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.

How gut microbiota may impact ocular surface homeostasis and related disorders.

Changes in the bacterial flora in the gut, also described as gut microbiota, are readily acknowledged to be associated with several systemic diseases, especially those with an inflammatory, neuronal, psychological or hormonal factor involved in the pathogenesis and/or the perception of the disease. Maintaining ocular surface homeostasis is also based on all these four factors, and there is accumulating evidence in the literature on the relationship between gut microbiota and ocular surface diseases. The mechanisms involved are mostly interconnected due to the interaction of central and peripheral neuronal networks, inflammatory effectors and the hormonal system. A better understanding of the influence of the gut microbiota on the maintenance of ocular surface homeostasis, and on the onset or persistence of ocular surface disorders could bring new insights and help elucidate the epidemiology and pathology of ocular surface dynamics in health and disease. Revealing the exact nature of these associations could be of paramount importance for developing a holistic approach using highly promising new therapeutic strategies targeting ocular surface diseases.

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.

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).

Possible Strategies to Mitigate Placebo or Vehicle Response in Dry Eye Disease Trials: A Narrative Review.

Many candidate drugs for dry eye disease (DED) have been assessed over the years in pursuit of demonstrating efficacy in both signs and symptoms. However, patients with DED have very limited treatment options for management of both signs and symptoms of DED. There are several potential reasons behind this including the placebo or vehicle response, which is a frequent issue observed in DED trials. A high magnitude of vehicle response interferes with the estimation of a drug's treatment effect and may lead to failure of a clinical trial. To address these concerns, Tear Film and Ocular Surface Society International Dry Eye Workshop II taskforce has recommended a few study design strategies to minimize vehicle response observed in DED trials. This review briefly describes the factors that lead to placebo/vehicle response in DED trials and focuses on the aspects of clinical trial design that can be improved to mitigate vehicle response. In addition, it presents the observations from a recent ECF843 phase 2b study, wherein the study design approach consisted of a vehicle run-in phase, withdrawal phase, and masked treatment transition, and led to consistent data for DED signs and symptoms and reduced vehicle response post randomization.

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.

Patient-reported burden and overall impact of dry eye disease across eight European countries: a cross-sectional web-based survey.

OBJECTIVE: Dry eye disease (DED) is a multifactorial disease involving the tears and ocular surface. It impacts a patient's quality of life (QoL) and ability to perform daily activities. This study assessed the burden of self-reported DED among adults in eight European countries. DESIGN: Online cross-sectional survey. SETTING: General population in France, Italy, Germany, Greece, the Netherlands, Portugal, Spain and Sweden. PARTICIPANTS: Adults aged ≥18 years with (n=6084) and without (n=6161) self-reported DED were recruited via emails and screened. MAIN OUTCOME MEASURES: All participants completed National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25) and EuroQol-5 Dimension-5 Level Questionnaire (EQ-5D-5L). All DED participants completed the Eye Dryness Score (EDS) Visual Analogue Scale, and Ocular Comfort Index and Work Productivity and Activity Impairment Questionnaire: Specific Health Problem questionnaires. In addition, half of the respondents with DED completed Survey A (Impact of Dry Eye on Everyday Life) and the other half completed Survey B (Standard Patient Evaluation of Eye Dryness Questionnaire) and Dry Eye Questionnaire-5. RESULTS: Participants with self-reported DED had lower functional vision and lower overall health status than participants without self-reported DED as measured by the NEI-VFQ and EQ-5D-5L, respectively.Increasing self-reported DED severity as measured by the EDS was shown to correspond with worse symptom severity/frequency, lower functional vision, higher impact on work productivity, daily activities and QoL. CONCLUSION: This study showed that patients' reported burden of self-reported DED was similar across the eight European countries. Those with self-reported DED reported lower health status and functional vision compared to those without self-reported DED and these parameters worsen with increasing disease severity.

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.

Management of inflammation in dry eye disease: Recommendations from a European panel of experts.

