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Toward Dropless In� ammation Control in Cataract SurgeryKENNETH A. BECKMAN, MD Developing novel pharmaceuticals and improving upon available agents have been of longstanding interest in ophthalmology. An exciting current trend is taking established drugs and delivering them to the eye by novel mechanisms in order to reduce the burden of drops on patients and improve pharmacodynamics, safety, and outcomes. Newly approved and pipeline agents are forwarding the universal trend toward dropless in� ammation control post-cataract surgery.

Surgical techniques, while steadily evolving to become safer and less traumatic in recent decades, still remain traumatic to the eye, by inciting infl ammation on molecular (eg, prostaglandin formation, chemokinase release), microvascilar (eg, increased permeability, vasodilation), and tissue (eg, smooth muscle con-traction, macular edema) level. When infl ammation is poorly controlled, patients undergoing even routine ocular surgery are thought to be at increased risk for discomfort, impaired recovery, and complications including synechia, cystoid macular edema (CME), and suboptimal visual outcomes.1

EVOLVING TOPICAL OPTIONSSurgeons vary in their approach to reducing post surgical

infl ammation (Figure 1). Most prescribe a topical ocular corti-costeroid, dosed multiple times per day for a period of several weeks following surgery. Corticosteroids’ broad and reliable anti-infl ammatory activity derives from blockade of phospholipase A and inhibition of prostaglandin formation early in the cascade. Progress has been made in recent years toward the development of safer alternatives to conventional high potency corticosteroids,

such as difl uprednate and prednisolone acetate. Loteprednol etabonate has intermediate potency and poses a lower risk for side eff ects due to a unique molecular structure that undergoes rapid metabolism and deactivation by ocular surface enzymes.2,3 While most corticosteroids approved for post-operative pain and infl ammation control are dosed four times daily, a novel, recently US Food and Drug Administration (FDA)-approved formulation of loteprednol etabonate – InVeltys (loteprednol eta-

ISSUE 26

A CONTINUINGMEDICAL EDUCATION

PUBLICATIONCME

CONTINUING MEDICAL EDUCATION

See INSIDE for:Essential Fatty Acids in Antiinfl ammatory Therapy for Dry Eye Disease by Joseph Tauber, MD

FIGURE 1 Slit lamp photo of a postop day one after cataract surgery. (Courtesy of Dr. Beckman.)

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STATEMENT OF NEEDThe control of ocular infl ammation is a critical aspect of medical and surgical ophthalmic practice. Despite their side eff ects, antiinfl ammatory drugs are used to treat a very wide range of conditions throughout the eye, from ocular surface disease and allergic conjunctivitis to poste-rior segment conditions. Use of antiinfl ammatory agents is also critical in ocular surgery, contributing greatly to patient comfort and positive outcomes.The ocular antiinfl ammatory landscape is changing as research reveals more about the role of infl ammation in a range of ocular conditions and as new antiinfl ammatory agents enter the market.1,2 Twenty years ago, for example, the idea of using a topical corticosteroid to treat dry eye and/or allergic conjunctivitis was viewed with alarm; today, it is accepted practice. Although corticosteroids and nonsteroidal antiinfl am-matory drugs (NSAIDs) have been the mainstays of the ocular anti-infl ammatory armamentarium, a number of new agents with novel mechanisms of action (and new ocular drug delivery systems) have come to market or are being made ready for market.3,4

As indications expand and change, and as new drugs, formulations, and delivery systems become available, clinicians require up-to-date protocols for drug selec-tion and use. Such protocols are also needed for routine (but nevertheless off -label) uses of corticosteroids and NSAIDs because important diff erences in effi cacy, safety, and tolerability exist between these classes and among formulations within each of these classes.5,6

By putting the latest published evidence into the context of current clinical practice, Topics in Ocular Antiinfl amma-tories equips ophthalmologists to maintain competen-cies and narrow gaps between their actual and optimal infl ammation management practices, across the range of clinical situations in which current and novel ocular antiinfl ammatories may be used.

REFERENCES1. Song JS, Hyon JY, Lee D, et al. Current practice pattern

for dry eye patients in South Korea: a multicenter study. Korean Journal of Ophthalmology. 2014;28(2):115-21.

2. Ciulla TA, Harris A, McIntyre N, Jonescu-Cuypers C. Treat-ment of diabetic macular edema with sustained-releaseglucocorticoids: intravitreal triamcinolone acetonide, dexamethasone implant, and fl uocinolone acetonide implant. Expert Opin Pharmacother. 2014;15(7):953-9.

3. Maya JR, Sadiq MA, Zapata LJ, et al. Emerging therapies for noninfectious uveitis: what may be coming to the clinics. J Ophthalmol. 2014;2014:310329.

4. Sheppard JD, Torkildsen GL, Lonsdale JD, et al, andthe OPUS-1 Study Group. Lifi tegrast ophthalmic solu-tion 5.0% for treatment of dry eye disease: resultsof the OPUS-1 phase 3 study. Ophthalmology. 2014Feb;121(2):475-83.

5. Fong R, Leitritz M, Siou-Mermet R, Erb T. Loteprednol etabonate gel 0.5% for postoperative pain and infl am-mation after cataract surgery: results of a multicenter trial. Clin Ophthalmol. 2012;6:1113-24.

6. Singer M, Cid MD, Luth J, et al. Incidence of corneal melt in clinical practice: our experience vs a meta-analysis of the literature. Clin Exp Ophthalmol. 2012;S1:003.

OFF-LABEL USE STATEMENTThis work may discuss off -label uses of medications.

