Highlights from a symposium conducted in conjunction with theNovember 2010 Annual Scientific Meeting of the American College of Allergy, Asthma & Immunology held in Phoenix, Arizona

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Target AudienceThis activity is intended for practicing allergists/immunologists; fellows in allergy/immunology, primary care physicians andallied health professionals in the field ofallergy, asthma and immunology.

Learning ObjectivesUpon completion of this activity, participantsshould be able to:• Describe the close relationship of allergic

conjunctivitis to allergic rhinitis in affectingquality of life

• Explain quality of life measures used inallergic eye disorders

• Discuss how allergic eye disorders canadd to the direct and indirect cost burdenof disease

• Explain the role that cells play in the inflam-matory reaction characteristic of allergicconjunctivitis

• Describe the role the cytokines play in theinflammatory reaction characteristic ofallergic conjunctivitis

• Explain the differences in the inflammatoryresponse seen in allergic conjunctivitis andthat seen in other allergic eye disorders

• Discuss the various treatment topical ophthalmic agents, e.g. antihistamines,multiple action agents, NSAIDs,cyclosporine and steroids

Educational Needs For many Americans, allergic conjunctivitisis a major health issue, associated with vasthealthcare costs and significant morbidity.Through a comprehensive and up-to-dateeducational program regarding the etiology,diagnosis, and treatment of both allergic andnonallergic conjunctivitis, healthcare profes-sionals can be kept abreast of the latestimprovements in patient care, thereby help-ing to reduce the overall burden. This educa-tional activity can provide a unique set ofperspectives that underline the importanceof innovative treatments for these allergicand nonallergic eye symptoms. We examinethe impact of various treatments on inflam-mation, including the class of ocular antihist-amine mast cell stabilizers. In addition, there

Possible causes of allergic con junctivalinflammation include seasonal and peren-nial allergic conjunctivitis, atopic kerato-conjunctivitis, vernal conjunctivitis, and

giant papillary con-junctivitis. The basicfeatures of each condition suggest animmune / a l l e r g i cpathogenesis.

Many features ofthese conditions sup-port the role of IgE-mediated sensitivity in

their production. In sea-sonal and perennial allergic conjunctivi-tis there is elevated IgE in serum and tears,eosinophil infiltration, eosinophil cellularcontents in tears, allergen-specific IgE intears, mast cell mediators in tears, andupregulated adhesion molecules.

Histopathologic findings of atopic ker-atoconjunctivitis are diagnostically specificand include a mixture of mast cell,eosinophil, and lymphocyte infiltration intothe conjunctival epithelium. It is the ocularcounterpart of atopic dermatitis. Atopickeratoconjunctivitis has a Th2 cytokineprofile (primarily interleukin [IL]-4, IL-5,and IL-13). Langerhans-bearing cells haveIgE on their surface, and the epithelium ofthe ocular surface is impaired.

In vernal conjunctivitis, there is con-

junctival infiltration with eosinophils,degranulated mast cells, basophils, plasmacells, lymphocytes, and macrophages.Histopathology suggests a mixture of Th2- and Th1-driven pathology. Tear fluidcontains mast cell and eosinophil media-tors. About 20% to 30% of patients withthis condition have phenotypically char-acteristic vernal conjunctivitis but are notallergic.

Giant papillary conjunctivitis is asso-ciated with the infiltration of basophils,eosinophils, plasma cells, and lymphocytes,which suggests a mixed mast cell- and lymphoctye-mediated process. There isincreased messenger RNA for Th2cytokines (IL-3, IL-4, and IL-5). There isneutrophilic chemotactic factor in tearfluid.

Complex Allergic Response in the EyeComplex pathogenesis is involved in all ofthese diseases. A study comparing atopicand nonatopic subjects in which one eye inthe atopic subjects was challenged, whilethe other eye was left unchallenged, com-pared to nonatopic subjects in whom oneeye was challenged showed that mediatorsassociated with allergy and mast celldegranulation were released into the tearsof the challenged eye in allergic individu-als but not in nonallergic individuals.1

A study of individual cellular levels in

Sponsored by the American College ofAllergy, Asthma & Immunology.

Supported by an independent educational grant from ISTA Pharmaceuticals.

Pathophysiology of ConjunctivalInflammationPhillip L. Lieberman, MD

Advances in the Understanding and Treatment of Allergic andNonallergic Conjunctivitis

A CME-Certified Newsletter Release Date: June 1, 2011 • Expiration Date: June 1, 2012Estimated time for completion: 60 minutes

is a growing number of patients with signsand symptoms of allergic conjunctivitis yetthere is no evidence of atopy upon testing.This nonallergic conjunctivitis is quite simi-lar to nonallergic rhinitis syndromes, such asvasomotor rhinitis. A review of the currentunderstanding of this disease process isneeded. There have been advancements inthe understanding of the quality-of-lifeimpact, pathophysiology and treatmentoptions available for allergic conjunctivitis.By becoming more aware of the most con-temporary issues in allergic conjunctivitis,practitioners in allergy and immunology set-tings can benefit from this important update.

AccreditationThe American College of Allergy, Asthma &Immunology (ACAAI) is accredited by theAccreditation Council for ContinuingMedical Education (ACCME) to provide con-tinuing medical education for physicians.

