Curr Allergy Asthma Rep (2013) 13:308–314

DOI 10.1007/s11882-013-0345-0

ALLERGIC AND IMMUNOLOGIC DISORDERS OF THE EYE AND NERVOUS SYSTEM (CH KATELARIS, SECTION EDITOR)

Use of Cyclosporine A and Tacrolimus in Treatment

of Vernal Keratoconjunctivitis
Pakit Vichyanond & Panida Kosrirukvongs

Published online: 28 April 2013

# Springer Science+Business Media New York 2013

Abstract Vernal keratoconjunctivitis is a sight-threatening
inflammatory disease of conjunctiva and cornea. It is fre-
quently observed in young children with the onset usually
occurring in the first decade of life. Mild cases of VKC tend
to remit with nonspecific and supportive therapy. In con-
trast, severe cases are usually more protracted with
remission/relapse occurring for a prolonged period of time.
Although VKC is classified as an allergic eye condition, the
role of allergens as an inciting factor is not clear.
Pathogenesis of VKC involves roles for IgE, cytokines,
chemokines, and inflammatory cells (T and B lymphocytes,
mast cells, basophils, neutrophils, and eosinophils) with the
release of their granular proteins, proliferation of fibroblasts,
and laying down exuberant amounts of collagen fibers in the
conjunctival tissue. In severe VKC cases—often of tarsal
VKC—diagnostic giant papilla are classically observed on
the upper tarsal plate, giving the classic ‘cobble-stone’ ap-
pearance. Corneal ulcer can occur from the effect of eosin-
ophilic granular proteins on corneal epithelium and by
physical trauma by intense eye rubbing. Topical corticoste-
roids, often required for controlling symptoms and signs in
severe VKC, can lead to serious ocular complications.
Immunomodulators that have been investigated for VKC
treatment include topical ocular preparations of cyclospor-
ine A and tacrolimus. Severe VKC responds promptly to
topical cyclosporine A and tacrolimus, mostly within
P. Vichyanond
Division of Allergy and Immunology, Faculty Of Medicine Siriraj
Hospital, Mahidol University, Bangkok, Thailand
P. Kosrirukvongs
Department Of Ophthalmology, Faculty Of Medicine Siriraj
Hospital, Mahidol University, Bangkok, Thailand
P. Vichyanond (*)
Department Of Pediatrics, Faculty of Medicine Siriraj Hospital,
Mahidol University, 2 Prannok Street, Bangkok 10110, Thailand
e-mail: pakit.vic@mahidol.acth
1 month of therapy. Prolonged use of cyclosporine A and
tacrolimus in VKC is safe and is tolerated by most patients
without significant side effects. Recent investigations on the
use of these two agents in VKC are the main purpose of this
review. The use of cyclosporine A and tacrolimus are a
major breakthrough in treatment for severe VKC, a debili-
tating allergic eye disease in children.
Keywords Vernal keratoconjunctivitis . VKC .
Cyclosporine A . CsA . Tacrolimus . FK-506
Abbreviations
AD Atopic dermatitis
CsA Cyclosporine A
FK-506 Tacrolimus
VKC Vernal keratoconjunctivitis
Introduction
Vernal keratoconjuctivitis (VKC) is a severe inflammatory
ocular disease involving conjunctiva and cornea. It can be
viewed as the severe end of the spectrum of allergic eye
disease, despite the fact that pathogenesis of VKC may not
be entirely ‘allergy’ related’. It generally occurs in young
children with the age of onset around 4–7 years [1–3]. If not
properly treated, the disease can continue into late childhood
and adolescence. Although many cases of VKC spontane-
ously enter a remission phase, in some the disease continues
into adulthood. VKC is a sight-threatening disease and can
lead to blindness due to various reasons such as corneal
opacity, glaucoma, and cataract.
VKC is diagnosed by its classic presenting symptoms
and signs. The patients are usually males around 10 years
of age [3]. They generally present with intense eye itching
and rubbing, eye irritation, tearing, ropy and thick eye
discharge, and photophobia. Generally, three major types
Curr Allergy Asthma Rep (2013) 13:308–314
of VKC have been described, i.e., limbal, tarsal, and mixed.
