One Soul and Several Faces of Evaporative Dry Eye Disease.

The ocular surface system interacts with, reacts with, and adapts to the daily continuous insults, trauma, and stimuli caused by direct exposure to the atmosphere and environment. Several tissue and para-inflammatory mechanisms interact to guarantee such an ultimate function, hence maintaining its healthy homeostatic equilibrium. Evaporation seriously affects the homeostasis of the system, thereby becoming a critical trigger in the pathogenesis of the vicious cycle of dry eye disease (DED). Tear film lipid composition, distribution, spreading, and efficiency are crucial factors in controlling water evaporation, and are involved in the onset of the hyperosmolar and inflammatory cascades of DED. The structure of tear film lipids, and subsequently the tear film, have a considerable impact on tears' properties and main functions, leading to a peculiar clinical picture and specific management.

Preventing and Managing Iatrogenic Dry Eye Disease during the Entire Surgical Pathway: A Study Focusing on Patients Undergoing Cataract Surgery.

Patient expectations for cataract surgery are continuously increasing, and dry eye disease (DED) represents a major cause of patient dissatisfaction in eye surgery. The present opinion paper aims to provide useful insights to improve the entire pathway of a patient undergoing cataract surgery, from the preoperative setting to the postoperative one. The available evidence from main clinical trials published on this topic is presented in association with experience-based points of view by the authors. Ocular surface disease (OSD) is common in patients presenting for cataract surgery, and more than half of these patients have DED and meibomian gland dysfunction (MGD), even in the absence of symptoms. Therefore, there is a need to encourage preoperative assessments for the risk of DED development or worsening in all patients as a routine approach to cataract surgery. New all-in-one diagnostic machines allow for fast and noninvasive screening of the ocular surface status. Once a preoperative diagnosis of DED/OSD is reached, ocular surface optimization should be obtained before surgery. In the case of unresolved OSD, the decision to delay surgery should be considered. The surgical procedure can be optimized by avoiding large incisions, limiting microscope light intensity and exposure, and avoiding an aspirating speculum or preserved eye drops. Postoperatively, the continued avoidance of preserved agents is advisable, as well as a limited exposure to epitheliotoxic antibiotics and nonsteroidal anti-inflammatory drugs. Short-term, preservative-free, soft corticosteroids may be useful for patients with extensive or persistent inflammation.

Uncommon Blepharitis.

Blepharitis is a common chronic inflammatory condition affecting the eyelid margins; the pathophysiology of blepharitis is complex and not fully understood. The disease is anatomically divided into anterior (inflammation of eyelashes) and posterior (meibomian gland dysfunction) types. Diagnosis relies on clinical examination, revealing characteristic features like scurf, vascular changes, and meibomian gland dysfunction. The main goals of blepharitis treatment are symptom relief, recurrence prevention, and complication risk minimization. Treatment options include lid hygiene, topical and systemic antibiotics, topical corticosteroids, and omega-3 supplements. However, it is important to highlight reported cases of blepharitis as side effects of systemic therapies, particularly in the context of chemotherapy, bortezomib, cetuximab, TNFα inhibitors, and dupilumab. It is crucial to monitor patients undergoing such treatments regularly and attentively in order to promptly set up adequate supportive therapy. Of even more importance is future research on the pathophysiological mechanisms responsible for the occurrence of these ocular side effects in order to find a nosological cure for the issue.

Dry eye in mind: Exploring the relationship between sleep and ocular surface diseases.

PURPOSE: Dry Eye Disease (DED) is regarded as the most common ocular surface disease worldwide, entailing symptoms that have a major impact on the physical and psychological well-being of DED patients. In this context, the impact of sleep quality on DED has recently attracted attention. Indeed, although little is known about the mechanisms underlying the relationship between sleep and ocular surface diseases, recent evidence suggests that a reciprocal relationship exists between sleep quality and DED. Aim of the study was to investigate such relationship by means of both survey-based and instrumental analysis in a large population. PATIENTS AND METHODS: The present cross-sectional study included 1182 DED patients who completed the Insomnia Severity Index (ISI) and the Ocular Surface Disease Index (OSDI) questionnaires. Moreover, tear break-up time (TBUT) and ocular surface staining (OSS) data of included patients were collected by physicians. RESULTS: According to the findings of this study, in DED patients, the severity of dry eye symptoms and signs, assessed by OSDI score, TBUT, and ocular surface staining, is associated with more severe insomnia symptoms. Furthermore, higher severity of DED symptoms seems to be associated with the occurrence of nocturnal awakenings rather than with problems in falling asleep. CONCLUSIONS: Present work contributes to the understanding of the complex relationship between DED and insomnia by showing that in a large population of DED patients, the more severe the insomnia, the more severe the DED symptoms and signs.

