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.

miR-204–containing exosomes ameliorate GVHD-associated dry eye disease

MSC-exo eye drops alleviate GVHD-associated dry eye disease by shifting M1 macrophages to M2 via miR-204.

Comparison of Relapsing Polychondritis Patients with and Without Respiratory Involvement Based on Chest Computed Tomography: A Retrospective Cohort Study

Background Relapsing polychondritis (RP) patients with tracheal cartilage involvement are different from other patients. The objectives of this study were to compare the clinical features and disease patterns between respiratory involvement subgroup and non-respiratory involvement subgroup according to chest computed tomography. Method We performed a retrospective cohort study collected RP patients hospitalized at the Beijing Chao-Yang Hospital between January 2012 - August 2021. Results The incident of costochondritis was more frequent in RP patients with respiratory involvement(p=0.03), the incidence of inflammatory eye disease(p=0.001) and auricular chondritis(p=0.001) was less frequent in RP respiratory involvement patients, compared with those of RP patients without respiratory involvement. Correlation analysis showed that a negative correlation between respiratory involvement and auricular chondritis (r=-0.58, p < 0.01), and between respiratory involvement and inflammatory eye disease (r=-0.45, P < 0.01). Auricular chondritis was positively correlated with inflammatory eye disease (r=0.49, P < 0.01). Compared with non-respiratory involvement subgroup, the incidence of pulmonary infection marginally increased in respiratory involvement subgroup(p=0.06). Inflammatory indexes except for CAR were significantly higher in respiratory involvement subgroup, subgroup analysis found that there was no significant relationship between inflammatory indexes and pulmonary infection. Conclusion RP patients with respiratory involvement was characterized by higher rate of costochondritis and pulmonary infection, fewer inflammatory eye disease and auricular chondritis compared to non-respiratory involvement. Increase inflammatory indexes may suggested that patients with respiratory involvement had a higher disease activity index of RP. The probability of survival was not significant between two subgroups.

A Tear Metabolomic Profile Showing Increased Ornithine Decarboxylase Activity and Spermine Synthesis in Thyroid-Associated Orbitopathy

About half of patients with Graves’ disease develop an orbitopathy related to an inflammatory expansion of the periorbital adipose tissue and muscles. We used a targeted metabolomic approach measuring 188 metabolites by mass spectrometry to compare the metabolic composition of tears in patients with active (n = 21) versus inactive (n = 24) thyroid-associated orbitopathy. Among the 44 metabolites accurately measured, 8 showed a significant alteration of their concentrations between the two groups. Two short-chain acylcarnitines, propionylcarnitine and butyrylcarnitine, and spermine showed increased concentrations in the tears of patients with active orbitopathy, whereas ornithine, glycine, serine, citrulline and histidine showed decreased concentrations in this group. In addition, the ratio putrescine/ornithine, representing the activity of ornithine decarboxylase, was significantly increased in patients with active compared to inactive orbitopathy (p = 0.0011, fold change 3.75). The specificity of this candidate biomarker was maintained when compared to a control group with unclassified dry eye disease. Our results suggest that the stimulation of ornithine decarboxylase by TSH receptor autoantibodies in orbital fibroblasts could lead to increased synthesis of spermine, through the increased activity of ornithine decarboxylase, that may contribute to periorbital expansion in Graves’ ophthalmopathy.

Benefits and Safety of Astaxanthin in the Treatment of Mild-To-Moderate Dry Eye Disease

Objectives: To evaluate the effect of astaxanthin in the treatment of mild-to-moderate dry eye disease (DED) in middle-aged and elderly patients.Methods: 120 eyes of 60 middle-aged and elderly patients with mild-to-moderate DED were enrolled in this prospective, one-group, quasi-experimental study. Six milligram Astaxanthin tablets (Weihong Haematococcus Pluvialis Astaxanthin, Hangzhou Xinwei Low Carbon Technology R&amp;D Co., Ltd., China) were administered orally, twice daily for 30 ± 2 days. History of eye diseases, treatment, systemic disease, and medication before the test were recorded. In addition, the ocular surface disease index (OSDI) questionnaire, non-invasive tear break-up time (NIBUT), fluorescein break-up time (FBUT), corneal fluorescein staining (CFS) score, eyelid margin signs, meibomian gland (MG) expressibility, meibum quality, meibomian gland dropout (MGDR), Schirmer I test (SIt), tear meniscus height (TMH), bulbar conjunctiva congestion degree, blink frequency, incomplete blink rate, and thickness of tear film lipid layer were collected before treatment, 2 weeks after the initiation of treatment, and at the end of treatment. Visual acuity (VA), intraocular pressure (IOP), anterior segment, fundus, discomfort symptoms and other adverse reactions were also monitored throughout the study to assess the safety.Results: OSDI score, NIBUT, BUT, CFS score, eyelid margin signs, MG expressibility, meibum quality, and blink frequency improved significantly to varying degrees after treatment compared with those before the treatment (P &lt; 0.05), while TMH, SIt, conjunctival congestion, the thickness of tear film lipid layer, MGDR, incomplete blink rate, VA and IOP did not differ (P &gt; 0.05).Conclusions: Oral administration of astaxanthin improves the symptoms and signs of middle-aged and elderly patients with mild-to-moderate DED.

