issue 22 prophylaxis and treatment of seasonal … · to obtain cme credit for this activity, go to...

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 1Supported by an unrestricted educational grant from Shire.

Prophylaxis and Treatment of Seasonal Allergic ConjunctivitisRICHARD W. YEE, MD Treatment of seasonal allergic conjunctivitis can be improved by knowing regional and seasonal allergen patterns, making judicious use of allergen avoidance and preventive therapies, and collaborating with allergists and other specialists.

Allergic eye disease may aff ect upwards of 30% of the population, with seasonal allergic conjunctivitis (SAC) being the most common form.1 SAC follows a predictable pattern for most aff ected patients and, while it is typically transient, can signifi cantly aff ect quality of life. Th e clinical picture—red, swollen, itchy eyes—can be complicated by other ocular surface issues, such as dry eye, blepharitis, or even infection; thus careful history and slit-lamp exam are vital for diff erential diagnosis and optimal management.

SAC is a type I hypersensitivity reaction mediated by immunoglobulin E (IgE). In sensitized individuals, exposure to seasonal allergens (grass or tree pollen, outdoor molds) initiates a rapid cascade of events: allergen particles bind to and crosslink IgE on mast cell surfaces, allowing the release of early-phase infl ammatory mediators, namely histamine.2,3

Continued IgE activation causes further disruption of mast cell membranes and the generation of other infl am-matory mediators (eg, prostaglandins and leukotrienes) that contribute to the late-phase allergic response, in which more infl ammatory cells are recruited and eosinophils, basophils, and neutrophils infi ltrate the tissue.2,3

Perennial allergic conjunctivitis (PAC), like SAC, is a type I hypersensitivity reaction, oft en triggered by animal dander, dust mites, and other allergens that are present year-round.

More serious allergic eye diseases, such as vernal keratocon-junctivitis (VKC) and atopic keratoconjunctivitis (AKC) con-stitute type IV (delayed) hypersensitivity reactions, mediated by T cells, and may be chronic or seasonal in nature; VKC and AKC can cause severe papillary hypertrophy and corneal scarring.3 Correctly diff erentiating among these diseases helps facilitate optimal treatment.

CONFIRMING SACTh e hallmark signs and symptoms of SAC (rapid onset of

itching, tearing, and redness) can also apply in other ocular surface conditions. For example, itching, to varying degrees, is reported by some patients with dry eye disease (DED), blepharitis, or infectious conjunctivitis.

In SAC, itching is typically severe and localized to the eyelids and inner canthal region. At the slit lamp, diff use con-junctival hyperemia is present, oft en associated with lid edema and tenderness, but there is usually no corneal involvement. In some cases, depending on the severity of itching, there may be associated physical trauma exacerbating the fi ndings of the eyelids, and even the cornea, in the form of punctate epithelial erosions.

Because the red eye is a diagnostic challenge, it is essen-tial to determine at the slit lamp what type of conjunctival

ISSUE 22

A CONTINUINGMEDICAL EDUCATION

PUBLICATIONCME

CONTINUING MEDICAL EDUCATION

See INSIDE for:The Potential Complications of Topical Antiinfl ammatory Agents by Victor L. Perez, MD

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/2 Topics in OCULAR ANTIINFLAMMATORIES

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.

REFERENCES 1. 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-release glucocorticoids: 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, and the OPUS-1 Study Group. Lifi tegrast ophthalmic solu-tion 5.0% for treatment of dry eye disease: results of the OPUS-1 phase 3 study. Ophthalmology. 2014 Feb;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-

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DATE OF ORIGINAL RELEASE April 2018. 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.

