Interventions for Dry Eye: An Overview of Systematic Reviews.

Importance: Dry eye is a common ocular disease that can have substantial morbidity. Systematic reviews provide evidence for dry eye interventions and can be useful for patients, clinicians, and clinical guideline developers. Overviews of reviews use explicit and systematic methods to synthesize findings from multiple systematic reviews, but currently, there are no overviews of systematic reviews investigating interventions for dry eye. Objective: To summarize the results of reliable systematic reviews of dry eye interventions and to highlight the evidence gaps identified. Evidence Review: We searched the Cochrane Eyes and Vision US satellite database and included reliable systematic reviews evaluating dry eye interventions published from 2016 to 2022. We reported the proportion of systematic reviews that were reliable with reasons for unreliability. Critical and important outcomes from reliable systematic reviews were extracted and verified. Critical outcomes included dry eye-related patient-reported outcome measures. Results were synthesized from reliable systematic reviews to provide summaries of evidence for each intervention. Evidence for each intervention was defined as conclusive or inconclusive depending on whether high-certainty evidence across systematic reviews was available according to Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria and whether findings reached statistical or clinical significance. Recommendations were made for further research. Findings: Within the Cochrane Eyes and Vision US satellite database, 138 potentially relevant systematic reviews were identified, 71 were considered eligible, and 26 (37%) were assessed as reliable. Among reliable systematic reviews, no conclusive evidence was identified for any dry eye intervention. Inconclusive evidence suggested that environmental modifications, dietary modifications, artificial tears and lubricants, punctal occlusion, intense pulsed light therapy, vectored thermal pulsation therapy (Lipiflow), topical corticosteroids, topical cyclosporine A, topical secretagogues, and autologous serum may be effective. Only unreliable systematic reviews evaluated lifitegrast, oral antibiotics, and moisture chamber devices. Conclusions and Relevance: This overview of systematic reviews found some evidence that dry eye interventions may be effective, but no conclusive evidence was available. The conduct and reporting of most systematic reviews for dry eye interventions warrant improvement, and reliable systematic reviews are needed to evaluate lifitegrast, oral antibiotics, and moisture chamber devices.

Ocular surface changes in primary open-angle glaucoma on anti-glaucoma medications versus treatment-naïve patients.

PURPOSE: To examine the ocular surface disease in primary open-angle glaucoma (POAG) patients already on treatment versus POAG patients without treatment. METHODS: A prospective cohort study was conducted on 120 eyes of 60 POAG patients: 60 treatment-naïve eyes (group I) and 60 eyes already on topical anti-glaucoma medications (AGMs) (group II). All patients had filled out the Ocular Surface Disease Index (OSDI) questionnaire and underwent a comprehensive glaucoma workup. Tear break-up time (TBUT) test, Schirmer's test (type I), corneal sensitivity, anterior segment-optical coherence tomography (AS-OCT), and corneal and conjunctival staining were done at day 1, 1 month, 3 months, 6 months, and 12 months follow-up. RESULTS: On presentation, TBUT, Schirmer's test, tear meniscus height (TMH), and tear meniscus depth (TMD) were significantly higher in group I compared to group II. No significant difference was noted in OSDI score, corneal sensitivity, and tear meniscus area (TMA) between the groups on presentation. Both, lissamine green and rose bengal staining, had higher grades in group II compared to group I. Worsening of ocular surface disease was noted in both groups on follow-up. OSDI score, TBUT, Schirmer's test, TMH, and TMD had better values in group I in comparison to group II on follow-up. CONCLUSION: The study has identified glaucoma patients on AGMs to be more affected by dry eye disease (DED) compared to treatment-naive glaucoma patients. We found statistically significant differences in values of TBUT, Schirmer tests, lissamine and rose bengal staining, and AS-OCT parameters at baseline and 3, 6, and 12 months follow-up. OSDI scores showed significant differences at 6 and 12 months of follow-up. We recommend consideration of evaluation and management of DED/ocular surface disease in glaucoma patients on topical AGMs, particularly multiple drugs and doses.

