Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
To purchase hard copies of this book, please contact the representative in India:
CBS Publishers & Distributors Pvt. Ltd.
www.cbspd.com
|
customercare@cbspd.com
Ocular surface inflammation is one of the major features of dry eye disease (DED) according to the definition proposed by the Tear Film and Ocular Surface Society (TFOS) International Dry Eye Workshop (DEWS) in 2007 and 2017. This chapter discusses the potential pathomechanism of the DED vicious cycle and focuses on the role of chronic inflammation and flares in DED pathophysiology. Ocular inflammation may be regarded as both a cause and effect of DED. The current understanding of the mechanism responsible is that the repeating desiccating stress accompanied by hyperosmolarity induces the immune system reaction, leading to the chronic inflammation and apoptosis of ocular surface cells. On the cellular level, there is growing evidence from experimental, animal, and human studies that Th17 lymphocytes play a crucial role in DED pathogenesis. Also, potential methods of anti-inflammatory methods of treatment are discussed, such as eye lubricants, autologous serum eye drops, topical steroids, oral and topical immunomodulation drugs, and N-acetylcysteine (NAC). Understanding the role of inflammation on the cellular and molecular level may lead to improve treatment options for patients. A new approach to DED treatment should be focused to target not only symptoms but also break the pathological dry eye cycle.
Clinical Department of Ophthalmology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
Ophthalmology Department, District Railway Hospital, Katowice, Poland
*Address all correspondence to: anna.nowinska@sum.edu.pl
1. Introduction
Dry eye disease is a multifactorial 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 [1].
Historically, dry eye was mostly considered to be caused by a simple tear deficiency. According to the current definition of the disease, proposed by the Tear Film and Ocular Surface Society (TFOS) International Dry Eye Workshop (DEWS) in 2017, inflammation is one of the major features of the disease accompanied by tear film instability and hyperosmolarity, ocular surface damage, and neurosensory abnormalities. The proposed mechanism of the disease is the self-perpetuating vicious cycle, in which the loss of homeostasis of the tear film plays a major role. The mechanism was broadly introduced in 2007, further adopted by the TFOS DEWS II committee, and remains the leading concept of DED pathophysiology [2, 3]. Meibomian gland dysfunction (MGD) is at the center of the vicious cycle of DED. As shown in Figure 1, MGD is a key trigger of tear film instability, inflammation, ocular surface apoptosis, and neurosensory abnormalities. Understanding the pathophysiology of DED has significant implications for the methods of diagnosis and methods of treatment. Anti-inflammatory therapies are already available in DED treatment, but understanding their role and differences among them is crucial in successful patient management.
Figure 1.
The simplified vicious cycle of DED based on [1, 2, 3].
2. Epidemiology, forms, severity, symptoms, signs, and risk factors of DED
DED remains one of the global health problems characterized by the significant impact on the quality of life of patients. It has a global prevalence ranging from 20 to 50%. Data on the prevalence of DED reported over the last 10 years vary widely, which is related to, among others, different standardization of study groups, the lack of uniform diagnostic criteria, the selection of subjective tests (questionnaires of vision quality), and ocular surface examinations to confirm the DED diagnosis. The results of studies based on subjective symptoms indicate the prevalence of DED in the range from 5 to 50%, while studies based on ocular tests indicate the prevalence of up to 75% of the population. International epidemiological studies have estimated the prevalence of DED from 5% to 30% in the population over 50 years of age. The disease is more common in women (1.3–1.5 times more prevalent than in men) and Asians, and its prevalence increases with age [4].
There are two major forms of DED: evaporative DED (EDE) and aqueous deficient dry eye (ADDE). EDE is a predominant form of DE responsible for about 70% of cases. MGD is considered to be the main cause of EDE. MGD is at the center of the vicious cycle of DED. International workshop on MGD defines MGD as a chronic diffuse abnormality of MG that is commonly characterized by terminal duct obstruction or qualitative or quantitative changes in glandular secretion [5]. Key pathophysiological features of MGD are gland blockade due to hyperkeratinization, ductal stenosis, and chronic stagnation of the meibum. That ultimately leads to gland atrophy and alternations in the lipid tear film layer. MGD may be considered a key trigger of tear film instability, inflammation, apoptosis, and neurosensory abnormalities.
