what, why, how about dry eye disease management 1 - - what, why, how about dry eye disease...

18
10/26/2015 1 - - What, Why, How about Dry Eye Disease Management Paul M. Karpecki, OD, FAAO Director of the OSD Center at KVG Lexington KY - - Paul M. Karpecki, OD, FAAO Financial Disclosures: iCare USA Imprimis J&J Konan Medical MacuLogix Oculus Beaver Visitech OM Solutions Ocular Solutions Reichert Shire Pharmaceuticals Science Based Health TearLab TearFilm Innovations TLC Vision Topcon Vmax AMO Alcon Labs Allergan Inc Akorn Arctic Dx Bausch & Lomb Inc BioTissue Bruder Healthcare Ocusoft Essilor SightRisk Focus Laboratories Nicox Rigel Pharma Eleven BioTherapeutics Freedom Meditech - - Ocular Surface Disease 20 years since starting my first dry eye clinic 14 of those years were…. frustrating Dry Eye Disease Understanding has Changed - - Predisposing factors Age Gender Environment Anterior Segment Disease Medications CL Wear Refractive or cataract surgery Systemic Disease - - Gender Sjogren’s: Dry eye is characterized by a triad of dry eye, dry mouth, and associated auto- immune disorders Prevalence 0.4% 85% women - - Prevalence of Dry Eye (continued) Prevalence by Age and Gender – WHS Study 0 2 4 6 8 9 11 13 15 55-59 60-64 65-69 70-74 75+ Prevalence of Dry Eye (%) Age Group (years) Women Men

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10262015

1

- -

What Why How about

Dry Eye Disease

Management

Paul M Karpecki OD FAAO

Director of the OSD Center at KVG

Lexington KY

- -

Paul M Karpecki OD FAAO Financial Disclosures

iCare USA

Imprimis

JampJ

Konan Medical

MacuLogix

Oculus

Beaver Visitech

OM Solutions

Ocular Solutions

Reichert

Shire Pharmaceuticals

Science Based Health

TearLab

TearFilm Innovations

TLC Vision

Topcon

Vmax

AMO

Alcon Labs

Allergan Inc

Akorn

Arctic Dx

Bausch amp Lomb Inc

BioTissue

Bruder Healthcare

Ocusoft

Essilor

SightRisk

Focus Laboratories

Nicox

Rigel Pharma

Eleven BioTherapeutics

Freedom Meditech

- -

Ocular Surface Disease

ndash 20 years since starting my first dry eye clinic

ndash 14 of those years werehellip frustrating

Dry Eye Disease Understanding has Changed

- -

Predisposing factors

bull Age

bull Gender

bull Environment

bull Anterior

Segment

Disease

bull Medications

bull CL Wear

bull Refractive or

cataract surgery

bull Systemic Disease

- -

Gender

bull Sjogrenrsquos Dry eye is characterized by a triad

of dry eye dry mouth and associated auto-

immune disorders

bull Prevalence

ndash 04

ndash 85 women

- -

Prevalence of Dry Eye (continued)

Prevalence by Age and Gender ndash WHS

Study

0

2

4

6

8

9

11

13

15

55-59 60-64 65-69 70-74 75+

Pre

vale

nce o

f D

ry E

ye (

)

Age Group (years)

Women

Men

10262015

2

- -

Environment

bull Air conditioners or heaters

bull Airline travel

bull Winter months allergy season

bull Ceiling fan

bull Exogenous irritants (smoking)

bull Reading time

bull Digital device use

- -

DTS Clinical Categories in 2006

bull Most common presentation ldquoNo lid margin diseaserdquo

bull Treatment decision based on severity level

Dysfunctional Tear Syndrome

Lid Margin

Disease

Altered Tear

Distribution

No Lid Margin

Disease

Behrens et al submitted

- -

Anterior Blepharitis

- -

Anterior Blepharitis

- -

OcuSoft Tea Tree Kit

bull Contains Tea Tree Oil + Buckthorn seed oil

bull Bland Ung QHS

bull OcuSoft Lid Scrub Plus

- -

BlephEx Treatment

10262015

3

- -

Frothy Foamy Tears = MGD

38

Key Components to MGD

bull Obstruction

bull Inflammation

bull Biofilm development

bull Tear film alterationsinstability

14

Not present in all cases

38

Obstruction

bull Lid margin debridementscaling

bull Commercial WC (eg Bruder

TranquilEyes etc)

bull Cold or manual expression

bull Mechanical thermal pulsation

15

Obstruction Debridement-Scaling

bull Debridement-scaling of the line of Marx and keratinized lid margin improves MG function and reducing symptoms

bull Korb DR1 Blackie CA Debridement-scaling a new procedure that increases Meibomian gland function and reduces dry eye symptoms Cornea 2013 Dec32(12)1554-7

bull Ong BL Hodson SA Wigham T et al Evidence for keratin proteins in normal and abnormal human meibomian fluids Curr Eye Res 1991 Dec10(12)1113-9

16 14

7

Warm Compress Effectiveness

bull Olson MC1 Korb DR Greiner JV Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction Eye Contact Lens 2003 Apr29(2)96-9

bull Romero JM Biser SA Perry HD et al Conservative treatment of meibomian gland dysfunction Eye Contact Lens 2004 Jan30(1)14-9

bull Effective Requires continuous heat and temperature

bull Commercial compresses (eg Bruder) favored especially if they can provide hydration

17 14

7

Bruder Eye Hydrating Compress

18

10262015

4

Thermal Pulsation LipiFlow

bull Greiner JV A single LipiFlowreg Thermal Pulsation System treatment improves meibomian gland function and reduces dry eye symptoms for 9 monthsCurr Eye Res 201237272-278 3

bull Conclusion Single 12 minute procedure statistically improved MG secretions TFBUT and OSDI at 9 months

19 14

7

20

The device applies controlled heat to

the inner upper and lower palpebral

conjunctival surfaces and lid margins

while simultaneously applying

pulsating pressure over the upper and

lower (outer) eyelids

THERMODYNAMIC TX TO EXPRESS AND EVACUATE MGs

THE LIPIFLOW (TearScience Inc Morrisville NC)

A new thermodynamic treatment to express amp evacuate the MGs

Heat applied to both inner lid surfaces

Pulsatile pressure applied to outer lids

FDA approved LipiFlow July 2011

Thermal Pulsation LipiFlow

bull Blackie CA Carlson AN Korb DR Treatment for meibomian gland dysfunction and dry eye symptoms with a single-dose vectored thermal pulsation a review Curr Opin Ophthalmol 2015 Jul26(4)306-13

bull Review of 31 peer-reviewed reports on vectored thermal pulsation therapy at the time of the search (eight manuscripts and 23 meeting abstracts)

bull Effective Optimal temperature for entire time back surface simultaneous expression

21 14

7

38

BioFilm Development

bull Lid hygiene products (eg Ocusoft Lid

scrub plus or Sterilid etc)

bull Canister options seem to work well

bull Surfactant and hypochlorus acid

versions

bull Mechanical with surfactant cleaner (eg

Blephex)

22

Inflammation and MGD

bull Suzuki T Teramukai S Konoshita S Meibomian Glands and Ocular Surface Inflammation Ocul Surf 2015 Apr13(2)133-149

bull Baudouin C Revisiting meibomian gland dysfunctionJ Fr Ophtalmol 2014 Dec37(10)757-62

bull Aragona P Aguennouz M2 Rania L et al Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease Ophthalmology 2015 Jan122(1)62-71

bull Enriacutequez-de-Salamanca A1 Castellanos et al Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease Mol Vis 2010 May 1916862-73

23 14

7

The Cycle of Inflammation

Sym

pto

ms I

ncre

ase

Potential Long-term Damage Inflammation

Stasis inspissation and obstruction of the Meibomian Glands

Meibomian Gland Dysfunction (MGD)

Tissue Changes

Decrease in Meibomian secretions

Decrease in tear film stability increased aqueous tearing1

Increase in evaporative stress

Ocular surface exposure (between blinks) amp Micro-trauma (during blinking)

24

1 Arita R et al Increased Tear Fluid Production as a Compensatory Response to

Meibomian Gland Loss A Multicenter Cross-sectional Study Ophthalmology 2015

Jan 24 pii S0161-6420(14)01195-6 doi 101016jophtha201412018 [Epub

ahead of print]

10262015

5

38

Inflammation in MGD

bull Combination agents amp steroid agents

bull Topical AzaSite

bull Cyclosporine (Restasis)

bull Omega fatty acids

bull PO doxycycline or azithromycin

25

Clinical Reseach on Corticosteroids in MGD

Aragona P1 Aguennouz M2 Rania L3 et al Ophthalmology Matrix metalloproteinase-9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease 2015 Jan122(1)62-71 2014 Sep 18 Akyol-Salman I1 Azizi S Mumcu UY et al J Ocul Pharmacol Ther Comparison of the efficacy of topical N-acetyl-cysteine and a topical steroid-antibiotic combination therapy in the treatment of meibomian gland dysfunction 2012 Feb28(1)49-52

26

Clinical Research on Cyclosporine and MGD

bull Prabhasawat P Tesavibul N Mahawong W A randomized double-masked study of 005 cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction Cornea 2012 Dec31(12)1386-93

bull Conclusions OSDI TFBUT lid margin inflammation meibomian gland expressibility and tarsal injection showed significant improvement from baseline in group A (Plt001 Plt001 Plt0001 Plt005 and Plt0001 respectively) In group B only the OSDI improved significantly from baseline at 3 months (P=0003)

27

Clinical Research on Cyclosporine and MGD

bull International Workshop on MGD Report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction Gerd Geerling Joseph Tauber Christophe Baudouin et al

bull Reviewed MGD and cyclosporine data in MGD as favorable

bull Perry H Doshi-Carnevale S Donnenfeld E et al Efficacy of Commercially Available Topical Cyclosporine A 005 in the Treatment of Meibomian Gland Dysfunction Cornea 200625171ndash175

bull At the 3-month visit statistical improvements (plt 005) in lid margin vascular injection tarsal telangiectasis and NaFl staining Most significant finding (P = 0001) was the greater decrease in the number of meibomian gland inclusions in the tCsA group compared with the placebo group

28

Clinical Research on Cyclosporine and MGD

bull Rubin M Rao S Efficacy Topical Cyclosporine 005 in the Treatment of Posterior Blepharitis Ocular Pharmacology and Therapeutics Nov 2006 22 (1)

bull Conclusions Comparison of Cyclosporine to Tobradex for MGD after 12 weeks greater improvements in Schirmers scores (P lt 0001) and TBUT(P = 0018) than tobramycindexamethasone

bull Mean improvement in meibomian gland secretion quality was significantly greater with cyclosporin (P = 0015)

bull Higher percentage of patients in the cyclosporin treatment group had improvements in symptoms of blurred vision burning and itching and more cyclosporin-treated patients experienced resolution of lid telangiectasia

29

Clinical Research on Cyclosporine and MGD

bull Schechter BA Katz RS Friedman L Efficacy of Topical Cyclosporine for the Treatment of Ocular Rosacea Adv Ther (2009) 26(6)651-659

bull Conclusions Statistical improvement in Schirmer (with anesthesia)(Plt0001) meant TFBUT corneal staining scores (Plt0001) OSDI (P=0022) compared to artificial tears at 3 months

30

10262015

6

- -

Mild MGD

bull HotWarm compresses

bull Lid hygiene

bull Lipid based tears-mildmoderate

bull Osmolarity lowering drops in

moderatesevere

- -

ModerateAcute

bull Tobradex ST

bull Zylet

bull AzaSite

bull Tobradex generic

bull Steroid drops or ung bull (loteprednol preservative-free ung

QhS)

- -

Long Term

bull Pulse dose medications

periodically

bull Restasis bid

bull Essential fatty acids

ndash EPA

ndash DHA

ndash GLA

- -

Moderatesevere or not improving

bull Add PO tetracycline

bull Recommendation

bull Doxycycline 50mg bid x 4-12 weeks then taper to qd

bull Doxycycline 20 mg bid x 4-12 weeks then taper to qd (periostat concern $$$)

