allergy issue of cornea & contact lenses · nus ranging from age 25 to 51. patients were...

ALLERGY ISSUE

INSIDE:Scratching the Itch:Ocular Allergy and Contact Lenses P. 8

DOUBLE TROUBLE:When Allergy andDry Eye Coexist P. 10

EnvironmentalConsiderations:How the World andthe Ocular SurfaceRelate P. 14

Understanding OphthalmicAntihistamines andHistamine Receptors P. 18

STAYING ON TARGET:Managing the ComplexAllergic Reaction P. 24

Are You Allergicto Change? P. 34

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RCCLRCCLREVIEW OF CORNEA & CONTACT LENSES

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Review of Cornea & Contact Lenses | March 2016

departments

contents

features

10Double Trouble: When

Allergy and Dry Eye CoexistIf one presents hand-in-hand with the other, use these tips to diff erentiate and resolve.By Heidi Wagner, OD, MPH

14Environmental Considerations: How the World and the Ocular Surface RelateKeeping in mind potential external factors can help you better regulate your patient’s health.By Harry M. Green, OD, MPH

24CE — Staying on Target: Managing the Complex Allergic ReactionUnderstanding the pathophysiology of ocular allergic responses is paramount to determining optimal therapy. Here’s a review. By Gregory A. Caldwell, OD

News Review4Promising New Dry Eye Therapy;

Scleral Lens Treatment for

Keratoconic Dry Eye?

My Perspective 6Contact Lens Biosensors:

The Holy Grail?

By Joseph P. Shovlin, OD

Practice Progress8Scratching the Itch

By Mile Brujic, OD, and Jason R. Miller, OD, MBA

Springtime for Sclerals

By Robert Ensley, OD, andHeidi Miller, OD

Pharma Science & Practice32

The GP Experts30

A Firm Foundation

By Elyse L. Chaglasian, OD, and Tammy Than, MS, OD

Are You Allergic to Change?

By Gary Gerber, OD

Out of the Box34

18Understanding Ophthalmic Antihistamines and Histamine Receptors Experts discuss the complex mechanics of the human allergic reaction.By Brett P. Bielory, MD, Steven Shah, MD,

and Leonard Bielory, MD

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4 REVIEW OF CORNEA & CONTACT LENSES | MARCH 2016

News Review

Promising New Dry Eye Therapy

Application of topical tumor necrosis factor (TNF)-stimulated gene protein-6 (TSG-6) may

be a suitable alternative to cyclo-sporine use in patients with infl am-mation-mediated dry eye, suggests a study published online in the journal Cornea.1 Previous research on the protein produced by mesenchymal stem/stromal cells within the body has indicated therapeutic effects in animal models of the heart, cornea, brain and other organs; however, further research and widespread clinical application remains limited due to production issues and varia-tions in chemical stability.2,3

In this investigation, researchers at Seoul National University Hospital in Korea divided NOD.B10.H2b-infected mice into four subgroups characterized by administration of one of four treatments for a peri-od of seven days. The NOD.B10.H2b strain manifests clinical signs in mice similar to that of Sjögren’s syndrome in humans.

Treatments included recombi-nant TSG-6 (i.e., 1µg in a 10µL phosphate buffered solution) QID, Restasis (0.05% cyclosporine oph-thalmic emulsion, Allergan) BID, Pred Forte (1% prednisolone) QID and phosphate buffered solution QID. Currently, Restasis and Pred Forte are considered standards of infl ammation-mediated dry eye treatment; however, certain imme-diate side effects, including ocular stinging and burning, as well as the longer-term issues associated with corticosteroid use, make these treatments somewhat controversial. An additional group of C57BL/6-infected mice was used for control purposes.

At start, all NOD.B10.H2b mice

exhibited similar decreased tear production in comparison with the control group; however, following the seven-day administration period, tear production of NOD.B10.H2b mice receiving the TSG-6, Restasis and Pred Forte treatments was markedly increased in comparison with that of the NOD.B10.H2b mice receiving phosphate buffered solution. All remained below that of the control group, however. Researchers also noted levels of proinfl ammatory cytokines TNF and INF were reduced following treatment with the three aforemen-tioned applications.

With respect to corneal stain-ing, both the NOD.B10.H2b mice receiving TSG-6 and those receiving Restasis had decreased levels, while those receiving Pred Forte did not.

“Together, data demonstrated that topical administration of 0.1% TSG-6 was as effective in improving signs of DED as 0.05% cyclospo-rine or 1% prednisolone ophthalmic solution,” the researchers say. “In addition, both TSG-6 and cyclospo-rine signifi cantly reduced punctate corneal epithelial staining, but prednisolone did not.” These results suggest TSG-6 could be considered as a future dry eye treatment on par with cyclosporine; further study, however, on the effects of TSG-6 on dry eye parameters like tear fi lm stability and tear osmolarity are nec-essary, as is investigation into mass production. RCCL 1. Kim YJ, Ryu JS, Park SY, et al. Comparison of topical application of TSG-6, cyclosporine and pred-nisolone for treating dry eye. Cornea. 2016. [epub ahead of print]. 2. Milner CM, Higman VA, Day AJ. TSG-6: a plurip-otent infl ammatory mediator? Biochem Soc Trand. 2006;34:446-50.3. Prockop DJ. Concise review: two negative feed-back loops place mesenchymal stem/stromal cells at the center of early regulators of infl ammation. Stem Cells. 2013;31:2042-46.

IN BRIEF

■ A once-rare pathogen may be more prevalent than initially believed in cases of fungal keratitis, reports new research published online in Cornea.1 Researchers identifi ed 47 of 1,542 culture-proven cases of keratomycosis as being caused by Exserohilum, which is generally associated with paranasal sinus, skin and subcutaneous infections.

“To our knowledge, this is the largest

case series so far on keratitis caused by Exserohilum,” the researchers say. Pa-tients in hot and humid areas appear to be most at risk, and further research is necessary to identify the best treatment protocols.

1. Rathi H, Venugopal A, Rameshkumar G, et al. Fun-gal keratitis caused by Exserohilum, an emerging pathogen.

■ Moisture chamber spectacles (MCS) may be useful to treat dry eye, suggests a study in the February 2016 issue of Optometry & Vision Science.1 Research-ers in China randomized 30 patients with dry eye into a group instructed to wear MCS for 90 minutes and a second group instructed to instill a drop of ster-ile non-preserved 0.9% sodium chloride

solution. Results indicated improve-ments in ocular comfort, tear meniscus height (TMH) and noninvasive tear fi lm break-up time (NIBUT) in the former.

“The present study is the fi rst to show that the use of MCS had a signifi cant positive eff ect on TMH and NIBUT, demonstrating that tear fi lm stability was improved after MCS wear,” the researchers say. “MCS may be a safe and

promising alternative treatment for dry eye, especially for patients who work in adverse environmental conditions.” 1. Shen G, Qi Q, Ma X. Eff ect of moisture chamber spectacles on tear functions in dry eye disease. 2016 Feb. 93(2):158-164.

■ Bausch + Lomb has announced the release of new Ultra lenses for Presby-

opia. The multifocal lenses are specifi -cally designed to combine the compa-ny’s three-zone progressive design in the Biotrue OneDay for Presbyopia daily disposable lenses with its MoistureSeal lens technology.■ Blanchard Contact Lenses has an-nounced its list of cities and dates for the 2016 Beyond the Limbus Scleral

Lens Workshop tour. A component of the company’s educational division for the sixth year running, the workshops are designed to provide scleral lens training for eye care practitioners. The list is available at blanchardlab.com/blanchard-u/events-education/.

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Scleral Lens Treatment

for Keratoconic Dry Eye?

Short-term scleral contact lens wear may be benefi -cial for patients with ker-atoconus who also suffer

from dry eye, reports a study in the February 2016 Optometry & Vision Science.1 The rigid lenses are currently indicated for use in patients with severe corneal irregularities, including keratoco-nus, and have also been slated as a means to manage dry eye due to their ability to improve ocular surface integrity. To date, how-ever, no study has investigated the effects of scleral lens wear on the ocular surface physiology of patients with keratoconus.

In an effort to remedy this discrepancy, researchers at the Complutense University of Madrid in Spain conducted an experimental pilot study involv-ing 26 patients with keratoco-nus ranging from age 25 to 51. Patients were separated into those with an intrastromal corneal ring, and those without; each was fi t with a 16.5mm scleral lens design that provided clearance thickness between 300µm and 400µm.

The research team administered the Ocular Surface Disease Index (OSDI) questionnaire and mea-sured tear osmolarity, Schirmer score, tear break-up time, matrix metalloproteinase-9 (MMP-9) concentration and Ap4A con-centration before and after eight hours of lens wear. No signifi cant changes were identifi ed during the Schirmer test and tear break-up time following lens wear. OSDI scores and osmolarity were lower and MMP-9 concentration was higher, however, in both groups

following lens wear. Lastly, Ap4A concentration was lower follow-ing lens wear in the keratoconus group, but not the corneal ring group. These results, the research-ers say, demonstrate that “symp-tomatology, osmolarity and Ap4A concentration decrease after short-term scleral lens wear in KC patients, but MMP-9 concentra-tion rises signifi cantly.”

The researchers note that the lenses used in the study were manufactured using a high Dk material and 0.3mm of central thickness. “There is no evidence of the infl uence of the physical properties and scleral lens design over the ocular surface physiol-ogy,” they say. “In the future, however, it might be interesting to evaluate the differences between different scleral lens designs, taking into account the central thickness, overall diameter and adaption period.

“In conclusion, short-term scleral lens wear improves the symptomatology and some signs of dry eye, such as osmolarity and Ap4A concentration, in keratoconus patients. However, there is an increase of MMP-9 concentration, probably because of tear fi lm stagnation and the use of preserved saline for fi lling the lenses.” RCCL

1. Carracedo G, Blanco MS, Martin-Gil A, et al. Short-term eff ect of scleral lens on the dry eye biomarkers in keratoconus. 2016 Feb;93(2):150-7.

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By Joseph P. Shovlin, OD

My Perspective


There exists a fascinating observation in technol-ogy circles known as Moore’s Law, which states that the number

of transistors in a computer chip doubles every two years. In that same vein, the law also indicates that the size of computer chip circuitry like processors, sensors and memory storage is also cut in half every two years. Moore’s Law has held true since its original formula-tion in 1965, and Intel predicts that 10nm computer chips will arrive within the next few years.1 Such an advancement could have profound implications for integrating biosen-

sors into contact lenses, allowing for revolutionary applications like monitoring the levels of glucose in a diabetic patient.

Comprised of a number of differ-ent components, the tear fi lm has enormous potential to provide us with valuable medical information about the health and wellbeing of the patient. A contact lens used as a biosensor could easily capture data on the various proteins, enzymes, lipids and salts within the tear fi lm and translate it to practitioners in real time.2 Prototype biosensor lenses have already been used to in-

vestigate glucose levels and monitor intraocular pressure.2-4

POTENTIAL SETBACKS

Measuring tear glucose levels using diagnostic devices is not a new con-cept. Reports of this technique being used date back at least two decades, and biosensor patents are a dime a dozen. Yet, some obstacles remain in the path of bringing such a device to market. The fi rst is the problem of technology: glucose-monitoring contact lens devices are not yet refi ned enough for marketable use. In fact, the only contact lens device currently on the market is used to assess intraocular pressures.

The second hurdle that must be overcome is more practical—sup-ply and demand for such a device. Aside from considerations like manufacturing costs, there are a handful of medical conditions that would actually benefi t from—or even require—continuous monitor-ing. Developing devices that require FDA approval for marketing is an expensive initiative. Accordingly, potential sponsors or manufac-turers may be reluctant to commit the funding needed to bring such a product to market.2

Despite these issues, however, it’s

no surprise that contact lens bio-sensors are still viewed with excite-ment. Several different types have been considered, including colo-rimetric fl uorescent sensors and elec-trochemical contact lenses sensors.2

Another question remains, however: what impact will alternative wireless continuous monitors (for measur-ing other body fl uids as well) have on the future development of lens sensors? Alternative devices are al-ready available for patients using an insulin pump or other attachment devices worn on the arm or abdo-men.2,3 Other concerns relate to the variability of tear compositions and lag time for biomarkers to appear in tears compared with blood serum levels and the lag in recording time.2,3

I remain optimistic that as this technology evolves, contact lenses

will eventually be used beyond their current indication for glaucoma and diabetes. Time will tell if we truly reach the “Holy Grail” or whether alternative devices will overtake the quest for the best contact lens biosensor in the diagnostic sector. For now, we’ll continue to watch as the story unfolds and prototypes advance. RCCL

1. Clark D. Intel Rechisels the Tablet on Moore’s Law. Wall Street Journal, July 16, 2015, Available at: blogs.wsj.com/digits/2015/07/16/intel-rechisels-the-tab-let-on-moores-law/.2. Phan CM, Subbaraman L, Jones LW. The use of contact lenses as biosensors. Optom & Vis Sci. 2015 Dec. [Epub ahead of print].3. Kudo, H, Arakawa T, Mitsubayashi K. Status of soft contact lenses biosensor development for tear sugar monitoring: A review. Wiley Peer Review Resources. 2014 Nov.4. Zhang J, Hodge W, Hutnick C, Wang X. Non-invasive diagnostic devices for diabetes through measuring tear glucose. J Diabetes Sci Technol. 2011 Jan 1;5(1):166-72.

“Data on demand” could revolutionize the care of patients with diabetes or glaucoma.

Contact Lens Biosensors:Finding the Holy Grail?

“THE HUMAN TEAR FILM HAS ENORMOUS POTENTIAL TO PROVIDE US WITH VALUABLE

MEDICAL INFORMATION.”

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By Mile Brujic, OD, and Jason Miller, OD, MBA

Practice Progress


Scratching the ItchOcular allergies can complicate contact lens fi ttings. Here’s how to manage them.

Congratulations, you have ocular allergies. Most eye care pro-fessionals have never

uttered this statement offhand to their patients, but for those with ocular allergy sufferers who may be interested in wearing contact lenses, it’s an important point to consider. Proactively identifying contact lens candidates who may experience allergy-related dis-comfort gives us the opportunity to turn a possible negative into a positive before it becomes a larger issue.

