Current perspectives on topical antiallergics

Authors: Nikhil S Gokhale

Abstract

Allergy is one of the most common diagnoses in an ocular surface clinic, and its treatment can range from a simple lubricant to the most complex combinations of medications belonging to several diverse classes. Antiallergics are the most commonly used medication overall in all forms of allergy. Several options are available, and it is important to understand how to start, select, and continue their use. Understanding the nature and severity of allergy is key to understand the effectiveness and limitations of this class of drugs in each patient. The article provides a brief overview of antiallergics in the for the busy practitioner.

Allergy is an abnormal hypersensitive immune reaction of the body to typically harmless substances called allergens in the environment. Ocular allergy and dry eye are among the most common surface problems that we see in our clinics. A large data analytic study from India revealed the prevalence of allergy to be 10.12% in the ≤21 years age group, with a male preponderance of 1.[1] Ocular allergy has a wide spectrum from mild self-limited disease to the extremely severe blinding disease. Despite advances in science, treatment of allergy continues to evolve in an effort to provide better inflammation control, minimize complications and their impact on vision, prevent visual loss, and improve the patient’s quality of life. The primary aim of this article is to give current perspectives on the use of topical antiallergics restricted to mast cell stabilizers, antihistamines, and dual acting agents.

The hallmark symptom of all forms of allergic eye disease is itching. A common dictum is “No Itch No Allergy.” In addition, redness, tearing, lid swelling, photophobia, mucus discharge, and foreign body sensation are common.[2] Ocular allergy has been traditionally classified into four subtypes, that is, seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC,) and atopic keratoconjunctivitis (AKC). Based upon the pathogenic mechanism, ocular allergy could be classified [Table 1] as IgE mediated and non-IgE mediated.[3] More recently, ocular allergies have been classified based on phenotype and endotype, and this will help in future to provide more pathway-specific therapeutic strategies.[3] Allergic conjunctivitis is often associated with other systemic allergies, most commonly allergic rhinitis and asthma.

The normal ocular surface has an epithelial barrier function, which prevents the movement of allergens across the conjunctival epithelium. Breakdown of this function is key to the pathogenesis of all forms of allergies. Allergens have intrinsic proteolytic properties to aid penetration. Ocular rubbing, inflammation, tear film dysfunction, mechanical irritation, and preservatives such as benzalkonium chloride can all cause a breakdown of the epithelial barrier and enhance the movement of allergens into the conjunctiva.[4] While the conjunctiva is involved in all types of ocular allergy, the cornea and limbus are also secondarily involved in the more severe forms of ocular allergy, that is, VKC and AKC. The pathogenic mechanisms and tissue involvement play an important role in selecting the treatment options and dictating the response to treatment.

Seasonal and Perennial Allergic Conjunctivitis

These are the most prevalent forms of allergy; they are responsible for more than 95% of the cases and affect 15%–40% of the world population. They affect both sexes and can occur at all ages. Seasonal or perennial, as the name implies, refers to the course of disease. While outdoor allergens like grass pollens cause SAC and are therefore seasonal, indoor allergens like dust mite and animal dander cause PAC and continue all year round. These are IgE-mediated type 1 hypersensitivity reactions that are triggered by the binding of the allergen to an allergen-specific IgE on the surface of mast cells, which leads to mast cell degranulation and release of several mediators like histamine, leukotrienes, and prostaglandins. This results in an acute-onset inflammatory allergic reaction, which is followed by a more delayed response due to recruitment of mast cells, eosinophils, and other inflammatory cells in the conjunctiva. Corneal involvement is extremely rare in these forms of allergies.[35]

Vernal Keratoconjunctivitis

This is a more severe form of allergy, which is common in children (males >females), especially in warm and tropical regions. Inflammation involves the tarsal conjunctiva, limbus, or both and eventually affects the cornea in severe cases. Papillae, cobblestone formation, limbal thickening, Horner–Trantas dots, punctate keratitis, shield ulcers, scars, keratoconus, and limbal deficiency are often seen in these children. VKC is associated with type 1 and a type 4 (Th2) immune mechanism mediated by CD4 T lymphocytes.[35] It can be seasonal (intermittent episodes with remissions) or may present as a chronic disease with seasonal exacerbations. Though severe, it is most often a self-limiting disease that abates after puberty, though in some people, it may persist into adulthood. More recently, three distinct clusters of presentation have been described. Cluster 1 is traditional VKC, which resolves at puberty and is associated with low levels of serum IgE and eosinophil counts. Cluster 2 is an early-onset AKC/VKC, which may be associated with intermediate IgE levels and high eosinophil counts. Cluster 3 is puberty-onset AKC, which is associated with high serum IgE and eosinophil counts and is the most severe variant with a prolonged course.[6]

