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Evolving Paradigm in the Management of Allergic Rhinitis-Associated Ocular Symptoms

Posted on: Thursday, 17 April 2008, 09:00 CDT

By Blaiss, Michael S

Key words: Allergic conjunctivitis - Allergic eye symptoms - Intranasal corticosteroids - Ocular allergy ABSTRACT

Background: Along with nasal symptoms, ocular symptoms such as itching, tearing, and redness are common, bothersome components of the allergic rhinitis (AR) profile. Treatment of the patient with ocular allergy symptoms should take into account a variety of factors, including severity of symptoms, convenience/compliance issues, and patient preferences.

Objectives: To review from the primary care perspective the epidemiology, pathophysiology, and management of ocular symptoms associated with AR, and to evaluate the emerging role of intranasal corticosteroids (INSs).

Findings: A search of the PubMed database identified clinical trials that assessed efficacy of agents in reducing ocular allergy symptoms. Internet searches identified further information including data on over-the-counter agents for treatment of ocular symptoms. Searches were conducted using search terms such as pathophysiology, epidemiology, ocular allergy, quality of life, drug class, and drug names. Primary care physicians are often the first point of contact for patients with seasonal AR (SAR) or perennial AR (PAR) symptoms. Ocular allergy associated with SAR and PAR (seasonal and perennial allergic conjunctivitis, respectively) is characterized by both early- and late-phase reactions, with symptoms often persisting long after allergen exposure. Non-pharmacologic measures such as allergen avoidance, use of artificial tears, and cool compresses are pertinent for all ocular allergy sufferers, but may not afford adequate symptom control. Pharmacotherapy options have traditionally included topical ophthalmic products for cases of isolated ocular symptoms, and oral antihistamines for patients with both nasal and ocular symptoms. However, this paradigm is changing with new evidence regarding the efficacy of INSs in reducing ocular symptoms. A number of meta-analyses and individual studies, most of which studied ocular symptoms as secondary variables, have demonstrated the ocular effects of INSs versus topical and oral antihistamines. Additional prospective studies on this topic are encouraged to provide further evidence for these findings.

Conclusions: In light of their well-established efficacy in reducing nasal allergy symptoms, INSs offer a comprehensive treatment option in patients with nasal and ocular symptoms. Oral antihistamines and/or topical eye drops may also be necessary depending on symptom control.

Introduction

Allergic rhinitis (AR) is an extremely prevalent and bothersome disease, ranking among the top ten diagnoses for frequency of visits to primary care clinics in the United States1. Current estimates suggest that approximately 10% of the general population suffer from seasonal allergic rhinitis (SAR), while perennial allergic rhinitis (PAR) is even more common, affecting up to 20% of people worldwide2,3. In the United States alone, AR conditions impact an estimated 20-40 million individuals3-6. Although these figures describe a widespread disease, it is likely that they underestimate the true prevalence of AR, given the potential for misdiagnosis and patient tendencies to self-treat with over-the-counter (OTC) remedies7.

The scope of AR symptoms reaches beyond the classic triad of sneezing, rhinorrhea, and nasal obstruction8. Other symptoms can include eye symptoms (often termed allergic conjunctivitis), itchy palate, itchy inner ear, postnasal drip, fatigue, irritability, loss of smell, and headache89. A greater awareness has developed regarding the quality-of-life detriments associated with AR, which include impaired professional, academic, or social functioning; disturbed sleep; and emotional difficulties8. In many cases, the ocular components of AR (eye itching, tearing, and redness) are prominent and may be among the most initially disabling features11"2.

Primary care practitioners are on the front line of AR management and are often the first point of contact for patients seeking medical intervention'3. Unsurprisingly, the majority of patients who consult a physician for AR tend to have moderate to severe and/or persistent symptoms814. Effective management of these patients entails a proper diagnosis, appropriate and effective therapy, and necessary follow-up/monitoring. It is critical that ocular symptoms be identified and targeted along with nasal complaints in order to effectively manage the entire AR spectrum, including a restoration of functional status and quality of life.

Overview of allergic conjunctivitis

Classification

Allergic conjunctivitis encompasses several categories of ocular allergic diseases of varying severity. These include seasonal allergic conjunctivitis (SAC) and perennial allergic conjunctivitis (PAC), which account for about 95% of ocular allergies in the United States15. The more severe conditions, i.e., vernal and atopic keratoconjunctivitis, occur infrequently and require an ophthalmologist's care; as such they are beyond the scope of the current review1617. Seasonal allergic conjunctivitis and PAC commonly present in tandem with other symptoms of SAR or PAR18. This article will focus on SAC and PAC, reviewing the features and general treatment of allergic eye symptoms, and specifically explore the clinical evidence regarding the ocular symptom effects of intranasal corticosteroids (INSs).

Epidemiology

The clinical characteristics of SAC and PAC are essentially similar, although they differ in their chronicity, with PAC often requiring ongoing, as opposed to seasonal, treatment18. Ocular symptoms appear to be more prominent in patients with SAR compared with PAR19. In a French cohort of patients with severe allergy, conjunctivitis was noted in 81% of individuals with documented pollen allergy compared with 58% of those with mite allergy14.