In terms of severity, the predominant forms of DED are mild and moderate. Severe cases are mostly related to systemic, autoimmune diseases (such as rheumatoid arthritis, polyarteritis nodosa, systemic sclerosis), Sjogren syndrome (Sjogren syndrome dry eye; SSDE), and graft-versus-host disease (GVHD).
The impact of DED on the quality of patients’ life is significant. This disease has been shown to have a negative impact on patient’s daily activities. Due to DED, affected patients may experience decreased productivity as a result of irritating and chronic symptoms. There are several studies underlining the relationship between DED and sleep disorders or depression [6, 7]. Major complaints include pain, eye irritation, foreign body sensation, blurred vision, burning, dryness or watery eyes, fluctuating vision, and photophobia.
If symptoms are accompanied by ocular signs, namely homeostasis markers including decreased tear breakup time (TBUT), increased hyperosmolarity, and positive ocular surface staining the diagnosis of DED may be made. Further, division based on ocular signs includes evaporative and aqueous deficiency DED, as presented in Figure 2.
Figure 2.
Diagnostic algorithm of a patient with DED. OSDI—ocular surface disease index; NIBUT—non-invasive tear break up time; MGD—meibomian gland dysfunction; TMH—tear meniscus height; the following sequence of diagnostic tests is recommended: NIBUT, osmolarity test, FBUT with fluorescein (fluorescein tear break up time), ocular surface staining. The diagnostic algorithm is based on the TFOS DEWS II methodology recommendation [8].
Risk factors of DED were established based on studies with different evidence levels. The epidemiology committee of TFOS DEWS II gathered all risk factors and divided them into mostly consistent, probable, or inconclusive factors. Factors were also stratified into non-modifiable and modifiable risk factors [4]. The risk factors of DED were presented in Table 1.
Risk factor
Non-modifiable
Modifiable
Consistent
Aging Female sex Asian race Meibomian gland dysfunction Connective tissue diseases Sjőgren Syndrome
DED is a disease of many etiological factors, multiple forms, and different severity; therefore, the various management and therapeutic options according to disease form and severity should be considered. Also, regarding the strong association with indoor and outdoor environmental factors, the management and therapy report committee recommends the following strategies, as a part of the initial management of the disease, education regarding the condition, its management, treatment, and prognosis, modification of the local environment, education regarding potential dietary modifications (including oral essential fatty acid supplementation), and identification and potential modification/elimination of offending systemic and topical medications [9].
Understanding the role of inflammation on the cellular and molecular level may lead to improve treatment options for DED patients. Ocular inflammation may be regarded as both a cause and effect of DED. The current understanding of the mechanism responsible is, that the repeating desiccating stress accompanied by hyperosmolarity induces the immune system reaction leading to the chronic inflammation and apoptosis of ocular surface cells. It is important to acknowledge, that different form of DED, such as SS-DED (SS—Sjogren syndrome) and non-SS DED are related to various inflammatory microenvironment. Also, there are significant differences between an acute and chronic state of DED in term of the inflammatory response.
It is also worth emphasizing that regardless of the underlining cause, DED and ocular surface allergy (OA) share common pathognomonic pathways [10]. The chronic and acute reaction of the immune system in atopy, OA, and DED is related to ocular inflammation on the cellular level and its impact on the molecular homeostasis. Inflammatory biomarkers, which are significantly elevated in both conditions include matrix metalloproteinase-9 (MMP-9), Interferon-gamma (INFγ), IL-1α, IL-2, IL-6, IL-8, IL-17, and IL-22. Moreover, cytokines previously regarded as specific to OA are also elevated in DED, and those include IL-4, IL-5, and IL-13. MMP-9 is a proteolytic enzyme, expressed by eosinophils, correlated to the epithelial, and conjunctival cells interruption. MMP-9 level may be assessed in DED and OA patients using commercially available tests. IFN-γ is an inflammatory cytokine secreted by numerous cells such as epithelial cells, CD+T cells, and NK cells. It is one of the major indicators of the ocular surface inflammation. IL-17, IL-22, and IL-6 are the known effector cytokines of Th17 lymphocytes, which are characteristic for both DED and OA [11].
