Acknowledgments
The authors express our sincere thanks to Ms. Catherine Oshima for administrative support and editing of the manuscript.
Conflicts of Interest
Vilavun Puangsricharern, Louis Tong, and Chi Hoang Viet Vu report no conflicts of interest.
Murat Dogru reports grants from Icom, Kobayashi Pharmaceuticals and Otsuka Pharmaceutical.
Takashi Kojima reports personal fees from Staar Surgical, personal fees from Santen Pharmaceutical, personal fees from Otsuka Pharmaceutical, personal fees from Johnson & Johnson, personal fees from Alcon, outside the submitted work.
Zuguo Liu reports his consultancy and research funding received from Santen, Xingqi, Haoshili, and Shengyuan. Personal fees from Alcon, Johnson & Johnson, Narvites, and Zhuhaiyisheng.
Chi Chin Sun—to be confirmed.
Kazuo Tsubota reports his position as CEO of Tsubota Laboratory, Inc., Tokyo, Japan, a company working on treatment, prevention, and medical devices for dry eye. Also, consultancy and research funding received from Santen Pharmaceutical Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. Research funding from Jins, Inc., Wakasa Seikatsu Corp, Wakamoto Pharmaceutical Co., Ltd., AMO Japan K.K., Pfizer, R-Tech Ueno, Ophtecs, Alcon Japan, and Rohto Pharmaceutical Co., Ltd. Investment or patent with Tear Solutions, Tissue Tech, Inc. and Kowa Company.
Norihiko Yokoi has received personal fees from Santen Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and consultancies from Rohto Co., Ltd. and Alcon Japan Co., Ltd., and patents for the ophthalmologic apparatus with Kowa Co., Ltd.
Introduction
Dry eye disease (DED) is a significant public health problem in many parts of the world, not only because it causes restriction of social and daily activities but it causes undeniable economical burden due to health-related costs and loss of working hours. DE has been reported to be more prevalent in Asia compared to the rest of the world, which might be related to genetics or lifestyles of Asians, and some ophthalmic diseases are more prevalent in Asia, such as myopia. Recently, DE has been considered to be due to lifestyle changes such as increased use of visual display terminals (VDTs), using smartphones for longer hours, diet, lack of omega 3 fatty acid diet, lack of exercise, or sleep disorders. Likewise, myopia is recently considered to be a lifestyle disorder and related to sleep, omega 3 fatty acid intake, exercise, outdoor activities, in addition to VDT use. , The overall prevalence of symptomatic DED in Asia ranged between 14.4% and 24.4%. Symptomatic DE is also prevalent in high school students in China and Japan, where the prevalence ranged between 21% and 24% , which was considerably higher than rates in adults, of 9.8%–11.5% in men and 18.7%–19.4% in women. , , South East Asian Studies using DE definition showed the highest prevalence rates of symptomatic DED, ranging from 20.0% to 52.4%. In Singapore, two studies showed a prevalence of only 6.5% and 12.3%. , In Korea, using a strategy based on definition, the prevalence of symptomatic DED was reported to be around 20%.
In the 1990s, tear deficiency was still the central concept in DE. Large-scale epidemiological studies performed in China, Singapore, Korea and Japan on the role of longer hours of VDT work and smart phone use suggesting a higher incidence of resultant short tear film break-up time (TBUT) type of DEs started to cause a paradigm shift in diagnosis and treatment of DED favoring the tear instability as a core factor in diagnosis and treatment. Japan, China, and Korea established the Asia Dry Eye Society (ADES) in 2012. As a result of successive meetings held in 2013 and 2014, the society published the definition in a separate report as “Dry eye is a multifactorial disease characterized by unstable tear film causing a variety of symptoms and/or visual impairment, potentially accompanied by ocular surface damage.” According to the new definition, presence of symptoms of either discomfort or visual disturbance is essential. The ADES report concluded that DE questionnaires outlined in the DEWS report including Ocular Surface Disease Index (OSDI), McMonnies questionnaire, Women’s Health Study Questionnaire or the recently reported DE-related quality of life (QOL) score (DEQS), appear as useful tools, but questionnaires assessing the visual impairment in daily life may provide additional and helpful information in the context of this new definition.
