Ocular Surface Disorders: Diagnosing an Elusive ArrayPreeya K. Gupta, MD

Point-of-care (POC) testing has revolutionized the diagnosis of dry eye. Previously, clinicians began an investigation on the basis of patient complaints

or late signs, such as corneal staining. Objective data ac-quired from the tear fi lm now can provide earlier diag-nosis and allow earlier treatment, which may improve outcomes. Point-of-care testing can be used to monitor therapeutic response as well as identify masquerading ocular surface disease that is not specifi cally dry eye.

Dry eye is common in the patient population pre-senting for cataract surgery. In a prospective study of 120 consecutive cataract surgery patients, 80% had at least 1 abnormal tear test, and 40% had 2 abnormal tests, with positive corneal staining observed in 39%.1 The series included 46 asymptomatic patients, of whom 85% had at least 1 abnormal tear test.

Several POC tests are available that can provide a com-prehensive assessment of the ocular surface (Table). Un-derstanding the rationale, benefi ts, and limitations of each test can assist clinicians with providing optimal state-of-the-art management of their patients’ ocular surface.

OSMOLARITY TESTINGTear osmolarity can be measured using a Clinical

Laboratory Improvement Amendments (CLIA)-waived, in-offi ce–based osmometer.2,3 A single-use microchip embedded in a handheld device uses gold electrodes to measure the electrical impedance of a 50-nL tear fl uid sample.3 The osmolarity test should be performed before any drops are instilled in the eye.3

Osmolarity �308 mOsmol/L in either eye is consid-ered diagnostic for dry eye disease (DED).2,4,5 That cut-off had 88% specifi city and 75% sensitivity in mild to moderate disease and 95% sensitivity in severe disease.2 Inter-eye variability of �8 mOsmol/L is also diagnostic for DED.2,4,5 Inter-eye variability, with repeated osmo-larity determinations, is signifi cantly greater in patients with DED compared with controls.2,6

Osmolarity does not distinguish the subtype of DED—abnormal osmolarity can occur in both meibo-mian gland disease and aqueous-defi cient dry eye. Be-cause the test is highly specifi c for DED, an alternate diagnosis can be pursued if a patient with a suspicion of dry eye has normal osmolarity.

MATRIX METALLOPROTEINASE-9 TESTINGMatrix metalloproteinase-9 (MMP-9) is a nonspecifi c

infl ammatory enzyme that can interrupt tight junctions in the ocular surface epithelium as well as increase corneal desquamation and surface irregularity when concentra-tions rise (Figure 1).5,7,8 Measuring MMP-9 has become a POC tool for diagnosing infl ammatory dry eye, and a CLIA-waived commercial immunoassay with 85% sen-sitivity and 94% specifi city is available.9,10

As with sampling for osmolarity testing, MMP-9 test-ing should be performed before administering any agents into the eye.11 A sampling fl eece is patted along the con-junctiva until it glistens, indicating saturation has been achieved. Samples �5 µL will give negative results.11 The sample and buffer are placed within the test cassette, with the result being available within 10 minutes. A positive outcome, based on an MMP-9 cutoff concentration of 40 ng/mL or greater, produces a red line.11 Samples with �40 ng/mL MMP-9 produce a blue line, although a faint positive line may be seen between 30 and 40 ng/mL.11

Limitations of MMP-9 testing include the nonspecifi c-ity of the test for the source of infl ammation.5 Elevation in MMP-9 levels has been observed in patients with Sjogren syndrome, conjunctivochalasis, vernal keratoconjunctivi-tis, keratoconus, and extended contact lens wear.11

A positive result may support initiating anti-infl ammatory therapy, such as use of corticosteroids, lifi tegrast, or cyclosporine.11 A recent study included patients with �3 DED criteria (ocular surface disease

Table. Point-of-Care Testing for Ocular Surface Disease

Test

Osmolarity

Inflammation: matrix metalloproteinase-9

Meibomian gland imaging

Lipid layer thickness

Lactoferrin/Sjogren syndrome

Allergy panel

Immunoglobulin E

Source: Preeya Gupta, MD.

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index [OSDI] score �12, tear fi lm breakup time [TBUT] �10 seconds, and Schirmer I test result �10 mm/5 min-utes and/or corneal staining grade �1) who were treated with topical cyclosporine ophthalmic emulsion 0.05% twice daily for 1 month.12 A semiquantitative grading method was used with the commercial test to assign 4 levels of MMP-9 positivity.13 The subgroup of 17 eyes with positive or strong-positive MMP-9 results at base-line had signifi cantly improved OSDI, TBUT, corneal staining, and Schirmer test at 1 month.12 These outcomes were unchanged in the subgroup of 14 eyes that were MMP-9–negative at baseline, with 2 eyes becoming pos-itive or strong-positive despite cyclosporine treatment. These observations suggested that increased manage-ment benefi ts may be possible with a quantitative test.12

Research to develop improved next-generation devices is under-way, including a single device that can measure both osmolar-ity and MMP-9 quantitatively. In addition to providing more effi -cient diagnosis, the device is ex-pected to have the potential for disease stratifi cation.

DYNAMIC MEIBOMIAN GLAND IMAGING

Dynamic meibomian gland im-aging uses infrared light to observe meibomian gland silhouette mor-phology.5 Visualizing meibomian gland morphology can be useful in stratifying disease severity, as sig-nifi cant disease may be overlooked without using this modality. Features such as meibomian gland dilatation and atrophy can be helpful to the eye care provider in associating abnor-mal structure with dysfunction (Fig-ure 2). Meibography is also useful for patient education, as it is easy to convey the structural damage that is occurring in the form of meibomian gland atrophy as part of meibomian gland disease. Meibography alone may not be adequate to diagnose meibomian gland dysfunction, so the results should be coordinated with clinical examination fi ndings and other testing.5

LIPID LAYER INTERFEROMETRYA POC interferometer is available that provides au-

tomated measurement of tear fi lm lipid layer thickness (LLT).5 A signifi cant correlation was observed between expressible meibomian glands and LLT (P�.0001) in a retrospective analysis of 199 eyes.14 Using a cutoff value of �75 nm provided 66% sensitivity and 63% specifi c-ity for diagnosing meibomian gland dysfunction.14 At a more severely reduced LLT of �60 nm, sensitivity was 48% and specifi city increased to 90%.14 Another study reported a signifi cant inverse linear relationship between LLT and dry eye symptoms (P=.0014)—74% of patients with severe symptoms had an LLT of �60 nm, and 72% of patients with no symptoms had an LLT �75 nm.15 Cur-rent technology (ie, LipiView II) allows for dynamic mei-bomian imaging, visualization and quantization of lipid

MMP = matrix metalloproteinase; Na+ = sodium.Source: Pfl ugfelder SC, et al.8 Open Access.3

Figure 1. MMP-9 and Dry Eye

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layer thickness, near-infrared surface imaging, and partial blink detection with a single instrument.16

LACTOFERRIN TESTINGLactoferrin is a glycoprotein secreted primarily by

the lacrimal gland.17 Lactoferrin in tear fi lm has anti-infl ammatory, antioxidant, and antimicrobial activi-ties. Its concentration in healthy tears is approximately 1.4 mg/mL. However, lactoferrin decreases in the pres-ence of some eye pathologies, including aqueous-defi cient dry eye, meibomian gland dysfunction, and Sjogren syndrome–associated dry eye, as well as with aging.17,18 Using a cutoff of 1.1 ng/mL, lactoferrin levels detected DED with 79% sensitivity and 78% specifi c-ity.19 The commercially available lactoferrin assay uses a 0.5-µL sample and has a 83% sensitivity and 98% speci-fi city, with a �9% coeffi cient of variation, using a cutoff of 0.9 mg/mL.18,20,21 The test is regulated as CLIA class II; that is, it is of moderate complexity and requires licensing for all persons taking, processing, or reading the laboratory samples.22

SJOGREN SYNDROME TESTINGThe nonspecifi c and variable symptoms associated

with Sjogren syndrome contribute to common diag-nostic delays.23 Early diagnosis allows prompt treat-ment initiation and possible avoidance of other sys-temic autoimmune conditions. Objective diagnostic factors include the autoantibodies anti-Sjogren syn-drome–related antigen A/Ro and antigen B/La, antinu-clear antibody, and rheumatoid factor. However, these traditional biomarkers have limited usefulness in early cases. A more recent diagnostic panel (Sjo test) adds detection of salivary gland protein-1, parotid secretory protein, and carbonic anhydrase-6 to the 4 traditional analytes, with a resulting greater specifi city and sen-sitivity for early detection. Blood samples obtained by fi nger prick can be applied to a card, or a normal blood sample can be sent for laboratory analysis. Dry eye and dry mouth are common presenting complaints in pa-tients with Sjogren syndrome; thus, eye care and dental professionals should work with rheumatologists to pro-vide optimal diagnosis and management.

ALLERGY TESTINGOcular allergies are estimated to affect up to 20% of

the population in the United States.24 A commercial POC test that is US Food and Drug Administration–approved is available and in use by many clinicians, including al-lergists, dermatologists, and primary care physicians.25 The “no needle” test provides results in 15 minutes for the presence of 60 geographically specifi c antigens.

Patients should be given a list of medications to avoid for 48 hours to 5 days, depending on the specifi c drug, before undergoing the test. They should understand that the test does not need to be done during an allergic epi-sode. Test administration, waiting time, and interpreta-tion are typically completed in 35 minutes. Counseling after allergy testing includes advising the patients to avoid activities that expose them to culprit allergens, with follow-up in 1 month to examine outcomes.

IMMUNOGLOBULIN E LEVELSSystemic immunoglobulin E (IgE) antibodies can be

detected in most cases of allergic conjunctivitis.5 Point-of-care assessment of IgE levels in tears is now possible, using a 0.5-µL sample, with 80 ng/mL representing the cutoff for allergic conjunctivitis.26 The diagnostic kit for lactoferrin can also determine IgE levels as a CLIA class II test.26 Results can help to determine which patients may benefi t from topical antihistamine and/or cortico-steroid therapy. For patients with severe allergies, eye care specialists should work with an allergist to facilitate optimum care.