INTRODUCTION: Early initiation of anti-inflammatory therapies is recommended for dry eye disease (DED) to break the vicious cycle of pathophysiology. However, there is limited guidance on how to implement topical ciclosporin (CsA) and corticosteroid treatment into clinical practice. This expert-led consensus provides practical guidance on the management of DED, including when and how to use topical CsA. METHODS: A steering committee (SC) of seven European DED experts developed a questionnaire to gain information on the unmet needs and management of DED in clinical practice. Consensus statements on four key areas (disease severity and progression; patient management; efficacy, safety and tolerability of CsA; and patient education) were generated based on the responses. The SC and an expanded expert panel of 22 members used a nine-point scale (1 = strongly disagree; 9 = strongly agree) to rate statements; a consensus was reached if ≥75% of experts scored a statement ≥7. RESULTS: A stepwise approach to DED management is required in patients presenting with moderate corneal staining. Early topical CsA initiation, alone or with corticosteroids, should be considered in patients with clinical risk factors for severe DED. Patient education is required before and during treatment to manage expectations regarding efficacy and tolerability in order to optimise adherence. Follow-up visits are required, ideally at Month 1 and every 3 months thereafter. Topical CsA may be continued indefinitely, especially when surgery is required. CONCLUSION: This consensus fills some of the knowledge gaps in previous recommendations regarding the use of topical corticosteroids and CsA in patients with DED.

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 [...].

Special Issue "Managing Dry Eye Disease over Time: An Italian Consensus Conference".

Dry eye disease (DED) is a chronic, progressive, highly prevalent condition affecting 5 to 33% of the global adult population [...].

Management Strategies for Evaporative Dry Eye Disease and Future Perspective.

Dry eye disease (DED) is a common disorder that remains challenging from a clinical perspective. Unstable or deficient tear film is a major factor contributing to DED and the inability to resolve the loss of tear film homeostasis that accompanies DED can result in a vicious circle of inflammation and treatment-refractory disease. Recently recognized as a multifactorial disease, the main etiological subtypes of DED are aqueous-deficient and evaporative which exist on a continuum, although evaporative dry eye (EDE) is the more frequent classification. Although attaining greater recognition in recent years, there is currently no consensus and no clear recommendation on how to manage EDE. Clarity on the early diagnosis and treatment of EDE may facilitate the avoidance of progression to chronic inflammation, permanent damage to the ocular surface, and treatment-refractory disease. The purpose of this review was to identify current best practice for management of EDE in order to help clinicians in providing accurate diagnosis and optimized treatment. We summarize recent literature considering the role of the lipid layer on tear film stability, the importance of its composition and of its dynamic behavior, and the link between its malfunction and the insurgence and maintenance of tear film-related diseases. We have provided an assessment of the best management of lipid-deficient EDE based upon an understanding of disease pathophysiology, while indicating the flow of current treatments and possible future evolution of treatment approaches. Lipid containing eye drops may be considered as a step closer to natural tears from artificial aqueous tears because they more closely mimic the aqueous and lipid layers and may be used in combination with other management approaches. As a next step, we recommend working with a wider expert group to develop full guidelines to enable patient-centered management of EDE. Key pointsDry eye is a multifactorial disease of variable presentation with the tendency to become a chronic disease for which it is essential to identify and treat the main pathogenic mechanisms involved and tailor the treatment to the individual patient.Early intervention is needed to prevent the vicious cycle of DED and may require a multi-faceted management approach.EDE is not just a problem of MGD but can be the result of anything affecting blinking, mucin spreading, aqueous layer volume and content.Lipid-containing eye drops may provide significant relief of symptoms by improving the lipid layer and its spreading ability and, as such, are an appropriate component of the overall management of lipid-deficient EDE; natural lipid-containing eye drops should be the preferred treatment.

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 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.

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.

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.

The Subtle Role of Para-inflammation in Modulating the Progression of Dry Eye Disease.

In patients with DED, the continuous stimuli induced by excessive or persistent cold fiber sensors and overstimulation of nociceptors, as well as tear hyperosmolarity induced by evaporative stress, induce a transitory protective adaptation response called para-inflammation to restore ocular surface homeostasis. This mild subclinical inflammatory status (a type of hormetic response) can become chronic if the stimuli or tissue malfunction is present for a sustained period, causing persistent symptoms and damage to ocular surface epithelia.We review the mechanisms that characterize the transition from para-inflammation to a persistent inflammatory status of the ocular surface, including accumulation of biological waste and damaged/dysfunctional proteins, which, in normal conditions, are eliminated by autophagy, activation of the inflammasomes, and what is currently known about their role in DED pathogenesis. Furthermore, we analyze current treatments that can modulate the inflammatory response of the ocular surface and speculate about new possible therapies to treat para-inflammation.