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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. She is a consultant to Allergan, Alcon, Abbott Medical Optics, Bausch + Lomb, FOCUS Laboratories, Shire, OCuSOFT, Altaire, Bio-Tissue, BlephEx, Oculus USA, and Optical Express.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 has received grant/research support from Shire. He is also a consultant for Al-lergan, Alcon, Bausch + Lomb, EyeGate Pharma, and Shire.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.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 has received grant/research support from Shire. He is also a consultant for Al-lergan, Alcon, Bausch + Lomb, EyeGate Pharma, and Shire.Richard W. Yee, MD, practices at Richard Yee PLLC in Houston, TX. Dr. Yee 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 22reaction is evident. A pale, boggy ap-pearance to the bulbar conjunctiva, and small, elevated nodules (papillae) on the palpebral conjunctiva are typical of SAC.4 Th ough it can be challenging, it is useful to diff erentiate papillae from the follicular reaction oft en seen on the pal-pebral conjunctiva of patients with viral infections (See box, Papillae vs Follicles).

Medical and family history are key to determining an allergic, and more specifi cally seasonal, presentation. Ask about prior experience of seasonal or perennial allergy, involving the sinuses, airways, skin, or even digestive tract: this may take the form of asthma, al-lergic rhinitis, bronchitis, eczema, or food allergies. SAC may be associated with other systemic allergic reactions (eg, rhinitis), or the eyes may be the only or most prominently aff ected system.

More than one disease mechanism may be at play in any acute red eye presentation. For example, a chronic follicular conjunctivitis and an allergic reaction could be present simultane-ously. More severe forms of ocular al-lergy, such as AKC or VKC, should be suspected where there are signifi cant symptoms, papillary reaction, copious ropy discharge, and corneal involve-ment, as well as other atopic conditions.4

ALLERGEN AWARENESS AND AVOIDANCE

SAC is distinguished from PAC on the basis of its allergen triggers, and most patients, with a little prompting, will be able to identify the time(s) of year when they experience symptoms.

It behooves clinicians to know about the seasonal patterns in their areas and to be attentive to predictions of weather, pollen, and mold levels. Where I practice, in southeast Texas, it is allergy season for much of the year; but we generally know that around February and August, we need to start preparing patients with SAC for the onslaught of pollens to come in March and September.

Beyond what patients are able to piece together by observing the annual timing of their symptoms, specifi c test-ing by an allergist can provide more targeted avoidance and even treatment

To obtain CME credit for this activity, go to http://cme.ufl .edu/ed/self-study/toai/ Topics in OCULAR ANTIINFLAMMATORIES 3

strategies. I recommend ophthalmologists align themselves with a trusted allergist to refer appropriate patients for skin testing. In addition, some in-offi ce skin tests are becoming available for use in eyecare practices. However, allergists may provide a more detailed battery of tests and can help treat as-sociated systemic allergies.

Armed with knowledge from the allergist and tools such as pollen and mold trackers (the American Academy of Allergy, Asthma & Immunology’s National Allergy Bureau is a good resource), patients can begin to prepare themselves for allergy season before it starts.

STRATEGIC SEASONAL PROPHYLAXIS When thinking about preventive treatment for SAC, the

most important thing is to know the local climate and when the seasonal allergy peaks tend to be. Again, in our area, we start thinking about the spring allergy season around Valen-tine’s Day, in anticipation of peak pollen counts in March; but somewhere like Milwaukee might not hit this peak until May. Knowing these patterns, we can guide patients to initiate SAC prophylaxis with a topical and/or systemic mast cell stabilizer before the allergy season peaks.

Th is is also when specifi c knowledge of allergic triggers is particularly useful: in addition to medical prophylaxis

CORE CONCEPTS ✦ SAC is a type I hypersensitivity reaction mediated by IgE.

✦ Because some amount of seasonal predictability is inherent in the condition, SAC can be managed prophylactically.

✦ Medical and family history and a detailed exam to diff erentiate from other ocular surface and/or allergic conditions are key to diagnosis.

✦ Knowledge of local weather and patterns of seasonal pollen and mold peaks is important for both patients and physicians.

✦ Allergen avoidance and nonpharmaceutical management strategies should be prioritized.

✦ Mast cell stabilizers or dual-action antihistamine mast cell stabilizers are good choices for prophylaxis, since they act early in the allergic cascade.

✦ Corticosteroids and immunomodulatory agents may be reserved for more severe cases.