Atopic Keratoconjunctivitis

AKC is the most severe form of ocular allergy and is the ocular manifestation of atopic dermatitis. It is a scarring disease that involves the ocular surface as well as the eyelids. It is more common in males and peaks in the 20–50 years age group in patients with a history of atopic dermatitis and other allergies like asthma, eczema, and urticaria. Keratinization, symblepharon, inferior tarsal involvement, eyelid deformities, herpes infections, corneal ulcers, and scarring are often seen in them, unlike the other allergy variants. AKC is a type 1 and type 4 (Th1)-mediated inflammation. Secondary complications like corneal scarring, limbal deficiency, keratoconus, cataract, and glaucoma can often lead to vision loss.[35]

Treatment of Allergic Conjunctivitis

A wide variety of nonpharmacologic, pharmacologic, and surgical approaches are available for managing ocular allergy. A step ladder approach is recommended based on the nature and severity of allergy. Selection of options is based on several variables such as the

Severity/grading of allergy (Bonini/Gokhale) – Presence or absence of corneal involvement is an important determinant.[789]Periodicity of disease – Intermittent with complete remissions/chronic with seasonal exacerbations/chronic severe disease[8]Nature of inflammation – Acute onset/chronic continuous/acute on chronicType of allergy – SAC, PAC, VKC, AKC, associated systemic allergiesAge of the patient and expected duration of disease aheadAdverse effects of previous treatment, such as steroid response, cataract, etc.Coexisting pathology – Glaucoma, cataract, keratoconus, scarring, etc.Effects of allergy on daily functioning and quality of life

This article will focus on antiallergic drugs which act through mast cells and histamine receptors. These drugs act by promoting stabilization of mast cell membranes and/or blocking histamine receptors, thereby controlling allergic inflammation. Tryptase and chymase are neutral proteases secreted by degranulated mast cells and are the basis for classifying mast cells. Mast cells that contain tryptase (MCT) are mucosal mast cells located in the mucosa of the nose and lungs. Connective tissue mast cells contain tryptase and chymase (MCTC), and are usually located in the conjunctiva and skin. MCT are found in increasing numbers in allergic eye disease. Activated mast cells release tryptase, raising their levels in tears in active allergy.[1011]

Histamine has a broad range of biological functions affecting virtually every organ in the body. It acts through four receptors, namely, H1, H2, H3, and H4. Broadly, H1 receptors mediate allergic inflammation, H2 receptors mediate gastric acid secretion, H3 receptors modulate neurotransmission, and H4 receptors have immunomodulatory actions. H1 receptors mediate itching, swelling, and an increase in vascular permeability in ocular allergy. H2 receptors have been shown to cause vasodilatation and increased vascular permeability in ocular allergy. Azelastine, epinastine, and alcaftadine have significant H2 blocking activity.[12] H3 receptors mediate nasal congestion; use of fexofenadine, which has H1 and H3 antagonist action, is more effective in relieving nasal congestion in allergic rhinitis. H4 receptors mediate chemotaxis and recruitment of inflammatory cells and exacerbate the inflammatory reaction. They are being investigated as a potential target for antiallergy therapy. They have also been found to mediate pruritus in ocular allergy. An H1 and H4 antagonist will have synergistic effect in controlling symptoms of ocular allergy.[12] Alcaftadine has additional novel H4 blocking capability.[13] Increased expression of H1, H2, and H4 receptors is seen in VKC tissues, and this indicate their important role in pathogenesis of ocular allergy. In contrast, H3 is rarely present in normal and inflamed conjunctiva in VKC [Table 2].[14]

Antiallergics are the first line of treatment for all forms of allergy. Since they do not address Th1 and Th2 mechanisms (non-IgE pathways), they have limited efficacy in the more severe forms of allergies. Available drugs, mechanism of actions, their pros and cons, indications of usage, and selection criteria will be discussed.

