Newer Approaches to the Long-Term Management of Dry Eye Disease

Supported by an educational grant from Allergan.

FACULTY:

Richard G. Fiscella, RPh, MPH
Clinical Professor
Department of Pharmacy Practice
Adjunct Assistant Professor
Department of Ophthalmology
University of Illinois at Chicago

FACULTY DISCLOSURE STATEMENTS:

The faculty reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CE activity:

U.S. Pharmacist does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
Program No.: 430-000-08-012-H01-P; 430-000-08-012-H01-T
Credits: 2.0 hours (0.20 ceu)

TARGET AUDIENCE:

This accredited program is targeted to pharmacists and pharmacy technicians. Estimated time to complete this monograph and posttest is 90 to 120 minutes.

METHOD OF PARTICIPATION:

There are no fees for participating and receiving CE credit for this activity. During the period July 1, 2008 through July 31, 2010, participants must:

1. read the learning objectives and faculty disclosure;
2. study the educational activity;
3. complete the posttest by recording the best answer to each question in the answer key on the evaluation form;
4. complete the evaluation form; and
5. mail or fax the evaluation form with answer key to the address listed on the form. For faster service, enter your answers on the Internet at www.uspharmacist.com. A statement of credit will be issued upon receipt of a completed activity evaluation form and a completed posttest with a score of 70% or better.

DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients’ conditions and possible contraindications or dangers in use, review of any applicable manufacturer’s product information, and comparison with recommendations of other authorities.

GOAL:

To educate pharmacists on the epidemiology, pathophysiology, and economic impact of dry eye disease (DED) and provide strategies to determine the most appropriate long-term treatment approaches based upon updated clinical guidelines.

OBJECTIVES:

After completing this program, participants will be able to:

1. Review the epidemiology, pathophysiology, and diagnosis of dry eye disease (DED);*
2. Describe the clinical and economic factors that may be associated with DED;*
3. Discuss standard and updated guidelines in DED, with emphasis on long-term treatment;*and
4. List strategies for pharmacists to identify patients with DED and to make appropriate treatment recommendations.

*Also applies to pharmacy technicians.

One of the most common complaints to the ophthalmologist and optometrist office is dry eye. It is estimated that over eight million people suffer from dry eye in the United States. Although dry eye disease (DED) is extremely common in people over age 55 of both sexes, it is intrinsically two to three times more common in women of any age.

Although DED is not a frequent cause of blindness, it is still an important public health problem. DED is associated with a decreased ability to perform activities that require visual attention, such as reading and driving a car.

It is obvious to the pharmacist that treatment response to DED must be rather limited just by observing the row of artificial tear products commercially available in the pharmacy. However, recent research into the causes of DED has been promising.

In the past, patients with DED have often been limited to trying another artificial tear, gel, or ointment if they initially did not receive benefit or did not tolerate the original product. Eye care professionals were also frustrated, knowing that they have limited treatment options and may see these patients for many years with few treatment alternatives available. The abundance of products will require many pharmacies to limit their shelf space to the best-selling products, as newer products continue to be released each year. Therefore, relief from DED is not easily obtained based upon the number of lubricating products sold each year.

This monograph will discuss findings of the current research into DED and improved treatment options that are now available to treat not only the palliative signs and symptoms of the disease, but to help address its underlying pathophysiology.

EPIDEMIOLOGY

Signs and Symptoms

Patients with DED often have ocular complaints of photophobia, a sandy or gritty feeling, burning and stinging, itching, dryness, eye fatigue, and pain.^1-3 Patients may also develop blurry vision, redness, contact lens intolerance, and, sometimes, a mucous discharge.

Interestingly, some patients present with complaints of excessive tearing that is often considered a paradoxical reflex tearing because the basal tear production is reduced in DED. Often the dryness is worse later in the day.

For many patients, they do get some relief from the use of topical artificial tear products. However, in many cases, as the signs and symptoms worsen, patients use more tear supplements and/or seek advice from eye care professionals or pharmacists for their complaints.