- -

Tetracyclines

bull Antibiotics inhibit

bacterial protein

synthesis by binding 30S ribosome

bull Anti-inflammatory properties

ndash decreases IL-1 TNF-

ndash decreases NO production

ndash decreases HLA Class II antigen expression

ndash decreases metalloproteinase production and

activation

bull Decrease symptoms and joint destruction in RA

- -

Contraindications

bull Pregnant or child bearing age

bull Children

10262015

7

- -

Cautions

bull Photosensitivity

bull Chelates with dairy products

antacids etc

bull Minocycline may cause vestibular

toxicity

bull Number one drop-out reason

bull GI problems

- -

Systemic medications bull Antihistamines

bull Diuretics

bull Antihypertensives

bull Anticholinergics

bull Antidepressants

bull Cardiac antiarrhythmic

bull Oral contraceptives

bull Hormone replacement therapy

- -

Contact lens wear

bull Schedule amp Care

bull Type of Lens

ndash Daily Disposable

bull DT1 TruEye

ndash Non-ionic low water content weekly disposable

bull Hydrogel Vision icuity

ndash SiHy 30 day

bull BampL Ultra

- -

Refractive surgery

bull Common for first 3-6 months

ndash Neurotrophic

ndash Goblet cell density

ndash Tear flow

- - Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mean

Go

ble

t C

ells

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 001 vs

baseline tears and

CsA 6 weeks

Mean Goblet Cell Density

Temporal Bulbar Conjunctiva

bull Significantly increased goblet cell density after 12 weeks of topical cyclosporine

- -

Mean Goblet Cell Density

Inferior Bulbar Conjunctiva

Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mea

n G

ob

let

Cel

ls

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 01 vs

baseline and

artificial

tears

bull Significantly increased goblet cell density

after 6 and 12 weeks of topical cyclosporine

10262015

8

- -

Systemic Disease

bull Diabetes

bull Rheumatoid Arthritis

ndash Sjogrenrsquos syndrome

bull Thyroid Disease

bull Dermatological eg rosacea

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 04 prevalence

bull Women gt Men (younger

women)

bull Much lower androgen counts

bull Treat underlying immune

disorder

- -

Which of these conditions are Sjogrenrsquos patients 46x

more likely to develop

A Leukemia

C Diabetes

B Lymphoma

D Cardiac Arrythmia

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 5-8 incidence of B-cell non-

Hodgkins Lymphoma

bull 463x more often

ndash Moutsopoulos HM et all

- -

Sjogrenrsquos Syndrome

bull Medical Treatments Secretagogues ndash Salagen 5 mg

bull Pilocarpine tablets

bull Avoid in asthma patients GI ulcer acute iritis or narrow angles

ndash Evoxac 30 mg TIDndash saliva stimulating drug bull Very effective with a lot less side effects

- -

Symptoms of Dry Eye

bull Burning

bull Stinging

bull Transient blur

bull Dryness

bull Photophobia

bull Epiphora

bull Blurred vision

bull Contact lens intolerance

bull Injection

bull Foreign body sensation

bull Grittiness

bull Increased blink rate

10262015

9

- -

Epiphora

bull SLEx finding -

Conjunctivochalasis or

trichiasis

bull Nasolacrimal sac obstruction

bull Lid Laxity conditions- ectropion

bull Dry Eye

- -

- -

- -

Clinic-cytologic study of conjunctivochalasis and its relation to thyroid autoimmune

diseases prospective cohort study

de Almeida SF de Sousa LB Vieira LA Chiamollera MI Barros Jde N

Department of Ophthalmology External Diseases and Cornea Service Federal University of Sao Paulo-Paulista Medical School Sao Paulo

Brazil sandraflaviaclick21combr

Abstract

PURPOSE To determine the prevalence of conjunctivochalasis in patients with immune thyroid diseases to determine whether

there is any association between the 2 diseases and to determine cytologic study of conjunctivochalasis through the cytology

impression test

METHODS A clinical prospective cohort study carried out by the External Diseases Department in the Ophthalmology Sector

and the Thyroid Department in the Endocrinology Sector at Federal University of Sao Paulo (UNIFESP) The patients included

were divided into 2 groups following these inclusion criteria a control group of 25 patients without thyroid diseases confirmed

after clinical and laboratory examinations (thyroid hormones) or any other ocular diseases The study group consisted of 31

patients with thyroid diseases the diagnosis of which was confirmed by the Endocrinology Sector The thyroidopathies included

were autoimmune diseases but excluded nonautoimmune diseases A protocol endorsed by the UNIFESP was followed using

clinical and ophthalmological history biomicroscopy and impression cytology

RESULTS Fifty-two percent of patients without thyroid diseases and 88 of patients with thyroid diseases presented with

conjunctivochalasis The risk ratio was 1705 (Pr gt chi(2) = 00038) indicating that there is an association between them For the

impression cytology in inferior bulbar conjunctiva there was an association between the result of the impression cytology and

conjunctivochalasis (Pearson chi(2) = 101190 Pr = 0006)

CONCLUSION The prevalence of conjunctivochalasis in patients with autoimmune thyroid diseases was 88 Patients with

autoimmune thyroidopathy presented higher percentages of conjunctivochalasis than the control group confirming the

association between them The cytologic study showed the highest prevalence of abnormal surface features in eyes with

conjunctivochalasis

- -

External examination

bull Skin

bull Eyelids

bull Cranial nerve function

bull Hands

- -

10262015

10

- -

Diagnostic Tests 2014

bull Pt history

bull Tear meniscus height

bull Tear break-up

bull NAFL Dye

bull Rose Bengal or Lissamine Green

bull Schirmer test - phenol thread test

- -

Diagnostic Testing NowFuture

1 Pt questionnaire- SPEED

2 TearLab osmolarity

3 Slit lamp examination

1 CCH anterior bleph incomplete closure

4 MG Expression

5 NAFL Dye

1 Tear meniscus heightTFBUT

2 Corneal staining- late indicator

6 Meibography

7 Blink analysis

- -

Osmolarity

- -

- -

- -

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

2

- -

Environment

bull Air conditioners or heaters

bull Airline travel

bull Winter months allergy season

bull Ceiling fan

bull Exogenous irritants (smoking)

bull Reading time

bull Digital device use

- -

DTS Clinical Categories in 2006

bull Most common presentation ldquoNo lid margin diseaserdquo

bull Treatment decision based on severity level

Dysfunctional Tear Syndrome

Lid Margin

Disease

Altered Tear

Distribution

No Lid Margin

Disease

Behrens et al submitted

- -

Anterior Blepharitis

- -

Anterior Blepharitis

- -

OcuSoft Tea Tree Kit

bull Contains Tea Tree Oil + Buckthorn seed oil

bull Bland Ung QHS

bull OcuSoft Lid Scrub Plus

- -

BlephEx Treatment

10262015

3

- -

Frothy Foamy Tears = MGD

38

Key Components to MGD

bull Obstruction

bull Inflammation

bull Biofilm development

bull Tear film alterationsinstability

14

Not present in all cases

38

Obstruction

bull Lid margin debridementscaling

bull Commercial WC (eg Bruder

TranquilEyes etc)

bull Cold or manual expression

bull Mechanical thermal pulsation

15

Obstruction Debridement-Scaling

bull Debridement-scaling of the line of Marx and keratinized lid margin improves MG function and reducing symptoms

bull Korb DR1 Blackie CA Debridement-scaling a new procedure that increases Meibomian gland function and reduces dry eye symptoms Cornea 2013 Dec32(12)1554-7

bull Ong BL Hodson SA Wigham T et al Evidence for keratin proteins in normal and abnormal human meibomian fluids Curr Eye Res 1991 Dec10(12)1113-9

16 14

7

Warm Compress Effectiveness

bull Olson MC1 Korb DR Greiner JV Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction Eye Contact Lens 2003 Apr29(2)96-9

bull Romero JM Biser SA Perry HD et al Conservative treatment of meibomian gland dysfunction Eye Contact Lens 2004 Jan30(1)14-9

bull Effective Requires continuous heat and temperature

bull Commercial compresses (eg Bruder) favored especially if they can provide hydration

17 14

7

Bruder Eye Hydrating Compress

18

10262015

4

Thermal Pulsation LipiFlow

bull Greiner JV A single LipiFlowreg Thermal Pulsation System treatment improves meibomian gland function and reduces dry eye symptoms for 9 monthsCurr Eye Res 201237272-278 3

bull Conclusion Single 12 minute procedure statistically improved MG secretions TFBUT and OSDI at 9 months

19 14

7

20

The device applies controlled heat to

the inner upper and lower palpebral

conjunctival surfaces and lid margins

while simultaneously applying

pulsating pressure over the upper and

lower (outer) eyelids

THERMODYNAMIC TX TO EXPRESS AND EVACUATE MGs

THE LIPIFLOW (TearScience Inc Morrisville NC)

A new thermodynamic treatment to express amp evacuate the MGs

Heat applied to both inner lid surfaces

Pulsatile pressure applied to outer lids

FDA approved LipiFlow July 2011

Thermal Pulsation LipiFlow

bull Blackie CA Carlson AN Korb DR Treatment for meibomian gland dysfunction and dry eye symptoms with a single-dose vectored thermal pulsation a review Curr Opin Ophthalmol 2015 Jul26(4)306-13

bull Review of 31 peer-reviewed reports on vectored thermal pulsation therapy at the time of the search (eight manuscripts and 23 meeting abstracts)

bull Effective Optimal temperature for entire time back surface simultaneous expression

21 14

7

38

BioFilm Development

bull Lid hygiene products (eg Ocusoft Lid

scrub plus or Sterilid etc)

bull Canister options seem to work well

bull Surfactant and hypochlorus acid

versions

bull Mechanical with surfactant cleaner (eg

Blephex)

22

Inflammation and MGD

bull Suzuki T Teramukai S Konoshita S Meibomian Glands and Ocular Surface Inflammation Ocul Surf 2015 Apr13(2)133-149

bull Baudouin C Revisiting meibomian gland dysfunctionJ Fr Ophtalmol 2014 Dec37(10)757-62

bull Aragona P Aguennouz M2 Rania L et al Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease Ophthalmology 2015 Jan122(1)62-71

bull Enriacutequez-de-Salamanca A1 Castellanos et al Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease Mol Vis 2010 May 1916862-73

23 14

7

The Cycle of Inflammation

Sym

pto

ms I

ncre

ase

Potential Long-term Damage Inflammation

Stasis inspissation and obstruction of the Meibomian Glands

Meibomian Gland Dysfunction (MGD)

Tissue Changes

Decrease in Meibomian secretions

Decrease in tear film stability increased aqueous tearing1

Increase in evaporative stress

Ocular surface exposure (between blinks) amp Micro-trauma (during blinking)

24

1 Arita R et al Increased Tear Fluid Production as a Compensatory Response to

Meibomian Gland Loss A Multicenter Cross-sectional Study Ophthalmology 2015

Jan 24 pii S0161-6420(14)01195-6 doi 101016jophtha201412018 [Epub

ahead of print]

10262015

5

38

Inflammation in MGD

bull Combination agents amp steroid agents

bull Topical AzaSite

bull Cyclosporine (Restasis)

bull Omega fatty acids

bull PO doxycycline or azithromycin

25

Clinical Reseach on Corticosteroids in MGD

Aragona P1 Aguennouz M2 Rania L3 et al Ophthalmology Matrix metalloproteinase-9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease 2015 Jan122(1)62-71 2014 Sep 18 Akyol-Salman I1 Azizi S Mumcu UY et al J Ocul Pharmacol Ther Comparison of the efficacy of topical N-acetyl-cysteine and a topical steroid-antibiotic combination therapy in the treatment of meibomian gland dysfunction 2012 Feb28(1)49-52

26

Clinical Research on Cyclosporine and MGD

bull Prabhasawat P Tesavibul N Mahawong W A randomized double-masked study of 005 cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction Cornea 2012 Dec31(12)1386-93

bull Conclusions OSDI TFBUT lid margin inflammation meibomian gland expressibility and tarsal injection showed significant improvement from baseline in group A (Plt001 Plt001 Plt0001 Plt005 and Plt0001 respectively) In group B only the OSDI improved significantly from baseline at 3 months (P=0003)

27

Clinical Research on Cyclosporine and MGD

bull International Workshop on MGD Report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction Gerd Geerling Joseph Tauber Christophe Baudouin et al

bull Reviewed MGD and cyclosporine data in MGD as favorable

bull Perry H Doshi-Carnevale S Donnenfeld E et al Efficacy of Commercially Available Topical Cyclosporine A 005 in the Treatment of Meibomian Gland Dysfunction Cornea 200625171ndash175

bull At the 3-month visit statistical improvements (plt 005) in lid margin vascular injection tarsal telangiectasis and NaFl staining Most significant finding (P = 0001) was the greater decrease in the number of meibomian gland inclusions in the tCsA group compared with the placebo group

28

Clinical Research on Cyclosporine and MGD

bull Rubin M Rao S Efficacy Topical Cyclosporine 005 in the Treatment of Posterior Blepharitis Ocular Pharmacology and Therapeutics Nov 2006 22 (1)

bull Conclusions Comparison of Cyclosporine to Tobradex for MGD after 12 weeks greater improvements in Schirmers scores (P lt 0001) and TBUT(P = 0018) than tobramycindexamethasone

bull Mean improvement in meibomian gland secretion quality was significantly greater with cyclosporin (P = 0015)

bull Higher percentage of patients in the cyclosporin treatment group had improvements in symptoms of blurred vision burning and itching and more cyclosporin-treated patients experienced resolution of lid telangiectasia

