Download VKC and the Allergy Rogues Gallery

Review
Therapeutic Topics
VKC and the Allergy
Rogues Gallery
What sets vernal keratoconjunctivitis apart from other allergic
conditions, and how to create targeted treatments for it.
Mark B. Abelson, MD, CM, FRCSC, FARVO and James McLaughlin, PhD, Andover, Mass.
O
phthalmology textbooks will
tell you that there are five or six
types of ocular allergies: seasonal; perennial; atopic; vernal; and drug- or
contact lens-induced. Perhaps at one
time, these different conditions were
all a single diagnosis in the same way
that all cancers were once considered
the same disease. Those times are
long past, and so it is with ocular allergy. As new therapies are tested and
refined, as basic scientific inquiry further elucidates cellular mechanisms
and pathways, the distinctions between these different types of ocular
allergy come into focus. What we’ve
learned, as have many medical subspecialties, is that one size doesn’t fit
all. This month, we will focus on one
of these types of ocular allergy, vernal
keratoconjunctivitis. While we examine the features of VKC we’ll see how
it differs from other types of allergy,
and discuss how these differences
are being used to identify therapeutic
strategies for each type.
Webster’s defines the adjective
“vernal” as relating to, or occurring
in the spring. A secondary definition
is that it refers to something fresh,
young or youthful. Both of these defi-
nitions are appropriate descriptors
for VKC, a chronic allergic disorder
that typically presents as a seasonal
conjunctivitis in patients who average
5 to 10 years of age. It’s the chronic
nature of the disease that makes VKC
so potentially devastating to its sufferers. Without aggressive, long-term
therapy, the disease can lead to corneal ulcers, keratoconus and permanent
visual impairment.
Descriptions of VKC in the ophthalmic literature date back several
hundred years.1 Despite the apparent
allergic nature of the disease, the precise causes have remained obscure.
Many prominent features of the disorder don’t fit the criteria established
for ocular allergy in general. Foremost among these is the prevalence
in prepubertal boys, the geographic
restriction to equatorial regions and
the tendency of the disease to recur
and intensify in the absence of typical
allergic triggers. There are uncertainties regarding an often-suggested association between atopy and VKC,
as many of the features commonly
observed in atopic patients are absent in those with VKC.2 For example,
skin sensitization tests, radioallergo-
80 | Review of Ophthalmology | February 2012
sorbent tests and serum or tear IgE
levels are equivocal in these patients,
with some studies showing a correlation and others showing none. Patterns of cytokine production are also
inconclusive; a recent analysis of patients with VKC demonstrated increases in both the allergy-associated
IL-4 and the inflammatory cytokine
interferon-γ.3 The picture that emerges is a disease with some allergic components in combination with a prominent chronic inflammatory response.
Another feature of VKC that reflects a complex etiology is its prevalence in boys. The disease is three
times more common in boys than
girls, and tends to resolve spontaneously as patients of both sexes progress through puberty. While there
are other examples of ocular surface
diseases in which hormones such as
estrogen or testosterone are known to
play a role (e.g., dry-eye disease), the
mechanisms that underlie this effect
are unclear. Similarly, the geographic
distribution of VKC is well-established but not entirely understood.
In the Middle East and in African
countries, from the Mediterranean
to as far south as central Africa, VKC
This article has no commercial sponsorship.
accounts for approximately 5 percent
of all ophthalmic patients.4 It is also
common in Central America and in
India. In contrast, surveys conducted
in Europe and in the United States
show an overall incidence that is in
the range of 0.01 to 0.03 percent, or
less than 1 percent of that observed in
more equatorial regions.4
Recent epidemiological reports
provide evidence of a genetic component to the disease. Studies of patients
living in regions where the disease is
rare (such as Europe) show that the
majority of VKC sufferers are first- or
second-generation immigrants from
areas where the disease is endemic.1,4
Other studies have established that
a reduction in tear diamine oxidase
activity is also associated with VKC,
at least in some patients.5 This enzyme deficiency results in significant
increases in ocular histamine and
thus could represent an early event
in a chronic disease cascade. Such
single-enzyme defects can often be
the result of inheritable mutations,
and so may provide a molecular basis
for the geographically and genetically
restricted nature of the disease. Additional studies on the association
between diamine oxidase deficiency and VKC are needed to address
these possibilities.
Signs and Symptoms of VKC
The initial presentation of VKC
may not be significantly different
from that of seasonal allergic conjunctivitis. Patients typically complain
of bilateral ocular itching, pain and
photophobia. They also may present
with hyperemia, tearing and a stringy
ocular discharge.6 As the disease progresses, however, several features that
are classically diagnostic for VKC develop that distinguish it from either
seasonal or perennial allergic disease.
These include the characteristic “cobblestone” tarsal papillae and limbal
gelatinous infiltrates. Most often pa-
VKC’s initial presentation can be similar to that of seasonal allergic
conjunctivitis. As it progresses, however, the classic “cobblestone” tarsal
papillae can develop, along with gelatinous limbal infiltrates.
tients present with either tarsal or
limbal signs, but more severe cases
with both features may also occur.
