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Topical Tacrolimus 0.03% as Sole Therapy in

Vernal Keratoconjunctivitis
A Randomized Double-Masked Study
Guilherme Gubert Mller, M.D., Newton Kara Jos, Ph.D., Rosane Silvestre de Castro, Ph.D.
Eye Contact Lens. 2014;40(2):79-83.

Abstract and Introduction

Abstract
Objective: This study sought to evaluate the efficacy of the isolated use of tacrolimus compared
with the combined use of tacrolimus and olopatadine for the treatment of severe vernal
keratoconjunctivitis (VKC).
Methods: Twenty-one patients with severe VKC were randomized into two groups: one treated
with 0.03% tacrolimus ointment combined with 1% olopatadine ophthalmic solution and the
other with 0.03% tacrolimus ointment combined with placebo eye drops. The clinical signs and
symptoms were graded from 0 to 3, and the efficacy of treatment was determined by the
difference between the score at the beginning of treatment and after 30 days. The clinical
impression of improvement as perceived by the evaluator and the self-assessment provided by
the patient were scored at day 30 of treatment and compared between the groups.
Results: The scores for symptoms decreased between the assessments in both groups (1.73.9
in the experimental group; 0.61.6 in the control group), with no significant difference between
groups (P=0.205). The scores for clinical signs decreased between the assessments in the
experimental group (1.12.7) and increased in the control group (0.30.9) but with no
significant differences (P=0.205). There was no significant difference between the groups
regarding the self-assessment (P=0.659) and the clinical impression of the evaluator (P=0.387).
Conclusions: The isolated use of tacrolimus and the combined use of tacrolimus and olopatadine
seems to have the same efficacy, although controlled studies with larger samples are required to
confirm this hypothesis.

Introduction
Vernal keratoconjunctivitis (VKC) is a chronic condition that affects children and young adults.
This condition appears before 10 years of age and lasts for 2 to 10 years, with spontaneous
recovery during puberty. The diagnosis is essentially clinical, with intense itching and
photophobia, papillary reaction of the upper tarsal or limbal conjunctiva, formation of giant
papillae, epithelial keratitis, and shield ulcer.[13]
Vernal keratoconjunctivitis differs from seasonal allergic conjunctivitis and perennial allergic
conjunctivitis because it is a condition mediated by Th2 lymphocytes. However, the precise roles
of mast cells, eosinophils, fibroblasts, and their cytokines in the inflammatory process and the
remodeling of conjunctival tissue remain poorly established.[46]
The topical use of antihistamines, mast cell stabilizers (MCSs), and, more recently, drugs with
both effects, termed dual-action drugs (DADs), represent the first-line treatment for VKC. In the
more severe forms, corticosteroids are used for a short period to induce the remission of the
allergic crisis.[79] However, there are cases where it is not possible to withdraw the corticosteroid
without any clinical worsening, thus leaving patients susceptible to risks caused by the prolonged
use of these drugs, such as cataract, glaucoma, and corneal complications.[10,11] For the past two
decades, immunomodulators have been used as substitutes for corticosteroids in allergic crisis
control and the maintenance of asymptomatic VKC patients because of the need for alternative
therapies with potent anti-inflammatory action and fewer side effects.[12]
Tacrolimus, a macrolide derived from the bacterium Streptomyces tsukubaensis, is a potent
immunomodulator capable of decreasing the production of inflammatory mediators by T
lymphocytes through the inhibition of calcineurin, an intracytoplasmic protein essential for
interleukin (IL)-2 and IL-4 transcription.[13,14] Tacrolimus was first used as an immunosuppressant
in liver transplants but was subsequently introduced for other solid-organ transplants.[15,16] In
addition, this drug has been successfully used in the treatment of atopic dermatitis, vitiligo, and
other skin disorders for more than 10 years.[17]
There are numerous reports of the successful use of tacrolimus for the treatment of autoimmune
diseases of the ocular surface, such as dry eye, scleritis, Mooren ulcer, cicatricial conjunctivitis,
atopic, and VKC.[1822] Recent clinical trials have also shown that, like corticosteroids, tacrolimus
and other immunosuppressive drugs have similar efficacy in allergic crisis control and
maintenance therapy for VKC but with a low incidence of side effects.[2325] In addition to
inhibiting the activation of CD4 lymphocytes, tacrolimus has also been reported to inhibit the
release of histamine and its action. This drug has also been shown to inhibit prostaglandin
synthesis in mast cells and basophils,[26,27] similar to the effect of DAD; therefore, the need for the
concomitant use of these two drugs should be evaluated.
A prospective randomized double-masked trial was developed to evaluate the efficacy of the
isolated use of tacrolimus when compared with the combined use of tacrolimus and olopatadine
for the treatment of severe VKC.