Increased expression of neutrophil CD15 correlates with the severity of anterior ocular surface damage in type II diabetes mellitus.

BACKGROUND: Diabetes mellitus is associated with increased risk of ocular surface diseases in elderly. We consider neutrophil CD15 as a potential marker of ocular surface damage in type II diabetes mellitus patients. AIM: We aimed to evaluate expression of neutrophil CD15 and correlate it with results of conjunctival impression cytology and routine objective anterior ocular surface tests (TMH, NIBUT, LLT, MGD) in T2DM patients. MATERIALS AND METHODS: We prospectively enrolled sixty type II diabetes mellitus patients (120 eyes) into a study group. The control group included forty (80 eyes) age- and sex-matched healthy individuals. All patients underwent comprehensive ophthalmological examination, and tear meniscus height test (TMH), noninvasive tear break-up time (NIBUT), lipid layer thickness measurement (LLT), Meibomian gland dysfunction evaluation (MGD), conjunctival impression cytology (CIC) and expression of CD15. RESULTS: Abnormal Nelson's grades of squamous metaplasia (grades 2 and 3) were observed in 50% (60 eyes) of the study group, and 13.8 (11 eyes) of the control group. Fifteen patients with type II diabetes mellitus suffered from grade 3 squamous metaplasia. Nelson's grades of squamous metaplasia have shown a positive correlation with the level of CD15 expression either in the study and control groups (rs = 0.628, p = <0.0001; rs = 0.746, p < 0.0001; respectively). CONCLUSIONS: The research shows significantly reduced values of routine objective ocular tests in type II diabetes mellitus patients in comparison to healthy participants older than 60 y.o. Increased CD15 in the peripheral blood is associated with the development of squamous metaplasia and may be used to evaluate the severity of ocular surface damage in type II diabetes mellitus patients.

Long-Term Activity and Safety of a Low-Dose Hydrocortisone Tear Substitute in Patients with Dry Eye Disease.

PURPOSE: A clinical trial was conducted to evaluate the activity of a new artificial tear containing hyaluronic acid (HA) and low-dose hydrocortisone to control dry-eye disease (DED) symptoms. METHODS: a randomized, controlled, double-masked study was carried out at the Ocular Surface and Dry Eye Center, "Luigi Sacco" University Hospital (Milan, Italy), between June 2020 and June 2021. The study involved patients with DED for at least 6 months. After an initial 7-day treatment with corticosteroid, the treatment with the new artificial tear (four-times a day for 6 months) was compared with a control HA solution. RESULTS: A total of 40 patients were considered. We observed a significant improvement in the frequency and intensity of DED symptoms in both groups. After corticosteroid discontinuation, the maintenance of the therapeutic advantage was observed only in the treatment group, which also showed a significant improvement of the tear film break-up time (p ≤ 0.05) and infiltrated macrophages (p < 0.05). A significant reduction in fluorescein and Lissamine staining (p < 0.05) was observed in the treatment group, suggesting damage reduction at both corneal and conjunctival levels. Intraocular pressure did not change at the end of the treatment period and was maintained within the normal range, sustaining the product's safety. CONCLUSIONS: Our findings support the prolonged use of the new eye drop with low-dose hydrocortisone, also in the DED initial stages, to prevent the degenerating towards a chronic condition (http://www.isrctn.com/ISRCTN16288419).

TFOS lifestyle: Impact of societal challenges on the ocular surface.

Societal factors associated with ocular surface diseases were mapped using a framework to characterize the relationship between the individual, their health and environment. The impact of the COVID-19 pandemic and mitigating factors on ocular surface diseases were considered in a systematic review. Age and sex effects were generally well-characterized for inflammatory, infectious, autoimmune and trauma-related conditions. Sex and gender, through biological, socio-economic, and cultural factors impact the prevalence and severity of disease, access to, and use of, care. Genetic factors, race, smoking and co-morbidities are generally well characterized, with interdependencies with geographical, employment and socioeconomic factors. Living and working conditions include employment, education, water and sanitation, poverty and socioeconomic class. Employment type and hobbies are associated with eye trauma and burns. Regional, global socio-economic, cultural and environmental conditions, include remoteness, geography, seasonality, availability of and access to services. Violence associated with war, acid attacks and domestic violence are associated with traumatic injuries. The impacts of conflict, pandemic and climate are exacerbated by decreased food security, access to health services and workers. Digital technology can impact diseases through physical and mental health effects and access to health information and services. The COVID-19 pandemic and related mitigating strategies are mostly associated with an increased risk of developing new or worsening existing ocular surface diseases. Societal factors impact the type and severity of ocular surface diseases, although there is considerable interdependence between factors. The overlay of the digital environment, natural disasters, conflict and the pandemic have modified access to services in some regions.

