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Advances in the Understanding

and Treatment of Allergic and


Nonallergic Conjunctivitis
Release Date: June 1, 2011 Expiration Date: June 1, 2012
Estimated time for completion: 60 minutes

A CME-Certified Newsletter

Sponsored by the American College of


Allergy, Asthma & Immunology.
Supported by an independent
educational grant from
ISTA Pharmaceuticals.

Target Audience
This activity is intended for practicing
allergists/immunologists; fellows in allergy/
immunology, primary care physicians and
allied health professionals in the field of
allergy, asthma and immunology.

Learning Objectives
Upon completion of this activity, participants
should be able to:
Describe the close relationship of allergic
conjunctivitis to allergic rhinitis in affecting
quality of life
Explain quality of life measures used in
allergic eye disorders
Discuss how allergic eye disorders can
add to the direct and indirect cost burden
of disease
Explain the role that cells play in the inflammatory reaction characteristic of allergic
conjunctivitis
Describe the role the cytokines play in the
inflammatory reaction characteristic of
allergic conjunctivitis
Explain the differences in the inflammatory
response seen in allergic conjunctivitis and
that 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 conjunctivitis
is a major health issue, associated with vast
healthcare costs and significant morbidity.
Through a comprehensive and up-to-date
educational program regarding the etiology,
diagnosis, and treatment of both allergic and
nonallergic conjunctivitis, healthcare professionals can be kept abreast of the latest
improvements in patient care, thereby helping to reduce the overall burden. This educational activity can provide a unique set of
perspectives that underline the importance
of innovative treatments for these allergic
and nonallergic eye symptoms. We examine
the impact of various treatments on inflammation, including the class of ocular antihistamine mast cell stabilizers. In addition, there

Highlights from a symposium conducted in conjunction with the


November 2010 Annual Scientific Meeting of the American College
of Allergy, Asthma & Immunology held in Phoenix, Arizona

Pathophysiology of Conjunctival
Inflammation
Phillip L. Lieberman, MD

ossible causes of allergic conjunctival


inflammation include seasonal and perennial allergic conjunctivitis, atopic keratoconjunctivitis, vernal conjunctivitis, and
giant papillary conjunctivitis. The basic
features of each
condition suggest an
immune/allergic
pathogenesis.
Many features of
these conditions support the role of IgEmediated sensitivity in
their production. In seasonal and perennial allergic conjunctivitis there is elevated IgE in serum and tears,
eosinophil infiltration, eosinophil cellular
contents in tears, allergen-specific IgE in
tears, mast cell mediators in tears, and
upregulated adhesion molecules.
Histopathologic findings of atopic keratoconjunctivitis are diagnostically specific
and include a mixture of mast cell,
eosinophil, and lymphocyte infiltration into
the conjunctival epithelium. It is the ocular
counterpart of atopic dermatitis. Atopic
keratoconjunctivitis has a Th2 cytokine
profile (primarily interleukin [IL]-4, IL-5,
and IL-13). Langerhans-bearing cells have
IgE on their surface, and the epithelium of
the ocular surface is impaired.
In vernal conjunctivitis, there is con-

junctival infiltration with eosinophils,


degranulated mast cells, basophils, plasma
cells, lymphocytes, and macrophages.
Histopathology suggests a mixture of
Th2- and Th1-driven pathology. Tear fluid
contains mast cell and eosinophil mediators. About 20% to 30% of patients with
this condition have phenotypically characteristic vernal conjunctivitis but are not
allergic.
Giant papillary conjunctivitis is associated with the infiltration of basophils,
eosinophils, plasma cells, and lymphocytes,
which suggests a mixed mast cell- and
lymphoctye-mediated process. There is
increased messenger RNA for Th2
cytokines (IL-3, IL-4, and IL-5). There is
neutrophilic chemotactic factor in tear
fluid.
Complex Allergic Response in the Eye
Complex pathogenesis is involved in all of
these diseases. A study comparing atopic
and nonatopic subjects in which one eye in
the atopic subjects was challenged, while
the other eye was left unchallenged, compared to nonatopic subjects in whom one
eye was challenged showed that mediators
associated with allergy and mast cell
degranulation were released into the tears
of the challenged eye in allergic individuals but not in nonallergic individuals.1
A study of individual cellular levels in
1

Advances in the Understanding and Treatment of Allergic and Nonallergic Conjunctivitis


is a growing number of patients with signs
and symptoms of allergic conjunctivitis yet
there is no evidence of atopy upon testing.
This nonallergic conjunctivitis is quite similar to nonallergic rhinitis syndromes, such as
vasomotor rhinitis. A review of the current
understanding of this disease process is
needed. There have been advancements in
the understanding of the quality-of-life
impact, pathophysiology and treatment
options available for allergic conjunctivitis.
By becoming more aware of the most contemporary issues in allergic conjunctivitis,
practitioners in allergy and immunology settings can benefit from this important update.