In limbal VKC, perhaps the most common type [2, 3], the
classic Horner-Tranta’s dots are observed around the limbus.
In tarsal VKC, classic giant papilla can be seen mainly on
upper tarsal conjunctiva, upon inversion of the upper eye
lids. Pathologically, the conjunctiva is infiltrated by a
variety of inflammatory cells such as mast cells, basophils,
T and B lymphocytes, neutrophils, and classically by eosin-
ophils [4].The giant papilla are large collections of collagen
fibers laid down by conjunctival fibroblasts [5]. On-going
research indicates that ocular inflammation in VKC is the
culmination of the roles of IgE (although not all VKC
patients, particularly those of limbal type, are atopic), Th2
lymphocytes, eosinophilic degranulation, and histamine-
induced chemotaxis of fibroblasts [6–8]. Release of growth
factors such as PDGF, VEGF, nerve growth factors with up-
regulation of adhesion molecules and release of chemokines
for eosinophil chemotaxis (such as eotaxin) have been doc-
umented in conjunctiva of VKC patients [4, 9]. These events
lead to intense inflammation and remodeling of conjunctival
tissue, particularly with a confluent laying down of collagen
types I and III forming giant papilla on conjunctival surface.
Such intense inflammation and repair cycles render VKC a
remodeling ocular allergic eye disease akin to subepithelial
fibrosis of the lungs seen in asthma. Corneal injury can
occur as a result of the release of eosinophil granular pro-
teins along with neutrophil elastase which are destructive to
corneal epithelium [10]. Corneal complications include su-
perficial punctate keratitis, abrasion, shield ulcers,
keratoconus, pseudogerontoxon and ultimately corneal
opacification [11]. Posterior subcapsular cataract and glau-
coma are not uncommonly observed due to prolonged use of
topical steroids to control ocular inflammation and for
symptomatic relief [12]. Ultimately, in severe VKC, without
proper intervention, loss of vision is a grave possibility.
Conventional Therapy for VKC
Conventional therapy for VKC include physical removal of
conjunctival debris and inflammatory components (cells,
mediators, irritants, allergens) from the conjunctival surface
by eye rinsing and compressing with cool, soothing saline
solution or with artificial tears. Various topical ophthalmic
preparations are used as first-line therapy for VKC. These
include ophthalmic preparations of antihistamines (such as
levocabastine and epinastine), mast cell stabilizers (such as
sodium cromoglycate, ketotifen, and lodoxomide) and dual-
acting agents such as olopatadine [2, 13–16]. In mild VKC,
these treatments are usually sufficient and can bring the
disease under control [17]. However, in severe VKC, par-
ticularly in the tarsal and mixed types, inflammation is often
severe and frequently requires topical corticosteroids to
309
induce remission. VKC is generally a relapsing disease with
frequent recurrences and thus severe cases are prone to
develop complications such as corneal complications and
steroid-related complications. Over the last 2 decades, at-
tempts have concentrated on identifying immune modula-
tors to suppress chemical and cellular components of the
inflammation/repair cycle and to be steroid-sparing. In this
review, recent developments on the use of cyclosporine A
and tacrolimus in VKC are reviewed to give readers an
update on the ongoing attempts to alter the course of severe
VKC.
Cyclosporine A (CsA)
Interest in using immunomodulators in treating VKC began
long before current pathogenesis for this condition became
apparent. Since corticosteroids are frequently used in the
treatment of exacerbations, patients as well as physicians
relied on this potent type of medications to suppress eye
irritation and to reduce serious corneal ulcer development.
Serious ophthalmic complications from corticosteroids,
such as posterior subcapsular cataract, increased intraocular
pressure,glaucoma, corneal changes, and superimposed in-
fections (bacterial and fungal), are major problems from
prolonged topical steroid use [12].
CsA is a cyclic undecapeptide metabolite of the fungus
Tolypocladium inflatum. CsA inhibits calcineurin, a calcium-
dependent intracellular signaling protein by binding to its
receptor, cyclophilin. As a result, production of major cyto-
kines and chemokines from effector cells including T helper
cells are inhibited. IL-4 and IL-5 production from Th2 cells
are inhibited by cyclosporine [18, 19]. Topical CsA has been
indicated for treatment of inflammation of the ocular surface
resulting from decreased tear production in dry eyes [20].
