to obtain cme credit for this activity, go to http://cme.ufl .edu/toai Topics in Ocular antiinflammatOries 1Supported by an unrestricted educational grant from Bausch + Lomb, Inc.

Prevention of Pseudophakic Cystoid Macular Edema

Pseudophakic CME, which aff ects thousands of Ameri-cans each year, is the leading cause of unexpected vision dete-rioration following cataract surgery.1 Estimates of its incidence vary, infl uenced by a range of factors including characteristics of the population studied, prophylactic antiinfl ammatory regimen, criteria used to defi ne CME, and timing of the ex-amination following surgery. Overall, somewhere between 0.1% and 4% of patients who undergo routine small incision phacoemulsifi cation surgery with IOL implantation develop clinical CME.1-5

A higher proportion of patients develop detectable macular edema without associated symptoms. Studies that have exam-ined pre- and post-surgical macular appearance (regardless of patients’ symptoms) have found rates of subclinical CME of

4% to 11% by optical coherence tomography (OCT) and 9% to 19% by fl uorescein angiography.2,4

Th e apparent discrepancy between the numbers in the clinical and subclinical categories can be better understood by examining the composition of the latter group. First, some patients with OCT evidence of CME are truly subclinical, with no symptoms, no visual aberrations, and near normal visual acuity. Such patients may have swelling due to minor vessel leakage.3 Other patients may notice a small amount of visual loss but don’t feel the need to report it or it simply goes un-noticed because it pales in comparison to the dramatic overall improvement from the surgery.

Conceivably, a third category of “subclinical” patient might be more accurately characterized as simply “undiagnosed.” Patients expect their surgery to be uneventful; and since most cases of subclinical CME resolve spontaneously over weeks to months, surgeons may be tempted to reassure patients

figuRe 1 Pre- and postoperative Oct of a patient who developed clinically signifi cant cme following phacoemulsifi cation surgery with iOl implantation. note the increase in retinal thickness and the complete loss of the foveal depression following surgery. (Photo

courtesy of the author.)

ISSUE 1

keith A. WALteR, Md Thanks to today’s microsurgical techniques, sophisticated intraocular lenses (IOLs), and antiinfl ammatory drugs, cataract surgery patients often go into surgery expecting marvelous results. Many hope to achieve freedom from glasses altogether. And while these results are certainly possible—and frequently achieved—postoperative vision may still be compromised by a variety of conditions, one of which is pseudophakic cystoid macular edema (CME). Now more than ever, preventing CME is a priority for cataract surgeons.

A CONTINUINGMEDICAL EDUCATION

PUBLICATIONCME

CONTINUING MEDICAL EDUCATION

2 Topics in Ocular antiinflammatOries to obtain cme credit for this activity, go to http://cme.ufl .edu/toai

stAteMent of needthe indications for topical ophthalmic antiinfl ammatory drugs (both steroidal and nonsteroidal) are evolving rapidly, as new agents and new applications emerge. many of these are novel—eg, the perioperative use of nonsteroidal antiinfl ammatory drugs (nsaids) to prevent cystoid macular edema—and/or fl y in the face of older thinking—eg, the use of steroids to calm infl ammation and reduce the risk of melting or scarring from infection. neither of these important applications is on-label.

in addition, new steroidal and nonsteroidal agents continue to come to market, expanding the utility of both classes. antiinfl ammatory drugs are now used for: the treatment of ocular surface disease and allergic conjunctivitis; prevention of perioperative pain and infl ammation in ocular surgery; infection management; cystoid macular edema prophylaxis following cataract surgery; haze prevention in PrK; and much more.

What has regrettably not followed this expansion of indications, formulations, and new molecular entities are protocols for drug selection and use.1 these are vital because signifi cant diff erences in safety, tolerability, and effi cacy exist between and within both antiinfl ammatory drug classes. c-20 ester steroids, for example, have a demonstrated lower risk of intraocular pressure (iOP) elevation than ketone steroids.2,3 since a range of steroid formulations and concentrations is available, clinicians need up-to-date information about the indications and optimum uses for each.3

although topical nsaid formulations have been associated with signifi cant adverse events (keratopathy ranging from superfi cial punctate keratitis to corneal melt), recent work shows these to be uncommon and less severe with newer formulations.4 indeed, novel nsaids make use of lower concentrations and less frequent dosing, potentially impacting safety profi les and reducing risk from long-term use.5

although both are “antiinfl ammatory,” steroids and nsaids act at diff erent points in the infl ammatory cascade, and thus off er opportunities for physicians to fi ne-tune their drug selection. and although they are frequently used together, whether or not the two drug classes can act synergistically is controversial. in the context of recent clinical data, a clear mechanistic understanding of each drug class generally—and of newer formulations specifi cally—will equip clinicians to make eff ective, evidence-based prescribing decisions across the many situations that call for ocular infl ammation control.

RefeRences1. dua Hs, attre r. treatment of post-operative

infl ammation following cataract surgery —a review. European Ophthalmic Review. 2012;6(2):98-103.

2. comstock tl, decory H. advances in corticosteroid therapy for ocular infl ammation: loteprednol etabonate. International Journal of Infl ammation. 2012; doi:10.1155/2012/789623.

3. fong r, leitritz m, siou-mermet r, erb t. loteprednol etabonate gel 0.5% for postoperative pain and infl ammation after cataract surgery: results of a multicenter trial. Clin Ophthalmol. 2012;6:1113-24.

4. 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.

5. cable m. comparison of bromfenac 0.09% Qd to nepafenac 0.1% tid after cataract surgery: pilot evaluation of visual acuity, macular volume, and retinal thickness at a single site. clin Ophthalmol. 2012;6:997-1004.

off-LABeL use stAteMent this work discusses off -label uses of antiinfl ammatory medications.

geneRAL infoRMAtion this cme activity is sponsored by the university of florida college of medicine and is supported by an unrestricted educational grant from Bausch + lomb, inc.

directions: select one answer to each question in the exam (questions 1–10) and in the evaluation (questions 11–16). the university of florida college of medicine designates this activity for a maximum of 1.0 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, tear out or photocopy the answer sheet and send it to:

university of florida cme Offi cePO Box 100233, Gainesville, fl 32610-0233PHONE: 352-733-0064 FAX: 352-733-0007

Or you can take the test online at http://cme.ufl .edu/toaisystem requirements for this activity are: For PC users: Windows® 2000, xP, 2003 server, or Vista; internet explorer® 6.0 or newer, or mozilla® firefox® 2.0 or newer (Javascript™ and Java™ enabled). For Mac® users: mac Os® x 10.4 (tiger®) or newer; safari™ 3.0 or newer, mozilla® firefox® 2.0 or newer; (Javascript™ and Java™ enabled).

