Aqueous-deficient Dry Eye Research Articles

Sjögren's Syndrome, Non-Sjögren's Syndrome, and Graft-Versus-Host Disease Related Dry Eye.

I have reviewed available literature on dry eye related to Sjögren's syndrome (SS), non-Sjögren's syndrome (non-SS), and graft-versus-host disease (GVHD) to examine aqueous tear deficient dry eye as a subtype of dry eye. This section will focus on clinical studies regarding those subtypes of dry eye. I searched the PubMed database from 1990-2017 for discussion of clinical features, diagnostic criteria, and risk factors of SS, non-SS, and GVHD-related dry eye. In addition, therapeutic options for each subtype of dry eye are described. Although the clinical presentations of SS and chronic graft-versus-host disease (cGVHD) are similar, ocular surface fibrotic changes are characteristic of ocular GVHD but not SS- or non-SS-related dry eye. Recently, diagnostic criteria for each disease have been proposed and include the American College of Rheumatology/European League Against Rheumatism (ACR-EULAR) for SS and the International Chronic Ocular GVHD consensus criteria. Although there has been gradual progress, there are currently no specific therapies and few approved treatment options for these intractable diseases, including SS and GVHD. As judged by the findings, these subtypes of dry eye are different clinical entities from simple dry eye. Therefore, novel therapies, specific to these subtypes of dry eye, may be required in the future.

Tear Film-Oriented Diagnosis and Tear Film-Oriented Therapy for Dry Eye Based on Tear Film Dynamics.

In December 2010 and January 2012, 3% diquafosol sodium ophthalmic solution and 2% rebamipide ophthalmic suspension, respectively, appeared first in Japan as prescription drugs for the treatment of dry eye (DE). Since then, not only the diagnosis and treatment but also the understanding of the pathophysiology of DE have greatly advanced, and a new concept of layer-by-layer diagnosis and treatment for DE, respectively termed "tear-film-oriented diagnosis" (TFOD) and "tear-film-oriented therapy" (TFOT) was born. This new concept is currently in the process of expanding from Japan to other Asian countries. TFOD is the method used for the differential diagnosis of DE, which includes aqueous-deficiency DE (ADDE), decreased wettability DE (DWDE), and increased evaporation DE (IEDE), through the dynamics of tear film (TF) and breakup patterns (BUPs) after the eye is opened. BUPs and/or each diagnosed DE subtype are/is able to distinguish the insufficient components of the ocular surface that are responsible for each BUP in a layer-by-layer fashion. Aqueous fluid, membrane-associated mucins (especially MUC16), and the lipid layer and/or secretory mucins must be insufficient in ADDE, DWDE, and IEDE, respectively, and this allows for a layer-by-layer treatment to be proposed for each BUP via the supplementation of the insufficient components, using the topical therapy currently available. In Japan, TF breakup is regarded as a visible core mechanism for DE, and an abnormal breakup time (i.e., ≤5 seconds) and symptoms are currently used for the diagnosis of DE. Therefore, TFOD and TFOT could be an ideal and practical pathway for clinicians to manage DE.

Clinical subtypes of dry eye in youthful clinical sample in Ghana.

To evaluate in a cohort of patients with dry eye disease (DED) the distribution of patients with asymptomatic and symptomatic dry eye involving aqueous deficient or the evaporative subtype of DED. This was a clinic-based cross-sectional study of consecutive patients visiting the University of Cape Coast eye clinic for a comprehensive eye examination. Eligible participants completed the Ocular Surface Disease Index (OSDI), ocular surface staining and tear break up time. Subjects with dry eye (symptomatic or asymptomatic) underwent clinical examination comprising lid margin assessments, meibomian gland expressibility and quality assessments, and Schirmer 1 test. A total of 172 patients were included in the study. The mean age of the eligible participants was 22.7 (±3.7) years, with a range of 17-35 years. There were 83 males and 89 females in the sample. There was an association between the form of the dry eye whether symptomatic or asymptomatic and sex, (X2 = 6.51 df = 1 p = 0.011). The frequency of symptomatic aqueous-deficient dry eye was 9(5.2%) whiles that of the symptomatic evaporative dry eye was 20(11.6%). The frequencies of the asymptomatic aqueous-deficient dry eye and asymptomatic evaporative dry eye were 9(5.2%) and 12(7.0%) respectively. The frequency of symptomatic mixed dry eye was 30(17.4%) and the asymptomatic mixed dry eye was 8(4.7%). The distribution of unclassifiable dry eye among the symptomatic dry eye group was 41(23.8%) and 43(25%) among the asymptomatic dry eye group. The number of patients exhibiting signs of the evaporative dry eye resulting from meibomian gland dysfunction far outnumbers those of aqueous deficient dry eye but there remains a high unclassifiable group with an unknown etiology. Further, studies are needed to explore the other etiology or etiologies of dry eye apart from meibomian gland dysfunction and reduced aqueous production.

