Download Dry Eye Syndrome: An Ocular Surface Inflammatory Disease (OSID

Dry Eye Syndrome: An Ocular Surface
Inflammatory Disease (OSID)
Ocular Surface Disease
• Dry Eye Syndrome is a common and
under-recognized ocular surface
inflammatory disease (OSID)
• Inflammation is a hallmark of
dry eye1,2
• A group of disorders of the tear film
due to reduced tear production or
excessive tear evaporation1,3
– Affects tear quantity and quality
– Associated with symptoms of ocular
discomfort
– Associated with significant ocular
morbidity
Ben Gaddie, O.D., F.A.A.O.
Louisville, KY
COPE #13171-AS
Adapted with permission from Torkildsen G et al.
Rev Ophthalmol. 2005;11:35-38.
1. McDonald MB. Refract Eyecare. 2005;9(suppl):3-6.
2. Stern ME et al. Exp Eye Res. 2004;78:409-416.
3. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
Epidemiology of Dry Eye Syndrome
• Approximately 25% of eye care visits are due to Dry Eye1
• Up to 40 million Americans may either have symptoms of Dry
Eye or are at risk for it2
– Incidence of Dry Eye increases with age
• Up to 51% of patients older than 65 years3
• Up to 31% of women between 40 and 59 years of age3
Dry Eye Syndrome:
Under-recognition Due to Self-Treatment
• Many patients use OTC artificial tears and lubricants, which
are mostly palliative1
– Estimated artificial tears USA sales >$145.4 million in 20052
• Self-treatment with OTC agents may delay diagnosis and
effective therapy
– Untreated inflammation associated with Dry Eye can lead to
significant irreversible ocular damage
• Despite these numbers, Dry Eye remains remarkably
under-diagnosed4
1. O’Brien PD, Collum LMT. Curr Allergy Asthma Rep. 2004;4:314-319.
2. Sheppard JD. Manag Care. 2003;12(suppl):6-8.
3. National Drug Treatment Information (NDTI) Sample Data. 2004-2005:701-702.
4. Perry HD, Donnenfeld ED. Curr Opin Ophthalmol. 2004;15:299-304.
Dry Eye Syndrome: Predisposing Factors1
•
•
•
•
Age
Gender
Environment
Anterior segment disease
•
•
•
•
Medications
Contact lenses
Surgery
Systemic diseases
OTC = over-the-counter.
Systemic Diseases Associated With
Dry Eye Syndrome1-3
•
•
•
•
•
Diabetes mellitus
Acne rosacea
Thyroid disease
Lymphoma
Inflammatory diseases
– Allergy
– Asthma
– Vasculitis
1. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
1. Calonge M. Surv Ophthalmol. 2001;45(suppl 2):S227-S239.
2. IMS Dataview 2005.
• Sjögren’s syndrome
• Autoimmune diseases
– Rheumatoid arthritis
– Lupus
• Neuromuscular disorders
– Parkinson’s disease
– Bell’s palsy
1. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
2. O’Brien PD, Collum LMT. Curr Allergy Asthma Rep. 2004;4:314-319.
3. Dalzell MD. Manag Care. 2003;12(suppl): 9-13.
1
Ocular Diseases Associated With
Dry Eye Syndrome
Dry Eye Syndrome: Classification
• Dry Eye can exist in association with several other ocular
surface inflammatory diseases (OSIDs)
–
–
–
–
DRY EYE
SYNDROME
Seasonal allergic conjunctivitis (SAC)1
Giant papillary conjunctivitis (GPC)1
Blepharitis2,3
Meibomitis2,3
Deficient Aqueous
Tear Production
Sjö
Sjögren
Syndrome
NonNon-Sjö
Sjögren
Syndrome
Increased
Evaporative Loss
Blepharitis
Meibomian Gland
Dysfunction
1. Howes JF. Pharmazie. 2000;55:178-183.
2. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
3. O’Brien PD, Collum LMT. Curr Allergy Asthma Rep. 2004;4:314-319.
Pathophysiology of Dry Eye Syndrome:
Ocular Surface Inflammation
• Numerous studies have recognized that inflammation plays a key
role in the pathogenesis of Dry Eye1-5
• The role of T-cells along with several other inflammatory
mediators have been clearly demonstrated in both humans and
animal models3,5-7
• Several animal models are currently in use to better understand
the pathophysiology of Dry Eye Syndrome5,8,9
Inflammation Underlies Dry Eye Syndrome
• Inflammation affects the external ocular surface components1
–
–
–
–
Eyelids
Bulbar and palpebral conjunctival epithelium
Lacrimal and meibomian glands
Corneal epithelium
• Inflammation affects tear production1,2
– Decreased quantity of “normal” tears
– Excessive “dysfunctional” tears/mucus
1. Stern ME et al. Exp Eye Res. 2004;78:409-416.
2. O’Brien PD, Collum LMT. Curr Allergy Asthma Rep. 2004;4:314-319.
Inflammation as an Underlying Factor in
the Pathophysiology of Dry Eye
Syndrome1-3
Neural Regulation of Normal
Tear Production
Lacrimal
Gland
Other Factors
1. Contact Lenses
2. Blink Abnormality
3. Environmental
Adapted with permission from Lemp MA. CLAO J. 1995;21:221-231.
American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
1. Perry HD, Donnenfeld ED. Curr Opin Ophthalmol. 2004;15:299-304. 2. McDonald MB. Refract Eyecare. 2005;9(suppl):3-6.
3. Pflugfelder SC et al. Cornea. 2000;19:644-649. 4. Wilson SE. Manag Care. 2003;12(suppl):14-19.
5. Stern ME et al. Exp Eye Res. 2004;78:409-416. 6. Gao J et al. Cornea. 1998;17:654-663.
7. Stern ME et al. Invest Ophthalmol Vis Sci. 2002;43:2609-2614. 8. Hoffman RW et al. Arthritis Rheum. 1984;27:157-165.
9. Jabs DA, Prendergast RA. Invest Ophthalmol Vis Sci. 1988;29:1437-1443.
Secretomotor Nerve
Impulses
Exposure
Inflammatory Cellular Infiltration
Central
Nervous
System
Tissue Scarring
Sensory
Nerve
Impulses
Ocular
Surface
Inflammation
Lacrimal Gland Dysfunction
Meibomian Gland/
Goblet Cell Dysfunction
Decreased Aqueous
Tear Production
Defective Tear Lipid Film/Layer
Increased Evaporative Loss
Adapted with permission from McDonald MB. Refract Eyecare. 2005;9(suppl):3-6.