Effect on Quality of Life

Patients with DED may experience symptoms so constant and severe that reading, driving, working, and participating in other vision-related activities of daily life are difficult or impossible. One utility assessment paper compared patients with moderate-to-severe DED with published scores of angina and hip fracture patients.⁴ As the symptoms worsen, patients’ quality of life is negatively affected. Patients with moderate or severe DED had a mean time trade-off score comparable to that of patients with moderate or severe angina. Patients with disabling hip fractures and monocular painful blindness had lower mean scores.⁴

PATHOPHYSIOLOGY

Normal Tear Composition

The normal tear composition is more complex than most would believe. Many clinicians now refer to the lacrimal functional unit (LFU) when discussing DED.^2,5 The LFU consists of the lacrimal glands, the ocular surface including the cornea and conjunctiva, the eyelids, meibomian glands, ocular nerves, and, often, the goblet cells.

The outer layer of the tear film is made up of a lipid layer that prevents evaporation of the tear film from the ocular surface.⁶ The meibomian and a few minor accessory glands are responsible for the secretion of this layer. Blepharitis or inflammation of the eyelids may contribute to poor lipid production.

The lacrimal gland and accessory glands produce the aqueous component consisting of a complex mixture of proteins, mucins, electrolytes, cytokines, and growth factors. Since the cornea is an avascular tissue, the tear film provides critical lubrication and optical qualities, nutrients, foreign body and microbe removal, and antibacterial and wound healing substances for homeostasis. Finally, the mucin layer provides stability and an interface between the corneal and conjunctival epithelium and the tear film during the normal blink cycle. This layer promotes even distribution of tear film across the corneal surface.

Looking at the complexity of the tear film, it is obvious that as DED progresses or further factors exacerbate the dry eye, simple substitution of an artificial tear product will not provide the same relief as the natural components of our own tear film. In fact, in some rare cases patients with severe DED or DED refractory to conventional therapy have even had pharmacies compound autologous serum tears. In these instances patients’ blood is drawn and the serum is diluted in artificial tear. In a few small studies autologous serum tears provided a benefit in patients with severe DED by supplying constituents closer to the tear film than were provided by commercially available products.^7,8 Obviously, this is a rather complex and expensive extemporaneously compounded option that has many inherent limitations.

Factors Influencing Tear Film and Ocular Surface Discomfort

DED is a result of many factors that may contribute to poor tear function. Often the tear film becomes hyperos-molar, which can occur from low aqueous flow or excessive tear evaporation.⁶ This hyperosmolarity may lead to an inflammatory condition on the ocular surface and produce tear film instability. The one fact that has become evident with more recent studies is that underlying inflammation is a key consideration irregardless of the inciting factor(s). Increased T-cell infiltration of the lacrimal gland and production of inflammatory cytokines, which are then released onto the ocular surface, are main contributors to this inflammatory cascade.^9-11

Identifying Patients with DED

Patients with DED most often include perimenopausal and postmenopausal women, the elderly, contact lens wearers, patients having undergone refractive surgery, those exposed to environmental and occupational factors, those with disease state-related conditions (eg, autoimmune disease, Parkinson’s disease, diabetes mellitus), and those on certain systemic and topical medications.^12,13 In many of these instances, it may be a combination of these factors that tips the balance from minor symptoms to more moderate-to-severe dry eye complaints.

Some clinicians divide DED etiology into either aqueous deficient or evaporative causes (Table 1).^5,6 Under the aqueous-deficient category, the two main categories are Sjögren- or non-Sjögren-related causes. The Sjögren-related causes are often secondary to autoimmune-related diseases such as rheumatoid arthritis or systemic lupus erythematosus.

Table 1. DED Etiology Aqueous-Deficient Causes Sjögren-Related • Rheumatoid arthritis • Systemic lupus erythematosus Non-Sjögren-Related • Age-related causes • Secondary to lacrimal gland infiltration associated with various diseases including AIDS, sarcoidosis, and lymphoma • Sensory block causes such as refractive surgery, contact lens wear, or herpes simplex keratitis • Motor block causes such as anticholinergic medications or damage to cranial nerve VII Evaporative Causes • Meibomian gland dysfunction (eg, ocular rosacea and use of isotretinoin) • Eyelid disorders (eg, thyrotoxicosis and poor lid apposition often noted in the elderly) • Blink disorders (eg, Parkinson’s disease and stroke) • Ocular surface disease (eg, allergic conjunctivitis)

Non-Sjögren-related causes are most often age-related or are secondary to lacrimal gland infiltration associated with various diseases including AIDS, sarcoidosis, and lymphoma. Sensory block causes are most often associated with refractive surgery, contact lens wear, or herpes simplex keratitis. Motor block-related causes include anticholinergic medications or, possibly, damage to cranial nerve VII.