Immune Response Targeting Sjögren's Syndrome Antigen Ro52 Suppresses Tear Production in Female Mice.

Autoantibodies reactive against Ro52 are present in 70% of Sjögren’s syndrome patients and are associated with higher disease severity. However, their role in causing aqueous deficient dry eye, a major cause for morbidity in Sjögren’s syndrome, is unclear. To investigate whether immune responses targeting Ro52 contribute towards the dry eye, male and female NZM2758 mice were immunized with recombinant Ro52. Tear production was measured by the phenol red thread test. Sera were analyzed for anti-Ro52 levels by immunoprecipitation. Lacrimal glands were evaluated for inflammatory foci and IgG deposits. Our results showed that, although all mice generated anti-Ro52 antibodies, only females developed a significant drop in tear production. None of the mice developed severe lacrimal gland inflammation, and female mice with anti-Ro52 showed higher levels of IgG deposits within their glands. Passive transfer of anti-Ro52 sera caused reduced tear production in female mice, but not in males. This study demonstrates for the first time that immune responses initiated by Ro52 induce aqueous dry eye, and this may be driven by anti-Ro52 antibodies. Furthermore, the sexual dimorphism in glandular dysfunction suggests that the lacrimal glands in females are more susceptible to autoantibody-mediated injury.

Five Misconceptions Related to Punctal Plugs in Dry Eye Management.

Punctal plugs are an effective treatment option for patients with aqueous-deficient dry eye refractory to topical medications. However, punctal plugs are not commonly used in clinical practice mainly because of various misconceptions, rather than clinical complications. We analyzed previous studies and present 5 misconceptions related to punctal plugs. The first and most important misconception is that ocular surface inflammation should be sufficiently controlled before punctal plug insertion. However, it is unclear how ocular surface inflammation can be sufficiently controlled in patients refractory to conventional topical medications. The second misconception is that silicone punctal plugs are made of nonabsorbable materials and, therefore, permanent. In fact, silicone plugs are reversible and can be easily removed if necessary. Therefore, depending on the specific type, nonabsorbable plugs may be classified as reversible or permanent. The third misconception is that punctal plugs disrupt normal tear drainage. However, punctal plugs maintain natural tears on the ocular surface for extended periods and reduce the frequency of artificial tear use. The fourth is that all punctal and canalicular plugs have similar effects. The efficacy and complication rates differ depending on plug types. The fifth misconception about punctal plugs is that they are effective only in aqueous-deficient dry eye disease. Many studies have reported that plugs are effective in a variety of ocular diseases and conditions. Understanding these 5 misconceptions may provide an opportunity to rethink the use of silicone punctal plugs in clinical practice.

Quality of life measures and health utility values among dry eye subgroups

BackgroundTo determine whether quality of life (QOL) and health utility are affected to the same extent among dry eye (DE) patients with short tear film break-up time dry eye (TBUT-DE) with minimal clinical signs were as severe as aqueous-deficient dry eye (ADDE).MethodsA multicenter cross-sectional study was conducted among DE patients who visited one of 10 eye clinics in Japan. Among the 463 registered patients, this study involved 449 patients with DE who were aged 20 years or older. Ophthalmic examination findings were assessed, including tear film break-up time (TBUT), Schirmer I value, and keratoconjunctival staining score. QOL was evaluated with the Dry Eye-Related Quality-of-Life Score (DEQS; 0 [best], 100 [worst]) and health utility (1 [total health], 0 [worst]) with the Health Utilities Index Mark 3 (HUI-3); scores were stratified by DE subgroup.ResultsMedian (interquartile range) of DEQS and HUI-3 scores across all participants were 21.7 (10.0–40.0) and 0.82 (0.69–0.91), respectively. Median (interquartile range) DEQS and HUI-3 scores in the ADDE group were 23.3 (10.0–40.0) and 0.79 (0.69–0.88), respectively; those in the short TBUT-DE group were 23.3 (13.3–38.3) and 0.82 (0.74–0.92), respectively. There were no significant between-group differences in questionnaire scores. Among the ophthalmic examination findings, a weak significant correlation between TBUT, corneal staining score and keratoconjunctival staining score to DEQS; TBUT and Schirmer test values to HUI-3, were seen.ConclusionsThe burden of short TBUT-DE on QOL as assessed by the DEQS and HUI-3 was as severe as that in ADDE. Our findings suggest that clinicians should be aware of the impact of short TBUT-DE on patients QOL and utility values.Trial registrationUniversity Hospital Medical Information Network (registration no. UMIN 000015890). Registered 10th December 2014, retrospectively registered.

