An Update on Diagnosis and Treatment of Refractory Ocular Surface Disease

Transcription

1 An Update on Diagnosis and Treatment of Refractory Ocular Surface Disease Kendall E. Donaldson, MD, MS Associate Professor of Ophthalmology Bascom Palmer Eye Institute Royal Hawaiian Eye, Maui, HI 2018

2 Alcon Allergan Bausch and Lomb Johnson and Johnson Novabay Omeros Quidel Shire SUN Disclosures

3 Dry eye disease is everywhere! >25 Million Americans suffer from dry eye disease $3.8 Billion spent on dry eye symptom relief annually in the U.S. alone Most frequently encountered disease state by eye care professionals Market Scope 2013 Comprehensive Report on the Global Dry Eye Products Market

4 Two primary forms of dry eye 1. Evaporative (lipid deficient caused by MGD) Occurs when the water (or aqueous) in tears evaporates at a faster rate than normal 2. Aqueous deficient Occurs when aqueous generation from the lacrimal gland is insufficient to keep the eyes moist Lemp MA, et al. Distribution of aqueous deficient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cornea. 2012:31(5):

5 Diagnosis -Subjective -Objective

6 Talk to the Patient OSDI SPEED

7 Other underlying diseases or medications? Thorough medication history Antihistamines/Decongestants/Antidepressants Eye drops GLAUCOMA!!! Systemic history Sjogren s (New Sjo test) Rheumatoid Rosacea Thyroid dysfunction Lupus Hormonal changes

8 Don t forget! Targeted Systemic Work-up Systemic Medications Anatomic defects Lid anomalies post-surgical or other Sjogren s Syndrome Thyroid dysfunction Ocular Cicatricial Pemphigoid (OCP) Graft versus Host Disease Other autoimmune dysfunction

9 OSDI Diagnostic Tests Corneal and Conjunctival staining Fluorescein, lissamine green, rose bengal Tear film break-up time Schirmer testing Meibography Fluorophotography TearLab Osmolarity System LipiView RPS InflammaDry Detector (Rapid Pathogen Screening) detects MMP-9 Touch Tear MicroAssay System measures lactoferrin

10 The problem with diagnostic testing

11 Dry Eye Syndrome: Making the Diagnosis Easier for Confusing Cases

12 Corneal Topography Tomey SAI and SRI Oculus Keratograph 5M Tomey Tear Stability Analysis System

13 Hot spots and Irregularly shaped placido disk is abnormal! **Image courtesy of Elizabeth Yeu, MD.

14 Tear Osmolarity Normal subjects exhibit low and stable osmolarity Normal tear osmolarity = 290 mosms/l Dry eye subjects exhibit elevated and unstable osmolarity Variability is the hallmark of DED >8 mosms/l between eyes Osmolarity was found to be the least variable of all common signs.

15 Future of Tear Biomarker Analysis: TearLab Next Generation Platform Quantitative Ability to measure Osmolarity Inflammation biomarkers Allergy biomarkers Etc. Rapid testing (< 2 minutes) Multiplexed biomarkers EHR Integration Clinical Application: Normalization using osmolarity Customized chips with designed sensitivity & specificity

16 Meibomian Gland Dysfunction Disease Identification

17 LipiView : Assess Tear Film Lipid Layer LipiView Useful for screening and identifying subtype of dry eye Helps patient visualize the tear film Provides objective measure of lipid layer thickness Operates on interferometric technology

18 Dynamic Surface Illumination Normal meibomian gland structure Structural change (truncation with dilation) Structural change (severe gland atrophy and drop out) Surface lighting originates from multiple sources to virtually eliminate glare Adaptive Transillumination Normal meibomian gland structure Structural change (truncation with dilation) Structural change (severe gland atrophy and drop out) Adaptive Transillumination device changes light intensity across the surface of the illuminator to compensate for lid thickness variations between patients.

19 RPS Inflammadry - MMP-9 Detector

20 Dry Eye & Inflammation Not all dry eye patients have clinically significant inflammation Only 40-60% of symptomatic patients have inflammation 1 Traditional dry eye testing methods (TBUT, Schirmer, osmolarity) CANNOT predict which patients have inflammation 2 Identifying elevated MMP-9/inflammation helps guide therapeutic decision making 3 [1] Sambursky R, Davitt WF 3rd, Friedberg M, Tauber S. Prospective, multicenter, clinical evaluation of point-of-care matrix metalloproteinase-9 test for confirming dry eye disease. Cornea Aug;33(8): [2] Lanza NL, McClellan A, Batawi H, et al. Dry eye profiles in patients with a positive elevated surface matrix metalloproteinase 9 point of care test versus negative patients. Ocular Surface Accepted. [3] Kaufman HE. The practical detection of MMP-9 diagnoses ocular surface disease and may help prevent its complications. Cornea Feb;32(2):