Treating current lens wearers’ ocular allergies will also allow those who are experiencing limited wearing success to more comfortably enjoy the benefi ts of contact lens wear. Some of these patients may have been told by other eye care professionals that nothing can be done to ease their symptoms and may have resorted to dropping out of contact lens wear during allergy season to avoid discomfort. So, if you are able to offer the possibility of comfortable contact lens wear during allergy season, you may very easily earn yourself a lifelong patient. But, how do you achieve this? Here are some tips to help you manage this unique group of patients.

1. Ask the right questions at the right time. Many practi-

tioners employ technical staff to discuss symptoms with the patient at the beginning of the exam and help administer medication as needed. While patients who

present with an ocular infection typically report continual symp-toms during the period of infec-tion, patients with ocular allergies may only experience symptoms during certain times of the year—which may not be during the time of their exam. These patients often neglect to mention their allergies when discussing their eye history for the simple reason that it slips their mind, so tailor your symptom questionnaire to catch them even during the offseason. By asking the right questions, you may be surprised how many aller-gy sufferers go undiagnosed and untreated in your practice.

Even if the patient indicates no allergy-related discomfort (i.e., their contact lenses become more diffi cult to wear during certain times of the year, or while in their

work environment), make sure to ask follow-up questions during the anterior ocular exam. Peek around the slit lamp and ask, “Do your eyes ever burn, itch or water, or do your eyelids ever swell or turn red?” Look closely for mild eyelid and conjunctival edema and/or redness (Figure 1).

Evert the upper and lower eyelids to reveal the presence of papillae or other complicating factors. These can often be seen more easily when visualized with the use of fl uorescein. You can also follow up with, “Do you ever experience intermittent blur with your contact lenses during certain times of the year?” These fac-tors, while not directly related to contact lens comfort, can also be indicative of possible allergies that may eventually lead to lens issues.

Fig. 1. Inferior palpebral conjunctival papillae and redness due to ocular

allergies.

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2. Address the issue and treat the underlying condition.

Patients are often surprised to hear that their allergies are responsible for their issues with contact lens wear, especially if the reaction is mild. Once informed of their diagnosis, however, they are now aware and looking for solutions. Take the appointment a step further by informing them that there are still possible contact lens options.

Daily disposables are one suit-able option for patients who suffer from ocular allergies. Because surface allergens do not build up on these daily replacement lens-es, patients’ clinical reactions are limited.1 Additionally, there are no compliance issues that could further aggravate a patient’s aller-gic reaction because a clean lens is placed on the eye each day. If your patients have not heard about these lenses already, this is an ideal time to educate them.

3. Individualize the approach.In some cases, the patient’s

contact lens fi tting and allergic treatment regimen may collide. This is because the presence of ocular allergies may decrease lens awareness or reduce vision during the fi tting, complicating the process. Also, if the patient is using topical steroids through-out the day, lens wear would be contraindicated.

This is the time to customize a treatment plan according to the patient’s particular needs. Take a step back and explain to them how their allergic condition may need

specifi c medical attention (and not just an OTC product) and what steps would be required to clear it. For example, they may need to remove their lenses for a period of time, treat the allergic state and then consider other lens options. Be sure to stress that the treatment will help them with symptoms.

CASE IN POINT

A 26-year-old female patient presented complaining of frequent itching and burning. She reported using OTC Visine-A Allergy Relief Drops (Johnson & Johnson) to no relief. She is an IT consultant who has never worn contact lenses be-cause she was informed in the past she could not wear them. During her examination, it was evident ocular allergies were the cause of her issues. Her inferior palpebral conjunctiva was red, infl amed and chemotic in both eyes (Figure 2).

The patient was treated with a topical ocular steroid for two

weeks, then moved to a daily antihistamine/mast-cell stabilizer for maintenance. After fi nishing the steroid eye drops, she was successfully fi t into hydrogel daily disposable lenses. This made a huge difference in her ocular irrita-tion, even compared to no contact lenses. She had less allergic symp-toms throughout the day, and she enjoyed the convenience her new daily contact lenses provided.

Above all, the challenge with current contact lens wearers

and allergy sufferers is identifying allergies as the underlying cause of symptoms. Many eye care profes-sionals look to place the “blame” on their patient’s current contact lenses. Instead, consider identifying and treating any underlying condi-tions prior to a successful contact lens fi t. RCCL

1. Stiegemeier M, Thomas S. Seasonal allergy relief with daily disposable lenses. Contact Lens Spect. 2001:April;16(4):24-8.

Fig. 2. Conjunctival injection and chemosis from an ocular allergic reaction.

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Though El Niño tempered this year’s winter weather in parts of the country, the promise of spring is still

an inviting one. For many patients, spring means warmer temperature and more daylight—and more time spent outdoors. As such, spring can also mean an exacerbation of the itchy, red and watery eyes common-ly associated with seasonal aller-gic conjunctivitis. While “allergy season” is often attributed to the increased presence of airborne pol-len in the spring, many symptomat-ic patients continue to present into summer and autumn, depending on local climate and temperature.

Allergic conjunctivitis may not be the only culprit responsible for seasonal discomfort, however: recent research still indicates a clear seasonal pattern with respect to presentations of dry eye, as the condition was most common in the winter and spring and least com-mon in the summer.1 The pattern was ascribed to low humidity in the winter and seasonal allergens in the spring; as such, the fi ndings suggest allergy may not be the only factor in seasonal eye disease.

When an affected patient presents to the clinic, clinicians must ask: Is it allergy or dry eye—or both? Reviewing the epidemiology, clinical examination and treatment of both allergic conjunctivitis and dry eye can further our understanding of these coexisting conditions and help clarify a diagnosis. Additionally, recognizing how each can present

clinically and identifying which pa-tients are most likely to be affected can help guide providers in tailoring the treatment regimen to the indi-vidual patient.

DEFINING THE CONDITION

The International Dry Eye Workshop (DEWS) classifi ed dry eye as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear fi lm instabil-ity that may cause damage to the ocular surface. It is accompanied by increased osmolarity of the tear fi lm and infl ammation of the ocular sur-face.2 Similarly, the committee iden-tifi ed allergic conjunctivitis as an extrinsic cause of dry eye. In their model, conjunctival and corneal irregularities (e.g., punctate keratitis and shield ulcers) can destabilize the tear fi lm and contribute to dry eye.2,3 In chronic disease, meibo-mian gland dysfunction further contributes to dry eye by interfering with the lipid layer of the tears.

These defi nitions suggest that the two conditions share elements of the underlying disease process and reinforce that infl ammation is a key component of both. For example, a past study of allergic conjunctivitis reported that patients with itchy eyes were more than twice as likely to experience dry eye as patients with non-itchy eyes.4 As such, signifi cant symptoms of itching in conjunction with dry eye may also suggest coexisting atopic disease. Patients with allergic conjunctivitis

who exhibit disruptions in tear fi lm integrity, symptoms of burning or both may also be suffering from coexisting dry eye disease.

PATTERNS OF PREVALENCE

Although it’s diffi cult to isolate the affected populations for conditions as common and multifactorial as allergy and dry eye, some epidemio-logic patterns have been document-ed in the literature.

• Allergic Conjunctivitis.Conventional wisdom holds that approximately 15% to 20% of the United States population suffers from ocular allergy.5 However, 40% of the participants in the third National Health and Nutrition Examination Survey reported symptoms of ocular allergy at least once during the previous year.6

Older allergy suffers (those above age 50) were more likely to report isolated ocular symptoms, while younger suffers were more likely to report nasal and ocular symptoms. This observation is consistent with the present understanding that dry eye tends to increase with age while

ABOUT THE AUTHOR

Dr. Wagner is a professor of

clinical optometry at Ohio

State University, where

she also serves as the

director of extern programs.

She is a diplomate in the

Cornea, Contact Lenses

and Refractive Technologies

Section of the American

Academy of Optometry and a member of

the American Optometric Contact Lens

Educators, the American Optometric

Association and the Association for Research

in Vision in Ophthalmology.

If one presents hand-in-hand with the other, use these tips to diff erentiate and resolve.

By Heidi Wagner, OD, MPH

DOUBLE TROUBLE:When Allergy and Dry Eye Coexist

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symptoms related to atopy tend to decrease with age.6 It’s also note-worthy that seasonal and perennial allergic conjunctivitis is often pres-ent in both genders from childhood through middle age, while vernal keratoconjunctivitis is more likely to present in young males under the age of 18 years.7 Allergic conjunc-tivitis is often associated with nasal symptoms and history of prior aller-gic events.8

• Dry Eye. This condition has been reported in 5% to 30% of the population. Variations in these estimates may be the result of differing diagnostic criteria across studies. Importantly, low estimates may refl ect patients with moderate to severe disease while high rates may also include patients with more mild forms of the condition.9

Large studies of dry eye, including the Women’s Health Study and the Physician’s Health Study, estimate that nearly fi ve million Americans age 50 or older suffer from moder-ate to severe dry eye, with approx-imately twice as many women as

men presenting with the condition.10,11

In addition to female gender and older age, other reported risk factors for dry eye include LASIK and refractive excimer laser surgery, connective tissue disease, antihista-mine use, radiation therapy, hema-topoietic stem cell transplantation, vitamin A defi ciency, hepatitis C infection and androgen defi ciency.9

IDENTIFYING THE CULPRIT

Symptoms of allergic conjunctivitis include tearing, itching, burning, foreign body sensation and dryness. The clinical exam should begin with a thorough case history, followed by a careful physical evaluation. A personal or family history of atopic disease is common and may occur in isolation or with nasal symp-toms. Signs of allergic conjunctivitis include conjunctival hyperemia and chemosis, papillae, lid edema and watery discharge.

While pollen is a trigger of sea-

sonal allergic conjunctivitis, other environmental irritants such as pet dander and mold can also exacerbate symptoms. The presence of large papillae at the upper tarsal conjunctiva or limbus is a hallmark of the vernal form of the disease.

If itching is considered the hallmark symptom of allergy, then burning and foreign body sensa-tion are preeminent symptoms of dry eye. While there is variation in clinical practice, most clinicians use a variety of measures to diagnose dry eye. Clinical observations typically include severity and fre-quency of ocular discomfort, visual symptoms like fl uctuating vision, conjunctival and corneal staining, conjunctival injection and disrup-tions in tear fi lm quantity, quality or both. Common measures of health and tear fi lm integrity include tear break-up time, tear meniscus, Schirmer’s or phenol red thread test and rose bengal or lissamine green. Less commonly available measures include tear osmolarity and impres-sion cytology.

Examination typically includes lids and lashes due to their direct infl uence on the tear fi lm. Recently, this examination includes sur-veillance for Demodex due to the association of these mites with mei-bomian gland dysfunction. While Demodex is diffi cult to view during a standard biomicroscopic exam, clinicians should be aware that cylindrical dandruff at the base of the lash and peculiar skin debris are associated with the condition.2

Point-of-care tests like matrix metalloproteinase 9 (MMP-9), while non-specifi c, can be used to

Diff erentiating between dry eye and allergic conjunctivitis can take

some eff ort. Which one is present here?



support a diagnosis and to iden-tify patients who would benefi t from anti-infl ammatory therapy.12

Similarly, tear osmolarity testing can be used for both initial diagno-sis and for monitoring the treatment response of patients with dry eye.

The two traditional classifi cations of dry eye—aqueous tear-defi cient and evaporative dry eye (intrinsic and extrinsic)—are based upon etiology.13 However, recent work suggests that as dry eye progress-es, hybrid forms of the condition can develop.14 Identifi cation may require the practitioner to prescribe additional treatment modalities to address the spectrum of disease. Thus, advanced aqueous-defi -cient dry eye includes meibomian gland dysfunction and vice-versa. Furthermore, there has been a shift in emphasis from the aqueous-defi -cient model of dry eye to a lipid-de-fi cient evaporative dry eye model that is associated with meibomian gland dysfunction. As a result, current treatments emphasize the strategies typically recommended for evaporative dry eye.

TREATING THE DISEASE

Clinicians and patients are for-tunate to have a multitude of treatment options that range from simple lifestyle adjustments and home remedies to over-the-counter or prescription medications:

• Allergic Conjunctivitis.Avoidance of the allergen, cool compresses and preservative-free lubricants may suffi ce for some patients. When these non-pharma-cological treatments are inadequate, topical antihistamines, mast-cell stabilizers and nonsteroidal anti-in-fl ammatory agents make up the mainstay of treatment for allergic conjunctivitis due to their effi ca-cy and safety profi le. Short-term judicious use of steroids for patients with severe allergic conjunctivitis is

commonly advocated when other treatments are inadequate. Newer corticosteroids provide signifi cant relief with fewer side effects (e.g., ocular hypertension, cataract and infection), but still require supervi-sion by an eye care provider.

Contact lens wear may require modifi cation depending on its asso-ciation with symptoms of allergic conjunctivitis. Lens wear may even need to be discontinued temporar-ily. Reducing lens wearing time, in-creasing lens replacement frequency (in particular, advocating single-use lenses during allergy episodes) and prescribing a preservative-free lens care regimen are management op-tions for mild to moderate presenta-tions of allergic conjunctivitis.

• Dry Eye. Often, signs and symptoms of dry eye do not cor-relate. This requires the clinician to take a holistic approach in assess-ing disease severity and initiating treatment. Treatment regimens can then be modifi ed based upon the patient’s initial response. Preservative-free artifi cial tears, gels and ointments are the mainstay of dry eye treatments. In addition to tear supplements, management often includes modifi cation of the environment (e.g., adjustments to humidity and temperature) and treatment of any complications like punctate keratopathy, fi lamentary keratitis or vision problems.

Cyclosporin A has tradition-ally been indicated to suppress infl ammation in the aqueous-defi -cient form of dry eye. In contrast, evaporative dry is managed using therapies that target meibomian gland dysfunction such as gland expression and heat application. Eyelid scrubs and mechanical devices like LipiFlow (TearScience) can also help manage evaporative dry eye. Treatment may also include topical or oral antibiotics with anti-infl ammatory properties. As

with allergic conjunctivitis, topical corticosteroids may also be used for short-term therapy to increase overall treatment effi cacy.

