cated lens, followed by secondary IOL retropupillary placement. The IOL may tion of the anterior segment should be implantation. be placed in the posterior chamber with performed, including the conjunctiva, PPV. Using a standard 3-port vit- either iris or scleral fixation. However, sclera, cornea, angles, and iris. Dilated rectomy setup, the surgeon performs these posterior chamber techniques posterior segment examination with an anterior and core vitrectomy to are more surgically challenging and scleral depression, including assessment gain access to the posteriorly dislo- time-consuming, and are generally less of the lens capsule, vitreous, and retina, cated crystalline lens or IOL-capsule stable, than ACIOL implantation. is essential. Ultrasound B scan or, occa- complex. Ideally, posterior vitreous Several variants of scleral fixation sionally, ultrasound biomicroscopy may detachment is induced (if not already have been described,2-4 wherein the be useful for locating a lens posteriorly present) and completed before the lens IOL haptics are either externalized and dislocated behind the iris around the is manipulated to minimize unintended fixated intrasclerally or are secured vitreous base. vitreoretinal traction. intraocularly via nonabsorbable transs- In or out of the capsular bag? In- Removal of the crystalline lens. For cleral fixation sutures.

38 • OCTOBER 2017 Conclusion Lenticular instability leading to posterior subluxation or dislocation is a relatively common problem encountered in the practice of general ophthalmology. With timely detection and intervention, many of the potential complications can be avoided. Careful preoperative planning and intraoperative assessment of ocular and patient factors are essential to achieve excellent EyeNet outcomes.

1 Drolsum L. J Cataract Refract Surg. 2003;29(3): 498-503. Corporate 2 Todorich B et al. Ocul Immunol Inflamm. Pub- lished online Oct. 11, 2016. doi:10.1080/0927394 8.2016.1231328. Lunches 3 El Gendy HA et al. J Ophthalmol. Published online Aug. 10, 2016. www.ncbi.nlm.nih.gov/ EyeNet® Magazine helps you make pmc/articles/PMC4995346/. 4 McAllister AS, Hirst LW. J Cataract Refract the most of your time at AAO 2017 Surg. 2011;37(7):1263-1269. by bringing you free corporate educational program lunches* Dr. Soh is an ophthalmology resident at Singa- onsite at the Ernest N. Morial pore National Eye Centre. Dr. Ting is an associate consultant in the Singapore National Eye Centre Convention Center. and assistant professor at the Duke-National University Singapore (NUS) Medical School. Dr. Wong is the head of the surgical retina department in the Singapore National Eye Centre and an adjunct associate professor at the Duke-NUS Medical School. Relevant financial disclosures: None. Saturday, Nov. 11, Sunday, Nov. 12, and Monday, Nov. 13 MORE AT THE MEETING Room R02-04, 2nd Floor Ernest N. Morial Convention Center Expand your techniques for managing Check-in and Lunch IOLs that are malposi- 12:15-12:30 p.m. Lunches are provided on tioned or lack capsular sup- a first-come basis, so be sure to arrive on port with the following events. time to secure your meal and seat. An Innovative Approach to Iris Fixation of an IOL Without Cap- Programs sular Support (Lab117). When: 12:30-1:30 p.m. Sunday, Nov. 12, 10:00-11:00 a.m. Where: Room 350. Access: Ticket required. (Also presented For updated program information: as Lab126 on Nov. 12, 11:30 a.m.- aao.org/eyenet/corporate-events 12:30 p.m., in the same location.) * These programs are non-CME and are developed independently by Management of Malpositioned industry. They are not affiliated with the official program of AAO 2017 or IOLs (431). When: Monday, Nov. Subspecialty Day. By attending a lunch, you may be subject to reporting 13, 9:00-11:15 a.m. Where: Room under the Physician Payment Sunshine Act. 383. Access: Academy Plus course pass required.

EYENET MAGAZINE • 39 Unlock Your Clinic’s Full Potential with Lean Practice Management

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“ After three months [using lean], our practice saw 23 percent growth.” JOSE AGUSTIN MARTINEZ MD AUSTIN RETINA ASSOCIATES

BC-1998 American Academy of Ophthalmic Executives® WHAT’S YOUR DIAGNOSIS? MORNING ROUNDS

The Case of a Second-Look Surprise

ne Friday afternoon, after 2 We Get a Look 1 days of gradually increasing Ms. McGuire told us that she had never Opain, redness, and blurry experienced such symptoms before vision in her right eye, Meryl McGuire,* this episode. In addition to her con- the 62-year-old director of her county’s cerns about visual loss and increasing beautification department, decided to eye pain, she was worried about the see her optometrist. possibility of needing an intraocular injection or laser treatment for neovas- Initial Office Visit cular glaucoma. Ms. McGuire described the vision in In our examination, we noted her right eye as being “greased over,” vessels on the iris (Fig. 1). Gonioscopy and she felt as if the eye was swollen. revealed microhyphema, grade III-IV She reported having pain in that eye as angles, and fine blood vessels in the well as intermittent severe headaches angle. No iris nodules or transillumi- concentrated around it. nation defects were apparent. We also History. The patient’s ocular history found 4+ cells in the anterior chamber, was significant for chronic low-grade which appeared to comprise both red iritis in the right eye, which had been blood cells and white blood cells. Cor- EXAM FINDING. Iris vessels were noted stable for many years, and uncompli- neal examination revealed fine keratic at the pupillary margin in the right eye. cated cataract surgery in both eyes a precipitates. few years ago. Her medical history was Dilated fundus exam of both eyes by many conditions; the most common significant for diabetes mellitus, which revealed optic nerves with a cup-disc include diabetic retinopathy, retinal was under good control. ratio of 0.4, normal macula, vessels, vascular occlusion, and carotid artery Findings from the first exam.When and periphery. There was no evidence occlusive disease. Given the patient’s examined at her optometrist’s office, of retinal vascular attenuation, hemor- normal fundus exam, we considered Ms. McGuire had visual acuity of 20/30 rhages, neovascularization, or chorio- uveitis to be the most likely cause of the in the right eye and 20/20 in the left. retinal scars in either eye. neovascularization. There was no relative afferent pupillary A second look. However, when we defect. Confrontation visual fields were Making the Diagnosis stepped back and looked again at our full in both eyes, and motility was in- The presence of abnormal vessels on patient, we noted that her right iris had tact. She had 3+ conjunctival injection the iris and in the iridocorneal an- a lighter color than the left (Fig. 2). in the right eye. Intraocular pressure gles, together with increased IOP, was When we mentioned this, Ms. McGuire (IOP) was 50 mm Hg in the right eye certainly suggestive of neovascular recalled that she had been noted to and 20 mm Hg in the left. glaucoma. Neovascularization of the have different-colored eyes, depending Her optometrist noted neovascu- iris and angle typically develops as a on the ambient light, for most of her larization of the iris in the right eye result of elevated levels of vascular adult life. With this information, we and, suspecting neovascular glaucoma, endothelial growth factor from retinal arrived at a diagnosis of Fuchs hetero- emergently referred the patient to us. ischemia.1 The ischemia can be caused chromic iridocyclitis (FHI), as she had some of the hallmarks of this condition, including fine keratic precipitates, iris

Mohan N. Iyer, MD Mohan N. Iyer, BY THAO LE AND MOHAN N. IYER, MD. EDITED BY STEVEN J. GEDDE, MD. heterochromia, prior cataract, and fine

EYENET MAGAZINE • 41 vessels on the iris surface and in the 2 iridocorneal angle. We contacted her optometrist and learned that she had indeed been diagnosed with FHI approximately 10 years ago. During that time, she had undergone a laboratory workup for uveitis, which was negative.

Discussion FHI accounts for 1% to 3% of all ON SECOND LOOK. Iris heterochromia, with the lighter-colored (bluer) iris in the uveitides; the actual prevalence may be affected right eye. The difference is more noticeable when viewed in daylight (top) higher, as it often goes undiagnosed. It than in the lighting of the exam room (bottom). is commonly diagnosed in the third to fourth decades of life, and there is no factors contributing to increased IOP prescribed dorzolamide-timolol and racial or sex predilection. include anterior synechiae formation, brimonidine 0.2% drops and, given the In 1906, the Austrian ophthalmolo- abnormal angle vessels, trabecular presence of microhyphema, a tapering gist Ernst Fuchs described the first large scarring, corticosteroid-induced ocular course of topical steroid eyedrops. series of patients with chronic, typically hypertension, and hyphema. When Ms. McGuire returned for unilateral inflammation and cataract It is sometimes difficult to clinically follow-up 3 days later, her IOP had affecting the lighter-colored eye. Dr. distinguish FHI with secondary glau decreased to 19 mm Hg in the right Fuchs hypothesized that the normal de- coma from Posner-Schlossman syn eye, and the inflammation and con- velopment of uveal pigmentation was drome, a condition characterized by junctival injection had improved. She inhibited, leading to iris heterochromia, recurrent glaucomatocyclitic crises and was happy to report that her vision was followed by a low-grade inflammation. the occasional finding of iris hetero better and the eye pain and redness had Possible etiologies. Since then, chromia. However, the glaucoma resolved—and she was particularly re- several theories regarding the etiology associated with Posner-Schlossman lieved to know that she did not require have been proposed, including hered- syndrome is thought to be related to an intraocular injection or laser. ity; adrenergic denervation; infection trabeculitis and responds rapidly to by Toxoplasma gondii, rubella virus, low-dose topical steroid treatment, *Patient name is fictitious. or herpes simplex virus; immunologic while the glaucoma in FHI is typically 1 Sivak-Callcott JA et al. Ophthalmology. 2001; response; and ocular trauma.2 Although unresponsive to topical steroid therapy. 108(10):1767-1778. many associations have been made, the Hyphema. It is unclear whether the 2 Jones NP. Surv Ophthalmol. 1993;37(4):253-272. exact etiology of FHI has not been con- vessels on the iris and in the irido- firmed and may well be multifactorial; corneal angle are truly neovascular or Ms. Le is a premedical student and a recent grad- therefore, the diagnosis of FHI is based simply abnormal iris vasculature, but uate of the University of Georgia. Dr. Iyer is in on clinical findings. they can bleed easily. Amsler’s sign (a private practice at Athens Retina Center, Athens, Characteristics. Classic clinical hyphema that occurs when the vessels Ga., and affiliated with the Augusta University/ findings of FHI include iris hetero in the angle are disturbed during University of Georgia Medical Partnership. Rele- chromia and atrophy; fine, stellate, paracentesis) may be present in FHI. vant financial disclosures: None. keratic precipitates; vitreous floaters, Hyphema has also been reported after cells, or debris; fine vessels on the iris gonioscopy, applanation tonometry, surface and in the angle; cataract; and mydriasis, and even spontaneously MORE AT low-grade iridocyclitis. The degree of or—more likely—from minor trau- THE MEETING heterochromia can be variable, but it ma associated with eye rubbing. Test your diagnostic is an important feature. The differen- In contrast to typical anterior skills at these case- tial diagnosis for iris heterochromia uveitis, symptoms of pain, photo study symposia: includes congenital Horner syndrome, phobia, and redness are usually absent “Diagnose This” Live Waardenburg syndrome, diffuse iris in FHI. In Ms. McGuire’s case, we (Sym60). When: Saturday, Nov. melanoma, oculodermal melanosis, hypothesized that intraocular bleeding 11, 2:00-4:00 p.m. Where: Room and herpes simplex uveitis. led to the marked increase in IOP and 275. Access: Free. Secondary and related conditions. associated ocular pain and congestion. Grand Rounds: Cases and FHI is often associated with secondary Experts From Across the Nation cataract and glaucoma. In most cases, Our Patient’s Course (Sym15) . When: Sunday, Nov. 12, the glaucoma is associated with an We instilled glaucoma drops in Ms. 2:00-3:15 p.m. Where: La Nou- open angle and is thought to occur as a McGuire’s right eye and noted that velle Orleans C. Access: Free.

result of chronic inflammation. Other the IOP started trending down. We MD Mohan N. Iyer,

42 • OCTOBER 2017

44 • OCTOBER 2017 The Lowdown on High-Tech IOLs

Peek at several IOL technologies that your international colleagues are using.

By Annie Stuart, Contributing Writer

ATARACT SURGERY HAS COME A LONG WAY SINCE THE EARLY 1980S, when the FDA first approved intraocular lenses (IOLs) for use in the United States. CSince that time, patient interest in personalized visual solutions has mushroomed, and the market has responded with a great diversity of designs, materials, and approaches. However, much of that innovation reaches international markets before it comes to the United States. For curious U.S. ophthalmologists, EyeNet offers an armchair traveler’s look at several lenses available abroad that represent a potentially significant advance in IOL technol ogy. In the opinion of EyeNet Cataract Section Editor Kevin M. Miller, MD, new and inno vative IOLs include the Alcon IQ PanOptix trifocal; Zeiss AT LISA trifocal and trifocal toric IOL; RxSight Light Adjustable Lens; Morcher Xtra Focus Pinhole aperture IOL; and Rayner Sulcoflex IOL. Below, international and U.S. ophthalmologists talk about their experiences with and insights about these and similar lenses. Although Dr. Miller noted that many accommodative lenses are also in the pipeline, he did not include any in his list, as all are a long way from possible introduction in the United States. In fact, the lenses mentioned in this article aren’t guaranteed to achieve FDA approval

Alfred T. Kamajian T. Alfred in the United States—though some have completed or are about to start clinical trials, possi bly paving their way for introduction into American practices.

EYENET MAGAZINE • 45 Trifocal Lenses: you’re reading, the pupil constricts.” When the pupil The Promise of Spectacle Independence aperture becomes larger, added Dr. Kanellopoulos, the With increasing use of computers, tablets, and smart peripheral steps are progressively exposed, with increas phones in recent years, more patients desire better ing amounts of light available for distance vision and intermediate vision. This also happens to be the range less light dedicated to the near and intermediate focal of vision essential for activities such as cooking, garden points. “This gradual decrease of the step height from ing, and viewing the speedometer in a car, said A. John center to periphery has been shown to reduce halos, Kanellopoulos, MD, who practices in Athens, Greece, which are generated by defocused light under mesopic and in New York City. The development of trifocal IOLs and scotopic light conditions,” he said. has gone a long way in addressing this need. By the end of 2017, the FineVision trifocal will be Lens design. Diffractive multifocal lenses work based available in a hydrophobic material, said Dr. Daya. “This on a diffractive optical element on an intraocular lens material helps prevent capsular opacification and that also provides a different point of focus on the optical secures the IOL in the eye, reducing tilting or shifting, axis, said Sheraz M. Daya, MD, at the Centre for Sight which is important because any tilt whatsoever with in East Grinstead, United Kingdom. Because they are trifocals decreases functionality.” diffractive, he said, they have properties of constructive AT LISA. With a plate haptic design and preloaded interference, creating several focal points depending on into an injector, the AT LISA uses a diffractive pattern the diffractive order. that provides trifocal function only over the central “This design is quite clever because the second order 4.34-mm region of the IOL, of the intermediate range (+1.75 with FineVision, for with a more conventional example) doubles and coincides with the reading addi bifocal diffractive pattern tion (+3.50), thus harnessing light that would otherwise extending from 4.34 mm to be lost and adding to the focal point at near,” said Dr. 6.0 mm diameter, said Dr. Daya. “In the past, it was thought that bifocality was the Kanellopoulos. “Differing ultimate because interfering with another focal point— from the FineVision, the adding a third point of focus—would cause visual ab trifocal diffractive structure asymmetrically directs in normalities, such as halos and vision disturbances when cident light to distant (50%), intermediate (20%), and driving. As it turns out, that’s not the case.” near (30%) focal points, independent of pupil diameter With trifocal IOLs, said Dr. Kanellopoulos, the dif (up to 4.5 mm),” he said. fractive pattern manipulates the light so that a portion AcrySof IQ PanOptix. “For simplicity’s sake, this of the light energy is taken to a different focus or to one IOL can be viewed as a quadrifocal IOL manipulated to of the principal foci so it is not lost, as happens with act as a trifocal,” said Dr. Kanellopoulos. The extended conventional diffractive bifocal designs. intermediate focal point These are 3 of the trifocal IOLs now available outside (120 cm) is redistributed to the United States—the FineVision trifocal lens (Phys the distance focal point for IOL), AT LISA trifocal IOL (Carl Zeiss Meditec), and amplified performance and AcrySof IQ PanOptix (Alcon). results in the creation of 3 All 3 companies now offer toric trifocals, which foci: distance, intermediate correct astigmatism in addition to other refractive errors. at 60 cm, and near at 40 cm, This reduces the need for additional surgical procedures he said. “At a 3-mm pupil diameter, PanOptix transmits such as relaxing incisions, LASIK, PRK, or asigmatic 88% of light to the retina, possibly more light than the keratotomy. Dr. Daya uses a femtosecond laser to cor FineVision and AT LISA,” said Dr. Kanellopoulos. rect astigmatism up to 1.5 D. “Past that point, I choose Benefits and best candidates.Trifocals are the best a toric lens,” he said. choice for patients with bilateral cataracts who desire FineVision. Codesigned by Damien Gatinel, MD, at spectacle independence, said Tim Schultz, MD, at the Rothschild Ophthalmology Foundation in Paris, the Ruhr University Eye Hospital in Bochum, North Rhine- first trifocal lens on the market contains 2 overlapping Westphalia, Germany. For instance, studies have shown diffractive zones (1 for distance and near vision and 1 for that more than 95% of patients with trifocal IOLs distance and intermediate focus) of more than 30 optical become spectacle independent.1-3 “Especially under steps, thus decreasing in height from the center of the good light conditions, patients are happy,” he said. “The lens to the periphery, said newer toric versions are also getting very good results Dr. Kanellopoulos. for distance, intermediate, and near vision in patients “The apodized surface with astigmatism.”4 provides a higher power The lenses can benefit anyone without a contrain for reading at its center,” dication for a multifocal lens, added Dr. Daya, such as said Dr. Daya, “which macular degeneration, advanced glaucoma, or increased makes sense because when risk for diabetic retinopathy. “In my practice, more than