Accreditation
The American College of Allergy, Asthma &
Immunology (ACAAI) is accredited by the
Accreditation Council for Continuing
Medical Education (ACCME) to provide continuing medical education for physicians.

Designation
The American College of Allergy, Asthma &
Immunology (ACAAI) designates this enduring material for a maximum of 1.0 AMA PRA
Category 1 Credit TM. Physicians should
claim only the credit commensurate with the
extent of their participation in the activity.

Disclosure Policy and


Disclosures
As required by the Accreditation Council for
Continuing Medical Education (ACCME) and
in accordance with the American College of
Allergy, Asthma & Immunology (ACAAI)
policy, all educational planners, presenters,
instructors, moderators, authors, reviewers,
and other individuals in a position to control
or influence the content of an activity must
disclose all relevant financial relationships
with any commercial interest that have
occurred within the past 12 months. All
identified conflicts of interest must be
resolved and the educational content thoroughly vetted for fair balance, scientific
objectivity, and appropriateness of patient
care recommendations.
All identified conflicts of interest have been
resolved.
Warner W. Carr, MD
Editor
Associate Medical Director, Southern
California Research, Mission Viejo, CA
Speaker: AstraZeneca
Speaker/Consultant/Advisory Board:
Alcon, ISTA, MEDA

Phillip L. Lieberman, MD
Clinical Professor of Medicine and
Pediatrics, Departments of Internal
Medicine and Pediatrics, University of
Tennessee 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, MD
Clinical Professor of Pediatrics and
Medicine, University of Tennessee Health
Science Center, Memphis
Speaker/Honorarium/Consultant/Advisory
Board: 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, MD
Director, STARx Allergy and Asthma Center,
LLC, Medicine, Pediatrics, Ophthalmology
and 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, and
Jerini
Education Staff has no relevant financial
relationships to disclose.

Off-label Uses of Products


This review contains no discussion of offlabel use of products except for clinical trial
data pertaining to potential uses of new and
emerging treatment modalities.

Directions to the Learner


To complete this activity and receive AMA
PRA Category 1 Credit the learner must
1) Review the education information.
2) Read through the activity and reflect on
the content as applicable to the learners
practice.
3) Complete all components of this activity;
the minimum passing score on the
posttest is 80%.
4) Complete an Evaluation
5) Claim credit earned, as directed
After successful completion, a certificate
indicating the number of credits earned will
be made available, as indicated. Physicians
will receive a certificate of credit. Other
healthcare professionals will receive a
certificate of attendance.
For credit to be awarded, all posttests,
evaluations, and claiming of credit must be
submitted prior to the expiration date of
June 1, 2012.
Credit should not be claimed by participants
who received credit by attending this session at the ACAAI 2010 Annual Scientific
Meeting in Phoenix, Arizona. Participants
may be contacted at a later date and
requested to complete a follow-up outcomes 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 post
test online.
Published by: American College of Allergy,
Asthma & Immunology, Inc., Arlington
Heights, IL.
2011 American College of Allergy, Asthma
& Immunology, Inc.
No content may be reproduced in any form
without the prior written permission of the
publishers. The opinions expressed herein
are those of the speakers and do not necessarily reflect the opinions or recommendations of their affiliated institutions, the
publishers, or any other person or entity.

Advances in the Understanding and Treatment of Allergic and Nonallergic Conjunctivitis


the substantia propria of bulbar conjunctival biopsy specimens 6 hours after allergen challenge in 9 atopic and 22 normal
subjects revealed a broad-based inflammatory response involving CD4 cells, CD8
cells, B cells, and neutrophils.1
Upregulation of adhesion molecules
occurs after allergen challenge, and drugs
downregulate that expression. A study
by Choi and Bielory traced mediators after
a single allergen challenge.2 Some mediators were bimodal and some were not
bimodal, and there was multiple mediator
release.
The Importance of the Mast Cell
The mast cell is central to conjunctival
inflammation.3 The majority of the mast
cells in the conjunctiva are MCT cells (i.e.,
connective tissue mast cells). There is
ingress of MCT cells during pollen season
or allergen exposure. In a mast cell deletion animal model, both the early phase
and late phase allergic responses to allergen exposure were blunted.4
Non-IgE Mediated Pathways
In addition to the classic IgE-mediated
response, other pathways are operative.

It has been found that


allergen exposure primes
ocular allergic disease.

