The Hunt for Dry Eye Instigators

RCCL MAY 2014 REVIEW OF CORNEA & CONTACT LENSES

EARNARN 2 CECE CREDITSREEDITDITS The Hunt for Dry Eye Instigators Treatment optionsns thtthathatt ttargetarargeet iniinflnfl amaammatorymmamatotory mmediatorseeddiai totorsr in the tear fi lm may help clinicians achieve victory over this often diffi cult to manage condition.

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Controlling the ocular immune response • bring sjÖgren’s out of the shadows

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RCCL0514_Alcon Dailies.indd 1 4/15/14 2:09 PM contents Review of Cornea & Contact Lenses | May 2014

departments

4 News Review A New Treatment for Allergic Conjunctivitis?; features A Balanced Dry Eye Diet Controlling the 6 My Perspective Ocular Immune Response LSCD—It May Be the Lenses We must strive to limit its untoward eff ects without undermining its essential role in By Joseph P. Shovlin, OD protection and healing. 12 By Aaron Bronner, OD 7 Lens Care Insights Wash Away Your Old Hygiene Strategy It’s Time to Bring Sjögren’s By Christine W. Sindt, OD Out of the Shadows This autoimmune disease can go undiagnosed for years. By working closely with other health Pharma Science & Practice care providers, we may be able to detect it in 8 its earliest stages. 16 By Arthur B. Epstein, OD, The Source of the Irritation By Elyse L. Chaglasian, OD, and Paul M. Karpecki, OD and Tammy P. Than, OD, MS

10 The GP Expert Surveyor of the Surface By Stephanie L. Woo, OD 20

Corneal Consult 30 CE — The Hunt for Stemming the Tide Dry Eye Instigators By James Thimons, OD Treatment options that target inﬂ ammatory mediators in the tear ﬁ lm may help clinicians achieve victory over this often diffi cult to manage condition. Derail Dropouts 32 By Michelle M. Hessen, OD Patch It Up By Mile Brujic, OD, and Clinical image on the cover courtesy of Mark Abelson, MD/Ora, Inc. Jason R. Miller, OD, MBA

34 Out of the Box Can’t We All Just Get Along? By Gary Gerber, OD

REVIEW OF CORNEA & CONTACT LENSES | MAY 2014 3 /ReviewofCorneaAndContactLenses #rcclmag

003_rccl0514_TOC (v2).indd 3 4/25/14 4:57 PM News Review

IN BRIEF A New Treatment for

• Google has applied for a pat- Allergic Conjunctivitis? ent to fit a camera into a contact lens. According to the application, inserting the camera into the lens se of tacrolimus score decreased to 5.9. The mean will not dramatically increase the 0.1% eye drops is total score of clinical symptoms thickness of the lens. The addition of cameras will allow the lenses highly effective in decreased from 8.1 at baseline to process images and collect a treating refractory to 1.8 at fi nal observation. Ad- variety of data, such as motion, U allergic conjuncti- ditionally, both giant papillae colors, face, etc. Additionally, the vitis, according to a study pub- and corneal lesions were reduced contact lenses may include sen- lished in the April 2 online British signifi cantly (p<0.001) following sors that would be used to track blinking, which could be used to Journal of Ophthalmology. use of tacrolimus 0.1%. control or trigger devices remote- The prospective observational Prior to initiating tacrolimus ly via blinks. study evaluated the eyes of 1,436 therapy, 239 patients were treated patients with refractory aller- with cyclosporine 0.1% eye drops • Johnson & Johnson announced gic conjunctivitis who did not for at least one month; these pa- that the company is now accept- respond favorably to prior treat- tients exhibited giant papillae or ing research proposals related to meibography and tear film ment with conventional allergy corneal epithelial disorder scores stability with contact lens wear. drugs, topical steroids and/or greater than two at initiation of Specifically, J&J is looking for topical cyclosporine. treatment. Following one month research proposals in the areas During the trial, tacrolimus of tacrolimus use their clinical of correlating clinical findings to 0.1% drops were administered signs score decreased from 16.8 to meibomian gland image analysis and tear film stability, and cat- twice daily to each patient. The 6.7, and their clinical symptoms egorizing the magnitude of mei- researchers rated 10 clinical signs score decreased from 9.1 to 1.9. bomian gland changes to contact (palpebral conjunctiva hyperemia, The researchers noted adverse lens type or length of wear. To diffuse edema, follicles, papillae, reactions in 117 patients, with the inquire about proposal submis- giant papillae, bulbar conjunctiva only major reaction being a burn- sion, contact the Clinical Research Administrator at RA-VISUS- hyperemia, bullous edema, limbal ing sensation (45 cases). [email protected]. trantas’ dot, swelling and corneal Additionally, two cases of epithelial signs) and six clinical bacterial keratitis, two cases of • Smoking tobacco has a nega- symptoms (itching, discharge, herpetic keratitis and one case of tive impact on the healing lacrimation, photophobia, foreign bacterial corneal ulceration were process of corneal insults. In a body sensation and eye pain) on a observed. Atopic dermatitis or study published in the May 2014 Cornea, researchers reviewed the four-grade scale (0=none, 1=mild, asthma was noted as an underly- charts of 87 patients with corneal 2=moderate and 3=severe). ing condition in these cases. abrasions and 52 patients with Patients were graded at base- Initially developed as an immu- keratitis between 1990 and 2010. line, one month, two months, nosuppressant for use following The study demonstrated that three months and six months. The organ transplantation, tacrolimus epithelial healing is delayed 1.1 days on average in smokers vs. total score of both the 10 clinical is now used clinically for multiple non-smokers, and 23.9 days on signs (range 0-30) and six clinical immune-mediated conditions. The average in smokers with keratitis. symptoms (range 0-18) decreased researchers suggest that the use of Additionally, neurotrophic corneas signifi cantly from baseline to the topical tacrolimus is both safe and and fungal infections also exhib- one-month evaluation (p<0.001), effective in treating patients with ited a prolonged healing period in smokers. indicating the agent’s ability to severe allergic conjunctivitis. provide rapid relief. Fukushima A, et al. Therapeutic effects of Jetton JA, et al. Effects of tobacco At baseline, the mean total 0.1% tacrolimus eye drops for refractory aller- smoking on human corneal wound gic ocular diseases with proliferative lesion or healing. Cornea. 2014 May;33(5):453-6. score of clinical signs was 15.3; at corneal involvement. Br J Ophthalmol. 2014 fi nal observation, the mean total Apr 2. [Epub ahead of print]

4 REVIEW OF CORNEA & CONTACT LENSES | MAY 2014

004_rccl0514_news.indd 4 4/25/14 5:11 PM RCCL REVIEW OF CORNEA & CONTACT LENSES

JOBSON PROFESSIONAL PUBLICATIONS GROUP 11 Campus Blvd., Suite 100 Newtown Square, PA 19073 Telephone (610) 492-1000 A Balanced Dry Eye Diet Fax (610) 492-1049 Editorial inquiries (610) 492-1003 Advertising inquiries (610) 492-1011 E-mail [email protected] Mediterranean diet D was inversely correlated with EDITORIAL STAFF may actually have a the infl ammatory marker soluble EDITOR-IN-CHIEF negative effect on dry interleukin-2 receptor. Jack Persico [email protected] eye symptoms, while Each patient was asked to fi ll ASSOCIATE EDITOR A Frank Auletto [email protected] increased intake of vitamin D may out a 2005 Block Food Frequency CLINICAL EDITOR have a small but positive effect, Questionnaire and the 5-item Dry Joseph P. Shovlin, OD, [email protected] EXECUTIVE EDITOR according to a study published in Eye Questionnaire. Additionally, Arthur B. Epstein, OD, [email protected] the May 2014 Cornea. an ocular surface examination ASSOCIATE CLINICAL EDITOR Two hundred forty-seven male consisting of tear osmolarity Christine W. Sindt, OD, [email protected] CONSULTING EDITOR patients between 55 and 95 years evaluation, tear break-up time, Milton M. Hom, OD, [email protected] old (mean age 69) at the Miami corneal staining, Schirmer’s test SENIOR ART/PRODUCTION DIRECTOR Joe Morris [email protected] Veteran’s Affairs eye clinic with was conducted on each patient. GRAPHIC DESIGNER normal eyelid, corneal and con- Patients who adhered to the Matt Egger [email protected] junctival anatomy were recruited Mediterranean diet were actually AD PRODUCTION MANAGER Scott Tobin [email protected] to undergo dry eye testing follow- found to have an increased risk of BUSINESS STAFF ing dietary changes. dry eye (p=0.007). Patients who VICE PRESIDENT OPERATIONS The subjects adhered to the reported a higher Mediterranean Casey Foster [email protected] Mediterranean diet, which in- diet score on the food frequency SALES MANAGER, NORTHEAST, MID ATLANTIC, OHIO cludes a relatively high intake of questionnaire (i.e., those who James Henne [email protected] fruits, vegetables, monounsaturat- adhered to the plan) demonstrated SALES MANAGER, SOUTHEAST, WEST Michele Barrett [email protected] ed fat, fi sh, whole grains, legumes abnormal meibum quality, abnor- and nuts, as well as moderate mal staining and higher Schirmer’s EDITORIAL BOARD Mark B. Abelson, MD alcohol consumption. In addition, test scores. Vitamin D levels ex- James V. Aquavella, MD the overall intake of red meat, hibited no signifi cant association Edward S. Bennett, OD Aaron Bronner, OD saturated fat and refi ned grains is with dry eye parameters; however, Brian Chou, OD signifi cantly decreased. increased levels of vitamin D S. Barry Eiden, OD Gary Gerber, OD Previous studies have demon- were signifi cantly associated with Susan Gromacki, OD strated that the Mediterranean a decreased presence of dry eye Brien Holden, PhD Bruce Koffler, MD diet may be a protective factor symptoms (p<0.01). Jeffrey Charles Krohn, OD against all-cause mortality, coro- While the Mediterranean diet Kenneth A. Lebow, OD Kelly Nichols, OD nary heart disease and diabetes. has been shown to improve Robert Ryan, OD Because the diet is linked to a systemic health, there was no ben- Jack Schaeffer, OD Kirk Smick, OD decrease in infl ammatory markers, efi cial effect on dry eye symptoms. Barry Weissman, OD there is plausibility that it may However, higher levels of vitamin REVIEW BOARD have an effect on dry eye disease. D exhibited a small but favorable Kenneth Daniels, OD Desmond Fonn, Dip Optom M Optom Additionally, the researchers effect on dry eye disease. Robert M. Grohe, OD examined the effects of increased Galor A, Gardener H, Pouyeh B, et al. Effect Patricia Keech, OD of a Mediterranean dietary pattern and Jerry Legerton, OD vitamin D intake on dry eye vitamin D levels on dry eye syndrome. 2014 Charles B. Slonim, MD disease, as 25-hydroxy vitamin May;33(5):437-41. Mary Jo Stiegemeier, OD Loretta B. Szczotka, OD Michael A. Ward, FCLSA Barry M. Weiner, OD Advertiser Index Alcon Laboratories ...... Cover 2, Cover 4 CooperVision ...... Cover 3 Hydrogel Vision ...... Page 19

REVIEW OF CORNEA & CONTACT LENSES | MAY 2014 5

004_rccl0514_news.indd 5 4/28/14 9:32 AM My Perspective By Joseph P. Shovlin, OD

LSCD—It May Be the Lenses We must be on the lookout for limbal stem cell deﬁ ciency early in its course, especially in contact lens wearers, to avoid the need for surgical intervention.

very year we see a defi ciency, with a special focus on pression, often are not an option handful of soft con- treatment options. because both eyes are generally tact lens wearers who involved (though the fellow eye present with signifi cant LOOK FOR THE SIGNS may be subclinical). This requires Estem cell defi ciency Early signals of stem cell defi ciency allograft surgery with immuno- (LSCD). Unlike acute stem cell (exhaustion) can encompass a suppression, using either cadaver changes associated with chemical multitude of signs. A few examples or living relative limbal stem cell injury, surgery, radiation, trauma include a whorl keratopathy and a donors.2,3 or congenital defi ciencies caused confl uent staining in a saw-tooth There are several options for by aniridia, stem cell defi ciencies pattern, representing a diffi culty in immunosuppression, including associated with lens wear have repopulating the epithelium in that medications such as cyclosporine, features that include chronicity.1-3 region of the cornea.1 tacrolimus, mycophenolate mofetil And that distinction gives us a All of this ultimately leads to a and corticosteroids.1 Also, patients window of opportunity to control non-healing defect and extensive will require very close monitoring its course. irregularity of the corneal surface; for possible side effects.1 The cause is most likely multi- conjunctivalization of the cornea Practitioners should continue to factorial and seems to be driven can also occur wherein the con- pay close attention to the limbus by an underlying infl ammation junctiva grows past the limbus and peripheral corneal epithelium, and hypoxia, toxicity from the use because there is no intact barrier.1-3 as well as any accompanying ocu- of multipurpose solutions, and a A marked drop in acuity (increase lar surface disease in every soft lens mechanical component from over- in with-the-rule astigmatism), tear- wearer. Ongoing surveillance for wear of soft lenses. ing, foreign body sensation and mild forms of the disease is critical! Many of the patients I’ve seen pain may occur. Remember the hallmarks—LSCD with this condition also have an One method of identifying is insidious and recalcitrant, and accompanying ocular surface LSCD, impression cytology, is done I suspect it’s an under-recognized disease such as rosacea, meibo- by pressing fi lter paper to the lim- complication of lens wear.3 mian gland dysfunction, dry eye bus. This simple procedure can de- It’s important to stress that early or other additional drivers of tect a defi ciency by confi rming the recognition and intervention may infl ammation. Of great interest, a presence and density of goblet cells prevent the need for surgical inter- disproportionate number of female from the cornea and conjunctiva. vention.3 Additionally, a lens wear wearers are affected, perhaps due Confocal microscopy and even holiday or hiatus with a modifi ca- to additional confounding fac- OCT imaging can help detect early tion in wearing time, a change in tors (e.g., number of hours of lens changes of stem cell defi ciency by solution or a switch to GP lenses wear, make-up, dry eye, etc.).3 characterizing the stem cell niche may help ward off potentially seri- As eye care practitioners who fi t or palisades of Vogt.1 ous complications associated with contact lenses and manage their Holland and Schwartz have this disease. RCCL complications, it’s important to proposed a grading system fi rst recognize the problem, and whereby >50% clock-hour involve- 1. Raju LV: Stem cell deficiency: how to recognize it, what to do about it. Ocular Surgery second to be able to manage the ment and/or visual axis incursion News (suppl.); Feb., 2014. complication in a timely and ap- constitutes severe disease.3 Unfor- 2. Jeng BH, Halfpenny CP, Meisler DM, Stock EL: Management of limbal stem cell propriate fashion. tunately, when left unchecked and deficiency associated with soft contact lens In this month’s Corneal Consult untreated, progression may require wear. Cornea. 2011 Jan.;30(1):18-23. column (page 30), Jim Thimons surgical intervention. 3. Chan CC, Holland EJ: Severe limbal stem cell deficiency from contact lens highlights the many facets of early Stem cell autografts, although wear:patient clinical features. Am J Ophthal- recognition of limbal stem cell negating the need for immunosup- mol. 2013 Mar;155(3)544-549.