Adjunctive therapy may include nutritional support (i.e., ingestion of fi sh oil and omega-3 fatty acids to reduce infl ammation) and patient education regarding avoidance of preservatives and other envi-ronmental irritants. Tea tree oil treatments and lid scrubs have been advocated to eradicate Demodexand ocular infl ammation associ-ated with this condition.15 While mild dry eye may benefi t from the previously described modifi cations in contact lens wear, scleral lenses have been used successfully as a treatment option to ameliorate the signs and symptoms of moderate to severe dry eye.16

NEW OPTIONS

Additionally, there are a number of emerging treatments for both dry eye and allergic conjunctivitis. These build on existing treatment regimens and our understanding of the immunopathophysiology for both diseases. With the recognition that dry eye and allergic conjunc-tivitis coexist, pharmaceutical management can target both diseas-es.15,17 Future treatments will likely target ocular surface infl ammation with fewer side effects than with traditional glucocorticoids.18

It is important to differentiate between these two overlapping conditions, considering both have signifi cant health indications. They are commonly encountered in clin-ical practice and have the potential to impair quality of life and incur signifi cant health care costs from professional services, therapies and pharmacological treatments.5,6,9,19-23

Recognition of the coexistence of dry eye and allergic conjunctivitis allows the eye care provider to treat the presenting problem more

DOUBLE TROUBLE: WHEN ALLERGY AND DRY EYE COEXIST


effectively. For example, dry eye treatments in the winter months could emphasize lubricants, while treatments in the spring and sum-mer could incorporate anti-infl am-matory agents.1

Perhaps most important, treat-ment options for one condition can actually worsen the coexisting condition. Case in point: aller-gic conjunctivitis treatments that emphasize the use of oral antihis-tamines may exacerbate dry eye symptoms.

Dry eye and allergic conjunctivi-tis can mean “double trouble.”

When the eye is dry, allergies tend to be worse, and the converse is also true. Therefore, clinicians should also be vigilant in their surveillance of dry eye and allergic conjunctivitis as comorbidities and modify treatment options accord-

ingly to address each in the best way possible. RCCL

1. Kumar N, Feuer W, Lanza NL, Galor A. Sea-sonal variation in dry eye. Ophthalmology. 2015;122(8):1727-1729.2. Hom MM, Mastrota KM, Schachter SE. Demodex. Optom Vis Sci. 2013;90(7):e198-e205.3. Abelson MB, Smith L, Chapin M. Ocular allergic disease: mechanisms, disease subtypes, treatment. Ocul Surf. 2003;1(3):127-49. 4. Hom MM, Nguyen AL, Bielory L. Allergic conjunc-tivitis and dry eye syndrome. Ann Allergy Asthma Immunol. 2012;108(3):163-6. 5. Rosario N, Bielory L. Epidemiology of allergic conjunctivitis. Curr Opin Allergy Clin Immunol. 2011;11(5):471-476.6. Singh K, Axelrod S, Bielory L. The epidemiology of ocular and nasal allergy in the United States 1988-1994. J Allergy Clin Immunol. 2010;126(4):778-783.7. Leonardi A, Piliego F, Castegnaro A, et al. Allergic conjunctivitis: a cross-sectional study. Clin Exp Allergy. 2015;45(6):1118-25. 8. Bielory L, Friedlaender MH. Allergic conjunctivitis. Immunol Allergy Clin North Am. 2008;28(1):43-58.9. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the Internation-al Dry Eye Workshop. Ocul Surf. 2007;5(2):93-107.10. Schaumberg DA, Sullivan DA, Buring JE, Dana MR. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136(2):318-26.11. Schaumberg DA, Dana R, Buring JE, Sullivan DA. Prevalence of dry eye disease among US men: estimates from the Physicians’ Health Studies. Arch Ophthalmol. 2009;127(6):763–8.12. Kaufman HE. The practical detection of mmp-9 diagnoses of ocular surface disease may help pre-

vent its complications. Cornea. 2013;32(2):211-6.13. The Defi nition and Classifi cation of Dry Eye Disease: Report of the Defi nition and Classifi cation Subcommittee of the International Dry Eye Work-Shop. 2007;5(2):75-92.14. Bron AJ, Yokoi N, Gafney E, Tiff any JM. Predicted phenotypes of dry eye: proposed consequences of its natural history. Ocul Surf. 2009;7(2):78-92.15. Thode AR, Latkany RA. Current and emerg-ing therapeutic strategies for the treatment of meibomian gland dysfunction (MGD). Drugs. 2015;75(11):1177-85.16. Bavinger JC, DeLoss K, Mian SI. Scleral lens use in dry eye. Curr Opin Ophthalmol. 2015;26(4):319-324.17. Syed BA, Kumar S, Bielory L. Current options and emerging therapies for anterior ocular infl am-matory disease. Curr Opin Allergy Clin Immunol. 2014;14(5):485-9.18. Nye M, Rudner S, Bielory L. Emerging therapies in allergic conjunctivitis and dry eye syndrome. Expert Opin Pharmacother. 2013;14(11):1449-65. 19. Palmares J, Delgado L, Cidade M, et al. Allergic conjunctivitis: a national cross-sectional study of clinical characteristics and quality of life. Eur J Oph-thalmol. 2010;20(2):257–264. 20. Miljanović B, Dana R, Sullivan DA, Schaumberg DA. Impact of dry eye syndrome on vision-related quality of life. Am J Ophthalmol. 2007;143(3):409-15.21. Schiff man RM, Walt JG, Jacobsen G, et al. Utility assessment among patients with dry eye disease. Ophthalmology. 2003;110(7):1412–1419.22. Reddy P, Grad O, Rajagopalan K. The economic burden of dry eye: a conceptual framework and preliminary assessment. Cornea. 2004;23(8):751-61.23. Syed BA, Kumar S, Bielory L. Current options and emerging therapies for anterior ocular infl am-matory disease. Curr Opin Allergy Clin Immunol. 2014;14(5):485-9.

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The ocular surface is part of a complex network of mucous membranes spread throughout the body. While membranes

exhibit similar essential charac-teristics, each has its own unique attributes as well. For example, the mucous membrane of the nose and throat produces signifi cant quantities of mucus to help enable the capture of airborne pathogens. Cilia then move the contaminated mucus upward, where it is expelled through the nose and mouth.

The eye is no exception to this, possessing a specialized epithelium that maintains and protects the ocular surface. However, because of the tremendous sensory advan-tage the eye’s external structures gives an individual, the conjuncti-val and corneal epithelium is also exposed to an almost constant environmental assault—more so than any other mucous membrane. Environmental toxins, ambient humidity and allergens in the envi-ronment are some of the assailants that must be defended against. This article discusses their effects and methods of patient management.1,2

HUMIDITY

Low ambient humidity can have a signifi cant effect on the tear fi lm evaporation and evaporative dry eye.3 Geographic considerations for humidity vary not only with

local weather patterns and with altitude. Humidity levels vary both with local weather patterns and altitude: as such, patients locat-ed in different areas of the vast and varied geographic makeup that comprises the United States may be affected differently. For example, as altitude increases, air pressure decreases, reducing the amount of water vapor the air can hold. Temperature has the inverse relationship, with air of a higher temperature able to contain more water than that of a colder temperature.

The importance of ambient humidity is often overlooked in patients with dry eye symptoms for one reason: it’s a local environ-mental factor that remains rela-tively consistent from day to day. Thus, it often fails to even register as an external infl uence. However, a factor that is easily augmented in both the home and work environ-ments with commercially available humidifi ers, which come in two basic varieties: heated and cool-mist. Heated humidifi ers produce warm steam and are highly effec-tive at quickly modulating indoor humidity. Cool-mist humidifi ers, in contrast, use ultrasonic pulses to create water vapor. While not as effective as heated humidifi ers, they are less likely to raise the temperature of the room or cause water to condensate on the walls.

ENVIRONMENTAL TOXINS

Chemical or irritative conjuncti-vitis may develop in response to signifi cant irritation brought on by environmental toxins. These include smoke, chlorine in swimming pools, air pollution and volatile organic compounds.4,5 Effective treatments include limiting exposure to the offending chemical, if possible, in-creasing local ventilation and wash-ing remaining toxins away from the ocular surface. In extreme cases this may require lavage, but generally frequent use of nonpreserved arti-fi cial tears is suffi cient and will not only help clear the toxin, but also help soothe the ocular surface.

ALLERGENS

Most common environmental irritants are not toxic in and of themselves; rather, the human body’s inappropriate infl ammatory response to them, known as allergy, is what results in discomfort. The word antigen is derived from the word antibody and the Greek suffi x -gen, meaning “that which induces production” of something (in this case, antibodies).

By Harry M. Green, OD, PhD

ENVIRONMENTALCONSIDERATIONS:

ByByBB HHHaraararaaarryryryryryy MMMMMMM GGrGrGreee nnnnn OOOOODDDDDDD PPPPPhhhDhDhD

How The World and the Ocular Surface RelateBBBBBB

Keeping in mind potential external factors

can help you better regulate your patient’s

eye health.

ABOUT THE AUTHOR

Dr. Green is an assistant

clinical professor at the

UC Berkeley School of

Optometry. He also serves

as the director of UC

Berkeley Digital Health and

Berkeley Optometry Online

Education.

014_EnvironOSD_Feat-5.indd 14014_EnvironOSD_Feat-5.indd 14 3/3/16 4:32 PM3/3/16 4:32 PM


Antigens are not limited to trig-gering allergic reactions; rather, they encompass anything the immune system reacts to. This can be virtual-ly anything in the environment that is not essential for life.

The subcategory of infectious antigens is comprised of proteins and molecules produced by various microorganisms, while allergic anti-gens are innocuous substances that pose no threat to the health of the individual, yet elicit an inappropri-ate immune response. For example, pollens responsible for the mating and fertilization of different plants are not harmful if inhaled, but can be responsible for triggering an al-lergic response. Other common en-vironmental allergens include mold, pet dander and dust mite feces.6

When considering the pathophys-iology of allergy and allergic eye disease, it is crucial to understand some fundamental key concepts. First and foremost is the recognition that, at the cellular level, allergic responses are essentially initiated the same way no matter where they occur in the body. From an immu-nology standpoint, key players in the allergic response to environmen-tal allergens include T-cells and the action of mast-cell degranulation that produces the symptomatology we are familiar with.

To adequately counter-act any potential threats and protect the body, the human immune system must be prepared to halt anything it perceives as threatening, even though it may not know what it might encounter. A new-born infant’s immune system is considered the most naïve in that it has not encountered much prior to exiting the womb. After birth, however, it is immedi-

ately subjected to an onslaught of antigens. Each initial encounter may trigger the development of an immune response, known as T-cell priming and sensitization. If the re-sponse is to an antigen that poses no threat to the individual, it is then, by defi nition, allergic. It can take 10 to 14 days to set the stage for an initial allergic response.7

During subsequent encounters, when the T-cell encounters the allergen, it communicates with B-cells to mass-produce IgE subtype antibodies—Y-shaped proteins that tightly bind to the antigens they are indicated for upon an encounter. Once created, these antibodies are released from the B-cells into the bloodstream, where they locate mast cells that reside in superfi cial layers in the skin and mucosa. These mast cells include a receptor on their surface that binds to the antibodies and are packed with granules that contain many factors. When an allergen encounters the tethered IgE antibodies, it triggers degranulation, spilling infl ammatory factors like histamines into the surrounding tissue.

The release of histamine is respon-sible for much of the signs and symptoms we observe in allergic eye disease. Upon binding to recep-tors on nearby blood vessels, they

elicit vasodilation and increased the permeability of the nearby vascu-lature. Vasodilation is responsible for the hyperemic appearance of the conjunctiva characteristic of ocular allergies; this increase in permea-bility of blood vessels also allows leakage of serum components into the surrounding tissues, causing chemosis. Histamine release also induces signifi cant pruritis, or the moderate to intense itching most commonly associated with allergic conjunctivitis.

MILD TO MODERATE

OCULAR ALLERGY

Simple allergic conjunctivitis can be divided into two primary subtypes: seasonal allergic conjunctivitis (SAC) and perennial allergic con-junctivitis (PAC). Together, SAC and PAC account for 95% of allergic conjunctivitis presentations in the United States.8 While this distinction may suggest they are two different clinical entities, the terms are in fact more descriptive of the timing of on-set and types of allergens involved.

Though spring is predominantly thought of as allergy season, differ-ent pollens are produced at different times of the year depending upon the plant variety and geographic weather patterns such as average temperature and prevailing winds. As such, certain offending allergens may in fact peak in the summer, fall, winter or even during multiple seasons throughout the year.

Perennial allergic conjunctivitis, in contrast, does not follow seasonal patterns because it involves allergens that do not fl uctuate throughout the year; these include mold spores, pet dander and dust mite feces.

Common clinical fi ndings associ-ated with these conditions include chemosis of the bulbar conjuncti-va, hyperemia of the bulbar and palpebral conjunctivae and the formation of small papillae on the

Fig. 1. Hyperemia and papillary response of the

conjunctiva in seasonal allergic conjunctivitis.



upper and lower tarsal conjunctiva (Figure 1).9,10 Many patients also report moderate to intense itch and watery or mucoid discharge.

To differentiate between the mu-coid discharge in allergic conjuncti-vitis and the mucopurulent dis-charge of bacterial conjunctivitis, ask the patient to describe the color and intensity of discharge upon wakening. Discharge from bacterial conjunctivitis tends to be yellowish or greenish in color, and lids are often matted shut upon wakening, while in the case of allergic con-junctivitis, discharge is typically grey or white in color. Discharge from allergic conjunctivitis can also matte the eyelids shut, though this is not as common as in bacte-rial conjunctivitis. To differentiate between allergic conjunctivitis and viral conjunctivitis—which presents similarly—note the presence of pruritis.

