Case 1 61 year old female with 4 day history of am eyes being shut closed. Very itchy and sore. On Latanoprost OU. Vision no change.

Transcription

1 Allergic Conjunctivitis: Current Trends and Advancements 2014 ASCRS JCAHPO Boston, MA., U.S.A. Saturday, April 26, 2014 Session A 3:30pm Dr. John T. Huang M.D., FRCSC, Dipl ABO Dr. Peter T. Huang M.D., FRCSC, Dipl ABO University of Calgary, Faculty of Medicine Synopsis & Educational Value: Course will review the diagnosis, investigation, and treatment of allergic conjunctivitis. New treatments and current trends in research will be reviewed. Objectives: Attendees will be able to describe the clinical presentation, the differential diagnosis and investigations of allergic conjunctivitis, and treatments available. Relationships with Commercial Interests: None Case 1 61 year old female with 4 day history of am eyes being shut closed. Very itchy and sore. On Latanoprost OU. Vision no change. Case 2 23 year old female with 9 month history of sore, itchy and scratchy eyes. Has been on lots of different drops with little resolution. Thinks some were antibiotics. Runny nose. Vision unchanged. Case 3 54 year old female with sore eye. Has been on three courses antibiotic drops and also tried Visine. No help. Eye bit blurry. Case 4 74 year old female with 3 week history of sore, itchy eyes and eyelids. Bit blurry. On Combigan drops. 1

2 Case 5 37 year old farmer with long standing redness, itching and blur. Has seen many doctors and only some relief. Also, stuffy nose that is worse every spring. Case 6 78 year old male with chronic redness and discomfort. No blur. Growing spot on OS. Had scraping on OD in past. Estimated Prevalence of Allergic Conjunctivitis Seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC) account for ~95% of all ocular allergy cases in the United States 1 More than half of allergic conjunctivitis cases are seasonal or intermittent 2 Over 41 million bottles of over thecounter (OTC) and 4 million bottles of prescription anti allergy ophthalmics are consumed yearly 3 95% SAC & PAC Allergic Response: Multiple Inflammatory Mediators Allergen Mast Cell Early Phase (0 1 hour) Neosynthesis Itch Tryptase Redness Chymase Histamine Heparin Chemosis Late Phase (1 24 hours) Basophil s chemotaxis Mast Cells Eosinophils ~20% population affected, of these 59% affected year round and 46% affected quality of life (2013 AAO PPP Conjunctivitis) 5% Other 1. Butrus S et al. Ophthalmol Clin North Am. 2005;18(4): Bielory BP et al. ACTA Ophthalmol. 2011: Slonim CB and Boone R. Formulary. 2004;39: Histamine Itch Redness Chemosis Hingorani M et al. "Conjunctivitis." Allergy, 2nd Ed. London: Mosby, 2002 PAF Chemosis PGs LTs Arachidonic Acid derived Redness Pain/Itch Chemosis Discharge Cytokines Proteins LTs=leukotrienes; PAF=platelet activating factor; PGs=prostaglandins American Academy of Ophthalmology PPP Conjunctivitis Allergic Seasonal Allergic Vernal Atopic Giant Papillary Conjunctivitis (also has a mechanical component) Mechanical/Irritative/Toxic SLK Contact lens related Floppy eyelid Giant Fornix Pediculosis Medication Conjunctival chalasis 2013 American Academy of Ophthalmology PPP Conjunctivitis Viral Adenoviral HSV VZV Molluscom Contagiosum Bacterial Bacterial( including gonococcal and nongonococcal) Chlamydial 2

3 2013 American Academy of Ophthalmology PPP Conjunctivitis Immune Mediated Ocular Mucous Membrane Pemphigoid Graft versus host disease Stevens Johnson Syndrome Neoplastic Sebaceous Cell Carcinoma Ocular surface squamous neoplasia Melanoma Associated/predisposing factors/natural lhistory/clinical lsigns Seasonal(Perennial) Allergic Conjunctivitis Environmental allergens, allergic rhinitis Recurrent Bilateral Conjunctival injection, chemosis, watery discharge, mild mucous discharge Vernal Keratoconjunctivitis Environmental allergens More in hot, dry climates( eg. Mexico, North and South America) Onset in childhood, males, chronic with acute, decrease over 2 20 years, 90% assoc. atopic conditions such as asthma, eczema, allergic rhinitis Palpebral and Limbal subtypes Bilateral, giant papillary hypertrophy (superiorcobblestone), bulbar injection, conj scars, watery/ mucoid discharge, limbal Trantas dots, corneal erosions/ neovascular/ vernal plaque/shield ulcer Atopic Keratoconjunctivitis Genetic predisposition(5 20% population; 20 40% of atopic dermatitis pts., 85% asthma, more male, peak years) Environmental allergens acute episodes, Type 1 and 4 reaction Childhood onset, chronic with acute Bilateral, eczematoid blepharitis, eyelid thickening/scar/lash loss/papillary hypertrophy(inferior), conj scarring,watery/mucoid discharge, corneal neo/ulcer/scar, PEK. Associated with keratoconus/ subcap cataract/herpes keratitis Atopic Keratoconjunctivitis Periocular eczema Corneal pannus and haze 3