DesignationThe American College of Allergy, Asthma &Immunology (ACAAI) designates this endur-ing material for a maximum of 1.0 AMA PRACategory 1 Credit TM. Physicians shouldclaim only the credit commensurate with theextent of their participation in the activity.

Disclosure Policy andDisclosuresAs required by the Accreditation Council forContinuing Medical Education (ACCME) andin accordance with the American College ofAllergy, Asthma & Immunology (ACAAI)policy, all educational planners, presenters,instructors, moderators, authors, reviewers,and other individuals in a position to controlor influence the content of an activity mustdisclose all relevant financial relationshipswith any commercial interest that haveoccurred within the past 12 months. Allidentified conflicts of interest must beresolved and the educational content thor-oughly vetted for fair balance, scientificobjectivity, and appropriateness of patientcare recommendations.

All identified conflicts of interest have beenresolved.

Warner W. Carr, MDEditorAssociate Medical Director, SouthernCalifornia Research, Mission Viejo, CA

Speaker:AstraZeneca

Speaker/Consultant/Advisory Board:Alcon, ISTA, MEDA

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Phillip L. Lieberman, MDClinical Professor of Medicine andPediatrics, Departments of InternalMedicine and Pediatrics, University ofTennessee College of Medicine, Memphis

Speaker/Consultant/Advisory Board:AstraZeneca, GlaxoSmithKline, Intelliject,Pfizer, Novartis, Genentech, Schering, Dey,MEDA

Speaker/Research Grant/Consultant/Advisory Board: Alcon, Ipsen

Michael S. Blaiss, MDClinical Professor of Pediatrics andMedicine, University of Tennessee HealthScience Center, Memphis

Speaker/Honorarium/Consultant/AdvisoryBoard: Novartis, Genentech, AstraZeneca,Sunovion, Alcon, Sanofi

Speaker/Research Grant/Honorarium:GlaxoSmithKline

Speaker/Research Grant/Honorarium/Consultant/Advisory Board: Merck

Honorarium/Consultant/Advisory Board:Proctor and Gamble

Leonard Bielory, MDDirector, STARx Allergy and Asthma Center,LLC, Medicine, Pediatrics, Ophthalmologyand Visual Sciences, Rutgers University,Center for Environmental Prediction,Springfield, New Jersey

Consultant/Advisor: Allergan, Genentech,ISTA, SARCode, GlaxoSmithKline

Stock/Consultant/Advisory Board:Ocusense

Research/Consultant/Advisory Board:Schering-Plough

Research Grant: ViroPharma, Dyax, andJerini

Education Staff has no relevant financialrelationships to disclose.

Off-label Uses of ProductsThis review contains no discussion of off-label use of products except for clinical trialdata pertaining to potential uses of new andemerging treatment modalities.

Directions to the LearnerTo complete this activity and receive AMAPRA Category 1 Credit™ the learner must1) Review the education information.2) Read through the activity and reflect on

the content as applicable to the learner’s practice.

3) Complete all components of this activity; the minimum passing score on the posttest is 80%.

4) Complete an Evaluation5) Claim credit earned, as directedAfter successful completion, a certificateindicating the number of credits earned willbe made available, as indicated. Physicianswill receive a certificate of credit. Otherhealthcare professionals will receive a certificate of attendance.

For credit to be awarded, all posttests, evaluations, and claiming of credit must besubmitted prior to the expiration date ofJune 1, 2012.

Credit should not be claimed by participantswho received credit by attending this ses-sion at the ACAAI 2010 Annual ScientificMeeting in Phoenix, Arizona. Participantsmay be contacted at a later date andrequested to complete a follow-up out-comes assessment for CME purposes.Questions may be directed to ACAAI at 847-427-1200.

Alternatively, to receive credit quickly,please go directly to:

http://www.acaai.org/Pages/CONJUNCT2011.aspx

and complete the entire activity and posttest online.

Published by: American College of Allergy,Asthma & Immunology, Inc., ArlingtonHeights, IL.

©2011 American College of Allergy, Asthma& Immunology, Inc.

No content may be reproduced in any formwithout the prior written permission of thepublishers. The opinions expressed hereinare those of the speakers and do not neces-sarily reflect the opinions or recommenda-tions of their affiliated institutions, thepublishers, or any other person or entity.

Advances in the Understanding and Treatment of Allergic and Nonallergic Conjunctivitis

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the substantia propria of bulbar conjunc-tival biopsy specimens 6 hours after aller-gen challenge in 9 atopic and 22 normalsubjects revealed a broad-based inflam-matory response involving CD4 cells, CD8cells, B cells, and neutrophils.1

Upregulation of adhesion moleculesoccurs after allergen challenge, and drugsdownregulate that expression. A studyby Choi and Bielory traced mediators aftera single allergen challenge.2 Some media-tors were bimodal and some were notbimodal, and there was multiple mediatorrelease.

The Importance of the Mast CellThe mast cell is central to conjunctivalinflammation.3 The majority of the mastcells in the conjunctiva are MCT cells (i.e.,connective tissue mast cells). There isingress of MCT cells during pollen seasonor allergen exposure. In a mast cell dele-tion animal model, both the early phaseand late phase allergic responses to aller-gen exposure were blunted.4

Non-IgE Mediated PathwaysIn addition to the classic IgE-mediatedresponse, other pathways are operative.