For example, upregulation of chemokine


receptor 4 and chemokine receptor 5 are
seen. 5 In vernal conjunctivitis, there is
increased chemokine receptor 4 6 and
matrix metalloproteinases 4 and 9,7 which
is unexpected. There also is upregulation
of toll receptors 3, 4, and 9.8 IL-12 (i.e.,
T-helper-driven response) enhances the late
phase response in animal models.9
Ragweed pollen causes mast degranulation via reactive oxygen species. 10
Reactive oxygen species are found unrelated to the allergic response. This molecule has an innate ability to produce
pathophysiology in the eye.
Surprisingly, neurokinins play a role

in ocular disease. Nerve growth factor and


vasoactive intestinal polypeptide enrich the
pathophysiology of allergic eye disease.11
Additionally, endogenous mediators play
a role in allergic ocular disease. There are
downregulation symptoms associated with
every pathology. The late phase response
of ocular allergy is downregulated by
prostaglandin E2 via the EPR3 receptor.
It has been found that allergen exposure primes ocular allergic disease. An eye
that is challenged with allergen and subsequently given a hyperosmolar challenge will react to a greater extent than
prior to challenge.12
Vasomotor conjunctivitis causes red
eyes but is not an allergic condition. There
is no IgE involved.
In conclusion, the immunopathogenesis of allergic eye disease is complex and
involves classic IgE-mediated responses as
well as Th1-driven activity and the recruitment of other pathways, especially in vernal
conjunctivitis and atopic keratoconjunctivitis. The level of each is dependent on
the disease involved. The inflammation is
probably accompanied by endogenous
downregulating activity, and it results in
nonspecific hyperactivity.

Impact of Ocular Inflammation on the Patient


Michael S. Blaiss, MD

asal symptomatology is the hallmark


of allergic rhinitis, but ocular symptoms
can be just as important. In fact, historic
definitions of allergic rhinitis included
ocular symptoms as important components
of the total symptom
complex.
Allergic Conjunctivitis
Epidemiology
Allergic conjunctivitis
is more common in
males under age 15
and in females over
age 15. There are no
differences in incidence
between races. Allergic conjunctivitis
improves with age, just as rhinitis does.
Almost all allergic conjunctivitis patients
have a family history of atopy. Eighty-eight
percent of allergic conjunctivitis patients
have allergic rhinitis, 17% have asthma,
and 11% have atopic dermatitis.
A study by Vanna et al. in Brazil
showed that 13% of 6- to 7-year-olds and
13% of 13- to 14-year-olds had ocular
allergy symptoms.13 A study by Hesselmar
et al. in Sweden found that 19% of 12- to

13-year- old children had eye symptoms


and positive skin tests. Over half (54%) of
them had taken medication for ocular
allergy in the past year.14 Wthrich et al.
evaluated 509 seasonal allergy patients in
primary care physician offices in Austria.15
They found that 85% had conjunctivitis
symptoms. Eye symptoms predominated
in 22% of patients, nasal symptoms in
25%, and both in 53%. The authors concluded that eye symptoms are at least as
severe as nasal symptoms in patients with
hay fever. Eye symptoms are present in
almost all hay fever patients and they are
clinically relevant in about 70% of patients.
An observational, descriptive, crosssectional study was performed on allergic
patients treated by 340 allergy specialists
in private and public consultations in the
Spanish health system. 16 Clinical, epidemiologic, diagnosis, therapeutic, social,
and healthcare data were collected from
4,991 allergic patients treated for the
first time in the practices of the researchers.
A diagnosis of allergic rhinitis was made
in 2,771 (55.5%) patients (65% had
rhinoconjunctivitis and 35% had rhinitis).
There were slightly more women (55%)

than men (45%) in the rhinoconjunctivitis subsample.


A national cross-sectional study was
conducted in Portugal to characterize clinical and demographic aspects of allergic
conjunctivitis using a structured questionnaire.17 Patients were evaluated by ophthalmologists in different hospital settings.
A total of 220 patients were enrolled (mean
age 31.418.5 years). One-quarter of these
patients had more than five episodes of
ocular allergy in the past year, and 59.3%
had year-round episodes. Most patients
presented with associated comorbidities
(e.g., allergic rhinitis in 45.9%, asthma in
15.5%). They had significant impairment of their overall quality of life during
an acute episode. Over 45% had a score of
6 or greater on a 10-point severity scale.

Allergic conjunctivitis is
more common in males under
age 15 and in females
over age 15.

Advances in the Understanding and Treatment of Allergic and Nonallergic Conjunctivitis


About 20% had an appointment with an
ophthalmologist as a first action and most
(56.1%) started with self-treatment measures. Only 37.2% of patients had a previous evaluation for allergy.

In Juniper's Rhinoconjunctivitis
Quality-of-Life Questionnaire
(RQLQ), one of the major
domains measured is eye
symptoms, specifically itchy,
watery, swollen, and sore eyes.