46 • OCTOBER 2017 95% of patients receive a trifocal lens, including my “But with RxSight’s Light Adjustable Lens (RxLAL), we 87-year-old mother.” Patient satisfaction appears to be can now do an office-based alignment after surgery and much better than with older models of bifocal IOLs, get the refraction the patients want.” added Dr. Kanellopoulos, but larger prospective studies Lens design. Codeveloped by Daniel M. Schwartz, will offer more concrete data. MD, founder of RxSight (formerly Calhoun Vision) in Potential challenges. As with many lenses, there are Pasadena, California, the lens has a foldable, 3-piece challenges with trifocal IOLs. silicone platform with a 6-mm, square-edged optic, said Communicating with patients. Patient preparation Dr. Schultz. The lens ma is key, said Dr. Schultz. It’s important to counsel patients terial is a flexible silicone so they know what to expect. polymer matrix with Surgical challenges. There is a learning curve in mobile, photosensitive adjusting the A-constant because it is different from macromers. the one surgeons are accustomed to using, said Dr. About 2-4 weeks after Kanellopoulos. Since keratometry and biometry are surgery, when wound quite challenging, surgeons can employ intraoperative healing is complete, the physician does a simple office aberrometry for better outcomes. In addition, said Dr. procedure, which takes just a few minutes, said Dr. Schultz, in very high myopes with astigmatism, the toric Schultz. The physician uses a small contact lens to versions of the IOL can potentially rotate. A capsule stabilize the eye and applies a cool, low-intensity beam tension ring may reduce rotations in these eyes. of ultraviolet (UV) light, using a digital light source Visual outcomes. Although light allocation and the similar to a slit lamp. Where light strikes, macromers introduction of a third focal point with trifocal IOLs respond, adding thickness and reshaping the lens. may provide a wide range of vision, these features could “Working with the patient, you can try different also impact the quality of near and distance vision, said refractions until you achieve the ideal prescription,” Dr. Kanellopoulos. “Emmetropia is quite crucial in the said Dr. Schultz, “and then lock it in with another dose success of these lenses. Even small residual refractive of light to the whole optic.” Steven D. Vold, MD, of errors can limit visual performance and may require Vold Vision in Fayetteville, Arkansas, implanted many enhancements with laser vision correction (LVC).” RxLALs during a U.S. clinical trial in which physicians Additionally, some patients cannot tolerate the retina’s did 2 adjustments and 2 lock-in sessions to ensure the process of neurally adapting to multiple images, he power didn’t shift. said, and this may require that the IOL be explanted Dr. Vold suspects this and exchanged. protocol will eventually Visual side effects. Compromise of the posterior evolve to minimize the capsule is a relative contraindication to using the tri number of office visits focal lenses, as all 3 models are single-piece foldable for required. endocapsular implantation, said Dr. Kannelopoulos. Benefits and best Glare, halos, ghost images, and asthenopia are other candidates. As it pro possible side effects, although Dr. Daya has not had to vides 2 D of correction explant lenses on account of unbearable night vision Light-adjustable lens 7 years for hyperopia, myopia, troubles. When it comes to night vision, however, it after implantation. and astigmatism, the may still be somewhat challenging to read very small lens can be used with letters in dim light, added Dr. Schultz. most patients, said Dr. Schultz, who is part of Burkhard Current status. In 2010, the FineVision IOL was Dick’s and Fritz Hengerer’s group, which has used it the first trifocal to be introduced, but all 3 of these with more than 400 patients and achieved excellent models are now used widely around the world, said Dr. outcomes. The lens is best, however, for those who have Kannelopoulos. Despite some minor differences, he a clear idea of the activities they want to do after sur said, several peer-reviewed reports have found generally gery, he said. In addition, it may be particularly helpful similar clinical results for these trifocal IOLs. in correcting residual astigmatism, whether naturally Although the FDA approved the first extended- occurring or surgically induced. Also, the IOL already depth-of-focus IOL last year with the Tecnis Symfony,5 has an optimized A-constant, said Dr. Schultz. it has yet to approve any of the trifocal IOLs. “The optics on this lens are incredibly good—the best of any I’ve seen,” said Dr. Vold, who’s used nearly The Light Adjustable Lens: every lens on the market in the United States. “I used to Customization After Surgery dance around the office when I got a patient to 20/20 Cataract surgeons have long been challenged to achieve after cataract surgery, but with this lens, more than half precise refractive results. “In fact, a Swedish study6 us have achieved 20/15 or better.” ing national data showed that we reach desired refrac Potential challenges. Patient selection is very im

Tim Schultz, MD Tim tion in only around 50% of patients,” said Dr. Schultz. portant, said Dr. Vold. “For example, you don’t want

EYENET MAGAZINE • 47 to put these lenses in people with herpetic disease because the light treatment can activate the herpesvirus. In addition, a silicone lens may not be ideal in patients at risk 1 2 for severe retinal issues such as diabetic retinopathy and retinal detachment.” The lens may also not be a good choice for patients who want simultaneous distance and near vision in the same eye. This is a smart technology that provides a highly personalized treatment, said Dr. Schultz, so it is nec essary to work closely and spend some time with the patient to achieve the desired refraction. “However, I’ve found that many of my patients are willing to pay extra 3 for it.” The IOL behaves like a monofocal IOL with minimal 4 halo and glare, but until the IOL is locked in, UV light can change the refraction of the IOL, said Dr. Schultz. Therefore, patients must wear special glasses for 2-4 weeks after surgery to protect against ultraviolet light. Compliance is critical to avoid fixing the lens with the wrong power, added Dr. Vold. “In safety trials, however, we’ve seen no problems with the retina or endothelium from the dose of UV light,” said Dr. Schultz. Dr. Vold said that future enhancements may help further improve the device. For example, he is hopeful Imaging from a patient in whom the XtraFocus lens was the company will develop a better injector system, as implanted to help correct corneal aberrations resulting well as a single-piece lens for ease of use. from her earlier radial keratotomy. (1) External photog- Current status. Dr. Schultz’s hospital was involved raphy, (2) anterior segment OCT, (3) central hole caliper, in early trials of the lens, which has been available in and (4) transillumination. Europe since 2008. Phase 3 clinical trials in the United States are now closed. “After a year of follow-up, the light through the pupil, which reduces the visual impact company has gone to the FDA for approval, which they of corneal aberrations,” he said. “Its genius is that it hope to receive some time in 2018,” said Dr. Vold. blocks visible light but is transmissible by infrared light, which allows physicians to view the retina with optical XtraFocus Pinhole Implant: coherence tomography.” Addressing Corneal Aberrations Benefits and best candidates.This IOL is designed Patients with severe corneal aberrations will likely for patients with significant corneal aberrations, irreg become the main beneficiaries of an IOL developed ular astigmatism, or even severe iris defects that cannot by Claudio Trinidade, MD, from Instituto de Oftalmo be corrected, said Dr. Osher. That includes patients with logia Cançado Trindade in Belo Horizonte, Brazil. keratoconus, as well as those who’ve experienced corne Lens design. Dr. Trindade introduced the innovative al scarring or trauma from 1 or more refractive corneal concept of a small-aperture IOL, said Robert H. Osher, procedures, such as radial keratotomy (RK), LASIK, or MD, at the College of Medicine, University of Cincin penetrating keratoplasty, said Luca Gualdi, MD, with nati and Cincinnati Eye Institute. Similar to a piggy the Studio Oculistico Gualdi in Rome. back IOL, the XtraFocus “If it is used as a secondary implant in the sulcus Pinhole Implant (Morcher) of eyes with normal corneas and monofocal IOLs, the is implanted in the cili XtraFocus can also increase the depth of focus, allowing ary sulcus during either a improved near vision without the use of glasses,” he primary cataract surgery or said, adding that the occlusive device does not hamper in a secondary procedure. peripheral vision. Its foldable black hydrophobic acrylic material blocks Retinal pathologies in general, glaucoma, and central light by creating an occlusive shield surrounding the corneal opacities or haze are the main contraindications aperture, said Dr. Osher. for this device, said Dr. Gualdi. Using early prototypes

“The central 1.3-mm pinhole allows a straight ray of of the device, he had excellent results with 3 patients. of Luca Gualdi, MD Courtesy

48 • OCTOBER 2017 About 3 years ago, Dr. Osher was the first to implant the University Hospital Antwerp in Belgium. the XtraFocus in an American patient. The woman had Benefits and best candidates.The company has undergone RK in the 1980s and had recently been re designed the IOL with a range of powers, allowing for ferred to Dr. Osher. “She had sutures in her cornea and spherical correction of 11 diopters of astigmatism, with glare and photophobia residual pseudophakic that couldn’t be corrected but was so intense she’d ametropia, multifocal become housebound.” correction of pseudopha Calling the results “spectacular,” Dr. Osher said her kic presbyopia, and toric astigmatism was significantly reduced, allowing her to correction of residual read 20/40, and later improving further to 20/30 and pseudophakic corneal 20/25. “More importantly, the IOL reduced her glare, astigmatism. Dr. Daya has chosen not to use the multi light sensitivity, and all the aberrations that were keep focal Sulcoflex lens because he’s had patients who’ve ing her from enjoying her life,” he said. experienced night vision issues such as halos following Potential challenges. Morcher made a few adap implantation. tations to the IOL based on Dr. Osher’s experience as The IOL can be used in a primary piggyback proce well as that of his patient. This included tapering the dure or as an enhancement following implant surgery. cylinder at the aperture to prevent unwanted reflec Piggyback procedure. “Before the trifocal lenses had tions of light and developing an injector that could be toric offerings, I used this as a way of correcting high compatible with the lens. The haptics were also opened, astigmatism as a primary procedure,” said Dr. Daya. “I eliminating the closed-loop design, making the lens would put the trifocal lens in the bag and then add the easier to implant, he said. Sulcoflex toric lens on top. It produced good outcomes, Its use as a piggyback lens does come with potential but now that I have access to trifocal toric lenses, I don’t challenges, said Dr. Osher. “For example, any time you bother with 2 lenses.” put an extra lens into the eye, you want to be careful Enhancement. For patients who’ve previously had about a pupillary block, angle closure, intralenticular a cataract operation, said Dr. Daya, this provides an opacification, and completely removing ophthalmic option for correction of any residual refractive error. viscoelastic devices. And, of course, you’re concerned “If the company developed a trifocal Sulcoflex lens,” he about getting a second lens through a smaller inci added, “that might make it possible for patients with sion and not creating more astigmatism.” However, the older monofocal lenses to become spectacle free.” he pointed out that the Morcher-designed injector Dr. Tassignon was involved with the Sulcoflex soon addresses this issue. after its release, about 7 years ago. “Because our center Although Dr. Gualdi found that working with the is relatively well known for handling difficult cases, we lens involved a short learning curve, he said surgeons at had performed many IOL exchanges for dissatisfied pa first may find it a little challenging to handle this lens, tients,” she said. As an alternative, she began implanting which is thinner than others. In addition, to achieve the the Sulcoflex in some patients to correct their residual desired results, it is critical to carefully center the lens, refractive errors. he said. Although she said the multifocal Sulcoflex is useful Current status. The device was recently CE Marked in certain cases, especially in children, she said the and is currently available in the European market. Accor results of a clinical study she conducted were somewhat ding to Dr. Trindade, Michael Snyder, MD, from Cinci disappointing. Some patients were very happy with nnati, is currently engaged with Morcher to develop a the results and could see both near and far, she said. clinical trial in the United States. But about half of the study participants were unhappy, and around 40% asked to have the lens explanted. Dr. Sulcoflex: Tassignon suspects that the dual-optic system is re A Supplementary Lens sponsible because it is less precise and can create more Another type of piggyback lens, the Sulcoflex (Rayner), aberrations than does a single lens. Fortunately, the lens is implanted through a 2-mm incision behind the iris is easily explanted, she said. into the sulcus. “It’s a less aggressive option for manag Potential challenges. None of Dr. Tassignon’s patients ing refractive surprises than is replacing the lens in the have experienced serious complications from the pres capsular bag,” said Dr. Daya. ence of the lens. “However, because it is positioned in Lens design. The Sulcoflex is a hydrophilic acrylic the sulcus, you have to consider preoperatively whether injectable IOL with undulating haptics and posterior or not the eye can accommodate it,” she said, adding haptic angulation. “The haptics are quite bulky for that ophthalmologists often don’t think enough about positioning in the sulcus. When explanting them, I the lens design and biometric parameters of the eye, found that they were often covered by a layer of pig which can then lead to surprises. Dr. Daya agreed: “The ment, which means that they were reacting with the diameter and width of patients’ sulci differ, as well as the ciliary body,” said Marie-José Tassignon, MD, PhD, of space between the iris and the capsule. That variation

EYENET MAGAZINE • 49 can influence how well a lens will behave inside the eye.” Kanellopoulos, who uses them in about 80% of routine Fixation is a potential challenge. “If the lens moves, cataract procedures. there’s a danger of pigment dispersion, which can cause Dr. Schultz has been involved in trials with the Acu inflammation and glaucoma or uveitis,” said Dr. Daya. focus IC-8 IOL, which he’s looking forward to using. And although the large haptics increases stability of the “Its small aperture works like a pinhole, allowing only lens, added Dr. Tassignon, it can also cause irritation of a straight line of light in,” he said. “This produces more the iris, which required removal of the IOL in one of near vision, but without some of the disadvantages of Dr. Daya’s patients. multifocal IOLs.” To help with fixation, especially with a toric lens, Dr. Medicem has developed an extended depth-of-focus Daya sometimes stitches the IOL into the iris to keep lens without haptics, inserted through a 2-mm incision, it from moving. “In 4 cases, I actually opened up the said Dr. Daya. “Within 24-48 hours of insertion into the anterior capsular bag and moved the Sulcoflex so there capsular bag, it grows from 7.0 mm to 9.2 mm. The lens were 2 lenses inside the bag.” These maneuvers require has ‘polyfocal’ optics and, in many ways, is analogous manipulation inside the eye and should be explained to to the human crystalline lens. The visual outcomes are patients in advance, he said. very satisfactory—and with such a large optic, the view It’s important to consider the biocompatibility of the of the retina is unbelievable.” lens materials, said Dr. Tassignon. She has found that a Dr. Kanellopoulos predicts even greater advances buildup of deposits, requiring cleaning, can occur around to come: “Future development of electronic lenses that the add-on lens or between the 2 lenses, even when they are adjustable in power and magnification and might are in separate spaces. Years ago, she proposed the con include sensors that measure body temperature, glu cept of adding a sticker to the existing lens—calling it cose, or hormones may one day revolutionize cataract “a true add-on lens” and suggesting that eliminating the surgery altogether!” interface might minimize these kinds of interactions. Current status. According to Rayner, the Sulcoflex is 1 Mendicute J et al. J Cataract Refract Surg. 2016;42(2):203-210. not yet approved for use in the United States. 2 Marques EF and Ferreira TB. J Cataract Refract Surg. 2015;41(2):354-363. Coming Attractions? 3 Bilbao-Calabuig R et al. Am J Ophthalmol. 2017;179:55-66. Whether trifocal IOLs, customized treatment, or add- 4 Mojzis P et al. J Cataract Refract Surg. 2015;41(12):2695-2706. on devices for solving intransigent refractive problems, 5 U.S. Food and Drug Administration. “FDA approves first intraocular cataract surgeons have a lot to be excited about. “Toric lens with extended range of vision for cataract patients.” www.fda. IOLs have also been a pivotal paradigm change in gov/NewsEvents/Newsroom/PressAnnouncements/ucm511446.htm. my personal practice over the last 12 years,” said Dr. 6 Behndig A et al. J Cataract Refract Surg. 2012;38(7):1181-1186.

Meet the Experts

Sheraz M. Daya, MD, FACP, FACS, FRCS(Ed), financial disclosures: None. FRCOphth Chairman and medical director of Marie-José Tassignon, MD, PhD, FEBO Centre for Sight in East Grinstead, U.K. Rele- Chief and head of the Department of vant financial disclosures: Carl Zeiss Meditec: Ophthalmology and Immediate Past Med C; PhysIOL: C; Rayner: C. ical Director at the University Hospital Luca Gualdi, MD Physician at Studio Oculis Antwerp in Belgium. Relevant financial tico Gualdi and Diagnostica Oftalmologica e disclosures: None. Microchirurgia Ambulatoriale (D.O.M.A) in Tim Schultz, MD Senior physician at the Rome, Italy. Relevant financial disclosures: University Eye Hospital in Bochum, Germa None. ny. Relevant financial disclosures: None. A. John Kanellopoulos, MD Medical Direc Steven D. Vold, MD Physician at Vold tor at Laservision Institute in Athens, Greece, Vision in Fayetteville, Arkansas. Relevant and clinical professor of ophthalmology at financial disclosures: Calhoun Vision: S. New York University Medical School in New NOTE: Kevin M. Miller, MD, who selected York City. Relevant financial disclosures: the lenses that were discussed, is professor None. of ophthalmology at UCLA Stein Eye Insti Robert H. Osher, MD Professor of ophthal tute in California. Relevant financial disclo- mology at the College of Medicine, Universi sures: Alcon: C,L,S; Calhoun Vision: S. ty of Cincinnati, and Medical Director Emer See the disclosure key, page 10. For full disclosures, itus at the Cincinnati Eye Institute. Relevant view this article at aao.org/eyenet.

50 • OCTOBER 2017 FNL_Optos_Pillar MD Ad_AAO EYENET_080317.qxp_Full pg 8/3/17 9:14 AM Page 1

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NOW APPROVED FOR GIANT CELL ARTERITIS (GCA) IN ADULT PATIENTS1 PrimaryIn the Endpoint: ACTEMRA Sustained + Steroid* Remission Taper Arms, More Patients Experienced AchievedSustained in 4x MoreRemission Patients at 52 Weeks vs Placebo + Steroid Taper Arms2

Sustained Remission at 52 Weeks: ITT Population2

Primary Endpoint Key Secondary Endpoint 100 Most patients in the 90 p<0.0001 p<0.0001 ACTEMRA arms were 80 steroid free from Week 26 p<0.0001 p=0.0002 through Week 522 WHEN IS THE 70 60 56% 53.1% 56% 53.1% TIME TO START 50 The most commonly 40 ACTEMRA? reported adverse reactions 30 were nasopharyngitis, headache, and 20 17.6% 14% peripheral edema2 Sustained remission (% of patients) Sustained remission 10

0 ACTEMRA ACTEMRA placebo ACTEMRA ACTEMRA placebo QW + 26w Q2W + 26w + 26w QW + 26w Q2W + 26w + 52w steroid taper steroid taper steroid taper steroid taper steroid taper steroid taper n=100 n=49 n=50 n=100 n=49 n=51

GiACTA was a randomized, double-blind, multicenter study in patients with active GCA. Patients (N=251) were randomized to one of four treatment arms. 1 Two SC doses of ACTEMRA (162 mg QW and 162 mg Q2W) were compared to two different placebo control groups (pre-specified prednisone-taper regimen SUPERIOR EFFICACY AND STEROID-SPARING SUSTAINED REMISSION over 26 weeks and 52 weeks) randomized 2:1:1:1.

