Dry Eye Disease and the Role of Inflammation

Dry eye is a complex and multifactorial disease with a multitude of clinical presentations and causes. The complexity and number of risk factors associated with the disease, the variety of ways in which it can present, and in particular, the lack of a direct correlation between a patient's signs and symptoms, make diagnosing and treating dry eye disease (DED) a complex and sometimes difficult clinical dilemma.

Some of the more common causes of DED include:

• meibomian gland dysfunction
• skin diseases such as rosacea and atopy
• systemic and topical medications
• hormonal deficiencies or imbalance, e.g. post menopause
• disorders of the eyelid
• reduced blink rate, e.g. Parkinson's disease
• contact lens wear
• topical preservatives in eye drops
• Sjögren's disease
• surgery-induced lacrimal deficiency, and iatrogenic causes due to ocular and refractive surgery.¹

While all these aetiologies have different mechanisms that induce dry eye, a pathway common to all is that, eventually, inflammation plays a role. Inflammation can be both a cause and an effect of dry eyes. Inflamed eyes will become dry and dry eyes will invariably become inflamed. Therefore, treating the inflammation in dry eye plays an important role in any effective long-term management plan.²

While other causes of dry eye must be addressed to reduce the risk of inflammation returning, failing to address the important role that inflammation plays in creating a positive feedback cycle, and ongoing chronic dry eye issues, will invariably lead to failure of treatment and a recurrence of symptoms.

This article addresses some potential treatments for inflammation that occurs in DED, which include:

• ciclosporin
• omega-3 supplements
• tacrolimus
• testosterone
• non-steroidal anti-inflammatory drugs
• intense pulsed light treatment
• Demodex treatment
• oral tetracyclines
• topical azithromycin
• gastrointestinal and ocular flora.

Ciclosporin

Ciclosporin was the first topical anti-inflammatory to be approved for use in the treatment of dry eye by the United States Food and Drug Administration (FDA). Subsequently, it was recommended as a step 2 treatment option by the Tear Film and Ocular Surface Society's Dry Eye Workshop,³ and has been approved by the Therapeutic Goods Administration (TGA) in Australia since 2020 for the treatment of dry eye.

Ciclosporin is a calcineurin inhibitor and an immunosuppressant that has been shown to both reduce inflammatory mediators in the tears and increase tear production in patients with keratoconjunctivitis sicca.

It works by binding with cyclophilin, which in turn blocks the phosphatase activity of calcineurin. This then decreases the production of inflammatory cytokines by T lymphocytes, giving its anti-inflammatory effect.

From the ophthalmic perspective, ciclosporin has traditionally been limited in its efficacy and tolerability due to its chemical formulation. The ciclosporin molecule is hydrophobic, meaning it dissolves well in lipids but does not dissolve well in water. This limits its ability to transport through the tear film to the ocular surface and thus limits the concentration that can reach the ocular surface. In addition to this, its propensity to sting and cause a generalised ocular ache has meant that increasing doses of ciclosporin, while potentially therapeutically beneficial, have traditionally been poorly tolerated by patients.⁴

Cequa (ciclosporin 900 microgram/mL) eye drops increase tear production in patients with moderate to severe keratoconjunctivitis sicca (dry eye) where prior use of artificial tears has not been sufficient.⁵ Cequa has been engineered to deliver ciclosporin where it is needed most, using nanomicelles composed of polymers that encapsulate the ciclosporin molecule. The ciclosporin molecule is dissolved in a hydrophobic core, which in turn is coated in a hydrophilic shell. This hydrophilic shell allows transport through the tear film to the ocular surface. This improves both the tolerability and clinical efficacy of the compound.^{5, 6, 7}

Cequa is administered as one drop to both eyes twice a day, in a non-preserved single-use vial similar to most lubricants. Clinically, its mechanism of action takes around eight to 12 weeks to start having an effect, so patients do need to be on the medication for at least that period of time to start noticing a significant clinical benefit.⁶

Unlike other topical anti-inflammatories, in particular steroids,⁸ ciclosporin does not cause raised intraocular pressure or cataracts. This gives it a distinct safety advantage over those medications as an anti-inflammatory treatment in dry eye.

A second ciclosporin preparation is also approved for use in Australia: ciclosporin 0.1% (Ikervis). This preparation is administered once daily to each eye. Like Cequa, Ikervis is a preservative-free formulation. The Ikervis formulation includes medium chain triglycerides as a cationic nanoemulsion to facilitate tear film penetration.

Editor's note: Ikervis and Cequa are both PBS-listed (Authority Required) for chronic severe dry eye disease with keratitis. Ikervis was listed from October 2021 and Cequa from June 2023.