GENERAL INFORMATIONThis CME activity is sponsored by the University of Florida College of Medicine and is supported by an unrestricted educational grant from Shire.The University of Florida College of Medicine designates this activity for a maximum of 1 AMA PRA Category 1 Credit™. There is no fee to participate in this activity. In order to receive CME credit, participants should read the report, and then take the posttest. A score of 80% is required to qualify for CME credit. Estimated time to complete the activity is 60 minutes. On completion, take the test online at http://cme.ufl .edu/ed/self-study/toai/System requirements for this activity are: For PC us-ers: Windows® 2000, XP, 2003 Server, or Vista; Internet Explorer® 6.0 or newer, or Mozilla® Firefox® 2.0 or newer

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DATE OF ORIGINAL RELEASE February 2019. Approved for a period of 12 months.

ACCREDITATION STATEMENTThis activity has been planned and implemented in ac-cordance with the accreditation requirements and poli-cies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the University of Florida College of Medicine and Candeo Clinical/Science Communications, LLC. The University of Florida College of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

CREDIT DESIGNATION STATEMENTThe University of Florida College of Medicine designates this enduring material for a maximum of 1 AMA PRA Cate gory 1 Credit™. Physicians should claim only the credit commensurate with the extent of their participa-tion in the activity.

EDITORIAL BOARD/FACULTY ADVISORSMarguerite B. McDonald, MD, FACS, practices at Ophthalmic Consultants of Long Island, and is a clinical professor of ophthalmology at the New York University School of Medicine. She is also an adjunct clinical profes-sor of ophthalmology at Tulane University Health Sciences Center. Dr. McDonald is a consultant for Allergan, Alcon, Bausch + Lomb, BlephEx, FOCUS Laboratories, Shire, and J&J Vision.Victor L. Perez, MD, is a professor of ophthalmology at the Duke University School of Medicine. He is also the director of Duke Eye Center’s Ocular Immunology Center and Ocular Surface Program. Dr. Perez is a consultant for Allergan, Shire, EyeGate, and TopiVert. He is also a stock shareholder for EyeGate.Matthew J. Gray, MD, is an assistant professor in the Department of Ophthalmology at the University of Florida College of Medicine. He states that in the past 12 months, he has not had a fi nancial relationship with any commercial organization that produces, markets, resells, or distributes healthcare goods or services consumed by or used on patients relevant to this manuscript.Kenneth A. Beckman, MD, FACS, is Director of Corneal Services at Comprehensive EyeCare of Central Ohio and a clinical assistant professor of ophthalmology at The Ohio State University, Columbus, Ohio. Dr. Beckman is a consultant for Omeros and EyePoint Pharmaceuticals and is a stock shareholder for Ocular Science.Joseph Tauber, MD, is the founder of Tauber Eye Center in Kansas City, MO where he specializes in anterior seg-ment surgery, corneal transplantation, the treatment of corneal and external diseases, and laser vision correction procedures. He states that in the past 12 months, he has not had a fi nancial relationship with any commercial organization that produces, markets, resells, or distributes healthcare goods or services consumed by or used on patients relevant to this manuscript.

DISCLAIMERParticipants have an implied responsibility to use the new-ly acquired information to enhance patient outcomes and professional development. The information presented in this activity is not meant to serve as a guideline for patient care. Procedures, medications, and other courses of diag-nosis and treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, applicable manufacturer’s product information, and comparison with recommendations of other authorities.

COMMERCIAL SUPPORTERS This activity is supported by an unrestricted educational grant from Shire.

TOPICS IN OCULAR ANTIINFLAMMATORIES, ISSUE 26bonate ophthalmic suspension) 1% (Kala Pharmaceuticals, Waltham, MA) employs a nanoparticle technology called mucus-penetrating particles (MPP) designed to increase tissue penetration and allow for twice daily dosing.4,5

Many surgeons also routinely pre-scribe a nonsteroidal antiinfl ammatory drug (NSAID) as an adjunct to cortico-steroids for cataract surgery as the two molecules employ separate mechanisms of action, a practice once reserved for pa-tients with diabetes or other risk factor for CME. A smaller subset of surgeons relies entirely on NSAIDs for their perisurgical antiinfl ammatory regimen. Nonsteroidal antiinf lammatory drugs work down-stream from the site of corticosteroid ac-tion by blocking cyclooxygenase enzymes COX-1 and COX-2 required for prosta-glandin synthesis.6 Currently available topical ocular NSAIDs include once daily formulations of bromfenac (Bromday and Prolensa; Bausch & Lomb, Tampa, FL, Bromsite; Sun Pharmaceuticals) and nepafenac (Ilevro; Alcon, Ft Worth, TX), welcome improvements over past NSAID generations which required up to four times daily dosing.6

In addition to blocking infl ammation, NSAIDs support intraoperative mydria-sis, reduce pain, and decrease photopho-bia following surgery.7 Ketoralac is one of the two mydriatic agents with distinct mechanisms of action comprising OMID-RIA® (phenylephrine and ketorolac intra-ocular solution) 1%/0.3% (Omeros Corp, Seattle, WA), an agent that is commonly added to the irrigation solution during cataract surgery.6 Omidria is indicated for prevention of intraoperative miosis and postoperative pain only; its eff ects on postsurgical infl ammation or complica-tions are unknown.8 However, due to the ketorolac component suff using the eye at the time and site of greatest insult and prostaglandin production, an incidental antiinfl ammatory benefi t is likely.