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AccReditAtion stAteMent this activity has been planned and implemented in accordance with the essential areas and Policies of the accreditation council for continuing medical education (accme) through the joint sponsorship 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 stAteMent the university of florida college of medicine designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

fAcuLty And discLosuRe stAteMents Lisa B. Arbisser, Md (faculty advisor), is an adjunct associate professor at the university of utah moran eye center in salt lake city, ut, and an ophthalmologist at eye surgeons associates Pc in Bettendorf, ia. she states that in the past 12 months, she has participated in a stand-alone B+l advisory board meeting.

Penny A. Asbell, Md, fAcs, MBA (faculty advisor), is a professor of ophthalmology and director of the cornea and refractive services at icahn school of medicine at mount sinai. she states that in the past 12 months, she has been as consultant for r-tech, senju, and B+l, has given cme lectures for merck, and has received a research grant from alcon.

William e. smiddy, Md (faculty advisor), is a professor of Ophthalmology at the Bascom Palmer eye institute, university of miami miller school of medicine. He states that in the past 12 months, he has attended a steering committee meeting of alimera scientifi c.

Pravin u. dugel, Md, is managing partner of retinal consultants of arizona in Phoenix; clinical associate professor of ophthalmology, doheny eye institute, Keck school of medicine at the university of southern california, los angeles; and founding member of the spectra eye institute in sun city, az. dr. dugel states that he is a consultant for alcon, amO, arcticdx, Ora, regeneron, and thromboGenics.

terrence P. o’Brien, Md, is a professor of ophthalmology, charlotte Breyer rodgers distinguished chair and co-director of ocular microbiology at the Bascom Palmer eye institute of the university of miami school of medicine in Palm Beach, fl. dr. O’Brien has served as a non-salaried ad hoc consultant to alcon, allergan, Bausch + lomb, nicox, Omeros, rapid Pathogen screening, inc, and santen.

keith A. Walter, Md, is an associate professor of ophthalmology at Wake forest university. He states that in the past 12 months, he has served as a consultant for Bausch + lomb and abbott medical Optics and as a member of the Bausch + lomb speakers bureau.

discLAiMeR Participants have an implied responsibility to use the newly 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 diagnosis 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 Bausch + lomb, inc.

TOPICS IN OCULAR ANTIINFLAMMATORIES, ISSUE 1rather than investigate low-level visual complaints following surgery. Th is is unfortunate, since resolution of clini-cal CME can be expedited by treatment with antiinfl ammatory medication.1

PAtient PResentAtion And diAgnosis

Patients with pseudophakic CME typically complain of worsening or blurry vision beginning roughly 4 to 6 weeks aft er surgery—although symp-toms can begin as early as 2 weeks or as late as 12 weeks—aft er having enjoyed excellent vision in the prior few weeks. In some cases, the patient’s visual acuity may be within a line or two of 20/20, yet the patient has a sense that something isn’t quite right with his vision. Th e pa-tient may say, “I just can’t see very well,” or describe a washed-out appearance to things in low-contrast situations, such as a white golf ball against a blue sky. Th is loss of contrast sensitivity, even with normal visual acuity, may be a sign of macular swelling.1 CME can be docu-mented and monitored inexpensively at home by patients by careful Amsler grid observation. Patients may observe lower contrast or graying out in the central grid that moves with fi xation. Once CME is present contrast sensitivity never fully resolves, even with resolution of the edema and restoration of Snellen acuity. If CME persists long enough there will be permanent reduction of Snellen acuity aft er fi nal resolution of the CME itself.

CME can be particularly problem-atic in the multifocal lens patient. Th e complex optics of multifocal IOLs, particularly those with diff ractive optics (which divide light between two images), signifi cantly reduce contrast sensitivity in normal circumstances; and CME fur-ther reduces quality of vision, especially in low light conditions. Th e matter may be further complicated by the patient’s very high expectations for the lenses.

Various anterior segment fi ndings may be present on the post op exami-nation, including mild iritis.1 On oph-thalmoscopy, the eye may show retinal thickening, loss of foveal depression, or, in a minority of cases, appear normal (Figure 1).1,3,4 Diagnosis is facilitated by

to obtain cme credit for this activity, go to http://cme.ufl .edu/toai Topics in Ocular antiinflammatOries 3

infl ammation and prevent CME.NSAIDs work in the cytoplasm where they directly inhibit

COX-1 and COX-2 enzymes, blocking prostaglandin synthe-sis. NSAIDs are lipophilic and pass readily through the cell membrane to their target. Halogenated NSAIDs are even more lipophilic; the bromine atom at the C-4 position of bromfenac, for example, enhances its lipophilicity and cell penetration, as well as its ability to block COX-2.6 Even though formulated at low concentration (0.07%), it is still approved for once-a-day dosing, with the same clinical activity as higher concentra-tion (0.09%).7 Th e recent reformulation of nepafenac—in this case raising its concentration—also allows once-a-day dosing.

nsAid-onLy PRoPhyLAXisMany surgeons regard NSAIDs and steroids as synergistic

and use both for infl ammation control aft er cataract surgery. Th is practice stems from studies showing that adding an NSAID to a steroid-based regimen reduced infl ammation more eff ectively than a steroid alone.8-10 But these studies lacked an NSAID-only arm, so we were not able to learn what an NSAID might be capable of on its own.

As newer research continues to demonstrate advantages to NSAID monotherapy for antiinfl ammatory prophylaxis, a paradigm shift could be underway.11-14 Seeing that generic steroids were oft en substituted for name brands, possibly af-fecting the effi cacy of combination prophylaxis, I began using an NSAID-only approach (with bromfenac) in 2010.