6 REVIEW OF CORNEA & CONTACT LENSES | MAY 2014

006_rccl0514_mp.indd 6 4/25/14 11:41 AM Lens Care Insights By Christine W. Sindt, OD

Wash Away Your Old Hygiene Strategy Early impressions of a new eyelid cleansing option to help keep your patients’ eyes clean and microbe-free.

t really is no secret that harbor organisms up to 70% of the ing capability without extraneous clean eyelids promote time.5 Additionally, substantial lid ingredients such as surfactants. healthy contact lens wear. bioburden is associated with a 2.5- Pure hypochlorous acid 0.01% As we’ve all seen clinically, fold greater risk of substantial lens has shown to be fast acting against patients who have blephari- bioburden, and is likely the major the fi ve major bacterial pathogens I 5 tis exhibit signifi cant differences in route of lens contamination. associated with blepharitis during tear physiology than those within-vitro laboratory tests. Although out blepharitis.1 Tear lipids are A NEW OPTION some conventional lid scrubs may oxidatively stable in their native Keeping the lids clean, which in lack antimicrobial activity even environment because meibomian turn keeps the lens clean, directly after prolonged exposure, effi cacy glands predominantly secrete only benefi ts patient comfort, safety and of pure hypochlorous acid 0.01% saturated and monounsaturated quality of vision. The “old-school” was documented after just seconds lipids.2 Stable lipids don’t degrade lid hygiene method included the use of exposure, according to NovaBay and don’t cause discomfort or blur. of diluted baby shampoo to remove Pharmaceuticals. In direct compari- Blepharitis and meibomian gland debris and contaminants. While it sons, the company says, pure hypo- dysfunction (MGD) patients typi- remains convenient and inexpen- chlorous acid 0.01% demonstrated cally experience heavy deposits of sive, this is not as safe or simple as a similar antibacterial spectrum of lipids on their lenses. This phenom- it may sound. activity to Betadine—with 1,000 enon is not limited to these patients, Baby shampoos—as well as some times less toxicity. however. These lipid deposits may eyelid cleansers—contain cocami- Its antibacterial properties make also be seen in those with no ap- dopropyl betaine, a surfactant and i-Lid Cleanser a welcome addition parent MGD due to the individual lathering agent that may cause an to any blepharitis or MGD-related composition of the meibum. Over eyelid dermatitis.6 Surfactants, the dry eye treatment regimen. Addi- time, lipids associated with the key ingredient in most lid scrub tionally, the product can be useful in contact lens will become unstable products, are also known to dry the make-up removal and as an adjunct and degrade. Once formed, these skin and strip the area of oil—ironi- to contact lens wear. RCCL deposits impair optical quality and cally, inducing increased production 1. McCann LC, et al. Tear and meibomian the wettability of the lens surface of oil in the glands. gland function in blepharitis and normals.. (with the latter resulting in a quick A novel product, i-Lid Cleanser Eye Contact Lens. 2009 Jul;35(4):203-8. break-up of the tear fi lm), which (NovaBay Pharma ceuticals), which 2. Panaser A, Tighe BJ. Evidence of lipid degradation during overnight contact lens can eventually lead to intolerance to contains pure hypochlorous acid wear: gas chromatography mass spectrom- contact lens wear.3 0.01%, offers practitioners a new etry as the diagnostic tool. IOVS. March 2014;d55(3):1798. In addition to affecting the tear option for lid hygiene. Hypochlo- 3. Craig JP, et al. The TFOS international fi lm, vision and comfort, the lids rous acid is a naturally occurring workshop on contact lens discomfort: report of the contact lens interactions with the tear play host to myriad microorgan- chemical released by neutrophils to fi lm subcommittee. Invest Ophthalmol Vis isms. Bacterial contamination of kill microorganisms and neutral- Sci. 2013 Oct 18;54(11):TFOS71-97. 4. Willcox MD, et al. Potential sources of soft lenses is associated with micro- ize toxins released from pathogens bacteria that are isolated from contact bial keratitis and corneal infl amma- and infl ammatory mediators. As lenses during wear. Optom Vis Sci. 1997 Dec; tory events. Normal ocular organ- it is neutralized quickly, it’s non- 74(12):1030-8. 5. Stapleton F, et al. Changes to the ocular isms include coagulase-negative toxic to the ocular surface. Other biota with time in extended- and daily-wear Staphylococci, Corynebacterium hypochlorous acid products (e.g., disposable contact lens use. Infect Immun. 1995 Nov; 63(11):4501-5. species, Micrococcus species, Bacil- Dakin) contain impurities (such as 6. Welling JD, et al. Chronic eyelid derma- lus species and Propionibacterium bleach), which are toxic to the ocu- titis secondary to cocamidopropyl betaine 4 allergy in a patient using baby shampoo species. The lid margin, commonly lar surface. In my experience, i-Lid eyelid scrubs. JAMA Ophthalmol. 2014 Mar colonized by microbes, is found to Cleanser offers excellent lid cleans- 1;132(3):357-9.

REVIEW OF CORNEA & CONTACT LENSES | MAY 2014 7

007_rccl0514_lenscare.indd 7 4/25/14 11:42 AM Pharma Science & Practice By Elyse L. Chaglasian, OD, and Tammy Than, MS, OD

The Source of the Irritation Updated information from SCUT and a new in-ofﬁ ce diagnostic test may help us provide better treatment options for many patients.

cular infl amma- nor did they experience an increased • There is some thought that the tion contributes incidence of side effects.2 steroid benefi t may be delayed. to a number of Those who presented with the • Immune-mediated tissue dam- patient symptoms most central, severe corneal ulcers— age may be reduced, corneal remod- Oand, in some cases, which resulted in visual acuity of eling may occur and the scar density can even result in a loss of visual count fi ngers or worse—did appear may be reduced well after steroid acuity. This month’s column will to benefi t from steroid use at the use has been discontinued. review recently released informa- three-month evaulation.2 While this Following this 12-month analysis tion that may provide guidance study may not have had a radical (note that steroid use had been dis- to manage the often-devastating impact on clinical practice, it did continued for over 11 months), the effects of corneal infl ammation as- provide some reassurance to those researchers concluded that adjunc- sociated with microbial keratitis. who opt to use steroids in corneal tive topical steroid therapy might be Additionally, we will cover a new, ulcer management. associated with long-term clinical in-offi ce test that can aid practitio- Additionally, this trial exemplifi es improvement in corneal ulcers not ners in diagnosing ocular surface why it is often important to read caused by Nocardia organisms. infl ammation and selecting an ap- more than just the abstract to un- In a small case series that exam- propriate treatment regimen. derstand the nuances of a study. For ined fi ve patients from SCUT, Mc- example, just 3% of the patients Clintic et al. published dramatic im- REVISITING SCUT were recruited from the US, while ages at presentation, three months We’re all aware of what causes a the remaining 97% were from India and 12 months. Over the course of corneal ulcer: the infectious agent (of which 44% were agricultural the study, the density of the opacity adheres to the corneal epithelium workers).3 As such, the organisms in each patient was dramatically and penetrates into the stroma. The causing the ulcers were different reduced by the 12-month evalua- response to the infection is infl am- than those expected in a study tion. Additionally, when compared mation, degradation of corneal population primarily from the US. to the three-month visits, these structural proteins, ulceration and Another factor to consider: only patients also exhibited improved scarring.1 Because steroid use eight of the 500 subjects were CL BCVA (when fi tted with rigid con- to manage infectious keratitis is wearers—a statistic atypical of a tact lenses) at the 12-month follow controversial, many were hopeful population presenting in the US up.7 This case series demonstrates that the NEI’s Steroids for Corneal with corneal ulcers. Also, the ste- that corneal scars may continue Ulcers Trial (SCUT) would provide roid used was prednisolone phos- to improve for many months after insight on this topic when it was phate rather than acetate; ocular the ulcer has healed and the topical published. To some extent, it did. penetration is much poorer in the steroid has been discontinued. SCUT enrolled 500 patients with former once the cornea has re-ep- culture-confi rmed bacterial ulcers ithelialized.4 This choice of steroid EXAMINE THE TEARS and randomized them to either prompts the question: Had the ac- Matrix metalloproteinases (MMP), prednisolone or a vehicle with a etate formulation been used, would a family of proteolytic enzymes tapering dose over a three-week the outcome have been different? involved in remodeling of normal period; all patients fi rst received Now, with new 12-month SCUT and pathological tissue, have the moxifl oxacin for two days. As we data published on BSCVA and cor- ability to degrade all components of learned in 2012, the study found neal scar size in 399 cases from the the extracellular matrix.8 that a majority of subjects did not original sample, we’ve learned:5,6 While the number of distinct demonstrate an improved outcome • Myofi broblasts and fi broblasts— MMP enzymes continues to grow, in best spectacle-corrected visual active during wound healing—may one is of particular interest to acuity (BSCVA) at three months, help restore corneal transparency. eye care professionals. MMP-9,

8 REVIEW OF CORNEA & CONTACT LENSES | MAY 2014

008_rccl0514_PSP.indd 8 4/25/14 2:48 PM produced by stressed epithelial cells Table 1. Severity Levels of Tear Dysfunction on the ocular surface, is detected and Corresponding Average MMP-9 Levels11 in higher levels as a non-specifi c Severity Level Average MMP-9 Level infl ammatory marker of ocular One 35.57ng/mL surface disease. Elevated MMP-9 Two 66.16ng/mL levels are found in a number of con- Three 101.42ng/mL ditions, including ocular rosacea, Four 381.24ng/mL meibomitis, Sjögren’s syndrome and recurrent corneal erosions.9 The collector should be dabbed Overall, the test may help to Studies have shown that the six to eight times, moving from tem- better determine appropriate treat- range of MMP-9 in normal tears is poral to nasal, allowing the patient ments for our dry eye patients. The between 3ng/mL and 40ng/mL.10 to blink after each two dabs. A fi nal company also suggests it may be of A level greater than 40ng/mL is fi ve-second press on the nasal pal- benefi t to identify elevated MMP-9 indicative of infl ammation. Addi- pebral conjunctiva is recommended levels in patients prior to surgery tionally, there is a direct correlation to ensure adequate saturation of the (e.g., refractive surgery). Pre-surgical between MMP-9 concentration and sampling pad. The collector is then intervention with anti-infl ammatory the severity of dry eye. (Table 1).11 snapped into the test cassette and therapy for patients with elevated Solomon et al. showed that placed in buffer for 20 seconds. MMP-9 levels could then improve MMP-9 levels increased 66-fold The results are available in 10 post-surgical outcomes and reduce 12 in patients with meibomian gland minutes. A single blue line indicates potential complications. RCCL dysfunction and 90-fold in patients a good test and a normal MMP-9 1.Tull SS, et al. Science and strategy for prevent- with Sjögren’s syndrome when com- level, while an additional red line of ing and managing corneal ulceration. Ocul Surf. pared to normal controls.9 any intensity confi rms the MMP-9 2007;5(1):23-39. 2.Srinivasan M, et al. Corticosteroids for bacterial In February 2014, Rapid Plasma is at least 40ng/mL. The line inten- keratitis. Arch Ophthalmol. 2012;130(2):143-50. Screening (RPS) received FDA sity provides a semi-quantitative 3.Srinivasan M, et al. The steroids for corneal CLIA-waived approval for a new indicator of the concentration of ulcers trial. Arch Ophthalmol. 2012;130(2):151-57. 4.Bartlett JD, Siret DJ. Clinical ocular pharmacolo- in-offi ce test called Infl ammaDry. It MMP-9s; a lighter shade of red in- gy, 5th edition. St. Louis: Butterworth Heinemann uses a process in which two antigen- dicates lower MMP-9 levels, while a Elsevier, 2008. 5.Srinivasan M, et al. The steroids for corneal specifi c antibodies capture the darker line signifi es higher levels. ulcers trial (SCUT): secondary 12-month clinical outcomes of a randomized controlled trial. Am J MMP-9 antigens. The test is confi r- A multi-center trial noted a sen- Ophthalmol. 2014;157(2):327-33. matory for infl ammation if MMP-9 sitivity of 85% and a specifi city of 6.Hassell JR, Birk DE. The molecular basis of cor- levels are 40ng/mL or higher. 94% for Infl ammaDry. In the clini- neal transparency. Exp Eye Res. 2010;91(3):326-35. 7.McClintic SM, et al. Improvement in cor- Those familiar with the Adeno- cal setting, we may be able to use neal scarring following bacterial keratitis. Eye. Plus detection test from the same this test to identify dry eye patients 2013;27(3):443-6. 8.Verma RP, Hansch C. Matrix metalloproteinases manufacturer will note that the who have an infl ammatory compo- (MMPs): chemical-biological functions and (q) sample collector and test cassette nent. These patients would benefi t sars. Bioorg Med Chem. 2007;15(6):2223-68. 9.Solomon A, et al. Pro- and anti-inflammatory look identical. However, the way from anti-infl ammatory therapy, forms of interleukin-1 in the tear fluid and conjunctiva of patients with dry-eye disesase. IOVS. samples are collected is different. such as corticosteroids, cyclosporine 2001;42(10):2283-92. With AdenoPlus, the collector and doxycycline—all of which have 10.Sambrusky R, et al. Sensitivity and specificity of a point-of-care matrix metalloproteinase 9 should be dabbed and dragged along been shown to inhibit MMP-9 ac- immunoassay for diagnosing inflammation related the inferior palpebral conjunctiva to tivity. Conversely, we could also use to dry eye. JAMA Ophthalmol. 2013;131(1):24-8. 11.Chotikavanich S, et al. Production and activity rupture the follicles (freeing adenovi- the test to determine when to avoid of matrix metalloproteinase-9 on the ocular ral hexon proteins). When collecting therapies in patients with normal surface increase in dysfunctional tear syndrome. IOVS. 2009;50(7):3203-09. a sample with Infl ammaDry, the levels of MMP-9; this might help to 12. www.rpsdetectors.com/in/products/about/ dragging motion is omitted. avoid treatment failures. product-information accessed 4/12/2014.

REVIEW OF CORNEA & CONTACT LENSES | MAY 2014 9

008_rccl0514_PSP.indd 9 4/25/14 2:49 PM The GP Expert By Stephanie L. Woo, OD

Surveyor of the Surface Corneal topographers are great diagnostic tools for contact lens specialists —if you know how to use them. Here are several key points.

magine trying to steer your tools, as they are capable of distin- car while looking through guishing between regular astigma- a ship’s porthole—and then tism and irregular astigmatism. If a suddenly one day being patient presents with a high amount I able to use a luxuriously of astigmatism and does not reach large windshield instead. That’s 20/20 through best-corrected acuity, akin to the impact that corneal it is necessary to use topography to topography had on contact lens rule out irregular astigmatism. If fi tting when it became commer- the astigmatism has an hourglass cially available in the 1990s.1 shape with symmetry (e.g., the Topographers offer practitioners superior half of the cornea is almost a more comprehensive evaluation of a mirror refl ection of the inferior the cornea than traditional manual half), you’re most likely dealing Fig. 3. Elevation maps reveal the keratometers, which measure only with regular astigmatism (Figure 1). cornea’s highest and lowest points. about 3mm to 4mm of the central Conversely, if the topography print- The ability to map the entire cornea, whereas topographers out does not reveal symmetry, it’s surface of the cornea has given measure the entire corneal surface. reasonable to consider it irregular practitioners the ability to diagnose As such, they often reveal critical astigmatism (Figure 2). and manage corneal surface abnor- information that manual keratom- malities such as keratoconus and eters may miss. Corneal curvature pellucid marginal degeneration. in diopters or millimeters can be as- Additionally, this technology helps sessed on any portion of the cornea, us to spot many other causes of a virtue that’s especially useful when irregular astigmatism. Post-trans- designing larger diameter GP lenses. plant and post-refractive surgery Topographers display a number patients have also greatly benefi ted of corneal maps, which can be used from this technology. to analyze various types of valuable • Elevation maps are incredibly information. Different topographers useful resources that, curiously, have unique functions and features, many practitioners do not take full but all are extremely helpful in GP Fig. 1. An axial map of regular advantage of. This map highlights lens design and evaluation. You do astigmatism. “high” and “low” areas of the not need to be an expert on topog- cornea. Higher areas of the cornea raphy or spend hours learning how will appear as warm colors (e.g., red to manipulate the equipment or and yellow), while the lower areas interpret the report to fi nd success appear as cooler colors (e.g., green with these powerful tools. This and blue) (Figure 3). month, I’ll discuss some easy ways This map is particularly useful for to understand topography—and use scleral lens design—it can determine it to its full potential. areas where corneal touch may occur, so that the lens can be designed FOLLOW THE MAPS to vault it. Once a scleral lens has The following maps can be essential been placed on the eye, it is neces- in GP lens fi tting: sary to examine the highest area of • Axial power maps are very im- Fig. 2. An axial map showing the cornea, as shown by the eleva- portant and very useful diagnostic irregular astigmatism. tion map—this area will likely have

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010_rccl0514_gpe.indd 10 4/25/14 11:48 AM the thinnest amount of clearance The comparison map allows you underneath the lens and should be to assess the effectiveness of treat- monitored very carefully. ment, as it shows a dioptric power An important point to remember: change induced in the cornea. the steepest point of the cornea is not always the tallest point on the OTHER MEASUREMENTS cornea; I repeat, the steepest part These can be handy, too: of the cornea is not always the • Ruler. Most topography tallest point on the cornea! This software includes a ruler feature, misconception is common among which measures the precise corneal practitioners. I encourage you to diameter. This can assist practitio- quickly compare the axial map and ners in determining appropriate lens Fig. 5. The ruler can measure the elevation map on every patient— diameters in both GP designs and entire corneal diameter. you may be surprised by where the soft custom toric lenses as well. highest point of the cornea is on Measuring the overall corneal uses sag or sagittal height, simply some patients. diameter is as simple as dragging choose the fi rst diagnostic lens • Tangential maps are used to the ruler from one edge of the closest to this measurement. For defi ne points of curvature change. cornea to another (Figure 5). It is this example, that would mean This map is particularly useful for often advantageous to measure at a selecting a lens that is close to your keratoconus patients, as it will 45° angle since the upper and lower 3.759 sag, which would likely allow you to measure the exact size lids/lashes can sometimes overlap be approximately 3.8 sag. Tak- and shape of the cone, which can the limbus/peripheral cornea, po- ing advantage of the sagittal help to determine an ideal GP lens tentially resulting in an inaccurate height feature will help reduce the design and optic zone size.2 measurement. Because it is estimat- amount of lenses needed during a For example, if topography ed that one out of four patients fall trial lens fi tting. reveals the patient has an oval cone outside the range of normal corneal that is decentered inferiorly, perhaps diameters (11.6mm to 12.0mm), Topographers are a great diagnos- a nipple cone lens design would not measuring corneal diameter can be tic tool for contact lens practitio- be the best choice. Tangential curva- very important to success of your ners, and can help tremendously GP ture is also very helpful for corneal contact lens wearers.3,5 lens design. Spending a few extra reshaping (i.e., orthokeratology). • The sagittal height feature is moments with your topographer’s The tangential curve comparison especially useful when fi tting scleral software can reduce chair time by map can be used to track progres- contact lenses. To begin, simply selecting appropriate lenses right sion of the reshaping process from set the chord length to 10.0mm off the bat and help monitor patient visit to visit (Figure 4). and fi nd the height of the cornea. conditions more effectively. RCCL Next, take the sagittal height 4 1. Agarwal, S, et al. Step by step corneal measurement and add 2,000. topography. Jaypee brothers medical pub- For example, if we used a sagittal lishing. New Delhi, India. 2006; 44-68. 2. Anderson, D., et al. Topography: a clini- height measurement of 1,759 and cal pearl. Optometric Management. Feb 1, added 2,000 to it, we would have 2007. a total of 3,759. This tells us the 3. Kojima, R., et al. Designing GPs with corneal topography. Contact Lens Spectrum. approximate height of the cornea Oct 1, 2009. at a set chord length, which in this 4. Kojima, R. Eye shape and scleral lenses. example is 3,759 microns. Contact Lens Spectrum. April 1, 2013. Fig. 4. Tangential maps can help to 5. Corneal topography key to custom fi tting determine an ideal GP lens design. For a scleral lens fi tting set that soft lenses. Optometry Times. Oct 25, 2013.

