KEEPING THE OCULAR SURFACE HEALTHY IN THE GLAUCOMA PATIENT

Although topical glaucoma therapies are a proven strategy to lower IOP, their negative impact on the ocular surface can’t be overlooked. DR ROHAN GUPTA and A/PROF CHAMEEN SAMARAWICKRAMA argue for a more preventative approach, from prioritising ocular surface disease detection and the use of preservative-free therapies and lubricants, to surgical interventions.

Glaucoma remains the leading cause of irreversible blindness in the world, affecting 1.5-3.4% of Australians over the age of 40.1 The majority of these patients are treated with topical therapy to lower their intraocular pressure (IOP).

Unfortunately, many topical therapies used in the management of glaucoma can initiate and/ or exacerbate ocular surface disease (OSD). OSD in glaucoma patients can result in increased morbidity, reduced quality of life, poorer quality of vision and reduced compliance with glaucoma therapy leading to disease progression. 2 As such, it is important for clinicians to minimise the symptoms of OSD in glaucoma patients as much as possible.

In this article, we will outline the pathogensis and impact of OSD in glaucoma patients; methods to diagnose and monitor OSD; and strategies to manage OSD in glaucoma patients. Based on the results of the LiGHT Trial from the UK, 3 we will also discuss the need for a paradigm shift in the initial management of glaucoma, with a focus on using selective laser trabeculoplasty (SLT) as a first line treatment for open angle glaucoma and ocular hypertension to reduce the ocular toxicity of topical glaucoma therapy.

Pathogenesis Of Ocular Surface Disease In Glaucoma Patients

OSD is a multifactorial disorder involving tear production, tear film quality, conjunctival and corneal epithelial status, and lacrimal and meibomian gland function. OSD can occur as a result of various factors including aging, hormone imbalance, systemic comorbidities, systemic medications, environmental exposure and drop toxicity. OSD is estimated to occur in 10-25% of the general population, however, this number increases to 50-60% in glaucoma patients on topical IOP lowering therapy. 4

The mechanism for OSD in glaucoma patients relates to changes in various inflammatory pathways. Long-term topical glaucoma therapy upregulates the production of several proinflammatory mediators including IgE and Class II antigen HLA-DR, resulting in reduced density of goblet cells, meibomian gland dysfunction, squamous metaplasia of the conjunctival epithelium and conjunctival and corneal desquamation. 5

The consequence of these changes is a reduction in tear quantity and quality resulting in symptomatic OSD.

Glaucoma medications can cause/exacerbate OSD either as a direct consequence of their active ingredient or from added preservatives. The four main classes of topical therapy for IOP lowering are prostaglandin analogues, beta blockers, alpha agonists and carbonic anhydrase inhibitors. Each of these classes of medications induces/exacerbates OSD via a different pathway.

• Prostaglandin analogues are associated with obstructive meibomian gland dysfunction.

Dr Rohan Gupta (MBBS (Hons), MMed (Ophth Sci), Grad Dip (Refrac Surg), FRANZCO) Cataract, Refractive and Glaucoma Surgeon Nexus Eyecare, Sydney Lindfield Eyecare, Sydney

A/Prof Chameen Samarawickrama

BSc(Med) MBBS, PhD, FRANZCO

NHMRC Investigator Fellow Director, Translational Ocular Research and Immunology Consortium (TORIC) Westmead Institute for Medical Research | Save Sight Institute Sydney University Nexus Eyecare, Blacktown and Norwest

• B eta blockers reduce basal tear turnover rate by acting on beta receptors in the lacrimal gland.

• Alpha agonists induce ocular allergy and upregulate IgE.

• Carbonic anhydrase inhibitors decrease the viability of the corneal epithelial cells resulting in apoptosis.

• Preservatives used to prevent microbial contamination include benzalkonium chloride (BAK), oxychloro complex and polyquaternium1. These substances initiate/exacerbate OSD by inducing squamous metaplasia of the conjunctival epithelium and destabilising the conjunctival goblet cells resulting in tear film instability. 5

The relationship between ocular inflammation and topical glaucoma therapy is dose-dependant, thus patients on multiple topical therapies for prolonged periods are more likely to develop symptomatic OSD. This is particularly relevant to patients with ocular hypertension, as 49% of these patients will be on two or more topical therapies within five years of diagnosis. 4 Additionally, patients with primary open angle glaucoma (POAG) have been shown to have a lower basal tear turnover rate compared to normal controls, further increasing their risk of developing OSD.

Impact Of Osd In Glaucoma Patients

Symptoms of OSD and chronic ocular inflammation include burning, irritation, itching, tearing, and decreased visual acuity. These symptoms can occur as early as three months after starting topical therapy.6 The negative impact on quality of life of these symptoms can result in many patients being non-compliant with topical therapy. Studies have shown that compliance with topical therapy among glaucoma patients is often less than 50%, with OSD side-effects of topical therapy reported as one of the primary reasons.7

Additionally, the decrease in visual quality caused by OSD is compounded in glaucoma patients who already suffer from reduced contrast sensitivity, causing greater negative impact on their visual function, quality of life and increasing falls risk.

