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REVIEW ARTICLE
Year : 2023 | Volume
: 13
| Issue : 1 | Page : 3-12
Dry eye disease: A review of anti-inflammatory therapies
Annie Nguyen1, Ajay Kolluru2, Talia Beglarian2
1 Keck School of Medicine of University of Southern California; Department of Ophthalmology, USC Roski Eye Institute, Los Angeles, California, USA
2 Keck School of Medicine of University of Southern California, Los Angeles, California, USA
Correspondence Address:
Dr. Annie Nguyen
1450 San Pablo Street, Suite 4700, Los Angeles, California 90033
USA
Source of Support: None, Conflict of Interest: None
DOI: 10.4103/2211-5056.369606
Dry eye disease (DED) is a common chronic ocular disease. DED can have a significant impact on visual function, causing disturbances to comfort, daily activities, and general quality of life. The varied nature of DED makes it difficult to point to a specific cause of the syndrome. However, current literature agrees that the inflammation of the cornea and conjunctiva plays a major role in its pathogenesis. Therapies targeted toward inflammation have shown varied success in the treatment of DED. The purpose of this review is to provide an overview of the prevalence and inflammatory pathophysiology of DED and discussion of the available anti-inflammatory therapies including the following: Nonsteroidal anti-inflammatory drugs, corticosteroids, and other hormonal therapies, nonsteroidal immunomodulators, biological tear replacement, antibiotics, dietary supplements, tea tree oil, and intense pulsed light.
Keywords: Anti-inflammatory agent, dry eye disease, eyedrop
Dry eye disease (DED) is a common chronic ocular disease. The current working definition of DED according to the Tear Film and Ocular Surface Society Dry Eye Workshop II (DEWS II) 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] DED can have a significant impact on visual function, causing disturbances to comfort, daily activities, and general quality of life. The varied nature of DED makes it difficult to point to a specific cause of the syndrome.[2] However, current literature agrees that the inflammation of the cornea and conjunctiva plays a major role in its pathogenesis.[3] Therapies targeted toward inflammation have shown varied success in the treatment of DED.
The prevalence of DED ranges from 5% to 50% due to varying definitions and methods for diagnosing DED in ophthalmology practices and research studies. DED epidemiology remains challenging due to the lack of a standardized definition and diagnostic criteria.[4] Studies show that prevalence and incidence of DED continue to increase every year.[2],[4] In recent years, there has been increased interest in the prevention of DED by identifying the risk factors earlier. The consistent risk factors for DED include female sex, coexisting comorbidities such as autoimmune disease and diabetes, increasing age, race, prior ophthalmic surgery, and concurrent medication use. Recent studies have also shown that higher psychological stress, reduced sleep, increased screen time, mask wearing, daily contact lens wear, and poorer self-perceived health status also result in the increased incidence of DED.[5],[6] Inflammatory diseases such as rheumatoid arthritis, Sjögren's syndrome, scleroderma, and polymyositis have all been associated with the higher incidence of DED.[6] Due to the numerous factors that can increase risk of DED incidence, it is difficult to attribute one specific cause to the onset of DED in patients.
The pathophysiology of DED is complex due to itsmultifactorial etiology.[7] The primary mechanism leading to DED is hyperosmolarity of the tear film and inflammation of the ocular surface.[8] The tear film of the eye consists of aqueous, mucous, and lipid components. Instability of one or more of these components can cause tear film breakdown, resulting in symptoms of DED. Activation of the sensory nerves of the ocular surface through hypersensitivity of the nerves, inflammatory reactions, and tear hyperosmolarity is also thought to play a role in the symptomatology of DED. There is also evidence that tear hyperosmolarity can result in an inflammation cascade leading to worsening tear film breakup and instability.[9] Consequently, tear hyperosmolarity can cause tear film break up and result in pain associated with DED.
DED was classically thought to be classified in two distinct categories, those caused by decreased tear production, known as aqueous deficiency dry eye and those caused by increased evaporation, or evaporative dry eye (EDE). However, recent studies show that EDE is more common, with meibomian gland dysfunction (MGD) being a major cause, although most patients generally present with both categories of DED.[1] The DEWS II report acknowledges that DED exists on a continuum rather than distinct categories and providers should consider both aqueous deficiency and EDE in their clinical diagnoses.