Since tear film instability is pivotal in the definition of DE, the measurement of TBUT is a mandatory step. The major problems in dealing with DED are a lack of consensus on the appropriate diagnostic criteria, classification of disease states, the aim of specific diagnostic tests, the role of symptoms in disease and treatment response assessment, and interpretation of results. Despite attempts to attain a consensus in diagnosis, classification, and treatment protocols of DED in Asia, there appears to be a significant regional variation in such protocols resulting from availability of different eye drops and cultural influences.
This chapter aims to provide an insight to DE diagnostic and treatment preferences in different parts of Asia.
Current Dry Eye Therapies in China
DE is the most common disease in eye clinics, with an incidence of 6.1%–59.1% in China. , The incidence of DE is higher compared to western countries. With the arrival of the era of “screen reading,” the incidence of DE is fast increasing in China. Therapies for DE are diverse and complex in China. Individualized and comprehensive treatment is recommended to all patients. , A healthy lifestyle such as sufficient sleep, adequate exercise, and a healthy diet is emphasized in the treatment.
Pharmacotherapy
More than 20 commercial artificial tears are available in China, which include water and viscosity-enhancing agents such as sodium hyaluronate, carboxymethocel, hydroxypropyl methyl cellulose, poly-vinyl, povidone, polyethylene glycol, and capom 940 (polyacrylic Acid). Three percent diquafosol tetrasodium, a purinergic P2Y2 receptor agonist that stimulates water and mucin secretion, was approved as an ophthalmic solution for the mucin deficiency DE 3 years ago. Eye drops that promote corneal epithelial healing are used for DE patients with corneal defects. Two such kinds of eye drops are fibroblast growth factor and epidermal growth factor eye drops. , They also show the effect of increasing the goblet cells and mucin secretion. An eyedrop from the deproteinized calf blood extract which was proved to promote corneal epithelial repair and improve microenvironment of ocular surface is also commercially available for moderate and severe DE patients. The autologous serum could be a treatment option for severe patients who do not react to routine treatment. A consensus on how to prepare the autologous serum was published recently.
Glucocorticoids, nonsteroidal antiinflammatory drugs (NSAIDs), and immunosuppressants are commonly used antiinflammatory drugs for DE patients. Several glucocorticoids with different concentrations are available for clinician selection. The 0.05%, 1% cyclosporine A and 0.1% tacrolimus are prescribed for moderate to severe DE patients depending on their severity. NSAIDs are a common choice for mild and moderate DE patients who do not respond to artificial tears but have no related immune disorders. It is also used as an alternative choice for DE patients who cannot bear the side effects of glucocorticoids. Several antibiotics that have both antibacterial and antiinflammatory effects, such as tetracycline and azithromycin, are used for meibomian gland dysfunction (MGD) patients with abnormal eyelid and blepharitis.
Physical Therapy
Physical therapies are very popular in China, which include a wide range of strategies, from lid hygiene, hot compress and fumigation, massage of meibomian gland, intense pulsed light, LipiFlow (LipiFlow Tear Science, Morrisville, NC, USA) to traditional Chinese medicine (TCM) therapies. Appropriate eyelid hygiene is important in managing lid conditions that cause DE (particularly blepharitis) and can reduce lipid by-products and lipolytic bacteria associated with lid diseases. Lid scrubs are gentle cleansers for helping lid hygiene, including a mild dilution of baby shampoo or professional eye wipes and cleaning fluids containing hypochlorous acid, tea tree oil, and its derivatives 4-turpentine alcohol or okra. Heat from a warm compress can soften or liquefy the increased viscosity meibum and thus help patients with DE to improve or restore the meibomian gland function. Patients could receive domestic hot compress items such as hot towel, hot compress eye mask, heated steam mask, etc. Fumigation treatment performed by professional caregivers can promote meibum flow and remove obstruction. Under the guidance of TCM, special TCM ingredients can be prescribed to patients with DE, including wild chrysanthemum, mulberry leaf, or honeysuckle for fumigation. Meibomian gland massage is commonly used in treating DE patients, which includes finger massage for home use and professional massage in hospital using rigid objects such as glass rod, meibomian pad forceps, and squeezing. The purpose of meibomian gland massage is to improve and/or restore the function of the glands by ameliorating or removing ductal obstruction, thus allowing the glands to be functional. Intense pulsed light delivers intense pulses of noncoherent light from 500 to 1200 nm in wavelength and LipiFlow is also a common selection for the treatment of MGD and DE.
