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1 Slide 1 Slide 4 Allergic Response Mechanisms of Type 1 hypersensitivity allergic reaction, IgE-mediated mast cell degranulation, and release of inflammatory mediators Antigen Derek N. Cunningham, O.D., FAAO derek.n.cunningham@gmail.com Antigen Antigen Release of Mediators Antigen-Presenting Capillary Cell Mast Cell Epithelium IgE Activation Production Antigen IgE Mediators Capillary Clinical Presentation Effects/ Lumen Ca ++ Rises Signs and Symptoms TH2 IL-4, IL-13 B Cell Cell IFNy IL-3, IL-4 IL-4 IL-5 IL-6 GM-CSF TNF-α IL-8 IL-9 Inflammatory Cell Activation 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: Accessed February 7, Slide 2 Slide 5 Components of an Allergic Response T helper cells (Type-1 and Type-2) Mast Cells Histamine Eosinophils Neutrophils Cytokines Adhesion Molecules Slide 3 Treatment vs Management Slide 6 Early- and Late-Phase Inflammatory Mediators Early-Phase Mediators Mast Cell Membrane Phospholipids Late-Phase Mediators Phospholipase A 2 Activity Arachidonic Acid Histamine Heparin Proteases (tryptase, chymase) PAF Cyclo-oxygenase Pathway Lipoxygenase Pathway Cyclic Endoperoxides Hydroperoxides (5-HPETE) Prostaglandins Prostacyclin Thromboxane A 2 (PGF 2α, PGD 2, PGE 2) (PGI 2) (TXA 2) Adapted with permission from Donnenfeld ED. Refract Eyecare. 2005;9(suppl): Slonim CB. Rev Ophthalmol. 2000: HHT, MDA Leukotrienes (LTC 4, LTD 4, LTE 4, LTB 4)

2 Slide 7 Eosinophils Main Characters Slide 10 Neutrophils Cytokines Adhesion Molecules Slide 8 Secondary Mediators Slide 11 PRIMING 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 In allergy there is an up-regulation of the receptors on the epithelial surface that bind eosinophils and neutrophils. Slide 9 Secondary/Late phase mediators Slide 12 Common Factor Responsible for development of severe disease Carry the risk of scarring Are self perpetuating All allergic conditions itch. All allergy involves mast cell activation Release inflammatory mediators Recruit inflammatory cells

3 Slide 13 Seasonal Allergic Conjunctivitis Slide 16 Early-Phase Reactions Definition: Common, recurrent, bilateral ocular inflammatory process often initiated by airborne allergens 1 Manifested by mild to severe symptoms of ocular discomfort 1,2 Mast cell: common denominator in all types of ocular allergies 1,3 Type I immediate-ige hypersensitivity allergic reaction 1,4 Pathogenesis involves a complex interactive mechanism between IgE-mediated mast cell degranulation and the release of inflammatory mediators 1 Occurs approximately 20 minutes after the initial antigen challenge and persists for 1-2 hours 3,4 Mast cell degranulation marks the beginning of the acute early-phase reaction 1,2 Histamine is released along with cytokines and other preformed mediators 1,2 These events elicit the immediate signs and symptoms of the ocular allergic reaction 1,2 The duration of these signs and symptoms in the acute, early phase of the allergic reaction is correlated with their intensity 2 1. Bhargava A et al. Drugs Today. 1998;34: Shulman DG et al. Ophthalmology. 1999;106: Abelson MB et al. Ocul Surf. 2003;1: Bonini S, Ghinelli E. Acta Ophthalmol Scand. 2000;78: Bhargava A et al. Drugs Today. 1998;34: Abelson MB et al. Ocul Surf. 2003;1: Nichols KK et al. Optometric Mgmt April Bielory L et al. Medscape Gen Med 2007; 9(3):35 Slide 14 Pathophysiology of Seasonal Allergic Conjunctivitis: Chemical Mediators 1-3 Slide 17 We need an Antihistamine 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) King of the allergy treatments Proven safety for long term use Instant relief 1. Slonim CB, Boone S. Formulary. 2004;39: Slonim CB. Rev Ophthalmol. 2000: Bhargava A et al. Drugs Today. 1998;34: Slide 15 Mast Cell Slide 18 Side Effects Primary cellular component of the ocular allergic reaction 1 Main source of early, preformed inflammatory mediators and a variety of cytokines 1 Mediators and cytokines are responsible for the initiation and progression of the allergic inflammatory reaction, respectively 2 Cytokines play a central role in the immunoregulatory mechanism of the ocular allergic response 3 1. Abelson MB et al. Ocul Surf. 2003;1: Slonim CB. Rev Ophthalmol. 2000: Bhargava A, et al. Drugs Today. 1998;34:

4 Slide 19 Late-Phase Reactions Slide 22 Corticosteroids Clinical and histopathological phenomenon characterized by the release of newly formed mediators and the recruitment of inflammatory cells 1,2 Causes further tissue damage 2 Continues the inflammatory cycle 3 Occur 4 to 8 hours after the initial antigen challenge, and persists for up to 24 hours 1 Dependent on the initial antigen dose 2 Clinically characterized by the persistence of signs and symptoms 2 The time course for the development of these signs and symptoms has been well established 2 Will control prostaglandins and leukotrienes STOPS THE INFLAMMATION CASCADE Suppresses inflammation Allows for reestablishment of the neural feed back loop 1. Bonini S et al. Acta Ophthalmol Scand. 2000;78(suppl 230): Abelson MB et al. Ocul Surf. 2003;1: Donnenfeld ED. Refract Eyecare. 2005;9: Slide 20 We need something more Slide 23 Conjunctival Time Course of Selected Inflammatory Cells and Mediators The 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 Late phase mediators 120 can occur as early as 6 hours after initial antigen 90 challenge Median Values Time (hour) Histamine Leukotrienes 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, Slide 21 Corticosteroids Slide 24 All Early- and Late-Phase Mediators 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 1. Slonim CB. Rev Ophthalmol. 2000: Slonim CB, Boone R. Formulary. 2004;39: Nichols KK, Morris S, Weibel KA. Get the reaction you want. Optometric Management. April Available at: Accessed January 9, 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: Accessed January 28, 2008.