Evaporative conditions include meibomian gland dysfunction (eg, ocular rosacea and use of isotretinoin), eyelid disorders (eg, thyrotoxicosis and poor lid apposition often noted in the elderly), blink disorders (eg, Parkinson’s disease and stroke), and ocular surface disease (eg, allergic conjunctivitis).

DIAGNOSIS

Criteria for Diagnosis of DED

The criteria for the diagnosis of DED vary somewhat among clinicians. Patients have different tolerability to ocular discomfort and some patients with significant clinical DED may have few complaints whereas others with minor physiologic changes may have more vocal complaints of ocular irritation and dryness.

Most Common Testing for DED

Symptoms and signs are often combined with various diagnostic tests for determining the diagnosis of DED. Symptoms can also be quantified by a validated dry eye questionnaire such as the Ocular Surface Disease Index Questionnaire (OSDI).^6,14 Tear film stability is assessed with the tear breakup time test (TBUT). In the TBUT, the patient has fluorescein dye instilled in the eye and is observed with the eye open. Generally, the first breakup of the tear film under 10 seconds is considered abnormal. Other dyes such as lissamine green and rose bengal have also been used to observe ocular surface damage.

The Schirmer's test also is used as a diagnostic tool. It assesses the tear flow when a small piece of paper is placed in the lower lid and the amount of wetting of the paper is measured. The Schirmer's test, when administered with anesthesia, is said to measure basal tear production, which is thought to be reduced in patients with DED. The Schirmer's test administered without anesthesia measures more accurately reflex tearing.

Other tests such as impression cytology to detect goblet cell density and corneal topography have also been utilized but less commonly. In a consensus paper of leading dry eye experts throughout the world, the most commonly used diagnostic tests for evaluating a patient with probable DED were rated.¹⁵ Flurorescein staining (100%) was performed by everyone, with TBUT (94%), Schirmer's test (71%), rose bengal staining (65%), corneal topography (41%), impression cytology (24%), and tear fluorescein clearance (24%) performed by a smaller percentage of the clinicians. Other tests less commonly performed included the OSDI, National Eye Institute Vision Function Questionnaire-25 (NEIVFQ-25), tear osmolarity, and conjunctival biopsy.

TREATMENT GUIDELINES

In previous years patients would be given an artificial tear product by their eye care professional and be instructed to use it as frequently as needed. Often the first use of an artificial tear product may have come via a recommendation by pharmacists when patients first developed symptoms of DED. What has been frustrating to eye care professionals in the past is that treatment options and understanding of DED were limited. In fact, until recent years patients would try a multitude of artificial tear or gel products with little relief. With a better understanding of the complex nature of DED and some advances in pharmacologic treatment, the options that exist today for patients with DED are much improved. Treatment recommendations now exist that are based upon expert consensus and provide eye care professionals with a rationale approach to treating DED.^8,15 These guidelines were established to provide both nonpharmacological and pharmacological approaches to the treatment of patients with DED (Table 2).

Table 2. A Modified Delphi Technique to Obtain Consensus on the Treatment of Dry Eye Disease Severity Level   Signs & Symptoms   Recommended Treatment 1   Mild-to-moderate symptoms & no signs   Mild-to-moderate conjunctival signs    Patient counseling, preserved tears,   environmental management, allergy eye drops,   H2O intake, hypoallergenic products. If NI,   add level 2. 2   Moderate-to-severe symptoms   Tear film signs   Mild corneal punctate staining   Conjunctival staining   Visual signs    Unpreserved tears, gels, ointments, topical   cyclosporine A, secretagogues, topical   steroids, nutritional support (flaxseed oil).   If NI, add level 3. 3   Severe symptoms   Marked corneal punctate staining   Central corneal staining   Filamentary keratitis    Tetracycline, punctal plugs   If NI, add level 4 4   Severe symptoms   Severe corneal staining, erosions   Conjunctival scarring    Systemic anti-inflammatory therapy, oral   cyclosporine, moisture goggles,   acetylcysteine, punctal cautery, surgery At least one sign and one symptom of each category should be present to qualify for corresponding level assignment. Adapted from Behrens A, et al. Cornea. 2006;22:61-66.