Punctal occlusion, moisture chamber spectacles, and contact lenses are also available in China. Punctal occlusion is used for patients with aqueous-deficient DE, especially for moderate to severe DE patients whose symptoms cannot be relieved by artificial tears. Moisture chamber spectacles are able to reduce evaporation of the tears by providing a humid environment and minimizing airflow over the ocular surface. Therapeutic soft contact lens with high oxygen permeability is preferable among patients with corneal epithelium injuries or noninfectious eyelid diseases.
Traditional Chinese Medicine
TCM is currently the best-preserved and most influential traditional medical system with the largest number of users worldwide. In recent years, the trend of adopting TCM in DE has increased greatly in China. The application of TCM in DEs includes herbal, natural products, and Chinese medicine and acupuncture.
Herbal or natural products and chinese medicine
Topical and oral herbal or natural products have been widely used in China for thousands of years. However, relatively few randomized clinical trials have compared herbal medicine with conventional therapies due to the inherent challenges of the way of prescribing herbal medicine. Many of these therapies are based on the traditional “yin” and “yang” theory of Chinese medicine, and practitioners usually treat DE patients with a combination of different Chinese herbs. Chinese medicine can be prepared and used in eye drops, eye patches, and steam inhalations. Chinese medicine eye drops have been applied in patients with DE for many years in China, such as houttuynia eye drops and ZhenZhuMingMuDiYanYe (HaiBao). Recently, a randomized, double-blinded, placebo-controlled clinical trial of our group showed houttuynia atomized liquid had good curative effects on MGD-related DE. Furthermore, Chinese medicine eye patch showed a significant improvement in symptoms of DE.
Acupuncture
Acupuncture is a long-standing intervention in China to treat a wide variety of conditions. Studies have shown that stimulation of the peripheral nervous system with a concomitant central effect by acupuncture could be the mechanism of pain relief, which might then affect pain perception, alter inflammation or peripheral sensations, or “retrain” peripheral nerves in pain sensation. Acupuncture has been reported to improve TBUT, Schirmer scores, and corneal staining to a greater degree than artificial tears.
Therapeutic Strategies for Different Types of Dry Eye in China
Strategies for managing DE are based on classification and grading of DE. DEs are classified into five types in China. Table 12.1 below shows the therapeutic choices.
| Treatments/Classification | Pharmacotherapy | Physical Therapy and Others |
|---|---|---|
| Aqueous deficient type |
|
|
| Abnormal lipid type |
|
|
| Abnormal mucin type |
|
|
| Abnormal tear dynamics type |
|
|
| Mixed type | Comprehensive considerations | |
Dry Eye Therapy in Japan Based on TFOD and TFOT
Introduction and Epidemiology
Since 1995, the DE diagnostic criteria in Japan focused on objective measures of tear stability, tear quantity assessment, and presence of positive vital stainings. Participation of Japan to the International DE workshop during 2004–07 resulted in recognition of the importance of symptom assessment which led to the incorporation of symptoms into Japanese diagnostic criteria and a surge of questionnaire-based epidemiological studies which revealed a prevalence of between 8.7% and 30.1%. These studies also revealed that the short BUT type of DED especially among office workers and due to extensive use of smart phones was much more prevalent in Japan. Such findings of those epidemiological studies and introduction of mucin secretagogue eye drops in Japan resulted in a revision of Japanese DE diagnostic criteria which supports the conduct of TBUT tests and symptom assessment to diagnose the majority of DEs. The diagnostic recommendations include checking the vital stainings and tear quantity to diagnose the subtypes. Recently, classifying DEs from break up patterns is a hot topic of investigation in Japan. The section of DE management in Japan covers the logical reasons for the changes of diagnostic guidelines in Japan in alignment with ADES.
