Efficacy and safety of 1% and 2% rebamipide clear solution in dry eye disease: a multicenter randomized trial.

BACKGROUND: To evaluate the efficacy of 1% and 2% rebamipide clear solution in the treatment of dry eye disease (DED). METHODS: Two hundred twenty patients with DED were randomly assigned to one of three groups: the 1% rebamipide, 2% rebamipide, or placebo (eye drops containing the same ingredients, except for the active components). Each eye drop was instilled four times daily for 12 weeks. Changes in tear film break-up time (TBUT), corneal and conjunctival staining score, Schirmer 1 test, and the Ocular Surface Disease Index (OSDI) from baseline to 12-week visit between the study groups were compared for efficacy assessment. RESULTS: The mean age of study patients was 43.8±14.2 years. The 1% and 2% rebamipide groups showed greater improvement in TBUT (1.99±1.87 and 2.02±2.21 s) at 12 weeks from baseline than the placebo group (1.25±2.93 s). The 2% rebamipide group showed greater improvement in the corneal staining score (- 3.15±2.00) at 12 weeks from baseline than the placebo group (- 2.85±1.80). The 1% and 2% rebamipide groups showed improvement in Schirmer 1 test (1.27±3.86 and 1.50±4.14 mm) at 12 weeks of treatment, but not the placebo group (0.55±2.99 mm). Both the rebamipide groups and the placebo group showed significantly improved OSDI after treatment for 12 weeks; however, there was no significant difference among the three groups. CONCLUSIONS: 1% and 2% rebamipide clear solutions are an effective therapeutic option for improving TBUT and tear volume, and stabilizing the corneal staining score in DED.

Clinical characteristics of dry eye with ocular neuropathic pain features: comparison according to the types of sensitization based on the Ocular Pain Assessment Survey.

BACKGROUND: To compare the clinical characteristics of dry eye patients with ocular neuropathic pain features according to the types of sensitization based on the Ocular Pain Assessment Survey (OPAS). METHODS: Cross-sectional study of 33 patients with dry eye and ocular neuropathic pain features. All patients had a comprehensive ophthalmic assessment including detailed history, the intensity and duration of ocular pain, the tear film, ocular surface, and Meibomian gland examination, and OPAS. Patients with < 50% improvement in pain intensity after proparacaine challenge test were assigned to the central-dominant sensitization group (central group) and those with ≥50% improvement were assigned to the peripheral-dominant sensitization group (peripheral group). All variables were compared between the two groups. RESULTS: No significant differences were observed in age, sex, underlying diseases, history of ocular surgery, duration of ocular pain, tear film, ocular surface and Meibomian gland parameters (all p > 0.05). Ocular pain and non-ocular pain severity and the percentage of time spent thinking about non-ocular pain were significantly higher in the central group than in the peripheral group (all p < 0.05). Central group complained more commonly of a burning sensation than did the peripheral group (p = 0.01). CONCLUSIONS: Patients with central-dominant sensitization may experience more intense ocular and non-ocular pain than the others and burning sensation may be a key symptom in those patients.

Goblet Cells Contribute to Ocular Surface Immune Tolerance-Implications for Dry Eye Disease.

Conjunctival goblet cell (GC) loss in dry eye is associated with ocular surface inflammation. This study investigated if conjunctival GCs contribute to ocular surface immune tolerance. Antigens applied to the ocular surface, imaged by confocal microscopy, passed into the conjunctival stroma through goblet cell associated passages (GAPs) in wild type C57BL/6 (WT), while ovalbumin (OVA) was retained in the epithelium of SAM pointed domain containing ETS transcription factor (Spdef) knockout mice (Spdef-/-) that lack GCs and are a novel model of dry eye. Stimulated GC degranulation increased antigen binding to GC mucins. Induction of tolerance to topically applied OVA measured by cutaneous delayed type hypersensitivity (DTH) was observed in WT, but not Spdef-/-. OTII CD4⁺ T cells primed by dendritic cells (DCs) from the conjunctival draining lymph nodes of Spdef-/- had greater IFN-γ production and lower Foxp3 positivity than those primed by WT DCs. These findings indicate that conjunctival GCs contribute to ocular surface immune tolerance by modulating antigen distribution and antigen specific immune response. GC loss may contribute to the abrogation of ocular surface immune tolerance that is observed in dry eye.