Numerous studies support inflammation playing a key role in the pathophysiology of DED.[10] Increased levels of pro-inflammatory markers recruit leukocytes to the inflamed ocular surface, resulting in an inflammatory response and ocular surface damage. As such, many current therapies target inflammatory markers to reduce the vicious inflammatory cycle observed in DED.[11] Several cytokines, including Th1 and Th17, are thought to contribute to the inflammatory response seen in DED. The pathogenesis of DED begins with the release of pro-inflammatory mediators into the conjunctival epithelium such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), IL-6, and T-cell attracting chemokines such as CCL5, CXCL9, and CXCL10.[12] This results in an amplification stage where there is T-cell differentiation. T-helper (Th)-1 cells also play a vital role in the chronic cycle of inflammation. Interferon (IFN)-gamma, a cytokine released from Th-1 cells, has been shown to cause ocular hyperplasia and promotes apoptosis at the conjunctival epithelium.[13] Th-17 cells secrete IL-17, which are cytokines that produce matrix metalloproteinases (MMP) and fibroblasts, resulting in disruption of the corneal surface. Both IFN-gamma and IL-17 contribute to the vicious cycle of inflammation observed in DED.[14] The integrin lymphocyte function-associated antigen-1 (LFA-1) and its ligand intracellular adhesion receptor 1 (ICAM-1) are the important cell-surface proteins that play vital roles in the pathophysiology of DED.[15] The interaction between LFA-1 and ICAM-1 is thought to assist in T-cell differentiation, activate effector T-cells at the ocular surface, recruit T-cells to the ocular surface, increase levels of cytokines and chemokines at the ocular surface, which plays a role in the inflammation and symptoms seen in DED.
Given the central role that inflammation plays in the pathophysiology of DED, several types of anti-inflammatory therapies have been developed and utilized in the management of DED. These various anti-inflammatory therapies available are reviewed below [Table 1].
Anti-Inflammatory TherapiesNonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the production of prostaglandins by blocking cyclooxygenase (COX) enzymes and therefore decreases inflammation.[16] Although clinical trials have shown the use of topical NSAIDs to be efficacious in DED in reducing ocular discomfort, NSAID use has also been associated with reduced corneal sensation, which can exacerbate already damaged corneal epithelium in DED with its long-term use.[17],[18] Moreover, reports of corneal melting with topical NSAID use have also been described.[19],[20] Most studies on NSAID use in DED are shorter than 1 month, even though DED is a chronic disease. NSAIDs' exact effects on corneal melting is still not clear; hypothesized mechanism include activation of MMP, neurotrophic effect, and impaired wound healing from anesthetic action.[21] Although short-term use of NSAIDs can alleviate discomfort from DED, they should be used with caution and with close monitoring given risks to the corneal epithelium.
Corticosteroids
Corticosteroid therapy is used in DED treatment to suppress the inflammation by the inhibition of pro-inflammatory cytokine release along with the stimulation of anti-inflammatory cytokine release. In a study involving 41 patients with moderate-to-severe DED, administration of topical 0.1% fluorometholone corresponded with greater improvement in corneal and conjunctival staining, hyperemia, and tear breakup time (TBUT) compared to a control group (polyvinyl alcohol drops).[22] Within the same study, corticosteroid therapy was also shown to be more effective in alleviating worsening dry eye symptoms after a 2-h exposure to adverse environments, including humidity and airflow directed to the eye. Similar studies have shown corticosteroids to be effective in reducing inflammatory marker expression in conjunctival cells. One study enrolled 20 subjects who were given artificial tears exclusively for 14 days, followed by exposure to a low-humidity environment for 90 min. The following 14 days consisted of dexamethasone topical treatment followed by low-humidity exposure. At the end of each adverse exposure, human leukocyte antigen (HLA)-DR RNA transcripts were measured in conjunctival cells by impression cytology, an indicator of inflammatory cell presence. The was a significant decrease in the levels of HLA-DR transcripts, indicating that corticosteroids were effective in suppressing inflammatory marker expression.[23] Although corticosteroid use in DED treatment is beneficial, there are also adverse effects that have been reported with long-term use, such as increased intraocular pressure (IOP), risk of infection, and cataract development. To mitigate these issues, loteprednol has been identified as a safer alternative corticosteroid. One study tracked Schirmer values, TBUT, keratoepitheliopathy, and IOP in groups of patients treated with either loteprednol or 0.1% fluorometholone. After a 24-month period, both treatments were found to be equally effective in improvement of dry eye symptoms, while mean IOP was reportedly lower in patients treated with loteprednol.[24] The use of corticosteroids, especially short-term, may be considered for DED; however, potential side effects should be considered.