Our study suggests that bromfenac alone is at least equiva-lent to steroids in the control of postsurgical infl ammation and prevention of CME. Initiating NSAID therapy 2 days before surgery inhibits intraocular COX-1 and COX-2 production well before any tissue insult occurs. My current practice is to use only the NSAID in all patients regardless of CME risk. It is given once a day starting 2 days before surgery and contin-ued for approximately 30 days aft erwards. In my experience, patients’ eyes appear as quiet the day aft er surgery as they were when I used steroids; and I have seen only one case of CME in the last 1,300 eyes.

fl uorescein angiography or OCT, which is less invasive and currently the more popular option. OCT typically reveals mild to moderate thickening or even a cystic space in the macula, evidence of CME.2 (Technically, cysts should be present to meet the defi nition of CME.)

MechAnisM And RiskCME is thought to result from multiple processes that

culminate in the development of a fl uid-fi lled cyst within the macula; infl ammation plays a primary role.1 Surgery (of any type) causes damage to cell membranes, which releases phospholipids and leads to activation of phospholipase. Th is is the start of a series of chemical events that leads eventually to the production and release of prostaglandins. Th e resulting prostaglandins (and other mediators) can migrate from the front to the back of the eye, where they may cause increased vascular permeability, compromise the integrity of the blood-ocular barrier, and allow pooling of fl uid in the outer layers of the retina.3,4

Th e risk of developing CME following ocular surgery is increased in patients with certain ocular comorbidities or intraoperative factors.3 Ocular conditions that disrupt retinal homeostatic mechanisms—including diabetic retinopathy, age-related changes, hypertension, epiretinal membrane, and retinal vein occlusion—increase the risk of further disruptions induced by surgical infl ammation.1-3,5

Other patients at increased risk of CME include diabetics (with or without retinal pathology) and patients with acute uveitis, a history of CME in the fellow eye, or preoperative exposure to prostaglandin analogs (typically used for IOP control in glaucoma).3,5

Complicated surgery with additional tissue manipulation is also associated with increased infl ammation and CME risk. Problematic events include iris trauma, broken posterior cap-sule, vitreous prolapse, retained lens fragments, and prolonged surgical time.1,3

AntiinfLAMMAtoRy PRoPhyLAXisPre- and postoperative treatment with antiinfl ammatory

drops is now standard in many centers to reduce surgically induced infl ammation and CME risk. Corticosteroids are the most commonly used; they work by penetrating into the nucleus and binding DNA receptors to shut down the formation of arachidonic acid. Th ey prevent the formation of prostaglandins by blocking arachidonic acid formation in the very fi rst stages of the infl ammatory cascade.

Steroids present considerable downsides, however. Steroids are lipophobic, which limits their ability to reach their target. A second problem is that most steroid formulations are sus-pensions that require patients to shake the bottle numerous times for the active agent to distribute properly within the supernatant. Th is can be diffi cult for some elderly patients to do. A third factor relates to compliance. Steroids may re-quire dosing 4 (or more) times per day, and many patients do not remember to use them that frequently. Because of these limitations, many surgeons have turned to NSAIDs to control

coRe concePts ✦ symptomatic pseudophakic cme occurs at a low rate

but is numerically common due to the large number of cataract surgeries performed.

✦ more patients have subclinical cme detectable by Oct or angiography than clinical cme with symptoms.

✦ suspect cme in patients with reduced vision quality (not due to a multifocal iOl) and/or reduced visual acuity.

✦ infl ammation is central to cme pathophysiology; a susceptible retina and intraoperative complications increase risk.

✦ use of an nsaid alone for antiinfl ammatory prophylaxis provides pharmacokinetic, effi cacy, safety, and convenience profi les comparable to single-agent steroid regimens.

4 Topics in Ocular antiinflammatOries to obtain cme credit for this activity, go to http://cme.ufl .edu/toai

study ResuLtsOur research also supports the use of NSAID alone to

control infl ammation. My colleagues and I studied two groups of patients who underwent cataract surgery at our institution before and aft er our switch to NSAID-only prophylaxis: group A included 200 surgeries between January and August 2010 in which patients received postsurgical prednisolone acetate 1% (four times daily for 2 weeks followed by a 3 week taper); group B included 200 eyes operated on between September 2010 and May 2011 who received only bromfenac 0.09% either once or twice daily beginning 2 days prior to surgery through 4 weeks aft er. Approximately 20% of eyes in group A received adjunctive NSAID due to risk factors such as diabetes.15

CME rates were low in both groups: there were two cases of CME (1%) in group A and one case (0.5%) in group B. Best cor-rected visual acuity and measures of infl ammation (anterior chamber cell and fl are) were equivalent between the groups. Aft er correcting for two cases of retained lens fragment, a higher proportion of steroid-exposed patients developed elevated IOP compared to those exposed to NSAID only: 8% vs 2.5%, respectively (P = 0.02).15

Small studies of other NSAIDs, including diclofenac and nepafenac, have demonstrated effi cacy comparable to steroids for preventing CME.12,13 Th ere are presently three ophthalmic NSAIDs available on the US market that are approved for once daily dosing: bromfenac 0.09% and 0.07% and nepafenac 0.3%, the latter being a tripled concentration formulation of its three-times-daily predecessor nepafenac 0.1%.7,16-18 Nepafenac is a prodrug, requiring conversion by ocular tissue hydrolase enzymes to amfenac, its active form. In theory nepafenac activity may be somewhat compromised in patients with low hydrolase levels, such as dry eye syndrome, but this has not been reported.

Even those surgeons who routinely use NSAID-only prophylaxis may sometimes find an adjunctive steroid helpful for patients with pain or evidence of infl ammation on follow-up examination. Since switching to NSAID-only prophylaxis, my group has prescribed adjunctive steroid in just 1% of patients.

convenience, coMPLiAnce, And costSimpler dosing regimens have eased the burden of remem-

bering to take drops for patients and their families. Patients no longer have to create elaborate charts, and children or grandchildren providing care for an older family member are less burdened by repeated dosing. Compliance is enhanced because patients feel as if they can handle what is being asked of them; the family is happier; and the results are the same as with more complicated regimens.

