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.

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.

Defining Dry Eye from a Clinical Perspective.

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.

The correct diagnosis and therapeutic management of tear dysfunction: recommendations of the P.I.C.A.S.S.O. board.

PURPOSE: To describe a standard approach to manage tear dysfunction (TD), in order to obtain a clinically favourable outcome. TD is a highly prevalent, yet largely underdiagnosed, condition that affects from 5 to 30% of the population above 50 years old. Left untreated, TD is associated with eye discomfort and ocular surface disease, substantially affecting quality of life. Although the prevalence of this problem is increasing significantly, a standard approach to its prevention and treatment is not available yet. METHODS: In September 2015, a team of Ocular Surface Italian Experts convened for a roundtable to discuss on the latest knowledge about diagnosis and treatments for TD and the real issues in the management of these patients. The discussion centred on the appropriate definition of TD, proposing a new classification of risk factors and how to identify them, how to make a correct diagnosis choosing the rational therapy (questionnaires, symptoms' time relation, seasonality, low tech diagnostic manoeuvres, specific tests for the detection of tear film disturbances leading to recognition of the level of disease and of the ocular system elements involved), which artificial tear matches the ideal profile for a rational therapy and which questions should be done to the patient. RESULTS: A multi-item flowchart for tear film dysfunction, with point-by-point explanatory guide, to better identify and manage the patient with this disorder is provided. CONCLUSIONS: The growing prevalence of TD demands increased attention. An appropriate prevention and a treatment pattern for the patient, combined with greater patient-practitioner interaction, and patient education is offered.

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.

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.

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.

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.

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).

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.

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.

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.

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 [...].

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.

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 [...].

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.

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.

Updated definition and classification of dry eye disease: Renewed proposals using the nominal group and Delphi techniques.

The aim of our research was to obtain expert consensus for updated definition and classification of dry eye disease using formal methodology. The nominal group technique (NGT) involved a steering committee of four ophthalmologists began with collection of ideas followed by group discussion. The ideas were collated, refined, and voted upon. The main characteristics considered, each with different degrees of severity in types I, II, and III, were the ability or not of the ocular surface to re-equilibrate itself, frequency of symptoms, presence of inflammation, epithelial alterations, and possible alterations in the quality of vision. This was followed by three rounds of a "mini-Delphi" involving an expert panel of 13 ophthalmologists, with the last round including all 17 ophthalmologists. Consensus in the final round of voting (⩾75% of votes) was reached on the definition of dry eye disease and on criteria for its classification in three forms. Type I is a transient and reversible form with subclinical inflammation, possible epithelial alterations, and occasional alterations in vision. Type II is a recurrent form characterized by a reduced ability to re-equilibrate the ocular surface, frequent symptoms and alterations in vision with clinically-evident inflammation, and clear evidence of epithelial alterations. Type III is a chronic form with inability to re-equilibrate the ocular surface and accompanied by clinically-evident and chronic inflammation, persistent epithelial alterations, and frequent alterations in quality of vision. The vast majority of patients with dry eye disease can be easily classified into one of these three forms. Dry eye disease definition was updated accordingly.

Modern approach to the treatment of dry eye, a complex multifactorial disease: a P.I.C.A.S.S.O. board review.

Dry eye disease (DED) is a growing public health concern affecting quality of life and visual function, with a significant socio-economic impact. It is characterised by the loss of homoeostasis, resulting in tear film instability, hyperosmolarity and inflammation of the ocular surface. If the innate immune response is unable to cope with internal bodily or environmental adverse conditions, the persistent, self-maintaining vicious circle of inflammation leads to the chronic form of the disease. Treatment of DED should be aimed at the restoration of the homoeostasis of the ocular surface system. A proper diagnostic approach is fundamental to define the relevance and importance of each of the DED main pathogenic factors, namely tear film instability, epithelial damage and inflammation. Consideration also needs to be given concerning two other pathogenic elements: lid margin changes and nerve damage. All the factors that maintain the vicious circle of DED in the patient's clinical presentation have to be considered and possibly treated simultaneously. The treatment should be long-lasting and personalised since it has to be adapted to the different clinical conditions observed along the course of the disease. Since DED treatment is frequently unable to provide fast and complete relief from symptoms, empathy with patients and willingness to explain to them the natural history of the disease are mandatory to improve patients' compliance. Furthermore, patients should be instructed about the possible need to increase the frequency and/or change the type of treatment according to the fluctuation of symptoms, following a preplanned rescue regimen.