In vivo confocal microscopy (IVCM) allowed us to broaden our knowledge regarding the cellular changes in DED. Specific changes are as follows: the increased stromal nerve thickness and tortuosity, the decreased density of basal epithelial cells, stromal keratocytes, and subbasal nerves, and the presence of dendritic cells, leukocytes, activated keratocytes, and increased level of epithelial and stromal reflectivity [12, 13]. All those features revealed by the IVCM exam, which are characteristic for DED provides a direct, clinical proof, the inflammation plays a crucial role in DED pathogenesis.
On a molecular level, it has been established that proinflammatory cytokines (IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-13, IL-17, IL-22, TNFα, tumor necrosis factor α, and INFγ) are over-expressed in the tear film and ocular surface of patients DED [14].
3.1 Cytokines
Inflammation in DED may begin as an acute immune reaction in response to desiccating stress. Mitogen-activated protein (MAP) kinases and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) play a crucial role in initiating and maintaining the immune reaction, leading to the release of pro-inflammatory cytokines, such as TNF-α, IL-1β, and IL-6 on the ocular surface. Activation of toll-like receptor 4 (TLR4) also causes the activation and secretion of pro-inflammatory cytokines, such as IL-1β. At the same time, regardless of the TLR4-mediated pathway, the release of reactive oxygen species (ROS) induces activation of caspase-8 and NLRP3 inflammasome, also promoting the IL-1β release. The process leads to increased expression of MMP-9, a proteolytic enzyme known to break the epithelial corneal barrier and cause punctate keratitis.
3.2 CD+ T cells
There is growing evidence from experimental, animal, and human studies that CD+ T cells play a crucial role in DED pathogenesis. The initiating factor results in the loss of the ocular surface immune homeostasis, and the activation of CD4+ T cells are the leading factors of the tear film instability, hyperosmolarity, ocular surface damage, and neurosensory abnormalities. It is well proved that CD+ T cells differentiate in response to the local microenvironment of cytokines and are defined by their transcription factor expression. With an excess concentration of INFγ and IL-12, CD+ T cells differentiate into Th1 lymphocytes, while in the concentration of Il-6 and TGF-β (transforming growth factor beta), they may differentiate into Th17 lymphocytes. Further, ocular surface damage is caused by proinflammatory cytokines released by Th1 and Th17 lymphocytes, which stimulate the production of MMP-3, and MMP-9. Th17 lymphocytes produce Il-17, which damages the epithelial barrier function and causes apoptosis. Moreover, Th17 lymphocytes are characterized by phenotypic and functional plasticity, which lineage throughout the disease initiation, perpetuation, and sustention. Th17 cells are plastic and can differentiate into Th1 or Th2 subsets depending on environmental stimuli. Recently a new, autoimmune model of DED pathogenesis was proposed based on the concept of Th17 cells mediated disruption of ocular surface immune homeostasis that leads to DED [14]. This model is presented in Table 2.
1. Hyperosmolar stress, desiccating stress
2. Induction of adaptive Th17 cells immunity in the ocular surface
2.1. Release of TNF-α, IL-1β, and IL-6 by mucosal lining cells
2.2. Ocular surface infiltration of monocytes, macrophages, NK cells
2.3. Activation of antigen-presenting cells (APC) on the corneal and conjunctival epithelium
2.4. Lymphatic vessels formation
3. Reaction in the draining lymph nodes
3.1. T cell priming and Th17 cells differentiation
3.2. Dysfunction of inflammation-limiting regulatory T cells (Treg)
3.3. Expansion and full activation of Th17 cells
3.4. Th 17 cells humoral activation: IL-17, IFN-γ
4. Peripheralization of effector Th17 cells
5. Ocular surface damage, punctate epitheliopathy caused by Th17 cells through humoral response: IL-17, IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF)
Table 2.
