Complex and Growing Problem

Allergies are on the rise, presenting challenges to medical professionals.

By Paul M. Karpecki, OD, FAAO

Optometrists are the number one eyecare prescribers of ocular allergy drops in the United States,¹ so I’m sure it comes as no surprise to most of us that 70% to 80% of people who have allergies report ocular symptoms.² Although estimates vary widely, some researchers report that as many as 40% of the people in the United States are affected by allergic conjunctivitis.³ Today’s presentations focus on seasonal and perennial allergic conjunctivitis, which comprises 95% of all cases.⁴

Value of Professional Care

Itching is the most common symptom of allergic conjunctivitis, and redness is the most common sign, but we may also see swelling, tearing or watery discharge, and we are likely to hear complaints of burning, stinging and foreign body sensation. Given the discomfort, it’s not surprising that people with ocular allergy want relief.

More than 41 million bottles of over-the-counter (OTC) and 4 million bottles of prescription anti-allergy ophthalmic medications are consumed annually,⁵ and a 2009 Gallup survey found that only 25% of patients who use eye drops for symptom relief use prescription eye drops.⁶ As these statistics suggest, many people try to alleviate their symptoms on their own. Ocular allergy sufferers often choose OTC eye drops that may exacerbate their symptoms. Vasoconstrictors, for example, provide temporary relief and can lead to rebound hyperemia with long-term use.⁷

This underscores the importance of professional care to confirm a diagnosis of allergic conjunctivitis, which can be complicated by confounding factors and comorbidities. For instance, ocular itch is also a symptom of blepharitis, and researchers have found that people with dry eyes are prone to ocular allergies.^8,9 In addition, the use of oral antihistamines can contribute to dry eye symptoms,¹⁰ which may complicate the diagnosis and treatment of allergic conjunctivitis.

Complex Problem

Given the complex nature of the allergic response, as well as the factors that can complicate diagnosis and treatment, medical professionals need therapies that can provide fast relief. In the articles that follow, Dr. Storms and I discuss the mechanisms and phases of the allergic response and how they lead us to appropriate treatment.

Dr. Karpecki is director of corneal services and ocular surface disease research at the Koffler Vision Group in Lexington, Ky.

The Pathophysiology of Allergic Conjunctivitis

Differentiating the phases of the allergic response can guide your treatment choices.

By William W. Storms, MD

The allergic response is a two-phase, globulin E-mediated hypersensitivity reaction. The early phase begins when an allergen triggers mast cell degranulation, causing the subsequent release of the preformed mediators histamine, tryptase, chymase and heparin. When the response manifests in the eyes, ocular itching, redness and chemosis occur within seconds of exposure and can last up to 40 minutes. The tryptase and histamine promote chemotaxis of basophils and eosinophils, which contribute to the late-phase response.¹¹

The late phase usually begins 4 to 6 hours after initial exposure, leading to chemotaxis and the release of the newly formed mediators platelet-activating factor (PAF), leukotrienes, prostaglandins, cytokines and chemokines. Additional inflammatory cells, the neutrophils and eosinophils, are recruited into the conjunctiva 6 to 10 hours after exposure, with later infiltration of lymphocytes. This activity perpetuates the immune response up to 24 hours after exposure, causing itching, redness and chemosis to intensify.¹¹

Understanding the phases of the immune response not only aids our diagnosis but helps us choose an appropriate treatment.

Calm the Itch

Numerous options exist for treating allergic conjunctivitis. These include allergen avoidance, which can be difficult for many people, use of artificial tears to wash away allergens, non-steroidal anti-inflammatory agents, mast cell stabilizers, antihistamines (often with mast cell stabilizing activity), and corticosteroids. When patients are in the acute phase of the allergic response — when itching is the chief complaint — I believe an excellent first-line choice is the dual-acting antihistamine-mast cell stabilizer bepotastine besilate ophthalmic solution 1.5% (Bepreve).

I choose bepotastine besilate ophthalmic solution 1.5% because it is a highly selective H1 receptor antagonist that inhibits eosinophil migration and activation but has no significant binding affinity for other receptors associated with sedation and dry eye, which are common side effects of some anti-allergy drugs.^12-14 Bepotastine besilate ophthalmic solution 1.5% prevents the release of histamine from the mast cell, thereby inhibiting production of leukotrienes, PAF and interleukin-5.¹³ The efficacy and safety of bepotastine besilate ophthalmic solution 1.5% have been confirmed in clinical trials.

