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Over the past decades, the number of patients with dry eye disease (DED) has increased dramatically. The incidence of DED is higher in Asia than in Europe and North America, suggesting the involvement of cultural or racial factors in DED etiology. Although many definitions of DED have been used, discrepancies exist between the various definitions of dry eye disease (DED) used across the globe. This article presents a clinical consensus on the definition of DED, as formulated in four meetings with global DED experts. The proposed new definition is as follows: “Dry eye is a multifactorial disease characterized by a persistently unstable and/or deficient tear film (TF) causing discomfort and/or visual impairment, accompanied by variable degrees of ocular surface epitheliopathy, inflammation and neurosensory abnormalities.” The key criteria for the diagnosis of DED are unstable TF, inflammation, ocular discomfort and visual impairment. This definition also recommends the assessment of ocular surface epitheliopathy and neurosensory abnormalities in each patient with suspected DED. It is easily applicable in clinical practice and should help practitioners diagnose DED consistently. This consensus definition of DED should also help to guide research and clinical trials that, to date, have been hampered by the lack of an established surrogate endpoint.

Purpose To evaluate the efficacy and safety of TriMix, a new multiple-action tear substitute in patients with dry eye disease (DED). Methods This was a randomized, multicenter, single-masked, hyaluronic acid (HA)-controlled clinical trial conducted between July, 2023 and May, 2024. A total of 115 patients were randomly allocated to receive either TriMix tear substitute or 0.15% HA tear substitute 3 times daily. Clinical outcomes include ocular surface disease index (OSDI) questionnaire, non-invasive tear film break-up time (NIBUT) and Schirmer I test (ST) without anesthesia at 3 and 6 months of follow-up. Results Of the 115 patients randomized, 80 completed the study (TriMix, n  = 56; HA, n  = 24). At months 3 and 6, improvements from baseline were statistically greater with TriMix tear substitute compared to HA 0.15% tear substitute for OSDI: -3.7 points (95% CI, -6.9 to -0.6; p  = 0.011) and − 7.5 points (95% CI, -10.3 to -4.6; p  < 0.001), respectively. Similar results were reported for NIBUT: 0.9 s (95% CI, 0.3 to 1.6; P  = 0.040) and 1.6 s (95% CI, 0.7 to 2.6; P  < 0.001), respectively. Regarding safety, no serious ocular adverse events occurred. Three patients complained of burning after instillation of TriMix tear substitute. Conclusion This RCTs demonstrate that TriMix tear substitute provides statistically significant and clinically evidence of the reduction of DED symptoms with a satisfactory safety profile through 6 months of follow-up. Findings suggest the use of this tear substitute, but results should be confirmed independently over longer time periods. Key messages What is known Given the high prevalence and significant impact of DED on patients’ quality of life, developing effective treatments is crucial. Among the various therapeutic options, tear substitutes remain the first step in the treatment of DED. The study was conducted to evaluate the efficacy and safety of TriMix, a new multiple-action tear substitute, in patients with DED. New information The study found that the instillation of TriMix tear substitute 3 times daily significantly improved DED symptoms and signs, with rapid efficacy and a satisfactory safety profile over a 6-month follow-up period

To evaluate the tear levels of Lymphotoxin-alpha (LT-α) and the clinical efficacy of intense pulsed light (IPL) treatment in patients with dry eye disease (DED). This randomized study included 28 participants with DED who received 3 IPL therapies at Week 0 (Baseline), Week 3(3W), and Week 6(6W) ( N  = 30 eyes), or 2 IPL therapies at Baseline, 3W and a sham IPL therapy at 6W ( N  = 26 eyes). All participants were examined at Baseline, 3W, 6W, Week 9(9W), and Week 12(12W) for non-invasive break-up time (NITBUT), LT-α, meibomian gland quality (MGQ), tear meniscus height (TMH), conjunctivocorneal staining score (CFS), meibomian gland expression (MGEx), tear-film lipid layer (TFLL), and ocular surface disease index (OSDI). Baseline measures exhibited no significant differences between the groups ( all p > 0.05 ). At 6W, NITBUT, MGEx, CFS, and OSDI were significantly improved compared with the Baseline ( p  <  0.05 ). At 12W, a comparison between the 3 IPL therapy group and 2 IPL therapy group found significant improvements in the NITBUT ( p = 0.002 ), TMH ( p  = 0.011), TFLL ( p  =  0.009 ), MGEx ( p = 0.011 ), MGQ ( p = 0.021 ), LT-α ( p = 0.034 ), while the CFS ( p  =  0.104 ), OSDI ( p  =  0.189 ) had no significant improvements. IPL treatment can improve the clinical symptoms and signs of DED. The potential long-term benefit of 3 IPL treatments is better than 2 treatments. Trial registration : ClinicalTrials.gov, TRN: NCT0626923, Registration date: 21 February 2024.