DROPLESS MOVEMENTTopical antibiotics are also com-

monly prescribed prophylactically around surgery, principally for prevention of the sight-threatening complication—en-dophthalmitis. Th us, all in all, patients undergoing routine cataract surgery are apt to be burdened with three or more individual medications requiring dos-

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ing multiple times per day for multiple weeks following their procedure. High dosing burden, confusing regimens, diffi culty instilling drops (common in elderly populations), and medication costs all may contribute to reduced compliance with drops. Non-compliance with antiinfl ammatory and/or antibiotic prophylaxis places patients at increased risk for complications. Further, the use of drops introduces risks for ocular surface toxicity (related to active ingredient, preservatives or excipients) and infection due to the possible contamination of the medication. A dropless approach to infl ammation control and infection prophylaxis around surgery holds considerable appeal to patients, surgeons, and surgical staff .

While the current trend toward dropless cataract surgery is in its infancy in the U.S., eff orts to simplify the post-operative regimens for patients have gained traction. Combining drops reduces the number of bottles and drops that a patient must handle; for example, an antibiotic, NSAID, and corticosteroid can be placed in a single bottle by a compounding pharmacy. Use of more potent drugs and newer formulations allow for reduced dosing frequency. Intracameral injection of unpreserved cefu-roxime or moxifl oxacin (Vigamox), with or without adjunctive post-surgical topical antibiotics has been shown to reduce risk for endophthalmitis.9-11 Adverse events associated with intracameral antibiotics appear to be rare.9-11 Uveitis and retinal toxicity have been reported in conjunction with intracameral cefuroxime dos-ing error.9,11 In Europe, intracameral antibiotics are in routine use with cataract procedures. An approved, prepackaged single-use cefuroxime formulation for intraocular injection is available and indicated for endophthalmitis prophylaxis during surgery. Such intracameral agent is currently not available in the US (surgeons must mix their own preparation in the surgical suite), which likely contributes to lower rates of intracameral antibiotic use among US surgeons, although interest and use is growing.9

A minority of cataract surgeons are already largely “drop-less”, choosing to administer combination corticosteroid and antibiotic obtained from a compounding pharmacy for intra-cameral injection at the end of surgery.12 As with intracameral antibiotic injection, concerns regarding the lack of a branded, pre-prepared solution present a barrier for some surgeons as compounded products raise concerns about dilution error or contamination.9 Fortunately, several novel antiinfl ammatory delivery mechanisms are likely to hit the market soon, which are poised to partially bridge the gap until more comprehensively dropless technology becomes available.

INTRACAMERAL CORTICOSTEROIDDEXYCU™ (dexamethasone intraocular suspension) 9%

(EyePoint Pharma, Watertown MA) is a novel, unpreserved, long-acting formulation of dexamethasone indicated for the treatment of postoperative inf lammation.13 Dexycu, which contains dexamethasone 517 mcg in a proprietary biodegrad-able liquid drug delivery vehicle called Verisome R, is injected as a single 0.005 mL dose into the posterior chamber inferiorly behind the iris at the end of ocular surgery, and medication is released over about 21 days.13,14

With its approval by the FDA in February 2018 and transi-tional pass-through and reimbursement approval by the Centers for Medicare and Medicaid Services (CMS) in October 2018,

CORE CONCEPTS ✦ Novel formulations and delivery systems of

corticosteroids and NSAIDs aim to improve potency and safety and reduce dosing frequency

✦ Loteprednol etabonate-MPP is the fi rst topical corticosteroid dosed BID

✦ A newly approved injectable dexamethasone administered as a single intraocular dose at the end of ocular surgery has become available

✦ Clinical trials of Dexycu showed anterior chamber clearing at day 8 in 66% of treated eyes and safety similar to placebo through day 90 postoperatively

✦ Pipeline agent Dextenza is a bioabsorbable intracanalicular device that supplies the ocular surface with a gradually tapering dose of dexamethasone

Dexycu will soon be a new option for surgeons in the U.S., pav-ing the way for an at least partially dropless approach to cataract surgery.15

Clinical trialsA multicenter randomized, double-masked, placebo-

controlled phase 3 clinical study compared 342 mcg and 517 mcg of IBI-10090 (intraocular dexamethasone) to placebo intraocular injection in 394 eyes undergoing cataract surgery by phacoemulsifi cation.16 Th e primary effi cacy endpoint was anterior chamber cell (ACC) clearing (zero cells) at day 8, and patients were followed for safety and adverse events for 90 days postoperatively. Th e proportion of eyes treated with the higher dose of IBI-10090 (Dexycu) that had ACC clearing at day 8 was 66%, compared with 25% among placebo-treated eyes (P < 0.001). Need for rescue anti-infl ammatory medication on post-operative day (POD) 7 was 16.3% and 1.9% among placebo-treated and Dexycu-treated patients, respectively.16

Adverse events were similar between treatment groups overall; no serious adverse events were reported through POD 90. Intraocular pressure (IOP) increase of at least 10mmHgfrom baseline was observed among 29% of Dexycu-treated eyes vs. 13% in placebo-treated eyes. IOP did not exceed 21mmHgat any measurement in any group. Other treatment-emergentadverse events, including corneal edema, pain, infl ammationin the anterior chamber, and dry eye, occurred in < 15% of eyes. Infl ammatory adverse events including macular edema, eyeinfl ammation, and iritis were more common in placebo-treated eyes. CME as diagnosed by OCT was seen in 3.8% of placebo-treated and 3.2% of Dexycu-treated eyes.16

In a separate multicenter, randomized, open-label study, Dexycu (dexamethasone intraocular suspension) 9% administered intracamerally at the end of surgery was compared to prednisolone acetate 1.0% drops administered four times daily for 3 weeks fol-lowing surgery in patients undergoing cataract surgery (N = 194).17 Safety through POD 90 was the primary endpoint. Overall, safety of the two treatment groups were similar. Th ree serious adverse events were reported in the Dexycu group, one related to diabetic retinopathy and two that were systemic; all were considered unre-

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lated to study medication. Change in endothelial cell density was not signifi cantly diff erent between groups.