29

Clinical Research on Cyclosporine and MGD

bull Schechter BA Katz RS Friedman L Efficacy of Topical Cyclosporine for the Treatment of Ocular Rosacea Adv Ther (2009) 26(6)651-659

bull Conclusions Statistical improvement in Schirmer (with anesthesia)(Plt0001) meant TFBUT corneal staining scores (Plt0001) OSDI (P=0022) compared to artificial tears at 3 months

30

10262015

6

- -

Mild MGD

bull HotWarm compresses

bull Lid hygiene

bull Lipid based tears-mildmoderate

bull Osmolarity lowering drops in

moderatesevere

- -

ModerateAcute

bull Tobradex ST

bull Zylet

bull AzaSite

bull Tobradex generic

bull Steroid drops or ung bull (loteprednol preservative-free ung

QhS)

- -

Long Term

bull Pulse dose medications

periodically

bull Restasis bid

bull Essential fatty acids

ndash EPA

ndash DHA

ndash GLA

- -

Moderatesevere or not improving

bull Add PO tetracycline

bull Recommendation

bull Doxycycline 50mg bid x 4-12 weeks then taper to qd

bull Doxycycline 20 mg bid x 4-12 weeks then taper to qd (periostat concern $$$)

- -

Tetracyclines

bull Antibiotics inhibit

bacterial protein

synthesis by binding 30S ribosome

bull Anti-inflammatory properties

ndash decreases IL-1 TNF-

ndash decreases NO production

ndash decreases HLA Class II antigen expression

ndash decreases metalloproteinase production and

activation

bull Decrease symptoms and joint destruction in RA

- -

Contraindications

bull Pregnant or child bearing age

bull Children

10262015

7

- -

Cautions

bull Photosensitivity

bull Chelates with dairy products

antacids etc

bull Minocycline may cause vestibular

toxicity

bull Number one drop-out reason

bull GI problems

- -

Systemic medications bull Antihistamines

bull Diuretics

bull Antihypertensives

bull Anticholinergics

bull Antidepressants

bull Cardiac antiarrhythmic

bull Oral contraceptives

bull Hormone replacement therapy

- -

Contact lens wear

bull Schedule amp Care

bull Type of Lens

ndash Daily Disposable

bull DT1 TruEye

ndash Non-ionic low water content weekly disposable

bull Hydrogel Vision icuity

ndash SiHy 30 day

bull BampL Ultra

- -

Refractive surgery

bull Common for first 3-6 months

ndash Neurotrophic

ndash Goblet cell density

ndash Tear flow

- - Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mean

Go

ble

t C

ells

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 001 vs

baseline tears and

CsA 6 weeks

Mean Goblet Cell Density

Temporal Bulbar Conjunctiva

bull Significantly increased goblet cell density after 12 weeks of topical cyclosporine

- -

Mean Goblet Cell Density

Inferior Bulbar Conjunctiva

Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mea

n G

ob

let

Cel

ls

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 01 vs

baseline and

artificial

tears

bull Significantly increased goblet cell density

after 6 and 12 weeks of topical cyclosporine

10262015

8

- -

Systemic Disease

bull Diabetes

bull Rheumatoid Arthritis

ndash Sjogrenrsquos syndrome

bull Thyroid Disease

bull Dermatological eg rosacea

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 04 prevalence

bull Women gt Men (younger

women)

bull Much lower androgen counts

bull Treat underlying immune

disorder

- -

Which of these conditions are Sjogrenrsquos patients 46x

more likely to develop

A Leukemia

C Diabetes

B Lymphoma

D Cardiac Arrythmia

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 5-8 incidence of B-cell non-

Hodgkins Lymphoma

bull 463x more often

ndash Moutsopoulos HM et all

- -

Sjogrenrsquos Syndrome

bull Medical Treatments Secretagogues ndash Salagen 5 mg

bull Pilocarpine tablets

bull Avoid in asthma patients GI ulcer acute iritis or narrow angles

ndash Evoxac 30 mg TIDndash saliva stimulating drug bull Very effective with a lot less side effects

- -

Symptoms of Dry Eye

bull Burning

bull Stinging

bull Transient blur

bull Dryness

bull Photophobia

bull Epiphora

bull Blurred vision

bull Contact lens intolerance

bull Injection

bull Foreign body sensation

bull Grittiness

bull Increased blink rate

10262015

9

- -

Epiphora

bull SLEx finding -

Conjunctivochalasis or

trichiasis

bull Nasolacrimal sac obstruction

bull Lid Laxity conditions- ectropion

bull Dry Eye

- -

- -

- -

Clinic-cytologic study of conjunctivochalasis and its relation to thyroid autoimmune

diseases prospective cohort study

de Almeida SF de Sousa LB Vieira LA Chiamollera MI Barros Jde N

Department of Ophthalmology External Diseases and Cornea Service Federal University of Sao Paulo-Paulista Medical School Sao Paulo

Brazil sandraflaviaclick21combr

Abstract

PURPOSE To determine the prevalence of conjunctivochalasis in patients with immune thyroid diseases to determine whether

there is any association between the 2 diseases and to determine cytologic study of conjunctivochalasis through the cytology

impression test

METHODS A clinical prospective cohort study carried out by the External Diseases Department in the Ophthalmology Sector

and the Thyroid Department in the Endocrinology Sector at Federal University of Sao Paulo (UNIFESP) The patients included

were divided into 2 groups following these inclusion criteria a control group of 25 patients without thyroid diseases confirmed

after clinical and laboratory examinations (thyroid hormones) or any other ocular diseases The study group consisted of 31

patients with thyroid diseases the diagnosis of which was confirmed by the Endocrinology Sector The thyroidopathies included

were autoimmune diseases but excluded nonautoimmune diseases A protocol endorsed by the UNIFESP was followed using

clinical and ophthalmological history biomicroscopy and impression cytology

RESULTS Fifty-two percent of patients without thyroid diseases and 88 of patients with thyroid diseases presented with

conjunctivochalasis The risk ratio was 1705 (Pr gt chi(2) = 00038) indicating that there is an association between them For the

impression cytology in inferior bulbar conjunctiva there was an association between the result of the impression cytology and

conjunctivochalasis (Pearson chi(2) = 101190 Pr = 0006)

CONCLUSION The prevalence of conjunctivochalasis in patients with autoimmune thyroid diseases was 88 Patients with

autoimmune thyroidopathy presented higher percentages of conjunctivochalasis than the control group confirming the

association between them The cytologic study showed the highest prevalence of abnormal surface features in eyes with

conjunctivochalasis

- -

External examination

bull Skin

bull Eyelids

bull Cranial nerve function

bull Hands

- -

10262015

10

- -

Diagnostic Tests 2014

bull Pt history

bull Tear meniscus height

bull Tear break-up

bull NAFL Dye

bull Rose Bengal or Lissamine Green

bull Schirmer test - phenol thread test

- -

Diagnostic Testing NowFuture

1 Pt questionnaire- SPEED

2 TearLab osmolarity

3 Slit lamp examination

1 CCH anterior bleph incomplete closure

4 MG Expression

5 NAFL Dye

1 Tear meniscus heightTFBUT

2 Corneal staining- late indicator

6 Meibography

7 Blink analysis

- -

Osmolarity

- -

- -

- -

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

3

- -

Frothy Foamy Tears = MGD

38

Key Components to MGD

bull Obstruction

bull Inflammation

bull Biofilm development

bull Tear film alterationsinstability

14

Not present in all cases

38

Obstruction

bull Lid margin debridementscaling

bull Commercial WC (eg Bruder

TranquilEyes etc)

bull Cold or manual expression

bull Mechanical thermal pulsation

15

Obstruction Debridement-Scaling

bull Debridement-scaling of the line of Marx and keratinized lid margin improves MG function and reducing symptoms

bull Korb DR1 Blackie CA Debridement-scaling a new procedure that increases Meibomian gland function and reduces dry eye symptoms Cornea 2013 Dec32(12)1554-7

bull Ong BL Hodson SA Wigham T et al Evidence for keratin proteins in normal and abnormal human meibomian fluids Curr Eye Res 1991 Dec10(12)1113-9

16 14

7

Warm Compress Effectiveness

bull Olson MC1 Korb DR Greiner JV Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction Eye Contact Lens 2003 Apr29(2)96-9

bull Romero JM Biser SA Perry HD et al Conservative treatment of meibomian gland dysfunction Eye Contact Lens 2004 Jan30(1)14-9

bull Effective Requires continuous heat and temperature

bull Commercial compresses (eg Bruder) favored especially if they can provide hydration

17 14

7

Bruder Eye Hydrating Compress

18

10262015

4

Thermal Pulsation LipiFlow

bull Greiner JV A single LipiFlowreg Thermal Pulsation System treatment improves meibomian gland function and reduces dry eye symptoms for 9 monthsCurr Eye Res 201237272-278 3

bull Conclusion Single 12 minute procedure statistically improved MG secretions TFBUT and OSDI at 9 months

19 14

7

20

The device applies controlled heat to

the inner upper and lower palpebral

conjunctival surfaces and lid margins

while simultaneously applying

pulsating pressure over the upper and

lower (outer) eyelids

THERMODYNAMIC TX TO EXPRESS AND EVACUATE MGs

THE LIPIFLOW (TearScience Inc Morrisville NC)

A new thermodynamic treatment to express amp evacuate the MGs

Heat applied to both inner lid surfaces

Pulsatile pressure applied to outer lids

FDA approved LipiFlow July 2011

Thermal Pulsation LipiFlow

bull Blackie CA Carlson AN Korb DR Treatment for meibomian gland dysfunction and dry eye symptoms with a single-dose vectored thermal pulsation a review Curr Opin Ophthalmol 2015 Jul26(4)306-13

bull Review of 31 peer-reviewed reports on vectored thermal pulsation therapy at the time of the search (eight manuscripts and 23 meeting abstracts)

bull Effective Optimal temperature for entire time back surface simultaneous expression

21 14

7

38

BioFilm Development

bull Lid hygiene products (eg Ocusoft Lid

scrub plus or Sterilid etc)

bull Canister options seem to work well

bull Surfactant and hypochlorus acid

versions

bull Mechanical with surfactant cleaner (eg

Blephex)

22

Inflammation and MGD

bull Suzuki T Teramukai S Konoshita S Meibomian Glands and Ocular Surface Inflammation Ocul Surf 2015 Apr13(2)133-149

bull Baudouin C Revisiting meibomian gland dysfunctionJ Fr Ophtalmol 2014 Dec37(10)757-62

bull Aragona P Aguennouz M2 Rania L et al Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease Ophthalmology 2015 Jan122(1)62-71

bull Enriacutequez-de-Salamanca A1 Castellanos et al Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease Mol Vis 2010 May 1916862-73

23 14

7

The Cycle of Inflammation

Sym

pto

ms I

ncre

ase

Potential Long-term Damage Inflammation

Stasis inspissation and obstruction of the Meibomian Glands

Meibomian Gland Dysfunction (MGD)

Tissue Changes

Decrease in Meibomian secretions

Decrease in tear film stability increased aqueous tearing1

Increase in evaporative stress

Ocular surface exposure (between blinks) amp Micro-trauma (during blinking)

24

1 Arita R et al Increased Tear Fluid Production as a Compensatory Response to

Meibomian Gland Loss A Multicenter Cross-sectional Study Ophthalmology 2015

Jan 24 pii S0161-6420(14)01195-6 doi 101016jophtha201412018 [Epub

ahead of print]

10262015

5

38

Inflammation in MGD

bull Combination agents amp steroid agents

bull Topical AzaSite

bull Cyclosporine (Restasis)

bull Omega fatty acids

bull PO doxycycline or azithromycin

25

Clinical Reseach on Corticosteroids in MGD

Aragona P1 Aguennouz M2 Rania L3 et al Ophthalmology Matrix metalloproteinase-9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease 2015 Jan122(1)62-71 2014 Sep 18 Akyol-Salman I1 Azizi S Mumcu UY et al J Ocul Pharmacol Ther Comparison of the efficacy of topical N-acetyl-cysteine and a topical steroid-antibiotic combination therapy in the treatment of meibomian gland dysfunction 2012 Feb28(1)49-52

26

Clinical Research on Cyclosporine and MGD

bull Prabhasawat P Tesavibul N Mahawong W A randomized double-masked study of 005 cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction Cornea 2012 Dec31(12)1386-93

bull Conclusions OSDI TFBUT lid margin inflammation meibomian gland expressibility and tarsal injection showed significant improvement from baseline in group A (Plt001 Plt001 Plt0001 Plt005 and Plt0001 respectively) In group B only the OSDI improved significantly from baseline at 3 months (P=0003)