✦ Referral to an allergist is recommended for detailed assessment and multi-system treatment, where appropriate.

✦ Most cases of SAC are manageable, if intrusive for patients; but consequences of leaving SAC untreated could be severe.

strategies, patients can be encouraged to watch pollen or mold counts and take more concerted avoidance measures, such as wearing wraparound sunglasses, washing hair at the end of the day, and administering artifi cial tears frequently.

I oft en liken the ocular surface to a car’s windshield, which can become visibly coated with tree pollen in the springtime; and I tell patients to look for ways to keep that windshield clear—either by blocking allergens physically, eg, with a scarf and sunglasses, or even contact lenses, or by diluting them with artifi cial tears. When using antiallergy medications, patients can be advised to “rinse” their eyes with artifi cial tears before instilling the active antiallergy agent, especially when coming in from outdoors and feeling acutely symptomatic.

Indeed, in addition to recommending avoidance strategies, a prescription for acute or prophylactic SAC treatment is best accompanied by reminders about nonpharmaceutical thera-pies. Artifi cial tears and cold compresses have been shown to improve allergic conjunctivitis symptoms and signs (as com-pared with no treatment, in a controlled adverse environment study).5 In this same study, researchers demonstrated that cold compresses measurably enhanced the pharmaceutical eff ect of the topical antihistamine/mast cell stabilizer epinastine.5

AVAILABLE AGENTSTopical ophthalmic antihistamines and mast cell stabiliz-

ers are among the most common SAC treatments. Most newer topical antihistamines selectively block the H1 histamine receptor, inhibiting the eff ects of histamine that has already

PAPILLAE VS FOLLICLESBoth papillae and follicles present as roundish elevations on

the palpebral conjunctiva, associated with a red eye. One way of diff erentiating the two is to closely examine how the vasculature is positioned in relation to the elevations.

Papillae are vascular at the center, surrounded by infl ammatory cells, and tend to appear redder at the surface. Papillae can vary quite a bit in size and shape, from small and smooth to fl attened and cobblestone-like in appearance (Figure 1).

Follicles, on the other hand, tend to be more rounded and are avascular; vessels can be seen growing around or overlying follicular elevations. Thus, follicles tend to appear paler at the surface. Follicles are often (though not exclusively) concentrated on the inferior palpebral conjunctiva, especially when associated with viral infection; papillae, in the case of SAC, tend to be found on the superior palpebral conjunctiva.

Papillae are not pathognomonic for SAC—they can occur as a result of other allergic or infectious conditions—but in the context of an acute, itchy red eye, diff erentiation between papillae and follicles can be very helpful.1

1. American Academy of Ophthalmology. Basic and Clinical Science Excerpt: Papillary versus follicular conjunctivitis. https://www.aao.org/bcscsnippetdetail.aspx?id=9d2ac3f7-43cb-4096-9c26-3c7b6d052e20 Accessed January 3, 2018.

FIGURE 1 Papillae on the superior tarsal conjunctiva of a patient with SAC. (Image courtesy of Dr. Yee.)


been released; while mast-cell stabilizers work earlier in the allergic cascade, to prevent mast cell degranulation. Dual-acting agents (such as epinastine, olopatadine, bepotastine besilate, and alcaft adine) have a relatively rapid onset of eff ect and are good fi rst-line options for patients who are acutely symptomatic and in the midst of allergy season.6

Newer dual-acting agents also carry the advantage of less frequent dosing (once or twice daily) than single agents.6 Th e authors of a systematic review published in 2015 noted that in general, topical antihistamines and mast cell stabilizers are safe, well tolerated, and eff ective in reducing symptoms and signs of SAC and PAC; but heterogeneity of outcome measures and statistical methods made comparison between diff erent agents diffi cult.7

Topical nonsteroidal antiinfl ammatory drugs (NSAIDs) can be used to treat allergic conjunctivitis and have a dem-onstrated eff ect on itching and redness.8 NSAIDs inhibit the production of cyclooxygenase (COX) enzymes and the production of prostaglandins, and as such, operate fairly late in the allergic cascade.