1. O’Brien PD, Collum LMT. Curr Allergy Asthma Rep. 2004;4:314-319.
2. Pflugfelder SC et al. Cornea. 2000;19:644-649.
3. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
2
Dry Eye Syndrome:
Tear Film Inflammatory Response
• Tear film has a complex biochemical structure1
– External layer that covers and protects the ocular surface
epithelium
• Abnormality in tear film composition leads to inflammation2
• Increased concentration of inflammatory cells and other
mediators in tears—“hot” tears2
• Inflammation of the tear film can affect the tear-secreting
glands
• Abnormal tear film composition, production, and clearance
perpetuates the inflammatory cycle → chronic inflammation3
Inflammatory Mediators of the Tear Film1-4
• T-cells
• Matrix-degrading enzymes
– ↑ MMP-9
– ↑ Protease activity
• Inflammatory cytokines
–
–
–
–
↑ IL-1β
↑ TNF-α
↑ TGF-β
↓ IL-1RA
• Immunoglobulins
– ↑ IgM
– ↑ IgG
– ↓ IgA
• Proinflammatory neural
transmitters
– Substance P
– CGRP
• Adhesion molecules
– ICAM-1
– VCAM-1
1. McDonald MB. Refract Eyecare. 2005;9(suppl):3-6.
2. Perry HD, Donnenfeld ED. Curr Opin Ophthalmol. 2004;15:299-304.
3. Wilson SE. Manag Care. 2003;12(suppl):14-19.
4. Stern ME et al. Exp Eye Res. 2004;78:409-416.
1. Pflugfelder SC et al. Cornea. 2000;19:644-649.
2. McDonald MB. Refract Eyecare. 2005;9(suppl):3-6.
3. Perry HD, Donnenfeld ED. Curr Opin Ophthalmol. 2004;15:299-304.
Inflammatory Cycle of Dry Eye Syndrome
Chronic Irritation
Development
of Signs and
Symptoms
Immune Activation
Signs and Symptoms of Dry Eye
Syndrome1,2
Signs
• Conjunctival
hyperemia/injection
• Chemosis
• Epiphora
• Mucus discharge
• Increased blinking frequency
Symptoms
• Red eye
• Irritation
• Dryness, itching
• Foreign body sensation
• Burning/stinging
• Poor/blurred vision
• Contact lens intolerance
• Photophobia, epiphora
Inflammation
1. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
2. McDonald MB. Refract Eyecare. 2005;9(suppl):3-6.
Adapted with permission from Wilson SE. Manag Care. 2003;12(suppl):14-19.
Misdiagnosis of Dry Eye Syndrome
• Diagnosis is primarily based on clinical signs and symptoms
reported by patients1,2
• Poor correlation exists between clinical signs and reported
symptoms1
• Several tests are available, but not one specific diagnostic test1-3
• Misdiagnosis leads to under-recognition and under-treatment
• Long-standing, untreated inflammation → ocular complications
Inflammation Associated with Dry Eye
Syndrome Can Lead to Ocular Complications1,2
•
•
•
•
Infection
Ocular surface keratinization
Corneal ulceration
Conjunctival squamous metaplasia
These conditions can result in permanent structural
damage with possible loss of visual function1
1. O’Brien PD, Collum LMT. Curr Allergy Asthma Rep. 2004,4:314-319.
2. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
3.Perry HD, Donnenfeld ED. Curr Opin Ophthalmol. 2004;15:299-304.
1. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
2. Sheppard JD. Manag Care. 2003;12(suppl):6-8.
3
Need for Early Diagnosis and Treatment
• Inflammation is often present long before clinical signs1
• Goal is to arrest inflammation before damage is irreversible2
– Institute immediate therapy that is safe and effective
– Ensure adequate dose and duration of therapy
Dry Eye International Task Force:
Diagnostic Recommendations
• A panel of experts achieved consensus on diagnostic parameters for Dry Eye
• Dry Eye Syndrome severity classification, based on signs and symptoms
Level 1
Mild to moderate symptoms
No corneal signs
Mild to moderate conjunctival signs
Level 2
Moderate to severe symptoms
Tear film signs, visual signs
Mild corneal punctate staining
Conjunctival staining
Level 3
Severe symptoms
Marked corneal punctate staining
Central corneal staining
Filamentary keratitis
Level 4
Extremely severe symptoms/altered lifestyle
Severe corneal staining, erosions
Conjunctival scarring
• Early diagnosis and proper treatment lead to better
outcomes2
1. O’Brien TP. Refract Eyecare. 2005;9(suppl):7-11.
2. Sheppard JD. Manag Care. 2003;12(suppl):20-25.
Dry Eye Syndrome:
Optimal Diagnostic Approach
• Complete patient history and physical examination1
• One or more diagnostic tests2,3
– Completed over a period of time
– Best approach to increase sensitivity and specificity in diagnosis
Adapted with permission from O’Brien TP. Refract Eyecare. 2005;9(suppl):7-11.
