Long-term clinical outcomes and predictive factors in patients with chronic ocular graft-versus-host disease.

We investigate long-term clinical outcomes and predictive factors associated with poor vision outcomes in patients with ocular graft-versus-host disease (oGVHD). This retrospective cohort study involved 94 patients with chronic oGVHD, classified into severe (n = 25) and non-severe (n = 69) groups. Factors associated with oGVHD severity and poor vision outcomes were examined using multivariate logistic regression. In the severe oGVHD group, the disease activity pattern tended to be persistent, whereas flare-up episodes were more frequent and occurred over shorter intervals in this group. Myelodysplastic syndrome (MDS) and lung GVHD were more common and systemic calcineurin inhibitors were used more frequently in the severe group than in the non-severe group. Finally, 5-year survival rates were poorer in the severe group. Multivariate analysis revealed that MDS, lung GVHD involvement, and no history of systemic calcineurin inhibitor use were risk factors for severe oGVHD. Risk factors for poor vision outcomes were conjunctival scarring and persistent epithelial defects. In conclusion, MDS, lung GVHD, and no history of systemic calcineurin inhibitors are associated with severe oGVHD. Conjunctival scarring and persistent epithelial defects are risk factors for poor vision outcomes.

Effects of eye drops containing a mixture of 3% diquafosol sodium and tocopherol acetate (vitamin E) on the ocular surface of murine dry eye.

PURPOSE: To investigate the efficacy of topical application of 3% diquafosol sodium (DQS) and tocopherol (TCP) acetate mixtures in a mouse model of experimental dry eye (EDE). METHODS: After exposure to desiccating stress for 5 days, eye drops consisting of 3% DQS alone, 0.01% TCP alone, or 3% DQS and 0.005% or 0.01% TCP mixture were applied for the treatment of EDE. Tear volume, tear film break-up time (TBUT), corneal fluorescein staining scores (CFSS), and tear film lipid layer grades (TFLLG) were measured at 0, 5 and 10 days after treatment. The 2',7'-dichlorodihydrofluorescein diacetate assay (DCFDA) for reactive oxygen species (ROS) production, enzyme-linked immunosorbent assay (ELISA) for malondialdehyde (MDA), and flow cytometry for CD4 + interferon (IFN)-γ+ T cells were evaluated on the ocular surface at 10 days after treatment. In addition, levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and chemokine CC motif ligand 4 (CCL4) in the conjunctiva were measured using a multiplex immunobead assay, and conjunctival goblet cells were counted by periodic acid-Schiff staining at 10 days after treatment. RESULTS: Both the TCP mixture groups indicated a significant improvement in TBUT, ROS production, and MDA concentrations compared to those in the DQS alone group. Furthermore, the 0.01% TCP mixture group also showed higher tear film lipid layer grades and conjunctival goblet cell density and lower corneal fluorescein staining scores, number of CD4 + IFN-γ+ T cells, and levels of TNF-α, IL-1ß, and CCL4 than the DQS alone group (P < 0.05). CONCLUSIONS: Application of eye drops containing the mixture of DQS and TCP could stabilize the tear film lipid layer, improve TBUT and corneal epithelial damages, decrease ROS production, inflammatory molecules, and T cells, and increase conjunctival goblet cell density on the ocular surface. Topical DQS and TCP mixtures may have a greater therapeutic effect on clinical signs, oxidative damage, and inflammation of dry eye than DQS eye drops.

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.

Effects of Eurya japonica extracts on human corneal epithelial cells and experimental dry eye.

Eurya japonica (EJ) leaves have been indicated to exert anti-oxidative and anti-inflammatory effects. Dry eye disease (DED) is a chronic inflammatory disease and oxidative stress is closely associated with DED. The aim of the present study was to analyze the therapeutic efficacy of EJ in DED using human corneal epithelial (HCE) cells and a mouse model of experimental dry eye (EDE). EJ extracts (0.001, 0.01 and 0.1%) were used to treat HCE cells. Cell viability and mitochondrial function were detected using a EZ-Cytox cell viability assay kit and mitochondrial membrane potential assays. Dichlorofluorescein diacetate (DCF-DA) assay was used to measure cellular reactive oxygen species (ROS) levels. Subsequently, eye drops consisting of BSS or 0.001%, 0.01 and 0.1% EJ extracts were applied for treatment of EDE. At 7 days, conjunctival ROS production was measured using a DCF-DA assay. Tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, 10 kDa interferon gamma-induced protein 10 (IP-10) and monokine induced by interferon-γ (MIG) levels in the conjunctiva were analyzed using a multiplex immunobead assay. Tear film and ocular surface parameters were measured. Treatment with EJ extracts in HCE cells effectively improved cell viability, ROS levels and mitochondrial function. Mice treated with 0.01 and 0.1% EJ extracts indicated a significant decrease in ROS, TNF-α, IL-1ß, IP-10 and MIG levels compared with the EDE or BSS groups. Furthermore, a significant improvement in all clinical parameters was observed in the 0.01 and 0.1% EJ extract groups. EJ extracts could decrease cytotoxicity and ROS production in HCE cells. Additionally, topical EJ extracts reduced oxidative damage and inflammation and improved clinical signs of EDE, suggesting that EJ extracts may be used as an adjunctive therapy for DED.