The Allergies in America Study, published in 2006-2007, looked at 2,500 adult


Americans in all 50 states with a history of
allergic rhinitis, nasal allergy, or hay fever
who were symptomatic and/or on treatment. When the researchers asked about
symptoms during the worst month in the
past year, 25% of survey respondents
reported watery eyes every day and 15%
on most days. Twenty percent reported that
watering eyes was extremely bothersome
and 31% reported it to be moderately bothersome. Red, itching eyes was reported by
23% to be extremely bothersome and by
30% to be moderately bothersome. When
asked about the most bothersome symptom of nasal allergies, 10% said red, itching eyes and 5% said watering eyes.
In the Allergies in Latin America
Study, which included eight countries, 33%
of survey respondents reported red or itching eyes every day or most days during the
worst month in the past year. Watering eyes
was also reported by 33%. Itching eyes was
considered extremely bothersome by 41%
of respondents and moderately bothersome
by 32%. Watery eyes were considered
extremely bothersome by 37% and moderately bothersome by 36%.
The Allergies in Asia-Pacific Study
reported similar findings as the United
States and Latin America studies. The highest rate of watering or tearing eyes during
the worst month was reported in the
Philippines, followed by Australia. The
lowest rate was in Korea.
Questionnaires in Quality of
Life with Ocular Allergy
In Junipers Rhinoconjunctivitis Qualityof-Life Questionnaire (RQLQ), one of the
major domains measured is eye symptoms,
specifically itchy, watery, swollen, and sore
eyes. The emotional function domain
includes embarrassed by nose or eye
symptoms.
4

A quality-of-life questionnaire for


children with vernal keratoconjunctivitis was developed in 2007 in Italy
(Questionnaire to Assess QOL in Children
with VKC [QUICK]). 18 The symptom
found to be most bothersome was burning in your eyes, followed by trouble
staying in air-conditioned rooms, having
to use tissues, puffy eyes, problems in the
light, and tearing.
Another quality-of-life measurement
tool is the Eye Allergy Patient Impact
Questionnaire. It looks at symptomatology and quality of life associated with
ocular allergy. It asks patients to rate on
a scale of 1 to 6 how often in the past week
they suffered from each of the following
eye allergy symptoms: swollen/puffy eyes
or eyelids, watery eyes, red eyes, itchy/burning eyes, and dry eyes. The questionnaire
also asks about the impact of eye allergy
symptoms on activities (e.g., reading, driving, going outdoors, sleeping, concentrating on daily tasks, and putting
on/wearing make-up). It also addresses
emotional issues associated with eye allergy
(e.g., fatigue, frustration, irritability, embarrassment, and discomfort in social and business settings). The questionnaire also asks
the patient to rate their satisfaction with
treatment of eye allergy symptoms.
A study by Alexander et al. helped
to validate the Eye Allergy Patient Impact
Questionnaire.19 They demonstrated a correlation between severity of eye symptoms
and impact on daily life and impact on
psychosocial factors.
A study from Spain looked at the quality- of -life aspects and economic consequences of seasonal allergic conjunctivitis
among patients at private eye clinics.20 The
study included 201 patients with seasonal
allergic conjunctivitis diagnosed by ophthalmologists and 200 controls between
10 and 80 years of age. They used four
questionnaires for these patients: EQ-5D
Health Questionnaire (a generic qualityof -life questionnaire), National Eye
Institute Visual Functioning Questionnaire
25 (VFQ-25) (the impact of a disease on
visual functioning), RQLQ, and Health
Economic and Demographic Questionnaire
(HEDQ).
Compared to the control group,
patients with seasonal allergic conjunctivitis had a higher rate of comorbidities,
including perennial allergic conjunctivitis,
nasal symptoms, asthma, food allergies,
and other allergies. On the EQ-5D Health
Questionnaire, poorer quality of lifeas
measured by factors such as mobility, selfcare, ability to engage in usual activities,
pain, discomfort, anxiety, and depression
was seen in patients with seasonal allergic
conjunctivitis compared to controls.

On the VFQ-25, patients with seasonal allergic conjunctivitis scored statistically significantly worse than controls on
distance vision, ocular pain, mental health,
dependency on others, role limitations, and
overall vision.
On the RQLQ patients with seasonal
allergic conjunctivitis scored statistically
significantly worse in all domains (e.g.,
activity, sleep, nose and eye symptoms,
practical problems, nasal symptoms, eye
symptoms, and emotional symptoms).
The HEDQ questionnaire found that
20% of patients with seasonal allergic conjunctivitis missed work due to their condition, and 45% reported that they had
decreased productivity of 35% (18.58%).

The HEDQ questionnaire


found that 20% of patients with
seasonal allergic conjunctivitis
missed work due to their
condition, and 45% reported
that they had decreased
productivity of 35% (18.58%).
Costs of Allergy
Healthcare costs are divided into direct and
indirect costs. Direct costs encompass the
monies spent on the course of managing
the disease, including medical services (e.g.,
outpatient costs, physician fees, and laboratory procedures), pharmaceutical agents,
and allergen immunotherapy. Indirect costs
encompass all the non-healthcare costs
associated with the illness. These include
monies lost due to missing work and
decreased productivity due to the illness.
Other indirect costs include the monetary
value of missing school and unpaid caregivers time to care for a sick child.
In the Allergies in America Study
1,315 of the 2,500 participants were fulltime workers. When they were having no
symptoms, their productivity was 95%.
When they experienced symptoms at their
worst, productivity dropped to 72%. There
was about a 20% drop in productivity
related to nasal and ocular symptomatology in this survey. Looking at work interference from allergies, 10% of participants
missed work, 22% reported symptoms
only interfered with work, and 20% both
missed work and had decreased productivity.
In conclusion, both asthma and allergic rhinitis lead to significant impairment
in quality of life and increased healthcare
costs. Research is clearly showing that
ocular allergy worsens quality of life and
adds to healthcare costs.