Diagnostic Tests for Dry Eye Syndrome
• Standard in-office diagnostic tests1,2
– Schirmer test
– Fluorescein tear breakup time
– Ocular surface dye staining
• Rose bengal
• Lissamine green
• Fluorescein
• Other available (out-of-office) diagnostic tests
– Tear film osmolarity
– Tear lactoferrin
– Impression/brush cytology
1. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
2. Perry HD, Donnenfeld ED. Curr Opin Ophthalmol. 2004;15:299-304.
3. O’Brien PD, Collum LMT. Curr Allergy Asthma Rep. 2004;4:314-319.
Diagnostic Tests for Dry Eye Syndrome (cont)
• More sophisticated laboratory tests1,2
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Fluorescein tear clearance/tear function index
Lacrimal gland function test
Meibography
Tear film osmolarity
Tear fluid protein immunoassays
Tear lactoferrin
Impression/brush cytology
1. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
2. O’Brien PD, Collum LMT. Curr Allergy Asthma Rep. 2004;4:314-319.
Dry Eye International Task Force:
Therapeutic Recommendations
• A panel of experts achieved consensus on therapeutic parameters for Dry
Eye
• TreatmentLevel
options
corresponding
Patient educationto the 4 severity levels
1
Level 2
Level 3
Level 4
1. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
2. O’Brien PD, Collum LMT. Curr Allergy Asthma Rep. 2004;4:314-319.
Environmental modifications
Control systemic medications
Preserved tears
Allergy control
If no improvement, add level 2 treatments
Unpreserved tears
Gels/nighttime ointments
Nutritional support
Topical corticosteroids
Cyclosporine
Secretagogues
If no improvement, add level 3 treatments
Tetracyclines
Punctal plugs (once inflammation is controlled)
If no improvement, add level 4 treatments
Systemic antiinflammatory therapy
Acetylcysteine
Moisture goggles
Surgery (punctal cautery)
Adapted with permission from O’Brien TP. Refract Eyecare. 2005;9(suppl):7-11.
4
Dry Eye Syndrome:
Current Treatment Options1-3
Dry Eye Syndrome:
Pharmacologic Therapy1-3
• Medical management
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•
•
–
–
–
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OTC agents
Prescription agents
Occlusive spectacles/goggles
Moisture chambers
• Surgical management
– Lid abnormality correction
– Punctal occlusion for severe cases
– Tarsorrhaphy for severe cases
Topical corticosteroids
Immunomodulation therapy
Secretagogues
Mucolytics
Cholinergic agonists
Antibiotics
Systemic anti-inflammatory therapy
1. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
2. Calonge M. Surv Ophthalmol. 2001;45(suppl 2):S227-S239.
3. National Drug Treatment Information (NDTI) Sample Data. 2004-2005;701-702.
OTC = over the counter.
1. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
2. Calonge M. Surv Ophthalmol. 2001;45(suppl 2):S227-S239.
3. National Drug Treatment Information (NDTI) Sample Data. 2004-2005;701-702.
Immunomodulation Therapy
Cyclosporine: Pivotal Studies1
• Cyclosporine ophthalmic emulsion 0.05%
• Cyclosporine ophthalmic emulsion 0.05% was compared with
placebo for the treatment of moderate to severe
keratoconjunctivitis sicca
• Four randomized, adequate, well-controlled, multicenter
studies (n=1200)
• Patients treated with immunomodulator or vehicle twice per
day for 6 months
• At 6 months, 15% of treated versus 5% of placebo patients
had an increase in Schirmer wetting test of 10 mm
• The most common adverse event was ocular burning in 17%
of patients treated with cyclosporine
– Approved by the FDA in December 2002 for treatment of Dry
Eye1
– Immunosuppressive (T-cell specific) agent1
• Inhibits T-cell activation2-4
• Downregulates T-cell–mediated cytokines2-4
1. Pflugfelder SC. Am J Ophthalmol. 2004;137:337-342.
2. Restasis® (cyclosporine ophthalmic emulsion) 0.05% prescribing information. Allergan, Incorporated; 2004.
3. O’Brien PD, Collum LMT. Curr Allergy Asthma Rep. 2004;4:314-319.
4. American Academy of Ophthalmology. Preferred Practice Pattern®: Dry Eye Syndrome. 2003.
FDA = Food and Drug Administration.
Percentage of Patients With a Positive
Schirmer Wetting Test (10 mm)
50
Cyclosporine
Placebo
% of Patients
40
Restasis® (cyclosporine ophthalmic emulsion) 0.05% prescribing information. Allergan, Incorporated; 2004.
Topical Corticosteroids
• Broad-spectrum, anti-inflammatory ophthalmic products1
• Mechanism of action spans virtually every aspect of the
inflammatory response1
– Nuclear
30
• Decreases production of inflammatory precursor proteins
– Cellular
20
• Suppresses proliferation of mast cells and lymphocytes1
– Biochemical
10
• Inhibits synthesis and enhances breakdown of histamine1
• Immediately effective2
0
2 Months
(not measured)
4 Months
(not measured)
6 Months
Restasis® (cyclosporine ophthalmic emulsion) 0.05% prescribing information. Allergan, Incorporated; 2004.
1. Slonim CB, Boone R. Formulary. 2004;39:213-222.
2. McDonald MB. Refract Eyecare. 2005;9(suppl):3-6.
5
Topical Corticosteroids Work Early to Block Multiple
Pathways of Inflammatory Cascade
Topical Corticosteroids: Limitations
Progenitor Cell Proliferation
Mast Cell
Topical Steroids
Work Here
Membrane Phospholipids
Topical Steroids
Work Here
Phospholipase A2
Arachidonic Acid
Tryptase Heparin Histamine
Chymase
CycloCyclo-Oxygenase
Lipoxygenase
Cyclic Endoperoxides
Hydroperoxides
Prostacyclin
(PCI2)
Membrane
Stabilization
Cyclosporine
Works Here
T-Cells
• With most topical corticosteroids, complications are a concern with
long-term use1
– Increased IOP
– Cataract formation
– Exacerbation of viral and/or fungal infections
Need for an optimal corticosteroid
that allows for safe longlong-term use
PAF
Leukotrienes
Thromboxane A2
(LTC4, LTD4, LTE4, LTB4)
(TXA2)
Prostaglandins
(PGF2, PGD2, PGE2)
PAF = platelet-activating factor.
Adapted with permission from Donnenfeld ED. Refract Eyecare. 2005;9(suppl):12-16.