SYSTEMIC AND OCULAR MEDICATIONS ASSOCIATED WITH DED

The contribution of systemic medications for the treatment of patients with DED should not be over-looked. Clinicians should carefully review their patients’

Meibography image shows mild meibomian gland atrophy.Source: Preeya K. Gupta, MD.

Figure 2. Meibography

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medical records for use of systemic or ocular medica-tions that increase the risk of DED.27 Among the top 100 best-selling systemic drugs in the United States in 2009, 22 were possibly associated with dry eye and dry mouth.27 Many drugs that are commonly used in the older population have a higher prevalence of dry eye compared with younger persons and are associated with an increased risk of dry eye. Topical ocular drugs, including agents to treat allergies, may also cause or aggravate dry eye. Agents in several drug classes used to treat glaucoma, as well as topical anesthetics, non-steroidal anti-infl ammatory drugs, decongestants, and antiviral agents, can also cause the development or worsening of dry eye. Eye care professionals should pay special attention to caring for the ocular surface in patients with increased risk for DED.

SUMMARYPoint-of-care testing facilitates

rapid, uncomplicated, and earlier diagnosis of DED. Measuring these “ocular vital signs” can aid clini-cians in making an accurate diag-nosis and facilitate the timely initia-tion of appropriate treatment.

CASEA 47-year old man complains

of chronic foreign body sensation (FBS) and red eyes. He has been treated with several products over the previous 9 months, includ-ing cyclosporine, azithromycin, and doxycycline. He recently dis-continued prescription treatments because he did not detect any im-provement. He continues with ar-tifi cial tears as needed and warm compresses. He has no signifi cant past medical history.

A typical ocular work-up was performed. Matrix metalloproteinase-9 was positive in both eyes. Osmolarity was nor-mal (290 mOsmol/L in the right eye and 293 mOsmol/L in the left eye). Dynamic meibomian imag-ing revealed mild gland atrophy, with 2+ meibomian gland dys-function. His cornea was clear, al-though he had some conjunctival injection, with a mild ectropion (Figure 3).

This patient typifi es what is often referred to as a “tough dry eye patient.” This type of patient has been to several doctors, has taken several medications, and is frustrated with the lack of results. Point-of-care testing can help assess all ocular surface situations that could be contributing to patients’ complaints. Meibomian gland imaging can identify patients who have atrophy, which was not evident from other diagnostic investigations. Tear chemistry, including osmolarity and MMP-9, pro-vides an indication of the microenvironment bathing the eye. External anatomy examination can comprise assess-ing lid position and function, including the completeness of the blink and the resulting spread of tear fi lm.

Due to the mild ectropion, the examination continued with eversion of the eyelids, revealing extreme fl oppy eyelid syndrome (FES) (Figure 4). Ulcerations and

Images show mild conjunctival injection and ectropion (A) and 2+ meibomian gland dysfunction (B).Source: Preeya K. Gupta, MD.

Figure 3. Case: Dynamic Meibomian Imaging

A

B

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papillary reaction were evident at the lid margin. Therefore, his FBS was assumed to be due to fl oppy eyelid-related chronic mechanical trauma from the overriding lids, producing ulceration.

The patient was treated with a topical steroid with taper and initiation of lifi tegrast 5% as well as artifi cial tear ointment at bed-time. At his fi rst follow-up visit, he was 60% improved. He was referred to an oculoplastics spe-cialist for a lid-tightening proce-dure, which resolved his symp-toms completely.

This case also exemplifi es the importance of reviewing the pa-tient’s medical record. He had ob-structive sleep apnea, which has been noted to be associated with FES.28 Sleep apnea could provide a fi rst diagnostic suspicion, warranting specifi c FES investigations.

Not all patients’ FBS and redness is DED. Point-of-care testing can provide a more comprehensive assess-ment that can lead to an accurate diagnosis. As with this case, a multidisciplinary approach is sometimes neces-sary to resolve symptoms.

References1. Gupta PK, Drinkwater OJ, VanDusen KW, Brissette AR,

Starr CE. Prevalence of ocular surface dysfunction in pa-tients presenting for cataract surgery evaluation. J Cataract Refract Surg. 2018;44(9):1090-6.

2. TearLab Osmolarity System – Clinical Utility Guide. https://www.tearlab.com/pdfs/TearLab Clinical Utility Guide.pdf. Accessed February 6, 2019.

3. TearLab Osmolarity System – User Manual. https://www.tearlab.com/resources/930066_-_REV_C_-_UserManual_-_ENGLISH.pdf. Accessed February 6, 2019.

4. Jackson MA. Deciphering the dry eye code: A framework for diagnostic and treatment protocols. Ophthalmology Management. 2016; March:8,10,22.

5. Wolffsohn JS, Arita R, Chalmers R, et al. TFOS DEWS II Diagnostic Methodology report. Ocul Surf. 2017;15(3):539-74.

6. Bunya VY, Fuerst NM, Pistilli M, et al. Variability of tear osmolarity in patients with dry eye. JAMA Ophthalmol. 2015;133(6):662-7.

7. Kaufman HE. The practical detection of MMP-9 diagnoses ocular surface disease and may help prevent its complica-tions. Cornea. 2013;32(2):211-6.

8. Pfl ugfelder SC, Fang B, De Paiva C. Matrix metalloproteinase-9 in the pathophysiology and diagnosis

of dry eye syndrome. Metalloproteinases In Medicine. 2017;4:37-46.

9. Infl ammaDry [Package insert]. Sarasota, FL: RPS, Inc.; 2014.

10. Sambursky R, Davitt WF 3rd, Latkany R, et al. Sensitivity and specifi city of a point-of-care matrix metalloproteinase 9 immunoassay for diagnosing infl ammation related to dry eye. JAMA Ophthalmol. 2013;131(1):24-8.

11. Lanza NL, Valenzuela F, Perez VL, Galor A. The matrix metalloproteinase 9 point-of-care test in dry eye. Ocul Surf. 2016;14(2):189-95.

12. Park JY, Kim BG, Kim JS, Hwang JH. Matrix metallo-proteinase 9 point-of-care immunoassay result predicts re-sponse to topical cyclosporine treatment in dry eye disease. Transl Vis Sci Technol. 2018;7(5):31.

13. Brujic M, Kading D. Making matrix metalloproteinase-9 levels more meaningful. Presented at: Global Specialty Lens Symposium; January 21-24, 2016; Las Vegas, NV.

14. Finis D, Pischel N, Schrader S, Geerling G. Evaluation of lipid layer thickness measurement of the tear fi lm as a di-agnostic tool for meibomian gland dysfunction. Cornea. 2013;32(12):1549-53.

15. Blackie CA, Solomon JD, Scaffi di RC, Greiner JV, Lemp MA, Korb DR. The relationship between dry eye symptoms and lipid layer thickness. Cornea. 2009;28(7):789-94.

16. LipiView II ocular surface interferometer. https://tearscience.com/lipiview/. Accessed February 9, 2019.

17. Rusciano D, Pezzino S, Olivieri M, et al. Age-related dry eye lactoferrin and lactobionic acid. Ophthalmic Res. 2018;60(2):94-9.

18. Willcox MDP, Argueso P, Georgiev GA, et al. TFOS DEWS II tear fi lm report. Ocul Surf. 2017;15(3):366-403.

19. Wang HF, Fukuda M, Shimomura Y. Diagnosis of dry eye. Semin Ophthalmol. 2005;20(2):53-62.

20. Product brochure. http://www.advancedteardiagnostics.

Eyelid eversion examination revealed fl oppy eyelid syndrome (left panels) and ulcerations and papillary reaction (right panel).Source: Preeya K. Gupta, MD.

Figure 4. Case: Eyelid Eversion Examination

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com/wp/resources/papers-articles/. Accessed February 9, 2019.

21. Ford L. Incorporating lactoferrin and immunoglobin test-ing. Optometry Times. http://www.optometrytimes.com/modern-medicine-cases/incorporating-lactoferrin-and-immunoglobin-testing. Accessed February 6, 2019.

22. Resources. http://www.advancedteardiagnostics.com/wp/resources/. Accessed February 9, 2019.

23. Beckman KA, Luchs J, Milner MS, Ambrus JL Jr. The po-tential role for early biomarker testing as part of a modern, multidisciplinary approach to Sjogren’s syndrome diagno-sis. Adv Ther. 2017;34(4):799-812.

24. Almaliotis D, Michailopoulos P, Gioulekas D, et al. Allergic conjunctivitis and the most common allergens in Northern Greece. World Allergy Organ J. 2013;6(1):12.

25. Point-of-Care Testing Pays Off. Ophthalmology

Management. https://www.ophthalmologymanagement.com/supplements/2014/april-2014/point-of-care-testing-pays-off/point-of-care-testing-pays-off. Accessed February 6, 2019.

26. Hemphill N. New test changes the way some ODs di-agnose and treat dry eye, allergy. https://www.healio.com/optometry/cornea-external-disease/news/print/primary-care-optometry-news/%7Bdb1c6a99-4376-4a3d-8540-acda0c20e21b%7D/new-test-changes-the-way-some-ods-diagnose-and-treat-dry-eye-allergy. Accessed February 6, 2019.

27. Fraunfelder FT, Sciubba JJ, Mathers WD. The role of medica-tions in causing dry eye. J Ophthalmol. 2012;2012:285851.

28. Chambe J, Laib S, Hubbard J, et al. Floppy eyelid syndrome is associated with obstructive sleep apnoea: a prospective study on 127 patients. J Sleep Res. 2012;21(3):308-15.

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Dry eye disease (DED) is a symptomatic condi-tion that affects hundreds of millions of people worldwide.1 Although DED has 2 recognized

forms—aqueous-defi cient dry eye (ADDE) and evapora-tive dry eye (EDE)—fewer than 10% of patients have isolated ADDE.1,2 Meibomian gland dysfunction, a con-tributor to EDE, is involved in more than 80% of DED cases.3 Three major management guidelines were recently published, exemplifying the increasing recognition of the importance of ocular surface health and emphasizing the importance of proper diagnosis.

