About the Author(s)


Solani D. Mathebula Email symbol
Department of Optometry, Faculty of Health Sciences, University of Limpopo, Polokwane, South Africa

Lerato Mmusi-Landela symbol
Department of Optometry, Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa

Citation


Mathebula SD, Mmusi-Landela L. Pathophysiology of dry eye disease and novel therapeutic agents. Afr Vision Eye Health. 2024;83(1), a874. https://doi.org/10.4102/aveh.v83i1.874

Review Article

Pathophysiology of dry eye disease and novel therapeutic agents

Solani D. Mathebula, Lerato Mmusi-Landela

Received: 15 Aug. 2023; Accepted: 03 Apr. 2024; Published: 12 June 2024

Copyright: © 2024. The Author(s). Licensee: AOSIS.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Background: Dry eye disease (DED) is one of the most common ocular surface diseases, which is caused by decreased tear production or increased evaporation. It is a growing public health concern as it influences the quality of life and work and visual function.

Aim: This review will update health care professionals about some of the latest research concerning DED and its treatment.

Method: An extensive literature search was conducted on studies that investigated the aetiology, pathophysiology and treatment options of DED.

Results: The search returned 51 articles that were included in this review. All reviewed papers showed that DED is characterised by the loss of homeostasis, resulting in tear film instability, hyperosmolarity and inflammation of the ocular surface.

Conclusion: The causes of DED are complicated and multifactorial but currently, inflammation of the ocular surface is believed to be the main cause. The many different potential topical and systemic treatments have evolved to provide a targeted and effective treatment option from which clinicians can choose. Most of the potential new drugs have been designed to control inflammation and restore the usual or normal quantity of tears.

Contribution: The goal of treatment should be to improve the patient’s symptoms and/or may be even the signs if present, and a good relationship between the patient and doctor is crucial for the management plan.

Keywords: dry eye; DEWS; homeostasis; health-related quality of life; ocular surface; hyperosmolarity; inflammation; tear film instability.

Introduction

Dry eye disease (DED) is a relatively common ocular condition with a prevalence ranging from 5% to 50% in the middle-aged and adult population of various age groups across different countries and worldwide.1,2,3,4,5,6,7,8,9 It has been reported that DED can affect any race and is more common in women than in men. In women at the ages of 50–52 years of age, there is an imbalance between the oestrogen and androgen hormones when menopause occurs.8,9 This imbalance incites inflammation in the lacrimal gland and ocular surface, disrupting the normal homeostatic mechanism of the lacrimal gland and ocular surface.4

Dry eye disease is a disabling disease that can have detrimental effects on both visual function and on an individual’ health-related quality of life (HRQL) and can have a significant socio-economic impact.10,11,12,13,14,15 Because of financial costs and its impacts on quality of life, DED is a true public health care issue as it affects the ability to perform certain crucial daily activities (such as driving, reading, watching television and computer related work), which need visual attention and thus affects the quality of life.10,11,12,13,14,15

Dry eye is understood entirely differently today as compared to two decades ago; however the disease itself has not changed, but the understanding has improved. Traditionally, DED was defined as a disorder of the eye caused by the instability of the tear film because of tear deficiency or excessive evaporation and causes damage to the ocular surface.16 In 2017, the International Dry Eye Workshops17 (DEWS) of the Tear Film and Ocular Surface Society (TFOS) defined DED as a:

[M]ultifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular surface inflammation and damage and neurosensory abnormalities play etiological roles.

This definition is a minor revision of the International DEWS of the TFOS that was published in 2007.18 Both the DEWS and DEWS II recognise dry eye as a disease, which suggests that there must also be diagnostic and management criteria.19 Loss of homeostasis is a term that accounts for a variety of unknown factors.

Homeostasis is currently defined as a self-regulating process by which biological systems maintain stability while adjusting to changing external conditions.20 It is a dynamic process that can change internal conditions as required to survive external challenges. Tear homeostasis is achieved automatically by the lacrimal function unit (LFU), which consists of the ocular surface structures (cornea, eyelids, conjunctiva and meibomian glands), goblet cells and the lacrimal glands and the neural connections. Even the innate and adaptive immune systems are involved in regulating the ocular surface environment to protect and maintain ocular homeostasis.20,21,22,23

The open eye is constantly subjected to dehydrating stress because of evaporation of tears and adverse environmental conditions, such as excessive and prolonged use of visual display unit, low relative humidity and/or excessive wind or air conditioning but is protected from drying up and damage by homeostatic mechanisms that regulate tear secretion and distribution in response to negative feedback cycle signals from the ocular surface. Failure or disruption of homeostatic mechanisms leads to a vicious cycle of hyperosmolarity and instability of the tear film, wetting defects, increased friction and mechanical irritation at the ocular surface, inflammation of the ocular surface and the lacrimal gland and neurosensory abnormalities.24,25

With the increasing cases of DED in recent years, the disease is receiving much more attention as it can lead to ocular discomfort that affects the work and quality of life of an individual. Hence, the purpose of this paper was to update health care professionals on the latest research of DED and related treatments.