21 MMP-9 = Ocular Surface Disease

22 Adjunctive Testing Sjo Testing and Allergy Testing

23 Treatment

24 Diagnosis and Tracking Treatment 1. OSDI 2. Tear Osmolarity 3. RPS Inflammadry MMP-9 Detector

25 Not all patients are created equal Artificial tears, gels Warm compresses Restasis Punctal plugs Moisture goggles Humidifiers Environmental modifications Reassurance

26 The talk Forming a supportive relationship This is a chronic condition Awareness of environmental triggers Emphasizing that the patient needs to play an active role. Not an instant fix Don t be a victim

27 Forming a Supportive Partnership

28 Teaching!!

29 Dynamic Surface Illumination Normal meibomian gland structure Structural change (truncation with dilation) Structural change (severe gland atrophy and drop out) Surface lighting originates from multiple sources to virtually eliminate glare Adaptive Transillumination Normal meibomian gland structure Structural change (truncation with dilation) Structural change (severe gland atrophy and drop out) Adaptive Transillumination device changes light intensity across the surface of the illuminator to compensate for lid thickness variations between patients.

30 Artificial Tears Artificial tears provide a palliative relief of eye irritation in patients with aqueous tear deficiency, but do not prevent the underlying inflammation or reverse conjunctival squamous metaplasia in chronic dry eye 1 [1] Stern ME, Schaumburg CS, Pflugfelder SC. Dry Eye as a Mucosal Autoimmune Disease. International Reviews of Immunology. 2013;32(1): [2] Aragona P, Aguennouz M, Rania L, Postorino E, Sommario MS, Roszkowska AM, De Pasquale MG, Pisani A, Puzzo Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease. Ophthalmology Jan;122(1):

31 A variety of Anti-inflammatory agents Steroids NSAIDS Cyclosporin 0.05% Lifitegrast 5%

32 Punctal Occlusion 2010 Cochrane review of punctal occlusion for dry eye ( ) 7 randomized controlled studies 305 participants; 601 eyes Conclusions: Limited data; Poorly controlled trials - subjective Data supports use and efficacy of silicone plugs and/or temporary collagen plugs

33 Punctal Occlusion Punctal occlusion has been shown to improve objective and subjective measures of dry eye to and to exacerbate ocular surface inflammation in subjects with overt clinical inflammation 1 Punctal occlusion does not reduce inflammatory mediators such as MMP- 9 2 The Delphi treatment guidelines for ocular surface disorders recommends that inflammatory conditions be treated before punctal occlusion 3 [1] Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol Feb;137(2): [2] Tong L, Beuerman R, Simonyi S, Hollander DA, Stern ME. Effects of Punctal Occlusion on Clinical Signs and Symptoms and Tear Cytokine Levels in Patients With Dry Eye. Ocul Surf Jan 13. [3]mBehrens A, Doyle JJ, Stern L, et al. The Dysfunctional Tear Syndrome Study Group. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea. 2006;25:

34 What else can we add? Nutriceuticals Autologous serum tears Manual expression Lipiflow Treatment of Demodex PROSE AMTs Treatment of systemic disease

35 Omega Supplementation can be confusing!

36 Delta-4 Desaturase Omega- 3 Essential Fatty Acids Omega- 6 Black Currant Seed Oil 18:2w3 Alpha linolenic (ALA) Anti-inflammatory Fatty Acids Flaxseed Oil (Parent) (Parent) 18:2w6 Linoleic Acid (LA) Black Currant Seed Oil Delta-6 desaturase Rate-Limiting Only 15-20% of ALA converts to EPA 18:4w 3 SDA 18:3w6 GLA Black Currant Seed Oil Elongase 20:4w ETA Delta-5 Desaturase 20:3w DGLA Fish Oil 20:5w EPA COX 20:4w6 Arachidonic Acid Fish Oil 20:6w DHA GOOD Prostaglandins BAD Prostaglandins LBT and PGE GOOD Prostaglandins 36

37 Multi-center, randomized, controlled trial (Baylor Med. Coll., VA Eye Consultants) 38 postmenopausal women with Dry Eye given HydroEye / placebo for 6 mos In SUMMARY: Patients showed Significant improvement in irritation symptoms & significantly better symptom scores vs. placebo Significantly better corneal smoothness vs. placebo Significantly lower levels of inflammatory markers vs. placebo.

