Retrospective Review on the Use of Topical Cyclosporin A 0.05% for Paediatric Allergic Conjunctivitis in Hong Kong Chinese

Purpose. To evaluate the efficacy of using topical cyclosporin A 0.05% (Restasis) for the treatment of paediatric allergic conjunctivitis. Methods. This retrospective study included consecutive cases of paediatric allergic conjunctivitis treated with Restasis between 2010 and 2013. Subjects with follow-up time less than 3 months after using Restasis were excluded. Itch severity score, symptom score, and sign score were compared before (baseline) and 3 months after using Restasis. Results. In 27 eyes of 14 patients (mean age 10.8 ± 3.2 years), 44.4% had allergic conjunctivitis, 33.3% had vernal keratoconjunctivitis, and 22.2% had atopic keratoconjunctivitis. The mean duration of ocular symptoms was 20.4 ± 13.2 months. 92.6% of subjects were using steroid eye drop before Restasis. After 3 months of topical Restasis, there were statistically significant reductions in the symptom, sign, and itch severity scores compared with baseline (all P ≤ 0.001) and 78.6% of subjects were able to be tapered off steroid eye drops. Conclusion. Topical Restasis was effective and safe in significantly reducing ocular itchiness, sign, and symptom scores at 3 months after use in paediatric allergic ocular conditions.


Introduction
Allergic conjunctivitis is an important disease entity that greatly impacts the quality of life in children as well as the healthcare expenditure [1,2]. Previous studies have shown a worldwide variation in the prevalence of allergic conjunctivitis and it may be related to ethnic, genetic, and environmental difference [3][4][5][6]. There is an increasing prevalence of allergic diseases among Asian children [7].
Hong Kong has a high prevalence of allergic rhinoconjunctivitis. In a large survey conducted in 1997, it was found that 14% of Hong Kong children between 6 and 7 years of age and 24% of 13-14-year olds were affected by allergic rhinoconjunctivitis [6]. Another survey conducted by a local university in 2009 revealed that about 30% of Hong Kong children less than 12 years old were affected by allergic conjunctivitis [8].
Ocular allergies often coexist with allergic rhinitis, asthma, and atopic dermatitis, thus necessitating joint management by ophthalmologists, paediatricians, dermatologists, and immunologists. Ocular allergies can be broadly classified into seasonal (SAC) or perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), and giant papillary conjunctivitis (GPC). This immunemediated disorder involves the conjunctiva and, in severe VKC and AKC, corneal involvement may have sightthreatening consequences.
Current treatment aims include (1) relieving symptoms of redness, chemosis, itchiness, blurring of vision, and tearing; (2) limiting the inflammatory process; and (3) preventing damage to the ocular surface. First line treatment often includes avoidance of allergens, cold compress, lubricants, topical antihistamine, nonsteroidal anti-inflammatory drugs, or mast cell stabilizers. Topical steroids are used in patients with more severe and debilitating symptoms. However, steroid drops are notorious for inducing glaucoma and cataract with prolonged usage especially in the paediatric population and some refractory cases may have very limited relief with topical steroids [8]. Oral antihistamine and steroids are sometimes used in severe cases but they are not without side effects.  Restasis (cyclosporin A 0.05%; Allergan Inc., Irvine, CA, USA) is a newer and safer steroid-sparing alternative. Restasis is approved by the United States Food and Drug Administration for the treatment of keratoconjunctivitis sicca or chronic dry eyes. Data on its use in the paediatric population below the age of 16 is lacking [9].
Recently, there have been evidence to support the offlabel use of Restasis for allergic conjunctivitis in adult as well as in children, but data pertaining to the Asian population is lacking [10][11][12][13][14].
The aim of this study was to evaluate the efficacy of using Restasis for the treatment of paediatric allergic conjunctivitis in a Chinese population.