5 Slide 25 Late-Phase Review Slide 28 Leukotriene and IL-5 Eosinophils, and other mediators are recruited Denburg JA, Ed.; Allergy and Allergic Diseases: The New Mechanisms and Therapeutics; Humana Press; ISTA Pharmaceuticals, Inc. All rights reserved. OPH BRV910-3/11 Slide 26 Functions of other Immune Cells Slide 29 Seasonal Conjunctivitis Tear film Conjunctiva Cornea is almost never involved Few Papillae Often itches more than it would appear Stroma Lots of symptoms and little to no signs Eosinophils release a variety of toxic proteins that can damage the conjunctival epithelium Denburg JA, Ed.; Allergy and Allergic Diseases: The New Mechanisms and Therapeutics; Humana Press; ISTA Pharmaceuticals, Inc. All rights reserved. OPH BRV910-3/11 Slide 27 NSAIDS Slide 30 QD for Allergy? Reduce itching as well as burning and itching Patients with multiple symptoms may benefit

6 Slide 31 Perennial Conjunctivitis Slide 34 Modalities for treating itching associated with Allergic Conjunctivitis 1 Symptoms persist past allergy season May be atopic, with an immune dysregulation Benefit from allergist consult Allergen Avoidance Rx Mast Cell Stabilizers Lubrication/ Cool Compresses Artificial Tears Rx Topical Corticosteroids OTC topical antihistamines, vasoconstrictors Rx NSAIDs Rx Dual-Action Antihistamine/Mast Cell Stabilizers BEPREVE Indicated for the treatment of itching associated with allergic conjunctivitis Slide 32 Atopic Conjunctivitis Threat EVERY EFFORT MUST BE MADE TO CONTROL THE DISEASE BEFORE THE CORNEAL CHANGES OCCUR Slide 35 Treating seems easy. How do we Manage? Watch for constellation of conjunctivitis, rhinitis, asthma, eczema Slide 33 Why do we fail? 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

7 Slide 37 Mast cell stabilization Slide 40 Co-morbidities 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. Allergy Dry Eye Lid disease Inflammation Slide 38 Mast cell stabilization in the presence of inflammation Slide 41 HOT TEARS? 38 Slide 39 Slide 42 DRY EYE

8 Slide 43 Create a Barrier Slide 46 Thiazide Diuretics Tear film is the best barrier When to prescribe artificial tears 43 Slide 44 Limit Exposure Slide 47 Which one comes first? Slide 45 What is the main function of the tear film? Slide 48 Dry Eye Treatments Lubricate Nourish Anti-microbial Clean the surface Transport oxygen Acts as a barrier Optical surface Treatment vs Management

9 Slide 49 The Asclepius Panel Recommended Treatment Model for Dry Eye Inflammation Slide 52 High prevalence of bleph possibly due to poor diet Thereafter Lotemax QID (loteprednol etabonate ophthalmic suspension 0.5%) Lotemax BID (loteprednol etabonate ophthalmic suspension 0.5%) Lotemax up to QID for flare-ups (loteprednol etabonate ophthalmic suspension 0.5%) Restasis BID (cyclosporine ophthalmic emulsion) 0.05%) Artificial Tears Adapted from Holland EJ. Ophthalmol Times. 2007;32:3-11. Slide 50 Antihistamines causing dry eye Slide 53 Patients may not be well educated on nutrition 53 Slide 51 Blepharitis Not Easy Slide 54 Blepharitis Chronic Uncertain etiology Coexisting ocular disease Itchy eyelids!!!!! 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

10 Slide 55 Culprits Slide 58 Antibiotics? Staphylococcus epidermidis S. aureus Toxin production Cell mediated immunity Staph antigens cause inflammation 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 mg/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 56 Bleph Treatments? Slide 59 Doxy Are warm compresses and lid scrubs necessary? Artificial tears Antibiotics Oral or topical? What about the inflammation? Doxycycline--a role in ocular surface repair Br. J. Ophthalmol., May 1, 2004; 88(5): Doxycycline irreversibly inhibits corneal MMP- 2 activity by chelating the metal ions that are catalytically and structurally essential. Slide 57 Antibiotics Slide 60 Omega-3 Topical Bacitracin Great for the bacteria, not so much for the inflammation Combos Zylet and Tobradex Tobramycin 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

11 Slide 61 Omega-3 Slide 64 Slide 62 How can we make our lives more difficult? Slide 65 Slide 63 GPC Slide 66 All Early- and Late-Phase Mediators 1. Slonim CB. Rev Ophthalmol. 2000: Slonim CB, Boone R. Formulary. 2004;39: Nichols KK, Morris S, Weibel KA. Get the reaction you want. Optometric Management. April Available at: Accessed January 9, 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: Accessed January 28, 2008.

12 Slide 67 NSAIDS with contacts? Slide 68 THANK YOU Thank you