Download TFOS Research Update 2012

Disclosures
•  K. Nichols
TFOS Ocular Surface
Research Update
Kelly K. Nichols, OD, MPH, PhD
FERV Professor
University of Houston College of Optometry
Chair, TFOS International Meibomian Gland Workshop
TFOS Governing Board Member
WHAT WAS STATE OF THE
ART IN DRY EYE © 2007?
WHAT HAS HAPPENED
SINCE?
What’s New?
•  Research support
–  Paid consultant to:
•  Alcon
•  Allergan
•  B+L
•  Celtic/ Resolvyx
•  Eleven Biotherapeutics
•  Forest
•  InSite
•  Ista
•  SARcode
•  TearLab
–  CL Tear Film Lab (OSU)
•  Alcon
•  CIBA
•  Inspire
•  TearLab
•  Pfizer
•  Vistakon
–  National Eye Institute
•  R01 EY015519 (PI)
•  R01 EY017951 (Co-I)
•  R34 EY017626 (Co-I)
Updated Dry Eye Definition
“Dry eye is a multifactorial disease of the tears
and ocular surface that results in symptoms of
discomfort, visual disturbance, and tear
instability with potential damage to the ocular
surface. It is accompanied by increased
osmolarity of the tear film and inflammation of
the ocular surface.”
MGD Contributes to Dry Eye
•  Growing awareness of link between
blepharitis (esp. MGD) and dry eye
–  Lemp et al report
•  Younger people are more prone than older people
to blepharitis (contrary to dogma)
•  ECPs report 37-47% of patients have blepharitis
•  Blepharitis management paradigms are shifting…
–  from antibiotic ointment and warm compress therapy
–  to prescription therapy for anterior and posterior
blepharitis
DEWS Definition and classification report. Ocular Surface 2007
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A call for change—
Epidemiology
•  In the 2007 DEWS report three goals were
presented:
–  Summarize the epidemiology of DED
•  Prevalence
•  Incidence
•  Natural history
–  Review risk factors for DED
–  Review existing questionnaires for DED
Evaluating “change”
Since DEWS 2007…
1096 articles with keyword “dry eye” published
•  PubMED searches for existing literature
using key words “DRY EYE,”
“PREVALENCE,” and “Incidence”
•  Review of clinicaltrials.gov
•  Review of surveys utilized in clinical trials
Population-based studies of DED
Global Prevalence of Dry Eye-2011
Singapore Malay
Sumatra
8
Studies
Range
5-30%
Taiwan
Tibet
Beijing
Mongoiia
Japanese High School Students
Japanese VDT users
16
Studies
Range 5-55%
US Women's Health Study
US Male Physicians
Melbourne
Blue Mountains (AUS)
Beaver Dam (US)
Maryland USA
Spain
0%
10%
20%
30%
40%
50%
60%
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What’s New?
Prevalence of DED, by Age
Women and Men
•  Dry Eye Epidemiology
–  Schaumberg et al report men have increasing
dry eye with age
•  3.90% among men aged 50 to 54 years
•  7.67% among men 80 years and older
•  Additional male risk factors:
–  hypertension, benign prostatic hyperplasia, and
antidepressant use
Number of Americans with DED
Incidence of Dry Eye
•  Data from the largest US studies (≥50 y)
•  Beaver Dam Eye Study
–  Women’s Health Study
–  Physicians’ Health Study
Severe
Symptoms
1.09
Diagnosed
Women
Men
0.78
2.21
Severe Sx or
Dx
1.37
3.23
0
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–  13.3% developed dry eye over 5 years
–  21.6% developed dry eye over 10 years
(Moss, 2008)
–  Higher incidence in older ages
•  But effect of age relatively modest magnitude
1.62
2
3
4
5
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Number Affected (Millions)
–  No difference by sex at 5 years
–  Incidence was greater in women (25.0%) than
men (17.2%, p < 0.001) at 10 years (Moss,
2008)
What’s New?