NONPHARMACOLOGICAL TREATMENT OPTIONS

Avoidance of wind, drafts, smoky environments, and dry air are recommended for patients with DED. Obviously, these are not easy lifestyle or workplace changes to make. However, any modification that can be implemented would help to lessen some of the aggravating factors associated with DED. Other preventative measures include moving desks away from air vents, use of humidifiers in the workplace, taking breaks while working on computers, and placing drops from artificial tear products prior to onset of symptoms. Another consideration is to avoid medications that may cause dryness. Patients may not realize that over-the-counter (OTC) antihistamines used for managing allergy or sleep, topical decongestants, or prescription items that have anticholinergic activity may contribute to exacerbating DED.

PHARMACOLOGICAL AND OTHER TREATMENT OPTIONS

Tear Supplementation

Artificial tears have always been considered the primary treatment option for patients with DED. The options include various products that are mainly composed of viscosity-increasing agents that allow for a prolonged contact time on the ocular surface. The most common agents include cellulose products [eg, carboxymethylcellulose (CMC) and hydroxypropyl methylcellulose], polyvinyl alcohol, and polyethylene or propylene glycol. Some products are composed of castor oil (Refresh Dry Eye Therapy^®) or mineral oil (Soothe^® Lubricant Eye Drops) that produce a “water in oil” emulsion that is believed to supplement the lipid layer of the tear film. Another product containing a hydroxypropyl-guar combination (Systane^® Lubricant Eye Drops) is thought to help supplement the mucin layer by forming a bioadhesive gel on the tear film. Some products contain electrolytes to produce a more isotonic solution whereas others contain hypotonic solutions that when applied to the hypertonic tear film will help the tear film become isotonic. In addition, a combination product containing CMC and glycerin (Optive^™ Lubricant Eye Drops) is believed to provide protection against osmotic stress to the corneal surface. Any of these agents may be dosed as frequently as needed for relief of symptoms.

Many ophthalmic solutions contain benzalkonium chloride (BAK), a detergent preservative, that may disrupt corneal epithelium and the tear film and cause potential ocular irritation. It is contained in products such as Visine^® and Murine^®. Some products are preservative-free whereas others contain less irritating preservatives that are better tolerated in the tear film. Purite^®, a stabilized oxy-chloro complex, is an oxidative preservative that breaks down to sodium chloride and water when exposed to UV light. It is a very well tolerated preservative even in patients with severe DED. It is an ingredient in various Refresh^® and Optive^™ dry eye products. Another preservative, sodium perborate, is converted to sodium hydroxide and water and is believed to be less toxic to the ocular surface. It is found in GenTeal^® dry eye products.

Some products contain carbomers in gel formulations that cause less blurry vision than petrolatum ointments and are better tolerated. In some cases these may be preservative-free gel formulations. The gel and ointments are often used at bedtime just to avoid complaints of blurry vision. There is one multi-dose artificial tear product that is preservative-free in a special dispensing system that is designed to prevent contamination (Visine^® Pure Tears).

It is evident that all of these artificial tear products have associated risks and benefits that may apply to one patient but not another patient with DED. In most cases the selection of an artificial tear product is determined by which product is most comfortable and provides sustained relief. However, all artificial tear products provide palliative treatment and do not address the underlying pathophysiology of DED.

Eyelid Hygiene

Proper lid function is vital, especially in patients with meibomian gland dysfunction. Patients are often instructed to apply warm compresses, perform lid massage, and clean the lids with non-irritating soaps to help restore more normal lid function. Products such as Eye-Scrub^® or OCuSOFT^® contain polyethylene glycol and other non-irritating surfactants that can clean the lid of debris and do not irritate the eye. Good eyelid hygiene may be beneficial in preventing DED.