Advances in the Understanding and Treatment of Allergic and Nonallergic Conjunctivitis

Current and Future Treatment Options in


Allergic and Nonallergic Conjunctivitis
Leonard Bielory, MD

new set of practice parameters for the


treatment of allergic conjunctivitis have
been written and are currently under
review. In this documentAllergic
Conjunctivitis Practice Parameters
seasonal allergic conjunctivitis and perennial allergic conjunctivitis are divided into
intermittent (symptoms present less than
4 days a week or for
less than 4 weeks) and
persistent (symptoms
present greater than
4 days a week and for
greater than 4 weeks).
Treatment of allergic conjunctivitis
involves a step-up approach, beginning
with allergen avoidance and environment
control, followed by lubricants and cool
compresses, oral antihistamines, topical
agents, and immunotherapy.
Ocular Allergy Treatments
Primary treatment for both acute and
chronic ocular allergy symptoms is with
cool compresses and lubrication.21 Cold
compresses decrease nerve C fiber stimulation and reduce superficial vasodilation.
For patients with chronic allergy symptoms
who wear contact lenses, use of disposable
daily contact lenses is advised. Secondary
treatment for both acute and chronic ocular
allergy involves topical agents. Antihistamines can be used for pruritus. The
particular agent must be carefully chosen,
especially because antihistamines have anticholinergic properties and thus may cause
dry eyes, which can complicate the disease.
A form of dry eye called tear film dysfunction commonly occurs concurrently
with ocular allergy. This may occur in a
person who works long hours staring at
a computer screen. The treatment is topical cyclosporine.
Decongestants are useful for erythema.
Multiple action agents are recommended
for evolving perennial rhinoconjunctivitis.
Mast cell stabilizing agents (e.g., cromolyn)
may be used for healing corneal defects
associated with the more chronic forms of
ocular allergy.
In general, steroids are reserved for
cases of severe seasonal allergy. Steroid
burst therapy may be used for 2 to 3 days.
Steroids should not be used in combination with an antibiotic. If an antibiotic is

needed for an infection, the steroid should


be used with extra caution unless working
with an ophthalmologist or other eye care
professional. Topical steroids are commonly used in the treatment of chronic
forms of ocular allergy, such as atopic or
vernal keratoconjunctivitis.
The new practice parameters use a
graded approach to pharmacotherapy
for allergic conjunctivitis, involving progressive treatment in a step-wise fashion
until adequate control is achieved (see
Figure 1). Grade 0 is quiescent and no treatment is necessary. Grade 1 is mild intermittent. Treatment is allergen avoidance,
disposable contact lenses, or oral antihistamines. Grade 2 is moderate intermittent
or moderate persistent. Treatment is with
daily administration of multiple action
agents. Grade 3 is severe. Additional treatments may include topical cyclosporine or
a short burst of topical steroids. For grade
4 (very severe) oral steroids may be added.
Immunotherapy or nasal steroids are used
to treat comorbidities, such as allergic
rhinitis.
Secondary Treatments
Topical mast cell stabilizers include cromolyn, lodoxamide, nedocromil, and
pemirolast. They require premedication
(commonly weeks). Cromolyn prevents
release of mediators and is effective for
allergic diseases, especially those associated with corneal changes. It relieves mildto-moderate symptoms of vernal keratoconjunctivitis. It may be associated with
burning, stinging, periorbital erythema,

and chemosis. It requires dosing four times


per day. Lodoxamide has in vitro antieosinophilic properties. It is greater than
100 times more potent than cromolyn in
vitro. Nedocromil is a cromolyn derivative
that is effective with twice-daily dosing. It
can cause yellow staining on clothing.
Pemirolast is indicated for ocular pruritus
and is effective when dosed twice to four
times a day.
Topical antihistamines (e.g., levocabastine, emedastine) relieve signs and
symptoms of pruritus (and erythema).
Dosing is one to four times daily. They are
safe and effective for patients 3 years old
and older. Topical NSAIDs (e.g., ketorolac) relieve pruritus. Stinging and/or burning on instillation is experienced in up to
40% of patients.
Topical antihistamine and decongestant combination drugs (e.g., antazolinenaphazoline, pheniramine-naphazoline)
are available without a prescription. They
have quick onset of action, are more effective than systemic antihistamines, have limited duration of action, require frequent
dosing, and are not recommended for regular use due to the potential for conjunctivitis medicamentosa.
There are several topical multiple
action agents (antihistamine, mast cell stabilizer, cytokine), including olopatadine,
ketotifen, azelastine, epinastine, and the
most recently approved bepotastine 22
and alcaftadine23. They treat itch and are
more effective at relieving symptoms than
other classes of agents. They have longer
duration of action and are safe and effec-