Myoepithelial cell-driven acini contraction in response to oxytocin receptor stimulation is impaired in lacrimal glands of Sj\xf6gren\u2019s syndrome animal models

The purpose of the present studies was to investigate the impact of chronic inflammation of the lacrimal gland, as occurs in Sjögren’s syndrome, on the morphology and function of myoepithelial cells (MECs). In spite of the importance of MECs for lacrimal gland function, the effect of inflammation on MECs has not been well defined. We studied changes in MEC structure and function in two animal models of aqueous deficient dry eye, NOD and MRL/lpr mice. We found a statistically significant reduction in the size of MECs in diseased compared to control lacrimal glands. We also found that oxytocin receptor was highly expressed in MECs of mouse and human lacrimal glands and that its expression was strongly reduced in diseased glands. Furthermore, we found a significant decrease in the amount of two MEC contractile proteins, α-smooth muscle actin (SMA) and calponin. Finally, oxytocin-mediated contraction was impaired in lacrimal gland acini from diseased glands. We conclude that chronic inflammation of the lacrimal gland leads to a substantial thinning of MECs, down-regulation of contractile proteins and oxytocin receptor expression, and therefore impaired acini contraction. This is the first study highlighting the role of oxytocin mediated MEC contraction on lacrimal gland function.

Meibomian gland dropout in Sjögren's syndrome and non-Sjögren's dry eye patients.

The purpose of this study is to explore the differences in ocular symptoms and signs between Sjögren's syndrome (SS) and non-SS aqueous-deficient dry eye (ADDE) patients. Twenty-two eyes of 22 SS patients (Group 1) and 22 eyes of 22 non-SS ADDE patients (Group 2) were enrolled. The evaluated variables included the Standard Patient Evaluation of Eye Dryness (SPEED), the Ocular Surface Disease Index (OSDI), tear meniscus height, first and average non-invasive keratographic breakup time (fNIKBUT and avNIKBUT), Schirmer I test, lipid layer thickness (LLT), meibomian gland expressibility, Marx line, corneal staining, conjunctival congestion, incomplete blinking, and meibomian gland dropout using two novel, non-invasive instruments, the Keratograph and LipiView II. Ocular signs of the NIKBUT (fNIKBUT: 3.8 (2.7, 5.2)s and 6.3 (3.7, 8.9)s, P = 0.024; avNIKBUT: 5.4 (4.5, 8.9)s and 7.6 (5.8, 13.7)s, P = 0.041), meibomian gland dropout of the upper eyelid (35.5% (29.1%, 54.8%) and 21.9% (16.7%, 24.9%), P = 0.000), and corneal staining (P = 0.050) were more severe but were associated with less severe symptoms, i.e., a lower SPEED score (P = 0.001), in SS subjects than in non-SS subjects. SS patients exhibit more severe meibomian gland destruction of the upper eyelid than non-SS patients. Meibomian gland dysfunction is another key cause of SS-associated dry eye.

Diagnosis of dry eye disease

Dry eye disease (DED) is one of the most common ophthalmological diseases with an increasing prevalence in recent years. Numerous general and ocular risk factors exist for the development of DED. The pathogenesis of DED is multifactorial and complex, characterized by aloss of homeostasis of the tear film, inflammatory mechanisms at the ocular surface, hyperosmolarity of tears and neurosensory abnormalities. DED is classified into the two sub-categories, aqueous deficient dry eye and evaporative dry eye. Apart from adetailed patient history, basic and complementary diagnostic tests are necessary to enable an individualized and efficient therapy. Moreover, subjective symptom questionnaires and interdisciplinary cooperations are beneficial in athorough work-up of these patients.

