Current Advances in Mechanisms and Treatment of Dry Eye Disease: Toward Anti-inflammatory and Immunomodulatory Therapy and Traditional Chinese Medicine

Dry eye is currently one of the most common ocular surface disease. It can lead to ocular discomfort and even cause visual impairment, which greatly affects the work and quality of life of patients. With the increasing incidence of dry eye disease (DED) in recent years, the disease is receiving more and more attention, and has become one of the hot research fields in ophthalmology research. Recently, with the in-depth research on the etiology, pathogenesis and treatment of DED, it has been shown that defects in immune regulation is one of the main pathological mechanisms of DED. Since the non-specific and specific immune response of the ocular surface are jointly regulated, a variety of immune cells and inflammatory factors are involved in the development of DED. The conventional treatment of DED is the application of artificial tears for lubricating the ocular surface. However, for moderate-to-severe DED, treatment with anti-inflammatory drugs is necessary. In this review, the immunomodulatory mechanisms of DED and the latest research progress of its related treatments including Chinese medicine will be discussed.

A study to assess the efficacy of topical cyclosporine A 0.05% in the management of dry eye with meibomiam gland dysfunction

: Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. Meibomian Gland Dysfunction (MGD) is an abnormality of the meibomian gland that blocks the secretion of lipids. Without sufficient lipid production, tears evaporate quickly causing Dry Eye.MGD is associated with multiple pathological mechanisms including inflammation, microbial factors and lipid deficiencies. Topical Cyclosporine A (CsA) 0.05% is a calcineurin inhibitor that reduces inflammation by specifically inhibiting T‑cell activity, which reduces ocular surface inflammation and improves tear film dynamics. This was a prospective observational study done on 100 patients at the Department of Ophthalmology Basaveshwar teaching and general hospital, on patients of dry eyes due to meibomian gland dysfunction. Patients who were diagnosed with dry eyes due to meibomian gland dysfunction were invited to take part in the study. Patients were divided randomly into two groups of 50 patients each. This study, was explained in detail to them. An informed consent was obtained. Patients fulfilling the inclusion criteria were listed.All OSDI scores (symptom intensity, frequency and aggravation) revealed decreasing patterns throughout the observation period in both the groups. In single analysis, the cyclosporine A 0.05% group showed a significant improvement for each score at 3 months (p < 0.01, p = 0.01, p = 0.02, respectively). The mean TBUT after treatment in the group A (cyclosporine A group) increased to 12.36± 3.58(p<0.001) seconds, and in the group B (Control group) the TBUT score increased to 11.01±3.06 seconds. After 3 Months, there was statistically significant improvement in the mean Schirmer’s scores in both the treatment groups, however improvement was significantly greater in Cyclosporine A group. Prior to the treatment in group A (Cyclosporine A) mean Lissamine staining score was 2.73±0.15 and post treatment it reduced to 1.32±0.15 which was statistically significant (P<0.001). In group B (Control group) score before treatment was 2.46±0.15 and after treatment it reduced to 2.39±0.27 (p=0.11), not much difference was seen. : Findings from our study showed that there were significant improvements in the dry eye conditions due to defect in meibomian gland by treatment of topical Cyclosporine A 0.05% and sodium hyaluronate 0.1%.

TLR4-Dependent DUOX2 Activation Triggered Oxidative Stress and Promoted HMGB1 Release in Dry Eye

Dry eye disease (DED) is one of the most common ocular surface diseases worldwide. DED has been characterized by excessive accumulation of reactive oxygen species (ROS), following significant corneal epithelial cell death and ocular surface inflammation. However, the key regulatory factor remains unclear. In this study, we tended to explore whether DUOX2 contributed to DED development and the underlying mechanism. Human corneal epithelial (HCE) cells were treated with hyperosmolarity, C57BL/6 mice were injected of subcutaneous scopolamine to imitate DED. Expression of mRNA was investigated by RNA sequencing (RNA-seq) and quantitative real-time PCR (qPCR). Protein changes and distribution of DUOX2, high mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), and 4-hydroxynonenal (4-HNE) were evaluated by western blot assays and immunofluorescence. Cell death was assessed by Cell Counting Kit-8 (CCK8), lactate dehydrogenase (LDH) release, and propidium iodide (PI) staining. Cellular ROS levels and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. RNA-seq and western blot assay indicated a significant increase of DUOX2 dependent of TLR4 activation in DED both in vitro and in vivo. Immunofluorescence revealed significant translocation of HMGB1 within corneal epithelial cells under hyperosmolar stress. Interestingly, after ablated DUOX2 expression by siRNA, we found a remarkable decrease of ROS level and recovered MMP in HCE cells. Moreover, knockdown of DUOX2 greatly inhibited HMGB1 release, protected cell viability and abolished inflammatory activation. Taken together, our data here suggest that upregulation of DUOX2 plays a crucial role in ROS production, thereafter, induce HMGB1 release and cell death, which triggers ocular surface inflammation in DED.