Through the accumulated report for the tears, tear film, and DE, the primary mechanisms that are associated with subjective eye symptoms in DE are the instability of tear film and increased friction, because a stable tear film can cover the ocular surface epithelium within the interpalpebral zone via the stability of tear film when the eye is kept open and tears function as a lubricant during blinking. Those primary mechanisms, when they are activated via the respective dysfunction of tear film or tears, may result in a variety of ocular surface epithelial damage, inflammation, and neurosensory response, each of which may explain a variety of symptoms in DE. In this comprehensive understanding for DE, only unstable tear film and resultant epithelial damage can be visualized simply by fluorescein-assisted slit-lamp biomicroscopy. Thus, one of the objective signs, tear film break-up, can become a clue to understand not only the mechanism but also symptoms for DE. Accordingly, unstable tear film, one of the visible characteristics in DE, from the clinical aspect, is emphasized in the definition and diagnostic criteria for DE not only in Asia but also in Western countries. , ,
Tear Film–Oriented Diagnosis and Tear Film–Oriented Therapy
In Japan, a paradigm shift has come in the diagnosis and therapy for DE, after new eye drops have become available from December 2010 to January 2012 as prescribed eye drops to treat DE, first in the world. Those new eye drops include diquafosol sodium and rebamipide which enable to, respectively, supplement aqueous fluid and mucins (both secretory and membrane associated), either of which contribute to the stabilization of tear film leading to the elongation of break-up time of tear film. The availability of those eye drops facilitated the born of a new concept that are layer-by-layer diagnosis and therapy for DE that had not been appeared in the world. , , Those new idea for the diagnosis and therapy for DE first born in Japan were coined, respectively, as Tear Film–Oriented Diagnosis (TFOD) and Tear Film–Oriented Therapy (TFOT) ( Fig. 12.1 ) , which are currently expanding to the other Asian countries.
TFOD is a diagnostic method which suggests two points: (1) insufficient component of the ocular surface (aqueous tears, secretory mucins, membrane-associated mucins, and meibomian lipids) and (2) DE subtype of aqueous-deficient DE [ADDE], decreased wettability DE [DWDE], and/or increased evaporation DE [IEDE], latter of those two constitute short TBUT DE, based on the observation of the upward movement of fluorescein-stained aqueous tear film and the fluorescein break-up patterns (BUPs). , , , In addition, TFOD enables the clinician to propose the most effective treatment for DE, which is coined as TFOT, via the stabilization of tear film through the supplementation of insufficient components to the ocular surface in DE. It is reported that fluorescein BUPs are classified into essentially five categories comprising Area, Line, Spot, Dimple, and Random breaks and are caused by a different pathophysiology depending on the insufficient components of the ocular surface, including aqueous tears, secretory mucins in the aqueous tear film, membrane-associated mucins, and component of ocular surface epithelium. Area and line breaks suggest that the insufficient component of the ocular surface is aqueous tears which are specific to ADDE as DE subtype and DE presenting area or line break can be treated, respectively, by punctal plugs or diquafosol sodium eye drops as TFOT. Spot and dimple breaks suggest the insufficiency of membrane-associated mucins, especially the longest mucin MUC16, corresponding to DWDE, can be treated via the supplementation of diquafosol sodium and/or rebamipide as TFOT. Random break suggests the insufficiency of MUC5AC and/or meibomian lipids, corresponding to IEDE, can be treated by either by hyaluronic acid having water-retentive property, diquafosol, or rebamipide via the increase of goblet cells, or treatment for MGD in DE cases with MGD. Therefore, through TFOD, insufficient components of ocular surface are looked through and DE subtypes are determined and either of which can propose the optimal treatment as TFOT for DE ( Fig. 12.2 ).
In addition, in our recent progress, understanding for blink-related friction has been advancing and blink-related friction has become effectively treated using rebamipide, in which goblet cells at the lid wiper can be increased to attenuate blink-related friction between the lid wiper and eye ball surface during blinking which lead to the attenuation of the symptoms associated with increased friction via the resolution of lid-wiper epitheliopathy, filamentary keratitis, superior limbic keratoconjunctivitis, and conjunctival epithelial damage which are likely to be seen especially in ADDE. Together with the progress in TFOD/TFOT concept, more optimal diagnosis and treatment has been advancing in Japan.
Treatment of Dry Eye in Korea
Introduction
According to the Korea National Health and Nutrition Examination Survey 2010–11, the overall prevalence of patients with DE was reported to be 16% among 11,666 participants 19 years of age and older. However, the prevalence of DE has a tendency to increase due to aging and environmental factors.