Anti-inflammatory effects of glycine thymosin ß4 eye drops in experimental dry eye.

The aim of the present study was to investigate the anti-inflammatory effects of glycine thymosin ß4 (Gly-Tß4) eye drops, and to compare the efficacy of topical Gly-Tß4 with Cyclosporine A (CsA) in a mouse model of experimental dry eye (EDE). Eye drops consisting of balanced salt solution (BSS), 0.1% Gly-Tß4 or 0.05% CsA were used for treatment of EDE. Tear volume, tear film break-up time and corneal staining scores were measured after 7 and 14 days. Periodic acid-Schiff staining for conjunctival gobleT cells, TUNEL assay for corneal apoptotic positive cells, multiplex immunobead assay for interleukin (IL)-1ß, IL-6, tumor necrosis factor-α and interferon-γ levels, and flow cytometry for CD4+/CCR5+ T cells were performed after 14 days. All clinical parameters showed improvement in the Gly-Tß4 and CsA groups (all P<0.05). Significantly increased conjunctival gobleT cells and decreased corneal TUNEL positive cells were observed in the Gly-Tß4 and CsA groups. The Gly-Tß4 and CsA treated groups showed significantly reduced inflammatory cytokine levels and T cells in the conjunctiva compared with the EDE and BSS groups (all P<0.05). However, there were no significant differences observed in the inflammatory and clinical parameters between the Gly-Tß4 and CsA treatment groups. Topical application of 0.1% Gly-Tß4 significantly reduced inflammation on the ocular surface, as well as clinical parameters of EDE, with a similar efficacy to that of 0.05% CsA emulsions, suggesting that Gly-Tß4 eye drops may be used as a therapeutic agent for treatment of dry eye disease.

Effect of epidermal growth factor ointment on persistent epithelial defects of the cornea.

BACKGROUND: Healthy corneal epithelium acts as a barrier against damage to the deeper structures in the eye. Failure in the mechanisms of corneal epithelization can lead to persistent epithelial defects of the cornea (PEDs) and can compromise its function. Epidermal growth factor (EGF) promotes the proliferation, migration, and differentiation of epithelial cells, endothelial cells, and fibroblasts during wound healing and may be beneficial in treating patients with PEDs. We, therefore, investigated the effect of EGF ointment on patients with PEDs. METHODS: Fifteen patients with PEDs refractory to conventional treatment were treated twice a day with EGF ointment. Patient demographics and comorbidities were noted. The epithelial healing time was determined along with the primary outcome measures in the areas of the epithelial defects, visual acuity, visual analog scale (VAS) scores, and esthesiometer scores 1 month and 2 months after treatment. RESULTS: Five eyes of herpetic keratitis (33.3%), 3 eyes of dry eye disease (20.0%), 3 eyes of bacterial keratitis (20.0%), 2 eyes of limbal stem cell deficiency (13.3%), 1 eye of diabetic neurotrophic keratitis (6.7%), and 1 eye of filamentary keratitis (6.7%) were associated with PEDs, respectively. Two months following treatment with EGF ointment, there was a reduction in the area of the epithelial defects (5.7 ± 3.9 to 0.1 ± 0.3 mm2) as well as a significant improvement in best-corrected visual acuity (0.9 ± 0.8 to 0.6 ± 0.5 LogMAR) and VAS scores (4.5 ± 1.2 to 2.5 ± 0.7) in 12 eyes (80%). Among these cases, the mean epithelial healing time was 5.5 ± 1.8 weeks. Amniotic membrane transplantation was performed on the remaining 3 (20.0%) patients that did not respond to EGF treatment. CONCLUSIONS: EGF ointment could reduce symptoms and promotes corneal epithelialization of refractory PEDs. It may, therefore, be well-tolerated and a potentially beneficial addition in the management of refractory PEDs.

Therapeutic Effect of Topical Adiponectin-Derived Short Peptides Compared with Globular Adiponectin in Experimental Dry Eye and Alkali Burn.