Efficacy Established

Bepotastine besilate ophthalmic solution 1.5% was evaluated in two phase 3 clinical trials, using a conjunctival allergen challenge (CAC).^13,15 In both trials, patients received bepotastine besilate ophthalmic solution 1.5% or placebo 15 minutes, 8 hours and 16 hours prior to CAC, and they assessed their ocular itching at 3, 5 and 7 minutes post CAC. Investigators evaluated conjunctival hyperemia at 7, 15 and 20 minutes post CAC, and they evaluated tolerability by adverse events, visual acuity, slit lamp biomicroscopy, intraocular pressure and dilated fundoscopy.

Within 15 minutes of the challenge, 77% and 88% of patients with severe itching responses (CAC grade ≥3, N = 17 and 23, respectively) to grasses and ragweed showed significant decreases in ocular itching when treated with bepotastine besilate ophthalmic solution 1.5% compared with placebo in a sub analysis of the entire study population.¹⁶ Another post hoc analysis of the two clinical trials showed that 68% of patients with severe itching responses reported no itching at 3 minutes when treated with bepotastine besilate ophthalmic solution 1.5% 15 minutes before allergen exposure (N=104 eyes), compared with 3% of patients who received placebo (N=98 eyes).¹⁷ Eyes treated with bepotastine besilate ophthalmic solution 1.5% had a rapid and clinically significant reduction (≥1U) of ocular itch within 15 minutes of administration. Among all patients, regardless of their itch severity, 95% of eyes treated with bepotastine besilate ophthalmic solution 1.5% had improvement within 15 minutes (N=156 eyes) compared with 47% of those receiving placebo.

Further analysis found that ocular itch relief was sustained for 8 hours after bepotastine besilate ophthalmic solution 1.5% was administered, and the drug reduced ocular itch by one or more units in 90% of treated eyes (N=156 eyes) compared with only 40% of placebo eyes.¹² These results show that not only is the product effective in most patients, even those with severe symptoms, but relief is sustained for a long period.

Safety Confirmed

In a 6-week safety trial, more than 800 patients received either bepotastine besilate ophthalmic solution 1.5% or vehicle, 1 drop twice a day for 6 weeks.¹⁸ Investigators assessed visual acuity, slit lamp biomicroscopy, physical examinations, IOP, dilated ophthalmolscopy, noncontact specular microscopy, ocular comfort (as reported by patients at instillation and 5 minutes post instillation) and adverse events. They found no statistical difference between patients receiving bepotastine besilate ophthalmic solution 1.5% and those receiving placebo in eye irritation, headache or other issues; 25% of patients noticed a mild taste with bepotastine besilate ophthalmic solution 1.5%.

Also of note, on a scale of 0 to 3, more than 92% of the 6,400+ ocular comfort scores were 0, indicating that those patients/subjects had no discomfort from instillation of bepotastine besilate ophthalmic solution 1.5%.¹⁹ That’s important, because if an eye drop stings, patients may not be likely to use it. There were no clinically significant differences in ocular comfort between bepotastine besilate ophthalmic solution 1.5% and placebo after 1 or 3 weeks of dosing in the safety population.

Rapid, Durable Relief

In summary, bepotastine besilate ophthalmic solution 1.5% is a dual-acting antihistamine-mast cell stabilizer that is selective for the H1 receptor. It provides rapid, durable relief of ocular itching, and it has efficacy against a wide range of itch severity caused by a broad spectrum of allergens. It is comfortable on instillation and has a low incidence of adverse events.

Anyone who treats allergic conjunctivitis knows that no single therapy will alleviate all signs and symptoms in every case. Dr. Karpecki will discuss appropriate treatment for patients experiencing the late phase of the allergic response, when symptoms in addition to itching may be problematic. ■

Dr. Storms is an allergy and immunology specialist, who practices in Colorado Springs, Colo. He is a clinical professor at the University of Colorado Health Sciences Center in Denver.

Beyond the Itch

Treatment protocols may change when patients present with signs and symptoms beyond the itch.

By Paul M. Karpecki, OD, FAAO

The early phase of the allergic response involves predominantly histamine release from mast cells, resulting in significant itching, redness and chemosis. In the late phase, not only mast cells, but also basophils and eosinophils come into play. They are recruited to the conjunctival tissue where they release additional inflammatory mediators — platelet-activating factor, leukotrienes, prostaglandins, cytokines and chemokines — all of which exacerbate and perpetuate the immune response.^5,11