Natural history of dry eye
•  10-year incidence data
•  Minimal to no studies of progression
•  Progression between severity groups (ITF/
Delphi) in a non-treatment group has been
assessed in one small-scale study and is a
concept warranting further investigation
–  Moss et al report dry eye incidence of 21.6%
•  Risk factors:
–  age
–  female gender
–  poorer self-rated health
–  antidepressant or oral steroid use
–  thyroid disease untreated with hormone
Rao SN. Topical cyclosporine 0.05% for the preven9on of dry eye disease progression. J Ocul Pharmacol Ther. 2010 Apr;26(2):157-­‐64. 3
Goal 2. Risk Factors for DED 2007
Risk factors for DED (Moss et al, 2008)
•  Increased incidence was associated with:
–  Age
–  Female gender
–  Poorer self-rated health
–  Antidepressant or oral steroid use, and
–  Thyroid disease untreated with hormone.
•  It was lower for those:
–  Using angiotensin-converting enzyme inhibitors or a
–  Sedentary lifestyle.
Moss SE, Klein R, Klein BE. Long-­‐term incidence of dry eye in an older popula9on. Optom Vis Sci. 2008 Aug;85(8):668-­‐74. Risk factors for men (new data)
Systemic co-morbidities
•  Benign prostatic hyperplasia
•  Ischaemic heart disease (OR =
1.36)
•  Hyperlipidaemia (OR = 1.68)
•  Peripheral vascular disorders
(OR = 1.57)
•  Migraines (OR = 1.76)
•  Myasthenia gravis (OR = 2.85)
•  RA (OR = 2.86)
•  Systemic lupus (OR = 3.98)
•  Pulmonary circulation
disorders (OR = 1.37),
–  OR=1.26, CI=1.09 to 1.44
•  Hypertension
–  OR=1.28, CI=1.12 to 1.45
•  Medications to treat BPH
–  OR=1.35, CI=1.01 to 1.80
•  Antidepressant medications
–  OR=1.90, CI=1.39 to 2.61
Schaumberg DA, Dana R, Buring JE, Sullivan DA. Arch Ophthalmol. 2009 Jun;127(6):763-­‐8. Goal 3. Review questionnaires
•  Diabetes with complications
(OR = 1.31)
•  Hypothyroidism (OR = 1.94)
•  Liver diseases (OR =1.71)
•  Heptic ulcers (OR = 1.76)
•  Hepatitis B (OR = 1.64),
•  Depression (OR = 2.11)
•  Psychoses (OR = 1.87)
•  Solid tumors without
metastasis (OR = 1.41)
Wang TJ, Wang IJ, Hu CC, Lin HC. Comorbidi9es of dry eye disease: a na9onwide popula9on-­‐based study. Acta Ophthalmol. 2010 Aug 31. [Epub ahead of print] Since DEWS…
211 registered DRY EYE trials
•  Identify purpose of questionnaire:
screening, clinical, epidemiologic studies
•  Assess available data on validation,
reproducibility, and responsiveness
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Since DEWS…
76 Currently active trials
Clinicaltrials.gov: Summary 2010
Primary outcome (s) OSDI (n=13) or other Sx Staining Schirmer TBUT 19 13 6 4 IntervenBonal ObservaBonal 48 9 I II III IV Not listed 3 12 6 16 20 Oral Topical Surgical or other 5 39 4 Industry University/Government 39 18 Design Phase IntervenBons (n=48) Sponsor Dry eye surveys
•  OSDI ocular surface disease severity ratings
across the scale (0-100) have been reported:1
–  Normal 0-12, Mild 13-22, Moderate 23-32, and
Severe 33-100, and a 7 unit change was noted as
clinically significant; sub-scale analysis may also have
importance
•  The DEQ-5 comprises:2
–  Frequency of watery eyes (r=0.48), discomfort
(r=0.41), and dryness (r=0.35), and late day (PM)
intensity of discomfort and dryness (r=0.42, 0.36) all
significantly correlated to SA-Sev (p<0.01)
1. Miller KL et al. Minimal Clinically Important Difference for the Ocular Surface Disease Index. Arch Ophthalmol. 2010;128(1):94-­‐101. 2. Chalmers RL, Begley CG, Caffery B. Valida9on of the 5-­‐Item Dry Eye Ques9onnaire (DEQ-­‐5): Discrimina9on across self-­‐assessed severity and aqueous tear deficient dry eye diagnoses. Cont Lens Anterior Eye. 2010 Apr;33(2):55-­‐60. Surveys: ocular comfort
•  The Ocular Comfort Index (OCI) uses Rasch
analysis to produce estimates on a linear interval
scale.3
•  The OCI measure exhibited a positive correlation
with the OSDI score (p < 0.0001) and a negative
correlation with TBUT (p < 0.0001) and was able
to detect improvement in symptoms of dry eye in
individuals before and after treatment (P <
0.0001)
Johnson ME, Murphy PJ. Measurement of ocular surface irrita9on on a linear interval scale with the ocular comfort index. Invest Ophthalmol Vis Sci. 2007 Oct;48(10):4451-­‐8. Diagnosis
•  Dr. Nichols, is there a new, easy,
inexpensive, and accurate way to
diagnosis dry eye (maybe something a
technician could do)?