IOP = intraocular pressure.
1. Donnenfeld ED. Refract Eyecare. 2005;9(suppl):12-16.
The Ideal Ophthalmic Corticosteroid Therapy
for Dry Eye Syndrome
•
•
•
•
Broad-spectrum anti-inflammatory properties
Rapid onset of action
Targeted, site-specific activity
Complete symptom control
The Role of LOTEMAX®
in Dry Eye Inflammation
– eg, burning, stinging
• Potent, but safe for prolonged use
• Minimal adverse events
• Works synergistically with immunomodulators
Loteprednol Etabonate:
The Only Ester Corticosteroid
Loteprednol Etabonate: Clinical Benefits of
the Only Ester Corticosteroid
• Unique topical steroid
• Benefits of the ester group
– Retrometabolic drug design1-4
• Modification of an existing molecule to reduce or eliminate unwanted adverse events
• Prednisolone derivative
• Position 20 ester group replaces the ketone group
CH2OH
Prednisolone
CH3
HO
Position 20 Ketone
C=O
OH
OCH2CI
CH3
Position 20 Ester
CH3
HO
CH3
• High lipophilicity leads to better penetration1,2
• Lipophilic index 10 times higher than dexamethasone1,2
• Rapid/targeted receptor binding leads to enhanced therapeutic
effect3,4
• 4.3 times greater binding affinity to steroid receptors than
dexamethasone5
– Safety
C=O
O
– Efficacy
OCO2C2H5
Loteprednol
Etabonate
• Unlike any other corticosteroid, loteprednol etabonate only becomes
activated when bound to receptor5
• Rapid inactivation of unbound drug by circulating esterases leads to
an inactive metabolite and minimal adverse events3,4
– Significantly reduced incidence of IOP increase5
– Decreased risk of cataract6
O
1. Bodor N. Pharmazie. 2001;56(suppl 1):S67-S74.
2. Novack GD et al. J Glaucoma. 1998;7:266-269.
3. Howes J, Novack GD. J Ocul Pharmacol Ther. 1998;14:153-158.
4. Holland EJ. Refract Eyecare. 2005;9(suppl):17-19.
1. Alberth M et al. J Biopharm Sci. 1991;2:115-125.
2. Howes JF. Pharmazie. 2000;55:178-183.
3. Novack GD et al. J Glaucoma. 1998;7:266-269.
4. Howes J, Novack GD. J Ocul Pharmacol Ther. 1998;14:153-158.
5. Holland EJ. Refract Eyecare. 2005;9(suppl):17-19.
6. Manabe S et al. J Clin Invest. 1984;74:1803-1810.
6
Lotemax® for the Treatment of
Dry Eye Inflammation
Efficacy of Lotemax® in Patients With
Moderate Symptoms of Dry Eye Inflammation*
40
Improvement
– 32 patients treated with Lotemax
– 34 patients treated with placebo
Subjects With Corneal Staining Score ≥10 and
Conjunctival Hyperemia Score ≥2 at Baseline
Percentage Change
From Baseline
• Lotemax was compared with placebo for the treatment of the
inflammatory component of Dry Eye in patients with delayed
tear clearance
• Randomized, double-masked, placebo-controlled, multicenter
comparison
• Patients with Dry Eye (n=66)
• Subjects received either Lotemax or placebo QID in both eyes
for 4 weeks
Lotemax
20
0
-22.2
-40
-60
12.5
0.0
-10.1
-20
33.3
Placebo
3.8
-11.1
-21.1
-25.0
-28.6
Inferior
Tarsal
Inferior
Bulbar
Nasal
Bulbar
-35.7
-47.1
-50.1
Primary
Primary
Subjective Objective
Outcome† Outcome‡
Central
Corneal
Staining
4.4
Redness
Hyperemia
QID = 4 times per day.
1. Pflugfelder SC et al. Am J Ophthalmol. 2004;138:444-457.
*Seen at 2 weeks and maintained after 4 weeks.
†Worst symptom.
‡Composite corneal staining score for worst eye.
Adapted with permission from Pflugfelder SC et al. Am J Opthalmol. 2004;138:444-457.
Efficacy of Lotemax® in Patients With Moderate
Symptoms of Dry Eye Inflammation (cont)
Efficacy of Lotemax® in Patients With Moderate
Symptoms of Dry Eye Inflammation (cont)
• The Lotemax-treated group showed greater improvement than
the vehicle group in both primary subjective and primary
objective outcomes
• Lotemax resulted in greater improvement than the vehicle group
in multiple indices of conjunctival hyperemia
• Lotemax showed much greater improvement than the vehicle
group in central corneal staining score
• Improvements achieved in the Lotemax-treated group at 2
weeks were maintained after 4 weeks of treatment when
compared with the vehicle group
• Improvement in central corneal staining was associated with a
significant improvement in the surface regularity index at
2 weeks (P=.05)1
– Videokeratoscopy performed in a subset of patients
• Clinically relevant improvement: central corneal staining is
positively correlated with a potential improvement in visual
acuity1,2
1. Pflugfelder SC et al. Am J Ophthalmol. 2004;138:444-457.
2. de Paiva CS, Pflugfelder SC. Ophthalmology. 2003;110:1102-1109.
1. Pflugfelder SC et al. Am J Opthalmol. 2004;138:444-457.
Safety of Lotemax® in Patients With Moderate
Symptoms of Dry Eye Inflammation
• Reported adverse events were similar for both the Lotemax
and the placebo groups1
• There were no clinically significant IOP changes in either
group1
• There were no signs of cataract formation1
• Safety of loteprednol etabonate has been further supported
by several long-term follow-up studies1,2
IOP = intraocular pressure.