TFOS DEWS II MANAGEMENT AND THERAPY REPORT

The Management and Therapy Subcommittee of the Tear Film and Ocular Surface Society (TFOS) Dry Eye Workshop II (DEWS II) published a thorough evidence-based review of current therapies and management op-tions for patients with DED, emphasizing that “diagnosis precedes therapy.”4 Clinicians should determine the con-tribution of EDE and/or ADDE, as well as the possible presence of other ocular conditions, before developing a management plan. The ultimate goal of DED manage-ment is restoring homeostasis, which may require mul-tiple and long-term treatments to address specifi c issues with the ocular surface condition.

The complexity of DED and its heterogeneity among patients precludes having a rigid, stepwise management approach and requiring consideration of both disease eti-ology and severity.4 The TFOS DEWS II staged manage-ment and treatment recommendations begin with con-ventional low-risk and commonly available therapies for early-stage disease, progressing to more advanced ther-apies with increasing disease severity (Table 1). Clini-cians should use these recommendations as a guide and adapt them as warranted to provide optimal management of their individual patients with DED.

The TFOS Subcommittee acknowledged that due to its heterogeneity, managing patients with DED remains somewhat of an art.4 Eye care providers must be prepared to use their clinical expertise to judge the signifi cance of the various pathogenic processes that can produce simi-lar symptoms and signs.

CEDARS DYSFUNCTIONAL TEAR SYNDROME: DIAGNOSTIC-BASED APPROACH

A panel of experts from the Cornea, External Dis-ease, and Refractive Society (CEDARS) developed a diagnostic-based approach to managing dysfunctional tear syndrome.5 They defi ned dysfunctional tear syn-drome as a disorder in tear fi lm quality and/or quantity, with a variety of etiologies, resulting in various signs and symptoms. Their management recommendations related to 4 diagnostic subtypes: tear defi ciency, goblet cell/mu-cin defi ciency, blepharitis/meibomian gland dysfunction, and exposure keratopathy (Figure 1).

DRY EYE SYNDROME PREFERRED PRACTICE PATTERN The American Academy of Ophthalmology updated

their Dry Eye Syndrome Preferred Practice Pattern in 2018.6 Treatment recommendations are divided among mild, moderate, and severe disease (Table 2). As with TFOS DEWS II, the American Academy of Ophthalmol-ogy acknowledged that this is not a rigid system and that there can be crossover as clinicians use their experience and expertise together with patient preference to develop optimum management strategies.

PUTTING IT ALL TOGETHER: TREATMENT STRATEGIESReports from 3 major professional societies recom-

mended similar approaches for managing DED.4-6 Targeted treatment strategies should be based on disease severity, etiology, and patient signs and symptoms. Patients make offi ce visits in response to their symptoms; thus, symptom resolution is a key objective in patient management.4-6

Pretreatment StrategiesA patient’s management plan should include identi-

fying contributing factors for which interventions can be made before starting treatment. If relevant changes are not made, treatments may not be successful. Medi-cations that may cause or exacerbate dry eye should be discontinued if possible.4-6 Collaborating with the prescribing physician may be warranted to determine whether alternative options for required medications exist. As with all clinicians, eye care specialists should counsel their patients who smoke about quitting.

Treating Ocular Surface Disease With Conventional TherapiesFrancis S. Mah, MD

7

Table 1. TFOS DEWS II Staged Management of Dry Eyea,b,c

Step 1:

Education regarding the condition, its management, treatment, and prognosisModification of local environmentEducation regarding potential dietary modifications (including oral essential fatty acid supplementation)Identification and potential modification/elimination of offending systemic and topical medicationsOcular lubricants of various types (if MGD is present, then consider lipid-containing supplements)Lid hygiene and warm compresses of various types

Step 2:

If above options are inadequate, consider:Nonpreserved ocular lubricants to minimize preservative-induced toxicityTea tree oil treatment for Demodex (if present)Tear conservationPunctal occlusionMoisture chamber spectacles/gogglesOvernight treatments (such as ointment or moisture chamber devices)In-office, physical heating and expression of the meibomian glands (including device-assisted therapies, such as LipiFlow)In-office intense pulsed light therapy for MGDPrescription drugs to manage DEDd

Topical antibiotic or antibiotic/steroid combination applied to the lid margins for anterior blepharitis (if present)Topical corticosteroid (limited-duration)Topical secretagoguesTopical non-glucocorticoid immunomodulatory drugs (such as cyclosporine)Topical LFA-1 antagonist drugs (such as lifitegrast)Oral macrolide or tetracycline antibiotics

Step 3:

If above options are inadequate, consider:Oral secretagoguesAutologous/allogeneic serum eye dropsTherapeutic contact lens optionsSoft bandage lensesRigid scleral lenses

Step 4:

If above options are inadequate, consider:Topical corticosteroid for longer durationAmniotic membrane graftsSurgical punctal occlusionOther surgical approaches (eg, tarsorrhaphy, salivary gland transplantation)

DED = dry eye disease; lymphocyte function-associated antigen-1; MGD = meibomian gland dysfunction.aPotential variations within the disease spectrum are acknowledged to exist between patients and the management options listed above are not intended to be exclusive. The severity and etiology of the DED state will dictate the range and number of management options selected from one or more steps.bOne or more options concurrently within each category can be considered within that step of the dry eye disease state. Options within a category are not ranked according to importance and may be equally valid.cIt should be noted that the evidence available to support the various management options differs and will inevitably be lower for newer management options. Thus, each treatment option should be considered in accordance with the level of evidence available at the time management is instigated.dThe use of prescription drugs needs to be considered in the context of the individual patient presentation and the relative level of evidence supporting their use for that specifi c indication, as this group of agents differs widely in mechanism of action.

Source: Reprinted from Jones L, et al4 © 2017 with permission from Elsevier.

8

Benefi cial environmental changes should also be ex-plored. Ambient air should be adequately humidifi ed, and drafts should be avoided.4-6 Shields and/or chang-ing the characteristics of airfl ow in patients’ cars as well as at work and at home may be helpful.4-6

Computer screens should be below eye level to de-crease lid aperture.6 Reading and computer use should include regular scheduled breaks, attention to increasing blink frequency, and increased use of topical lubrication.6

Some eye conditions that contribute to DED can be treated. Clinicians can address lid malposition and abnor-malities such as entropion/ectropion and lagophthalmos.4-6

LubricantsUse of lubricants, in the form of artifi cial tears as

emulsions or solutions, gels, ointments, and sustained release formulations, is the usual fi rst therapy.4-6 Ingre-dients can include hyaluronic acid, methylcellulose, and lipids. When possible, benzalkonium chloride preserva-tives should be avoided.4-6

NutritionOral supplementation with essential fatty acids has

been widely recommended to relieve dry eye symptoms. Recently, the multicenter DREAM study randomized 349 patients with moderate to severe dry eye to a daily oral dose of 3 g of fi sh-derived n-3 eicosapentaenoic and

docosahexaenoic acid and 186 to an olive oil control.7 The primary outcome of mean change from baseline in Ocular Surface Disease Index (OSDI) score, based on the mean obtained at 6 and 12 months, was similar in the treatment (-13.9 points) and control (-12.5 points) groups (P=.21) and was consistent across all prespeci-fi ed subgroups.7 Secondary outcomes were also similar between groups.7 The authors concluded that supple-mentation with 3 g of n-3 fatty acids for 12 months did not improve outcomes compared with those who received placebo. However, some argue that both the placebo group and the omega-3 group had signifi cant improvements from baseline in their OSDI scores and objective tests of DED and that the olive oil used as a placebo was not a fair comparator.

Vitamin A has been compounded as a 0.01% all-trans retinoic acid topical ointment and used off-label to treat goblet cell defi ciency.5 However, this treatment has not been studied in robust clinical trials and any investiga-tional use is at the discretion of the clinician.5

Lid Margin Disease ManagementConventional treatment for lid margin disease

includes warm compresses and lid massage.4-6 Dis-advantages of this approach include diffi culty main-taining adequate temperature and poor compliance. Lid scrubs are available, some of which contain

CEDARS = Cornea External Disease and Refractive Society; DHEA = dehydroepiandrosterone; GD = meibomian gland dysfunction. Source: Data from Milner MS, et al.5 Open Access.

Figure 1. CEDARS Dysfunctional Tear Syndrome: Diagnostic-based Approach

9

hypochlorous acid. Tea tree oil scrubs can be used for Demodex mite infestation.4-6

In-offi ce procedures include lid margin cleansing and meibomian gland expression for anterior and posterior blepharitis.4-6 Several devices are available with differ-ent mechanisms of action, including microblepharoex-foliation. In addition to motorized mechanical devices, thermal pressure and pulsation, intraductal probing, and intense pulsed light can be used.4-6

Anti-infl ammatory Agents: Topical Cyclosporine 0.05%

In 2003, a 0.05% cyclosporine emulsion became the fi rst prescription medication approved by the US Food and Drug Administration (FDA) for treating DED.8 Data from approximately 1200 patients enrolled in 4 randomized trials supported its approval.9 The primary endpoint—increased Schirmer wetting of at least 10 mm at 6 months—was observed in approximately 15% of cyclosporine-treated patients compared with 5% of vehicle-treated patients.9

Treatment with cyclosporine is associated with im-proved ocular surface health, including increased tear

production and decreased activated lymphocytes, with decreased corneal staining and blurred vision.10,11 Re-ductions in artifi cial tear use suggest improved patient comfort, and tolerability and safety for up to 4 years were demonstrated in clinical trials.12 Potential ad-ditive improvements in artifi cial tears were observed in patients with concomitant punctal plugs.13 Contact lens–intolerant patients experienced increased comfort and wear.14 Patients with dry eye who were undergoing LASIK experienced faster recovery and better outcomes.15

The initial cyclosporine formulation was provided in preservative-free, single-use vials.9 A proprietary sterile, multidose, preservative-free vial is now available, which has a unidirectional valve and air fi lter.16

