Effect of Topical Cyclosporine 0.05% in Allergic Conjunctivitis

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1 Effect of Topical Cyclosporine 0.05% in Allergic Conjunctivitis Delhi J Ophthalmol 2015; 25 (3): DOI: * Sonali Bhalla, SK Sachan **, AM Jain ** * Bhalla Medical Centre, Birhana Road, Kanpur, ** Professor, Departt. of Ophthalmology, GSVM Medical College, Kanpur, India *Address for correspondence Sonali Bhalla MS 15/59, L, Civil Lines, Kanpur, UP, Pin sonalibhalla@yahoo.com Purpose: The aim of this study was to evaluate the efficacy and adverse effects of Topical Cyclosporine 0.05% in allergic conjunctivitis with special reference to vernal catarrh. Methods: Non randomized controlled trial of 140 eyes was done for 12 months from Feb2007 to Jan 2008 at Department of Ophthalmology, GSVM Medical College, Kanpur. All patients coming to the outpatient department with complaints of itching, watering, redness or foreign body sensation of eyes were evaluated for inclusion in study. Patients were categorized into 2 groups: Group A: patients of Simple chronic conjunctivitis either not responding to steroids or having a recent relapse after cessation of steroids; Group B: patients of Vernal Keratoconjunctivitis. Patients were treated with topical Cyclosporine 0.05% thrice a day. Symptoms and signs were scored on the day of enrolment and then on 5th, 12th, 20th and 30th day of treatment. Conjunctival scrapings were obtained before the treatment to detect the presence of eosinophils to confirm the diagnosis of ocular allergic disease. The statistical analyses were conducted using the formula Standard error of difference between two means. Results: A total of 140 patients were included in the study, of which 20 cases were excluded as they were lost to follow up after first week. Eosinophils were detected in pre-treatment conjunctival scrapings in 30 patients in Group A and 41 patients in Group B, which supported the diagnosis of allergic eye disease. All patients were in active phase of disease and showed no improvement in clinical symptoms and signs with Cyclosporine treatment during one month period. 20 patients were lost to follow up and remaining required to be shifted to either steroids alone or combination of mast cell stabilizer-antihistaminic along with steroid. Conclusion: Topical Cyclosporine 0.05% is ineffective in alleviating the signs and symptoms of allergic conjunctivitis and vernal keratoconjunctivitis. Keywords : allergic conjunctivitis vernal keratoconjunctivitis cyclosporine Allergic conjunctivitis is the most common allergic eye disease and it occurs when the eye is exposed to antigens in the environment. 1 It may be divided into 5 major subcategories: Seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC), atopic keratoconjunctivitis (AKC), giant papillary conjunctivitis (GPC). Allergic conjunctivitis and vernal keratoconjunctivitis in particular is a problem for clinicians and patients in hot climates. 2 There are 3 reasons for this. First, a large number of children are affected. Second, the management of the disease is time consuming and frustrating. Typically a child seen with VKC is treated with mast cell stabilizer and is seen again a few months later apparently no better. Over 50% patients may still have symptoms after 5 years. Third, patients may be blinded by the disease. Corneal ulcers, extensive corneal pannus can lead to loss of vision. These patients need adequate treatment with good patient education, counselling and regular long term follow up. The management of allergic conjunctivitis involves prevention and treatment with pharmaceutical agents. 3,4 Prevention includes steps like avoiding the allergen, applying cold compresses, using refrigerated ocular medications, frequent washing hands and face, avoiding rubbing of eyes and reduce exposure to dust. The pharmaceutical agents used in the management of allergic conjunctivitis fall into 3 categories: Primary agents ocular lubricants, secondary agents topical antihistamines, topical decongestants, mast cell stabilizers, topical non-steroidal anti-inflammatory drugs and tertiary agents- steroids, oral antihistamines and immunomodulating drugs (Cyclosporine A). 5 The topical steroids are effective in 171