From a surgical glaucoma perspective, chronic OSD causes scarring of the conjunctiva and tenons, resulting in higher bleb failure rates in patients undergoing glaucoma filtering surgery.6

Diagnosing And Monitoring Osd

The diagnosis of OSD is obtained through both subjective and objective measurements. Subjective measurements include a thorough history specifically asking about foreign body sensation, redness, epiphora and/or a feeling of tired/heavy eyes. Patients should also be asked if they have visual fluctuations which improve with blinking, symptoms which are worse in the morning or evening and checking for other risk factors such as a history contact lens wear, snoring or systemic inflammatory conditions which may exacerbate OSD.

Subjective Measurements

Quality of life questionnaires are a useful tool to help standardise responses so that the severity of OSD can be monitored from visit to visit. 8 Two such questionnaires are the Ocular Surface Disease Index (OSDI) and the Glaucoma Quality of Life-15 (GQL-15) form. The OSDI is composed of 12 questions, used to measure ocular discomfort, visual function and environmental triggers, with higher scores corresponding to worsening OSD. The GQL-15 is composed of 15 questions aimed at measuring the impact of glaucomatous optic neuropathy on daily visual function, with lower scores corresponding to worsening disease.

Objective Measurements

Objective measurements of OSD are obtained through clinical examination and various newer technologies. Factors that should be assessed include eyelid position, tear meniscus, tear film quality, tear quantity (Schirmer’s test), tear film break-up time (TBUT; less than 10 seconds being abnormal), meibomian gland dysfunction and any ocular surface staining with fluorescein.

Clinical examination can be augmented by several new technologies such as tear osmolarity testers and ocular surface analysers which measure lipid layer thickness (LLT), capture blink dynamics, and image meibomian gland structures. These technologies can be helpful in diagnosing OSD and monitoring progression. 8 They can also be used to perform baseline tests before initiating topical glaucoma therapy.

Management Of Osd In Glaucoma Patients

OSD in glaucoma patients occurs as a consequence of their topical therapy and the traditional approach to managing OSD in glaucoma patients has been reactive (that is: treating symptoms of OSD after they arise). However, with the results of the LiGHT Trial, the advances in minimally invasive glaucoma surgery (MIGS) and the abundance of preservative-free glaucoma medications on the market, there is an argument to be made for a more preventative approach, which utilises therapies other than preserved topical therapy to lower IOP while maintaining ocular surface health. Below, we have outlined a step-wise approach to managing glaucoma and keeping the ocular surface healthy.

1. Non-invasive procedural intervention: SLT SLT is a non-invasive treatment which can be performed in clinic. It utilises short pulses of low-energy light to heat the trabecular meshwork resulting in a mild and transient inflammatory response which reduces trabecular resistance and increases aqueous outflow thereby reducing intraocular pressure without the need for topical therapy or as a supplementary treatment to reduce drop burden.

The LiGHT trial – this was a recently published multicentre randomised control trial in the Lancet, which compared SLT with topical therapy as a first line treatment in patients with primary open angle glaucoma and ocular hypertension. The results showed that three years after a single SLT treatment, 78% of patients were able to maintain adequate IOP control without the need for topical therapy.

The patients who received SLT had better IOP control at more visits (93·0%) compared to the eye drops group (91·3%) and had a lower rate of progression to glaucoma surgery. 3 From an OSD perspective, patients in the SLT arm reported significantly less adverse symptoms compared to patients receiving topical therapy (30 events vs 150 aesthetic side effects/allergic reactions). 3

The results from SLT can last for up to four years, and the procedure can be repeated, however, the IOP lowering becomes less effective with successive treatments. The main benefits of SLT are that it reduces drop burden, thereby reducing OSD symptoms; removes the risk of non-compliance; reduces IOP fluctuations which can occur with topical therapy; and removes the challenges of cognitive impairment and failing grip strength which are common amongst older patients with glaucoma.7

The main limitations of SLT are that it cannot be used in all forms of glaucoma (specifically uveitic and angle closure glaucoma) and in more severe cases, it may be insufficient. The IOP lowering effects also wear off after time, however, this ‘limitation’ is offset by the improved quality of life during the period the laser is effective. There is also an initial upfront cost, however, this is typically less than the cost of topical therapy over a three-year period, especially if patients also require additional lubricating drops to offset the symptoms of OSD. 3