–  Sorry, not yet…
–  Newer diagnostic tools are not ready for the
“average” clinic
•  Technology intensive and expensive
–  Osmometers
–  Tearscope
–  OCT
–  Fluorophotometry
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Mechanism of action for
therapeutics
•  Stimulation of natural tear constituents
•  Inhibition of inflammation of the ocular
surface
•  Stabilization of the tear film
•  Decreasing tear osmolarity
But first, Dx….Grading
Scheme
Osmolarity in Diagnosis & Grading of Dry Eye Summary—Advancing Epi
•  Advances have been made in the global
prevalence assessment (~17% total; ~30% Asia)
of dry eye as a symptom-based disease
•  New 10-year incidence data (21%) and risk
factor assessment (antidepressants, Asian race,
systemic comorbidities) refines our existing
knowledge base
•  Further research regarding Natural History, the
ability of newer surveys to monitor change (DEQ
short version, OCI),and the impact of MGD on
dry eye is needed.
Diagnosis
Osmolarity Severity Analysis 6
Summary—from TearLab Treatments
•  Osmolarity is the best single test for DED – 
– 
– 
– 
– 
– 
Highest correla9on to disease severity Quan9ta9ve, Objec9ve Operator Independent Test (reduces need for training) No site-­‐to-­‐site varia9on Rapid (< 30 seconds for 2 eyes) Most sensi9ve test for discrimina9ng small changes •  DiagnosBc Cutoff > 308 mOsms/L –  PPV = 85% •  Suggested inclusion criteria for clinical trials •  Hierarchical options
based on severity
The preferred treatment for
mild dry eye patients,
ASK about symptoms at every
visit –  One eye > 328 mOsms/L –  Opposite eye > 316 mOsms/L Level 1 Treatments
What’s New?
•  Environmental and dietary modifications
•  Essential Fatty Acids
–  Essential Fatty Acids
•  Recommended in principle, no dosing given
–  Environmental Considerations
•  Avoid desiccating stresses
–  Low humidity, air conditioning drafts
•  Computer users
–  Take breaks, lower monitor below eye level to limit lid
aperture
•  Use humidifier
–  Kokke et al report omega-6 (300 mg γ-linolenic acid/
d) improve symptoms and tear meniscus height in
contact lens wearers
–  Macsai reports omega-3 (3.3 g α-linolenic acid/d)
improves symptoms and decreases saturated fat in
meibum
–  Call for RCT in literature
•  Which is better, or is it a combination?
–  Rashid et al report topical form improves dry eye in
mice
What’s New?
What’s New?
•  Environment
•  Education (Jackson)
–  Guillon et al report that contact lens wear is
associated with greater evaporation of the
tear film and this effect lasts for at least 24
hours after lens removal
–  Blink rate reduced with long sessions of…
•  Reading
•  TV watching
•  Computer
–  Use ATs if engaging in one of these activities
–  Avoid hot, windy, low-humidity, high altitude
areas if possible
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Level 1 Treatments
What’s New?
•  Elimination of offending systemic
medications
•  A related note
–  Avoid systemic anticholinergics
•  Antihistamines, antidepressants
–  Leung et al and Rossi et al report ocular
surface disease is common in glaucoma and
increases with each BAK-preserved glaucoma
drop used
–  Glaucoma field moves toward
recommendation of non-BAK medications and
concomitant preservative-free AT use
What’s New?
Level 1 Treatments
•  Acupuncture
•  Artificial tear substitutes, gels/ointments
–  Lee et al used a meta-anaylsis approach to
suggest that acupuncture is a least a good as
artificial tears for TBUT, Schirmer, and
staining
–  A significant part of report
–  New tears with LIPID targeting MGD
Artificial Tears
Artificial Tear Preservatives
•  AT use can improve symptoms, but they
persist
•  A beneficial effect of ATs on the health of
the ocular surface has not been proven
•  Main variables in composition:
•  “Single most critical advance in the
treatment of dry eye came with the
elimination of preservatives, such as
benzalkonium chloride (BAK)...”