Concerns about cost are almost universal among patients. Simplifying the prophylactic regimen helps reduce the num-ber of patient co-pays, easing their fi nancial burden. Since I prescribe a branded drug, I preempt callbacks by preparing

patients for the cost of their medication. Th is brief conversa-tion goes a long way in managing expectations.

concLusionFor many cataract surgery patients, an NSAID alone may

provide adequate and eff ective antiinfl ammatory prophylaxis. Th e advantages of NSAID monotherapy include increased safety and convenience compared to steroids.

Keith A. Walter M.D. is an associate professor of ophthalmology at Wake Forest University. He serves as a consultant for Bausch + Lomb and Abbott Medical Optics, and as a member of the Bausch + Lomb speakers bureau. Medical writer Noelle Lake, MD, assisted in the preparation of this manuscript.

RefeRences 1. Ray S, D’Amico DJ. Pseudophakic cystoid macular edema. Semin Ophthalmol.

2002;17:167-80. 2. Kim SJ, Bressler NM. Optical coherence tomography and cataract surgery.

Curr Opin Ophthalmol. 2009 Jan;20(1):46-51. 3. Lobo C. Pseudophakic cystoid macular edema. Ophthalmologica. 2012;227:

61-7. 4. Yonekawa Y, Kim IK. Pseudophakic cystoid macular edema. Curr Opin

Ophthalmol. 2012;23:26-32. 5. Henderson BA, Kim JY, Ament CS, et al. Clinical pseudophakic cystoid

macular edema. Risk factors for development and duration after treatment. J Cataract Refract Surg. 2007;33:1550-8.

6. Cho H, Wolf KJ, Wolf EJ. Management of ocular infl ammation and pain following cataract surgery: focus on Bromfenac ophthalmic solution. Clin Ophthalmol. 2009;3:199-201.

7. Prolensa® (bromfenac ophthalmic solution) 0.07% product information. Tampa, FL: Bausch and Lomb; 2013.

8. Wittpenn JR, Silverstein S, Heier J, et al. A randomized, masked comparison of topical ketorolac 0.4% plus steroid vs steroid alone in low-risk cataract surgery patients. Am J Ophthalmol. 2008;146:554-60.

9. Wolf EJ, Braunstein A, Shih C, et al. Incidence of visually signifi cant pseu-dophakic macular edema after uneventful phacoemulsifi cation in patients treated with nepafenac. J Cataract Refract Surg. 2007;33:1546-9.

10. Almeida DR, Johnson D, Hollands H, et al. Eff ect of prophylactic nonsteroi-dal antiinfl ammatory drugs on cystoid macular edema assessed using optical coherence tomography quantifi cation of total macular volume after cataract surgery. J Cataract Refract Surg. 2008;34:64-9.

11. Miyake K, Masuda K, Shirato S, et al. Comparison of diclofenac and fl uoro-metholone in preventing cystoid macular edema after small incision cataract surgery: a multicentered prospective trial. Jpn J Ophthalmol. 2000;44:58-67.

12. Miyake K, Ota I, Miyake G, et al. Nepafenac 0.1% versus fl uorometholone 0.1% for preventing cystoid macular edema after cataract surgery. J Cataract Refract Surg. 2011;37:1581-8.

13. Asano S, Miyake K, Ota I, et al. Reducing angiographic cystoid macular edema and blood-aqueous barrier disruption after small-incision phacoemul-sifi cation and foldable intraocular lens implantation: multicenter prospective randomized comparison of topical diclofenac 0.1% and betamethasone 0.1%. J Cataract Refract Surg. 2008;34:57-63.

14. Wang QW, Yao K, Xu W, et al. Bromfenac sodium 0.1%, fl uorometholone 0.1% and dexamethasone 0.1% for control of ocular infl ammation and preven-tion of cystoid macular edema after phacoemulsifi cation. Ophthalmologica. 2013;229:187-94.

15. Walter KA, Estes AJ, Watson S, et al. Management of ocular infl ammation following routine cataract surgery: topical corticosteroid (prednisolone) versus topical non-steroidal (bromfenac). US Ophthalmic Review. 2011;4:97-100.

16. Ilevro (nepafenac ophthalmic suspension) 0.3% product information. Fort Worth, TX: Alcon; 2012.

17. Nevanac (nepafenac ophthalmic suspension) 0.1% product information. Fort Worth, TX: Alcon; 2011.

18. Bromday® (bromfenac ophthalmic solution) 0.09% product information. Tampa, FL: Bausch and Lomb; 2012.

to obtain cme credit for this activity, go to http://cme.ufl .edu/toai Topics in Ocular antiinflammatOries 5

originate from toxin exposure, infec-tion, injury or autoimmune disease. Iritis, for example, may be an isolated occurrence or related to a systemic au-toimmune process such as rheumatoid arthritis. Similarly, intermediate uveitis may occur in isolation, as may happen in younger people, or secondary to a sys-temic process such as multiple sclerosis.

Inf lammation of the retina may be due to a broad range of conditions. When it occurs, the first task is to discern whether the infl ammation is primary or secondary. For example,

retinitis related to acute retinal necrosis is a primary condi-tion originating in the retina. On the other hand, uveitis involving multiple compartments including the retina, eg, chorioretinitis, or the vitreous, vitritis, could represent sec-ondary involvement.

Although perhaps not primarily infl ammatory in etiology, several common diseases of the retina, including diabetic reti-nopathy and age-related macular degeneration, are thought to have infl ammatory components.5

New Perspectives on Ocular Antiinfl ammatory Drugs

While we like to think of the eye as a series of compart-ments—the ocular surface, the anterior segment, and the pos-terior segment—these “compartments” are far from watertight, and infl ammatory mediators formed in one compartment can easily aff ect adjacent tissues. We see this in uveitis when an in-fl amed uveal tract extends its eff ects to multiple ocular tissues or, more commonly, when mediators from focal infl ammation in response to cataract surgery diff use to the back of the eye where they can interfere with the integrity of the blood-ocular barrier, leading to postoperative cystoid macular edema (CME) or chronic uveitis.1,2

Anatomical compartmentalization remains useful as a basis for thinking about the eye and for understanding and managing the wide range of infl ammatory conditions oph-thalmologists endeavor to prevent and/or treat. We shall make use of it in the following brief review of the sources of ocular infl ammation and current and coming ocular antiinfl amma-tory agents for management thereof.

souRces of infLAMMAtionTh e systematic evaluation of the ocular infl ammation

involves three steps: 1) identifying the tissue that is infl amed, 2) determining the cause of the infl ammation (in particular, whether that cause is infectious), and 3) determining whether the ocular infl ammation is primary or the result of an underly-ing systemic condition.