Laterality in allergic eye disease is approached by many clinicians as absolute. There is a miscon-ception that symptoms must be bilateral and symmetric because the response is to a factor that is ubiquitous in the environment, and therefore would cause similar reactions in both eyes. While true overall, there are two scenarios that may lead to a unilateral or asym-metric presentation. The fi rst is that the patient is allergic to something

that is not airborne, but rather is trans-ferred to the ocular surface via a vector like the patient’s hand. The second is individ-uals with an allergy to dust mite feces who regularly sleep on their side.11

Treatment for SAC and PAC is often confi ned to pallia-tive measures like cold compresses and nonpreserved artifi cial tears. For patients who require pharmaceu-tical intervention, however, a non-drowsy oral antihistamine should be used. Allergy sufferers can often achieve relief from multiple allergic conditions. In the case of a patient with signifi cant ocular symptoms who also presents with severe dry eye, try treating with a multimodal antiallergy drop such as ketotifen, olopatadine or alcaftadine.

MODERATE TO

SEVERE ALLERGIES

The two more severe ocular aller-gic conditions are atopic kerato-conjunctivitis (AKC) and vernal keratoconjunctivitis (VKC). These are chronic allergic infl ammatory conditions with acute exacerbations that have severe visual consequences because of the potential for cor-

neal involvement. In addition to fi ndings of simple allergic conjunc-tivitis, AKC and VKC sufferers often report more discomfort and photophobia. These symptoms can have a profound impact on quality of life.12

Many of the clinical fi ndings associated with AKC and VKC are characteristic of

both conditions. Patients typically develop large papillae on the tarsal conjunctiva of the upper lid (Figure 2). Additionally, gelatinous lesions referred to as Horner points or Trantas dots form on the limbus, and a fi lamentary keratitis is some-times present. Pseudomembranes can materialize in the lower and up-per fornix and should be removed to prevent eventual formation of symblepharon. If left untreated, the corneal epithelium will begin to de-compensate, with the potential for shield ulcers that leave the patient open to a higher risk of infection and eventual corneal scarring. Scarring of the upper palpebral con-junctiva from chronic infl ammation can lead to shortening of the fornix and corneal scarring secondary to trichiasis.13

Distinguishing AKC from VKC relies on a few key clinical features. VKC typically affects preadoles-cent to early-adolescent males and may become exacerbated in certain seasons over others. Papillae on the upper tarsal conjunctiva are large, giving the appearance of cobble-stones on exam.

AKC, by contrast, has a late adolescence to early adulthood onset and generally does not show a gender predilection. Additionally, though the conjunctival papillary response can be pronounced, it is

HOW THE WORLD AND THE OCULAR SURFACE RELATE

Fig. 3. Anterior subcapsular cataract in a patient

with atopic keratoconjunctivitis.

Fig. 2. Giant papillae in atopic keratoconjunctivitis.


generally less so than with VKC. Most AKC patients have an asso-ciated atopic dermatitis (eczema) on or around the lids, though this is not always the case. One unique feature of AKC is the development of a “polar bear rug” cataract, or an anterior subcapsular cataract with a characteristic appearance that earns its nickname (Figure 3).

Acute episodes of VKC and AKC are typically treated with topical steroids such as loteprednol or prednisolone drops. Due to the multitude of negative side effects, however, long-term steroid use should be avoided. New research suggests that immune modulators like cyclosporin A and tacrolimus may actually be better options for long-term management; how-ever, these treatment options are still experimental and considered off-label.14-16

The environment poses a con-stant threat to the ocular

surface. The key to minimizing its effects is avoidance of the causative environmental agents and using supportive and therapeutic measures when avoidance is not practical or, as is often the case, not possible. RCCL

1. Sundbom F, Malinovschi A, Lindberg E, et al. Ef-fects of poor asthma control, insomnia anxiety and depression on quality of life in young asthmatics. J Asthma. 2015 Dec 15:1-17.2. Bielory L, Skoner DP, Blaiss MS, et al. Ocular and nasal allergy symptom burden in America: the allergies, immunotherapy, and rhinoconjunctivitis (AIRS) surveys. Allergy Asthma Proc. 2014 May-Jun;35(3):211-8.3. Abusharha AA, Pearce EI. The eff ect of low humidity on the human tear fi lm. Cornea. 2013 Apr;32(4):429-34.4. Granet D. Allergic rhinoconjunctivitis and dif-ferential diagnosis of the red eye. Allergy Asthma Proc. 2008 Nov-Dec;29(6):565-74.5. Wieslander G, Norbäck D. Ocular symptoms, tear fi lm stability, nasal patency and biomarkers in nasal lavage in indoor painters in relation to emissions from water-based paint. Int Arch Occup Environ Health. 2010 Oct;83(7):733-41.6. Lambrecht BN, Hammad H. Allergens and the airway epithelium response: gateway to allergic sensitization. J Allergy Clin Immunol. 2014 Sep;134(3):499-507.

7. Weston WL, Bruckner A. Allergic contact derma-titis. Pediatr Clin North Am. 2000;47(4):897-907, vii.

8. Butrus S, Portela R. Ocular allergy: diagnosis and treatment. Ophthalmol Clin North Am 2005; 18:485–492; v.

9. Bielory L, Friedlaender MH. Allergic conjunc-tivitis. Immunol Allergy Clin North Am. 2008; 28:43–58; vi.

10. Castillo M, Scott NW, Mustafa MZ, et al. Topical antihistamines and mast cell stabilizers for treating seasonal and perennial allergic conjunctivitis. Co-chrane Database Syst Rev. 2015 Jun 1;6:CD009566.

11. Blochmichel E, Helleboid L, Corvec MP. Chronic allergic conjunctivitis. Ocul Immunol Infl amm. 1993;1(1-2):9-12.

12. Zicari AM, Nebbioso M, Lollobrigida V, et al. Ver-nal keratoconjunctivitis: atopy and autoimmunity. Eur Rev Med Pharmacol Sci. 2013 May;17(10):1419-23.

13. Chen JJ, Applebaum DS, Sun GS, Pfl ugfelder SC. Atopic keratoconjunctivitis: A review. J Am Acad Dermatol. 2014 Mar;70(3):569-75.

14. Vichyanond P, Kosrirukvongs P. Use of cyclo-sporine A and tacrolimus in treatment of vernal keratoconjunctivitis. Curr Allergy Asthma Rep. 2013 Jun;13(3):308-14.

15. Tzu JH, Utine CA, Stern ME, Akpek EK. Topical calcineurin inhibitors in the treatment of ste-roid-dependent atopic keratoconjunctivitis. Cornea. 2012 Jun;31(6):649-54.

16. Al-Amri AM. Long-term follow-up of tacrolimus ointment for treatment of atopic keratoconjunctivi-tis. Am J Ophthalmol. 2014 Feb;157(2):280-6.

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Eye disorders are wide-ly prevalent, with an estimated 3.5 million Americans age 40 years or older exhibiting some

form of impaired vision. Though some of these are rare inherited conditions, more common issues make up a large segment of the group. Allergic conjunctivitis affects approximately 40% of the population yearly, including an increase in incidence over the last decade.7 Meanwhile, anterior ocu-lar infl ammatory diseases (AOID) like ocular allergy, dry eye and tear fi lm dysfunction can pres-ent as comorbidities in patients with bacterial or viral infections.6

Clinicians are actively aware of the mechanisms that cause symptoms, yet many of these cases remain hard to treat.

Currently, a signifi cant amount of research exists with regards to decreasing ocular infl ammation from ocular allergies, infections and dry eye. Multi-drug therapies target the mediators responsible for clinical signs and symptoms, while mast-cell stabilizers com-bined with antihistamines enhance treatment effects throughout the body. The purpose of this article is to discuss the spectrum of recep-tors responsible for maintaining the homeostatic environment by modulating the innate and adap-tive immune system.8

PASSING GO

When an initial allergen penetrates through the physical barriers of the body, antigen-presenting cells (APC) grab it and migrate to the nearest lymph node, where they bind to the T-helper cells pres-ent there. The bound B-cell then awaits a cytokine signal from the Th2 cell in the form of interleukin IL-4. This signal triggers the for-mation of IgE-antibodies specifi c to the allergen within the B-cell that fl ow throughout the body, binding to mast cells that prompt a release of histamine and leukot-rienes in response. Th2 helper cells also release cytokines, activating both basophils and eosinophils, which produce mediators to assist with the release of histamines and leukotrienes. This further amplifi es the body’s allergic response; hista-mine release in particular accounts for many of the symptoms attribut-ed to allergic conjunctivitis.

Following primary exposure, the allergens present in the body bind to the IgE on mast cells, triggering a release of mediators and IL-4, which causes the B-cells to produce more IgE antibodies in a positive feedback loop.9 Understanding this allergen pathway allows clinicians to target specifi c cells and media-tors to control symptoms.

Allergic conjunctivitis constitutes a range of allergic infl ammatory disorders that affect the anterior

surface of the eye—namely, acute, seasonal and perennial conjunctivi-tis, and chronic allergic forms like atopic keratoconjunctivitis, vernal conjunctivitis and giant papillary conjunctivitis.1-3,6,7 Stored media-tors like histamine and de novo chemicals (including derivatives of the arachadonic acid cascade comprising of leukotrienes and prostaglandins) initiate the acute phase reaction, while the late phase response is initiated by cytokines that facilitate the infi ltration of eosinophils.10 The late phase is also the basis for chronic allergic disorders, with remodeling that involves stimulation, activation and localization of lymphocytes

ABOUT THE AUTHORS

Dr. Brett Bielory was previously

an Ocular Pathology Fellow

at Bascom Palmer Eye

Institute in Miami, Florida.

He is currently a resident

in ophthalmology with an

interest in corneal and ocular

surface diseases at New York

Medical college in Valhalla, NY.

Dr. Steven Shah is a graduate

of the Medical University

of Lublin in Poland. He is

currently working as a clinical

research associate at the

STARx Asthma and Allergy

Center in Springfi eld, NJ.

Dr. Leonard Bielory is an

allergist-immunologist in

New Jersey who is affi liated

with multiple hospitals in

the area, including Robert

Wood Johnson University

Hospital and St. Barnabas

Medical Center.

Understanding OphthalmicAntihistamines and

Histamine Receptors

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within the follicles and papillae of the conjunctival surface. Acute pre-sentations of allergic conjunctivitis can be controlled with different topical ocular agents, while more severe forms may require a multi-disciplinary approach in partner-ship with an ophthalmologist.3,10

COMPARING THE EARLY

AND LATE RESPONSES

An examination of the tear fl uid content of an affected patient typically reveals the presence of a “soup” containing various pre-formed and de novo mediators like IgE antibody, histamine, leukot-rienes and tryptase.10 Preformed mediators like histamine, trypt-ase and bradykinin immediately disperse following exposure to an allergen, while release of de novo mediators like leukotrienes and prostaglandins peaks at rough-ly eight to 24 hours following

exposure. Cytokine release helps mediate both early- and late-phase responses to the allergen; these are direct contributors to the signs and symptoms of AOID. Early respons-es to allergen exposure typically present as pruritus and conjuncti-val erythema, which results from the release of histamine.3,7,10 Due to the direct relationship between ear-ly symptoms and histamine, ear-ly-phase reactants tend to respond best to antihistamine therapy for symptom relief.10

The allergic late phase, in con-trast, is a delayed response without sustained exposure to the allergen. This phase involves a greater in-fl ammatory response than the early phase, and is not primarily the re-sult of histamine; this characteristic in fact contributes to the ineffec-tiveness of antihistamine therapy in patients with chronic allergic diseases.3,10 Unlike the immediacy

of the early phase, the late phase can occur months after the initial allergen exposure and is marked by the recruitment of immune cells (i.e. dendrocytes, basophils, and eosinophils) to the site of the allergic response. Symptoms of late phase allergic responses include edema, pruritus, erythema, exces-sive tearing and lid and conjuncti-val edema. If corneal involvement is present, photophobia may also develop.

Dual action H1 subtype antihis-tamines in conjunction with mast cell stabilization are much more effective in combating symptoms of late-phase allergic reactions; however, the best available therapy for late phase symptoms may be steroids like loteprednol. Due to their ineffectiveness in the early phase and ocular side effects, how-ever, steroids should not be consid-ered as fi rst-line therapy.1,2,7,10

Fig. 1. Treatment path of ocular allergy. Source: Leonard Bielory, MD. Reproduced with permission of the author.

By Brett P. Bielory, MD, Steven Shah, MD, and Leonard Bielory, MD

Experts discuss the complex mechanics of

the human allergic reaction.