38 Multicenter, Prospective, Interventional, randomized, Double-Masked, placebo-controlled 105 subjects completed the study 54 in treatment group - received 2 grams reesterified omega 3 (EPA & DHA) 51 in placebo group

39 End Points Primary: To determine the effect of PRN Dry Eye Omega Benefits omega-iii nutritional regimen on tear osmolarity. Secondary: OSDI (Symptoms) Tear Film Break-Up Time Corneal Staining Lipid Layer Thickness Schirmer s Test MMP 9 Omega-3 Index Score

40 Cyclosporine 0.05% Topical Cyclosporine A in the Treatment of Dry Eye: A Systematic Review and Meta-analysis. Zhou XQ, Wei RL. Cornea 2014, July 33(7); Methods: 12 RCTs; 3034 eyes, 1660 participants Results: Improved: TBUT and Schirmer (- anesthesia) Unchanged: OSDI and Schirmer (+anesthesia)

41 Percentage of Patients Cyclosporin 0.05% Increased Tear At 6 months: Production 15% of RESTASIS patients had an increase in Schirmer score 10 mm 1 Three times more tears were produced in the RESTASIS group (n = 293) compared to vehicle (n = 292) 2 Percentage of Patients With Increase in Schirmer Score of 10 mm (6 20% Months) 15% 10% RESTASIS Cyclosporin Vehicle 0.05% Vehicle 5% 0% 15% 5% RESTASIS Prescribing Information; 2. CsA NDA: Integrated Summary of Efficacy, 1999.

42 Percent Change Cyclosporin Corneal Staining 1,2 Percent Change in Corneal Staining Score From Baseline 0% Month 1 Month 3 Month 4 Month 6-5% -10% -15% -20% -25% -30% -23% % % % % P.05-20% % -25% Cyclosporin RESTASIS Vehicle -35% P =.008 Baseline mean values for corneal staining ranged from 2.61 (Vehicle) to 2.77 (RESTASIS ) n = 585; pooled data from 2 pivotal trials Sall et al. Ophthalmology. 2000; 2. Data on file, Allergan Inc.,1999.

43 Percentage of Patients With a Worsening of Dry Eye Severity Level Change in Dry Eye Severity Level at Month % 30% 25% 20% a P <.007 vs REFRESH ENDURA *Severity level determined according to Consensus Guidelines published in Cornea % Cyclosporin RESTASIS REFRESH ENDURA ENDURA 15% 10% RESTASIS (2/36) REFRESH ENDURA (7/22) 5% 0% 6% a Rao. J Ocul Pharmacol Ther. 2010; 2. Behrens et al. Cornea

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45 Lifitegrast 5%

46 Treatment of Dry Eye Loteprednol showed a 66% reduction in MMP-9 expression while MGD patients showed a 42% reduction 1 Cyclosporine showed a 50% reduction in MMP-9 activity 2 Artificial tear eye drops alone failed to demonstrate any reduction in MMP-9 levels 1 [1] Aragona P, Aguennouz M, Rania L, Postorino E, Sommario MS, Roszkowska AM, De Pasquale MG, Pisani A, Puzzo Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease. Ophthalmology Jan;122(1): [2] Gürdal C, Saraç O, Genç, et al. Ocular surface and dry eye in Graves' disease. Curr Eye Res.2011;36:

47 Response to Anti-Inflammatory Therapy Topical corticosteroids and cyclosporine do not fully diminish dry eye symptoms in all patients 1-4 N=70 pts: Corticosteroid treatment only helped in ~ 80% of moderate to severe patients 2 N=64 pts: Patients with dry eye and delayed tear clearance were randomly assigned to receive either loteprednol or vehicle 4 times a day for 4 weeks 3 Symptoms regressed moderately (43%) or completely (57%) N=115 pts: Only 39% of patients treated with topical cyclosporine 0.1% for 6 months had a moderate response to treatment 4 [1] D. Dursun, M.C. Kim, A. Solomon, S.C. Pflugfelder. Treatment of recalcitrant recurrent corneal epithelial erosions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids Am J Ophthalmol, 132 (2001), pp [2] McCabe E, Narayanan S. Advancements in anti-inflammatory therapy for dry eye syndrome. Optometry. [3] Pflugfelder SC1, Maskin SL, Anderson B, et al. A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. Am J Ophthalmol Sep;138(3): [4] Sall K. "Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease" (vol 107, pg 631, 2000). 2009;80(10):

48 What more can we do? The next step Autologous Serum Tears Manual Expression Meibomian Gland Thermal Pulsation AMTs PROSE 48

49 What s the REAL scoop on Autologous Serum Tears? Cochrane Database of Systematic Reviews 360 titles 4 Randomized trials, 72 patients Variability in age, testing, duration, no control Results: 1 study: No improvement, 1 month 2 studies: improved symptoms at 2 weeks 1 study: improved symptoms, Increased TBUT by 2 sec Conclusions: may be effective Larger, longer, randomized trial with objective testing

