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Rhinitis, sinusitis, and ocular diseases
Update review
Allergic conjunctivitis: Update on
pathophysiology and prospects for future
treatment
Santa Jeremy Ono, BA, PhD,
a
and Mark B. Abelson, MD
b
London, United Kingdom, and
Boston, Mass
Allergic conjunctivitis is in actuality a group of diseases
affecting the ocular surface and is usually associated with type
1 hypersensitivity reactions. Two acute disorders, seasonal
allergic conjunctivitis and perennial allergic conjunctivitis,
exist, as do 3 chronic diseases, vernal keratoconjunctivitis,
atopic keratoconjunctivitis, and giant papillary conjunctivitis.
The ocular surface inflammation (usually mast cell driven)
results in itching, tearing, lid and conjunctival edema–redness,
and photophobia during the acute phase and can lead to
a classic late-phase response (with associated eosinophilia and
neutrophilia) in a subset of individuals. As is the case in other
allergic diseases, a chronic disease can also develop,
accompanied by remodeling of the ocular surface tissues. In
severe cases the patient experiences extreme discomfort and
sustains damage to the ocular surface. For such cases, there
is no highly effective and safe treatment regimen. Topical
administration of corticosteroids is used in severe cases but is
associated with an increased risk for the development of
cataracts and glaucoma. Thus there is a worldwide search for
new biotargets for the treatment of these diseases. Here we
provide a brief update of the clinical symptoms associated with
these diseases, the rationale for disease classification, recent
advances in our understanding of the pathogenesis of the
diseases, and an update on both preclinical and clinical
advances toward refined therapies for these diseases.
(J Allergy Clin Immunol 2005;115:118-22.)
Key words: Allergic, eye, conjunctivitis
SEASONAL AND PERENNIAL ALLERGIC
CONJUNCTIVITIS
Although there are several types of ocular allergy,
seasonal and perennial allergic conjunctivitis (PAC)
represent the majority of all ocular allergy cases, whereas
the severe conditions of atopic keratoconjunctivitis (AKC)
and vernal keratoconjunctivitis (VKC) affect a smaller
group of patients. Fig 1 shows representative photographs
of eyes from individuals with the various forms of allergic
conjunctivitis and also provides unique features distin-
guishing the forms of the disease. The incidence of the
severe ocular allergy varies markedly with geographic
region, with individuals in Italy, Japan, and other warm
climates being more likely to have these conditions. De-
spite these differences in disease classification and in-
cidence, the allergic response in conjunctivitis is typically
elicited by ocular exposure to allergen that causes cross-
linkage of membrane-bound IgE, which triggers mast cell
degranulation, releasing a cascade of allergic and inflam-
matory mediators. One such mediator, histamine, is the
primary contributor to the development of early-phase
signs and symptoms of seasonal allergic conjunctivitis
(SAC),
1
usually in distinct waves that reflect allergen
exposure.
The pathognomonic symptom of ocular allergy is
itching. Without itching, a condition should not be con-
sidered ocular allergy. The accompanying vasodilation
appears superficial and pink rather than a deep red.
Chemosis, swelling of the conjunctiva, can be present,
although it is usually subtle and thus only visible on slit
lamp examination. More readily observable is the glassy
appearance of the eye. Swelling can also become apparent
in the lids. Although lid swelling peaks within 15 to 30
minutes after exposure, it tends to dissipate slowly and is
often more visible on examination. Although transient, the
initial intensity of this swelling can induce structural
changes in the delicate collagen fibers of the skin sur-
rounding the eye.
2,3
From
a
the Department of Immunology, University College London, Institutes
of Ophthalmology and Child Health and Moorfields Eye Hospital, NHS
Trust, London, and
b
the Department of Ophthalmology, Harvard Medical
School and Schepens Eye Research Institute, Boston.
Received for publication October 25, 2004; revised October 28, 2004; accepted
for publication October 29, 2004.
Reprint requests: Santa Jeremy Ono, PhD, University College London,
Institute of Ophthalmology, 11-43 Bath St, London, EC1V 9EL. E-mail:
santa.ono@ucl.ac.uk.
0091-6749/$30.00
Ó2005 American Academy of Allergy, Asthma and Immunology
doi:10.1016/j.jaci.2004.10.042
Abbreviations used
AKC: Atopic keratoconjunctivitis
PAC: Perennial allergic conjunctivitis
SAC: Seasonal allergic conjunctivitis
VKC: Vernal keratoconjunctivitis
118
Rhinitis, sinusitis, and
ocular diseases
An accurate history of the ocular allergic patient
typically reveals an atopic family or personal history, as
well as the environmental triggers that might elicit this
reaction (ie, trees, grasses, ragweed, or pet-animal dan-
der). Signs of rhinitis, asthma, or both might also be
present, including runny nose, sneezing, and/or wheezing.
