Treating the 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.

Tear Proteomics

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 Preparations

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

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.

Omega-3 Supplements

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

Conclusion

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.

References:

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