Topical Cyclosporine in the Treatment

of Allergic Conjunctivitis
A Meta-analysis
Kelvin Ho-Nam Wan, MBChB,1,2 Li Jia Chen, PhD,1,2 Shi Song Rong, MMed,2 Chi Pui Pang, DPhil,1,2
Alvin L. Young, MMedSc(Hons), FRCSI,1,2
Purpose: To assess the efcacy and safety of topical cyclosporine versus placebo in the treatment of allergic
conjunctivitis.
Design: Systematic review and meta-analysis.
Participants: Seven qualied studies incorporating 306 eyes of 153 patients were analyzed.
Methods: Searches of randomized controlled trials were conducted in MEDLINE, EMBASE, the Cochrane
Central Register of Controlled Trials, ClinicalTrials.gov, and the World Health Organization International Clinical
Trials Registry Platform.
Main Outcome Measures: We assessed the methodologic quality of individual included trials and
performed meta-analyses using the random effects model if P<0.1 in the test for heterogeneity, or otherwise used
the xed effects model. We assessed scores of composite signs and symptoms, reduction in steroid eye drop use
in steroid-dependent patients, and safety outcomes (i.e., stinging or burning sensation).
Results: At 2 weeks of follow-up or longer, evidence suggests a statistically signicant improvement in
the composite signs (standardized mean difference [SMD],
1.21; 95% condence interval [CI],
1.80 to
0.62;
I2 71%) and symptoms (SMD,
0.84; 95% CI,
1.51 to
0.16; I2 80%) after topical cyclosporine treatment
for allergic conjunctivitis regardless of the dosage of treatment. There was a signicant reduction (mean difference,
61.16; 95% CI,
101.61 to
20.72; I2 58%) in the use of steroid eye drops in patients with steroiddependent allergic conjunctivitis. Stinging or burning sensation (odds ratio, 2.56; 95% CI, 0.19e35.06;
I2 73%) was common in both the cyclosporine and placebo groups.
Conclusions: This systematic review and meta-analysis suggests topical cyclosporine could be an effective
and safe treatment method for allergic conjunctivitis. Further randomized controlled trials with larger sample sizes
and standardized outcome measurements, follow-up periods, and cyclosporine concentrations are warranted to
determine the short- and long-term efcacy and safety and the minimal effective dosage of topical cyclosporine
for allergic conjunctivitis.
Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed
in this article. Ophthalmology 2013;120:2197-2203 2013 by the American Academy of Ophthalmology.

Allergic conjunctivitis is a condition that encompasses

a spectrum of severity and chronicity ranging from seasonal
or perennial allergic conjunctivitis, atopic keratoconjunctivitis (AKC), vernal conjunctivitis (VKC) to giant papillary
conjunctivitis.1 It is estimated to affect 20% to 30% of the
world population.2,3 The key diagnostic signs and symptoms of allergic conjunctivitis are conjunctival hyperemia
and ocular itching.4
The severity of symptoms such as itching, tearing,
discomfort, photophobia, discharge, and signs such as
conjunctival papillae or follicles and corneal involvement can
help to differentiate the various forms of ocular allergies.5
However, a common allergen sensitization may be the basis
of this spectrum of disorders, despite the differences in
clinical presentations, immunopathogenic mechanisms, and
therapeutic responses.6 Different pharmacologic eye drops
 2013 by the American Academy of Ophthalmology
Published by Elsevier Inc.

have been used in the management of allergic conjunctivitis,

including antihistamines, mast cell stabilizers, nonsteroidal
anti-inammatory drugs, corticosteroids, and immunomodulators such as cyclosporine.7,8
Topical corticosteroid is highly effective in relieving
ocular allergic signs and symptoms and is the main treatment for the more severe forms of allergic conjunctivitis.
However, its prolonged use can result in elevated intraocular
pressure with subsequent glaucoma, cataract, and increased
susceptibility to microbial infection, leading to associated
visual morbidity.9 Therefore, alternative medications with
a comparable treatment effect without the above steroidassociated risks are being sought.
Cyclosporine is a nonsteroid immunomodulatory agent that
acts primarily by inhibiting antigen-dependent T-cell activation, which is an important component in inammatory ocular
ISSN 0161-6420/13/$ - see front matter
http://dx.doi.org/10.1016/j.ophtha.2013.03.044