INDICATION neutrophils, platelets, lipids, and liver function tests. Dosage modi cations of ACTEMRA in patients with preexisting or recent-onset The most common types of infections across all treatment groups were B:11.125” T:10.875” ACTEMRA is indicated for the treatment of giant cell arteritis (GCA) in may be required. demyelinating disorders. nasopharyngitis, upper respiratory tract infection, bronchitis, and urinary S:10.375” adult patients. Neutropenia: Treatment with ACTEMRA was associated with a higher Active Hepatic Disease and Hepatic Impairment: Treatment with tract infection. IMPORTANT SAFETY INFORMATION incidence of neutropenia. It is not recommended to initiate ACTEMRA ACTEMRA is not recommended in patients with active hepatic disease or Injection-Site Reactions: The frequency of injection-site reactions was treatment in patients with a low neutrophil count i.e., absolute neutrophil hepatic impairment. 6% (6/100) in the ACTEMRA SC weekly group, and 14% (7/49) in the BOXED WARNING: RISK OF SERIOUS INFECTIONS 3 count (ANC) less than 2000 per mm . In patients who develop an ANC less Avoid use of live vaccines concurrently with ACTEMRA. ACTEMRA SC every other week group, as compared to 10% (5/50) in the Patients treated with ACTEMRA are at increased risk for developing 3 Vaccinations: than 500 per mm treatment is not recommended. No data are available on the secondary transmission of infection from placebo + 26 week prednisone taper and 2% (1/51) in the placebo + 52 serious infections that may lead to hospitalization or death, Thrombocytopenia: Treatment with ACTEMRA was associated with a week taper groups. No injection site reaction was reported as a serious including tuberculosis (TB), bacterial, invasive fungal, viral, or other persons receiving live vaccines to patients receiving ACTEMRA or on the reduction in platelet counts. It is not recommended to initiate ACTEMRA effectiveness of vaccination in patients receiving ACTEMRA. Patients adverse event or required treatment discontinuation. opportunistic infections. If a serious infection develops, interrupt 3 in patients with a platelet count below 100,000 per mm . In patients should be brought up to date on all recommended vaccinations prior to DRUG INTERACTIONS ACTEMRA until the infection is controlled. 3 who develop a platelet count less than 50,000 per mm , treatment is initiation of ACTEMRA therapy. Reported infections include: In GCA patients, no effect of concomitant corticosteroid on ACTEMRA not recommended. ADVERSE REACTIONS exposure was observed. • Active tuberculosis, which may present with pulmonary or Elevated Liver Enzymes: Treatment with ACTEMRA was associated extrapulmonary disease. Patients should be tested for latent GIANT CELL ARTERITIS (GCA) Cytochrome P450s in the liver are down-regulated by infection and with a higher incidence of transaminase elevations. These elevations did in ammation stimuli including cytokines such as IL-6. Exercise caution tuberculosis before ACTEMRA use and during therapy. Treatment not result in apparent permanent or clinically evident hepatic injury in In the Phase III clinical trial, the most common adverse events (>20% of for latent infection should be initiated prior to ACTEMRA use. patients treated with ACTEMRA-SC) during the 52-week study were: when coadministering ACTEMRA with CYP3A4 substrate drugs where clinical trials. Increased frequency and magnitude of these elevations was decrease in effectiveness is undesirable, e.g., oral contraceptives, observed when potentially hepatotoxic drugs (e.g., methotrexate) were • Invasive fungal infections, including candidiasis, aspergillosis, PBO + 26 weeks PBO + 52 weeks TCZ 162mg SC QW TCZ 162 mg SC Q2W lovastatin, atorvastatin, etc. and pneumocystis. Patients with invasive fungal infections may used in combination with ACTEMRA. prednisone taper prednisone taper + 26 weeks + 26 weeks USE IN PREGNANCY present with disseminated, rather than localized, disease. – It is not recommended to initiate ACTEMRA treatment in patients with prednisone taper prednisone taper (%) (%) (%) (%) • Bacterial, viral and other infections due to elevated transaminases ALT or AST >1.5x ULN. In patients who develop There is a pregnancy exposure registry that monitors pregnancy opportunistic pathogens. elevated ALT or AST >5x ULN, treatment is not recommended. Headache 32.0 23.5 27.0 20.4 outcomes in women exposed to ACTEMRA during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged Lipid Abnormalities: Treatment with ACTEMRA was associated with Nasopharyngitis 18.0 25.5 29.0 24.5 The risks and bene ts of treatment with ACTEMRA should be Peripheral Edema 16.0 11.8 16.0 24.5 to register themselves by calling 1-877-311-8972. carefully considered prior to initiating therapy in patients with increases in lipid parameters such as total cholesterol, triglycerides, LDL chronic or recurrent infection. cholesterols, and/or HDL cholesterol. Dizziness 12.0 15.7 6.0 20.4 The limited available data with ACTEMRA in pregnant women are not The overall safety pro le observed in the ACTEMRA treatment groups was suf cient to determine whether there is a drug-associated risk for major Patients should be closely monitored for the development of Immunosuppression: The impact of treatment with ACTEMRA on birth defects and miscarriage. signs and symptoms of infection during and after treatment with the development of malignancies is not known, but malignancies generally consistent with the known safety pro le of ACTEMRA. There ACTEMRA, including the possible development of tuberculosis in were observed in clinical studies with ACTEMRA. ACTEMRA is an was an overall higher incidence of infections in GCA patients relative to You may report side effects to the FDA at (800) FDA- 1088 or patients who tested negative for latent tuberculosis infection prior to immunosuppressant, and treatment with immunosuppressants may result RA patients. www.fda.gov/medwatch. You may also report side effects to initiating therapy. in an increased risk of malignancies. Infections: The rate of infections was 200.2 per 100 patient-years in Genentech at (888) 835- 2555. CONTRAINDICATION Hypersensitivity Reactions: Hypersensitivity reactions, including the ACTEMRA SC weekly group and 160.2 per 100 patient-years in the Please see following brief summary of Prescribing Information, including anaphylaxis, have been reported in association with ACTEMRA. For ACTEMRA SC every other week group, as compared to 156.0 per 100 Boxed WARNING, for additional important safety information. ACTEMRA is contraindicated in patients with known hypersensitivity patient-years in the placebo + 26 week prednisone taper and 210.2 per to ACTEMRA. ACTEMRA subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity 100 patient-years in the placebo + 52 week taper groups. References: 1. ACTEMRA [package insert]. South San Francisco, CA: WARNINGS AND PRECAUTIONS reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop The rate of serious infections was 9.7 per 100 patient-years in the Genentech, Inc. 2. Data on le, GiACTA CSR, Genentech, Inc. South Gastrointestinal Perforations: Events of gastrointestinal (GI) perforation administration of ACTEMRA immediately and discontinue ACTEMRA ACTEMRA SC weekly group and 4.4 per 100 patient-years in the San Francisco, CA. have been reported in clinical trials, primarily as complications of permanently. Do not administer ACTEMRA to patients with known ACTEMRA SC every other week group, as compared to 4.2 per 100 Q2W=every-other-week dose; QW=every-week dose. diverticulitis in RA patients. Use ACTEMRA with caution in patients who hypersensitivity to ACTEMRA. patient-years in the placebo + 26 week prednisone taper and 12.5 per *Prednisone. may be at increased risk for GI perforation. Promptly evaluate patients Demyelinating Disorders: The impact of treatment with ACTEMRA on 100 patient-years in the placebo + 52 week prednisone taper groups. presenting with new-onset abdominal symptoms for early identi cation demyelinating disorders is not known, but multiple sclerosis and chronic of GI perforation. in ammatory demyelinating polyneuropathy were reported rarely in Laboratory Parameters: Laboratory monitoring is recommended due to clinical studies. Monitor patients for signs and symptoms of demyelinating potential consequences of treatment-related laboratory abnormalities in disorders. Prescribers should exercise caution in considering the use © 2017 Genentech USA, Inc. All rights reserved. ACT/071217/0075 08/17

FS:7.375” FS:7.375” F:8.125” F:8.125” 10751079_GCA_NOW_JA_EYE_M1.indd 1 8/14/17 5:19 PM

PREPARED BY FCB Releasing as: PDFx1A Production: Maria Abreu x3124 Job #: 10751079 Colors: 4/1 (4C Process/Black) AD: Trent Orvis x2492 Client: Genentech Flat Size: 16.25”w X 10.875”h AE: Katie Majewski x7927 Product: Actemra Bleed: 16.5”w X 11.125”h Producer: Karisa Williams x3721 Client Code: ACT/071217/0075 Trim: 16.25”w X 10.875”h QC: L.Powell Date: August 14, 2017 5:19 PM Safety: 15.75”w X 10.375”h Digital Artist: VA, Add’l Size Info: PI Page Dimensions - Trim 8.125”w X 10.875”h; Live 7.875”w Proof: M1 X 10.625”h; Bleed 8.375”w X 11.125”h Fonts: Helvetica Neue LT Std, Avenir M1 Spellcheck: Jacob Albrecht FR Spellcheck: Path: PrePress:Genentech:10751079:10751079_GCA_NOW_JA_EYE_M1 4C GCA 2017 Journal Ad: Eyenet B:16.5” T:16.25” S:15.75”

Sustained Remission at 52 Weeks: ITT Population2

INDICATION neutrophils, platelets, lipids, and liver function tests. Dosage modi cations of ACTEMRA in patients with preexisting or recent-onset The most common types of infections across all treatment groups were B:11.125” T:10.875” ACTEMRA is indicated for the treatment of giant cell arteritis (GCA) in may be required. demyelinating disorders. nasopharyngitis, upper respiratory tract infection, bronchitis, and urinary S:10.375” adult patients. Neutropenia: Treatment with ACTEMRA was associated with a higher Active Hepatic Disease and Hepatic Impairment: Treatment with tract infection. IMPORTANT SAFETY INFORMATION incidence of neutropenia. It is not recommended to initiate ACTEMRA ACTEMRA is not recommended in patients with active hepatic disease or Injection-Site Reactions: The frequency of injection-site reactions was treatment in patients with a low neutrophil count i.e., absolute neutrophil hepatic impairment. 6% (6/100) in the ACTEMRA SC weekly group, and 14% (7/49) in the BOXED WARNING: RISK OF SERIOUS INFECTIONS 3 count (ANC) less than 2000 per mm . In patients who develop an ANC less Avoid use of live vaccines concurrently with ACTEMRA. ACTEMRA SC every other week group, as compared to 10% (5/50) in the Patients treated with ACTEMRA are at increased risk for developing 3 Vaccinations: than 500 per mm treatment is not recommended. No data are available on the secondary transmission of infection from placebo + 26 week prednisone taper and 2% (1/51) in the placebo + 52 serious infections that may lead to hospitalization or death, Thrombocytopenia: Treatment with ACTEMRA was associated with a week taper groups. No injection site reaction was reported as a serious including tuberculosis (TB), bacterial, invasive fungal, viral, or other persons receiving live vaccines to patients receiving ACTEMRA or on the reduction in platelet counts. It is not recommended to initiate ACTEMRA effectiveness of vaccination in patients receiving ACTEMRA. Patients adverse event or required treatment discontinuation. opportunistic infections. If a serious infection develops, interrupt 3 in patients with a platelet count below 100,000 per mm . In patients should be brought up to date on all recommended vaccinations prior to DRUG INTERACTIONS ACTEMRA until the infection is controlled. 3 who develop a platelet count less than 50,000 per mm , treatment is initiation of ACTEMRA therapy. Reported infections include: In GCA patients, no effect of concomitant corticosteroid on ACTEMRA not recommended. ADVERSE REACTIONS exposure was observed. • Active tuberculosis, which may present with pulmonary or Elevated Liver Enzymes: Treatment with ACTEMRA was associated extrapulmonary disease. Patients should be tested for latent GIANT CELL ARTERITIS (GCA) Cytochrome P450s in the liver are down-regulated by infection and with a higher incidence of transaminase elevations. These elevations did in ammation stimuli including cytokines such as IL-6. Exercise caution tuberculosis before ACTEMRA use and during therapy. Treatment not result in apparent permanent or clinically evident hepatic injury in In the Phase III clinical trial, the most common adverse events (>20% of for latent infection should be initiated prior to ACTEMRA use. patients treated with ACTEMRA-SC) during the 52-week study were: when coadministering ACTEMRA with CYP3A4 substrate drugs where clinical trials. Increased frequency and magnitude of these elevations was decrease in effectiveness is undesirable, e.g., oral contraceptives, observed when potentially hepatotoxic drugs (e.g., methotrexate) were • Invasive fungal infections, including candidiasis, aspergillosis, PBO + 26 weeks PBO + 52 weeks TCZ 162mg SC QW TCZ 162 mg SC Q2W lovastatin, atorvastatin, etc. and pneumocystis. Patients with invasive fungal infections may used in combination with ACTEMRA. prednisone taper prednisone taper + 26 weeks + 26 weeks USE IN PREGNANCY present with disseminated, rather than localized, disease. – It is not recommended to initiate ACTEMRA treatment in patients with prednisone taper prednisone taper (%) (%) (%) (%) • Bacterial, viral and other infections due to elevated transaminases ALT or AST >1.5x ULN. In patients who develop There is a pregnancy exposure registry that monitors pregnancy opportunistic pathogens. elevated ALT or AST >5x ULN, treatment is not recommended. Headache 32.0 23.5 27.0 20.4 outcomes in women exposed to ACTEMRA during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged Lipid Abnormalities: Treatment with ACTEMRA was associated with Nasopharyngitis 18.0 25.5 29.0 24.5 The risks and bene ts of treatment with ACTEMRA should be Peripheral Edema 16.0 11.8 16.0 24.5 to register themselves by calling 1-877-311-8972. carefully considered prior to initiating therapy in patients with increases in lipid parameters such as total cholesterol, triglycerides, LDL chronic or recurrent infection. cholesterols, and/or HDL cholesterol. Dizziness 12.0 15.7 6.0 20.4 The limited available data with ACTEMRA in pregnant women are not The overall safety pro le observed in the ACTEMRA treatment groups was suf cient to determine whether there is a drug-associated risk for major Patients should be closely monitored for the development of Immunosuppression: The impact of treatment with ACTEMRA on birth defects and miscarriage. signs and symptoms of infection during and after treatment with the development of malignancies is not known, but malignancies generally consistent with the known safety pro le of ACTEMRA. There ACTEMRA, including the possible development of tuberculosis in were observed in clinical studies with ACTEMRA. ACTEMRA is an was an overall higher incidence of infections in GCA patients relative to You may report side effects to the FDA at (800) FDA- 1088 or patients who tested negative for latent tuberculosis infection prior to immunosuppressant, and treatment with immunosuppressants may result RA patients. www.fda.gov/medwatch. You may also report side effects to initiating therapy. in an increased risk of malignancies. Infections: The rate of infections was 200.2 per 100 patient-years in Genentech at (888) 835-2555. CONTRAINDICATION Hypersensitivity Reactions: Hypersensitivity reactions, including the ACTEMRA SC weekly group and 160.2 per 100 patient-years in the Please see following brief summary of Prescribing Information, including anaphylaxis, have been reported in association with ACTEMRA. For ACTEMRA SC every other week group, as compared to 156.0 per 100 Boxed WARNING, for additional important safety information. ACTEMRA is contraindicated in patients with known hypersensitivity patient-years in the placebo + 26 week prednisone taper and 210.2 per to ACTEMRA. ACTEMRA subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity 100 patient-years in the placebo + 52 week taper groups. References: 1. ACTEMRA [package insert]. South San Francisco, CA: WARNINGS AND PRECAUTIONS reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop The rate of serious infections was 9.7 per 100 patient-years in the Genentech, Inc. 2. Data on le, GiACTA CSR, Genentech, Inc. South Gastrointestinal Perforations: Events of gastrointestinal (GI) perforation administration of ACTEMRA immediately and discontinue ACTEMRA ACTEMRA SC weekly group and 4.4 per 100 patient-years in the San Francisco, CA. have been reported in clinical trials, primarily as complications of permanently. Do not administer ACTEMRA to patients with known ACTEMRA SC every other week group, as compared to 4.2 per 100 Q2W=every-other-week dose; QW=every-week dose. diverticulitis in RA patients. Use ACTEMRA with caution in patients who hypersensitivity to ACTEMRA. patient-years in the placebo + 26 week prednisone taper and 12.5 per *Prednisone. may be at increased risk for GI perforation. Promptly evaluate patients Demyelinating Disorders: The impact of treatment with ACTEMRA on 100 patient-years in the placebo + 52 week prednisone taper groups. presenting with new-onset abdominal symptoms for early identi cation demyelinating disorders is not known, but multiple sclerosis and chronic of GI perforation. in ammatory demyelinating polyneuropathy were reported rarely in Laboratory Parameters: Laboratory monitoring is recommended due to clinical studies. Monitor patients for signs and symptoms of demyelinating potential consequences of treatment-related laboratory abnormalities in disorders. Prescribers should exercise caution in considering the use © 2017 Genentech USA, Inc. All rights reserved. ACT/071217/0075 08/17