Figure 1: Pharmacotherapy Guidelines for Allergic Conjunctivitis


Grade 4
Grade 2
Grade 1
Mild
Intermittent

Moderate
Intermittent
Persistent

Grade 3

Very Severe

Severe

Oral steroids

Short burst of topical steroids

Grade 5

Topical cyclosporine

Evolution

Topical Vasoconstrictors/Lubricants/Cool Compresses

Grade 0
Quiescent

Avoidance

Daily Administration of

Disposable
Contact Lenses

Multiple action antihistamine/mast cell stabilizers agents

No treatments

Oral
Antihistamines

NSAIDs
Treatment of Comorbidities Allergic Rhinitis
Immunotherapy, Intranasal Steroids

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

Advances in the Understanding and Treatment of Allergic and Nonallergic Conjunctivitis

Table 1: Dosing and Adverse Effects of Multiple Acting Agents


Azelastine
(Optivar)

Epinastine
(Elestat)

Ketotifen
(Zaditor)

Olopatadine
(Patanol)

Olopatadine
(Pataday)

Bepotastine
(Bepreve)

Alcaftadine
(Lastacaft)

Rx

itch

itch

itch

itch

itch

itch

itch

Dose

1 gtt OU bid

1 gtt OU
bid >3yrs

1 gtt OU bid
8-12 hrs

1 gtt OU
6-8 hrs

1 gtt OU
every day

1 gtt OU bid
>2 yrs

1 gtt OU
every day

Adverse
effects

Transient sting,
headache,
bitter taste (<1%
discontinued
due to adverse
effects)

Burning,
infection
(URI/cold
symptoms)
10%

Headache and
conjunctival
injection

Transient sting/
burn (<5%),
headache (7%)

Transient sting/
burn (<5%),
headache (7%),
flu-like symptoms
(10%)

Taste perversion
<25%, eye
irritation,
headache,
nasopharyngitis
(<5%)

Transient sting/
burn, headache,
flu-like symptoms
(<4%)

Manufacturer

MEDA

Allergan

Novartis

Alcon

Alcon

ISTA

Allergan

tive for patients 2 to 3 years old and older.


Dosing and potential adverse effects are
listed in Table 1.
Bepotastine and alcaftadine are excellent antipruritic agents that have also
demonstrated effects on mast cells, eosinophils, and various cytokines involved in the
allergic response. Bepotastine is dosed at
1 gtt OU twice day and alcaftadine is dosed
at 1 gtt OU once a day. Potential adverse
effects are similar and include transient
sting/burn, headache, and flu-like symptoms (experienced by less than 4% of
patients).
Among the topical corticosteroids,
loteprednol is approved for allergic conjunctivitis. It relieves all facets of the inflammatory response (primarily late phase),
including erythema, edema, and pruritus
(not histamine induced). It is dosed four
times a day and is appropriate for shortterm use only. It is contraindicated in
patients with viral infections. It is adjunctive therapy, although it may be considered
in conjunction with allergic rhinitis and
asthma. It is a prodrug that is metabolized
on the surface, and therefore does not cause
as much intra-ocular pressure as drugs that
penetrate deeply.

Future Therapy
New treatments under investigation include
a contact lens with ketotifen. Preliminary
results show no adverse effects. A ketotifen
patch is also being studied. In addition,
NSAIDs, such as topical bromfenac, are
being studied for allergic conjunctivitis and
potentially for tear film dysfunction (a
common comorbid state with ocular
allergy).
Histamine Receptors in Ocular Tissue
Histamine is one of the most common
chemical mediators causing pruritus. In
addition to histamine (specifically H1 and
H 2), other sensory molecules on nerves
include opioids, leukotriene B4, prostaglandin E, osmolarity, neurokinins, proteases, among others.
Several histamine receptors are in
ocular tissue. Histamine binding to H 1
receptors causes ocular itch. Stimulation
of H 2 receptors in blood vessels causes
vasodilation. A study by Abelson and Udell
showed that instillation of a known H2 agonist (dimaprit) induced hyperemia.24 Onset
was at 10 minutes and peak effect was at
30 minutes. There was no itch associated
with H2 receptor stimulation. Itch occurs