4 Atopic Keratoconjunctivitis Increasing corneal pannus Invading visual axis Atopic Keratoconjunctivitis Symblepharon Posterior subcapsular cataract Table. Major Differentiating Factors Between VKC and AKC Characteristics VKC AKC Age at onset Generally presents at a younger age than AKC Sex Males are affected preferentially. No sex predilection Seasonal variation Typically occurs during spring Generally perennial months Discharge Thick mucoid discharge Watery and clear discharge Conjunctival scarring Higher incidence of conjunctival scarring Horner Trantas dots Horner Trantas dots and shield Presence of Horner Trantas dots is ulcers are commonly seen. rare. Corneal neovascularization Not present Deep corneal neovascularization tends to develop Presence of eosinophils in conjunctival scraping Conjunctival scraping reveals eosinophils to a greater degree in Presence of eosinophils is less likely VKC than in AKC Giant Papillary Conjunctivitis Contact lens misuse, poor fit, allergy to solutions. Suture and prosthesis exposure. Gradual increase, type 1 and type 4 reaction Papillary hypertrophy (>0.3mm),superior papillary hypertrophy, mucoid discharge, lid swelling, ptosis Superior limbic keratoconjunctivitis (SLK) Dysthyroid state, middle aged, female Subacute, wax and wane over years Bilateral superior bulbar injection/edema/keratin ization, fine upper papillary reaction, PEK, Corneal filaments(superior). Contact lens related keratoconjunctivitis Contact lens related mechanical irritation, hypoxia, preservatives Subacute to acute Subacute to acute May take time to resolve Diffuse conj hyperemia, corneal neo. Punctate keratopathy, papillary hypertrophy. Limbal stem cell deficiency? 4

5 Contact lens related keratoconjunctivitis Contact lens wear can cause a change in corneal physiology, which can lead to epithelial, stromal, and endothelial compromise. Other complications include lens deposition, allergic conjunctivitis, giant papillary conjunctivitis, peripheral infiltrates, microbial keratitis, and neovascularization Floppy eyelid syndrome Obesity, sleep apnea, upper lid laxity, upper eyelid over lower (lid imbrication),ptosis Chronic irritation due to nocturnal eyelid ectropion( tarsus contact bedding) Upper lid edema, easily everted, diffuse papillary reaction, PEK, pannus, bilateral, keratoconus associated Floppy eyelid syndrome Presenting symptoms Unilateral or bilateral chronic eye irritation and burning Tearing Ropy, mucoid discharge; usually worse in the morning Decreased vision, if there is an associated keratopathy Daytime somnolence Morning headaches Giant fornix syndrome Elderly women(8 th 10 th decade),upper lid ptosis with large fornix, mucopurolent material(waxes and wanes). Enlarged superior fornix Results in a chronic staphylococcal pseudomembranous conjunctivitis that arises from a self perpetuating infection of a nidus of protein coagulum located in the expansive upper conjunctival fornices of the elderly Similar to floppy eyelid More often unilateral Pediculosis palpebrarum(phthirus pubis) Sexually transmitted, pubic lice, alert if in children Blepharitis/conjunctivitis Uni/Bilateral follicular conjunctivitis,lice at base of lash/nits on shaft/bloody debris Medication induced keratoconjunctivitis (Toxic) Glaucoma topical meds, topical antibiotics, antivirals, preservatives, Other irritants O Polypharmacy, increased frequency, worsens over times Conjunctival injection, inferior fornix/bulbar conj follicles,eyelid erythema/ dermatitis 5