In one study (n = 200) approximately 90% of patients with
rhinitis indicated they had experienced at least 1 day of
ocular symptoms within the past week.
4
Patient-reported
signs and symptoms are critical to the diagnosis of allergic
conjunctivitis because signs and symptoms might not be
present at the time of the visit.
The conjunctiva represents the upper extremity of the
respiratory system, which maintains a drainage system into
the nose through the nasolacrimal duct. The ocular surface
can be considered a relatively large collection window,
having an area of several hundred square millimeters, for
the entry of allergens into the body. Allergens, allergic
mediators released from the mast cell, or antiallergy eye
drops drain to the nose by way of this pathway, contrib-
uting to nasal symptomatology. Ocularly instilled therapy
has been shown to reduce rhinitis symptoms, such as
sneezing, runny and itchy nose, and blocked nostrils.
5,6
It
is hypothesized that this effect is due to the inhibition of the
allergic reaction and mast cell degranulation at the ocular
surface, drainage of medication to the nose through the
nasolacrimal duct, or both. Additional evidence for this
pathway of drainage from eye to nose comes from the
conjunctival allergen challenge model, in which the ocular
instillation of allergen can induce nasal symptoms, in-
cluding itching of the nose and palate, rhinitis, sneezing,
and, more rarely, wheezing.
5,6
Cold compresses, eyewashes with tear substitutes, and
avoidance of allergens are nonspecific measures to which
the allergic patient can turn in attempting to alleviate aller-
gic symptoms; however, these are often impractical or
ineffective. The use of topical therapy is pharmacokineti-
cally and clinically the most appropriate approach for the
treatment of allergic conjunctivitis because it allows for
direct and local application of therapy while avoiding the
ocular drying effects evident with the use of systemic
antihistamines.
7,8
SAC and PAC are ideally treated with combination
antihistamine–mast cell stabilizers, the newest generation
of dual-mechanism antiallergic agents. The advantage of
these therapeutic molecules is the rapidity of symptomatic
relief given by immediate histamine receptor antagonism
coupled with the long-term disease-modifying benefit of
mast cell stabilization. Not all are equivalent, and there is
an extensive body of comparative studies of such agents. In
selecting a dual-action agent, one should look for a potent
and long-lasting agent with the ability to relieve all the
signs and symptoms of allergy, including itching, redness,
lid swelling, and chemosis. Patients might benefit from
FIG 1. Four types of ocular allergy.
J ALLERGY CLIN IMMUNOL
VOLUME 115, NUMBER 1
Ono and Abelson 119
Rhinitis, sinusitis, and
ocular diseases
single-action mast cell stabilizers, but onset of action is not
immediate, typically requiring a loading period. It is im-
portant to keep in mind the heterogeneity of mast cells
when selecting a dual-action or mast cell–stabilizing agent.
Mast cell subtypes vary by tissue and species in parame-
ters, including neutral protease content and responsiveness
to therapeutic agents. In selecting therapy, an agent that has
been developed primarily through testing on other tissues
or species might have less efficacy in the human eye than
would an agent developed specifically for ocular use and
researched by using human conjunctival mast cells.
Topical antihistamines are also effective, although for
shorter duration, and might be considered most useful
for as-needed treatment of sporadic allergic reactions for
which a prolonged seasonal therapy is unnecessary. In
addition, corticosteroids are a treatment option, although
considering the potential side effects, including cataracts,
increased intraocular pressure, and corneal melts, the use
of corticosteroids is typically reserved for patients not
responsive to other therapy or for use in the severe forms
of allergy, such as AKC or VKC. One topical nonsteroidal
anti-inflammatory drug is also approved for the relief of
itching associated with SAC.
VKC AND AKC
VKC and AKC are chronic allergic diseases that origi-
nate from more complex mechanisms than SAC. Eosino-
phils, resident conjunctival fibroblasts, and epithelial
cells, mast cells, and T
H
2 lymphocytes, through allergic-
inflammatory endocrine-immune stimuli, provoke multiple
dysfunctions in conjunctival biochemistry and histology.
Giant papillary conjunctivitis is not a true ocular allergic
reaction, as is the case with SAC, AKC, and VKC. It is
caused by repeated mechanical irritation (as in the case of
contact lens wearers) and is aggravated by concomitant
allergy.