Does the Conjunctivochalasis Accompanied by Pseudoexfoliation Syndrome Affect the Ocular Surface and Anterior Segment Structures?

Purpose: Probability of coexistence of conjunctivochalasis and pseudoexfoliation syndrome (PES) in same individual may increase with aging. We investigated effects of conjunctivochalasis accompanied by PES on ocular surface (OS) and anterior segment (AS) structures.Methods: Cases with only conjunctivochalasis were determined as group-1 (n=62), cases with conjunctivochalasis accompanied by PES as group-2 (n=45), and healthy cases as group-3 (n=56). OS and AS parameters of groups were compared.Results: Compared to group-1, group-2 had higher grade-3 conjunctivochalasis (17.7% vs 46.7%, p=0.039), greater mean grade of conjunctivochalasis (MGC) (1.72±0.24 vs 2.29±0.32, p=0.036), higher total conjunctivochalasis score (TCS) (4.27±1.13 vs 6.12±1.35, p=0.025), shorter tear-film break-up time (TBUT) (9.17±2.53 vs 5.41±1.32, p=0.010), greater OS disease index (OSDI)-score (16.28±3.15 vs 27.36±4.12, p=0.037). Compared to group-3, both group-1 and group-2 had shorter TBUT (group 3-1: p=0.004; group 3-2: p<0.001) and greater OSDI score (group 3-1: p=0.042; group 3-2: p=0.019). Schirmer tests, central corneal thicknesses, keratometries, axial lengths, anterior chamber depths and lens thicknesses of groups were similar (p>0.05). In group-1 and group-2, as age increased, both MGC (r=0.349, p=0.043; r=0.403, p=0.022, respectively) and TCS (r=0.322, p=0.046; r=0.372, p=0.031) increased. In group-2, as both MGC and TCS increased, TBUT (r=-0.370, p=0.034; r=-0.401, p=0.025) decreased and OSDI score (r=0.338, p=0.045; r=0.362, p=0.040) increased.Conclusions: To our knowledge, this was the first study comprehensively investigating effects of conjunctivochalasis accompanied by PES on OS and AS structures together. We found that conjunctivochalasis might cause OS disease, while presence of PES in conjunctivochalasis cases might worsen OS disease and conjunctivochalasis findings.

Comparison of cytotoxicity effects induced by four different types of nanoparticles in human corneal and conjunctival epithelial cells

The impact of particulate matter (PM) on ocular surface health has attracted increased attention in recent years. Previous studies have reported that differences in the chemical composition of PM can affect the toxicological response. However, available information on the toxic effects of chemical components of PM on the ocular surface is insufficient. In this paper, we aimed to investigate the toxicity effects of chemical components of PM on the ocular surface, focusing on the effects of four different types of nanoparticles (NPs) in human corneal epithelial cells (HCECs) and human conjunctival epithelial cells (HCjECs), which include titanium dioxide (TiO2), carbon black (CB), zinc dioxide (ZnO), and silicon dioxide (SiO2). We found that the in vitro cytotoxic effects of CB, ZnO, and SiO2 NPs are dependent on particle properties and cell type as well as the exposure concentration and time. Here, the order of increasing toxicity was SiO2 → CB → ZnO, while TiO2 demonstrated no toxicity. Moreover, toxic effects appearing more severe in HCECs than HCjECs. Reactive oxygen species (ROS)-mediated oxidative stress plays a key role in the toxicity of these three NPs in HCECs and HCjECs, leading to apoptosis and mitochondrial damage, which are also important contributors to aging. Sirtuin1 (SIRT1) as an NAD+-dependent protein deacetylase that seems to play a potential protective role in this process. These findings implied that ROS and/or SIRT1 may become a potential target of clinical treatment of PM- or NP-related ocular surface diseases.

A multi-parameter grading system for optimal fitting of scleral contact lenses

Background: While scleral lens practise has improved over the years due to factors such as availability of lenses with better materials and designs as well as experience of practitioners, a lack of objectivity appears to remain in terms of assessment of scleral lens fitting. This prospective observational work aimed to achieve standardization on this front through proposing a grading system for scleral lens fitting. Methods: After application of prosthetic replacement of ocular surface ecosystem (PROSE) devices on the participants’ eyes, four fundamental components for understanding scleral lens fitting such as central and limbal corneal clearance, mid-haptic compression, and alignment of lens edge over anterior sclera were assessed through a series of slit-lamp biomicroscopy imaging as well as with anterior segment optical coherence tomography. FitConnect® was used to modify the device parameters to simulate different grading patterns on the proposed scale. Serial imaging was done for all the different lenses to compose the grading scale. Results: A clinically relevant grading scale was constructed that pictorially demonstrated grades for the different aspect of scleral lens fitting. The grades were conveniently scaled within three categories: “optimal”, “acceptable” and “not acceptable”. Conclusion: The gradation of scleral lens fitting parameters would take a step towards objectifying the assessment patterns in practise. This will also help reducing the gap between a novice and an experienced practitioner in terms of understanding of scleral lens fitting.