Punctal Plugs and Related Options

Punctal plugs are often used in patients with DED. They are placed in the puncta to provide a pooling effect of tear film. They are categorized as being absorbable or nonabsorbable. The Delphi panel has concluded that because the lacrimal gland in patients with DED secretes an abundance of activated T-cells and inflammatory cytokines onto the ocular surface, if required, it is preferable to place punctal plugs after anti-inflammatory therapy has been initiated.¹⁵

In patients with severe DED and who have been refractory to other therapies (usually those with filamentary keratitis or Sjögren’s syndrome), therapeutic contact lenses have been used to help retain tear film and promote ocular surface healing. In particular, the Boston Scleral Lens is indicated for severe refractory ocular surface disease. The Boston Scleral Lens is an oxygen permeable optical shell that fits under the lids and over the front surface of the eye. It is designed to rest entirely on the tough, relatively insensitive white sclera and immerse the sensitive diseased cornea in a pool of artificial tears. In addition to devices such as therapeutic contact lenses, patients with severe DED may even wear special goggles to help reduce the amount of tear film evaporation.

In patients who have severe DED and develop complications such as corneal ulcers or have impaired healing after surgical procedures, a tarsorrhaphy (surgical closing of the eyelids) may be required to help promote healing and protect the ocular surface. In other severe cases, special goggles to preserve moisture on the ocular surface are indicated and may avoid more invasive surgical procedures in some patients.

Nutritional Supplements

There is some clinical evidence to suggest that essential fatty acids provide a beneficial effect in restoring meibomian gland lipid production and reducing lid inflammation.¹⁶ Omega-3 oils from either flaxseed or fish oil have been shown to help improve symptoms more than placebo in patients with DED.^15,16 Although further study is needed to establish specific recommendations, this approach seems to be a reasonable option as noted by the International Task Force (ITF).¹⁵

Corticosteroids

Corticosteroids provide reduction of the inflammatory response in patients with DED. The concern with long-term steroid use is associated side effects including glaucoma, cataract formation, and secondary infection. The recommended use in patients with DED, especially those with limited intraocular penetration, is short-term administration, usually around four weeks.

In one double-blind, placebo-controlled study, 64 patients with DED received either lotepredenol etabonate 0.5% or placebo QID for four weeks. Both groups received relief from their treatment, but the patients who demonstrated moderate clinical inflammation were also more likely to show benefit from receiving lotepredenol.⁹

Another study compared a steroid (fluorometholone) as well as an NSAID (flurbiprofen) with placebo.¹⁷ Patients on the steroid demonstrated significantly improved symptom scores at two weeks and a month versus both groups. An interesting aspect of this study is that corneal staining and goblet cell density improved in the group on the steroid versus the other two groups.

Some clinicians have suggested that steroid use should be initiated in conjunction with cyclosporine to help reduce the inflammatory reaction. The concurrent use of a topical steroid with cyclosporine also helps reduce complaints of ocular stinging associated with cyclosporine.

Cyclosporine

Topical cyclosporine 0.05% (Restasis^®) is the first prescription medication approved for the treatment of DED. It is dosed twice daily and is extremely well tolerated, with no requirements for systemic monitoring, since serum concentrations are below detectable levels.¹⁸

From a topical standpoint, in clinical trials ocular burning and stinging (14.7% and 3.4% for cyclosporine versus 6.5% and 1.4% for placebo, respectively) were the main side effects with no reports of glaucoma or secondary infection.¹⁸ The initial phase III pivotal clinical trials found that at six months 59% of patients on topical cyclosporine 0.05% achieved a 1 to 10 mm or more improvement from baseline in Schirmer’s test scores and three times as many demonstrated a statistically significant increase of 10 mm or more versus placebo (15% vs. 5%, respectively).¹⁹

The aforementioned study results demonstrated that Schirmer's test (with anesthesia) scores are a clinically relevant endpoint for determining efficacy of dry eye therapies and they indicate improved tear production and reduced ocular surface dryness. The FDA also agreed that Schirmer's test scores strongly correlate with an improvement in corneal staining and a reduction in key keratoconjunctivitis sicca symptoms (ie, dryness, itching, blurred vision, and photophobia).