VKC is a disease of childhood, with greater prevalence
in male subjects living in warm climates. In tarsal VKC, in
addition to all clinical features of allergic conjunctivitis,
tarsal cobblestone-like papillae are also present. In limbal
VKC gelatinous yellow-gray infiltrates are observed on
the limbus, the circumference of which might appear
thickened and opaque, with a peripheral and superficial
neovascularization. Intense itching, tearing, mucous se-
cretion, and severe photophobia characterize all forms of
VKC. Research has also documented that histaminase
deficiency exists with VKC.
9
AKC occurs more frequently in men aged 30 to 50
years. A family history of allergies, asthma, urticaria, and/
or hay fever is often present. Typically, patients have
atopic dermatitis or eczema since childhood, with ocular
symptoms developing later in life. The primary symptom
of AKC is intense bilateral itching of the lid skin,
periorbital area, and conjunctiva. Tearing, burning, pho-
tophobia, blurred vision, and a stringy, rope-like mucus
discharge are also observed. Atopic blepharitis is evident,
with tylosis and swollen eyelids that have a scaly in-
durated appearance, with meibomian gland dysfunction
and associated dry eye. The conjunctiva can be hyperemic
and edematous, and tarsal conjunctival papillae are
common. Gelatinous nodules can be present around the
limbus with or without Tranta dots. Treatment of VKC and
AKC involves the same agents used in allergic conjunc-
tivitis, as well as pulse therapy with steroids.
The serious nature of these conditions warrants close
attention, although one should keep in mind that AKC and
VKC represent just 2% of all ocular allergies. Conversely,
the 98% of patients with ocular allergy having SAC and
PAC are much more commonly seen, and the incidence is
increasing. SAC and PAC can often go undiagnosed, or the
ocular component of allergic rhinoconjunctivitis can go
untreated. The signs and symptoms of allergic conjuncti-
vitis have a meaningful effect on patients’ quality of life,
4
health, and comfort. Brief diagnostic questioning, exam-
ination, and prescription of appropriate topical ocular
therapy or addition of this therapy to an existing medica-
tion regimen are the keys to appropriate management of
ocular allergy and maintenance of patient health and
satisfaction.
PATHOPHYSIOLOGY OF OCULAR ALLERGY:
IMPLICATIONS FOR DRUG DEVELOPMENT
In addition to the clinical approaches mentioned above,
there is a clear need for the development of new drugs for
the treatment of both SAC and the more severe forms of the
disease.
10
Over the past 3 years, there has been significant
progress in our understanding of the pathophysiology of
allergic conjunctivitis. These data have been obtained from
both direct examination of patient samples–conjunctival
biopsy specimens (taken from patients with seasonal or
more chronic ocular allergies) and the evaluation of refined
murine models of ocular allergy.
One new area of investigation has involved an analysis
of the genetics of ocular allergy. It has been known for
some time that different mouse strains are more or less
responsive to specific allergen challenge in the eye, and the
linkage analysis of these mice is now underway to define
disease susceptibility genes for ocular allergy.
11
Notably,
Bundoc and Keane-Myers
12
have identified divergent
local production of IL-10 in different mouse strains and
have shown that this affects the propensity of the con-
junctival mast cell to become activated by allergen. Thus
modulation of IL-10 production in situ might represent one
new therapy for ocular allergy. A linkage analysis in
human subjects has shown that although some suscepti-
bility loci are shared with other allergic diseases, there are
unique genetic loci (eg, the eotaxin 1 locus) associated
with SAC.
13,14
Similar genome-wide analyses for VKC
are now nearing completion. It is hoped that these data will
point to unique disease-associated gene products that
might be exploited for new drug design.
The study of conjunctival tissue has identified both T
H
1
and T
H
2 lymphocytes in the conjunctiva of patients with
VKC and both T
H
2-associated cytokines and b-chemo-
J ALLERGY CLIN IMMUNOL
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120 Ono and Abelson
Rhinitis, sinusitis, and
ocular diseases
kines in the tears of patients with both SAC and VKC.
15,16
More work is required to understand the pathogenetic role
for the T
H
cells in VKC, but the isolation of T-cell lines
from patients with VKC should pave the way for such
research. It is very important to determine the clonality of
T cells infiltrating the conjunctiva and the functional roles
of the different T-cell subsets in disease.
One growing area of focus has been on the resident
dendritic cells within the conjunctiva. This stems from the
pioneering work of Allam et al
17
that has shown that early
dendritic cell activation by allergen is a very early step in
disease pathogenesis, with dermal allergy as the prototype.