Data gathered between 1988 and 1994 as part of the National Health and Nutrition Examination Survey III revealed that more than 40% of the US adult population reported experiencing watery, itchy eyes at some point during any 12-month interval5. Among a large cohort of French patients with intermittent AR, 52% reported ocular itching. Taken together, these findings suggest a significant personal and medical burden of AR-related eye symptoms.

Quality-of-life impact

Surveys of affected patients consistently document a high rate of personal morbidity and detriment to quality of life. The severity of ocular symptoms seems to have a greater impact on quality of life than the duration of such symptoms8. Respondents in the Allergies in America survey ranked red, itching eyes among the top four most bothersome symptoms of AR along with nasal symptoms6. Two recent quality-of-life studies in England20 and Spain21 specifically targeted patients suffering from SAC. In the former study, results of the European Quality of Life Questionnaire (EuroQuol5D) indicated that patients with SAC experienced greater pain and discomfort compared with controls (p = 0.018); these patients also had a lower perception of health as measured by EuroQuol-Visual Analog Scale (EQ- VAS) scores (p = 0.039).

Rhinoconjunctivitis Quality of Life Questionnaire scores, including eye symptoms, were also significantly higher (higher score = poorer quality of life) in SAC patients than in controls (p < 0.001). The US National Eye Institute Visual Functioning Questionnaire 25 (VFQ-25) data showed statistically (p < 0.001) and clinically greater ocular pain in the SAC group20. The Spanish study also reported significant quality-oflife reductions in patients with SAC relative to nonsufferers in specific ocular function domains as well as domains of overall health perception21.

The Eye Allergy Patient Impact Questionnaire (EAPIQ) is a relatively new, validated quality-oflife instrument developed specifically to assess the impact of ocular allergy symptoms on daily activities, emotions, and normal functioning1222. Among 132 patients with ocular allergy symptoms who completed the EAPIQ, the most frequently reported symptoms were itchy, burning eyes (18%) and dry eye (14%). Patients reported being 'extremely troubled' when in the outdoors, as well as feeling fatigued/tired. The results of this survey clearly illustrate the variability in quality-of-life impact from eye symptoms. About one-fourth of patients reported being able to perform normally in spite of their ocular allergy complaints; at the other extreme, 17% of respondents reported being unable to perform tasks on any day when ocular symptoms were present12.

The negative quality-of-life impact of allergic conjunctivitis extends into the domains of productivity and finances, as well. Ocular symptoms can be associated with lost work or school productivity, either directly from symptoms (i.e., fatigue, poor sleep, vision problems, absenteeism) or as a consequence of medication side effects20. Among 201 Spanish patients suffering from SAC, slightly fewer than half of respondents indicated experiencing reduced productivity related to their ocular symptoms, and 20% reported taking time away from work21.

Treatment of the AR symptom complex also accounts for tremendous medical expenses, with more than $6 billion spent on prescription medications to treat this condition in 200023.

Pathophysiology

The external eye is at high risk of exposure to environmental allergens and foreign substances. The eye has some, but few, mechanical barriers to protect itself from allergens, including the brows, eyelids, eyelashes, and tear film15. However, the eye is well equipped to mount an immune response to offending substances when these barriers fail24. The tarsal and bulbar conjunctiva contain significant numbers of mast cells, along with a localized potential for IgE synthesis25. Upon direct exposure to the ocular mucosa surface, pollens and other environmental allergens interact with pollen-specific IgE on these mast cells24. Common pollens leading to eye symptoms are trees and grasses in the spring and weeds in the fall. In PAC, common household allergens such as dust mites, molds, and animal dander are likely culprits24. As with other allergic reactions, allergic conjunctivitis is characterized by both early- and late-phase reactions. The early phase occurs when an allergen binds to IgE on conjunctival mast cells. Subsequent degranulation of mast cells releases inflammatory mediators, including histamine, leukotrienes, prostaglandins, tryptase, and cytokines. Histamine is the principal mediator in ocular allergy, causing itching, redness, and swelling. Prostaglandins and leukotrienes trigger increased mucus secretion and vascular permeability17,26. The early phase is characterized by an immediate elevation in neutrophil concentration in conjunctival scrapings or tears, followed by eosinophil recruitment within 6-10 h. Lymphocytes and monocytes follow, triggering delayed inflammatory processes (late phase). Latephase symptoms are facilitated by eosinophils, T lymphocytes, and other mediators. Eye redness and foreign-body sensation, along with a smaller degree of itching and tearing, can persist long after allergen exposure. Cytological analysis of conjunctival scrapings or tears demonstrates evidence of inflammatory changes 6 h following allergen challenge27,28.