Influence of Meibomian Gland Dysfunction and Friction-Related Disease on the Severity of Dry Eye

To evaluate the effect of meibomian gland dysfunction (MGD) and friction-related disease (FRD) on the severity of dry eye disease (DED). Cross-sectional observational study. This study enrolled 449 patients with DED (63 men and 386 women; mean age, 62.6±15.7 years [range, 21-90 years]) for analysis. Subjective symptoms, the ocular surface, tear function, and the presence of MGD and FRD (superior limbic keratoconjunctivitis, conjunctivochalasis, and lid wiper epitheliopathy) were investigated. Schirmer value, tear film breakup time (TBUT), and keratoconjunctival score. We classified the participants into aqueous-deficient dry eye (ADDE; n= 231 [51.4%]) and short TBUT dry eye subtype (TBUT-DE; n= 109 [24.3%]) subgroups. The TBUT was shorter in patients with MGD than in those without MGD, whereas other ocular signs showed no difference (TBUT: MGD present, 1.97±1.02 seconds; MGD absent, 2.94±1.63 seconds [P < 0.001]; ADDE/MGD present, 1.94±1.08 seconds; ADDE/MGD absent, 2.77±1.61 seconds [P < 0.001]; short TBUT-DE/MGD present, 2.07±0.97 seconds; short TBUT-DE/MGD absent, 2.94±1.23 seconds [P= 0.01]). The ADDE patients with FRD showed a worse TBUT than ADDE patients without FRD (TBUT: ADDE/FRD present, 2.08±1.39 seconds; ADDE/FRD absent, 2.92±1.54 seconds; P<0.001). This study showed associations between MGD, FRD, or both and ocular signs in DED. In the presence of MGD, FRD, or both, TBUT was significantly shortened regardless of the dry eye status or subtype.

Alteration in nerves and neurotransmitter stimulation of lacrimal gland secretion in the TSP-1-/- mouse model of aqueous deficiency dry eye.

The purpose of this study is to determine neural, vascular, protein secretion, and cellular signaling changes with disease progression in lacrimal glands of the thrombospondin-1−/− (TSP-1−/−) mouse model of dry eye compared to C57BL/6 wild type (WT) mice. Neural innervation was reduced in TSP-1−/− lacrimal glands compared to WT controls, whereas the number of blood vessels was increased. Intracellular Ca2+ stores and the amount of lysosomes, mitochondria and secretory granules, but not the endoplasmic reticulum, were reduced in TSP-1−/− compared to WT acini at 12 weeks of age. Ex-vivo high KCl-evoked secretion was decreased in TSP-1−/− compared to WT lacrimal gland tissue pieces. The α1D-adrenergic agonist-stimulated response was increased in TSP-1−/− at 4 and 24 weeks but decreased at 12 weeks, and the ATP and MeSATP-stimulated peak [Ca2+]i responses were decreased at 24 weeks. These changes were observed prior to appearance of mononuclear infiltrates. We conclude that in the lacrimal gland the absence of TSP-1: injures peripheral nerves; blocks efferent nerve activation, decreases protein secretion, and, alters intracellular Ca2+ stores. Through these effects the absence of TSP-1 leads to disruption of ocular surface homeostasis and development of dry eye.

Goblet cell loss abrogates ocular surface immune tolerance.

Intestinal epithelial cells condition tolerogenic properties in DCs. Aqueous-deficient dry eye is associated with goblet cell (GC) loss and increased IFN-γ expression in the conjunctiva. We hypothesized that loss of GCs reduces tolerance-inducing properties of antigen presenting cells (APCs) in the conjunctiva and draining nodes. Mice lacking the SAM pointed domain containing ETS transcription factor (Spdef) that is required for GC differentiation had an increased frequency of macrophages in the conjunctiva and CD11b+CD11c+ DCs in the conjunctiva and draining nodes, and these cells had greater IL-12 expression than WT mice. Conditioned media from cultured WT conjunctival GCs suppressed LPS-induced IL-12 production by conjunctival APCs. OVA antigen-specific OTII CD4+ T cells primed by Spdef-KO draining lymph node APCs showed greater proliferation, lower frequency of Foxp3+, increased frequency of IFN-γ+ and IL-17+ cells, and greater IFN-γ production than those primed by WT APCs. The immune tolerance to OVA antigen topically applied to the conjunctiva measured by cutaneous delayed type hypersensitivity (DTH) reaction, OVA-specific T cell proliferation, Foxp3 induction, and IFN-γ production observed in WT mice was lost in the Spdef-KO mice. We concluded that conjunctival GCs condition tolerogenic properties in APCs that suppress IL-12 production and Th1 polarization.