•  …”the absence of preservatives is of more
critical importance than the particular
polymeric agent”…
–  Preservative type
–  Electrolyte concentration
–  Osmolarity
–  Viscosity agent
–  Lipid
–  Unfortunately, non-preserved solutions do not
improve the surface inflammation
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Artificial Tear Preservatives
Electrolyte composition
•  Report gave special consideration to
“vanishing” preservatives
•  Most useful ones…
–  Sodium chlorite
•  Degrades upon exposure to UV light
–  Potassium to maintain corneal thickness
–  Bicarbonate to help recovery of epithelial
barrier function and maintain mucin layer
–  Sodium perborate
•  Degrades on contact with tear film
Osmolarity
Viscosity Agent
•  Dry eye patients have high tear osmolarity
•  Influence contact time
•  Can provide protection by hydrating the
gel-forming mucin and bind to epithelium
•  Lower molecular weight agents minimize
blur and lash crusting
–  Results in cellular morphology changes and is
proinflammatory
•  Hypotonic tears may reduce swelling in
dysfunctional cells
–  HP-guar
–  Castor oil
–  Mineral oil
Artificial Tear Summary
What’s New?
•  So which one is best?
•  “Vanishing” Preservatives
–  Available studies suggest a variety of
preparations can help signs and symptoms
–  No preparation is superior to another
•  Symptoms and inflammation remain
–  Preservative-free preparations are generally
better tolerated
–  Consider lipid containing products with MGD
–  Epstein et al report that sodium perborate
causes at least some tissue damage
–  Yamazaki et al report that glaucoma patients
who were switched to SofZia-preserved
travaprost from latanoprost had a decrease in
SPK
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MGD IN CL WEARERS
Disease Pathway
What’s New?
•  Viscosity Agent
–  Uchiyama et al report RCT where HP-guar
has a longer residence time than saline
–  Wang et al report randomized trial comparing
HP-guar gel versus carbomer gel
•  Both improved signs and symptoms, slight edge to
carbomer group
–  In meta-analysis, Doughty et al report
treatment can help about 25%, but with no
difference between carbomer gels and
hyaluronic acid (HA) products
What’s New?
What’s New?
•  Osmolarity
•  Ocular Inserts
–  Suzuki et al report tear osmolarity is
correlated with DEWS severity scale
–  Bernelli et al report artificial tears lower
osmolarity up to 10 points after instillation
–  Koffler et al report hydroxypropyl cellulose
inserts improve signs and symptoms of dry
eye beyond habitual treatment and are
generally tolerated
–  Consider for Sjogren’s patients
•  Blurred vision most common problem
•  Sterile, preservative-free, Rx only
•  Extends duration of treatment
•  Low rate (2.5%) of adverse events
Level 1 Treatments
Rapidheatpacks.com
•  Eye lid therapy
–  No details given in DEWS report
–  MGD workshop report
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What’s New?
Ocular Ointments and Gels
•  Eyelid therapy
•  Ointments do not need preservatives
because the mineral oil or petrolatum base
do not support bacterial growth
•  Consider gels with carbomers
–  Blackie et al recommend warm compress
regimen
•  Heat compress to 104° F
•  Maintain good contact
•  Have multiple warm compresses ready, switch prn
•  Perform for at least 4 minutes
•  AKA Acrylic acid polymers
–  Longer retention time, less blurring
•  Recommendations to avoid products with:
–  Lanolin – irritation, delayed corneal healing
–  Parbens – a poorly tolerated preservative
–  Petrolatum base – visual blurring
Level 2 Treatments
•  Topical Anti-Inflammatory Therapy
–  Cyclosporin A Emulsion
•  Improves symptoms, staining, and Schirmer values
•  Increases Goblet Cell density
•  Decreases IL-6, T-cells, and apoptotic markers
–  Pimecrolimus
–  Tacrolimus
–  Androgen (testosterone)
•  Improve symptoms, meibum quality, TBUT, lipid
layer thickness
What’s New?
Level 2 Treatments
•  Topical Anti-Inflammatory Therapy
•  Anti-Inflammatory Therapy
•  Kim et al report Vitamin A is as effective as
cyclosporine in treating signs and symptoms of dry
eye and recommend it as a adjunct therapy to
artificial tears
•  Foulks et al report topical azithromycin can
improve evaporative dry eye by restoring the
disordered lipids in MGD
•  Still under development
–  Corticosteroids
•  Quite effective in reducing ocular surface
symptoms and inflammation
–  Loteprednol etabonate, fluoromethalone,
methyprednisone, etc.