Topical corticosteroids, while broadly eff ective, can usually be reserved for more severe, prolonged allergic conjunctivi-tis presentations; most cases of SAC can be managed with avoidance/supportive measures and antihistamine/mast cell stabilizers. Oral or intranasal corticosteroids may be appro-priate for patients with severe, refractory SAC and involve-ment of other systems.9 Loteprednol etabonate 0.2% (which is indicated for SAC) or fl uorometholone 0.1% may be used on a short-term basis to quell an acute fl are. Relative to other corticosteroids, these may pose a lower risk of IOP elevation, but a short course and careful monitoring are nonetheless warranted. Loteprednol etabonate has also been studied and used for SAC prophylaxis.10

Other topical ophthalmic immunomodulatory agents, such as cyclosporine 0.1% or 0.05% and tacrolimus 0.1%, have been investigated for the treatment of allergic conjunctivitis—again, for severe/refractory cases or AKC/VKC patients.3,9 Patients with other autoimmune/infl ammatory diseases, man-aged in conjunction with a rheumatologist or other provider, may be treated with systemic immunosuppressive agents; very rarely, those with severe atopic conditions aff ecting multiple systems may be treated with apheresis.11

Another preventive approach with the potential to im-pact SAC is immunotherapy, administered subcutaneously or sublingually, with the goal of desensitizing the immune system to a specifi c allergen.9 Again, working with an allergist, patients who are aff ected by concomitant systemic reactions to a specifi c allergen may be good candidates for this approach, in conjunction with other therapies.

RISKSSAC is important to manage, not only because it can be

signifi cantly disruptive for patients’ lives, but also because of more serious potential consequences and associations. Severe itching may prompt more eye rubbing, which may exacerbate the progression of corneal ectatic disorders in predisposed

patients. Indeed, there is a known association between allergic conjunctivitis and keratoconus; a recent large case-control study found the prevalence of ocular allergy was signifi cantly higher in patients with keratoconus than controls, and allergic conjunctivitis and VKC were signifi cantly associated with keratoconus severity.12

Eye rubbing may also cause corneal epithelial trauma and introduce microorganisms onto the ocular surface. Th e pres-ence of corneal epithelial erosions and mucous discharge in a case of SAC may prompt additional monitoring and treatment with antibiotic drops if secondary bacterial infection is sus-pected. Th e use of NSAIDs in patients with corneal defects is oft en avoided due to concerns about ulceration and melting.13

Like any infl ammatory ocular surface condition, over the long-term, untreated allergic conjunctivitis could potentially lead to changes of the eyelid margins, scarring of the conjunc-tiva, and loss of goblet cells.14

LOOKING AHEADMost cases of SAC can be managed successfully using

available ophthalmic agents. To the degree that allergen triggers can be known and predicted, prophylaxis strategies can signifi cantly help patients control SAC symptoms and minimize their impact. More severe, multisystem allergies, treated in conjunction with an allergist, immunologist, or rheumatologist, might benefi t from recent advances in targeted immunosuppressant drugs.

Ophthalmic agents in development specifi cally for allergic conjunctivitis include small molecule inhibitors and biolog-ics.15,16 A proprietary topical formulation of high-concentration hypochlorous acid is currently being evaluated in a phase 2 study for the treatment of allergic conjunctivitis.17

Richard W. Yee, MD, practices at Richard Yee PLLC in Houston, TX. Dr. Yee 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 Jennifer Zweibel of Candeo Clinical/Science Communications, LLC, assisted in the preparation of this manuscript.

REFERENCES 1. Leonardi A, Castegnaro A, Valerio A, Lazzarini D. Epidemiology of allergic

conjunctivitis: clinical appearance and treatment patterns in a population-based study. Curr Opin Allergy Clin Immunol. 2015;15(5):482-8.