Efficacy of meibomian gland expression combined with Home-Based therapy in the management of dry eye Disease: A systematic review and Meta-Analysis.

PURPOSE: To compare the effectiveness of meibomian gland expression (MGX) combined with home-based therapy versus home-based therapy alone for the treatment of dry eye disease (DED) caused by meibomian gland dysfunction (MGD). METHODS: A systematic review of randomized controlled studies (RCTs), reporting the effects of MGX combined with home-based therapy in 2 databases, PubMed and Web of Science, was performed according to the PRISMA statement. The search period was until August 20, 2023. According to the heterogeneity, a random or fixed effects model was performed in the meta-analysis. The standardized mean difference (SMD) was calculated to analyze dry eye symptoms (DES) score, tear film break-up time (TBUT), total corneal fluorescein staining (tCFS) and meibomian glands expressibility (MGE). All analyses were performed by RevMan Web, version 5.7. The Cochrane risk of bias tool was used to analyze the quality of the studies selected. RESULTS: Two RCTs with a total of 99 patients were included. The studies reported that MGX combined with home-based therapy improves DES score, TBUT, tCFS and MGE compared to the home-based therapy. However, the meta-analysis indicated that MGX combined with home-based therapy only seems to be beneficial in reducing DES score (SMD -0.49; 95 % CI: -0.89 to -0.08; P = 0.02; I2 = 0 %). In addition, although TBUT, tCFS and MGE reported a slight trend in favor of MGX combined with home-based therapy, it was non-significant. CONCLUSIONS: While MGX combined with home-based therapy seem to show some evidence of alleviating dry eye symptoms, there is insufficient evidence to conclude the effects of this treatment definitively particularly in improving dry eye signs caused by MGD, such as TBUT, tCFS and MGE. Therefore, further RCTs are needed to elucidate these results.

Electroacupuncture for mild-to-moderate dry eye: study protocol for a multicentre, randomised, single-blind, sham-controlled trial.

INTRODUCTION: Dry eye (DE) is a multifactorial ocular surface disease causing considerable medical, social and financial implications. Currently, there is no recognised long-term, effective treatment to alleviate DE. Clinical evidence shows that electroacupuncture (EA) can improve DE symptoms, tear secretion and tear film stability, but it remains controversial whether it is just a placebo effect. We aim to provide solid clinical evidence for the EA treatment of DE. METHODS AND ANALYSIS: This is a multicentre, randomised, sham-controlled trial. A total of 168 patients with DE will be enrolled and randomly assigned to EA or sham EA groups to receive 4-week consecutive treatments and follow-up for 24 weeks. The primary outcome is the change in the non-invasive tear break-up time (NIBUT) from baseline to week 4. The secondary outcomes include tear meniscus height, the Schirmer I test, corneal and conjunctival sensation, the ocular surface disease index, corneal fluorescein staining, the numerical rating scale and the Chinese DE-related quality of life scale. ETHICS AND DISSEMINATION: The trial protocol and informed consent were approved by the Ethics Committee of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine Affiliated to Shanghai University of Traditional Chinese Medicine (identifier: 2021-119), Shanghai Eye Disease Prevention and Treatment Center (identifier: 2022SQ003) and Eye and ENT Hospital of Fudan University (identifier: 2022014). TRIAL REGISTRATION NUMBER: NCT05552820.

Safety and efficacy of intense pulsed light in the treatment of severe chronic ocular graft-versus-host disease.