The autoimmune model of DED pathogenesis based on [14].
3.3 Differences in inflammatory response in relation DED form and chronicity
There is a difference between an acute and chronic DED in terms of the inflammation activation. Chronic DED is principally mediated by effector memory of Th17 cells because Th17 cells persist in chronic phase of DED. After the resolution of acute inflammation on the ocular surface, a part of effector Th17 cells pool (both eTh17 and eTh17/1 cells) converts into long-lived memory Th17 cells (mTh17). This population of cells is responsible for chronic inflammation. Based on animal studies it was proved, that aged mice (12–14 months) develop a more severe DED than in young mice (6–8 weeks). Aged mice had increased frequencies of conjunctival and draining lymph nodes Th17 cells compared to young mice [15]. Therefore, anti-IL-15 was proposed to reduce the memory of Th17 cells and further the severity of DED.
There is also a difference between immune response in Sjogren (SS-DED) and non-Sjogren DED (non-SS DED). The main feature of SS-DED is the lymphocytic infiltration of the lacrimal glands. The subpopulation of cells consists of primarily CD4+ T cells with minor number of B cells. Several immune mechanisms are common for both DED forms, including Th17 cells activation and overexpression of cytokines such as IL-6, IL-17, and IL-22. However, there is a significant difference in the levels of CXCL chemokine (chemokine C-X-C motif) ligand family and macrophage inflammatory proteins chemokine family. Above are highly expressed in SS-DED compared to non-SS DED. Paired box protein Pax-6 (PAX6) is one of the conjunctival protein biomarkers associated with an increased ocular surface damage. Downregulation of PAX6 in SS-DED was significantly related with epithelial damage [11].
3.4 Clinical demonstration of ocular surface inflammation
Resembling other chronic inflammatory conditions, patients with DED have inflammatory flares, typically with rapid exacerbation of symptoms such as redness, eye irritation, and blurred vision. It is postulated that acute inflammation related to DED flare begins with a nonspecific innate immune response, which is usually followed by a slower but more specific adaptive immune response [16]. Various tests are used in scientific studies and clinical practice to assess the level of ocular surface inflammation in patients. Analysis of tear film cytokines and chemokines using ELISA or LUMINEX systems, flow cytometry of conjunctival epithelial cells, impression cytology, or confocal microscopy are rather used in clinical studies. In daily practice, a simplified qualitative test of MMP-9 and lissamine green staining may be used. Lysamine green is a vital dye, which stains epithelial cells only if the cell membrane is damaged, irrespective of the presence of mucin. The result correlates with the level of inflammation on the ocular surface. Examples of ocular surface irritation are presented in Figure 3.
Figure 3.
Ocular surface photos demonstrating inflammation related to DED. a. Slit lamp photo (mag. 10×). Note the visible vascularization of the eyelid margin and conjunctival superficial irritation. b. Slit lamp photo (mag. 10×, installation of lysamine green). Note the plugging of the meibomian glands, vascularization, and Marx line stained with lissamine green. c. Slit lamp photo (mag. 10×, after installation of lysamine green). A positive score of lissamine green staining in a patient with severe dry eye. d. (mag. 10×, after installation of fluorescein; blue-yellow filter applied). A positive score of fluorescein staining showed punctate keratopathy and breaks in the tear film layer.