Methods

A comprehensive literature search was conducted using Medline and ScienceDirect. A total of 210 articles published from 1980 to 2023 were found in relation to dry eye treatment or management. Of these, 51 articles were included in this analysis (see Figure 1). Exclusion criteria included case reports, non-English studies and articles that were unrelated to the primary subject of this review.

FIGURE 1: Flow diagram of study selection for review.

Ethical considerations

Ethical clearance to conduct this study was obtained from the University of Limpopo, Research Ethics Committee (No. TREC/196/2015:IR).

Results

The database search identified 210 articles. After removing 33 duplicates, the titles and abstracts of the remaining 177 articles were screened. After the screening, 66 articles were further excluded as they were irrelevant to the topic. The full text of the remaining 60 articles was reviewed. There were a further 60 articles that did not clearly report the pathogenesis of DED, and they were excluded; hence 51 articles were finally included in this review.

Discussion

The ocular surface is covered with a specialised stratified epithelium that serves as a barrier to environmental, microbial and inflammatory insults. Conjunctival epithelium has a high density of mucus-producing goblet cells and a variety of resident immune cells that function primarily in antimicrobial defence. The open eye, especially the cornea epithelium, is constantly subjected to extrinsic desiccating stress through evaporation of tears, but the eyes withstand daily environmental challenges from damage by the homeostatic mechanisms that regulate tear secretion and distribution in response to signals from the ocular surface.6,17,18.21,22 It has been reported that the lacrimal gland and ocular surface epithelia also produce several antimicrobial factors that are present in the tear film to maintain a microenvironment.24,25

Dysfunction of more than one tear producing cells and/or glands leads to unstable tear film. Increased tear osmolarity (hyperosmolarity) is the hallmark or core mechanism of DED that activates stress signalling pathways in the ocular surface epithelium and triggers production of innate inflammatory molecules that initiate a vicious cycle that leads to decline in tear function and worse symptoms. The inflammatory cascades induce and contribute to corneal epithelial cell death and loss of goblet cells.

Tear hyperosmolarity is common to all subtypes of DED. Numerous extrinsic and/or intrinsic factors promote an unstable hyperosmolar tear film, which creates a vicious inflammatory cycle that leads to ocular surface damage. Hyperosmolar stress has a direct proinflammatory effect on the ocular surface epithelium as it activates mitogenic-activated protein kinase that stimulates secretion of proinflammatory cytokines and chemokines and induces apoptosis.24 This is an important source of symptoms and compensatory responses that ultimately lead to chronic ocular surface damage.24,25 Stress to the ocular surface (extrinsic or intrinsic) is believed to be the pathogenic triggering mechanism.

Diagnosis of dry eye disease

The common symptoms of DED include gritty feeling, burning or itching in the eyes, foreign body sensation, dryness of eyes, eye redness, pain, excess tearing, photophobia in some cases, blurred vision, fluctuating vision and visual fatigue.18,26,27,28,29 Sometimes the symptoms are associated with a stringy discharge.18 However, the cause of DED can be difficult to determine because of seasonal weather conditions, most notably wind and sunshine. It is important that a proper diagnostic approach considers all the factors that contribute to the vicious cycle during the patient’s clinical presentation, so that an effective, long-lasting and personalised treatment can be administered.

Dry eye disease has multifactorial aetiologies and pathophysiology that lead to tear instability and signs and symptoms of ocular surface disease. However, there is a poor correlation between the signs and symptoms of DED. The diagnosis of DED is based on the combination of symptoms, signs and clinical test given that any one of these alone could misdiagnose patients. Although clinical history and examination remain the key DED diagnostics, ancillary testing with newer imaging technology has added much-needed resources. Although the invasive tear breakup time (TBUT) and Schirmer test are the traditional testing methods and remain essential components for tear film stability and volume (production), they are subjective and influenced by many factors, such as fluorescein volume.30 Several non-invasive tests now provide objective measure of the tear film stability, such as tear meniscus height, lipid layer thickness and non-invasive TBUT, tear osmolarity, inflammatory biomarkers and meibomian gland imaging.31,32

Ocular surface cell staining is one of the evaluation indexes of the severity of dry eye. When the integrity of ocular surface cells has been damaged, they can be stained to display the defects. The degree and area of staining are related to the severity of the ocular surface damage and can be used to evaluate the barrier function and integrity of epithelial cells.33 Although fluorescein sodium stain is commonly used in clinical setting, lissamine green and rose Bengal staining are sometimes used.