27

Clinical Research on Cyclosporine and MGD

bull International Workshop on MGD Report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction Gerd Geerling Joseph Tauber Christophe Baudouin et al

bull Reviewed MGD and cyclosporine data in MGD as favorable

bull Perry H Doshi-Carnevale S Donnenfeld E et al Efficacy of Commercially Available Topical Cyclosporine A 005 in the Treatment of Meibomian Gland Dysfunction Cornea 200625171ndash175

bull At the 3-month visit statistical improvements (plt 005) in lid margin vascular injection tarsal telangiectasis and NaFl staining Most significant finding (P = 0001) was the greater decrease in the number of meibomian gland inclusions in the tCsA group compared with the placebo group

28

Clinical Research on Cyclosporine and MGD

bull Rubin M Rao S Efficacy Topical Cyclosporine 005 in the Treatment of Posterior Blepharitis Ocular Pharmacology and Therapeutics Nov 2006 22 (1)

bull Conclusions Comparison of Cyclosporine to Tobradex for MGD after 12 weeks greater improvements in Schirmers scores (P lt 0001) and TBUT(P = 0018) than tobramycindexamethasone

bull Mean improvement in meibomian gland secretion quality was significantly greater with cyclosporin (P = 0015)

bull Higher percentage of patients in the cyclosporin treatment group had improvements in symptoms of blurred vision burning and itching and more cyclosporin-treated patients experienced resolution of lid telangiectasia

29

Clinical Research on Cyclosporine and MGD

bull Schechter BA Katz RS Friedman L Efficacy of Topical Cyclosporine for the Treatment of Ocular Rosacea Adv Ther (2009) 26(6)651-659

bull Conclusions Statistical improvement in Schirmer (with anesthesia)(Plt0001) meant TFBUT corneal staining scores (Plt0001) OSDI (P=0022) compared to artificial tears at 3 months

30

10262015

6

- -

Mild MGD

bull HotWarm compresses

bull Lid hygiene

bull Lipid based tears-mildmoderate

bull Osmolarity lowering drops in

moderatesevere

- -

ModerateAcute

bull Tobradex ST

bull Zylet

bull AzaSite

bull Tobradex generic

bull Steroid drops or ung bull (loteprednol preservative-free ung

QhS)

- -

Long Term

bull Pulse dose medications

periodically

bull Restasis bid

bull Essential fatty acids

ndash EPA

ndash DHA

ndash GLA

- -

Moderatesevere or not improving

bull Add PO tetracycline

bull Recommendation

bull Doxycycline 50mg bid x 4-12 weeks then taper to qd

bull Doxycycline 20 mg bid x 4-12 weeks then taper to qd (periostat concern $$$)

- -

Tetracyclines

bull Antibiotics inhibit

bacterial protein

synthesis by binding 30S ribosome

bull Anti-inflammatory properties

ndash decreases IL-1 TNF-

ndash decreases NO production

ndash decreases HLA Class II antigen expression

ndash decreases metalloproteinase production and

activation

bull Decrease symptoms and joint destruction in RA

- -

Contraindications

bull Pregnant or child bearing age

bull Children

10262015

7

- -

Cautions

bull Photosensitivity

bull Chelates with dairy products

antacids etc

bull Minocycline may cause vestibular

toxicity

bull Number one drop-out reason

bull GI problems

- -

Systemic medications bull Antihistamines

bull Diuretics

bull Antihypertensives

bull Anticholinergics

bull Antidepressants

bull Cardiac antiarrhythmic

bull Oral contraceptives

bull Hormone replacement therapy

- -

Contact lens wear

bull Schedule amp Care

bull Type of Lens

ndash Daily Disposable

bull DT1 TruEye

ndash Non-ionic low water content weekly disposable

bull Hydrogel Vision icuity

ndash SiHy 30 day

bull BampL Ultra

- -

Refractive surgery

bull Common for first 3-6 months

ndash Neurotrophic

ndash Goblet cell density

ndash Tear flow

- - Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mean

Go

ble

t C

ells

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 001 vs

baseline tears and

CsA 6 weeks

Mean Goblet Cell Density

Temporal Bulbar Conjunctiva

bull Significantly increased goblet cell density after 12 weeks of topical cyclosporine

- -

Mean Goblet Cell Density

Inferior Bulbar Conjunctiva

Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mea

n G

ob

let

Cel

ls

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 01 vs

baseline and

artificial

tears

bull Significantly increased goblet cell density

after 6 and 12 weeks of topical cyclosporine

10262015

8

- -

Systemic Disease

bull Diabetes

bull Rheumatoid Arthritis

ndash Sjogrenrsquos syndrome

bull Thyroid Disease

bull Dermatological eg rosacea

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 04 prevalence

bull Women gt Men (younger

women)

bull Much lower androgen counts

bull Treat underlying immune

disorder

- -

Which of these conditions are Sjogrenrsquos patients 46x

more likely to develop

A Leukemia

C Diabetes

B Lymphoma

D Cardiac Arrythmia

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 5-8 incidence of B-cell non-

Hodgkins Lymphoma

bull 463x more often

ndash Moutsopoulos HM et all

- -

Sjogrenrsquos Syndrome

bull Medical Treatments Secretagogues ndash Salagen 5 mg

bull Pilocarpine tablets

bull Avoid in asthma patients GI ulcer acute iritis or narrow angles

ndash Evoxac 30 mg TIDndash saliva stimulating drug bull Very effective with a lot less side effects

- -

Symptoms of Dry Eye

bull Burning

bull Stinging

bull Transient blur

bull Dryness

bull Photophobia

bull Epiphora

bull Blurred vision

bull Contact lens intolerance

bull Injection

bull Foreign body sensation

bull Grittiness

bull Increased blink rate

10262015

9

- -

Epiphora

bull SLEx finding -

Conjunctivochalasis or

trichiasis

bull Nasolacrimal sac obstruction

bull Lid Laxity conditions- ectropion

bull Dry Eye

- -

- -

- -

Clinic-cytologic study of conjunctivochalasis and its relation to thyroid autoimmune

diseases prospective cohort study

de Almeida SF de Sousa LB Vieira LA Chiamollera MI Barros Jde N

Department of Ophthalmology External Diseases and Cornea Service Federal University of Sao Paulo-Paulista Medical School Sao Paulo

Brazil sandraflaviaclick21combr

Abstract

PURPOSE To determine the prevalence of conjunctivochalasis in patients with immune thyroid diseases to determine whether

there is any association between the 2 diseases and to determine cytologic study of conjunctivochalasis through the cytology

impression test

METHODS A clinical prospective cohort study carried out by the External Diseases Department in the Ophthalmology Sector

and the Thyroid Department in the Endocrinology Sector at Federal University of Sao Paulo (UNIFESP) The patients included

were divided into 2 groups following these inclusion criteria a control group of 25 patients without thyroid diseases confirmed

after clinical and laboratory examinations (thyroid hormones) or any other ocular diseases The study group consisted of 31

patients with thyroid diseases the diagnosis of which was confirmed by the Endocrinology Sector The thyroidopathies included

were autoimmune diseases but excluded nonautoimmune diseases A protocol endorsed by the UNIFESP was followed using

clinical and ophthalmological history biomicroscopy and impression cytology

RESULTS Fifty-two percent of patients without thyroid diseases and 88 of patients with thyroid diseases presented with

conjunctivochalasis The risk ratio was 1705 (Pr gt chi(2) = 00038) indicating that there is an association between them For the

impression cytology in inferior bulbar conjunctiva there was an association between the result of the impression cytology and

conjunctivochalasis (Pearson chi(2) = 101190 Pr = 0006)

CONCLUSION The prevalence of conjunctivochalasis in patients with autoimmune thyroid diseases was 88 Patients with

autoimmune thyroidopathy presented higher percentages of conjunctivochalasis than the control group confirming the

association between them The cytologic study showed the highest prevalence of abnormal surface features in eyes with

conjunctivochalasis

- -

External examination

bull Skin

bull Eyelids

bull Cranial nerve function

bull Hands

- -

10262015

10

- -

Diagnostic Tests 2014

bull Pt history

bull Tear meniscus height

bull Tear break-up

bull NAFL Dye

bull Rose Bengal or Lissamine Green

bull Schirmer test - phenol thread test

- -

Diagnostic Testing NowFuture

1 Pt questionnaire- SPEED

2 TearLab osmolarity

3 Slit lamp examination

1 CCH anterior bleph incomplete closure

4 MG Expression

5 NAFL Dye

1 Tear meniscus heightTFBUT

2 Corneal staining- late indicator

6 Meibography

7 Blink analysis

- -

Osmolarity

- -

- -

- -

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

4

Thermal Pulsation LipiFlow

bull Greiner JV A single LipiFlowreg Thermal Pulsation System treatment improves meibomian gland function and reduces dry eye symptoms for 9 monthsCurr Eye Res 201237272-278 3

bull Conclusion Single 12 minute procedure statistically improved MG secretions TFBUT and OSDI at 9 months

19 14

7

20

The device applies controlled heat to

the inner upper and lower palpebral

conjunctival surfaces and lid margins

while simultaneously applying

pulsating pressure over the upper and

lower (outer) eyelids

THERMODYNAMIC TX TO EXPRESS AND EVACUATE MGs

THE LIPIFLOW (TearScience Inc Morrisville NC)

A new thermodynamic treatment to express amp evacuate the MGs

Heat applied to both inner lid surfaces

Pulsatile pressure applied to outer lids

FDA approved LipiFlow July 2011

Thermal Pulsation LipiFlow

bull Blackie CA Carlson AN Korb DR Treatment for meibomian gland dysfunction and dry eye symptoms with a single-dose vectored thermal pulsation a review Curr Opin Ophthalmol 2015 Jul26(4)306-13

bull Review of 31 peer-reviewed reports on vectored thermal pulsation therapy at the time of the search (eight manuscripts and 23 meeting abstracts)

bull Effective Optimal temperature for entire time back surface simultaneous expression

21 14

7

38

BioFilm Development

bull Lid hygiene products (eg Ocusoft Lid

scrub plus or Sterilid etc)

bull Canister options seem to work well

bull Surfactant and hypochlorus acid

versions

bull Mechanical with surfactant cleaner (eg

Blephex)

22

Inflammation and MGD

bull Suzuki T Teramukai S Konoshita S Meibomian Glands and Ocular Surface Inflammation Ocul Surf 2015 Apr13(2)133-149

bull Baudouin C Revisiting meibomian gland dysfunctionJ Fr Ophtalmol 2014 Dec37(10)757-62

bull Aragona P Aguennouz M2 Rania L et al Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease Ophthalmology 2015 Jan122(1)62-71

bull Enriacutequez-de-Salamanca A1 Castellanos et al Tear cytokine and chemokine analysis and clinical correlations in evaporative-type dry eye disease Mol Vis 2010 May 1916862-73

23 14

7

The Cycle of Inflammation

Sym

pto

ms I

ncre

ase

Potential Long-term Damage Inflammation

Stasis inspissation and obstruction of the Meibomian Glands

Meibomian Gland Dysfunction (MGD)

Tissue Changes

Decrease in Meibomian secretions

Decrease in tear film stability increased aqueous tearing1

Increase in evaporative stress

Ocular surface exposure (between blinks) amp Micro-trauma (during blinking)

24

1 Arita R et al Increased Tear Fluid Production as a Compensatory Response to

Meibomian Gland Loss A Multicenter Cross-sectional Study Ophthalmology 2015

Jan 24 pii S0161-6420(14)01195-6 doi 101016jophtha201412018 [Epub

ahead of print]

10262015

5

38

Inflammation in MGD

bull Combination agents amp steroid agents

bull Topical AzaSite

bull Cyclosporine (Restasis)

bull Omega fatty acids

bull PO doxycycline or azithromycin

25

Clinical Reseach on Corticosteroids in MGD

Aragona P1 Aguennouz M2 Rania L3 et al Ophthalmology Matrix metalloproteinase-9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease 2015 Jan122(1)62-71 2014 Sep 18 Akyol-Salman I1 Azizi S Mumcu UY et al J Ocul Pharmacol Ther Comparison of the efficacy of topical N-acetyl-cysteine and a topical steroid-antibiotic combination therapy in the treatment of meibomian gland dysfunction 2012 Feb28(1)49-52

26

Clinical Research on Cyclosporine and MGD

bull Prabhasawat P Tesavibul N Mahawong W A randomized double-masked study of 005 cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction Cornea 2012 Dec31(12)1386-93

bull Conclusions OSDI TFBUT lid margin inflammation meibomian gland expressibility and tarsal injection showed significant improvement from baseline in group A (Plt001 Plt001 Plt0001 Plt005 and Plt0001 respectively) In group B only the OSDI improved significantly from baseline at 3 months (P=0003)