Infl ammation of the ocular surface can have several causes: allergy, infection, toxins and trauma, including injury related to ocular surgery.3 Th e complex group of conditions that can produce dry eye disease are a common cause of ocular surface infl ammation.4 In addition, chronic ocular surface irregulari-ties, such as pinguecula and pterygia, can sometimes become infl amed.3

Within the eye, conditions associated with signifi cant infl ammation include episcleritis, anterior scleritis, and an-terior uveitis (iritis, iridocyclitis or pars planitis), which may

teRRence P. o’BRien, Md, AND PRAvin u. dugeL, MdAlthough infl ammation is a normal physiologic response to injury, in a delicate tissue like the eye an overly robust or misplaced infl ammatory reaction can lead to tissue destruction, ocular disease and loss of vision. A variety of pharmacotherapeutic agents from several classes are available to tame ocular infl ammation, and new corticosteroids and NSAIDS—with fresh capabilities and formulations—have recently received approval for ophthalmic use. More exciting, innovative immunomodulators, entirely new classes of agents for the control of ocular infl ammation, like selective glucocorticoid receptor agonists (SEGRAs), as well as novel biologic response modifi ers are in the pipeline.

coRe concePts ✦ evaluation of ocular infl ammation should address three

key variables: anatomical involvement, underlying cause (infectious vs. noninfectious), and whether the infl ammation is primary (and isolated) or secondary to a larger systemic process (eg, autoimmune disorder).

✦ antiinfl ammatory drug delivery may involve topical application, periocular injection, intracameral, intravitreal injection, or systemic administration. the aim is to employ the safest means to obtain an eff ective drug concentration.

✦ Whenever possible, treatment should address the underlying cause of infl ammation.

✦ Perioperative antiinfl ammatory application serves multiple purposes including reducing cme risk.

✦ steroids and nsaids are the most commonly prescribed ocular antiinfl ammatory agents.

✦ seGras bind the same intracellular receptor as steroids but trigger a select subset of gene activation functions; they are expected to become a new antiinfl ammatory class option with a strong safety profi le.

✦ immunomodulators are potent antiinfl ammatories that eff ect immune cell function.

6 Topics in Ocular antiinflammatOries to obtain cme credit for this activity, go to http://cme.ufl .edu/toai

APPRoAching AntiinfLAMMAtoRy tReAtMentMedical treatment of infl ammation begins with an attempt

to target the underlying cause. When an active infection is the cause, antimicrobial agents can decrease infl ammation by eliminating the inciting infection. (Even aft er the infectious organisms have been eliminated, however, endotoxins left be-hind can continue to incite infl ammation.) For non-infectious ocular surface infl ammatory conditions like dry eye, lubricat-ing drops can make eyes more comfortable by restoring physi-ologic osmolarity, reducing friction between the ocular surface and the lid, limiting tissue damage and removing a source of infl ammation. Although their action is indirect—lubricating drops reduce friction, which means less tissue damage, which means less incite-ment to infl ammation—these drops can be said to be eff ectively “antiinfl ammatory.”

An ideal antiinfl ammatory agent for treating the ocular surface and anterior chamber would have several characteristics. First, its formulation should make it comfortable to apply, so that patients are not bothered by taking it and will comply with their regimen given excellent tolerability. Drug formulation also determines viscosity and pH, factors that can infl uence absorption and penetra-tion. Higher viscosity can result in greater retention time on the ocular surface thus allowing increased contact time for enhanced penetrability across the corneal epithelial barrier.

Ideally, a topical antiinf lammatory agent would also have analgesic properties, as the surface of the eye is abundantly supplied with sensory nerve endings, making it exquisitely sensitive to pain. Th e analgesic eff ect improves comfort while the anti-infl ammatory action takes place. Of course, antiinfl ammatory agents should be nontoxic to ocular cells with excellent biocompatibility. Ideally, they would also contain some of the molecules present in tears and serum that promote healing.

toPicAL dRoPs And intRAocuLAR stRuctuResTopically administered drug can penetrate the cornea to

reduce infl ammation in the anterior chamber, including the iris, providing one route to the intraocular space. However, rapid reduction of intraocular infl ammation is essential to limit damage and preserve or reestablish the blood-ocular barrier. To achieve these ends, two additional drug delivery routes are avail-able, with selection based on the compartment to be reached.

Periocular (subconjunctival or sub-Tenon’s) injection creates a depot of drug adjacent to the sclera that can gradu-ally diff use out to achieve tissue concentrations that cause immunosuppression in nearby compartments and spaces. Intravitreal injection provides a bolus of drug directly into the posterior cavity that can act immediately and sometimes last over the course of 7 to 10 days in the posterior eye. Typically the drug of choice for injection is a longer-acting corticosteroid. Of note, no corticosteroid agent has received FDA approval for

intravitreal treatment of uveitis, so the choice of an (off -label) drug must be based on other factors. Triamcinolone acetonide is readily accessible, cost eff ective, and therefore commonly used for intravitreal antiinfl ammatory therapy.

Systemic antiinfl ammatory delivery via oral or intrave-nous routes may be necessary for severe or recalcitrant cases, although this route risks limitation of eff ective absorption into ocular tissues and potential creation of systemic side ef-fects. Systemically administered steroids have measured low bioavailability in the eye.