Materials and Methods

The present study was conducted in a single center after selecting VKC patients refractory to
conventional therapy in which topical tacrolimus was introduced to replace corticosteroids.
Refractory, in this context, meant that the clinical condition was maintained or worsened during
the use of topical corticosteroids or that there was a relapse after withdrawal.
Individuals concomitantly using topical corticosteroids, those who underwent subconjunctival
corticosteroid injection in the previous 4 months, or who refused to sign the informed consent
form were excluded from the study. Patients with a history of ocular herpes were excluded
because of reports of reactivation of the infection by the tacrolimus.[23] The use of tacrolimus
before recruitment ranged between 1 and 6 months.
Individuals with symptoms of recurrent or persistent conjunctivitis, pruritus, mucus
hypersecretion, photophobia and watering combined with the presence of a papillary reaction in
the upper tarsal conjunctiva with at least one giant papilla, characterizing the tarsal form of VKC,
or the presence of limbal papillae with at least one Horner Tantras dots, characterizing the limbal
form of VKC, in both eyes were considered VKC patients. All patients enrolled to the study
presented the tarsal form of VKC.
For the sample size calculation, a symptom reduction rate of 30% for tacrolimus treatment was
assumed based on previous studies.[23] Therefore, a sample of 46 patients (23 per group) was
required to have an 80% probability of detecting a difference as small as 50% in the
experimental group. Twenty-five subjects were selected between August and November 2012.
Because additional participants were not included in the subsequent months, it was decided to
continue the study with the sample already established.
In both groups, 0.03% tacrolimus ointment (Protopic; Astellas Pharma Tech Co, Toyama, Japan)
was applied directly to the conjunctival fornix every 12 hours. This dermatological formulation
was chosen because of reports in the literature of good tolerance with a low toxic effect on the
ocular surface.[2832]
In the experimental group, in addition to tacrolimus ointment, lubricant eye drops (Systane;
Alcon, Fort Worth, TX) were prescribed for use every 12 hours as placebo. In the control group,
0.1% olopatadine ophthalmic solution (Patanol; Alcon) was prescribed. Both eye drops had
similar flasks, with no identification, and were given to the patients together with the ointment.
In addition to the medication given, only the use of lubricant eye drops was allowed in both
groups. If other topical medications were being used, the patients were asked to provide this
information to the team, and, if necessary, these subjects were removed from the study.
For double masking of the study, the eye drop flasks were numbered and contained no
identification of the drug. The content of the flasks was only revealed after the end of the data
collection period.
The randomization was performed using a block system. Envelopes were prepared, with each
one containing four flasks of eye drops (two experimental and two control). To open a new
envelope, all flasks from the previously opened envelope had to be empty.

After the initial approach and after the individuals were assigned to the groups, a protocol for the
objective assessment of signs and symptoms, which was adapted from clinical trials with similar
methods and objectives,[23,3335] was applied. Symptoms of itching, tearing, foreign body
sensation, discharge, and photophobia were assessed, in addition to clinical signs of conjunctival
hyperemia, tarsal papillary reaction, epithelial keratitis, limbal neovascularization, and
conjunctival fibrosis. Each symptom and sign was graded on a scale from 0 to 3 ( and ). The
symptoms and signs were assessed before the introduction of therapy and after 30 days, when the
follow-up was ended. The variables were analyzed individually and grouped by summing the
scores for comparison between the assessments and groups.
Table 1. Scores of VKC Symptoms
Itching

0: no desire to scratch
1+: occasional desire to scratch
2+: frequent desire to scratch
3+: continuous desire to scratch

Tearing

0: normal production of tears

1+: occasional tearing
2+: Intermittent tearing
3+: constant tearing

Foreign body
sensation

0: absent
1+: discrete, occasional foreign body sensation
2+: mild, frequent foreign body sensation
3+ severe, continuous foreign body sensation

Photophobia

0: no photophobia
1+: mild, squints in bright light
2+: moderate, needs sunglasses
3+: severe, cannot withstand bright light even when wearing sunglasses

Discharge

0: no discharge
1+: little, in the fornix
2+: moderate, in the fornix, with crusting on eyelashes
3+: abundant, wakes up with eyes stuck shut or washes them several
times a day

Table 2. Scores for Clinical Signs

Conjunctival hyperemia

0: absent
1+: dilation of some blood vessels
2+: dilation of several blood vessels
3+: generalized dilation of blood vessels

