Dry eye is a complex and multifactorial disease. There are a multitude of complex factors and interplays that lead to the end outcome of ocular surface disease and dry eyes. The recent Dews II Report from the Tear Film and Ocular Surface Society1 is an excellent summary of the physiologic and pathologic mechanisms of dry eye and also many of the treatments available. This report highlights the complexity of the disease and, while one short article cannot possibly address all of the treatments or processes involved, it summarises some of the most effective and readily available treatments for controlling inflammation in dry eye disease.
The Role of Inflammation
Inflammation plays a role in dry eye as both a cause and an effect of ocular surface disease. As a primary cause, conditions such as Sjögren’s syndrome are systemic inflammatory diseases that lead to fibrosis and scarring of the lacrimal gland and decreased aqueous production.2 Obviously there are other significant systemic complications and findings that occur in Sjögren’s syndrome, and dry eye is only one of these. The disease is closely associated with a cluster of autoimmune conditions.3 At a more local level, inflammation of the meibomian glands, as occurs in meibomian gland dysfunction, can also be both a cause and effect of dry eye.4 Topical glaucoma medications, particularly prostaglandins, have been associated with significant levels of blepharitis and dry eye, and similarly, meibomian gland dysfunction due to other etiologies, causes inflammation of the glands, eyelids and associated lid and ocular surface disease.
The role of tear proteomics is an evolving one in the diagnosis and monitoring of the inflammatory components of dry eye. Tear film osmolality has been available for a long time as a measure of the osmolality of tears, but matrix metalloproteinase-9 (MMP-9) point of care testing has also become more commonly used.5 At least one point of care MMP-9 test is commercially available in Australia and this can be of benefit to clinicians in the diagnosis of dry eye where inflammation plays an important role. Identifying inflammatory mediators in the tears helps inform a clinician’s treatment and management plan.6 Many companies are working on further point of care testing for both infectious and inflammatory causes to make the diagnoses of numerous ocular surface conditions easier and more readily available.7
It is a testament to the importance of addressing inflammation that pharmaceutical companies have invested the resources and money into making new formulations of topical anti-inflammatories
Ciclosporin has been used in dry eye and inflammatory ocular surface disease for many years.8 There are numerous preparations of ciclosporin available internationally and clinicians have been able to access these through the Special Access Scheme in Australia or through compounding pharmacies for many years. Ciclosporin is a calcineurin inhibitor that works as an immunomodulator to reduce inflammation. Ciclosporin itself is a hydrophobic compound, meaning it does not dissolve well in water, and this chemical property has always limited its efficacy topically as hydrophilic medications are better transported through the tear film and onto the ocular surface.
New nanomicellar technology and chemistry has allowed the development of new ciclosporin products such as CEQUA. This technology encapsulates the ciclosporin in a hydrophobic core which is surrounded by a hydrophilic shell. This allows the encapsulated ciclosporin to be more soluble in the aqueous form and to be released into cells once it has passed through the aqueous layer of the tear film.9 CEQUA is now available in a 0.09% non-preserved preparation and is now approved by the Therapeutic Goods Administration in Australia, meaning the medication is much more readily accessible for both prescribers and patients.
Topical steroids obviously have a fairly rapid onset and a very effective anti-inflammatory effect, and depending on the steroid chosen, this will either have a predominantly ocular surface effect or also an intraocular anti-inflammatory effect.10 While short term topical steroids are effective in resolving severe ocular surface inflammation, in the longer term, side effects including cataract formation and raised intraocular pressure don’t make them a viable effective option for the overwhelming majority of cases of dry eye.
Systemic and Topical Antibiotics
Both systemic and topical antibiotics have been shown to have anti-inflammatory properties and other beneficial effects on the ocular surface. The non-antibiotic properties of tetracycline antibiotics are the most commonly used topical and systemic medications for dry eye. The antimicrobial properties of tetracycline include an interaction with matrix metalloproteinases (MMP) growth factors and cytokines. They have a role in modulating inflammation, the immune system and angiogenesis and have been used for other conditions such as acne, rheumatoid arthritis and cutaneous sarcoid for a long time.11 Systemic doxycycline has been used as therapy for meibomian gland dysfunction for many years and topical preparations of azithromycin have also been shown to be an effective anti-inflammatory in this condition. All of these uses are either off-label, compounded or through the Special Access Scheme in the case of topical azithromycin.