Treatment for dry eye disease

The treatment of DED is challenging because of a lack of a single clinical assessment and the variation of symptoms. The medical management of DED may range from education, environmental or dietary modifications, artificial tears and topical and/or systematic anti-inflammatory medications.33,34,35,36,37,38,39,40,41,42

Artificial tears are the first line of treatment.33,34,35,36,37,38,39,40,41,42 They are used as lubricant eye drops. Preservatives are added to some artificial tears to reduce the risk of bacterial contamination and to prolong shelf-life, but potentially may become a risk of adverse effects with frequent use for an individual.28 In moderate-to-severe DED with ocular surface inflammation, anti-inflammatory and immune-suppressive treatments are essential.26,27 The control and reduction of ocular surface inflammation is another key component of any treatment regime as it is an important contributor to the vicious cycle of DED. Non-steroidal anti-inflammatory drugs (NSAIDs), such as pranoprofen and sodium hyaluronate, can relieve the symptoms of DED by effectively stimulating the secretion of tears.31 However, NSAIDS are not recommended for patients with mild DED because of low humidity and smoke exposure. Non-steroidal anti-inflammatory drug ointments contain antibiotics (such as erythromycin and bacitracin), which are commonly used for treatment of meibomian gland dysfunction.39

Topical corticosteroids (such as prednisolone, fluometholone, dexamethasone and loteprednol etabonate) are effective in the treatment of moderate-to-severe DED for 2–4 weeks as prolonged use may result in complications such as glaucoma, cataract and ocular infection.18,41 Topical cyclosporine A is an immunosuppressant, which is used for management of ocular surface inflammation of moderate-to-severe DED.40 Unlike corticosteroids, cyclosporine A requires a longer period to become effective in controlling inflammation.

Vitamin A (retinol) is naturally present in tear film of healthy eyes, and it plays a pivotal role in production of the mucin layer (the innermost layer of the tear film).26,41 Vitamin A deficiency leads to loss of the mucin layer, which is crucial for a healthy tear film.41 Vitamin A drops protect the eye from inflammation, toxins and allergens. It has been reported that cyclosporin A eye drops combined with Vitamin A was found to significantly increase the amount of tear secretion in dry eye of rats, prolonged the tear film break up time.42 Oral supplementation with essential fatty acids (omega-3 and omega-6) has been reported to decrease inflammatory mediators in dry eye patients by improving ocular irritation symptoms and tear stability and can inhibit conjunctival dendritic cell maturation.39 Omega-3 fatty acid may be suggested nowadays to help relieve DED. As supplementation with commensal microbiota has anti-inflammatory effect in autoimmune conditions (such as diabetes mellitus and inflammatory bowel disease), it is possible that metabolites of commensal bacteria or probiotic could have a therapeutic potential for DED.

Future of dry eye disease treatment

Dry eye disease, whether a result of aqueous deficiency or evaporative disorder, is both a primary and secondary disease because of many different pathological conditions of the eye. It has been treated as an inflammatory process and has benefited many patients; however, there is a need for drugs to target the inflammatory cascade. There are numerous promising pharmaceutical agents that are being developed for treatment of DED.43,44,45,46,47,48,49,50,51

Rebamipide (Otsuka Pharmaceutical Co, Tokyo, Japan) is a mucin secretagogue, which is used for the treatment of gastric mucosal disorders and gastritis.45 Goblet cell loss in the conjunctiva and decreased mucin of the corneal surface are recognised features of aqueous tear deficiency. Rabamipide is a potential drug to stabilise the mucin component of the tear film. Nerve growth factor has been shown to have mucin secretagogue activity in conjunctival cells and can play a role in corneal wound healing.44 Human serum albumin (R-Tech Ueno, Tokyo, Japan) is being investigated for the treatment of severe DED.45,46

Devices are being developed for dry eye therapy. The Oculoeve neurostimulator device (Oculeve Inc, San Fransisco, CA, USA) will be inserted into the mucosa membrane in the nasal cavity to stimulate tear production.45,46 The EyeGate II system (EyeGate, MA, USA) I designed to deliver drugs to the conjunctiva and sclera while a small current will be applied to the ocular surface to create an electric field that will mobilise charged particles across the anterior and posterior segment of the eye will also be helpful.45,46 The drug delivered by this system may achieve higher concentration than it would if delivered topically.

Autologous serum tears provide a natural substitute for many bioactive proteins, vitamins and lipids that are typically present in human tears, and they provide symptomatic relief in many subtypes of DED.47,48,49

Dry eye disease is a difficult disease to pin down considering its many possible aetiologies, signs and symptoms. Artificial intelligence promises to potentially aid DED diagnosis and management in the future.50,51

Conclusion

The purpose of this review was to update health care professionals of the challenges and management of DED, as lubrication with a variety of artificial tear supplements is palliative and not corrective of the underlying pathology of the disease. An effective approach for the treatment of DED should include assessment of the patients’ lifestyle and pharmacological interventions. The goal of treating DED is to improve patients’ symptoms and signs while restoring tear homeostasis.

Acknowledgements

Competing interests

The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article.

Authors’ contributions

Both authors, S.D.M. and L.M-L., contributed equally to this work.

Funding information

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

Data availability

The data that support the findings of this study are available on reasonable request from the corresponding author, S.M.

Disclaimer

The views and opinion expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.

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