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We must strive to limit its untoward eff ects without undermining its essential role in protection and healing.

n eye care, there is a tendency symptomatic, treatment becomes tion, migration, proliferation and to characterize ocular infl am- indicated. Fortunately, clinicians recruitment of immune cells. mation as something inher- have myriad ophthalmic anti-in- Secondarily, steroids inhibit pro- ently negative that needs to be fl ammatories to consider, of which duction of infl ammatory molecules Icombated at all costs. In reality, the two broad classes are of course such as prostaglandins (PGs), pro- however, the infl ammatory response the steroids and the NSAIDs. mote stability of granulocytes such is part of the body’s natural self- This article will provide an as mast cells and basophils, reduce defense and tissue repair system, overview of the available options permeability of vascular beds, and and is required to ensure normal and my clinical impressions of the reduce both angiogenesis and fi bro- functioning of the eye. When ocular decision-making process. Given the genesis.2,5 tissue is exposed to an irritant or a many inherent differences in practi- While systemic steroids have a di- perceived threat, the body responds tioners’ comfort level and patients’ rect impact on the development and by sending chemical mediators circumstances, individualization is a differentiation of immune-compe- and infl ammatory cells to clear the necessity and practice patterns will tent cells, topical steroids probably antigen, remove compromised tissue vary. exert their effect by reducing local and assist in tissue reconstruction. tissue permeability and decreas- There are many times indeed when Corticosteroids ing production of cytokines and we should be grateful rather than The most important class of topical chemokines within local immune fearful. anti-infl ammatory medications, cells.2 Due to their broad range of These complex processes involve corticosteroids have been a staple target cells, corticosteroids have the immune cells (e.g., lymphocytes, of medical care since the early widest (though least specifi c) anti- granulocytes, antigen-presenting 1950s.2,3,6 Despite this long tenure, infl ammatory effect of any topically cells) chemical mediators of ongo- their exact anti-infl ammatory mech- used agent. ing infl ammation (e.g., cytokines, anism is still not fully understood.3 Mitigating to some extent the prostaglandins, chemokines) and What we do know is that nearly all dramatically positive anti-infl am- immune tissue (e.g., regional lymph cells of the body express a receptor matory effect of glucocorticoids are nodes, secondary lymph tissue for these chemicals (the glucocorti- their side effects. Though topically and primary lymph tissue such as coid receptor, or GR), which helps administered corticosteroids are bet- the thymus).1 Potential catalysts explain the wide-ranging effects— ter tolerated than systemic formula- are many, but the reaction most and side effects—of this class of tions, they have the well-known side commonly follows injury, allergy, medications. 3,5-7 effects within the eye of accelerating infection or autoimmunity. The primary anti-infl ammatory The subsequent effect could be mechanism of corticosteroids is like- ABOUT THE AUTHOR mild and self-contained or severe ly their role in inhibiting cytokines Dr. Bronner is a staff optom- and destructive; the outcome and chemokines.2,3,5,7 Though these etrist at the Pacifi c Cata- ract and Laser Institute depends on the trigger and host chemical mediators are a cellular of Kennewick, Washing- events. In cases when the infl am- byproduct of infl ammation, they are ton. He has no fi nanicial matory response is excessive—with also probably among the primary interest in any products or services described in potential for permanent damage mediators of the entire infl amma- this article. to ocular tissue—or the patient is tory cascade. They promote activa-

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012_rccl0514F1.indd 12 4/25/14 4:52 PM By Aaron Bronner, OD IMMUNE REPSONSE cataract formation, increasing intra- • the site of infl ammation (for a smaller retrospective analysis of ocular pressure, increasing risk of example, intraocular penetration is their use in iritis showed an IOP infection or prolonging pre-existing unnecessary and ultimately unwant- increase of 20mm Hg or more in infectious processes and may very ed in cases of infl ammatory con- 19% of patients recalcitrant to rarely cause systemic effects such as junctivitis or superfi cial keratitis) prednislone who were switched to increased blood sugar or psycho- • the magnitude of the infl amma- difl uprednate.14,15 The study design, logical effects such as anxiety and tory response treatment duration (as long as 16 insomnia. Therefore, use of topical • the likelihood of inducing ste- weeks in some eyes) and population ophthalmic steroids is a decision in roidal side effects within a patient, (7% of whom were on no steroid which the balance of benefi t and the possible magnitude of that side prior to beginning difl urprednate) risk should be carefully assessed, as effect for a given agent and the limit broad application of these cavalier use may lead to substantial patient-specifi c consequences of fi ndings to other populations, but worsening of ocular health. those effects it highlights the importance of IOP Complicating things further, Below are broad overviews of monitoring when considering difl u- penetration of glucocorticoids is several available preparations, in prednate for long periods. impeded by the corneal epithelium. descending order of effi cacy. Regardless, given its potency, Lipophilic bases such as alcohols • Difl uprednate emulsion (Du- there is no doubt Durezol is a use- and acetates, and higher viscosity rezol, Alcon). The newest ophthal- ful part of the clinical armament, delivery vehicles that increase con- mic corticosteroid on the market, particularly in cases of moderate to tact time generally increase intra- difl uprednate has the greatest theo- severe intraocular infl ammation or ocular penetration of most topical retical anti-infl ammatory effect and when only a short course of treat- corticosteroids, and therefore highest in vivo potency of available ment is expected and with careful increase aqueous concentrations. options.10 Anecdotally, I have used monitoring for IOP spikes when However, in many cases of ante- Durezol to good effect on eyes that treatment duration is extended. rior segment use, it’s worth asking have had infl ammation recalcitrant whether or not you want anterior to prednislone acetate 1%, includ- chamber penetration of a steroid.3-6 ing my own eye during fl are-ups After all, the weaker the steroid of uveitis. It also has the benefi t penetration, the less potential for of a more uniform distribution, IOP response and cataract develop- with dosing based on the emulsion ment there is. vehicle, and doesn’t require shaking Lastly, each commercially avail- prior to use, unlike the suspension- able ophthalmic steroid has its based steroids. own pharmacokinetic properties, Does this increased potency affect strength of anti-infl ammatory effect the propensity for IOP response? Sectoral episcleritis: Frontline and propensity for steroid-induced Reports vary based upon treatment treatment is an oral NSAID or side effects. Therefore, selection populations and study design. A topical steroid. With scleritis, topical steroids should generally be of an appropriate corticosteroid large study showed only transient avoided—in some subtypes, their should derive from the full clinical differences in IOP between pred- use may accelerate scleral thinning picture, including: nisolone and difl uprednate, while by potentiating collagenase activity.

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• Prednisolone acetate 1% (Pred for choosing FML in its higher- clinical effi cacy of the original lote- Forte, Allergan or generic). This is concentration form.5 prednol products has been shown to a good general purpose, cortisone- be quite good, lagging only slightly based anti-infl ammatory that most behind that of prednisolone ac- eye care providers are quite famil- etate.5,10,11 Its safety profi le has also iar with. Though increasing the been clinically shown to be good, concentration from 0.25% to 1% with a lower degree of IOP spikes increases its effi cacy, any further in the setting of known steroid increase in concentration would responders.5,11,13 yield no benefi t; therefore, 1% is The recent change of Lotemax the highest concentration available from a suspension to a gel delivery commercially.4,5 increases uniformity between drops It is well described in eye care Infi ltrative keratitis responds well and increases maximum tissue to treatment with corticosteroids. that the branded version of the Loteprednol or FML are great concentrations within the cornea medication exhibits superior choices in an eye like this. and conjunctiva compared to the distribution and dose uniformity suspension form.11 Given its safety within the suspension than the Fluorometholone is reported to and anti-infl ammatory profi le, generic, although both require be somewhat weaker than pred- loteprednol is a terrifi c option in re-suspension with shaking.16 Both nisolone acetate both in vitro and most forms of ocular surface and branded and generic prednisolone within the anterior chamber.3 It moderate forms of deeper infl am- acetate are good steroid choices for does not penetrate as readily into mation. Out-of-pocket cost to the many forms of anterior segment the chamber, although in certain oc- patient in some circumstances may infl ammation, though severe cases ular surface scenarios it is generally need to be addressed. may occasionally require a greater reported to be equivalent.4 Fluoro- potency medication. metholone has a lower incidence Non Steroidal • Dexamethasone. The steroidal of IOP spike than prednisolone Anti-Inflammatories king of the combination drugs, acetate.5,9 Because of its enhanced Where can you turn when you dexamethasone is also one of the safety profi le over prednisolone want the benefi t of an anti-in- most potent anti-infl ammatories of acetate and roughly equivalent fl ammatory without the steroid- all corticosteroids. Though the mol- anti-infl ammatory effect when used associated eye effects? NSAIDs, of ecule of dexamethasone has roughly at the ocular surface, it is a good al- course. six times the anti-infl ammatory ternative to prednisolone acetate or As mentioned above, one effect effect of prednisolone, its topi- (when cost is an issue) loteprednol of corticosteroids is inhibition cal formulation is 10 times more for ocular surface disease. Current- of pro-infl ammatory molecules dilute (prednisolone acetate 1% vs. ly, availability of fl uorometholone such as prostaglandins, a group of dexamethasone 0.1%) and does not has been limited in some (but not eicosanoids derived from arachi- penetrate into the anterior chamber all) areas of the country, as a hand- donic acid via the cyclo-oxygenase as readily.3-5 Thus, topical predniso- ful of its manufacturers have ceased enzymes COX-1 and COX-2.5,12 lone acetate 1% is a slightly more producing it. COX-1 is an enzyme that plays potent corticosteroid as dosed.4,5 • Loteprednol etabonate a role in mediation of physiologic The tendency of IOP response (Lotemax, Alrex, Bausch + Lomb). function. Therefore, the PGs that it with dexamethasone is thought to This ester-based steroid was de- produces are created under normal be similar to that of prednisolone veloped in the early 1990s as an circumstances. COX-2, on the acetate. alternative to prednisolone acetate other hand, mediates production • Fluorometholone. Unlike pred- with a better safety profi le.5,11 Ex- of pro-infl ammatory PGs. The nisolone’s cortisol base, fl uorometh- cess unbound loteprednol molecules exact mechanism that PGs play in olone is progesterone derived. The undergo metabolic transformation the infl ammatory cascade is not 0.1% version of the drug is roughly after a relatively short time, result- fully understood, but it appears equivalent in effi cacy to and better ing in fewer unwanted side effects they primarily enhance vascular in safety than the 0.25% version. such as increased IOP and cataract permeability and also sensitize pain As a result, there is limited rationale development. Theoretical and receptors.5,12

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012_rccl0514F1.indd 14 4/25/14 4:52 PM As NSAIDs are inhibitors of tions at our disposal should allow COX enzymes, they reduce their clinicians to prescribe case-specifi c infl ammatory product —prosta- anti-infl ammatories, where extent glandins. Given that inhibition of and location of infl ammation are PGs is only one of the many anti- taken into account. As a result, the infl ammatory effects of steroids, it’s patient is subsequently offered the no surprise that they have a broader safest available option. RCCL effect in suppressing infl ammation 1. Bouchard C. The Ocular Immune Response. In: than NSAIDs. That’s not to say that Krachmer JH, Mannis MJ, Holland EJ eds. Cor- steroids are superior in all ways, A pyogenic granuloma. These nea. 2nd ed. St Louis: Mosby;2004:59-93. capillary-based, reactionary growths 2. BenEzra D. Immunosuppression and immu- however. A number of studies show often respond well to treatment nomodulation. Ocular Inflammation: Basic and NSAIDs are objectively more effec- with topical corticosteroids. Clinical Concepts. BenEzra D, Ed. Martin Dunitz 1999:1-24. tive in helping reestablish the blood- 3. McGhee CN. Pharmacokinetics of ophthalmic aqueous barrier than glucocorti- more uniform. Permeability and corticosteroids. British Journal of Ophthalmol- coids, and pairing the two drugs half-life are both enhanced with ogy. 1992;76:681-4. 4. McGhee CH, et al. Penetration of Synthetic may yield even greater benefi t.12 nepafenac (a prodrug) and bromfe- Corticosteroids into Human Aqueous Humor. Excess PG production has been nac, and only ketorolac is approved Eye. 1990;4:526-530. 5. Jaanus SD, et al. Antiinflammatory Drugs. In: strongly implicated in a number of for allergic conjunctivitis, but all Bartlett JD and Jaanus SD eds: Clinical Ocular Pharmacology. 4th Ed. Butterworth-Heine- retinal disorders, such as diabetic perform somewhat comparably at mann;2001:265-314. macular edema and the develop- their recommended dosages. Of the 6. Greaves MW. Anti-inflammatory action of ment of choroidal neovascular group, only fl urbiprofen 0.03% has corticosteroids. Post Graduate Medical Journal. 1976;52:631-3. 12 membranes. Given the role PGs been shown to be less effective than 7. Van der Velden VH. Glucocorticoids: seem to play in enhancing vascular others in the treatment of cataract mechanism of action and anti-inflammatory potential in asthma. Mediators of Inflammation. 12 permeability, perhaps it’s no sur- surgery-induced infl ammation. 1998;7:229-37. prise that NSAIDs are widely used As stated, the primary benefi t 8. Ricciotti E, FitzGerald GA. Prostaglandins and Inflammation. Arterioscler Thromb Vasc Biol. in the prevention and treatment of of NSAIDs is to offer some of the 2011;31:986-1000. cystoid macular edema. For anterior anti-infl ammatory effects of cortio- 9. Morrison E, Archer DB. Effects of fluorometholone (FML) on the intraocular pressure segment use, NSAIDs are useful costeroids without their side effects. of corticosteroid responders. British Journal of for their analgesic effect—which is Interestingly, despite PG analogs be- Ophthalmology. 1984;68:581-4. 10. Weiner G. Savvy Steroid Use. American not paired with an anesthetic effect, ing widely employed for glaucoma Academy of Ophthalmology www.aao.org/ unlike proparacaine and similar therapy, there is no apparent net ef- publications/eyenet/201302/feature.cfm 17 11. Coffey MJ, DeCory HH, Lane SS. Develop- drugs. This makes NSAIDs useful fect on IOP with the ophthalmic use ment of a non-settling gel formulation of 0.5% for managing pain with corneal of NSAIDs, whose chief mechanism loteprednol etabonate for anti-inflammatory use as an ophthalmic drop. Clinical Ophthalmology. trauma, as the analgesia provides is to reduce PG, and they have not 2013;7:299-312. some pain relief without compro- been linked to cataract formation. 12. Kim SJ, et al. Nonsteroidal Anti-inflammatory 5,12 Drugs in Ophthalmology. Survey of Ophthalmol- mising healing of the cornea. NSAIDs are generally quite safe, ogy. 2010;55:108-133. At my clinic, we use topical though reports of corneal melts 13. Bartlett JD, et al. Intraocular pressure Response to Loteprednol Etabonate in Known NSAIDs with our PRK patients in have rarely been reported. Most Steroid Responders. Journal of Ocular Pharma- the postoperative period to help typically these events have been cology. 1993;9:157-165. 14. Birnbaum, AD et al. Elevation of Intraocu- alleviate pain, as well as in other attributed to generic diclofenac, but lar Pressure in Patients With Uveitis Treated painful presentations. Of course, the event has been reported with all With Topical Difluprednate. Arch Ophthalmol. some eyes are more sensitive than members of the ophthalmic NSAID 2011;129:664-676. 15. Foster CS, et al. Durezol (Difluprednate Oph- others, so NSAIDs may not be suffi - class except fl urbiprofen.12 thalmic Emulsion 0.05%) compared with Pred Forte 1% ophthalmic suspension in the treatment cient for pain control in some cases of endogenous anterior uveitis. J Ocul Pharma- of corneal abrasion. Conclusion col Ther. Oct 2010;26(5):475-483. 16. Stringer W, Bryant R. Dose. Uniformity of While the different commercial Though not all ophthalmic infl am- topical corticosteroid preparations: diflurpred- preparations of corticosteroids have matory events require pharma- nate ophthalmic emulsion 0.05% versus branded and generic prednislone acetate ophthalmic quite different properties given their ceutical intervention, you will be suspension 1%. Clinical Ophthalmology. 2010; varied anti-infl ammatory effects, frequently required to prescribe an 4:1119-1124. 17. Mycek MJ, et al. Antiinflammatory Drugs. In permeability and side effect profi les, anti-infl ammatory. Thankfully, the Harvey RA and Champe PC eds, Pharmacology NSAIDs as a class seem to be a bit number and diversity of medica- 2nd Ed. Lippincott Williams and Wilkins. 401-418.

