Predisposing factors. Gender. Ocular Surface Disease. Ocular Surface Disease Health. Building a Dry Eye Practice

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1 Ocular Surface Disease Health Building a Dry Eye Practice Paul M. Karpecki, OD, FAAO Koffler Vision Group Lexington, KY Discuss the associated pathology of dry eye Discuss modalities of diagnosis, etiology and predisposing factors Latest research of dry eye treatments Ocular Surface Disease Predisposing factors Keratoconjunctivitis Sicca Irregular and Poorly Lubricated Corneal Surface Altered Barrier Function Gender Sjogren s: Dry eye is characterized by a triad of dry eye, dry mouth, and associated auto-immune disorders Prevalence of Dry Eye (continued) Prevalence by Age and Gender WHS Study Prevalence 0.4% 85% women 1

2 Environment Air conditioners or heaters Airline travel Winter months, allergy season Ceiling fan Exogenous irritants Reading time/computer Environment Top 3 intake causes of dry eye? Smoking Caffeine (more than moderate) Diet Also alcohol and systemic medications are top intake causes of dry eye Anterior Segment Disease Blepharitis/Meibomitis Patients are 2 x more likely to have dry eye symptoms Could be related to systemic conditions such as acne rosacea DTS: Clinical Categories No Lid Margin Disease Dysfunctional Tear Syndrome Altered Tear Distribution Lid Margin Disease Most common presentation: No lid margin disease Treatment decision based on severity level Behrens et al, submitted What is the early or acute presentation of meibomitis? Mild/Acute A. Inspissated glands B. Telangiectasia Hot compresses Lid hygiene C. Frothy tear film D. Oil in the tear film 2

3 Multiple-Dose Rabbit: Study Design 1 AzaSite Multiple-Dose Rabbit Study AzaSite administered according to package insert (BID days 1-2, QD days 3-7); total=9 drops Pigmented rabbits (N=156; 4 per timepoint) Tissue samples collected: Cornea, conjunctiva, and eyelids Days 1-6: predose, 0.5 and 1 hr post-dose Day 7: predose, 5, 15 and 30 min; 1, 2, 8, 12, 24, 48, 72, 96, 120 and 144 hr after last dose LC/MS/MS was used to determine the tissue concentrations 1. Data on file. Inspire Pharmaceuticals Inc, Study report I 04U0207 Multiple-Dose Rabbit: Azithromycin Concentrations in Rabbit Eyelid 1 Physicochemical Differences in Normal vs MGD Patients ,3 Lipid order at 34 C (% trans rotamers) Normal MGD Phase transition temperature ( C) 30 Normal MGD The thickened and turbid MG secretions in patients with MGD can be attributed to a more ordered lipid structure. 20 Increased phase transition temperature noted with MGD correlates with the more ordered lipid structure seen in the graph on the left. 1. Data on file. Inspire Pharmaceuticals Inc, Study report I 04U Data on file. Inspire Pharmaceuticals Inc, NDA Study Report Data on file. Inspire Pharmaceuticals Inc, NDA Study Report Foulks GN, Bron AJ. Ocul Surf. 2003;1: ; Foulks GN et al. Modification of meibomian gland lipids by topical azithromycin. Poster presented at: ARVO 2009 Annual Meeting; May 3-7, 2009; Fort Lauderdale, FL. 20 Quickly and Significantly Improves the Quality of MG Secretions 4-week, open-label study in MGD (posterior blepharitis) (n=17) Meibomian glands were expressed at each visit; samples of meibum were collected for analysis Long Term Hydrocarbon chain order at 33.4ºC (% trans) Enrolled in AzaSite Study Enrolled in AzaSite Study Stopped Stopped MGD 55 * Treatment *P<0.01 MGD Treatment *P< * * 50 * * * 32 * * AzaSite At 2 At AzaSite At 2 At Baseline Baseline weeks weeks Baseline Baseline weeks weeks Normal Foulks, GN, Borchman, D, Yappert, CM, Modification of Meibomian Gland Lipids by Topical Azithromycin, Cornea, in press Phase transition temperature (ºC) Normal Pulse dose AzaSite periodically Restasis bid Omega-3s EPA DHA 46 3

4 Potential Chronic Changes Telangiectasia Dislocation of meibomian glands/ gland atrophy Scarring Moderate/severe or not improving Add PO tetracycline Recommendation: Doxycycline bid x 4-8 weeks then taper to Periostat (20 mg doxycycline) bid OcuSoft: 20 mg Contraindications Cautions Photosensitivity Chelates with dairy products, antacids etc. Minocycline may cause vestibular toxicity Number one drop-out reason? - (25% in HD) Tetracyclines How to Minimize Stomach Problems with Tetracycline Antibiotics inhibit bacterial protein synthesis by binding 30S ribosome Anti-inflammatory properties decreases IL-1, TNF- decreases NO production decreases HLA Class II antigen expression decreases metalloproteinase production and activation Decrease symptoms and joint destruction in RA