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Ophthalmology Volume 120, Number 11, November 2013

Potentially relevant articles
identified: 556
MEDLINE: 205
EMBASE: 300
CENTRAL: 14
Clinical Trials: 33
WHO ICTRP: 4
Duplicates: 119
Titles and Abstracts
screened: 437
Not eligible: 416
Articles obtained for full
text review: 21
Study excluded: 14
Non-RCTs: 7
Unqualified interventions: 3
Unqualified outcome measures: 4
Eligible RCTs: 7
Figure 1. Flow chart showing selection of publications for inclusion in this meta-analysis. CENTRAL Cochrane Central Register of Controlled Trials;
RCT randomized control trial; WHO ICTRP World Health Organization International Clinical Trials Registry Platform.

surface diseases.10,11 Randomized controlled trials (RCTs)

reported to date have shown varying results in the efcacy and
safety of cyclosporine in treating allergic conjunctivitis.12,13
Moreover, the sample sizes of individual trials were small.
In view of the conicting evidence, we conducted a systematic
review and meta-analysis of RCTs on topical cyclosporine
versus placebo in treating allergic conjunctivitis to evaluate the
treatment efcacy and safety of topical cyclosporine.

Methods
Search Strategy
We searched MEDLINE and EMBASE via the OVID platform, the
Cochrane Central Register of Controlled Trials, ClinicalTrials.gov
(www.clinicaltrials.gov), and the World Health Organization
International Clinical Trials Registry Platform for RCTs that
evaluated topical cyclosporine versus placebo for allergic
conjunctivitis. We used the Cochrane highly sensitive search
strategy14 and combined our search terms as described in Appendix
1 (available at http://aaojournal.org). We manually searched the
references of all potentially relevant articles to identify studies
not found by the electronic searches. We did not apply any
language restrictions. The nal search was performed on August
10, 2012, for all databases.

Inclusion and Exclusion Criteria

Two reviewers (K.H.W. and S.S.R.) independently assessed the
titles and abstracts to identify those that fullled the inclusion

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criteria: RCTs; included patients from all age groups with allergic
conjunctivitis, which includes the spectrum of seasonal or perennial allergic conjunctivitis, VKC, AKC and giant papillary
conjunctivitis; compared cyclosporine versus placebo; and examined at least one of the following outcomes: composite signs score,
composite symptoms score, usage of steroid eye drops, and
occurrence of adverse events, including stinging or burning
sensation. We included only those trials that dened and tabulated
their own composite scores. Typically, the composite signs score
was determined by averaging the scores of at least one of the
following signs: hyperemia, swelling, papillae and giant papillae
on the tarsal conjunctiva, hyperemia and edema of the bulbar
conjunctiva, or corneal involvement. Similarly, the composite
symptoms score was calculated in the same manner by averaging
the scores of at least one of the individual symptoms: redness,
tearing, burning, discomfort, foreign body sensation, discharge,
and photophobia. We excluded studies that did not quantify the
signs and symptoms, studies that did not use a placebo or vehicle
eye drops as a control, or studies that presented data on patient subgroups only.

Data Extraction
Two reviewers (K.H.W. and L.J.C.) independently performed the
data extraction that met the inclusion criteria. We used a customized
form to record the author of study, year of publication, location of
trials, sample size, mean age, gender, duration of follow-up, interventions, and outcome measures. The extracted outcomes were
based on the data from the double-masked (participants and
outcome assessors), placebo-controlled phase of the respective
studies. Outcomes at a follow-up time point, rather than the change

Wan et al

Cyclosporine for Allergic Conjunctivitis

Table 1. Characteristics of included trials

Study (Year)

Country

Pts/Eyes
(n)

13

Daniell (2006)
Kilic (2006)18
Akpek (2004)21

Australia
Turkey
US/UK

35/70
20/40*
20/40

Pucci (2002)19
Gupta (2001)22
Hingorani (1998)12
Secchi(1990)20

Italy
India
UK
Italy

24/48*
24/48
21/42
9/18*

Mean Age (Yr) SD

Male/Female

FU
(wk)