Advances in the Understanding and Treatment of Allergic and Nonallergic Conjunctivitis

For example, upregulation of chemokinereceptor 4 and chemokine receptor 5 areseen.5 In vernal conjunctivitis, there isincreased chemokine receptor 46 andmatrix metalloproteinases 4 and 9,7 whichis unexpected. There also is upregulationof toll receptors 3, 4, and 9.8 IL-12 (i.e., T-helper-driven response) enhances the latephase response in animal models.9

Ragweed pollen causes mast degran-ulation via reactive oxygen species.10

Reactive oxygen species are found unre-lated to the allergic response. This mole-cule has an innate ability to producepathophysiology in the eye.

Surprisingly, neurokinins play a role

in ocular disease. Nerve growth factor andvasoactive intestinal polypeptide enrich thepathophysiology of allergic eye disease.11

Additionally, endogenous mediators playa role in allergic ocular disease. There aredownregulation symptoms associated withevery pathology. The late phase responseof ocular allergy is downregulated byprostaglandin E2 via the EPR3 receptor.

It has been found that allergen expo-sure primes ocular allergic disease. An eyethat is challenged with allergen and sub-sequently given a hyperosmolar chal-lenge will react to a greater extent thanprior to challenge.12

Vasomotor conjunctivitis causes redeyes but is not an allergic condition. Thereis no IgE involved.

In conclusion, the immunopathogen-esis of allergic eye disease is complex andinvolves classic IgE-mediated responses aswell as Th1-driven activity and the recruit-ment of other pathways, especially in vernalconjunctivitis and atopic keratoconjunc-tivitis. The level of each is dependent onthe disease involved. The inflammation isprobably accompanied by endogenousdownregulating activity, and it results innonspecific hyperactivity. ■

It has been found that allergen exposure primes ocular allergic disease.

Nasal symptomatology is the hallmarkof allergic rhinitis, but ocular symptomscan be just as important. In fact, historicdefinitions of allergic rhinitis includedocular symptoms as important components

of the total symptomcomplex.

Allergic ConjunctivitisEpidemiologyAllergic conjunctivitisis more common inmales under age 15and in females overage 15. There are nodifferences in incidence

between races. Allergic conjunctivitisimproves with age, just as rhinitis does.Almost all allergic conjunctivitis patientshave a family history of atopy. Eighty-eightpercent of allergic conjunctivitis patientshave allergic rhinitis, 17% have asthma,and 11% have atopic dermatitis.

A study by Vanna et al. in Brazilshowed that 13% of 6- to 7-year-olds and13% of 13- to 14-year-olds had ocularallergy symptoms.13 A study by Hesselmaret al. in Sweden found that 19% of 12- to

13-year- old children had eye symptomsand positive skin tests. Over half (54%) ofthem had taken medication for ocularallergy in the past year.14 Wüthrich et al.evaluated 509 seasonal allergy patients inprimary care physician offices in Austria.15

They found that 85% had conjunctivitissymptoms. Eye symptoms predominatedin 22% of patients, nasal symptoms in25%, and both in 53%. The authors con-cluded that eye symptoms are at least assevere as nasal symptoms in patients withhay fever. Eye symptoms are present inalmost all hay fever patients and they areclinically relevant in about 70% of patients.

An observational, descriptive, cross-sectional study was performed on allergicpatients treated by 340 allergy specialistsin private and public consultations in theSpanish health system.16 Clinical, epi-demiologic, diagnosis, therapeutic, social,and healthcare data were collected from4,991 allergic patients treated for thefirst time in the practices of the researchers.A diagnosis of allergic rhinitis was madein 2,771 (55.5%) patients (65% hadrhinoconjunctivitis and 35% had rhinitis).There were slightly more women (55%)

than men (45%) in the rhinoconjunctivi-tis subsample.

A national cross-sectional study wasconducted in Portugal to characterize clin-ical and demographic aspects of allergicconjunctivitis using a structured question-naire.17 Patients were evaluated by oph-thalmologists in different hospital settings.A total of 220 patients were enrolled (meanage 31.4±18.5 years). One-quarter of thesepatients had more than five episodes ofocular allergy in the past year, and 59.3%had year-round episodes. Most patientspresented with associated comorbidities(e.g., allergic rhinitis in 45.9%, asthma in15.5%). They had significant impair-ment of their overall quality of life duringan acute episode. Over 45% had a score of6 or greater on a 10-point severity scale.

Impact of Ocular Inflammation on the PatientMichael S. Blaiss, MD

Allergic conjunctivitis is more common in males under

age 15 and in females over age 15.

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About 20% had an appointment with anophthalmologist as a first action and most(56.1%) started with self-treatment mea-sures. Only 37.2% of patients had a pre-vious evaluation for allergy.