2 Bhalla S et al ISSN managing acute flare-ups and hyperacute cases of ocular allergy as well as late response seen in chronic allergies. The presence of other medical problems may affect the use of steroids. They may cause cataract, glaucoma or make them worse. Steroids may make existing infections worse or may cause new infections. Topical Cyclosporine 2% has been proven to be effective in the long term treatment of VKC, significantly improving signs and symptoms As cyclosporine is poorly soluble in water but soluble in oil, this emulsion is prepared in pharmacy in 2% oil base either peanut or corn oil. This preparation has poor absorption due to poor partition - coefficient due to oil base. This preparation also has side effects like lid skin maceration, blurring, burning and stinging hence topical Cyclosporine 2% was useful only to a limited population. Recently Cyclosporine has been mixed in a lipid vehicle in a concentration of 0.05% and is commercially available. This formulation contains Cyclosporine 0.05%, Castor oil, Polysorbate80, Carbomer, Glycerine and Purified water (RESTASIS - Allergan, Inc, USA). This oil in water emulsion helps in better penetration and efficacy at lower concentration with lesser adverse events. This study was done to evaluate the efficacy and adverse effects in patients with allergic conjunctivitis with special reference to Vernal Keratoconjunctivitis. Materials and Methods Non randomized controlled trial of 140 eyes of allergic conjunctivitis was done for 12 months from Feb 2007 to Jan 2008 at Department of Ophthalmology, GSVM Medical College, Kanpur. All patients coming to the outpatient department with complaints of itching, watering, redness or foreign body sensation of eyes were evaluated for inclusion in study. The patients and the parents of minor patients were informed and written consent was taken regarding inclusion in the study. Their complete history, duration of illness, chief complaints and treatment taken were recorded. Criteria for exclusion from study Patient having any active infection, history of any other ocular pathology or medical condition that could result in patient s inability to complete the study, pregnant and lactating females. Patients were categorized into 2 groups: Group A: patients of Simple chronic conjunctivitis either not responding to steroids or having a recent relapse after cessation of steroids; Group B: patients of Vernal Keratoconjunctivitis Group A: Symptoms and signs of the disease were graded according to prefixed scale 12 and scores were assigned. Patients were asked to grade symptoms of itching/ watery discharge/ foreign body sensation/ photophobia and signs Palpebral conjunctival hyperemia / bulbar conjunctival hyperemia / chemosis / Papillae were graded by slit lamp examination. The grades were scored as: 0 (absent), 1 (mild), 2 (moderate), 3 (severe) Group B: Symptoms included ropy discharge other than the symptoms of Group A. Similarly, signs included giant papillae, limbal infiltration and Horner Trantas spots for grading other than the signs of Group A. Patients were asked to discontinue all previous ophthalmic medications. The daily treatment was only topical 0.05% Cyclosporine eye drops 3 times a day until the end. No other concomitant treatment was used. At enrolment, patients were asked about any other systemic allergy. Blood samples were collected to determine peripheral blood eosinophil counts. Conjunctival scrapings were obtained before the treatment to detect the presence of eosinophils to confirm the diagnosis of ocular allergic disease. The slides were labelled with the patient s name and placed in a completely covered container filled with 70% alcohol. The scrapings were taken with a kimura spatula from the site of maximal disease. The collected material was quickly and evenly smeared on the glass slide and immediately the slide was reimmersed in the fixative and send for cytology. Statistical Analyses The statistical analyses were conducted using the formula Standard error of difference between two means. Results Patient demographics: A total of 140 patients were included in the study, of which 20 cases were excluded as they were lost to follow up after first week. Age distribution in both the groups is shown in (Table 1 & 2). Distribution of symptoms and signs (pre-treatment) in both the groups is shown in (Table 3 & 4). Of 50 patients in group B, 30 had mixed tarsal- limbal VKC, 12 had tarsal form, and 8 had limbal form. In Group A, 10 patients had asthma and 4 had atopic dermatitis. In Group B, 5 patients had asthma and 1 had food allergy. patients in Group A and 12 in Group B had raised peripheral serum eosinophil counts. Eosinophils were detected in pre-treatment conjunctival scrapings in 30 patients in Group A and 41 patients in Group B, which supported the diagnosis of allergic eye disease Table 5 & 6 show the severity grades for symptoms and signs before treatment and at 5th, 12th, 20th and 30th