There has also been a phase III extension trial completed of topical cyclosporine 0.05% to further evaluate its safety for up to three years.²⁰ Adverse events were mild to moderate, consisting of mostly burning and stinging (10.9% and 3.9%, respectively). Over 95% of patients treated with topical cyclosporine 0.05% indicated that they would continue with their therapy and 98% indicated that they would recommend it to others.²⁰

A recent study demonstrated that patients on topical cyclosporine 0.05% showed significant improvement in goblet cell density compared with no improvement in patients on placebo.²¹ Another investigator demonstrated that earlier treatment with topical cyclosporine 0.05% may lessen the progression of DED.²²

A small study of punctal plugs versus cyclosporine versus a combination of each demonstrated that all three regimens effectively treated DED, but whereas the plugs increased wetness initially, topical cyclosporine 0.05% promoted long-term health.²³ The investigators concluded that the effects may be additive and that those treated only with punctal occlusion may benefit from also receiving topical cyclosporine 0.05%.

Although the Schirmer's test was a critical factor in the phase III studies for topical cyclosporine 0.05%, all eye care professionals do not perform it. As discussed previously, eye care professionals can determine the diagnosis of DED from symptoms and signs, and these vary from patient to patient. Therefore, it is not necessarily a requirement that Schirmer's tests be completed to diagnose DED. Because patients may be at different stages of the disease and may have varying symptomatic complaints, it is up to the eye care professional to rule out other causes of ocular irritation.

Oral Tetracyclines

Oral tetracyclines, in particular doxycycline, have been used to help promote proper lid function, especially in patients with ocular rosacea. There is clinical evidence to suggest that these agents work by an anti-inflammatory mechanism of action rather than via an anti-infective one. Whether this is a result of inhibition of matrix metalloproteinase activity or inflammatory cytokines is still being evaluated. The clinical study data are not strong, but rather suggestive that oral tetracyclines provide a beneficial response in patients with ocular rosacea. Many clinicians prefer low-dose doxycycline 20 mg because there is less systemic exposure of the patient to the antibiotic and fewer side effects.

NSAIDs

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) have been studied and have had some positive response in patients with DED. Diclofenac was found to reduce filaments more rapidly in patients with secondary Sjögren's syndrome and filamentary keratitis and demonstrated symptomatic improvement faster than with saline drops.²⁴

Treatment with ketorolac in a six-week study of 52 patients with DED did result in decreased symptoms and some improvement in corneal staining when used with cyclosporine versus cyclosporine alone.²⁵ However, some safety concerns have developed with the long-term use of topical NSAIDs, especially with diclofenac because of reduced corneal sensitivity. Reports postoperatively and in patients with compromised corneas and complex treatment regimens have suggested that these agents should be used cautiously, if at all, in patients with DED.^26,27

Secretagogues

Cholinergic agents have been found to increase ocular secretions in patients with aqueous-deficient DED. However, agents such as pilocarpine and cevimeline, when given orally, will often produce cholinergic side effects (eg, nausea, diarrhea, increased sweating, and headache). This has limited their clinical utilization in patients with DED. New topical secretagogues are currently in clinical trials and may become another alternative in the future for the treatment of DED.

Investigational Agents

There are a number of agents currently under investigation for the treatment of DED. P2Y 2 receptor agonists are now under study. They are believed to help coordinate mucosal hydration and mucociliary clearance in the eyes and other organs. Diquafosol (INS365) is an ophthalmic preparation in development to help stimulate the P2Y 2 on the ocular surface and eyelid to increase secretion of mucin, salt, lipids, and water. It is currently awaiting FDA approval.

Topical androgens are also under investigation and may demonstrate some relief from DED, especially in perimenopausal and postmenopausal women. Acetylcysteine eye drops have been compounded for many years and are believed to be of some assistance in patients with DED, although their use is very limited with the currently available options.

TREATMENT RECOMMENDATIONS BASED UPON ITF GUIDELINES

Guidelines from ITF were developed classifying DED on severity levels (1 to 4) based upon signs and symptoms. The ITF guidelines also recommended treatment based upon the severity level and the presence or absence of lid margin disease (Table 2). The Dry Eye Workshop (DEW) report later published a modified DED grading scheme similar to the ITF recommendations but more specific for the clinician.⁵ The ITF and the DEW reports have helped eye care professionals to more appropriately grade patients with DED.