AntiinfLAMMAtoRy cLAsses Agents with direct antiinfl ammatory action fall into one

of four principle categories, of which corticosteroids and nonsteroidal antiinfl ammatory drugs (NSAIDs) are the two most clinically relevant groups in ophthalmology. A third antiinflammatory class, selective glucocorticoid receptor agonists (or SEGRAs) is emerging. SEGRAs are neither steroid nor NSAID. Th e fourth category includes immunomodulators (eg, cyclosporine, tacrolimus) that act on immune cells rather than specifi c enzymes or receptors.

steRoids

Corticosteroids have been used in medicine for over 50 years to reduce infl ammation and treat conditions of excess immunological activity. Corticosteroids block multiple steps in the infl ammatory cascade, including the conversion of membrane-bound phospholipids into arachidonic acid that is catalyzed by phospholipase A (Figure 1). Topical cortico-steroids—including prednisolone acetate, prednisolone phos-phate, loteprednol etabonate, dexamethasone, fl uorometho-lone, rimexolone, difl uprednate, and others—are mainstays for controlling infl ammation related to surgically induced trauma.

Newer ophthalmic steroids have been structurally modi-fi ed to improve upon certain properties of their parent mol-ecules. Dual fl uorination of C-6 and C-9 atoms increases the binding specifi city of difl uprednate ophthalmic emulsion

Membrane-bound phospholipids

Phospholipase A2

Arachidonic acid

Tissue-specific isomerases

COX-1

COX-2

NSAIDs, ASA

Coxibs

O2

PGG2

PGH2

PGD2 PGE2 PGF2 PGI2 TxA2

figuRe 1 the root from insult to infl ammation via prostaglandin and thromboxane biosynthesis. (Adapted from Cho, et al 2009, reference 8.)

COX = cyclooxygenase; Coxibs = cOx-2 inhibitors; PG = prostaglandin; TxA2 = thromboxane a2; NSAID = nonsteroidal antiinfl ammatory drug; ASA = aspirin

to obtain cme credit for this activity, go to http://cme.ufl .edu/toai Topics in Ocular antiinflammatOries 7

0.05% to glucocorticoid receptors and thus increases its po-tency. Additionally, difl uprednate has a butyrate ester at C-17 and an acetate ester at C-21 which further increase potency and improve corneal penetration. Emulsion formulation—dif-fi cult to achieve with steroids, which are lipophilic—improves consistency of dosing over suspension corticosteroid formu-lations. As with all steroids, increased intraocular pressure (IOP), cataractogenesis and potentiation of infection is a risk.6

Loteprednol etabonate represents another advance in ste-roid design, this time with a retrometabolic approach focused on improved safety. Loteprednol etabonate contains an ester group (rather than the typical ketone) at the C-20 position; and natu-rally occurring esterases in ocular tissues quickly break lotepre-dnol down into inactive metabolites. Th us, with less active agent lingering in ocular tissue the risk of steroid-related complica-tions, including IOP elevation and cataract formation, may be reduced with loteprednol. Potency has been shown to be similar to other steroids including rimexolone and difl uprednate.7

nsAidsRelative to steroids, NSAIDs work further downstream

in the infl ammatory cascade where they inhibit the enzymes cyclooxygenase (COX) 1 and 2. Acting at that point in the cascade, they block the conversion of arachidonic acid to prostaglandins (Figure 1).8 COX is primarily expressed in the anterior segment including the iris and ciliary body. COX-1 is constitutive, meaning it is always present and active whereas COX-2 is inducible, becoming upregulated during trauma. Topical ophthalmic NSAIDs include diclofenac, ketorolac, nepafenac, and bromfenac.8

Ocular NSAIDs (and steroids as well) are most frequently prescribed to control and prevent infl ammation caused by ocular surgery. In ocular surgery cell membranes are dam-aged causing arachidonic acid to be released. In intraocular surgeries, such as cataract surgery, arachidonic acid in the anterior chamber stimulates the formation and release of prostaglandins, followed by a predictable sequence of events: leukocyte migration, increased vascular permeability, and protein accumulation in the aqueous humor, all of which leads to ocular erythema, chemosis, and pain.

Some patients are at greater risk for infl ammation than others: those whose surgeries take longer and/or involve more manipulation of the iris; younger patients (who tend to have a more robust infl ammatory response than older patients); patients with prior history of eye surgery or of ocular infl am-matory disorders, such as uveitis; non-Caucasian race; diabetic patients; and patients with brown irides.

NSAIDs, which may be given prior to surgery, provide a means to interrupt this cycle before it begins, limiting prostaglandin formation and keeping the proverbial “horse from leaving the barn.” In addition to reducing infl amma-tion and potentially preventing CME, perioperative NSAIDs perform two additional functions: they provide analgesia that supplements anesthetic agents, and they sustain intraopera-tive pupillary mydriasis, further reducing the risk of surgical

complications. NSAIDs are also oft en co-administered with corticosteroids following surgery to control pain and infl am-mation and to treat CME should it develop. In contrast to steroids, NSAIDs do not increase risk for infection, develop-ment of cataract or raised IOP.8

(edıtor’s note: Many ophthalmologists today start ste-roids preoperatively and claim that the eyes are quieter on day one. Of note, steroids also fortify tight junctions between en-dothelial cells, theoretically reducing the likelihood of edema [although this is not strictly an antiinfl ammatory eff ect, and NSAIDS have no such action].)

segRAsSelective glucocorticoid receptor agonists (SEGRAs)

comprise a class of experimental compounds in development for the treatment of chronic ocular infl ammation and other infl ammatory disorders. Th e aim in developing them is to im-prove on the therapeutic index of steroids.9,10 Th ese molecules are structurally similar to steroids and bind the same glucocor-ticoid receptor (GR) that is ubiquitous in cells. SEGRAs are not steroids, however, in that, once bound to the GR, they modulate genes diff erently, ie, more selectively. By virtue of their design, SEGRAs maintain the transrepressive actions of steroids, which underlie their antiinfl ammatory effi cacy, but are “dis-sociated” from transactivation, which is thought to underlie side eff ects such as increased IOP and cataract formation.9