Omega-3 supplements

Omega-3 supplements have long been used for the treatment of dry eye and ocular surface disease. The anti-inflammatory benefits of long chain omega-3 fatty acids have been reported in numerous clinical trials. They have been documented to be beneficial for corneal nerve regeneration after refractive surgery and have also been shown to speed the healing of epithelium after excimer surface ablation refractive surgical procedures.⁹

While they are generally used systemically, some studies have shown a benefit to topical fatty acid treatments for dry eye, however no commercial preparations are approved by the TGA and available in Australia.¹⁰

Omega-3 fatty acids have been documented to have an anti-inflammatory role in numerous systemic diseases, including osteoarthritis and rheumatoid arthritis. Some conjecture exists as to the best form of omega-3 supplementation, with a few studies suggesting that krill oil preparations are more beneficial than fish oil preparations. The role of esterification has also been discussed extensively in the literature.¹¹

Many patients perceive that when a clinician recommends omega-3 fatty acid supplementation, they are acknowledging the role of nutritional and complementary medicines. This will often ingratiate the clinician with patients who would prefer a less medical and a more holistic approach to the treatment of their disease.

Tacrolimus

Tacrolimus has similar immunosuppressive properties to ciclosporin. It inhibits calcineurin and its role in T-cell mediated inflammation. Tacrolimus was discovered from the fermentation of a Japanese soil sample that contained the bacterium Streptomyces tsukubaensis.

Like ciclosporin, tacrolimus is used in solid organ transplantation to avoid systemic rejection. Currently, there is no TGA-approved topical ocular tacrolimus preparation available in Australia, however some are approved overseas.

Tacrolimus suffers the same problems chemically as ciclosporin. It is hydrophobic but unfortunately, to date there is no preparation that incorporates the same nanomicelle technology used in Cequa for tacrolimus.¹² While tacrolimus is considered a significantly more potent anti-inflammatory compound than ciclosporin, the lack of a TGA-approved preparation precludes it from being a mainstay of anti-inflammatory treatment in dry eye.

Testosterone

The role of sex steroids in dry eye has been clearly documented over many years.

Most patients presenting with dry eye and meibomian gland dysfunction (MGD) are postmenopausal women and thus, epidemiologically, it has been known for some time that oestrogen, progesterone, and testosterone must have some significant role.

There have been numerous studies over the years looking particularly at the role of oestrogen and progesterone. The results of these studies have been fairly equivocal, with some showing a correlation with systemic hormone levels and some not. Topical testosterone has more potential as an anti-inflammatory in DED.¹³ The meibomian glands have been shown to express testosterone receptors, so whether the application of topical testosterone simply improves the function of the meibomian glands with a secondary effect on inflammation, or whether it works as a primary anti-inflammatory, is yet to be determined. Certainly, the presence of testosterone in the tears has been shown to have an influence on anti-inflammatory cytokines in lacrimal tissues and in the tears themselves.¹⁴

Currently, there is no commercially available testosterone preparation for the treatment of any ocular disease, including dry eyes and MGD.

The treatment of keratoconjunctivitis sicca with topical androgen preparations is really only limited to isolated case studies and animal models at this stage, though it does represent a potential new therapeutic strategy in the treatment of this condition.¹⁵

Non-steroidal anti-inflammatory drugs

Currently there are no topical non-steroidal anti-inflammatory drug (NSAID) preparations approved for use for dry eye or ocular surface disease internationally.

One of the most common side effects of topical NSAIDs tends to be exacerbation of ocular surface symptoms and, as such, it would be unlikely that there would be any particular focus on looking to NSAIDs as a therapeutic modality in this condition.

The role of systemic NSAID medications is similarly extremely limited in DED. Some small studies have documented the effect of low dose aspirin on dry eye parameters. However, a clinician would need to be extremely cautious about the risk profile of such a treatment and the studies are very limited, with only ocular surface disease index questionnaire studies having been done, not basic science or systematic reviews.¹⁶

Quite the opposite response is generally the case with systemic NSAIDs. Typically, an exacerbation of dry eye symptoms is a well-known and clearly documented side effect of these medications, so they really have a very limited role as anti-inflammatory agents in dry eye and meibomian gland dysfunction.