Purpose: To evaluate the efficacy of adiponectin (APN)-derived short peptides (ADPs) 355 compared with globular APN in a mouse model of experimental dry eye (EDE) and corneal alkali burn. Methods: EDE and chemical burn were induced in C57BL/6 mice by desiccating stress and application of NaOH, respectively. Eye drops consisting of 0.01% globular APN, 0.01% ADPs, 0.1% ADPs, or balanced salt solution (BSS) were applied. Tear volume, tear film break-up time, and corneal staining scores were measured. Concentrations of interleukin (IL)-1ß, interferon (IFN)-γ, IL-6, CXCL-9, and CXCL-10 using multiplex immunobead assay were evaluated, and flow cytometry were performed. Corneal epithelial defects and haze degree were analyzed, and enzyme-linked immunosorbent assay for IL-1ß and transforming growth factor (TGF)-ß levels were observed. Results: All treatment groups showed an improvement in clinical parameters and CD4+CCR5+ T cell and CD11b+ cell infiltrations in the conjunctiva (all P < 0.05). Both ADPs groups had significantly decreased concentrations of IL-1ß, IFN-γ, IL-6, CXCL-9, and CXCL-10 in the conjunctiva than the EDE or BSS group. Significantly improved parameters of epithelial defect, degree of haze, and concentrations of IL-1ß and TGF-ß were observed in all treatment groups. However, no significant differences were noted in clinical or experimental parameters among treatment groups. Conclusion: Topical ADPs could effectively improve clinical signs and inflammation of ocular surface in the EDE or alkali burn, and its efficacy and potency were similar to those of globular APN.

Expression of Nod-like Receptors and Clinical Correlations in Patients With Dry Eye Disease.

PURPOSE: To investigate the expression pattern of nucleotide-binding oligomerization domain (Nod)-like receptors that detects "danger" intracellular signaling and its correlation with clinical dry eye (DE) markers. DESIGN: Cross-sectional study. METHODS: A total of 50 participants with 50 eyes were included: 23 eyes with Sjögren syndrome (SS)-DE, 14 eyes with non-SS-DE, and 13 healthy controls with non-DE. Ocular Surface Disease Index (OSDI) was self-answered and clinical tests including the tear film breakup time (TBUT), Schirmer test, and corneal fluorescein staining (CFS) were performed. Specimens for expression pattern analysis were obtained by conjunctival impression cytology and biopsy. Nod-1, inhibitor kappa B kinase-alpha (IκKα), and nuclear factor kappa B (NF-κB) expression was determined by reverse transcription quantitative real-time polymerase chain reaction and Western blot. Correlations between Nod-1 and ocular surface parameters were determined. RESULTS: Patients with SS-DE had significantly higher OSDI and CFS scores and lower TBUT and Schirmer test scores than those with non-SS-DE patients (all P < .05). Compared with the control group, both the SS-DE and non-SS-DE groups showed significant upregulation in mRNA expression levels of Nod-1 (relative 3.48-fold and 1.72-fold upregulation, respectively, P < .01), IκKα (relative 1.83-fold and 1.24-fold upregulation, respectively, P < .01), and NF-κB (relative 1.84-fold and 1.32-fold upregulation, respectively, P < .01). Western blot analysis showed that Nod-1 protein expression increased in both the SS-DE and non-SS-DE groups (relative 2.71-fold and 1.64-fold upregulation, respectively, P < .05) compared with that in the control group. Similar findings were observed for IκKα and NF-κB. In DE participants, the expression of Nod-1 significantly correlated with the OSDI (R2 = 0.61, r = 0.78, P < .01), Schirmer test score (R2 = 0.44, r = -0.66, P < .01), and CFS (R2 = 0.46, r = 0.68, P < .01) but did not significantly correlate with TBUT (R2 < 0.01, r = 0.08, P = .66). CONCLUSIONS: Nod-1 expression was increased in the conjunctiva of DE, especially SS-DE, and was associated with disease severity. Expression of Nod-like receptors might play an important role in initiating the inflammatory response in DE.

Effectiveness of photodynamic therapy with verteporfin combined with intrastromal bevacizumab for corneal neovascularization in Stevens-Johnson syndrome.

PURPOSE: To investigate the effectiveness of combined photodynamic therapy with verteporfin and intrastromal injection of bevacizumab for the treatment of corneal neovascularization in patients with Stevens-Johnson syndrome (SJS). METHODS: Eight eyes of eight patients with SJS having corneal neovascularization who were refractory to 1% prednisolone instillation received photodynamic therapy with verteporfin (6 mg/m2) combined with intrastromal bevacizumab injection (2.5 mg/0.1 mL). Best-corrected visual acuity and intraocular pressure were assessed, and slit-lamp biomicroscopic examination was performed before treatment and at 1 week and every month. A chronic ocular manifestation score was assigned based on the involvement area or the severity before treatment. The cumulative length of corneal blood vessels and area of corneal neovascularization were measured by anterior segment photographs before and after treatment. RESULTS: At 3 and 6 months after treatment, all eyes showed regression of corneal neovascularization. Complete regression was achieved in five eyes (62.5%) and partial regression in three eyes (37.5%). Among five patients who were followed up for more than 1 year, two eyes maintained complete regression and one eye maintained partial regression at 1 year. However, two eyes with severe chronic ocular manifestation showed revascularization. CONCLUSIONS: Combined photodynamic therapy with intrastromal bevacizumab injection can effectively inhibit corneal neovascularization in patients with SJS. However, patients with severe chronic ocular manifestation may exhibit revascularization.