The Allergies in America Study, pub-lished in 2006-2007, looked at 2,500 adultAmericans in all 50 states with a history ofallergic rhinitis, nasal allergy, or hay feverwho were symptomatic and/or on treat-ment. When the researchers asked aboutsymptoms during the worst month in thepast year, 25% of survey respondentsreported watery eyes every day and 15%on most days. Twenty percent reported thatwatering eyes was extremely bothersomeand 31% reported it to be moderately both-ersome. Red, itching eyes was reported by23% to be extremely bothersome and by30% to be moderately bothersome. Whenasked about the most bothersome symp-tom of nasal allergies, 10% said red, itch-ing eyes and 5% said watering eyes.

In the Allergies in Latin AmericaStudy, which included eight countries, 33%of survey respondents reported red or itch-ing eyes every day or most days during theworst month in the past year. Watering eyeswas also reported by 33%. Itching eyes wasconsidered extremely bothersome by 41%of respondents and moderately bothersomeby 32%. Watery eyes were consideredextremely bothersome by 37% and mod-erately bothersome by 36%.

The Allergies in Asia-Pacific Studyreported similar findings as the UnitedStates and Latin America studies. The high-est rate of watering or tearing eyes duringthe worst month was reported in thePhilippines, followed by Australia. Thelowest rate was in Korea.

Questionnaires in Quality of Life with Ocular AllergyIn Juniper’s Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ), one of themajor domains measured is eye symptoms,specifically itchy, watery, swollen, and soreeyes. The emotional function domainincludes “embarrassed by nose or eyesymptoms.”

A quality-of-life questionnaire for children with vernal keratoconjuncti-vitis was developed in 2007 in Italy(Questionnaire to Assess QOL in Childrenwith VKC [QUICK]).18 The symptomfound to be most bothersome was “burn-ing in your eyes,” followed by “troublestaying in air-conditioned rooms,” havingto use tissues, puffy eyes, problems in thelight, and tearing.

Another quality-of-life measurementtool is the Eye Allergy Patient ImpactQuestionnaire. It looks at symptomatol-ogy and quality of life associated withocular allergy. It asks patients to rate ona scale of 1 to 6 how often in the past weekthey suffered from each of the followingeye allergy symptoms: swollen/puffy eyesor eyelids, watery eyes, red eyes, itchy/burn-ing eyes, and dry eyes. The questionnairealso asks about the impact of eye allergysymptoms on activities (e.g., reading, dri-ving, going outdoors, sleeping, concen-trating on daily tasks, and puttingon/wearing make-up). It also addressesemotional issues associated with eye allergy(e.g., fatigue, frustration, irritability, embar-rassment, and discomfort in social and busi-ness settings). The questionnaire also asksthe patient to rate their satisfaction withtreatment of eye allergy symptoms.

A study by Alexander et al. helpedto validate the Eye Allergy Patient ImpactQuestionnaire.19 They demonstrated a cor-relation between severity of eye symptomsand impact on daily life and impact on psychosocial factors.

A study from Spain looked at the qual-ity- of -life aspects and economic conse-quences of seasonal allergic conjunctivitisamong patients at private eye clinics.20 Thestudy included 201 patients with seasonalallergic conjunctivitis diagnosed by oph-thalmologists and 200 controls between10 and 80 years of age. They used fourquestionnaires for these patients: EQ-5DHealth Questionnaire (a generic quality-of -life questionnaire), National EyeInstitute Visual Functioning Questionnaire25 (VFQ-25) (the impact of a disease onvisual functioning), RQLQ, and HealthEconomic and Demographic Questionnaire(HEDQ).

Compared to the control group,patients with seasonal allergic conjunc-tivitis had a higher rate of comorbidities,including perennial allergic conjunctivitis,nasal symptoms, asthma, food allergies,and other allergies. On the EQ-5D HealthQuestionnaire, poorer quality of life—asmeasured by factors such as mobility, self-care, ability to engage in usual activities,pain, discomfort, anxiety, and depression—was seen in patients with seasonal allergicconjunctivitis compared to controls.

On the VFQ-25, patients with sea-sonal allergic conjunctivitis scored statis-tically significantly worse than controls ondistance vision, ocular pain, mental health,dependency on others, role limitations, andoverall vision.

On the RQLQ patients with seasonalallergic conjunctivitis scored statisticallysignificantly worse in all domains (e.g.,activity, sleep, nose and eye symptoms,practical problems, nasal symptoms, eyesymptoms, and emotional symptoms).

The HEDQ questionnaire found that20% of patients with seasonal allergic con-junctivitis missed work due to their con-dition, and 45% reported that they haddecreased productivity of 35% (±18.58%).

Costs of AllergyHealthcare costs are divided into direct andindirect costs. Direct costs encompass themonies spent on the course of managingthe disease, including medical services (e.g.,outpatient costs, physician fees, and labo-ratory procedures), pharmaceutical agents,and allergen immunotherapy. Indirect costsencompass all the non-healthcare costsassociated with the illness. These includemonies lost due to missing work anddecreased productivity due to the illness.Other indirect costs include the monetaryvalue of missing school and unpaid care-givers’ time to care for a sick child.

In the Allergies in America Study1,315 of the 2,500 participants were full-time workers. When they were having nosymptoms, their productivity was 95%.When they experienced symptoms at theirworst, productivity dropped to 72%. Therewas about a 20% drop in productivityrelated to nasal and ocular symptomatol-ogy in this survey. Looking at work inter-ference from allergies, 10% of participantsmissed work, 22% reported symptomsonly interfered with work, and 20% bothmissed work and had decreased produc-tivity.