Clinical presentation and diagnosis

Ocular signs and symptoms associated with AR are commonly characterized by recurrent bilateral conjunctival inflammation with pronounced itching and possibly tearing and/or burning18'26. The conjunctiva may appear milky or pale pink secondary to vascular congestion, which may progress to Chemosis (conjunctival swelling), particularly during high-pollen seasons26. Other, more non-specific findings may include dryness and the sensation of the presence of a foreign body18. The cornea is rarely affected, but if so, can result in blurred vision24. The severity of the reaction appears to be dependent upon the allergen dose and the patient's degree of sensitivity25. As with other allergic diseases, there appears to be a strong genetic component to atopy, easily ascertained through family history questioning3.

Unfortunately, ocular symptoms such as redness, tearing, and irritation are quite non-specific, and it is important to rule out other potential etiologies before commencing treatment. The differential diagnosis should include considerations of both infectious (viral, bacterial) and non-infectious (dry eye, toxic/ chemical reaction, contact lens complications, foreign body, etc.) causes29. Figure 1 presents an algorithm for the differential diagnosis of patients with red eye symptoms, including clinical situations that may call for ophthalmologic referral. Particular symptoms that are not generally associated with allergic conjunctivitis and may warrant such a referral include pain, photophobia, or blurred vision (that fails to clear with blinking)29.

One of the most important distinctions is to rule out an infectious origin for the ocular symptoms. History of onset will often provide important clues: ocular allergic reaction generally presents with bilateral eye involvement, while eye infections often present initially in a single eye and migrate to the other within a few days. Itching is certainly one of the hallmark symptoms of allergic conjunctivitis, although it can also be associated with blepharitis, dry eyes, and in some cases with infectious etiology. However, an eye that demonstrates redness without complaints is not likely an allergyrelated phenomenon. The nature of ocular discharge can also differentiate between allergic and infectious pathology; allergic conditions usually manifest serous (watery) or mucoid (stringy) discharge, while bacterial infection is commonly characterized by mucopurulent or purulent discharge, often associated with crusting and difficult eye opening in the morning29.

Figure 1. Algorithm for the differential diagnosis of red eye. Adapted with permission from Morrow and Abbott19

Treatment

When evaluating a patient with allergic conjunctivitis symptoms, treatment recommendations should take into account a number of factors:

* nature and history of the allergy (perennial vs. seasonal, duration, etc.);

* scope of allergy symptoms (ocular, nasal, systemic);

* severity of the condition;

* patient characteristics (age, occupation, other health issues);

* past treatment experience, including tolerance and efficacy of previous and current therapies;

* patient preferences (oral medications vs. nasal sprays; willingness to use eye drops).

There are a number of potential treatment options available, many of which may be more or less appropriate, depending on the specific clinical situation.

Non-pharmacologic measures

Certain non-pharmacologic measures can and should be recommended as adjunctive measures for all patients suffering from allergic conjunctivitis. As with any allergy, avoidance of the offending allergen is of great importance, if possible24. Patients with significant morning symptoms should be encouraged to wash their hair in the evening. Electrostatically charged hair can attract pollen, smoke, and other allergens and transfer them onto a pillow overnight, prolonging further eye contact30. Lubrication with artificial tears is an inexpensive option that can help remove or dilute allergen and mediator concentrations in the tear film, and may provide some symptom relief if eyes are dry or irritated24. Refrigeration of these agents can provide some additional, acute relief, particularly for itching24,31,32. Other cooling techniques, such as cold compresses or gel-filled face masks, can also be beneficial. Patients should be instructed to resist rubbing the eyes, which can actually lead to additional mast cell degranulation and worsen symptoms30.

Pharmacotherapy

A variety of topical and systemic drug products have traditionally been used for the management of allergic conjunctivitis, including topical vasoconstrictors, antihistamines, mast cell stabilizers, non-steroidal antiinflammatory drugs (NSAIDs), oral antihistamines, and INSs (Table 1). A brief review of these drug classes, providing some perspective on the relative merits and drawbacks of each class and individual agents, is presented.

Topical treatments

When allergy symptoms are isolated to the eye or severe eye symptoms are present, topical ophthalmic treatments are the treatment of choice. These products provide direct, local delivery of medication at the site of the allergic manifestation with minimal risk of systemic side effects25.

Vasoconstrictors

Topical vasoconstrictors deserve mention mainly because of their wide OTC availability and consumer appeal. These agents (phenylephrine, naphazoline, oxymetazoline, tetrahydrozoline) reduce Chemosis and conjunctival redness through alpha-adrenergicmediated vasoconstriction. Their effect is very rapid (minutes), but short lived (approximately 2 h), creating a need for frequent re- instillation and the possible development of tolerance to treatment over time. The use of these products should be discouraged in allergic conjunctivitis patients because excessive use can result in rebound conjunctival redness35. Furthermore, vasoconstrictors have no effect on the allergic reaction itself, and are useful only for reducing redness17.

Table 2. Pharmacologie classes and individual agents available for the management of rhinoconjunctivitis symptoms*

Topical antihistamines

The first topical ophthalmic products developed for treating ocular allergy symptoms contained antihistamine compounds, and these agents remain widely used. Topical antihistamines bind with H1 receptors on the conjunctiva, with a resulting significant reduction in symptoms, primarily itching17. Compared with oral antihistamines, these agents offer faster and greater relief with fewer adverse events17,26.