FS:7.375” FS:7.375” F:8.125” F:8.125” 10751079_GCA_NOW_JA_EYE_M1.indd 1 8/14/17 5:19 PM

ACTEMRA® (tocilizumab) Treatment-related reduction in platelets was not associated with serious bleeding events in Injection, for intravenous use clinical trials [see Adverse Reactions (6.1, 6.2)]. Injection, for subcutaneous use – It is not recommended to initiate ACTEMRA treatment in patients with a platelet count below This is a brief summary. Before prescribing, please refer to the full Prescribing 100,000 per mm3. In patients who develop a platelet count less than 50,000 per mm3 treatment Information. is not recommended. – Monitor platelets 4 to 8 weeks after start of therapy and every 3 months thereafter. WARNING: RISK OF SERIOUS INFECTIONS For recommended modifications based on platelet counts see [Dosage and Patients treated with ACTEMRA are at increased risk for developing serious infections Administration (2.8)]. that may lead to hospitalization or death [see Warnings and Precautions (5.1), Adverse Elevated Liver Enzymes Treatment with ACTEMRA was associated with a higher incidence of Reactions (6.1)] . Most patients who developed these infections were taking concomitant transaminase elevations. These elevations did not result in apparent permanent or clinically immunosuppressants such as methotrexate or corticosteroids. If a serious infection evident hepatic injury in clinical trials [see Adverse Reactions (6.1, 6.2)]. Increased frequency and develops, interrupt ACTEMRA until the infection is controlled. magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were Reported infections include: used in combination with ACTEMRA. • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. In one case, a patient who had received ACTEMRA 8 mg per kg monotherapy without Patients should be tested for latent tuberculosis before ACTEMRA use and during elevations in transaminases experienced elevation in AST to above 10x ULN and elevation in therapy. Treatment for latent infection should be initiated prior to ACTEMRA use. ALT to above 16x ULN when MTX was initiated in combination with ACTEMRA. Transaminases • Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. normalized when both treatments were held, but elevations recurred when MTX and Patients with invasive fungal infections may present with disseminated, rather than ACTEMRA were restarted at lower doses. Elevations resolved when MTX and ACTEMRA localized, disease. were discontinued. • Bacterial, viral and other infections due to opportunistic pathogens. – It is not recommended to initiate ACTEMRA treatment in patients with elevated transaminases The risks and benefits of treatment with ACTEMRA should be carefully considered prior ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than to initiating therapy in patients with chronic or recurrent infection. Patients should be 5x ULN treatment is not recommended. closely monitored for the development of signs and symptoms of infection during and – Monitor ALT and AST levels 4 to 8 weeks after start of therapy and every 3 months thereafter. after treatment with ACTEMRA, including the possible development of tuberculosis in When clinically indicated, other liver function tests such as bilirubin should be considered. For patients who tested negative for latent tuberculosis infection prior to initiating therapy recommended modifications based on transaminases see [Dosage and Administration (2.8)]. [see Warnings and Precautions (5.1)]. Lipid Abnormalities Treatment with ACTEMRA was associated with increases in lipid parameters 1 INDICATIONS AND USAGE such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol [see Adverse 1.1 Rheumatoid Arthritis (RA) Reactions (6.1, 6.2)]. ACTEMRA® (tocilizumab) is indicated for the treatment of adult patients with moderately to – Assess lipid parameters approximately 4 to 8 weeks following initiation of ACTEMRA therapy, severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more then at approximately 24 week intervals. Disease-Modifying Anti-Rheumatic Drugs (DMARDs). – Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia. 1.2 Giant Cell Arteritis (GCA) 5.4 Immunosuppression ® ACTEMRA (tocilizumab) is indicated for the treatment of giant cell arteritis (GCA) in adult The impact of treatment with ACTEMRA on the development of malignancies is not known but patients. malignancies were observed in clinical studies [see Adverse Reactions (6.1)]. ACTEMRA is an 4 CONTRAINDICATIONS immunosuppressant, and treatment with immunosuppressants may result in an increased risk ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA [see Warnings of malignancies. and Precautions (5.5)]. 5.5 Hypersensitivity Reactions, Including Anaphylaxis Hypersensitivity reactions, including anaphylaxis, have been reported in association with 5 WARNINGS AND PRECAUTIONS ACTEMRA [see Adverse Reactions (6)] and anaphylactic events with a fatal outcome have 5.1 Serious Infections been reported with intravenous infusion of ACTEMRA. Anaphylaxis and other hypersensitivity Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of viral, protozoal, or other opportunistic pathogens have been reported in patients receiving patients in the 6-month controlled trials of intravenous ACTEMRA, 0.2% (8 out of 4009) of immunosuppressive agents including ACTEMRA. The most common serious infections included patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis 6-month controlled RA trials, and in 0.7% (10 out of 1465) of patients in the subcutaneous all- and bacterial arthritis [see Adverse Reactions (6.1)]. Among opportunistic infections, tuberculosis, exposure population. Reactions that required treatment discontinuation included generalized cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with ACTEMRA. erythema, rash, and uticaria. Injection site reactions were categorized separately [see Adverse Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, Reactions (6) ]. coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized B:11.125” T:10.875” In the postmarketing setting, events of hypersensitivity reactions, including anaphylaxis and S:10.625” disease, and were often taking concomitant immunosuppressants such as methotrexate or death have occurred in patients treated with a range of doses of intravenous ACTEMRA, corticosteroids which in addition to rheumatoid arthritis may predispose them to infections. with or without concomitant therapies. Events have occurred in patients who received Do not administer ACTEMRA in patients with an active infection, including localized infections. premedication. Hypersensitivity, including anaphylaxis events, have occurred both with and The risks and benefits of treatment should be considered prior to initiating ACTEMRA in patients: without previous hypersensitivity reactions and as early as the first infusion of ACTEMRA • with chronic or recurrent infection; • who have resided or traveled in areas of [see Adverse Reactions (6.5)]. ACTEMRA for intravenous use should only be infused • who have been exposed to tuberculosis; endemic tuberculosis or endemic mycoses; or by a healthcare professional with appropriate medical support to manage anaphylaxis. • with a history of serious or an • with underlying conditions that may For ACTEMRA subcutaneous injection, advise patients to seek immediate medical attention opportunistic infection; predispose them to infection. if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other Closely monitor patients for the development of signs and symptoms of infection during and hypersensitivity reaction occurs, stop administration of ACTEMRA immediately and discontinue after treatment with ACTEMRA, as signs and symptoms of acute inflammation may be lessened ACTEMRA permanently. Do not administer ACTEMRA to patients with known hypersensitivity to due to suppression of the acute phase reactants [see Dosage and Administration (2.5), Adverse ACTEMRA [see Contraindications (4) and Adverse Reactions (6)]. Reactions (6.1), and Patient Counseling Information (17)]. 5.6 Demyelinating Disorders Hold ACTEMRA if a patient develops a serious infection, an opportunistic infection, or sepsis. A The impact of treatment with ACTEMRA on demyelinating disorders is not known, but multiple patient who develops a new infection during treatment with ACTEMRA should undergo a prompt sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA and complete diagnostic workup appropriate for an immunocompromised patient, initiate clinical studies. Monitor patients for signs and symptoms potentially indicative of demyelinating appropriate antimicrobial therapy, and closely monitor the patient. disorders. Prescribers should exercise caution in considering the use of ACTEMRA in patients Tuberculosis Evaluate patients for tuberculosis risk factors and test for latent infection prior to with preexisting or recent onset demyelinating disorders. initiating ACTEMRA. 5.7 Active Hepatic Disease and Hepatic Impairment Consider anti-tuberculosis therapy prior to initiation of ACTEMRA in patients with a past history Treatment with ACTEMRA is not recommended in patients with active hepatic disease or hepatic of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, impairment [see Adverse Reactions (6.1), Use in Specific Populations (8.6)]. and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis 5.8 Vaccinations infection. Consultation with a physician with expertise in the treatment of tuberculosis is Avoid use of live vaccines concurrently with ACTEMRA as clinical safety has not been established. recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate No data are available on the secondary transmission of infection from persons receiving live for an individual patient. vaccines to patients receiving ACTEMRA. Closely monitor patients for the development of signs and symptoms of tuberculosis including No data are available on the effectiveness of vaccination in patients receiving ACTEMRA. patients who tested negative for latent tuberculosis infection prior to initiating therapy. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is It is recommended that patients be screened for latent tuberculosis infection prior to starting recommended that all patients, particularly pediatric or elderly patients, if possible, be brought up ACTEMRA. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. to date with all immunizations in agreement with current immunization guidelines prior to initiating Patients with latent tuberculosis should be treated with standard antimycobacterial therapy ACTEMRA therapy. The interval between live vaccinations and initiation of ACTEMRA therapy before initiating ACTEMRA. should be in accordance with current vaccination guidelines regarding immunosuppressive Viral Reactivation Viral reactivation has been reported with immunosuppressive biologic therapies agents. and cases of herpes zoster exacerbation were observed in clinical studies with ACTEMRA. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened 6 ADVERSE REACTIONS positive for hepatitis were excluded. Because clinical studies are conducted under widely varying conditions, adverse reaction rates 5.2 Gastrointestinal Perforations observed in the clinical studies of a drug cannot be directly compared to rates in the clinical Events of gastrointestinal perforation have been reported in clinical trials, primarily as studies of another drug and may not predict the rates observed in a broader patient population complications of diverticulitis in patients treated with ACTEMRA. Use ACTEMRA with caution in in clinical practice. patients who may be at increased risk for gastrointestinal perforation. Promptly evaluate patients 6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous presenting with new onset abdominal symptoms for early identification of gastrointestinal ACTEMRA (ACTEMRA-IV) perforation [see Adverse Reactions (6.1)]. The ACTEMRA-IV data in rheumatoid arthritis (RA) includes 5 double-blind, controlled, multicenter 5.3 Laboratory Parameters studies. In these studies, patients received doses of ACTEMRA-IV 8 mg per kg monotherapy (288 Approved Adult Indications patients), ACTEMRA-IV 8 mg per kg in combination with DMARDs (including methotrexate) (1582 Neutropenia Treatment with ACTEMRA was associated with a higher incidence of neutropenia. patients), or ACTEMRA-IV 4 mg per kg in combination with methotrexate (774 patients). Infections have been uncommonly reported in association with treatment-related neutropenia in The all exposure population includes all patients in registration studies who received at least one long-term extension studies and postmarketing clinical experience. dose of ACTEMRA-IV. Of the 4009 patients in this population, 3577 received treatment for at least 6 – It is not recommended to initiate ACTEMRA treatment in patients with a low neutrophil count, months, 3309 for at least one year; 2954 received treatment for at least 2 years and 2189 for 3 years. i.e., absolute neutrophil count (ANC) less than 2000 per mm3. In patients who develop an All patients in these studies had moderately to severely active rheumatoid arthritis. The absolute neutrophil count less than 500 per mm3 treatment is not recommended. study population had a mean age of 52 years, 82% were female and 74% were Caucasian. – Monitor neutrophils 4 to 8 weeks after start of therapy and every 3 months thereafter [see The most common serious adverse reactions were serious infections [see Warnings and Clinical Pharmacology (12.2)]. For recommended modifications based on ANC results, [see Precautions (5.1)]. Dosage and Administration (2.8)]. The most commonly reported adverse reactions in controlled studies up to 24 weeks (occurring Thrombocytopenia Treatment with ACTEMRA was associated with a reduction in platelet counts. in at least 5% of patients treated with ACTEMRA-IV monotherapy or in combination with

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DMARDs) were upper respiratory tract infections, nasopharyngitis, headache, hypertension and *For a description of these studies, see Section 14, Clinical Studies. increased ALT. In the all-exposure population, the elevations in ALT and AST remained consistent with what was The proportion of patients who discontinued treatment due to any adverse reactions during the seen in the 24 week, controlled clinical trials. double-blind, placebo-controlled studies was 5% for patients taking ACTEMRA-IV and 3% for Lipids Elevations in lipid parameters (total cholesterol, LDL, HDL, triglycerides) were first assessed placebo-treated patients. The most common adverse reactions that required discontinuation at 6 weeks following initiation of ACTEMRA-IV in the controlled 24 week clinical trials. Increases of ACTEMRA-IV were increased hepatic transaminase values (per protocol requirement) and were observed at this time point and remained stable thereafter. Increases in triglycerides to serious infections. levels above 500 mg per dL were rarely observed. Changes in other lipid parameters from Overall Infections In the 24 week, controlled clinical studies, the rate of infections in the baseline to week 24 were evaluated and are summarized below: ACTEMRA-IV monotherapy group was 119 events per 100 patient-years and was similar in the – Mean LDL increased by 13 mg per dL in the ACTEMRA 4 mg per kg+DMARD arm, 20 mg methotrexate monotherapy group. The rate of infections in the 4 mg per kg and 8 mg per kg per dL in the ACTEMRA 8 mg per kg+DMARD, and 25 mg per dL in ACTEMRA 8 mg per kg ACTEMRA-IV plus DMARD group was 133 and 127 events per 100 patient-years, respectively, monotherapy. compared to 112 events per 100 patient-years in the placebo plus DMARD group. The most – Mean HDL increased by 3 mg per dL in the ACTEMRA 4 mg per kg+DMARD arm, 5 mg per dL in commonly reported infections (5% to 8% of patients) were upper respiratory tract infections and the ACTEMRA 8 mg per kg+DMARD, and 4 mg per dL in ACTEMRA 8 mg per kg monotherapy. nasopharyngitis. – Mean LDL/HDL ratio increased by an average of 0.14 in the ACTEMRA 4 mg per kg+DMARD The overall rate of infections with ACTEMRA-IV in the all exposure population remained arm, 0.15 in the ACTEMRA 8 mg per kg+DMARD, and 0.26 in ACTEMRA 8 mg per kg consistent with rates in the controlled periods of the studies. monotherapy. Serious Infections In the 24 week, controlled clinical studies, the rate of serious infections in – ApoB/ApoA1 ratios were essentially unchanged in ACTEMRA-treated patients. the ACTEMRA-IV monotherapy group was 3.6 per 100 patient-years compared to 1.5 per 100 Elevated lipids responded to lipid lowering agents. patient-years in the methotrexate group. The rate of serious infections in the 4 mg per kg and In the all-exposure population, the elevations in lipid parameters remained consistent with what 8 mg per kg ACTEMRA-IV plus DMARD group was 4.4 and 5.3 events per 100 patient-years, was seen in the 24 week, controlled clinical trials. respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group. Immunogenicity In the 24 week, controlled clinical studies, a total of 2876 patients have been In the all-exposure population, the overall rate of serious infections remained consistent with tested for anti-tocilizumab antibodies. Forty-six patients (2%) developed positive anti-tocilizumab rates in the controlled periods of the studies. The most common serious infections included antibodies, of whom 5 had an associated, medically significant, hypersensitivity reaction leading pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis to withdrawal. Thirty patients (1%) developed neutralizing antibodies. and bacterial arthritis. Cases of opportunistic infections have been reported [see Warnings and The data reflect the percentage of patients whose test results were positive for antibodies to Precautions (5.1)]. tocilizumab in specific assays. The observed incidence of antibody positivity in an assay is highly Gastrointestinal Perforations During the 24 week, controlled clinical trials, the overall rate of dependent on several factors, including assay sensitivity and specificity, assay methodology, gastrointestinal perforation was 0.26 events per 100 patient-years with ACTEMRA-IV therapy. sample handling, timing of sample collection, concomitant medication, and underlying disease. In the all-exposure population, the overall rate of gastrointestinal perforation remained consistent For these reasons, comparison of the incidence of antibodies to tocilizumab with the incidence with rates in the controlled periods of the studies. Reports of gastrointestinal perforation were of antibodies to other products may be misleading. primarily reported as complications of diverticulitis including generalized purulent peritonitis, Malignancies During the 24 week, controlled period of the studies, 15 malignancies were lower GI perforation, fistula and abscess. Most patients who developed gastrointestinal diagnosed in patients receiving ACTEMRA-IV, compared to 8 malignancies in patients in the perforations were taking concomitant nonsteroidal anti-inflammatory medications (NSAIDs), control groups. Exposure-adjusted incidence was similar in the ACTEMRA-IV groups (1.32 events corticosteroids, or methotrexate [see Warnings and Precautions (5.2)]. The relative contribution per 100 patient-years) and in the placebo plus DMARD group (1.37 events per 100 patient-years). of these concomitant medications versus ACTEMRA-IV to the development of GI perforations In the all-exposure population, the rate of malignancies remained consistent with the rate is not known. observed in the 24 week, controlled period [see Warnings and Precautions (5.4)]. Infusion Reactions In the 24 week, controlled clinical studies, adverse events associated with the Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 4 or 8 mg per infusion (occurring during or within 24 hours of the start of infusion) were reported in 8% and 7% kg ACTEMRA-IV plus DMARD and at least 1% greater than that observed in patients on placebo of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD group, respectively, plus DMARD are summarized in Table 2. compared to 5% of patients in the placebo plus DMARD group. The most frequently reported event on the 4 mg per kg and 8 mg per kg dose during the infusion was hypertension (1% for Table 2 Adverse Reactions Occurring in at Least 2% or More of Patients on 4 or 8 mg per both doses), while the most frequently reported event occurring within 24 hours of finishing an kg ACTEMRA plus DMARD and at Least 1% Greater Than That Observed in Patients on infusion were headache (1% for both doses) and skin reactions (1% for both doses), including Placebo plus DMARD rash, pruritus and urticaria. These events were not treatment limiting. 24 Week Phase 3 Controlled Study Population Anaphylaxis Hypersensitivity reactions requiring treatment discontinuation, including anaphylaxis, ACTEMRA Metho- ACTEMRA ACTEMRA Placebo + associated with ACTEMRA-IV were reported in 0.1% (3 out of 2644) in the 24 week, controlled 8 mg per trexate 4 mg per 8 mg per DMARDs trials and in 0.2% (8 out of 4009) in the all-exposure population. These reactions were generally kg kg + kg + observed during the second to fourth infusion of ACTEMRA-IV. Appropriate medical treatment MONO- DMARDs DMARDs B:11.125” T:10.875” should be available for immediate use in the event of a serious hypersensitivity reaction [see THERAPY S:10.625” Warnings and Precautions (5.5)]. Laboratory Abnormalities N = 288 N = 284 N = 774 N = 1582 N = 1170 Neutropenia In the 24 week, controlled clinical studies, decreases in neutrophil counts below Preferred Term (%) (%) (%) (%) (%) 1000 per mm3 occurred in 1.8% and 3.4% of patients in the 4 mg per kg and 8 mg per kg Upper Respiratory 7 5 6 8 6 ACTEMRA-IV plus DMARD group, respectively, compared to 0.1% of patients in the placebo Tract Infection plus DMARD group. Approximately half of the instances of ANC below 1000 per mm3 occurred Nasopharyngitis 7 6 4 6 4 within 8 weeks of starting therapy. Decreases in neutrophil counts below 500 per mm3 occurred Headache 7 2 6 5 3 in 0.4% and 0.3% of patients in the 4 mg per kg and 8 mg per kg ACTEMRA-IV plus DMARD, Hypertension 6 2 4 4 3 respectively, compared to 0.1% of patients in the placebo plus DMARD group. There was no ALT increased 6 4 3 3 1 clear relationship between decreases in neutrophils below 1000 per mm3 and the occurrence of Dizziness 3 1 2 3 2 serious infections. Bronchitis 3 2 4 3 3 In the all-exposure population, the pattern and incidence of decreases in neutrophil counts Rash 2 1 4 3 1 remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings Mouth Ulceration 2 2 1 2 1 and Precautions (5.3)]. Abdominal Pain 2 2 3 3 2 Thrombocytopenia In the 24 week, controlled clinical studies, decreases in platelet counts Upper below 100,000 per mm3 occurred in 1.3% and 1.7% of patients on 4 mg per kg and 8 mg Gastritis 1 2 1 2 1 per kg ACTEMRA-IV plus DMARD, respectively, compared to 0.5% of patients on placebo plus Transaminase 1 5 2 2 1 DMARD, without associated bleeding events. increased In the all-exposure population, the pattern and incidence of decreases in platelet counts Other infrequent and medically relevant adverse reactions occurring at an incidence less than 2% remained consistent with what was seen in the 24 week controlled clinical studies [see Warnings in rheumatoid arthritis patients treated with ACTEMRA-IV in controlled trials were: and Precautions (5.3)]. Infections and Infestations: oral herpes simplex Elevated Liver Enzymes Liver enzyme abnormalities are summarized in Table 1. In patients Gastrointestinal disorders: stomatitis, gastric ulcer experiencing liver enzyme elevation, modification of treatment regimen, such as reduction in Investigations: weight increased, total bilirubin increased the dose of concomitant DMARD, interruption of ACTEMRA-IV, or reduction in ACTEMRA-IV Blood and lymphatic system disorders: leukopenia dose, resulted in decrease or normalization of liver enzymes [see Dosage and Administration General disorders and administration site conditions: edema peripheral (2.6)]. These elevations were not associated with clinically relevant increases in direct bilirubin, Respiratory, thoracic, and mediastinal disorders: dyspnea, cough nor were they associated with clinical evidence of hepatitis or hepatic insufficiency [see Warnings Eye disorders: conjunctivitis and Precautions (5.3)]. Renal disorders: nephrolithiasis Table 1 Incidence of Liver Enzyme Abnormalities in the 24 Week Controlled Period of Endocrine disorders: hypothyroidism Studies I to V* 6.2 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous ACTEMRA Metho- ACTEMRA ACTEMRA Placebo + ACTEMRA (ACTEMRA-SC) 8 mg per trexate 4 mg per 8 mg per DMARDs The ACTEMRA-SC data in rheumatoid arthritis (RA) includes 2 double-blind, controlled, kg kg + kg + multicenter studies. Study SC-I was a non-inferiority study that compared the efficacy and MONO- DMARDs DMARDs safety of tocilizumab 162 mg administered every week subcutaneously (SC) and 8 mg/kg THERAPY intravenously (IV) every four weeks in 1262 adult subjects with rheumatoid arthritis. Study SC-II was a placebo controlled superiority study that evaluated the safety and efficacy of tocilizumab N = 288 N = 284 N = 774 N = 1582 N = 1170 162 mg administered every other week SC or placebo in 656 patients. All patients in both studies (%) (%) (%) (%) (%) received background non-biologic DMARDs. AST (U/L) The safety observed for ACTEMRA administered subcutaneously was consistent with the known > ULN to 3x ULN 22 26 34 41 17 safety profile of intravenous ACTEMRA, with the exception of injection site reactions, which were > 3x ULN to 5x ULN 0.3 2 1 2 0.3 more common with ACTEMRA-SC compared with placebo SC injections (IV arm). Injection Site Reactions In the 6-month control period, in SC-I, the frequency of injection site > 5x ULN 0.7 0.4 0.1 0.2 <0.1 reactions was 10.1% (64/631) and 2.4% (15/631) for the weekly ACTEMRA-SC and placebo SC ALT (U/L) (IV-arm) groups, respectively. In SC-II, the frequency of injection site reactions was 7.1% (31/437) and 4.1% (9/218) for the every other week SC ACTEMRA and placebo groups, respectively. > ULN to 3x ULN 36 33 45 48 23 These injection site reactions (including erythema, pruritus, pain and hematoma) were mild to > 3x ULN to 5x ULN 1 4 5 5 1 moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation. > 5x ULN 0.7 1 1.3 1.5 0.3 Immunogenicity In the 6-month control period in SC-I, 0.8% (5/625) in the ACTEMRA-SC arm and 0.8% (5/627) in the IV arm developed anti-tocilizumab antibodies; of these, all developed ULN = Upper Limit of Normal