References
1. Bacon AS et al. Tear and conjunctival changes during the allergen-induced early- and latephase responses. J Allergy Clin Immunol. 2000;106(5):948-954. 2. Choi SH, Bielory L. Latephase reaction in ocular allergy. Curr Opin Allergy Clin Immunol. 2008;8(5):438-444. 3. Bielory
L. Allergic and immunologic disorders of the eye. Part I: immunology of the eye. J Allergy Clin
Immunol. 2000;106(5):805-816. 4. Fukuda K et al. Critical role of IgE-dependent mast cell activation in a murine model of allergic conjunctivitis. J Allergy Clin Immunol. 2009;124(4):827833. 5. Baudouin C et al. CCR 4 and CCR 5 expression in conjunctival specimens as differential
markers of T(H)1/T(H)2 in ocular surface disorders. J Allergy Clin Immunol. 2005;116(3):614619. 6. El-Asrar AM et al. Expression of T lymphocyte chemoattractants and activation markers in vernal keratoconjunctivitis. Br J Ophthalmol. 2002;86(10):1175-1180. 7. Kumagai N
et al. Active matrix metalloproteinases in the tear fluid of individuals with vernal keratoconjunctivitis. J Allergy Clin Immunol. 2002;110(3):489-491. 8. Ueta M et al. Toll-like receptor
3 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 conjunctival
epithelium regulates late-phase reaction of experimental allergic conjunctivitis. J Allergy Clin
Immunol. 2009;123(2):466-471. 10. Bacsi A et al. Effect of pollen-mediated oxidative stress on
immediate 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 neurotransmitter receptors and neuromediators in vernal keratoconjunctivitis. Arch Ophthalmol.
2006;124(4):462-468. 12. Sacchetti M et al. Hyperosmolar conjunctival provocation for the
evaluation of nonspecific hyperreactivity in healthy patients and patients with allergy. J Allergy
Clin Immunol. 2006;118(4):872-877. 13. Vanna AT et al. International Study of Asthma and
Allergies in Childhood: validation of the rhinitis symptoms quesionnaire and prevalence of rhinitis in schoolchildren in So Paulo, Brazil. Pediatr Allergy Immunol. 2001;12(2):95-101.
14. Hesselmar B et al. Allergic rhinoconjunctivitis, eczema, and sensitization in two areas with
differing climates. Pediatr Allergy Immunol. 2001;12(4):208-215. 15. Wthrich B et al.
Epidemiological survey in hay fever patients: symptom prevalence and severity and influence on

first, followed by redness. Pretreatment of


the paired eye with the H2 antagonist cimetidine decreased hyperemia. Pretreatment
with an H1 antagonist had no significant
effect. H2 receptors are clinically important in the eye.
Katagiri et al. showed that eye itch will
be reduced if the H1 receptor is blocked
with an antagonist.25 Adding an H2 receptor antagonist has minimal, if any, effect.26
H3 receptor antagonists have the effect of
increasing itching.27 H4 is a novel receptor
that has been shown to reduce itching, 28
and some binding to this receptor has been
noted with alcaftadine and with higher
doses of the standard H1 agents.29
The direct effect of histamine (H1 and
H2) is vasodilation and increased permeability, and this is a commonly sought after
property in several of the ophthalmic
agents. H1 plus H4 antagonism has been
shown in knockout mice to reduce itching. 26 Scratching behavior was almost
totally abated in experimental pruritus
with H1 plus H4 antagonism. Histamine
H4 receptor antagonists may have a therapeutic role in the future for relieving
pruritus in patients with allergic conjunctivitis.

patient management. Schweiz Med Wochenschr. 1998;128(5):139-143. 16. Navarro et al.


Epidemiology of allergic rhinitis in allergy consultations in Spain: Alergolgica-2005. J Investig
Allergol Clin Immunol. 2009;19 Suppl 2:7-13. 17. Palmares J et al. Allergic conjunctivitis: a
national 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 children with vernal keratoconjunctivitis questionnaire. Am J Ophthalmol. 2007;144(4):557563. 19. Alexander M et al. The reliability, validity, and preliminary responsiveness of the Eye
Allergy 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 in
a Spanish setting. Ophthalmic Epidemiol. 2005;12(4):233-242. 21. Bielory L. Ocular allergy
guidelines: a practical treatment algorithm. Drugs. 2002;62(11): 1611-1634. 22. Torkildsen
GL et al. Bepotastine besilate ophthalmic solution for the relief of nonocular symptoms provoked 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 conjunctivitis 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 ocular
surface. Arch Ophthalmol. 1981;99(2):302-304. 25. Katagiri K et al. Fexofenadine, an H1receptor antagonist, partially but rapidly inhibits the itch of contact dermatitis induced by
diphenylcyclopropenone 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 analogues
and histamine. Br J Clin Pharmacol. 1980;9(5):461-465. 27. Sugimoto Y et al. Pruritus-associated response mediated by cutaneous histamine H3 receptors. Clin Exp Allergy. 2004;34(3):456459. 28. Dunford PJ et al. Histamine H4 receptor antagonists are superior to traditional
antihistamines 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 antagonists
with the human histamine H4-receptor. Mol Pharmacol. 2009;76(5):1019-1030.