Tarsal papillary reaction

0: no papillae
1+: papillary reaction without giant papillae
2+: some giant papillae
3+: giant papillae all over the tarsal conjunctiva

Punctate keratopathy

0: intact epithelium
1+: punctate in 1/3 of the cornea
2+: punctate in 2/3 of the cornea
3+: diffuse punctate

Limbal neovascularization

0: no neovessels
1+: neovessels in 1 quadrant
2+: neovessels in 2 quadrants
3+: neovessels in 3 or 4 quadrants

Conjunctival fibrosis

0: no scars
1+: subepithelial fibrosis
2+: fornix shortening
3+: symblepharon

Clinical impression of the progress of each case and the self-assessment provided by the patient
were assessed using an objective 0 to 5 scale (0=cure, 1=significant improvement, 2=mild
improvement, 3=unchanged condition, 4=mild worsening, 5=significant worsening). For the
significance analysis and the comparison between the groups, scores 2 (clinical improvement)
and 3 (worsening or maintenance of the condition) were grouped. Because of the bilateral
nature of VKC, the whole evaluation was based on the examination of both eyes, always
considering the eye with findings of greater intensity.
To assess the safety and side effects of the treatment, intraocular pressure, lens opacification,
secondary infections, or other possible complications were assessed. The incidence of cataract
was evaluated during biomicroscopical evaluation by LOCS II cataract grading system.
Infections and others complications were also assessed during biomicroscopy.

The Student's t test for independent samples and the nonparametric MannWhitney test were
used to compare the variation of the results between the two groups. To compare the results for
the two assessment times, within each group, the Student t test for paired samples and the
nonparametric Wilcoxon test were used. When comparing the 2 groups regarding the qualitative
variables, Fisher exact test and the chi-square test were used. P-values less than 0.05 were
considered significant.
The present study was conducted in accordance with the Declaration of Helsinki and was
initiated after approval by the Research Ethics Committee of the School of Medical Sciences of
the University of Campinas (Faculdade de Cincias Mdicas da Universidade de Campinas
Unicamp) was granted.

Results
From the 25 subjects recruited, two refused to participate after reading the informed consent
form. The others were assigned to the study groups, including 12 to the experimental group and
11 to the control group. One patient was excluded from each group during the study because of
the introduction of a topical corticosteroid. The remaining 21 subjects completed the treatment
and had their data analyzed (Fig. 1). From these 21 patients, 7 were female and 14 male, aged
between 5 and 23 years. Regarding gender and age, there was no significant difference between
the groups (). Regarding the initial score, there was also no significant difference between the
groups (P=0.673).
Table 3. Homogeneity of the Treatment Groups
Characteristic

Experimental

Control

Total

Gender

0.537

Male

14

Female

10.8 (5.2)

10 (2.8)

10.4 (4.1)

Age (SD)

0.667

Figure 1.

Participant flowchart.

There was no significant difference when comparing the variation in the score for symptoms
between the groups at the end of 30 days (P=0.205). There was an improvement in both groups,
with a mean decrease of 1.7 points in the sum and a standard deviation of 3.9 between
assessments in the experimental group and 0.6 points with a standard deviation of 1.6 in the
control group. In the individual assessment of each symptom, there were no significant variations
between the assessments or the groups (Fig. 2).

Figure 2.

Distribution of the scores for ocular symptoms.

There was no significant difference when comparing the variation in the score for clinical signs
between groups at the end of 30 days (P=0.205). Improvement was observed in the experimental
group, with a mean decrease of 1.1 points in the sum and a standard deviation of 2.7 between the
assessments, whereas in the control group, there was a worsening of the signs, with an average
increase of 0.3 points and standard deviation of 0.9, although both were not significant. In the
individual assessment of each clinical sign, there was a significant worsening only in
conjunctival hyperemia in the control group when compared with the experimental group
(P=0.035) (Fig. 3).

Figure 3.

Distribution of the scores for ocular clinical signs.

