Eyelid blood vessel and meibomian gland changes in a sclerodermatous chronic GVHD mouse model.

PURPOSE: To investigate pathological changes in blood vessels and meibomian glands (MGs) in the eyelids of sclerodermatous chronic graft-versus-host disease (cGVHD) model mice. METHODS: We used an established major histocompatibility complex compatible, multiple minor histocompatibility antigen-mismatched sclerodermatous cGVHD mouse model. Blood vessels and MGs of eyelids from allogeneic bone marrow transplantation (allo-BMT) recipient mice and syngeneic bone marrow transplantation (syn-BMT) recipient mice were assessed by histopathology, immunohistochemistry and transmission electron microscopy. Peripheral blood samples from the recipients were examined by flow cytometry. RESULTS: Allo-BMT samples showed dilating, tortuous and branching vessels and shrunk MGs in the eyelids; showed significantly higher expression of VEGFR2 (p = 0.029), CD133 (p = 0.016), GFP (p = 0.006), and α-SMA (p = 0.029) in the peripheral MG area; showed endothelial damage and activation, fibrotic change, and immune cell infiltration into MGs compared with syn-BMT samples. Fewer Ki-67+ cells were observed in allo- and syn-BMT samples than in wild-type samples (p = 0.030). Ultrastructural changes including endothelial injury and activation, fibroblast activation, granulocyte degranulation, immune cell infiltration into MGs, and necrosis, apoptosis of MG basal cells were found in allo-BMT samples compared with syn-BMT samples. CONCLUSION: A series of our studies indicated that cGVHD can cause eyelid vessel and MGs changes, including endothelial injury and activation, neovascularization, early fibrotic changes, immune cell infiltration, MG basal cell necrosis and apoptosis, and resultant MG atrophy.

Long-Term Topical Diquafosol Tetrasodium Treatment of Dry Eye Disease Caused by Chronic Graft-Versus-Host Disease: A Retrospective Study.

OBJECTIVES: The aim of this study was to assess the safety and efficacy of long-term use of 3% diquafosol ophthalmic solution (DQS), an eye drop for mucin production and water secretion, for treating dry eye disease (DED) caused by chronic graft-versus-host disease (cGVHD). METHODS: We retrospectively evaluated the safety and efficacy of DQS in 10 patients with mild to moderate cGVHD-induced DED. The efficacy was assessed by (1) degree of symptoms, (2) Schirmer I test value, (3) tear film breakup time (TFBUT), and (4) fluorescein and rose bengal scores. RESULTS: The median duration of DQS treatment was 12.0 months (range 6-17 months). DQS was effective for relieving severe pain caused by cGVHD-related DED. Although the Schirmer I test value was enhanced only marginally, the long-term application of DQS significantly improved the corneal/conjunctival epitheliopathy and tear film stability: the fluorescein score improved from 5.9±0.6 to 1.3±1.1 points (P=1.771×10); rose bengal staining from 4.7±1.6 to 2.0±1.5 points (P=0.008); and TFBUT from 2.6±0.9 to 4.6±1.6 mm (P=0.009). Furthermore, the long-term DQS treatment caused no major adverse events. CONCLUSIONS: This study suggested that long-term DQS treatment is a safe and robust approach for alleviating cGVHD-related DED.

In Vivo Confocal Microscopy Evaluation of Ocular Surface with Graft-Versus-Host Disease-Related Dry Eye Disease.

Dry eye disease (DED) is often elicited by graft-versus-host disease (GVHD), an extensive complication of hematopoietic stem cell transplantation (HSCT). To unravel the mechanism of this type of DED, in vivo confocal microscopy (IVCM) was used to investigate alterations in the state of the sub-basal nerves, dendritic cells (DCs) and globular immune cells (GICs) in the central cornea and limbal epithelia. In this study, we examined 12 HSCT recipients with GVHD-caused DED and 10 HSCT recipients without GVHD-associated DED and evaluated the clinical parameters in the 2 groups. Analysis of the central cornea and limbal epithelia using IVCM was conducted to investigate the density of the corneal sub-basal nerves, DCs and GICs as well as the tortuosity and branching of the sub-basal nerves. As suggested by our data, the clinical variables in the GVHD group were significantly different from those in the non-GVHD group. Additionally, GVHD-triggered DED conceivably increased the density of DCs and GICs in the central cornea and the density of DCs in limbal epithelia and altered the morphology of the sub-basal nerves. These phenomena are presumably correlated with the degree of inflammation. Thus, our findings may be translated into non-invasive diagnostic methods that indicate the severity of inflammation on the ocular surface in HSCT recipients.

Effectiveness of bandage contact lens application in corneal epithelialization and pain alleviation following corneal transplantation; prospective, randomized clinical trial.

