How to stop

Niti Susila

Department of Ophthalmology , Medical School, University of Udayana Denpasar, 28 Mei 2016 How Many People Are Affected?

• According to the Gallup Study of *:

50% of the population has allergies 83% of sufferers experience ocular symptoms

* Data from 2003-2004 survey. Ocular Symptoms No Ocular Symptoms Incidence of Ocular Allergies by Type of Allergic Eye Disease

All Others SAC/PAC 90% - 95% of all ocular allergies are estimated to be SAC/PAC

Abelson M. Allergic Diseases of the Eye. Philadelphia, PA: W.B. Saunders Co; 2000. Age distribution of patients with allergic conjunctival diseases

Japanese Ocular Allergology Society. [Guidelines for theclinical management of allergic conjunctival disease (2nd edition)]. Nippon Ganka Gakkai Zasshi [J Jpn Ophthalmol Soc]2010;114:831-70 Ocular Allergies and the Mast Cell

• Primary cell involved in the allergic response in the body

• 50 million mast cells in the human conjunctiva

Isolated conjuctival mast cell showing pre- formed granules. Allergic Cascade

IgE Classification of Allergic conjunctival diseases Classification of ocular allergic diseases

Disease Timing Age Prevalence Keratoph Sight course group aty threatening SAC seasonal >> very no no Mild, resolves +, Children common progressive - & young adult PAC Perennial Adult common common no Serious -, progressive - PKC Seasonal children uncommo yes Yes Serious, resolves +Perennia n 2 – 10 years good l if severe outcome if well managed, can change into AKC AKC Perennial Adult Rare Yes Yes Serious and progressive Top Allergy Symptoms Experienced* (Among allergy users)

Sneezing Runny nose Itchy Eyes 72% Stuffy nose/Congestion Itchy Nose Sinus Pressure Headaches Watery Eyes Sinus Pain Coughing/Wheezing

*Includes 40% or more mentions only. The 2005 Gallup Study of Allergies – Phase II Report Allergic conjunctivitis

Symptoms Signs

Itching Lid edema Burning Conjunctival Tearing injection Edema Chemosis Hypheremie Papillary hypertrophy Seasonal / Perennial conjunctivitis

Seasonal Perennial conjunctivitis conjunctivitis during the spring & throughout the year  worse in summer the autumn more common allergen : house dust mites, allergens : tree & grass animal dander & fungal pollens less common tends to be milder than the seasonal form Vernal keratoconjunctivitis

Pathogenesis  both types I and IV hypersensitivity reactions VKC  a seasonally recurring (springtime) in tropical climates  the disease may persist year-round bilateral >> male children > have a personal / family history of atopy Diffuse papillary atrophy

Giant papillae

cr

Coble stone papillae

macropapipllae Progression of vernal keratopathy

Punctate epitheliopathy Plaque formation (shield ulcer)

Epithelial macroerosions Subepithelial scarring Atopic keratoconjunctivitis

• AKC is primarily a type IV reaction  the use of mast- cell therapy may not be effective • + 1/3 of patients with atopic dermatitis  develop manifestations of AKC • Atopic individuals show signs of type I immediate hypersensitivity responses as well as depressed systemic cell-mediated immunity Giant papillary conjunctivitis

Mechanical irritation due to : Contact lenses Suture knots Ocular prostheses Differentiating feature of common types of conjunctiva Clinical sign Bacterial Viral Allergic chlamydial Conjunctival injection Marked Moderate Mild to Moderate moderate Chemosis ++ ± ++ ±

Subconjunctival ± ± - - bleeding Discharge Purulent Watery Ropy/watery Mucopurulent Papillae ± - ++ ±

Follicles - + - ++ Pseudomembrane ± ± - - Pannus - - - ( except + vernal) Preauricular lymp node + ++ - ± Differentiating feature of common types of conjunctiva

Cytological feature Bacterial Viral Allergic chlamydial

Neutrophils + + (early) - +

Eosinophils - - + -

Lymphocytes- - + - +

Plasma cells - - - +

Multinuclear cells - + - -

Inclusion body cytoplasmic - +(Pox), - + nuclear + (herpes) Micro-organisms + - - - Management of Allergic Conjunctivitis Non pharmacologic interventions :

Avoidance of allergen exposure (pets, dust, mites, moulds, spores) Glasses or goggles  serve as physical barriers Climatotherapy ( home air-conditioning or relocation to a cooler environment) Cold compresses : - vaso-constriction - decrease itching Avoid rubbing Lubricating ED  diluting & flushing away allergens & other inflammatory mediators Form of Prescription Allergy Medication Prescribed in 2005 (Among allergy medication users whose doctor prescribed allergy medication)

Oral (pills or liquid) 70%

Nasal Sprays 56%

Inhalants 18%

Eye Drops 9%

Other 1%

Other Eye Drops Inhalants Nasal Sprays Oral (pills or liquid)

The 2005 Gallup Study of Allergies – Phase II Report Tear substitutes

• Barrier function-improve 1st line of defense • Dilute allergens and mediators • Flush allergens and all mediators out of the eyes Treatment: medical care