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neutralizing antibodies. In SC-II, 1.6% (7/434) in the ACTEMRA-SC arm compared with 1.4% Data (3/217) in the placebo arm developed anti- tocilizumab antibodies; of these, 1.4% (6/434) in the Animal Data An embryo-fetal developmental toxicity study was performed in which pregnant ACTEMRA-SC arm and 0.5% (1/217) in the placebo arm also developed neutralizing antibodies. Cynomolgus monkeys were treated intravenously with tocilizumab at daily doses of 2, 10, or 50 A total of 1454 (>99%) patients who received ACTEMRA-SC in the all exposure group have mg/ kg during organogenesis from gestation day (GD) 20-50. Although there was no evidence been tested for anti-tocilizumab antibodies. Thirteen patients (0.9%) developed anti-tocilizumab for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in antibodies, and, of these, 12 patients (0.8%) developed neutralizing antibodies. the incidence of abortion/embryo-fetal death at doses 1.25 times and higher the MRHD by The rate is consistent with previous intravenous experience. No correlation of antibody the intravenous route at maternal intravenous doses of 10 and 50 mg/ kg. Testing of a murine development to adverse events or loss of clinical response was observed. analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the Laboratory Abnormalities pre- and postnatal development phase when dosed at 50 mg/kg intravenously with treatment Neutropenia During routine laboratory monitoring in the 6-month controlled clinical trials, a every three days from implantation (GD 6) until post-partum day 21 (weaning). There was no decrease in neutrophil count below 1 × 109/L occurred in 2.9% and 3.7% of patients receiving evidence for any functional impairment of the development and behavior, learning ability, immune ACTEMRA-SC weekly and every other week, respectively. competence and fertility of the offspring. There was no clear relationship between decreases in neutrophils below 1 x 109/L and the Parturition is associated with significant increases of IL-6 in the cervix and myometrium. The occurrence of serious infections. literature suggests that inhibition of IL-6 signaling may interfere with cervical ripening and Thrombocytopenia During routine laboratory monitoring in the ACTEMRA-SC 6-month controlled dilatation and myometrial contractile activity leading to potential delays of parturition. For clinical trials, none of the patients had a decrease in platelet count to ≤50,000/mm3. mice deficient in IL-6 (ll6-/- null mice), parturition was delayed relative to wild-type (ll6+/+) mice. Elevated Liver Enzymes During routine laboratory monitoring in the 6-month controlled clinical Administration of recombinant IL-6 to ll6-/- null mice restored the normal timing of delivery. trials, elevation in ALT or AST ≥3 x ULN occurred in 6.5% and 1.4% of patients, respectively, 8.2 Lactation receiving ACTEMRA-SC weekly and 3.4% and 0.7% receiving ACTEMRA SC every other week. Risk Summary Lipid Parameters Elevations During routine laboratory monitoring in the ACTEMRA-SC 6-month No information is available on the presence of tocilizumab in human milk, the effects of the drug clinical trials, 19% of patients dosed weekly and 19.6% of patients dosed every other week and on the breastfed infant, or the effects of the drug on milk production. Maternal immunoglobulin 10.2% of patients on placebo experienced sustained elevations in total cholesterol > 6.2 mmol/l G (IgG) is present in human milk. If tocilizumab is transferred into human milk, the effects of local (240 mg/dL), with 9%, 10.4% and 5.1% experiencing a sustained increase in LDL to 4.1 mmol/l exposure in the gastrointestinal tract and potential limited systemic exposure in the infant to (160 mg/dL) receiving ACTEMRA-SC weekly, every other week and placebo, respectively. tocilizumab are unknown. The lack of clinical data during lactation precludes clear determination 6.3 Clinical Trials Experience in Giant Cell Arteritis Patients Treated with Subcutaneous of the risk of ACTEMRA to an infant during lactation; therefore the developmental and health ACTEMRA (ACTEMRA-SC) benefits of breastfeeding should be considered along with the mother’s clinical need for The safety of subcutaneous ACTEMRA (tocilizumab) has been studied in one Phase III study ACTEMRA and the potential adverse effects on the breastfed child from tocilizumab or from the (WA28119) with 251 GCA patients. The total patient years duration in the ACTEMRA GCA underlying maternal condition. all exposure population was 138.5 patient years during the 12-month double blind, placebo- 8.5 Geriatric Use controlled phase of the study. The overall safety profile observed in the ACTEMRA treatment Of the 2644 patients who received ACTEMRA in Studies I to V [see Clinical Studies (14)], a total of groups was generally consistent with the known safety profile of ACTEMRA. There was an overall 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years higher incidence of infections in GCA patients relative to RA patients. The rate of infection/serious and older. Of the 1069 patients who received ACTEMRA-SC in studies SC-I and SC-II there were infection events was 200.2/9.7 events per 100 patient years in the ACTEMRA weekly group and 295 patients 65 years of age and older, including 41 patients 75 years and older. The frequency 160.2/4.4 events per 100 patient years in the ACTEMRA every other week group as compared to of serious infection among ACTEMRA treated subjects 65 years of age and older was higher than 156.0/4.2 events per 100 patient years in the placebo + 26 week prednisone taper and 210.2/12.5 those under the age of 65. As there is a higher incidence of infections in the elderly population in events per 100 patient years in the placebo + 52 week taper groups. general, caution should be used when treating the elderly. 8.6 Hepatic Impairment 7 DRUG INTERACTIONS The safety and efficacy of ACTEMRA have not been studied in patients with hepatic impairment, 7.1 Concomitant Drugs for Treatment of Adult Indications including patients with positive HBV and HCV serology [see Warnings and Precautions (5.7)]. In RA patients, population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. 8.7 Renal Impairment No dose adjustment is required in patients with mild or moderate renal impairment. ACTEMRA Concomitant administration of a single intravenous dose of 10 mg/kg ACTEMRA with 10-25 has not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3)]. mg MTX once weekly had no clinically significant effect on MTX exposure. ACTEMRA has not been studied in combination with biological DMARDs such as TNF antagonists [see Dosage and 10 OVERDOSAGE Administration (2.1)]. There are limited data available on overdoses with ACTEMRA. One case of accidental overdose In GCA patients, no effect of concomitant corticosteroid on tocilizumab exposure was observed. was reported with intravenous ACTEMRA in which a patient with multiple myeloma received 7.2 Interactions with CYP450 Substrates a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, B:11.125” T:10.875” cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab may although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia. S:10.625” restore CYP450 activities to higher levels than those in the absence of tocilizumab leading In case of an overdose, it is recommended that the patient be monitored for signs and symptoms to increased metabolism of drugs that are CYP450 substrates. In vitro studies showed that of adverse reactions. Patients who develop adverse reactions should receive appropriate tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, symptomatic treatment. CYP2B6, CYP2C9, CYP2C19, CYP2D6 and CYP3A4. Its effect on CYP2C8 or transporters is unknown. In vivo studies with omeprazole, metabolized by CYP2C19 and CYP3A4, and 17 PATIENT COUNSELING INFORMATION simvastatin, metabolized by CYP3A4, showed up to a 28% and 57% decrease in exposure See FDA-approved patient labeling (Medication Guide) one week following a single dose of ACTEMRA, respectively. The effect of tocilizumab on CYP Patient Counseling enzymes may be clinically relevant for CYP450 substrates with narrow therapeutic index, where Advise patients of the potential benefits and risks of ACTEMRA. Physicians should instruct their the dose is individually adjusted. Upon initiation or discontinuation of ACTEMRA, in patients patients to read the Medication Guide before starting ACTEMRA therapy. being treated with these types of medicinal products, perform therapeutic monitoring of effect • Infections: (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) and the individual Inform patients that ACTEMRA may lower their resistance to infections. Instruct the patient of the dose of the medicinal product adjusted as needed. Exercise caution when coadministering importance of contacting their doctor immediately when symptoms suggesting infection appear ACTEMRA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., in order to assure rapid evaluation and appropriate treatment. oral contraceptives, lovastatin, atorvastatin, etc. The effect of tocilizumab on CYP450 enzyme • Gastrointestinal Perforation: activity may persist for several weeks after stopping therapy [see Clinical Pharmacology (12.3)]. Inform patients that some patients who have been treated with ACTEMRA have had serious side 7.3 Live Vaccines effects in the stomach and intestines. Instruct the patient of the importance of contacting their Avoid use of live vaccines concurrently with ACTEMRA [see Warnings and Precautions (5.8)]. doctor immediately when symptoms of severe, persistent abdominal pain appear to assure rapid evaluation and appropriate treatment. 8 USE IN SPECIFIC POPULATIONS • Hypersensitivity and Serious Allergic Reactions: 8.1 Pregnancy Assess patient suitability for home use for SC injection. Inform patients that some patients Pregnancy Exposure Registry who have been treated with ACTEMRA have developed serious allergic reactions, including There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed anaphylaxis. Advise patients to seek immediate medical attention if they experience any to ACTEMRA during pregnancy. Physicians are encouraged to register patients and pregnant symptom of serious allergic reactions. women are encouraged to register themselves by calling 1-877-311-8972. Instruction on Injection Technique Risk Summary Perform the first injection under the supervision of a qualified healthcare professional. If a The limited available data with ACTEMRA in pregnant women are not sufficient to determine patient or caregiver is to administer subcutaneous ACTEMRA, instruct him/her in injection whether there is a drug-associated risk for major birth defects and miscarriage. Monoclonal techniques and assess his/her ability to inject subcutaneously to ensure proper administration antibodies, such as tocilizumab, are actively transported across the placenta during the third of subcutaneous ACTEMRA and the suitability for home use [see Patient Instructions for Use]. trimester of pregnancy and may affect immune response in the in utero exposed infant [see Prior to use, remove the prefilled syringe from the refrigerator and allow to sit at room temperature Clinical Considerations]. In animal reproduction studies, intravenous administration of tocilizumab outside of the carton for 30 minutes, out of the reach of children. Do not warm ACTEMRA in any to Cynomolgus monkeys during organogenesis caused abortion/embryo-fetal death at doses other way. 1.25 times and higher than the maximum recommended human dose by the intravenous route of Advise patients to consult their healthcare provider if the full dose is not received. 8 mg per kg every 2 to 4 weeks. The literature in animals suggests that inhibition of IL-6 signaling A puncture-resistant container for disposal of needles and syringes should be used and should may interfere with cervical ripening and dilatation and myometrial contractile activity leading to be kept out of the reach of children. Instruct patients or caregivers in the technique as well as potential delays of parturition [see Data]. Based on the animal data, there may be a potential risk proper syringe and needle disposal, and caution against reuse of these items. to the fetus. Pregnancy Exposure Registry The estimated background risk of major birth defects and miscarriage for the indicated population Inform patients that there is a pregnancy registry to monitor fetal outcomes of is unknown. All pregnancies have a background risk of birth defect, loss or other adverse pregnant women exposed to ACTEMRA [see Use in Specific Populations (8.1)]. outcomes. In the U.S. general population, the estimated background risk of major birth defects Pregnancy and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Inform female patients of reproductive potential that ACTEMRA may cause fetal harm Clinical Considerations and to inform their prescriber of a known or suspected pregnancy [see Use in Specific Fetal/Neonatal adverse reactions Monoclonal antibodies are increasingly transported across the Populations (8.1)]. placenta as pregnancy progresses, with the largest amount transferred during the third trimester. Risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to ACTEMRA in utero [see Warnings and Precautions (5.8)].

10751079_GCA_NOW_JA_EYE_M1.indd 4 PREPARED BY FCB 8/14/17 5:19 PM Releasing as: PDFx1A Production: Maria Abreu x3124 Job #: 10751079 Colors: 4/1 (4C Process/Black) AD: Trent Orvis x2492 Client: Genentech Flat Size: 16.25”w X 10.875”h AE: Katie Majewski x7927 Product: Actemra Bleed: 16.5”w X 11.125”h Producer: Karisa Williams x3721 Client Code: ACT/071217/0075 Trim: 16.25”w X 10.875”h QC: L.Powell Date: August 14, 2017 5:19 PM Safety: 15.75”w X 10.375”h Digital Artist: VA, Add’l Size Info: PI Page Dimensions - Trim 8.125”w X 10.875”h; Live 7.875”w Proof: M1 X 10.625”h; Bleed 8.375”w X 11.125”h Fonts: Helvetica Neue LT Std, Avenir M1 Spellcheck: Jacob Albrecht FR Spellcheck: Path: PrePress:Genentech:10751079:10751079_GCA_NOW_JA_EYE_M1 4C GCA 2017 Journal Ad: Eyenet PATIENT EDUCATION TOOLS Turn Your Patients into Informed Partners

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From Bundled Codes to Foiled Surgeries: Test Your Coding Competency, Part 2

arlier this year, Savvy Coder chal- A. The latter. Whether you are Q14. How often must we have the lenged you to tackle 9 questions selecting from the Evaluation and patient fill out new paperwork for the E(see “Test Your Coding Compe- Management (E&M) codes or the Eye Review of Systems (ROS) and Past, tency,” May, which is available at aao. visit codes—and whether or not you’re Family, and Social History (PFSH)? org/eyenet?may-2017). using the new taxonomy designation— A. Prior documentation can be ref- In Part 2, you get another chance to you must select an established patient erenced at each exam (if medically nec- demonstrate your coding savvy. code. essary and pertinent to today’s visit), Q12. A hospital inpatient requires but new paperwork is only needed if/ 9 More Questions to Tackle an ophthalmologic evaluation. The when the rules change or if the patient Q10. The CPT codes for glaucoma patient is transported to your office is “new” again. OCT (92133) and retina OCT (92134) for the exam. Which of the follow- Q15. Sometimes a physician is are bundled together under the Na- ing statements is true: a) place of forced to terminate a surgical proce- tional Correct Coding Initiative (NCCI, service is office, b) place of service dures. Such procedures have a global usually shortened to CCI). Typically, 2 is hospital, or c) the patient himself period—true or false? bundled codes—also known as a CCI is responsible for payment of this A. False. Surgical procedures ap- edit—can’t both be billed when the 2 noncovered exam. pended with modifier –53, indicating services were performed by the same A. Place of service is hospital. When that the procedure was discontinued, physician on the same eye on the same patients are in your records as inpa- do not have a global period. day. But under certain circumstances, tients, they can’t have an outpatient Q16. What component of the bill some CCI edits can be unbundled, exam until they are released from the isn’t paid by Medicare Part B while which means that the 2 codes in hospital. the patient is in a skilled nursing the CCI edit can both be billed. Is it Q13. Payers think it is acceptable facility? appropriate to unbundle CPT codes to document an exam by copying and A. Medicare Part B will not pay for 92133 and 92134 as long as you have pasting from, or pulling forward from, the technical component of any test, 2 separate diagnosis codes? a previous exam—true or false? any drug injected, or postoperative A. No. They are bundled together A. Absolutely false! While you may cataract glasses. with a CCI mutually exclusive edit, think this is a time-saving benefit of Q17. Regarding CPT code 92226 which means they can never be unbun- your electronic health record (EHR) (extended ophthalmoscopy, subse- dled. system, it is the payer’s No. 1 area of quent), payment is made whether Q11. The retina specialist refers a review. From the payer perspective, there is a change or not, as long as a patient to the glaucoma specialist in payment is made from the information picture is drawn—true or false? the same office. When the patient obtained today and pertinent to today’s A. False. Payment is for drawing and sees the glaucoma specialist, should exam. For this reason, some audits labeling the change in pathology from it be billed as a service involving a request a series of exams rather than a the past visit. “new” or an “established” patient? single exam note. Q18. Before hiring a new physician, it’s best to check the Medicare exclu- sion list maintained by the Office of BY SUE VICCHRILLI, COT, OCS, ACADEMY DIRECTOR OF CODING; JENNY Inspector (OIG)—true or false? EDGAR, CPC, CPCO, OCS, ACADEMY CODING SPECIALIST; ELIZABETH A. True. If action has been taken COTTLE, CPC, OCS; JOY WOODKE, COE, OCS; AND MATTHEW BAUGH, against a physician, no payments can MHP, COT, OCS. be made to that physician by Medicare.