6 Conjunctival chalasis History previous eye surgery, dry eye, redundant conj Chronic irritation, similar symptoms to dry eyes Rd Redundant d conjunctiva Significant but selective inflammatory markers in conjunctival chalasis, including pro matrix metalloproteinase 9 and cytokines IL 6 and IL 1 beta (Acera et al. Ophthalmic Res 2008) Treatment Seasonal Allergic Conjunctivitis OTC/prescription antihistamines/h1 receptor blockers Mast cell stabilizers Corticosteroids Lubricants/other measures See later Vernal Conjunctivitis Adjust environment Topical/oral antihistamines Acute topical steroids Cyclosporine 0.05% for keratoconjunctivitis Steroid injection(supratarsal) Over 2 years age topical pimecrolimus/tacrolimus Shield ulcer scrape plaque/topical antibiotic Atopic Conjunctivitis Adjust environment Topical/oral antihistamines Acute topical steroids Cyclosporine 0.05% for keratoconjunctivitis Steroid injection Over 2 years age topical pimecrolimus/tacrolimus Shield ulcer scrape plaque/topical antibiotic Photograph c/o Logan et al Giant Papillary Conjunctivitis Rid causative agent Mast cell stabilizers Treat aqueous deficiency, blepharitis i Short term topical steroids 6

7 Superior limbic keratoconjunctivitis (SLK)(2013 AAO Conjunctivitis PPP) Treat dry eye component Mast cell stablizer/ topical cyclosporine Filamentary keratitis topical 10% acetylcysteine/hypertonic 5% saline. Tight upper eyelid with loose superior bulbar conj Surgery? Correct thyroid problems. Rare vision loss keratinization of the epithelium (see the keratohyaline granules and anucleate squamous cells here), acanthosis (notice the thickening to the far right), and cellular infiltration with lymphocytes, plasma cells Superior limbic keratoconjunctivitis (SLK) SLK has been treated with, mast cell stabilizers, silver nitrate or thermal cauterisation of the superior bulbar conjunctiva, pressure patching, and large diameter bandage contact lenses (BCL), topical ltrans retinoic ti i acid 0.1%, and recession or resection of the superior bulbar conjunctiva.over 50% of patients with SLK are said to have keratoconjunctivitis sicca and upper punctal plugs have been used to treat SLK (Watson et al. BJO 2002) Topical liquid nitrogen cryo ( John T., Ocular surgery news, Jan 2012) Contact lens related keratoconjunctivitis Hypoxia of limbal stem cells PEK, pannus,neo Stop contact Topical steroids Cyclosporine 0.05% Orthokeratology related pseudomonas ulcer Floppy eyelid syndrome Unsuccessful trials of artificial tears, vasoconstrictors, or topical steroids and antibiotics have already occurred before the correct diagnosis is made Taping lids shut Lubricants Upper lid horizontal shortening Ptosis repair Keratoconus associated Treat sleep apnea Rule out Mitral valve prolapse Giant fornix syndrome Staph aureus treat topical antibiotics Treat nasolacrimal obstruction/infection Culture given increasing rates MRSA?Correct ptosis Topical steroids, oral antibiotics, sweeping upper fornices conjunctivoplasty with resection of redundant forniceal conjunctiva with subconjunctival antibiotics( Nabavi CB et al, Ophthal Plast Reconstr Surg 2013 Jan Feb) Pediculosis palpebrarum(phthirus pubis) Remove lice and nits Smother nits with erythromycin/bacitracin ointment yellow mercuric oxide 1%; ammoniated mercuric oxide 3%; cholinesterase inhibitors; fluorescein 20%; and 2.5% pyrethrum cream Treat rest of body Notify contacts and school 7