IOP elevation was observed in 11.1% of patients in the Dexycu group compared with 3.6% of the topical prednisolone group; iritis (6.3%) and anterior segment infl ammation (9.5%) were also higher among Dexycu-treated eyes. Proportion of eyes with anterior chamber cell clearing on POD 8 was 51.6% and 50.9% in Dexycu- and prednisolone-treated eyes, respectively (P = NS).17 Among Dexycu-treated patients, 68.7% strongly agreed that not having to use drops was “very convenient”; and 39.2% of patients who received drops stated a strong preference to a dropless approach.17

New ConsiderationsConvenience and direct action at the site of infl ammation

are advantages of a single-dose, intracameral medication delivery mechanism; but there are also potential disadvantages. For ex-ample, it remains unclear whether a single-dose injectable corti-costeroid like Dexycu would provide suffi cient antiinfl ammatory activity for patients with a baseline infl ammatory conditions, such as iritis, or autoimmune conditions, such as rheumatoid arthritis. Such patients might require additional corticosteroid drops in the post-operative period. In addition, some patients might benefi t from more fi nely controlled dosing made possible by topical therapy. For example, should a patient with history of herpetic keratitis experience a recurrence post-operatively, or patient with glaucoma experience an IOP spike, one would want the ability to taper a topical corticosteroid. While there are no contraindications to Dexycu as per the label, the potential for IOP elevation, delayed healing, infection exacerbation, and cataract progression are included as warnings.13

INTRACANALICULAR CORTICOSTEROIDAnother mode for dropless, sustained delivery of dexametha-

sone (or other topical ocular medication) is via drug-eluting intracanalicular delivery device. A leading device in this category is Dextenza (dexamethasone insert) 0.4mg for intracanalicular use; (Ocular Th erapeutix, Bedford, MA), which is currently under FDA review for treatment of postoperative ocular infl ammation and pain.18

With Dextenza, active drug is housed in a polyethylene glycol (PEG) hydrogel vehicle that has been conjugated with fl uorescein, making it visible by blue light for easy confi rmation of placement and retention. Once in place in the canaliculus, the device provides sustained and tapered release of unpreserved dexamethasone over 30 days, after which time the vehicle soft ens and is cleared or reabsorbed though the nasolacrimal duct.19 One advantage a drug-eluting intracanalicular device has over an intracameral injection, as discussed above, is the option to access the device in the event of IOP elevation or other corticosteroid-related adverse event. Also, placement of a drug-eluting intracanalicular device can be performed in the offi ce, making it more fl exible to use. Th us, surgeons who opt for something like Dextenza would provide their patients with a dropless option while retaining the ability to withdraw corti-costeroid if a need arose.

A theoretical disadvantage (relative to intracameral injection) is that, like drops, the drug is topical and must penetrate several

tissue layers to reach the site of infl ammation; whereas intracam-eral injection places the drug directly at the site of infl ammation. Further, some patients, such as those with stenotic or congenitally small puncta, might theoretically have diffi culty with placement or retention of the device and may be poor candidates.

Clinical TrialsA multicenter, randomized, double-masked, vehicle-con-

trolled phase 3 clinical trial aimed to demonstrate effi cacy and safety of Dextenza placed in the inferior distal canaliculus at the end of surgery in patients who underwent unilateral phacoemul-sifi cation (N = 60).19 Primary endpoints were the absence of pain at day 8 and absence of ACC at day 14. Other endpoints included ACC, anterior chamber fl are (ACF), retainment of device at various time points. Patients who met designated criteria for infl ammation were given rescue anti-infl ammatory treatment.

On POD 8, ACC clearing among Dextenza-treated patients was 20.7%, compared with 10% among patients with sham device (P = 0.15). Although this endpoint was not met with statistical signifi cance, ACC clearing at POD 14 (34.5% vs. 3.4%; P = 0.0027) and POD 30 (62.1% vs. 13.8%; P = 0.0002) was signifi cantly more common among patients in the intracanalicular dexamethasone group vs. placebo. Th e proportion of pain-free patients on POD 8 and all other time points was signifi cantly higher with intra-canalicular dexamethasone treatment vs. placebo (P < 0.002). Further, ACC and ACF were markedly reduced with intracana-licular dexamethasone through day 30 (P < 0.0251). Need for rescue medication was signifi cantly lower with intracanalicular dexamethasone.19

Th ere was no diff erence in IOP elevations as adverse events (one patient in each group). Overall adverse events were more common among placebo-treated vs. Dextenza-treated eyes (43.3% vs. 13.8%). Ninety-three percent of physicians reported that the device was “easy” or “very easy” to insert; 100% reported that it was “easy” or “very easy” to visualize.19 Among participants who responded to a post-study interview, 96% rated the conve-nience of Dextenza treatment as “very convenient” or “extremely convenient”; and 84% reported that they would be willing to pay more for the insert if they could forego drops.20