50 Long-term use of autologous serum 50% eye drops for the treatment of dry eye disease Hussain M, Shtein RM, Sugar A, Soong K, Woodward MA, DeLoss K, Mian SI Cornea 33 (12); , Purpose: To study outcomes of 50% serum tears after long-term usage Methods: Retrospective, Results: 123 eyes, 63 patients 12 months Improvements in fluoro staining; Schirmers No complications Conclusions: Safe and effective

51 % of patients with Improvement BPEI Improvement with ASTs 80% 7/9 (78%) 7/9 (78%) 70% 60% 4/7 (57%) 5/8 (63%) 50% 4/8 (50%) 40% 30% 20% 10% 0% OSDI OSM TBUT CORNEAL STAINING Dry Eye Evaluation Tests Performed SHIRMER'S

52 Conclusions on AST Autologous serum tears are Eliminating patient symptoms Healing the corneal epithelium (PEEs) A useful adjunct in refractory cases when used in conjunction with standard medical care HOWEVER, we are in need of controlled trials!!!

53 Demodex

54 Demodex Treatment

55 Manual expression

56 MiBo Thermoflo Treatment

57 Lipiflow Thermal Pulsation System Korb, DR, Blackie, CA. Meibomian gland therapeutic expression: quantifying the applied pressure and the limitation of resulting pain. Eye Contact Lens. 2011;37(5):

58 Lipiflow Treatment

59 PROSE the missing link The goals of BostonSight PROSE treatment are to: Reduce symptoms and support healing by restoring a healthy ocular surface environment Improve blurry vision by masking surface corneal irregularities Prevent damage by protecting the cornea against the environment and eyelids

60 Indications for PROSE Ocular Surface Disease Corneal Ectasia/Irreg Astig Dry eye/k sicca Sjogren s Rheumatoid Post-radiation GVHD Limbal stem cell deficiency Epidermal Ocular Disorders Neurotrophic keratitis Exposure keratopathy Corneal Degenerations Keratoconus Pellucid Terrien s Salzman s Corneal Dystrophy Granular Lattice Post-operative Astigmatism RK/PK/LASIK/PRK Corneal Scarring Trauma/Infection

61 HZO Corneal Scarring 20/70 20/20

62 Ocular Cicatricial Pemphigoid 20/150 20/25 20/150 20/25

63 The role of Amniotic Membranes ProKera Amdiodisc Moria AMT

64 CryoTek Cryopreserved Amniotic Membrane Maintains Critical Components Needed for Regenerative Healing CryoTek Cryopreservation is the ONLY method that retains: ECM components that regulate and promote regenerative tissue processes. 1,2,3 HC-HA/PTX-3 complex Stops adult inflammatory immune response 4,5 Suppresses T-cell activation Inhibits giant cell formation Controls MMP production 6 Promotes regenerative healing 7 Growth factors Collagens (types I, III, IV, V and VI) Fibronectin Laminin HC-HA/PTX3 Complex * Promotes regenerative healing *This critical component is degraded or completely absent in dehydrated amniotic membrane 1. Rinastiti M, et al. Int J Oral Maxillofac Surg. 2006;35: , 2. Jin CZ, et al. Tissue Eng. 2007;13: Niknejad H, et al. Eur Cell Mater. 2008;15: He H, et al. J Biol Chem. 2009;284: He, et al. J Biol Chem. 2014;288(36): Heiligenhaus A, et al. Invest Ophthalmol Vis Sci. 2005; 46: Hopkinson A, et al. Invest Ophthalmol Vis Sci. 2006;47:

65 The role of AMTs in Ocular Surface Disease

66 In practical terms 1. Physician Extenders 2. Two Tracks 1. Complete ocular surface evaluation 2. Dry eye Express

67 OSDI Complete Ocular Surface Evaluation Corneal and Conjunctival staining Fluorescein, lissamine green, rose bengal Tear film break-up time Schirmer testing Meibography Fluorophotography TearLab Osmolarity System LipiView RPS InflammaDry Detector (Rapid Pathogen Screening) detects MMP-9 Touch Tear MicroAssay System measures lactoferrin

68 Dry eye Express 1. OSDI 2. Tear Osmolarity 3. RPS Inflammadry MMP-9 Detector

69 Summary These are our most challenging patients. Time consuming and frustrating. Often see many providers doctor shopping. Signs and symptoms are often conflicting. They may be the most rewarding patients. Appreciate your time investment. Small improvements in symptoms may make dramatic functional improvements.

70 Special thanks to Victor Perez, MD Alice T. Epitropoulos, MD Hector Cintron, MD and Xavier Quinines, MD Bascom Palmer Ocular Surface Center

71 THANK YOU