A recent study utilizing the ITF guidelines enrolled 183 patients for treatment of DED.²⁸ ITF guidelines were implemented for three months in newly diagnosed patients. Of the patients enrolled, 70% were without lid margin disease (LMD) and 74% (124/167) had no apparent ocular surface inflammation. Thirty-five percent presented in severity level 1 and 91% had no LMD or apparent inflammation. Fifty-nine percent presented in severity level 2 with no LMD present in 58% but 74% presented with inflammation. Punctal plugs were placed in only 2 of 183 subjects after cyclosporine administration to prevent inflammatory factors from remaining on the ocular surface. Physicians believed that if artificial tears and patient education did not resolve severity level 1 complaints, they were more likely to use cyclosporine earlier to interrupt inflammatory cycles and to prevent disease progression.

PATIENT INFORMATION AID ON DRY EYE DISEASE What is Dry Eye Disease (DED)? DED occurs when the eye does not produce tears properly, or when the tears are not of the correct consistency and evaporate too quickly. In addition, inflammation of the surface of the eye may occur along with DED. If left untreated, this condition can lead to pain, ulcers, or scars on the cornea, and some loss of vision. However, permanent loss of vision from DED is uncommon. DED can make it more difficult to perform some activities, such as using a computer or reading for an extended period of time, and it can decrease tolerance for dry environments, such as the air inside an airplane. Are There Other Names for DED? DED is sometimes called dry eye syndrome, keratoconjunctivitis sicca (KCS), dysfunctional tear syndrome, lacrimal keratoconjunctivitis, evaporative tear deficiency, aqueous tear deficiency, and LASIK-induced neurotrophic epitheliopathy (LNE). What Are the Types of DED? There are two basic types of DED. Aqueous tear-deficient dry eye is a disorder in which the lacrimal glands fail to produce enough of the watery component of tears to maintain a healthy eye surface. Evaporative dry eye may result from inflammation of the meibomian glands, also located in the eyelids. These glands make the lipid or oily part of tears that slows evaporation and keeps the tears stable. Who Is Likely To Develop DED? Elderly people frequently experience dryness of the eyes, but DED can occur at any age. Nearly five million Americans 50 years of age and older are estimated to have DED. Of these, more than three million are women and more than one and a half million are men. Tens of millions more have less severe symptoms. DED is more common after menopause. Women who experience menopause prematurely are more likely to have eye surface damage from DED. What Are the Symptoms Associated with DED? Symptoms associated with DED may include any of the following: Stinging or burning of the eye A sandy or gritty feeling as if something is in the eye Episodes of excess tears following extended periods of DED A stringy discharge from the eye Pain and redness of the eye Episodes of blurred vision Heavy eyelids Inability to cry when emotionally stressed Uncomfortable contact lenses Decreased tolerance of reading, working on the computer, or any activity that requires sustained visual attention Eye fatigue What Medication Is Used To Treat DED? Depending on the causes of DED, your eye care professional may use various approaches to relieve the symptoms. DED can be managed as an ongoing condition. The first priority is to determine if a disease is the underlying cause of the dry eye (such as Sjögren's syndrome or lacrimal and meibomian gland dysfunction). If it is, then the underlying disease needs to be treated. Cyclosporine (Restasis®), an anti-inflammatory medication, is the only prescription drug available to treat DED. It decreases corneal damage, increases basic tear production, and reduces symptoms associated with DED. It may take three to six months of twice-a-day dosages for the medication to work. In some cases of severe DED, short-term use of corticosteroid eye drops that decrease inflammation is required. If DED results from taking a medication, your eye care professional may recommend switching to a medication that does not cause the dry eye side effect. Adapted from the National Eye Institute, National Institutes of Health

RECOMMENDATIONS FOR PHARMACISTS

Since pharmacists are the most readily available healthcare professionals, it is natural that they would encounter patients with DED who have questions about treatment and appropriate product selection. There are a number of areas that pharmacists should consider before making a recommendation of an artificial tear product to a patient.

Referral or Self-Treatment

It is very important for pharmacists to be cognizant of new treatment advances in DED. Patients who come into the pharmacy for recommendation of an artificial tear product should be asked some simple questions. It would be reasonable to ask patients about their symptoms, assessing why they are considering use of or are currently using an artificial tear product. If patients are using an artificial tear product more than four times daily, it may be time to refer them to their eye care professional for further evaluation.