2. Niederkorn JY. Immune regulatory mechanisms in allergic conjunctivitis: in-sights from mouse models. Curr Opin Allergy Clin Immunol. 2008;8(5):472-6.

3. Mishra GY, Tamboli V, Jwala J, Mitra AK. Recent patents and emerging therapeutics in the treatment of allergic conjunctivitis. Recent Pat Infl amm Allergy Drug Discov. 2011;5(1):26-36.

4. Bielory L, Dinowitz M, Rescigno R. Ocular allergic diseases: diff erential diagnosis, examination techniques, and testing. J Toxicol. 2002;21(4):329-51.

5. Bilkhu PS, Wolff sohn JS, Naroo SA, Robertson L, Kennedy R. Eff ectiveness of nonpharmacologic treatments for acute seasonal allergic conjunctivitis. Ophthalmology. 2014;121:72-8.

6. Carr W, Schaeff er J, Donnenfeld E. Treating allergic conjunctivitis: a once-daily medication that provides 24-hour symptom relief. Allergy Rhinol. 2016;7:e107-14.

YEE REFERENCES continue on page 7


The Potential Complications of Topical Antiin� ammatory AgentsVICTOR L. PEREZ, MD Topical antiin� ammatory agents are associated with side e� ects of varied severity and frequency of occurrence. Understanding what these side e� ects are and how they can be minimized is vital for informed decision-making in managing in� ammatory ocular surface disorders.

Infl ammation is characteristic of a wide variety of ocular surface diseases. Th ese range from blepharitis, dry eye disease (DED), and allergies to more serious entities such as Stevens-Johnsons syndrome, ocular cicatricial pemphigoid, and chemical or thermal burns. Unlike most other body tissues, infl ammation of the ocular surface is easily visible. Th is, and the fact that the eye is directly accessible as the target organ, are perhaps two underlying factors that drive the heavy use of such topical antiinfl ammatory agents as corticosteroids in eye care.

While topical antiinfl ammatory agents are important therapeutic tools in managing ocular surface disorders, one major limiting factor in their clinical applications is their potential adverse events. Systemic side eff ects may be rare with topically applied agents, but local complications are not uncommon, especially when long-term treatment is required. Here, we discuss the side eff ects associated with ophthalmic antiinf lammatory agents and the appropriate preventive strategies.

CURRENT OPTIONSCurrently available ophthalmic antiinfl ammatory agents

fall into three distinct therapeutic groups: corticosteroids, nonsteroidal antiinfl ammatory drugs (NSAIDs), and T-cell inhibitors. Each has its mode of action and therapeutic roles.

Corticosteroids remain the most eff ective and also the most commonly used therapies against ocular infl ammatory diseases. Th ey act rapidly and broadly as inhibitors of phospho-lipase A2 and aff ect gene expression pathways. Nonsteroidal antiinfl ammatory agents (NSAIDs) are thought to inhibit prostaglandin synthesis by blocking cyclooxygenases (COX) 1 and 2—enzymes downstream to phospholipase A2. Th ey work more eff ectively as analgesics than as antiinfl ammatory agents. Topical NSAIDs are known for their use in ameliorat-ing postsurgical pain and discomfort; their role in nonsurgical eye care is relatively limited.

T-cell inhibitors are steroid-sparing immunosuppressants that specifi cally target T lymphocytes, which are believed to be a perpetrator of infl ammatory tissue damage in DED and other chronic ocular surface diseases.1,2 Th e fi rst successful topical T-cell inhibitor was cyclosporine (0.05%), a calcineurin inhibitor approved for use in patients where tear production

is presumably suppressed by infl ammation associated with DED. Topical cyclosporine is also prescribed as a treatment for contact lens intolerance, vernal or atopic keratoconjunc-tivitis, limbal stem cell dysfunction, and autoimmune ocular infl ammatory disease.