day after starting Cyclosporine treatment. The outcome comparison of scores in symptoms and signs after starting Cyclosporine treatment is shown in Table 7 & 8. The comparison charts show that the actual difference between two means is less than twice the standard error of difference between two means; hence there was no significant improvement in symptoms and signs of patients while using Cyclosporine treatment. The adverse effects noticed by patients while using cyclosporine Table1: Age distribution in Group A Age n = years 8 (11.5%) years 13 (18.5%) years 28 (40.0%) years 11 (15.7%) years 8 (11.5%) years 2 (2.8%) Table 2: Age distribution in Group B Age n = years 5 (10%) 5-10 years 20 (40%) 10-15years 15 (30%) years 10 (20%) 172 Del J Ophthalmol 2015;25(3)

3 Effect of Topical Cyclosporine 0.05% in Allergic conjunctivitis Table 3: Distribution of Symptoms (Pre-treatment) Symptoms Group A(n=70) Group B(n=50) Itching 70(100%) 50(100%) Watering 63(90%) 43(87%) Photophobia 38(55%) 15(30%) Foreign body sensation 10(13%) 20(40%) Ropy discharge - 39(81%) Table 4: Distribution of Signs (Pre-treatment) Signs Group A(n=70) Group B(n=50) Bulbar conjunctival hyperemia 70(100%) 50(100%) Palpebral conjunctival hyperemia 63(90%) 38(75%) Chemosis 14(20%) 08(15%) Papillae 70(100%) 43(87.5%) Giant papillae - 40(81%) Limbal infiltrate - 43(87%) Trantas spots - 26(52%) are shown in (Table 9). The most common adverse effect informed by patients was a burning sensation in both the study groups while other complaints were few and far in between. Discussion In this study, efficacy of Topical Cyclosporine on clinical signs and symptoms of Allergic conjunctivitis and vernal keratoconjunctivitis was evaluated and adverse effects on eye related to Cyclosporine use were also evaluated. All patients were in active phase of disease and showed no improvement in clinical symptoms and signs with Cyclosporine treatment during one month period. 20 patients were lost to follow up and remaining required to be shifted to either steroids alone or combination of mast cell stabilizer-antihistaminic along with steroid. Previous studies have shown efficacy of Cyclosporine 1% or 2% ophthalmic emulsion in castor oil or olive oil for the treatment of Vernalkeratoconjunctivitis. However these preparations were associated with local complications like maceration, blurring, burning and stinging These complications restricted the use of this preparation in the hands of cornea specialists. Recently, Cyclosporine has been mixed in a lipid vehicle in a concentration of 0.05%. This formulation contains Cyclosporine 0.05%, Castor oil, Polysorbate 80, Carbomer, Glycerin and Purified water (RESTASIS, Allergan, Inc). It is oil- in- water ophthalmic emulsion. Here Cyclosporine is dissolved in Castor oil. Oil phase is then emulsified with the help of Polysorbate80 and Carbomer. On instillation into the eye, the Carbomer matrix is dissolved by electrolytes which release Cyclosporine into tears. High partition -coefficient drives Cyclosporine into surface ocular tissues. This drug delivery system ensures effective delivery to ocular tissues even at lower concentrations. In this study, non-randomized controlled trial of 140 eyes was done. Patients were categorized into 2 groups: Group A: patients of Simple chronic conjunctivitis either not responding to steroids or having a recent relapse after cessation of steroids; Group B: patients of Vernal Keratoconjunctivitis. In Group A, maximum number of patients was in the age group years (Table 1) while in group B maximum number of patients belonged to 5-10 years (Table 2).Other studies have also shown that most of the children with vernal keratoconjunctivitis will outgrow their disease upon attaining puberty. 1 Itching was the most common symptom in both the groups (Table 3). Watering was also present in most of the patients in both groups. Ropy discharge being the characteristic feature of vernal Table 5: Mean severity grades for symptoms before treatment and at 5 th, 12 th, 20 th and 30 th day after starting Cyclosporine treatment Before treatment 5th day 12th day 20th day 30th day Group A / Group B Group A / Group B Group A / Group B Group A / Group B Group A / Group B Total symptom score 14.7/ / / / /15.8 Itching 6.2/ / / / /8.7 Watering 4.5/ / / / /4.2 Foreign body sensation 2.5/ / / / /1.7 Photophobia 1.5/ / / / /1.1 Ropy discharge -/1.0 - /1.1 - /1.2 -/ / 1.1 Table 6: Mean severity grades for signs before treatment and at 5th, 12th, 20th and 30th day after starting Cyclosporine treatment Before Treatment 5 th day 12 th day 20 th day 30 th day Group A/Group B Group A/Group B Group A/Group B Group A/Group B Group A/Group B Total sign score 18.1/ / / / /21.8 Bulbar conjunctival hyperemia 6.7/ / / / / 7.0 Palpebral conjunctival hyperemia 4.1/ / / / /5.3 Papillae 5.3/ / / / /3.0 Giant papillae - / / /1.9 - /2.1 - /2.0 Limbal thickening - / / /2.2 - /2.0 - /1.8 Trantas spots - /1.5 - /1.2 - /1.3 - /1.1 - /