Older antihistamine compounds, such as pheniramine and antazoline, are available without a prescription and can be obtained in combination with a vasoconstrictor (naphazoline). The combination of naphazoline and pheniramine has also been found to be significantly more effective than either component used alone for the reduction of redness36. Nevertheless, these products are not the ideal treatment for allergic conjunctivitis. Despite the rapid and effective relief of itching and redness they afford, the duration of action extends for only about 2 h, thus requiring frequent dosing. Furthermore, as discussed earlier, overuse of vasoconstrictors poses risks for rebound conjunctival congestion. For limited use, antihistamine/ vasoconstrictors can offer fast ocular symptom relief (itching and redness) and are helpful when taken on an as-needed basis.

Newer topical antihistamines, such as levocabastine hydrochloride and emedastine difumarate, have longer durations of action (around 3- 4 h), although dosing is still required up to four times daily15.

Mast cell stabilizers

Topical mast cell stabilizers are not useful for acute symptom relief, but serve an important preventive role. These agents decrease the release of earlyphase inflammatory mediators (histamine, proteases, lipid-derived, cytokines) by stabilizing the mast cell membrane and preventing degranulation. Mast cell stabilization must be accomplished prior to antigen exposure, wherein therapy must be implemented consistently for several weeks for maximum efficacy. Compliance can be a limiting aspect of mast cell stabilizer treatment, considering the need for regular, multiple daily applications over a long period of time during which the patient is asymptomatic15. These treatments are particularly useful for patients with regular, cyclic seasonal allergies or those anticipating exposure to a known allergen (e.g., visiting a home with a pet), keeping in mind the need for regular and prolonged use prior to such exposure. A meta-analysis of clinical trials comparing topical antihistamines and topical mast cell stabilizers in patients with SAC found insufficient evidence that either of these classes of medication is superior to the other for relieving ocular symptoms, although there was some support for a faster onset with antihistamine products37.

Antihistamines with mast-cell stabilizing activity

Several newer antihistamine compounds (olopatadine 0.1% and 0.2%, ketotifen, epinastine, azelastine) also have mast-cell stabilizing effects. These drugs offer the combined benefits of acute symptom relief from histamine blockade and proactive prevention of future mediator release1538. All compounds in this class are indicated only for relief of itching, with the exception of olopatadine 0.1 %, which is indicated for twice daily dosing for all signs and symptoms of ocular allergy15. Olopatadine 0.2%, epinastine, and ketotifen have been proven to improve redness as well as itching in conjunctival allergy challenge models. Epinastine 0.05% (one drop per eye on two separate visits) was found to reduce ocular itching, tearing, and redness compared with vehicle in 67 asymptomatic subjects with a history of allergic conjunctivitis39.Treatment with ketotifen 0.025% (one drop in each eye twice daily for 4 weeks)40 and one dose of olopatadine 0.2%38 resulted in reduced signs of both redness and itching.

Because of their broad range of pharmacologic activity, a number of conjunctival allergen challenge studies have found topical antihistamines with mast cell stabilizing activity to provide statistically significantly greater and/or faster relief of ocular symptoms compared to other classes of agents. Ocular itching and redness scores were significantly lower for olopatadine 0.1% in 68 subjects who were randomized by eye to receive olopatadine or the pure antihistamine levocabastine 0.05%41.Treatment over a 6-week period with olopatadine 0.1% (n = 91) twice daily reduced symptoms of ocular itching and redness to a significantly greater degree than cromolyn 2% four times daily (n = 94)42. Olopatadine 0.1% has been found to be significantly more effective than the pure mast cell stabilizer nedocromil 2% in reducing ocular itching even when subjects randomized to nedocromil received the drug during a 2-week loading period43. Ketotifen resulted in a statistically significant reduction in ocular itching relative to nedocromil in 59 subjects randomized by eye to receive study medication44.

More effective attenuation of ocular itching and redness has been reported with olopatadine 0.1% versus ketorolac 0.5%45 and versus loteprednol etabonate 0.2% with a 14-day loading period46.

James et al. reported equivalent efficacy of azelastine 0.05% twice daily compared with sodium cromoglycate four times daily for symptoms of itching, tearing, and redness47. Another study reported olopatadine 0.1% to be at least as effective as nedocromil, both dosed twice daily, in 28 subjects with PAC48.

Non-steroidal anti-inflammatory drugs

One NSAID, ketorolac 0.5%, is formulated as a topical ophthalmic product for the treatment of allergic conjunctivitis. Ketorolac blocks prostaglandin synthesis through inhibition of cyclo- oxygenase15. Ketorolac inhibits only a portion of the inflammatory cascade and does not influence histamine release or mast cell degranulation17. While ketorolac is officially indicated only for ocular itching, it also has been shown in a double-blind, paired- comparison study of 148 patients with SAC to significantly improve signs and symptoms of inflammation, tearing, foreign body sensation, and conjunctival infection when taken once daily for 7 days49. Discomfort after instillation is the most common side effect, which could lead to compliance problems15.