Th e latest addition to the category of topical T-cell inhibi-tors, in 2017, is lifi tegrast (5.0%), a small molecule integrin an-tagonist approved for the treatment of the signs and symptoms of DED. Both cyclosporine and lifi tegrast are presumed to exert antiinfl ammatory eff ects primarily by inhibiting T-cell activation and production of infl ammatory cytokines, albeit through diff erent molecular pathways.3,4 Lifi tegrast may also have the potential to block recruitment of T cells to the ocular surface, another critical step in the cycle of T-cell-mediated infl ammation in DED.5

THE SIDE EFFECTSCorticosteroids are effi cient antiinfl ammatory therapies,

but with their clinical effi cacy comes the risk for serious adverse eff ects. Th eoretically, any form of antiinfl ammatory therapy that suppresses the local immune response of an al-ready compromised ocular surface could weaken host defense and increase the susceptibility to microbial infection. Of the three antiinfl ammatory types, topical corticosteroids are the main drug class that has been associated with an increased risk of infections, presumably as a result of their potent and broad actions (Figure 1). Other potential complications of corticosteroids include elevated intraocular pressure (IOP), cataract formation, and delayed wound healing.6,7

Topical NSAIDs are less potent than corticosteroids as an-tiinfl ammatory therapies, but they also have a less signifi cant side eff ect profi le. Th e most common side eff ects of ophthalmic

FIGURE 1 Infectious Pseudomonas aeruginosa keratitis developed in a patient on chronic topical steroid for allergic conjunctivitis. (Image courtesy of Dr. Perez.)


they are used more as analgesics—to address discomfort and pain associated with DED rather than infl ammation.

MITIGATING THE RISKSTo get the most therapeutic benefi t from antiinfl ammatory

therapies, clinicians need to know not only what the poten-tial side eff ects are but also how to minimize their impact. As already mentioned, tolerability is in general of greater concern than safety with long-term use of the topical T-cell inhibitors. For patients with chronic DED, a brief course of topical corticosteroid therapy preceding the introduction of cyclosporine treatment has been found to improve the latter’s effi cacy while decreasing stinging or burning that oft en oc-cur upon instillation of cyclosporine eye drop and in severe cases can result in discontinuation of therapy.18,19 Since topical NSAIDs are associated with potential deleterious eff ects on the ocular surface, patients may require closer follow-up during treatment, especially if they already have compromised corneal epithelial integrity.

Although topical corticosteroids are associated with seri-ous ocular side eff ects, judicious usage can minimize the oc-currences. Generally speaking, it is prudent to keep the dose low and the duration of treatment short for all corticosteroid regimens. In addition, patients need to be educated about what to watch for (eg, cataract) and, once therapy starts, to be closely monitored.

In the general population, about one-third of adults are “steroid responders,” who will experience signifi cant increases in IOP with the use of topical corticosteroids.20,21 If the pa-tient has a documented history of IOP increase in response to corticosteroid therapy or a family history of glaucoma, the clinician must then weigh in the higher risk for IOP elevation in treatment decisions. Clinicians might consider

NSAIDs are mild and transient and include burning, stinging, and conjunctival hyperemia.8 Additionally, topical NSAIDs are associated with various forms of corneal toxicity, includ-ing superfi cial punctate keratitis, subepithelial infi ltrates, and epithelial defects.9-11 One particularly severe complication that has historically been linked to topically applied NSAIDs is corneal melting. Following the spike in corneal melting cases among patients undergoing routine cataract and refractive surgeries in the 1990s, the use of topical NSAIDs declined. Although most of the cases back then involved use of a generic formulation of diclofenac, and subsequent clinical studies sug-gest that corneal melting likely has a multifactorial etiology and rarely occurs with newer NSAIDs.12,13

By comparison, topical T-cell inhibitors as a drug class are considered safer, with only minor side eff ects. Th e most frequently reported adverse eff ects of topical cyclosporine and lifi tegrast are stinging and burning upon instillation. More a matter of tolerability than of safety, such side eff ects rarely lead to discontinuation of treatment. Of course, lifi tegrast has been on the market for far less time than cyclosporine, and it is likely that real-world clinical experience will give new insight into its safety profi le. Based on the currently available evidence, lifi tegrast, like cyclosporine, is not associated with any serious complications, even in long-term use.14