A second phase 3 clinical trial of similar design compared dexamethasone 0.4mg intracanalicular insert to vehicular control in patients who underwent phacoemulsifi cation in 21 centers in the US (N = 438).21 In addition to the much larger patient sample, diff erences in study design included placement of the device on POD 1 (instead of intraoperatively) and primary endpoints of percent of patients ocular pain-free at POD 8 (same as Walters et al) and percent of patients with ACC clearing at POD 14. Primary endpoints were met: the proportion of patients with ACC clearing on POD 14 was 52.3% vs 31.1% (P < 0.0001); and the proportion pain-free on POD 8 was 79.6% vs. 61.3% (P < 0.0001) among Dextenza-treated and placebo-treated groups, respectively. Ocular infl ammation was diminished as early as day 4 and pain as early as day 2 with Dextenza relative to placebo. Adverse events were similar between the two groups.21

BECKMAN continues on page 8

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Essential Fatty Acids in Antiin� ammatory Therapy for Dry Eye DiseaseJOSEPH TAUBER, MD Dietary supplementation of essential fatty acids (EFA) for the treatment of dry eye disease (DED) remains controversial based on con� icting data, although signi� cant anecdotal experience among ophthalmologists supports its use in patients. The goal of EFA supplementation is to alter the corneal surface of the DED patient from a proin� ammatory to an antiin� ammatory state and to supplement the inadequate lipid milieu of the tear � lm caused by meibomian gland dysfunction and excess tear evaporation. Omega-3 fatty acid is considered to play an important role in this regard and may well be as critical to ocular health as it has proven to be in reducing the risk of several other diseases, including cardiovascular and autoimmune disease.

RISK FACTORS FOR DEVELOPING DEDDED is a common yet complex condition that is character-

ized by an impaired or dysfunctional tear fi lm for which there are two major clinical forms: an aqueous defi cient form due to insuffi cient production of tears from the lacrimal gland and an evaporative form due to excessive tear loss, most oft en due to defi cient or abnormal tear lipids in the tear fi lm. Oft en both clinical manifestations are present simultaneously, though to variable degrees in patients.1 Increased tear osmolarity and ensuing epithelial cell desiccation, loss of the glycocalyx that surrounds cell membranes, inflammation and cell apoptosis occur in both manifestations and lead to the frequent signs and symptoms experienced by DED patients. Th ese include eye red-ness, itching, foreign-body sensation, contact lens intolerance, tearing, pain, blurred vision and, if left untreated, visual loss.1

Women and individuals aged 65 years or older are at high-est risk of developing DED mostly due to hormonal changes (believed to be reduced androgen levels, either age-related or due to surgical/chemical castration for the treatment of cancer). However, other risk factors include having autoimmune forms of arthritis, osteoporosis, allergies, thyroid disease, severe headaches, migraines and head injury, and the use of certain medications including antihistamines, benzodiazepine, anti-depressants and steroids.2 Th e prevalence of symptomatic DED among adults in the US is approximately 14% with an estimated 3.23 million women suff ering from the condition.2 Th e annual cost of medical care and productivity loss combined equate to more than US$55 billion.3

THE ROLE OF EFA IN MAINTAINING HEALTH OF THE OCULAR SURFACE

Maintaining a normal lipid milieu in the tear fi lm that has a balance of the fundamental components of water, oils and mu-cins/lipids reduces ocular surface dehydration and infl ammation

and prevents the pathologic mechanisms that lead to DED. Th is composition is altered in DED and is characterized by elevations in tear osmolarity, increased numbers of proinfl ammatory cells, a higher expression of cytokines (including interleukin [IL]-1β, IL-6 and IL-10) and matrix metalloproteinase-9 (MMP-9), a proteolytic enzyme that is produced by stressed ocular epithelial cells.4,5 Since the body is not able to synthesize adequate levels of EFA to meet all its physiological needs, dietary sources of EFAs are critical to maintaining both ocular and general health.

Th ere are two “essential” fatty acids that are important in maintaining ocular health, namely omega-6 fatty acid (linoleic acid; LA) which is the precursor to the “conditional” fatty ac-ids gamma-linoleic acid (GLA), dihomo-gamma-linoleic acid (DGLA) and arachidonic acid (AA), and omega-3 fatty acid (alpha-linoleic acid; ALA) which is the precursor to the “condi-tional” fatty acid eicosapentaenoic acid (EPA) which then gives rise to docosahexaenoic acid (DHA).6 Th e “conditional” fatty acids are those that may be required under disease conditions when the body is unable to synthesize quantities suffi cient to meet pathophysiologic needs.7 While both omega-6 fatty acids and omega-3 fatty acids are essential for general optimal health, the ratio of consumption is important due to diff erences in their proinfl ammatory (omega-6 fatty acid) versus antiinfl ammatory (omega-3 fatty acid) nature.6

Common dietary sources of omega-6 fatty acids are plant-based oils from nuts and seeds, such as saffl ower oil, corn oil, soybean oil and sesame oil. Both omega-6 and omega-3 fatty ac-ids are present in walnut oil, sunfl ower seeds and fl axseed, while fi sh is a common source of omega-3 fatty acid. GLA is present in less commonly consumed foods like borage oil, black currant oil and hemp oil. Overall, Mediterranean diets, which are olive oil-based, and far-east Asian diets show higher consumption of EFA than the typical Western diet.

CORE CONCEPTS ✦ Maintaining a normal lipid milieu in the eye reduces

ocular surface infl ammation and prevents the pathologic mechanisms that lead to DED.

✦ Both “essential” fatty acids (omega-6 and omega-3 fatty acid) and “conditional” fatty acids (eicosapentaenoic acid, docosahexaenoic acid and gamma-linoleic acid) are important for maintaining ocular health.