Following initial presentation, signs
and symptoms can wax and wane for
years. Typically VKC displays a seasonality such that recurrences develop in spring, but often the severity
and precise timing of disease symptomatology are sporadic.1,2,6
Differential diagnosis involves a
number of factors.1,2,7 The geography
of disease prevalence overlaps with
the distribution of trachoma, so patients will often have these two eye
diseases simultaneously. Of course,
initial treatment should address this
possibility. Patients with AKC can be
distinguished from those with VKC in
that atopic disease occurs later in life
(after 30 years of age), typically occurs
in combination with atopic dermatitis
or eczema, and rarely exhibits tarsal
or limbal features of VKC. Cytology,
including corneal scraping or impression cytology, reveals prominent immune cell infiltration of the conjunctiva, and this trait may be maintained
even during periods between outbreaks of symptomatic disease. Progressive growth of papillae results in
expansion of the tarsal epithelium and
reduction of the stromal layer. In the
limbal form of the disease, aggregates
of immune cells and fibroblasts form
punctate limbal bodies called Tranta’s
dots. Without treatment, chronic inflammation of the ocular surface can
lead to formation of corneal shield
ulcers, corneal neovascularization and
possible keratoconus.
Targeting Chronic Inflammation
Current therapy of VKC is aimed at
halting progression of the disease by
minimizing signs and symptoms while
reducing recurrences. The number
of relapses shows a strong correlation
with the long-term corneal damage.
A recent report established a descriptive diagnostic staging of the disease
and a corresponding treatment regimen based upon the assessment of
disease severity.6 Initial therapy typically consists of a topical mast cell
stabilizer with or without an antihistamine. As the disease severity progresses, there is an increasing need
for anti-inflammatory therapy such as
salicylates or steroids.
The introduction of aspirin as a
February 2012 | Revophth.com | 81
Review
Therapeutic
Topics
therapy for VKC was a major advance,
and it established the understanding
of the central role inflammation plays
in the etiology of the disease.8 Other
non-steroidal anti-inflammatories
such as ketorolac or nepafenac are
sometimes used to provide relief for
pain and inflammation, although they
are relatively ineffective at treating
the more severe forms of the disease.
For example, they don’t have a significant effect on size or inflammation of tarsal papillae.9 In addition,
aspirin-like compounds are associated
with an increased risk of Reye’s syndrome, a particular concern in the
young population of VKC patients.
For these reasons corticosteroids
are generally accepted as the antiinflammatory of choice.6,7,9
Short courses of topical steroids
are often necessary for moderate to
severe outbreaks of VKC, especially
those that feature tarsal or limbal inflammation. The course of required
treatment can be several weeks, and
severe cases often require multiple
courses. Even with such regimens,
resolution of papillae can take many
months and thus often lags behind
complete symptomatic relief. While
continuous steroid therapy can hasten the healing, it also increases the
likelihood of the side effects that limit
all ocular steroid therapy, namely increases in intraocular pressure and
risk of cataract. One recent study reported that steroid-induced cataracts
may occur in as many as 10 percent of
all AKC patients.4
The severity of the disease, in combination with risk factors associated
with the use of either NSAIDs or corticosteroids in a pediatric population,
has led to an increase in efforts to
identify alternative therapeutic strategies for VKC.
Several recent clinical trials 10-14
have examined the efficacy of antiinflammatories such as cyclosporine or tacrolimus for treatment
of VKC. Topical cyclosporine is a
drug that is approved for ocular use
and has an extensive track record
for safety and a low risk of adverse
events. It’s currently used in patients with aqueous-deficient dryeye disease as a topical emulsion
containing 0.05% cyclosporine.15
The severity of VKC, in
combination with the
risk factors associated
with either NSAIDs
or corticosteroids in a
pediatric population,
has led to an increase
in efforts to identify
alternative therapies.
Trials of cyclosporine for VKC have
employed a range of concentrations
(0.05% to 2%) as well as a diversity of formulations. A key aspect of
these efforts is the attempt to identify
a therapeutic “sweet spot” that can
suppress inflammation and reduce
symptomatic recurrences. When used
at relatively high (1% to 2%) concentrations, the drug can effectively ameliorate signs and symptoms of severe
VKC; at 2%, cyclosporine was shown
to be as effective as the corticosteroid
dexamethasone (0.1%).11,12 However,
both of these studies showed that
such brief, high-dose therapy had no
significant effect on recurrence following cessation of therapy. Higher
concentrations of cyclosporine are
thought to increase the probability
of epithelial cell damage, so without
long-term benefit the risk of using
such high concentrations of the drug
82 | Review of Ophthalmology | February 2012
may not be warranted.
Several other studies employed
lower dose regimens of cyclosporine.
In one such trial, follow-up at two
years showed a reduction in seasonal
recurrences of VKC with 0.05% cyclosporine.13 In the same study, however, a higher dose, 0.1%, wasn’t as
effective as dexamethasone at treating acute signs and symptoms. However, another study employing similar
concentrations of the drug (0.05%
and 0.1%) in a different formulation
showed that both concentrations
provided statistically significant improvement in both corneal staining and subjective symptoms for
acute VKC following one month of
treatment. (Amrane M, et al. IOVS
2011;52:ARVO e-abstract 6415)
Collectively, these studies show
that given the proper formulation, a
low-dose anti-inflammatory such as
cyclosporine may provide relief for
both acute VKC and the recurrences
of the disease that can lead to such
devastating long-term consequences
for ocular health.14
Is VKC a Model for Allergy?