Nonsteroidal immunomodulators
Cyclosporine A
Cyclosporine A is a calcineurin inhibitor that blocks T-cell activation, which is thought to lead to a reduced inflammatory response.[25] The current literature continues to agree that cyclosporine plays an important role in mitigating the symptoms of DED. A recent study investigated the efficacy and safety of cyclosporine in the setting of DED. The study recruited 32 patients with diagnoses of keratoconjunctivitis sicca with or without Sjögren's syndrome using a 12-week treatment phase. The results demonstrated a significant improvement in visual acuity, TBUT, and Schirmer scores.[26] Differing formulations of cyclosporine have also shown promise in reducing the symptoms of DED. Studies have shown that no therapeutic benefits were found after the application of increased concentrations of CsA, but there is increased stinging and discomfort when higher CsA concentrations were used; therefore, a dose-ranging, randomized trial showed that concentrations of CsA from 0.05% to 0.1% yielded the best balance between efficacy and side effects.[27] A study investigated the efficacy and safety of a topical water-free 0.1% CsA solution. In a 12-week, double-blind, prospective study, 328 participants were enrolled, and the results showed that cyclosporine solution was effective in treating the symptoms of DED and significantly reduced corneal conjunctival staining.[28] Safety and efficacy of CsA solutions are well-documented with few to no associated adverse effects with topical CsA use in patients with DED.[29] Its use can be considered early in DED management, especially in patients with pro-inflammatory causes. Commercially available formulations are available in many countries.
Tacrolimus
Tacrolimus is an immunosuppressive agent that has been shown to be effective in stabilizing the tear film and improving the ocular status in DED patients. Tacrolimus inhibits T-cell activation, preventing the release of inflammatory cytokines such as IL-3, IL-5, IL-8, and IFN-gamma. The reduction of inflammatory markers is thought to lead to an increase in tear production and reduced experienced symptoms in patients with DED.[30] A recent study investigated the clinical outcome of the treatment of DED using 0.03% tacrolimus eye drops. Eight patients were enrolled in the study and were instructed to use eye drops twice a day. Primary outcomes of the study were measured using Schirmer test, TBUT, corneal fluorescein, and rose Bengal staining score. Results showed a statistically significant improvement in staining after 14, 28, and 90 days.[31] Another study compared the efficacy of tacrolimus 0.03% eye drops with CsA 0.05% solution in patients with Sjögren's syndrome displaying dry eye symptoms. Sixty patients were randomized in two groups receiving the respective treatments. The patients were evaluated at baseline and at 90-and 180-day intervals using Ocular Surface Disease Index Questionnaire (OSDI), fluorescein staining, and TBUT. The study showed significant improvement in patient symptoms; however, there was no significant difference between the efficacy of tacrolimus and CsA.[25] Tacrolimus eyedrops, which may need to be obtained from compounding pharmacies, has been shown to be safe; however, some studies have described patients feeling a transient burning sensation on use that was unrelated to its efficacy in treatment.[32]
Lifitegrast
Lifitegrast is an LFA-1 antagonist that inhibits LFA-1 from binding to its ligand, ICAM-1. Lifitegrast has been shown to decrease the proliferation of lymphocytes that would normally cause an inflammatory immune response, exacerbating the symptoms of DED.[33] A retrospective study of 1429 participants investigated the efficacy of lifitegrast 5.0% solution in patients with moderate-to-severe DED as compared to placebo. The primary outcomes being measured were clinically meaningful improvement in symptoms. Results showed a composite responder rate that favored lifitegrast compared to the placebo, and significant association with clinically meaningful improvement.[34] A phase-III clinical study was also conducted to investigate the efficacy and safety of lifitegrast in DED.[35] The primary outcome measure studied was change in baseline to endpoint eye dryness score (EDS). At the endpoint, the study showed a statistically significant improvement in baseline EDS in those using lifitegrast as compared to placebo. The most common ocular adverse effect found in patients using lifitegrast was irritation around the application site, which was considered mild-to-moderate in severity and occurred in 18.2% of patients studied. Other nonocular adverse effects noted were dysgeusia, which occurred in 12.9% of patients. There was no evidence of systemic toxicities or infections that occurred secondary to lifitegrast use.