1. Pflugfelder SC et al. Am J Ophthalmol. 2004;138:444-457.
2. Novack GD et al. J Glaucoma. 1998;7:266-269.
Efficacy and Safety of Lotemax® in Patients With
Moderate Symptoms of Dry Eye Inflammation1
• When used as monotherapy, Lotemax resulted in greater
improvement in objective signs and symptoms of Dry Eye than
placebo at both 2 and 4 weeks
• Lotemax also improved the surface regularity index and corneal
staining, which are correlated with visual acuity
• Lotemax demonstrated no clinically significant IOP elevation
following 1 month of therapy for Dry Eye
• Treatment of Dry Eye patients with Lotemax beyond 2 weeks
carries an excellent benefit-to-risk ratio
IOP = intraocular pressure.
1. Pflugfelder SC et al. Am J Ophthalmol. 2004;138:444-457.
7
Lotemax®: Potential Use of Concomitant
Therapy in Dry Eye Inflammation
Zylet®: Site-Active Corticosteroid Plus
Broad-Spectrum Aminoglycoside
• Topical corticosteroids have a rapid onset of action for faster relief and
can be used concomitantly with cyclosporine1
Loteprednol Etabonate 0.5%1
• Site-active corticosteroid
• Inhibits inflammatory response
to a variety of inciting agents
– Cyclosporine may require up to 6 months to produce a clinically
therapeutic effect
• In clinical practice, concomitant therapy of Lotemax and cyclosporine
for Dry Eye has been reported to be far more effective than either
therapy used alone2,3
– May act by inducing
phospholipase A2 inhibitory
proteins, collectively known
as lipocortins
– Clinical trials have yet to be completed
• Lotemax may help minimize adverse events such as burning and
stinging associated with cyclosporine2,3
• Lotemax may help improve patient compliance and satisfaction with
topical cyclosporine therapy2,3
• Lotemax is the #1 corticosteroid used in combination with cyclosporine
for the treatment of Dry Eye Inflammation4
1. Pflugfelder SC. Am J Ophthalmol. 2004;137:337-342.
2. O’Brien TP. Refract Eyecare. 2005;9(suppl):7-11.
3. Donnenfeld ED. Refract Eyecare. 2005;9(suppl):12-16.
4. National Drug Treatment Information (NDTI) Sample Data. 2004-2005:701-702.
Loteprednol Etabonate 0.5%:
First and Only Ester Corticosteroid
Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension)
Zylet® is a trademark of Bausch & Lomb Incorporated.
Tobramycin 0.3%1
• Broad-spectrum
aminoglycoside
• Inhibits bacterial protein
synthesis
– Binds to bacterial ribosomes
1. Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) [package
insert]. Tampa, Fla: Bausch & Lomb Incorporated; 2005.
Loteprednol Etabonate 0.5%:
Single-Step Metabolism1
Ester vs. Ketone
Corticosteroids
Ester1-3
• Loteprednol
Ketone1-3
• Prednisolone
• Fluorometholone
• Dexamethasone
• Medrysone
• Rimexolone
1. Lotemax [package insert]. Tampa, Fla: Bausch & Lomb Incorporated; 2002.
2. Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) [package insert].
Tampa, Fla: Bausch & Lomb Incorporated; 2005.
3. Howes J et al. J Ocul Pharmacol Ther. 1998;14:153-158.
Common Tobramycin
Susceptible Bacterial Pathogens1,2
•
•
•
•
•
•
•
Staphylococci
Streptococci
Pseudomonas aeruginosa
Escherichia coli
Klebsiella pneumoniae
Enterobacter aerogenes
Proteus mirabilis
•
•
•
•
•
•
•
1. Druzgala P et al. Curr Eye Res. 1991;10:933-937.
Key Zylet® Clinical Studies:
Efficacy and Safety
Tobramycin: No impact on Loteprednol Etabonate
0.5% Bioavailability
Morganella morganii
Proteus vulgaris (most strains)
Haemophilus influenzae
Haemophilus aegyptius
Moraxella lacunata
Acinetobacter calcoaceticus
Neisseria (some species)
1. Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) [package insert]. Tampa, Fla: Bausch & Lomb Incorporated; 2005.
2. Tobrex [package insert]. Forth Worth, Tex: Alcon Laboratories, Inc; 1980.
Analysis of intent-to-treat population1
.Zylet
Zylet
®
.
®
(loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension)
is a trademark of Bausch & Lomb Incorporated.
1. Data on file, Bausch & Lomb Incorporated, 2004.
8
Loteprednol Etabonate: No Impact on
Tobramycin Antimicrobial Activity
• Zylet was tested versus tobramycin ophthalmic solution,
USP, 0.3%1
• 20 Test organisms were evaluated in vitro1
• Zylet was found to have equivalent antimicrobial activity as
tobramycin alone1
Clinical Studies
Efficacy
Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension)
Zylet® is a trademark of Bausch & Lomb Incorporated.
1. Data on file, Bausch & Lomb Incorporated.
How Effective is Loteprednol Etabonate 0.5% in
Treating Anterior Chamber Inflammation
Following Cataract Surgery?
Two Studies:
Loteprednol Etabonate 0.5%:
Post-cataract Surgery Inflammation
Resolution of anterior chamber inflammation1
Patients at Risk
(combined), N
Resolution of
Inflammation, n (%)
Loteprednol etabonate
0.5%
211
26 (12)
(Days 2-6)
Placebo
213
13 (6)
3
(Days 7-12)
Loteprednol etabonate
0.5%
198
77 (39)
Placebo
175
31 (18)
4
(Days 13-20)
Loteprednol etabonate
0.5%
191
123 (64)
Placebo
146
57 (39)
Loteprednol etabonate
0.5%
211
126 (60)*
Placebo
213
61 (29)
Visit
Novack GD1; Stewart R2
2
Objective:
Two identical, randomized, placebo-controlled, doublemasked, parallel-group, multicenter trials were carried out to
determine the efficacy of loteprednol etabonate 0.5% in
reducing anterior chamber inflammation following cataract
surgery with intraocular lens implantation1,2
Final visit
Treatment Group
*P<.001 vs. placebo.