To paraphrase our earlier assessment: When it comes to ocular allergies, one drug does not treat all. And
as we learn more about the defining
features of the rogues in our gallery,
we discover why some drugs work
well for some conditions and not for
others. So it is with VKC. While many
practitioners in the United States may
never see a patient with this disorder, understanding the pathophysiology of VKC has provided us clues
to properly diagnose and treat all
ocular allergies.
Cromolyn sodium, the archetypical
mast cell stabilizer, was introduced
first for VKC in the 1970s, and was
later used for patients with seasonal
allergic conjunctivitis.15 We now know
that this drug has a slow preventionbased mechanism of action and so
is suited to VKC, but is not an effective therapy for seasonal allergies
(particularly when compared with
topical antihistamines). Despite this,
mast cell stabilizers are still being
prescribed for seasonal allergies by
some clinicians.
This brings us back to the misconception that all ocular allergies are
variations of the same disease. We do
know that all ocular allergies—seasonal, perennial, atopic, iatrogenic
and vernal—share a mixed immunological and inflammatory etiology. But
despite these similarities, it’s the differences between them that provide
the most useful clues in the search for
improved therapies. So while seasonal
allergy and AKC are the two conditions with the most prominent immunological etiology, their treatments
are completely different. Season allergies respond well to antihistamines,
while AKC requires aggressive corticosteroid therapy. When we fully
understand the nuances that make
perennial allergy different from AKC
or VKC, then we’ll be in a position
to deliver the optimal therapy for
each disease.
Dr. Abelson is a clinical professor
of ophthalmology at Harvard Medical
School and Senior Clinical Scientist at
the Schepens Eye Research Institute.
Dr. McLaughlin is a medical writer at
Ora Inc., in Andover.
1. Kumar S. Vernal Keratoconjunctivitis: A Major Review. Acta
Ophthalmol 2009;87:133-147.
2. Bonini S, Coasssin M, Aronni S, Lambiase A. Vernal
Keratoconjunctivitis. Eye 2004;18:345-351.
3. Leonardi A, Fregona IA, Plebani M, Secchi AG, Calder VL. Th1
and Th2-type cytokines in chronic ocular allergy. Graefe’s Arch
Clin Exp Ophthalmol 2006;244:1240-1245.
4. Bremond-Gignac D, Donadieu J, Leonardi A, et al. Prevalence
of vernal keratoconjunctivitis: A rare disease? Br J Ophthalmol
2008;92:1097-102.
5. Abelson MB, Leonardi AA, Smith LM, et al. Histaminase activity
in patients with vernal keratoconjunctivitis. Ophthalmology
1995;102:12: 1958-63.
6. Sacchetti M, Lambiase A, Mantelli F, et al. Tailored approach
to the treatment of vernal keratoconjunctivitis. Ophthalmology
2010;117:7:1294-9.
7. Abelson MB, ed. Allergic diseases of the Eye. Philadelphia: WB
Sauders, 2000:179-196.
8. Abelson MB, Butrus SI, Weston JH. Aspirin therapy in vernal
conjunctivitis. Am J Ophthalmol.1983;95:4:502-5.
9. Kumar S, Gupta N, Vivian AJ. Modern approach to managing
vernal keratoconjunctivitis. Curr Allergy Asthma Rep 2010;
10:3:155-62.
10. Ohashi Y, Ebihara N, Fujishima H,et al. A randomized placebo
controlled clinical trial of tacrolimus ophthalmic suspension
0.1% in severe allergic conjunctivitis. J. Ocul. Pharm. Ther 2010;
26:165-173.
11. De Smedt S, Nkurikiye J, Fonteyne Y, et al. Topical ciclosporin
in the treatment of vernal keratoconjunctivitis in Rwanda, Central
Africa: A prospective, randomised, double-masked, controlled
clinical trial. Br J Ophthalmol 2011 Oct 14. [Epub ahead of print]
12. Tesse R, Spadavecchia L, Fanelli P, et al. Treatment of severe
vernal keratoconjunctivitis with 1% topical cyclosporine in an
Italian cohort of 197 children. Pediatr Allergy Immunol 2010;21(2
Pt 1):330-5.
13. Lambiase A, Leonardi A, Sacchetti M, et al. Topical cyclosporine
prevents seasonal recurrences of vernal keratoconjunctivitis in a
randomized, double-masked, controlled 2-year study. J Allergy
Clin Immunol 2011;128:4:896-897.
14. Restasis Package insert, revised 02/2010. Allergan, Inc. Irvine,
Calif.
15. Easty D, Rice NS, Jones BR. Disodium cromoglycate (Intal)
in the treatment of vernal kerato-conjunctivitis. Trans Ophthalmol
Soc U K. 1971;91:491-9.
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