To explore the therapeutic effect of estrogen replacement therapy combined with autologous serum therapy in controlling severe dry eye disease in perimenopausal women. A total of 1249 perimenopausal female patients who visited Ziyang Hospital of West China Hospital, Sichuan University from January 2021 to December 2023 were included in this study. After screening, the patients were randomly divided into the normal group, control group, estrogen replacement therapy group (ERT), autologous serum group (AS), and estrogen replacement therapy + autologous serum group (ERT + AS). There were 20 cases in each group, totaling 100 cases. Eye surface data, total luteinizing hormone (LH), estradiol (E2), follicle stimulating hormone (FSH), and endometrial changes were collected before and after treatment in each group. After treatment, the corneal staining area and staining intensity in the ERT + AS group decreased. Compared with the average tear film rupture time of the normal group (15.16 ± 0.73) s, the Control group (5.11 ± 0.45) s decreased to the lowest level while the ERT group (8.27 ± 0.59) s, AS group (8.15 ± 0.72) s, and ERT + AS group (13.37 ± 0.85) s increased, and the ERT + AS group had the most significant increase. Besides, the Schirmer experiment results showed a consistent trend with BUT, with a statistically significant difference ( P  < 0.05). Meanwhile, our research had shown that after estrogen replacement therapy, FSH and LH in the ERT group and ERT + AS group were significantly reduced, while E2 was significantly increased. There was no statistically significant difference between the two groups ( P  > 0.05). The Elisa experiment results showed that compared with the normal group, the expression intensity of VEGF, IL-1β, PGE2, and TNF-α inflammatory factors was significantly increased in the control group. After treatment with ERT, AS, and ERT + AS, the expression of thses inflammatory factors gradually decreased, with the ERT + AS group showing the most significant downregulation ( P  < 0.05). The HE staining results of the endometrium indicated that after intervention measures, the thickness of the endometrium in the ERT group and ERT + AS group significantly increased, the connective tissue arrangement of the endometrium was tight, the structure of the uterine glands was dense, and there was a single layer of columnar epithelium covered with circular uterine glands. The Kupperman score demonstrated that with the prolongation of treatment time, the Kupperman scores of the ERT group and ERT + AS group gradually decreased. After 4 weeks of treatment, both groups had the lowest values, and there was no statistically significant difference between the groups ( P  > 0.05). Furthermore, the results of the Elisa experiment on endometrial tissue protein fluid showed that compared with the normal group, the expression intensity of IFN-α, IL-12, and TNF-α inflammatory factors was significantly increased in the control group. After treatment with ERT, AS, and ERT + AS, the expression of IFN-α, IL-12, and TNF-α inflammatory factors in the ERT group and ERT + AS group gradually decreased. There was no statistically significant difference between the two groups ( P  > 0.05). The Elisa experiment results showed that compared with the normal group, the expression intensity of LZM, LF, ALB and sIgA in the control group was significantly decreased, and the difference between the two groups was statistically significant ( P  < 0.05). After treatment with ERT, AS, and ERT + AS, the expression of inflammatory factors LZM, LF, ALB and sIgA gradually increased, with the ERT + AS group showing the most significant upregulation, and the difference was statistically significant ( P  < 0.05). The combination of estrogen replacement therapy and autologous serum therapy can effectively ameliorate the symptoms of severe dry eye disease in perimenopausal women and improve their quality of life, which is worthy of further research.

Background Sjögren’s syndrome (SS) is a chronic inflammatory autoimmune disorder affecting salivary and lacrimal glands, leading to distressing ocular symptoms. Existing therapeutic approaches for SS-associated dry eye syndrome (DES) show insufficient efficacy. This study investigates the use of topical MSC-derived exosomes in primary SS-related DES. Methods In phase 1 and 2, triple-blinded, randomized trial, two vials of eye drops are given to each participant, one with code A and one with code B and only the supervisor knows the content of each vial. The treatment group ( n  = 8 eyes) received 10 µg of MSC-derived exosomes twice daily for two weeks and the control group ( n  = 8 eyes) received Phosphate buffered saline(PBS) for their respective eyes. Safety was assessed through ophthalmic exams, while DES assessment tests evaluated treatment effectiveness. Non-parametric tests employed to examine assumptions. The differences of ocular examination results between day 0 and month 3 were analyzed using a paired Student’s t test. Measurement data that were not normally distributed are represented by the median (interquartile range), and comparisons were performed using the Wilcoxon rank-sum test. Results The treatment showed promising results, with significant improvements observed in various indicators such as reduced Ocular Surface Disease Index scores, increased tear secretion, lower fluorescein scores, and longer tear-film break-up time before and after treatment and between the controls and the treated groups. Our results showed a significant increase in multifunctional proteins such as Epidermal Growth Factor and thrombospondin-1 and conversely, the levels of pro-inflammatory cytokines, including interleukin-6 and Matrix metalloproteinase-9 significantly decreased in tear of participant before and after treatment and between the controls and the treated groups. Conclusions Our study underscores the safety and substantial therapeutic potential of using MSC-derived extracellular exosomes eye drops to treat SS-associated DES. Trial registration IRCT20211102052948N1 The study protocol has been approved in Iranian Registry of Clinical Trials at 2022-04-20.