1. Loteprednol Etabonate Postoperative Inflammation Study Group 2. Ophthalmology. 1998;105:1780-1786.
2. Stewart R et al. J Cataract Refract Surg. 1998;24:1480-1489.
Loteprednol Etabonate 0.5%:
Post-cataract Surgery Inflammation
1. Data on file, Bausch & Lomb Incorporated, 1997.
Was Loteprednol Etabonate 0.5% Found to
be Safer Than Prednisolone Acetate in
Treating Acute Anterior Uveitis?
Lower incidence of treatment failure1
Two Studies:
Novack GD1
Objective:
Two virtually identical, randomized, active-controlled, doublemasked, parallel-group, multicenter trials were carried out
sequentially to determine the safety and efficacy of loteprednol
etabonate 0.5% in the treatment of acute anterior uveitis1,2
*Significant difference in favor of loteprednol etabonate 0.5% (P<.001).
1. Data on file, Bausch & Lomb Incorporated, 1997.
1. Loteprednol Etabonate US Uveitis Study Group. Am J Ophthalmol. 1999;127:537-544.
2. Data on file, Bausch & Lomb Incorporated, 1997.
9
Loteprednol Etabonate 0.5%:
Acute Anterior Uveitis
Loteprednol Etabonate 0.5%:
Acute Anterior Uveitis
Anti-inflammatory efficacy1,2
Resolution of anterior chamber cell reaction1
Loteprednol Etabonate
0.5%
Prednisolone Acetate
1.0%
Cell
72% (58/81)
87%* (77/89)
Flare
66% (52/79)
82%* (72/88)
Pain
90% (69/77)
85% (75/88)
Photophobia
79% (58/73)
78% (64/82)
Parameter
*P=.015
Intent-to-treat N=170
*P=.015
†36 to 72 hours after end of treatment
1. Data on file, Bausch & Lomb Incorporated, 1997.
2. Loteprednol Etabonate US Uveitis Study Group. Am J Ophthalmol. 1999;127:537-544.
Loteprednol Etabonate 0.5%:
Acute Anterior Uveitis
1. Data on file, Bausch & Lomb Incorporated, 1997.
How Effective is Loteprednol Etabonate 0.5%
in the Treatment of Contact Lens-associated
Giant Papillary Conjunctivitis?
Resolution of anterior chamber flare reaction1
Two Studies:
Asbell P1; Friedlaender MH2
Objective:
Two randomized, double-masked, placebo-controlled,
parallel-group, prospective, multicenter trials with identical
designs were carried out to determine the efficacy of
loteprednol etabonate 0.5% in the treatment of contact
lens-associated giant papillary conjunctivitis1,2
Intent-to-treat N=170
*P=0.017
†36 to 72 hours after end of treatment
1. Data on file, Bausch & Lomb Incorporated, 1997.
Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension)
Zylet® is a trademark of Bausch & Lomb Incorporated.
1. Asbell P et al. CLAO J. 1997;23:31-36.
2. Friedlaender MH et al. Am J Ophthalmol. 1997;123:455-464.
Loteprednol Etabonate 0.5%:
Giant Papillary Conjunctivitis
Loteprednol Etabonate 0.5%:
Giant Papillary Conjunctivitis
Significant improvement in primary efficacy parameters1-3
Significant improvement in secondary efficacy parameters1-3
Response
Response
Number of
Patients
Papillae
Itching
Lens
Intolerance
Loteprednol
etabonate 0.5%
221
76%
94%
91%
Placebo
222
51%
79%
78%
<.001
<.001
<.001
P value
1. Asbell P et al. CLAO J. 1997:23:31-36.
2. Friedlaender MH et al. Am J Ophthalmol. 1997;123:455-464.
3. Data on file, Bausch & Lomb Incorporated, 1994.
Number of
Patients
Investigator
Global
Assessment
Palpebral
Injection
Bulbar
Injection
Loteprednol
etabonate 0.5%
221
85%
68%
79%
Placebo
222
58%
48%
43%
<.001
<.001
<.001
P value
1. Asbell P et al. CLAO J. 1997:23:31-36.
2. Friedlaender MH et al. Am J Ophthalmol. 1997;123:455-464.
3. Data on file, Bausch & Lomb Incorporated, 1994.
10
How Effective is Loteprednol Etabonate 0.5%
in the Treatment of Contact Lens-Associated
Giant Papillary Conjunctivitis?
How Effective is Loteprednol Etabonate 0.5%—
the Anti-inflammatory Component of Zylet —
in Preventing Seasonal Allergic Conjunctivitis?
®
One Study:
Key results:
• Patients on loteprednol etabonate 0.5% experienced significantly
greater improvement in all 3 primary efficacy variables (papillae,
itching, lens intolerance) compared with those on placebo
– Intergroup differences favored loteprednol etabonate 0.5% by
25% for reduction in size and severity of papillae, 15% for
reduction in itching, and 13% for improved contact lens
tolerance (P<.001 for each)1-3
– Two additional studies found that loteprednol etabonate 0.5%
was both well tolerated and clinically effective in the treatment of
giant papillary conjunctivitis4,5
Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension)
Zylet® is a trademark of Bausch & Lomb Incorporated.
1. Asbell P et al. CLAO J. 1997:23:31-36.
2. Friedlander MH, et al. Am J Ophthalmol. 1997;123:455-464.
3. Data on file, Bausch & Lomb Incorporated; 1994.
4. Laibovitz RA et al. Invest Ophthal Vis Sci, 1991;32:734. Abstract 344–50.
5. Bartlett JD et al. Curr Eye Res. 1993;12:313-321.
Dell SJ1
Objective:
A randomized, double-masked, placebo-controlled, parallelgroup, multicenter trial was carried out to determine the
efficacy of loteprednol etabonate 0.5% as prophylaxis
against seasonal allergic conjunctivitis1
Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension)
Zylet® is a trademark of Bausch & Lomb Incorporated.
1. Dell SJ et al. Am J Ophthalmol. 1997;123:791-797.
How Effective is Loteprednol Etabonate 0.5%
in Preventing Seasonal Allergic Conjunctivitis?