Intense pulsed light treatment

Intense pulsed light (IPL) treatment has been used as a treatment for evaporative dry eye disease for some time, with multiple approved devices now available for the treatment of dry eye due to MGD.¹⁷ There has always been a very clear association between DED and inflammatory skin conditions of both the eyelids and face, particularly facial rosacea. IPL treatment is widely accepted as a treatment for skin rosacea by dermatologists and, anecdotally, improvement in DED has been noted by patients for some time. Further studies have elucidated the beneficial therapeutic effect of IPL on DED.¹⁸

The mechanism of action of IPL is not well understood, both for facial inflammatory conditions and for dry eye. There are multiple proposed mechanisms of action, including thrombosis of abnormal blood vessels, heating of the meibum, reducing epithelial turnover, photomodulation, activating fibroblasts, enhancing collagen synthesis, eradicating Demodex, modulating the secretion of pro- and anti-inflammatory molecules, and suppression of matrix metalloproteinases.

In skin conditions, it is known that IPL treatment decreases the concentration of matrix metalloproteinases. This effect seems to be by down-regulation at the mRNA level. TNF-alpha is also down-regulated by IPL.¹⁹

IPL may also have an up-regulation effect on anti-inflammatory cytokines as well as an inhibitory effect on inflammatory cytokines. Interleukin-10 (an anti-inflammatory protein that inhibits cytokine production) has been shown to be significantly up-regulated in patients treated with IPL.²⁰

IPL treatment is the exception to the rule in this article, in that all of the other treatment modalities involve ingestion of medications or use of eye drops. The advantage of IPL treatment is that the issue of compliance is obviously removed from the equation; patients will often enjoy a long-lasting benefit and improvement in their dry eye symptoms without having to adopt a daily eye care regime or continuously use eye drops.

Intense pulsed light treatment.

Demodex treatment

A common cause of blepharitis and very inflamed eyelids is Demodex infestation. Demodex is a common incidental finding in patients without significant DED. It has an increasing incidence with increasing age. Its incidence has been reported to be as high as 70% in patients at 70 years of age.²¹

Demodex infestation has classic hallmarks, with particularly inflamed eyelid margins and telangiectatic vessels, classic collarettes at the base of the eyelashes, and significant anterior blepharitis.²² Numerous treatments have been tried, none of which will achieve eradication of Demodex mites, however controlling them can significantly improve the symptoms in some patients.

Some of the treatments that have been tried include oral ivermectin and topical compounded ivermectin preparations applied to the eyelids and lashes.

A more common approach is simple eyelid hygiene, often with a tea tree-based eyelid cleanser. Tea tree and Manuka honey-based products, such as Optimel, have been shown to kill Demodex mites.²³ Often, a very thorough lid clean is required at the slit lamp by the eye care practitioner. Removing the Demodex collarettes is delicate and time-consuming but really does need to be performed thoroughly to significantly improve the patient's symptoms.

Use of mechanical devices, such as the BlephEx device combined with tea tree scrubs, can significantly speed up the process, removing all evidence of the mites and the associated debris.

Demodex treatment will often need to be repeated on multiple occasions to control the number of mites and, accordingly, the patient's symptoms. This needs to be patient-driven with over-the-counter eyelid hygiene preparations, however patients do need to be educated on the use of these. It is important that patients perform a physical scrub of the eyelids and lashes to break up the biofilm and debris that can accumulate. The simple application of foam to the eyelids, washed off soon afterwards, does not provide the mechanical disruption required to significantly affect the colonisation.

Demodex mites have been implicated as a potential causative organism in some subtypes of facial rosacea. IPL treatment is thought to potentially kill the mites, however IPL as a treatment for dry eye really is not applied to the base of the eyelash follicle where the Demodex mite infests.

Oral tetracyclines

Tetracyclines were the first broad-spectrum antibiotics effective against gram-positive and gram-negative bacteria as well as some rickettsial diseases. Further experience with their use proved them to be effective antimalarial drugs. Both minocycline and doxycycline have been shown to have anti-inflammatory and anti-protease activities. Doxycycline is widely used for its anti-inflammatory effects, and particularly for its ability to inhibit matrix metalloproteinases (MMPs), which contribute to tissue destruction in not only ocular and corneal diseases, but also dental conditions.²⁴

MMPs are a broad family of endopeptidases. They can be broken up into subgroups that specifically lyse particular protein groups: collagenases, gelatinases, stromelysins, and membrane type MMPs.

Inhibition of MMPs is thought to be by both inhibition of their expression and by direct inhibition of the activity of the molecule itself.

It is believed that the direct inhibition pathway occurs through direct interaction between the metal ions within the MMP and the tetracycline molecule itself. Doxycycline shows a much stronger anti-collagenase effect in rabbit corneas than the other tetracycline antibiotics. The mechanism by which tetracyclines inhibit the expression of MMPs is not yet clearly understood.

