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Derek N. Cunningham, O.D., [email protected]
Slide 2
Slide 3 Treatment vs Management
Slide 4
Adapted with permission from Ghaffar A. Hypersensitivity Reactions. In: Microbiology and Immunology On-Line. University of South Carolina School of Medicine Web Site. Available at: http://pathmicro.med.sc.edu/ghaffar/hyper00.htm. Accessed February 7, 2007.
Allergic Response
Antigen-PresentingCell
TH2Cell
Capillary Lumen
Mechanisms of Type 1 hypersensitivity allergic reaction, IgE-mediated mast cell degranulation, and release of inflammatory mediators
Capillary Epithelium
BCell
Ca++ Rises
GM-CSF TNF-αIL-8 IL-9
Inflammatory CellActivation
IgE
IL-4, IL-13
IL-3,
IL-4
Mediators
IL-4 IL-5 IL-6
ClinicalEffects/
Signs andSymptoms
Release ofMediators
Mast CellActivationIgE
ProductionAntigen
Presentation
Antigen
Antigen Antigen
IFNy
Slide 5 Components of an Allergic Response
•T helper cells (Type-1 and Type-2)
•Mast Cells
•Histamine
•Eosinophils
•Neutrophils
•Cytokines
•Adhesion Molecules
Slide 6 Early- and Late-Phase Inflammatory Mediators
Phospholipase A2Activity
Arachidonic Acid
LipoxygenasePathway
Cyclo-oxygenasePathway
Mast CellMembrane Phospholipids
HHT, MDA
Adapted with permission from Donnenfeld ED. Refract Eyecare. 2005;9(suppl):12-16.Slonim CB. Rev Ophthalmol. 2000:101-112.
Late-PhaseMediators
Early-PhaseMediators
Hydroperoxides(5-HPETE)
Leukotrienes(LTC4, LTD4, LTE4, LTB4)
Prostaglandins(PGF2α, PGD2, PGE2)
Cyclic Endoperoxides
Prostacyclin(PGI2)
Thromboxane A2
(TXA2)
HeparinHistamine PAFProteases (tryptase, chymase)
Slide 7 Main Characters
• Eosinophils
• Neutrophils
• Cytokines
• Adhesion Molecules
Slide 8 Secondary Mediators
• Leukotrienes - vascular permeability, sm contraction• Prostaglandins - vasodilation, sm contraction,
platelet activation• Bradykinin - vascular permeability, sm contraction• Cytokines - numerous effects incl. activation of
vascular endothelium, eosinophil recruitment and activation
Slide 9 Secondary/Late phase mediators
• Responsible for development of severe disease• Carry the risk of scarring • Are self perpetuating
Slide 10
Slide 11 PRIMING
• In allergy there is an up-regulation of the receptors on the epithelial surface that bind eosinophils and neutrophils.
Slide 12 Common Factor
• All allergic conditions itch.
• All allergy involves mast cell activation– Release inflammatory mediators– Recruit inflammatory cells
Slide 13 Seasonal Allergic Conjunctivitis
Definition:Common, recurrent, bilateral ocular inflammatory process
often initiated by airborne allergens1
Manifested by mild to severe symptoms of ocular discomfort1,2
Mast cell: common denominator in all types of ocular allergies1,3
Type I immediate-IgE hypersensitivity allergic reaction1,4
Pathogenesis involves a complex interactive mechanism between IgE-mediated mast cell degranulation and the release of inflammatory mediators1
1. Bhargava A et al. Drugs Today. 1998;34:957-971.2. Shulman DG et al. Ophthalmology. 1999;106:362-369.3. Abelson MB et al. Ocul Surf. 2003;1:127-149.4. Bonini S, Ghinelli E. Acta Ophthalmol Scand. 2000;78:41.
Slide 14 Pathophysiology of Seasonal Allergic Conjunctivitis: Chemical Mediators1-3
• Generated through the inflammatory cascade– Play a key role in the inflammatory reaction of the
ocular allergic response
• Created through the cascade as– Early-phase chemical mediators (preformed)– Late-phase chemical mediators (newly formed)
1. Slonim CB, Boone S. Formulary. 2004;39:213-222.2. Slonim CB. Rev Ophthalmol. 2000:101-112.3. Bhargava A et al. Drugs Today. 1998;34:957-971.
Slide 15 Mast Cell
Primary cellular component of the ocular allergic reaction1
Main source of early, preformed inflammatory mediators and a variety of cytokines1
Mediators and cytokines are responsible for the initiation and progression of the allergic inflammatory reaction, respectively2
Cytokines play a central role in the immunoregulatory mechanism of the ocular allergic response3
1. Abelson MB et al. Ocul Surf. 2003;1:127-149.2. Slonim CB. Rev Ophthalmol. 2000:101-112. 3. Bhargava A, et al. Drugs Today. 1998;34:957-971.