27

Clinical Research on Cyclosporine and MGD

bull International Workshop on MGD Report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction Gerd Geerling Joseph Tauber Christophe Baudouin et al

bull Reviewed MGD and cyclosporine data in MGD as favorable

bull Perry H Doshi-Carnevale S Donnenfeld E et al Efficacy of Commercially Available Topical Cyclosporine A 005 in the Treatment of Meibomian Gland Dysfunction Cornea 200625171ndash175

bull At the 3-month visit statistical improvements (plt 005) in lid margin vascular injection tarsal telangiectasis and NaFl staining Most significant finding (P = 0001) was the greater decrease in the number of meibomian gland inclusions in the tCsA group compared with the placebo group

28

Clinical Research on Cyclosporine and MGD

bull Rubin M Rao S Efficacy Topical Cyclosporine 005 in the Treatment of Posterior Blepharitis Ocular Pharmacology and Therapeutics Nov 2006 22 (1)

bull Conclusions Comparison of Cyclosporine to Tobradex for MGD after 12 weeks greater improvements in Schirmers scores (P lt 0001) and TBUT(P = 0018) than tobramycindexamethasone

bull Mean improvement in meibomian gland secretion quality was significantly greater with cyclosporin (P = 0015)

bull Higher percentage of patients in the cyclosporin treatment group had improvements in symptoms of blurred vision burning and itching and more cyclosporin-treated patients experienced resolution of lid telangiectasia

29

Clinical Research on Cyclosporine and MGD

bull Schechter BA Katz RS Friedman L Efficacy of Topical Cyclosporine for the Treatment of Ocular Rosacea Adv Ther (2009) 26(6)651-659

bull Conclusions Statistical improvement in Schirmer (with anesthesia)(Plt0001) meant TFBUT corneal staining scores (Plt0001) OSDI (P=0022) compared to artificial tears at 3 months

30

10262015

6

- -

Mild MGD

bull HotWarm compresses

bull Lid hygiene

bull Lipid based tears-mildmoderate

bull Osmolarity lowering drops in

moderatesevere

- -

ModerateAcute

bull Tobradex ST

bull Zylet

bull AzaSite

bull Tobradex generic

bull Steroid drops or ung bull (loteprednol preservative-free ung

QhS)

- -

Long Term

bull Pulse dose medications

periodically

bull Restasis bid

bull Essential fatty acids

ndash EPA

ndash DHA

ndash GLA

- -

Moderatesevere or not improving

bull Add PO tetracycline

bull Recommendation

bull Doxycycline 50mg bid x 4-12 weeks then taper to qd

bull Doxycycline 20 mg bid x 4-12 weeks then taper to qd (periostat concern $$$)

- -

Tetracyclines

bull Antibiotics inhibit

bacterial protein

synthesis by binding 30S ribosome

bull Anti-inflammatory properties

ndash decreases IL-1 TNF-

ndash decreases NO production

ndash decreases HLA Class II antigen expression

ndash decreases metalloproteinase production and

activation

bull Decrease symptoms and joint destruction in RA

- -

Contraindications

bull Pregnant or child bearing age

bull Children

10262015

7

- -

Cautions

bull Photosensitivity

bull Chelates with dairy products

antacids etc

bull Minocycline may cause vestibular

toxicity

bull Number one drop-out reason

bull GI problems

- -

Systemic medications bull Antihistamines

bull Diuretics

bull Antihypertensives

bull Anticholinergics

bull Antidepressants

bull Cardiac antiarrhythmic

bull Oral contraceptives

bull Hormone replacement therapy

- -

Contact lens wear

bull Schedule amp Care

bull Type of Lens

ndash Daily Disposable

bull DT1 TruEye

ndash Non-ionic low water content weekly disposable

bull Hydrogel Vision icuity

ndash SiHy 30 day

bull BampL Ultra

- -

Refractive surgery

bull Common for first 3-6 months

ndash Neurotrophic

ndash Goblet cell density

ndash Tear flow

- - Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mean

Go

ble

t C

ells

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 001 vs

baseline tears and

CsA 6 weeks

Mean Goblet Cell Density

Temporal Bulbar Conjunctiva

bull Significantly increased goblet cell density after 12 weeks of topical cyclosporine

- -

Mean Goblet Cell Density

Inferior Bulbar Conjunctiva

Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mea

n G

ob

let

Cel

ls

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 01 vs

baseline and

artificial

tears

bull Significantly increased goblet cell density

after 6 and 12 weeks of topical cyclosporine

10262015

8

- -

Systemic Disease

bull Diabetes

bull Rheumatoid Arthritis

ndash Sjogrenrsquos syndrome

bull Thyroid Disease

bull Dermatological eg rosacea

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 04 prevalence

bull Women gt Men (younger

women)

bull Much lower androgen counts

bull Treat underlying immune

disorder

- -

Which of these conditions are Sjogrenrsquos patients 46x

more likely to develop

A Leukemia

C Diabetes

B Lymphoma

D Cardiac Arrythmia

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 5-8 incidence of B-cell non-

Hodgkins Lymphoma

bull 463x more often

ndash Moutsopoulos HM et all

- -

Sjogrenrsquos Syndrome

bull Medical Treatments Secretagogues ndash Salagen 5 mg

bull Pilocarpine tablets

bull Avoid in asthma patients GI ulcer acute iritis or narrow angles

ndash Evoxac 30 mg TIDndash saliva stimulating drug bull Very effective with a lot less side effects

- -

Symptoms of Dry Eye

bull Burning

bull Stinging

bull Transient blur

bull Dryness

bull Photophobia

bull Epiphora

bull Blurred vision

bull Contact lens intolerance

bull Injection

bull Foreign body sensation

bull Grittiness

bull Increased blink rate

10262015

9

- -

Epiphora

bull SLEx finding -

Conjunctivochalasis or

trichiasis

bull Nasolacrimal sac obstruction

bull Lid Laxity conditions- ectropion

bull Dry Eye

- -

- -

- -

Clinic-cytologic study of conjunctivochalasis and its relation to thyroid autoimmune

diseases prospective cohort study

de Almeida SF de Sousa LB Vieira LA Chiamollera MI Barros Jde N

Department of Ophthalmology External Diseases and Cornea Service Federal University of Sao Paulo-Paulista Medical School Sao Paulo

Brazil sandraflaviaclick21combr

Abstract

PURPOSE To determine the prevalence of conjunctivochalasis in patients with immune thyroid diseases to determine whether

there is any association between the 2 diseases and to determine cytologic study of conjunctivochalasis through the cytology

impression test

METHODS A clinical prospective cohort study carried out by the External Diseases Department in the Ophthalmology Sector

and the Thyroid Department in the Endocrinology Sector at Federal University of Sao Paulo (UNIFESP) The patients included

were divided into 2 groups following these inclusion criteria a control group of 25 patients without thyroid diseases confirmed

after clinical and laboratory examinations (thyroid hormones) or any other ocular diseases The study group consisted of 31

patients with thyroid diseases the diagnosis of which was confirmed by the Endocrinology Sector The thyroidopathies included

were autoimmune diseases but excluded nonautoimmune diseases A protocol endorsed by the UNIFESP was followed using

clinical and ophthalmological history biomicroscopy and impression cytology

RESULTS Fifty-two percent of patients without thyroid diseases and 88 of patients with thyroid diseases presented with

conjunctivochalasis The risk ratio was 1705 (Pr gt chi(2) = 00038) indicating that there is an association between them For the

impression cytology in inferior bulbar conjunctiva there was an association between the result of the impression cytology and

conjunctivochalasis (Pearson chi(2) = 101190 Pr = 0006)

CONCLUSION The prevalence of conjunctivochalasis in patients with autoimmune thyroid diseases was 88 Patients with

autoimmune thyroidopathy presented higher percentages of conjunctivochalasis than the control group confirming the

association between them The cytologic study showed the highest prevalence of abnormal surface features in eyes with

conjunctivochalasis

- -

External examination

bull Skin

bull Eyelids

bull Cranial nerve function

bull Hands

- -

10262015

10

- -

Diagnostic Tests 2014

bull Pt history

bull Tear meniscus height

bull Tear break-up

bull NAFL Dye

bull Rose Bengal or Lissamine Green

bull Schirmer test - phenol thread test

- -

Diagnostic Testing NowFuture

1 Pt questionnaire- SPEED

2 TearLab osmolarity

3 Slit lamp examination

1 CCH anterior bleph incomplete closure

4 MG Expression

5 NAFL Dye

1 Tear meniscus heightTFBUT

2 Corneal staining- late indicator

6 Meibography

7 Blink analysis

- -

Osmolarity

- -

- -

- -

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

5

38

Inflammation in MGD

bull Combination agents amp steroid agents

bull Topical AzaSite

bull Cyclosporine (Restasis)

bull Omega fatty acids

bull PO doxycycline or azithromycin

25

Clinical Reseach on Corticosteroids in MGD

Aragona P1 Aguennouz M2 Rania L3 et al Ophthalmology Matrix metalloproteinase-9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease 2015 Jan122(1)62-71 2014 Sep 18 Akyol-Salman I1 Azizi S Mumcu UY et al J Ocul Pharmacol Ther Comparison of the efficacy of topical N-acetyl-cysteine and a topical steroid-antibiotic combination therapy in the treatment of meibomian gland dysfunction 2012 Feb28(1)49-52

26

Clinical Research on Cyclosporine and MGD

bull Prabhasawat P Tesavibul N Mahawong W A randomized double-masked study of 005 cyclosporine ophthalmic emulsion in the treatment of meibomian gland dysfunction Cornea 2012 Dec31(12)1386-93

bull Conclusions OSDI TFBUT lid margin inflammation meibomian gland expressibility and tarsal injection showed significant improvement from baseline in group A (Plt001 Plt001 Plt0001 Plt005 and Plt0001 respectively) In group B only the OSDI improved significantly from baseline at 3 months (P=0003)

27

Clinical Research on Cyclosporine and MGD

bull International Workshop on MGD Report of the Subcommittee on Management and Treatment of Meibomian Gland Dysfunction Gerd Geerling Joseph Tauber Christophe Baudouin et al

bull Reviewed MGD and cyclosporine data in MGD as favorable

bull Perry H Doshi-Carnevale S Donnenfeld E et al Efficacy of Commercially Available Topical Cyclosporine A 005 in the Treatment of Meibomian Gland Dysfunction Cornea 200625171ndash175

bull At the 3-month visit statistical improvements (plt 005) in lid margin vascular injection tarsal telangiectasis and NaFl staining Most significant finding (P = 0001) was the greater decrease in the number of meibomian gland inclusions in the tCsA group compared with the placebo group

28

Clinical Research on Cyclosporine and MGD

bull Rubin M Rao S Efficacy Topical Cyclosporine 005 in the Treatment of Posterior Blepharitis Ocular Pharmacology and Therapeutics Nov 2006 22 (1)

bull Conclusions Comparison of Cyclosporine to Tobradex for MGD after 12 weeks greater improvements in Schirmers scores (P lt 0001) and TBUT(P = 0018) than tobramycindexamethasone

bull Mean improvement in meibomian gland secretion quality was significantly greater with cyclosporin (P = 0015)

bull Higher percentage of patients in the cyclosporin treatment group had improvements in symptoms of blurred vision burning and itching and more cyclosporin-treated patients experienced resolution of lid telangiectasia

29

Clinical Research on Cyclosporine and MGD

bull Schechter BA Katz RS Friedman L Efficacy of Topical Cyclosporine for the Treatment of Ocular Rosacea Adv Ther (2009) 26(6)651-659

bull Conclusions Statistical improvement in Schirmer (with anesthesia)(Plt0001) meant TFBUT corneal staining scores (Plt0001) OSDI (P=0022) compared to artificial tears at 3 months

30

10262015

6

- -

Mild MGD

bull HotWarm compresses

bull Lid hygiene

bull Lipid based tears-mildmoderate

bull Osmolarity lowering drops in

moderatesevere

- -

ModerateAcute

bull Tobradex ST

bull Zylet

bull AzaSite

bull Tobradex generic

bull Steroid drops or ung bull (loteprednol preservative-free ung

QhS)

- -

Long Term

bull Pulse dose medications

periodically

bull Restasis bid

bull Essential fatty acids

ndash EPA

ndash DHA

ndash GLA

- -

Moderatesevere or not improving

bull Add PO tetracycline

bull Recommendation

bull Doxycycline 50mg bid x 4-12 weeks then taper to qd

bull Doxycycline 20 mg bid x 4-12 weeks then taper to qd (periostat concern $$$)