In vitro studies have shown that the experimental SEGRA mapracorat is associated with reduced expression of mamma-lian myocilin, a trabecular meshwork protein the production of which is boosted by steroids. Th is may represent the mecha-nism of steroid-induced glaucoma.11 Studies in rabbits have shown a reduced propensity to increase IOP with mapracorat compared with dexamethasone.12 Mapracorat is in develop-ment for the treatment of dry eye (phase 2) and post-cataract surgery infl ammation (phase 3).13

iMMunoModuLAtoRsImmunomodulatory agents do not bind receptors; rather

they work directly or indirectly on lymphocytes, neutrophils, macrophages, and other eff ector cells of the immune system. Topical cyclosporine is a T-cell modulator that reduces infl am-mation on the ocular surface associated with dry eye. Cyclo-sporine has been shown to increase aqueous tear production as well as improve tear fi lm stability in patients with meibomian gland dysfunction.14

Tacrolimus is another T-cell modulator but with greater potency and diff erent pharmacokinetics compared to cyclo-sporine. Although not FDA approved, tacrolimus has been useful in the treatment of severe infl ammatory ocular surface diseases, including atopic keratoconjunctivitis, cicatrizing conjunctivitis, necrotizing scleritis, and Moorens ulcer.15

BioLogicsBiologic response modifi ers (oft en referred to as biologics)

are proteins produced by recombinant DNA or monoclonal

8 Topics in Ocular antiinflammatOries to obtain cme credit for this activity, go to http://cme.ufl.edu/toai

antibody technology designed to block specific mediators of the cell-mediated immune response. These biologic agents have been used with considerable success in managing challeng-ing uveitic conditions, thereby reducing the need for chronic corticosteroids.16,17

Systemic biologics, including TNF-alpha inhibitors, are potent immunosuppressives, and are not recommended for the treatment of infectious uveitis. Class effects of such biologics include risk of serious infection, most significantly reactiva-tion of tuberculosis and fungal infections, as well as increased risk of malignancy.

Biologics are potent new medications that may benefit some patients with refractory noninfectious posterior uveitis. Side effects of biologics are common and can be potentially serious. Cost is also significantly greater than steroids and can be a limiting issue. Biologics are typically reserved for patients for whom the potential benefits outweigh the risks and justify the costs of these potent agents.

Looking AheAdHuman amniotic membrane, as a transplant or bandage

contact lens, has been used as a means of treating ocular surface burns, severe dry eye, severe bacterial keratitis, and other diseases of the cornea that have a significant inflamma-tory component.17-20 The success of human amnion, at least in part, derives from the wealth of natural immunosuppressive factors it contains and its low immunogenicity. In the future, the ability to identify, extract, and formulate critical bioactive components of amniotic membrane tissue could pave the way for new classes of very potent natural antiinflammatory agents to manage ocular surface disorders.

Terrence P. O’Brien, MD, is a professor of ophthalmology, Charlotte Breyer Rodgers Distinguished Chair and co-director of ocular microbiology at the Bascom Palmer Eye Institute of the University of Miami School of Medicine in Palm Beach, FL. Dr. O’Brien has served as a non-salaried ad hoc consultant to Alcon, Allergan, Bausch + Lomb, Nicox, Omeros, Rapid Pathogen Screening, Inc, Santen and Senju. Pravin U. Dugel, MD, is managing partner of Retinal Consultants of Arizona in Phoenix; clinical associate professor of ophthal-mology, Doheny Eye Institute, Keck School of Medicine at the University of Southern California, Los Angeles; and founding member of the Spectra Eye Institute in Sun City, AZ. Dr. Dugel states that he is a consultant for Alcon, AMO, ArcticDx, Ora, Regeneron, and ThromboGenics. He can be reached via

email at pdugel@gmail.com. Medical writer Noelle Lake, MD assisted in the preparation of this article.

RefeRences 1. Scholl S, Kirchhof J, Augustin AJ. Pathophysiology of macular edema.

Ophthalmologica. 2010;224 Suppl 1:8-15. 2. Patel C, Kim SJ, Chomsky A, et al. Incidence and risk factors for chronic

uveitis following cataract surgery. Ocul Immunol Inflamm. 2013;2:130-4. 3. Kim SJ, Flach AJ, Jampol LM. Nonsteroidal anti-inflammatory drugs in

ophthalmology. Surv Ophthalmol. 2010;55:108-33. 4. Calonge M, Enríquez-de-Salamanca A, Diebold Y, et al. Dry eye disease as

an inflammatory disorder. Ocul Immunol Inflamm. 2010;18:244-53. 5. Bringmann A, Reichenbach A, Wiedemann P. Pathomechanisms of cystoid

macular edema. Ophthalmic Res. 2004;36:241-9. 6. Donnenfeld ED. Difluprednate for the prevention of ocular inflammation

postsurgery: an update. Clin Ophthalmol. 2011;5:811-16. 7. Amon M, Busin M. Loteprednol etabonate ophthalmic suspension 0.5%:

efficacy and safety for postoperative anti-inflammatory use. Int Ophthalmol. 2012;32:507-17.

8. Cho H, Wolf KJ, Wolf EJ. Management of ocular inflammation and pain following cataract surgery: focus on Bromfenac ophthalmic solution. Clin Ophthalmol. 2009;3:199-201.

9. Schäcke H, Berger M, Rehwinkel H, Asadullah K. Selective glucocorticoid receptor agonists (SEGRAs): novel ligands with an improved therapeutic index. Mol Cell Endocrinol. 2007 Sep 15;275(1-2):109-17.

10. Zhang JZ, Cavet ME, VanDerMeid KR, et al. BOL-303242-X, a novel selec-tive glucocorticoid receptor agonist, with full anti-inflammatory properties in human ocular cells. Mol Vision. 2009;15:2606-16.

11. Pfeffer BA, DeWitt CR, Salvador-Silva M, et al. Reduced myocilin expres-sion in cultured monkey trabecular meshwork cells induced by a selective glucocorticoid receptor agonist. Invest Ophthalmol Vis Sci. 2010;51:437-46.

12. Budzynski ESA, López FJ, Ward KW. BOL-303242-X, a selective glucocor-ticoid receptor agonist (SEGRA), offers a better in vivo side effect profile than dexamethasone on intraocular pressure elevation in normotensive rabbits. ARVO Annual Meeting; 2009 May 3-7; Fort Lauderdale (FL).

13. Clinical trials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT01163643?term=bol-303242-x&rank=1 and http://clinicaltrials.gov/ct2/show/NCT01591161?term=mapracorat&rank=3 Accessed July10, 2013.