Patients and Methods
A retrospective review of medical records with the diagnosis of allergic conjunctivitis on Restasis treatment was performed at Caritas Medical Centre in Hong Kong, between 2010 and 2013. Cases were eligible for the study if they had unilateral or bilateral allergic conjunctivitis previously treated with at least 3 months of Restasis. Those with incomplete clinical data, allergies to cyclosporin A, or follow-up duration less than 3 months were excluded. Restasis 2 to 4 times daily was added in addition to the subject's topical medication regimen and topical steroids were titrated up or down based on individual clinical response.
The following data were recorded: age, sex, systemic allergic diseases, ophthalmic diagnoses, symptom duration, previous and current medications including steroid use, follow-up duration, and the 3 disease scores: itch severity score (ISS), symptom score, and sign score. The 3 disease scores were recorded before (baseline) and 3 months after using Restasis.
The ISS was adopted which was previously used for the assessment of skin pruritis in our assessment of ocular itchiness. The ISS is a self-reported score with a 0-10 numeric rating scale for itchy symptoms, with 10 being the most severe [15,16]. The symptom score and sign score measurements were adopted from Ozcan et al. (Table 1) [12].
Normality of the data was confirmed by D' Agostino'ssquared test. The paired -test was used to compare allergic ocular disease scores at baseline and 3 months after Restasis. Pearson correlation was used to evaluate the associations between the duration of symptoms and symptom score (baseline and 3 months after treatment), ISS (baseline and 3 months after treatment), and sign score (baseline and 3 months after treatment).
value ≤ 0.05 was considered statistically significant.
female ratio was 13 : 1. The distribution of the allergic ocular conditions was as follows: allergic conjunctivitis (12/27 eyes, 44.4%); VKC (9/27 eyes, 33.3%); and AKC (6/27 eyes, 22.2%). The mean duration of ocular symptoms was 20.4 ± 13.2 months. Allergic systemic associations were present in 8/14 (57.1%) of subjects including eczema, asthma, and allergic rhinitis. All but one patient (92.6%) were using steroid eye drops before start of Restasis (Table 2). After 3 months of topical Restasis treatment, there were statistically significant reductions in the symptom, sign, and ISS scores compared with baseline (Table 3). Eleven out of our fourteen patients were able to be tapered off steroid drops after instillation of Restasis.

Discussion
Ocular allergic reaction is a type 1 hypersensitivity reaction with a series of IgE mediated inflammatory reactions involving mast cells, neutrophils, eosinophils, macrophages, and basophils, over the course of hours [17,18]. Eosinophils can also attract lymphocytes which are more frequently found in chronic atopic disease and may initiate the formation of scars. Atopy is associated with an inherited mutation in the receptor for IL-4 that is associated with enhanced IgE production by B cells and increased T helper cells. The prevalence of allergic conjunctivitis in children with other systemic allergic manifestations can be as high as 15-40% [19].
Cyclosporin is an immunomodulator and it primarily has 2 actions in decreasing inflammation. One is to block cell proliferation and inhibit histamine release from mast cells through inhibition of calcineurin, a phosphate that plays a role in the high-affinity IgE receptor-(Fc RI-) mediated exocytosis of preformed mediators from mast cells. The second action involves NFAT, a transcriptor regulator for the production of inflammatory cytokines, which is regulated by calcineurin. Therefore, cyclosporin also blocks the release of NFAT-mediated cytokines from T lymphocytes and mast cells, thus reducing eosinophil infiltration and decreasing cellular adhesion to the site of inflammation [12].
Topical cyclosporin has been shown to be effective in the treatment of AKC and VKC but also for allergic conjunctivitis [20], ocular rosacea [21], and refractory seasonal allergic conjunctivitis [22].
Children with VKC have been demonstrated to benefit from Restasis by both a clinical reduction in ocular symptoms and signs and a reduction in inflammatory cell density on impression cytology specimens of the conjunctiva [13]. In our series of Restasis-treated allergic conjunctivitis in a Chinese paediatric population, Restasis significantly reduced both symptoms and signs in allergic, vernal, and atopic The Scientific World Journal 5 conjunctivitis. Meanwhile, 11 out of 14 patients were able to stop using topical steroids, minimizing its potential blinding complications in children. Our findings were consistent with Hingorani et al. 's randomized, placebo-controlled trial of using topical cyclosporin 2% for steroid-dependent AKC. They similarly reported a mean reduction in steroid use together with a reduction in clinical signs and symptoms [10].
The duration of symptoms on presentation showed no statistically significant correlation with disease scores 3 months after treatment, signifying that the drug benefits patients irrespective of their symptom duration and can be useful even in those with prolonged disease. We did not encounter any side effects aside from the transient ocular burning after the application of Restasis which is often the case following most eye drops use. Hingorani et al. used a higher concentration (2%) of cyclosporin and subjects reported intense stinging sensations after use as an indirect result of the diluents used to prepare these eye drops [10].
Akpek et al. and Ozcan et al. later showed that using a lower concentration (0.05%) of cyclosporin resulted in almost no side effects while the efficacy of the drug was still preserved in terms of its steroid-sparing properties in those with AKC [11,12]. At the time of writing, 12 out of 14 patients were still on Restasis due to the continued beneficial effects.
Our study was limited by the relatively small sample size, single centre, short follow-up, and the lack of a control group. Further randomized-control trials with a larger sample size and longer follow-up duration would provide us with more information about the long-term efficacy of using Restasis for allergic ocular conditions. Nevertheless, our study demonstrated the clinical usefulness of topical 0.05% cyclosporin eye drops for paediatric allergic ocular conditions without significant side effects.