Anakinra
IL-1, a pro-inflammatory cytokine produced by injured epithelial cells, is a key mediator in the inflammatory cascade and is overexpressed on the ocular surface and in tears in DED.[36] Anakinra, a human recombinant IL-1 receptor agonist (IL-1Ra), effectively suppresses IL-1-mediated inflammation and is FDA-approved to treat rheumatoid arthritis, cryopyrin-associated periodic syndromes, and deficiency of interleukin-1 receptor antagonist. It has been used off-label topically at the level of the ocular surface to treat DED. In a randomized, vehicle-controlled clinical trial, treatment with topical anakinra 2.5% compared to vehicle for 12 weeks was safe and significantly reduced symptoms (improved OSDI scores), corneal epitheliopathy (improved corneal fluorescein staining), and improved TBUT and meibomian gland secretion quality in patients with DED.[37]
Other hormonal therapies
Androgens
Androgens have been proven to be important in the regulation of the ocular surface and adnexa, through the regulation of conjunctival goblet cells, meibomian glands, and aqueous tear secretion. Androgens also promote the synthesis of anti-inflammatory cytokine TGF-β while inhibiting synthesis of IL-1 β and TNF-α. As a result, androgen deficiency can lead to lacrimal and MGD. A study conducted on patients receiving anti-androgen therapy for the treatment of prostate cancer was designed to determine whether androgen deficiency corresponds with dry eye symptoms and MGD. Upon the examination of patients who had been treated with anti-androgen medication anywhere between 3 and 96 months, results showed that patients had significant increased ocular surface staining, decreased TBUT, and significant changes in the lipid content of meibomian gland secretions as compared to healthy controls.[38] Because androgen plays an important role in DED, patients with androgen deficiency experiencing dry eye symptoms can benefit from transdermal androgen treatment. In a study in Northern Thailand, 50 postmenopausal women and andropausal men with dry eye symptoms were treated with either transdermal androgen or a placebo for 4 weeks. The transdermal androgen treatment group showed significant differences in TBUT, corneal fluorescein staining, and Schirmer values from their baseline values.[39] Thus, the use of transdermal androgen therapy in patients with androgen deficiency can be an effective treatment for dry eye symptoms.
Progesterone and other female hormones
Transdermal progesterone and estradiol have also been shown to improve dry eye symptoms, though to a lesser extent than androgen therapy. The proposed mechanism is that progesterone and estrogen promote the inhibition of pro-inflammatory cytokines within lacrimal glands, which improves tear production.[40] A study testing the effects of hormone replacement therapy (HRT) on dry eye symptoms was conducted among menopausal women, in which women were either treated with transdermal 17 β-estradiol and medroxyprogesterone acetate or did not receive treatment for dry eye symptoms for 6 months. The results showed a significant increase in basal and stimulated lacrimal secretion in the treated group, as well as a significant decrease in self-reported ocular symptoms.[41] A similar study tested the effects of HRT on meibomian gland inflammation, to determine whether estrogen and progesterone could produce a protective, anti-inflammatory effect.[42] However, other studies have shown contradictory results, in which HRT exacerbated dry eye symptoms. One study found that systemic HRT treatment in post-menopausal women without dry eye symptoms led to the development of worsening TBUT, Schirmer values, and MGD.[43] The route of administration (systemic or topical) may be a contributing factor in different outcomes when treating DED with hormone therapy, although more research may need to be conducted to better understand the mechanism involved.