Application of 2 % cyclosporine eye preparation as an alter-
native treatment of severe VKC began in the early 1990s [21,
22]. In these pilot reports, response to cyclosporine was rapid,
i.e, within 15 days of therapy. However, relapse was observed
soon after the therapy was discontinued. A randomized
placebo-controlled trial among Italian children with VKC by
Pucci et al., confirmed the efficacy for 2 % cyclosporine eye
drops prepared in olive oil [1]. Patients who received cyclo-
sporine demonstrated improvement of ocular symptoms and
signs within 2 weeks of therapy. At the end of 4 months,
patients derived approximately 70 % improvement in symp-
tom scores. However, giant papilla were less responsive to
CsA [1]. Cyclosporine in oil is irritating and could lead to
blepharitis, thus a more aqueous solution was desirable.
Further investigation from Turkey by Kilic et al., using 2 %
cyclosporine dispersed in artificial tears, indicated that pa-
tients derived similar rates of improvement at 2 weeks [23].
Similarly, Spadavecchia et al., utilizing cyclosporine eye
310
drops in a lower concentration of 1.25 and 1 % prepared in
artificial tears, also showed a similar and even more impres-
sive improvement in symptoms and signs, suggesting that
CsA in liquid form could be more efficacious than oil-based
preparation [24].
Recently, a new aqueous solution of CsA, utilizing
polyoxyl 40 stearate (MYS-40) as a surfactant, has been
released in Japan for the treatment of recalcitrant aller-
gic conjunctival disease, not responding to conventional
treatment. A much lower concentration of CsA (0.1 %)
was formulated into an aqueous base. Due to the aque-
ous nature of the solution, tissue distribution of the
drug, as studied in rabbit eyes, was found to be 28.5
and 3.1 times higher than from CsA in oil-base and
emulsion-in-oil preparations, respectively [25]. Tissue
drug concentrations of CsA in bulbar conjunctival tissue
were 1,373, 464 ,and 876 ng-eg/gm after 1 min of
application of aqueous CsA versus emulsion-in-oil ver-
sus oil-base CsA preparations, respectively [25].
Subsequently, a 6-month post-marketing study of this
preparation in the treatment of a large population with
VKC and AKC among Japanese patients by Ebihara et
al. became available [26]. Notably, the age of AKC
patients in this study was quite young (17 years, similar
to VKC of 16 years). This indicates overlapping pre-
sentations between VKC and AKC. Moreover, several
atopic features (such as asthma, allergic rhinitis, and
atopic dermatitis) can be observed among typical VKC
patients. Patients with VKC responded promptly to the
use of this new aqueous solution (within 1 month) and
had minimal symptoms by the end of the 6-month
observation period. Improvement in corneal lesions
was from 21.6 to 8.6 %. A large number of VKC
patients were able discontinue topical steroids (over
30 %) as well as CsA during the study.
Side effects of CsA eye preparations are limited to burn-
ing and eye stinging, which is usually restricted to a short
period of time after initiation (less than 2 weeks), although
close to 10 % of study participants dropped out due to
adverse events from this lower concentration of CsA (0.
1 % aqueous solution).
Efficacy studies of responses to CsA were mostly of
short duration (less than 6 months). Results from these
studies indicate that, although response to CsA occurred
promptly, the magnitude of response was not large.
Nonetheless, response to prolonged use of CsA could
deliver further benefit, and it was suggested from these
studies that CsA should be used on a longer and con-
tinuing basis in order to exert the most benefit and to
be steroid-sparing. In a recent publication by Lambiase
et al., 0.05 % emulsion-in-oil preparation of CsA was
compared to ketotifen eye drops in preventing recur-
rence of VKC relapse over a 2-year period [27]. CsA
Curr Allergy Asthma Rep (2013) 13:308–314
was almost twice as effective as ketotifen in preventing
recurrences of VKC. However, the use of CsA for the
treatment of relapse was not as effective as dexametha-
sone. The result of this study confirmed earlier short-
term studies that treatment with CsA does not complete-
ly eliminate the need of the use of topical steroids [28].