Reducing omission of eye drops during hospital admission

Background/aims Chronic ophthalmic conditions, such as glaucoma and dry eye disease, are frequently encountered debilitating eye conditions that can lead to substantial reduction in vision and quality of life. However, there is ongoing evidence to suggest that topical ophthalmic therapy is inappropriately omitted on admission to hospital. The primary aim of this audit was to investigate the trust adherence to the National Institute for Health and Care Excellence guideline on the prescribing standard of eye drops during hospital admission. The secondary aim was to raise awareness and ensure successful compliance with national standards to reduce unintentional omission of eye drops on admission and subsequent complications. Method Electronic medical records of all medical and surgical adult inpatients were studied prospectively on two different occasions. The quality of documentation of eye drops in clerking notes, the length of time taken between the admission and prescription of eye drops, and the accuracy of the prescription were examined. Following the initial audit, interventions focusing on clinician education were implemented. This includes highlighting the importance of eye drops in all departmental mandatory introductory sessions and putting up posters on all the wards as prompts. The same data collection method was used in the reaudit. Results In the initial audit, 64 (mean age 81.8±8.9 years) patients with regular prescriptions for eye drops were identified; 38 (59.4%) patients had eye drops for dry eye disease only, 20 (31.3%) patients had eye drops for glaucoma only, and six (9.4%) patients had eye drops for both. In the reaudit, 57 (mean age 76.7±15.3 years) patients were identified; 42 (73.7%) patients had eye drops for dry eye disease only, 10 (17.5%) patients had eye drops for glaucoma only, and five (8.8%) patients had eye drops for both. Following the intervention, there was a significant improvement in documentation of ocular diagnosis and eye drops on clerking notes from 41% to 65% (P=0.008), and eye drop reconciliation within 24 hours of admission improved from 45% to 75% (P=0.0008). All patients (100%) received the correct eye drop prescription before and after the intervention. Conclusions Education is effective in promoting adherence to national guidelines and reducing the incidence of inappropriate omission of eye drops on admission to hospital.

Potential Therapeutic Role of Pituitary Adenylate Cyclase-Activating Polypeptide for Dry Eye Disease

Dry eye disease (DED) is caused by a reduction in the volume or quality of tears. The prevalence of DED is estimated to be 100 million in the developed world. As aging is a risk factor for DED, the prevalence of DED is expected to grow at a rapid pace in aging populations, thus creating an increased need for new therapies. This review summarizes DED medications currently in clinical use. Most current medications for DED focus on stimulating tear secretion, mucin secretion, or suppressing inflammation, rather than simply replenishing the ocular surface with moisture to improve symptoms. We recently reported that the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) induces tear secretion and suppresses corneal injury caused by a reduction in tears. Moreover, it has been reported that a PACAP in water and a 0.9% saline solution at +4 °C showed high stability and achieved 80–90% effectiveness after 2 weeks of treatment. These results reveal PACAP as a candidate DED medication. Further research on the clinical applications of PACAP in DED is necessary.

The Association Between Dry Eye Disease With Depression, Anxiety and Sleep Disturbance During COVID-19

Objective: This study aimed to investigate the relationship between dry eye disease (DED) with anxiety and depression. Additionally, the mediating effect of sleep quality on this relationship was explored.Methods: 321 patients with DED were recruited from Tianjin Medical University Eye Hospital clinic and surveyed using demographic questionnaires, the Ocular Surface Disease Index (OSDI), Hospital Anxiety and Depression Scale (HADS), and Pittsburgh Sleep Quality Index (PSQI). Regression analysis and the bootstrap method were used to investigate the influence of sleep on the relationship between DED, anxiety and depression.Results: Among the patients with DED, 86 (26.79%), 85 (26.48%), and 54 (16.82%) patients presented with anxiety, depression, and both anxiety and depression respectively. The OSDI and PSQI score were positively correlated with depression and anxiety (all p &lt; 0.01). The direct effects of OSDI on depression and anxiety were significant (P &lt; 0.01). Additionally, the bootstrap test showed significant mediating effects of subjective sleep quality [95% CI [0.003–0.016] (depression); [0.001–0.011] (anxiety)] and sleep latency [95% CI [0.001–0.010] (depression); [0.001–0.008] (anxiety)]. These results indicated that the severity of DED symptoms, as measured by the OSDI score, affected anxiety and depression through a direct and an indirect pathway mediated by subjective sleep quality and sleep latency.Conclusions: The results indicated that there was a significant correlation between DED and anxiety and depression. Moreover, subjective sleep quality and sleep latency were a mediator of the relationship between DED symptoms and anxiety and depression.

LRG1 as a novel therapeutic target in eye disease

Retinal and choroidal diseases are major causes of blindness and visual impairment in the developed world and on the rise due to an ageing population and diabetes epidemic. Standard of care is centred around blockade of vascular endothelial growth factor (VEGF), but despite having halved the number of patients losing sight, a high rate of patient non-response and loss of efficacy over time are key challenges. Dysregulation of vascular homoeostasis, coupled with fibrosis and inflammation, are major culprits driving sight-threatening eye diseases. Improving our knowledge of these pathological processes should inform the development of new drugs to address the current clinical challenges for patients. Leucine-rich α-2 glycoprotein 1 (LRG1) is an emerging key player in vascular dysfunction, inflammation and fibrosis. Under physiological conditions, LRG1 is constitutively expressed by the liver and granulocytes, but little is known about its normal biological function. In pathological scenarios, such as diabetic retinopathy (DR) and neovascular age-related macular degeneration (nvAMD), its expression is ectopically upregulated and it acquires a much better understood pathogenic role. Context-dependent modulation of the transforming growth-factor β (TGFβ) pathway is one of the main activities of LRG1, but additional roles have recently been emerging. This review aims to highlight the clinical and pre-clinical evidence for the pathogenic contribution of LRG1 to vascular retinopathies, as well as extrapolate from other diseases, functions which may be relevant to eye disease. Finally, we will provide a current update on the development of anti-LRG1 therapies for the treatment of nvAMD.