Topical SteroidsTopical corticosteroids are used to treat several ocu-

lar infl ammatory conditions.17 Although not specifi cally indicated to treat DED, the loteprednol etabonate 0.5% suspension is indicated for treating steroid-responsive infl ammatory conditions of the palpebral and bulbar conjunctiva, cornea, and anterior segment of the globe.18

Table 2. American Academy of Ophthalmology Dry Eye Syndrome Preferred Practice Pattern: Management

Disease Severity Management Recommendation

Mild • Education and environmental modifi cations• Elimination of offending topical or systemic medications• Aqueous enhancement using artifi cial tear substitutes, gels, and/or ointments• Eyelid therapy (warm compresses and eyelid hygiene)• Treatment of contributing ocular factors, such as blepharitis or meibomianitis (see Blepharitis

Preferred Practice Pattern)• Correction of eyelid abnormalities (eg, trichiasis, lid malposition)

Moderate In addition to the above treatments:• Anti-infl ammatory agents (topical cyclosporine and corticosteroids) • Lifi tegrast• Systemic omega-3 fatty acids supplements• Punctal plugs• Spectacle side shields and moisture chambers• Slow-release hydroxypropyl cellulose inserts• Intranasal neurostimulation• Labial mucous membrane and minor salivary gland transplantations

Severe In addition to the above treatments:• Systemic cholinergic agonists (pilocarpine and cevimeline) • Mucolytic agents (eg, acetylcysteine 10%)• Autologous (or allogeneic) serum tears• Self-retaining amniotic membrane • Permanent punctal occlusion • Tarsorrhaphy• Contact lenses

Source: Data from Akpek EK, et al.6

10

Treatment for postoperative infl ammation can be given during the fi rst 2 weeks after surgery. Corticosteroids have been reported to decrease ocular irritation and corneal fl uorescein staining, which were also observed in a study that provided corticosteroid pretreatment for 2 weeks before punctal occlusion.17

A small study of 64 patients with dry eye and de-layed tear clearance compared loteprednol with vehicle administered 4 times daily for 4 weeks.19 The subset of patients with at least moderate clinical infl ammation had signifi cant improvement at 2 weeks compared with the vehicle group, which remained numerically but not statistically greater at 4 weeks.19 A signifi cant increase in increased intraocular pressure was not observed in the loteprednol group. A later randomized trial of 118 patients with mild to moderate DED examined the effects of 2 weeks of pretreatment with loteprednol eta-bonate 0.5% compared with artifi cial tears, followed by the addition of cyclosporine treatment for an addi-tional 6 weeks.20 Signifi cantly less stinging associated with cyclosporine administration was observed in the loteprednol group. In addition, the loteprednol group experienced superior improvement in Schirmer testing, fl uorescein staining, and lissamine green staining, with signifi cantly greater OSDI score improvement com-pared with the artifi cial tears group. Intraocular pres-sure did not increase in either group.20 Nonetheless, patients prescribed corticosteroids for the treatment of DED should be monitored for increased intraocular pressure, corneal melting, and cataract formation.20

Loteprednol suspension requires vigorous shaking before use.18 A nonsettling gel formulation is now avail-able to facilitate administration.21,22 The inverted bottle is shaken once to fi ll the tip. The formulation includes glycerin and propylene glycol, which have a humectant effect and are expected to contribute to patient comfort by retaining moisture on the eye surface.21

Lifi tegrast 5%The lymphocyte function-associated antigen-1

(LFA-1) antagonist lifi tegrast received FDA approval for the treatment of the signs and symptoms of DED in 2016.23 By binding to LFA-1 (a leukocyte cell surface protein), the interaction is blocked between LFA-1 and its cognate ligand, intercellular adhesion molecule-1 (ICAM-1). In DED, ICAM-1 may be overexpressed in the cornea and conjunctiva, with the LFA-1/ICAM-1 interaction contributing to T-cell activation and migra-tion to target tissues.23 Based on in vitro studies, lifi te-grast may also inhibit infl ammatory cytokine secre-tion, although its exact mechanism of action in DED is not known.23

Data contributing to the FDA approval of lifi tegrast were reported from 4 sequentially designed, 12-week studies that included 1067 patients who received lifi te-grast 5% in a phase 2 dose-fi nding study and the phase 3 OPUS studies.23-25 The primary outcomes for the stud-ies were day 84 status of inferior corneal staining score (ICSS) (phase 2; N=116), change from baseline in ICSS (signs) and the visual-related function subscale of a symptom scale (symptoms) (OPUS-1; N=588), change in ICSS and eye dryness score (EDS) from baseline (OPUS-2; N=718), and change in EDS from baseline (OPUS-3; N=711).23-25

The symptoms endpoint was not met in OPUS-1, which enrolled patients with mild to moderate DED.25 However, a post hoc analysis of the subgroup with more severe symptoms (EDS �40) at baseline and prior arti-fi cial tear use revealed improved EDS in the lifi tegrast group compared with placebo.25

Based on OPUS-1 fi ndings, OPUS-2 eligibility re-quired moderate to severe baseline DED symptomatol-ogy.25,26 Although the symptoms primary endpoint was signifi cantly reduced compared with placebo (P�.0001), the signs primary endpoint was not met (P=.6186). Post hoc analyses showed signifi cantly greater EDS change from baseline at days 14 and 42 in the lifi tegrast patients compared with placebo.25,26

OPUS-3 was undertaken to confi rm the symptom improvement fi ndings in OPUS-2 in additional patients with moderate to severe DED.24 The primary endpoint—EDS change from baseline to day 84—was again signifi -cantly improved in the lifi tegrast group compared with placebo (P=.0007).24

In 5 clinical trials in which 1287 participants re-ceived at least 1 dose of lifi tegrast 5%, the most com-mon adverse reactions reported in 5% to 25% of pa-tients were instillation site irritation, dysgeusia, and reduced visual acuity.23 The SONATA 1-year safety study included 220 lifi tegrast and 111 placebo patients with DED.27 The primary outcome was percent and se-verity of treatment-emergent adverse events (TEAEs), with secondary ocular safety measures taken at 7 visits during the 360-day treatment interval. Ocular TEAEs were experienced by 52.6% and 34.2% of lifi tegrast and placebo group subjects, respectively.27 Most were mild to moderate, and no serious ocular TEAEs were noted. Discontinuations due to TEAEs were 12.3% and 9.0%, respectively.27 The most common TEAEs were instillation site irritation (15.0% and 4.5%), instillation site reaction (13.2% and 1.8%), reduced visual acuity (11.4% and 6.3%), dysgeusia (16.4% and 1.8%), and dry eye (1.8% and 5.4%).27 The authors concluded that twice-daily lifi tegrast was safe and well tolerated. The

11

safety profi le was similar to that observed in the 12-week studies, with no unexpected TEAEs.27

Punctal OcclusionPunctal occlusion with semipermanent silicone or

collagen plugs is widely used to conserve tears. In patients with DED, punctal plugs may decrease the osmolarity of hyperosmolar tears and signifi cantly re-lieve symptoms.28,29 However, punctal plugs may ex-acerbate symptoms in eyes with ocular surface infl am-mation; therefore, they should be used with caution in these patients.5,6

Many studies reported benefi ts of punctal plugs in the management of patients with DED.30 A review of 2499 patients from 27 qualifying studies determined that level II and III evidence supports that the plugs are well tolerated, improved signs, and resulted in a �50% im-provement in symptoms of moderate dry eye that are not improved with topical lubrication.31 Epiphora occurred in 9% (range: 1.9% to 36.5%) of patients in 15 trials of punctal plugs. However, a Cochrane review of 18 poorly reported trials (711 participants; 1249 eyes) of collagen or silicone punctal plugs in symptomatic patients con-cluded that their benefi ts are inconclusive.32 The au-thors noted that although the plugs are considered to be relatively safe, there is a risk for epiphora.32 Infl amma-tory conditions, including dacryocystitis, were observed less frequently.32

Spectacle Side Shields/Moisture ChambersSpecialized moisture retention eyewear and moisture

chambers provide a noninvasive means to treat evapora-tive dry eye.33,34 Although these may be poorly tolerated because of negative cosmetic effects, new designs of commercially available eyewear may be more acceptable.

Moisture InsertsHydroxypropyl cellulose delivered by a dissolvable

insert on the ocular surface has been available for more than 30 years.4 However, this is not widely used due to discomfort and poor effi cacy. A water-soluble, slow-release, preservative-free device is now available that is placed into the inferior cul-de-sac using a reusable applicator.35 The device dissolves over approximately 12 hours, thickening the precorneal tear fi lm.35 It is indi-cated for patients with moderate to severe DED, particu-larly in those who remain symptomatic after an adequate trial of artifi cial tears.35 Once-daily treatment is recom-mended, although some patients may require twice-daily use. Several studies have supported the effi cacy and safety of the insert.36 Patients should be provided with clear ad-ministration instructions.36

SecretagoguesOral cholinergic agonists, including pilocarpine and

cevimeline, stimulate salivary and lacrimal gland secre-tion by activating muscarinic acetylcholine.5 They are not indicated for treating DED, have signifi cant sys-temic adverse effects, and do not have robust support-ing evidence as an effective therapy for DED.5 A small, 12-week, single-center, randomized study of 57 patients with Sjogren syndrome with dry eye symptoms reported signifi cant improvement with pilocarpine compared with artifi cial tears (P�.001).37 Objective tests revealed signifi cant improvement in rose Bengal staining but not Schirmer test results.37

Two topical secretagogues from other drug classes are available in some countries outside the United States.38,39 Currently, there are no registered US studies of the P2Y2 receptor agonist diquafosol or the quinolinone derivative rebamipide.

Treatment of Filamentary KeratitisDry eye disease is the most common cause of fi la-

mentary keratitis, where strands of degenerated epithe-lial cells and mucus attach to the cornea.40 Resulting friction between the fi laments and the eyelid can exac-erbate the condition, which often becomes chronic and increasingly infl ammatory.

