March 19, 2015 Financial Disclosures Consultant: Alcon Allergan Bausch & Lomb Modernizing Medicine Ophthalmologyweb.co m Investor: Novabay Ophthotech Ocular Surface Disease Ocular surface disease is often multifactorial and requires thorough history, examination, and workup. To keep this presentation within the allotted time frame the focus for this presentation will be on non-infectious causes of dysfunctional tear syndrome 1
Symptoms Symptoms include: Dryness Itching Irritation Blurred vision Light sensitivity Foreign body sensation Excessive tearing Symptoms are often exacerbated by: Desiccating environments caused by air conditioner drafts, fan and airplane environments Decreased blink rate from prolonged visual concentration What are some new Diagnostics? Tear film MMP-9 levels Tear film osmolarity Lipid layer evaluation Blood testst Allergy tests Tear Film MMP-9 Matrix metalloproteinases (MMP) are proteolytic enzymes that are produced by stressed epithelial cells on the ocular surface 1 MMP-9 in Tears Non-specific inflammatory marker Normal range between 3-41 ng/ml Correlates with clinical exam findings 1 Ocular surface disease (dry eye) demonstrates elevated levels of MMP-9 in tears 1 [1] Chotiakavanich S, de Paiva CS, Li de Quan, et al. Invest Ophthalmol Vis Sci 2009; 50(7): 3203-3209. 2
Dry Eye Disease and MMP-9 MMP-9 in Tears Elevated MMP-9 causes epithelial cell disruption that leads to corneal staining Corneal cell disruption leads to primary ocular symptoms of dry eye including pain, fluctuating vision, and tearing Elevated MMP-9 precedes corneal staining MMP-9 is a more sensitive marker of ocular surface disease than other clinical signs [1] Chotiakavanich S, de Paiva CS, Li de Quan, et al. Invest Ophthalmol Vis Sci 2009; 50(7): 3203-3209. Dry Eye Disease and MMP-9 Increased concentrations of MMP-9 can be found in other diseases or conditions, including: Ocular rosacea Meibomian gland disease Sjögren s syndrome Corneal ulcers Corneal erosions MMP-9 Levels in two types of Dry Eye MMP-9 Activity in Tear Samples NL Normal MGD Meibomian Gland Disease EVAPORATIVE DRY EYE SS Sjögren ssyndrome AQUEOUS DEFICIENCY P < 0.001 compared with normal subjects [1] Solomon A, Dursun D, Liu Z, Xie Y, Macri A, Pflugfelder SC. Pro- and anti-inflammatory forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disease. Invest Ophthalmol Vis Sci. 2001 Sep;42(10):2283-92. 3
Inflammadry Intended Use InflammaDry is a rapid, immunoassay test for the visual, qualitative in vitro detection of elevated levels of the MMP-9 protein in human tears from patients suspected of having dry eye. InflammaDry is to be used to aid in the diagnosis of dry eye, in conjunction with other methods of clinical evaluation. This test is intended for prescription use at point-of-care sites. Inflammadry Test Test includes 1 foil pouch containing a sterile sample collector 1 foil pouch containing a test cassette 1 buffer vial Shelf life = 24 months Store InflammaDry between 39 and 77 F (4-25 C) Assembled Test Inflammadry 4-Step Process * * Release the lid after every 2-3 dabs. Allow the sampling fleece to rest along the conjunctiva for 5 seconds. 4
Tear Osmolarity Measuring osmolarity allows us to evaluate an objective physiologic marker rather than relying only on subjective signs of the diseasesuch such asstainingstaining or tear break up time. Inter Eye Differences The DED process is characterized by a loss of tear film homeostasis resulting in hyperosmolarity and an unstable tear film An inter-eye difference >8 mosm/l is an indication of tear film instability, frequently an early manifestation in the development of disease DED is a bilateral and often asymmetrical disease Normal Tear Film Tears in proper homeostasis should be equivalent to blood osmolarity which is between 280 295 mosm/l Inter eye osmolarity difference should be <8 mosm/l International Dry Eye Workshop (DEWS). The definition & classification of dry eye disease. Ocul Surf 2007. Lemp MA, Bron AJ, Baudouin C, Benítez Del Castillo JM, Geffen D, Tauber J, Foulks GN, Pepose JS, Sullivan BD. Tear osmolarity in the diagnosis and management of dry eye disease. Am. J. Ophthalmol. 2011 May; 151(5):792 798. Keech A, Senchyna M, Jones L. Impact of time between collection and collection method on human tear fluid osmolarity. Curr. Eye Res. 2013 Apr; 38(4):428 36 Hyperosmolarity Upregulates EMMPRIN/MMP-9 Huet E et al. Am J Pathol. 2011;179. 5