APPLICATIONS IN DED THERAPYInfl ammation has been recognized as a key pathogenic

factor in DED and therefore an important disease component to treat.3 Because DED is chronic in nature and long-term cor-ticosteroid therapy is inclined to produce side eff ects, topical corticosteroids are most appropriate for short-term “pulse” treatment of acute exacerbations. Marsh and Pfl ugfelder fi rst demonstrated such use of topical corticosteroids in a small clinical study published in 1999.15 Th ey showed that 2 weeks of corticosteroid therapy (topical nonpreserved methylpred-nisolone, dosed three to four times a day) is highly eff ective in improving signs and symptoms of dry eye associated with Sjögren’s syndrome—a fi nding consistent with the notion that infl ammation is a key pathogenic factor in chronic DED. Among those receiving prolonged therapy, however, the re-searchers encountered corticosteroid-related complications, including IOP elevation and cataract formation.

Th e T-cell inhibitors, considered a safer alternative to corticosteroids for the absence of serious side eff ects in their antiinfl ammatory actions, have been widely used as a fi rst-line antiinfl ammatory therapy for the treatment of DED. Symptom-wise, lifi tegrast seems to have a more rapid onset of eff ect than cyclosporine: clinical studies show that patients receiving the treatment have noticed symptom relief in as early as two weeks.16,17 It is speculated that underlying the faster relief of symptoms is lifi tegrast’s potential to inhibit T-cell recruitment as well as T-cell activation.

Th e role of topical NSAIDs in the treatment of chronic DED is still an open question. Th ese nonsteroidal agents do not produce severe side eff ects over extended use as corticosteroids do, but they are not as effi cacious either. When they are used,

CORE CONCEPTS ✦ Infl ammation plays a role in many forms of ocular surface

disease.

✦ Antiinfl ammatory agents from diff erent therapeutic classes have pronounced diff erences in the potential for side eff ects. Minimizing the occurrence of side eff ects is a key aspect of eff ective antiinfl ammatory therapy.

✦ Corticosteroids can be safely used in chronic DED as short-term induction therapy prior to initiation of long-term cyclosporine treatment.

✦ While topical NSAIDs have a better side eff ect profi le than corticosteroids, as antiinfl ammatory agents they have a limited role in the management of ocular surface disorders.

✦ Topical T-cell inhibitors, including cyclosporine and lifi tegrast, are a safe fi rst-line antiinfl ammatory therapy for chronic DED with few side eff ects. Their long-term use is most often associated with tolerability rather than safety concerns.


agents known to have a lower likelihood of adverse eff ects, eg, loteprednol etabonate, which has been shown to cause no signifi cant IOP elevation or cataract formation when used as a long-term therapy for DED patients.22-24 Or maybe it is best to avoid corticosteroids altogether and resort to the nonsteroidal alternatives.

Reduction of side eff ects is one main focus of the current eff ort made in developing novel ophthalmic antiinfl amma-tory therapeutics. A nanoparticle formulation of loteprednol etabonate promises to enhance ocular exposure for the cor-ticosteroid by increasing its retention and penetration across the ocular surface. With the new formulation, it may be pos-sible to achieve infl ammation control with lower doses and decreased potential for side eff ects. Th e successful use of topical T-cell inhibitors like cyclosporine and lifi tegrast has encour-aged exploration of local immunomodulatory agents, such as biologic molecules that antagonize critical proinfl ammatory cytokines. By acting more selectively, it is hoped that they will deliver eff ective antiinfl ammatory action with less side eff ects.

Victor L. Perez, MD, is professor of ophthalmology and director of the Duke Center for Ocular Immunology at Duke University School of Medicine in Durham, NC. Dr. Perez has received grant/research support from Shire. He is also a consultant for Allergan, Alcon, Bausch + Lomb, EyeGate Pharma , and Shire. Medical writer Ying Guo, MBBS, PhD, assisted in the preparation of this manuscript.