Mast Cells

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Antihistamines act as antagonists to histamine receptors, inhibiting the release of acute-phase allergic reactants.6,7 Many antihistamines differ in their ability to treat spe-cifi c AOID symptoms due to their varying affi nities for each subtype of histamine receptor. Symptomatic relief is directly correlated with a clinician’s ability to fi nd the antihistamine that targets the right receptor, and, since mast cells are responsible for the late-phase aller-gen response, the role of antihis-tamines and their relative potency are extremely valuable to patient care. Comparing the binding affi n-ity of each antihistamine to each of the four subtypes of histamine re-ceptors can help a clinician choose a more targeted therapy plan for the patient.2,3,7

The ability to bind with his-tamine receptors is based on the rate the drug binds to receptors, the duration of binding and the maintenance of the drug-receptor complex. These factors combine to enable the drug’s ability to antag-onize the activation of histamine receptor to achieve symptomatic control and minimize side effects.3,7

Commonly, antihistamines work by binding to the active site of receptors, leading to the inacti-vation of histamine. Inhibition of histamine receptors is achieved when enough of the drug is pres-ent to prevent activation of the receptor. Drugs that have poor binding affi nities require higher concentrations to achieve the same inhibition, compared to drugs with a higher binding affi nity. As such, a drug’s affi nity for a targeted histamine receptor can be used to predict how potent its antihista-mine effects will be.3,7

Drug vs. histamine binding at the receptor is a competitive process, as both the drug and histamine bind to and release from the receptor. As such, the com-pound that spends the most time bound to the receptor will cause the receptor to be stimulated or in-hibited. Effi cacy of antihistamines can be greatly enhanced by rapid equilibrium and onset of action, or by slow dissociation rates from the receptor.3,6,7,10 Note, however, antihistamines carry an anti-cho-linergic effect that can cause ocular drying. This side effect is the result

of muscarinic receptor inhibition. In some cases, however, it can be used for the treatment of insomnia or excessive allergic rhinorrhea. Thus, it is important to understand binding affi nities for muscarinic receptors of current antihistamines to prevent adverse side effects without affecting the effi cacy of the treatment provided.1-3,6,7

HISTAMINE RECEPTOR

SUBTYPES

Histamine is considered both an autacoid and a neurotransmit-ter; nearly all organs and a wide range of biological functions are affected by it. These effects are mediated through the distribution of four types of G-coupled pro-teins. Histamine binds to receptors throughout the body based on location of the necessary receptors and the physiological response that triggered its release. All histamine receptors exhibit constitutive activity, however, and are able to function without bound histamine. Research has also indicated that H1 and H2 receptors are more widely expressed than H3 and H4

receptors.7,9,10

Histamine receptors are triggered via a second messenger system associated with G-coupled proteins. All his-tamine receptors are heptahelical transmem-brane molecules that transduce extracellular signals by way of G proteins to intracellular second messenger systems. These include Ca2+, cGMP in H1,

UNDERSTANDING OPHTHALMIC ANTIHISTAMINES AND HISTAMINE RECEPTORS

H1 H2 H3 H4

Immunomodulatory eff ects

Itching

Swelling

Erythema

Vascular permeability

Pain

Vasodilation

Nasal congestion

Table 1. Histamine Receptor Subtypes7



cAMP in H2, Ca2+ and MAP kinase for H3 and H4 receptors. Different cell types and their physiological locations give histamine its ability to trigger varying effects based on its target receptor.7-10

With respect to the four subtypes described in Table 1, H1 receptors are predominately located in the bronchi, heart, central nervous sys-tem (CNS) and arterial and intesti-nal smooth muscle.7,9 The sedative effect of H1 antagonism seen in fi rst generation oral antihistamines, (i.e., diphenhydramine) is the result of their ability to cross the blood-brain barrier, while the appearance of histamine receptors in smooth muscle contributes to the cardiac side effects present in some oral

antihistamines.2,7 H1 stimulation is associated with infl ammation, prostaglandin production, head-ache, hypotension, tachycardia, and bronchoconstriction. H1 is the only histamine responsible for pain, and is also the subtype most contributory to itching. Research has indicated H1 antagonism pre-vents cytokine release and ocular itching associated with allergic conjunctivitis, and also increases vascular permeability.6,7,10

H2 receptors are located in the parietal cells of the gastric mucosa, CNS, uterus and the heart. Drugs like cimetidine and famotidine inhibit this receptor’s role in gastric acid secretion. H2 receptors cause increased vascular permeability,

fl ushing and relaxation of bronchi-al smooth muscle relaxation. H2

receptors also have a vasodilatory effect and have been shown to prevent stimulated vasodilation with prior administration of H2

antagonists.7,10

H3 receptors are present in neurons throughout the CNS and peripheral nervous systems, as well as in the heart and bronchioles. H3

receptors are located pre-synapti-cally, and their stimulation enhanc-es modulation of the blood-brain barrier while inhibiting release of histamine and other neurotrans-mitters. H3 receptors are respon-sible for bronchial relaxation, inhibition of sympathetic neuro-transmission, decrease in gastric

HISTAMINES ON THE MARKET

Olopatadine is a selective H1 receptor antagonist and cell-stabilizing agent. The 0.1% formulation is unique in that it is also approved for use in allergic conjunc-tivitis. Most other H1 blockers are only approved for ocular itching. In previous studies, Olopatadine was found to be superior to ketotifen when it came to the alleviation of ocular itching. Pataday (olopatadine, Alcon) is an increased concentration formulation for once-daily dosing. Allergic rhinitis can now also be treated with a once-a-day olopatadine intranasal formulation.1,2,6,7,10

Azelastine is a selective H1 receptor antagonist that also exhibits H2 blocking properties. Azelastine also blocks the release of histamine from mast cells, and formation of leukotrienes. It has a relatively low pH of 5.0–6.5, making its major side eff ect mild ocular irritation on administration. It is relatively long acting, being effi cacious for up to eight hours when used twice daily and is available in an intranasal formula-tion as well.1,2,6,7,10

Epinastine is an antihistamine with a high affi nity for H1 receptor and H2 receptor antagonism, with mast cell-stabilizing properties as well. Originally approved for rhinitis, with ocular administration it has shown signifi cant improvement of itching, swelling and tearing compared with the placebo. It is recom-mended twice daily with duration of eight hours or longer. Side eff ects include burning and infection, and it is generally well tolerated for up to eight hours after instillation.

Bepotastine is an H1 receptor selective antagonist with mast cell-stabilizing and eosinophil modulating

properties. It is approved as an ophthalmic solution for the treatment of itching associated with allergic conjunctivitis. It was eff ective in controlling ocular itching and tearing, but shows little eff ect on con-junctival redness. Bepotastine has been shown to have rapid onset and can give symptomatic relief in as soon as three minutes after administration and last for up to eight hours with a statistically signifi cant number of patients achieving complete relief. Bepo-tastineb besilate 1.0% was able to inhibit vascular permeability due to histamine blockade substantially better than olopatadine 0.1%. In addition to ketotifen, bepotastine has shown an ability to inhibit eosinophil infi ltration into the conjunctiva.1,2,5-8

Alcaftadine is a tricyclic piperidine aldehyde ap-proved for the treatment of itching associated with allergic conjunctivitis. It is administered once daily and demonstrates substantial relief of symptoms at both the 15-minute and 16-hour mark after adminis-tration. Both oral and ophthalmic formulations show very similar pharmacokinetic activity. Cytosolic en-zymes via aldehyde oxidation metabolize alcaftadine to its acid metabolite. It is believed that cytochrome p450 enzymes play a minor role in the metabolism of the drug.6 Alcaftadine exhibits antagonistic activity on H1 and H2 subtype receptors, as well as low affi nity for the H4 subtype. Furthermore, alcaftadine prevents the recruitment of eosinophils and inhibits mast cell degranulation. Treatment with alcaftadine has shown less eosinophil infi ltration into the conjunctiva compared to olopatadine and the placebo in murine models. In direct comparison with other ocular aller-gy agents, alcaftadine has shown to provide similar relief to current marketable agents.3,6,7



UNDERSTANDING OPHTHALMIC ANTIHISTAMINES AND HISTAMINE RECEPTORS

acid production and control of vasoactive mediators. These effects are kept in mind when targeting H3 receptors to control insomnia, obesity, infl ammatory diseases, schizophrenia and certain disease states mediated by neurotransmit-ter release.7,10

H3 receptor antagonism has been shown to aggravate pruritic symp-toms, which appears to contradict the normal histamine-induced pruritus pathway. It was found to increase the incidence of scratching behavior in mice; further research indicated intradermal injections of an H3 receptor antagonist (lodophenpropit or clobenpropit) triggered a signifi cant increase in scratching behavior in both mast-cell defi cient and wild type mice. H3

antagonism-induced pruritus ap-pears to be mediated by substance P, a known pruritus-causing agent. Some speculation has occurred that clobenpropit induced a pruritic response through H3 subtype an-tagonism in combination with H4 subtype agonist.6,7,9,10

As such, H3 blockade may provide relief of nasal congestion symptoms. Research supports the opinion that H3 receptors are in-volved with sympathetic transmis-sion, and that combined H1 and H3

antagonism can provide treatment for allergic rhinitis symptoms. This is useful in patients that continue to be symptomatic when only using an antihistamine as a treatment regimen. Combination H1 antagonism (chlorpheniramine)

and H3 antagonism (clobenpropit or thioperamide) revealed signif-icant decongestive effects, while evading hypertension. Further re-search into combining H1 receptor antagonist (fexofenadine) with a novel H3 antagonist found statisti-cally signifi cant relief of subjective symptoms like rhinorrhea, itching and sneezing compared with the placebo.3,4,7

The H4 receptor is directly related to pruritus as well. It is expressed on hematopoietic cells and plays a crucial role in the function of mast cells, eosinophils, monocytes, dendritic cells and T-cells. Studies have identifi ed that the chemotactic response of mast cells, eosinophils, dendritic cells, monocytes and natural killer cells to histamine is through the H4

subtype receptor.10 These recep-tors are involved in autoimmune reactions, allergies and, specifi -cally, symptoms of pruritus. The immunomodulating effects of the H4 subtype receptor are currently under investigation for its uses in anti-allergy therapy. H4 receptor antagonism is also being investi-gated for treating immune-related diseases like asthma. H1 receptor antagonism alone has been shown to be ineffective in the treatment of asthma, but in combination with H4 receptor blockade may provide symptomatic relief.2,3,6,7,8,10

H4 subtype antagonism has been studied in a long-term experi-mental murine model of pruritus associated with a chemical-induced

contact dermatitis induced by repeated challenge with 2,4,6-trini-trochlorobenzene [TNCB].10 H4

antagonist [JNJ7777120] was administered and shown to reduce pruritus and resolve skin lesions in a dose-dependent manner. Compared to when managing H1

receptor antagonism with fex-ofenadine, however, relief was not seen in both infl ammation and pruritus.7 It was also demonstrated that H4 receptor agonists elicited a scratching response that can be ameliorated by pretreating with a selective H4 receptor antagonist, and that when H1 and H4 subtype receptors are both antagonized, scratching behavior was near-ly completely relieved. Pruritic symptoms were also brought under control with H1 antagonism in H4 subtype receptor knockout mice.6,7,10

Murine models have hypoth-esized the concept of synergistic control of symptoms relating to allergic disease states. Studies have shown that in murine mod-els with induced pruritus, there is statistically increased symptomatic control when H1 and H4 receptor antagonists were used concur-rently. It was also noted that any pruritus in the H4 knockout mice was resolved with administration of diphenhydramine.7

THE TIES THAT BIND

Literature comparing the binding affi nities of 19-marketed anti-his-tamines has indicated differenc-es in receptor affi nity and drug potency—namely, a larger binding affi nity value [i.e., Ki] correlates with a weaker binding affi nity of the drug for the receptor. If the binding affi nity of the drug to the receptor is weak, a larger dose of the drug will be needed to achieve the same inhibition as a drug with a lower Ki.

H1 Receptor [nM] H2 Receptor [nM]

Olopatadine 35.0nM 1,00,000nM

Azelastine 6.8nM 4,200nM

Ketotifen 1.3nM 1,000nM

Epinastine 9.8nM 4,030nM

Table 2. Binding Affi nity [Ki] Comparison



Relative potency can also be determined using these Ki values. Antihistamines marketed for mus-carinic receptor inhibition were compared for potency and possi-ble trends in anti-cholinergic side effects; these studies of binding affi nities were separate studies and were not in direct comparison, but some trends become apparent.6,7,10

The binding affi nity for his-tamine to the H1 receptor is 1,80,000nM. Thioperamide has the lowest affi nity for H1 recep-tor with a Ki of 2,80,000nM. Pyrilamine had a Ki value of 0.8nM, giving it the highest affi n-ity for the H1 receptor of all the agents compared. The fi rst-gen-eration drug diphenhydramine is also a very potent binder, with a Ki of 12.5nM, while potency was variable with regards to the second-generation compounds. Desloratidine (Ki 4nM) and cetirizine (Ki 6.3nM) showed the highest affi nity, while loratadine (Ki 35nM) and fexofenadine (Ki 83nM) had much lower binding affi nities. Topical ophthalmic for-mulations have very high potency, with olopatadine (35nM) having the lowest affi nity and ketotifen (1.3nM) and emedastine (1.3nM) having the highest affi nity.7,10

H2 receptors have much weak-er binding affi nities compared to those of the H1 receptor.7 The binding affi nities for H2 subtypes are two to four orders of magni-tude weaker than those for the H1 receptor. Ranitidine showed the greatest affi nity for the H2

receptor with a Ki of 187nM. Olopatadine [Ki 1,00,000nM] had the weakest binding affi nity to the H2 receptor whereas diphenhydr-amine, azelastine, epinastine and ketotifen showed binding affi ni-ties in the range of cimetidine [Ki >10,000nM]. Using histamine’s affi nity to H2 subtype receptors,

we can model the drug’s ability to compete and produce the desired antihistamine affect. Histamine’s affi nity to H2 subtype receptors is 18,350nM, but it can be inferred that drugs such as emedastine (Ki 49,067nM) and olopatadine would need much higher concen-trations to overcome competition with histamine for the H2 recep-tor.1,2,7,10 H3 and H4 subtypes have more similarities between the two than the H1 and H2 subtypes. The highest affi nity for H3 was thioperamide (Ki 79,400nM) and olopatadine (Ki 79,400nM) exhib-ited the lowest affi nity for the H3

receptor.7

Available data on H4 receptor affi nities is limited. Only fi ve antihistamines were compared: thioperamide [Ki 27nM] had the greatest affi nity while cimetidine and ranitidine [Ki >10,000nM] exhibited relatively low affi nity for the H4 subtype receptor. More in-depth research into H4 receptors and their function must be con-ducted to determine the suitability of using H4 subtype agonists or antagonists for treatment of con-ditions as it relates to allergic and infl ammatory disease processes.7,10

Due to the ability of some antihistamines to exert an effect on muscarinic receptors, antihista-mines that offer the least amount of anticholinergic activity while maintaining high antihistamine po-tency would be ideal. Drugs such as desloratidine have shown the greatest effect on muscarinic recep-tors.1,2,6,7,10 Ketotifen is a strong H1

antagonist and mast cell stabilizer with leukotriene inhibition. It is the only topical ophthalmic agent available without a prescription in the United States. If administered twice daily, it has been found to be effective in the prevention of itch-ing, redness and general symptoms of allergic conjunctivitis compared

to the placebo. Emedastine difu-murate was compared to ketotifen fumarate; both showed marked improvement in the incidence of itching compared with the placebo.1,2,6,7,8,10

The ever-increasing incidence of AOIDs suggests clinicians

must continue to develop new, innovative treatments to alle-viate patient symptoms. Of the four known types of histamine receptors, each has varied effects dependent on location and physi-ological signal. Additionally, each exhibits its own specifi c response to acute infl ammation; thus, understanding each receptor’s unique and localized actions is key for targeting treatment. Persistent research relating to the affi nity of antihistamines and the ability to target subtypes may also open the door for new allergic disease man-agement techniques; as such, these may be the next step in managing AOIDs. RCCL

1. Bielory BP, OBrien TP, Bielory L. Management of seasonal allergic conjunctivitis: guide to therapy. Acta Ophthalmol 2012; 90(5): 399-407.2. Bielory L. Allergic conjunctivitis: the evolution of therapeutic options. Allergy Asthma Proc 2012; 33(2): 129-39.3. Bielory L, Meltzer EO, Nichols KK, Melton R, Thomas R, Bartlett JD. An algorithm for the man-agement of allergic conjunctivitis. Allergy Asthma Proc 2013; 34(5): 408-420.4. Bielory L, Skoner DP, Blaiss MS, et al. Ocular and nasal allergy symptom burden in America: the Allergies, Immunotherapy, and Rhinoconjunctivitis (AIRS) surveys. Allergy Asthma Proc 2014; 35(3): 211-18.5. Bielory L, Duttachoudhury S, McMunn A. Bep-otastine besilate for the treatment of pruritus.” Expert Opinion in Pharmacotherapy 2013.6. Syed BA, Kumar S, Bielory L. Current options and emerging therapies for anterior ocular infl am-matory disease. Curr Opin Allergy Clin Immunol 2014; 14(5): 485-489.7. Wade L, Bielory L, Rudner S. Ophthalmic anti-histamines and H1-H4 receptors. Curr Opin Allergy Clin Immunol 2012; 12(5): 510-16.8. Bielory L. Allergic conjunctivitis: the evolution of therapeutic options. Allergy Asthma Proc 2012; 33:129-39.9. Kumar V, Abbas A, Aster JC. Robbins & Cotran Pathologic Basis of Disease. Ninth Edition, Elsevier Saunders, 2011.10. Bielory L, Lien KW, Bigelson S. Effi cacy and tol-erability of newer antihistamines in the treatment of allergic conjunctivitis. Drugs 2005; 65:215-28.