Again, the major difference between these latter reports
from the Ebihara study [26] was the difference in vehi-
cle use in preparing CsA eye drops.
Tacrolimus
Tacrolimus is a 23-membered macrolide lactone compound
discovered in 1984 from a fermentation of broth soil with a
bacteria, Streptomyces tsukubaensis. It possesses immunosup-
pressant effects via inhibition of T cell activation. Tacrolimus
binds to immunophilin FK-binding protein (FKBP-12), which
in turn inhibits calcineurin, an intracytoplasmic signaling pro-
tein, downstream from calcium-dependent calmodulin activa-
tion. Such inhibition leads to further inhibition of NF-AT
activation and further transcription of IL-2 [29]. Tacrolimus
was approved for use as an immunosuppressant for liver
transplantation in 1994, and was further extended to other
organ transplantation. Tacrolimus was found to inhibit the
release of histamine and production of inflammatory media-
tors, such as LTC4 from human basophils, when stimulated
with Der p I, anti-IgE, and calcium ionophore-A23187 [30].
The ratio of inhibition from tacrolimus when compared to that
of CsA was up to 50-fold.
Recently, tacrolimus has been introduced into a ther-
apeutic regimen for atopic dermatitis (AD). AD is a
relapsing skin disorder in children caused by immuno-
regulatory defects characterized by overproduction of
cytokines of both Th1 and Th2 in various phases of
the disease. Since prolonged use of topical steroids in
AD can lead to systemic absorption, topical tacrolimus
was investigated as an alternative therapy AD for a
steroid-sparing effect. Large numbers of adults and chil-
dren with AD were subjected to a controlled trial with
0.1 % tacrolimus ointment. In an adult trial by Ruzicka
et al., improvement of skin condition was seen as early
as day 3 of therapy, with 83 % of subjects showing
significant improvement after 3 weeks of treatment with
this drug [31]. Despite a large area of application,
systemic absorption of tacrolimus was minimal. A trial
in pediatric AD by Boguniewicz et al. indicated a
similar efficacy and safety profile as in adult AD [32].
Based on these earlier studies, topical tacrolimus be-
comes a part of main therapy for acute as well for
maintenance therapy for AD [33, 34]. With this reason,
we became interested in applying tacrolimus to the
treatment of VKC.
Curr Allergy Asthma Rep (2013) 13:308–314
Since the pathogenesis of VKC, in a manner similar to AD,
includes intensive activation of inflammatory cells, the use of
an immunomodulator such as tacrolimus appears to be an
appropriate alternative for these patients, particularly for those
who do not respond well to CsA. In fact, in a model of human
basophils, tacrolimus was found to be almost 50 times as
effective as CsA in inhibiting histamine release [30]. Using a
rat model with OVA-sensitized, experimental allergic/immune-
mediated blepharoconjunctivits, Nishino et al. were able to
show an inhibition of conjunctival infiltrations with lympho-
cytes and eosinophils by topical tacrolimus applied prior to a
challenge with OVA eye drops [35]. During a similar period,
our group became interested in using tacrolimus for the treat-
ment of VKC, since severe VKC patients did not respond
satisfactorily to topical CsA in oil in our hands [2]. Since
tacrolimus is lipophilic and does not dissolve well in aqueous
solution, we prepared tacrolimus into a 1 % ophthalmic oint-
ment using a standard opthalmic ointment base. In our pilot
trial, single and multiple doses of 1 % topical tacrolimus
ophthalmic ointment was well tolerated among patients with
VKC. No immediate or delayed adverse effects were noted. We
therefore proceeded to a 4-week open trial of topical tacrolimus
among 10 pediatric patients with severe recalcitrant VKC, who
did not respond well to conventional VKC treatment [36].
Seven of nine patients failed CsA 0.5 % in oil treatment. All
patients required topical steroids intermittently for control of
their exacerbations. Frequency of use of tacrolimus was once
daily in 6 patients and twice daily in 4 patients. Most patients
responded to tacrolimus within 1 week of treatment with a
reduction of symptoms of about 30 %. By the end of 4 weeks
treatment, symptoms reduced to 20 % of baseline [36]. In fact,
most patients were without any symptoms by the end of the
4-week trial. No significant adverse effect was noted.