In conclusion, both asthma and aller-gic rhinitis lead to significant impairmentin quality of life and increased healthcarecosts. Research is clearly showing thatocular allergy worsens quality of life andadds to healthcare costs. ■

Advances in the Understanding and Treatment of Allergic and Nonallergic Conjunctivitis

In Juniper's RhinoconjunctivitisQuality-of-Life Questionnaire(RQLQ), one of the majordomains measured is eye

symptoms, specifically itchy,watery, swollen, and sore eyes.

The HEDQ questionnaire found that 20% of patients withseasonal allergic conjunctivitis

missed work due to their condition, and 45% reported

that they had decreased productivity of 35% (±18.58%).

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Anew set of practice parameters for thetreatment of allergic conjunctivitis havebeen written and are currently underreview. In this document—AllergicConjunctivitis Practice Parameters—

seasonal allergic con-junctivitis and peren-nial allergic conjunc-tivitis are divided intointermittent (symp-toms present less than4 days a week or forless than 4 weeks) andpersistent (symptomspresent greater than

4 days a week and forgreater than 4 weeks).

Treatment of allergic conjunctivitisinvolves a step-up approach, beginningwith allergen avoidance and environmentcontrol, followed by lubricants and coolcompresses, oral antihistamines, topicalagents, and immunotherapy.

Ocular Allergy TreatmentsPrimary treatment for both acute andchronic ocular allergy symptoms is withcool compresses and lubrication.21 Coldcompresses decrease nerve C fiber stimu-lation and reduce superficial vasodilation.For patients with chronic allergy symptomswho wear contact lenses, use of disposabledaily contact lenses is advised. Secondarytreatment for both acute and chronic ocularallergy involves topical agents. Anti-histamines can be used for pruritus. Theparticular agent must be carefully chosen,especially because antihistamines have anti-cholinergic properties and thus may causedry eyes, which can complicate the disease.A form of dry eye called tear film dys-function commonly occurs concurrentlywith ocular allergy. This may occur in aperson who works long hours staring ata computer screen. The treatment is topi-cal cyclosporine.

Decongestants are useful for erythema.Multiple action agents are recommendedfor evolving perennial rhinoconjunctivitis.Mast cell stabilizing agents (e.g., cromolyn)may be used for healing corneal defectsassociated with the more chronic forms ofocular allergy.

In general, steroids are reserved forcases of severe seasonal allergy. Steroidburst therapy may be used for 2 to 3 days.Steroids should not be used in combina-tion with an antibiotic. If an antibiotic is

needed for an infection, the steroid shouldbe used with extra caution unless workingwith an ophthalmologist or other eye careprofessional. Topical steroids are com-monly used in the treatment of chronicforms of ocular allergy, such as atopic orvernal keratoconjunctivitis.

The new practice parameters use agraded approach to pharmacotherapyfor allergic conjunctivitis, involving pro-gressive treatment in a step-wise fashionuntil adequate control is achieved (seeFigure 1). Grade 0 is quiescent and no treat-ment is necessary. Grade 1 is mild inter-mittent. Treatment is allergen avoidance,disposable contact lenses, or oral antihis-tamines. Grade 2 is moderate intermittentor moderate persistent. Treatment is withdaily administration of multiple actionagents. Grade 3 is severe. Additional treat-ments may include topical cyclosporine ora short burst of topical steroids. For grade4 (very severe) oral steroids may be added.Immunotherapy or nasal steroids are usedto treat comorbidities, such as allergic rhinitis.

Secondary TreatmentsTopical mast cell stabilizers include cro-molyn, lodoxamide, nedocromil, andpemirolast. They require premedication(commonly weeks). Cromolyn preventsrelease of mediators and is effective forallergic diseases, especially those associ-ated with corneal changes. It relieves mild-to-moderate symptoms of vernal kerato-conjunctivitis. It may be associated withburning, stinging, periorbital erythema,

and chemosis. It requires dosing four timesper day. Lodoxamide has in vitro anti-eosinophilic properties. It is greater than100 times more potent than cromolyn invitro. Nedocromil is a cromolyn derivativethat is effective with twice-daily dosing. Itcan cause yellow staining on clothing.Pemirolast is indicated for ocular pruritusand is effective when dosed twice to fourtimes a day.

Topical antihistamines (e.g., levo-cabastine, emedastine) relieve signs andsymptoms of pruritus (and erythema).Dosing is one to four times daily. They aresafe and effective for patients 3 years oldand older. Topical NSAIDs (e.g., ketoro-lac) relieve pruritus. Stinging and/or burn-ing on instillation is experienced in up to40% of patients.

Topical antihistamine and deconges-tant combination drugs (e.g., antazoline-naphazoline, pheniramine-naphazoline)are available without a prescription. Theyhave quick onset of action, are more effec-tive than systemic antihistamines, have lim-ited duration of action, require frequentdosing, and are not recommended for reg-ular use due to the potential for conjunc-tivitis medicamentosa.