Mast Cell Stabilizers

These drugs inhibit mast cell activation and degranulation, prevent the release of inflammatory mediators and cytokines, and reduce the influx of inflammatory cells [Table 3]. They include 2% and 4% sodium cromoglycate, nedocromil sodium 2%, spaglumic acid 4%, N-acetyl-aspartyl-glutamate 6%, and lodoxamide tromethamine 0.1%.[9] They have to be used four to six times a day. Their action starts after a delay of a few weeks, so that they are more useful for prophylaxis, rather than for acute symptom suppression. Nedocromil also acts on eosinophils, neutrophils, monocyte–macrophages, and platelets to inhibit inflammation. Lodoxamide acts by inhibition of eosinophil activation and degranulation.[9] These drugs are well tolerated and cause minimal side effects such as transient burning sensation. They are safe for long-term use.

Antihistamines

These drugs [Table 3] block the effects of histamine released during the allergic cascade by blocking the H1 receptors. They reduce itching and swelling and are useful in acute phases. However, their duration of action is short and they may need to be used up to four times a day. They are well tolerated, but may cause burning sensation and dryness. The newer selective H1 blockers such as levocabastine hydrochloride 0.5% and emedastine difumarate 0.05% are preferred for their longer action and reduced side effects compared to the older agents like pheniramine and antazoline.[9] Bilastine 0.6% is a new introduction in a preservative-free formulation that is well tolerated and effective and preserves the ocular surface epithelial integrity.[1516]

Dual Acting Agents

Dual acting agents [Table 3] combine the benefits of mast cell stabilization with antihistaminic activity, and therefore provide immediate as well as more sustained relief for patients with ocular allergy. Newer dual acting agents, that is, olopatadine 0.1%, 0.2%, and 0.7%, bepotastine besilate 1.5%, and alcaftadine 0.25%, are currently available in India. Azelastine 0.05%, Ketotifen 0.025% and Epinastine 0.05% are now no more available In India. The newer dual acting agents also exhibit diverse immunoactive properties, including inhibition of interleukin-5 (IL-5), leukotrienes, platelet activating factor, and eosinophil migration.[9] Alcaftadine also blocks the H4 receptors, which work in tandem with H1 receptor in the allergic cascade.[13] Mild burning, stinging, and ocular irritation are common with dual acting agents. Bepotastine also causes an abnormal taste sensation.

Comparative Studies of Antiallergics

A plethora of studies (experimental and clinical) which compare the various drugs in each group and across the groups are available. Most of them tend to show comparable effects and tolerance of the medications. Since several parameters are chosen for analysis, one drug may seem to be more effective than the other for a given parameter. What seems more important is to know when to use, what to expect, and the limitations of this class of drugs. Availability, preservative used and its concentration, dosing, and tolerance are important parameters to look for when selecting an agent. Unfortunately, no preservative-free antiallergic medications are currently available in India.

Mast Cell Stabilizers and Antihistamines

Several clinical studies comparing cromolyn versus nedocromil have consistently shown superiority of nedocromil over cromolyn in suppressing the signs and symptoms of allergic eye disease.[1718] Lodoxamide has been shown to be superior to cromolyn and levocabastine in clinical studies.[1920] Bilastine has shown noninferiority to ketotifen, with the added advantage of protecting the epithelial barrier as it is preservative free and formulated in sodium hyaluronate.[1516]

Dual Acting Agents

Several comparative studies are available from India. In a survey conducted in India by Priyadarshini and Das,[21] the most frequently prescribed antiallergics were the dual acting agents (40%), followed by mast cell stabilizers (31.1%) and antihistamines in 10%. Olopatadine and cromolyn were the most commonly used drugs in this report. The survey specifically looked at alcaftadine usage and efficacy as observed by respondents, but more than half of them had never used it and the observations with usage seem inconclusive, given the small numbers. Ayyappanavar et al.[22] conducted a prospective observer-masked study in 180 patients comparing alcaftadine 0.25% once daily, bepotastine 1.5% twice daily, and olopatadine 0.2% once daily in patients with mild to moderate allergy. They concluded that all three medications were safe and effective in the treatment of allergic conjunctivitis. However, bepotastine and alcaftadine appeared to outweigh olopatadine in resolving the symptoms of allergic conjunctivitis and in reducing hyperemia at the day 14 visit. In a similar study, Dudeja et al.[23] compared alcaftadine 0.25% twice daily, bepotastine 1.5% twice daily, and olopatadine 0.1% twice daily and could not demonstrate any difference in the efficacy of the three drugs [Table 4].