2. Reducing preservative burden SLT cannot be used in all forms of glaucoma and may be insufficient in achieving IOP lowering in some patients. In these instances, topical therapy needs to be used. Conventional topical glaucoma therapies typically contain added preservatives to prevent microbial contamination of the bottle. The preservative BAK is the most commonly used preservative in ophthalmic preparations, and reducing exposure to BAK has been shown to reduce the severity of OSD and increase compliance with topical therapy.7 Reducing BAK exposure can be achieved through the use of preservative-free or preservative reduced medications, or by prescribing glaucoma medications which contain alternative preservatives that are less damaging to the ocular surface. Studies comparing the efficacy of BAK-preserved and preservative-free preparations showed no difference in the amount or duration of IOP reduction. 9

Reducing the preservative burden has been shown to significantly reduce OSD in glaucoma patients and aid with compliance. There are some drawbacks with preservative-free preparations. Preservative-free drops have a theoretical increased risk of contamination, however, this risk can be mitigated by prescribing single use medications. Cost can be a barrier, with many preservative-free preparations being more expensive than their preserved counterparts. In these instances, patients, especially those who have evidence of pre-existing OSD, should be educated on the potential benefits of a preservative-free preparation. For many of these patients, an improved quality of life may justify the extra expense.

3. Improving ocular surface

As mentioned earlier, glaucoma medications can cause OSD as a result of their active ingredient. In patients who have OSD despite the use of preservative-free medications or in whom a preservative-free option is not suitable, strategies to improve ocular surface health should be employed to minimise the symptoms to OSD and reduce the risk of non-compliance. The mainstay of treatment includes the use of intensive preservative-free lubricants to provide symptomatic relief. Co-existing lid margin disease and meibomian gland dysfunction should also be addressed with hot compress and

PBS Information: Xalatan (latanoprost 0.005% eye drops, 2.5 mL) is listed on the PBS as antiglaucoma preparations and miotics.

Before prescribing please review Product Information available via www.aspenpharma.com.au/products or call 1300 659 646.

Minimum Product Information: XALATAN® (Latanoprost 50 μg/mL) Eye Drops. Indication: Reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Contraindications: Hypersensitivity to ingredients. Precautions: Change in eye colour due to increased iris pigmentation, heterochromia; eyelid skin darkening; eyelash and vellus hair changes; aphakia; pseudophakia; macular oedema; other types of glaucoma; contact lenses; severe or brittle asthma; herpetic keratitis; driving or using machines; elderly; children; lactation. Pregnancy: Category (B3)

Interactions: other prostaglandins, thiomersal. See PI for details. Adverse Effects: Iris hyperpigmentation; eye irritation (burning, grittiness, itching, stinging and foreign body sensation); eyelash and vellus hair changes (increased length, thickness, pigmentation and number of eyelashes); mild to moderate ocular hyperaemia; punctate keratitis; punctate epithelial erosions; blepharitis; eye pain; excessive tearing; conjunctivitis; blurred vision; eyelid oedema, localised skin reaction on eyelids; myalgia, arthralgia; dizziness; headache; skin rash; eczema; bronchitis; upper respiratory tract infection; abnormal liver function. Uncommon: Iritis, uveitis; keratitis; macular oedema; photophobia; chest pain; asthma; dyspnoea. Rare: periorbital and lid changes resulting in deepening of the eyelid sulcus; corneal calcification. See PI for details and other AEs. Dosage and Administration: One eye drop in the affected eye(s) once daily. Other eye drops should be administered at least 5 minutes apart. (Based on PI dated 2 March 2021)

References: 1. NHMRC Guidelines for the screening, prognosis, diagnosis, management and prevention of glaucoma 2010 2. Australian Commission on Safety and Quality in Healthcare Active Ingredient Prescribing Guide - list of medicines for brand consideration December 2020

Aspen Australia includes Aspen Pharmacare Australia Pty Ltd (ABN 51 096 236 985) and Aspen Pharma Pty Ltd (ABN 88 004 118 594). All sales and marketing requests to: Aspen Pharmacare Pty Ltd, 34-36 Chandos Street, St Leonards NSW 2065. Tel: +61 2 8436 8300 Email: aspen@aspenpharmacare.com.au Web: www.aspenpharma. com.au Trademarks are owned by or licensed to the Aspen group of companies. © 2021 Aspen group of companies or its licensor. All rights reserved. Prepared: June 2021 AF05768 ASP2528 massage, lid wipes +/- oral tetracycline.

Studies have shown that the use of topical lubricants in glaucoma patients improved mean OSDI scores, increased goblet cell density, improved TBUT, reduced lid margin inflammation and improved conjunctival injection.10

In more severe cases of OSD that are resistant to the above treatment options, topical cyclosporine 0.05% twice daily can also be considered. One study showed that a six-month course of topical cyclosporine in glaucoma patients on long-term therapy significantly improved corneal sensitivity and partially reversed surface toxicity from preserved glaucoma medications.11

4. Surgical intervention (MIGS)

With the advent and widespread adoption of MIGS over the past 10 years, surgical intervention for managing OSD in glaucoma patients is now a viable and relatively safe option.