Conc.
of CsA

Regimen;
duration

26.2  18
26.2  16.3 15/2
13/5
7.9  2.2
12/8
42.3  10.6 42.9  17.8 6/4
6/4

12
2
4

0.05%
2%
0.05%

8.4  1.6
16/8
10.8  3.5 10.6  4.6 10/2
12/0
33.9  13.5 35.7  13.8 8/4
4/5
11.2  7.2
N/A

2
16
12
15 days

2%
2%
2%
2%

4 times/day; 3 mo
5 times/day; 2 wk
6 times/day; 2 wk and
4 times/day; 2wk
4 times/day; 2 wk
4 times/day; 4 mo
4 times/day; 3 mo
4 times/day; 15 days

CsA

Placebo

CsA

Placebo

Completion of FU
CsA

Placebo

17/20

18/20
N/A

10/10

10/12
N/A

12/12
12/12

12/12
9/9
9/9

Conc. concentration; CsA cyclosporine; FU follow-up; mo months, N/A data not available; Pts patient; SD standard deviation;
US United States; UKUnited Kingdom; wk weeks; Yr years
*53 patients were randomly assigned to receive topical cyclosporine in one eye, whereas the fellow eye was treated with placebo.17-19 Of the remaining
patients, 51 were randomly assigned to receive topical cyclosporine in both eyes, and 49 patients were randomly assigned to receive placebo in both eyes.20-23
For the latter group, the outcomes were evaluated on a patient-basis.

from baseline, were extracted and analyzed.15,16 In studies that used

a scale where the scores of signs and symptoms decreased with
severity, we reversed the values of our extracted data to ensure the
scales in our meta-analysis point in a unied direction (i.e., a higher
numerical value means more severe signs and symptoms). We obtained standard deviations and standard errors from P values
following methods outlined in the Cochrane Handbook for
Systematic Reviews of Interventions.16 We interpolated outcome
measures from gures if the numerical values were not reported in
the texts. The results presented are based on participants who
completed the follow-up in individual studies.

Assessment of Risk of Bias

We assessed the risk of bias of included studies using the Cochrane
risk of bias tool.17 We evaluated random sequence generation and
allocation concealment (selection bias), masking of participants
and personnel (performance bias), masking of outcome
assessment (detection bias), incomplete outcome data (attrition
bias), and selection reporting (reporting bias). We graded each
domain as: low, unclear, and high risk of bias according to the
criteria outlined in the Cochrane Handbook for Systematic
Review of Interventions.17 Two reviewers (K.H.W. and S.S.R.)
independently assessed the risk of bias and resolved
discrepancies by discussion.

Statistical Analysis
We used Review Manager software version 5.2 (The Nordic
Cochrane Centre, The Cochrane Collaboration, Copenhagen,
Denmark) for meta-analyses. We analyzed the scores of composite
signs and symptoms and the reduction in steroid eye drop use as
continuous variables, whereas the side effects were used as
dichotomous variables. Notably, all the included studies reported
a composite score of signs and symptoms, but each study tabulated
its own composite score differently using a combination of signs
and symptoms. For this reason, we used the standardized mean
difference as the summary measure to analyze results on a uniform
scale. Standardized mean difference expresses the size of the
intervention effect in each study with respect to the variability
within that study and is reported in units of standard deviation.
Because the absolute value is difcult to interpret on its own, it
should be interpreted together with the P value and condence
interval (CI).15 We used standardized mean difference for scores of
composite signs and symptoms, mean differences for reduction of

steroid eye drops use, and the Mantel-Haenszel odds ratio for
occurrence of adverse events, namely stinging or burning
sensation.
Statistical heterogeneity of the included studies was analyzed
using the Cochrane Q-statistics chi-square test and I2 statistic. If
signicant heterogeneity was observed between studies, a random
effects model was used for pooling the data; otherwise, a xed
effects model was used. We conducted a sensitivity analysis to
examine the inuence of each individual study on the overall metaanalysis estimate.17

Results
We identied 556 titles and abstracts through our literature search
and retrieved 21 articles for a full text review. We included 7 RCTs
in this systematic review and meta-analysis (Fig 1).12,13,18e22