1 CE Credit (COPE Approval

Pending)

MANAGING THEOCULAR

By Gregory A. Caldwell, OD

While a seeming-ly simple ail-ment, ocular allergy is, in fact, multifac-

eted, encompassing multiple diag-nostic categories differentiated by a complex cascade of infl ammato-ry mediators, cytokines and other chemicals. As such, while group-ing these disparate conditions into a single diagnostic category called “allergic conjunctivitis” can ease treatment selection, doing so can also result in therapeutic fail-ure. Instead, approaching ocular allergy as a spectrum of different diseases—each with its own ini-tiating factors, presentations and methods of management—can help clinicians select more appro-priately targeted therapies to en-hance the likelihood of resolution.

The human allergic response is classically considered an overreac-tion of the body’s immune system to foreign substances perceived as a threat to ocular health (i.e., allergens). Said substances are not necessarily pathogenic, but rather perceived as so.1 In effect, an allergic reaction is a result of a benefi cial immune response that has gone awry.

Allergies can be subdivided into four categories based on the cascade of events that comprise each reaction and the time it takes for them to occur. Of the four, Type I and Type IV are considered true ocular allergy. Immediate

hypersensitivity reactions, or Type I ocular allergies, include season-al allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis and atopic keratoconjunctivitis. Delayed hypersensitivity reac-tions, or Type IV ocular allergies, include contact dermatitis.

A Type I allergic reaction begins with a sensitization phase in which the patient is exposed to the offending antigen. Additional re-exposure results in an ear-ly-phase response and subsequent late-phase response. The early re-sponse is the degranulation of the mast cell, which has preformed mediators—the most common being histamine. Most patients in this phase exhibit the hallmark symptom of itching in conjunction with mild conjunctival hyperemia, chemosis and a conjunctival pap-illary response. At times, a stringy white mucus or concurrent rhini-tis is also present. Antihistamines and mast-cell stabilizers, or better yet agents that combine both properties, are the best treatment methods for the early phase.

The ensuing late-phase allergic response involves white blood cell (i.e., eosinophil and baso-phil) infi ltration that results in cell-mediated cytotoxicity or tissue damage and edema. The late-phase reaction typically commences between four and six hours after sustained mast cell degranulation.2,3 T-lymphocyte

activation and infi ltration of the conjunctival mucosa by eosin-ophils, neutrophils, monocytes and basophils are hallmarks of the late phase.4,5 If intervention is initiated while the allergic reac-tion is predominately in the early phase, control can be achieved using anti-allergy products that have antihistamine and mast cell stabilizing effects. Once Type I allergies have progressed to the late phase, however, more potent anti-infl ammatory agents in the form of topical corticosteroids or non-steroidal anti-infl ammatory agents (NSAIDs) may be neces-sary to mitigate the infl ammatory/immune response.

UNDERSTANDING

THE PRESENTATION

Determining whether patients with seasonal or perennial allergic conjunctivitis are in the early or late phase can be completed using details from their patient history and results from a clinical exam. When performing the exam, note type, severity and duration

ABOUT THE AUTHOR

Dr. Caldwell is a 1995 graduate

of the Pennsylvania College

of Optometry who later

completed a one-year

residency in primary

care and ocular disease

at the Eye Institute in

Philadelphia. He is a fellow

of the American Academy of

Optometry and a diplomate of the American

Board of Optometry, and currently works in

Duncansville and Johnstown, Pennsylvania as

an ocular disease consultant.

024_AllergyMediators_CE.indd 24024_AllergyMediators_CE.indd 24 3/3/16 4:55 PM3/3/16 4:55 PM


COMPLEXALLERGIC REACTIONof signs and symptoms: patients in the early phase present with itching and chemosis, while those in the late phase exhibit evidence of eosinophil and basophil infi l-tration and accumulation in the ocular tissues.

In the case of vernal kerato-conjunctivitis (VKC), which is seen primarily in children, the allergic reaction moves rapidly from the early to late phase. In this instance, the accumulation of eosinophils and basophils in the limbal area of the bulbar conjunc-tiva are known as Horner’s points or Trantas’ dots, and are a classic example of cell-mediated cytotox-icity or tissue damage.

Treatments for allergic conjunc-tivitis consist of reducing or elim-inating the antigen when possible and prescribing pharmaceuticals to prevent or decrease the immune response; however, non-pharma-cological interventions can also be benefi cial as a fi rst line of defense. Examples for managing both Type I early and late phases and Type IV hypersensitivities include:

• Allergen/antigen avoidance.Using air conditioners and HEPA fi lters can prevent pollen from in-fi ltrating indoor areas. Instructing patients to avoid outdoor activi-ties during high pollen periods is also benefi cial, though not always possible. Patients can track tree, grass and weed pollen counts and mold spore counts one of numer-ous smartphone apps; this may

assist patients in reducing antigen-ic exposure.

• Artifi cial tears. Though these can fl ush away antigens from the ocular surface, sporadic use makes this option only marginally effective, especially in more severe cases. Excessive lacrimation in al-lergic conjunctivitis is an example of the body’s attempt to emulate this action.

• Cold compresses. Applying chilled temperatures triggers vaso-constriction and limits the eosino-philic response. Cold compresses may also have a psychological benefi t, in that patients have something to occupy their hands with rather than scratching, which increases mast cell degranulation, eosinophil release and subsequent-ly, severity of itching.

• Washing hair before going bed. Hair—particularly longer strands—acts as a fi lter to trap airborne allergens throughout the day. These allergens transfer to the pillow when the patient lies down and then into the eyes overnight. Rinsing hair before bed reduces and even eliminates this problem.

THE TYPE I

ALLERGIC RESPONSE

Pharmacologic options for man-aging Type I acute phase allergic responses include:

• Prescription topical anti-histamine/mast-cell stabilizers. These agents employ multiple mechanisms of action to bring relief; antihistamine competes for and reversibly blocks hista-mine receptors in the conjunctiva and eyelids, while the mast-cell stabilization properties inhibit mast-cell degranulation. Most patients prefer to use antihista-mine/mast-cell stabilizers instead of other options because of the rapid onset of relief they provide. Examples include Patanol (ol-opatadine hydrochloride 0.1%, Alcon), Pataday (olopatadine hydrochloride 0.2%, Alcon), Pazeo (olopatadine hydrochloride 0.7%, Alcon), Lastacaft (alcafta-dine ophthalmic solution 0.25%, Allergan), Bepreve (bepotastine besilate 1.5%, Bausch + Lomb), Optivar (azelastine hydrochloride 0.05%, Meda Pharmaceuticals) and Elestat (epinastine hydrochlo-ride 0.05%, Allergan).

Release Date: March 2016Expiration Date: March 1, 2019Goal Statement: This course covers signs, symptoms and the treatment of ocular allergy.Faculty/Editorial Board: Gregory A. Caldwell, ODCredit Statement: COPE approval for 1 hour of continuing education credit is pending for

this course. Check with your state licensing board to see if this counts toward your CE requirements for relicensure.Joint-Sponsorship Statement: This con-tinuing education course is joint-spon-sored by the Pennsylvania College of Optometry. Disclosure Statement: Dr. Caldwell has no financial interest in any products men-tioned in this article.



• Over-the-counter (OTC) top-ical antihistamine/mast-cell sta-bilizers. Often more cost-effective than their prescription counter-parts, OTC topical antihistamine/mast-cell stabilizers are also less effective due to their lower affi nity for histamine receptors and inhibited mast-cell stabiliza-tion effects.7 However, they still maintain a place in many treat-ment regimens. Examples include Zaditor (ketotifen fumarate 0.025%, Alcon), Claritin Eye (ke-totifen fumarate 0.025%, Bayer) and Alaway (ketotifen fumarate 0.035%, Bausch + Lomb).

• Topical mast-cell stabilizers/cromones. When a patient cannot tolerate antihistamines due to allergy or severe dry eye, agents like Crolom (cromolyn sodium 4%, Bausch + Lomb), Alomide (lodoxamide tromethamine 0.1%, Alcon), and Alocril (ne-docromil sodium 2%, Allergan) make suitable alternatives. Alamast (pemirolast potassi-um 0.1%, Vistakon) is another option, but is no longer available on the market. Note, these drugs’ mechanism of action is slow in comparison, and relief is delayed, compared to the aforementioned options. They are much less effec-tive than dual-action medications due to their limited action.

• Topical antihistamines. Emadine (emedastine difumarate 0.05%, Alcon) is a single-agent antihistamine. It provides rapid relief like mast-cell stabilizers, but is limited in effi cacy due to its single mechanism of action.

• Topical NSAIDs. These may help with itching in the Type I acute allergic phase when other medications are not effective. Topical NSAIDs have analgesic and anti-infl ammatory activity; this is why they are indicated

for ocular pain and postoper-ative infl ammation in patients who have undergone cataract extraction or corneal refractive surgery. In this case, the analge-sic benefi t would help manage the itch (pain). Examples like Acular LS (ketorolac trometh-amine 0.4%, Allergan), Xibrom (bromfenac 0.09%, Mylan), Voltaren (diclofenac 0.1%, Novartis) or Nevanac (nepafenac 0.1%, Alcon) could be used when needed.

Therapeutic options for man-aging a Type 1 late-phase allergic response include:

•Topical steroids. Cortico-steroids inhibit the infl ammatory process by stabilizing vascular membranes to decrease capillary dilation and permeability, which restricts eosinophils, basophils and macrophages from invading tissues. Corticosteroids function primarily by obstructing the ara-chidonic acid pathway via inhibi-tion of phospholipase A2 to stop formation of the infl ammatory mediators prostaglandin, throm-boxane and leukotriene. Note: extended use can lead to elevated intraocular pressure in susceptible individuals.

MANAGING THE COMPLEX OCULAR ALLERGIC REACTION

Moderate contact dermatitis secondary to application of topical 0.2%

brimonidine tartrate solution.

The same patient one week later after discontinuing the topical 0.2%

brimonidine tartrate solution and applying OTC hydrocortisone cream 1%.



An additional side effect of cat-aract formation is also especially prevalent with use of acetate or phosphate topical steroids; these include Pred Forte (prednisolone acetate suspension 1%, Allergan), Pred Mild (prednisolone acetate suspension 0.12%, Allergan), Durezol (difl uprednate emulsion 0.05%, Alcon) and FML (fl uo-rometholone suspension 0.1%, Allergan).

These higher-risk steroids are used in certain cases, such as when drug formularies may limit or dictate a treatment regimen. The release of newer generation site-specifi c or ester-based steroids like loteprednol etabonate have helped decrease many ocular com-plications associated with topical steroids; examples include Alrex (loteprednol etabonate suspension 0.2%, Bausch + Lomb), Lotemax (loteprednol etabonate suspen-sion 0.5%, Bausch + Lomb) and Lotemax gel (loteprednol etabon-ate gel 0.5%, Bausch + Lomb). Still, monitoring for the above signs is key for protecting a patient from further adverse effects.

• Topical immunosuppressants.Cyclosporine offers potent immu-nosuppressive properties, refl ecting its ability to block transcription of cytokine genes in activated T-cells. This makes cyclosporin A a highly potent inhibitor of T-cell activation and, as such, a potential alterna-tive for patients unable to tolerate topical steroids, such as those with glaucoma.8 Cyclosporin A may also be used in conjunction with topical steroids, however.

Restasis (cyclosporine ophthal-mic emulsion 0.05%, Allergan) is one option for treatment of the late phase response. A second, not-yet-FDA-approved drug, lifi tegrast (Shire)—being studied for the treatment of dry eye—may also

have an off-label use in the late-phase allergic reaction due to its ability to inhibit T-cell migration and activation.9

• Oral NSAIDs. These are a good alternative when steroids are contraindicated; for example, in patients allergic to corticosteroids or those with glaucoma. As al-ready mentioned, topical NSAIDs have analgesic and anti-infl amma-tory activity. The anti-infl ammato-ry benefi t is key in the late-phase as a means to relieve infl ammation.

THE TYPE IV

ALLERGIC RESPONSE

Type IV ocular allergies typical-ly present as contact dermatitis on the upper and lower eyelids. The patient usually presents with itching, burning and red and scaly eyelids, often quickly following exposure to a noxious substance. When contact dermatitis is persistent, the eyelids typi-cally thicken. As such, more aggressive treat-ments supersede the supportive therapies men-tioned above.