Oral antihistamines

Oral antihistamines have been studied extensively for their impact on the total constellation of allergy symptomatology. Recently, more attention has been given to their specific benefits on ocular symptoms, and they have been shown to effectively alleviate ocular complaints of itching, tearing, and redness26,33. Antihistamines effectively block the early, histaminemediated phase of the allergic reaction by blocking H1 receptors, and attenuate some manifestations of the late-phase reaction, such as swelling and redness26.

Study findings suggest rapid, moderate effects on ocular symptoms with antihistamine compounds. Loratadine 10 mg once daily, administered for 7 days prior to conjunctival provocation, significantly reduced ocular symptom severity 30 min post challenge in a double-blind, randomized, placebo-controlled, parallelgroup study of 20 patients with SAR50. In 346 subjects with SAR tested in a multicenter, double-blind, randomized, placebo-controlled, parallel-group study during the spring pollen season, a 28% improvement in ocular symptom scores, averaged over the 2-week study period, was noted with desloratadine 5 mg once daily, compared with a 12.5% improvement with placebo51. Desloratadine 5 mg once daily has been shown to produce a noticeable reduction in total symptom scores, including ocular itching and tearing, as early as the first dose52. A randomized, double-blind, conjunctival challenge study in 12 patients with rhinoconjunctivitis reported early- and late-phase clinical improvements in symptoms of itching, hyperemia, lacrimation, and eyelid swelling with the use of cetirizine 10 mg twice daily53.

There are few comparative data to suggest differences in ocular symptom activity between individual antihistamine compounds. In a multinational, doubleblind, randomized, placebo-controlled, parallel- group study in 688 patients with SAR, fexofenadine 120 mg once daily for 14 days was found to be significantly better than loratadine 10 mg once daily in improving 24-h scores for itchy, watery, red eyes19.

Since their development in the 1940s, antihistamine compounds have undergone continued refinement in an effort to preserve their histamine-blocking action (effects on H^sub 1^ receptors)54, while minimizing adverse event potential (effects on other receptors). First-generation antihistamines, now available OTC (diphenhydramine, chlorpheniramine, brompheniramine)54, have relatively non-selective binding affinity. In addition to the desired effects on H^sub 1^ receptors, these compounds react with a number of non-H^sub 1^ receptors, including muscarinic M^sub 2^ receptors in the heart and other cholinergic and alphaadrenergic receptors, producing undesirable effects such as dry mouth, blurred vision, tachycardia, and urinary retention26. These agents also have a greater capacity for central nervous system penetration, leading to higher rates of sedation compared with secondgeneration antihistamines54. Sedating antihistamines have also been shown to cause impairment in tests of driving performance or other objective psychometric and performance tests54. These compounds also have eye-related side effects that particularly hinder their usefulness for managing allergic eye symptoms, most notably ocular dryness26,55. Decreased tear production impairs the eye's capacity for cleansing allergens from the surface, potentially worsening conjunctivitis symptoms15. In light of these issues, the use of first-generation antihistamines should be strongly discouraged for managing allergic conjunctivitis54.

Newer, second-generation antihistamines (loratadine, desloratadine, fexofenadine, cetirizine, levocetirizine) bind more selectively to peripheral H^sub 1^ receptors and have a lower affinity for cholinergic and alphaadrenergic receptors26,56. As a result, these compounds have fewer sedative and anticholinergic effects, although the potential remains, especially at higher doses54. Loratadine is available OTC, while the other agents in this category are available by prescription only. A published review of 16 clinical studies concluded that use of second-generation antihistamines may present a small risk of impaired driving performance, depending on factors such as dose, gender, and time relationship between testing and drug ingestion57. In placebocontrolled studies, desloratadine and fexofenadine have not been found to impact psychomotor function26,57,58.

Intranasal therapy

Antihistamines

Azelastine is a second-generation antihistamine that has been formulated for intranasal administration. Excessive sedation prevented this compound from development for oral use, but local administration limits systemic absorption, minimizing this side effect59. For overall symptomatic relief of AR symptoms, intranasal azelastine is considered to be as effective as oral antihistamines59. The most common complaint with azelastine nasal spray is bitter taste34.

There are limited data regarding the effects of azelastine nasal spray on ocular conjunctivitis symptoms. Azelastine nasal spray has been found to significantly improve watery eyes and itchy eyes/ears/ throat/palate in patients with SAR when dosed twice daily, but not once daily60,61.