- -

Tetracyclines

bull Antibiotics inhibit

bacterial protein

synthesis by binding 30S ribosome

bull Anti-inflammatory properties

ndash decreases IL-1 TNF-

ndash decreases NO production

ndash decreases HLA Class II antigen expression

ndash decreases metalloproteinase production and

activation

bull Decrease symptoms and joint destruction in RA

- -

Contraindications

bull Pregnant or child bearing age

bull Children

10262015

7

- -

Cautions

bull Photosensitivity

bull Chelates with dairy products

antacids etc

bull Minocycline may cause vestibular

toxicity

bull Number one drop-out reason

bull GI problems

- -

Systemic medications bull Antihistamines

bull Diuretics

bull Antihypertensives

bull Anticholinergics

bull Antidepressants

bull Cardiac antiarrhythmic

bull Oral contraceptives

bull Hormone replacement therapy

- -

Contact lens wear

bull Schedule amp Care

bull Type of Lens

ndash Daily Disposable

bull DT1 TruEye

ndash Non-ionic low water content weekly disposable

bull Hydrogel Vision icuity

ndash SiHy 30 day

bull BampL Ultra

- -

Refractive surgery

bull Common for first 3-6 months

ndash Neurotrophic

ndash Goblet cell density

ndash Tear flow

- - Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mean

Go

ble

t C

ells

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 001 vs

baseline tears and

CsA 6 weeks

Mean Goblet Cell Density

Temporal Bulbar Conjunctiva

bull Significantly increased goblet cell density after 12 weeks of topical cyclosporine

- -

Mean Goblet Cell Density

Inferior Bulbar Conjunctiva

Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mea

n G

ob

let

Cel

ls

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 01 vs

baseline and

artificial

tears

bull Significantly increased goblet cell density

after 6 and 12 weeks of topical cyclosporine

10262015

8

- -

Systemic Disease

bull Diabetes

bull Rheumatoid Arthritis

ndash Sjogrenrsquos syndrome

bull Thyroid Disease

bull Dermatological eg rosacea

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 04 prevalence

bull Women gt Men (younger

women)

bull Much lower androgen counts

bull Treat underlying immune

disorder

- -

Which of these conditions are Sjogrenrsquos patients 46x

more likely to develop

A Leukemia

C Diabetes

B Lymphoma

D Cardiac Arrythmia

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 5-8 incidence of B-cell non-

Hodgkins Lymphoma

bull 463x more often

ndash Moutsopoulos HM et all

- -

Sjogrenrsquos Syndrome

bull Medical Treatments Secretagogues ndash Salagen 5 mg

bull Pilocarpine tablets

bull Avoid in asthma patients GI ulcer acute iritis or narrow angles

ndash Evoxac 30 mg TIDndash saliva stimulating drug bull Very effective with a lot less side effects

- -

Symptoms of Dry Eye

bull Burning

bull Stinging

bull Transient blur

bull Dryness

bull Photophobia

bull Epiphora

bull Blurred vision

bull Contact lens intolerance

bull Injection

bull Foreign body sensation

bull Grittiness

bull Increased blink rate

10262015

9

- -

Epiphora

bull SLEx finding -

Conjunctivochalasis or

trichiasis

bull Nasolacrimal sac obstruction

bull Lid Laxity conditions- ectropion

bull Dry Eye

- -

- -

- -

Clinic-cytologic study of conjunctivochalasis and its relation to thyroid autoimmune

diseases prospective cohort study

de Almeida SF de Sousa LB Vieira LA Chiamollera MI Barros Jde N

Department of Ophthalmology External Diseases and Cornea Service Federal University of Sao Paulo-Paulista Medical School Sao Paulo

Brazil sandraflaviaclick21combr

Abstract

PURPOSE To determine the prevalence of conjunctivochalasis in patients with immune thyroid diseases to determine whether

there is any association between the 2 diseases and to determine cytologic study of conjunctivochalasis through the cytology

impression test

METHODS A clinical prospective cohort study carried out by the External Diseases Department in the Ophthalmology Sector

and the Thyroid Department in the Endocrinology Sector at Federal University of Sao Paulo (UNIFESP) The patients included

were divided into 2 groups following these inclusion criteria a control group of 25 patients without thyroid diseases confirmed

after clinical and laboratory examinations (thyroid hormones) or any other ocular diseases The study group consisted of 31

patients with thyroid diseases the diagnosis of which was confirmed by the Endocrinology Sector The thyroidopathies included

were autoimmune diseases but excluded nonautoimmune diseases A protocol endorsed by the UNIFESP was followed using

clinical and ophthalmological history biomicroscopy and impression cytology

RESULTS Fifty-two percent of patients without thyroid diseases and 88 of patients with thyroid diseases presented with

conjunctivochalasis The risk ratio was 1705 (Pr gt chi(2) = 00038) indicating that there is an association between them For the

impression cytology in inferior bulbar conjunctiva there was an association between the result of the impression cytology and

conjunctivochalasis (Pearson chi(2) = 101190 Pr = 0006)

CONCLUSION The prevalence of conjunctivochalasis in patients with autoimmune thyroid diseases was 88 Patients with

autoimmune thyroidopathy presented higher percentages of conjunctivochalasis than the control group confirming the

association between them The cytologic study showed the highest prevalence of abnormal surface features in eyes with

conjunctivochalasis

- -

External examination

bull Skin

bull Eyelids

bull Cranial nerve function

bull Hands

- -

10262015

10

- -

Diagnostic Tests 2014

bull Pt history

bull Tear meniscus height

bull Tear break-up

bull NAFL Dye

bull Rose Bengal or Lissamine Green

bull Schirmer test - phenol thread test

- -

Diagnostic Testing NowFuture

1 Pt questionnaire- SPEED

2 TearLab osmolarity

3 Slit lamp examination

1 CCH anterior bleph incomplete closure

4 MG Expression

5 NAFL Dye

1 Tear meniscus heightTFBUT

2 Corneal staining- late indicator

6 Meibography

7 Blink analysis

- -

Osmolarity

- -

- -

- -

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

6

- -

Mild MGD

bull HotWarm compresses

bull Lid hygiene

bull Lipid based tears-mildmoderate

bull Osmolarity lowering drops in

moderatesevere

- -

ModerateAcute

bull Tobradex ST

bull Zylet

bull AzaSite

bull Tobradex generic

bull Steroid drops or ung bull (loteprednol preservative-free ung

QhS)

- -

Long Term

bull Pulse dose medications

periodically

bull Restasis bid

bull Essential fatty acids

ndash EPA

ndash DHA

ndash GLA

- -

Moderatesevere or not improving

bull Add PO tetracycline

bull Recommendation

bull Doxycycline 50mg bid x 4-12 weeks then taper to qd

bull Doxycycline 20 mg bid x 4-12 weeks then taper to qd (periostat concern $$$)

- -

Tetracyclines

bull Antibiotics inhibit

bacterial protein

synthesis by binding 30S ribosome

bull Anti-inflammatory properties

ndash decreases IL-1 TNF-

ndash decreases NO production

ndash decreases HLA Class II antigen expression

ndash decreases metalloproteinase production and

activation

bull Decrease symptoms and joint destruction in RA

- -

Contraindications

bull Pregnant or child bearing age

bull Children

10262015

7

- -

Cautions

bull Photosensitivity

bull Chelates with dairy products

antacids etc

bull Minocycline may cause vestibular

toxicity

bull Number one drop-out reason

bull GI problems

- -

Systemic medications bull Antihistamines

bull Diuretics

bull Antihypertensives

bull Anticholinergics

bull Antidepressants

bull Cardiac antiarrhythmic

bull Oral contraceptives

bull Hormone replacement therapy

- -

Contact lens wear

bull Schedule amp Care

bull Type of Lens

ndash Daily Disposable

bull DT1 TruEye

ndash Non-ionic low water content weekly disposable

bull Hydrogel Vision icuity

ndash SiHy 30 day

bull BampL Ultra

- -

Refractive surgery

bull Common for first 3-6 months

ndash Neurotrophic

ndash Goblet cell density

ndash Tear flow

- - Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mean

Go

ble

t C

ells

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 001 vs

baseline tears and

CsA 6 weeks

Mean Goblet Cell Density

Temporal Bulbar Conjunctiva

bull Significantly increased goblet cell density after 12 weeks of topical cyclosporine

- -

Mean Goblet Cell Density

Inferior Bulbar Conjunctiva

Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mea

n G

ob

let

Cel

ls

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 01 vs

baseline and

artificial

tears

bull Significantly increased goblet cell density

after 6 and 12 weeks of topical cyclosporine

10262015

8

- -

Systemic Disease

bull Diabetes

bull Rheumatoid Arthritis

ndash Sjogrenrsquos syndrome

bull Thyroid Disease

bull Dermatological eg rosacea

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 04 prevalence

bull Women gt Men (younger

women)

bull Much lower androgen counts

bull Treat underlying immune

disorder

- -

Which of these conditions are Sjogrenrsquos patients 46x

more likely to develop

A Leukemia

C Diabetes

B Lymphoma

D Cardiac Arrythmia

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 5-8 incidence of B-cell non-

Hodgkins Lymphoma

bull 463x more often

ndash Moutsopoulos HM et all

- -

Sjogrenrsquos Syndrome

bull Medical Treatments Secretagogues ndash Salagen 5 mg

bull Pilocarpine tablets

bull Avoid in asthma patients GI ulcer acute iritis or narrow angles

ndash Evoxac 30 mg TIDndash saliva stimulating drug bull Very effective with a lot less side effects

- -

Symptoms of Dry Eye

bull Burning

bull Stinging

bull Transient blur

bull Dryness

bull Photophobia

bull Epiphora

bull Blurred vision

bull Contact lens intolerance

bull Injection

bull Foreign body sensation

bull Grittiness

bull Increased blink rate

10262015

9

- -

Epiphora

bull SLEx finding -

Conjunctivochalasis or

trichiasis

bull Nasolacrimal sac obstruction

bull Lid Laxity conditions- ectropion

bull Dry Eye

- -

- -

- -

Clinic-cytologic study of conjunctivochalasis and its relation to thyroid autoimmune

diseases prospective cohort study

de Almeida SF de Sousa LB Vieira LA Chiamollera MI Barros Jde N

Department of Ophthalmology External Diseases and Cornea Service Federal University of Sao Paulo-Paulista Medical School Sao Paulo

Brazil sandraflaviaclick21combr

Abstract

PURPOSE To determine the prevalence of conjunctivochalasis in patients with immune thyroid diseases to determine whether

there is any association between the 2 diseases and to determine cytologic study of conjunctivochalasis through the cytology

impression test

METHODS A clinical prospective cohort study carried out by the External Diseases Department in the Ophthalmology Sector

and the Thyroid Department in the Endocrinology Sector at Federal University of Sao Paulo (UNIFESP) The patients included

were divided into 2 groups following these inclusion criteria a control group of 25 patients without thyroid diseases confirmed

after clinical and laboratory examinations (thyroid hormones) or any other ocular diseases The study group consisted of 31

patients with thyroid diseases the diagnosis of which was confirmed by the Endocrinology Sector The thyroidopathies included

were autoimmune diseases but excluded nonautoimmune diseases A protocol endorsed by the UNIFESP was followed using

clinical and ophthalmological history biomicroscopy and impression cytology

RESULTS Fifty-two percent of patients without thyroid diseases and 88 of patients with thyroid diseases presented with

conjunctivochalasis The risk ratio was 1705 (Pr gt chi(2) = 00038) indicating that there is an association between them For the

impression cytology in inferior bulbar conjunctiva there was an association between the result of the impression cytology and

conjunctivochalasis (Pearson chi(2) = 101190 Pr = 0006)

CONCLUSION The prevalence of conjunctivochalasis in patients with autoimmune thyroid diseases was 88 Patients with

autoimmune thyroidopathy presented higher percentages of conjunctivochalasis than the control group confirming the

association between them The cytologic study showed the highest prevalence of abnormal surface features in eyes with

conjunctivochalasis

- -

External examination

bull Skin

bull Eyelids

bull Cranial nerve function

bull Hands

- -

10262015

10

- -

Diagnostic Tests 2014

bull Pt history

bull Tear meniscus height

bull Tear break-up

bull NAFL Dye

bull Rose Bengal or Lissamine Green

bull Schirmer test - phenol thread test

- -

Diagnostic Testing NowFuture

1 Pt questionnaire- SPEED

2 TearLab osmolarity

3 Slit lamp examination

1 CCH anterior bleph incomplete closure

4 MG Expression

5 NAFL Dye

1 Tear meniscus heightTFBUT

2 Corneal staining- late indicator

6 Meibography

7 Blink analysis

- -

Osmolarity

- -

- -

- -

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

7

- -

Cautions

bull Photosensitivity

bull Chelates with dairy products

antacids etc

bull Minocycline may cause vestibular

toxicity

bull Number one drop-out reason

bull GI problems

- -

Systemic medications bull Antihistamines

bull Diuretics

bull Antihypertensives

bull Anticholinergics

bull Antidepressants

bull Cardiac antiarrhythmic

bull Oral contraceptives

bull Hormone replacement therapy

- -

Contact lens wear

bull Schedule amp Care

bull Type of Lens

ndash Daily Disposable

bull DT1 TruEye

ndash Non-ionic low water content weekly disposable

bull Hydrogel Vision icuity

ndash SiHy 30 day

bull BampL Ultra

- -

Refractive surgery

bull Common for first 3-6 months

ndash Neurotrophic

ndash Goblet cell density

ndash Tear flow

- - Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mean

Go

ble

t C

ells

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 001 vs

baseline tears and

CsA 6 weeks

Mean Goblet Cell Density

Temporal Bulbar Conjunctiva

bull Significantly increased goblet cell density after 12 weeks of topical cyclosporine