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How to Boost Website Accessibility for Those With Low Vision or No Vision

or people with low or no vision, the computer is a powerful means Busting 2 Myths About Online Accessibility Fof gaining independence, said Brad Martin, who has been blind since Myth 1: Practices can’t afford to optimize their web pages for low (and no) birth. “Before modern web technology, vision. It is a common misconception that it is expensive and time-consuming I had a much harder time paying bills, to make web content accessible to those with low vision. A few minor tweaks buying things from a catalog, or reading may be all that is needed to make your practice “visible” to all of your pa- a newspaper without sighted assistance. tients. Now I can do all of those things.” Myth 2: Sighted people will be turned off by web pages that are opti- Websites can help—or hinder— mized for low (and no) vision. “A good website can incorporate certain com- patients with low vision. “When you ponents that help those with low or no vision, and these will be completely make your website accessible, you open undetectable to the sighted user,” said Mr. Martin. “Although these elements the door to allowing people like me to make a website easier for people with low vision to read, you can still build a access the content you are offering,” perfectly attractive, usable, and popular website.” said Mr. Martin, who works with the United Way of Southwest Alabama in Mobile. “Conversely, if your site is inaccessible, I am likely to abandon it • the total number of “errors” found, recommendations for web accessibility and move on to another that meets my • the type of error, around the world. You can make your needs.” • where on the page the error is located, website more accessible by following and those guidelines, which are based on Getting Started • how it should be corrected. the POUR principle of web design: Can your practice website do more to “This is a great way to determine • Perceivable: The content is available to accommodate those with low vision what improvements can be made, and the senses either through the browser and blindness? Here are some steps to it is where the Alabama Institute for the or through other assistive technologies take. Deaf and Blind started when restruc- (e.g., screen readers or screen magni- First, evaluate your site. One of the turing their website,” said Stephen M. fiers). quickest and easiest ways to determine Sullivan, PhD, who has been teaching • Operable: Users can access all controls whether your website is accessible to about computers at the Institute for and interactive elements using a mouse, low vision and no vision visitors is to 25 years. Dr. Sullivan also speaks from keyboard, or other assistive device. use the free online Web Accessibility experience, as he has low vision. • Understandable: The content is clear, Evaluation Tool (WAVE; available at Seek guidance from reliable re- without confusion and ambiguity. Keep http://wave.webaim.org). sources. The Web Content Accessibility your wording simple and concise. Simply type in the URL of the page Guidelines (WCAG; www.w3.org/TR/ • Robust: If you follow best practices you want to assess, and the results WCAG20/) were developed by the when building web pages—by, for are displayed within seconds. WAVE Worldwide Web Consortium (W3C), instance, following HTML/XHTML identifies: and they provide the foundational specifications and using form labels and frame titles appropriately—then you will make it easier for screen readers BY LESLIE BURLING-PHILLIPS, CONTRIBUTING WRITER, INTERVIEWING and other tools to convey your infor- BRAD MARTIN AND STEPHEN M. SULLIVAN, PHD. mation to the user.

EYENET MAGAZINE • 61 Create a User-Friendly Website use black letters on a blue background “There is nothing worse than filling out Stick with the basics. According to just because the blue matches the color an entire form and then getting stuck at Dr. Sullivan, the most significant, least in your logo.” the end because you cannot complete expensive improvements a practice can Use an easily readable font. Text the captcha, particularly when there is make involve (1) implementing minor should be displayed in a clear font that no one home who can see to get you adjustments to contrast and font and is universally available such as Times out of the jam,” said Mr. Martin. “If you (2) creating a concise and clutter-free New Roman or Arial. Other fonts may must use a captcha, consider the type organizational pattern on the practice’s be used, as long as they are not unnec- that asks the submitter to solve a simple website. essarily complicated and as long as the math problem; for instance, ‘What is 3 You don’t need to add expensive letters are easily distinguishable. added to 5?’ or ‘What is 5 take away 3?’” accessibility tools. An organization doesn’t need to incorporate accessibility Features to Avoid Use Alternate Text tools—such as magnification options From flashing images and fancy fonts Provide alternate text for images. or audio feedback—for those with low to elaborate borders and pop-ups, Websites commonly fail to use a simple or no vision. Adding such tools “can be “developers tend to frill things up and helpful tactic: labeling images and an expensive endeavor, and it is totally try to make their sites look cool. While buttons with alternative text that can unnecessary. Anyone coming to the web these may be visually appealing to be read by a screen reader. This is done with low or no vision will already have some, they actually divert [the visitor’s using an HTML element called an “alt the tools they need to navigate your attention] away from the information tag.” A basic descriptor is enough—for site. If you incorporate this addition- that you are trying to deliver,” said Dr. example, a photo of a Snellen chart al functionality, I have an entire new Sullivan, who added that the premise should include alternate text within system to learn, and it is a redundant of KISS—keep it simple, stupid—is a the source code that states the photo is addition,” said Dr. Sullivan. good rule of thumb to follow. Adding of a Snellen Chart. And this isn’t just too much embellishment “only mud- helpful for users with screen readers; if Focus on Legibility dies the water, and these elements are somebody has a slow connection, the Contrast is key. It is difficult for in- not important to the end user.” alternative text might appear instead of dividuals with low vision to navigate Avoid pop-ups. Pop-ups are an an- the image. websites with color combinations that noyance to just about everyone online, Provide alternate text for buttons. are not easy to differentiate. Some but they can be particularly problem- Alt tags are especially important for users, for example, prefer white letters atic for individuals with low vision. For buttons (e.g., Home, About Us, Blog, on a black background rather than example, they can be difficult to navi- and Contact Us) on your website. Mr. black letters on a white background; gate away from. Many pop-ups can be Martin explained, “When a designer others prefer a black font on a yellow closed by clicking on an “x.” Someone uses a button with text in it and then background because it produces less who is sighted can readily recognize saves that button as an image file—such glare. These options can be adjusted that a pop-up has appeared and swiftly as a JPEG image—the screen reader by the end user via their web browser. get rid of it by clicking on the “x,” said does not know how to interpret that You can help, said Mr. Martin, by using Dr. Sullivan. However, if you are using information without an alt tag.” The “text and background colors that allow a screen magnifier, and can see only a result is that the screen reader reads for easy reading. Don’t, for example, small section of the Web page—per- the image as “Graphic” and then reads haps even just a few words—it might the URL that the button links to (e.g., not be easy to find out how to close “graphic/forms/contact.php”). “But the pop-up. Indeed, you might not be when an alt tag is incorporated, the Patient Resources aware that a pop-up has appeared. blind user hears the words provided in Do not use sliders. When seeking the tag, such as ‘Contact Us,’ which the The Academy’s initiative in vision input from your patients and website sighted user does not see because the rehabilitation includes a handout for visitors through surveys, avoid us- image is displayed instead.” patients that can be downloaded for ing sliders to gain feedback. “There Mr. Martin is a program coordinator for the free. Go to aao.org/low-vision-and- is no way to manipulate them with a United Way of Southwest Alabama in Mobile. vision-rehab and scroll down to “Ma- keyboard, and a blind person cannot Relevant financial disclosures: None. terials for Patients With Low Vision.” effectively control a mouse,” said Mr. Dr. Sullivan is case manager and project director The handout explains common Martin. for the Alabama Institute for Deaf and Blind in types of vision loss, offers reassur- Avoid using captchas. A captcha is Mobile. Relevant financial disclosures: None. ance that the impact on daily activi- a submission tool that is used to prove ties can be minimized, lists resources, that a visitor is a human rather than a MORE ONLINE. Read this and explains how occupational ther- malign software application (or “bot”). article at aao.org/eyenet to apy through a rehabilitation program A captcha might, for example, ask you learn what Facebook has done to boost can help patients remain active. to discern letters from a distorted image. accessibility.

62 • OCTOBER 2017 New Solutions Enhance Patient Care With New Insights at AAO 2017 Hear from thought leaders in every subspecialty about their latest treatment strategies to improve patient care. • Predict future potential therapies of molecularly targeted agents in oculoplastic surgery. • Learn how to manage infections following procedures such as endothelial keratoplasty and LASIK. • Hear about recent advancements in anti- glaucomatous medications and drug delivery systems. • Determine better methods to handle cataract complications. Join Your Colleagues AAO 2017 November 11 – 14 Subspecialty Day November 10 – 11 AAOE Program November 11 – 14

Register and Book Your Room October 13 • Last day for U.S. attendees to register and have your badge and meeting materials mailed to you before the meeting (international deadline has passed). • Last day to preregister with discounted fees.

aao.org/registration.

View this short video at aao.org/2017 to see what new opportunities await you at AAO 2017 — Where all of ophthalmology meets®.

The American Academy of Ophthalmology is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. New Strategies

aao.org/2017 #aao2017 Annual Meeting — Learn from and connect Grow Your Network with ophthalmology’s best and brightest from around the world. There’s always and Career as something new at the Academy’s annual meeting — Where all of ophthalmology Part of a Global meets® (a $975 value). Ophthalmic News & Education (ONE®) Community Network — Stay on top of the latest clinical developments. Access and comment on Renew your Academy thousands of instructional videos, self- membership to maintain access assessment questions, interactive quizzes, and courses — plus Ophthalmology®, EyeNet® to the most valuable benefits Magazine and 10 other journals. within our profession. Find an Ophthalmologist — Market your practice and let potential patients find you easily by area or subspecialty. You can also connect with your peers and see extended members-only details of your colleagues.

Activate your benefits and renew your valuable membership today. aao.org/benefits Academy Notebook NEWS ● TIPS ● RESOURCES

WHAT’S HAPPENING

Orbital Gala Auction Opens Next Month Tickets to the Academy Foundation’s Orbital Gala at AAO 2017 in New Orleans are available for purchase until Nov. 6. This year’s auction features a wide variety of items including BID ON THE OPTOS CALIFORNIA. This device an Optos California ultra-widefield allows you to capture 200 degrees (or up to 82%) retinal imaging unit, a stay at the of the retina in a single image. Occidental Grand Papagayo in Costa Rica, gift certificates for Marion Parke names were drawn in the raffle to win participating in MIPS and satisfy the luxury footwear, fine wine, scotch, complimentary accommodations (up minimum 90-day performance period and more. Join the bidding during to 5 nights) at the Hyatt Regency New for the 3 performance categories that the Orbital Gala on Nov. 12 in New Orleans during AAO 2017 in November. contribute to your final score: quality, Orleans. The Academy conducts a biennial advancing care information (ACI), and Unable to attend the Orbital Gala? practice environment survey to learn improvement activities. (Note: If you are U.S. members can use their mobile about members’ general attitudes toward reporting quality via the IRIS Registry, device to bid on auction items starting ophthalmology, and to gather infor- you can enter data for quality measures Nov. 6. mation on practice demographics and retroactively, but claims-based report- For an auction preview and to buy patient services. The primary objective ing of quality measures must be done tickets to the gala, visit aao.org/foun of the research is to capture practice in real time.) dation. environment statistics and gain a better By Oct. 31, sign up for the IRIS Reg- understanding of member needs. The istry web portal. You can use the IRIS TAKE NOTICE findings will enable the Academy to Registry web portal to manually report develop programs and services that are quality measures, ACI measures, and Raffle Winners From truly responsive and relevant to the improvement activities. (Note: If you Academy Member Survey ophthalmologist community. A sum- have already signed up for IRIS Regis- The winners of the raffle prize for mary of the results will be published in try, including for EHR integration, you completing the Academy’s ophthal- the November issue of EyeNet. don’t need to sign up again for the web mology practice environment member portal.) survey are Clint W. Gregg, MD, from MIPS Alert! Don’t Miss To sign up for the IRIS Registry web Lubbock, Texas, and Dan K. Sakamoto, the October Deadlines portal, visit aao.org/iris-registry and MD, from Torrance, California. Their If you are participating in the Merit- click “Sign up.” Based Incentive Payment System For more information on MIPS, (MIPS), be sure to note the 2 upcoming visit aao.org/medicare. deadlines. For a comprehensive guide to By Oct. 2, start your 90-day MIPS, check out EyeNet’s MIPS performance period. CMS has des- Manual 2017 at aao.org/eyenet/mips- ignated Oct. 2 as the last day to start manual-2017.

EYENET MAGAZINE • 65 ACADEMY STORE tion will be posted on the Academy’s Affairs. Involved with legislative and website (aao.org/about/governance/ regulatory issues at the federal and state Hone Your Skills With Virtual elections) by Dec. 18, 2017. level collaborating with ophthalmol- Cases on the ONE Network ogy leaders, executives, lobbyists, and Continue your lifelong learning with national medical associations (such as virtual cases that provide CME self- CANDIDATES’ VIEWS the AMA and ACS) to advance quality assessment credits. For example, check patient care. Advanced international George A. Williams, MD out “Down on the Farm” to solve the advocacy issues by sharing knowledge Board of Trustees Nominee for case of a 63-year-old woman struck and strategy. President-Elect in her right eye with hay while Leadership experience. Academy working in the field. She went Career. Vitreoretinal Senior Secretary for Advocacy past 3 to her optometrist, who surgeon since 1984 in years. Arizona Medical Association removed the foreign body both full-time academ- board member and Arizona Ophthal- from her cornea. Review her ic and private practice. mological Society president in 2000. history, assess test results, and Partner at Associated Graduated from the Academy’s Lead- make your diagnosis. Retinal Consultants in ership Development Program II, class For a full list of virtual cas- Royal Oak, Michigan; of 2000, then served as LDP director es, visit aao.org/onenetwork. Dr. Williams professor and chair for 6 years. Served on the Academy’s of ophthalmology at committees on aging, membership, Subscribe to Oakland University William Beau- and awards, as well as the Committee Ophthalmology Retina mont School of Medicine; director at for State Organizational Development. The Academy’s Ophthalmology Retina, Beaumont Eye Institute. Trained 102 Served as Associate Secretary for State a peer-reviewed journal focused exclu- residents and 62 fellows. Past president Affairs, and Secretary for State Affairs sively on the latest advances in retina, of Michigan Society of Eye Physicians overseeing the committees for state is now available for order. The new and Surgeons and ASRS. Member of organizational development and state publication reports the same high qual- Association of University Professors of governmental affairs as well as the Sur- ity of work seen in Ophthalmology, but Ophthalmology, Retina Society, Macula gical Scope Fund Committee. Currently topics are specialized for retina readers. Society, ASRS, and Club Jules Gonin. serve on the OMIC and Pan-American Subscriptions are available to members Fellow of ARVO. Current Chair, OMIC Association of Ophthalmology boards. for $299 (12 issues). Board of Directors. Grandfathered Clinical experience. Comprehensive To subscribe, visit store.aao.org/ ABO diplomate in 1983, recertified in ophthalmologist for 27 years facing the ophthalmology-retina.html. 2005, 2016. challenges of private practice. Medi- AAO service. Past Trustee-at-Large; cal director of large ASC for 17 years. FOR THE RECORD current Secretary, Federal Affairs; Committed to advocating for quality current member, AMA Relative Value patient care and our profession on the Annual Business Meeting Update Committee. Past member of state and national levels. Notice is hereby given that the Annu- Health Policy Committee, Executive al Business Meeting of the American Committee, Nominations Committee. William S. Clifford, MD Academy of Ophthalmology will be Goal. To work with all stakehold- Board of Trustees Nominee for held Sunday, Nov. 12, in the Great Hall ers to further the Academy’s mission Trustee-at-Large of the Morial Convention Center in of protecting sight and empowering New Orleans from 8:30 to 10:30 a.m. lives through continued excellence and I am a comprehensive ophthalmologist Candidates for membership will be innovation in education, clinical care, in an underserved area of rural South approved during this meeting. For the and advocacy. west Kansas. Prior to joining Dr. Luther full list of names, visit aao.org/mem Fry in 1995, I spent a year at the King ber-services/candidates. To see the full Daniel J. Briceland, MD Khaled Eye Specialist Hospital in order of business, refer to the Opening Board of Trustees Nominee for Senior Riyadh. I completed residency and fel- Session page of the Meeting Guide. Secretary for Advocacy lowship at the University of Oklahoma, where I specialized in both glaucoma Academy Election Advocacy experience. and cornea/refractive surgery. The election for open posi- More than 23 years on My Academy experience is broad tions on the Board of Trustees state medical and oph- in both clinical education and advo- begins on Monday, Nov. 13, thalmology legislative cacy. For 10 years I was a member and and closes after 30 days. Elec- and PAC committees, subsequent Chair of the Practicing tion materials will be sent to and 17 years with the Ophthalmologists Advisory Committee all voting Academy fellows and Academy’s Secretariat for Education, as well as the Glaucoma members. Results of the elec- Dr. Briceland for State and Federal Editor for Focal Points. I currently

66 • OCTOBER 2017 represent Kansas on the Academy’s D.C. REPORT Council, and I am on the OphthPAC Committee. In 1999, I graduated Academy Pushes for Zero Penalties with the first Academy Leadership Develop- for 2019 ment class. The Academy is urging ophthalmologists to take advantage of Medi- Our profes- care’s significant flexibility in the first year of the Medicare-Based sion is held in Incentive Payment Program. Doing so will ensure that physicians do high esteem not receive a penalty impacting 2019 Medicare pay. The Academy’s by both the advocacy efforts helped secure major concessions from the Centers public and public for Medicare & Medicaid Services for the inaugural reporting period servants. As a for its new Medicare physician payment program. Now, our Zero Pen- Trustee-at-Large, Dr. Clifford alties campaign is working to ensure that every Academy member I will encourage understands what they need to do to avoid a 4% negative payment our members to increase their engage- adjustment. ment with policymakers. I thank you One step to avoid penalties. There is an easy step you can take for allowing me to be your voice as today to avoid any Medicare reimbursement penalties based on 2017 your representative on the Board of reporting. If you report one quality measure for one patient just once Trustees. in 2017, you will avoid a hit to your bottom line in 2019. It will take no more than 5 minutes, and will save you $20,000-35,000 in Medicare Lynn K. Gordon, MD, PhD revenue. You must complete this step by Dec. 31, 2017, to avoid any Board of Trustees Nominee for penalties in 2019. The Academy strongly recommends completing Council Chair this step immediately. To get started, visit aao.org/zeropenalty2019. I am a professor of ophthalmology at the Stein Eye Institute and senior associate dean at the David Geffen School of Medicine at UCLA. After residen- advocacy. It would be a great honor Achievement Award, Leadership Devel- cy, I spent 5 years in private practice to serve as the Council Chair to help opment Award, and Leo Award. Other before returning to the university as a promote these goals. leadership: Board of Directors of the physician-scientist. These experiences Tennessee Academy of Ophthalmology, allow me to understand Sarwat Salim, MD, FACS Wisconsin Academy of Ophthalmol- the challenges of Board of Trustees Nominee for ogy, Commission on Accreditation of clinical practice in Council Vice Chair Ophthalmic Medical Programs, and different settings. Women in Ophthalmology; American My profes- My career has been in academic med- Glaucoma Society (Patient Care sional society icine. Currently, I am professor of Committee, Commissioner involvement ophthalmology at the Medical to JCAHPO, and Annu- with the Acade- College of Wisconsin in Mil- al Meeting Program my includes my waukee, where my practice fo- Planning Committee); Dr. Gordon current position cuses on medical and surgical ABO (Glaucoma as the Vice Chair management of glaucoma. Exam Development for the Council. Past involvement Academy involvement: the Committee, Content includes being a councilor for both Council as ACS Councilor, Outline Revision Com- the State and Subspecialty/Specialized Deputy Section Leader, and mittee, and Oral Board Interest Sections. Committee activities Section Nominating Committee Dr. Salim Examiner). included the BCSC Neuro-Ophthal Member; Focal Points Editorial I would be honored mology Section, Nominating Commit- Board; Section Lead Editor for Glau- to use my experience, skill sets, and tee, Awards Committee, and Credentials coma for EyeWiki; Knowledge Base broad perspective in understanding the Committee. I am also a graduate of Glaucoma Panel Committee; Digital needs of the members and facilitating the Leadership Development Program Media Committee Managing Editor for communication and coordination (2008). Glaucoma DVD; Young Surgeon Rep- between them and the Board. I look I am dedicated to the Academy’s resentative to ACS. Awards received: forward to contributing further as Vice mission in its quest to preserve sight Senior Achievement Award, Award for Chair of the Council. and empower lives through outstand- Exemplary Contributions as Glaucoma ing, equitable patient-centered care, Section Lead Editor of EyeWiki, Special For the full statements, visit aao. surgery by surgeons, education, and Recognition Award, Secretariat Award, org/about/governance/elections.

