Dry Eye in Clinical Practice Filling in the Gaps

ROSACEA

Rosacea is a common skin disorder typically affecting women more than men, although ocular rosacea has a similar preponderance between the sexes.¹ The diagnostic features of rosacea are phymatous changes (Figure 1), commonly on the nose, or persistent centrofacial redness that can intensify periodically.³ Other major features are flushing, papules and pustules.³ 

Ocular involvement can occur in 60–70% of rosacea patients, with the cornea being involved in up to 30–40% of ocular rosacea cases.⁴ Ocular rosacea is an inflammatory disorder with increased inflammatory mediators found in tears of ocular rosacea patients.⁴ Interestingly, demodex infestation has been found in facial rosacea cases, raising the possible role of demodexinduced inflammation in ocular rosacea.⁴ 

A 2013 survey of Australian optometrists found that most optometrists considered patient symptoms to be the driver of their dry eye disease management process…

Figure 1. Phymatous changes (thickened skin,
and enlarged pores, commonly on the nose) are
a diagnostic feature of rosacea.

OCULAR ROSACEA

Ocular rosacea can be present with or without skin disease.^1,3 Lid margin telangiectasia, blepharitis, keratitis, conjunctivitis and anterior uveitis are features of ocular rosacea.³ Symptoms of ocular rosacea can be non-specific and include tearing, redness, foreign body sensation, burning, itching and photophobia.⁴ 

Mild ocular rosacea can be managed with well-known measures of managing ocular surface disease such as lid hygiene, topical lubricants and cyclosporine.^4,5 Systemic treatment with Doxycycline has been useful as an adjunct therapy to topical options, especially in moderate and severe cases of ocular rosacea.^3,4 A unique dose of modified-release doxycycline 40mg daily is recommended as systemic treatment for ocular rosacea with or without skin disease.⁵ It is unfortunate however, that this special formulation of slow release low dose doxycycline is not commercially available in Australia.

DRY EYE QUESTIONNAIRES

A 2013 survey of Australian optometrists found that most optometrists considered patient symptoms to be the driver of their dry eye disease management process, however less than 5% used standardised questionnaires in practice.⁶ 

Dry eye questionnaires are used in research as they allow for quantifiable measurement of patient symptoms. For this reason, questionnaires can be useful in clinical practice as well, as they allow for a quantifiable measurement of improvement in symptoms with any prescribed treatment plan. Dry eye questionnaires can be given to patients for them to fill out in the waiting room or discussed in the consulting room with the patient.

The Tear Film and Ocular Surface (TFOS) DEWS II committee recommends the use of the Dry Eye Questionnaire-5 (DEQ-5) or Ocular Surface Disease Index (OSDI).⁷ DEQ-5 consists of only five questions with multiple choice answers that are easily scored. A score of greater than six on DEQ-5 suggests positive DED. OSDI consists of 12 questions on a single A4 sheet. The second page of the OSDI questionnaire provides a simple explanation of how to score the answers, accounting for any questions the patient has not answered. On the OSDI, a score below 12 points would be considered normal, a mild DED score is 13–22 points, a moderate DED score is 23–32 points and a score above 33 points indicates severe DED.

OSDI and DEQ-5 have been shown to relate well with Sjogren’s syndrome and Non-Sjogren’s syndrome dry eye patients.8 OSDI may be superior to DEQ-5, as it had greater accuracy in diagnosing clinical dry eye disease based on ocular signs.⁹ Recently published research from the School of Optometry and Vision Science at University of New South Wales has shown that both OSDI and DEQ-5 can successfully be administered in children to measure dry eye symptoms, although children may require more assistance in completing OSDI than DEQ-5.¹⁰ 

Figure 2. A simple grading scale.

LID WIPER EPITHELIOPATHY

The term Lid Wiper Epitheliopathy (LWE), is derived from the action of the inner part of the eyelids that is responsible for wiper-like action in a blink to spread tears. It is hypothesised that this region is damaged, resulting in LWE, when the tear film is inadequate or, in the case of contact lens wearers, with constant rubbing against the lens.¹¹ Vital dyes, such as fluorescein and lissamine green (LG), are necessary to view any damage to the lid wiper region. Certain LG stain strips have been show to stain better than others eg. GreenGlo showed more staining than Lissaver.¹² Careful lid eversion, through only touching the eyelashes, is required as practitioners’ fingers can easily spread the dye over the lid wiper region to give a false positive result.

No specific grading scale exists for LWE, however, a simple scale of absent, mild, moderate and severe (Figure 2), is adequate for clinical use. Practitioners should note that a thin line posterior to meibomian glands (as seen in grade 0 of Figure 2) is normal and not indicative of a positive LWE. Figure 3 shows the variations in LWE presentation with different types of staining.¹³

LWE is hailed as a diagnostic tool for dry eye disease. Randomised control studies of symptomatic dry eye patients and asymptomatic non-dry eye patients found that LWE was present in 75–90% of symptomatic patients and only 10–15% of asymptomatic patients.14,15 Detection of LWE may be hampered by limited use of LG in clinical practice; it is used by only 6% of general optometrists and 22% of specialist dry eye practitioners or researchers in Australia.⁶

There is, perhaps, a greater role for LWE in evaluating contact lens discomfort, with the TFOS workshop on CL discomfort concluding that LWE may be a clinical sign ‘truly associated with dryness in (contact) lens wearers’.¹⁶ 

Topical Cyclosporine A is an immunosuppressant primarily preventing T-cell activity at the ocular surface and hence supressing the inflammatory processes

CYCLOSPORINE

TFOS DEWS II report suggests the use of prescription drugs including cyclosporine in step two of dry eye disease management, after ocular lubricants, lid hygiene and environmental and dietary modifications are not effective enough.⁷

Topical Cyclosporine A is an immunosuppressant primarily preventing T-cell activity at the ocular surface and hence supressing the inflammatory processes, which is thought to underpin much of dry eye disease.17 Cyclosporine A is also thought to protect conjunctival and corneal cells from cell death, a common sequelae of chronic inflammation at the ocular surface.¹⁷ 

Figure 3. Types of lid wiper epithelium staining.