Dealing with the Persistent Pathogenic Issues of Dry Eye Disease: The Importance of External and Internal Stimuli and Tissue Responses.

The immune system plays a central role in protecting the ocular surface from exogenous and endogenous insults, maintaining tissue homeostasis thanks to the mechanism of para-inflammation. This physiological adaptive response may induce resident macrophages/monocytes to produce cytokines and growth factors in order to promote epithelial cell recovery. In case of well-controlled para-inflammation, caused by a low amount of stress, cell viability and function are maintained. When stress becomes too intense, there is a response characterized by the activation of autophagic pathways and consequent cell death. Dysregulated homeostasis and chronic sub-clinical inflammation are the starting points for the development of a stable, chronic inflammatory disease, which leads to ocular surface damage, and, in turn, to the onset or progression of chronic dry eye disease (DED). The long-term management of DED should consider all of the pathogenic issues involved in the disease, including the control of persistent external or internal stresses that are capable of activating and maintaining the para-inflammatory adaptive mechanisms, potentially leading to full-blown inflammation. Dysregulated para-inflammation can be corrected by means of the prolonged use of tear substitutes containing minimal doses of safe corticosteroids or other anti-inflammatory molecules (e.g., corticosteroid, cyclosporine) in order to re-equilibrate ocular surface homeostasis.

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.

The Management of Dry Eye Disease: Proceedings of Italian Dry Eye Consensus Group Using the Delphi Method.

Dry eye disease (DED) is a highly prevalent, chronic and progressive condition that affects 5-33% of the world's adult population [...].

Patient perspectives on dry eye disease and chronic ocular surface pain: Insights from a virtual community-moderated dialogue.

PURPOSE: To understand patients' perspectives on living with dry eye disease (DED), and on the unmet needs in DED and chronic ocular surface pain (COSP) management. METHODS: A moderated, structured discussion with patients with ocular surface diseases and healthcare professionals (HCPs) was conducted using a virtual platform to capture patients' journey with DED, their opinion on unmet needs, and design and conduct of clinical trials in DED and COSP. RESULTS: Nine participants, including four patient representatives from patient organisations, one ophthalmologist and one optometrist participated in the discussion. Patients had DED of varying severity and aetiology; three patients had Sjögren's. Over 4 weeks, 785 posts were entered on the platform. Prior to diagnosis, patients rarely associated their symptoms with DED. Convenience and symptomatic relief scored higher than treating the disease. Patients expressed the need for plain language information and dialogue with knowledgeable and sensitive HCPs. Online forums and social media were suggested as key recruitment resources, whereas convenience and safety concerns were highlighted as main barriers to enrolment. The need for the inclusion of outcome measures that have a real impact on patients' experience of their condition was highlighted. Both target product profiles were received positively by participants, highlighting the twice-daily dosing regimen and convenience of the products. Participants acknowledged the value of digital tools and suggested the need to feel valued post-trial. CONCLUSIONS: This moderated dialogue provided actionable insights on the unmet needs in DED and useful inputs for consideration when designing future clinical trials for DED and COSP.

Artificial Tears: Biological Role of Their Ingredients in the Management of Dry Eye Disease.

Dry eye disease (DED) is the most common ocular surface disease, characterized by insufficient production and/or instability of the tear film. Tear substitutes are usually the first line of treatment for patients with DED. Despite the large variety of tear substitutes available on the market, few studies have been performed to compare their performance. There is a need to better understand the specific mechanical and pharmacological roles of each ingredient composing the different formulations. In this review, we describe the main categories of ingredients composing tear substitutes (e.g., viscosity-enhancing agents, electrolytes, osmo-protectants, antioxidants, lipids, surfactants and preservatives) as well as their effects on the ocular surface, and we provide insight into how certain components of tear substitutes may promote corneal wound healing, and/or counteract inflammation. Based on these considerations, we propose an approach to select the most appropriate tear substitute formulations according to the predominant etiological causes of DED.

Is dry eye disease the same in young and old patients? A narrative review of the literature.