In a 2-week, multicenter, randomized, comparison study of azelastine nasal spray, one spray (0.14 mg) per nostril twice daily, and oral cetirizine, 10 mg once daily, in 136 patients with SAR62, a greater improvement in ocular scores (sum of eye lacrimation, erythema, irritation, and swelling) was observed on Day 7 of treatment with cetirizine (-60.8%) compared with azelastine nasal spray (-46.4%), although statistical significance was not achieved (p = 0.3). By Day 14, the decrease in baseline ocular scores was similar for the two treatments (cetirizine, -60.8% vs. azelastine, - 65%; p = 0.89). An analysis compared two double-blind, placebocontrolled, crossover studies of azelastine nasal spray and the topical nasal corticosteroid flunisolide. Fortyfour subjects with PAR confirmed by symptom history, physical exam, and skin testing were randomized using Balaam's design. One group was treated with azelastine nasal spray or placebo saline spray, and the other group was treated with flunisolide or placebo sahne spray (two sprays in each nostril twice daily for both groups). Initial therapy was continued for 4 weeks, after which subjects in each group were crossed over to the other treatment in that arm for another 4 weeks (active to placebo, or vice versa). Patients maintained daily diary entries in which they rated allergy symptom score severity (range, 0 [none] to 4 [severe]). Summary scores were averaged for Weeks 4 and 8 for comparison. This study found flunisolide to be superior to azelastine for improvement of ocular itching. Neither treatment, however, showed significant improvement compared with placebo63. The absence of statistical improvement versus placebo with either medication may be indicative of the lesser ocular symptom burden associated with PAR than SAR. In addition, ocular symptom reporting was limited to the specific complaint of itching, and effectiveness of study treatments on other symptoms, such as tearing and/or redness, was not detailed. Furthermore, ocular allergy symptoms were not a prerequisite for participation in this trial.

Corticosteroids

Intranasal corticosteroids, indicated in the United States for treatment of nasal symptoms of AR, have established efficacy in the control of nasal congestion and other nasal symptoms of AR when used regularly. A growing body of clinical data is warranting a reappraisal of the broader role these products might play in the comprehensive management of AR, including ocular symptoms. The International Primary Care Respiratory Group recently published evidencebased guidelines for primary care practitioners on the management of AR32. Within their recommendations, the use of INSs is supported as having an effect on ocular symptoms associated with AR. The guidelines further recommend that the use of antihistamine or cromone eye drops be reserved for significant ocular symptoms that persist despite the use of INSs or oral antihistamines.

It is not fully understood how INSs improve ocular allergy symptoms. One theory suggests that the corticosteroid normalizes the heightened neural reflex activity demonstrated in allergy patients, with carryover effects on ocular irritation64. It is also possible that INSs improve nasolacrimal drainage through their anti- inflammatory effects, which, in turn, reduces conjunctival retention of allergens and mediators65,66. There are no data to suggest this is a systemic effect, and there are no data to suggest the effects are due to the medication entering the eye via the nasolacrimal duct or from systemic absorption. As with other forms of corticosteroid therapy, the degree of symptom relief may increase over a number of days before maximal effect is achieved.

For the most part, INSs have an excellent safety and tolerability record. There remains some lingering hesitation to use these products in children, even though the accumulating evidence suggests negligible risk of growth suppression, especially with the newer compounds that exhibit almost no systemic availability when used intranasally (e.g., mometasone furoate nasal spray [MFNS], fluticasone propionate [FP], fluticasone furoate [FF], ciclesonide)6768. Common side effects with INSs include epistaxis, nasal dryness, pharyngitis, and cough69"74.

A number of studies have assessed the effects on allergic conjunctivitis symptoms of INSs as compared with other active treatments and placebo.

Intranasal corticosteroids versus placebo

Table 2 summarizes a selection of 11 placebocontrolled clinical studies/analyses in which the effects of an INS on ocular symptoms associated with AR were reported65,75"84. While not intended to be a systematic review of published literature on the subject, many of these studies represent some of the largest populations reported to date and are intended to illustrate the potential ocular effects of INSs as a class. While many older INS trials reported ocular symptoms as secondary variables, more recent studies with newer compounds (e.g., MFNS, FF) have included more focused analyses of this topic, and these are of particular interest. To date, only two trials7883 represent prospective investigations of ocular allergy benefits of INSs. Additional prospective research in this area is needed to provide further evidence of INS benefits.

In almost all trials/analyses shown in Table 2, each INS tested (triamcinolone acetonide, budesonide, MFNS, FP, and FF) was demonstrated to be significantly more effective than placebo in reducing ocular symptom severity. Exceptions were noted in trials reported by Ciprandi et al.77, in which only budesonide, not FP, was superior to placebo, and by Ratner et al.M, in which ciclesonide was not shown to improve reflective non-nasal symptom scores, including ocular itching/burning, tearing, and redness, in subjects with SAR.

Table 2. Selection of placebo-controlled studies reporting the effects of intranasal corticosteroid (INS) treatment on ocular symptoms associated with allergic rhinitis

DeWester et al. analyzed pooled data (N = 1645) from FP and placebo arms of seven randomized, double-blind trials to evaluate the efficacy of FP in relieving ocular symptoms associated with SAR. In each study, FP was given at a dose of 200 [mu]g once daily. Three studies were conducted in the spring (28 days in duration), two in the fall (14 days each), and two in the winter (mountain cedar pollen allergies; 14 days each). Clinicians assessed the severity of four ocular symptoms (itching, tearing, redness, puffiness), and scores were summed to obtain the total ocular symptom score (TOSS). In addition, patients recorded an overall ocular symptom rating on daily diary cards. Fluticasone propionate subjects experienced significantly greater reductions in TOSS and greater reductions in the four individual symptoms at 7 and 14 days of treatment. The FP group also showed significantly greater reductions in patient-rated overall symptoms at both weeks (Figure 2A)65.