OBJECTIVE: To investigate the safety and efficacy of intense pulsed light (IPL) in the treatment of severe chronic ocular graft-versus-host disease (coGVHD). METHODS: A prospective cohort study. Seventeen patients with severe coGVHD were selected for inclusion in this study. All subjects were treated with IPL every fortnight together with conventional treatment, observation time points were pre-treatment (W0), 4 weeks post-treatment (W4), 8 weeks post-treatment (W8) and 12 weeks post-treatment (W12). Dry eye related examinations include Tear meniscus height (TMH), Non-invasive break-up time (NIBUT), Schirmer I test, Tear film lipid layer thickness (LLT), Ocular surface staining (OSS) and assessment of meibomian gland. Corneal epithelial cell morphology and inflammatory cell infiltration were analyzed by corneal confocal microscopy, while goblet cell density and squamous epithelial grade were assessed by conjunctival imprinted cytology. RESULTS: Patients did not experience any adverse reactions during the follow-up period. All subjects showed significant improvement in clinical symptoms and most signs after IPL treatment. The corneal confocal microscopy showed that the number of dendritic cells infiltrates in the corneal stroma was significantly reduced after IPL treatment (p < 0.001). Conjunctival blot cytology suggested an increase in the number of conjunctival goblet cells from 5.12 ± 2.71 cells/mm2 before treatment to 22.00 ± 4.58 cells/mm2 after treatment, with a statistically significant difference (p < 0.001). An improvement in conjunctival epithelial cell morphology and a decrease in squamous epithelial grade was also observed. CONCLUSIONS: IPL treatment can effectively increase tear film stability in patients with severe coGVHD without significant side effects.

Dry eye disease due to meibomian gland dysfunction treated with Pinggan Yuyin Qingre formula: a stratified randomized controlled trial.

OBJECTIVE: To observe the clinical efficacy on improving the quality of meibum in patients suffer from dry eye disease (DED) due to meibomian gland dysfunction (MGD) with hyperactivity ofdue todeficiency pattern after being treated with Pinggan Yuyin Qingre formula (, PGYYQR). METHODS: Totally 120 patients who met the inclusion criteria were included and stratified into three levels according to the level of MGD (1-3), and patients in each level was randomly allocated into the treatment group and control group according to a 1∶1 ratio. Both groups were treated with sodium hyaluronate eye drops, and the treatment group was also given PGYYQR granules. Both groups were treated continuously for eight weeks. The score of the properties of meibomian gland (MG) secretion, the score of the palpebral margins, the average noninvasive tear breakup time (NITBUTav), lipid layer thickness (LLT), and Traditional Chinese Medicine (TCM) syndrome efficacy were compared between the two groups after treatment. RESULTS: A total of 116 cases were included in the statistical analysis. The differences were statistically significant in the score of the properties of MG secretion, the score of the palpebral margins, and NITBUTav between the two groups after treatment, the treatment group was superior to the control group; there was no evidence of a difference in LLT. In terms of TCM syndrome efficacy, the total effective rate was 84.7% in the treatment group and 50.9% in the control group, with the statistically significant difference. None of the included cases had adverse reactions. CONCLUSIONS: PGYYQR is effective in improving the quality of meibum, and the tear film stability which thereby relieving the ocular symptoms in MGD-related DED patients with hyperactivity ofdue todeficiency pattern.

Efficacy of intense pulsed light therapy on signs and symptoms of dry eye disease: A meta-analysis and systematic review.

This study reviewed the efficacy and safety of intense pulsed light (IPL) for the treatment of dry eye disease (DED). The PubMed database was used to conduct the literature search, which used the keywords "intense pulsed light" and "dry eye disease". After the authors evaluated the articles for relevancy, 49 articles were reviewed. In general, all treatment modalities were proven to be clinically effective in reducing dry eye (DE) signs and symptoms; however, the level of improvement and persistence of outcomes differed amongst them. Meta-analysis indicated significant improvement in the Ocular Surface Disease Index (OSDI) scores post-treatment with a standardized mean difference (SMD) = -1.63; confidence interval (CI): -2.42 to -0.84. Moreover, a meta-analysis indicated a significant improvement in tear break-up time (TBUT) test values with SMD = 1.77; CI: 0.49 to 3.05. Research suggests that additive therapies, such as meibomian gland expression (MGX), sodium hyaluronate eye drops, heated eye mask, warm compress, lid hygiene, lid margin scrub, eyelid massage, antibiotic drops, cyclosporine drops, omega-3 supplements, steroid drops, and warm compresses along with IPL, have been found to work in tandem for greater effectiveness; however, in clinical practice, its feasibility and cost-effectiveness have to be taken into consideration. Current findings suggest that IPL therapy is suitable when lifestyle modifications such as reducing or eliminating the use of contact lenses, lubricating eye drops/gels, and warm compresses/eye masks fail to improve signs and symptoms of DE. Moreover, patients with compliance issues have been shown to benefit well as the effects of IPL therapy is sustained for over several months. DED is a multifactorial disorder, and IPL therapy has been found to be safe and efficient in reducing its signs and symptoms of meibomian gland dysfunction (MGD)-related DE. Although the treatment protocol varies among authors, current findings suggest that IPL has a positive effect on the signs and symptoms of MGD-related DE. However, patients in the early stages can benefit more from IPL therapy. Moreover, IPL has a better maintenance impact when used in conjunction with other traditional therapies. Further research is needed to assess cost-utility analysis for IPL.