Corticotropin
Adrenocorticotropic hormone is another anti-inflammatory therapy that has been shown to be effective in treating DED. It achieves this effect by stimulating the production of endogenous steroids within the body. A case report from 1955 followed a patient with keratoconjunctivitis sicca secondary to rheumatoid arthritis. Following treatment with oral and topical cortisone, corticotropin was administered, which was able to relieve the patient's ocular and arthritic symptoms, although Schirmer values were not increased.[44] A recent pilot study of 12 subjects with refractory DED receiving corticotropin gel injections showed improvement in corneal and conjunctival staining and SANDE (Symptom Assessment iN Dry Eye, a 2-item frequency-and severity-based Visual Analog Scale) scores without significant adverse events.[45] Although no side effects were observed in these case reports, corticotropin gel injections have been linked to an increased risk of developing Cushing syndrome, blood glucose increase, hypertension, and weight gain, due to its effects on steroid production. However, in a study tracking long-term effects in patients treated with corticotropin gel, mild adverse events (such as dizziness) were found to be improved with dose reduction. Furthermore, corticotropin gel treatment was also less likely to contribute to severe steroid-related adverse events in comparison to glucocorticoid treatment, while still providing anti-inflammatory benefits.[46]
Tetracyclines and macrolides and other antibiotics
Antibiotics such as tetracycline derivatives and macrolides also have therapeutic effects regarding treating dry eye symptoms. Doxycycline, a tetracycline-derivative, down-regulates pro-inflammatory cytokines, such as TNF and IL-1 β, making it useful in treating DED.[47] A study analyzed 150 patients with chronic MGD and divided participants into groups receiving systemic low dose doxycycline (20 mg twice a day), high dose doxycycline (200 mg twice a day), or placebo. After 1 month, both the low and high dose groups showed significant differences in TBUT and Schirmer values as compared to baseline test, indicating that low-dose doxycycline can treat dry eye symptoms associated with MGD.[47] Minocycline is another tetracycline derivative that has been proven to be effective in the treatment of dry eye symptoms.[48]
Macrolide treatment options include azithromycin, which can reduce dry eye symptoms due to its anti-inflammatory properties and alleviate MGD by inducing the lipid production and differentiation. Macrolide accumulation within the cells correlates with the inhibition of inflammatory molecules IL-6 and PGE2. The proposed mechanism of action for its anti-inflammatory effects is the inhibition of eicosanoids downstream of COX. A study was conducted to examine the efficacy of azithromycin eye drops in patients with MGD-associated posterior blepharitis. Compared to a control group treated with warm compresses alone, the azithromycin group experienced significant improvement in TBUT, meibum score, and tear osmolarity after two weeks of treatment.[49]
Biological tear replacement
Autologous serum tears and other blood-derived substitutes
Serum, which is the fluid component of blood that remains after clotting, is rich in proteins, growth factors (including epithelial and nerve growth factors) and several anti-inflammatory factors (e.g., IL-1Ra, soluble TNF-receptors, MMP inhibitors, etc.) to inhibit mediators of the ocular surface inflammatory cascade in dry eye leading to increased expression of goblet cells, and mucin expression. Several clinical and in vitro studies have reported improved corneal epithelial wound healing with serum tears and other blood-derived products. In a prospective observational case-series including 100 patients who were treated with autologous serum tears (AST) for DED, AST treatment in severe DED significantly reduced dry eye symptoms with higher patients' satisfaction scores.[50] In another study involving 12 patients with chronic GVHD-associated severe DED treated with cord blood serum for 6 months reported statistically significant improvement in symptom score, corneal sensitivity, TBUT, and corneal staining.[51] In a Cochrane review was published in 2017 which including 5 randomized controlled trials (RCT) looking at the use of autologous serum tears compared to traditional artificial tears (3 studies) or saline solution (2 studies).[52] Overall, there was better improvement in symptoms after 2 weeks in the groups treatment with autologous serum tears compared to either saline or artificial tears; however, longer benefits were unclear. Another systematic review that included 39 RCTs reported good the short-term efficacy and safety profile of biological tear substitutes, including autologous serum, autologous platelet lysate, platelet-rich plasma, and cord blood serum.[53]