EYENET MAGAZINE • 67 Get live access to experts on timely topics

Introducing a New Clinical Webinar Series

Each month the American Academy of Ophthalmology brings you ophthalmic leaders and experts to discuss important topics like OCT, neuro-ophthalmology, retina and surgical complications.

Join us live or watch on demand. Visit aao.org/store ACRYSOF® IQ RESTOR® FAMILY OF MULTIFOCAL IOLS IMPORTANT PRODUCT INFORMATION CAUTION: Federal (USA) law restricts this device to the sale by or on the order of a physician. INDICATIONS: The AcrySof® IQ ReSTOR® Posterior Chamber Intraocular Multifocal IOLs include AcrySof® IQ ReSTOR® and AcrySof® IQ ReSTOR® Toric and are intended for primary implantation for the visual correction of aphakia secondary to removal of a cataractous lens in adult patients with and without presbyopia, who desire near, intermediate and distance vision with increased spectacle independence. In addition, the AcrySof® IQ ReSTOR® Toric IOL is intended to correct pre-existing astigmatism. The lenses are intended to be placed in the capsular bag.

WARNINGS/PRECAUTIONS: Careful preoperative evaluation and sound clinical judgment should be used by the surgeon to decide the risk/benefit ratio before implanting a lens in a patient with any of the conditions described in the Directions for Use labeling for each IOL. Physicians should target emmetropia, and ensure that IOL centration is achieved. Care should be taken to remove viscoelastic from the eye at the close of surgery. The ReSTOR Toric IOL should not be implanted if the posterior capsule is ruptured, if the zonules are damaged, or if a primary posterior capsulotomy is planned. Rotation can reduce astigmatic correction; if necessary lens repositioning should occur as early as possible prior to lens encapsulation. Some patients may experience visual disturbances and/or discomfort due to multifocality, especially under dim light conditions. A reduction in contrast sensitivity may occur in low light conditions. Visual symptoms may be significant enough that the patient will request explant of the multifocal IOL. Spectacle independence rates vary; some patients may need glasses when reading small print or looking at small objects. Posterior capsule opacification (PCO), when present, may develop earlier into clinically significant PCO with multifocal IOLs. Prior to surgery, physicians should provide prospective patients with a copy of the Patient Information Brochure available from Alcon informing them of possible risks and benefits associated with the AcrySof® IQ ReSTOR® IOLs. Do not resterilize; do not store over 45° C; use only sterile irrigating solutions such as BSS® or BSS PLUS® Sterile Intraocular Irrigating Solutions.

ATTENTION: Reference the Directions for Use labeling for each IOL for a complete listing of indications, warnings and precautions. NEW ORLEANS Please Join Us

THE GRAND ESSENTIAL OF PRESBYOPIA CORRECTION THE DIFFERENCE IS IN THE DISTANCE Join us for an evening of dynamic discussions around real world success with AcrySof® IQ Moderator & Panel Faculty ReSTOR® +2.5 Toric with the ACTIVEFOCUS™ design focusing on cases utilizing: • The one eye at a time method • Modern Toric calculator tips

® ® • ORA SYSTEM with VerifEYE + Technology Bonnie Henderson, MD* Zaina Al-Mohtaseb, MD* Jeff Horn, MD* Steve Scoper, MD* Moderator Faculty Faculty Faculty • Femto and Manual techniques *All physicians are Alcon paid consultants. Location Agenda River City Complex at Mardi Gras World November 10, 2017 1400 Port of New Orleans 5:30 – 6:15 pm Registration with light hors d’oeuvres New Orleans, LA 6:15 – 7:15 pm Symposium 7:15 – 8:00 pm Reception at the Grand Oaks Mansion Register Here to Join Us bit.ly/ACTIVEFOCUSToric

This event is not affiliated with the official program of the AAO Meeting. No continuing education credits will be available. © 2017 Novartis 8/17 US-RES-17-E-2275 Destination AAO 2017 GET READY FOR NEW ORLEANS l PART 5 OF 6

BEAT THE CLOCK

Book Your Room Now The Academy has secured discounted hotel rooms, but space is limited. Book online. Visit aao.org/hotels for an interactive map listing hotel ameni- ties and availability, reservations, and information on international group reservations. Book by phone or email. Agents at REGISTER BY OCT. 13 TO AVOID LINES AND ADDITIONAL FEES. AAO 2017 is held Expovision, the Academy’s official hotel at Ernest N. Morial Convention Center Nov. 11-14, preceded by Subspecialty Day reservation company, can assist you Nov. 10-11. U.S. attendees must register by Oct. 13 to have badge and meeting mate- from Monday to Friday, 8:30 a.m.-5:30 rials mailed before the meeting. p.m., Eastern Daylight Time. Call 866- After Oct. 13, you can still register online, as well as purchase tickets and the 774-0487 (toll-free from the United Academy Plus course pass, but you will pick up your badge and/or tickets at the States and Canada) or 703-205-0235 Express Registration-Self Service area in Hall C when you arrive at Ernest N. Morial (from elsewhere), or email aaohotels@ Convention Center. expovision.com. To register, visit aao.org/registration. For an interactive map, visit aao. org/hotels. reporting under the Physician Payment calendar for AAO 2017. Sunshine Act. For more information and to view Schedule Time for EyeNet Breakfasts. Check-in/meal pickup: offerings, visit aao.org/programsearch. Corporate Events 6:45-7:00 a.m. Program: 7:00-8:00 a.m. Be sure to leave room in your schedule Lunches. Check-in/meal pickup: Alumni and Related Group this year for EyeNet’s complimentary 12:15-12:30 p.m. Program: 12:30-1:30 Events corporate educational events on p.m. Connect with old friends and make Saturday, Nov. 11, Sunday, Nov. 12, For more information, visit aao.org/ new connections at alumni and related and Monday, Nov. 13, located onsite at eyenet/corporate-events. events during AAO 2017. Registration Ernest N. Morial Convention Center. for these meetings is separate from These non-CME events are developed Personalize Your Schedule AAO 2017 registration. independently by industry—they are Start planning which sessions to attend To view the list of get-togethers, not affiliated with the official programs by viewing full course listings and visit aao.org/annual-meeting/alumni- of AAO 2017. By attending these abstracts online. Look up information events or look in the Mobile Meeting presentations, you may be subject to by presenter, keyword, or event num- Guide at aao.org/mobile. ber. Search the program by topic (e.g., “Cataract”), event type (e.g., “Sympo- HALL HIGHLIGHTS sia”), or special interest (e.g., “Endorsed by Young Ophthalmologist Commit- Between Sessions, Try tee”). Log in to get up-to-the-minute the EyePlay Experience information and begin building your EyePlay Experience, a new area, is

EYENET MAGAZINE • 71 located in Hall I2, open Saturday, Sun- and Ethics, “Practical Ethics in Oph- day, and Monday, 9:00 a.m.-5:00 p.m. thalmology” (Sym41, Monday, Nov. 13, Experience virtual and augmented re- 2:30-3:30 p.m.). ality, attend a cooking demonstration, To view all named lectures, visit aao. build customized hygiene kits for those org/annual-meeting/named-lectures. in need, relax in a beer garden, and play games. The popular Story Wall will also Hot Practice Management be housed within EyePlay—share your Courses thoughts with fellow attendees. More than 350 instruction courses will be offered in New Orleans—all are Learning Lounge included in the Academy Plus course Visit the Learning Lounge in Hall G, SHARE YOUR STORY. Visit the Story pass. Be sure to add the offerings below Booth 3847, for small-group discus- Wall to contribute your thoughts and to your schedule. sions and presentations. Find the read those of fellow attendees. • The Merit-based Incentive Payment schedule online through the Program System (MIPS) in 2018 (224, Sunday, Search, posted on the Mobile Meeting • Studying Impact of Anti-VEGFs on Nov. 12, 2:00-3:00 p.m.) Guide, and printed in the Meeting Pro- Glaucoma (Mathew W. MacCumber, • How the IRIS Registry Helps You gram. Topics include extended depth- MD, PhD) Participate in MIPS (260, Sunday, Nov. of-focus IOLs, positive and negative • Treatment Patterns for Patients 12, 3:15-4:15 p.m.) dysphotopsias, pediatric uveitis, and the With DME (Jeffrey R. Willis, MD) • Advancing Care Information/FAQs: future of American Board of Ophthal- • New Insights in Retina (George A. Let’s Clear It Up! (273, Sunday, Nov. 12, mology certification. Join your col- Williams, MD) 4:30-5:30 p.m.) leagues for interactive learning that is • Data From the New Glaucoma • Advancing Care Information facilitated by experts in the field. Float Center (Joshua D. Stein, MD, MS) 101 (481, Monday, Nov. 13, 4:30- among theaters—new topics begin When: Saturday, Nov. 11, 12:15-1:15 5:30 p.m.) every 15 minutes. p.m. Where: Room 255-257. Access: Also be sure to check out The Lean To view topics, visit aao.org/pro Free. Practice: Concrete Strategies for gramsearch or look in the Mobile Unlocking Your Practice’s Meeting Guide at aao.org/mobile. Special Lectures Profitability and Patient Don’t miss the named lec- Satisfaction (Spe05, Technology Pavilion tures. These are easy to fit Saturday, Nov. 11, 1:30- Check out the Technology Pavilion in into your schedule and are 5:30 p.m.). This special Hall I1, Booth 5347, for user-friendly free. This year’s lectures session is a ticketed item presentations addressing the latest in include the following: that must be purchased hardware, software, Internet, and mo- • Daniel F. Martin, MD, separately. bile solutions. The schedule is available presents the Jackson Me- online in the Program Search, posted in morial Lecture, “Evolution Daniel F. Martin, MD Breakfast With the Mobile Meeting Guide, and printed of Intravitreal Therapy the Experts in the Meeting Program. for Retinal Diseases: From Roundtables For more information, visit aao.org/ CMV to CNV” (Sunday, Enjoy a buffet-style programsearch or look in the Mobile Nov. 12, 9:31-9:58 a.m. breakfast while experts Meeting Guide at aao.org/mobile. during the Opening lead informal, small- Session) group discussions on the PROGRAM • Russell N. Van Gelder, latest trends. There are MD, PhD, presents the C. 76 roundtables to choose How the IRIS Registry Is Stephen and Frances Foster Russell N. Van Gelder, from. The breakfasts will Accelerating the Evolution Lecture on Uveitis and MD, PhD take place Sunday, Nov. of Clinical Science Immunology, “Idiopathic 12, through Tuesday, Nov. What happens when big data meets Ocular Inflammatory Dis- 14, 7:30-8:30 a.m. in Hall ophthalmology’s clinical innovation? ease: Lessons From Deep C. Tickets can be pur- Discover the answer at a lunchtime DNA Sequencing” (Sym33, chased in advance for $30 symposium—The Value of the IRIS Monday, Nov. 13, 12:45- or onsite for $40. Members Registry: What Can We Learn From 1:45 p.m.). in Training automatically 100 Million Patient Records? (Sym03). • Thomas S. Harbin, receive a 50% discount. William L. Rich III, MD, FACS, will MD, presents the Dr. Allan Purchase tickets when provide an update on the IRIS Registry Jensen and Claire Jensen you register for AAO 2017 and introduce 4 presentations: Lecture in Professionalism Thomas S. Harbin, MD at aao.org/registration.

72 • OCTOBER 2017 Mobile Meeting Guide Your Essential Meeting Resource aao.org/mobile

• Access up-to-date program information and your calendar • Retrieve course handouts • Submit evaluations • View posters and videos • Navigate the exhibition • Send messages to your colleagues • Find events and meetings

No need to visit the app store. Just type aao.org/mobile into any device to start exploring AAO 2017.

Supported by Zeiss MYSTERY IMAGE

BLINK edit Peter R. Pavan, MD, University of South Florida Eye Institute, Morsani College of Medicine, Tampa, Fla. Tampa, of Medicine, Morsani College Institute, of South Florida Eye University MD, R. Pavan, Peter

WHAT IS THIS MONTH’S MYSTERY CONDITION? Join the conversation at aao.org/eyenet, where you can post a comment on this image.

LAST MONTH’S BLINK Metabolic Cataract: A Presenting Sign of Uncontrolled Diabetes Mellitus

55-year-old taxi driver with hypertension and dyslipid- Aemia presented to our clinic with blurred vision in his left eye that had been deteriorating for the past 2 months and was interfering with his work. On examination, visual acuity in his left eye was counting fingers at 5 ft and 20/100 in the right. He had advanced bilateral cortical and posterior subcapsular cataracts in both eyes. During tice today, a young adult with rapidly maturing routine blood tests prior to surgery, fasting serum bilateral cortical cataracts should have a diabetic

glucose measured 212 mg/dL with hemoglobin A1c workup. of 9.7%. The patient was subsequently diagnosed 1 Gong J et al. Br J Gen Pract. 2014;64(629):614-615. with diabetes mellitus (DM) and started on sita- 2 Koffler M et al. Isr J Med Sci. 1990;26(7):393-394. gliptin/metformin 50/1,000 mg and glimepiride 2 mg. Cataract surgeries were unremarkable, and the patient’s vision improved to 20/20 bilaterally. WRITTEN BY ASAF ACHIRON, MD, THE EDITH Early diagnosis of DM can be challenging. WOLFSON MEDICAL CENTER, HOLON, ISRAEL, Blurred vision and visual loss commonly present AND URI AVIV, MD, SACKLER SCHOOL OF MEDI- as initial symptoms.1,2 Although acute diabetic CINE, TEL AVIV UNIVERSITY, ISRAEL. PHOTO BY DR. cataracts are rarely encountered in clinical prac- ACHIRON.

74 • OCTOBER 2017 B:8.75” T:7.875” S:7”

6.2 Clinical Studies Experience 6.3 Immunogenicity Because clinical trials are conducted under widely varying conditions, adverse As with all therapeutic proteins, there is the potential for an immune response reaction rates observed in one clinical trial of a drug cannot be directly in patients treated with LUCENTIS. The immunogenicity data reflect the compared with rates in the clinical trials of the same or another drug and may percentage of patients whose test results were considered positive for not reflect the rates observed in practice. antibodies to LUCENTIS in immunoassays and are highly dependent on the The data below reflect exposure to 0.5 mg LUCENTIS in 440 patients with sensitivity and specificity of the assays. neovascular AMD in Studies AMD-1, AMD-2, and AMD-3; in 259 patients The pre-treatment incidence of immunoreactivity to LUCENTIS was 0%-5% with macular edema following RVO. The data also reflect exposure to 0.3 mg across treatment groups. After monthly dosing with LUCENTIS for 6 to 24 ® Brief summary–please see the LUCENTIS package LUCENTIS in 250 patients with DME and DR at baseline [see Clinical Studies (14 months, antibodies to LUCENTIS were detected in approximately 1%-9% of insert for full prescribing information. in the full prescribing information)]. patients. Safety data observed in Study AMD-4, D-3, and in 224 patients with mCNV The clinical significance of immunoreactivity to LUCENTIS is unclear at this time. 1 INDICATIONS AND USAGE were consistent with these results. On average, the rates and types of adverse Among neovascular AMD patients with the highest levels of immunoreactivity, LUCENTIS is indicated for the treatment of patients with: reactions in patients were not significantly affected by dosing regimen. some were noted to have iritis or vitritis. Intraocular inflammation was not 1.1 Neovascular (Wet) Age-Related Macular Degeneration (AMD) Ocular Reactions observed in patients with DME and DR at baseline, or RVO patients with the highest levels of immunoreactivity. 1.2 Macular Edema Following Retinal Vein Occlusion (RVO) Table 1 shows frequently reported ocular adverse reactions in LUCENTIS- treated patients compared with the control group. 6.4 Postmarketing Experience 1.3 Diabetic Macular Edema (DME) The following adverse reaction has been identified during post-approval use 1.4 Diabetic Retinopathy (DR) Table 1 Ocular Reactions in the DME and DR, AMD, and RVO Studies of LUCENTIS. Because this reaction was reported voluntarily from a population 1.5 Myopic Choroidal Neovascularization (mCNV) DME and DR AMD AMD RVO of uncertain size, it is not always possible to reliably estimate the frequency or 2-year 2-year 1-year 6-month establish a causal relationship to drug exposure. 4 CONTRAINDICATIONS • Ocular: Tear of retinal pigment epithelium among patients with 4.1 Ocular or Periocular Infections neovascular AMD LUCENTIS is contraindicated in patients with ocular or periocular infections. 7 DRUG INTERACTIONS Control Control Control Control 0.5 mg 0.5 mg 0.5 mg 0.3 mg LUCENTIS LUCENTIS LUCENTIS 4.2 Hypersensitivity LUCENTIS Drug interaction studies have not been conducted with LUCENTIS. LUCENTIS is contraindicated in patients with known hypersensitivity to Adverse Reaction n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260 LUCENTIS intravitreal injection has been used adjunctively with verteporfin ranibizumab or any of the excipients in LUCENTIS. Hypersensitivity reactions photodynamic therapy (PDT). Twelve (12) of 105 (11%) patients with may manifest as severe intraocular inflammation. Conjunctival hemorrhage 47% 32% 74% 60% 64% 50% 48% 37% neovascular AMD developed serious intraocular inflammation; in 10 of the 12 5 WARNINGS AND PRECAUTIONS patients, this occurred when LUCENTIS was administered 7 days (± 2 days) Eye pain 17% 13% 35% 30% 26% 20% 17% 12% 5.1 Endophthalmitis and Retinal Detachments after verteporfin PDT. Intravitreal injections, including those with LUCENTIS, have been associated Vitreous floaters 10% 4% 27% 8% 19% 5% 7% 2% 8 USE IN SPECIFIC POPULATIONS with endophthalmitis and retinal detachments. Proper aseptic injection Intraocular 8.1 Pregnancy technique should always be used when administering LUCENTIS. In addition, pressure increased 18% 7% 24% 7% 17% 5% 7% 2% Risk Summary patients should be monitored following the injection to permit early treatment Vitreous There are no adequate and well-controlled studies of LUCENTIS administration should an infection occur [see Dosage and Administration (2.7, 2.8) in the full detachment 11% 15% 21% 19% 15% 15% 4% 2% in pregnant women. prescribing information and Patient Counseling Information (17)]. Intraocular Administration of ranibizumab to pregnant monkeys throughout the period 5.2 Increases in Intraocular Pressure inflammation 4% 3% 18% 8% 13% 7% 1% 3% of organogenesis resulted in a low incidence of skeletal abnormalities at Increases in intraocular pressure have been noted both pre-injection and post- intravitreal doses 13-times the predicted human exposure (based on maximal injection (at 60 minutes) while being treated with LUCENTIS. Monitor intraocular Cataract 28% 32% 17% 14% 11% 9% 2% 2% serum trough levels [Cmax]) after a single eye treatment at the recommended pressure prior to and following intravitreal injection with LUCENTIS and manage Foreign body clinical dose. No skeletal abnormalities were observed at serum trough levels appropriately [see Dosage and Administration (2.8 in the full prescribing sensation in eyes 10% 5% 16% 14% 13% 10% 7% 5% equivalent to the predicted human exposure after a single eye treatment at the information)]. Eye irritation 8% 5% 15% 15% 13% 12% 7% 6% recommended clinical dose [see Animal Data]. 5.3 Thromboembolic Events Lacrimation Animal reproduction studies are not always predictive of human response, Although there was a low rate of arterial thromboembolic events (ATEs) increased 5% 4% 14% 12% 8% 8% 2% 3% and it is not known whether ranibizumab can cause fetal harm when observed in the LUCENTIS clinical trials, there is a potential risk of ATEs Blepharitis 3% 2% 12% 8% 8% 5% 0% 1% administered to a pregnant woman. Based on the anti-VEGF mechanism of following intravitreal use of VEGF inhibitors. ATEs are defined as nonfatal stroke, action for ranibizumab [see Clinical Pharmacology (12.1 in the full prescribing nonfatal myocardial infarction, or vascular death (including deaths of unknown Dry eye 5% 3% 12% 7% 7% 7% 3% 3% information)], treatment with LUCENTIS may pose a risk to human embryofetal cause). Visual disturbance development. Neovascular (Wet) Age-Related Macular Degeneration or vision blurred 8% 4% 18% 15% 13% 10% 5% 3% LUCENTIS should be given to a pregnant woman only if clearly needed. The ATE rate in the three controlled neovascular AMD studies (AMD-1, AMD-2, Eye pruritus 4% 4% 12% 11% 9% 7% 1% 2% AMD-3) during the first year was 1.9% (17 of 874) in the combined group of Data patients treated with 0.3 mg or 0.5 mg LUCENTIS compared with 1.1% (5 of Ocular hyperemia 9% 9% 11% 8% 7% 4% 5% 3% Animal Data 441) in patients from the control arms [see Clinical Studies (14.1 in the full Retinal disorder 2% 2% 10% 7% 8% 4% 2% 1% An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received intravitreal injections of prescribing information)]. In the second year of Studies AMD-1 and AMD-2, the Maculopathy 5% 7% 9% 9% 6% 6% 11% 7% ATE rate was 2.6% (19 of 721) in the combined group of LUCENTIS-treated ranibizumab every 14 days starting on Day 20 of gestation, until Day 62 at Retinal doses of 0, 0.125, and 1 mg/eye. Skeletal abnormalities including incomplete patients compared with 2.9% (10 of 344) in patients from the control arms. B:11.75” T:10.5”