Study Characteristics
Table 1 shows the characteristics of the included trials. We
included 7 studies, with a total of 153 participants and 306 eyes.
Two studies were conducted in Italy, and 1 study each was
conducted in the United States, the United Kingdom, Australia,
Turkey, and India. A total of 53 patients from 3 studies were
assigned randomly to receive topical cyclosporine in 1 eye,
whereas the fellow eye was treated with placebo (paired-eye
design).18e20 In the remaining 4 studies, 51 patients in total were
assigned randomly to receive topical cyclosporine in both eyes,
whereas 49 patients in total received placebo in both eyes, and the
outcomes were evaluated on a patient basis.12,13,21,22 Sample sizes
ranged from 9 to 35. More than 70% of the participants were male.
The follow-up periods of ranged from 2 to 16 weeks. The
concentration of topical cyclosporine was 2% or 0.05%.

Risk of Bias in Included Studies

Figures 2 and 3 (available at http://aaojournal.org) summarize
the risk of bias assessment of included studies. For selection
bias, 4 studies used a computer-generated randomization scheme.12,13,21,22 Two studies provided sufcient details on the
method of allocation concealment by having the allocation coding
kept by a person who was independent of the trial.12,22 For
performance and detection biases, all except one study19 were
double-masked (participants and outcome assessors) and placebocontrolled trials. Masking was achieved by using identical unit

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Figure 4. Graph showing the effect of topical cyclosporine (CsA) versus placebo on the combined outcome score of composite signs. CI condence
interval; IV inverse variance; SD standard deviation; Std. standardized.

bottles to hold the study treatment. We judged attrition bias to be of

low risk in 4 studies where reasons for and the numbers of
participants who exited the study were reported clearly and were
unlikely to affect the outcome.12,13,20,22 We could not comment on
the risk of selective reporting because we did not have access to the
study protocols, but all outcomes described in respective methodologies were reported. None of the studies were judged to be at
high risk of bias in any domain.

Discussion

Outcome Measures

Scores of Composite Signs and Symptoms

The meta-analytical results for the 4 outcomes are summarized in

Figures 4e7. All of the 7 studies reported scores for composite signs
and symptoms. Statistically signicant heterogeneity was detected
in the outcomes except for the reduction in steroid eye drop use.
Topical cyclosporine was associated with lower composite scores
of signs and symptoms of allergic conjunctivitis as compared with
placebo. The pooled standardized mean difference was
1.21 (95%
CI,
1.80 to
0.62; I2 71%; Fig 4) and
0.84 (95% CI,
1.51
to
0.16; I2 80%; Fig 5), respectively. Of the 3 studies that
recruited patients with steroid-dependent allergic conjunctivitis, 2
reported reduction in steroid eye drop use. The pooled mean
difference was
61.2 (95% CI,
101.6 to
20.7; I2 58%; Fig 6)
steroid eye drops per week in participants who had supplemented.
Six studies reported adverse effects. Three studies did not
observe any stinging or burning sensation on instillation of the
cyclosporine or placebo eye drops. Topical cyclosporine did not
show a higher observable rate of burning or stinging sensation
(odds ratio, 2.56; 95% CI, 0.19e35.06; I2 73%; Fig 7). Our
sensitivity analysis by omitting one study a time did not change
the results (data not shown).

The outcomes that quantied the treatment efcacy are

subjective. The signs were graded by the clinicians on
ophthalmologic examination and the symptoms were selfreported. Although these measurements are subjective and
an information bias is likely, clinical decisions usually are
based on such ndings in history taking and physical examination. Thus, we regard this methodology to evaluate the
outcome as acceptable and conclude that patients treated with
topical cyclosporine, regardless of the dose and treatment
regimen, demonstrated greater improvement in the manifestations of allergic conjunctivitis as compared with placebo.

The present systematic review and meta-analysis found that

topical cyclosporine is effective in alleviating the signs and
symptoms of allergic conjunctivitis and reducing the use of
topical steroid eye drops in steroid-dependent patients, while
maintaining similar safety prole as compared with placebo.