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012_rccl0514F1.indd 15 4/25/14 4:52 PM IT’S TIME TO BRING SJÖGREN’S

This autoimmune disease can go undiagnosed for years. By working closely with other health care providers, we may be able to detect it in its earliest stages.

jögren's syndrome has HOW TO SPOT SJÖGREN’S and peripheral neuropathy. All of a bit of a Dr. Jekyll/ When most of us think of these complications worsen quality Mr. Hyde duality Sjögren's syndrome, an archetypal of life, so it is important that we in eye care. On the patient readily comes to mind: the make the diagnosis early. We must Sone hand, we are all post-menopausal woman present- realize that we are treating more well aware of the condition and ing with a classic aqueous-defi cient than just the eyes of our Sjögren’s understand its ophthalmic associa- dry eye. Beyond the characteristic patients. tion. On the other, the prevalence fi ndings of dry eye and often—but of Sjögren’s is grossly underesti- not always—dry mouth, Sjögren’s DIAGNOSIS mated and infrequently mentioned syndrome is a chronic and sys- Staining is a hallmark sign of to patients. It is estimated that temic disease with the potential to Sjögren’s syndrome. In a 2010 Sjögren’s syndrome affects four affect many body systems. study, researchers compared 231 million people in the United States Lack of salivary production in patients with primary Sjögren's alone, yet three million of those the advanced stages of the disease syndrome to 89 patients with who suffer from this disease have leads to a number of additional aqueous-defi cient dry eye to deter- not yet been diagnosed.1 Clini- complications, including dental mine the objective signs that best cians routinely fail to recognize decay, diffi culty swallowing, bleed- differentiated the two conditions. and diagnose Sjögren’s patients at ing cracks in the gums and severely They found that rose bengal stain- an early enough stage to have an chapped lips. The autoimmune ing of the temporal conjunctiva impact on their quality of life. component of Sjögren’s, which is was the most important variable As with many autoimmune dis- more often the secondary form of that separated the two groups. This eases, the presentation of Sjögren’s the disease, has a deleterious effect staining and the severity of dry syndrome can be highly variable. on the organs. For example, it can mouth symptoms were the major In some patients, Sjögren’s can cause pneumonia, interstitial lung factors in distinguishing Sjögren’s present as a fairly aggressive, rap- disease and recurrent bronchitis syndrome patients from those with idly advancing, severe disease; in in the lungs; acid refl ux, esopha- aqueous-defi cient dry eye.2 others, it can present in a relatively gitis and diffi culty swallowing in Another telltale sign of Sjögren’s mild state. Because the presenta- the gastrointestinal system; and syndrome is an elevated tear os- tion of Sjögren’s can vary so much primary biliary cirrhosis as well molarity score. Typically, patients between patients, it can easily be as autoimmune hepatitis in the mistaken for typical dry eye or liver. There are also neurological ABOUT THE AUTHORS age-related dryness in its earlier symptoms, such as memory loss Dr. Epstein is the director of stages. and “brain fog.” cornea-external disease and clinical research at Phoenix Eye We must start to discuss Additionally, because Sjögren’s Care PLLC and head of the Dry Sjögren’s syndrome—with our affects all the body’s mucous mem- Eye Center in Phoenix, Az. peers and our patients—to fully branes, patients often experience Dr. Karpecki is the clinical director understand the disease and its sys- recurrent sinusitis, nosebleeds, acid of the Ocular Surface Disease temic manifestations, as well as the refl ux, breathing problems, bron- Center and heads the clinical most effective way of managing chitis, dry skin, Raynaud's phe- research department at Koffl er Vision Group in Lexington, Ky. patients who suffer from it. nomenon, abnormal liver function

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016_rccl0514_F2.indd 16 4/25/14 4:03 PM By Arthur B. Epstein, OD, and Paul M. Karpecki, OD OUT OF THE SHADOWS

with Sjögren’s exhibit scores of 330 parotid secretory protein) that have Sjögren’s patients, steroids are a and above—with some variance also been associated with Sjögren’s mainstay for the condition. How- between the two eyes. Due to the at an earlier stage of disease ever, proceed with caution with the absence of reﬂ ex tearing, non- progression. The eye care profes- use of steroids if the patient has

anaesthetized Schirmer's testing sional takes Photo: Mile Brujic, OD tends to be an accurate diagnostic blood samples measure in this group. This is un- (where allowed) usual because Schirmer's testing is from poten- often inaccurate in the general dry tial Sjögren’s eye population. patients in the The disease is most likely to clinic and re- initiate in women in their 30s and ceives accurate 40s. Additionally, it is typically lab results in more prevalent in patients with an days. existing autoimmune disease, such Sjögren’s of- as lupus or rheumatoid arthritis. ten accompanies While there is no cure for Sjögren’s, other autoim- the morbidity of the disease can be mune diseases. lessened thanks to new therapies. As such, when Most patients are diagnosed a patient with Sjögren’s syndrome late in its presents with Fluorescein staining revealing dry eye. Staining is a course. Unfortunately, due to the complaints of hallmark sign of Sjögren's syndrome and can be used to assist diagnosis of the disease in its early stages. progressive nature of the disease, dry eye, as well it is signifi cantly more diffi cult to as an autoimmune disease such as a poorly controlled autoimmune manage at that point. However, lupus or rheumatoid arthritis, it is disease. If there's a systemic com- the future of diagnosing Sjögren’s important to consider Sjögren’s im- ponent that is not well controlled, looks bright. As technology con- mediately. While there is a possible such as arthritis, there is a risk of a tinues to advance, new options for association between rheumatoid corneal melt or secondary infec- the early diagnosis of Sjögren’s are arthritis and dry eye, it is impor- tion when using corticosteroids. becoming available. tant to be mindful that a signifi cant Oral secretagogues have been For example, an in-offi ce panel number of these patients may have shown to be worthy alternative to test for early detection of Sjögren’s Sjögren’s syndrome in addition to steroids. These agents have a fa- (Sjö, Nicox) was recently launched an autoimmune disease.3 We must vorable safety profi le, and research in the United States. The test fi nd ways to differentiate between shows that cevimeline is safe and combines traditional Sjögren’s the two. effective in improving symptoms biomarkers (e.g., SSA (Ro), SSB of dry eye.4 Additionally, Sjögren’s (La), anti-nuclear antibody and THOUGHTS ON MANAGING patients respond well to preserva- rheumatoid factor) with additional SJÖGREN’S SYNDROME tive-free artifi cial tears because of biomarkers (e.g., salivary pro- Due to a lack of available topi- the hyper-osmolarity associated tein 1, carbonic anhydrase 6 and cal options for treating late-stage with the condition—particularly

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016_rccl0514_F2.indd 17 4/25/14 4:04 PM IT’S TIME TO BRING SJÖGREN’S OUT OF THE SHADOWS

artifi cial tears that can signifi cantly symptoms while involving other accompanying keratoconjunctivis lower hyper-osmolarity levels (e.g., physicians to assist in controlling sicca. Additionally, because of the TheraTears, Blink and FreshKote).5 the systemic component of the high correlation between lympho- Once a Sjögren’s syndrome disease. ma and Sjögren’s, it is also impor- patient is well controlled, he or she tant that the rheumatologist moni- can often be maintained on topical BUILDING RELATIONSHIPS tor for lymphoma. Because we are cyclosporine (Restasis, Allergan). Optometry is increasingly the fi rst more likely to diagnose Sjögren’s This must be done early, however, point of contact for many systemic in our severe dry eye patients, it is because once the scarring of the conditions, Sjögren’s syndrome our responsibility to communicate lacrimal gland occurs, Restasis included. If we diagnose Sjögren’s this closely with rheumatologists. will no longer be a viable option— early, we can track the progression When thinking of patients with Restasis can stimulate tear produc- of the disease more precisely and Sjögren’s it is also important to tion and reduce infl ammation, but work with primary care physicians consider the old adage, “when it cannot repair or restore tissue and other specialists to ensure you hear hoof beats you think of that is destroyed. Nutritional patients are followed, accruing horses—not zebras.” We too often supplements, such as HydroEye benefi ts along the entire path of think we are dealing with a case of (Science Based Health), may also the disease course, and its care, typical dry eye before we consider be useful for maintaining Sjögren's will follow for the patient. Sjögren’s syndrome. This wastes patients on a long-term basis. While optometrists commonly valuable health care resources and, A recent study demonstrated manage patients with Sjögren’s more importantly, can cause a that GLA (e.g., black currant syndrome, ophthalmologists may patient to suffer unnecessarily. seed oil) in the presence of DHA/ be less interested in doing so— Beginning discussions about EPA (i.e., fi sh oil) appears to managing Sjögren’s patients can Sjögren’s syndrome in the eye stimulate PGE1 signifi cantly in the be very time consuming, and dry care community is an important tears, which improved both signs eye work-ups are rather extensive and long overdue step in the right (corneal staining) and symptoms and sometimes unpleasant for the direction. By working closely (OSDI).6 Other options that have patient. with other health care provid- worked well include moisture The average time it takes for a ers, we will create opportunities chamber goggles, autologous patient with Sjögren’s to receive a to improve quality of life for our serum, warm compresses, humidi- diagnosis is 4.7 years.7 The idea Sjögren’s patients in sustainable fi ers, amniotic membrane rings, that these patients are fl oating ways. RCCL punctal occlusion and scleral lens- around undiagnosed for almost 1. Sjögren’s Syndrome Foundation. 2001. es. Some success has been achieved fi ve years is a signifi cant cost to Available at http://www.sjogrens.org. Ac- using bandage contact lenses made the health care system and to the cessed September 5, 2013. 2. Caffery B, Simpson T, Wang S, et al. Rose of newer hydrophilic materials. morbidity these patient endure. bengal staining of the temporal conjunctiva differentiates Sjögren's syndrome from keratoconjunctivitis sicca. Invest Ophthalmol Vis Sci. 2010;51(5):2381-7. “SJÖGREN’S OFTEN 3. Kassan SS, Moutsopoulos HM. Clini- cal manifestations and early diagnosis of Sjögren’s Syndrome. Arch Intern Med. ACCOMPANIES OTHER 2004;164: 1275-1284. 4. Ono M, Takamura E, Shinozaki K, et al. Therapeutic effect of cevimeline on dry AUTOIMMUNE DISEASES.” eye in patients with Sjögren's syndrome: a randomized, double-blind clinical study. Am J Ophthalmol. 2004;138(1):6-17. As is the case with treatment Optometrists and other health 5. Gilbard JP. Dry eye: pharmacological options for any condition, risks professionals tend to underes- approaches, effects, and progress. CLAO J. 1996 Apr;22(2):141-5. and benefi ts should be care- timate the potential for mutual 6. Aragona P, Bucolo C, Spinella R, Giuffrida fully weighed before making any cooperation. As such, communica- S, Ferreri G. Systemic omega-6 essential fatty acid treatment and pge1 tear content decisions. Until advanced medication is vital. The key to success in Sjögren's syndrome patients. Invest Oph- tions are developed for Sjögren’s is the patient’s rheumatologist thalmol Vis Sci. 2005 Dec;46(12):4474-9. 7. About Sjögren’s Syndrome. Sjögren’s Syn- patients, we must try our best to controlling the systemic disease, drome Foundation Web site. http://www. manage and control the ocular as this will greatly help with the sjogrens.org. Accessed November 11, 2013.

18 REVIEW OF CORNEA & CONTACT LENSES | MAY 2014

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n the seven years since to be invariably associated with IL-1β) and a decrease in the biologi- the International Dry Eye chronic infl ammation of the ocular cally inactive precursor IL-1β in the Workshop (DEWS) noted surface. As such, it is important to tear fi lm.13 Based on a number of that keratoconjunctivitis recognize the role of infl ammation immunohistochemical studies, the I sicca “is accompanied by in dry eye, as it has been a crucial conjunctival epithelium was origi- increased osmolarity of the tear factor in directing the proper course nally thought to be the source of the fi lm and infl ammation of the ocu- of treatment for the condition. increased levels of IL-1.13 However, lar surface,” researchers and clini- more recently, reactive nitrogen cians alike have worked diligently PATHOPHYSIOLOGY species expressed by conjunctival to update our understanding of Evidence gathered in the past epithelium have been recognized in its causes and consequences.1 The decade indicates that dry eye-related the pathogenesis or self-propagation identifi cation of infl ammation as ocular surface infl ammation is of SS-related dry eye.14 In the same a major component represented a mediated by lymphocytes.11 Based study, the researchers determined tremendous step forward in both on earlier immunohistopathologi- that IL-1β, IL-6, IL-8 and tumor the description and treatment of cal evaluations, patients with both necrosis factor (TNF)-α play a sig- a growing public health concern SS-related and non-SS dry eye nifi cant role in SS-related dry eye. that affects as many as 17% of demonstrated identical conjunctival The response of cells to extracel- women and 11.1% of men in infl ammation manifested by T-cell lular stimuli such as ocular surface the United States alone.2 (Actual infi ltrates and upregulation of CD3, stress (e.g., changes in tear fi lm prevalence numbers are likely CD4 and CD8.12 Such patients also composition, hyperosmolarity even higher, given the omission of exhibited identical lymphocyte acti- and ultraviolet light exposure) is unreported self-treating patients vation markers CD11a and HLA- mediated in part by a number of and mild/periodic cases with inter- DR.12 These results suggest that the intracellular kinase and phospha- mittent symptomology.) clinical symptoms of dry eye may tase enzymes.15 Mitogen-activated DEWS also sought to bring great- be dependent on T-cell activation protein (MAP) kinases are integral er precision to the loosely-termed and resultant autoimmune infl am- condition “dry eye” by recognizing mation. ABOUT THE AUTHOR

two subgroups based on pathogen- Several additional studies demon- Dr. Hessen received her Doctorate esis: aqueous defi cient and evapo- strated the role of pro-infl ammatory of Optometry degree from Nova Southeastern University in Florida. She rative. The former can be further cytokines and matrix metallopro- completed her optometry residency subcategorized based on Sjögren’s teinases (MMPs) in the pathogen- in ocular disease at the Baltimore VA Medical Center, which included syndrome (SS) involvement (see, esis of dry eye. Interleukin (IL)-1 is training in the ocular surface “In Search of Sjogren’s, p. 23). one of the most widely studied cyto- disease and dry eye clinic at Johns Hopkins Hospital. She While it is not known whether kines accompanying this condition. holds a faculty appoint- ment at the Wilmer Eye the local infl ammation is causative Dry eye patients have exhibited an Institute at Johns Hopkins or simply occurs as a consequence increase in the proinfl ammatory Hospital and leads the Dry of ocular dryness, dry eye seems forms of IL-1 (IL-1α and mature Eye Team.