Another retrospective pooled analysis was conducted of 991 subjects with SAR treated with MFNS 200 [mu]g once daily or placebo in four similarly designed randomized, double-blind, 14-day studies85. Patients enrolled in these studies were not required to have ocular symptoms at baseline. Although the inclusion of subjects with low baseline values likely decreased the overall mean scores for TOSS and individual ocular symptoms in the analysis population, thereby lowering the percentage reductions, significantly greater improvement in total and individual ocular symptoms (itching, tearing, and redness) were found with MFNS versus placebo (Figure 2B). Within this pooled population, a subgroup analysis was performed on data from subjects who had moderate to severe ocular symptoms at baseline (TOSS >/= 4; n = 602). This analysis also concluded that MFNS had significant results versus placebo in both the individual symptom and TOSS domains, even among patients with the greatest symptom burden82. Additional retrospective analysis showed that MFNS had a rapid effect _____ significant reductions in TOSS occurred as early as Day 3 and for individual symptoms on Day 2 (tearing) or Day 4 (itching, redness) _____ which was sustained over 15 days81. These findings corroborate those reported for smaller, non-pooled analyses79,85, including one comprised entirely of adolescent subjects, a demographic with a high incidence of SAR80.

Figure 2A. Mean change from baseline in patient-rated overall ocular symptom score at Weeks 1 and 2 (p < 0.001 vs. placebo) among patients with seasonal allergic rhinitis treated once daily with fluticasone propionate nasal spray (n = 821) or placebo nasal spray (n = 823) for 14 days. Data were pooled from seven individual studies of similar design. Reprinted with permission from DeWester et al.65. Copyright 2003, with permission from OceanSide Publications, Inc.

Figure 2B. Mean changes from baseline in total and individual ocular symptom scores among patients with seasonal allergic rhinitis treated once daily with mometasone furoate nasal spray (n = 494) or placebo nasal spray (n = 497) for 2 weeks (p < 0.05). Data were pooled from four individual studies of similar design. Reprinted with permisnon from Schenkel et al.82. Copyright 2007 by Hogrefe & Huber Publishers

The new INS, FF, has also been evaluated for efficacy against ocular symptoms of seasonal allergy in at least two double-blind, parallel-group trials involving 278 patients with fall SAR taking FF 110 [mu]g once daily78,83. After 2 weeks of treatment patients in the FF group scored significantly better than patients using placebo nasal spray on reflective total ocular symptom scores (rTOSS), each individual ocular score (itching, tearing, and redness), and morning pre-dose instantaneous total ocular symptom scores (iTOSS), suggesting that INSs can provide effective 24-h benefit in the ocular domain. This agent has approval in the United States for treatment of the nasal and non-nasal symptoms of SAR in patients 2 years and older.

Intranasal corticosteroids versus oral antihistamines

Over the past several decades, the majority of INS studies in the treatment of AR have focused heavily on the control of nasal symptoms, with ocular symptoms evaluated either as a secondary outcome or not at all. With mounting interest in the phenomenon of ocular symptom control using INSs, such data are receiving renewed attention. A number of meta-analyses have been performed using AR study data, extracting ocular symptom findings to compare the efficacy of INSs with other therapies. In 1998, Weiner et al.86 published a meta-analysis of 11 randomized, controlled studies published between 1985 and 1996 that reported treatment effects of oral antihistamines versus INSs on ocular symptoms of AR87-97. This analysis found no overall difference between the two treatments (Figure 3). While there was a significant degree of heterogeneity among study findings (p < 0.0005), the authors noted that most of the heterogeneity was related to three older trials involving beclomethasone86,87,96,97. Overall, there was no measurable difference in effects on eye symptoms between oral antihistamines and INSs.

Figure 3. Meta-analysis reported by Weiner et al.86 comparing intranasal corticosteroids and oral antihistamines on allergic rhinitis-related ocular symptoms. Significant heterogeneity in findings was retoted to studies involving the intranasal corticosteroid beclomethasone87,96,97. Overall, there was no measurable difference in treatment effect between the two modalities. Reprinted with permission from Weiner et al.86. Copyright 1998, with permission from British Medical Journal Publtehing Group Ltd

Additional studies comparing an INS with an oral antihistamine have been published subsequent to, or were not included in, the review by Weiner et al.m. In three randomized, double-blind studies using the antihistamine loratadine as a comparator, INS treatment was reported to be superior in two trials66,98 and equivalent to loratadine in one trial99.