Therapeutic options for managing Type IV allergic re-sponse include:

• Topical ste-roids. The most appropriate treatment ve-hicle in mild to moderate con-tact dermatitis is cream or oint-ment. Examples include the ointment forms

of Lotemax or FML, as well as OTC hydrocortisone 1% cream. Because limited options exist for topical corticosteroid ointments, it may be necessary to employ alternate preparations such as combination antibiotic/steroid ointments like Maxitrol (neo-mycin and polymyxin B sulfates and dexamethasone, Alcon) and Tobradex (tobramycin 0.3% and dexamethasone 0.05%, Alcon). Be aware, however, that some of these combination ointments may have antigenic properties themselves.

• Oral steroids. Severe contact dermatitis is most often responsive to a short course of oral cortico-steroids. Oral prednisolone can be given, but methylprednisolone may work best to treat this ocular allergy. The latter is available as a six-day Medrol 4mg dose-pack.

• Pazeo, Pataday and Lastacaft are the only once-a-day prescription topical antihistamine/mast-cell stabilizers available.

• Pazeo and Lastacaft are indicated in patients two years of age and older.

• All topical antihistamine/mast-cell stabilizers fall in the historic pregnancy category C except for Lastacaft, which is in the historic pregnancy category B.

• Single-agent mast-cell stabilizers and single-agent antihistamines all fall in the historic pregnancy category B.

• Lotemax gel does not require shaking, contains 70% less preservatives than its suspension and contains two moisturizers—propylene glycol and glycerin.10

• Topical NSAIDs inhibit cyclooxygenase, which blocks a segment of the arachidonic acid pathway. Thus, taking a topical antihistamine/mast-cell stabilizer in conjunction with topical NSAIDs would provide the most symptom relief.

• If cyclosporine is used as an alternative, it will need to be combined with a topical antihistamine/mast-cell stabilizer to relieve symptoms.

DOSE NOTES



MANAGING THE COMPLEX OCULAR ALLERGIC REACTION

The treatment of Type I and Type IV hypersensitivities has long

been based on the known abilities of antihistamines, mast-cell stabi-lizers/cromones, NSAIDs, immuno-suppressants and corticosteroids. However, none of these drugs completely eliminate the clinical features of these allergic reactions; furthermore, current estimates sug-gest that at least 20% of the overall population suffers from some form of allergic conjunctivitis, many who do not seek treatment at all.11

Identifying these patients in need is an opportunity to improve lives as well as our practices. The sec-ond step is to apply knowledge of how each individual drug works in combination with insights into the pathophysiological mechanisms of ocular allergy to refi ne your thera-peutic strategy and increase success of resolution. So, get out there and prepare for allergy season! RCCL

1. Chigbu DI. The management of allergic eye dis-eases in primary eye care. Cont Lens Anterior Eye. 2009;32(6):260-2.2. Chigbu DI. The pathophysiology of ocular allergy: a review. Cont Lens Anterior Eye. 2009;32(1):3-15.3. Cousins SW, Rouse BT. Chemical mediators of ocular infl ammation. In: Pepose JS, Holland GN, 4. 4. Wilhelmus KR, Eds. Ocular Infection and Immuni-ty. St. Louis: Mosby;1994:50-70.5. Abelson MB, Smith L, Chapin M. Ocular allergic disease: mechanism, disease sub-types, treatment. Ocul Surf. 2003;1(3):127-49.6. Bacon AS, Ahluwalia P, Irani AM, et al. Tear and conjunctival changes during the allergen-induced early- and late phase responses. J Allergy Clin Immunol. 2000;106(5):948-54.7. Torkildsen G, Narvekar A, Bergmann M. Effi cacy and safety of olopatadine hydrochloride 0.77% in patients with allergic conjunctivitis using a conjunc-tival allergen-challenge model. Clin Ophthalmol. 2015;9:1703-13.8. Yanni JM, Miller ST, Gamache DA, et al. Compar-ative eff ects of topical ocular anti-allergy drugs on human conjunctival mast cells. Ann Allergy Asthma Immunol 1997;79(6):541-5.9. Matsuda S, Koyasu S. Mechanisms of action of cy-closporine. Immunopharmacology 2000 May;47(2-3):119-25.10. Murphy CJ, Bentley E, Miller PE, et al. The pharmacologic assessment of a novel lymphocyte function-associated antigen-1 antagonist (SAR 1118) for the treatment of keratoconjunctivitis sicca in dogs. Invest Ophthalmol Vis Sci. 2011 May 16;52(6):3174-80.11. DeVivo AJ, Scheid T. Anti-infl ammatories in Ocular Allergy Treatment. Review of Optometry. 2013 Feb.12. Gomes PJ. Trends in prevalence and treatment of ocular allergy. Curr Opin Allergy Clin Immunol. 2014 Oct;14(5):451-6.

Above: a presentation of severe contact dermatitis. Below: the same patient

one week later after a six-day Medrol (methylprednisolone) Dosepak.



1. The Type I allergic reaction begins with which of the following?

a. Early-phase response. b. Late-phase response. c. Sensitization phase. d. Inflammatory phase.

2. How many categories of allergies are there?

a. 2. b. 3. c. 6. d. 4.

3. What is the most common type of preformed mediator involved in the allergic

response?

a. Histamine. b. Neutral protease. c. Proteogylcan. d. TNF-alpha.

4. How many hours after mast cell degranulation does the allergic late-phase

reaction commence?

a. 1 to 3. b. 4 to 6. c. 8 to 10. d. 12 to 14.

5. What is the primary purpose of antihistamine?

a. To block antihistamine receptors in the conjunctiva and eyelids. b. To inhibit mast-cell degranulation. c. To relieve conjunctival hyperemia. d. To prevent rhinitis.

6. Why are OTC topical antihistamine/mast-cell stabilizers considered less

effective than their prescription counterparts?

a. Longer shelf life. b. Lower afinity for histamine receptors. c. Better mast-cell stabilization effects. d. Contraindication for VKC.

7. What side effect(s) may accompany topical steroid use in treating allergies?

a. Inflammation. b. Elevated intraocular pressure. c. Cataract formation. d. B and C.

8. What combination of drugs is most likely to provide the most symptomatic

relief of ocular allergies?

a. Topical NSAIDs and topical antihistamine/mast-cell stabilizers. b. Topical steroids and topical NSAIDs. c. Topical immunosuppressants and topical antihistamines. d. Topical antihistamine/mast-cell stabilizers and topical NSAIDs.

9. What is the key hallmark sign of Type IV allergies?

a. Chemosis. b. Contact dermatitis. c. Giant papillary conjunctivitis. d. Cataract formation.

10. Current estimates suggest what percentage of the overall population suffers

from allergic conjunctivitis?

a. 10%. b. 20%. c. 30%. d. 60%.

CE TEST ~ MARCH 2016 EXAMINATION ANSWER SHEET

Staying on Target: Managing the Complex Ocular Allergic Reaction

Valid for credit through March 1, 2019

Online: This exam can also be taken online at www.reviewofcontactlenses.com. Upon passing the exam, you can view your results immediately. You can also view your test history at any time from the website.

Directions: Select one answer for each question in the exam and completely darken the appropriate circle. A minimum score of 70% is required to earn credit.

Mail to: Jobson Optometric CE, Canal Street Station, PO Box 488 New York, NY 10013

Payment: Remit $20 with this exam. Make check payable to Jobson Medical Information LLC.

Credit: COPE approval for 1 hour of CE credit is pending for this course.

Sponsorship: Joint-sponsored by the Pennsylvania College of Optometry

Processing: There is an eight-to-10 week processing time for this exam.

Answers to CE exam:

1. A B C D 6. A B C D

2. A B C D 7. A B C D

3. A B C D 8. A B C D

4. A B C D 9. A B C D

5. A B C D 10. A B C D

Evaluation questions (1 = Excellent, 2 = Very Good, 3 = Good, 4 = Fair, 5 = Poor)Rate the effectiveness of how well the activity: 11. Met the goal statement: 1 2 3 4 5

12. Related to your practice needs: 1 2 3 4 5

13. Will help improve patient care: 1 2 3 4 5 14. Avoided commercial bias/influence: 1 2 3 4 5

15. How do you rate the overall quality of the material? 1 2 3 4 5

16. Your knowledge of the subject increased: Greatly Somewhat Little 17. The difficulty of the course was: Complex Appropriate Basic

18. How long did it take to complete this course? _________________________

19. Comments on this course: _________________________________________

___________________________________________________________________

20. Suggested topics for future CE articles: ______________________________

___________________________________________________________________

Identifying information (please print clearly):

First Name

Last Name

Email

The following is your: Home Address Business Address

Business Name

Address

City State

ZIP

Telephone # - -

Fax # - -

By submitting this answer sheet, I certify that I have read the lesson in its entirety and completed the self-assessment exam personally based on the material present-ed. I have not obtained the answers to this exam by fraudulent or improper means.

Signature: ________________________________________ Date: _____________

Please retain a copy for your records. LESSON 112402, RO-RCCL-0316



By Robert Ensley, OD, and Heidi Miller, OD

The GP Experts

Once considered antiquated, this design has recently fl ourished as a way to help patients with ocular surface disease.

Springtime for Sclerals

Even Adolf Fick himself, who created the fi rst scleral contact lens in 1888, would be surprised by the longevity of his

creation. Composed of blown glass, Fick’s lenses and those that followed enjoyed relatively limited popularity due to diffi culties with manufactur-ing and poor oxygen transmission.1

Materials improvements weren’t enough to keep the design from being eclipsed by corneal-fi tted lenses, fi rst gas permeables and then hydrogels.

However, the intractable symp-toms experienced by patients with ocular surface disease and their persistent inability to comfortably wear contact lenses—coupled with developments in computer-aided de-sign—has led these specialty lenses to regain popularity in more recent

years.2 Sclerals are most commonly indicated for correction of irregular astigmatism in corneal conditions like keratoconus, or following surgical procedures like penetrating keratoplasty.

FITTING THE LENS

The appropriate fi t for a scleral contact lens is comprised of com-plete vault of the cornea, clearance of the limbus and alignment with the sclera, with little to no blanching of the conjunctival blood vessels. Vault, or corneal clearance, is defi ned as the space between the back surface of the scleral lens and the front surface of the cornea.8

Practitioners can use diagnostic lenses when trial fi tting a patient; additionally, they can employ optical section slit beam or anterior segment optical coherence tomogra-phy (OCT) to assist.

With the former, corneal clear-ance is determined via comparison of the known center thickness of the contact lens with the thickness of the post-lens tear fl uid reservoir. Instilling fl uorescein into the lens chamber may make assessment easier.

OCT, by contrast, employs a cross-sectional view of the cornea and scleral lens to generate a clear measurement of central vault. This minimizes the amount of subjective infl uence on vault assessment to provide a more precise measure-ment. OCT-guided fi tting is especial-ly useful for troubleshooting cases in which a patient may be experiencing discomfort, but the underlying cause is not evident during a slit lamp ex-amination. For example, if a patient

is complaining of rebound redness and soreness following a day of lens wear, but no conjunctival blanching is observed, the lens may be fi tting tighter than expected; this can be determined using OCT to assess the degree of lens settling.

Scleral contact lenses can be differentiated based on the overall diameter or location of lens bearing on the eye. Most recently, sclerals have been divided into two groups: corneo-scleral and full scleral. A corneo-scleral GP lens (12.5mm to 15.0mm in diameter) shares bearing on the cornea and the sclera. This is in contrast to a full scleral in which the entire lens bearing is on the sclera. The full scleral group can be further divided into mini-scleral (15.0mm to 18.0mm in diame-ter) and large scleral (18.0mm to 25.0mm in diameter).12 In compar-ison to corneal GP lenses, scleral lenses have minimal tear exchange, a thick tear layer and increased lens thickness. It is important to use materials with Dk values of 100 or more to increase oxygen transmissibility.10

Scleral lenses settle into the conjunctiva over a period of time, resulting in a reduction of corneal clearance by 100µm to 150µm. It is necessary to take this into account when evaluating the lens on the eye to ensure there is enough corneal clearance for the patient. In a study evaluating changes in over-refrac-tion after settling, there was no signifi cant change in over-refrac-tion.9 Therefore, visual acuity is not affected following lens settling.9

Though the amount of corneal vault prescribed varies, a minimum

Fig. 2. Central vault displayed using

optical section slit beam.

Fig. 1. Exposure keratopathy patient

secondary to incomplete eyelid

closure.

030_GPE-PSP.indd 30030_GPE-PSP.indd 30 3/3/16 5:01 PM3/3/16 5:01 PM


of 100µm to 400µm of sagittal depth post-settling is recommend-ed to avoid complications such as apical touch of contact lens on cornea, hypoxia and corneal edema. Some larger diameter scleral lenses may even require up to 500µm of clearance for a proper fi t. For patients with ocular surface disease in particular, a greater sagittal depth is typically best. Larger diameter scleral lenses also allow for more hydration of the complete ocular surface area.10

Practitioners should remain aware that the aforementioned rule may not always be the case. A study that attempted to establish an average central corneal vault at which dry eye patients were successful in scleral lenses did fi nd the average vault for successful patients was 380µm, with a standard deviation of 110µm. However, the range of successful vaults in the study led re-searchers to conclude that precision in central vault was not important in scleral contact lenses for a suc-cessful fi t over a compromised oc-ular surface. They also determined there was no correlation between vault and corneal curvature or vault and visual acuity. Patients with as low as 220µm and up to 600µm of central vault were able to achieve a visual acuity of 20/20.8 Ultimately, it is up to practitioners to determine what is best for each patient.