Amniotic membrane
Amniotic membrane, the innermost layer of the placenta, is composed of a superiorly layer of epithelium, a basement membrane, and a rich stroma that promotes re-epithelialization, reduces inflammation and neovascularization through cytokines, growth factors, and other plasma proteins.[54] The amniotic membrane is available commercially in two main forms, cryopreserved and dehydrated. Treatment of moderate-to-severe DED with positive results has been reported with both forms of the amniotic membrane.[55],[56] Furthermore, the use of amniotic membrane extract eye drops, prepared from harvested placenta from cesarean section deliveries, has also been reported with promising results in the treatment of OSD including DED without major risks of infection.[54],[57]
Derived-multiple allogeneic proteins paracrine signaling
Regener-Eyes® (generic name “derived-Multiple Allogeneic Proteins Paracrine Signaling [d-MAPPS]”; Regener-Eyes, LLC; Palm Harbor, FL, USA) is a proprietary, preservative-free, acellular ophthalmic solution containing many immunoregulatory factors to ameliorate inflammation on the ocular surface from DED. It is an engineered biological product made from human placenta and enriched with amniotic fluid-derived mesenchymal stromal cells (AF-MSC)-sourced exosomes to allow better penetration of the ocular surface to deliver immunoregulatory, angio-modulatory and trophic factors. Specifically, it contains IL-1Ra, soluble receptors of TNF-α, growth-related oncogene gamma, fatty acid-binding protein 1 (FABP1) and platelet factor 4 (PF4) which improve inflammation and ocular surface health. A retrospective study in 131 DED patients treated with Regener-Eyes showed improvement in ocular discomfort and pain during a 12-month period with decreased in VAS and SPEED scores and no reported adverse side effects.[58]
Dietary supplementation
Essential fatty acids
Essential fatty acids (EFA), “essential” since it must be ingested in dietary forms as they cannot by synthesized in the body yet is necessary for health, have been shown to have anti-inflammatory properties, blocking gene expression of pro-inflammatory cytokines (e.g., TNF-α, IL-1a and IL-1b, etc.). EFA are polyunsaturated and are divided into omega-3 (e.g., alpha-linoleic acid, eicosapentaenoic acid, and docosohexaenoic acid) and omega-6 (e.g., linoleic acid, gamma-linolenic acid, and arachidonic acid), with a higher ratio of omega-3 to omega-6 consumption better for health as omega-3 has been associated with reduction of inflammation whereas omega-6 has been linked to promoting inflammation.[59] Several clinical studies have shown benefits from omega-3 supplements.[37],[60] One multicenter, randomized, placebo-controlled controlled study observed that subjects treated with oral supplements of omega-3 EFA (1680 mg eicosapentaenoic acid and 560 mg docosohexaenoic acid) had statistically significant improvement in tear osmolarity, omega-3 index levels, TBUT, MMP-9, and OSDI symptoms scores as compared to control (3136 mg of omega-6 linoleic acid) after 12 weeks.[61] Contrasting the positive benefits reported in several studies, the Dry Eye Assessment and Management Study Research Group in 2018 published the results of a multicenter, clinical trial where patients with moderate-to-severe DED were randomly assigned to receive either oral omega-3 supplements (2000 mg eicosapentaenoic acid and 1000 mg docosahexaenoic acid daily) or an olive oil placebo (5000 mg daily dose) for 12 months. Although both groups improved significantly in terms of mean OSDI scores compared to baseline, there was no difference between the treatment and placebo group.[62] The most common potential side effects were temporary gastrointestinal problems. More studies are needed to gain better understanding of the role of EFA in treatment of DED.