Alcaftadine was reported to be superior to olopatadine in conjunctival allergen challenge[24] and clinical symptom scores.[25] McCabe and McCabe[26] found that bepotastine provided better relief of ocular allergy symptoms and rhinitis symptoms compared to olopatadine. This could be a factor in selecting this drug, preferably in patients with rhinoconjunctivitis.

Guidelines and Recommendations to Use Antiallergics in Managing Allergies

The basic guideline to treat allergic eye disease is to categorize and grade the severity of disease first and then select the appropriate treatment regimen. The best grading algorithms available and easy to use in clinical practice are described by Bonini et al.[7] and Gokhale[8] and help to avoid using a blanket standard approach to all allergy patients coming to the clinic.[9] It allows the treatment to be tailored to the individual patient based on symptom and signs noted at each visit. Undertreatment and overtreatment can both be deleterious in allergy. Following a treatment guideline helps to provide uniformity, improves treatment response, and reduces adverse effects. Step ladder treatment algorithms that are easy to follow are available.

Treatment for all forms of allergies should include allergen avoidance (A), lubricants (L), and antiallergics (H) (A + L + H) [Fig. 1].

Allergen avoidanceLubricants – Lubricants help to flush out allergens and inflammatory cytokines on the ocular surface and promote epithelial healing and maintain barrier function. They give symptomatic relief and are helpful in treating the dry eye, which is often associated with allergy.Antiallergics – They are the mainstay of treatment in the management of allergies. They are safe, well tolerated, and provide immediate and sustained relief from symptoms. Due to the short duration of action, frequent dosing needed, and no immediate response, pure mast cell stabilizers are not often used today. Only cromolyn eye drops are available and could be used for prophylaxis in chronic refractory allergy as an add-on therapy. Antihistamines are not available currently in India, but preservative-free bilastine 0.6% formulated in hyaluronate seems a promising drug, which has shown good response in clinical studies. Dual acting agents are most commonly used in practice in India. Among the three options available, that is, olopatadine, bepotastine, and alcaftadine, the efficacy is at best comparable overall [Table 4]. One should prefer non-Benzalkonium Chloride (BAK)–preserved options whenever possible. A higher drug concentration option may be preferable as it reduces the application frequency and also the load of preservative going onto the eye surface.[1516] Bepotastine may be more preferable when there is associated allergic rhinitis.[26] These drops start acting immediately on instillation, but their full benefit may be seen only after about 2 weeks. They need to be continued as a long-term measure to maintain their beneficial effect. Higher concentration of olopatadine (0.7%) is effective and well tolerated. Due to a once-daily application, it has a better patient compliance and acceptance.[27]A limitation of mast cell stabilizers, antihistamines, and dual acting agents is that they can only act on the IgE-mediated mechanisms and therefore play a supportive role in dual mechanism allergies like VKC and AKC. They should not be expected to provide inflammation control in severe allergies and need to be combined with other classes of drugs to achieve adequate control.Allergies which are moderate-chronic, severe, and blinding/Bonini grade 2b, 3, and 4, respectively, will require additional immunosuppressive medications to control the non-IgE–mediated inflammation pathways. Because these drugs are more likely to cause adverse effects, they should be continued till the inflammation is controlled to grade 0/1/2a level [Fig. 1]. Once this is achieved, therapy with A + L + H should be continued to maintain suppression or till a next step-up is needed due to exacerbation. Patients who cannot be controlled to these levels despite maximal therapy should continue A + L + H along with all other therapies.Over-the-counter use of vasoconstrictors drops with or without first-generation antihistamines like pheniramine is best avoided because they do not act on any of the allergic mediators, have short duration of action, are associated with rebound hyperemia, and lead to medicamentosa and toxicity with prolonged use.[4]When confronted with significant allergic rhinitis, systemic second-generation oral antihistamines can be used, though they may worsen ocular dryness due to anticholinergic effects. Oral leukotriene inhibitors are also useful in allergic rhinitis (though they are less effective than antihistamines), but have limited effects in ocular allergies.[4]In future, we should look forward to developing an ideal drop which is a potent blocker of H1, H2, and H4 receptors, is also a mast cell stabilizer, is preservative free, and is well tolerated.

Conflicts of interest

There are no conflicts of interest.