Other anti-inflammatory benefits of tetracyclines include inhibition of pro-inflammatory cytokine levels and scavenging of reactive oxygen species. It is for these anti-inflammatory effects that doxycycline and minocycline are widely used in skin conditions such as acne and rosacea.²⁵ Nitric oxide is a potent mediator of vessel permeability and oedema, and it has been implicated in the pathogenesis of acne, rosacea and the telangiectasia associated with MGD.²⁶

It is this multitude of anti-inflammatory effects of tetracycline antibiotics, and in particular doxycycline, that makes them widely used in the treatment of inflammation in dry eye and meibomian gland dysfunction.²⁷ It should be noted that in Australia, these medications are used off label for this purpose. They are not approved to be subsidised under the PBS for these indications.

It is important to understand the side effects of systemic tetracyclines and to warn patients about them. Doxycycline, in particular, can make patients more sensitive to sunburn, which is an issue in the Australian climate, especially in summer.

Doxycycline cannot be used in children under eight due to permanent discolouration of teeth. At the low doses at which doxycycline is used for DED, oral and other opportunistic candida infections are rare, however they can occur.

Similarly, the rate of Clostridium difficile infection is low. Typically the dose is 100 mg/day but some authors advocate 50 mg once or twice a day.

Topical azithromycin

The beneficial effects of topical azithromycin on MGD and DED are well documented. Azithromycin is a macrolide antibiotic that works by binding to the 50S subunit of the bacterial ribosome, inhibiting translation of mRNA. Its mechanisms of action in improving dry eye are thought to be both through alteration of the ocular flora and through an anti-inflammatory effect. Studies have also shown that systemic azithromycin benefits ocular surface symptoms, but topical azithromycin is a superior treatment that lacks the potential systemic side effects.²⁸

Studies have shown that the concentrations of interleukin-1 beta, interleukin-8, and MMP-9 in the conjunctival cells of the eye are reduced in patients receiving topical azithromycin.

It should be noted that the levels of these inflammatory mediators return to pre-treatment levels after stopping the topical medication. This highlights the fact that treating inflammation alone in DED is a short-term measure and that, if possible, the cause of the dry eye and inflammation should be addressed. As with the tetracycline antibiotics, the exact mechanism of anti-inflammatory action is not known, however the non-antibiotic effects of azithromycin appear to be particularly directed towards the inflammation associated with neutrophils, and the subsequent cascade associated with their activation.²⁹

Gastrointestinal and ocular flora

The role of the gastrointestinal flora in a multitude of autoimmune and inflammatory diseases is very much an emerging area of scientific exploration and interest. Alterations in the intestinal flora have been shown to potentially play a role in diseases ranging from Sjögren's syndrome³⁰ to cardiovascular disease, dementia, and a multitude of mental health and other conditions that would traditionally have been considered non-inflammatory. As an emerging area of science, at this stage there is no concrete or even empirical evidence to suggest that treating any of these conditions is as simple as prescribing a probiotic tablet for patients.

The discovery that there may be a connection between autoimmunity and the gut microbiome in inflammatory conditions, such as Sjögren's syndrome, certainly offers the promise of new treatments. Investigations into this connection are at the very early laboratory-based stages and certainly no useful clinical or therapeutic treatments are available. However, this does remain an exciting and interesting area of research, and one that many clinicians are watching with keen interest. The connection is not limited to conditions considered to be autoimmune: there is also thought to potentially be a gut-retina axis, with a correlation shown between age-related macular degeneration and the intestinal flora.³¹

Studies have also shown that the ocular flora of patients with significant MGD, blepharitis, and DED differs from that of those without the disease. Different bacteria have been implicated but, typically, Propionibacterium acnes and Staphylococcus aureus have been shown to be present in greater numbers in patients with dry eye than in patients without it. The different species of Demodex (folliculorum and brevis) have also been shown to be present in higher numbers in patients with this condition.³² An alteration in the ocular flora is a very obvious mechanism of action for both topical and systemic antibiotics used to treat dry eye. However, as discussed above, it is the anti-inflammatory properties of these medications, over and above their antimicrobial activity, that make them particularly useful.

Conclusion

Dry eye is the result of a complex and multifactorial cascade of events. While addressing the cause or causes of a patient's DED is critical to achieving long-term relief, inflammation is a common pathway in almost all patients. There are many safe and effective treatments for inflammation. Clinicians should specifically address the inflammatory component of each patient's disease to achieve effective and long-term control of the condition.

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The original article was sponsored by Sun Pharmaceutical Industries Pty Ltd.

This article was first published in mivision in 2023 and is republished with permission.