MANAGING OSD

Many practitioners have begun to use scleral lenses to manage dif-ferent ocular surface diseases—in-cluding keratoconjuctivitis sicca, graft-vs.-host disease, cicatrizing

conjunctivitis, neurotrophic keratopathy, exposure ker-atopathy and limbal stem cell defi cien-cy—in place of extensive artifi cial tear, topical cyclosporine, punctal occlu-sion or topical corticosteroid use.3-6 Scleral lens therapy may also bypass the need for more aggressive surgical interventions like tarsorrp-haphy, conjunctival fl ap or amniot-ic membrane grafting.6

Patients suffering from ocular surface disease who may be good candidates for scleral lens wear often display symptoms related to ocular pain, visual disturbance and tear fi lm instability.7 The continued hydration and protection provid-ed by these lenses both improves visual acuity and provides lasting comfort. A retrospective study in which 212 subjects were fi t with scleral lenses to evaluate the success of long-term therapy found that goals of better visual acuity, comfort, ocular surface protection and resolution of keratopathy were achieved in all but two subjects. Researchers noted the participants had attempted an average of 3.2 other forms of intervention prior to scleral lens wear; they concluded that commercially available scleral lenses are suitable for the manage-ment of moderate to severe ocular surface disease.6

TIPS FOR ALLERGIES

Ocular allergies affect up to 30% of the general population and have been shown to result in tear fi lm instability.11 In patients suffering from allergies, scleral lenses can pose more of a problem as the allergens remain in the lens reservoir for prolonged periods of time due to minimal tear exchange underneath the lens. Though little has been pub-lished on this topic, from personal experience scleral lens wear with allergies requires more maintenance to avoid bulbar injection and itchy, irritated eyes. A common issue with allergies is the development of a biofi lm on the front and back surface of the contact lens. This not only affects the quality of vision but can also lead to lens discomfort. Usually, patients remove their lenses, clean the front and back surface to remove any biofi lm or debris buildup and replenish the lens with non-preserved saline multiple times throughout the day.

Use of a prescription strength an-tihistamine and mast-cell stabilizer

(Continued on page 33)

Fig. 2. Central vault displayed using OCT.



By Elyse L. Chaglasian, OD, and Tammy Than, MS, OD

Pharma Science & Practice

A Firm FoundationNew mucin-enhancing drug could support tear fi lm stability from the ground up.

Dry eye treatment recently received a publicity boost when Allergan announced a licensing agreement

with Mimetogen Pharmaceuticals to develop and commercialize MIM-D3 in November 2015.1 MIM-D3 is an ophthalmic solu-tion of tavilermide that is current-ly in Phase III trials for treatment of ocular surface disease.

This stable, cyclic peptide that mimics part of the structure of nerve growth factor (NGF) and is mechanistically classifi ed as a partial TrkA receptor agonist.2

Like the recent column on lifi te-grast (Nov. 2015), discussion of this drug marks another encoun-ter with a novel mechanism that warrants an examination.

NGF belongs to the neurotro-phin family and is an essential protein in the differentiation and survival of neurons. Signaling of NGF is mediated by the activa-tion of a tyrosine kinase receptor (TrkA) and p75 neurotrophin receptor (p75NTR). When NGF binds to TrkA, numerous path-ways are activated including the phospholipase C-1 cascade.

Activation of P75NTR, which belongs to the tumor necrosis factor receptor family, often results in effects that oppose the TrkA receptors, including apop-tosis. This also stimulates growth of projections from a neuron cell body (i.e., neurite outgrowth).2,3 NGF and TrkA are present on the ocular surface suggesting a role in homeostasis, corneal healing and nerve function.3

Topically, NGF has demon-strated corneal healing in subjects with a variety of corneal diseases; however, despite these benefi ts, it has poor bioavailability, is costly to manufacture and stimulates pain due to neurite sprouting, making it a poor therapeutic op-tion. MIM-D3 is a partial TrkA receptor agonist with similar

effects to NGF at the TrkA recep-tors, with one difference: it does not bind to the p75NTR receptor, thereby minimizing the associated stimulated pain.2,3

THE BREAKDOWN

In cell culture experiments, re-searchers found NGF-stimulated secretion of mucin. Animal mod-els have also shown that topical

NGF increases goblet cell density. Therefore, interest in MIM-D3 as a novel mimicker of NGF is attractive. Using a rat model of dry eye, MIM-D3 showed a sig-nifi cant improvement in corneal staining.2

A Phase II study randomized 150 dry eye patients to one of three groups: tavilermide 1%, tavilermide 5% or placebo. Study participants used the medication twice a day for 28 days, while a controlled adverse environment (CAE) was incorporated to ex-acerbate and standardize dry eye presentations. Primary outcomes included one objective (i.e., fl uorescein corneal staining) and one subjective (i.e., diary worst symptom score over 28 days) measure. Patients rated symptoms

of burning, dry-ness, grittiness and stinging on a scale of zero to fi ve.

No serious ocu-lar adverse events occurred in any treatment group, but the primary endpoints were not met. There was, however, an improvement in

corneal staining. Additionally, in a subset of participants with higher symptom scores at the time of randomization, there was a signifi cant treatment effect not-ed in both treatment groups.3,4,5

Recently, a Phase III trial enrolling 403 dry eye patients to receive MIM-D3 1% or placebo concluded. The patients used the study medication twice a day

“MIM-D3 APPEARS TO BE AN EXCITING DRUG THAT MAY PROVIDE US WITH A NEW MECHANISM TO ESTABLISH A NORMAL, HEALTHY

OCULAR SURFACE.”



for 56 days and were stratifi ed into patients with cataracts and those with a normal crystalline lens. There was signifi cantly less fl uorescein corneal staining in the treatment groups after 56 days, and improvements in symptoms were also noted. A dramatic difference in treatment response was noted in the cataract group compared with those with no lenticular opacities. Patients with cataracts had signifi cant improve-ment in staining and the ocular surface disease index question-naire (OSDI). Those with normal lenses had improvement in the oc-ular discomfort symptom scores compared with the placebo.5,6

A second multi-center Phase III study is currently recruiting

patients with an estimated enroll-ment of 400 to be randomized to either receive MIM-D3 1% or placebo twice a day for 56 days. Primary outcome measures are corneal staining and ocular dis-comfort. The estimated comple-tion is July 2016.5

A decrease in conjunctival goblet cell density along with

a corresponding reduction in the secretion of ocular surface mucins may be noted in patients with dry eye. Although therapies rarely target this specifi c mechanism or these defi ciencies, MIM-D3 ap-pears to be an exciting drug in the pipeline that may provide us with a new mechanism to establish a normal, healthy ocular surface. RCCL

1. PR Newswire. Allergan Enters Into Licensing Agreement with Mimetogen Pharmaceuticals to Develop and Commercialize Tavilermide (MIM-D3) Topical Dry Eye Treatment. Available at: www.prnewswire.com/news-releases/aller-gan-enters-into-licensing-agreement-with-mi-metogen-pharmaceuticals-to-develop-and-com-mercialize-tavilermide-mim-d3-topi-cal-dry-eye-treatment-300171929.html. Accessed Dec 30, 2015.2. Jain P, Ruihong L, Lama T, et al. An NGF mimetic, MIM-D3, stimulates conjunctival cell glycoconjugate secretion and demonstrates therapeutic effi cacy in a rat model of dry eye. Exp Eye Res. 2011 Oct;93(4):503-12.3. Meerovitch K, Torkildsen G, Lonsdale J, et al. Safety and effi cacy of MIM-D3 ophthalmic solutions in a randomized, placebo-controlled Phase 2 clinical trial in patients with dry eye. Clin Ophthalmol. 2013;7:1275-85. 4. Ousler G, Meerovitch K. High CAE Responders show greater improvement in signs and symp-toms of dry eye after treatment with MIM-D3. IOVS 2013; 54; E-Abstract 4343.5. Clinical Trials.gov. A safety and effi cacy study of tavilermide (MIM-D3) ophthalmic solution for the treatment of dry eye. Available at: clinicaltri-als.gov/ct2/show/NCT02634853. Accessed Dec 30, 2015.6. Meerovitch K, Brazzell K, Ousler GW, Cumber-lidge G. Improvements in signs and symptoms of dry eye with MIM-D3 1% ophthalmic solution compared to placebo in diff erent patient popula-tions. IOVS 2015; 56: E-Abstract 4460.

THE GP EXPERTS: SPRINGTIME FOR SCLERALS(Continued from page 31)

combination drop is recommended prior to the application of scleral lenses. The use of non-preserved artifi cial tears several times through-out the day may be necessary. Adding a few drops of a non-pre-served artifi cial tear with higher viscosity into the lens reservoir may help slow tear exchange.

Giant papillary conjunctivitis (GPC) may occur with scleral lens wear due to mechanical irritation of the lid with potential lens surface debris buildup. GPC can also cause excessive debris issues on the surface of the lens and affect wettability. In patients with allergies, it is best to use a peroxide care system for over-night cleaning. Peroxide systems are neutral and safe to the eye and pro-

vide adequate disinfection. Special large cases made specifi cally for scleral lenses are available for those requiring peroxide cleaning.10

There are numerous scleral lens products available already, with

continued improvements in design and function being made daily. Scleral lenses now provide practi-tioners with a tool to better manage patients who suffer from ocular surface disease and help them regain clear and comfortable vision. RCCL

1. Mandell R. Contact Lens Practice. 4th ed. Sprin-fi eld, Ill., Thomas; 1988.2. Jacobs DS. Update on scleral lenses. Curr Opin Ophthalmol. 2008 Jul;19(4):298-301.3. Weyns M, Koppen C, Tassignon MJ. Scleral contact lenses as an alternative to tarsorrhaphy for the long-term management of combined exposure and neurotrophic keratopathy. Cornea. 2013

Mar;32(3):359-361.4. Grey F, Carley F, Biswas S, Tromans C. Scleral contact lens management of bilateral exposure and neurotrophic keratopathy. Cont Lens Anterior Eye. 2012 Dec;35(6):288-291.5. Schornack MM. Limbal stem cell disease: man-agement with scleral lenses. Clin Exp Optom. 2011 Nov;94(6):592-4.6. Schornack MM, Pyle J, Patel SV. Scleral lenses in the management of ocular surface disease. Oph-thalmology. 2014 Jul;121(7):1398-1405.7. Bavinger JC, DeLoss K, Mian SI. Scleral lens use in dry eye syndrome. Curr Opin Ophthalmol. 2015 Jul;26(4):319-24.8. Sonsino J, Mathe DS. Central vault in dry eye patients successfully wearing scleral lens. Optom Vis Sci. Sep 2013;90(9):e248-251; discussion 1030.9. S. Britton CB, Yeung D, Haines L, Sorbara L. Changes in over-refraction after scleral lens set-tling. Waterloo, Ontario, Canada: School of Optom-etry & Vision Science, University of Waterloo.10. van der Worp E SS. A Guide to Scleral Lens Fitting: College of Optometry, Pacifi c University. 2010.11. Fujishima H, Toda I, Shimazaki J, Tsubota K. Al-lergic conjunctivitis and dry eye. Br J Ophthalmol. 1996 Nov;80(11):994-997.12. Kauff man MJ, Gilmartin CA, Bennett ES, Bassi CJ. A comparison of the short-term settling of three scleral lens designs. Optom Vis Sci. 2014 Dec;91(12):1462-1466.


By Gary Gerber, OD

Out of the Box


Are You Allergic to Change?While getting past certain barriers to practice-building can take some eff ort,long-term benefi ts are worth it.

It feels like I’ve been discuss-ing the addition of dry eye and allergy services to eye care practices for a while now. So, when I began this

month’s column, I asked myself what other strategies I could possibly share with practitioners that I hadn’t already covered. After taking a step back to think for a moment, I realized the question should be: Why haven’t more adopted these ideas already? More to the point—why are prac-titioners so resistant? After all, with the prevalence of dry eye and ocular manifestations of allergy so high, it’s almost a given that these issues should be part of every primary eye care practice. So, why don’t more of us include them?

The answer, of course, is typical: change, and our resis-tance to it. More specifi cally, the uncomfortable confrontation of the inevitable fear that happens before a new action or policy is added. However, facing this emotion head-on is key to serving our patients—and ultimately, our practices and ourselves—better, so we must consider it.

OBSTACLES TO OVERCOME

Here are four reasons why many doctors are likely hesitant to include more dry eye and allergy care into their practice:

• Getting sucked into the dry eye “treatment fad of the month” vortex and forgoing individuali-ty. My teenage daughter has joked with me for years, “But Dad, all the cool kids are doing it!” In this case, “it” refers to a common

adolescent behavior that I can’t relate to but that my daughter wishes to partake in. Some eye care practitioners feel the same with dry eye and allergy and are happy to offer the same range of treatments to their patients as everyone else. Others, however, may feel doing so is effectively forfeiting their sense of autonomy and control over their practice to become “just another eye care practitioner.”

My advice is to get past this concern and realize that your patients will not see it this way. Going with the fl ow with dry eye and allergy actually provides nothing but patient benefi ts—af-ter all, with these being common enough problems, not providing them will, in fact, likely drive patients away. To alleviate some of the shock, try adding certain treatments before others and ask-ing for feedback from patients.

•We’re more comfortable with the devil we know. Few of us can honestly say our practices are perfect, but at least we’re familiar with our imperfections and their effects on our day-to-day opera-tion. However, no one can say for certain what offering a higher or different standard of care might do. Not knowing what’s around the corner can be extremely unnerving and potentially cause practice-building paralysis.

My advice: acknowledge and accept these fears. It’s true that you don’t know what awaits you if you make changes to your prac-tice. However, keep in mind that you also have no idea what the

future will bring. What if forgoing those changes in fact leads to a worse outcome? In this case, the best option is to institute careful planning and education prior to any decisions to mitigate disas-trous results and stack the odds in your favor. Plan to be successful, and you will be.

•My staff will hate me for this. On the contrary, it’s likely that nearly all—if not all—of your staff members are anxious to learn more and assist patients in a better capacity. Most staff mem-bers are excited to break away from routine activities to learn and execute something new. My advice is simply to avoid springing everything on them at once. Share with them some of the changes, let them digest and process the in-formation and then provide them with more.

•What if I can’t do this? Fear of clinical failure is a common reason many practitioners avoid change. This is even more the case with the legal ramifi ca-tions that can come with clinical missteps. However, if we never took any risks in an attempt to design a better solution, refrac-tions would still be performed with trial frames, and penlights would still be used for contact lens exams. It’s likely you have already learned new clinical skills repeatedly in the past and thought nothing of it. Why would now be any different? And as always, help can be found along the way in the form of literature and colleagues. So take a deep breath, and a step forward. RCCL

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allergy issue of cornea & contact lenses · nus ranging from age 25 to 51. patients were...

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