New Insights Into the Lipid Layer of the Tear Film and Meibomian Glands.

Meibomian glands secrete lipids (meibum) that form the surface lipid layer of the tear film and thereby prevent excessive evaporation of tear fluid. Meibomian gland dysfunction is a major cause of evaporative dry eye, which is more prevalent than aqueous-deficient dry eye. Noninvasive meibography with infrared light and an infrared charge-coupled device camera can detect morphological changes of meibomian glands in both upper and lower eyelids, whereas tear interferometry allows qualitative and quantitative evaluations of the lipid layer of the tear film. Such assessment of meibomian gland morphology provides clinical information that contributes to the diagnosis of evaporative dry eye, whereas that of the lipid layer of the tear film allows the monitoring of meibomian gland function. In addition, the balance between the lipid and aqueous layers of the tear film revealed by tear interferometry has provided both support for the operation of a compensatory system that maintains tear film homeostasis as well as insight into the pathophysiology of dry eye.

Aire-deficient mice provide a model of corneal and lacrimal gland neuropathy in Sjögren's syndrome.

Sjögren’s syndrome (SS) is a chronic, autoimmune exocrinopathy that leads to severe dryness of the mouth and eyes. Exocrine function is highly regulated by neuronal mechanisms but little is known about the link between chronic inflammation, innervation and altered exocrine function in the diseased eyes and exocrine glands of SS patients. To gain a better understanding of neuronal regulation in the immunopathogenesis of autoimmune exocrinopathy, we profiled a mouse model of spontaneous, autoimmune exocrinopathy that possess key characteristics of peripheral neuropathy experienced by SS patients. Mice deficient in the autoimmune regulator (Aire) gene developed spontaneous, CD4+ T cell-mediated exocrinopathy and aqueous-deficient dry eye that were associated with loss of nerves innervating the cornea and lacrimal gland. Changes in innervation and tear secretion were accompanied by increased proliferation of corneal epithelial basal cells, limbal expansion of KRT19-positive progenitor cells, increased vascularization of the peripheral cornea and reduced nerve function in the lacrimal gland. In addition, we found extensive loss of MIST1+ secretory acinar cells in the Aire -/- lacrimal gland suggesting that acinar cells are a primary target of the disease, Finally, topical application of ophthalmic steroid effectively restored corneal innervation in Aire -/- mice thereby functionally linking nerve loss with local inflammation in the aqueous-deficient dry eye. These data provide important insight regarding the relationship between chronic inflammation and neuropathic changes in autoimmune-mediated dry eye. Peripheral neuropathies characteristic of SS appear to be tightly linked with the underlying immunopathological mechanism and Aire -/- mice provide an excellent tool to explore the interplay between SS-associated immunopathology and peripheral neuropathy.

Lacrimal gland development: From signaling interactions to regenerative medicine.

The lacrimal gland plays a pivotal role in keeping the ocular surface lubricated, and protecting it from environmental exposure and insult. Dysfunction of the lacrimal gland results in deficiency of the aqueous component of the tear film, which can cause dryness of the ocular surface, also known as the aqueous-deficient dry eye disease. Left untreated, this disease can lead to significant morbidity, including frequent eye infections, corneal ulcerations, and vision loss. Current therapies do not treat the underlying deficiency of the lacrimal gland, but merely provide symptomatic relief. To develop more sustainable and physiological therapies, such as in vivo lacrimal gland regeneration or bioengineered lacrimal gland implants, a thorough understanding of lacrimal gland development at the molecular level is of paramount importance. Based on the structural and functional similarities between rodent and human eye development, extensive studies have been undertaken to investigate the signaling and transcriptional mechanisms of lacrimal gland development using mouse as a model system. In this review, we describe the current understanding of the extrinsic signaling interactions and the intrinsic transcriptional network governing lacrimal gland morphogenesis, as well as recent advances in the field of regenerative medicine aimed at treating dry eye disease. Developmental Dynamics 246:970-980, 2017. © 2017 Wiley Periodicals, Inc.