In 2014, the Korean guideline for the diagnosis and management of DE, mainly based on the DEWS classification, was published by the Korean Corneal Disease Study Group (KCDSG). According to the guideline, DED was defined as “a disease of the ocular surface that is associated with tear film abnormalities.” It has been accepted that inflammation in the lacrimal functional unit composed of the ocular surface and lacrimal glands plays a key role in the pathogenesis of DED. According to the guidelines for diagnosis, patients should have at least one DE symptom including ocular and visual symptoms and one objective sign; the ocular surface staining score by the Oxford system was the most important sign, followed by TBUT and Schirmer-1 test score ( Table 12.2 ). DE treatment options were recommended for each particular level (I ∼ IV), and the main treatment agents included preserved or nonpreserved artificial tears and antiinflammatory agents (topical corticosteroids and cyclosporine A). After the launching of topical secretagogues and the release of new perspectives on DE definition by the ADES in 2017, the importance of unstable tear film and decreased TBUT in the pathogenesis of DE was emphasized, and mucin secretagogue (diquafosol sodium) has been used as another main treatment agent. A new definition of DE reported by the TFOS DEWS II in 2017, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles, is now popularly accepted by Korean ophthalmologists. The resolution of theses etiological factors has become basic principles of DE treatment.
The treatment pattern of DE in Korea is interesting as preservative-free artificial tears (hyaluronic acid), antiinflammatory agents (cyclosporine A 0.05% and 0.1% emulsions), and secretagogues (diquafosol sodium) are the mainstay of treatment; these agents are frequently prescribed with insurance coverage, and treatment of MGD is popularly performed at the same time. In 2021, the Korean Dry Eye Society is establishing a revised guideline of DE diagnosis and treatment for DE subtypes including the aqueous deficiency dominant type, evaporation dominant type, and altered tear distribution type.
Specific Dry Eye Treatment Agents
Artificial tears
The growth rate of the artificial tears market is approximately 15% annually, which is the highest in the ophthalmic market in Korea. Hyaluronic acid (90%) is the most commonly used formulation of artificial tears, followed by carboxymethylcellulose (8%). Hyaluronic acid lubricants have several advantages including 1) increased tear stability facilitated by high viscosity between blinks, 2) uninterrupted blinking due to reduced viscosity under shear stress, 3) resistance to dehydration by binding to water, and 4) promotion of epithelial wound healing which improves ocular surface damages. Many formulations of hyaluronic acid artificial tears are commercially available and can be selected according to the presence of preservatives (preservative-containing and preservative-free), concentration (0.1%, 0.15%, 0.18%, and 0.3%), and tonicity (isotonic and hypotonic).
Preservative-free hyaluronic acid occupies more than 90% of the hyaluronic acid market. The KCDSG recommended the use of preservative-free artificial tears when instillation frequency exceeds 4 times a day. The toxic effects of preservatives such as benzalkonium chloride on the ocular surface have been well accepted by Korean ophthalmologists since 2010. Factors affecting toxicity include concentration, frequency of dosing, amount of tear secretion, and severity of ocular surface diseases. Benzalkonium chloride can induce cellular necrosis and apoptosis and inflammation of the corneal and conjunctival epithelium at concentrations of 0.01%–0.1%. Therefore, it may lead to ocular discomfort on instillation, stinging sensation, foreign body sensation, tearing, and itchy eyelids, and it has been associated with superficial punctate keratitis, conjunctival hyperemia, blepharitis, as well as reduced tear production and TBUT. Compared to preserved formulations, preservative-free formulations have been reported to be more effective in improving symptoms and signs, decreasing ocular inflammation, and increasing tear antioxidant contents in patients with DE. ,
Among the various concentrations of hyaluronic acid, 0.1% and 0.15% concentrations are the most frequently used, followed by 0.18% and 0.1% concentrations. In a clinical study comparing 0.1%, 0.15%, and 0.3% hyaluronic acid with 0.05% cyclosporine in Korean patients with DE, all three hyaluronic acids were effective in improving subjective symptoms and objective signs similar to 0.05% cyclosporine, and the 0.15% hyaluronic acid group showed a better improvement in Schirmer test scores at week 12 than the other groups. In an animal study comparing 0.1%, 0.18%, and 0.3% hyaluronic acid eye drops in the treatment of experimental DE, 0.3% hyaluronic acid was more effective than 0.1% and 0.18% hyaluronic acid in improving tear film instability and ocular surface staining and irregularity, increasing conjunctival goblet cell density, and decreasing corneal epithelial apoptosis. In clinical situations, higher concentrations of hyaluronic acid are preferred for aqueous deficient DE with moderate to severe corneal epithelial staining and evaporative DE with MGD.