Slide 16 Early-Phase Reactions
Occurs approximately 20 minutes after the initial antigen challenge and persists for 1-2 hours3,4
Mast cell degranulation marks the beginning of the acute early-phase reaction1,2
Histamine is released along with cytokines and other preformed mediators1,2
These events elicit the immediate signs and symptoms of the ocular allergic reaction1,2
The duration of these signs and symptoms in the acute, early phase of the allergic reaction is correlated with their intensity2
1. Bhargava A et al. Drugs Today. 1998;34:957-971. 2. Abelson MB et al. Ocul Surf. 2003;1:127-149.3. Nichols KK et al. Optometric Mgmt April 20064. Bielory L et al. Medscape Gen Med 2007; 9(3):35
Slide 17 We need an Antihistamine
• King of the allergy treatments
• Proven safety for long term use
• Instant relief
Slide 18 Side Effects
Slide 19 Late-Phase Reactions
Clinical and histopathological phenomenon characterized by the release of newly formed mediators and the recruitment of inflammatory cells1,2
Causes further tissue damage2
Continues the inflammatory cycle3
Occur 4 to 8 hours after the initial antigen challenge, and persists for up to 24 hours1
Dependent on the initial antigen dose2
Clinically characterized by the persistence of signs and symptoms2
The time course for the development of these signs and symptoms has been well established2
1. Bonini S et al. Acta Ophthalmol Scand. 2000;78(suppl 230):41.2. Abelson MB et al. Ocul Surf. 2003;1:127-149.3. Donnenfeld ED. Refract Eyecare. 2005;9:12-16.
Slide 20 We need something more
Slide 21 Corticosteroids
• Should be used whenever the eye looks inflammatory – Decreased tear production and tear clearance lead
to chronic inflammation (and lid friction) on the ocular surface
• Are often needed to prevent corneal involvement
• Should be used in a pulse regime
Slide 22 Corticosteroids
• Will control prostaglandins and leukotrienes • STOPS THE INFLAMMATION CASCADE• Suppresses inflammation• Allows for reestablishment of the neural feed
back loop
Slide 23 Conjunctival Time Course of Selected Inflammatory Cells and
MediatorsThe complete system complex is more than histamine. It has peaks and troughs well beyond the acute stage, therefore all of these mediators need to be treated when treating allergies
LeukotrienesHistamine Tryptase Neutrophils Eosinophils ICAM-1
Adapted from L Bielory, MD for UMDNJ - New Jersey Medical School UMDNJ - Center for Continuing and Outreach Education. Diagnosis and Management of Ocular Allergy: Update. CME-Certified slide kit on CD-ROM. Release date Nov 15, 2002.
-20
0
30
60
90
120
0.25 0.5 1 6 24
Time (hour)
Med
ian
Valu
es
0
Late phase mediators can occur as early as 6
hours after initial antigen challenge
Slide 24 All Early- and Late-Phase Mediators
1. Slonim CB. Rev Ophthalmol. 2000:101-112. 2. Slonim CB, Boone R. Formulary. 2004;39:213-222.7. Nichols KK, Morris S, Weibel KA. Get the reaction you want. Optometric Management. April 2006. Available at: http://findarticles.com/p/articles/mi_qa3921/is_200604/ai_n17174436. Accessed January 9, 2008. 8. Bielory L, Katelaris CH, Lightman S, Naclerio RM. Treating the ocular component of allergic rhinoconjunctivitis and related eye disorders. Medscape Gen Med. 2007;9(3):35. Available at: http://www.medscape.com/viewarticle/560750. Accessed January 28, 2008.
Slide 25 Late-Phase Review
Leukotriene and IL-5
Eosinophils, and other mediators are recruited
©2011 ISTA Pharmaceuticals®, Inc. All rights reserved. OPH BRV910-3/11
Denburg JA, Ed.; Allergy and Allergic Diseases: The New Mechanisms and Therapeutics; Humana Press; 1998
Slide 26 Functions of other Immune Cells
Eosinophils release a variety of toxic proteins that can damage the
conjunctival epithelium
Tear film
Conjunctiva
Stroma
©2011 ISTA Pharmaceuticals®, Inc. All rights reserved. OPH BRV910-3/11
Denburg JA, Ed.; Allergy and Allergic Diseases: The New Mechanisms and Therapeutics; Humana Press; 1998
Slide 27 NSAIDS
• Reduce itching as well as burning and itching
• Patients with multiple symptoms may benefit
Slide 28
Slide 29 Seasonal Conjunctivitis
• Cornea is almost never involved• Few Papillae • Often itches more than it would appear
• Lots of symptoms and little to no signs
Slide 30 QD for Allergy?
Slide 31 Perennial Conjunctivitis
• Symptoms persist past allergy season
• May be atopic, with an immune dysregulation
• Benefit from allergist consult
Slide 32 Atopic Conjunctivitis Threat
• EVERY EFFORT MUST BE MADE TO CONTROL THE DISEASE BEFORE THE CORNEAL CHANGES OCCUR
• Watch for constellation of conjunctivitis, rhinitis, asthma, eczema
Slide 33 Why do we fail?