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020_rccl0514_F3_CE.indd 20 4/25/14 4:07 PM Treatment options that target inﬂ ammatory mediators in the tear ﬁ lm may help clinicians achieve victory over this often diffi cult to manage condition. By Michelle M. Hessen, OD

Clinical photo: Mark Abelson, MD/Ora, Inc.

components of parallel MAP kinase terminal kinases and MAPK signal- signs and symptoms of affl icted cascades, which are activated in ling pathways. patients. response to a number of cellular All of the previously discussed • Cyclosporin A is commercially stresses, including infl ammatory cy- infl ammatory mediators and path- available as a topical agent in two tokines (e.g., Il-1 and TNF-alpha), ways are not only important to the forms: 0.05% (Restasis, Allergan) heat shock, bacterial endotoxin and pathogenesis of dry eye, but also and a 1% compounded prepara- ischemia. to the treatment strategies of the tion. These agents are frequently Activation of these MAP kinase condition. used to treat various infl amma- homologues mediates the transduc- tory ocular surface disorders.19 It tion of extracellular signals to the TREATING DRY EYE is recommended to dose topical nucleus; this activation is pivotal It is widely recognized that infl am- cyclosporine twice daily, but for in regulation of the transcription mation plays a signifi cant role in patients with severe dry eye who do events that determine functional the etiopathogenesis of dry eye, as it not demonstrate any improvement, outcome in response to such promotes ocular surface disruption a dosing frequency greater than stresses. and creates symptoms of irritation. twice per day may be benefi cial.6,20 These stress-activated protein As such, a number of anti-infl am- The immunomodulating effects of kinases have been identifi ed in the matory treatments are currently in cyclosporin A are achieved through tear fi lm of patients with dry eye. use for its management, and many binding with a group of proteins Activation of these stress pathways more are either in development or known as cyclophilins. Cyclophilin results in transcription of stress-re- undergoing clinical trials to test A is found in the cytosol. The lated genes, including MMPs—spe- their effi cacy. These agents inhibit cyclophilin-cyclosporin A complex cifi cally MMP-9.16 Another study the expression of infl ammatory inhibits calcineurin, a calcium/ found that MAP kinases stimulate mediators on the ocular surface, calmodulin-dependent phospha- the production of infl ammatory cy- thereby restoring the secretion of a tase.21 It is believed that this inhibi- tokines, including IL-β, TNF-α and healthy tear fi lm and reducing the tion halts the production of the MMP-9, resulting in ocular surface 17 damage. Release Date: May 2014 Credit Statement: COPE approval for As previously mentioned, hyper- Expiration Date: May 1, 2017 2 hours of CE credit is pending for this osmolarity contributes to ocular Goal Statement: This course covers the course. Check with your state licensing surface infl ammation; in human widely-accepted definition of dry eye dis- board to see if this counts toward your CE limbal epithelial cells, it increases ease as well as risk factors and associated requirements for relicensure. the expression and production of systemic conditions. A thorough description Joint-Sponsorship Statement: This pro-infl ammatory cytokines and of pathophysiology is described based on continuing education course is joint- chemokines, such as IL-1β, TNF-α identified inflammatory mediators. Clinically sponsored by the Pennsylvania College of and the C-X-C chemokine, IL-8.18 available and novel therapies are discussed. Optometry. It appears this process is mediated Faculty/Editorial Board: Disclosure Statement: The author has no through activation of the c-Jun N- Michelle Hessen, OD financial relationships to disclose.

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020_rccl0514_F3_CE.indd 21 4/25/14 4:07 PM THE HUNT FOR DRY EYE INSTIGATORS

transcription of T-cell activation by proteins and represses the expres- be monitored closely for known inhibiting IL-2.21 sion of pro-infl ammatory proteins. risks of cataract formation, glauco- Cyclophilin D is located in the However, recent work suggests ma, corneal thinning and infectious matrix of the mitochondria. The that the activated corticosteroid- keratitis.35 cyclosporin A-cyclophilin D com- glucocorticoid receptor complex • Topical NSAIDs treat infl am- plex modulates the mitochondrial also elicits nongenomic effects, mation by inhibiting the production permeability transition pore, which such as inhibition of vasodilation, of prostaglandins via the cyclo- induces mitochondrial dysfunc- vascular permeability and migration oxygenase enzyme.36 In addition, tion and cell death.22 The reduc- of leukocytes.30,32 a number of NSAIDs—specifi cally tion in infl ammation—achieved Several clinical studies have diclofenac—have been shown to via inhibition of T-cell activation demonstrated the effectiveness of reduce corneal sensitivity.37 This and down-regulation of infl amma- topical steroids in treating dry eye. reduction in sensitivity may lead to tory cytokines in the conjunctiva In a retrospective series, topical an adjunctive insult to disrupted and lacrimal gland—is thought to administration of non-preserved epithelium in patients with dry eye. allow enhanced tear production.23-27 methylprednisolone 1% solution, Several cases of corneal melt have Additionally, topical cyclosporine dosed three to four times daily for been described in the literature asso- increases goblet cell density and several weeks to patients with SS- ciated with topical NSAIDs, includ- decreases epithelial cell apoptosis, related dry eye, provided moderate ing diclofenac, ketorolac, nepafenac which is particularly good for dry- to complete relief of symptoms in and bronfenac.38-44 In each of these ness in rosacea patients.28 all patients.33 In addition to symp- cases, preexisting epitheliopathy • Corticosteroids. Topical steroids tom relief, there was a decrease in was identifi ed. can help to reduce ocular infl amma- corneal fl uorescein staining score While we do not currently know tion by suppressing cellular infi ltra- and complete resolution of fi la- the exact relationship between tion, capillary dilation, proliferation mentary keratitis. This therapy was corneal melt and the use of topical of fi broblasts and collagen deposi- effective even for patients suffering NSAIDs, a number of mechanisms tion. Additionally, they stabilize from severe dry eye who exhibited have been suggested: activation intracellular and extracellular mem- no improvement from maximum of MMPs, impairment of wound branes. Corticosteroids increase the aqueous tear enhancement/replace- healing and neurotrophic effect synthesis of lipocortins that block ment therapies. resulting from analgesic action of phospholipase A2 and inhibit his- A pilot study consisting of 64 these drugs.38 Short-term use of tamine synthesis in the mast cells.29 patients evaluated the effi cacy of NSAIDs can be useful in ameliorat- Inhibition of phospholipase A2, an loteprednol etabonate 0.5% (LE) ing symptoms of ocular discomfort essential step in the infl ammatory ophthalmic suspension for the treat- in dry eye; however, these agents cascade, prevents the conversion ment of the infl ammatory com- should be used with caution and pa- of phospholipids to arachidonic ponent of dry eye associated with tients should be monitored closely. acid. Corticosteroids also interfere aqueous tear defi ciency and delayed If the corneal epithelium shows any with transcription factor NF-kB, tear clearance.34 The LE-treated sign of damage, NSAIDs should be which regulates synthesis of numer- group was dosed four times daily discontinued immediately. ous pro-infl ammatory molecules, and compared to a placebo group. • Tetracycline derivatives. Vari- thereby stimulating lymphocyte Following two weeks of therapy, the ous dosages of oral doxycycline and apoptosis. subset of patients with moderate to minocycline, typically used for Corticosteroids mediate their severe clinical infl ammation showed 12 weeks or more, are commonly anti-infl ammatory effects primar- a signifi cant difference between the used to treat dry eye. Tetracycline ily through the modulation of the LE-treated group and vehicle-treat- derivatives uniquely possess both cytosolic glucocorticoid receptor at ed group in central corneal staining, antibacterial and anti-infl ammatory the genomic level.30,31 After cortico- nasal bulbar conjunctival hyperemia properties. Doxycycline has been steroids bind to the glucocorticoid and lid margin injection. shown to inhibit c-Jun N-terminal receptor in the cytoplasm, the acti- None of the patients experienced kinase and extracellular signal- vated corticosteroid-glucocorticoid a clinically signifi cant increase in related kinase mitogen-activated receptor complex migrates to the intraocular pressure following one protein kinase signaling in epithelial nucleus, where it upregulates the month of therapy. Patients treated cells of the ocular surface exposed expression of anti-infl ammatory with topical corticosteroids should to hyperosmolar stress, downregu-

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020_rccl0514_F3_CE.indd 22 4/28/14 2:34 PM eral anti-infl ammatory factors that In Search of Sjogren’s have the capability to inhibit soluble The aqueous-defi cient subgroup of dry eye is further divided into mediators of the ocular surface two major subgroups: Sjögren’s syndrome (SS)-dry eye and non-SS infl ammatory cascade of dry eye. dry eye. Typically, the American-European Consensus Group 2002 These include inhibitors of infl am- revised classifi cation criteria is used to diagnose SS. Either four matory cytokines (e.g., IL-1 RA and out of the six criteria or three out of the four objective criteria are soluble TNF-receptors) and MMP required for diagnosis. The six criteria include:3 inhibitors (e.g., TIMPs).54-56 Clinical • Subjective ocular dryness • Objective ocular dryness trials have shown autologous serum • Subjective oral dryness drops to improve ocular irritation • Objective oral dryness symptoms and conjunctival and • Presence of Sjögren-specifi c antibody A (SSA)/Ro, and/or corneal dye staining in SS-related Sjögren-specifi c antibody B (SSB)/La dry eye.57-59 Conversely, there is • Positive minor salivary gland biopsy greater risk of microbial growth—in However, a new classifi cation criteria for SS was endorsed in 2012 addition to antimicrobial agents, by the American College of Rheumatology. The new assessment autologous serum drops contain 4 requires at least two of the following three criteria to diagnose SS: high protein content and are gener- • Positive serum anti-SSA, and/or anti-SSB or rheumatoid factor or ally non-preserved.60 antinuclear antibody (titer>1:320) • A total ocular surface staining score greater than three Recent studies have investigated • Presence of focal lymphocytic sialadenitis (infl ammation of the cord serum drops (prepared from salivary gland) with a focus score greater than 1/4mm2 in labial sali- donor umbilical cord serum) and vary gland biopsy samples allogenic serum drops (from a According to the classifi cation criteria from the American-Euro- relative donor).61,62 A recent clinical pean collaboration, secondary SS consists of the features of primary trial, which enrolled 17 patients SS in addition to the features of an overt autoimmune connective with graft-versus-host-disease tissues disease (e.g., rheumatoid arthritis). Several systemic diseases (GVHD)-associated dry eye and have a well-known association with dry eye syndrome, including 13 patients with SS-associated rheumatoid arthritis, scleroderma, polymyositis, lymphoma, amyloi- dry eye, treated each patient with dosis, hemochromatosis, sarcoidosis and systemic lupus erythematosus.5 Autoimmune thyroid disease should also be considered when cord blood serum for a duration of evaluating patients with dry eye, as it has been shown to be a cause one month. Patients received cord of infl ammatory ocular surface disease with dry eye symptomology.6 blood containing 0.15ng epithelial Based on numerous epidemiological studies, women and older growth factor per drop once a day. individuals are commonly at risk for developing dry eye.7,8 As such, Patients reported a decrease in both perimenopausal and postmenopausal women appear to be discomfort symptoms, as measured at a particularly higher risk. Additionally, hormonal studies have with Ocular Surface Disease Index demonstrated that sex hormones infl uence ocular surface conditions score (OSDI). In addition, clinical through their effects on aqueous tear secretion, meibomian gland fi ndings such as impression cytology function and conjunctival goblet cell density.9,10 Thus, an altered hor- score, tear osmolarity and corneal monal state (e.g., following menopause) may be a potential cause of dry eye. sensation (measured with Cochet- Bonnet esthesiometer) improved signifi cantly.62 lating the expression of CXCL8 and ocular rosacea have benefi ted from Allogenic serum drops, prepared pro-infl ammatory cytokines IL-1β the use of doxycycline—it has using the blood from a family and TNF.45 been reported to reduce irrita- member, were also shown to be Doxycycline also inhibits MMP-9 tion symptoms, improve tear fi lm effective in treating patients with activity and supports ocular surface stability and decrease the severity GVHD. Following four weeks of integrity.46,47 Additionally, stud- of ocular surface disease.49-51 In ad- continuous use, patients exhibited a ies demonstrated that minocycline dition, when used in tandem with reduction in OSDI symptom scores, inhibits expression of cell-associated topical corticosteroids, doxycycline tear osmolarity and corneal stain- pro-infl ammatory molecules, in- has been useful in the treatment of ing. Additionally, both goblet cell cluding major histocompatibility corneal erosions.52,53 density and tear fi lm break-up time complex class II.48 Patients with • Autologous serum contains sev- increased.63

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020_rccl0514_F3_CE.indd 23 4/28/14 2:35 PM THE HUNT FOR DRY EYE INSTIGATORS

• Topical tacrolimus, available in suppresses the immune response copy revealed a signifi cant decrease 0.03% and 0.1% concentrations as by inhibiting the release of other in the numbers of central corneal both an ointment and compounded infl ammatory cytokines (e.g., IL-3, CD11b+ cells, lymphatic growth eye drops, is a promising dry eye IL-4, IL-5, IL-8, interferon-gamma and interleukin-1β expression after treatment option for patients with and TNF-alpha).77-80 treatment with IL-1Ra 5% and chronic GVHD and SS.64-66 Systemic methylprednisolone 1%, but not tacrolimus has been reported to EXPERIMENTAL cyclosporin A. This suggests that be effective for improving GVHD- TREATMENTS IL-1Ra is comparable to topical associated dry eye; however, there Although clinicians today have methylprednisolone in reducing in- are potential adverse reactions to many viable treatment options for fl ammation and improving clinical be aware of when administering infl ammatory-mediated dry eye, signs of dry eye. long-term systemic therapy.67 These investigators are actively exploring • Resolvin E1 (RvE1) is a new risks include an increased risk of new options to augment our efforts. class of endogenous immune nephrotoxicity, neurotoxicity and • Interleukin-1 receptor antago- response mediators derived from malignancy—especially lymphomas nist (IL-1Ra) is an endogenous IL-1 the lipoxygenation of the essential and skin malignancies. This topical receptor blocker produced primar- dietary omega-3 polyunsaturated fatty acids, eicosapentaenoic acid and docosahexaenoic acid.83 In ani- mal models, a treatment regimen of topical 100µg/mL (0.01%) omega-3 derivatives QID for one week has been shown to reverse corneal epithelial damage associated with dry eye. In this study, a specialized corneal module of a tomographer was used to study the corneas in vivo. The researchers noted increased tear fl ow (promoting a healthy epithelium), decreased cyclooxygenase-2 expression by Western Blot analysis and a decreased macrophage infi l- tration.84 A murine model of dry eye Conjunctival staining with lissamine green in a dry eye patient. demonstrated that 300µg/ml topical RvE1 QID improved both corneal anti-infl ammatory agent (previously ily by activated monocytes and staining and goblet cell density.85 known as FK506) is a macrolide an- tissue macrophages.81 It inhibits the The synthetic analog of RvE1, RX- tibiotic isolated from Streptomyces activities of the pro-infl ammatory 10045, is being tested in a Phase tsukubaensis fermentation.68 forms of IL-1 (IL-1α and IL-1β) by II clinical trial for the treatment of Although the mechanism of competitively binding to the IL-1 chronic dry eye. Preliminary data tacrolimus is similar to cyclosporin receptor-I.81 A murine model with of a 28-day, randomized, placebo- A, the potency in vitro has been environmentally induced dry eye controlled, 232-patient trial showed shown to be signifi cantly greater. was treated with 3µl of topical IL- dose-dependent and statistically Tacrolimus demonstrated effects Ra three times daily for nine days. signifi cant improvements using RX- similar to cyclosporin A, but at Following treatment, a signifi cant 10045; however, fi nal data has not concentrations 100 times lower.69 decrease in corneal fl uorescein stain- been published.86 Only when bound to immunophilin ing was observed with slit-lamp • Chemokine receptor an- does it become biologically active, biomicroscopy. Comparison treat- tagonist. Monocyte chemotactic thus effectively inhibiting calcineu- ments (methylprednisolone 1% and protein 1 (MCP-1) is secreted by rin, as well as T- and B-lymphocyte cyclosporin A 0.05%) were equally monocytes, memory T-cells, mac- activation via reduction in IL-2 syn- effective in this model.82 rophages, fi broblasts, endothelial thesis.70-76 Additionally, tacrolimus Additionally, confocal micros- cells and mast cells. It stimulates

