REVIEW CURRENT OPINION Topical antihistamines, mast cell stabilizers, and dual-action agents in ocular allergy: current trends Hadas Ben-Elia,b and Abraham Solomona 08/30/2018 on Rs1PdakgPaCH4O7LQlbMf8NyUWSEc9XUp15vFk8PWF4/ugjLnMHwCRzT33/heqB0YT63dE1qKLS2eX5iQ/s2VU/PXYwzL7gVpbZo4TpjglIAFUjz0e10PyX8KRreGoHc1KFmeUX+8Hs= by http://journals.lww.com/co-allergy from Downloaded Purpose of review Downloaded To address the current trends of therapeutic mechanisms for treatment of allergic conjunctivitis (AC), based on topical antihistamines and mast cell stabilizers (MCS). from http://journals.lww.com/co-allergy Recent findings The antihistamine drug alcaftadine has H4 receptor inverse agonism, anti-inflammatory and MCS activities. The antihistamines levocabastine and azelastine are more effective than placebo in treatment of AC symptoms in randomized controlled trials (RCTs). The topical dual-action antihistamines/MCS olopatadine, azelastine, ketotifen, and epinastine are commonly used in Europe and in the United States for mild by subtypes of AC. For the main symptoms of AC, ocular itch and conjunctival hyperemia, epinastine 0.05% Rs1PdakgPaCH4O7LQlbMf8NyUWSEc9XUp15vFk8PWF4/ugjLnMHwCRzT33/heqB0YT63dE1qKLS2eX5iQ/s2VU/PXYwzL7gVpbZo4TpjglIAFUjz0e10PyX8KRreGoHc1KFmeUX+8Hs= was superior to placebo, but equal or more effective than olopatadine 0.1%, while the later was more effective than ketotifen. High concentration olopatadine 0.77% had longer duration of action, better efficacy on ocular itch, and a similar safety profile to low-concentration olopatadine 0.2%. The new formulas of topical dual-action agents present longer duration of action, leading to a decreased frequency of use. Summary The topical dual-action agents are the most effective agents treating signs and symptoms of mild forms of AC. There is superiority to the high-concentration olopatadine drug over other agents on ocular itch, with prolonged effect when used once-daily. Keywords antihistamines, dual-action, mast cell stabilizers, ocular allergy, treatment INTRODUCTION conjunctivitis patients being 38 Æ 19 years. The per- Allergic diseases affect one third of the world popu- centage of subjects with SAC was 55% and was lation, with an estimated 40–60% of these cases similarly distributed among all age groups, followed having ocular involvement [1]. Allergic conjuncti- by 18% with PAC that increased with age, and 9% vitis is one of the most common ocular disorders with VKC which was common in under the age of 18 and represents a collection of hypersensitivity con- [7]. The ocular signs and symptoms of allergic con- ditions that affect the lid and conjunctiva [2]. The junctivitis included ocular itching, conjunctival estimated incidence of allergic conjunctivitis is redness, hyperemia, chemosis, lid skin swelling ranged between 10 and 36% of the US population and keratitis [8–10]. Among the allergens reported [3–5]. AC is classified into seasonal allergic conjunc- to trigger allergic conjunctivitis, there were pollen tivitis (SAC), perennial allergic conjunctivitis (PAC), sensitivities, exposure to nonspecific environmental vernal keratoconjunctivitis (VKC), atopic kerato- on conjunctivitis (AKC), contact blepharoconjunctivi- a 08/30/2018 tis, and giant papillary conjunctivitis (GPC) [2,3]. Department of Ophthalmology, Hadassah-Hebrew University Medical Center and bDepartment of Optometry and Vision Science, Hadassah The most two common subtypes of allergic conjunc- Accademic College, Jerusalem, Israel tivitis, SAC, and PAC are manifested with itching, Correspondence to Prof. Abraham Solomon, Department of Ophthal- redness, and tearing, as a result of human bodily mology, Hadassah-Hebrew University Medical Center, Kiryat Hadassah, exposure to specific allergens [6]. Ein-Kerem, POB 1200, Jerusalem 91120, Israel. Tel: +972 50 7874664; The epidemiology of allergic conjunctivitis was e-mail: [email protected] recently reported in an extensive European cohort Curr Opin Allergy Clin Immunol 2018, 18:411–416 of research subjects, with the mean age of allergic DOI:10.1097/ACI.0000000000000473 1528-4050 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-allergy.com Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Eye allergy histamine agonists (antihistamines) and mast cell KEY POINTS stabilizers, considered better options than anti- Mild subtypes of allergic conjunctivitis, SAC, and PAC inflammatory and immunosuppressant agents [6]. can be treated with nonpharmacological treatments, Other avenues of treatments for allergic conjuncti- such as cold compress, topical lubricants, and over-the- vitis are vasoconstrictors, anti-inflammatory agents counter drugs. that include non-steroidal anti-inflammatory drugs and corticosteroids, and in