Comparative Evaluation of Matrix Metalloproteinase-9 Immunoassay and Tear Osmolarity Measurement for Diagnosing Severity of Dry Eye Disease.

PURPOSE: To evaluate and compare the clinical efficacy of matrix metalloproteinase-9 (MMP-9) immunoassay and tear osmolarity measurement in diagnosing dry eye severity. METHODS: Dry eye disease (DED) patients underwent diagnostic tests including MMP-9 assay, tear osmolarity measurement, fluorescein tear breakup time, ocular surface staining, anesthetized Schirmer test, Ocular Surface Disease Index questionnaire, and slit-lamp examination. The dry eye parameters were compared according to positive MMP-9 status and increased tear osmolarity. The correlation between dry eye profiles and MMP-9 positivity and high tear osmolarity was also analyzed. RESULTS: Those who tested positive in MMP-9 immunoassay had significantly higher corneal fluorescein staining score and worse DED severity than those who tested negative. The intensity of MMP-9 positivity showed positive correlation with the corneal staining score and DED severity. However, DED patients with high tear osmolarity above 308 mOsm/L did not show significantly different dry eye signs and symptoms compared to those with lower tear osmolarity values. Tear osmolarity was associated with ocular surface staining score in severe DED patients. CONCLUSIONS: MMP-9 positivity was associated with ocular surface staining and worse dry eye severity. Therefore, it may be used as a useful indicator of disease severity in conjunction to other diagnostic tests.

Microbiologic Analysis of Removed Silicone Punctal Plugs in Dry Eye Patients.

This study analyzed the microbiologic results of removing silicone punctal plugs due to uncomfortable symptoms in dry-eye patients. Patients who were diagnosed with dry eye and received silicone punctal plugs-SuperEagle Punctum Plug™ (EagleVision, Denville, NJ, USA) or Parasol Punctum Plug™ (Beaver-Visitec international, Inc., Waltham, MA, USA)-into upper or lower puncta that were removed due to discomfort from January 2018 to June 2020 were enrolled and reviewed retrospectively. Out of the total 58 patients (64 eyes), 19 patients were male and 39 patients were female. Protrusion without granulation (21 patients, 32.8%) was the most common reason for plug removal, followed by protrusion with granuloma (19 patients, 29.7%). The positive rate of bacterial culture was 42.2% and Klebsiella aerogenes was the most common organism identified (18.5%). Vancomycin showed the highest susceptibility of 100% among all the antibiotics, third-generation cephalosporins were the most susceptible (88.5%) among cephalosporines, and levofloxacin was the most susceptible (81.0%) among quinolones. Among the patients who complained of discomfort after insertion of silicone punctal plugs, approximately 42% had a positive result in bacterial culture. Therefore, when removing punctal plugs in such patients, a microbiological examination may be needed for the appropriate selection of antibiotics.

Comparison of a preservative-free nonsteroidal anti-inflammatory drug and preservative-free corticosteroid after uneventful cataract surgery: multicenter, randomized, evaluator-blinded clinical trial.