Reduction in Steroid Eye Drop Use

The trial of Hingorani et al12 reported that topical
cyclosporine allowed patients with steroid-dependent AKC
to wean off topical corticosteroid, whereas the trial of
Daniell et al13 revealed no statistically signicant difference
between the steroid and placebo groups in patients with

Figure 5. Graph showing the effect of topical cyclosporine (CsA) versus placebo on the combined outcome in score of composite symptoms. CI
condence interval; IV inverse variance; SD standard deviation; Std. standardized.

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Wan et al

Cyclosporine for Allergic Conjunctivitis

Figure 6. Graph showing the effect of topical cyclosporine (CsA) versus placebo on the combined outcome of reduction in steroid eye drops use. CI
condence interval; IV inverse variance; SD standard deviation.

AKC or VKC. In these trials, the amount of steroid use was

modulated during the course of study, but the extent of
modulation varied and depended on the clinicians
subjective assessment of the patients clinical response,
which inevitably introduces information bias. The different
forms of steroid were adjusted by a factor to allow
comparison of their relative potencies.23 Although our
summary statistics showed a signicant reduction in steroid
eye drop use, interpretation should be made with caution
because the number of included studies and participants for
this outcome is small. Furthermore, the 2 trials used
different concentrations of cyclosporine 2% and 0.05%,
which could explain in part why reduction in steroid eye
drop use was observed in the study of Hingorani et al12 that
used a higher concentration. Moreover, the study of
Hingorani et al12 included AKC patients exclusively,
whereas that of Daniell et al13 included both AKC and VKC
patients, which suggests that topical cyclosporine may have
a role in reducing steroid eye drop use in AKC patients only.

Safety
The present study found that the safety prole of topical
cyclosporine is comparable with that of placebo when
stinging and burning sensation are used as indicators of
safety outcomes. Stinging and burning are the most common
adverse effects associated with topical cyclosporine in phase
3 studies of cyclosporine in dry eye patients.24,25 These
adverse effects may be attributed to the vehicle (e.g., olive,
maize, or castor oil) used to dissolve cyclosporine. A large-

scale multicenter RCT that examined topical cyclosporine in

dry eye patients showed that despite the occurrences of
adverse effects, only 2.4% of the patients in the cyclosporine
group discontinued the study because of intolerability
compared with 1.7% of the patients in the placebo group
over 6 months.25 Another phase 3 study of the safety
evaluation of ophthalmic cyclosporine in dry eye patients
reported that the participants continued their assigned
medication with no serious treatment-related adverse
effects over a mean follow-up of 19.8 months.24 The
comments on the safety of topical cyclosporine drawn
from our systematic review and meta-analysis are consistent with those from these large-scale clinical trials, suggesting that cyclosporine could be a safe and well-tolerated
treatment for allergic conjunctivitis.

Limitations and Perspectives

Quality of the Evidence. Our search was limited to studies
published in indexed journals and trial registers. The
included trials also vary in terms of population, the types of
allergic conjunctivitis, dosage and regime of cyclosporine,
measurement of clinical outcomes, follow-up period, and
qualities.
Patients across the included studies had different forms of
allergic conjunctivitis (AKC, VKC, or both), which could be
one source of clinical heterogeneity. However, both AKC and
VKC are subsets of allergic conjunctivitis with similar pathophysiologic features.26 Thus, we believe that the heterogeneity
that resulted from their pooling had a minimal impact on the

Figure 7. Graph showing the effect of topical cyclosporine (CsA) versus placebo on the combined outcome of stinging or burning sensation. There were 3
studiesdAkpek et al,21 Daniell et al,13 and Kilic and Gurler18dreporting that no side effects were detected; however, results of these studies were not
included in the pooled analysis. CI condence interval; df degrees of freedom; M-H Mantel-Haenszel.