The Enduring Experience in Dry Eye Diagnosis: A Non-Interventional Study Comparing the Experiences of Patients Living With and Without Sjögren's Syndrome.

INTRODUCTION: Previous studies have examined the patient experience regarding the diagnosis and management of dry eye disease (DED). The current study explored the ways in which the DED diagnostic pathway differs for those living with and without Sjögren's syndrome (SS), to identify aspects that influence the patient experience and associated quality of life (QoL). METHODS: An observational/descriptive, non-interventional, retrospective, self-reported online survey was conducted among adults living in France, Spain and Italy who were diagnosed with DED (with/without SS), were using topical DED treatments (≥ 6 months), and were not contact lens users. Recruitment was via an online database for non-SS participants and through local patient advocacy groups for SS respondents. RESULTS: The analysis included 827 respondents; 416 (50.3%) had SS and 82% were female. The mean age was 55 (SD 11; range 16-99) years. The mean age at diagnosis was 46 (SD 12; range 13-78) years and 50 (SD 10; range 21-73) years for SS and non-SS groups, respectively (p < 0.0001). The mean time to diagnosis was extended for SS participants [32 (SD 62) months] versus non-SS individuals [8.6 (SD 28) months (p < 0.0001)] and was associated with reduced QoL scores (r = 0.113; p = 0.0169). More SS participants (31%) consulted ≥ 4 healthcare professionals (HCPs) before DED diagnosis, versus non-SS individuals (6%) (p < 0.0001). Diagnosing clinician varied for SS respondents according to country, probably due to differences in healthcare systems/structures. More SS participants viewed their condition as a handicap than a discomfort, reporting greater QoL impact (p < 0.0001). CONCLUSIONS: Patient experiences in DED diagnosis vary substantially when comparing SS and non-SS individuals. Time to diagnosis significantly impacts QoL for SS patients, who see more HCPs ahead of DED diagnosis. The number of HCPs consulted before diagnosis and perceptions of DED are important for both groups. Country-specific variations highlight opportunities to improve consistency and efficiency across DED diagnostic pathways. These data should be considered alongside existing evidence from high-quality sources (e.g. clinical records).

The ocular microbiome and microbiota and their effects on ocular surface pathophysiology and disorders.

The ocular surface flora perform an important role in the defense mechanisms of the ocular surface system. Its regulation of the immunological activity and the barrier effect against pathogen invasion are remarkable. Composition of the flora differs according to the methods of investigation, because the microbiome, composed of the genetic material of bacteria, fungi, viruses, protozoa, and eukaryotes on the ocular surface, differs from the microbiota, which are the community of microorganisms that colonize the ocular surface. The observed composition of the ocular surface flora depends on harvesting and examining methods, whether with traditional culture or with more refined genetic analysis based on rRNA and DNA sequencing. Environment, diet, sex, and age influence the microbial flora composition, thus complicating the analysis of the baseline status. Moreover, potentially pathogenic organisms can affect its composition, as do various disorders, including chronic inflammation, and therapies applied to the ocular surface. A better understanding of the composition and function of microbial communities at the ocular surface could bring new insights and clarify the epidemiology and pathology of ocular surface dynamics in health and disease. The purpose of this review is to provide an up-to-date overview of knowledge about this topic.

Iatrogenic Dry Eye Disease: Dealing with the Conundrum of Post-Cataract Discomfort. A P.I.C.A.S.S.O. Board Narrative Review.

The incidence and prevalence of dry eye disease (DED) after cataract surgery is greatly underestimated. The severity of dry eye symptoms has been reported to peak 7 days after cataract surgery and may persist for months, significantly affecting patients' quality of life (QoL). The importance of considering surgical outcomes not only in terms of visual acuity, but also in terms of the patients' QoL, necessitates the assessment and evaluation of the ocular surface by the cataract surgeon prior to the procedure. This narrative review, drafted by the P.I.C.A.S.S.O. (Italian Partners for the Correction of Ocular Surface Alterations) board, analyses the physiopathology of post-cataract surgery DED and highlights the pre-, intra- and postoperative risk factors that may alter ocular surface homeostasis; it proposes a practical comprehensive algorithm for the prevention, treatment and management of DED associated with cataract surgery. Particular attention needs to be paid to the pre- and intraoperative risk factors to reduce the incidence of postoperative dry eye and to improve cataract surgery outcome.