PURPOSE: To compare the efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) and steroidal eyedrops for inflammation management after cataract surgery using slitlamp indicators. SETTING: 11 eye centers in South Korea. DESIGN: Randomized prospective multicenter study with a blinded evaluator. METHOD: In 125 (250 eyes) patients who underwent cataract surgery, bromfenac sodium hydrate 0.1% (NSAID group) was applied twice a day in 1 eye, whereas the other eye was treated with fluorometholone 0.1% (steroid group), 4 times a day for 4 weeks postoperatively. The primary efficacy outcome was the presence of anterior chamber cells and flare at 1 week postoperatively. Anterior chamber cells and flare at 4 to 8 weeks, corrected distance visual acuity, central corneal thickness, conjunctival hyperemia, dry eye parameters, foveal thickness, and ocular and visual discomfort were evaluated as secondary outcomes. RESULTS: At week 1, residual anterior chamber inflammation was not statistically significantly different between the groups (-1.03 ± 1.27 vs -0.95 ± 1.24, P = .4850). However, the NSAID group recovered from conjunctival hyperemia more rapidly than the steroid group (0.30 ± 0.52 vs 0.44 ± 0.81, P = .0144 at week 1). The increase in central corneal thickness in the NSAID group was less than that in the steroid group 1 week postoperatively (7.87 ± 22.46 vs 29.47 ± 46.60 µm, P < .0001). The change in foveal thickness in the NSAID group was significantly less than that in the steroid group (18.11 ± 68.19 vs 22.25 ± 42.37 µm, P = .0002). Lower levels of postoperative ocular and visual discomfort were reported in the NSAID group than in the steroid group under treatment. CONCLUSIONS: Preservative-free bromfenac was as effective as preservative-free fluorometholone eyedrops in anterior chamber inflammation control and showed better signs and symptoms after cataract surgery.

Clinical efficacy of eyelid hygiene in blepharitis and meibomian gland dysfunction after cataract surgery: a randomized controlled pilot trial.

The purpose of this randomized clinical trial is to evaluate the effect of eyelid hygiene on subjective symptoms, anterior blepharitis, and meibomian gland dysfunction (MGD) after cataract surgery. Subjects with obstructive MGD who underwent cataract surgery were randomly divided into two groups. In the eyelid hygiene group, eyelid hygiene was performed twice a day for 10 days from 3 days before to 1 week after cataract surgery. The control group did not perform eyelid hygiene. A subjective symptom questionnaire of SPEED, anterior blepharitis grade, and meibum quality and quantity was evaluated at baseline and at postoperative 1 and 4 weeks. The eyelid hygiene group (n = 36) showed decreased SPEED score after cataract surgery and the control group (n = 33) did not. Anterior blepharitis grade was worse 1 week after surgery in the control group but not in the eyelid hygiene group. The control group had significantly decreased meibum quality and quantity in both the upper and lower eyelids after cataract surgery, but the eyelid hygiene group did not. Eyelid hygiene before/after cataract surgery improved postoperative subjective symptoms and prevented postoperative exacerbation of anterior blepharitis and MGD. Thus, perioperative eyelid hygiene is recommended for patients with obstructive MGD who undergo cataract surgery.

Meibum Expressibility Improvement as a Therapeutic Target of Intense Pulsed Light Treatment in Meibomian Gland Dysfunction and Its Association with Tear Inflammatory Cytokines.

Many recent studies have demonstrated the efficacy of intense pulsed light (IPL) for the treatment of meibomian gland dysfunction (MGD); however, its effective treatment targets have not yet been elucidated. This study aimed to investigate the baseline characteristics associated with an improvement in symptoms after IPL treatment; to examine the course of change in inflammatory tear cytokines, meibomian gland function, and tear stability; and to investigate the correlation between cytokines and ocular surface parameters. Thirty participants underwent three sessions of IPL treatment. During each examination, tear film lipid layer interferometry, meibography, tear meniscus height measurement, tear sampling, and slit-lamp examination were performed, and the Ocular Surface Disease Index (OSDI) questionnaire was administered. Meibum quality, meibum expressibility, lid margin abnormality, tear film break-up time (TBUT), ocular surface staining, and the OSDI significantly improved after treatment. Poor meibum expressibility and short TBUT were associated with greater recovery in the OSDI after IPL. Tear levels of IL-4, IL-6, IL-10, IL-17A, and TNF-α decreased after IPL, and IL-6, and TNF-α were correlated with the improvement in meibum expressibility. Therefore, IPL treatment improved meibomian gland function, stabilized the tear film, and decreased ocular surface inflammation. Patients with obstructive MGD and tear instability were more likely to experience an improvement in ocular discomfort after IPL treatment.

A case of an asymptomatic intralenticular foreign body.