- -

Mean Goblet Cell Density

Inferior Bulbar Conjunctiva

Pflugfelder et al ARVO 2006

000

450

900

1350

1800

2250

Mea

n G

ob

let

Cel

ls

Baseline Artificial

Tears

CsA

6 wks

CsA

12 wks

P lt 01 vs

baseline and

artificial

tears

bull Significantly increased goblet cell density

after 6 and 12 weeks of topical cyclosporine

10262015

8

- -

Systemic Disease

bull Diabetes

bull Rheumatoid Arthritis

ndash Sjogrenrsquos syndrome

bull Thyroid Disease

bull Dermatological eg rosacea

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 04 prevalence

bull Women gt Men (younger

women)

bull Much lower androgen counts

bull Treat underlying immune

disorder

- -

Which of these conditions are Sjogrenrsquos patients 46x

more likely to develop

A Leukemia

C Diabetes

B Lymphoma

D Cardiac Arrythmia

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 5-8 incidence of B-cell non-

Hodgkins Lymphoma

bull 463x more often

ndash Moutsopoulos HM et all

- -

Sjogrenrsquos Syndrome

bull Medical Treatments Secretagogues ndash Salagen 5 mg

bull Pilocarpine tablets

bull Avoid in asthma patients GI ulcer acute iritis or narrow angles

ndash Evoxac 30 mg TIDndash saliva stimulating drug bull Very effective with a lot less side effects

- -

Symptoms of Dry Eye

bull Burning

bull Stinging

bull Transient blur

bull Dryness

bull Photophobia

bull Epiphora

bull Blurred vision

bull Contact lens intolerance

bull Injection

bull Foreign body sensation

bull Grittiness

bull Increased blink rate

10262015

9

- -

Epiphora

bull SLEx finding -

Conjunctivochalasis or

trichiasis

bull Nasolacrimal sac obstruction

bull Lid Laxity conditions- ectropion

bull Dry Eye

- -

- -

- -

Clinic-cytologic study of conjunctivochalasis and its relation to thyroid autoimmune

diseases prospective cohort study

de Almeida SF de Sousa LB Vieira LA Chiamollera MI Barros Jde N

Department of Ophthalmology External Diseases and Cornea Service Federal University of Sao Paulo-Paulista Medical School Sao Paulo

Brazil sandraflaviaclick21combr

Abstract

PURPOSE To determine the prevalence of conjunctivochalasis in patients with immune thyroid diseases to determine whether

there is any association between the 2 diseases and to determine cytologic study of conjunctivochalasis through the cytology

impression test

METHODS A clinical prospective cohort study carried out by the External Diseases Department in the Ophthalmology Sector

and the Thyroid Department in the Endocrinology Sector at Federal University of Sao Paulo (UNIFESP) The patients included

were divided into 2 groups following these inclusion criteria a control group of 25 patients without thyroid diseases confirmed

after clinical and laboratory examinations (thyroid hormones) or any other ocular diseases The study group consisted of 31

patients with thyroid diseases the diagnosis of which was confirmed by the Endocrinology Sector The thyroidopathies included

were autoimmune diseases but excluded nonautoimmune diseases A protocol endorsed by the UNIFESP was followed using

clinical and ophthalmological history biomicroscopy and impression cytology

RESULTS Fifty-two percent of patients without thyroid diseases and 88 of patients with thyroid diseases presented with

conjunctivochalasis The risk ratio was 1705 (Pr gt chi(2) = 00038) indicating that there is an association between them For the

impression cytology in inferior bulbar conjunctiva there was an association between the result of the impression cytology and

conjunctivochalasis (Pearson chi(2) = 101190 Pr = 0006)

CONCLUSION The prevalence of conjunctivochalasis in patients with autoimmune thyroid diseases was 88 Patients with

autoimmune thyroidopathy presented higher percentages of conjunctivochalasis than the control group confirming the

association between them The cytologic study showed the highest prevalence of abnormal surface features in eyes with

conjunctivochalasis

- -

External examination

bull Skin

bull Eyelids

bull Cranial nerve function

bull Hands

- -

10262015

10

- -

Diagnostic Tests 2014

bull Pt history

bull Tear meniscus height

bull Tear break-up

bull NAFL Dye

bull Rose Bengal or Lissamine Green

bull Schirmer test - phenol thread test

- -

Diagnostic Testing NowFuture

1 Pt questionnaire- SPEED

2 TearLab osmolarity

3 Slit lamp examination

1 CCH anterior bleph incomplete closure

4 MG Expression

5 NAFL Dye

1 Tear meniscus heightTFBUT

2 Corneal staining- late indicator

6 Meibography

7 Blink analysis

- -

Osmolarity

- -

- -

- -

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

8

- -

Systemic Disease

bull Diabetes

bull Rheumatoid Arthritis

ndash Sjogrenrsquos syndrome

bull Thyroid Disease

bull Dermatological eg rosacea

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 04 prevalence

bull Women gt Men (younger

women)

bull Much lower androgen counts

bull Treat underlying immune

disorder

- -

Which of these conditions are Sjogrenrsquos patients 46x

more likely to develop

A Leukemia

C Diabetes

B Lymphoma

D Cardiac Arrythmia

- -

Sjogrenrsquos Syndrome

bull Lymphocytic infiltration of

lacrimal and salivary glands

bull 5-8 incidence of B-cell non-

Hodgkins Lymphoma

bull 463x more often

ndash Moutsopoulos HM et all

- -

Sjogrenrsquos Syndrome

bull Medical Treatments Secretagogues ndash Salagen 5 mg

bull Pilocarpine tablets

bull Avoid in asthma patients GI ulcer acute iritis or narrow angles

ndash Evoxac 30 mg TIDndash saliva stimulating drug bull Very effective with a lot less side effects

- -

Symptoms of Dry Eye

bull Burning

bull Stinging

bull Transient blur

bull Dryness

bull Photophobia

bull Epiphora

bull Blurred vision

bull Contact lens intolerance

bull Injection

bull Foreign body sensation

bull Grittiness

bull Increased blink rate

10262015

9

- -

Epiphora

bull SLEx finding -

Conjunctivochalasis or

trichiasis

bull Nasolacrimal sac obstruction

bull Lid Laxity conditions- ectropion

bull Dry Eye

- -

- -

- -

Clinic-cytologic study of conjunctivochalasis and its relation to thyroid autoimmune

diseases prospective cohort study

de Almeida SF de Sousa LB Vieira LA Chiamollera MI Barros Jde N

Department of Ophthalmology External Diseases and Cornea Service Federal University of Sao Paulo-Paulista Medical School Sao Paulo

Brazil sandraflaviaclick21combr

Abstract

PURPOSE To determine the prevalence of conjunctivochalasis in patients with immune thyroid diseases to determine whether

there is any association between the 2 diseases and to determine cytologic study of conjunctivochalasis through the cytology

impression test

METHODS A clinical prospective cohort study carried out by the External Diseases Department in the Ophthalmology Sector

and the Thyroid Department in the Endocrinology Sector at Federal University of Sao Paulo (UNIFESP) The patients included

were divided into 2 groups following these inclusion criteria a control group of 25 patients without thyroid diseases confirmed

after clinical and laboratory examinations (thyroid hormones) or any other ocular diseases The study group consisted of 31

patients with thyroid diseases the diagnosis of which was confirmed by the Endocrinology Sector The thyroidopathies included

were autoimmune diseases but excluded nonautoimmune diseases A protocol endorsed by the UNIFESP was followed using

clinical and ophthalmological history biomicroscopy and impression cytology

RESULTS Fifty-two percent of patients without thyroid diseases and 88 of patients with thyroid diseases presented with

conjunctivochalasis The risk ratio was 1705 (Pr gt chi(2) = 00038) indicating that there is an association between them For the

impression cytology in inferior bulbar conjunctiva there was an association between the result of the impression cytology and

conjunctivochalasis (Pearson chi(2) = 101190 Pr = 0006)

CONCLUSION The prevalence of conjunctivochalasis in patients with autoimmune thyroid diseases was 88 Patients with

autoimmune thyroidopathy presented higher percentages of conjunctivochalasis than the control group confirming the

association between them The cytologic study showed the highest prevalence of abnormal surface features in eyes with

conjunctivochalasis

- -

External examination

bull Skin

bull Eyelids

bull Cranial nerve function

bull Hands

- -

10262015

10

- -

Diagnostic Tests 2014

bull Pt history

bull Tear meniscus height

bull Tear break-up

bull NAFL Dye

bull Rose Bengal or Lissamine Green

bull Schirmer test - phenol thread test

- -

Diagnostic Testing NowFuture

1 Pt questionnaire- SPEED

2 TearLab osmolarity

3 Slit lamp examination

1 CCH anterior bleph incomplete closure

4 MG Expression

5 NAFL Dye

1 Tear meniscus heightTFBUT

2 Corneal staining- late indicator

6 Meibography

7 Blink analysis

- -

Osmolarity

- -

- -

- -

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

9

- -

Epiphora

bull SLEx finding -

Conjunctivochalasis or

trichiasis

bull Nasolacrimal sac obstruction

bull Lid Laxity conditions- ectropion

bull Dry Eye

- -

- -

- -

Clinic-cytologic study of conjunctivochalasis and its relation to thyroid autoimmune

diseases prospective cohort study

de Almeida SF de Sousa LB Vieira LA Chiamollera MI Barros Jde N

Department of Ophthalmology External Diseases and Cornea Service Federal University of Sao Paulo-Paulista Medical School Sao Paulo

Brazil sandraflaviaclick21combr

Abstract

PURPOSE To determine the prevalence of conjunctivochalasis in patients with immune thyroid diseases to determine whether

there is any association between the 2 diseases and to determine cytologic study of conjunctivochalasis through the cytology

impression test

METHODS A clinical prospective cohort study carried out by the External Diseases Department in the Ophthalmology Sector

and the Thyroid Department in the Endocrinology Sector at Federal University of Sao Paulo (UNIFESP) The patients included

were divided into 2 groups following these inclusion criteria a control group of 25 patients without thyroid diseases confirmed

after clinical and laboratory examinations (thyroid hormones) or any other ocular diseases The study group consisted of 31

patients with thyroid diseases the diagnosis of which was confirmed by the Endocrinology Sector The thyroidopathies included

were autoimmune diseases but excluded nonautoimmune diseases A protocol endorsed by the UNIFESP was followed using

clinical and ophthalmological history biomicroscopy and impression cytology

RESULTS Fifty-two percent of patients without thyroid diseases and 88 of patients with thyroid diseases presented with

conjunctivochalasis The risk ratio was 1705 (Pr gt chi(2) = 00038) indicating that there is an association between them For the

impression cytology in inferior bulbar conjunctiva there was an association between the result of the impression cytology and

conjunctivochalasis (Pearson chi(2) = 101190 Pr = 0006)