Evaporative dry eye disease due to meibomian gland dysfunction: Preferred practice pattern guidelines for diagnosis and treatment.

Evaporative dry eye (EDE) due to meibomian gland dysfunction (MGD) is one of the common clinical problems encountered in ophthalmology. It is a major cause of dry eye disease (DED) and of ocular morbidity. In EDE, inadequate quantity or quality of lipids produced by the meibomian glands leads to faster evaporation of the preocular tear film and symptoms and signs of DED. Although the diagnosis is made using a combination of clinical features and special diagnostic test results, the management of the disease might be challenging as it is often difficult to distinguish EDE from other subtypes of DED. This is critical because the approach to the treatment of DED is guided by identifying the underlying subtype and cause. The traditional treatment of MGD consists of warm compresses, lid massage, and improving lid hygiene, all measures aimed at relieving glandular obstruction and facilitating meibum outflow. In recent years, newer diagnostic imaging modalities and therapies for EDE like vectored thermal pulsation and intense pulsed light therapy have emerged. However, the multitude of management options may confuse the treating ophthalmologist, and a customized rather than a generalized approach is necessary for these patients. This review aims to provide a simplified approach to diagnose EDE due to MGD and to individualize treatment for each patient. The review also emphasizes the role of lifestyle modifications and appropriate counseling so that patients can have realistic expectations and enjoy a better quality of life.

A randomized controlled study evaluating outcomes of intense pulsed light and low-level light therapy for treating meibomian gland dysfunction and evaporative dry eye.

Purpose: This randomized, controlled, blinded study evaluates the efficacy of intense pulsed light (IPL) therapy with low-level light therapy (LLLT) in the treatment of meibomian gland dysfunction (MGD) and evaporative dry eye (EDE) compared to a control group. Methods: Hundred patients with MGD and EDE were randomized into control (50 subjects, 100 eyes) and study group (50 subjects, 100 eyes). The study group underwent three sittings of IPL with LLLT 15 days apart and were followed up 1 month and 2 months after the last treatment sitting. The control group underwent sham treatment and was followed up at the same intervals. The patients were evaluated at baseline and 1 month and 3 months (post 1st treatment) for dry eye. Schirmer's test and tear breakup time (TBUT), OSDI, meibomian gland expression, and meibography. Results: The study group showed significant improvement in OSDI scores (P < 0.0001) compared to the control group and a significant improvement in TBUT (P < 0.005) compared to the control group. There was no change in schirmer's test and an improvement in the meibomian gland expression but not significant. Conclusion: The results show that a combined therapy of IPL with LLT is effective in treating MGD with EDE compared to controls, and repeated treatment sessions have a cumulative effect on the disease outcomes.

Omega-3 fatty acids supplements for dry eye - Are they effective or ineffective?