Lactoferrin
Lactoferrin–a multifunctional, iron-binding tear glycoprotein with anti-inflammatory, antimicrobial, anti-angiogenic, and immunomodulatory properties has been found to be in reduced levels in tears of DED patients in clinical studies.[63],[64] Lactoferrin can directly inhibit the production of several inflammatory cytokines, including TNF-α and IL-1 via receptor-mediated signaling pathways.[65] In a RCT evaluating the effect of oral lactoferrin supplementation (350 mg daily or nothing postoperatively for 60 days) in patients after small incision cataract surgery without preexisting dry eye, those in the treatment group had statistically higher TBUT, Schirmer test 1 scores, and better OSDI scores.[66] Another study comparing oral lactoferrin supplementation (270 mg daily) versus control in Sjögren's syndrome patients demonstrated significantly improved clinical parameters such as mean corneal sensitivity, TBUT, lipid layer thickness, vital staining scores, and goblet cell density. Interestingly, within 4 weeks of cessation of the lactoferrin supplementation, these parameters worsened.[67] More clinical studies are needed to evaluate the role of lactoferrin in DED although a handful of studies has shown some positive benefits.
Tea tree oil
Tea tree oil (TTO) is an essential oil derived from the leaves of Melaleuca alternifolia tree from Australia that has anti-inflammatory, anti-fungal, and anti-microbial properties. TTO has been found to effectively kill Demodex mites and decrease tear concentrations of inflammatory cytokines IL-1 h and IL-17.[68],[69] Demodex colonization in humans is common and increases with age and can lead to blepharitis, MGD, and EDE.[70] A clinical study found that Demodex is resistant to a wide range of antiseptic solutions, but weekly lid scrub with 50% TTO and daily lid scrub with tea tree shampoo is effective in eradicating ocular Demodex compared to 50% baby shampoo.[71] However, TTO can be toxic to the eye in its pure form and have side effects such as stinging and irritation and contact dermatitis to one or more of its ingredients. Terpinen-4-ol, which has both antimicrobial and anti-inflammatory roles, is the most effective ingredient for killing the mites and can be used alone for the treatment of Demodex. Commercially available formulations equivalent to 25% whole TTO are now available and decreases the risk of toxicity to the ocular surface and adverse reactions.[72]
Intense pulsed light
Intense-pulsed light (IPL) therapy, which utilizes a nonlaser, high-intensity light source delivering short pulses of light with wavelengths between 500 and 1200 nm to the skin, has been employed by dermatologists for many years for the treatment of pigmented and vascular skin lesions and for the treatment of rosacea.[73] Its role in dry eye treatment was first identified somewhat surreptitiously by Dr. Rolando Toyos in 2002 when patients undergoing IPL therapy for acne rosacea and other skin conditions who concomitantly also had DED noted improvement in their dry eye symptoms.[74] Hypothesized mechanisms whereby IPL can achieve clinical improvement in DED are multifactorial, including the following: thrombosis and elimination of periocular telangiectatic blood vessels that contribute to ocular inflammation, inhibition of inflammatory mediators, heating the meibomian glands and improving quality of meibum, reduction in bacterial and other pathogenic load on the eyelids, and reduction in levels of reactive oxidate species.[75] Both clinical and cytokine improvements have been shown from IPL treatment.[76],[77],[78],[79] A RCT evaluating changes in inflammatory markers in tears of DED from MGD after 3 consecutive IPL treatments (14–16 J/cm2) compared to sham treatment (0 J/cm2) in 12 weeks showed a statistically significant decline in the value of all inflammatory markers measured (IL-17A, IL-6, and PGE2) compared to baseline.[76] A retrospective review study evaluating the safety and efficacy of an augmented IPL protocol for DES and blepharitis in 47 patients reported without significant adverse events in vision (unchanged visual acuity before and after) with 100% of patients reporting improvement in their dry eye symptoms and/or blepharitis.[78] Overall, IPL appears to be a safe and effective treatment in DED from MGD with improvement in symptoms and inflammation.
ConclusionAlthough DED is a multifactorial condition, inflammation of the ocular surface plays a major role in perpetuating its pathogenesis. Current therapies targeting inflammation have shown varied success in the treatment of DED and should be considered as discussed in this review including NSAIDs, corticosteroids and other hormonal therapies, non-steroidal immunomodulators, biological tear replacement, antibiotics, dietary supplements, TTO, and intense pulsed light. Given that the role of inflammation in DED is now universally accepted, this knowledge alone will hopefully continue to further research and development of anti-inflammatory therapies that will address one of the root problems in DED.
Financial support and sponsorship
Nil.
Conflicts of interest
The authors declare that there are no conflicts of interests of this paper.
References
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