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6. McGhee CN, Dean S, Danesh-Meyer H. Locally administered ocular cor-ticosteroids: benefi ts and risks. Drug Saf. 2002;25(1):33-55.

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11. Shimazaki J, Saito H, Yang HY, et al. Persistent epithelial defect following penetrating keratoplasty: an adverse eff ect of diclofenac eyedrops. Cornea. 1995;14(6):623-7.

12. Congdon NG, Schein OD, von Kulajta P, et al. Corneal complications associ-ated with topical ophthalmic use of nonsteroidal antiinfl ammatory drugs. I. 2001;27(4):622-31.

13. Singer M, Cid MD, Luth J, et al. Incidence of corneal melt in clinical prac-tice: our experience vs. a meta-analysis of the literature. J Clinic Experiment Ophthalmol. 2012;S1:003.

14. Donnenfeld ED, Karpecki PM, Majmudar PA, et al. Safety of lifi tegrast oph-thalmic solution 5.0% in patients with dry eye disease: A 1-Year, Multicenter, Randomized, Placebo-Controlled Study. Cornea. 2016;35(6):741-8.

15. Marsh P, Pf lugfelder SC. Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren syndrome. Ophthalmology. 1999;106(4):811-6.

16. Holland EJ, Luchs J, Karpecki PM, et al. Lifi tegrast for the Treatment of Dry Eye Disease: Results of a Phase III, Randomized, Double-Masked, Placebo-Controlled Trial (OPUS-3). Ophthalmology. 2017;124(1):53-60.

17. Tauber J, Karpecki P, Latkany R, et al; OPUS-2 Investigators. Lifi tegrast Ophthalmic Solution 5.0% versus Placebo for Treatment of Dry Eye Dis-ease: Results of the Randomized Phase III OPUS-2 Study. Ophthalmology. 2015;122(12):2423-31.

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YEE REFERENCES continued from page 4

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

1. How is immunotherapy for SAC administered? A. By subconjunctival injection B. Sublingually C. By subcutaneous injection D. Both B and C

2. Which of the following statements is true about topical NSAIDs? A. They are more effective in

pain relief than in inflammation control

B. Their most common side effect is corneal melting

C. They serve as a safer alternative to corticosteroids in DED therapy

D. They inhibit prostaglandin synthesis

3. Ideally, a discussion and initiation of SAC prophylaxis would take place: A. 6 months before season

typically peaks B. 1 month before season

typically peaks C. 1 week before season typically

peaks D. Immediately after seasonal

symptoms begin

4. Lifitegrast is: A. A calcineurin inhibitor B. An integrin antagonist C. An analgesic D. None of the above is true

5. Which of the following is the most common side effect of topical cyclosporine? A. Stinging upon instillation B. IOP elevation C. Infections D. Conjunctival hyperemia

6. Which of the following agents is NOT appropriate for SAC prophylaxis? A. Cyclosporine 0.1% B. Loteprednol etabonate 0.2% C. Bepotastine besilate 1.5% D. Epinastine HCL 0.05%

7. Which of the following describes the role of topical corticosteroids in the management of chronic DED? A. Repeated pulse therapy for

exacerbations B. Long-term maintenance

antiinflammatory therapy C. Induction therapy prior

to initiation of cyclosporine treatment

D. Both a and c

8. Which of the following may have an adjunctive benefit to pharmaceutical treatment of SAC? A. Wearing sunglasses B. Using cold compresses C. Administering artificial tears D. All of the above

9. Approximately what percent of the general population will experience a significant elevation in IOP in response to topical corticosteroids? A. 10% B. 20% C. 30% D. Greater than 50%

10. Papillae are: A. Vascularized nodules B. Pathognomonic for SAC C. Always found on the inferior

tarsal conjunctiva D. Generally unilateral

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: March 31, 2019.

EXAMINATION QUESTIONS TOPICS IN OCULAR ANTIINFLAMMATORIES | ISSUE 22

issue 22 prophylaxis and treatment of seasonal … · to obtain cme credit for this activity, go to...

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