14. Prabhasawat P, Tesavibul N, Mahawong W. A randomized double-masked study of 0.05% cyclosporine ophthalmic emulsion in the treatment of mei-bomian gland dysfunction. Cornea. 2012 Dec;31(12):1386-93.

15. Lee YJ, Kim SW, Seo KY. Application for tacrolimus ointment in treating refractory inflammatory ocular surface diseases. Am J Ophthalmol. 2013 May;155(5):804-13.

16. Lim L, Suhler EB, Smith JR. Biologic therapies for inflammatory eye disease. Clin Experiment Ophthalmol. 2006;34:365-74.

17. Cunningham ET, Zierhut M. TNF inhibitors for uveitis: balancing efficacy and safety. Ocul Immunol Inflamm. 2010;18(6):421-3.

18. Xiao X, Luo P, Zhao H, et al. Amniotic membrane extract ameliorates ben-zalkonium chloride-induced dry eye in a murine model. Exp Eye Res. 2013 Jun 20.

19. Sheha H, Liang L, Li J, et al. Sutureless amniotic membrane transplantation for severe bacterial keratitis. Cornea. 2009;28:1118-23.

20. Lavaju P, Sharma M, Sharma A, et al. Use of amniotic membrane and autologous serum eye drops in Mooren’s ulcer. Nepal J Ophthalmol. 2013 Jan;5(9):120-3.

to obtain cme credit for this activity, go to http://cme.ufl.edu/toai Topics in Ocular antiinflammatOries 9

1. Compared to a steroid-only or steroid-NSAID regimen, NSAID-only CME prophylaxis:A. Is more difficult for patients to

manageB. May provide equivalent

prophylactic efficacyC. Is significantly more expensive D. All of the above are true

2. Which of the following is NOT a consideration in the evaluation of ocular inflammation?A. Underlying cause of the conditionB. Which tissues are involvedC. Relationship to systemic illnessD. Ratio of axial length to anterior

chamber depth

3. Which of the following patient situations warrants further evaluation for pseudophakic CME?A. Increasing blurriness at 5 weeks

after uneventful cataract/IOL surgery

B. Glare and halos while driving at night 2 weeks after multifocal lens implant

C. Normal acuity but reduced contrast sensitivity 6 weeks after complicated surgery

D. Both A and C are correct

examination answer sheet Topics in ocular anTiinflammaTories | issue 1

evALuAtion:1=Poor 2=fair 3=satisfactory 4=Good 5=Outstanding

11. extent to which the activity met the identified Objective 1: 1 2 3 4 5 Objective 2: 1 2 3 4 5 Objective 3: 1 2 3 4 5

12. rate the overall effectiveness of how the activity: related to my practice: 1 2 3 4 5 Will influence how i practice: 1 2 3 4 5 Will help me improve patient care: 1 2 3 4 5 stimulated my intellectual curiosity: 1 2 3 4 5 Overall quality of material: 1 2 3 4 5 Overall met my expectations: 1 2 3 4 5 avoided commercial bias/influence: 1 2 3 4 5

13. Will the information presented cause you to make any changes in your practice? Yes no

14. if yes, please describe: __________________________

________________________________________________

15. How committed are you to making these changes? 1 2 3 4 5

16. are future activities on this topic important to you? Yes no

if you wish to receive credit for this activity, please fill in the following information. retain a copy for your records. PLeAse PRint cLeARLy

________________________________________________________________first name last name deGree

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________________________________________________________________PHOne fax

________________________________________________________________e-mail address

this cme activity is jointly sponsored by the university of florida and candeo clinical/science communications, llc, and supported by an unrestricted educational grant from Bausch + lomb, inc. mail to: university of florida cme Office, PO Box 100233, Gainesville, fl 32610-0233. directiOns: select the one best answer for each ques-tion in the exam above (Questions 1–10). Participants must score at least 80% on the questions and complete the entire evaluation (Questions 11–16) to receive cme credit. cme exam expires July 31, 2014.

1. A B C D

2. A B C D

3. A B C D

4. A B C D

5. A B C D

6. A B C D

7. A B C D

8. A B C D

9. A B C D

10. A B C D

AnsWeRs:

4. At what point after surgery is pseudophakic CME most like to present?A. Within the first 24 hoursB. At 1 weekC. At 4 to 6 weeksD. At 15 to 20 weeks

5. Which of the following classes do NOT bind receptors?A. NSAIDsB. CorticosteroidsC. ImmunomodulatorsD. SEGRAs

6. Which of the following is NOT true of ophthalmic NSAIDs?A. They can be analgesic B. They block phospholipase AC. They sustain pupillary mydriasisD. They block cyclooxygenase

7. Which of the following statements about ophthalmic NSAIDs is true?A. NSAIDs may be given in advance

of surgery to reduce inflammationB. Halogenation does not affect

NSAID potencyC. NSAIDs are contraindicated in

patients with glaucomaD. Both A and C are true

8. Which of the following is NOT a risk factor for pseudophakic CME? A. Caucasian race B. Diabetes without retinopathy C. Prolonged duration of surgery D. Retained lens fragment

9. Which of the following mechanisms may allow inflammation in the anterior segment to affect the posterior segment?A. Diffusion of inflammatory

mediators between adjacent tissues

B. Enzyme transactivation C. Genetic transrepression D. A and B above are correct

10. Which of the following statements about ophthalmic steroid medications is accurate?A. Dual fluorination of difluprednate

allows for increased receptor binding

B. Loteprednol is associated with increased risk of IOP elevation

C. Esterases prolong the activity of loteprednol in the eye

D. Difluprednate was designed for increased safety

this cme program is sponsored by the university of florida college of medicine and supported by an unrestricted educational grant from Bausch + lomb, inc. directions: select the one best answer to each question in the exam (Questions 1–10) and in the evaluation (Questions 11–16) below by circling one letter for each answer. Participants must score at least 80% on the questions and complete the entire evaluation section on the form below. the university of florida college of medicine designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit™. there is no fee to participate in this activity. You can take the test online at http://cme.ufl.edu/toai.

examination Questions Topics in ocular anTiinflammaTories | issue 1