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Ophthalmology Volume 120, Number 11, November 2013

outcomes. Another possible source includes the different
concentration of topical cyclosporine used. A study suggested
that 1% cyclosporine may be the minimal effective treatment
regimen to control the manifestations of VKC,27 whereas for
AKC, the lowest concentration commercially available,
0.05% cyclosporine (Restasis; Allergan, Inc, Irvine, CA), was
shown to be effective.21 Therefore, any concentration higher
than 0.05% should be included for analysis.
The study design could be a source of methodologic
heterogeneity. Three studies included patients who
continued their usual topical steroid therapy during the
trial.12,13,21 Two studies had a washout period free of
drugs,18,22 whereas the remaining 2 studies stopped all drugs
before the start of the trial.19,20 The addictive benet of
topical cyclosporine to the patients usual treatment may lead
to an overestimation of its efcacy. Adequate randomization
within the original trials can balance the effect of such
heterogeneities. Moreover, the use of a standardized mean
difference as an outcome measure also addressed intra-study
variability. Another source of heterogeneity might have
resulted from the varied criteria for dening the scales of
allergic signs and symptoms across the included studies.
Finally, the periods of the double-masked controlled phases
varied across the studies (2e16 weeks), making the longterm efcacy and safety yet to be determined.
Implications for Practice. Our meta-analysis supports
the use of topical cyclosporine for treating allergic
conjunctivitis. It is more effective than placebo in alleviating
the overall signs and symptoms. The stinging and burning
sensation of topical cyclosporine is similar to that of
placebo. Topical cyclosporine also has been shown to have
a role in weaning off steroid eye drops in steroid-dependent
patients. Nevertheless, the clinical and methodologic
heterogeneities across the studies suggest that the overall
efcacy of topical cyclosporine should be appreciated with
caution. Further RCTs with larger sample sizes providing
sufcient statistical power to detect even a small difference
in the treatment effects, standardized study designs
including the use of precisely dened grading for the
severity of individual signs and symptoms, unied followup schedules, and different concentrations of cyclosporine
are warranted to determine the short- and long-term efcacy
and safety and the minimal effective dosage of topical
cyclosporine in treating allergic conjunctivitis.

References
1. Calonge M. Classication of ocular atopic/allergic disorders
and conditions: an unsolved problem. Acta Ophthalmol Scand
Suppl 1999;(228):103.
2. von Mutius E, Martinez FD, Fritzsch C, et al. Prevalence of
asthma and atopy in two areas of West and East Germany. Am
J Respir Crit Care Med 1994;149:35864.
3. Abelson MB, Smith L, Chapin M. Ocular allergic disease:
mechanisms, disease sub-types, treatment. Ocul Surf 2003;1:
12749.
4. Ono SJ, Abelson MB. Allergic conjunctivitis: update on
pathophysiology and prospects for future treatment. J Allergy
Clin Immunol 2005;115:11822.