The T
H
cells observed in situ in the conjunctiva of patients
with VKC might contribute to disease pathogenesis by
influencing the number and type of dendritic cells resident
in the conjunctiva. An analysis of the dendritic cell subsets
in human and mouse conjunctiva indicate that the phe-
notype of these key antigen-presenting cells is unusual in
the conjunctiva (M. Ohbayashi and S. J. Ono, unpublished
results). Thus there is a paucity of lymphoid dendritic cells
in the conjunctiva. There is also (as might be expected)
a remarkable dynamic change in the number and types of
dendritic cells detected in the sensitized eye, providing
possible opportunities for immunomodulation. Supportive
of this view has been the success by us and others in
treating ocular allergy in defined murine models using IL-1
receptor antagonist and CpG oligonucleotides.
18,19
Our
finding that IL-1 receptor antagonist strongly inhibits both
early- and late-phase inflammation underscores the im-
portance of the dendritic cell and other resident antigen-
presenting cells in allergic conjunctivitis. We hypothesize
that the arrested activation of resident antigen-presenting
cells in the conjunctiva of IL-1 receptor antagonist–treated
mice inhibits the release of mast cell costimulatory factors
(normally produced from allergen-activated antigen-pre-
senting cells), thus inhibiting both mast cell activation and
the late-phase response. The more limited success of CpG
therapy of allergic conjunctivitis in our preclinical model
might indicate that topical administration of this moiety
might not be effective (as opposed to systemic delivery)
but might also indicate that further refinement in ocular
drug delivery of CpG oligonucleotides is required for
therapeutic effect. The efficiency of systemic administra-
tion of CpG oligonucletides is consistent with what is
observed in other allergies and the pleiotropic effects of
CpG oligonucleotides on many immune cells.
Mast cell degranulation (either anaphylactic or piece
meal) can be identified in most biopsy specimens obtained
from patients with SAC or VKC and from murine models
of the diseases. Thus significant preclinical research is still
directed at understanding the biology of conjunctival mast
cell development and activation. The Wisconsin group is
doing the best work on human conjunctival mast cell
activation and on the mediators released from these cells
on FceRI cross-linking.
20
Other work focusing on mast
cell–deficient mice and chemokine gene-deficient mice is
also revealing unique pathways for conjunctival mast cell
priming and activation.
21
These data indicate that b-
chemokines are not only important for the recruitment of
leukocytes in the late-phase reaction but also play roles in
mast cell priming and activation. The data suggest that
macrophage inflammatory protein 1ais an obligate
priming signal for conjunctival mast cells and that eotaxin
1 provides an important costimulatory signal for conjunc-
tival mast cells during disease pathogenesis.
22
In view of
this, it is striking that eotaxin 1 is detected in both human
tears and murine conjunctival homogenates in samples
obtained from human subjects and animals with syn-
dromes resembling SAC or VKC.
23
The evidence from genetic analyses and direct analyses
of human and murine tissues implicating chemokines in
the pathogenesis of ocular allergy suggests that the antag-
onism of specific chemokines, their receptors, or both
might be of value in the treatment of ocular allergy. Indeed,
we have reported that antagonism of the receptor for
eotaxin 1 (CCR3) is able to inhibit both early- and late-
phase inflammation in the murine model of ocular al-
lergy.
24
Similar studies are underway for antagonism of
CCR1. In a parallel approach, we have also reported that
neutralization of eotaxin 1 in situ by using the humanized
anti-eotaxin 1 antibody (CAT-213) is able to inhibit the
activation of human conjunctival mast cells in an in vitro
passive sensitization system.
25
Thus chemokine antago-
nists hold significant progress as potential future antiocular
allergy drugs.
Finally, preclinical studies are also underway to probe
the roles of biomolecules essential for the late-phase re-
sponse. Thus work is underway to determine whether
blockade of molecules required for leukocyte recruitment
into the conjunctiva (eg, very late antigen 4 and vascular
cell adhesion molecule 1) can inhibit the late-phase re-
sponse and whether antagonism of the GPCR-CRTH2
affects early- and late-phase inflammation in ocular al-
lergy.
In conclusion, there has been tremendous progress in
the understanding of the clinical parameters of the syn-
dromes termed allergic conjunctivitis and the cell and mo-
lecular basis of these diseases. Current efforts are focused
on developing a new treatment regimen using existing
pharmaceuticals and on the identification of new biotargets
for rational drug design. Several targets have been iden-
tified by using genetic, RNA profiling, and proteomic
methods, and antagonists have been developed. The re-
sults of these preclinical trials are now becoming available
and indicate that there will indeed be a new generation
of ocular anti-inflammatory drugs. We hope that some of
these will prove to be safe and effective in the treatment
of this major ophthalmic condition.
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