Advanced age is one of the most evident risk factors for dry eye disease (DED), with male/female sex, chronic drug consumption, and prolonged device use. This article aims to review the literature about the changes of the ocular surface associated with DED in the elderly and patients < 40 years. The pathophysiologic changes of the ocular surface responsible for eye dryness are linked with inflammation and neurosensory abnormalities and may occur with a different feature in young patients compared with elders. Peculiar treatment strategies may be needed for young and older subjects with DED.

Is there a role for tapered topical dose steroidal treatment for dry eye disease? A randomized, pilot study.

PURPOSE: To evaluate the effect of tapered doses of loteprednol-etabonate in dry eye disease patients. MATERIALS AND METHODS: Dry eye and treatment outcomes were assessed by Schirmer I test, tear BUT, lissamine green conjunctival staining, fluorescein corneal staining, and HLA-DR expression on conjunctival cells. Patients received either loteprednol-etabonate 0.5% twice daily for 14 days tapered to once daily for 14 days, and then twice weekly for 28 days (n = 10), or NaCl 0.9%. RESULTS: A significant decrease of ocular surface inflammation and improvement of symptoms was recorded in the study group compared with controls at days 14 and 56. Change from baseline in HLA-DR expression in CD45+ conjunctival cells was significantly higher in treated patients at day 14. Intraocular pressure and best corrected visual acuity were preserved in all treated eyes. CONCLUSIONS: Tapered doses of loteprednol etabonate 0.5% suspension controlled ocular surface inflammation, improving dry eye symptoms.

Development of a Novel In Vitro Immuno-Competent Model of Dry Eye Disease and Its Use to Evaluate the Efficacy of an Ocular Surface Modulator.

PURPOSE: To develop an in vitro model of severe immunocompetent-dry eye disease (ic-DED) and to investigate the mechanism of action of a T-lysial ocular surface modulator. MATERIALS AND METHODS: The reconstructed human corneal epithelium (HCE) was exposed to dryness stimuli. THP-1 cell infiltration into HCE was monitored at 4 h and 24 h from T-lysial application by immunohistochemistry (CD14, CD86, AQP3) and molecular biology (AQP3, TLR4 and TNF-α). RESULTS: A reduction of CD14, CD86 and AQP3 was observed after T-lysial treatment at 24 h. TLR4 was overexpressed in ic-DED model and downregulated by T-Lysial after 24 h. TNF-α expression was not modified. CONCLUSION: The ic-DED model can be used to monitor the migration and differentiation of THP-1 into HCE. T-lysial was found to exert anti-inflammatory activity. This experimental model is a promising tool to study the crosstalk between epithelial and immune cells, providing new insights on the mechanisms of DED onset.

Review of Preclinical Outcomes of a Topical Cationic Emulsion of Cyclosporine A for the Treatment of Ocular Surface Diseases.

BACKGROUND: Cyclosporine A (CsA) has been used as a topical treatment for various ocular surface diseases including dry eye disease (DED). Several CsA formulations are available as solutions or emulsions. PURPOSE: This review describes the development and the preclinical testing of a cationic oil-in-water emulsion of CsA (CE-CsA) in terms of pharmacodynamics, pharmacokinetics, and ocular tolerance. Due to the cationic charge, CE electrostatically interacts with the negatively-charged ocular surface, improving its residence time. Compared to other CsA formulations, CE-CsA and CE itself were found to reduce the signs and symptoms of DED, by restoring tear film stability and properties, and inhibiting the expression and secretion of pro-inflammatory factors. No delay in wound healing nor ocular toxicity were observed using CE formulations. CONCLUSION: these findings indicate that the type of vehicle can significantly affect the performance of eye drops and play an ancillary role in DED treatment. CE appears as a promising strategy to deliver drugs to the ocular surface while maintaining its homeostasis.

Efficacy of Lifitegrast Ophthalmic Solution, 5.0%, in Patients With Moderate to Severe Dry Eye Disease: A Post Hoc Analysis of 2 Randomized Clinical Trials.