4 Bhalla S et al ISSN Table 7: Outcome comparison of scores in symptoms after starting Cyclosporine treatment Day 1 v/s Day 5 Day 5 v/s Day 12 Day 12 v/s Day 20 Day 20 v/s day 30 Group A Actual diff b/w two means SE of diff b/w two means# Group B Actual diff b/w two means SE of diff b/w two means# Table 8: Outcome comparison of scores in signs after starting Cyclosporine treatment Group A Group A Actualdifference between Two means SE of difference b/w two means# Group B Group B Actual difference b/w two means SE of difference b/w two means# Day 1 v/s Day 5 Day 5 v/s Day 12 Day 12 v/s Day 20 Day 20 v/s day # SE of diff b/w two means Standard error of difference between two means Table 9: Cumulative adverse effects occurring with Cyclosporine treatment Adverse effects Group A Group B Burning 35(50%) 20(40%) Conjunctival Hyperemia 15(21.4%) 05(10%) Discharge 00(0%) 00(0%) Foreign body sensation 05(7.1%) 02(4%) Eye pain 03(4.2%) 05(10%) Pruritus 02(2.8%) 05(10%) Visual disturbance 01(1.4%) 00(0%) keratoconjunctivitis was present in of group B (Table 3). Among signs, palpebral and bulbar conjunctival hyperemia was the most common in both groups. Papillae were also very evident in both study groups while giant papillae, limbal infiltrate and Horner-Trantas spots were evident in group B only (Table 4). The mean symptom score in Group A was 14.7 and 17.0 in Group B before treatment. These scores changed to 13.6 and 15.8 respectively after one month of treatment with Cyclosporine (Table 5). Similarly, the mean sign score in Group A was 18.1 and 23.5 in Group B before treatment. These scores changed to 16.2 and 21.8 respectively after one month of treatment with Cyclosporine (Table 6). The comparison charts (Table 7, 8) show that when the outcome of scores of symptoms and signs in both groups before starting treatment was compared with the scores during 5th, 12th, 20th, and 30th day of treatment with Cyclosporine, the actual difference between two means is less than twice the standard error of difference between two means; hence there was no significant improvement in symptoms and signs of patients while using Cyclosporine treatment. Although the drug is quiet tolerable and the most common adverse effect noted during the treatment was burning (Table 9) and the other complaints were few and far in between; still the preparation was unable to improve symptoms and signs score of the patients of allergic conjunctivitis and vernal keratoconjunctivitis. All patients were in active phase of disease and showed no improvement in clinical symptoms and signs with Cyclosporine treatment during one month period. 20 patients were lost to follow up and remaining required to be shifted to either steroids alone or combination of mast cell stabilizer-antihistaminic along with steroid. Previous studies have shown efficacy of Cyclosporine 1% or 2% ophthalmic emulsion in castor oil or olive oil for the treatment of vernal keratoconjunctivitis. However these preparations were associated with local complications like maceration, blurring, burning and stinging 6 11 These complications restricted the use of this preparation in the hands of cornea specialists. Although this preparation of Cyclosporine A (0.05%) is free of such complications but its efficacy as a solo drug for the management of allergic conjunctivitis and vernal keratoconjunctivitis is questionable. This inference is similar to a Australian study using 0.05% of commercially available Cyclosporine eye drops in allergic conjunctivitis by Daniell et al stating that the therapy was ineffective and provided no more benefit than placebo. 14 However, there are limitations in this study because all patients were in the active phase of the disease, denying Cyclosporine treatment and using placebo to a control group was considered unethical. Therefore, further controlled studies with more patients and longer follow-up period are needed to support our findings. Financial & competing interest disclosure The authors do not have any competing interests in any product/ procedure mentioned in this study. The authors do not have any financial interests in any product / procedure mentioned in this study. 174 Del J Ophthalmol 2015;25(3)

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