4. Anti-inflammatory potential of DED treatment methods
4.1 Eye lubricants
Eye lubricants have different properties, which vary between formulas and significantly influence the final effectiveness of treatment. These are viscosity, pH, osmolarity, and electrolyte concentration. Additionally, eye lubricants may contain preservatives, osmotic agents, osmoprotectants, bioprotectants, antioxidants, lipids, amino acids, and inactive agents, such as buffers. Historically, DED was considered to be largely due to tear insufficiency and was treated by prescribing tear replacement products, but these products do not target the underlying pathophysiology of DED. The group includes natural polymers such as HPMC, synthetic polymers (PVP), carbomer gels, and paraffin ointments. To enhance lubrication and prolong the retention time on the ocular surface, a variety of viscosity-enhancing agents are frequently incorporated into such formulas. The main disadvantage of this group of eye drops is the short time of relief of symptoms for the patient, most of them also contain preservatives.
It is already well recognized that chronic exposure of the ocular surface to preservatives induces toxicity and adverse changes to the ocular surface. There are multiple in vitro and in vivo studies demonstrating that BAK can induce corneal and conjunctival epithelial cell apoptosis, damage the corneal nerves, delay corneal wound healing, induce squamous metaplasia, interfere with tear film stability, and also can cause loss of goblet cells [17, 18, 19].
Hyaluronic acid is worth mentioning because its viscosity depends on shear rate and due to its non-Newtonian properties, it mimics the tear film behavior. When open, the eye benefits from a higher tear viscosity to prevent tear film breakup, whereas a lower tear viscosity during blinking prevents damage to the epithelial surface. Moreover, by binding to the CD44 receptor Hyaluronic acid provides enhancement of corneal epithelium healing, improvement of the ocular surface function and protection, and also restoration of the morphology and distribution of goblet cells [20, 21].
The new formulas of eye lubricants usually have complex compositions and treat not only symptoms but are designed to aim at the causes of the disease—hyperosmolarity, inflammation, and ocular surface damage.
The trehalose properties are worth underlining because it is unique in terms of high water retention capabilities but also has the dual properties of both bioprotection and osmoprotection. Trehalose has a protective effect against inflammation in DED. It suppresses proinflammatory cytokines, such as IL-1, 2, 6, 17, TNF-α, as well as proteolytic enzymes (MMP-9), and cell keratinization, which was proved in vitro, in animal, and human studies [22, 23, 24, 25, 26].
4.2 N-acetylcysteine (NAC)
NAC is a mucolytic agent but also possesses antioxidant and anti-inflammatory properties. It inhibits cytokine release and suppresses adhesion molecule and nuclear factor kappa-B (NF-κB) expression. The most common concentration in clinical settings in patients with DED and MGD ranges from 5 to 10% topical [27].
4.3 Serum eye drops
In recent years, attention has been paid to autologous peripheral blood serum (PBS), umbilical cord serum (UCS), and platelet-rich plasma (PRP). In clinical settings, autologous serum eye drops are usually applied in concentrations ranging from 20 to 100%. The composition may be regarded to be similar to natural tears, by the content of factors, such as epidermal growth factor (EGF), nerve growth factor (NGF), fibronectin, and vitamins. It has a positive effect on the regeneration of epithelial cells and also has the potential to reduce the activity of inflammatory cytokines and increase the production of mucin and the number of goblet cells [9].
4.4 Topical steroids
Topical corticosteroids are one of the most potent topically applied anti-inflammatory drugs to treat ocular inflammation. Topical corticosteroids are effective in reducing inflammation by stopping the inflammatory cascade at various levels, including (intercellular adhesion molecule 1) ICAM-1-mediated cell adhesion, reducing cytokines, chemokines, MMPs expression, induction of lymphocyte apoptosis, proliferation of fibroblasts, and collagen deposition. Corticosteroids increase the synthesis of lipocortins that block phospholipase A2 and inhibit histamine synthesis in mast cells. The drugs are widely used in all ocular diseases involving inflammation including keratitis, uveitis, ocular allergy, blepharitis, scleritis, and more. One should be aware of the differences among steroids related to the anti-inflammatory potential, drug duration of action, and the potential to incuse adverse events. There are several potential options in ophthalmic setting available such as hydrocortisone 3.35 mg/ml, 0.5% loteprednol etabonate, 0.1% fluorometholone acetate, 0.1% dexamethasone, 0.5% prednisolone acetate, and 0.05% difluprednate. However, soft corticosteroids (such as hydrocortisone 3.35 mg/ml, fluorometholone, or loteprednol 0.5%) may be ideal for the treatment of inflammatory flares in DED and may be considered mainstream anti-inflammatory therapy. Soft steroids have lower to no negative risks of ocular hypertension, cataracts, and infectious diseases, especially when used for a short duration (3–8 weeks).