Although it may seem logical to choose a drug to treat allergic conjunctivitis based on the amount of time a patient has been symptomatic, establishing a time frame may be difficult. I make my treatment decision based on my clinical examination and the patient’s chief complaint. When a patient says, “I have a severe itching in my eye,” I prefer to prescribe a dual-acting antihistamine-mast cell stabilizer, such as bepotastine besilate ophthalmic solution 1.5% (Bepreve). If a patient has itching but is equally concerned about burning/stinging, chemosis and redness, I prescribe a steroid, loteprednol etabonate ophthalmic suspension 0.2% (Alrex), because steroids act at the level of the arachidonic acid pathway to block the production of prostaglandins and leukotrienes and have an indication for multi-symptom resolution including redness. I choose this specific steroid because it is indicated for temporary relief of signs of seasonal allergic conjunctivitis as well as symptoms.²⁰ Most of the newer anti-histamine/mast cell stabilizers are indicated for either treatment of or prevention of itching associated with allergic conjunctivitis. The efficacy and safety of loteprednol 0.2% was examined in two identical, 6-week, randomized, double-masked, vehicle-controlled parallel-group multicenter studies.^21,22

Efficacy and Safety

In studies performed at the Dell Laser Vision Center (n=133) and the Shulman Center (n=135), patients were randomly assigned to loteprednol 0.2% or vehicle administered 4 times a day for 42 days. The primary endpoints were bulbar injection and itching at 14 days.^21,22

Investigators at both sites reported significant reductions in the severity of bulbar injection in the treatment groups after 14 days. In the Dell study, resolution favored the drug over placebo, 31% and 9%, respectively; in the Shulman study, resolution favored the drug over placebo, 36% and 15%, respectively. Changes from baseline to 2 hours after treatment in both studies were remarkable.

The steroid also controlled itching, but the difference was not statistically significant until 2 to 3 days in the Dell study and 7 days in the Shulman study.

In both studies, the safety profile for loteprednol 0.2% was comparable to that of placebo. No patient in the Dell study had an IOP rise of 10 mm Hg or more from baseline. In the Shulman study, one patient in each group (drug and placebo) had an IOP rise of 10 mm Hg or more from baseline. For more on steroid use in an eyecare practice, see “Use of Steroid Drops in Practice” above.

Another interesting fact about loteprednol 0.2% — I think — is that it contains two moisturizing components, glycerin and povidone.

In summary, loteprednol 0.2% covers early- and late-phase inflammatory mediators. It provides temporary relief of the signs and symptoms associated with seasonal allergic conjunctivitis, including redness, burning, stinging, discomfort, foreign body sensation, tearing and itching. Its incidence of IOP elevations is comparable to vehicle, and it contains moisturizing ingredients. This combination of properties translates to a robust therapy in clinical practice.

Real-world Scenarios

Most cases of seasonal allergic conjunctivitis are straightforward. For example, if a patient complains of itching eyes ranging from mild to incapacitating and it’s a first-time presentation, I prescribe bepotastine 1.5%. I often sample it in the office, and my patients have noted that their itching quickly subsides. If significant chemosis or edema is present, I recommend cool compresses, and I always recommend artificial tears to rinse away the allergens. I usually see the patient in 2 weeks, or sooner if he’s not improving or is getting worse. If signs and symptoms have resolved, patients can discontinue the drug, but if I still see some signs of papillae or hyperemia, I instruct them to finish the bottle.

Patients with perennial allergies can be difficult cases. They may have periods when their symptoms resolve and then recur, so I often advise them to keep bepotastine 1.5% on hand, so they can start treatment as soon as they feel symptoms of itching.

When a patient has significant signs such as chemosis or redness, I usually prescribe loteprednol etabonate 0.2%, 4 times a day for 1 or 2 weeks. If additional treatment is warranted, I monitor his IOP. I continue that treatment until signs and symptoms are fully controlled, which may be 1 to 2 months for more advanced cases. When itching symptoms are greater than signs of the condition, I typically choose a dual-acting agent such as bepotastine. If signs are significant, approaching the severity of the symptoms, or if they have been long-standing, I typically prescribe a steroid drop. In other words, itching symptoms = antihistamine-mast cell stabilizer, but multiple signs and symptoms associated with seasonal allergic conjunctivitis = steroid drop.

Suppose a patient has both signs and symptoms? Severity dictates the treatment protocol. If signs and symptoms are severe, I would likely prescribe both bepotastine 1.5% and loteprednol 0.2%, because itching may be playing a role in the severity. The patient may be rubbing his eyes and exacerbating his symptoms. If a patient has mild symptoms of itching and redness, I try to tease out which is worse and treat accordingly. If signs and symptoms are similar in severity I may prescribe the steroid first and save the antihistamine-mast cell stabilizer until later.

Fast, Sustained Relief

Ocular allergy can be a stressful condition for patients, and once they are in your office — often after trying to resolve their symptoms on their own — they are seeking fast and sustained relief. Two of the most effective therapies we can prescribe are bepotastine 1.5% for first-line, year-round relief of itching associated with signs and symptoms of allergic conjunctivitis and loteprednol etabonate 0.2% for temporary, multisymptom relief in patients with seasonal allergic conjunctivitis.³ ■

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