There was no significant difference in the score for the clinical impression between the groups
(P=0.387). The condition was worse or unchanged in 7 patients (70%) and improved in 3
patients (30%) from the control group. In the experimental group, the impression was improved
in 6 patients (54.6%) and worse or unchanged in 5 patients (45.5%).
In the self-assessment, there was no significant difference between the groups (P=0.659). Three
patients (30%) from the control group reported worsening or maintenance of the condition, and 7
patients (70%) reported improvement. In the experimental group, 5 patients (45.5%) reported a
worse or unchanged clinical condition, whereas 6 patients (54.6%) reported improvement in their
condition ().
Table 4. Relationship Between the Self-assessment and Clinical Impression
Clinical Impression
Significa
Unchang
Mild
Mild
Significant
nt
ed
Cur Tota
Worseni
Improveme Improveme
Worseni
Conditio
e
l
ng
nt
nt
ng
n
SelfSignificant
assessme
worsening
nt

Mild
worsening

Unchanged
condition

Mild
improveme
nt

Significant
improveme
nt

Cure

Total

10

21

The main complaint was associated with burning during the application of tacrolimus, which was
reported by 81% of the patients. During the study period, there was no significant change
regarding intraocular pressure, lens opacification, secondary infections, or other factors.

Discussion
Vernal keratoconjunctivitis is known to be one of the most severe forms of ocular allergy, with
the potential to cause corneal damage and permanent visual loss. Sacchetti et al.[36] observed that
VKC patients with corneal involvement or more than one recurrence per year have an increased
risk of permanent visual loss. In another study, Bonini et al.[10] observed that there was a good
ocular prognosis with permanent visual loss in only 6% of the patients treated with
antihistamines, MCS, and short periods of corticosteroids; however, in 52% of the patients, the
symptoms became worse or persisted after treatment.
Sacchetti et al.[36] also suggested grading VKC based on larger clinical signs (presence of ocular
symptoms, punctate keratitis, shield ulcer, and photophobia) for selecting the therapy. However,
these authors did not determine which approach should be used in patients who do not show
improvement even when using strong topical corticosteroids for a short period. Moreover,
tacrolimus has been shown to be effective when DAD combined with corticosteroids for a short
period is not enough to control the disease.
Several studies have considered topical tacrolimus an effective and safe alternative for allergic
crisis control and the maintenance of VKC symptoms.[24,28,32,37,38] In a randomized clinical trial,
Ohashi et al.[23] obtained significant clinical improvement in the group that used tacrolimus in
comparison with the placebo group. Labcharoenwongs et al.[25] compared 0.1% tacrolimus with
2% cyclosporine and reported clinical improvement in both groups, with no significant
difference between the two drugs. When comparing tacrolimus to corticosteroids, Shoji et al.[39]
found similar efficacy in suppressing subconjunctival eosinophilic and lymphocytic infiltration
in an animal model.
In the same assay, Ohashi et al.[23] delivered a dosage-ranging study with tacrolimus ophthalmic
suspension 0.01%, 0.03%, and 0.1%. The 0.1% concentration showed stronger improvement
with safety similar to the others. However, Moscovici et al.[18] showed that absorption of
tacrolimus 0.03% eye drops were well below that at which adverse effects were reported when
administered systemically. As in our experience, the 0.03% ointment showed great clinical
improvement with minimum discomfort.
The lack of a commercial tacrolimus ocular presentation (drops or ointment) is still a limiting
factor. The development of such formulations will be of great value in the treatment of allergy
and others inflammatory ocular surface diseases.
The use of antihistamines, MCS, and DAD was not controlled in any of the aforementioned
studies. Apparently, because tacrolimus is able to control the signs and symptoms of VKC, the
need for the concomitant use of these drugs can be questioned. However, the small variation
observed in the score for signs and symptoms in both groups from the present study supports the
hypothesis that the isolated use of tacrolimus is sufficient. Moreover, the unchanged condition

between the assessments in most cases, both in the clinical impression and in the self-assessment,
points to the same conclusion. Additionally, because these are drugs with preservative additives
(e.g., benzalkonium chloride) that need to be used for a prolonged period, there may be
secondary damages to the ocular surface.
In addition to burning sensation, there was no other adverse effect observed. Also, no great
complications have been described in literature about ocular use of tacrolimus (ointment or
drops). Only one case of herpes keratitis and other with throat irritation were described in one
study.[23]
One individual was excluded from each group because of the need for the introduction of
corticosteroids. This result indicates that, even with good efficacy, tacrolimus alone or combined
with olopatadine was not sufficient to control the disease in these cases. Moreover, the
significant worsening of the conjunctival hyperemia in the control group compared with the
experimental group may be because of the use of olopatadine, although the sample size is a
limiting factor for this conclusion.
In the present study, the isolated use of tacrolimus and the combined use of tacrolimus and
olopatadine showed similar efficacy. Controlled studies with larger samples are needed to
confirm this hypothesis; we suggest the individualized use of DAD on a case-by-case basis.
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The authors have no funding or conflicts of interest to disclose.

Eye Contact Lens. 2014;40(2):79-83. 2014 Lippincott Williams & Wilkins