Absorption of tacrolimus at the end of the 4-week study was
minimal (mean plasma level=0.29 ng/ml). After our first re-
port, tacrolimus has been reported to be effective in treating
various inflammatory disorders of the eyes such as anterior
segment diseases [37, 38], severe atopic blepharoconjunctivitis
[39], atopic keratoconjunctivitis [40], and giant papillary con-
junctivitis [41]. Interestingly, Attas-Fox reported an off-label
use of 0.03 % dermatological tacrolimus to treat severe intrac-
table conjunctivitis [42]. Patients were successfully treated
without any adverse effect and without systemic absorption
of the drug. In a report by Khierkan et al., 10 adult patients with
VKC were treated with tacrolimus suspended in balanced salt
solution in a very low concentration (0.005 %) but with more
frequent eye applications (4 times daily). VKC symptoms
rapidly declined within 1 month [43]. A reduction in papillary
size was observed with a prolonged duration of 15 months of
treatment. Interestingly, despite the fact that tacrolimus does not
dissolve well in aqueous salt solution, adequate relief in symp-
toms of patients in this study was seen, perhaps due to (1) high
frequency of use per day and (2) the prolonged period of the
311
trial [43]. Despite the fact that tacrolimus was earlier reported to
have no effect on fibroblasts and did not cause skin thinning in
prolonged use in AD, we have observed a significant reduction
in conjunctival papillary size during our 3-year use of
tacrolimus (Fig. 1; [44]). Such decrease in giant papillary size
was observed in other trials with CsA [23] as well as in
subsequent studies with tacrolimus [45, 46]. Interestingly, such
regression in giant papilla could be observed as early as 1 week
after the initiation of tacrolimus in the latter two trials [45, 46].
With such a promising effect, we proceeded to compare
1 % tacrolimus eye ointment with 2 % CsA eye drops in a
double-masked, controlled trial spanning a longer trial period
(8 weeks). Twenty patients were enrolled in a double-blind,
parallel trial. Again, most of the children in this study had
severe VKC with mostly mixed-type (tarsal + limbal) indicat-
ing a more recalcitrant degree of VKC. The sample size was
calculated based on 70% and 20 % efficacy of tacrolimus and
CsA at 2 weeks of therapy, respectively [1, 36]. To our
surprise, both drugs were found to deliver almost the same
efficacy throughout this 8-week trial as shown in Fig. 2 [47].
The fact that compliance in our second study was very good
and no patients dropped out may explain the similar efficacy
between the two drugs. In the additional 4 weeks after the
blinding period, both groups of patients received tacrolimus as
open trial to determine further response to the drug. Total
ocular symptom score (TOSS) further declined in both groups
[47]. This illustrated that prolonged use of topical CsA as well
as tacrolimus will continue to show further efficacy, as was
suggested in a long-term study with CsA by Lambiase et al.
[27]. However, adverse effects from CsA in our studies were
more apparent than from tacrolimus [47].
Perhaps the most recent interesting study with tacrolimus
was that by Ohashi et al., who employed a newly formulated
Fig. 1 External ocular photography of the left upper tarsal eye lid in
one of our patients (J.S.) treated with tacrolimus at 0, 1, 12. and
24 months. Note the marked improvement of conjunctival inflamma-
tion at 1 month. There was a continuing improvement of conjunctival
hyperemia and a decrease in giant papilla size over the entire 24 months
of therapy [44]
312
Fig. 2 Mean ± SE total subjective symptom scores (TSSS) of VKC
patients randomized to receive CsA and FK-506 (12 patients each) at
various time points. TSSS significantly decreased from baseline at the
4th and 8th weeks in both groups (*p<0.05, **p<0.01). No difference
was observed between groups at any time point (p>0.05). Plots of data
from the two groups, at each time point, are slightly overlapped. (This
figure was first published in the Asian Pacific Journal of Allergy and
Immunology [47])
aqueous suspension of tacrolimus (at a much lower concen-
tration of 0.1 %) in treating 41 AKC and 14 VKC. With this
novel preparation, dispersion of the drug was achieved by the
use of polyvinyl alcohol with benzalkonium chloride as pre-
servative. Dosage of this 0.1 % tacrolimus emulsion drops
was only one drop in each eye twice daily. This aqueous-
emulsion concept perhaps makes topical tacrolimus more
evenly distributed throughout the entire conjunctival tissue
as with CsA aqueous-emulsion [25]. Clinical response to this
aqueous preparation was observed as promptly as 1 week for
both AKC and VKC. Notably, corneal defects as well giant
papilla improved within 1 week and continued throughout the
4-week trial [46]. Apparently, interest in using tacrolimus in
ocular diseases is expanding, and we should look forward to
more encouraging results in the future [48].