Since 2015, the use of hypotonic hyaluronic acid drops has been gradually increasing in patients with inflammatory DE with ocular surface damage, especially those with Sjögren’s syndrome. Comparative studies have shown that hypotonic 0.18% hyaluronic acid drops (Kynex II, Alcon Korea, Seoul, Korea) were more effective in improving tear film stability and ocular surface staining and decreasing inflammatory cytokines, chemokines, and cells on the ocular surface of experimental and clinical DE compared to isotonic 0.1% hyaluronic acid (Kynex, Alcon Korea) or 0.5% carboxymethylcellulose (Refresh plus, Allergan, Irvine, CA, USA). , Similarly, 0.3% hypotonic hyaluronic acid was superior to 0.3% isotonic hyaluronic acid in improving corneal staining scores, decreasing inflammatory molecules, and increasing goblet cell counts in experimental DE. These data from Korean studies indicate that hypotonic artificial tears can be useful as an adjunctive treatment for inflammatory DE.
Ointments can be applied in moderate DE and are best used before bedtime since they cause blurring. Lipid-containing eye drops and ointments have grown in availability and can help restore the lipid layer in evaporative DE with MGD or lipid deficiency. Various lipid agents, such as mineral oil, lanolin, and carbomer with triglyceride, are commercially available in Korea.
Antiinflammatory agents
Based on the role of inflammation in DE, antiinflammatory agents, including corticosteroids and cyclosporine A, have been widely prescribed in Korea. Among topical corticosteroids, 0.1% fluorometholone is the most commonly used for treating acute DE, followed by 0.5% loteprednol. Recently, preservative-free 0.1% fluorometholone has been launched to reduce ocular damage and inflammation by benzalkonium chloride. Since long-term use of topical corticosteroids is a risk for glaucoma or cataract, it is not recommended. Short-term treatment (4 times a day for 2 weeks) with topical 1% methylprednisolone is recommended for cases with moderate to severe DE associated with Sjögren’s syndrome.
Topical cyclosporine A 0.05% anionic emulsion (Restasis, Allergan, Irvine, CA, USA), which can inhibit the activation of CD4+ T cells and consequently decrease HLA-DR, apoptosis markers, and inflammatory molecules in the ocular surface and lacrimal gland, was firstly launched in Korea in 2006. A prospective multicenter Korean study demonstrated that 3-month use of cyclosporine A 0.05% emulsion was tolerable and effective for the treatment of DE, as evidenced by improved ocular symptom scores, increased Schirmer scores, and decreased conjunctival staining and use of artificial tears. The KCDSG recommended the use of topical 0.05% cyclosporine A for inflammatory DE patients with mild to moderate corneal epithelial staining that corresponds to severity levels II and III. Cyclosporine A 0.05% emulsion was also proven to be effective in improving symptoms and signs of DE associated with graft-versus-host diseases and thyroid-associated ophthalmopathy as well as Sjögren’s syndrome. Other ocular formulations of 0.05% cyclosporine A including micelle-based solution (TJ cyporin, Taejoon, Seoul, Korea) and nanoemulsion (Clacier, Huons, Seoul, Korea) have also been developed and are available in the Korean market.
Cyclosporine A 0.1% cationic emulsion (Ikervis, Santen, Evry, France) was launched in Korea in 2017. It has been generally accepted that cyclosporine A 0.1% cationic emulsion is effective in reducing epithelial staining and inflammatory markers in the ocular surface as well as symptom scores, especially in patients with moderate to severe DE with severe keratitis, due to its higher concentration, longer residence time, and higher ocular bioavailability in the tear film.
A common pattern of antiinflammatory treatment by Korean ophthalmologists is that the initial combination of topical corticosteroids and cyclosporine A, followed by tapering of the steroid and eventual discontinuation after 2–4 weeks, while cyclosporine A is continued for as long as necessary.