The use of corticosteroids in DED has been shown to reduce the signs and symptoms associated with DES and prevent DES flares in many non-randomized trials in the clinical setting. Recently, two systemic reviews on the efficacy of topical administration of corticosteroids for the management of DED were published [28, 29]. The main conclusions are a good safety profile of topical steroids and the following benefits: provide small to moderate degrees of symptom relief beyond lubricants, small to moderate degrees of symptom relief beyond cyclosporin A (CsA), and less certain about the effects of steroids on improved tear film quality or quantity. Authors of both systemic reviews underline the need for randomized, controlled trials with larger sample sizes to provide higher-quality evidence to establish the role of steroids in DED.
Topical corticosteroid of limited duration is recommended in DED treatment as a “step 2” option recommended by the TFOS DEWS II guidelines [9].
Cyclosporine is a fungal antimetabolite that inhibits IL-2 activation of lymphocytes. Lifitegrast is a small molecule integrin antagonist, which acts as a competitive antagonist to block binding between lymphocyte function-associated antigen 1 (LFA-1) and ICAM-1. Azithromycin and tacrolimus are macrolide antibiotics that have immunosuppressive activity.
All immunomodulators have been proven to provide some degree of positive impact in experimental, animal, and human studies in DED, which solely proves the role of inflammation in DED. The exact treatment dosage and duration are not fully established and this matter requires more randomized clinical trials, as underlined by the TFOS DEWS II committee [9].
4.6 Oral diet supplementation
Essential fatty acids (EFAs) are believed to modulate systemic inflammation; however, the exact impact on inflammation is complex and not fully understood. At present oral EFAs, supplementation is recommended by the guidelines and is believed to support the anti-inflammatory effect of DED [9].
4.7 Oral macrolides and tetracycline derivatives
Both groups of oral antibiotics possess antibacterial and anti-inflammatory properties. The positive effect is reached by the inhibition of collagenase and also by the anti-chemotactic effects, which are believed to improve patients’ symptoms by stabilizing the lipid layer of the tear film. This treatment is recommended, especially in chronic blepharitis and MGD along with lid hygiene and warm compresses of various types. MGD is considered to be the main cause of EDE, which is a predominant form of DE responsible for about 70% of cases. Thus, MGD treatment plays a crucial role in DED management.
The treatment regimen for azithromycin seems unified for all clinical studies (500 mg on day 1 and then 250 mg/day for 4 days), while there are significant differences among doxycycline regimens (20–200 mg/day for 2–6 months). Some studies have even proposed the use of a low dose of doxycycline (20 mg) on a long-term basis [30]. Currently, there is no consensus on the unified treatment schedule with doxycycline.
Based on the current knowledge oral macrolide or tetracycline antibiotics are recommended in DED treatment as a “step 2” option recommended by the TFOS DEWS II guidelines [9].
Understanding the role of inflammation on the cellular and molecular level may lead to improve treatment options for patients. A new approach to DED treatment should be focused to target not only symptoms but also break the pathological dry eye cycle.