Slide 34 Modalities for treating itching associated with Allergic Conjunctivitis1
OTC topical antihistamines, vasoconstrictors
Rx Topical Corticosteroids
RxMast Cell Stabilizers
AllergenAvoidance Cool Compresses Lubrication/
Artificial Tears
Rx Dual-ActionAntihistamine/Mast Cell Stabilizers
BEPREVEIndicated for the treatment of itching associated
with allergic conjunctivitis
Rx NSAIDs
Slide 35 Treating seems easy.How do we Manage?
Slide 36 Artificial tears are necessary
• Tear Substitutes:– Barrier function - improve 1st line of defense;
– Dilute allergens and mediators in tears;
– Flush allergens and mediators out of the eye;
– Non-preserved are preferred;
– Keep refrigerated for added comfort
Slide 37 Mast cell stabilization
• Stabilization of mast cells can not take place in the presence of edema or inflammation.
• The receptors are bound by other factors and the mast cell stabilizers have a decreased ability to get to the binding site.
Slide 38 Mast cell stabilization in the presence of inflammation
38
Slide 39
Slide 40 Co-morbidities
Inflammation
Lid disease
AllergyDry Eye
Slide 41 HOT TEARS?
Slide 42 DRY EYE
Slide 43 Create a Barrier
• Tear film is the best barrier• When to prescribe artificial tears
43
Slide 44 Limit Exposure
Slide 45 What is the main function of the tear film?
• Lubricate• Nourish • Anti-microbial • Clean the surface • Transport oxygen• Acts as a barrier• Optical surface
Slide 46 Thiazide Diuretics
Slide 47 Which one comes first?
Slide 48 Dry Eye Treatments
• Treatment vs Management
Slide 49 The Asclepius Panel Recommended Treatment Model for
Dry Eye Inflammation
Adapted from Holland EJ. Ophthalmol Times. 2007;32:3-11.
Lotemax® QID(loteprednol etabonate ophthalmicsuspension 0.5%)
Artificial Tears
Lotemax® BID(loteprednol etabonate ophthalmicsuspension 0.5%)
Lotemax®…up to QID for flare-ups(loteprednol etabonate ophthalmicsuspension 0.5%)
Restasis® BID(cyclosporine ophthalmic emulsion) 0.05%)
Thereafter
Slide 50 Antihistamines causing dry eye
Slide 51 Blepharitis – Not Easy
• Chronic• Uncertain etiology • Coexisting ocular
disease
Itchy eyelids!!!!!
Slide 52 High prevalence of bleph possibly due to poor diet
52 60
Slide 53 Patients may not be well educated on nutrition
53
Slide 54 Blepharitis
• Constantly releases inflammatory factors into the tear film
• Tear film then provides vehicle to bath all tissues in these inflammatory factors
• Lack of proper tear film allows extended contact time between factor and tissue
Slide 55 Culprits
• Staphylococcus epidermidis
• S. aureus
• Toxin production
• Cell mediated immunity – Staph antigens cause inflammation
Slide 56 Bleph Treatments?
• Are warm compresses and lid scrubs necessary?
• Artificial tears • Antibiotics
– Oral or topical?
• What about the inflammation?
Slide 57 Antibiotics
• Topical– Bacitracin
• Great for the bacteria, not so much for the inflammation
• Combos– Zylet and Tobradex
• Tobramycin
Slide 58 Antibiotics ?
• Tetracycline analogues have been shown to decrease bacterial lipases, and demonstrate anti-inflammatory properties in the cornea
• Should be used with moderate bleph or MGD, and when corneal involvement is significant
• Doxy 50-200mg/day x 30 days (may need a maintenance dose of 100mg x up to 6 months)
• Use Minocycline if tolerability is an issue, or increased sun exposure
Slide 59 Doxy
• Doxycycline--a role in ocular surface repairBr. J. Ophthalmol., May 1, 2004; 88(5): 619 -625.
• Doxycycline irreversibly inhibits corneal MMP-2 activity by chelating the metal ions that are catalytically and structurally essential.
Slide 60 Omega-3
• Women Health Study – Harvard School of Public Health
• Consumption of Omega-3s was directly related to a decreased risk of dry eye
• Omega-6 counteracts benefits of Omega-3• Consumption of Omega-6s was correlated
with increased risk of dry eye
Slide 61 Omega-3
Slide 62 How can we make our lives more difficult?
Slide 63 GPC
Slide 64
Slide 65
Slide 66 All Early- and Late-Phase Mediators
1. Slonim CB. Rev Ophthalmol. 2000:101-112. 2. Slonim CB, Boone R. Formulary. 2004;39:213-222.7. Nichols KK, Morris S, Weibel KA. Get the reaction you want. Optometric Management. April 2006. Available at: http://findarticles.com/p/articles/mi_qa3921/is_200604/ai_n17174436. Accessed January 9, 2008. 8. Bielory L, Katelaris CH, Lightman S, Naclerio RM. Treating the ocular component of allergic rhinoconjunctivitis and related eye disorders. Medscape Gen Med. 2007;9(3):35. Available at: http://www.medscape.com/viewarticle/560750. Accessed January 28, 2008.