Mucin secretagogues
Diquafosol tetrasodium 3% (Diquas, Santen) which stimulates water and mucin secretion from conjunctival epithelial cells and goblet cells and consequently improves tear film stability in DE was introduced in Korea in 2013. Diquafosol has become a major therapeutic agent along with artificial tears and cyclosporine A. The main etiological target of diquafosol is unstable tear film, and the optimal indication of diquafosol use is short TBUT DE and evaporative DE with MGD. In addition, diquafosol is used popularly for patients with DE after cataract and refractive surgery. Preservative-free 3% diquafosol (Diquas-S, Santen), which was also developed for the management of patients with preexisting DE after cataract surgery, is commercially available in Korea.
In comparison with 0.05% cyclosporine A, 3% diquafosol was more effective in improving TBUT; however, cyclosporine A was more effective in decreasing conjunctival staining. Another clinical study demonstrated that diquafosol was more effective in increasing tear secretion, whereas cyclosporine A was more effective in improving optical aberrations in DE patients following cataract surgery.
Serum
Serum contains essential tear components, growth factors, neurotrophic factors, vitamin A, fibronectin, prealbumin, and oil; it provides the corneal and conjunctival epithelium with basic elements for epithelial regeneration. Autologous serum eye drops (20%) have been recommended for the treatment of moderate to severe DE (level III or higher) in Korea since 2010. Yoon et al. found that umbilical cord serum contains a higher concentration of essential tear components, growth factors, and neurotrophic factors than autologous serum, and umbilical cord serum eye drops (20%) can be safely and effectively applied in severe DE with or without Sjögren’s syndrome, graft-versus-host disease, persistent epithelial defects, neurotrophic keratopathy, recurrent corneal erosions, ocular chemical burn, and surface problems after corneal refractive surgery.
Antioxidants
The role of oxidative stress in addition to inflammation in the lacrimal functional unit in the pathogenesis of DE has been well elucidated in Korea since 2000. Oxidative stress generates reactive oxygen species that can cause deleterious alterations in DNA, protein, and lipid of corneal and conjunctival epithelial cells and induce cellular damages and apoptosis, and, as a result, promote ocular surface inflammation that results in DE. In 2008, a prospective multicenter study demonstrated the clinical effectiveness of oral antioxidant dietary supplements in DE patients.
Topical application of antioxidant medicinal plant extracts improved clinical signs, decreased inflammatory molecules and cells, and ameliorated oxidative stress markers and reactive oxygen species production on the ocular surface in a mouse model of experimental DE. Antioxidant glasses (Eye Plus Alpha II, BM Korea, Gwangju, Korea) containing extracts of medicinal plants could effectively improve subjective symptoms and objective signs including TBUT in DE, and they were approved by the Korean Food and Drug Administration in 2013.
Others
Punctal plugs (temporary and permanent) and therapeutic contact lenses are used in DE with higher severity levels. Periocular application of a TRMP8 agonist (Blephacool, Samil, Seoul, Korea) can increase tear secretion by activating efferent nerve signals and reduce ocular discomfort by inducing the perception of coolness. The commercially available TRPM8 agonist may be a promising therapeutic agent in DE patients with Sjögren’s syndrome and ocular neuropathic pain.
Proposed Treatment Guidelines
In 2014, the KCDSG developed the Korean guideline for DE management for the various levels (I ∼ IV) of the disease severity ( Table 12.3 ). The detailed treatment options for each severity level were recommended. This guideline was based on the DEWS guidelines and modified to simplify the grading scheme so that they could be used more easily in clinical practice. However, this guideline had several limitations, including the use of fewer topical therapeutic agents and their application for only aqueous deficient DE. The Korean Dry Eye Society is establishing a new guideline for DE diagnosis, classification, and management. DE can be diagnosed when ocular symptoms, TBUT <7 s, and/or low tear volume (Schirmer test value < 10 mm), and/or corneal or conjunctival staining exist. According to the proposed guideline, DE can be classified into three types: 1) aqueous deficiency dominant type including Sjögren’s syndrome, 2) evaporation dominant type including MGD and blepharitis, and 3) altered tear distribution type such as lipid wiper epitheliopathy ( Fig. 12.3 ). Regarding management of DE, a stepwise approach using therapeutic agents (steps I and II) combined with procedures is recommended according to each type ( Fig. 12.4 ). The key therapeutic agents are artificial tears, secretagogues, antiinflammatory agents (corticosteroids and cyclosporine A), and dietary modification (omega-3 and antioxidants).