recent years, multiple In mild to moderate cases of SAC and PAC, antihistamines or mast cell stabilizers can action and novel immunosuppressive agents such as be prescribed. cyclosporine and tacrolimus, for the chronic forms of allergic conjunctivitis such as AKC, VKC, and In severe forms of allergic conjunctivitis, such as atopic GPC [12]. Basic and clinical trials in past years keratoconjunctivitis and vernal keratoconjunctivitis, present a better understanding of the pathogenesis corticosteroids, NSAIDs or immunomodulator agents should be considered. of allergic conjunctivitis, leading to the emergence of new pharmacological agents, such as more potent The levocabastine and azelastine drugs, with mast cell stabilizers and the dual-action antihist- antihistamine effects, had superiority over placebo in amines/mast cell stabilizers combined agents. This RCTs treating allergic conjunctivitis. article reviews the current trends and latest data on Exclusive treatment with antihistamines or mast cell the most popular and effective treatments for aller- stabilizers is not sufficient, thus the combined dual- gic conjunctivitis; the topical anti-H1 agonists and acting agents are the medication of choice. mast cell stabilizers. The dual-action agents commonly used are olopatadine, azelastine, ketotifen, and epinastine. The new formulas are associated with prolonged duration ANTIHISTAMINES of action and therefore decrease the frequency of use. In allergic conjunctivitis, the interaction between histamine and its receptor is a main player in the genesis of allergic response. Histamine mediates the tissue response to conditions of mechanical or infec- conditions, pollutants, and cigarette smoke. Positive tious injury and also may serve as a neurotransmitter allergy tests to specific allergens were found in 82% for gastric acid secretion [6]. As such, blocking the out of 3545 patients with history of allergic con- histamine receptors serves as a primary therapeutic junctivitis [7]. path for topical allergy medications. So far, four The pathophysiology of allergic conjunctivitis is histamine receptors H1–H4 have been discovered mediated by immunoglobulin E-related mast cell (H1R, H2R, H3R, and H4R) in conjunctival epithe- activation, with release of histamine and other lium and goblet cells [13]. These receptors are asso- mediators promoting activation of other immune ciated with conjunctival hyperemia, cytokine cells and further inflammation [6,11]. The early secretion, fibroblast proliferation, adhesion mole- phase reaction of SAC and PAC lasts about 30 min cule expression, microvascular permeability, and and includes the interaction of allergens with production of procollagens [9]. These cellular immunoglobulin E (IgE), leading to IgE cross-link- events, known as the ’early-phase reaction,’ lead ing at the mast cell membrane with degranulation to classical symptoms of allergic conjunctivitis, such and release of histamine, tryptase, prostaglandins, as ocular itching, tearing, burning, redness, and/or and leukotrienes. The late phase reaction of mast eyelid swelling. The early response occurs several cell degranulation in the conjunctiva includes the minutes after the cross-linking of IgE antibodies to activation of vascular endothelial cells, leading to mast cells on the conjunctival tissue. Degranulation expression of cellular mediators and activation of of mast cells promotes release of inflammatory inflammatory cells, such as T lymphocytes, eosino- mediators, such as histamine, tryptase, proteogly- phils, and neutrophils. This prolonged phase is cans, and acid hydrolases. This said, histamine is associated with severe cases of allergic conjunctivitis considered to be the main player in the early-phase [5]. reaction [13]. The principal aims of treatment in allergic con- Topical antihistamines agents have demon- junctivitis are to minimize and control signs and strated a significant reduction in signs and symp- symptoms, such as redness, itching, tearing, and toms of conjunctival allergies compared with conjunctival swelling, as well as preventing the placebo in clinical trials [8], as their main action inflammatory cycle in prolonged and severe cases is to antagonize the vasodilator effects of histamine of allergic conjunctivitis [8]. Currently, the two [6]. Compared with oral antihistamines, the single- main therapeutic options for AC are inverse acting topical antihistamines also have more rapid 412 www.co-allergy.com Volume 18 Number 5 October 2018 Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved. Topical drugs for ocular allergy Ben-Eli and Solomon action on allergic conjunctivitis, do not cause seda- effective reducers of allergy signs and symptoms, but tion, and are also better