There are several topical multipleaction agents (antihistamine, mast cell sta-bilizer, cytokine), including olopatadine,ketotifen, azelastine, epinastine, and themost recently approved bepotastine22

and alcaftadine23. They treat itch and aremore effective at relieving symptoms thanother classes of agents. They have longerduration of action and are safe and effec-

Advances in the Understanding and Treatment of Allergic and Nonallergic Conjunctivitis

Current and Future Treatment Options in Allergic and Nonallergic ConjunctivitisLeonard Bielory, MD

Figure 1: Pharmacotherapy Guidelines for Allergic Conjunctivitis

Bielory L, Joint Task Force – Allergic Conjunctivitis Practice Parameter (2010 under review)

Grade 0Quiescent

Topical cyclosporine

Short burst of topical steroids

Oral steroids

EvolutionMild

Intermittent

No treatments

Grade 1 ModerateIntermittentPersistent

Grade 2 SevereGrade 3 Very Severe

Grade 4

Grade 5

Topical Vasoconstrictors/Lubricants/Cool Compresses

Avoidance

DisposableContact Lenses

OralAntihistamines

Daily Administration of

Multiple action antihistamine/mast cell stabilizers agents

NSAIDs

Treatment of Comorbidities – Allergic RhinitisImmunotherapy, Intranasal Steroids

Advances in the Understanding and Treatment of Allergic and Nonallergic Conjunctivitis

6

tive for patients 2 to 3 years old and older.Dosing and potential adverse effects arelisted in Table 1.

Bepotastine and alcaftadine are excel-lent antipruritic agents that have alsodemonstrated effects on mast cells, eosino-phils, and various cytokines involved in theallergic response. Bepotastine is dosed at1 gtt OU twice day and alcaftadine is dosedat 1 gtt OU once a day. Potential adverseeffects are similar and include transientsting/burn, headache, and flu-like symp-toms (experienced by less than 4% ofpatients).

Among the topical corticosteroids,loteprednol is approved for allergic con-junctivitis. It relieves all facets of the inflam-matory response (primarily late phase),including erythema, edema, and pruritus(not histamine induced). It is dosed fourtimes a day and is appropriate for short-term use only. It is contraindicated inpatients with viral infections. It is adjunc-tive therapy, although it may be consideredin conjunction with allergic rhinitis andasthma. It is a prodrug that is metabolizedon the surface, and therefore does not causeas much intra-ocular pressure as drugs thatpenetrate deeply.

Future TherapyNew treatments under investigation includea contact lens with ketotifen. Preliminaryresults show no adverse effects. A ketotifenpatch is also being studied. In addition,NSAIDs, such as topical bromfenac, arebeing studied for allergic conjunctivitis andpotentially for tear film dysfunction (acommon comorbid state with ocularallergy).

Histamine Receptors in Ocular TissueHistamine is one of the most commonchemical mediators causing pruritus. Inaddition to histamine (specifically H1 andH2), other sensory molecules on nervesinclude opioids, leukotriene B4, prosta-glandin E, osmolarity, neurokinins, pro-teases, among others.

Several histamine receptors are inocular tissue. Histamine binding to H1

receptors causes ocular itch. Stimulationof H2 receptors in blood vessels causesvasodilation. A study by Abelson and Udellshowed that instillation of a known H2 ago-nist (dimaprit) induced hyperemia.24 Onsetwas at 10 minutes and peak effect was at30 minutes. There was no itch associatedwith H2 receptor stimulation. Itch occurs

first, followed by redness. Pretreatment ofthe paired eye with the H2 antagonist cime-tidine decreased hyperemia. Pretreatmentwith an H1 antagonist had no significanteffect. H2 receptors are clinically impor-tant in the eye.

Katagiri et al. showed that eye itch willbe reduced if the H1 receptor is blockedwith an antagonist.25 Adding an H2 recep-tor antagonist has minimal, if any, effect.26

H3 receptor antagonists have the effect ofincreasing itching.27 H4 is a novel receptorthat has been shown to reduce itching, 28

and some binding to this receptor has beennoted with alcaftadine and with higherdoses of the standard H1 agents.29

The direct effect of histamine (H1 andH2) is vasodilation and increased perme-ability, and this is a commonly sought afterproperty in several of the ophthalmicagents. H1 plus H4 antagonism has beenshown in knockout mice to reduce itch-ing.26 Scratching behavior was almosttotally abated in experimental pruritus with H1 plus H4 antagonism. Histamine H4 receptor antagonists may have a thera-peutic role in the future for relieving pruritus in patients with allergic conjunc-tivitis. ■