The purpose of this article is to report a case of an asymptomatic intralenticular metallic foreign body that was retained for 6 months. A 66-year-old male visited our ophthalmology department because of decreased visual acuity in his left eye 6 months after he suffered ocular trauma while mowing. He had not been treated because he did not experience any discomfort. His corrected visual acuity was 0.4. Central corneal opacity, an intralenticular metallic foreign body, and an intact posterior capsule were observed on slit lamp examination. Phacoemulsification with posterior chamber lens implantation and simultaneous removal of the intralenticular foreign body was performed. Seventeen days after the operation, his corrected visual acuity was 1.0, the intraocular lens was well-seated, and there was no intraocular inflammation. In this case report, a patient was found to have an intralenticular metallic foreign body retained for 6 months. During this time he did not experience any ocular dysfunction due to the foreign body. Mowing accidents are common in Korea. Despite the absence of symptoms, patients reporting a history of lawn mowing should be thoroughly examined.

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.

Inhibition of corneal neovascularization by subconjunctival and topical bevacizumab and sunitinib in a rabbit model.

PURPOSE: To compare the effects of subconjunctival injection and topical application of bevacizumab and sunitinib on experimentally induced corneal neovascularization (CNV). METHODS: CNV was induced by sutures in the right eyes of 36 rabbits. After suture removal, the rabbits were divided into 6 groups with 6 rabbits in each group. In groups 1, 2, and 3, the eyes received a subconjunctival injection of 0.1 mL of normal saline, 2.5 mg/0.1 mL of bevacizumab, and 0.25 mg/0.1 mL of sunitinib, respectively, immediately after suture removal. A booster injection of the same agent was repeated 1 week later in each group. In groups 4, 5, and 6, the eyes received topical applications of saline, bevacizumab (5 mg/mL), and sunitinib (0.5 mg/mL), respectively. These solutions were applied twice a day for 2 weeks, starting immediately after suture removal. CNV was analyzed through biomicroscopy and through histological examination using hematoxylin and eosin and CD31 immunohistochemical staining. RESULTS: On day 14, the mean percentages of areas of CNV in sunitinib-treated eyes were smaller compared with saline-treated or bevacizumab-treated eyes in both the subconjunctival (P = 0.003 and 0.032, respectively) and topical groups (P < 0.001 in both). The topical administration of sunitinib was significantly more effective than the subconjunctival injection of the same drug at 1 week (P = 0.011). Upon histological examination of samples from the topical group, sunitinib-treated eyes showed lower vascularity than saline-treated and bevacizumab-treated eyes (P = 0.036 and 0.046, respectively). CONCLUSIONS: These results suggest that sunitinib is more effective than bevacizumab for the inhibition of CNV. Furthermore, topical administration of sunitinib yields better results than a subconjunctival injection of the same medication.

The role of Nod1 signaling in corneal neovascularization.

PURPOSE: Corneal neovascularization (CNV) is associated with Chlamydia trachomatis. The minimal components of bacterial cell walls are recognized by nucleotide-binding oligomerization domain-containing protein (Nod), which is important for host defense--a mechanism manifested in human corneal cells. We aimed to examine whether Nod stimulation is associated with CNV. METHODS: Three groups of mice with alkali-induced CNV were topically treated with tripeptide L-Ala-γ-D-Glu-meso-diaminopimelic acid (Tri-DAP, a Nod1 agonist), muramyl dipeptide (a Nod2 agonist), or phosphate-buffered saline twice daily for 8 days. The time course responses were quantified using biomicroscopic examinations and immunohistochemistry. Angiogenic factor expression was evaluated by quantitative real-time reverse transcription-polymerase chain reaction. To confirm the involvement of Nod1 signaling in CNV, RICK (an essential molecule in Nod signaling)-knockout mice treated with Tri-DAP were examined biomicroscopically and immunohistochemically 8 days after injury. RESULTS: According to the biomicroscopic camera images and histology, Tri-DAP and muramyl dipeptide promoted CNV. Significantly, Tri-DAP increased the number and size of the neovascularized areas. The messenger RNA expression level of vascular endothelial growth factor was elevated in the Tri-DAP-treated mice after alkali injury. Compared with wild-type mice, CNV was attenuated in RICK-deficient mice treated with Tri-DAP. CONCLUSIONS: These data suggest that Nod1 stimulation is an important inducer of CNV and that Nod1 might be useful in the development of CNV therapies.