In Study AMD-4, the ATE rates observed in the 0.5 mg arms during the first degeneration 1% 0% 8% 6% 5% 3% 1% 0% and/or irregular ossification of bones in the skull, vertebral column, and S:10” and second year were similar to rates observed in Studies AMD-1, AMD-2, and Ocular discomfort 2% 1% 7% 4% 5% 2% 2% 2% hindlimbs and shortened supernumerary ribs were seen at a low incidence AMD-3. in fetuses from animals treated with 1 mg/eye of ranibizumab. The 1 mg/eye Conjunctival dose resulted in trough serum ranibizumab levels up to 13 times higher In a pooled analysis of 2-year controlled studies (AMD-1, AMD-2, and a study of hyperemia 1% 2% 7% 6% 5% 4% 0% 0% than predicted Cmax levels with single eye treatment in humans. No skeletal LUCENTIS used adjunctively with verteporfin photodynamic therapy), the stroke Posterior capsule abnormalities were seen at the lower dose of 0.125 mg/eye, a dose which rate (including both ischemic and hemorrhagic stroke) was 2.7% (13 of 484) in opacification 4% 3% 7% 4% 2% 2% 0% 1% resulted in trough exposures equivalent to single eye treatment in humans. patients treated with 0.5 mg LUCENTIS compared to 1.1% (5 of 435) in patients No effect on the weight or structure of the placenta, maternal toxicity, or in the control arms (odds ratio 2.2 (95% confidence interval (0.8-7.1))). Injection site hemorrhage 1% 0% 5% 2% 3% 1% 0% 0% embryotoxicity was observed. Macular Edema Following Retinal Vein Occlusion 8.2 Lactation The ATE rate in the two controlled RVO studies during the first 6 months was Non-Ocular Reactions Risk Summary 0.8% in both the LUCENTIS and control arms of the studies (4 of 525 in the Non-ocular adverse reactions with an incidence of ≥ 5% in patients receiving There are no data available on the presence of ranibizumab in human milk, the combined group of patients treated with 0.3 mg or 0.5 mg LUCENTIS and 2 LUCENTIS for DR, DME, AMD, and/or RVO and which occurred at a ≥ 1% higher effects of ranibizumab on the breastfed infant or the effects of ranibizumab on of 260 in the control arms) [see Clinical Studies (14.2 in the full prescribing frequency in patients treated with LUCENTIS compared to control are shown milk production/excretion. information)]. The stroke rate was 0.2% (1 of 525) in the combined group of in Table 2. Though less common, wound healing complications were also LUCENTIS-treated patients compared to 0.4% (1 of 260) in the control arms. Because many drugs are excreted in human milk, and because the potential for observed in some studies. absorption and harm to infant growth and development exists, caution should Diabetic Macular Edema and Diabetic Retinopathy be exercised when LUCENTIS is administered to a nursing woman. Safety data are derived from studies D-1 and D-2. All enrolled patients had Table 2 Non-Ocular Reactions in the DME and DR, AMD, and RVO Studies The developmental and health benefits of breastfeeding should be considered DME and DR at baseline [see Clinical Studies (14.3, 14.4 in the full prescribing DME and DR AMD AMD RVO along with the mother’s clinical need for LUCENTIS and any potential adverse information)]. 2-year 2-year 1-year 6-month effects on the breastfed child from ranibizumab. In a pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3 in the full prescribing information)], the ATE rate at 2 years was 7.2% (18 of 250) with 8.3 Females and Males of Reproductive Potential 0.5 mg LUCENTIS, 5.6% (14 of 250) with 0.3 mg LUCENTIS, and 5.2% (13 of Infertility Control Control Control Control 0.3 mg 0.5 mg 0.5 mg 0.5 mg No studies on the effects of ranibizumab on fertility have been conducted. and it

250) with control. The stroke rate at 2 years was 3.2% (8 of 250) with 0.5 mg LUCENTIS LUCENTIS LUCENTIS LUCENTIS is not known whether ranibizumab can affect reproduction capacity. Based on LUCENTIS, 1.2% (3 of 250) with 0.3 mg LUCENTIS, and 1.6% (4 of 250) with Adverse Reaction n=250 n=250 n=379 n=379 n=440 n=441 n=259 n=260 control. At 3 years, the ATE rate was 10.4% (26 of 249) with 0.5 mg LUCENTIS the anti-VEGF mechanism of action for ranibizumab, treatment with LUCENTIS and 10.8% (27 of 250) with 0.3 mg LUCENTIS; the stroke rate was 4.8% (12 Nasopharyngitis 12% 6% 16% 13% 8% 9% 5% 4% may pose a risk to reproductive capacity. of 249) with 0.5 mg LUCENTIS and 2.0% (5 of 250) with 0.3 mg LUCENTIS. Anemia 11% 10% 8% 7% 4% 3% 1% 1% 8.4 Pediatric Use 5.4 Fatal Events in Patients with DME and DR at baseline Nausea 10% 9% 9% 6% 5% 5% 1% 2% The safety and effectiveness of LUCENTIS in pediatric patients have not been established. Diabetic Macular Edema and Diabetic Retinopathy Cough 9% 4% 9% 8% 5% 4% 1% 2% Safety data are derived from studies D-1 and D-2. All enrolled patients had 8.5 Geriatric Use DME and DR at baseline [see Clinical Studies (14.3, 14.4 in the full prescribing Constipation 8% 4% 5% 7% 3% 4% 0% 1% In the clinical studies, approximately 76% (2449 of 3227) of patients randomized information)]. Seasonal allergy 8% 4% 4% 4% 2% 2% 0% 2% to treatment with LUCENTIS were ≥ 65 years of age and approximately 51% A pooled analysis of Studies D-1 and D-2 [see Clinical Studies (14.3 in the full Hypercholesterolemia 7% 5% 5% 5% 3% 2% 1% 1% (1644 of 3227) were ≥ 75 years of age [see Clinical Studies (14 in the full prescribing information)]. No notable differences in efficacy or safety were seen prescribing information)], showed that fatalities in the first 2 years occurred in Influenza 7% 3% 7% 5% 3% 2% 3% 2% 4.4% (11 of 250) of patients treated with 0.5 mg LUCENTIS, in 2.8% (7 of 250) with increasing age in these studies. Age did not have a significant effect on of patients treated with 0.3 mg LUCENTIS, and in 1.2% (3 of 250) of control Renal failure 7% 6% 1% 1% 0% 0% 0% 0% systemic exposure. patients. Over 3 years, fatalities occurred in 6.4% (16 of 249) of patients treated Upper respiratory 10 OVERDOSAGE with 0.5 mg LUCENTIS and in 4.4% (11 of 250) of patients treated with 0.3 tract infection 7% 7% 9% 8% 5% 5% 2% 2% More concentrated doses as high as 2 mg ranibizumab in 0.05 mL have been mg LUCENTIS. Although the rate of fatal events was low and included causes Gastroesophageal administered to patients. No additional unexpected adverse reactions were of death typical of patients with advanced diabetic complications, a potential reflux disease 6% 4% 4% 6% 3% 4% 1% 0% seen. relationship between these events and intravitreal use of VEGF inhibitors cannot Headache 6% 8% 12% 9% 6% 5% 3% 3% 17 PATIENT COUNSELING INFORMATION be excluded. Advise patients that in the days following LUCENTIS administration, patients are 6 ADVERSE REACTIONS Edema peripheral 6% 4% 3% 5% 2% 3% 0% 1% at risk of developing endophthalmitis. If the eye becomes red, sensitive to light, The following adverse reactions are discussed in greater detail in other sections Renal failure chronic 6% 2% 0% 1% 0% 0% 0% 0% painful, or develops a change in vision, advise the patient to seek immediate of the label: Neuropathy care from an ophthalmologist [see Warnings and Precautions (5.1)]. • Endophthalmitis and Retinal Detachments [see Warnings and Precautions peripheral 5% 3% 1% 1% 1% 0% 0% 0% (5.1)] • Increases in Intraocular Pressure [see Warnings and Precautions (5.2)] Sinusitis 5% 8% 8% 7% 5% 5% 3% 2% • Thromboembolic Events [see Warnings and Precautions (5.3)] Bronchitis 4% 4% 11% 9% 6% 5% 0% 2% • Fatal Events in patients with DME and DR at baseline [see Warnings and Atrial fibrillation 3% 3% 5% 4% 2% 2% 1% 0% Precautions (5.4)] LUCENTIS® Arthralgia 3% 3% 11% 9% 5% 5% 2% 1% 6.1 Injection Procedure [ranibizumab injection] Serious adverse reactions related to the injection procedure have occurred Chronic obstructive Manufactured by: Initial US Approval: June 2006 pulmonary disease 1% 1% 6% 3% 3% 1% 0% 0% Genentech, Inc. Revision Date: LUC/021815/0050(2) 2017 in < 0.1% of intravitreal injections, including endophthalmitis [see Warnings ® and Precautions (5.1)], rhegmatogenous retinal detachment, and iatrogenic Wound healing A Member of the Roche Group LUCENTIS is a registered traumatic cataract. complications 1% 0% 1% 1% 1% 0% 0% 0% 1 DNA Way trademark of Genentech, Inc. South San Francisco, CA ©2017 Genentech, Inc. 94080-4990

PREPARED BY FCB Releasing as: Native le Production: Helen Sera n x3069 Job #: 107700 Colors: 4C AD: Emily Frost x7900 Client: Genentech Flat Size: n/a AE: Miten Soni x3208 Product: Lucentis Bleed: 8.75” x 11.75” Producer: Jazmin Acevedo x2933 Client Code: LUC/101916/0118(1) Small Trim: 7.875” x 10.5” QC: L. Powell x8654 Date: May 22, 2017 3:15 PM Safety: 7” x 10” Digital Artist: VA

Proof: FR Add’l Info: M1FR Spellcheck: FR Spellcheck: N/A Path: PrePress:Genentech:10770063_StudioRXExpress:10770063_17_JA_Pro_S_A_M1 4C1PMS 2017 Journal Ad Protool date A e B:8.75” T:7.875” S:7”

STRENGTH IN EVIDENCE The e cacy and safety of LUCENTIS were rigorously studied in 10 clinical trials1*

Approved for wet AMD, DR, DME, mCNV, and macular edema following RVO. B:11.75” T:10.5” S:10”

INDICATIONS ADVERSE EVENTS LUCENTIS® (ranibizumab injection) is indicated for the treatment • Serious adverse events related to the injection procedure that of patients with: occurred in <0.1% of intravitreal injections included endophthalmitis, • Neovascular (wet) age-related macular degeneration (wAMD) rhegmatogenous retinal detachment, and iatrogenic traumatic cataract • Macular edema following retinal vein occlusion (RVO) • In the LUCENTIS Phase III clinical trials, the most common ocular side • Diabetic macular edema (DME) effects included conjunctival hemorrhage, eye pain, vitreous floaters, • Diabetic retinopathy (DR) and increased intraocular pressure. The most common non-ocular side effects included nasopharyngitis, anemia, nausea, and cough • Myopic choroidal neovascularization (mCNV) IMPORTANT SAFETY INFORMATION Please see Brief Summary of LUCENTIS full Prescribing Information CONTRAINDICATIONS on adjacent page. • LUCENTIS is contraindicated in patients with ocular or periocular infections or known hypersensitivity to ranibizumab or any of the * The following randomized, double-masked clinical trials were conducted for the 5 excipients in LUCENTIS LUCENTIS indications: wAMD: MARINA—Phase III, multicenter, 2-year, sham injection– controlled study; primary end point at 1 year. ANCHOR—Phase III, multicenter, 2-year, WARNINGS AND PRECAUTIONS active treatment–controlled study; primary end point at 1 year. PIER—Phase IIIb, • Intravitreal injections, including those with LUCENTIS, have been associated 2-year, sham injection–controlled study; primary end point at 1 year.HARBOR —Phase III, multicenter, 2-year, active treatment–controlled dose-response study; primary end with endophthalmitis, retinal detachment, and iatrogenic traumatic point at 1 year. DR and DME: RISE and RIDE—Methodologically identical, Phase III, cataract. Proper aseptic injection technique should always be utilized multicenter, 3-year, sham injection–controlled studies; primary end point at 2 years. when administering LUCENTIS. Patients should be monitored following Protocol S—Phase III, multicenter, 2-year, active-controlled study; key clinical outcomes the injection to permit early treatment, should an infection occur at 2 years. mCNV: RADIANCE—Phase III, multicenter, 1-year, active-controlled study; • Increases in intraocular pressure (IOP) have been noted both pre-injection key clinical outcomes at month 3. RVO: BRAVO—Phase III, multicenter, 1-year, sham injection–controlled study; primary end point at 6 months.CRUISE —Phase III, and post-injection (at 60 minutes) with LUCENTIS. Monitor intraocular multicenter, 1-year, sham injection–controlled study; primary end point at 6 months.2-11 pressure prior to and following intravitreal injection with LUCENTIS and manage appropriately • Although there was a low rate of arterial thromboembolic events (ATEs) REFERENCES: 1. LUCENTIS [package insert]. South San Francisco, CA: Genentech, Inc; 2017. observed in the LUCENTIS clinical trials, there is a potential risk of ATEs 2. Rosenfeld PJ, et al; MARINA Study Group. N Engl J Med. 2006;355:1419-1431. 3. Brown DM, following intravitreal use of VEGF inhibitors. ATEs are defined as et al; ANCHOR Study Group. Ophthalmology. 2009;116:57-65. 4. Regillo CD, et al; PIER Study nonfatal stroke, nonfatal myocardial infarction, or vascular death Group. Am J Ophthalmol. 2008;145:239-248. 5. Busbee BG, et al; HARBOR Study Group. Ophthalmology. 2013;120:1046-1056. 6. Campochiaro PA, et al; BRAVO Investigators. (including deaths of unknown cause) Ophthalmology. 2010;117:1102-1112. 7. Brown DM, et al; CRUISE Investigators. Ophthalmology. • Fatal events occurred more frequently in patients with DME and DR 2010;117:1124-1133. 8. Brown DM, et al; RISE and RIDE Research Group. Ophthalmology. at baseline treated monthly with LUCENTIS compared with control. 2013;120:2013-2022. 9. Data on file. Genentech, Inc. South San Francisco, CA. 10. Nguyen QD, et al; RISE and RIDE Research Group. Ophthalmology. 2012;119:789-801. 11. Gross JG, et al; Although the rate of fatal events was low and included causes of death Writing Committee for the Diabetic Retinopathy Clinical Research Network. JAMA. typical of patients with advanced diabetic complications, a potential 2015;314:2137-2146. relationship between these events and intravitreal use of VEGF © 2017 Genentech USA, Inc. 1 DNA Way, South inhibitors cannot be excluded San Francisco, CA 94080-4990 All rights reserved. LUC/033117/0027 05/17 LU CENTIS.com/hcp

Proof: FR Add’l Info: M1FR Spellcheck: FR Spellcheck: N/A Path: PrePress:Genentech:10770063_StudioRXExpress:10770063_17_JA_Pro_S_A_M1 4C1PMS 2017 Journal Ad Protool date A e