✦ Omega-6 fatty acids can be proinfl ammatory while omega-3 fatty acids are antiinfl ammatory thus the correct ratio of dietary consumption and/or supplementation is important.

✦ Confl icting data exist as to whether omega-3 fatty acid supplementation is benefi cial in treating DED.

✦ EFA supplementation is benefi cial in older patients, who typically present with DED, for reducing hypertension, risk of heart attack, arthritis and Alzheimer’s disease.

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Research in animal models suggests that supplementation with omega-3 fatty acid has potential to produce signifi cant therapeutic benefi ts for treating dry eye.7 Th ese benefi ts have been shown also in prospective clinical studies in humans.9,10 One study of 32,470 women showed that tuna consumption was inversely associated with dry eye symptoms with 2-4 servings/week and 5-6 servings/week versus ≤ 1 serving/week (P = 0.005, for both comparisons) and that a higher ratio of omega-6 to omega-3 fatty acid consumption was associated with signifi cantly increased risk of dry eye symptoms (P = 0.01).11 Further, a meta-analysis of 790 subjects from 7 independent studies investigating

OMEGA-3 FATTY ACID SUPPLEMENTATION FOR TREATING DEDTh e rationale for EFA supplementation in the treatment of

DED is based on the fi nding that omega-3 fatty acid catabolism results in generation of antiinflammatory molecules that sup-press the inflammatory pathways found in meibomian gland disease. Secondly, omega-3 fatty acids change the fatty acid composition of the meibomian gland secretion so that it contains increased levels of unsaturated fatty acids, which prevent block-age of the meibomian gland ducts and meibum stagnation. Th is increases the quality of meibomian gland secretions and reduces tear film evaporation.8

TABLE 1 A comparison of the study design for the Epitropoulos et al study and DREAM studyEpitropoulos et al Study1 DREAM Study Research Group2

Design Prospective, randomized, interventional, double-masked

Prospective, randomized, interventional, double-masked

Number of sites Multicenter (number of sites not stated in primary publication)

27

Treatment and sample size (N = patients completing primary endpoint assessment)

Active treatment (1,680 mg EPA / 560 mg DHA): N=54vs.Control (3,136 mg LA): N=51

Active treatment (2,000 mg EPA / 1,000 mg DHA): N=329

vs.

Placebo (refi ned olive oil [68% oleic acid, 13% palmitic acid, 11% LA): N=170

Inclusion criteria ≥18 years of age

Previously confirmed diagnosis of DED

MGD stage 1 or 2

Tear osmolarity of ≥312 mOsm/L in at least one eye

≥18 years of ageSymptomatic moderate to severe DED ≥6 monthsUse/desire to use artifi cial tears ≥2 times per day 2 weeks prior to screeningOSDI score 25-80 at time of screening and 21-80 at eligibility confi rmation visit≥2 of 4 signs in at least one eye:Conjunctival lissamine-green staining score: ≥1 (scale 0-6)Corneal fl uorescein staining score: ≥4 (scale 0-15)TBUT: ≤7 secondsSchirmer’s test: 1-7 mm in 5 minutes

Exclusion criteria MGD stage 3

Use of topical cyclosporine 0.05%, corticosteroids, nonsteroidal anti-inflammatory drugs, glaucoma medications, or oral omega-3 fatty acids 3 weeks prior to screening

LASIK or PRK surgery within 1 year of screening

Use of systemic medication that might aff ect the ocular surface

Subjects instructed to discontinue contact lenses within 12 hours of study visits.

Not taking ≥90 % of run-in supplements (5/day)

Contact lenses worn 30 days prior to screening

LASIK or recent ocular surgery (within past 6 months)

Ocular infection

Regular use of DED treatments including omega−3 fatty acid supplements EPA plus DHA at <1200 mg daily

Systemic medications known to cause ocular dryness

Systemic glucocorticoids or other immunosuppressive agents allowed if patient committed to continued use for next 12 months

Medical history of thyroid disease, Sjögren’s syndrome, rheumatoid arthritis or infl ammatory diseases could be included.

Length of exposure to treatment

12 weeks 52 weeks

Key assessments Mean change in tear osmolarity, TBUT, OSDI, fluorescein corneal staining, Schirmer test, MMP-9 and omega-3 index at 12 weeks

Mean change from baseline in the OSDI score at 52 weeks (primary endpoint).

Percent of patients with a decrease from baseline in the OSDI score of ≥10 points, changes in the percentages of EPA and DHA in total fatty acids in red cells, changes in signs of DED (assessed by conjunctival staining score, corneal staining score, TBUT, Schirmer’s test), changes in Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) scores, changes in Brief Ocular Discomfort Index (BODI) scores, changes in treatments used for DED, changes in visual acuity and intraocular pressure, incidence of adverse events (key secondary endpoints).

EPA: eicosapentaenoic acid; DHA: docosahexaenoic acid; LA: linoleic acid (omega-3 fatty acid)1. Source: Epitropoulos AT, Donnenfeld ED, Shah ZA, Holland EJ, et al. Eff ect of oral re-esterified omega-3 nutritional supplementation on dry eyes. Cornea 2016; 35:

1185–1191.2. Source: The Dry Eye Assessment and Management Study Research Group. N−3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;

378: 1681-90.