8 Medication induced keratoconjunctivitis (Toxic) Stop offending agent Topical steroids Non preserved lubricant Sub epithelial fibrosistopical steroids Conjunctival chalasis Ocular lubricants Topical steroids Superficial conjunctival cauterization i may be an effective treatment for mild or moderate levels of conjunctival chalasis? Conjunctival resection with placement of AMT Black et Al. March 2012 Review of Optom Table 1. Comparison of Type 1 and Type 4 Hypersensitivity Reactions Type 1 Type 4 Antigen Exogenous external Endogenous tissues/organs Time Minutes Days Antibody IgE None Transfer Antibody T Cells Histology Eosinophils/basophils Lymphocyctes/monocytes Black et Al (March 2012) Type 1 Type 1 Type 1 and Type 4 Type1 and Type 4 Mechanical IgE IgE IgE/Tcell IgE/Tcell Lymphocyte mediated(type 1&4?) Table 2. Diagnostic Characteristics for the Different Forms of Allergic Conjunctivitis 10 SAC PAC VKC AKC GPC Age <10 <5 or Any Sex M=F M=F M>F M>F M=F Season Spring, Fall Perennial Spring, Fall, Any Any Perennial il Papillae Small Small Giant Frequent Giant Serum IgE 78% 78% Variable Constant Constant Eosinophils in Scraping 25% 43% Typical Typical Frequent Goblet Cells Increased Increased Increased Reduced Variable 2013 American Academy of Ophthalmology PPP Seasonal Allergic Conjunctivitis(SAC) Mild SAC can be treated with an over the counter antihistamine/vasoconstrictor agent or with the more effective second generation topical Histamine H1 receptor antagonists. Chronic use of vasoconstrictor agents can be associated with rebound vasodilation once the agent is stopped. If the condition is frequently recurrent or persistent, mast cell stabilizers can be utilized. May new medications combine antihistamine activity with mast cell stabilizing properties and can be utilized with either acute or chronic disease American Academy of Ophthalmology PPP Seasonal Allergic Conjunctivitis(SAC) If the symptoms are not adequately controlled, a brief course ( 1 or 2 weeks) of low potency topical corticosteroids can be added to the regimen. A NSAID drug, ketorolac, has also been approved by the FDA for the treatment of allergic conjunctivitis. Consultation with an allergist or dermatologist may be helpful for patients who have disease that cannot be adequately controlled with topical medications and oral antihistamines. The use of topical mast cell stabilizers can also be helpful in alleviating the symptoms of allergic rhinitis. 8

9 Ocular Therapy Mechanism Important Treatment Typical Therapies for Signs and Symptoms Considerations of SAC Antihistamines Histamine H1 receptor antagonists Block histamine action Only target histaminemediated responses Ocular Mast Cell Stabilizers Nonsteroidal Antiinflammatory Drugs (NSAIDs) Prevent mast cell degranulation and release of inflammatory mediators Inhibit activation of cyclooxygenases Prevent prostaglandin production Corticosteroids Broad spectrum anti inflammatory activity Inhibit activation of multiple types of inflammatory cells Limit production and cellular responses to pro inflammatory mediators Primarily target early phase inflammatory mediators Most effective when used prior to antigen exposure Do not reduce leukotriene production Do not inhibit histamine response Potential for adverse effects, including increased IOP and cataract formation Some may be useful in future. Bielory BP et al. Acta Ophthalmol. 2011:1 9. Therapeutic Targeting of Eosinophil Adhesion and Accumulation in Allergic Conjunctivitis(Baiula et al., Front Pharmacol. 2012;3:203) Accumulation of eosinophils in the eye is a key event in the onset and maintenance of allergic inflammation and is mediated by different adhesion molecules. Baiula et al. Cell adhesion based therapeutic strategies specifically target adhesion molecules. For example, bimosiamose, a selectin antagonist, blocks the recruitment of eosinophils mediated by E selectin selectin. The antihistamine levocabastine, several small antagonists, and the monoclonal antibody natalizumab can interfere with the interaction between α 4 β 1 integrin and VCAM 1, while efalizumab and levocabastine can affect α L β 2 /ICAM mediated adhesion. Current practical implications Bimosiamose (TBC 1269) blocks E selectin mediated leukocyte recruitment and attenuates late asthmatic reactions after allergen challenge in mild asthmatics. Efalizumab was approved for the treatment of moderate to severe plaque psoriasis (Frampton and Plosker, Am. J. Clin. Dermatol,2009), but was withdrawn ihd from the market in 2009 because of three cases of progressive multifocal leukoencephalopathy. Natalizumab (Tysabri ), used in patients with multiple sclerosis is complicated by rare cases of progressive multifocal leukoencephalopathy. Rupatadine is a selective and long acting new drug with a strong antagonistic activity toward both histamine H1 receptors and platelet activating factor receptors. It showed potent anti allergic activity in vitro, including inhibition of mast cell degranulation and eosinophil chemotaxis, and in vivo. Oral tablets effective in treatment of allergic rhino conjunctivitis (Compalati E. et al.,current Medical Research and Opinion,November 2013) Selective glucocorticoid receptor agonists (SEGRAs) Glucocorticoid efficacy is due in part to the prevention of eosinophil accumulation, activation, and induction of eosinophil apoptosis, suppression of the synthesis and release of eosinophil survival factors, and stimulation of eosinophil engulfment by phagocytic cell. It has been hypothesized that transrepression is the key mechanism of the antiinflammatory effects of glucocorticoids, whereas transactivation has been assumed to cause side effects. Glucocorticoids can either activate transcription (transactivation) by directly binding to the promoter region of target genes or by interacting with other transcription factors, such as activator protein 1, nuclear factor kappa B, and others, or it can suppress transcription(transrepression). Mapracorat (also known as ZK or BOL X) is a novel selective glucocorticoid receptor agonist that maintains a beneficial anti inflammatory activity but seems to be less effective in transactivation, resulting in a lower potential for side effects. Studies of this SEGRA and others is ongoing (Berlin M. Expert Opin. Ther. Pat 2010). 9