Purpose This pooled analysis of two pivotal studies (ESSENCE-1 and ESSENCE-2) evaluated treatment effects of a water-free ciclosporin 0.1% solution in dry eye disease (DED) patients in the overall population and in subgroups according to sex, age, and baseline severity of disease. Methods In these randomized, multicenter, double-masked, vehicle-controlled studies patients received ciclosporin 0.1% or vehicle (1:1 ratio) in both eyes twice daily for 85 and 29 days, respectively. Total and central corneal fluorescein staining (tCFS; cCFS; NEI scale, 0–15) were assessed at Day 15 and 29. Other endpoints included conjunctival staining and blurred vision scores. Safety and tolerability parameters comprised adverse events, ophthalmic examinations and drop comfort assessments. Results In total 1162 patients were included in the analysis (585 ciclosporin 0.1%; 577 vehicle). Patients age (mean [SD]: 58.3 [15.23] years) and gender distribution (73% females) are consistent with DED epidemiology. Change from baseline (LS mean [SE]) in tCFS significantly improved compared to vehicle, both at Day 15 (ciclosporin: -3.24 [0.112]; vehicle -2.71 [0.113]; Δ= -0.52 [0.144], p =0.0003) and Day 29 (ciclosporin: ‑3.83 [0.115]; vehicle:‑3.30 [0.116]; Δ: ‑0.53 [0.147], p=0.0003). 56.8% and 66.4% of patients responded to ciclosporin 0.1% with a tCFS improvement of ≥ 3 scores on Day 15 and 29, respectively. A consistent effect on tCFS favoring ciclosporin over vehicle was observed in all subgroups. Improvements favoring ciclosporin were seen in cCFS and conjunctival staining in the overall population and in blurred vision score in patients with significant corneal staining. Incidence of ocular adverse events was 13.2% in both treatment groups. Mild instillation site reactions were reported by 7.9% patients in the ciclosporin group. Discontinuation rates were low with 2.6% and 2.1% in ciclosporin and vehicle groups. Ciclosporin 0.1% was rated comfortable upon instillation by 84.7% of patients. Conclusion The pooled analysis confirmed that the water-free ciclosporin 0.1% solution is effective in improving ocular surface staining after 2 weeks of treatment to a clinically relevant extent in more than 50% of patients in the overall population and subgroups. With an early onset and good tolerability, the product has the potential to address an unmet medical need in DED. ClinicalTrials.gov identifier  NCT03292809 on 21-July-2017; NCT04523129 on 20-August-2020 Key messages What Was Known : Ciclosporin eye drops are a standard of care in dry eye disease (DED) therapy not controlled by artificial tears. A novel water-free ciclosporin 0.1% ophthalmic solution with improved efficacy has recently been commercialized in the United States and approved in the European Union. What This Paper Adds : The water-free cyclosporine 0.1% solution showed consistent and early improvement of ocular surface damage in patients with moderate and severe dry eye disease as well as in subgroups according to age and sex. Responder analysis showed the clinical relevance of these improvements in more than 50 % of treated patients after 2 weeks of treatments. This eye drop formulation was well tolerated and no new safety signals were detected.

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.

Human umbilical cord blood (HUCB) serum eye drops contain growth factors, neurotrophic agents, and antimicrobial compounds that may promote ocular surface healing and regeneration. Sjögren's syndrome is a chronic autoimmune condition characterized by reduced tear production and ocular surface damage, often resulting in severe dry eye symptoms. Mustard gas chemical veterans also suffer from similar debilitating ocular complications due to chronic inflammation and meibomian gland dysfunction. While conventional treatments offer symptomatic relief, they lack essential components of natural tears. This pilot randomized controlled trial will evaluate the efficacy of HUCB eye drops in three patient groups: (A) Sjögren's patients treated with HUCB drops, (B) Sjögren's patients receiving conventional treatment, and (C) mustard gas veterans receiving conventional treatment in the right eye and HUCB drops in the left eye. Patients will be assessed using subjective and objective tools, including the Ocular Surface Disease Index (OSDI), visual acuity, tear film breakup time (TBUT), SM tube test, and fluorescein staining based on SICCA criteria. Group allocation will follow a blocked randomization sequence for groups A and B; group C will follow a within-subject paired-eye design. Follow-up will occur at 30 and 60 days. This study aims to assess the regenerative potential of HUCB serum in patients with autoimmune and chemically induced dry eye. Its results may support broader clinical use of HUCB drops in treating severe ocular surface disorders, including conditions like Stevens-Johnson syndrome and industrial chemical exposures. This trial was registered at the Iranian Registry of Clinical Trials (Registration number: IRCT20230925059512N1, Registration date: 2024-08-11).

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.