Ocular surface temperature in patients with evaporative and aqueous-deficient dry eyes: a thermographic approach

Objective: In recent decades infrared thermography (IRT) has facilitated accurate quantitative measurements of the ocular surface temperature (OST), applying a non-invasive procedure. The objective of this work was to develop a procedure based on IRT, which allows characterizing of the cooling of the ocular surface of patients suffering from dry eye syndrome, and distinguishing among patients suffering from aqueous deficient dry eye (ADDE) and evaporative dry eyes (EDE). Approach: All patients examined (34 females and 4 males, 23–84 years) were divided into two groups according to their Schirmer I result (⩽ 7 mm for ADDE and > 7 mm for EDE), and the OST was recorded for 7 s at 30 Hz. For each acquisition, the temperatures of the central cornea (CC) as well as those of both temporal and nasal canthi were investigated. Main results: Findings showed that the maximum temperature variation (up to 0.75 ± 0.29 °C) was at the CC for both groups. Furthermore, patients suffering from EDE tended to have a higher initial OST than those with ADDE, explained by the greater quantity of the tear film, evenly distributed over the entire ocular surface, keeping the OST higher initially. Results also showed that EDE patients had an average cooling rate higher than those suffering from ADDE, confirming the excessive evaporation of the tear film. Significance: Ocular thermography paves the way to become an effective tool for differentiating between the two different etiologies of dry eye syndrome.

Lifting the lid on dry eye practice – part 6

In the latest in our series aimed at those thinking about setting up a specialised dry eye clinical service, Craig McArthur looks at the diagnosis and management of aqueous deficiency dry eye disease.

Strategies for Regenerating the Lacrimal Gland.

Aqueous deficient dry eye disease, a significant cause of morbidity worldwide, is due to dysfunction of the main and accessory lacrimal glands. Recent advances in efforts to regenerate lacrimal gland are reviewed. Several strategies are being explored: ex vivo culture models of human and non-human lacrimal gland epithelial and myoepithelial cells, isolation and characterization of adult precursor cells within lacrimal glands, directed differentiation of stem cells to lacrimal gland cells, and organogenesis and engraftment techniques. Conditions for primary cell culture and expansion are being established and will help in the characterization of lacrimal cells. Presumed adult precursor cells have been isolated, laying down foundations for regeneration. Stem cells have been induced to express features of lacrimal gland cells. Engraftment of ex vivo cultured lacrimal tissue is proof of concept that lacrimal gland regeneration and repopulation is possible.

Lifting the lid on dry eye practice – part 5: quantity, quality or both?

In the latest in our series aimed at those thinking about a specialised dry eye clinical service, Craig McArthur looks at the nature and aetiology of aqueous deficiency dry eye disease.

A Clinic-based Survey of Clinical Characteristics and Practice Pattern of Dry Eye in Japan.

The aim of this study was to investigate the clinical characteristics and practice pattern of patients with dry eye disease (DED) in eye clinics across Japan. A multi-center, cross-sectional study was conducted among patients with DED who visited eye clinics in Japan. Subjective symptoms, patient's background, ocular surface features, and tear function were evaluated. Main outcome measures were tear break-up time (TBUT), Schirmer I value, kerato-conjunctival staining score, and dry eye symptom questionnaire score. Initially, 463 subjects were enrolled, and 449 cases (63 male and 386 female; mean age, 62.6±15.7years) were included in the final analysis. Overall, 94.9% of patients had a shortened TBUT (≤5s), and 54.6% had an aqueous tear deficiency (Schirmer I value ≤5mm). The most prevalent subtype of dry eye was aqueous-deficient dry eye, which was present in 35.0% of all patients, followed by short-BUT-type dry eye, which was seen in 26.7%. The two most common DED subtypes were aqueous-deficient and short-BUT-type dry eye. Shortened TBUT is the most common feature of dry eye, regardless of subtype. The current treatment choice mainly consisted of hyaluronic acid, two novel mucin secretagogues, diquafosol and rebamipide, and steroidal eye drops. University Hospital Medical Information Network: UMIN (registries no. UMIN 000015890). Japan Dry Eye Society, Tokyo, Japan, and Santen Pharmaceutical Co., Ltd., Osaka, Japan.