Filamentary keratopathy can be treated by debrid-ing the fi laments with a cotton-tip applicator, dry cellu-lose sponge, or jeweler’s forceps.6 Off-label application of topical mucolytic agents, such as N-acetylcysteine 10% 4 times daily may also be effective. Because N-acetylcysteine is not available as an ophthalmic agent, it may be compounded for off-label use. It is also available as a 10% solution, which is indicated for nebulizer use in treating respiratory conditions with abnormal mucus se-cretion and as an antidote for acetaminophen overdose.41,42

Bandage contact lenses are another recommended treatment of fi lamentary keratitis. However, they can be poorly tolerated in cases of severe dry eye. Due to infec-tion risk, contact lenses should be used with caution in patients with associated neurotrophic keratopathy.6

Autologous SerumAutologous serum drops, which mimic the composi-

tion of natural tears, have been reported in some studies to improve symptoms and signs of several ocular sur-face disturbances, including DED, neurotrophic kerati-tis, persistent epithelial defects, Sjogren syndrome, and infl ammatory conjunctivitis such as that associated with graft-versus-host disease.5,6,43 Drops are not commercially available and must be compounded, with associated tech-nological and regulatory challenges.5,6,43 A 2017 updated

12

Cochrane review included 5 qualifying randomized con-trolled trials (92 participants) that compared autologous serum with artifi cial tears in patients with dry eye.43 The evidence was considered low or very low due to failure to report quantitative data for most outcomes and unclear or high risk of bias.43 Incomplete outcome reporting and heterogeneity among trials precluded performing a meta-analysis. The authors concluded that results were inconsistent regarding a potential benefi t for autologous serum. It may be benefi cial compared with artifi cial tears early in the treatment interval; however, they noted no evidence of an effect after 2 weeks.43 Conversely, a recent case series from a single center reported signifi -cant improvements in signs and symptoms of dry eye in 83 eyes of 47 patients treated with autologous serum for 9.8±15.5 months.44 Robust randomized controlled trials are warranted to further examine the potential benefi t of autologous serum.

Amniotic MembraneUse of amniotic membrane has a long history as

an adjuvant for tissue healing.45 Cryopreserved amni-otic membrane (CAM), available as a self-retaining

biological corneal bandage that can be left in the eye for 29 days, has been shown to be effective in eyes with DED.46,47 The retrospective DREAM study examined the effi cacy of CAM in 97 eyes of 84 patients with severe dry eye despite maximal medical treatments.46 The CAM were in place for 5.4±2.8 days (range: 2 to 11 days) and were removed from 4 eyes (4%) after 2 days due to in-tolerance.46 Improved ocular surface was noted in 88% of patients after removal.46 The dry eye severity score was reduced signifi cantly from 3.25 at baseline to 1.44, 1.45, and 1.47 at 1 week, 1 month, and 3 months (all P�.001).46 Ocular discomfort scores, visual symptom scores, corneal staining scores, and overall corneal signs scores were signifi cantly improved at 3 months (all P�.001).46 Patients continued to use their conventional treatments despite previous treatment failure.46 Prospec-tive controlled studies are warranted.

Amniotic membrane extract is used in other fi elds and has recently become commercially available as an eye drop formulation (Figure 2).45 One commercial amniotic cytokine extract (ACE) eye drop formula comprises a so-lution of more than 120 active cytokines, growth factors, and anti-infl ammatory molecules harvested from amniotic

Proposed mechanism of the role of amniotic membrane extract eye drops in promoting wound healing. bFGF = basic fi broblast growth factor; EGF = epidermal growth factor; HGF = hepatocyte growth factor; IL = interleukin; KGF = keratinocyte growth factor; TGF = transforming growth factor; TNF = tumor necrosis factor.Source: Murri MS, et al.45 Open Access.

Figure 2. Proposed Mechanism of Amniotic Membrane Extract Eye Drops

13

tissue using a proprietary cryopreservation technique.45,48 The product is covered under Section 361 of the Public Health Service Act and is not FDA regulated.45 Therefore, no clearance or premarket approval is required.

Outcomes using the ACE eye drops were examined in a retrospective chart review of 43 patients.48 Patients received 1 ACE drop twice daily for 4 weeks in the study eye, identifi ed as the eye with the highest total corneal staining at baseline. Signifi cant improvements were ob-served between baseline and week 4 in mean eye dryness score (68 vs 41), total corneal staining score (7.2 vs 3.2), and total conjunctival score (6.3 vs 5.1; all P�.05).48 Another retrospective chart review that included 45 patients who received ACE for 12 weeks also reported positive outcomes.49

Surgical Treatment for Dry EyeLimited tarsorrhaphy may be benefi cial in pa-

tients with severe dry eye who have not responded to other therapies.6 Tear evaporation reduction, resulting from the decreased eye opening, may improve ocular surface homeostasis.50

SUMMARYThe approach to treating DED is based on careful

assessment of the etiology, signs, symptoms, and se-verity of the disease. The armamentarium is expand-ing, and clinicians should be aware of the indications, limitations, risks, and benefi ts of each treatment option. Before initiating treatment, exacerbating factors should be eliminated when possible. Lubricant eye drops, gels, and ointments are available as fi rst-line therapies. Sub-sequent treatments are discussed in major reports from professional societies, which provide valuable manage-ment recommendations and guidance.

CASEA 54-year-old woman with a long-standing history of

rheumatoid arthritis is systemically stable on infl iximab. Recently, she complained of decreased vision and severe foreign body sensation, saying it feels as if there are ra-zor blades in her eyes. Eye examination reveals fi laments (Figure 3).

Her deformed hands complicated her management of vials for accurately applying eye drops or self-applied inserts. She has no available assistance in the home. A trial of self-retained amniotic membrane was short-termed and unsuccessful. She self-administers bottled artifi cial tears approximately 10 times per day.

She was given a short course of compounded topi-cal acetylcysteine 10% for the fi laments and lotepred-nol 0.5% gel for the infl ammation. She was able to use warm compresses and hypochlorous lid scrubs. She also was capable of using the multidose cyclosporine 0.05% bottle. Other possible interventions included neurostim-ulation, moisture chamber, and amniotic extract drops. Other options discussed included bandage contact lenses and tarsorrhaphy.

At the visit, the patient’s fi laments were removed with jeweler forceps, and she was seen 2 weeks later for follow-up. She felt better, which most likely was due to the manual removal of the fi laments as well as the lotepre-dnol therapy. She was tapered off the acetylcysteine 10% over 6 weeks and the loteprednol over 3 months. Amniotic extract drops were added, and she has been maintained on the multidose cyclosporine, amniotic extract drops, warm compresses, and hypochlorous lid scrubs for 1 year.

References

1. Craig JP, Nelson JD, Azar DT, et al. TFOS DEWS II Re-port Executive Summary. Ocul Surf. 2017;15(4):802-12.

(A) Radiograph of the patient’s hands shows severe deformity. (B) Eye examination shows fi lamentary keratitis. (C) Fluorescein staining of fi lamentary keratitis.Source: Francis S. Mah, MD.

Figure 3. A 54-Year-Old Woman With Rheumatoid Arthritis

A B C

14

2. Messmer EM. The pathophysiology, diagnosis, and treatment of dry eye disease. Dtsch Arztebl Int. 2015;112(5):71-81.

3. Lemp MA, Crews LA, Bron AJ, Foulks GN, Sullivan BD. Distribution of aqueous-defi cient and evaporative dry eye in a clinic-based patient cohort: a retrospective study. Cor-nea. 2012;31(5):472-8.

4. Jones L, Downie LE, Korb D, et al. TFOS DEWS II manage-ment and therapy report. Ocul Surf. 2017;15(3):575-628.

5. Milner MS, Beckman KA, Luchs JI, et al. Dysfunctional tear syndrome: dry eye disease and associated tear fi lm disorders – new strategies for diagnosis and treatment. Curr Opin Ophthalmol. 2017;27 Suppl 1:3-47.

6. Akpek EK, Amescua G, Farid M, et al; American Academy of Ophthalmology Preferred Practice Pattern Cornea and External Disease Panel. Dry Eye Syndrome Preferred Prac-tice Pattern. Ophthalmology. 2019;126(1):P286-P334.

7. Asbell PA, Maguire MG, Pistilli M, et al. N-3 fatty acid supplementation for the treatment of dry eye disease. N Engl J Med. 2018;378(18):1681-90.

8. Rhee MK, Mah FS. Clinical utility of cyclosporine (CsA) ophthalmic emulsion 0.05% for symptomatic relief in peo-ple with chronic dry eye: a review of the literature. Clin Ophthalmol. 2017;11:1157-66.

9. Cyclosporine ophthalmic emulsion [Prescribing informa-tion]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/050790s027lbl.pdf. Accessed February 25, 2019.

10. Kunert KS, Tisdale AS, Stern ME, Smith JA, Gipson IK. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol. 2000;118(11):1489-96.

11. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two mul-ticenter, randomized studies of the effi cacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dry eye disease. CsA Phase 3 Study Group. Ophthalmol-ogy. 2000;107(4):631-9.

12. Barber LD, Pfl ugfelder SC, Tauber J, Foulks GN. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emul-sion administered twice daily to dry eye disease patients for up to 3 years. Ophthalmology. 2005;112(10):1790-4.

13. Roberts CW, Carniglia P, Brazzo BG. Comparison of topi-cal cyclosporine, punctal occlusion, and a combination for the treatment of dry eye. Cornea. 2007;26(7):805-9.

14. Hom MM. Use of cyclosporine 0.05% ophthalmic emul-sion for contact lens-intolerant patients. Eye Contact Lens. 2006;32(2):109-11.

15. Salib GM, McDonald MB, Smolek M. Safety and effi cacy of cyclosporine 0.05% drops versus unpreserved artifi cial tears in dry-eye patients having laser in situ keratomileu-sis. J Cataract Refract Surg. 2006;32(5):772-8.

16. Cyclosporine ophthalmic emulsion multidose [Prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/050790s024s025lbl.pdf. Accessed Febru-ary 25, 2019.

17. Sheppard JD, Scoper SV, Samudre S. Topical loteprednol pretreatment reduces cyclosporine stinging in chronic dry eye disease. J Ocul Pharmacol Ther. 2011;27(1):23-7.