5 Systemic medications Antihistamines Diuretics Antihypertensives Anticholinergics Antidepressants Cardiac antiarrhythmic Oral contraceptives Hormone replacement therapy Contact lens wear Schedule & Care Type of Lens Disposable Non-ionic, low water content SiHy lens Refractive surgery Common for first 3-6 months Neurotrophic Goblet cell density Tear flow Systemic Disease Sjogren s Syndrome Lymphocytic infiltration of lacrimal and salivary glands 0.4% prevalence Women > Men (younger women) Much lower androgen counts Treat underlying immune disorder Which of these conditions are Sjogren s patients 46x more likely to develop? A. Leukemia C. Diabetes B. Lymphoma D. Cardiac Arrhythmia 5

6 Sjogren s Syndrome Lymphocytic infiltration of lacrimal and salivary glands 5-8% incidence of 46.3x more often Moutsopoulos HM et all Sjogren s Syndrome Medical Treatments: Secretagogues Salagen 5 mg Pilocarpine tablets Avoid in asthma patients, GI ulcer, acute iritis or narrow angles mg saliva stimulating drug Very effective with a lot less side effects Also proven to help dry eye (Ono et al) Symptoms of Dry Eye Burning Stinging Transient blur Dry eye sensation Photophobia Epiphora Contact lens intolerance Injection Increased blink rate Foreign body sensation Epiphora 6

7 External examination Examination Diagnostic Tests Pt questionnaire Tear meniscus height Tear break-up NAFL Dye Rose Bengal or Lissamine Green Schirmer test - phenol thread test Diagnostic Advances TearLab Osmolarity testing FDA approved in June, 2009 in US 10 milli-microliters of tears Instant measurements of osmolarity in your clinic! Treatment Treatment Emphasis chronic nature of the condition Eliminate exacerbating factors caffeine, air conditioner, meds. Drink 4-6 glasses of water per day Tear replacements 7

8 Treatment AT s Blink Tears FreshKote Soothe XP & Systane Balance Soothe XH Optive Systane Ultra Oasis Tears LACRISERT (hydroxypropyl cellulose ophthalmic insert) LACRISERT is indicated in patients with moderate to severe dry eye syndromes (DES), including keratoconjunctivitis sicca. LACRISERT is indicated especially in patients who remain symptomatic after an adequate trial of therapy with artificial tear solutions. LACRISERT is also indicated for patients with exposure keratitis, decreased corneal sensitivity, and recurrent corneal erosions. LACRISERT package insert. Aton Pharmaceuticals, Inc. Lawrenceville, NJ; [2007 PI p1, 8] Nutritional Supplements: Essential fatty acids Omega-3 fatty acids: EPA-DHA e.g. Fish oils Healthy Omega-6 fatty acids GLA-evening primrose oil or black currant see oil ALA- e.g. flaxseed oil Autologous Serum Patients blood is drawn Centrifuge serum away from RBC Serum contains various growth factors including epithelial growth factor Mix with artificial tears Patient doses 6 x per day Most Eyebanks are now offering this service Punctal Occlusion May worsen certain conditions Allergies MGD Ideal as final treatment option and in LASIK dry eye management Targeted Treatments Treatments aimed at local inflammatory processes Topical corticosteroids (Lotemax) Effective anti-inflammatory agents Site specific Steroids Cyclosporin A (Restasis) 8

9 Dry Eye Disease A Real Condition That Needs More Than a Palliative Solution Dry eye is a disorder of the tear film due to tear deficiency or excessive tear evaporation which can cause damage to the interpalpebral ocular surface. 1 Artificial tears provide temporary palliative relief 2 Corticosteroids Bind to nuclear receptors that bind DNA and regulate gene expression Interfere with transcription regulators [e.g., AP-1 & NF-kB] most inflammatory pathways cytokine production lipid mediators (PGs) cell adhesion molecules lymphocyte trafficking vascular permeability Ring modifications alter potency and membrane stabilizing effects 1. Lemp. CLAO J Stern et al. Cornea Nelson et al. Adv Ther Steroids and Dry Eye Symptomatic improvement in irritation symptoms in 83% and objective improvement ( redness, dye staining and tarsal papillae, FTC) in 80% of 70 patients treated for 2 weeks with non-preserved methylprednisolone Prabhasawat & Tseng BJO 1998 Steroids and Dry Eye Moderate (43%) or complete (57%) relief of irritation symptoms accompanied by corneal FL staining and resolution of filamentary keratitis in 21 SS patients treated for 2 weeks with non-preserved methylprednisolone (Marsh & Pflugfelder 1999) Patients often have long lasting relief after 2-week pulse therapy Steroid Treatment Loteprednol 0.2% (Alrex) Loteprednol 0.5% (Lotemax) Less side effects - M Abelson 88 patients 35 days IOP rise, secondary infection or PSC formation: 0% No reported cases of PCS cataract in over 6 Million prescriptions (IMS Health Data) Ester vs. Ketone Steroids are inactivated by naturally occurring esterases less side effects are not inactivated and have propensity to remain in anterior chamber post breakdown as active metabolites 9