IMPORTANCE: An investigation of the treatment effect of lifitegrast ophthalmic solution, 5.0%, in different subgroups by severity of dry eye disease (DED) seems warranted. OBJECTIVE: To explore the heterogeneity across different subgroups of DED and identify which participants were most likely to achieve clinically meaningful benefit with lifitegrast treatment. DESIGN, SETTING, AND PARTICIPANTS: This post hoc responder analysis was performed using the data from the phase 3 OPUS-2 and OPUS-3 studies, which were 12-week, prospective, double-masked, multicenter, placebo-controlled, randomized, parallel-arm clinical trials that previously demonstrated the efficacy of lifitegrast in DED. Pooled data were stratified into 4 subgroups based on severity of inferior corneal staining score (ICSS; ≤1.5 vs >1.5) and eye dryness score (EDS; <60 or ≥60) at baseline. Data were collected from December 7, 2012, to October 5, 2015, and post hoc analysis was performed from April 14, 2020, to July 30, 2021. INTERVENTIONS: Lifitegrast or placebo twice daily for 84 days. MAIN OUTCOMES AND MEASURES: Proportion of participants with (1) a clinically meaningful improvement in signs (ICSS or total corneal staining score [TCSS]) and symptoms (EDS or global visual analog scale [VAS]) and (2) a composite response for a given sign and symptom end point pair at day 84 were measured. Clinically meaningful improvement was defined as at least 30% improvement in symptoms (EDS or global VAS) and either at least a 1-point improvement in ICSS or at least a 3-point improvement in TCSS. For the composite responder analysis, the end point pairs were defined as at least a 30% reduction in EDS and at least a 1-point improvement in ICSS; at least a 30% reduction in EDS and at least a 3-point improvement in TCSS; at least a 30% improvement in global VAS and at least a 1-point improvement in ICSS; and at least a 30% improvement in global VAS and at least a 3-point improvement in TCSS. RESULTS: In total, 1429 participants (716 in the placebo group and 713 in the lifitegrast group) were analyzed (1087 women [76.1%]; mean [SD] age, 58.7 [14.3] years). For the overall pooled population, responder and composite responder rates favored lifitegrast vs placebo (odds ratio range, 1.29 [95% CI, 1.05-1.59] to 2.10 [95% CI, 1.68-2.61]; P ≤ .02). In the composite analysis, the subgroup with ICSS of greater than 1.5 and EDS of at least 60 at baseline (ie, moderate to severe DED) demonstrated a 1.70- to 2.11-fold higher odds of achieving clinically meaningful improvement with lifitegrast across all sign and symptom end point pairs (P ≤ .001). CONCLUSIONS AND RELEVANCE: These post hoc findings suggest that lifitegrast ophthalmic solution, 5.0%, treatment may be associated with a response in participants with moderate to severe signs and symptoms of DED. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02284516.

A Narrative Review of Current Understanding and Classification of Dry Eye Disease with New Insights on the Impact of Dry Eye during the COVID-19 Pandemic.

Dry eye disease (DED) is a complex, progressive and multifactorial condition that is commonly seen in clinical practice and can be challenging to accurately diagnose. Untreated or suboptimally managed dry eye can progress to severe, chronic disease which may become resistant to treatment. Symptoms include ocular irritation and visual impairment. Patients frequently report negative consequences regarding quality of life (QoL), productivity and psychological wellbeing. Certain lifestyle factors (e.g. use of screen-based devices, air conditioning) can induce or exacerbate symptoms of DED, leading to progressive and debilitating complications. Exposures to such triggers are likely to have increased significantly during the ongoing COVID-19 pandemic with people across the globe living with heightened levels of stress/anxiety while being forced to adapt most aspects of their daily lives (from work and education through to social activities) to accommodate social distancing, primarily through the use digital technologies. This review aims to provide a concise and practical overview of current understanding regarding DED, highlighting proposals for refined diagnostic categories and therapeutic terminologies that are designed to improve identification and management of dry eye as well as reduce or slow disease progression. Finally, the findings of a European survey are shared to illustrate the impact of the COVID-19 pandemic on the lives of people with DED. The survey was conducted during the first lockdown period (March-September 2020) and explored issues relating to psychological wellbeing, QoL and engagement with healthcare services. The results demonstrate the ways in which the pandemic amplified the impact of dry eye on daily life and may be valuable in enhancing understanding among clinicians of the challenges faced by people with DED, which extend beyond the signs and symptoms of disease.

Are there Clinical Ways to Assess Inflammation in Dry Eye Disease?

In the diagnostic process of dry eye disease, the detection of inflammatory activity is critical in order to evaluate the risk of progression and immunologic shift of the disease, to predict patient response to treatment, and to design an efficient therapeutic strategy, including artificial tear replacement, punctal occlusion or anti-inflammatory therapy.Even if it is difficult to quantify, some indicators of the presence of inflammation are collectible during the examination of the ocular surface in a first-line clinical setting. This review presents and critically discusses the assessment of inflammation in dry eye disease in clinical practice.