Loteprednol Etabonate 0.5%:
Seasonal Allergic Conjunctivitis
Significant improvement in primary efficacy variables1
Key result:
• Patients in the loteprednol etabonate 0.5% group never
developed moderate or severe ocular signs and symptoms
of allergy during the peak pollen season vs. patients in the
placebo group
– Loteprednol etabonate 0.5% was effective in the prophylaxis of
seasonal allergic conjunctivitis1
*P<.001
†P<.001
Primary composite end point = itching + bulbar injection
Itching was evaluated on a scale of 0 to 4
Bulbar injection was evaluated on a scale of 0 to 3
1. Data on file, Bausch & Lomb Incorporated, 1994.
Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension)
Zylet® is a trademark of Bausch & Lomb Incorporated.
1. Dell SJ et al. Am J Ophthalmol. 1997;123:791-797.
Loteprednol Etabonate 0.5%:
Low Incidence of Adverse Events
• Adverse events occurring in 5% to 15% of patients1,2:
Clinical Studies
Adverse Events
–
–
–
–
–
Abnormal vision/blurring
Burning on instillation
Chemosis
Discharge
Dry eyes
–
–
–
–
–
Epiphora
Foreign body sensation
Itching
Injection
Photophobia
• Only 0.2% of patients exhibited a serious adverse event considered
possibly or probably related to study medication²
• All of these patients experienced complete resolution upon
discontinuation of treatment2
1. Lotemax [package insert]. Tampa, Fla: Bausch & Lomb Incorporated; 2002.
2. Data on file, Bausch & Lomb Incorporated; 1997.
3. Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) [package insert]. Tampa, Fla: Bausch & Lomb Incorporated; 2005.
11
What Impact Does Loteprednol Etabonate
0.5% Have on Intraocular Pressure?
Loteprednol Etabonate 0.5%:
Intraocular Pressure
Two Studies:
No significant elevation in known steroid responders1
Bartlett JD1; Novack GD2
Objective:
Both were randomized, double-masked, crossover studies
of populations of known steroid responders and an analysis
of controlled, randomized trials in subjects treated for ≥28
days were carried out to determine the safety of loteprednol
etabonate 0.5% vs. prednisolone acetate 1.0% with regard
to elevation in intraocular pressure1,2
1. Bartlett JD et al. J Ocul Pharmacol. 1993;9:157-165.
2. Novack GD et al. J Glaucoma. 1998;7:266-269.
1. Adapted from Bartlett JD et al. J Ocul Pharmacol. 1993;9:157-165.
Loteprednol Etabonate 0.5%:
Intraocular Pressure
What Impact Does Loteprednol Etabonate
0.5% Have on Intraocular Pressure?
Low incidence of elevation with long-term treatment1
Key results:
• The mean intraocular pressure elevations induced in known steroid responders
were neither statistically nor clinically significant after 6 weeks with loteprednol
etabonate 0.5%
• Significant elevations in prednisolone acetate group [18.1 mm Hg at
baseline vs. 27.1 mm Hg on day 42 (P<.05)]1
• An analysis of controlled, randomized trials demonstrated a significant elevation in
intraocular pressure in only 1.7% of patients on loteprednol etabonate 0.5%
compared with 6.7% of patients on prednisolone acetate 1.0%2
1. Bartlett JD et al. J Ocul Pharmacol. 1993;9:157-165.
2. Novack GD et al. J Glaucoma. 1998;7:266-269.
1. Adapted from Novack GD et al. J Glaucoma. 1998;7:266-269.
Loteprednol Etabonate 0.5%:
Clinical Safety
Tobramycin 0.3%:
Low Incidence of Adverse Events
• Studied in >2000 patients in 20 clinical studies1-3
• Ocular Adverse Events:
• Adverse events occurring in <3% of patients1,2:
– Very low incidence of IOP rise that was generally transient
in nature1-3
– Only 15 (1.7%) of 901 patients treated 28 days or longer had an
IOP rise >10 mm Hg1
– 11 of 15 patients with a clinically significant (>10 mm Hg) IOP
response were in GPC studies1
–
–
–
–
Hypersensitivity reactions
Local ocular toxicity
Swelling and/or itching of eyelids
Conjunctival erythema
• Patients were allowed to wear lenses indicating possible reservoir
effect of lenses
1. Novack GD et al. J Glaucoma. 1998;7:266-269.
2. Bartlett JD et al. J Ocul Pharmacol. 1993;9:157-165.
3. Friedlaender MH et al. Am J Ophthalmol. 1997;123:455-464.
1. Tobrex [package insert]. Forth Worth, Tex: Alcon Laboratories, Inc; 1980.
2. Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) [package insert]. Tampa, Fla: Bausch & Lomb Incorporated; 2005.
12
Patients at Risk for Elevated IOP
Associated with Steroid Use
Zylet®: Adverse Reactions
42-Day Safety Study1
Ocular Events
Zylet
Placebo
n=112
n=56
Injection
21%
29%
IOP
10%
4%
Average IOP Increase
(1.6 mm Hg)
(1.1 mm Hg)
SPK
13%
18%
Sting/Burn
9%
4%
All Other
<4%
—
Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension)
Zylet® is a trademark of Bausch & Lomb Incorporated.
1. Zylet® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension)
[package insert]. Tampa, Fla: Bausch & Lomb Incorporated; 2005.
• 14 to 22 million people who are steroid responders1,2
• 3 to 6 million people with ocular hypertension3
• 3 million people with glaucoma3,4
1. EyeMDLink.com. Steroid induced glaucoma. Available at: http://www.eyemedlink.com/Condition.asp?ConditionID=419. Accessed November 16, 2004.
2. U.S. Census Bureau. U.S. POPClock projection. Available at: http://www.census.gov/cgi-bin/ popclock. Accessed November 16, 2004.
3. E-medicine Consumer Health. Ocular Hypertension. Available at:www.emdicinehealth.com/articles/37513-1.asp. Accessed November 16, 2004.
4. Lee J, Bailey G. Glaucoma: The second-leading cause of blindness in the US. Available at: http://www.allaboutvision.com/conditions/glaucoma.htm. Accessed November 16, 2004.