Purpose: To evaluate effectiveness of omega-3 fatty acid supplements in relieving dry eye symptoms and signs in symptomatic visual display terminal users (VDT). Methods: A randomized controlled study was done; eyes of 470 VDT users were randomized to receive four capsules twice daily for 6 months (O3FAgroup), each containing 180 mg of eicosapentaenoic acid and 120 mg docosahexaenoic acid. The O3FA group was compared with another group (n = 480) who received four capsules of a placebo (olive oil) twice daily. Patients were evaluated at baseline, 1, 3, and 6 months, respectively. The primary outcome was improvement in omega-3 index (a measure of EPA and DHA ratio in RBC membrane). Secondary outcomes were improvement dry eye symptoms, Nelson grade on conjunctival impression cytology, Schirmer test values, tear film breakup time (TBUT), and tear film osmolarity. Means of groups (pre-treatment, 1, 3, and 6-months) were compared with repeated measure analysis of variance. Results: At baseline, 81% patients had low omega-3 index. In the O3FA group, a significant increase in omega-3 index, improvement in symptoms, reduction in tear film osmolarity, and increase in Schirmer, TBUT, and goblet cell density was observed. These changes were not significant in the placebo group. Improvement in test parameters was significantly (P < 0.001) better in patients with low omega3 index (<4%) subgroup. Conclusion: Dietary omega-3 fatty acids are effective for dry eye in VDT users; omega-3 index appears to be the predictor to identify potential dry eye patients who are likely to benefit from oral omega-3 dietary intervention.

A comparative review of evaporative dry eye disease and meibomian gland dysfunction in dogs and humans.

Dry eye disease is a complex ophthalmic disorder that consists of two main subtypes, aqueous deficient dry eye (ADDE) and evaporative dry eye disease (EDED). Due to the complex underlying physiology, human dry eye disease can be difficult to model in laboratory animal species. Thus, the identification and characterization of a spontaneous large animal model of dry eye disease is desirable. Dogs have been described as an ideal spontaneous model of ADDE due to the similar pathophysiology between dogs and humans. Recently, EDED and meibomian gland dysfunction (MGD) have been increasingly recognized and reported in dogs. These reports on EDED and MGD in dogs have identified similarities in pathophysiology, clinical presentations, and diagnostic parameters to humans with the comparable disorders. Additionally, the tests that are used to diagnose EDED and MGD in humans are more easily applicable to dogs than to laboratory species due to the comparable globe sizes between dogs and humans. The reported response of dogs to EDED and MGD therapies are similar to humans, suggesting that they would be a valuable preclinical model for the development of additional therapeutics. Further research and clinical awareness of EDED and MGD in dogs would increase their ability to be utilized as a preclinical model, improving the positive predictive value of therapeutics for EDED and MGD in both humans and dogs.

Anti-Inflammatories in the Treatment of Dry Eye Disease: A Review.

Inflammation is an important driver of dry eye disease (DED) pathogenesis. An initial insult that results in the loss of tear film homeostasis can initiate a nonspecific innate immune response that leads to a chronic and self-sustaining inflammation of the ocular surface, which results in classic symptoms of dry eye. This initial response is followed by a more prolonged adaptive immune response, which can perpetuate and aggravate inflammation and result in a vicious cycle of chronic inflammatory DED. Effective anti-inflammatory therapies can help patients exit this cycle, and effective diagnosis of inflammatory DED and selection of the most appropriate treatment are therefore key to successful DED management and treatment. This review explores the cellular and molecular mechanisms of the immune and inflammatory components of DED, and examines the evidence base for the use of currently available topical treatment options. These agents include topical steroid therapy, calcineurin inhibitors, T cell integrin antagonists, antibiotics, autologous serum/plasma therapy, and omega-3 fatty acid dietary supplements.

Dry Eye Disease: What Is the Role of Vitamin D?

Dry eye disease (DED) is a multifactorial condition resulting from reduced tear secretion from the lacrimal glands, increased tear water evaporation or the production of poor-quality tears. Such tear instability can lead to inflammation and damage of the ocular surface, as well as to abnormal nociception. Historically, tear substitutes and corticosteroids have been the bastion of DED therapy, but a substantial number of patients still suffer from residual symptoms even after being treated with traditional treatments. Aiming to find safe and effective alternative therapies, recent efforts have been focused on the role of vitamin D in the cellular physiology of the eye. Possibly because of its positive effect in modulating the immune and inflammatory responses, the systemic supplementation of vitamin D seems, indeed, to be an effective therapeutic strategy, especially, but not only, for patients affected by DED that does not respond to conventional treatments. In this context, this review focuses on the literature reporting on the pathogenesis and treatment of DED, with a special emphasis on the recent investigations reporting on the potential role of the systemic administration of vitamin D as a therapeutic approach in the management of such condition.