BACKGROUND: To assess the efficacy of bandage contact lens (BCL) application to promote epithelialization and alleviate pain following corneal transplantation. METHODS: Twenty-six consecutive patients who underwent corneal transplantation were randomly assigned to undergo BCL application (BCL group, n = 14) or no BCL application (control group, n = 12) at the end of the surgery. Corneal epithelialization was analyzed by photography using fluorescein staining, and ocular pain was measured using a visual analog scale. RESULTS: The mean size of the epithelial defect relative to the graft area in the BCL group was 21.80 ± 35.10 % at the end of surgery, 18.20 ± 31.10 % on postoperative day 1, and 5.45 ± 11.10 % on postoperative days 3 to 5. These values in the control group were 9.64 ± 17.60 % at the end of surgery, 11.50 ± 25.70 % on postoperative day 1, and 0.00 ± 0.00 % on postoperative days 3 to 5. There were no significant differences in the speed of epithelialization between the two groups. The mean preoperative pain score in the BCL group was slightly higher than that control (4.27 ± 1.96 vs. 2.41 ± 2.18, respectively; P = 0.039). The scores significantly increased on postoperative day 1 and promptly returned to preoperative levels by day 7 in both groups, and there were no significant differences between the groups. CONCLUSIONS: No significant benefits of BCL application at the time of corneal transplantation were observed in this study. The efficacy and safety of BCLs in eyes with compromised epithelialization require further study. TRIAL REGISTRATION NUMBER: UMIN 000019091 . Date of registration: 2015/09/22.

Long-term rebamipide and diquafosol in two cases of immune-mediated dry eye.

PURPOSE: Two new drugs with mucin-inducing and secretion-promotive effects, rebamipide and diquafosol, were recently approved as topical dry-eye treatments. We report two cases in which the long-term use of mucin-inducing eye drops improved chronic ocular graft-versus-host disease (cGVHD)-related dry eye and ocular cicatricial pemphigoid (OCP)-like disease. CASE REPORTS: Case 1. A 61-year-old woman had cGVHD-related dry eye that resisted traditional medications. Next, we use topical diquafosol in addition to conventional treatments. The patient used diquafosol for 6 months without experiencing any side effects. The symptoms, including dry-eye sensation, ocular pain, foreign body sensation, and photophobia, as well as ocular surface findings including fluorescein and rose bengal scores and tear break-up time (TBUT), partly improved. To further improve the clinical signs and symptoms and decrease chronic inflammation, rebamipide was added to diquafosol. The symptoms, TBUT, and fluorescein and rose bengal scores markedly improved after long-term dual treatment without any side effects for 6 months. Case 2. A 77-year-old woman had OCP-like disease with dry eye. The patient did not improve using the currently available conventional treatments. Next, we use topical rebamipide in addition to conventional treatments. Symptoms including asthenopia, dry-eye sensation, ocular pain, and dull sensation, as well as fluorescein and rose bengal scores and TBUT, partly improved. Specifically, functional visual acuity was markedly improved after commencement of rebamipide. To further improve the clinical signs and symptoms and increase tear film stability and tear film volume, diquafosol was added to rebamipide. The combination of diquafosol and rebamipide worked for the patient. Improvements were seen in several symptoms, fluorescein and rose bengal scores, Schirmer test value, and TBUT without any side effects for 12 months. CONCLUSIONS: Long-term treatment with topical rebamipide and diquafosol can improve dry eye in patients with cGVHD or OCP-like disease.

Grading criteria for chronic ocular graft-versus-host disease: comparing the NIH eye score, Japanese dry eye score, and DEWS 2007 score.

Ocular graft-versus-host disease (GVHD) is a common complication after hematopoietic stem cell transplantation (HSCT). Here we compared the diagnostic rates of ocular GVHD, including its severity, prognosis and the agreement, obtained using three grading scales: the National Institutes of Health (NIH) eye score, Japanese dry eye score, and dry eye workshop score, by retrospectively reviewing the records of 82 patients who underwent HSCT. Tear dynamics and ocular surface assessments made 6-9 months after HSCT were used to determine ocular GVHD severity with the three scales. By the three scales, ocular GVHD was diagnosed in 56 patients (68.3%), 51 patients (62.2%), and 52 patients (63.4%), respectively. The Kappa coefficient was calculated to determine the agreement between scales for diagnosing ocular GVHD. The severity progression within two years after onset was also assessed by tear dynamics and ocular surface examination. The patients were categorized as no change, improved, or progressive. The three grading scales showed good agreement (Kappa = 0.87 to 0.97) in diagnosing patients with ocular GVHD, and the scores by all three were significantly associated with the patients' prognosis (p < 0.01). We recommend that multi-center research is needed for further validation and investigation.