Proven Clinical Experience with Tobramycin
Case Study #1
• Broad-spectrum aminoglycoside antibiotic with over 20 years
of real world experience1,2
• Active against both Gram-positive and Gram-negative ocular
pathogens1,2
• Binds to bacterial ribosomes, inhibiting protein synthesis1,2
• Generally bacteriostatic, but may be bactericidal in high
doses1,2
• Corneal penetration enhanced by lipid solubility1
• Low serum concentrations with ocular administration2
• 49 y/o myopic female seen in refractive
consultation. History of contact lens intolerance
over past 5 years with giant papillary conjunctivitis
(GPC)
• Medical history: Asthma; recent onset of
menopause
1. de Aguiar Moeller CT et al. Arq Bras Oftalmol. 1999;62. Available at: http://www.abonet.com.br/abo/abo62611.htm. Accessed September 13, 2004.
2. Robert P-Y et al. Drugs. 2001;61:175-185.
•
•
•
•
•
•
•
Mild GPC
Normal tear meniscus
BCVA 20/25 OU
3+ lissamine green conjunctival staining
1+ fluorescein corneal staining
Schirmer with anesthesia 5 OD/4 OS
Ocular Surface Disease Index (OSDI) = 0.39
– Corresponds to severe dry eye
‹
3+ Conjunctival Staining
• Scale 0-1; normal subjects score 0.05-0.10
13
• Started on Systane qid
• One month later:
– 2+ lissamine green conjunctival staining
– 1+ fluorescein corneal staining
– Schirmer 5 OD/5 OS
• Patient started on topical lotenpredenol (Lotemax)
BID and cyclosporine BID
• Two months later:
– BCVA 20/20 OU
– 1+ lissamine green conjunctival staining
– No fluorescein corneal staining
– Schirmer 11 OD/10 OS
– GPC resolves
• Patient undergoes uneventful LASIK
– Lotemax/cyclosporine treatment made this patient into
a LASIK candidate
14
Case Study #2
•
•
•
•
42 y.o. Caucasian Male
CC: FB Sensation, Dry burning eyes
Eyes constantly red
Can’t go outside - eyes hurt!
Predisposing factors
• Age
• Gender
• Environment
• Anterior Segment
Disease
Systemic Disease
• Diabetes
• Arthritis
–Sjogren’s
• Thyroid Eye Disease
• Medications
• CL Wear
• Refractive surgery
• Systemic Disease
Rosacea
• Erythema
• Telangiectasia
• Pustules
• Prominent sebaceous glands
• Rhinophyma
• Most missed systemic caused?
• Rosacea
15
Rosacea
Rosacea
• Presentation
• Women: cheeks
• Men: nose
• Meibomian gland dysfunction
• Dry eye
• Blepharitis
16
Ocular Rosacea
• 58% of all rosacea patients
• Presenting sign in :
• 20%!
17
Rosacea: Treatments
Tetracycline MOA
• Tetracyclines: Doxycycline 50mg bid x 1-2
months then qd
• Metrocream
• Education
• Periostat long term (20mg doxycycline)
• Accumulation in Oil Glands
• Anti-inflammatory component
• Regulate enzymatic activity of staph
Cautions
• Photosensitivity
• Chelates with dairy products, antacids
etc.
• Minocycline may cause vestibular toxicity
• Number one drop-out reason? - 25%
Tetracycline
Which of the following patients could be given
Doxycycline
A. Pregnant woman
B. 23 y.o. female with
Chlamydia
C. 8 y.o. child
D. 52 y.o. male with acne
rosacea
Which of the following medications should
someone on doxycycline avoid
• Pregnancy ratings:
• A, B, C, D, X
A. Antidepressants
B. Antacids
C. Tagamet
D. Birth control pills
• Rating on tetracycline: D
18
Which of the following complications may be related to
doxycycline?
A. Dry eye
B. Blepharitis
C. Pseudotumor Cerebri
D. Iritis
Nutritional Supplements: Essential fatty
acids
•
•
•
•
Flaxseed oil (1000 mg bid if tablet form)
Castor oil
Fish oils
Omega-3 fatty acids - linoleic acid
• Recommendation: Combination flax/fish oil
(500mg) begin qd then move to bid/tid
Case 3
Case #
• So why does her left eye hurt more than OD even though OD looks worse
• How do you counsel this patient?
• What is your topical course of therapy?
•
•
•
•
– NPAT
– Restasis/Steroids
– BSCL/Moisture goggle
56 YOWF presents with red eye and moderate pain
VA 20/25 bcc
History of “burned-out” arthritis
Slex as shown
• Do you use for systemic therapy?
– Hormone work-up
– Nutritional Support
– DCN
• What do you do about the filaments
• Do you plug immediately?
19
Case #
Lab Workup
• Differential diagnosis
•
•
•
•
•
•
•
•
–
–
–
–
Allergic conjunctivitis
Viral conjunctivitis
Episcleritis
Scleretis
• Phenylephrine testing
– Treatment and diagnostic managment
ACE
ANA
CBC w diff
Serum Lysozyme
RF
HLA-B27
ESR
VDRL/FTA-ABS
Case #
• 36 yowf 30-day extended wear FND 8.4 -6.50 OU normal VA
• Patient reports increased ocular comfort with contact lenses
on.
• Microcystic formation anterior cornea
• Stain with nafl
• Differential Dx
– SiHi immune reaction or other unknown mechanism
– Thygesson’s corneal dystrophy
20
Case #
•
•
•
•
•
•
•
38yowm
FND -5.00 OU
30 day EW x 2 years
Presents with red, light sensitive eye
2 days duration
No lens x 24 hours
Photos, management
Case #
Case Study #?
• Infectious or inflammatory?
• SiHi modulus
• Treatment-
•
•
•
•
– 3d vs 4th generation FQ
– Steroids and when?
42 y.o. male 1 month post LASIK
Transient Blur – worse in the evening
Throughout the day
No burning, stinging, dryness etc.
21