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 7

the eff ect of omega-3 fatty acids on dry eye symptoms found an improvement in Schirmer scores and TBUT although not Ocular Surface Disease Index (OSDI).12

Recognising the risks associated with omega-3 fatty acid sup-plementation through fi sh due to the bioaccumulation of mercury and carcinogens; a multicenter, prospective, interventional, place-bo-controlled, double-masked study in 105 subjects investigated the eff ects of commercial re-esterifi ed fish oil (developed through a process of detoxifying the oil) in subjects with DED. Results showed that, relative to controls, oral consumption of re-esterified omega-3 fatty acids was associated with a significant improvement in tear osmolarity and increased omega-3 index levels and tear break up time (TBUT; P = 0.002), a signifi cant reduction in MMP-9 positivity (P = 0.024) and decreased OSDI symptom scores (P = 0.002) by 12 weeks (and as early as 6 weeks).8 In contrast, a more recent prospec-tive, randomized study in 535 patients with DED (the DREAM study) showed there was no benefi t in patients receiving supple-ments containing 3,000 mg of omega−3 fatty acids for 12 months relative to those patients receiving a placebo as demonstrated by no diff erence between the groups in OSDI score, conjunctival staining score, corneal staining score, TBUT and Schirmer’s test.13

Diff erences in outcomes between the Epitropoulos et al study and the DREAM study may be explained by diff erences in sample size, patient eligibility criteria, dose of omega-3 fatty acid and length of treatment exposure (Table 1). Th e DREAM study was a much larger and longer study that refl ected a real-world patient popula-tion, however potential limitations include that the placebo was not completely inactive since it contained olive oil (although amounts were well below what would be consumed as a part of a Mediter-ranean diet). Potentially more problematic was the fact that patients could change their DED treatment during the study. Th e Epitro-poulos et al study was more focused on assessing dry eye associated with inadequate tear production as opposed to the evaporative type, while both clinical types were addressed in the DREAM study. In general, for all studies investigating the impact of EFA supplemen-tation in treating DED, the imprecision and irreproducibility of the metrics used for measuring the signs and symptoms of DED remains a barrier and oft en patient-reported quality of life mea-sures are the true metric of whether supplementation is benefi cial.

ADVISING PATIENTS REGARDING BENEFITS OF EFA SUPPLEMENTATION FOR DED

Th e question as to whether omega-3 fatty acid supplementa-tion provides any benefi t for DED remains controversial. Th e International Dry Eye Workshop and International Workshop on Meibomian Gland Dysfunction both recommended dietary supplementation with omega-3 fatty acids as a primary therapy.1,14 In contrast, the most recent American Academy of Ophthalmol-ogy Preferred Practice Pattern guidelines noted that omega−3 fatty acids without ethyl esters have been recommended and widely used although the current evidence does not establish a benefi t.15

In terms of advising patients, there is much data showing the benefi t of omega-3 fatty acid supplementation for reducing arthritis, coronary heart disease and Alzheimer’s disease.16-18

As such, there is no harm in ophthalmologists recommending supplementation for DED patients, particularly since DED pa-tients are older and at a higher risk of the above-stated diseases. It is not uncommon for DED patients to consider increasing

their dietary consumption of EFA without taking supplements. However, it is important they understand the vast quantities of foods, such as fi sh, they would need to consume to provide ad-equate EFAs to address the pathophysiological needs associated with DED beyond the normal physiological needs. Th is is where therapeutic supplementation is advantageous.

One issue relating to patients achieving adequate EFA supple-mentation is patient compliance, which is diffi cult to measure and mandate in real clinical practice. While it is possible to measure objectively concentrations of omega-3 fatty acid in blood relative to other fatty acids (typically 8-9%), such tests are expensive and there is signifi cant inter-laboratory variation (3-4-fold).19 Until there is a greater use of commercially available tests in clinics, it is diffi cult to know their accuracy for assessing omega-3 fatty acid levels in DED patients in supporting supplementation compliance.

THE FUTURE OF TREATING DED WITH LIPID-BASED THERAPIESCurrently, there are a plethora of over-the-counter oral ome-

ga-3 fatty acid supplements available for DED patients, however few are prescription-grade. Th e diff erential benefi ts of triglyceride-based formulations versus ester-based or re-esterifed formulations remain to be determined, although the former are better absorbed and potentially more bio-available.20 Many topical artifi cial tears are available yet a paucity of lipid-containing artifi cial tears.21

Th ere exist diff erences in viscosity in artifi cial tears with the thicker formulations conferring better outcomes for patients who present with lipid-defi cient tear fi lms, although visual blurring is reported. As regards lipid-containing artifi cial tears, mouse stud-ies have demonstrated a signifi cant decrease in corneal fl uorescein staining, CD11b(+) cell number and expression of corneal IL-1a and TNF-a22and signifi cant improvements in corneal irregu-larity scores, corneal fl uorescein staining and IL-17, IL-10 and 4-hydroxynonenal (HNE) concentrations23 in response to topical administration of omega-3 fatty acid. Th ese studies indicate the potential role of topical EFA in reducing infl ammatory mediators associated with dry eye. Th ere is only one commercially available preparation of topical EFA (RX-10045; Resolvyx, Celtic Pharma, Hamilton Bermuda), which has been shown to increase tear fi lm stability and improve ocular surface signs of the cornea.22-24

New therapies currently under investigation include antiin-fl ammatory agents, secretory stimulants and tear fi lm stabilizers. Lifi tegrast is a recently approved integrin blocker for the treatment of DED that has anti-infl ammatory eff ects by preventing LFA-1/ICAM-1 interaction preventing T cell activation and recruitment. Further, low dose brimonidine and lacritin supplementation are under clinical study, as are water-free, antievaporative eye drops.25,26

Joseph Tauber, MD is the founder of Tauber Eye Center in Kansas City, MO where he specializes in anterior segment surgery, corneal transplantation, the treatment of corneal and external diseases, and laser vision correction procedures. He states that in the past 12 months, he has not had a fi nancial relationship with any commercial organization that produces, markets, resells, or distributes healthcare goods or services consumed by or used on patients relevant to this manuscript. Medical writer Caroline Markey, PhD, of Markey Medical Con-sulting Pty Ltd, assisted in the preparation of this manuscript.