• Fundamentals of treatment – Antiallergic eye drops (basic treatment) – Steroid eye drops as necessary according to the severity

Severe ACDs (AKC and VKC) • Immunosuppressive eye drops, steroid oral, subtarsal steroid injection and surgical treatment (papillary resection) Pharmacologic management Topical eye drops

Vasoconstrictors Mast cell stabilizers (MCS) Dual action : anti histamines + MCS NSAID Corticosteroids TOPICAL vasoconstrictor

Drug name : Naphazoline Hcl ( α adrenergic agonist) The use of topical vasoconstrictors for more than 5-7 consecutive days  compensatory chronic vascular dilation Topical anti histamines

Blocking the receptors antihistamines ( H1- blockers)  reduce effects Act by competitive inhibition of histamine at the H1 receptor Block effects of endogenously released histamine Drug names: - , - hydrochloride - - - difumarate Mast cell stabilizers :

 decrease ongoing response to allergen  do not relieve existing symptoms  can be use as prophylaxis  “ long term use “   2500 times as effectively as cromolyn sodium  Traditional MCS such as cromolyn sodium, lodoxamide & pemirolast  take days to weeks to reach peak efficacy Non steroid anti-inflammatory drugs ( NSAID )

act on cyclo-oxygenase metabolic pathway & inhibit production of prostaglandins & thromboxanes no role in blocking mediators formed by the lipoxygenase pathway ( leukotrienes )  no effect on late phase symptoms SE : stinging , increase bleeding time Corticosteroids Most potent pharmacologic agents

Effectively block both cyclooxygenase & lipoxygenase pathways

The anti-inflammatory & immunosuppressive affects are non specific

Topical steroids should be reserved for exacerbations & for severe refractory cases, it should be used for a short period of time, because of ocular side effects

Systemic anti-inflammatory therapy should be reserved for very severe cases Immunosuppressive therapy

• Immunomodulatory agents are the substances that interact with immune system – Immunostimulation and immunosupression • Cyclosporin and tacrolimus for VKC • Gradual reduction of the doses of steroid eye drops • Combine with antiallergic eye drops and steroid eye drops Approved topical drugs

Anti Mast cell Generic name NSAID histamin stabilizer Eos

Ketorolac + Levocabastine + Antazoline, pheniramine

Sodium Chromoglycate + Lodoxamide + + Pemirolast + + + + + + + Emedastine +

Dual Mechanism of Action of Olopatadine

• Inhibit the effect of histamine at H1 receptor

• Inhibit the release of inflammatory mediators by stabilizing the mast cells PATANOL® (Olopatadine 0.1%)

• MOA: True & • Indication: Treatment of itching & redness and other signs & symptoms of allergic conjunctivitis • Dosing: BID • Onset of action: Fast, minutes • Rx: Rx Product • Side Effects – 7% headaches; Burning & Stinging < 5% • pH : 7.0 Allergic Cascade

IgE Where Olopatadine Works?

Mast cell stabilizer

IgE Mast cell stabilizer

antihistamine Allergic Conjuctivitis MATUR SUKSKSMA TERIMAKASIH THANK YOU Clinical StudyPATANOL Comparison® Comparative effects of topical ocular anti-allergy drugs on human conjunctival mast cells

Yanni, et al Ann Allergy Asthma Immunol 1997 Objective and Methodology

Objective: • To compare the effects of 3 ocular anti-allergic drugs (Nedocromil, Olopatadine, and Pemirolast) on mediator release from the target human conjunctival mast cell population with those of cromolyn sodium. The affinity of the compounds for the histamine H1 receptor was also compared Methods: • A monodispersed suspension of partially purified human conjunctival mast cells was prepared from cadaver conjunctival tissue • Mast cells (5 x103) were challenged with anti-human IgE in the presence or absence of test drugs • Histamine content of the cell supernatants was determined using a specific radioimmunoassay • H1 receptor binding activity was assessed using a radioligand binding assay Results

• Cromolyn and pemirolast failed to significantly inhibit histamine release from human conjunctival mast cells when preincubated with the cell preparations for 1 or 15 min prior to immunologic stimulation • Importantly, greater than 90% inhibition was noted with Olopatadine at the highest concentration tested (Fig 2) • As expected, cromolyn, nedocromil, and pemirolast were ineffective at relevant concentrations (up to 100 M). Olopatadine exhibited significant H1 receptor binding affinity (Fig 4) Results: Effect on Histamine release from human conjunctival mast cells Result: H1 receptor binding activity Conclusion

• Olopatadine was the only compound tested that produced a concentration dependent inhibition of histamine release from human conjunctival mast cells. Inhibition of release was greater than 90% with olopatadine

• Data showing that Cromolyn, Nedocromil, and Pemirolast lack of histamine H1 antagonist activity. Conversely, Olopatadine demonstrated significant H1 anti-histaminic activity. Clinically, this activity is manifest as a rapid onset of symptomatic relief Pharmacology, clinical efficacy and safety of olopatadine hydrochloride

Lichtenstein, Steven. Abelson, Mark B. Future drugs Ltd 2006

Anti inflammatory effects Comparative study Thank You