Low-Level Light Therapy Versus Intense Pulsed Light for the Treatment of Meibomian Gland Dysfunction: Preliminary Results From a Prospective Randomized Comparative Study.

PURPOSE: The purpose of this study was to evaluate and compare the safety and efficacy of low-level light therapy (LLLT) and intense pulsed light (IPL) for the treatment of meibomian gland dysfunction (MGD). METHODS: Forty eyes of 40 patients with MGD were randomized to receive either LLLT or IPL. Four weekly sessions of LLLT (MY MASK-E, Espansione Marketing S.p.A., Bologna, Italy) and IPL (Eye-light device, Espansione Marketing S.p.A., Bologna, Italy) were performed. The following parameters were evaluated before and 2 weeks after the last session for each treatment: Standard Patient Evaluation of Eye Dryness questionnaire, noninvasive break-up time, tear meniscus height, redness score, meiboscore, and meibomian gland loss. RESULTS: All patients completed regularly all the scheduled sessions, and no adverse events were reported in any of the groups. The Standard Patient Evaluation of Eye Dryness score significantly decreased after both LLLT and IPL (P < 0.001) although the improvement was significantly greater in the LLLT compared with the IPL group (-9.9 ± 3.2 vs. -6.75 ± 4.5; P = 0.014). Patients in the LLLT group showed a significantly higher increase in tear meniscus height compared with those in the IPL group (0.06 ± 0.10 mm vs. -0.01 ± 0.014; P = 0.040). In both groups, the noninvasive break-up time, redness score, meiboscore, and meibomian gland loss did not vary significantly after treatment (all P > 0.05). CONCLUSIONS: Both LLLT and IPL were safe and effective in improving ocular discomfort symptoms in patients with MGD; however, the former determined a greater improvement in symptoms and an improvement of tear volume.

Effects of electroacupuncture on dry eye: A pilot randomized controlled trial.

PURPOSE: The purpose of the study was to assess the efficacy of electroacupuncture on dry eye (DE). METHODS: Eighty-four DE patients were randomly assigned to receive electroacupuncture (EAG) three times a week or 0.1% sodium hyaluronate artificial tears (ATG) four times per day for 4 weeks. The primary outcomes were non-invasive tear film breakup time (NIBUT) and tear meniscus height (TMH). The secondary outcomes included the ocular surface disease index (OSDI), Schirmer I test (SIT), corneal sodium fluorescein staining (CFS) score, corneal topography descriptors surface asymmetry index (SAI) and surface regularity index (SRI), corneal sensitivity, 36-item Short-form Health Survey (SF-36) score and Hospital Anxiety and Depression Scale (HADS) score. All outcomes were assessed at Week 0 (baseline), Week 4 (after-treatment) and Week 8 (follow-up). RESULTS: Between-group comparisons showed significant differences in the changes in NIBUT (Week 4, p = 0.003; Week 8, p = 0.008), TMH (Week 4, p = 0.014; Week 8, p = 0.009), OSDI (Week 4, p = 0.029; Week 8, p = 0.022), CFS score (Week 8, p = 0.036) and SF-36 role-physical score (Week 4, p = 0.010), favouring EAG. Mean changes in SIT, SAI, SRI, corneal sensitivity and HADS scores were statistically equal between the two groups (all p > 0.05). Treatment with electroacupuncture was well-tolerated and showed minimal adverse events. CONCLUSIONS: Compared with artificial tears, electroacupuncture shows superior efficacy in improving tear film stability and symptoms of DE.

Intense Pulse Light Combined With Low-Level Light Therapy in Dry Eye Disease: A Systematic Review.