•  Inherent Hazards
–  IOP rise, Cataract
–  Androgen, Pimocrolimus,Tacrolimus
»  Used by some corneal specialists (ex keratoplasty,
cicatricial pemphigoid)
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What’s New?
Level 2 Treatments
•  Topical anti-inflammatory
•  Tetracyclines for MGD, rosacea
–  Steroidal burst for a few weeks, then transition
to non-steroidal treatment
•  Cyclosporine is still the only FDA approved Rx for
dry eye
–  Pavesio et al recommend treatment of dry eye
with loteprednol because its ester quality is
likely safer than the more common ketone
form of ocular steroids
–  Antibacterial
•  Less lipolytic exoenzymes and lipase production
–  Anti-inflammatory
•  Decrease MMPs, collagenase, TNF-α, IL-1, etc.
–  Anti-angiogenic
•  Potential for less benign vessel formation in
rosacea
–  20 mg of doxycycline per day may be enough
to treat MGD
Level 2 Treatments
What’s New?
•  Punctal Plugs
•  Punctal Plugs
–  Objective and subjective improvements for a
variety of ocular surface diseases
–  About 75% of dry eye patients report
improved symptoms
–  May interfere with normal feedback
mechanism and temporarily decrease tear
production
–  Chen et al report similar improvements in
signs and symptoms when plugs are placed in
either the upper or lower puncta
–  Burgess et al report equivalent efficacy of
SmartPlugs versus standard silicone plugs
Level 2 Treatments
What’s New?
•  Topical Secretogogues
•  Topical Secretogogues
–  Were under various stages of drug
development
–  P2Y2 agonist
•  Diquafosol improves aqueous and mucous
secretion
–  Still under development
•  Many failing to make endpoints so far
•  Ecabet sodium had positive results in Phase 2b
study and may go to Phase 3 trial in 2010
–  Mucous secretion stimulants
•  Rebamipide, gefarnate, ecabet sodium
–  MUC-1 Stimulant
•  15(S)-HETE
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Level 2 Treatments
What’s New?
•  Oral Secretogogues
•  Oral Dry Eye Treatment
–  Pilocarpine can improve ocular problems in
Sjogen Syndrome patients but has side
effects (esp. excessive sweating)
–  Cevimeline has been reported to improve
symptoms and increase tear production with
less side effects
–  Avni et al report a Phase 2 study where an
experimental A3 adenosine receptor agonist
improves staining, TBUT, and tear meniscus
height
•  An anti-inflammatory agent that down regulates a
host of inflammatory mediators (ex. autoreactive T
cells, TNF-α)
–  Chang et al report a small, but measurable,
improvement in signs and symptoms with 3
months of oral uridine (like topical Diquafosol)
Level 2 Treatments
•  Moisture Chamber Spectacles
–  Poorly documented in the literature
–  Reports of special spectacles increasing the
periocular humidity
–  Not very popular
•  Because an easy alternative is contact lenses??
7eye.co
m
Level 3 Treatments
What’s New?
•  Autologous Serum
•  Serum Eye Drops
–  Concentrations of 20-50% can decrease
staining and relieve symptoms better than
habitual eye drops
Patients with Schirmer scores ≤5mm/5min. AND central
corneal staining are level III
–  Kojima et al report a RCT where autologous
serum eye drops are more effective than
artificial tears
–  Yoon et al report umbilical cord serum is more
effective than autologous serum in relieving
signs and symptoms
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Level 3 Treatments
Level 3 Treatments
•  Contact Lenses
•  Permanent punctal occlusion
–  Used in severe dry eye
•  Ex. large diameter / scleral lenses
–  Can improve vision and comfort
–  Can health persistent epithelial defects
–  Overnight wear an option but brings added
risk in a dry eye patient
–  Little detail in report
–  Used as alternative to semi-permanent
punctal plugs
Level 4 Treatments
•  Beyond scope of this talk
•  Systemic anti-inflammatory agents
•  Surgery
–  Lid surgery, tarsorrhaphy
–  Transplantation of mucus membrane, salivary
gland, or amniotic membrane transplantation
Thank you for your attention!
[email protected]
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