Multiple randomised double-masked placebo controlled clinical trials of Omega-3 supplements have demonstrated their efficacy in the improvement of tear film stability production and ocular surface signs. They have shown a reduction in capping of the meibomian glands, reduced tear inflammatory cytokines and an improvement in anterior blepharitis. Numerous studies have documented the benefits of different types of long chain Omega-3 essential fatty acids though a consensus as to which form is best for ocular surface disease and the dose is yet to be determined.12 Numerous sources, including algae-based Omega-3s (which are appropriate for vegan patients), krill oil and fish oil have all been studied. The effects of re-esterification suggest that the chemical formulation of the Omega-3 and its systemic absorption do differ between different sources of Omega-3 and the chemical processing they undergo prior to their final point of sale form.13
A thorough understanding of all the inflammatory pathways involved in dry eye is more appropriate for a PhD thesis than a summary article but it is important that clinicians are aware of some of the pathways and the different approaches that can be taken to address ocular surface inflammation in the clinical setting. It is a testament to the importance of addressing inflammation that pharmaceutical companies have invested the resources and money into making new formulations of topical anti-inflammatories available to our patients and hopefully this trend will continue.
- Bjordal O, Norheim KB, Rødahl E, Jonsson R, Omdal R. Primary Sjögren’s syndrome and the eye. Surv Ophthalmol. 2019 Oct 18.
- Noaiseh G, Baer AN. Toward better outcomes in Sjögren’s syndrome: The promise of a stratified medicine approach. Best Pract Res Clin Rheumatol. 2020 Jan 28:101475.
- Yamaguchi T, Inflammatory Response in Dry Eye. Invest Ophthalmol Vis Sci. 2018 Nov 1;59(14):
- Kuo MT, Fang PC, Chao TL, Chen A, Lai YH, Huang YT, Tseng CY. Tear Proteomics Approach to Monitoring Sjögren Syndrome or Dry Eye Disease. Int J Mol Sci. 2019 Apr 19;20(8).
- Aragona P, Aguennouz M, Rania L, Postorino E, Sommario MS, Roszkowska AM, De Pasquale MG, Pisani A, Puzzolo D. Matrix metalloproteinase 9 and transglutaminase 2 expression at the ocular surface in patients with different forms of dry eye disease. Ophthalmology. 2015 Jan;122(1):62-71.
- Kloosterboer A, Dermer HI, Galor A. Diagnostic tests in dry eye. Expert Rev Ophthalmol. 2019;14(4-5):237-246.
- Tuan HI, Chi SC, Kang YN. An Updated Systematic Review With Meta-Analysis Of Randomized Trials On Topical Cyclosporin A For Dry-Eye Disease. Drug Des Devel Ther. 2020 Jan 17;14:265-274.
- Mandal A, Gote V, Pal D, Ogundele A, Mitra AK. Ocular Pharmacokinetics of a Topical Ophthalmic Nanomicellar Solution of Cyclosporine (Cequa®) for Dry Eye Disease. Pharm Res. 2019 Jan 7;36(2):36
- Comstock TL, Sheppard JD. Loteprednol etabonate for inflammatory conditions of the anterior segment of the eye: twenty years of clinical experience with a retrometabolically designed corticosteroid. Expert Opin Pharmacother. 2018 Mar;19(4):337-353.
- Federici TJ. The non-antibiotic properties of tetracyclines: clinical potential in ophthalmic disease. Pharmacol Res. 2011 Dec;64(6):614-23.
- Deinema LA, Vingrys AJ, Wong CY, Jackson DC, Chinnery HR, Downie LE.A Randomized, Double-Masked, Placebo-Controlled Clinical Trial of Two Forms of Omega-3Supplements for Treating Dry Eye Disease. Ophthalmology. 2017 Jan;124(1):43-52. Epub 2016 Nov 3.
- Epitropoulos AT1, Donnenfeld ED, Shah ZA, Holland EJ, Gross M, Faulkner WJ, Matossian C, Lane SS, Toyos M, Bucci FA Jr, Perry HD. Effect of Oral Re-esterified Omega-3 Nutritional Supplementation on Dry Eyes. Cornea. 2016 Sep;35(9):1185-91.