CONCLUSION The prevalence of conjunctivochalasis in patients with autoimmune thyroid diseases was 88 Patients with

autoimmune thyroidopathy presented higher percentages of conjunctivochalasis than the control group confirming the

association between them The cytologic study showed the highest prevalence of abnormal surface features in eyes with

conjunctivochalasis

- -

External examination

bull Skin

bull Eyelids

bull Cranial nerve function

bull Hands

- -

10262015

10

- -

Diagnostic Tests 2014

bull Pt history

bull Tear meniscus height

bull Tear break-up

bull NAFL Dye

bull Rose Bengal or Lissamine Green

bull Schirmer test - phenol thread test

- -

Diagnostic Testing NowFuture

1 Pt questionnaire- SPEED

2 TearLab osmolarity

3 Slit lamp examination

1 CCH anterior bleph incomplete closure

4 MG Expression

5 NAFL Dye

1 Tear meniscus heightTFBUT

2 Corneal staining- late indicator

6 Meibography

7 Blink analysis

- -

Osmolarity

- -

- -

- -

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

10

- -

Diagnostic Tests 2014

bull Pt history

bull Tear meniscus height

bull Tear break-up

bull NAFL Dye

bull Rose Bengal or Lissamine Green

bull Schirmer test - phenol thread test

- -

Diagnostic Testing NowFuture

1 Pt questionnaire- SPEED

2 TearLab osmolarity

3 Slit lamp examination

1 CCH anterior bleph incomplete closure

4 MG Expression

5 NAFL Dye

1 Tear meniscus heightTFBUT

2 Corneal staining- late indicator

6 Meibography

7 Blink analysis

- -

Osmolarity

- -

- -

- -

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

11

- -

Other Diagnostic Tests of Value

bull Light Seal Test -Transilluminate

bull Bink analysis

- -

Dr i-Coach

A patented sensor and software package that can help users develop and maintain proper

computer habits

- -

Features Include

bull Eye Fatigue Monitor (Blink Rate)

bull User Distance Monitor

bull Timer

bull Seated Height Detector

bull Environmental Light Detector

- -

Eye Fatigue Monitor (Blink Rate) ala Fitbit

bull Dr i-Coach can efficiently track the eye region detecting and

counting userrsquos blinks

bull Blink rate data will be available in an easy to read chart for the

use of the patient and their eye care professional

bull The Dr i-Coachreg software monitors and records the users

viewing time when there is any computer activity

bull After a viewing time between twenty to sixty minutes (pre-

selected by the user) the program alerts the viewer and reminds

them to take a break

- -

bull Based on distance head-track localization and screen tilt measured by an embedded gyroscope Dr i-Coach is able to determine if the user is seated at the proper height and reminds them to adjust accordingly

- -

Treatment

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

12

- -

Symptoms of DED but normal

osmolarity minimal other signs

bull DED that is well controlled

bull CL solutions related -PATH

bull Mild allergic conjunctivitis

bull EBMD- MDF dystrophy

bull Pinguecula amp early Pterygium

bull Infection - eg conjunctivitis

bull Anterior blepharitis

ndash Demodex

bull GPC

bull Asthenopia - vertical CI etc

bull Salzmannrsquos Nodular

Degeneration

bull Mildmod conjunctivochalasis

Patient with epiphora will actually

have osmolarity readings below

normal or very low (ie lt 280)

- -

Treatment

bull Emphasis chronic nature of the

condition

bull Eliminate exacerbating factors

ndash smoking air conditioner meds

bull Drink 4-6 glasses of water per day

bull Tear replacements

- -

Role of ATrsquos bull Osmolarity lowering

ndash Blink Tears amp TheraTears

bull EBMDcorneal staining ndash FreshKote

bull Lipid Deficient ndash Systane Balance Soothe XP Retaine MGD

Refresh Optive Advanced

bull Aqueous deficient ndash OptiveRefresh Systane Ultra

bull Severe ------gt SystaneGenteal gel or ung

- -

Nutritional Supplements

Essential fatty acids

bull Omega fatty acids

bull ALA- eg Flaxseed oil

bull EPA-DHA ndash eg Fish oils

bull GLA

ndash Black Currant Seed Oil etc

- -

HydroEye (HE) Clinical

Purpose Evaluate HE in

postmenopausal women with

moderate-severe KCS amp tear

dysfunction

Dual Sites Virginia Eye Consultants

amp Baylor University

Type Double-blind placebo-

controlled randomized

Duration 6 months

- -

Key Findings Symptoms

HydroEyereg therapy significantly decreased

the mean OSDI score over the treatment

period (p=0004) while the OSDI score

was essentially unchanged in the placebo

group

At the end of 24 weeks OSDI scores were

significantly reduced in the HydroEyereg

group compared to placebo (p=005)

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

13

- -

Primary Sign Improvement

- -

Primary Sign Improvement

- -

Targeted Treatments are KEY

bull Treatments aimed at local inflammatory

processes

ndash Topical corticosteroids (Lotemax)

bull Effective anti-inflammatory agents

bull Site specific Steroids

ndash Cyclosporin A (Restasis)

- -

Dry Eye DiseasemdashA Real Condition That Needs

More Than a Palliative Solution

bull ldquoDry eye is a disorder of the tear film due to tear deficiency

or excessive tear evaporation which can cause damage to

the interpalpebral ocular surfacerdquo1

bull Artificial tears provide temporary palliative relief2

ldquoArtificial tears are inadequate

because they failhellipto prevent

progression of Dry Eye diseaserdquo3

J Daniel Nelson MD

Corneal Specialist

University of Minnesota

1 Lemp CLAO J 1995

2 Stern et al Cornea 1998

3 Nelson et al Adv Ther 2000

- -

Corticosteroids

bull Bind to nuclear receptors that bind

DNA and regulate gene expression

bull Interfere with transcription regulators

[eg AP-1 amp NF-kB]

bull most inflammatory pathways

ndash cytokine production

ndash lipid mediators (PGs)

ndash cell adhesion molecules

ndash lymphocyte trafficking

ndash vascular permeability

bull Ring modifications alter potency

and membrane stabilizing effects

- -

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 amp Tseng BJO 1998

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

14

- -

Steroids and Dry Eye

bull 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 amp Pflugfelder 1999)

bull Patients often have long lasting relief after

2-week pulse therapy

- -

Pre-Steroid

Post-Steroid

Steroids

Effectively

Treat KCS (Marsh Ophthalmology 1999)

Sjoumlgrenrsquos Syndrome KCS

- -

Anti-inflammatory Therapy of KCS

Corticosteroids bull Improve signs and symptoms

bull Improve tear clearance

bull Normalize mucus production

bull Often have sustained benefit

after a 2 week pulse

bull Bioengineered steroid loteprenol

etabonate is effective

- -

Pflugfelder et al AJO 2004

- - Pflugfelder et al AJO 2004

- -

How Does Restasis Work

bull Restasistrade prevents T-cell activation (Kunert et al Arch Ophthalmol 20001181489)

ndash Activated T cells produce inflammatory

cytokines that result in

bull Recruitment of more T cells (Stern et al IOVS

2002432609)

bull More cytokine production (Pflugfelder et al Curr Eye

Res 199919201)

14

7

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

15

- -

Topical Cyclosporine

bull Restasis Ophthalmic Emulsion (Allergan) ndash Useful in long-term management of inflammatory DES

ndash BID dosage

ndash Cyclosporine A (CsA) 005 in castor oil vehicle

ndash Mechanism of action bull Inhibits activation of inflammatory T-lymphocytes and induces

immune cell apoptosis stimulating lacrimal gland tear production

ndash 3-4 months to achieve clinically significant effect 6 months for full therapeutic potential

ndash 59 Patients achieved improvement from baseline Schirmer scores at 6 months

ndash Excellent safety profile

Goblet Cell Density at 6 Months1

1 Data on file Allergan Inc1999

86

191

13 0

50

100

150

200RESTASISreg

Vehicle

N = 11

N = 12

aP = 014

RESTASISreg

Vehicle

Per

cen

t C

han

ge

Percent Increase in Goblet Cell Density From Baseline

In a study of patients with decreased tear production presumed to be due to ocular inflammation associated with Chronic Dry Eye1-3

Months 0-12

Me

an

Ch

ang

e in

Sta

inin

g S

co

res

Months 12-24

MONTHS 12-24 RESTASISreg (n = 20)

REFRESH ENDURAreg switched to RESTASISreg (n = 20)

-104

-164

-214

-244

-026 -036

-106

-156

0 -013

-064

-119

0 -012

-025 -032

-26

-19

-12

-05

02

87

Changes in Staining From Baseline1-3

1 Rao SN J Ocul Pharmacol Ther 2010 2 Rao SN J Ocul Pharmacol Ther 2011 3 Data on file Allergan Inc 2009

Month 24 mean change in staining from baseline12 29 decrease in patients continuously treated with RESTASISreg

20 decrease in patients switched from REFRESH ENDURAreg

to RESTASISreg at month 12

1

Baseline 8 Months 4 Months 12 Months 24 Months 16 Months 20 Months

Baseline mean values for staining in different treatment groups ranged from 786 to 8441

2

1

2

MONTHS 0-12 RESTASISreg (n = 36)

REFRESH ENDURAreg (n = 22)

Change in staining in baseline was calculated by subtracting the baseline score from the various time point scores (months 0-24) If a data point was missing the baseline was also excluded from that calculation (months 0-12)

aP lt 007 vs REFRESH ENDURAreg

Corneal and conjunctival staining Severity level determined according to Consensus Guidelines

published in Cornea 20062

- -

- -

Expectations During the First

6 Months of Therapy

Patients

notice

an onset of

benefit

Further

increase

in tear

production

Significant

improvement

in tear

production

Improvements

are maintained

with continuation

of therapy

1 month 3 months 6 months

- - 1 Small et al J Ocul Pharm Ther 2002

No Cyclosporine in Blood

bull No detectable cyclosporine in blood of any

RESTASISreg ophthalmic emulsionndashtreated patient1

bull Toxicity associated with systemic or oral

cyclosporine was not observed with cyclosporine

005 ophthalmic emulsion

Please see slides 6 amp 7 for important safety information

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

16

- -

Options for Non-

Responsive Patients

- -

Punctal Occlusion

bull May worsen certain conditions

ndash Allergies

ndash MGD

ndash Inflammatory dry eye

bull Treat those conditions first then plug

bull Ideal FIRST treatment option for

ndash Neurotrophic keratopathy

ndash Post-LASIK dry eye

ndash Lagophthalmos

- -

Neurotrophic keratitis

- -

Normal tears Autologous Serum

bull pH = 74

bull Osmolality = 298

bull EGF (ngml) = 02-30

bull TGF-b (ngml) = 2-10

bull Vitamin A (mgml) = 002

bull Lysozyme (mgml) = 14

bull Fibronectin (ugml) = 21

bull pH = 74

bull Osmolality = 296

bull EGF (ngml) = 05

bull TGF-b (ngml) = 6-33

bull Vitamin A (mgml) = 46

bull Lysozyme (mgml) = 6

bull Fibronectin (ugml) = 205

bull Hepatocyte GF NGF IGF-1

substance p Complement

Fibroblast GF c GRP other Ig

etc

- -

LACRISERTreg (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

- -

ProKera Amniotic Membrane

Class II medical device

comprising of CRYOTEKtrade

amniotic membrane into a

thermoplastic ring set

Combines the functionality of a

symblepharon ring with the

biologic actions of

CRYOTEKtrade amniotic

membrane to create a unique

treatment option for corneal

and limbal wound healing

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

17

- -

Clinical Evidence for PROKERAreg

bull A safe and effective method to promote healing of

the corneal surface with minimal side effects1

bull Inhibits abnormal angiogenic processes and

inflammation thus promoting scarless healing1-7

bull Stimulates healthy re-epithelialization of the corneal

wound without sutures124-68

bull Provides pain relief and reduces haze resulting in

improved visual acuity by a mean (SD) of 25 (26)

Snellen lines2 1 Pachigolla G et al Eye Contact Lens 20093572-75 2 Sheha H et al Cornea 2009281118-1123 3 Gomes JA et al Curr Opin Ophthalmol 200516233-240 4 Shay

E et al Cornea 201029359-361 5 Kheirkhah A et al Arch Ophthalmol 20081261059-1066

6 Shammas MC et al Am J Ophthalmol 2010149203-213 7 Shay E et al Invest Ophthalmol Vis Sci 2011522669-2678 8 Lazarro DR Eye Contact Lens

20103660-61

- -

SCLERAL LENSES

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

- -

PROKERAreg Insertion

bull Set patient expectations Inform the patient they may experience some initial stinging and foreign body sensation

bull Apply topical anesthesia

bull Rinse the PROKERAreg a with a sterile solution (saline BSS etchellip)

bull Hold the upper eyelid

bull Ask the patient to look down

bull Insert the PROKERAreg into the superior fornix preferably using your fingers to hold the ring

bull Slide the PROKERAreg under the lower eyelid

- -

- -

SCLERAL LENSES

- -

Scleral Lenses

Scleral lenses are large diameter

gas permeable lenses that rest

beyond the limits of the cornea

and extend onto the sclera

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom

10262015

18

- -

GLAUCOMA SIMILARITY

bull Look at the structure and functioning of the

MGs and ocular surface

bull Multiple testing

ndash IOP = osmolarity

ndash VF testing = corneal staining

ndash OCT = meibomographyLipiView

ndash MG expression = ONH examination

- -

FUTURE DENTAL MODEL

bull Tooth Brush amp Floss = Hydrating compress

and lid hygiene products

bull Scaling = Scalingdebridement of keratin

bull Dental cleaning = mechanical pulsation or

cleaning ie LipiFlow Blephex etc

bull Dental X-rays = MeibographyLipiview

Dry Eye Disease Conclusion

bull Understand the ramifications of not

treating this disease

bull The eyelids are key

bull Be aggressive in your treatment and then

reduce medications

bull The single largest medical eyecare

opportunity now and in the future

105 - -

ndash `

paulkarpeckicom

wwwophthalmicresourcescom