24 REVIEW OF CORNEA & CONTACT LENSES | MAY 2014

020_rccl0514_F3_CE.indd 24 4/25/14 4:46 PM the movement of leukocytes along a Tofacitinib subsequently modulates trolled trial of 230 patients with dry chemotactic gradient after binding adaptive and innate immunity, with eye, subjects were randomized to li- to its cell surface receptor, chemo- limited effects on hematopoiesis.92 fi tegrast (0.1, 1.0, 5.0%) or placebo kine receptor antagonist.87 The In Phase I and Phase II clinical eye drops twice daily for 84 days. critical role of the coupled MCP-1/ trials, topical tofacitinib 0.0003% Lifi tegrast showed dose-dependent chemokine receptor antagonist in to 0.005% was used to treat 327 and statistically signifi cant improve- infl ammation has been demon- patients with clinically signifi cant ments in corneal staining scores and strated using MCP-1 and chemo- aqueous defi cient dry eye for eight symptoms measured with OSDI kine receptor antagonist knockout weeks. Using Schrimer’s test with- (both total ocular surface disease mice, suggesting that inhibiting the out anesthesia and corneal fl uores- index and visual related function migration of chemokine receptor cein staining, a trend for improving questions) vs. placebo. Improve- antagonist-bearing mononuclear both signs and symptoms of dry ments in both tear production and cells may be an effective mechanism eye was observed.93 The topical symptoms were noted as early as to modulate disease progression in agent also demonstrated a reason- day 14. In addition, lifi tegrast was chronic infl ammation.88 able safety profi le.93 A sub-study well tolerated; no serious ocular A study of dry eye disease exam- of the Phase I/II trials showed a adverse events were reported.96 ined a murine model treated with reduction in infl ammation assessed OPUS-1, a recent Phase III clinical topical chemokine receptor antago- by change from baseline in con- trial, compared lifi tegrast 5% BID nist 5.0mg/ml BID for seven days. junctival cell surface expression of for 84 days to placebo in 588 adult The model exhibited a signifi cant human leukocyte antigen DR-1.94 subjects with dry eye.97 The results decrease in corneal fl uorescein stain- This was accomplished by study- of the study revealed that lifi tegrast ing following treatment. Real-time ing fl ow cytometry and tear level of signifi cantly reduced corneal fl uo- polymerase chain reaction revealed several cytokines and infl ammation rescein and conjunctival lissamine decreased infi ltration of corneal markers by microsphere-based im- staining, and also improved symp- CD11b(+) cells and conjunctival munoassays.94 toms of ocular discomfort and eye T-cells vs. both the vehicle treated • Lifi tegrast (previously known dryness compared with placebo. and untreated dry eye groups.89 The as SAR 1118) is a novel, investi- • Mapracorat (formerly ZK- chemokine receptor antagonist also gational, small-molecule lympho- 245186 and subsequently BOL- signifi cantly decreased messenger cyte function-associated antigen-1 303242-X) is a novel, selective RNA expression levels of IL-1α and antagonist engineered for topical glucocorticoid receptor agonist IL-1β in the cornea, and TNF-α and ophthalmic delivery.95,96 The binding currently under investigation. IL-1β in the conjunctiva. of lymphocyte function-associated The anti-infl ammatory effects of • Tofacitinib (CP-690,550) is antigen-1 on the surface of T-cells to mapracorat were assessed in an in a selective inhibitor of the janus intercellular adhesion molecule-1 on vitro osmotic stress model, which kinase (JAK) used orally to treat endothelial, epithelial and antigen simulates some of the pathophysi- rheumatoid arthritis. JAK signaling presenting cells is a critical step in ological changes seen in dry eye.98 is essential for immune cell activa- T-cell activation (normal immune Incubation of cells with mapracorat tion, pro-infl ammatory cytokine response and infl ammation). Thus, 0.1-1.0% applied three times a day production and cytokine signal- it has been proposed that a block- for seven to eight days inhibited ling.90 Tofacitinib inhibits JAK1, ade of lymphocyte function-associ- hyperosmolar-induced cytokine JAK2 and JAK3 in vitro, with func- ated antigen-1/intercellular adhesion release. The activity and potency tional cellular selectivity for JAK1 molecule-1 interaction may provide of mapracorat was comparable to and JAK3 over JAK2.91 Inhibition a therapeutic benefi t to patients the commonly used steroid, dexa- of JAK1 and JAK3 by tofacitinib with dry eye, breaking the chronic methasone. In a study using a rabbit blocks signaling through the com- cycle of T-cell-mediated infl amma- model, mapracorat was effective in mon γ-chain containing receptors tion and aiding in the recovery of maintaining tear volume and tear for several cytokines, including IL- the ocular surface. break-up time, with no increase in 2, IL-4, IL-7, IL-9, IL-1, and IL-21. Lifi tegrast is an effective inhibitor intraocular pressure.99 Additionally, inhibition of JAK1 of T-cell activation, adhesion, mi- results in attenuation of signaling by gration, proliferation and cytokine Regardless of whether or not an additional pro-infl ammatory cyto- release.95 In a multicenter, prospec- underlying systemic infl ammatory kines, such as IL-6 and interferon γ. tive, double-masked, placebo-con- condition can be identifi ed, dry

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14. Cejková J, Ardan T, Simonová Z, et al. Nitric 32. Stahn C, Buttgereit F. Genomic and nonge- eye is associated with chronic and oxide synthase induction and cytotoxic nitro- nomic effects of glucocorticoids. Nature Clini- sometimes subclinical infl ammation. gen-related oxidant formation in conjunctival cal Practice Rheumatol. 2008;4(10):525–533. If left unchecked, this infl ammation epithelium of dry eye (Sjögren’s syndrome) 33. Marsh P, Pfl ugfelder SC. Topical non- Nitric Oxide. 2007;17:10–7. preserved methylpresdnisolone therapy of may cause ocular surface damage. 15. Paul A, Wilson S, Belham CM, et al. Stress- keratoconjunctivits sicca in sjogren’s syndrome. Novel treatments, which target spe- activated protein kinases: activation, regulation Ophthalmology 1999;106: 811-816. and function. Cell Signal. 1997;9:403–10. 34. Pfl ugfelder SC, Maskin SL, Anderson B, et cifi c mediators in infl ammatory re- 16. Pfl ugfelder SC, de Paiva CS, Tong L, et al. al. A randomized, double-masked, placebo- actions associated with dry eye, are Stress-activated protein kinase signaling path- controlled, multicenter comparison of lotepre- ways in dry eye and ocular surface disease. dnol etabonate ophthalmic suspension, 0.5%, constantly evolving. It’s important Ocul Surf. 2005;3(Suppl 4):154–7. and placebo for treatment of keratoconjuncti- that we continue to look for the 17. Luo L, Li DQ, Doshi A, et al. Experimental vitis sicca in patients with delayed tear clear- underlying causes of dry eye, and dry eye stimulates production of infl ammatory ance. Am J Ophthalmol. 2004;138(3):444–457. cytokines and MMP-9 and activates MAPK sig- 35. McGhee CN, Dean S, Danesh-Meyer H. manage the condition based on the naling pathways on the ocular surface. Invest Locally administered ocular corticosteroids: clinical signs and symptoms with all Ophthalmol Vis Sci. 2004;45:4293–301. benefi ts and risks. Drug Saf. 2002;25(1):33-55. 18. Li DQ, Luo L, Chen Z, et al. JNK and ERK 36. Vane JR, Bakhle YS, Botting RM. Cyclooxy- currently available options. RCCL MAP kinases mediate induction of IL-1beta, genases 1 and 2. Annu Rev Pharmacol Toxicol. TNF-alpha and IL-8 following hyperosmolar 1998; 38:97–120 1. Lemp MA, Baudouin C, Baum J, et al. The stress in human limbal epithelial cells. Exp Eye 37. Aragona P, Tripodi G, Spinella R, et al. The defi nition and classifi cation of dry eye disease: Res. 2006;82:588–96. effects of the topical administration of non- report of the defi nition and classifi cation 19. Utine CA, Stern M, Akpek EK. Clinical re- steroidal anti-infl ammatory drugs on corneal subcommittee of the international dry eye view: topical ophthalmic use of cyclosporin A. epithelium and corneal sensitivity in normal workshop (2007). Ocul Surf. 2007;5:75-92. Ocul Immunol Infl amm. 2010;18(5):352-61. subjects. Eye. 2000;14:206-210. 2. Moss SE, Klein R, Klein BE. Prevalence of 20. Dastjerdi MH, Hamrah P, Dana R. High 38. Gokhale NS, Vemuganti GK. Diclofenac-in- and risk factors for dry eye syndrome. Arch frequency topical cyclosporine 0.05% in the duced acute corneal melt after collagen cross- Ophthalmol. 2000;118:1264-1268. treatment of severe dry eye refractory to linking for keratoconus. Cornea 2010;29:117–119. 3. Vitali C, Bombardieri S, Jonsson R, et al. twice-daily regimen. Cornea. 2009;28:1091- 39. Flach AJ. Corneal melts associated with Classifi cation criteria for Sjögren syndrome: a 1096. topically applied nonsteroidal anti- infl am- revised version of the European criteria pro- 21. Matsuda S, Koyasu S. Mechanisms of ac- matory drugs. Trans Am Ophthalmol Soc posed by the American-European consensus tion of cyclosporine. Immunopharmacology. 2001;99:205–212. group. Ann Rheum Dis. 2002;61:554-558. 2000;47(2-3):199-125. 40. Khalifa YM, Miffl in MD. Keratitis and corneal 4. Shiboski SC, Shiboski CH, Criswell LA, et al. 22. Stevenson W, Chauhan SK, Dana R. Dry Eye melt with ketorolac tromethamine after con- American College of Rheumatology Clas- Disease: an immune-mediated ocular surface dis- ductive keratoplasty. Cornea 2011;30:477–478. sifi cation Criteria for Sjögren’s Syndrome: A order. Arch Ophthalmology. 2012;130(1):90-100. 41. Di Pascuale MA, Whitson JT, Mootha VV. Data-Driven, Expert Consensus Approach 23. Pfl ugfelder SC, Wilhelmus KR, Osato MS, Corneal melting after use of nepafenac in a in the SICCA Cohort. Arthritis Care Res et al. The auto-immune nature of aqueous tear patient with chronic cystoid macular edema 2012;64(4):475–487. defi ciency. Ophthalmology. 1986;93;1513-1517. after cataract surgery. Eye Contact Lens 5. Djalilian AR, Hamrah P, Pfl ugfelder SC. Dry 24. Stern ME, Gao J, Siemasko KF, et al. The 2008;34:129–130. Eye. In: Krachmer JH, Mannis MJ, Holland EJ. role of the lacrimal gland functional unit in 42. Asai T, Nakagami T, Mochizuki M, et al. Cornea 2005;2(1):521-540. the pathophysiology of dry eye. Exp Eye Res. Three cases of corneal melting after instillation 6. Gupta A, Sadeghi PB, Akpek EK. Occult thy- 2004;78;409-416. of a new nonsteroidal anti-infl ammatory drug. roid eye disease in patients presenting with dry 25. Stevenson D, Tauber J, Reis BL. Effi cacy Cornea 2006;25:224–227. eye symptoms. Am J Ophthal 2009;147(5):919- and safety of cyclosporine A ophthalmic emul- 43. Isawi H, Dhaliwal DK. Corneal melting and 923. sion in the treatment of moderate to severe perforation in Stevens Johnson syndrome 7. The epidemiology of dry eye disease: Report dry eye disease: a dose-ranging, randomized following topical bromfenac use. J Cataract of the Epidemiology Subcommittee of the trial. The Cyclospoine A Phase 2 Study Group. Refract Surg. 2007;33:1644–1646. International Dry Eye Workshop (2007) Ocul Ophthalmology. 2000;107:967-974. 44. Prasher P. Acute Corneal Melt Associated Surf. 2007;5:93–107. 26. Sall K, Stevenson OD, Mundorf TK, et al. With Topical Bromfenac Use. Eye & Contact 8. Connor CG, Flockencier LL, Hall CW. The Two multicenter, randomized studies of the Lens. 2012;38:260–262. infl uence of gender on the ocular surface. J effi cacy and safety of cyclosporine ophthalmic 45. Solomon A, Rosenblatt M, Li D, et al. Am Optom Assoc. 1999;70:182–6. emulsion in moderate to severe dry eye dis- Doxycycline inhibition of interleukin-1 in 9. Krenzer KL, Dana MR, Ullman MD, et al. ease. CsA Phase 3 Study Group. Ophthalmol- the cornea epithelium. Am J Ophthalmol. Effect of androgen defi ciency on the human ogy. 2000;107:631-639. 2000;130(5):688. meibomian gland and ocular surface. J Clin 27. Laibovitz RA, Solch S, Andriano K, et al. 46. De Paiva CS, Corrales RM, Villarreal AL, et Endocrinol Metab. 2000;85:4874–82. Pilot trial of cyclosporine 1% ophthalmic oint- al. Corticosteroid and doxycycline suppress 10. Schaumberg DA, Buring JE, Sullivan DA. ment in the treatment of keratoconjunctivitis MMP-9 and infl ammatory cytokine expression, Hormone replacement therapy and dry eye sicca. Cornea. 1993;12;315-323. MAPK activation in the corneal epithe- syndrome. JAMA. 2001;286:2114–19. 28. Kunert KS, Tisdale AS, Gipson IK. Goblet lium in experimental dry eye. Exp Eye Res. 11. Kunert KS, Tisdale AS, Stern ME, et al. cell numbers and epithelial proliferation in the 2006;83(3):526-535. Analysis of topical cyclosporine treatment conjunctiva of patients with dry eye syndrome 47. De Paiva CS, Corrales RM, Villarreal AL, of patients with dry eye syndrome: effect on treated with cyclosporine. Arch Ophthalmol. et al. Apical corneal barrier disruption in conjunctival lymphocytes. Arch Ophthalmol. 2002;120:330-337. experimental murine dry eye is abrogated by 2000;118:1489–96. 29. Comstock T and DeCory H. Advances methylprednisolone and doxycycline. Invest 12. Stern ME, Gao J, Schwalb TA, et al. Con- in corticosteroid therapy for ocular infl am- Ophthalmol Vic Sci. 2006;47(7):2847-2856. junctival T-cell subpopulations in Sjögren’s and mation: loteprednol etabonate. Int J Infl am. 48. Nikodemova M, Watters JJ, Jackson SJ, et 2012;2012:789623. non-Sjögren’s patients with dry eye. Invest al. Minocycline downregulates MHC II expres- Ophthalmol Vis Sci. 2002;43:2609–14. 30. Rhen T, Cidlowski JA. Antiinfl ammatory sion in microglia and macrophages through action of glucocorticoids—new mechanisms for α 13. Solomon A, Dursun D, Liu Z, et al. Pro- and inhibition of IRF-1 and protein kinase C (PKC) / old drugs. NEJM. 2005;353(16):1711–1658. ΒII. J Biol Chem. 2007;282(20):15208-15216. anti-infl ammatory forms of interleukin-1 in the tear fl uid and conjunctiva of patients with 31. Newton R. Molecular mechanisms of glu- 49. Frucht-Pery J, Sagi E, Hemo I, et al. Ef- dry-eye disease. Invest Ophthalmol Vis Sci. cocorticoid action: what is important? Thorax. fi cacy of doxycycline and tetracycline in ocular 2001;42:2283–92. 2000;55(7):603–613. rosacea. Am J Ophthalmol. 1993;116:88-92.