Advances in the Understanding


and Treatment of Allergic and
Nonallergic Conjunctivitis
A CME-Certified Newsletter

Release Date: June 1, 2011 Expiration Date: June 1, 2012


Estimated time for completion: 60 minutes

Please complete the Self-Assessment Test, Evaluation and Credit Claim information. Mail a copy of these documents to the American College of
Allergy, Asthma & Immunology, 85 West Algonquin Road, Suite 550, Arlington Heights, IL 60005, or FAX to (847) 427-1294, Attn: CME Administrator.
Credit should not be claimed by participants who received credit by attending this session at the 2010 Annual Scientific
Meeting in Phoenix, Arizona. A minimum score of 80% must be achieved in order to earn a certificate of credit. For credit to be awarded,
all posttests, evaluations, and claiming of credit must be submitted prior to the Expiration Date of June 1, 2012.
Alternatively, to receive credit quickly, please go directly to http://www.acaai.org/Pages/CONJUNCT2011.aspx
and complete the entire activity and post test online.

Self-Assessment Test
After reading each item carefully, please select the best response (one) and enter your choice on the reverse.
1. Which of the following allergic eye disorders can exist in a non-IgE-mediated
(nonatopic) form?
A. Seasonal allergic conjunctivitis
B. Atopic keratoconjunctivitis
C. Perennial allergic conjunctivitis
D. Vernal conjunctivitis
2. Which one of the following conditions is most
commonly associated with atopic dermatitis?
A. Seasonal allergic conjunctivitis
B. Atopic keratoconjunctivitis
C. Perennial allergic conjunctivitis
D. Vernal conjunctivitis
3. Neutrophil chemotactic factor in tear fluid is
most characteristic of:
A. Seasonal allergic conjunctivitis
B. Giant papillary conjunctivitis
C. Perennial allergic conjunctivitis
D. Vernal conjunctivitis
4. A 32-year-old man is participating in a spring
allergy clinical study. The Rhinoconjunctivitis
Quality-of-Life Questionnaire (RQLQ) is
administered during the trial. Which of the
following 4 eye symptoms are assessed in
this patient by the RQLQ?
A. Itchy, watery, swollen, sore
B. Itchy, red, swollen, watery
C. Red, swollen, watery, sticky
D. Swollen, watery, red, sore

5. An 8-year-old boy is seen for vernal keratoconjunctivitis. The Questionnaire to Assess


QOL in Children with VKC (QUICK) is administered. Which item rated the greatest effect
on quality of life in children with atopic keratoconjunctivitis?
A. ...you felt burning in your eyes
B. ...you had to use tissues
C. ...you had problems in the light
D. ...you had trouble playing outside

6. A 32-year-old patient is seen for evaluation


of rhinoconjunctivitis which leads to trouble working as a computer programmer. You
tell the patient that productivity in adult
patients with rhinoconjunctivitis decreases
by what percentage when symptoms are at
their worst?
A. 5%
B. 10%
C. 20%
D. 40%
7 A 26-year-old mildly asthmatic woman
has been treated for several years with
immunotherapy for allergic rhinoconjunctivitis. She develops progressive irritation in
her right eye. Her eye initially had a ropey
white discharge from one eye. Her eyelids
appear to be stickier when she wakes up. On
examination, an opaque, yellowish mucus
strand is noted on the eyelid with moderate
injection of the conjunctiva. Which of the following is contraindicated?
A. Topical mast cell stabilizing agent
B. Lubricants
C. Cold compresses
D. Topical combined antibiotic and steroid
agent
8. A 48-year-old woman is referred for evaluation of allergic conjunctivitis due to recent
increase in ocular irritation in both eyes. She
has no history of asthma or any consistent
history of seasonal allergy. She has an
increase in ocular symptoms of itching and
grittiness with increased blinking in early
winter, especially when working at the computer. Conjunctiva were mildly injected bilaterally. She has a normal response to
histamine and saline with minimal reaction
to grass, pollen, and mixed trees. Skin tests
to indoor allergens are negative. Which of the
following is most likely to improve the underlying condition?

A. Ophthalmic mast cell stabilizer


(e.g., cromolyn)
B. Oral antihistamine
C. Intranasal steroid
D. 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 limousine
driver and is active in outdoor sports was
transferred to the Mid-Atlantic region from
the Upper Midwest 2.5 years ago. He presents with intermittent respiratory symptoms
previously treated with over -the -counter
medication. However, drowsiness from the
drugs disrupts his work. Symptoms include
nasal discharge, intermittent sneezing, itching of the nose, and tearing of the eyes. He
also experiences fatigue and lack of concentration while driving. Physical examination reveals swollen and pale nasal turbinates
bilaterally, moderate edema and darkened
suborbital regions. Allergy tests reveal large
reactions to grass, weed, and tree pollen and
moderate 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 steroid
D. Ophthalmic multiple action agent
(olopatadine, epinastine, bepatastine)
10. Antagonism of H1 plus ____ has been shown
in knockout mice to reduce itching.
A. H2
B. H3
C. H4
D. Leukotriene B4

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