10 Leukotriene Antagonists LTs are generated by a number of cells including mast cells, eosinophils,basophils, and neutrophils. They mediate chemotaxis, vascular permeability, edema, eosinophil migration, airway constriction, and smooth muscle contraction (Samuelsson et al., Science 1997). As their effect has a long time efficacy, these molecules are defined as slow reacting substances. There are two different LT inhibitors/modifiers: LT receptor antagonists (LTRAs; montelukast, zafirlukast, and Pranlukast). 5 Lypoxigenase inhibitor of LT synthesis (zileuton). How does it relate to ocular allergy? Leukotrienes play a role in the development of seasonal allergic conjunctivitis as well as the more severe forms as vernal keratoconjunctivitis and atopic keratoconjunctivitis (Leonardi et al., Clin. Exp. Immunol 2008). Montelukast(Singulair Merck) usage has been examine by Gane J. et al. (The Journal of Allergy and Clinical Immunology: In Practice Leukotriene Receptor Antagonists in Allergic Eye Disease: A Systematic Review and Meta analysis Jan 2013.) Eighteen trials, using the LTRA montelukast (in Allergic Conjunctivitis only), reviewed. Conclusion in SAC, LTRAs (evidence for montelukast only) are more efficacious than placebo but less efficacious than oral antihistamines, when treating patients aged 15 years or older. But El Hossary et al., Australian Journal of Basic and Applied Sciences, demonstrated effectiveness of topical form of montelukast. Not as effective as topical steroids. The prices are 2011 U.S. from Epocrates and a few from Canada(in brackets) but you get the idea Table 1: Costs for Available agents commonly used topical anti allergy medications. Prices were obtained from epocrates.com, January 8, Therapeutic Category Antihistamine/ Antazoline/naphazoli vasoconstrictor ne (Vasocon A ) Pheniramine/naphaz oline (Opcon A, Naphcon A, Visine A ) Antihistamine Emedastine 0.05% solution (Emadine ) Nonsteroidal antiinflammatory drugs suspension (Acular ) Ketorolac 0.5% Corticosteroids Loteprednol 0.2% suspension (Alrex ) Recommended Dosage Approximate Cost 2 4 times daily $18 for 15 ml; $10.50 for 30 ml qid $79 for 5 ml($31.7) qid $126 for 5 ml; $236 for 10 ml($22) qid $91 for 5 ml; $166 for 10 ml ($42) So keep the costs in mind given the duration of need. Table 1(continued): Costs for commonly used topical antiallergy medications. Prices were obtained from epocrates.com, January 8, Mast cell stabilizer Multiple acting agents Cromolyn sodium 4% solution (Crolom, Opticrom ) Lodoxamide 0.1% solution (Alomide ) Pemirolast 0.1% solution (Alamast ) Nedocromil 2% solution (Alocril ) Olopatadine 0.1% solution (Patanol ) Olopatadine 0.2% solution (Pataday ) Ketotifen 0.025% solution (Zaditor, Alaway, Refresh Eye Itch Relief, Claritin Eye, and Zyrtec Itchy Eye Drops) Azelastine 0.05% solution (Optivar ) Epinastine 0.05% solution (Elestat ) Bepotastine 1.5% solution (Bepreve ) 4 6 times daily qid qid qd $32 for 10 ml generic $103 for 10 ml ($24) $112 for 10 ml $93 for 5 ml($43) $116 for 5 ml($38) $112 for 2.5 ml $15 70 for 5 ml (Alaway is $12 in US for 10 ml bottle) ($41) $96 for 6 ml generic or $114 for 6 ml $117 for 5 ml $177 for 10 ml Case 1 Bacterial conjunctivitis Case 2 Seasonal Allergic Conjunctivitis 10

11 Case 3 Iritis right eye Case 4 Toxic conjunctivitis Case 5 Moderate allergic conjunctivitis only responsive to 0.2% loteprednol. Eventually had cataracts requiring removal. Case 6 Mild episcleritis. Patient happy with simple lubricants. What about the OS spot? Just swabbed it and Thank you Acknowledgments: Katherine Huang 11