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020_rccl0514_F3_CE.indd 26 4/25/14 4:09 PM 50. Zengin N, Tol H, Gunduz K, et al. Meibomian 67. Thomson AW, Bonham CA, Zeevi A. 83. Serhan CN, Chiang N, van Dyke TE. Resolv- gland dysfunction and tear fi lm abnormalities Mode of action of tacrolimus (FK506): mo- ing infl ammation: dual antiinfl ammation and in rosacea. Cornea. 1995;13:144-146. lecular and cellular mechanisms. Ther Drug pro-resolution lipid mediators. Nat Rev Immu- 51. Akpek EK, Merchant A, Pinar V, Foster CS. Monit.1995;17(6)584-591. nol. 2008;8:347-61. Ocular rosacea: patient characteristics and 68. Kino T, Hatanaka H, Miyata S, et al. FK-506, 84. Li N, He J, Scwartz CE, et al. Resolvin follow-up. Ophthalmology 1997;104:1863-1867. a novel immunosuppressant isolated from E1 improves tear production and decreases infl ammation in a dry eye mouse model. J Ocul 52. Dursun D, Kim MC, Solomon A, Pfl ugfelder Streptomyces. I. Fermentation isolation, and Pharmacol Ther. 2010;26:431-9. SC. Treatment of recalcitrant corneal epithelial physio-chemical and biological characteristics. erosions with inhibitors of matrix metallopro- J Antibiot (Tokyo). 1987;40:1249-1255. 85. De Paiva CS, Schwartz CE, et al. Resolvin E1 teinases-9, doxycycline and corticosteroids. 69. Attas-Fox L, Barkana Y, Iskhakov V, et al. (RX-10001) reduces corneal epithelial barrier Am J Ophthalmol. 2001;132:8-13. Topical tacrolimus 0.03% ointment for intrac- disruption and protects against goblet cell table allergic conjunctivitis: an open-label pilot loss in a murine model of dry eye. Cornea. 53. Hope-Ross MW, Chell PB, Kervick GN, Mc- 2012;31:1299-303. Donnell PJ, Jones HS. Oral tetracycline in the study. Curr Eye Res. 2008;33:545–549. 86. Cortina MS, Bazan HE. Docosahexaenoic treatment of recurrent corneal erosions. Eye. 70. Bertelmann E, Pleyer U. Immunomodula- tory therapy in ophthalmology—is there a acid, protectins and dry eye. Curr Opin Clin 1994;8:384-388. Nutr Metab Care. 2011;14(2):132-7 place for topical application? Ophthalmologica. 54. Liou LB. Serum and in vitro production 2004;218:359–367. 87. Tylaska LA, Boring L, Weng W et al. CCR2 of IL-1 receptor antagonist correlate with regulates the level of MCP-1/CCL2 in vitro 71. Fei WL, Chen JQ, Yuan J, et al. Preliminary C-reactive protein levels in newly diagnosed, and at infl ammatory sites and controls T cell untreated lupus patietns. Clin Exp Rheumatol. study of the effect of FK506 nanospheric- activation in response to alloantigen. Cytokine. 2001;19:515-523. suspension eye drops on rejection of pen- 2002;18(4) 184-190. etrating keratoplasty. J Ocul Pharmacol Ther. 55. Ji H, Pettit A, Ohmura K, et al. Critical roles 2008;24:235–244. 88. Oshima T, Sonoda KH, Tsutsumi-Miyaara C for interleukin 1 and tumor necrosis factor et al. Analysis of corneal infl ammation induced alpha in antibody-induced arthritis. J Exp Med 72. Fujita E, Teramura Y, Mitsugi K, et al. by cauterisation in CCR2 and MCP-1 knockout 2002; 196:77-85. Absorption, distribution, and excretion of mice. Br J Ophthalmol. 2006;90(2):218-222. 14C-labeled tacrolimus (FK506) after a single 56. Paramo JA, Orbe J, Fernandez J. Fibrinoly- 89. Goyal S, Chauhan S, Zhang Q, Dana R. or repeated ocular instillation in rabbits. J Ocul sis/proteolysis balance instable angina pectoris Amelioration of murine dry eye disease by Pharmacol Ther. 2008;24:333–343. in relation to angiographic fi ndings. Thromb topical antagonist to chemokine receptor 2. Haemost. 2001;86:636-639. 73. Fujita E, Teramura Y, Shiraga T, et al. Arch Ophthalmol. 2009;127:882-87. Pharmacokinetics and tissue distribution of 90. Ghoreschi K, Laurence A, O’Shea JJ. Janus 57. Fox RI, Chan R, Michelson JB, et al. Benefi - tacrolimus (FK506) after a single or repeated cial effect on artifi cial tears made with autolo- kinase in immune cell signaling. Immunol Rev. ocular instillation in rabbits. J Ocul Pharmacol 2009;228:273-287. gous serum in patients with Keratoconjunctivi- Ther. 2008;24:309–319. tis sicca. Arthritis Rheum. 1984;27:459-61. 91. Meyer DM, Jesson MI, Li X, et al. Anti-in- 74. Nishino K, Fukushima A, Okamoto S, et al. fl ammatory activity and neutrophil reduc- 58. Kono I, Kono K, Narushima K, et al. Benefi - Suppression of experimental immune-medi- cial effect of the local application of plasma tions mediated by the JAK1/JAK3 inhibitor, ated blepharoconjunctivitis in Brown Norway CP-690,550 in rat adjuvant-induced arthritis. J fi bronectin and autologous serum in patients rats by topical application of FK506. Graefes Infl amm. 2010;7:41. with Keratoconjunctivitis sicca of Sjogren’s Arch Clin Exp Ophthalmol. 2002;240:137–143. syndrome. Ryumachi. 1986;26:339-343. 92. Ghoreschi K, Jesson MI, Li X, et al. Modula- 75. Pleyer U, Lutz S, Jusko WJ, et al. Ocular tion of innate and adaptive immune responses 59. Tsubota K, Goto E, Fujita H, et al. Treatment absorption of topically applied FK506 from li- by tofacitinib (CP-690,550). J Immunol. of dry eye by autologous serum applica- posomal and oil formulations in the rabbit eye. 2011;186(7):4234-4343. tion in Sjogren’s syndrome. Br J Ophthamol. Invest Ophthalmol Vis Sci. 1993;34:2737–2742. 1999;83:390-395. 93. Liew SH, Nichols K, Klamerus K, et al. To- 76. Sasakawa Y, Sakuma S, Higashi Y, et al. facitinib (CP-690,550), a janus kinase inhibitor 60. Tananuvat N, Daniell M, Sullivan LJ, et FK506 suppresses neutrophil chemoattractant for dry eye disease: Results from a Phase 1/2 al. Controlled study of the use of autolo- production by peripheral blood mononuclear trial. Ophthalmology. 2012;119(7):e43-e50. gous serum in dry eye patients. Cornea. cells. Eur J Pharmacol. 2000;403:281–288. 94. Liew SH, Nichols K, Klamerus K, et al. 2001;20:802-6. 77. Reitamo S, Van Leent EJ, Ho V, et al.. Immunomodulatory effect of the topical 61. Versura P, Profazio V, Buzzi M, et al. Effi cacy Effi cacy and safety of tacrolimus ointment ophthalmic janus kinase inhibitor tofacitinib in standardized and quality-controlled cord compared with that of hydrocortisone acetate (CP-690,550) in patients with dry eye disease. blood serum eye drop therapy in the healing ointment in children with atopic dermatitis. J Ophthalmology. 2012;119(7):1328-1335. of severe corneal epithelial damage in dry eye. Allergy Clin Immunol. 2002;109:539–546. 95. Murphy CJ, Bentley E, Miller PE, et al. The Cornea. 2013;32(4):412-18. 78. Reitamo S, Rustin M, Ruzicka T, et al. pharmacologic assessment of a novel lympho- 62. Yoon KC, Jeong IY, Im SK, et al. Thera- Effi cacy and safety of tacrolimus ointment cyte function-associated antigen-1 antagonist peutic effect of umbilical cord serum for the compared with that of hydrocortisone butyrate (SAR 1118) for the treatment of keratoconjunc- treatment of dry eye associated with graft- ointment in adult patients with atopic dermati- tivitis sicca in dogs. Invest Ophthalmol Vis Sci. versus-host disease. Bone Marrow Transplant. tis. J Allergy Clin Immunol. 2002;109:547–555. 2011;52(6):3174-80. 2007;39(4):231-5. 96. Semba CP, Torkildsen GL, Lonsdale JD, 79. Reitamo S, Remitz A, Kyllönen H, et al. et al. A Phase II randomized, double-masked, 63. Na KS, Kim MS. Allogenic serum eye drops Topical noncorticosteroid immunomodulation placebo-controlled study of a novel integrin for the treatment of dry eye patients with in the treatment of atopic dermatitis. Am J Clin chronic graft-versus-host disease. J Ocul Phar- antagonist (SAR 1118) for the treatment of dry Dermatol. 2002;3:381–388. eye. Am J Ophthalmol. 2012;153(6):1050-60. macol Ther. 2012;28(5):479-83. 80. Aoki S, Mizote H, Minamoto A, et al. Sys- 97. Sheppard J, Torkildsen GL, Lonsdale J, et 64. Ryu EH, Kim JM, Laddha PM, et al. temic FK506 improved tear secretion in dry al. Lifi tegrast Ophthalmic Solution 5.0% for Therapeutic effect of 0.03% tacrolimus for eye associated with chronic graft versus host Treatment of Dry Eye Disease : Results of ocular graft versus host disease and vernal disease. Br J Ophthalmol. 2005;89(2):243-4. the OPUS-1 Phase 3 Study. Ophthalmology. keratoconjunctivits. Korean J Ophthalmol. 81. Gabay C, Porter B, Fantuzzi G, Arend WP. 2014;121(2):475-83. 2012;26(4):241-7. Mouse IL-1 receptor antagonist isoforms: 98. Cavet M, Harrington K, Ward K, et al. Mapra- 65. Tam PM, Young AL, Cheng AL, Lam PT. complementary DNA cloning and protein corat, a novel selective glucocorticoid receptor Topical 0.03% tacrolimus ointment in the expression of intracellular isoform and tis- agonist, inhibits hyperosmolar-induced cytokine management of ocular surface infl ammation sue distribution of secreted and intracellular release and MAPK pathways in human corneal in chronic GVHD. Bone Marrow Transplant. IL-1 receptor antagonist in vivo. J Immunol. epithelial cells. Mol Vis. 2010;16:1791-1800. 2010;45(5)957-8. 1997;159(12):5905–5913. 99. Shafi ee A, Bucolo C, Budzynski E, et al. In 66. Moscovici B, Holzchuh R, Chiacchio B, 82. Okanobo A, Chauhan SK, Dastjerdi MH, et vivo ocular effi cacy profi le of mapracorat, a et al. Clinical treatment of dry eye us- al. Effi cacy of topical blockade of interleukin-1 novel selective glucocorticoid receptor agonist, ing 0.03% tacrolimus eye drops. Cornea. in experimental dry eye disease. 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020_rccl0514_F3_CE.indd 27 4/25/14 4:09 PM THE HUNT FOR DRY EYE INSTIGATORS

CE TEST

1. The International Dry eye a. Interleukin (IL)-1 cyclooxygenase (COX) enzyme Worskshop (DEWS) definition of dry b. Matrix metallopeptidase (MMP)-9 b. Increasing the synthesis of lipocor- eye includes all of the following, c. Tumor necrosis factor (TNF)-α tins that block phospholipase A2 to except: d. Interleukin (IL)-7 prevent the conversion of phospholip- a. Increased tear film osmolarity ids to arachidonic acid b. Potential damage to the ocular 7. Mitogen activated protein (MAP) c. Inhibition of c-Jun N-terminal surface kinase cascades may be activated in kinase and extracellular signal-related c. Decreased tear film osmolarity response to: kinase mitogen-activated protein d. Symptoms of discomfort a. Heat shock kinase b. Ischemia d. All of the above 2. Based on the 2012 classification c. Inflammatory cytokines criteria for Sjogren’s syndrome, d. All of the above 12. When treating a patient with sig- endorsed by The American College nificant punctate epithelial erosions of Rheumatology, requires 2 of the 3 8. Cyclosporine has been shown to due to severe dry eye: criteria. The following are identified be effective in improving dry eye a. Topical NSAIDs should be pre- as possible criteria, except: through: scribed at a frequent dosage a. Positive anti-DNA antibody a. Decreasing goblet cell density b. Topical NSAIDs may cause corneal b. Positive anti-SSA and/or SSB b. Increasing epithelial cell apoptosis melt therefore should not be used c. Presence of lymphocytic sialad- c. Enhancing tear production until improvement of the epithelium is enitis with a focus score >1/4mm2 in d. None of the above noted labial salivary gland biopsy c. Topical NSAIDs should be pre- d. Total ocular surface staining score 9. Which of the following is true scribed prn to relieve the patient’s greater than 3 when prescribing topical cyclospo- symptoms of discomfort rine A: d. Topical NSAIDs have been shown to 3. Dry eye has a well-known a. It should always be dosed once improve corneal sensitivity in patients association with the following daily with severe ocular surface disease systemic disease: b. It should only be used for patients a. Rheumatoid arthritis with mild dry eye 13. Doxycycline has been reported to b. Systemic lupus erythematosus c. A frequency of greater than twice be effective in the treatment of: c. Thyroid disease daily may be more effective in improv- a. Fuchs' corneal dystrophy d. All of the above ing severe dry eye when no improve- b. Dry eye at the setting of ocular ment is noted with twice daily dosage rosacea 4. The following have been identified d. Compounded concentrations c. Recurrent corneal erosions as risk factors for dry eye, except: greater than 0.05% should never be d. B and C a. Older age prescribed as they have been shown b. Refractive laser surgery to be toxic to the corneal epithelium 14. Serum eye drops, for the treat- c. Male sex ment of dry eye, have been shown to: d. Smoking 10. Topical corticosteroids, for treat- a. Reduce tear osmolarity ment of dry eye, have been correlated b. Decrease discomfort symptoms as 5. Which of the following systemic with all of the following risks, except: measured with OSDI medications may exacerbate dry eye: a. Cataract formation c. Reduce corneal staining a. Antihistamines b. Corneal thinning d. All of the above b. Tetracyclines c. Infectious keratitis c. Diuretics d. Reduction of intraocular pressure 15. For the treatment of dry eye, topi- d. A and C cal tacrolimus was shown to have a 11. The mechanism by which topical mechanism of action similar to: 6. The following inflammatory medi- NSAIDs reduce inflammation for the a. Tetracyclines ators have been found to play a role treatment of dry eye is via: b. NSAIDs in dry eye, except: a. Inhibition of prostaglandins via the c. Cyclosporine A

28 REVIEW OF CORNEA & CONTACT LENSES | MAY 2014

020_rccl0514_F3_CE.indd 28 4/25/14 4:46 PM Examination Answer Sheet Valid for credit through May 1, 2017 This exam can be taken online at www.reviewofcontactlenses.com. Upon passing the exam, you can view your results immediately. You can also view your test history CE TEST at any time from the website.

The Hunt for Dry Eye Instigators, by Michelle M. Hessen, OD d. Autologous serum 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. 16. Tofacitinib (CP-690,550) is a novel treatment for dry eye, which Mail to: Jobson - Optometric CE, PO Box 488, Canal Street Station, New York, NY 10013 acts as a selective inhibitor of: Payment: Remit $35 with this exam. Make check payable to Jobson Medical Information LLC. a. Janus kinase (JAK) COPE approval for 2 hours of CE credit is pending for this course. b. Tumor necrosis factor (TNF) α This course is joint-sponsored by the Pennsylvania College of Optometry c. Transcription factor NF-kB There is an eight-to-ten week processing time for this exam.

d. Cyclooxygenase (COX) enzyme 1. A B C D 1 = Excellent 2 = Very Good 3 = Good 4 = Fair 5 = Poor 2. A B C D Rate the effectiveness of how well the activity: 17. The following are treatments 3. A B C D being studied for the treatment of 4. A B C D 21. Met the goal statement: 1 2 3 4 5 5. A B C D 22. Related to your practice needs: 1 2 3 4 5 inflammatory-mediated dry eye, 6. A B C D 23. Will help you improve patient care: 1 2 3 4 5 except: 7. A B C D 24. Avoided commercial bias/influence: 1 2 3 4 5 a. Interleukin-1 receptor antagonist 8. A B C D 25. How would you rate the overall (IL-1Ra) 9. A B C D quality of the material presented? 1 2 3 4 5

b. Resolvin E1 (Rx-10001) 10. A B C D 26. Your knowledge of the subject was increased: 11. A B C D Greatly Somewhat Little c. Ocriplasmin 12. A B C D 27. The difficulty of the course was: d. Chemokine receptor antagonist 13. A B C D Complex Appropriate Basic 14. A B C D How long did it take to complete this course? 18. Lifitegrast is an effective 15. A B C D

inhibitor of: 16. A B C D Comments on this course: 17. A B C D a. T-cell mediated inflammation 18. A B C D b. Cyclooxygenase (COX) enzyme 19. A B C D Suggested topics for future CE articles: c. Janus kinase (JAK) 20. A B C D d. All of the above

Please retain a copy for your records. Please print clearly. 19. A controlled clinical trial evaluat- You must choose and complete one of the following three identifier types: ing lifitegrast (0.1, 1.0, 5.0%), for the treatment of dry eye, found a dose- 1 SS # - - dependent and statistically signifi- Last 4 digits of your SS # and date of birth State Code and License #: (Example: NY12345678) cant improvements in: 2 - 3 a. Corneal staining scores b. Symptoms measured with OSDI First Name c. Corneal sensitivity Last Name d. A and B E-Mail

The following is your: Home Address Business Address 20. Mapracorat, currently being Business Name investigated for anti-inflammatory effects as it pertains to dry eye, acts Address as a(n): City State

a. Interleukin-1 receptor antagonist ZIP

b. Selective glucocorticoid receptor Telephone # - - agonist Fax # - - c. T-cell activator By submitting this answer sheet, I certify that I have read the lesson in its entirety and completed the self- d. Selective inhibitor of janus kinase assessment exam personally based on the material presented. I have not obtained the answers to this exam (JAK) by any fraudulent or improper means.