Hyperosmolarity Causes loss of Microplicae on the Corneal Epithelium Andrews PM. Journal Cell Bio. 1976;68:420 429 Measurement of Both Eyes is Essential MAXIMUM of the two eyes: >300 mosm/l demonstrates loss of homeostasis and likely to become pathogenic >308 DIFFERENCE between two eyes: Shows the stability of the tear film. Normal tears are stable and <300 mosm/l bilaterally. A difference of >8 mosm/l is a hallmark of tear instability Effect of Compensatory Mechanisms in Early Stage DED Blinking, aqueous tearing (mixing), increased lipid secretion excretion - all lower osmolarity transiently and asymmetrically < 5 mosm/l Variability mosm/l > 20 mosm/l A Bron, et al. The Ocular Surface 2009 Apr;7(2) 78 92. A Keech, et al. Curr Eye Res 2013 Apr;38(4) 428 36. 6
Understanding Tear Film Instability in Dry Eye Normal subjects exhibit low and stable osmolarity Normal tear osmolarity = Equivalent to blood osmolarity = 280 295 mosm/l Indicative of the tears being held in proper homeostasis Dry Eye subjects exhibit elevated and unstable osmolarity Osmolarity changes between eyes and over time Inter eye difference = hallmark of DED 1 ( > 8 mosm/l between eyes) 1 Lemp MA et al., Am J Ophthalmol. 2011 May;151(5):792 798 What if TO is normal but the ocular surface and/or symptoms indicate dry eye? Normal osmolarity but ocular surface irritation/complaints Partially treated DED Conjunctival chalasis CLand/or solution irritation Mild allergic conjunctivitis Epithelial Basement Membrane Dystrophy Pinguecula/early pterygia Infection Anterior blepharitis Demodex TearLab Osmolarity Testing Perform TearLab Osmolarity testing before other tests Wait 15 minutes after topical anesthetic and/or dilating drops Wait at least 2 hours after any other topically applied drops including artificial tears TearLab Test Card collects 50 nanoliters of fluid from the tear meniscus Results available within seconds The test can be performed by a technician 7
What if TO is elevated but the ocular surface is quiet and/or the patient is asymptomatic? Hyperosmolarity is a hallmark sign of DED as stated in dozens of peer review publications over the past 5 years and even decades of research prior to the development of TearLab (> 250 publications) The patient may not have reached hda point where visible iibl evidence is present e.g. corneal staining which is typically a late sign for DED and can also be present in other OSD conditions We now are seeing many publications showing hyperosmolarity can cause damage to corneal nerves leaving a neurotrophic condition with poor symptom recognition What if TO is normal but the ocular surface and/or symptoms indicate dry eye? Signs and symptoms do not correlate with each other and this also includes osmolarity There is significant overlap with other OSD conditions such as ocular allergy, conjunctival chalasis, etc. Patient may be partially treated Subjectivity of patient symptoms (e.g. stoic vs. whiner) Korb Meibomian Gland Evaluator First standardized metric to verify the presence of meibomian gland dysfunction. By mimicking the pressure of a deliberate blink (0.8-1.2 g/mm2), the Korb MGE allows the eye care professional to assess meibomian gland secretions and function at the slit lamp. The Korb MGE also tracks the progression of MGD and non-obvious obvious MGD with visit-to to-visit consistency and repeatability. Korb & Blackie, Cornea 2008; 27:1142-1147 8
Meiboscale AB F 29 yo LM F 56 yo SR F 51 yo Normal Truncated Severely Truncated ES F 22 yo Dilated Ducts AS F 58 yo Truncated Sjo 9
Allergy Testing Doctors Allergy Formula Doctor Allergy Matrix Newer Treatments Amniotic grafts Autologous serum tears Lacrisert Lipiflowifl IPL Laser Off label therapy (Tacrolimus/testosterone) Amniotic grafts 10
Amniotic Grafts BioD BioTissue (Prokera/Ambiograft) IOP Moria Seed Biotech Lacrisert Lipiflow 11
Lipiflow Korb, DR, Blackie, CA. Meibomian gland therapeutic expression: quantifying the applied pressure and the limitation of resulting pain. Eye Contact Lens. 2011 Sep;37(5):298-301. 34 IPL Laser Thank You 12