10 Ester vs. Ketone Steroids Anti-inflammatory Therapy of KCS Loteprednol Prednisolone Fluorometholone Dexamethasone Medrysone Rimexolone ester steroid ketone steroid Corticosteroids Improve signs and symptoms Improve tear clearance Normalize mucus production Often have sustained benefit after a 2 week pulse Bioengineered steroid loteprenol etabonate is effective How Does Restasis Work? Restasis prevents T-cell activation (Kunert et al, Arch Ophthalmol. 2000;118:1489) Activated T cells produce inflammatory cytokines that result in: Recruitment of more T cells (Stern et al, IOVS. 2002;43:2609) More cytokine production (Pflugfelder et al, Curr Eye Res. 1999;19:201) Pflugfelder et al AJO Topical Cyclosporine Restasis Ophthalmic Emulsion (Allergan) Useful in long-term management of inflammatory DES BID dosage Cyclosporine A (CsA) 0.05% in castor oil vehicle Mechanism of action: Inhibits activation of inflammatory T-lymphocytes, and induces immune cell apoptosis, stimulating lacrimal gland tear production 3-4 months to achieve clinically significant effect, 6 months for full therapeutic potential 59% Patients achieved improvement from baseline Schirmer scores at 6 months Excellent safety profile Increased Goblet Cell Density in Subset of 12 Patients Percentage Change in Goblet Cell Density from Baseline RESTASIS 191% P =.013 Patients treated with RESTASIS ophthalmic emulsion had a 191% increase in goblet cells. Arm treated with vehicle had no significant change from baseline. 1,2 10

11 Patients notice an onset of benefit Expectations During the First 6 Months of Therapy Further increase in tear production Significant improvement in tear production 1 month 3 months 6 months Improvements are maintained with continuation of therapy Cyclosporine Restasis Safety: Ocular Adverse Events (%) Burning upon instillation Stinging Discharge Foreign-body sensation Conjunctival hyperemia Pruritus Visual disturbance Pain Epiphora 0.05% Cyclosporine Vehicle Data on File, Allergan, Inc. Burning and stinging are the most important reasons that patients discontinue use of Restasis 17% of patients receiving Restasis experienced burning or stinging Patients with dry eye have chronic ocular disease and are more sensitive to ocular insults Patients with dry eye disease have anesthetic corneas with return of tear function there is a return of corneal sensation, burning and stinging Patients with dry eye are accustomed to treatment failure and are not willing to continue therapy which may make them feel temporarily worse Topical Loteprednol Improves Patient Compliance and Restasis Efficacy Corticosteroids have been shown to improve tear production by controlling inflammation 1 Corticosteroids decreases irritation associated with use of Restasis by 75% 2 Recommend a mild corticosteroid such as qid for two weeks and then bid for 2 weeks for patients who complain of irritation with Restasis, high maintenance patients, and patient who want more rapid relief 1 Marsh, Pflugfelder. Ophthalmology Shepard, ASCRS 2005 Established Safety Profile Favorable safety profile for RESTASIS ophthalmic emulsion Safety parameters monitored: Adverse events Blood chemistry Intraocular pressure (IOP) Visual acuity Biomicroscopy Conjunctival microbiology Cyclosporine blood levels Please see slides 6 & 7 for important safety information. 1. Small et al. J Ocul Pharm Ther No Cyclosporine in Blood No detectable cyclosporine in blood of any RESTASIS ophthalmic emulsion treated patient 1 Toxicity associated with systemic or oral cyclosporine was not observed with cyclosporine 0.05% ophthalmic emulsion Please see slides 6 & 7 for important safety information. 11

12 Progression of Dry Eye Disease LEVEL 1 DTS Treatment Algorithm If no improvement, add level 2 treatments Patient education Environmental modifications Control systemic medications Preserved tears Allergy control LEVEL 2 If no improvement, add level 3 treatments Unpreserved tears Gels/nighttime ointments Nutritional support Cyclosporin A Topical steroids Secretagogues Dry eye is a progressive, potentially irreversible disease Left untreated, the cycle of inflammation and dysfunction may cause permanent damage to the lacrimal gland LEVEL 3 LEVEL 4 If no improvement, add level 4 treatments Tetracyclines Punctal plugs (control inflammation 1st) Systemic anti-inflammatory therapy Acetylcysteine Moisture goggles Surgery (punctal cautery) 83 Behrens et al, submitted Regimen: Artificial Tears Manage contributing factors Omega-3 s Lotemax qid for 2 weeks then bid for 6 weeks then PRN Restasis bid to 6 months Punctal Plugs Dry Eye Disease Conclusion: Inflammation at the root of the pathology as a cause or effect with osmolarity Numerous new treatment options that now make treating dry eye enjoyable Likely the most common condition we will see over the next two decades Thank You paul@karpecki.com 12