18. Loteprednol etabonate ophthalmic suspension [Pre-scribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/1998/20583lbl.pdf. Accessed Feb-ruary 25, 2019.

19. Pfl ugfelder SC, Maskin SL, Anderson B, et al. A random-ized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspen-sion, 0.5%, and placebo for treatment of keratoconjunc-tivitis sicca in patients with delayed tear clearance. Am J Ophthalmol. 2004;138(3):444-57.

20. Sheppard JD, Donnenfeld ED, Holland EJ, et al. Effect of loteprednol etabonate 0.5% on initiation of dry eye treat-ment with topical cyclosporine 0.05%. Eye Contact Lens. 2014;40(5):289-96.

21. Loteprednol etabonate ophthalmic gel [Prescribing in-formation]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/202872s002lbl.pdf. Accessed February 25, 2019.

22. Coffey MJ, Decory HH, Lane SS. Development of a non-settling gel formulation of 0.5% loteprednol etabonate for anti-infl ammatory use as an ophthalmic drop. Clin Oph-thalmol. 2013;7:299-312.

23. Lifi tegrast ophthalmic solution [Prescribing informa-tion]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208073s002lbl.pdf. Accessed February 25, 2019.

24. Holland EJ, Luchs J, Karpecki PM, et al. Lifi tegrast for the treatment of dry eye disease: results of a phase III, ran-domized, double-masked, placebo-controlled trial (OPUS-3). Ophthalmology. 2017;124(1):53-60.

25. Holland EJ, Whitley WO, Sall K, et al. Lifi tegrast clini-cal effi cacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials. Curr Med Res Opin. 2016;32(10):1759-65.

26. Tauber J, Karpecki P, Latkany R, et al. Lifi tegrast ophthal-mic solution 5.0% versus placebo for treatment of dry eye disease: results of the randomized phase III OPUS-2 study. Ophthalmology. 2015;122(12):2423-31.

27. Donnenfeld ED, Karpecki PM, Majmudar PA, et al. Safety of lifi tegrast ophthalmic solution 5.0% in patients with dry eye disease: a 1-year, multicenter, randomized, placebo-controlled study. Cornea. 2016;35(6):741-8.

28. Balaram M, Schaumberg DA, Dana MR. Effi cacy and tolerability outcomes after punctal occlusion with sili-cone plugs in dry eye syndrome. Am J Ophthalmol. 2001;131(1):30-6.

29. Gibard JP, Rossi SR, Azar DT, Heyda KG. Effect of punctal occlusion by Freeman silicone plug insertion on tear osmo-larity in dry eye disorders. CLAO J. 1989;15(3):216-8.

30. Jehangir N, Bever G, Mahmood SM, Moshirfar M. Com-prehensive review of the literature on existing punctal plugs for the management of dry eye disease. J Ophthal-mol. 2016;2016:9312340.

31. Marcet MM, Shtein RM, Bradley EA, et al. Safety and effi cacy of lacrimal drainage system plugs for dry eye syn-drome: a report by the American Academy of Ophthalmol-ogy. Ophthalmology. 2015;122(8):1681-7.

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32. Ervin AM, Law A, Pucker AD. Punctal occlusion for dry eye syndrome. Cochrane Database Syst Rev. 2017;6:CD006775.

33. Shen G, Qi Q, Ma X. Effect of moisture chamber spec-tacles on tear functions in dry eye disease. Optom Vis Sci. 2016;93(2):158-64.

34. Waduthantri S, Tan CH, Fong YW, Tong L. Specialized moisture retention eyewear for evaporative dry eye. Curr Eye Res. 2015;40(5):490-5.

35. Hydroxypropyl cellulose ophthalmic insert [Prescribing information]. https://www.accessdata.fda.gov/drugsatfda_docs/label/2008/018771s017lbl.pdf. Accessed February 25, 2019.

36. Nguyen T, Latkany R. Review of hydroxypropyl cellulose ophthalmic inserts for treatment of dry eye. Clin Ophthal-mol. 2011;5:587-91.

37. Tsifetaki N, Kitsos G, Paschides CA, et al. Oral pilocar-pine for the treatment of ocular symptoms in patients with Sjogren’s syndrome: a randomised 12 week controlled study. Ann Rheum Dis. 2003;62(12):1204-7.

38. Kinoshita S, Oshiden K, Awamura S, et al. A random-ized, multicenter phase 3 study comparing 2% rebamipide (OPC-12759) with 0.1% sodium hyaluronate in the treat-ment of dry eye. Ophthalmology. 2013;120(6):1158-65.

39. Shimazaki J, Seika D, Saga M, et al. A prospective, ran-domized trial of two mucin secretagogues for the treat-ment of dry eye syndrome in offi ce workers. Sci Rep. 2017;7(1):15210.

40. Actis AG, Rolle T. Ocular surface alterations and topical antiglaucomatous therapy: a review. Open Ophthalmol J. 2014;8:67-72.

41. n-acetyl-l-cysteine [Package insert]. Lake Forest, IL: Ho-spira, Inc.; 2018.

42. Medscape. Acetylcysteine (Rx). https://reference.medscape.com/drug/n-acetylcysteine-mucomyst-acetylcysteine-343425. Accessed February 15, 2019.

43. Pan Q, Angelina A, Marrone M, Stark WJ, Akpek EK. Au-tologous serum eye drops for dry eye. Cochrane Database Syst Rev. 2017;2:CD009327.

44. Beylerian M, Lazaro M, Magalon J, et al. [Autologous se-rum tears: Long-term treatment in dry eye syndrome]. J Fr Ophtalmol. 2018;41(3):246-54.

45. Murri MS, Moshirfar M, Birdsong OC, Ronquillo YC, Ding Y, Hoopes PC. Amniotic membrane extract and eye drops: a review of literature and clinical application. Clin Ophthalmol. 2018;12:1105-12. Open Access.

46. McDonald MB, Sheha H, Tighe S, et al. Treatment out-comes in the DRy Eye Amniotic Membrane (DREAM) study. Clin Ophthalmol. 2018;12:677-81.

47. PROKERA Slim [Package insert]. Doral, FL: Bio-Tissue, Inc.; V3.

48. Linnehan R. Amniotic cytokine extract drops may be ef-fi cient therapy for dry eye. Ocular Surgery News. https://www.healio.com/ophthalmology/cornea-external-disease/news/print/ocular-surgery-news/%7Bab8b9f4a-118a-4601-9231-1e08c2f1d60c%7D/amniotic-cytokine-extract-drops-may-be-effi cient-therapy-for-dry-eye. Ac-cessed February 11, 2019.

49. Yeu E. Retrospective analysis of safety and effi cacy of am-niotic cytokine extract (PGE-2) in the treatment of dry-eye syndrome. Presented at: ASCRS-ASOA annual meeting 2017; May 8, 2017; Los Angeles, CA.

50. Zhang X, M VJ, Qu Y, et al. Dry eye management: target-ing the ocular surface microenvironment. Int J Mol Sci. 2017;18(7): pii:E1398. doi:10.3390/ijms18071398.

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Increasing research activity that focused on devel-oping treatments for ocular surface disease (OSD) resulted in the US Food and Drug Administration

(FDA) approval of topical cyclosporine in 2003 and li-fi tegrast in 2016.1 Encouragingly, industry involvement in dry eye disease (DED) research is increasing, with more than 20 companies sponsoring ongoing registered phase 1 through phase 3 DED studies in early 2019.2 Sev-eral agents with a spectrum of targets are also being inves-tigated in preclinical studies.3 In recent decades, research established DED as a chronic infl ammatory disease.1 However, current research and development activities are pursuing agents with noninfl ammatory mechanisms of action as well as those aimed at resolving infl ammation.

AUTOLOGOUS SERUMThe initial report describing subjective and objective

benefi ts using artifi cial tears made from 15 autologous serum donors to treat DED was published 35 years ago.4 Between 2015 and 2017, 11 basic research and 21 clinical studies were published on autologous serum and DED.5

The feasibility of using autologous serum is supported by the presence of many essential tear components in se-rum.5,6 Concentrations of each component are often vari-able between the 2 fl uids—for example, serum contains considerably less lactoferrin and considerably more al-bumin compared with natural tears. Replacing defi cient epidermal growth factor in eyes with an abnormal tear fi lm may promote growth and migration of ocular epi-thelial cells, supporting corneal epithelial function and morphology. Most studies use 20% autologous serum to closer approximate the concentrations of substances that might not be benefi cial at higher concentrations.6,7 Spe-cifi cally, the high concentrations of transforming growth factor-� in serum may have antiproliferative effects that could suppress ocular surface epithelium healing.

Drops prepared from autologous serum are among available treatment options, starting with second-line therapy recommendations by the Cornea, External Disease, and Refractive Society and the Tear Film and Ocular Surface Society Dry Eye Workshop II and are a recommended treatment option for severe dry eye dis-ease by the American Academy of Ophthalmology.8-10 Limitations to their expanded use include the paucity

of evidence from robust randomized trials, challenges in the preparation and preservation of the product, and possible development of new therapies based on specifi c benefi cial serum components.5,7 Some practitioners re-strict the use of autologous serum to patients with in-fl ammatory conjunctivitis, which is sometimes observed with Stevens-Johnson syndrome and graft-versus-host disease (GVHD).5,7

AMNIOTIC MEMBRANEAmniotic membrane can be a benefi cial adjunct for

the patient with persistent epithelial defect or severe dry eye with chronic epitheliopathy. It can be used either as a cryopreserved membrane applied directly to the ocular surface as a temporary graft or a dehydrated graft held in place with a bandage contact lens.11 The fi t of the con-tact lens is critical to the function and retention of the membrane.12 The cryopreserved membrane is indicated for treating infl amed or wounded tissue, whereas the de-hydrated graft is approved for wound coverage only.13-15

CYCLOSPORINE: NEW FORMULATIONSCompounded Preservative-free Cyclosporine 0.1%

A nonpreserved compounded formulation of cyclo-sporine 0.1% is available.16,17 The cyclosporine is com-bined with several lubricants in a chondroitin sulfate emulsion, which may also provide benefi ts. The prod-uct is currently available as a 503(a) compounded drug. That is, clinicians cannot order a supply to keep in stock; rather, they must order it on an individual patient basis.18

Nonaqueous Preservative-free Cyclosporine 0.1%

The oil-based emulsions in cyclosporine formula-tions can be associated with retention time and toler-ability issues. Clinical trials are underway, using a proprietary cyclosporine formulation without water, oils, surfactants, and preservatives.19 The technology is based on semifl uorinated alkanes, producing a low-viscosity liquid that spreads rapidly over the ocular surface. With a refractive index similar to water, visual disturbances are decreased compared with oil-based formulations.19 In vivo and ex vivo studies have shown

New and Up-and-Coming Treatment Modalities for Ocular Surface DiseaseEdward J. Holland, MD

17

greater local bioavailability compared with standard commercial cyclosporine formulations.