The full reference list for this article is available online at: http://cme.ufl.edu/ed/self-study/toai/

To obtain CME credit for this activity, go to http://cme.ufl.edu/ed/self-study/toai/8 Topics in OCULAR ANTIINFLAMMATORIES

1. Which of the following statements is accurate reading the newly approved product Dexycu (dexamethasone intraocular suspension) 9%? A. It contains triamcinolone B. It is formulated with mucus-

penetrating particles C. It is preservative-free D. It is formulated for intracanalicular

placement

2. Clinical trials Dextenza (dexamethasone insert) 0.4 mg for intracanalicular use have not demonstrated A. ACC clearing at post-operative day 14 B. No ocular pain at post-operative day 8 C. Low subjective scores from doctors

for visibility D. High subjective scores from patients

for convenience

3. The American Academy of Ophthalmology Preferred Practice Pattern guidelines state that: A. Omega-3 fatty acid products are

unequivocally beneficial for DED treatment

B. The ratio of dietary consumption of omega-3 and omega-6 fatty acids should be equal

C. There is insufficient evidence to establish the effectiveness of EFA for DED

D. Omega-6 fatty acids should be avoided for treating DED

4. Which of the following is NOT included among the warnings on the Dexycu label? A. Endothelial cell toxicity B. Cataract progression C. Infection exacerbation D. IOP elevation

5. The following can be stated about the DREAM study: A. The inclusion criteria were too

restrictive to be relevant to real clinical practice

B. The outcomes provide strong evidence for use of EFA for the treatment of DED

C. The study design reflected real clinical practice more than the Epitropoulos study

D. The placebo contained no EFA

6. Ophthalmologists should prescribe EFA supplementation for patients with DED because: A. The evidence for ocular benefits is

unambiguous B. Significant improvement in tear

osmolarity has been observed in all studies

C. Many DED patients are ≥ 65 years old and may benefit from EFA supplementation

D. Ophthalmologists should not prescribeEFA supplementation for DED

7. The composition of the tear film in patients with DED is characterized by: A. Increased levels of matrix

metalloproteinase-9 (MMP-9) B. Decreased tear osmolarity C. Elevated proinflammatory cells D. Both A and C

8. Which of the following agents work by blocking phospholipase A?A. Bromfenac B. Prednisolone acetateC. Loteprednol etabonate D. B and C

9. New treatments under investigation for the treatment of DED are:A. Lacritin supplementation B. Lifitegrast and water-free

antievaporative eye drops C. Low dose brimonidine D. A, B, and C

10. Which of the following is NOT currently a viable means for potentially lightening the post-operative drop burden for cataract patients? A. Intracameral NSAID injection at the

end of surgery B. Using NSAID with once daily dosing C. Intracameral Vigamox injection at

the end of surgery D. Use combination antibiotic/

corticosteroid from compounding pharmacy

This CME activity is sponsored by the University of Florida College of Medicine and is supported by an unrestricted educational grant from Shire. Participants must score at least 80% on this exam in order to receive credit. The University of Florida College of Medicine designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. To take this exam and obtain credit, please take the test online at http://cme.ufl.edu/ed/self-study/toai/. Expires: January 31, 2020.

CONCLUSIONOf course, drug delivery technology is also other being

applied to indications beyond cataract surgery. For example, a low dose loteprednol etabonate-MPP is in development for the treatment of dry eye disease;22 Dextenza is also in development for treatment of allergic conjunctivitis.18 By my estimation, we can look forward to better outcomes and happier patients as the march toward fewer drops and dropless delivery of medication continues.

Kenneth A. Beckman, MD, FACS, is Director of Corneal Services at Com-prehensive EyeCare of Central Ohio and a clinical assistant professor of oph-

thalmology at The Ohio State University, Columbus, Ohio. Dr. Beckman is a consultant for Omeros and EyePoint Pharmaceuticals and is a stock shareholder for Ocular Science. Medical writer Noelle Lake, MD assisted in the preparation of this manuscript.

REFERENCES1. Grzybowski A, Sikorski BL, Ascaso FJ, et al. Pseudophakic cystoid macular

edema: update 2016. Clin Interv Aging. 2016;11:1221-29.2. Comstock TL, Paterno MR, Singh A, et al. Safety and efficacy of loteprednol

etabonate ophthalmic ointment 0.5% for the treatment of inflammation and pain following cataract surgery. Clin Ophthalmol. 2011;5:177-86.

The full reference list for this article is available online at: http://cme.ufl.edu/ed/self-study/toai/

BECKMAN continued from page 4

EXAMINATION QUESTIONS TOPICS IN OCULAR ANTIINFLAMMATORIES | ISSUE 26

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BECKMAN REFERENCES from page 8

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20. Gira JP, Sampson R, Silverstein SM, et al. Evalu-ating the patient experience after implantationof a 0.4 mg sustained release dexamethasoneintracanalicular insert (Dextenza™): results ofa qualitative survey. Patient Prefer Adherence. 2017;11:487-94.

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