OBJECTIVES: To evaluate the improvement in symptoms and signs associated with intense pulse light (IPL) combined with low-level light therapy (LLLT) in the treatment of dry eye disease (DED). METHODS: A systematic review of full-length original studies reporting the effects of IPL combined with LLLT for DED in two databases, PubMed and Scopus, was performed according to the PRISMA statement. The quality assessment tool for case series studies from the National Heart, Lung, and Blood Institute was used to analyze the quality of the studies selected. RESULTS: The search provided a total of 393 articles, of which six were included. Significant decreases in the Ocular Surface Disease Index (OSDI) score, meibomian gland dysfunction (MGD) score, MGD grade, and meiboscore and increases in tear film stability, lipid layer thickness, and loss area of the meibomian gland have been reported. Concerning tear volume, tear meniscus height, and Schirmer test remained unchanged. In relation to tear osmolarity and corneal fluorescein staining, contradictory outcomes were found. CONCLUSIONS: Intense pulse light combined with LLLT for the treatment of dry eye improves OSDI, tear film stability, and meibomian gland function; thus, this treatment may be recommended for DED patients due to MGD.

Dry Eye Subtypes in the Dry Eye Assessment and Management (DREAM) Study: A Latent Profile Analysis.

Purpose: Dry eye disease (DED) is a heterogeneous condition with poorly characterized subtypes. The DREAM study was a large multicenter randomized clinical trial that did not find omega-3 to be more effective than placebo in treating symptomatic DED. We performed secondary analysis of DREAM data to characterize DED subtypes and their omega-3 response. Methods: A total of 535 patients with moderate-to-severe DED were randomized to omega-3 or placebo treatment for one year. We used latent profile analysis to identify subtypes based on baseline Ocular Surface Disease Index, tear break-up time (TBUT), anesthetized Schirmer's test, corneal and conjunctival staining, and meibomian gland dysfunction (MGD). We evaluated omega-3's effect for each subtype using generalized linear regression. Results: Five clinically meaningful DED subtypes were identified. They differed significantly in sex (P < 0.001) and race (P = 0.02). Subtype 1 had the most severe DED signs yet milder symptoms and was associated with more Sjögren's syndrome (21%, P < 0.001). Subtype 2 had the mildest DED signs except MGD. Subtype 3 had the most severe symptoms, out of proportion to DED signs. Subtype 4 had relatively milder symptoms and MGD. Subtype 5 had severe MGD and TBUT and was associated with rosacea (29%, P = 0.04). Omega-3 was not significantly more beneficial than placebo for any subtype. Conclusions: Five clinically meaningful DED subtypes differed significantly in demographics, symptoms, signs, and systemic disease associations. Omega-3 was not significantly more effective than placebo for any subtype. Translational Relevance: T3 translational research identifying subtypes in the DREAM study can improve DED clinical classification and targeted management.

Efficacy of Cordyceps cicadae (Ascomycota) Mycelium Supplementation for Amelioration of Dry Eye Symptoms: A Randomized, Double-Blind Clinical Pilot Study.

Dry eye disease (DED), a multifactorial inflammatory ocular surface disorder, affects up to 50% of individuals over 50 years old worldwide and is one of the most common reasons for seeking ophthalmologic care. Generally, topical eye drops or oral drugs are administered to treat DED; however, the use of preservatives in eye drops or the adverse effects of oral drugs are disadvantageous for long-term therapy. Cordyceps cicadae, a traditional Chinese medicinal fungus, possesses anti-inflammatory effects without evident toxicity and is obtainable at low price. Our previous study demonstrated that C. cicadae mycelium effectively ameliorates dry eye symptoms in the benzalkonium chloride (BAC)-induced mouse dry eye model by increasing tear volume and tear film breakup time (TBUT). However, the effects of C. cicadae mycelium for human dry eye amelioration remains unknown. Thus, the present study investigated the mitigation of dry eye conditions and related discomforts through oral supplementation of fermented C. cicadae mycelium. A total of 70 healthy individuals were recruited and randomly allocated to receive a daily oral dose of 1,050 mg preparation in sachet containing either freeze-dried C. cicadae mycelium powder with 0.3 mg of adenosine and 1.5 mg of HEA per gram or placebo for 90 days. The participants were subjected to anthropometric measurements, dry eye questionnaires (DEQ), Schirmer's tests, intraocular pressure (IOP) measurements, tear film breakup time (TBUT) tests, tear osmolality measurements, and tear electrolyte analysis prior to and right after completion of the study. The results showed a significantly increased TBUT as well as a significant decrease in tear osmolarity, in parallel with the decrease of tear electrolytes, especially Na+ and Cl ions. Although significant increase of tear volume was not observed, the increased TBUT suggests mitigation of dry eye through improvement of tear quality. Therefore, C. cicadae mycelium supplementation may be used for dry eye alleviation as a novel therapeutic intervention.