1.Craig JP, Nichols KK, Akpek EK, Caffery B, Dua HS, Joo CK, et al. TFOS DEWS II definition and classification report. The Ocular Surface. 2017;15:276-283. DOI: 10.1016/J.JTOS.2017.05.008
2.Baudouin C. A new approach for better comprehension of diseases of the ocular surface. Journal Français d'Ophtalmologie. 2007;30:239-246. DOI: 10.1016/S0181-5512(07)89584-2
3.Baudouin C, Aragona P, Messmer EM, Tomlinson A, Calonge M, Boboridis KG, et al. Role of hyperosmolarity in the pathogenesis and management of dry eye disease: Proceedings of the OCEAN group meeting. The Ocular Surface. 2013;11:246-258. DOI: 10.1016/j.jtos.2013.07.003
4.Stapleton F, Alves M, Bunya VY, Jalbert I, Lekhanont K, Malet F, et al. TFOS DEWS II epidemiology report. The Ocular Surface. 2017;15:334-365. DOI: 10.1016/J.JTOS.2017.05.003
5.Daniel Nelson J, Shimazaki J, Benitez-del-Castillo JM, Craig J, McCulley JP, Den S, et al. The international workshop on meibomian gland dysfunction: Report of the definition and classification subcommittee. Investigative Ophthalmology & Visual Science. 2011;52:1930-1937. DOI: 10.1167/IOVS.10-6997B
6.Magno MS, Utheim TP, Snieder H, Hammond CJ, Vehof J. The relationship between dry eye and sleep quality. The Ocular Surface. 2021;20:13-19. DOI: 10.1016/j.jtos.2020.12.009
7.Almutairi R, Algezlan S, Bayamin R, Alrumaih S, Almutairi R, Alkahtani R, et al. The association between dry eye and sleep quality among the adult population of Saudi Arabia. Cureus. 2022;14:e22736. DOI: 10.7759/cureus.22736
8.Wolffsohn JS, Arita R, Chalmers R, Djalilian A, Dogru M, Dumbleton K, et al. TFOS DEWS II diagnostic methodology report. The Ocular Surface. 2017;15:539-574. DOI: 10.1016/j.jtos.2017.05.001
9.Jones L, Downie LE, Korb D, Benitez-del-Castillo JM, Dana R, Deng SX, et al. TFOS DEWS II management and therapy report. The Ocular Surface. 2017;15:575-628. DOI: 10.1016/j.jtos.2017.05.006
10.Leonardi A, Modugno RL, Salami E. Allergy and dry eye disease. Ocular Immunology and Inflammation. 2021;29:1168-1176. DOI: 10.1080/09273948.2020.1841804
11.Zemba M, Ionescu MA, Pîrvulescu RA, Dumitrescu OM, Daniel-Constantin B, Radu M, et al. Biomarkers of ocular allergy and dry eye disease. Romanian Journal of Ophthalmology. 2023;67:250-259. DOI: 10.22336/rjo.2023.42
12.Alhatem A, Cavalcanti B, Hamrah P. In vivo confocal microscopy in dry eye disease and related conditions. Seminars in Ophthalmology. 2012;27:138-148. DOI: 10.3109/08820538.2012.711416
13.Villani E, Mantelli F, Nucci P. In-vivo confocal microscopy of the ocular surface. Current Opinion in Allergy and Clinical Immunology. 2013;13:569-576. DOI: 10.1097/ACI.0b013e328364ec92
14.Chen Y, Dana R. Autoimmunity in dry eye disease—An updated review of evidence on effector and memory Th17 cells in disease pathogenicity. Autoimmunity Reviews. 2021;20:102933. DOI: 10.1016/j.autrev.2021.102933
15.Foulsham W, Mittal SK, Taketani Y, Chen Y, Nakao T, Chauhan SK, et al. Aged mice exhibit severe exacerbations of dry eye disease with an amplified memory Th17 cell response. The American Journal of Pathology. 2020;190:1474-1482. DOI: 10.1016/j.ajpath.2020.03.016
17.Cha S-H, Lee J-S, Oum B-S, Kim C-D. Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro. Clinical & Experimental Ophthalmology. 2004;32:180-184. DOI: 10.1111/j.1442-9071.2004.00782.x