Patient Education

Patient education on the proper use of eye drops is helpful. Patient instruction and tables providing information on various ophthalmic products are available from the American Pharmacists Association Handbook of Nonprescription Drugs.²⁹ Patients may especially be concerned about the use of an eye ointment or gel and some reassurance that these are safe products to use in the eye may go a long way to help comfort them.

Nonpharmacological recommendations discussed earlier are reasonable to put in place for patients with DED. Nutritional interventions such as the use of omega-3 oils in flaxseed and fish oil seems reasonable to promote lid health. Lid scrubs with non-irritating soaps and warm compresses may also be of benefit to patients with lid disease.

Patients with concurrent ocular allergies may benefit from OTC topical eye drops to reduce symptoms of itching and redness. Patients should be instructed that OTC decongestant eye drops used to “get the red out” are usually detrimental to DED because these products often cause ocular drying and rebound hyperemia. A medication history including OTC medications is helpful to determine if certain medications may be exacerbating dry eye including antihistamines or other agents that possess anticholinergic effects.

Monitoring

Pharmacists noting frequent purchases of various dry eye products may wish to question patients about their DED. In some cases if patients receive little or no relief it may be important to refer them to see an eye care professional to rule out other ocular disease. If pharmacists note on prescription review that some medications may be exacerbating DED in these patients, it would be worth mentioning to these patients. If patients have used OTC decongestant drops for a prolonged period of time, they should probably be referred to an eye care professional.

Economic Considerations

Artificial tear products can be expensive and the proper use of these products may reduce cost. Unit dose artificial tear products are often more expensive than multi-dose bottles and the cost savings can be significant.

For those patients having punctal plugs placement, it may be more cost effective to have them treated with topical cyclosporine prior to punctal plug insertion. A recent study of a large commercial health plan suggested that the use of topical cyclosporine (step 2) prior to the insertion of punctal plugs (step 3) could result in a saving in overall treatment costs.³⁰ Approximately 21% of patients receiving punctal plugs subsequently received cyclosporine whereas only 11% of cyclosporine patients subsequently received punctal plugs. A retrospective study reviewing medical records concluded that after cyclosporine therapy was started patients had improvement in DED corneal staining and symptoms, and used fewer topical medications.³¹ Total medication orders dropped 55% among cyclosporine patients. In addition, there was less drug use for all categories (artificial tear products, NSAIDs, antibiotics plus steroids, steroids, antibiotics, and antihistamines) of topical medications (P=0.003) except for glaucoma medications, which did not change significantly.

A retrospective study analyzing real world patterns of cyclosporine use found that the majority of patients (73%) use one vial per day rather than the labeled amount of two vials per day.³² Real world utilization patterns may demonstrate how patients may further reduce costs surrounding their prescription medications.

Patient Adherence with Long-Term Use

Because cyclosporine provides relief of the underlying pathophysiology of DED, it has the potential to provide long-term relief, especially if or when the disease worsens. Pharmacists must reinforce the importance of continuing on cyclosporine even if there are some minor complaints of burning and stinging.

The vehicle of cyclosporine (Restasis^®) in the treatment of DED may provide immediate symptomatic relief, just as with any other artificial tear product. The pharmacologic effects of cyclosporine may take from a month to up to six months for full relief depending upon the severity of the DED. Therefore, patients must realize this is not an artificial tear product but a medication for the treatment of DED and, eventually, there should be relief from any complaints of burning and stinging.

CONCLUSION

Patients may seek assistance from pharmacists due to complaints of dry eye prior to being seen by an eye care professional. DED is a chronic disease that may wax or wane but often worsens over time. Pharmacists educated on new treatment guidelines for DED can help patients find relief earlier and possibly slow the progression of DED. Pharmacists may also intervene when patients are improperly using eye drops or systemic medication that may actually cause an increase in symptoms of DED and may exacerbate it. Over the long term, control of DED is possible but patient adherence and understanding is critical. Pharmacists are in an ideal position to be able to provide excellent education and recommendations for patients with DED.

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