Trabecular bypass devices, such as the iStent and Hydrus stent, can be inserted at the time of cataract surgery or as a standalone procedure in pseudophakic eyes, to reduce the need for topical therapy. Long-term data on these devices shows that at three years postoperatively, patients who underwent combined cataract and MIGS achieved 37% reduction in IOP and 68% reduction in topical therapy requirements, while patients who underwent a standalone MIGS achieved a 42% IOP reduction and 88% reduction in topical therapy requirements.12

Unlike traditional filtration surgery, which carries a higher risk of complications, MIGS procedures are relatively safe and appropriate for patients with mild-moderate glaucoma who have significant OSD from topical therapy. It should be noted that MIGS is still an intraocular surgery, and it therefore carries increased risk compared with non-invasive therapies. MIGS should only be considered after conservative therapies have failed.

Other surgical technologies are also on the horizon for managing OSD in glaucoma patients, specifically, a sustained-release bimatoprost implant. Although not available in Australia at present, the device is in Phase 3 trials. This device is injected intracamerally to provide a non-pulsatile, sustained release of bimatoprost over a 90-day period. The IOP lowering effects are comparable to those of topical bimatoprost, without the ocular surface toxicity of topical therapy.13

Conclusion

OSD is common condition among glaucoma patients which can limit their quality of life and reduce their compliance with treatment. OSD is caused/exacerbated by topical glaucoma medications via both the preservatives and the active ingredient.

SLT has been shown to be an effective treatment for IOP reduction and should be considered as a first line treatment in patients with open angle glaucoma and ocular hypertension. For patients in whom topical therapy is required, efforts should be made to limit the preservative burden. Symptomatic relief can be provided by lubricants and topical cyclosporin. It is important to manage any co-existing lid margin disease. In recalcitrant cases, surgical intervention can also be employed in the form of MIGS to help lower IOP and reduce drop burden.

REFERENCES:

1. Keel S, Xie J, Foreman J, Lee PY, Alwan M, Fahy ET, et al. Prevalence of glaucoma in the Australian National Eye Health Survey. British Journal of Ophthalmology. 2018;103(2):191–5

2. Mylla B oso AL, Gasperi E, Fernandes L, Costa VP, Alves M. Impact of Ocular Surface Disease Treatment in Patients with Glaucoma. Clin Ophthalmol. 2020;14:103-111

3. Gazzard G, Konstantakopoulou K, Garway-Heath D, Garg A, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): a multicentre randomised controlled trial. Lancet. 2019;393(10180):1505-1516

4. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17:350–355

5. Zhang X, Vadoothker S, Munir WM, Saeedi O. Ocular Surface Disease and Glaucoma Medications: A Clinical Approach. Eye Contact Lens. 2019;45(1):11-18

6. Saade CE , Lari HB, Berezina TL, Fechtner RD, Khouri AS. Topical glaucoma therapy and ocular surface disease: A prospective, controlled cohort study. Can J Ophthalmol. 2015;50(2):132–136

7. Tsai JC, McClure CA, Ramos SE, et al. Compliance barriers in glaucoma: a systematic classification. J Glaucoma. 2003;12:393–398

8. Mathews PM, Ramulu PY, Friedman DS, Utine CA, Akpek EK. Evaluation of ocular surface disease in patients with glaucoma. Ophthalmology. 2013;120(11):2241–2248

9. Ramli N, Supramaniam G, Samsudin A, Juana A, Zahari M, Choo MM. Ocular surface disease in glaucoma: Effet of polypharmacy and preservatives. Optom Vis Sci. 2015;92(9):e222–e226

10. Aragona P, Papa V, Micali A, Santocono M, Milazzo G. Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in patients with dry eye. Br J Ophthalmol. 2002;86(2):181–184

11. Saini M, Dhiman R Dada T, Tandon R, Vanathi M. Topical cyclosporine to control ocular surface disease in patients with chronic glaucoma after long-term usage of topical ocular hypotensive medications. Eye (Lond) 2015;29(6):808–814

12. Hengerer FH, Auffarth GU, Riffel C, Conrad-Hengerer I. Second-generation trabecular micro-bypass stents as standalone treatment for glaucoma: a 36-month prospective study. Adv Ther. 2019;36(7):1606–17

13. Craven E.R., Walters T., Christie W.C., Day D.G., Lewis R.A., Goodkin M.L., et al. 24-Month Phase I/II Clinical Trial of Bimatoprost Sustained-Release Implant (Bimatoprost SR) in

NOTE: Insight readers can scan the QR code or visit insightnews.com.au/cpd/ to access a link to this article to include in their own CPD log book.