18.Epstein SP, Chen D, Asbell PA. Evaluation of biomarkers of inflammation in response to benzalkonium chloride on corneal and conjunctival epithelial cells. Journal of Ocular Pharmacology and Therapeutics. 2009;25:415-424. DOI: 10.1089/jop.2008.0140
19.Baudouin C. Detrimental effect of preservatives in eyedrops: Implications for the treatment of glaucoma. Acta Ophthalmologica. 2008;86:716-726
20.Jun JH, Bang SP, Park HS, Yoon D, Ahn JY, Kim SJ, et al. A randomized multicenter clinical evaluation of sequential application of 0.3% and 0.15% hyaluronic acid for treatment of dry eye. Japanese Journal of Ophthalmology. 2022;66:58-67. DOI: 10.1007/S10384-021-00885-X
21.Kojima T, Nagata T, Kudo H, Müller-Lierheim WGK, van Setten G-B, Dogru M, et al. The effects of high molecular weight hyaluronic acid eye drop application in environmental dry eye stress model mice. International Journal of Molecular Sciences. 2020;21:3516. DOI: 10.3390/ijms21103516
22.Cejka C, Kossl J, Hermankova B, Holan V, Kubinova S, Olmiere C, et al. The healing of oxidative injuries with trehalose in UVB-irradiated rabbit corneas. Oxidative Medicine and Cellular Longevity. 2019;2019:1-10. DOI: 10.1155/2019/1857086
23.Brar S, Vanga HR, Ganesh S. Comparison of efficacy of trehalose-based eye drops versus topical 0.1% hyaluronic acid for Management of clinically significant dry eye using non-invasive investigational modalities. International Ophthalmology. 2021;41:3349-3359. DOI: 10.1007/s10792-021-01897-9
24.Panigrahi T, Shivakumar S, Shetty R, D’souza S, Nelson EJR, Sethu S, et al. Trehalose augments autophagy to mitigate stress induced inflammation in human corneal cells. The Ocular Surface. 2019;17:699-713. DOI: 10.1016/j.jtos.2019.08.004
25.Cagini C, Di Lascio G, Torroni G, Mariniello M, Meschini G, Lupidi M, et al. Dry eye and inflammation of the ocular surface after cataract surgery: Effectiveness of a tear film substitute based on trehalose/hyaluronic acid vs hyaluronic acid to resolve signs and symptoms. Journal of Cataract and Refractive Surgery. 2021;47:1430-1435. DOI: 10.1097/j.jcrs.0000000000000652
26.Cagini C, Torroni G, Mariniello M, Di Lascio G, Martone G, Balestrazzi A. Trehalose/sodium hyaluronate eye drops in post-cataract ocular surface disorders. International Ophthalmology. 2021;41:3065-3071. DOI: 10.1007/s10792-021-01869-z
27.Eghtedari Y, Oh LJ, Girolamo N, Watson SL. The role of topical N-acetylcysteine in ocular therapeutics. Survey of Ophthalmology. 2022;67:608-622. DOI: 10.1016/j.survophthal.2021.07.008
28.Prinz J, Maffulli N, Fuest M, Walter P, Bell A, Migliorini F. Efficacy of topical administration of corticosteroids for the management of dry eye disease: Systematic review and meta-analysis. Life. 1932;2022:12. DOI: 10.3390/life12111932
29.Liu S-H, Saldanha IJ, Abraham AG, Rittiphairoj T, Hauswirth S, Gregory D, et al. Topical corticosteroids for dry eye. Cochrane Database of Systematic Reviews. 21 Oct 2022;10(10):CD015070. DOI: 10.1002/14651858.CD015070.pub2
30.Yoo S-E, Lee D-C, Chang M-H. The effect of low-dose doxycycline therapy in chronic meibomian gland dysfunction. Korean Journal of Ophthalmology. 2005;19:258. DOI: 10.3341/kjo.2005.19.4.258
Written By
Anna Nowińska
Submitted: 26 June 2023Reviewed: 15 December 2023Published: 08 January 2024
Open access peer-reviewed chapter