Acupuncture for the management of dry eye disease.

The effectiveness of using acupuncture for dry eye disease (DED) is controversial. Thus, this systematic review investigated the effectiveness and feasibility of using acupuncture for DED in accordance with the 2020 PRISMA statement. The outcomes of interests were (1) to evaluate the efficacy of acupuncture in improving the ocular surface disease index (OSDI), Schirmer I test score, and tear breakup time from baseline to the last follow-up; (2) to determine possible complications of using acupuncture; and (3) to investigate the superiority of acupuncture over other commonly used treatments for DED. Data from 394 patients were collected. Results showed that acupuncture significantly prolonged the tear breakup time (P < 0.0001), significantly increased the Schirmer I test score (P < 0.0001), and significantly reduced the OSDI (P < 0.0001) from baseline to the last follow-up. Compared with the control group, the acupuncture group had significantly greater Schirmer I test score (P < 0.0001), significantly longer tear breakup time (P = 0.0004), and significantly lower OSDI (P = 0.002). These results suggest that acupuncture is effective and feasible in improving symptoms and signs of DED. No severe adverse effects of acupuncture were observed.

An Oral Polyphenol Formulation to Modulate the Ocular Surface Inflammatory Process and to Improve the Symptomatology Associated with Dry Eye Disease.

Due to their antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic effects, polyphenols are first-rate candidates to prevent or treat chronic diseases in which oxidative stress-induced inflammation plays a role in disease pathogenesis. Dry eye disease (DED) is a common pathology, on which novel phenolic compound formulations have been tested as an adjuvant therapeutic approach. However, polyphenols are characterized by limited stability and solubility, insolubility in water, very rapid metabolism, and a very short half-life. Thus, they show poor bioavailability. To overcome these limitations and improve their stability and bioavailability, we evaluated the safety and efficacy of an oral formulation containing among other compounds, polyphenols and omega-3 fatty acids, with the addition of a surfactant in patients with DED. Subjects were randomly assigned to one of four study groups including the study formulation (A), placebo (P), the study formulation + eye lubricant (A + L), and placebo + eye lubricant (P + L). Patients from the A and P groups were instructed to take two capsules every 24 h, while patients in the L groups also added one drop of lubricant twice a day for 12 weeks as well. Regarding safety, non-ocular abnormalities were observed during study formulation therapy. Liver function tests did not show any statistically significant difference (baseline vs. week 4). Concerning efficacy, there was a statistically significant difference between baseline, month 1, and month 3 in the OSDI (Ocular Surface Disease Index) test results in both treatment groups (group A and group A + L). Furthermore, both groups showed statistically significant differences between baseline and month 3 regarding the non-invasive film tear breakup time (NIF-BUT) score and a positive trend related to Shirmer's test at month 3. The non-invasive average breakup time (NIAvg-BUT) score showed a statistically significant difference at month 3 when compared with baseline in the A + L group. The P + L group showed a statistically significant difference in terms of the OSDI questionary between baseline and month 3. Regarding the lissamine green staining, the A + L group showed a statistical difference between baseline and month 3 (p = 0.0367). The placebo + lubricant group did not show statistically significant differences. Finally, the placebo group did not show any data with statistically significant differences. Consequently, this polyphenol formulation as a primary treatment outperformed the placebo alone, and the polyphenol oral formulation used as an adjuvant to artificial tears was superior to the combination of the placebo and the artificial tears. Thus, our data strongly suggest that this polyphenol oral formulation improves visual strain symptoms and tear film status in patients with mild to moderate DED.