Modified Tectonic Corneoscleral Graft For Management of Devastating Corneoscleral Infections

Purpose To analyze the clinical results and the efficacy of modified tectonic corneoscleral graft (TCG) in patients with devastating corneoscleral infections.Methods Twenty-five eyes from 25 patients who underwent modified TCG were enrolled. The recurrence, best-corrected visual acuity (BCVA), ocular surface stability, postoperative complications and graft survival condition were recorded.Results Among 25 patients, 19 cases were fungal infection and 6 cases were bacterial. The rate of recurrence was 8% with Pythium Insidiosum as a corresponding pathogen. The rate of monocular blindness declined from 100% to 57%. Changes in BCVA from preoperative to postoperative values were significant ( Z=4.22, P＜0.001). The survival of ocular surface stability was 73.6% and 43.9% at 1 and 3 years after surgery, respectively. Within the mean follow-up period of 17.5 ± 8.9 months, 21eyes (84.0%) had a stable ocular surface. The incidence rate of immune rejection was 36%. Corneal epithelial defects occurred in 7 patients and choroidal detachment occurred in 3 patients. No elevation of intraocular pressure was detected.Conclusions The modified TCG is effective in eradicating infection, salvaging the eyeball and saving some useful vision for devastating corneoscleral infections. Regular application of tacrolimus, timely addition of glucocorticoid and good compliance may decrease the postoperative course challenging.

Analysis of the first tear film break-up point in Sjögren’s syndrome and non-Sjögren’s syndrome dry eye patients

Background Tear film instability plays an important role in the course of Sjögren’s Syndrome dry eye (SSDE) even though it is generally classified as aqueous-deficient dry eye. The measurement of the first tear film break-up point (FTBUP) helps to evaluate the most unstable position of the tear film on ocular surface. We aim to investigate FTBUP in Sjögren’s Syndrome dry eye (SSDE) and non-Sjögren’s Syndrome dry eye (NSSDE) patients, and explore its correlation with dry eye indices. Methods Twenty-two SSDE patients (44 eyes) and 22 NSSDE patients (44 eyes) were enrolled in the study. Oculus Keratograph K5M was used to measure FTBUP, the first and average non-invasive keratographic breakup time (f-NIKBUT and av-NIKBUT), the tear meniscus height, and meibomian gland dropout. Other tests of tear film were also performed including Ocular Surface Dryness Index (OSDI), Schirmer I test, fluorescein break-up time and corneal fluorescein staining. Dry eye indices and the locations of the FTBUP were compared between SSDE and NSSDE patients. Generalized estimating equation (GEE) was used to ajusted the correlations between right and left eyes. The correlations between the FTBUP and ocular symptoms and signs were investigated using Pearson’s correlation coefficient test. Results The FTBUP occurred at the supranasal quadrant in 12/88 eyes, supratemporal quadrant in 8/88 eyes, inferonasal quadrant in 34/88 eyes, and inferotemporal quadrant in 34/88 eyes. The percentage eyes with inferior FTBUP was significantly higher in the SSDE than in the NSSDE subjects (86.3% vs 68.1%, P = .049). Moreover, in SSDE subjects, temporal breakup point was seen more often in those who presented corneal fluorescein staining in any location, while nasal breakup point was more frequent in those who did not present any corneal fluorescein staining (P = .045). Conclusion The location of the FTBUP in SSDE patients had specific characteristics. However, the diagnostic potential of FTBUP in early recognition of SSDE needs further validation.

INTENSE PULSED LIGHT (IPL) TREATMENT FOR DUPILUMAB INDUCED OCULAR SURFACE DISEASE (DIOSD)

PurposeTo report a case of dupilumab induced ocular surface disease (DIOSD) managed with intense pulsed light (IPL) as an effective adjunct therapy to topical steroids and topical immunomodulator lifitegrast.MethodsDiscussion of a patient’s case with accompanying anterior segment and meibography photos with diagnosed DIOSD for which adjunct therapy with IPL was an effective treatment after limited relief from and difficulty with adherence to traditional treatment with topical steroids and lifitegrast ophthalmic solutions. ConclusionThis case demonstrates the complexity of management required to treat patients with DIOSD and its chronic nature. IPL as a nonpharmaceutical adjunct therapy to topical steroids and immunomodulators in the treatment of DIOSD showed improved signs and symptoms of DIOSD.