Conclusions and Future Directions
Patients with VKC usually have significant disease upon
presentation, particularly among those with palpebral
(tarsal) types. It is not uncommon to see patients with upper
bilateral tarsal conjunctiva filled with large papilla greater
than 5 mm in diameter. Such patients can be found not only
Curr Allergy Asthma Rep (2013) 13:308–314
in ophthalmology clinics but also occasionally in general
pediatric clinics, as well as in allergy practices. Despite the
knowledge that VKC commonly has an onset at 4–7 years
of age, most patients were seen at age over 10 years [2, 3,
49, 50]. This indicates that diagnosis of VKC is usually
made late in the course of the disease. Partly, this is due to
under recognition of Tranta-Horner’s dot, failure to invert
the upper lid as a part of complete ophthalmologic exami-
nation for patients with severe conjunctivitis and lack of
awareness of the diagnosis of VKC in children.
Unfortunately, cytologic examination of conjunctival
scrapings is rarely performed in ophthalmology or allergy
clinics. With these shortcomings, several patients were not
correctly diagnosed for a prolonged period prior to seeing an
enthusiastic ‘allergy–ophthalmology’ specialist with a par-
ticular interest in allergic eye disease. There is a need to
improve early diagnosis of VKC so that early intervention
can be implemented to prevent serious complications from
topical steroids, damage to the cornea, or severe remodeling
of conjunctiva that is not amenable to medical treatment.
The natural history of VKC, particularly in the early
phase, is not fully understood. We do not understand why
some patients suffer from a milder limbal form of disease
while others go on to develop exuberant papilla on upper
tarsal surface. Why are upper tarsal surfaces in VKC more
vulnerable than lower tarsal plates? How soon can a small
follicle develop into large papilla? Or it would ever progress
at all? Does atopy play a major role in the progression of the
disease and, if so, would early intervention with CsA or
tacrolimus change the natural course of the disease? These
crucial questions are essential parts of VKC management
but have not been sufficiently addressed. Partly, this is due
to a lack of prospective studies to aid our understanding of
the natural history of the disease. In fact, risk factors for the
development of VKC have not been fully defined.
Moreover, lack of animal models to study VKC adds to
difficulty in understanding pathogenesis, progress, and
proper intervention.
A collaborative research effort between allergy and oph-
thalmology specialists in redefining better approach to di-
agnosis and early management of VKC is needed.
Unfortunately, such efforts are only available in limited
areas of the world (such as in Italy, Africa, and Japan).
Moreover, research in this specific area (of ophthalmology
or allergy or combined) has not received much attention in
either specialty, as judged by limiting number of publica-
tions in major journals, particularly in allergy. There is an
urgent need for proper training for early detection and
treatment of VKC as well for basic and clinical research
and for drug development for VKC such as with CsA and
tacrolimus. Improved diagnosis and therapy will eventually
lead to better visual acuity and better quality of life for these
unfortunate children.
Curr Allergy Asthma Rep (2013) 13:308–314
Acknowledgments Funding for the authors’ research in topical CsA
and FK-506 treatment for VKC came from the Research Funding of the
Faculty of Medicine Siriraj Hospital, Mahidol University.
Conflict of Interest Pakit Vichyanond declares that he has no con-
flict of interest.
Panida Kosrirukvongs declares that she has no conflict of interest.
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