References1. Bacon AS et al. Tear and conjunctival changes during the allergen-induced early- and late-phase responses. J Allergy Clin Immunol. 2000;106(5):948-954. 2. Choi SH, Bielory L. Late-phase reaction in ocular allergy. Curr Opin Allergy Clin Immunol. 2008;8(5):438-444. 3. BieloryL. Allergic and immunologic disorders of the eye. Part I: immunology of the eye. J Allergy ClinImmunol. 2000;106(5):805-816. 4. Fukuda K et al. Critical role of IgE-dependent mast cell acti-vation in a murine model of allergic conjunctivitis. J Allergy Clin Immunol. 2009;124(4):827-833. 5. Baudouin C et al. CCR 4 and CCR 5 expression in conjunctival specimens as differentialmarkers of T(H)1/T(H)2 in ocular surface disorders. J Allergy Clin Immunol. 2005;116(3):614-619. 6. El-Asrar AM et al. Expression of T lymphocyte chemoattractants and activation mark-ers in vernal keratoconjunctivitis. Br J Ophthalmol. 2002;86(10):1175-1180. 7. Kumagai Net al. Active matrix metalloproteinases in the tear fluid of individuals with vernal keratocon-junctivitis. J Allergy Clin Immunol. 2002;110(3):489-491. 8. Ueta M et al. Toll-like receptor3 enhances late-phase reaction of experimental allergic conjunctivitis. J Allergy Clin Immunol.2009;123(5):1187-1189. 9.Ueta M et al. Prostaglandin E receptor subtype EP3 in conjunctivalepithelium regulates late-phase reaction of experimental allergic conjunctivitis. J Allergy ClinImmunol. 2009;123(2):466-471. 10. Bacsi A et al. Effect of pollen-mediated oxidative stress onimmediate hypersensitivity reactions and late-phase inflammation in allergic conjunctivitis.J Allergy Clin Immunol. 2005;116(4):836-843. 11.Motterle L et al. Altered expression of neu-rotransmitter receptors and neuromediators in vernal keratoconjunctivitis. Arch Ophthalmol.2006;124(4):462-468. 12. Sacchetti M et al. Hyperosmolar conjunctival provocation for theevaluation of nonspecific hyperreactivity in healthy patients and patients with allergy. J AllergyClin Immunol. 2006;118(4):872-877. 13. Vanna AT et al. International Study of Asthma andAllergies in Childhood: validation of the rhinitis symptoms quesionnaire and prevalence of rhini-tis in schoolchildren in São Paulo, Brazil. Pediatr Allergy Immunol. 2001;12(2):95-101. 14.Hesselmar B et al. Allergic rhinoconjunctivitis, eczema, and sensitization in two areas withdiffering climates. Pediatr Allergy Immunol. 2001;12(4):208-215. 15. Wüthrich B et al.Epidemiological survey in hay fever patients: symptom prevalence and severity and influence on

patient management. Schweiz Med Wochenschr. 1998;128(5):139-143. 16. Navarro et al.Epidemiology of allergic rhinitis in allergy consultations in Spain: Alergológica-2005. J InvestigAllergol Clin Immunol. 2009;19 Suppl 2:7-13. 17. Palmares J et al. Allergic conjunctivitis: anational cross-sectional study of clinical characteristics and quality of life. Eur J Ophthalmol.2010;20(2):257-264. 18. Sacchetti M et al. Development and testing of the quality of life in chil-dren with vernal keratoconjunctivitis questionnaire. Am J Ophthalmol. 2007;144(4):557-563. 19. Alexander M et al. The reliability, validity, and preliminary responsiveness of the EyeAllergy Patient Impact Questionnaire (EAPIQ). Health Qual Life Outcomes. 2005;3:67. 20. Smith AF et al. The economic and quality of life impact of seasonal allergic conjunctivitis ina Spanish setting. Ophthalmic Epidemiol. 2005;12(4):233-242. 21. Bielory L. Ocular allergyguidelines: a practical treatment algorithm. Drugs. 2002;62(11): 1611-1634. 22. TorkildsenGL et al. Bepotastine besilate ophthalmic solution for the relief of nonocular symptoms pro-voked by conjunctival allergen challenge. Ann Allergy Asthma Immunol. 2010;105(1):57-64.23.Greiner JV et al. Evaluation of alcaftadine 0.25% ophthalmic solution in acute allergic con-junctivitis at 15 minutes and 16 hours after instillation versus placebo and olopatadine 0.1%.Clin Ophthalmol. 2011;5:87-93. 24. Abelson MB, Udell IJ. H2-receptors in the human ocularsurface. Arch Ophthalmol. 1981;99(2):302-304. 25. Katagiri K et al. Fexofenadine, an H1-receptor antagonist, partially but rapidly inhibits the itch of contact dermatitis induced bydiphenylcyclopropenone in patients with alopecia areata. J Dermatol. 2006;33(2):75-79. 26. Davies MG, Greaves MW. Sensory responses of human skin to synthetic histamine analoguesand histamine. Br J Clin Pharmacol. 1980;9(5):461-465. 27. Sugimoto Y et al. Pruritus-asso-ciated response mediated by cutaneous histamine H3 receptors. Clin Exp Allergy. 2004;34(3):456-459. 28. Dunford PJ et al. Histamine H4 receptor antagonists are superior to traditionalantihistamines in the attenuation of experimental pruritus. J Allergy Clin Immunol.2007;119(1):176-183. 29. Deml KF et al. Interactions of histamine H1-receptor antagonistswith the human histamine H4-receptor. Mol Pharmacol. 2009;76(5):1019-1030.