A phase 2 trial showed equivalent effi cacy with commercial 0.05% cyclosporine.19 Improved DED signs with the nonaqueous formation were observed starting at 2 weeks, which was earlier than the stan-dard formulation. Several outcomes were signifi cantly improved with the new formulation compared with both the vehicle and standard formulations. Symp-tom scores were similar for the 0.1% nonaqueous and 0.05% standard formulation.19

The ESSENCE trial was a pivotal, phase 2/3, vehicle-controlled study of the new formulation in 328 patients at 9 US sites.20 The sponsor announced that positive topline results were obtained, and complete outcome data are expected in the near future.21

Nanomicellar Cyclosporine 0.09%A 0.09% cyclosporine formulation approved by the

FDA in August 2018 is indicated to increase tear pro-duction in patients with dry eye.22 The cyclosporine is in a nanomicellar formulation that allows cyclosporine to overcome solubility challenges, achieving better pen-etration of the aqueous layer and preventing release of the active lipophilic molecule prior to penetration.23,24 In a 12-week, dose-ranging, phase 2/3 trial, both 0.05% and 0.09% doses met the conjunctival staining primary sign endpoint, whereas an approximate 30% decrease in global symptoms from baseline to day 84 was achieved in the 3 study arms, including placebo.23 Pivotal trial data from a total of 1048 patients with dry eye revealed that approximately 17% of treated patients achieved at least a 10-mm increase from baseline in Schirmer wetting, compared with approximately 9% of vehicle-treated controls.22

DRY EYE FLARE TREATMENT STRATEGYDry eye fl are is being increasingly encountered by

eye care professionals. A dry eye fl are is a rapid-onset, infl ammation-driven response to environmental trig-gers that typically cannot be adequately managed with artifi cial tears or other palliative treatments alone.25 Episodic fl ares are common, with approximately 80% of patients suffering from dry eye fl ares rather than continuous symptoms and experiencing 4 to 6 fl ares per year.25 Flares typically subside within a few days to weeks, followed by periods of few or no symp-toms. Flares can occur in patients being treated with long-term anti-infl ammatory therapies. These patients typically have more severe dry eye and experience more frequent fl ares than patients with less severe dry eye disease.25

MUCUS-PENETRATING PARTICLE DED DRUG DELIVERY

Although mucus performs an important role as part of innate defense mechanisms, it can impair ocular drug delivery.26 Theoretically, the outer mucin layer may trap and eliminate this foreign material and successfully remove the suspended drug from the ocular surface.27 Proprietary mucus-penetrating nanoparticles �500 nm, developed using excipients approved by the FDA for ophthalmic use, have been investigated for their ability to more effectively deliver loteprednol into ocular tis-sues by enhancing its penetration through the tear fi lm mucus layer.27 The small size is necessary to effectively penetrate the mucin meshwork and overcome the adhe-siveness of the ocular mucous layer. The investigational agent KPI-121 was shown in preclinical studies to pro-duce approximately 3-fold higher peak concentrations of loteprednol in ocular tissue following administration of a 0.4% nanoparticle formulation compared with the 0.5% commercial formulation of loteprednol.28

KPI-121 1% has been investigated as a twice-daily therapy for postoperative infl ammation and pain after cataract surgery.27 In 2 phase 3 randomized controlled trials, the coprimary effi cacy endpoints of complete res-olution of ocular infl ammation and pain at days 8 and 15 were achieved in signifi cantly more KPI-121 patients compared with controls, and adverse events were report-ed more frequently in control subjects.27

For treating DED, a phase 2 study and the phase 3 STRIDE 1 and 2 studies provided pivotal safety and effi cacy data for the October 2018 FDA submission of KPI-121 0.25% for 4-times daily administration.29 The phase 3 STRIDE 3 study is ongoing, with an estimated completion date in late 2019.30

OCU310: BRIMONIDINE 0.2% + LOTEPREDNOL 0.2% NANOEMULSION COMBINATION

Development efforts are also repurposing brimoni-dine tartrate, an existing glaucoma therapy.31 OCU300 is a novel ophthalmic preservative-free nanoemulsion for-mulation containing brimonidine tartrate, which is being investigated as a potential treatment for ocular GVHD under orphan drug status.32 After encouraging results in preclinical and early human studies suggesting that OCU300 0.18% may relieve ocular GVHD signs and symptoms, an ongoing phase 3 study is targeting an en-rollment of 60 participants, with completion anticipated in early 2020.33

The nanoemulsion OCU310, which is a combina-tion of brimonidine 0.2% and loteprednol 0.2%, is also being studied for the treatment of DED. The spon-sor announced that positive results were obtained in a

18

12-week, proof-of-concept, phase 2 trial,34 and a phase 3 trial, targeting an enrollment of 240 participants com-paring OCU310 2 times daily for 4 weeks with placebo, expects to be completed in 2019.35

THYMOSIN BETA 4: RGN-259 Thymosin beta 4 is a naturally occurring peptide that

promotes wound repair.36 Its specifi c actions include downregulating infl ammatory chemokine, cytokine, and metalloproteinase transcription as well as promoting cell migration and survival. Several small studies of RGN-259, a 0.1% formulation of thymosin beta 4, in patients with neurotrophic keratitis and severe DED established the rationale for further investigations of RGN-259 for treating ocular surface disorders.

A phase 2 study was performed in 72 subjects with moderate to severe dry eye whose condition was exacer-bated by a controlled adverse environment, which allows for greater standardization of environmental conditions during the study.36 Subjects instilled 1 to 2 drops of 0.1% RGN-259 or placebo twice daily for a total of 28 days.36 The single-center study failed to observe a signifi cant difference between treatment and control groups for the primary effi cacy endpoints of ocular discomfort scores and inferior corneal staining at day 29.36 However, sev-eral secondary endpoints were signifi cantly different in RGN-259 compared with placebo group subjects.36

In the ARISE 1 phase 2b/3 study completed in 2016, 317 subjects with dry eye were randomized to receive RGN-259 0.05% or 0.1% or placebo 4 times daily for 28 days.37,38 The primary endpoints were change from pre- to post-controlled adverse environment in total corneal fl uorescein staining score and ocular discom-fort score at day 29.37,38 Ocular discomfort after con-trolled adverse environment exposure was signifi cantly improved in both RGN-259 groups compared with the placebo group in a dose-dependent manner.38 Corneal staining was also signifi cantly improved in both treat-ment groups compared with placebo.38

Safety data from ARISE 1 and the phase 3 ARISE 2, which enrolled 601 subjects and was completed in early 2018,39 were accepted by the FDA; however, an additional phase 3 trial was required to demonstrate effi cacy.40 The sponsor announced that the study was initiated in Febru-ary 2019, targeting an enrollment of 700 patients, with completion expected in mid-2020.41

CENEGERMIN: APPROVAL FOR TOPICAL TREATMENT OF NEUROTROPIC KERATITIS

Neurotrophic keratopathy is a rare disease with or-phan status, reported to be associated with many sys-temic conditions, including herpes virus and diabetes

mellitus, as well as ocular conditions, including surgery and use of preserved medications.42,43 Historically, treat-ments with traditional OSD therapies provided nonspe-cifi c and often temporary relief. Recently, several new medical treatments have been investigated, with times to healing ranging from 16 to 61 days and rate of com-plete healing from 33% to 100%.42 Nerve growth factor, which is involved in the differentiation and maintenance of neurons to support corneal innervation and integrity, was one of the potential therapeutic agents.44

The recombinant human nerve growth factor ceneg-ermin is a fi rst-in-class agent that was approved by the FDA to treat neurotrophic keratitis in 2018.44,45 Pivotal data supporting its approval were acquired in 2 random-ized controlled trials that enrolled 151 patients with neu-rotrophic keratitis, with treatment applied 6 times daily for 8 weeks.44 Complete corneal healing was achieved by 65.2% and 16.7% of cenegermin and vehicle partici-pants, respectively, in study 0214 and 72.0% and 33.3%, respectively, in study 0212 (P<.01 for both compari-sons).44 In the 2 studies, recurrences after 8 weeks oc-curred in 14% and 20% of patients, respectively, who achieved healed corneas.44

PUNCTAL PLUG DELIVERY SYSTEMThe use of punctal plugs as a delivery system offers

an opportunity to target sustained treatment over weeks or months with several drugs.46,47 Development challenges include avoiding eye irritation, excessive tearing, ocular discomfort, and loss of the plug.47 The devices being de-veloped typically have a drug core that diffuses from a cross-section that is in contact with tears.46 Their poten-tial for delivering treatments for DED is under develop-ment but has not yet been explored in clinical trials.46,48

Glaucoma StudiesA latanoprost-releasing plug, designed to provide

unidirectional drug fl ow into the tear fi lm, was reported by the manufacturer to successfully reduce intraocu-lar pressure (IOP) in phase 2 studies at 3 months, with excellent retention.49 Ten of the 11 completed phase 2 studies investigated the latanoprost-releasing device.50 The most recent study, completed in December 2018, investigated a nepafenac punctal plug delivery system in 63 post-cataract surgery participants.51

Studies are also investigating drug release into the subpunctal canalicula. OTX-TP is a biodegradable intra-canalicular implant designed to release preservative-free travoprost for 3 months. A feasibility study of 17 patients with 26 devices showed that IOP reductions from baseline at days 10 and 30 were 24% and 16%, respectively.52 All plugs were present at 10 days, but

19

retention had declined to 42% at day 30.52 The spon-sor announced positive results and greater retention at 75 days in phase 2 studies.49

SUSTAINED DED OCULAR DRUG DELIVERY

In December 2018 the FDA approved OTX-DP, a resorbable intracanalicular device that elutes 0.4 mg of dexamethasone for up to 30 days following insertion into the canaliculus for treating ocular pain after ophthalmic surgery.53 The manufacturer announced that a supple-mental new drug application was submitted in January 2019 to extend the indication to treat ocular infl amma-tion following ophthalmic surgery.54

The device was also used to treat allergic conjuncti-vitis in 2 phase 3 studies.55,56 A 2016 conference report on a study that enrolled 73 subjects concluded that the device was effi cacious and well tolerated.57 Subsequent reports have not been published. In 2015, the company announced promising topline results from a phase 2 ex-ploratory trial of 43 patients with dry eye.58,59 However, the current development status for this indication is not clear.