Signature Date

Lesson 110123 RO-RCCL-0514

REVIEW OF CORNEA & CONTACT LENSES | MAY 2014 29

020_rccl0514_F3_CE.indd 29 4/25/14 4:46 PM Corneal Consult By James Thimons, OD

Stemming the Tide Much can be done to keep conjunctival tissue from breaching the cornea in patients with limbal stem cell disease. Here’s the latest thinking.

he diagnosis and like, saw-toothed shape that leads are typically related to toxicity from treatment of limbal towards the apex of the cornea. medications, chemical burns or stem cell disease This clinical abnormality oc- radiation exposure. Additionally, (LSCD) can be a curs because the absence of normal a number of surgical interventions T complex and chal- limbal stem cells causes the regenera- have been cited as etiologic factors, lenging situation at the primary tion of corneal epithelial cells to be and patients who have experienced care level. We have known for irregular; therefore, the section that cases of severe microbial keratitis decades of abnormal stem cell is abnormal will produce an atypical are sometimes left with LSCD pre- physiology, and its subsequent regenerative pattern that extends to- sentations. impact on the corneal surface. But wards the apex. Because the remain- In addition to visual identifi ca- only recently have defi nitive treating limbal cells are normal, their tion, LSCD can be diagnosed using ments for more advanced patients natural contribution will account for impression cytology—a process that become a reality. Once you have a the remaining aspect of the cornea. identifi es and reviews the pres- good sense of the condition and its The clinical appearance will be such ence of goblet cells on the corneal severity, you will be able to target that 75% to 80% of the cornea is surface. Impression cytology can your response appropriately. relatively normal while the remain- be used to determine if the limbal ing 20% to 25% demonstrates the stem cell barrier has been breached, WHAT YOU’LL SEE atypical regenerative pattern. indicating that LSCD is present. Patients who experience LSCD can In more severe cases, patients may Other diagnostic technologies have a variety of symptoms and experience non-healing epithelial include the use of ocular computed signs. For example, these patients defects. Also, it is possible for the tomography to identify corneal epi- may present with complications as cornea to become conjunctival- thelial characteristics unique to the simple as decreased vision, tear- ized—a condition in which the disease and confocal microscopy to ing, photophobia and hyperemia natural limbal barrier is disrupted, assess specifi c cellular morphology (which is usually accompanied by allowing cells from the conjunctiva and identify the underlying disease infl ammation). In more severe cases, to invade the corneal surface and state. patients will present with pain and produce an abnormal pattern and signifi cant loss of visual function. stratifi cation of epithelial cells. WHAT TO DO These cases are typically accom- Patients with partial limbal stem Appropriate treatment of LSCD panied by clinical signs indicative cell defi ciency make up less than will derive from the severity of the of severe cell damage, including one half of the affl icted popula- presentation. The vast majority of intense hyperemia at the limbal tion, while greater than one half cases seen at the primary care level junction and the development of of the population has the condi- are related to toxicity, overwear of a unique, whorl-like pattern of tion known as sub-total LSCD; the contact lenses, previous surgical corneal staining, which produces a differentiation is by magnitude of intervention or infectious disease dimensional change in the quality of tissue damage. tissue trauma. For cases such as the corneal epithelium. There are numerous etiologies these, traditional therapies using a In less severe cases, such as those for LSCD, which can range from bandage contact lens (BCL) with caused by contact lens overwear, a condition as simple as contact non-preserved lubricant drops and this is typically observed as an lens overwear syndrome or adverse ointments can be extremely effective abnormality of surface quality. This solution reaction to a more severe in reversing the damage. corneal irregularity can be seen presentation, such as an ocular cica- Typically, I will add a topical beginning at approximately the 10 tricial surface disease (e.g., Stevens- steroid (e.g., loteprednol etabonate) o’clock location and extending over Johnson syndrome or cicatricial on a QID basis for several weeks to to two o’clock, with a triangular- pemphigoid). Other causes of LSCD one month to decrease the infl am-

30 REVIEW OF CORNEA & CONTACT LENSES | MAY 2014

030_rccl0515_CC/DD.indd 30 4/25/14 11:51 AM matory response at the limbal junction, which is in part responsible for Corneoscleral Junction, What’s Your Function? the abnormal cellular proliferation. Limbal stem cells—composed of non-keratinized, stratifi ed squa- As previously mentioned, a num- mous epithelium—are located at the basal level of the epithelium, ber of interventional therapies have in the zone between the cornea and conjunctival epithelial cells. proven to be effi cacious in the lesser The primary role of limbal stem cells is to barricade or protect the stages of the defi ciency, and in many cornea from the invasion of conjunctival epithelium, which typically cases, can rejuvenate the corneal occurs as a result of trauma—creating and subsequently maintain- epithelium. These options include ing a clear, distinct boundary between two critical tissues in the lubrication, cessation of contact lens anterior segment. It is also responsible for the regeneration of new epithelial cells during normal physiology and following trauma. wear, non-preserved lubrication, ointments and topical applications, removal of the offending agents healing may benefi t from pressure and new cell growth can be en- (e.g., chemical and/or mechanical) patching and, in some cases, an hanced by stem cell transplantation. and the introduction of a topical amniotic membrane placement. When both eyes are involved, or a anti-infl ammatory in the initial Patients who present with sig- signifi cant segment of the limbal ar- phase of therapy. nifi cant LSCD as a result of more chitecture is damaged, limbal tissue I would recommend extending traumatic concerns (e.g., chemical can be grafted into the arcade. Once the duration of therapy for patients or thermal burns, surgical complica- the tissue is successfully grafted in who present with cases of LSCD tions or severe microbial infectious place, those cells will expand and that take weeks or months to disease), which leave the limbal repopulate the corneal surface. resolve. In such cases, it is impor- region damaged, typically require Another option for surgical inter- tant that the clinician be vigilant, more aggressive intervention. Over vention beyond amniotic membrane as chronic therapy may lead to the last several decades, signifi cant and limbal stem cell transplantation additional complications, such work has been done examining the is the use of conjunctival limbal as toxicity or IOP issues. In more use of tissue replacement, such as allografts. This procedure involves severe cases, I tend to implement stem cell transplants, conjunctival harvesting healthy limbal tissue additional intervention, such as oral limbal autografts (CLAU), living-re- with a conjunctival carrier from a doxycycline 100mg PO for four to lated conjunctival limbal allografts living relative and then transplant- six weeks. This provides inhibition and amniotic membrane transplan- ing it into the patient. One signifi - of MMP9-induced infl ammation tation. These techniques have been cant concern with this intervention and improves meibomian function. shown to have a greater level of suc- is the need for extended—if not life- Occasionally, you will encounter cess than previously used therapies. long—immunosuppression therapy. patients resistant to topical therapy. In patients with advanced LSCD, As such, this technique should be In such cases, I will debride the af- treatment protocols are based in only be selected in patients who fected area and place a BCL (along part on whether the disease is a have been unresponsive to tradi- with a topical anti-infective) over unilateral or bilateral condition. tional interventions. it while maintaining the previous For example, in unilateral disease Patients with unilateral LSCD regimen. Because LSCD eyes that presentations, the use of stem cell may benefi t from CLAU surgery, as are debrided can heal more slowly transplantation from the unaffected the harvesting is done from the fel- than typical epithelial defects, I will eye can be an effective therapy. Ad- low eye. This technique involves the usually leave the BCL on for sev- ditionally, once the original abnor- acquisition of two trapezoid-shaped eral days to a week to enhance the mal cellular zone has been removed, segments, each of which must con- corneal healing. In my experience, amniotic membrane transplantation tain approximately 6mm of tissue. patients presenting with recalcitrant has been shown to be successful, (Continued on page 33)

REVIEW OF CORNEA & CONTACT LENSES | MAY 2014 31

030_rccl0515_CC/DD.indd 31 4/25/14 11:51 AM Derail Dropouts By Mile Brujic, OD, and Jason Miller, OD, MBA

Patch It Up Providing specialized care to patients presenting with corneal insults can hasten their return to comfortable contact lens care.

re we providing the These patients are often very loyal As eye care professionals, we’re best contact lens to our practices, just typically un- no strangers to patients with vari- care for our medi- aware that they are supposed to see ous types of ocular surface disease. cal patients? A us for their urgent conditions. Patients who present with advanced A number of contact Most patients know to come to conditions, such as recurrent cor- lens wearers suffer from various us for vision exams, contact lens neal erosions, are typically treated conditions that may hinder their evaluations and medical treatment with the use of bandage soft contact ability to wear contacts, includ- for various conditions. But, most do lenses. In some cases, however, they ing dry eye, ocular allergies and not know that we provide urgent will need special biological therapies even glaucoma. But with these so care as well—and it’s our job to let to encourage corneal healing. Both ubiquitous in eye care practices, them know that we do. Giving your of these options can help relieve it is often diffi cult to separate patients this urgent medical care can pain and promote healing in pa- such patients from our “healthy” serve to both distinguish your prac- tients with trauma to the cornea. contact lens wearers. When we do, tice and further strengthen patient we tend to sideline their contact loyalty. This area of our practices BANDAGE CONTACT LENSES lens-wearing goals, thinking that’s may prove to offer the most growth Corneal abrasions are one of the an acceptable sacrifi ce for the potential in the near future. most common uses for these lenses greater good of restoring ocular While developing a medical in primary eye care. In the presence health. Sometimes, perhaps. But model and offering this service may of an abrasion, bandage contact not universally. take some internal changes (e.g., lenses shield the highly-enervated We also have patients we like to understanding medical billing and corneal surface from the constant call “silent sufferers.” These are educating your staff), it can be mechanical irritation of the eyelids. our contact lens wearers who don’t extremely rewarding. The medical This offers patients a high level of want to admit to having any type of treatment and procedures you will comfort almost immediately upon medical condition. Oftentimes, they perform will provide the patient lens insertion, and allows patients perceive this as an issue that may with the highest quality of care. to return to normal function by even prevent them from wearing Prior to conducting any medical controlling the pain.1 contact lenses in the future. Take procedure, it is important to have Unfortunately, not every insur- the time to identify any chronic or the patient sign an informed consent ance carrier will pay for this care. urgent underlying condition that form. Figure 1 shows an example of As such, it is necessary to fi rst con- will impact their corneal health— one used in Dr. Miller’s offi ce. tact the patient’s insurer to deter- and, in so doing, you’ll keep them mine which services (e.g., the fi tting, in their contact lenses long term. the lens, replacement of lost lenses, etc.), if any, are covered. Then, have DO YOU PROMOTE them sign an ABN before moving URGENT CARE? forward with any treatment. Too many times a patient visits their local urgent care facility to receive AMNIOTIC MEMBRANES eye care, only to be given nothing Prokera (Bio-Tissue) is an FDA more than an eye patch for a corneal class II medical device comprised of insult. Of course, these patients an amniotic membrane suspended are best cared for by their eye care between two plastic rings. The professional, who can treat the issue company describes it as a “biologic Fig. 1. Have patients fi ll out an using a bandage—be it a contact lens informed consent before conducting corneal bandage” that helps reduce or a biologically active substance. medical procedures. infl ammation and stimulate healing.

32 REVIEW OF CORNEA & CONTACT LENSES | MAY 2014

030_rccl0515_CC/DD.indd 32 4/25/14 11:51 AM It’ll Take More Than a Bandage A 57-year-old female with history of penetrating kerotaplasty OU and chronic recurrent corneal erosion presented with complaints of another painful red eye. She couldn’t remember any recent incident or trauma to her eye, and her only ocular therapy at the time was Pred Forte 1% QD. She had been treated multiple times with a bandage contact lens. We discussed the use of an amniotic membrane, explaining how it differs from simply putting on a contact lens. She consented and Fig. 2a. Exposure keratopathy before the amniotic membrane was applied. Her recurrent corneal erosions treatment with Prokera. healed in approximately one week, and then the device was removed. She is now six months post-treatment without recurrence.

Amniotic membranes naturally Using the aforementioned options promote epithelialization, suppress to manage these conditions may inﬂ ammation, and inhibit scarring allow the patient to return to com- and anti-microbial agents—without fortable full-time lens wear sooner the harmful side effects found in and more comfortably. Taking the topical and oral medications. These “extra steps” to improve the health devices have been instrumental in and comfort of these individuals Fig. 2b. The same eye post-treatment. the proper healing of many patients. may prove valuable in preventing Patients who suffer from chronic contact lens dropouts and further The therapy uses a cryopreserved ocular surface disease need our enhance patient loyalty. RCCL amniotic membrane as a novel help. Whether you are treating A special thank you to Walt alternative to traditional bandage these patients with bandage contact Whitley, OD, MBA, and Rachèle treatment options. These devices are lenses during an acute episode or M. Rivière, MBA, Associate Brand capable of treating many common amniotic membranes when ap- Director, Prokera, for their assis- corneal conditions, such as recur- propriate, taking the initiative to tance with this article. rent corneal erosions, corneal ulcers actively diagnose and treat these 1.Buglisi JA, Knoop KJ, Levsky ME, Euwema M. and ocular surface disease. They do patients is an important part of the Experience with bandage contact lenses for the treatment of corneal abrasions in a combat so by promoting active healing. healing process. environment. Mil Med. 2007 Apr;172(4):411-3.

Corneal Consult cally in the ability to differentiate improve healing characteristics of types of stem cell lines that are LSCD. (Continued from page 31) available for different purposes. Unfortunately, treatments such Other surgical techniques, such Human embryonic stem cells, tis- as penetrating keratoplasty have as kerato-limbal autografts and sue stem cells and pluripotent stem not been shown to be particularly combined conjunctival and kerato- cells have all evolved as potential successful in LSCD. As such, the limbal autografts, have been used in interventions for signifi cant limbal recent trend has been to replace the more severe presentations. stem cell defi ciency. Currently, all abnormal limbal stem cell beds and There have been signifi cant ad- of these modalities are being in- manage the resulting cell growth vances made in stem cell technol- versigated, and hold great promise to replace the corneal epithelial ogy in just the last decade—specifi - for the future as a mechanism to surface. RCCL

REVIEW OF CORNEA & CONTACT LENSES | MAY 2014 33

030_rccl0515_CC/DD.indd 33 4/25/14 11:51 AM Out of the Box By Gary Gerber, OD

Can’t We All Just Get Along? Understanding who your real competitors are—and perhaps even working in cooperation with them—will dramatically improve your contact lens practice.

hen you visit for colored lenses are aware of this colored contact lens practice would most OD In- fact. So, what motivates them to be something along the lines of, ternet forums, “add” color to their lenses? And, “Put the fi nishing touches on your blogs or trade if they didn’t do so, where would new hairstyle by changing your Wshow talks, that incremental spending take eye color,” or, “Working out to get you’ll inevitably hear constant place instead? Once you are able six-pack abs is hard; changing your tales of woe about the demise of to determine this information, you eye color is easy.” our profession. Many of these can then use that intelligence to doomsayers lament too many expand your practice. OVERCOMING INERTIA doctors graduating from too many Some practitioners describe Additionally, there is often an op- schools, all of which are compet- colored contact lenses as frivolous, portunity to cross-market your prac- ing for the same patients. time consuming and even nonsensi- tice with all of the above competi- Fortunately, this common belief cal in some cases. But, it’s impor- tors. Imagine this: a client walks into couldn’t be further from the truth tant to look at colored contact the nail salon and notices the salon in a contact lens practice. Consider lenses in a different way, as they operator’s brand new eye color. This this: approximately 80% of the US can increase both self-esteem and will inevitably lead the client to ask, population requires some form of self-confi dence in many patients. “Where and how did you do that?” vision correction, yet only about Wearers tend to describe these When the operator responds and 15% of the population wears con- lenses as life changing, fun, sexy tells the client it was done at your tact lenses. Even if we remove pa- and empowering. practice, you reap the benefi ts. tients who are diffi cult to fi t, there is Customers at a hair or nail salon, The concept above is easy to still obviously a huge opportunity to patients at a plastic surgeon’s or understand. The only barrier to grow your contact lens practice. cosmetic dentist’s offi ce, or clients executing this marketing mindset is Thanks to a healthy stream of of a personal trainer may use those inertia. While not cognitively com- new contact lens options hav- very same adjectives to describe the plex, it does require that you make ing reached the market in recent services they receive. In this case, use of some new marketing tech- months—including toric, multifo- what’s really preventing an increase niques. Specifi cally, you (or a rep- cal and colored lenses—the number in your colored lens practice isn’t resentative from your offi ce) must of patients who could successfully another practitioner at all—it’s physically visit the nail salon instead wear lenses has increased dra- the patients’ desire to spend their of simply making a Facebook post. matically. The question is: have money on services such as teeth But, like most well thought out you seen this change refl ected in whitening or six months of personal marketing initiatives, once it’s in your practice? Probably not, and training instead of contact lenses. place, actively tended to, monitored it’s likely because you’re having The point to consider here: the and constantly measured, it works. trouble overcoming the two biggest discretionary dollars the patient obstacles to expanding your prac- has allocated towards physical Of course, none of these strate- tice: competition and inertia. self-improvement can be spent on gies are limited to colored lenses— either colored contact lenses or they can be applied to all of your ASSESSING THE COMPETITION nail tips. Taking that into account, contact lens wearers. Have a fun A good way to determine exactly you should change your market- and engaging staff meeting and whom your practice is up against ing message from, “We can change put on your marketing thinking is to use colored contact lenses. your eye color from brown to caps to discuss where presbyopes Patients have the option of wear- blue,” to something that really might be spending their discretion- ing either clear or colored lenses to grabs these patients. Good exam- ary dollars, and use the exact same correct their vision. Those who opt ples of effectively marketing your concept as above. RCCL

34 REVIEW OF CORNEA & CONTACT LENSES | MAY 2014

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*In vitro measurement of unworn lenses 1. Thekveli S, Qiu Y, Kapoor Y, Kumi A, Liang W, Pruitt J. Structure-property relationship of delefi lcon A lenses. Cont Lens Anterior Eye. 2012;35(suppl 1):e14. 2. Based on the ratio of lens oxygen transmissibilities among daily disposable contact lenses. Alcon data on fi le, 2010. 3. Alcon data on fi le, 2011. 4. In a randomized, subject-masked clinical study, n=40. Alcon data on fi le, 2011. 5. Angelini TE, Nixon RM, Dunn AC, et al. Viscoelasticity and mesh-size at the surface of hydrogels characterized with microrheology. ARVO 2013;E-abstract 500, B0137. See product instructions for complete wear, care, and safety information. © 2013 Novartis 6/13 DAL13097JAD-B

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