Comparison of Efficacy of 0.05% Cyclosporine Ophthalmic Emulsion and Artificial Tear in Meibomian Gland Dysfunction Pinnita Prabhasawat, MD., Nattaporn Tesavibul, MD., Wannaree Mahawong, MD. Department of Ophthalmology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Products in the study were supported by Allergan(Thailand), Ltd.

Change of lipid composition Diseases induce MGD via inflammatory pathway. Anti-inflammatory agent might interrupt this vicious cycle. Infection MGD Obstruction Tear film instability Change of lipid composition Seborrhea Rosacea Medicamentosa Aging Androgen DHE Dry eye Infection Inflammation Inflammation Meibomian glands secrete lipid to stabilize tear film. Obstructive meibomian gland dystrophy (MGD) causes tear film instability Anti-inflammatory agent Inflammation Inflammation Purpose To compare the efficacy of topical 0.05% cyclosporine with non-preservative artificial tear in the treatment of meibomian gland dysfunction Methods Prospective, double blind, randomized controlled trial Department of ophthalmology, Siriraj hospital, Mahidol university, Bangkok, Thailand. 2007-2009 Statistic Method : Intragroup: Paired t-test, Wilcoxon sign ranked test, Marginal homogeneity test Intergroup: Independent t-test, Mann-Whitney U test, Chi-square test

Meibomian gland dysfunction Methods Inclusion criteria Exclusion criteria Meibomian gland dysfunction N = 40 pts, 40 eyes (Use right eye only) Symptoms - irritation - photophobia - tearing Signs - meibomian gland obstruction, inflammation - non-invasive tear break up time < 8 sec. Age < 18 years old Severe ocular surface abnormalities Topical CSA < 1 year Oral cyclosporine, anticholinergic within 2 months Immunocompromise patients Eye infection Allergic to eye drop Pregnancy or lactation Contact lens wearer Masking Randomized Study (19 pts) Control (20 pts) 0.05%CSA bid Tear (0.5%CMC) bid Tear as needed Tear as needed Stop med due to burning 1 case Examine every 1 M Schirmer I test Schirmer I test 0 M 1 M 2 M 3 M

< 1/3-total occlusion OSDI score Lid inflammation Meibomian gland secretion and expressibility Conjunctival injection Corneal staining Non-invasive (tear scope) and fluorescein tear break up time Examinations Severity grading score 1 2 3 4 Lid inflammation No Mild Moderate Severe - Conjunctival injection Meibomian gland secretion Clear fluid Cloudy fluid Cloudy particulate Toothpaste-like No secretion Meibomian gland expressibility Excellent >2/3 1/3-2/3 express < 1/3-total occlusion Corneal staining Fluorescein ( 0-15 ) Rose Bengal

Baseline : no significant among both groups Signs & Symptoms CSA ( N=19 ) Control ( N=20 ) Female: Male 16:3 15:5 Lid inflammation - no inflammation - mild inflammation - moderate inflammation 5 10 4 3 14 Meibomian gland secretion - clear fluid - cloudy fluid - cloudy particulate fluid - inspissated, toothpaste-like - no secretion 8 2 1 9 Expressibility of meibomian gland - 2/3 expressibility - 1/3-2/3 expressibility - <1/3-total occlude 12 13 Bulbar conjunctival injection - no injection - mild injection - moderate injection 16 15 Tarsal conjunctival injection - severe injection 6 Corneal fluoresceine stain score 1.74 2.75 Corneal Rose Bengal stain score 0.21 1.0 Non-invasive tear break-up time (TBUT) (sec.) 2.23 2.24 Fluoresceine tear break-up time (sec.) 2.32 2.05 Schirmer’s I test (mm.) 19.26 19.20 OSDI score 42.65 37.25 No significant among both groups

Non-invasive tear break up time (Tear scopeR) Fluorescein tear break up time (2 m)  #  #  #  #  #  # Fluorescein tear break-up time (sec.) Non-invasive tear break up time (sec.) CSA : Significant TBUT from baseline : Significant > Control P < 0.01 P < 0.01  p < 0.01 intragroup # p < 0.05 intergroup

  Ocular Surface Disease Index (OSDI) P < 0.01 Symptoms improve from baseline at 2, 3 M in both groups P < 0.01   + + OSDI score No different among both groups  , + p < 0.01 intragroup

Corneal Rose Bengal stain score Corneal Fluoresceine stain score Corneal staining Corneal Rose Bengal stain score Corneal Fluoresceine stain score Schirmer I test No significant from baseline No significant among groups Schirmer I test (mm) Tear volume by

Conjunctival injection Lid margin inflammation CSA : Significant improvement from baseline P < 0.05  +  + Number of patients Conjunctival injection No different among both groups and from base line Bulbar injection + CSA : Significant improvement from baseline + P < 0.05 +  Tarsal injection  , + p < 0.05 intragroup Baseline Month 1 Month 2 Month 3

Meibomian gland Secretion Expressibility P < 0.05 Baseline Month 1 No different among both groups. No improvement in both groups Secretion # CSA : Significantly improvement from baseline Expressibility P < 0.05 Baseline Month 1 Month 2 Month 3  p < 0.05 intragroup # p < 0.05 intergroup

Discussion Cyclosporine (CSA) : T-cell modulator, decrease inflammatory cytokine eg. Interleukin-6¹ Topical CSA in dry eye can improve²´³ - OSDI - Tear film stability, increase TBUT - Schirmer score - Goblet cell Topical CSA in MGD can improve⁴ - Lid margin inflammation - Tarsal conjunctival injection - Fluorescein staining References Turner K, et al. Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporine ophthalmic emulsion. Cornea 2000;19:492-6. Sall K, et al. Two Multicenter, Randomizied Studies of the Efficacy and Safety of Cyclosporine Ophthalmic Emulsion in Moderate to Severe Dry Eye Disease. Ophthalmology 2000;107:631-9. Kunert KS, et al. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol 2000;118:1489-96. Perry HD, et al. Efficacy of Commercially Available Topical Cycolsporine A 0.05% in the Treatment of Meibomian Gland Dysfunction. Cornea 2006;25:171-5.

Conclusion from this study Topical 0.05%CSA could improve tear film stability in MGD patients with or without aqueous tear deficiency. From baseline CSA : significantly improve Control: significantly improve Tear break up time OSDI score Lid margin inflammation Tarsal conjunctival injection MGD expressibility OSDI score Topical 0.05% CSA twice daily demonstrated superior effects over a non-preservative artificial tear in the treatment of meibomian gland dysfunction with tear film instability by increasing TBUT and improving MG function during the treatment