2202

5. Belfort R, Marbeck P, Hsu CC, Freitas D. Epidemiological

study of 134 subjects with allergic conjunctivitis. Acta Ophthalmol Scand Suppl 2000;(230):3840.
6. Leonardi A, De Dominicis C, Motterle L. Immunopathogenesis of ocular allergy: a schematic approach to different
clinical entities. Curr Opin Allergy Clin Immunol 2007;7:
42935.
7. Leonardi A. Emerging drugs for ocular allergy. Expert Opin
Emerg Drugs 2005;10:50520.
8. Bielory L. Ocular allergy treatment. Immunol Allergy Clin
North Am 2008;28:189224, vii.
9. Bonini S, Bonini S, Lambiase A, et al. Vernal keratoconjunctivitis revisited: a case series of 195 patients with longterm followup. Ophthalmology 2000;107:115763.
10. Power WJ, Mullaney P, Farrell M, Collum LM. Effect of
topical cyclosporin A on conjunctival T cells in patients with
secondary Sjgrens syndrome. Cornea 1993;12:50711.
11. el-Asrar AM, Tabbara KF, Geboes K, et al. An immunohistochemical study of topical cyclosporine in vernal keratoconjunctivitis. Am J Ophthalmol 1996;121:15661.
12. Hingorani M, Moodaley L, Calder VL, et al. A randomized,
placebo-controlled trial of topical cyclosporin A in steroiddependent atopic keratoconjunctivitis. Ophthalmology 1998;
105:171520.
13. Daniell M, Constantinou M, Vu HT, Taylor HR. Randomised controlled trial of topical ciclosporin A in steroid
dependent allergic conjunctivitis. Br J Ophthalmol 2006;90:
4614.
14. Lefebvre C, Manheimer E, Glanville J, Cochrane Information
Retrieval Methods Group. 6.4.11: search lters. In: Higgins JP,
Altman DG, eds. Cochrane Handbook for Systematic Reviews
of Interventions Version 5.1.0 [updated March 2011]. The
Cochrane Collaboration; 2011. Available at: http://handbook.
cochrane.org/. Accessed March 4, 2013.
15. Deeks JJ, Higgins JP, Altman DG, Cochrane Statistical Methods
Group. Analysing data and undertaking meta-analyses. In:
Higgins JP, Altman DG, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March
2011]. The Cochrane Collaboration; 2011. Available at: http://
handbook.cochrane.org/. Accessed March 4, 2013.
16. Higgins JP, Deeks JJ. 7.7.3: data extraction for continuous
outcomes. In: Higgins JP, Altman DG, eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.
0 [updated March 2011]. The Cochrane Collaboration; 2011.
Available at: http://handbook.cochrane.org/. Accessed March
4, 2013.
17. Higgins JP, Altman DG, Sterne JA, Cochrane Statistical
Methods Group, Cochrane Bias Methods Group. Assessing
risk of bias in included studies. In: Higgins JP, Altman DG,
eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane
Collaboration; 2011. Available at: http://handbook.cochrane.
org/. Accessed March 4, 2013.
18. Kilic A, Gurler B. Topical 2% cyclosporine A in preservativefree articial tears for the treatment of vernal keratoconjunctivitis. Can J Ophthalmol 2006;41:6938.
19. Pucci N, Novembre E, Cianferoni A, et al. Efcacy and safety
of cyclosporine eyedrops in vernal keratoconjunctivitis. Ann
Allergy Asthma Immunol 2002;89:298303.
20. Secchi AG, Tognon MS, Leonardi A. Topical use of cyclosporine in the treatment of vernal keratoconjunctivitis. Am J
Ophthalmol 1990;110:6415.
21. Akpek EK, Dart JK, Watson S, et al. A randomized trial of
topical cyclosporin 0.05% in topical steroid-resistant atopic
keratoconjunctivitis. Ophthalmology 2004;111:47682.

Wan et al

Cyclosporine for Allergic Conjunctivitis

22. Gupta V, Sahu PK. Topical cyclosporin A in the management of vernal keratoconjunctivitis. Eye (Lond) 2001;15:
3941.
23. Jaanus SD. Anti-inammatory drugs. In: Bartlett JD,
Jaanus SD, eds. Clinical Ocular Pharmacology. 2nd ed.
Boston: Butterworths; 1989:16397.
24. Barber LD, Pugfelder SC, Tauber J, Foulks GN. Phase III
safety evaluation of cyclosporine 0.1% ophthalmic emulsion
administered twice daily to dry eye disease patients for up to 3
years. Ophthalmology 2005;112:17904.

25. Sall K, Stevenson OD, Mundorf TK, Reis BL; CsA Phase 3
Study Group. Two multicenter, randomized studies of the efcacy and safety of cyclosporine ophthalmic emulsion in moderate
to severe dry eye disease. Ophthalmology 2000;107:6319.
26. Wong NN. Vernal vs. atopic keratoconjunctivitis. Clin Eye Vis
Care 1999;11:136.
27. Spadavecchia L, Fanelli P, Tesse R, et al. Efcacy of 1.25%
and 1% topical cyclosporine in the treatment of severe vernal
keratoconjunctivitis in childhood. Pediatr Allergy Immunol
2006;17:52732.

Footnotes and Financial Disclosures

Originally received: June 23, 2012.
Final revision: March 25, 2013.
Accepted: March 27, 2013.
Available online: June 4, 2013.
Manuscript no. 2012-918.
1
Department of Ophthalmology and Visual Sciences, Prince of Wales
Hospital, Shatin, New Territories, Hong Kong, China.
2
Department of Ophthalmology and Visual Sciences, The Chinese
University of Hong Kong, Hong Kong, China.

Financial Disclosure(s):
The author(s) have no proprietary or commercial interest in any materials
discussed in this article.
Correspondence:
Dr. Alvin L. Young, MMedSc(Hons), FRCSI, Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Prince
of Wales Hospital, Shatin, New Territories, Hong Kong, China. E-mail:
youngla@ha.org.hk.

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