SUSTAINED GLAUCOMA OCULAR DRUG DELIVERYAn ocular insert that provides topical bimatoprost has

been studied in patients with open-angle glaucoma and ocular hypertension (Figure 1). A phase 2, multicenter, noninferiority trial of 130 patients compared the active insert plus artifi cial tears with a placebo insert plus timo-lol twice daily for 6 months.60 A clinically relevant re-duction in IOP was observed over the 6-month treatment interval, although noninferiority with timolol was met at only 2 of 9 time points.60 The authors concluded that the insert was safe and well tolerated and may provide

an alternative to daily drops to improve adherence and delivery consistency. Studies of DED have not been reported, but other appli-cations of the ring platform for de-livering drugs to treat DED, ocular allergy, and postoperative infl am-mation were noted in the report as being under development.60

INTRANASAL NEUROSTIMULATION TO INCREASE TEAR PRODUCTION

A small study showed that na-sal mucosal anesthesia was asso-ciated with a signifi cant decrease in tear production.61 Subsequent development of an intranasal tear

neurostimulator led to marketing authorization by the FDA in 2017.62 Two pivotal trials of subjects with aque-ous-defi cient dry eye included a 1-day crossover study (study 1; N=48) and a single-arm, 180-day, prospec-tive, open-label cohort (study 2; N=89).63 During the single study 1 visit, participants applied the device in-tranasally (active application), to nasal skin outside the nares (active control), and sham intranasal stimulation (inactive control). The primary endpoint for study 1 was difference in Schirmer scores during device appli-cation compared with 2 control applications.63 Subjects in study 2 were to use the intranasal tear neurostimu-lator between 2 and 10 times daily and not exceeding 3 minutes per use. The primary endpoint for study 2 was the acute stimulated tear production at day 180, as measured by the difference between Schirmer test scores during and before stimulation.63

In study 1, mean Schirmer scores in the study eye were signifi cantly greater during active intranasal stimulation (25.3 mm) compared with active extrana-sal (9.5 mm) and sham intranasal (9.2 mm) application (P�.0001 for both comparisons).63 Similar results were observed in 35 qualifying fellow eyes; that is, eyes that met all inclusion criteria but had less severe dry eye than the study eye.63

At day 180, the mean Schirmer score in the study eye was signifi cantly higher during stimulation compared with the unstimulated eye (17.3 vs 9.4 mm; P�.0001).63 Qualifying fellow eyes achieved similar increases in tear production.63

A small, randomized, controlled trial was performed in 10 subjects with dry eye and in 5 subjects without signs or symptoms of tear dysfunction to explore the hypothesis that the intranasal tear neurostimulator may stimulate conjunctival goblet cell degranulation and

Source: Brandt JD, et al.60 Open Access.

Figure 1. Bimatoprost Ocular Insert

20

mucus secretion.64 After a screening visit, participants were seen for 2 additional visits to perform extranasal and intranasal tear neurostimulator application in ran-domized order. Anterior segment optical coherence tomography was performed before and immediately after the 3-minute application, and periodic acid-Schiff staining and MUC5AC immunostaining was performed on impression cytology samples obtained from the temporal and inferior bulbar conjunctiva.64 Preliminary results indicated that intranasal tear neurostimulation induced conjunctival goblet cell degranulation and mu-cin secretion.64

LID MARGIN DISEASE MANAGEMENT: THERMAL PULSATION

Vectored thermal pulsation treatment aims to simulta-neously evacuate the contents of both the upper and lower meibomian glands during a single treatment.65 Successful use of a device that received FDA clearance in 2011 has been reported in several studies. Recently, its effective-ness as a single treatment was examined in a small pilot study that enrolled 55 soft contact lens wearers with mei-bomian gland dysfunction (MGD) and evaporative dry eye. Primary effectiveness outcomes were meibomian gland secretion and SPEED (Standard Patient Evaluation of Eye Dryness) scores. The mean change between base-line and 3 months was signifi cant in both effi cacy out-comes (P�.0001 for both comparisons), with signifi cantly greater improvement in exploratory variables relative to controls.65 Mean comfortable contact lens wearing time in the treatment group increased 4.0±3.9 hours at 1 month and was sustained at 3 months, with no change observed in the control group.65 Another randomized controlled trial compared a 12-minute bilateral vectored thermal pulsation procedure with a 3-month course of oral doxycycline in 28 subjects with dry eye symptoms and evidence of MGD.66 Vectored thermal pulsation was signifi cantly more effective than doxycycline for improv-ing dry eye symptoms and was similar in effectiveness for improving meibomian gland function and associated signs of MGD.66

LID MARGIN DISEASE MANAGEMENT: INTENSE PULSED LIGHT

Intense pulsed light has received widespread use in treating diseases involving facial sebaceous glands and may be more effi cient and effective for treating MGD than many routine procedures.67 Its mechanism is not clear, but it has been hypothesized to be related to a photothermal effect, decreased infl ammation, and stimulation of meibo-mian gland activity. A recent prospective case series in-cluded 62 eyes of 31 patients with refractory obstructive

MGD.68 Eligibility criteria included failure of �3 standard MGD therapies or objective fi ndings for at least 1 year before study enrollment. Patients underwent 4 to 8 intense pulsed light treatments combined with meibomian gland expression at 3-week intervals.68 Dry eye symptoms and signs and MGD assessments were signifi cantly improved, except for meiboscore and Schirmer test value.68

MICROBLEPHAROEXFOLIATIONThe organized aggregate of microorganisms residing

in an extracellular polymeric matrix, or biofi lm, is esti-mated to be associated with approximately one-third of bacterial infections.69 Bacterial biofi lm plays an impor-tant role in the pathogenesis of MGD, beginning with its contribution to meibomian gland obstruction.70,71 Altered meibum combined with biofi lm, often called meibofi lm, provides a source of virulence factors and subsequent in-fl ammation as the disease progresses.

Microblepharoexfoliation is an in-offi ce procedure that may unclog meibomian gland orifi ces.72 The com-mercially available device comprises a hand-held unit that spins a disposable microsponge to provide lid mar-gin debridement and exfoliation. The device may be ben-efi cial in removing harmful bacterial biofi lms from the eyelids. A randomized controlled trial that compared tea tree wash with commercial lid scrub and lid scrub plus microblepharoexfoliation in 86 subjects with Demodex infestation reported similar outcomes in the 3 groups for Demodex reduction and symptom improvement.73

SUMMARYConsiderable advancements are being made in avail-

able treatments for ocular surface disease. Recent FDA approvals primarily provide novel delivery systems and devices for existing agents, whereas the recent approval of cenegermin for treating neurotrophic keratitis marks the fi rst approval of a topical ophthalmic biologic medi-cation. In-offi ce procedures supplement the options that clinicians can consider as part of their armamentarium. Research exploring new and improved treatments con-tinues, with many agents under FDA review and in late stages of clinical development.

CASE PRESENTATIONA 44-year-old woman complains of severe dry eyes

that started acutely about 1 year ago (Figure 2). She also has diffi culty exercising due to chronic fatigue and ach-ing knees and hips that started shortly before the dry eye symptoms. She complains of dry mouth and thirst. She is emmetropic and never needed vision correction. She has trouble seeing the computer monitor, especially late in the day, when her vision is blurry.

21

Numerous artifi cial tears and a short course of topical cyclosporine provided relief of the patient’s symptoms.

Her examination results (Table) warrant a suspicion of Sjogren syndrome. Subsequent tests for Sjogren syndrome A and Sjogren syndrome B antibodies were

positive. She was educated about Sjogren syndrome and referred to a rheumatologist for systemic workup and possible systemic therapy. She was also referred to a dentist who had experience managing patients with Sjo-gren syndrome.

Aggressive treatment was indicated, starting with loteprednol 0.5% 4 times daily, lifi tegrast twice daily, and nonpreserved artifi cial tears. Symptom persistence was followed by insertion of a punctal plug.

If she does not respond this therapy, a trial of autolo-gous serum drops and intranasal neurostimulation treat-ment would be recommended. Referral to a rheumatolo-gist for the initiation of disease-modifying antirheumatic drugs should be considered, as they help to slow or stop Sjogren syndrome from getting worse.

In addition to signs and symptoms of dry eye and dry mouth, Sjogren syndrome also presents with salivary gland enlargement and dental caries.74,75 Infl ammatory mononuclear infi ltrates involving the lacrimal and sali-vary glands lead to glandular destruction and dysfunc-tion. Sjogren syndrome has a 10-fold greater prevalence in women than men and is diagnosed most commonly in the fi fth to sixth decade of life.

Sjogren syndrome is not associated with an increase in overall mortality.74 It can coexist with a variety of other connective tissue diseases (secondary Sjogren syndrome) or exist without a defi nable connective tissue disease (primary Sjogren syndrome).

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Figure 2. Corneal and Conjunctival Staining

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