Table 1: Dosing and Adverse Effects of Multiple Acting Agents

Azelastine Epinastine Ketotifen Olopatadine Olopatadine Bepotastine Alcaftadine(Optivar) (Elestat) (Zaditor) (Patanol) (Pataday) (Bepreve) (Lastacaft)

Rx itch itch itch itch itch itch itch

Dose 1 gtt OU bid 1 gtt OU 1 gtt OU bid 1 gtt OU 1 gtt OU 1 gtt OU bid 1 gtt OUbid >3yrs 8-12 hrs 6-8 hrs every day >2 yrs every day

Adverse Transient sting, Burning, Headache and Transient sting/ Transient sting/ Taste perversion Transient sting/effects headache, infection conjunctival burn (<5%), burn (<5%), <25%, eye burn, headache,

bitter taste (<1% (URI/cold injection headache (7%) headache (7%), irritation, flu-like symptomsdiscontinued symptoms) flu-like symptoms headache, (<4%)due to adverse 10% (10%) nasopharyngitiseffects) (<5%)

Manufacturer MEDA Allergan Novartis Alcon Alcon ISTA Allergan

7

1. Which of the following “allergic” eye dis-orders can exist in a non-IgE-mediated(nonatopic) form?A. Seasonal allergic conjunctivitisB. Atopic keratoconjunctivitisC. Perennial allergic conjunctivitisD. Vernal conjunctivitis

2. Which one of the following conditions is mostcommonly associated with atopic dermati-tis?A. Seasonal allergic conjunctivitisB. Atopic keratoconjunctivitisC. Perennial allergic conjunctivitisD. Vernal conjunctivitis

3. Neutrophil chemotactic factor in tear fluid ismost characteristic of:A. Seasonal allergic conjunctivitisB. Giant papillary conjunctivitisC. Perennial allergic conjunctivitisD. Vernal conjunctivitis

4. A 32-year-old man is participating in a springallergy clinical study. The RhinoconjunctivitisQuality-of-Life Questionnaire (RQLQ) isadministered during the trial. Which of thefollowing 4 eye symptoms are assessed inthis patient by the RQLQ?A. Itchy, watery, swollen, soreB. Itchy, red, swollen, wateryC. Red, swollen, watery, stickyD. Swollen, watery, red, sore

5. An 8-year-old boy is seen for vernal kerato-conjunctivitis. The Questionnaire to AssessQOL in Children with VKC (QUICK) is admin-istered. Which item rated the greatest effecton quality of life in children with atopic kera-toconjunctivitis?A. ...you felt burning in your eyesB. ...you had to use tissuesC. ...you had problems in the lightD. ...you had trouble playing outside

6. A 32-year-old patient is seen for evaluationof rhinoconjunctivitis which leads to trou-ble working as a computer programmer. Youtell the patient that productivity in adultpatients with rhinoconjunctivitis decreasesby what percentage when symptoms are attheir worst?A. 5%B. 10%C. 20%D. 40%

7 A 26-year-old mildly asthmatic woman has been treated for several years withimmunotherapy for allergic rhinoconjunc-tivitis. She develops progressive irritation inher right eye. Her eye initially had a ropeywhite discharge from one eye. Her eyelidsappear to be stickier when she wakes up. Onexamination, an opaque, yellowish mucusstrand is noted on the eyelid with moderateinjection of the conjunctiva. Which of the fol-lowing is contraindicated?A. Topical mast cell stabilizing agentB. LubricantsC. Cold compressesD. Topical combined antibiotic and steroid

agent

8. A 48-year-old woman is referred for evalua-tion of allergic conjunctivitis due to recentincrease in ocular irritation in both eyes. Shehas no history of asthma or any consistenthistory of seasonal allergy. She has anincrease in ocular symptoms of itching andgrittiness with increased blinking in earlywinter, especially when working at the com-puter. Conjunctiva were mildly injected bilat-erally. She has a normal response tohistamine and saline with minimal reactionto grass, pollen, and mixed trees. Skin teststo indoor allergens are negative. Which of thefollowing is most likely to improve the under-lying condition?

A. Ophthalmic mast cell stabilizer (e.g., cromolyn)

B. Oral antihistamineC. Intranasal steroidD. An ophthalmic multiple action agent

(olopatadine, epinastine, bepotastine)E. Ophthalmic immune modulator

(i.e., cyclosporine)

9. A 27-year-old man who works as a limousinedriver and is active in outdoor sports wastransferred to the Mid-Atlantic region fromthe Upper Midwest 2.5 years ago. He pre-sents with intermittent respiratory symptomspreviously treated with over -the -countermedication. However, drowsiness from thedrugs disrupts his work. Symptoms includenasal discharge, intermittent sneezing, itch-ing of the nose, and tearing of the eyes. Healso experiences fatigue and lack of con-centration while driving. Physical examina-tion reveals swollen and pale nasal turbinatesbilaterally, moderate edema and darkenedsuborbital regions. Allergy tests reveal largereactions to grass, weed, and tree pollen andmoderate reactions to dust mite allergens.What is the best long-term treatment?A. Ophthalmic mast cell stabilizer

(e.g., cromolyn)B. Immunotherapy (aeroallergens and

perennial allergens)C. Short burst of an ophthalmic steroidD. Ophthalmic multiple action agent

(olopatadine, epinastine, bepatastine)

10. Antagonism of H1 plus ____ has been shownin knockout mice to reduce itching.A. H2

B. H3

C. H4

D. Leukotriene B4

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Advances in the Understanding and Treatment of Allergic andNonallergic Conjunctivitis

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