Intranasal corticosteroids versus intranasal antihistamines

In 2002, Yanez et al.'00 reported a meta-analysis of findings from four published clinical trials comparing the ocular effects of INSs versus intranasal antihistamines (Figure 4)63,101-103. Three of the studies101-103 included subjects with SAR, while one study63 included subjects with PAR. This meta-analysis demonstrated no overall significant difference between the two treatment modalities (standardized mean difference = -0.07; p = 0.4). The effect size (standardized mean difference between treatment modalities) reported in this study was similar to that reported in the meta-analysis by Weiner et ai.86 comparing INSs to oral antihistamines in reducing ocular symptoms (-0.04).

Intranasal corticosteroids versus topical antihistamines

In a recent single-center, randomized, doublemasked study, AR patients were randomly treated in a double-blind fashion with MFNS 200 [mu]g once daily, fexofenadine tablets 180 mg once daily, or olopatadine 0.1% ophthalmic solution twice daily for 1 week prior to conjunctival allergen challenge104. Study medication was administered based on approved labeling. The primary ocular efficacy variables assessed were itching and redness. The reduction in ocular itching following allergen challenge was significantly greater with olopatadine ophthalmic drops compared with either MFNS or oral fexofenadine at 3 min (p = 0.003 and p = 0.008, respectively) and 5 min (p = 0.007 and p = 0.013) after challenge. The conclusions of this study are confounded by the very short interval between study drug administration and allergen challenge (15 min). Corticosteroids are known to have their greatest pharmacologic effect on the late phase of the allergic reaction, and might not be expected to demonstrate measurable clinical activity within such a brief time interval following allergen challenge. In fact, effects of intranasal administration on nasal symptoms of AR should be evaluated over periods of hours or days, not minutes67. Fexofenadine onset of action is approximately 2 h105.

Intranasal corticosteroids plus topical treatments

Some data have suggested significant benefits with the combination strategy of an INS plus a topical antihistamine and/or mast cell stabilizer. In one doubleblind, two-site, parallel group study, 80 patients from an allergy database were randomly treated with one of the following combinations twice daily for 2 weeks prior to antigen challenge: (1) FP nasal spray + olopatadine 0.1% drops + placebo pill; (2) FP nasal spray 100 [mu]g + oral fexofenadine 60 mg + tear substitute; or (3) placebo nasal spray + placebo pill + tear substitute106. Two hours after study medications were administered, patients were subjected to a conjunctival allergen challenge. The combination of FP nasal spray and olopatadine eye drops was significantly (p < 0.05) more effective in reducing ocular itching compared with the combination of FP nasal spray and fexofenadine. Effects on nasal symptoms were similar regardless of whether FP was given with the eye drops or the oral antihistamine.

Figure 4. Pooled standardized mean difference between intranasal corticosteroids and topical antihistamines on ocular allergy symptoms. Width of horizontal line represents 95% confidence interval around point estimate (square). Size of point estimate represents restive weight of each trial in the pooled summary estimate (diamond). Reprinted with permission from Yanez and Rodrigo'00. Copyright 2002, with permusion from the American CoUege of Allergy, Asthma and Immunology

Conclusions

Primary care physicians play a major role in the management of AR, and are often the first health care professionals to be consulted. Ocular symptoms, whether the dominant feature or one component of a multifaceted allergic condition, can have a dramatic impact on quality of life and patient comfort. As such, these symptoms warrant medical consideration when forming treatment recommendations. Primary care physicians should question patients specifically about their history of ocular as well as nasal symptomatology. If ocular allergy symptoms are the sole complaint, topical ophthalmic products are likely to provide adequate relief and should be the treatments of choice. For patients experiencing both nasal and ocular allergy symptoms, evidence suggests that an INS may provide sufficient improvement for both types of symptoms. Further prospective research in this area is warranted, but current evidence suggests that INSs may present the opportunity to provide comprehensive allergy symptom relief with a single medication in some patients, with minimal systemic side effects. Single-agent treatment can have a number of advantages over multidrug therapy, including cost-effectiveness, better patient compliance, and fewer risks of side effects. Intranasal corticosteroids should be initiated in the primary care setting for the management of the entire spectrum of nasal AR symptoms and associated ocular symptoms. The addition of topical ocular medications can be particularly effective if combination therapy seems warranted. If ocular symptoms persist or are particularly severe, other classes of agents can and should be considered based on symptoms and patient needs.

While most cases of allergic eye symptoms can be effectively managed in the primary care setting, certain factors may warrant referral to an allergist for consultation and/or co-management, specifically in the case of patients with a questionable diagnosis and/or those who may require skin testing to confirm the diagnosis. Patients with persistent eye symptoms that are suspected to be related to other allergic conditions such as atopic dermatitis or contact dermatitis should also be referred to an allergist. In addition, some patients with severe allergic disease may need to be referred out for immunotherapy. Referral to an ophthalmologist is recommended for patients requiring topical steroid use, those with severe ocular symptoms of questionable allergic origin, and those with vernal keratoconjunctivitis.

Acknowledgments

Declaration of interest: This study was funded by the Schering- Plough Corporation. Editorial support was provided by Adelphi Inc. The author did not receive any payment for the development or submission of this manuscript.

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