Until the regulatory approval of Cequa (0.9mg/ml) and Ikervis (1mg/ml) for use in Australia, cyclosporine eye drops were required to be compounded and prescribed off label, or accessed under the Pharmaceutical Benefits Scheme Special Access Scheme (PBS SAS) as Cyclosporine 0.05% (Restasis).

Cyclosporine 0.09% eye drops can now be prescribed privately (not PBS) by optometrists, with twice a day dosage of one drop in each eye. Ikervis is expected to be available in late 2021 with recommended dosage of once-a-day in the evening. It should be noted that Cequa is indicated to increase tear production in patients with moderate to severe dry eye disease, while Ikervis is indicated for severe keratitis with dry eye disease.

A randomised double-masked control trial of Cyclosporine 0.09% (Cequa) found that three months of use resulted in reduced conjunctival and corneal staining.¹⁸ Schirmer test scores also increased by more than 10mm in 18% of patients.¹⁸ It is of note that both tear break up time (TBUT) and symptoms, measured via modified Symptom Assessment in Dry eye (SANDE) questionnaire, were not improved after three months of use.

Results of similar trials for Cyclosporine 0.1% (Ikervis) found an improvement in corneal staining with one month of use and at three and six months. Like Cequa, there was no significant improvement in TBUT or symptom scores after six months of use compared to control. However, unlike Cequa, Schirmer scores were not improved with six months use of Ikervis. It is noteworthy that one third of patients in Ikervis trials were Sjgoren’s positive.

Findings from trials of Cyclosporine 0.09% (Cequa) and Cyclosporine 0.1% (Ikervis) are consistent with previously reported findings with Cyclosporine 0.05%. That is, an improvement in tear production (measured with Schirmer with anaesthetic) occurred but no improvement in OSDI or TBUT scores were found.¹⁹

The most common adverse event noted with Cyclosporine 0.09% (Cequa) and Cyclosporine 0.1% (Ikervis) were pain on instillation at a mild-moderate level by 23% of users and eye irritation by 16% of users respectively.¹⁸

It should be noted that when Cyclosporine 0.09% (Cequa) and Cyclosporine 0.1% (Ikervis) become available on market, they will be on the ‘Black Triangle Scheme’ by the TGA. This scheme encourages patients and practitioners to report adverse events which occur with use of Cequa or Ikervis at www.tga.gov.au/reporting-problems. This is a common procedure for newly registered medicines and does not deem the medicine unsafe, rather it aims to build the safety profile of the medicine.

Sukanya Jaiswal graduated with a Bachelor’s degree in Optometry and Vision Science in 2013, Masters in Optometry in 2020 and is currently pursuing a PhD at the School of Optometry and Vision Science at UNSW Sydney. 

Blanka Golebiowski is an optometrist and Associate Professor in the School of Optometry and Vision Science at UNSW. Her research aims to understand the mechanisms of dry eye and eye pain, in order to inform the development of effective new treatments. 

Isabelle Jalbert is an optometrist and Associate Professor in the School of Optometry and Vision Science at UNSW Sydney. Her research focuses on evidence-based eye care, eye care quality and health education. 

References 

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2. Tan, Jerry, et al. Updating the diagnosis, classification and assessment of rosacea: recommendations from the global ROSacea CO nsensus (ROSCO) panel. British Journal of Dermatology 176.2 (2017): 431-438. 
3. Schaller, M, Almeida, L, Bewley, A et al. Recommendations for rosacea diagnosis, classification and management: update from the global ROS acea CO nsensus 2019 panel. 2020; 182: 1269-1276 
4. Vieira, ACMannis, MJJJotAAoD. Ocular rosacea: common and commonly missed. 2013; 69: S36-S41 
5. Schaller, M, Almeida, L, Bewley, A et al. Rosacea treatment update: recommendations from the global ROS acea CO nsensus (ROSCO) panel. 2017; 176: 465-471 
6. Downie, LE, Rumney, N, Gad, A et al. Comparing selfreported optometric dry eye clinical practices in Australia and the United Kingdom: is there scope for practice improvement? 2016; 36: 140-151 
7. Nelson, J, Craig, J,Akpek, EJOS. TFOS DEWS II report. 2017; 15: 802-812 
8. Caffery, B, Chalmers, RL, Begley, CJIO et al. Performance of the dry eye questionnaire 5 (DEQ-5) compared to ocular surface disease index (OSDI) in Sjogren’s and non-Sjogren’s dry eye subjects. 2011; 52: 3850-3850 
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10. Chidi-Egboka, NC, Golebiowski, B, Lee, SY et al. Dry eye symptoms in children: can we reliably measure them? 2021; 41: 105-115 
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18. Tauber, J, Schechter, BA, Bacharach, J et al. A Phase II/ III, randomized, double-masked, vehicle-controlled, doseranging study of the safety and efficacy of OTX-101 in the treatment of dry eye disease. 2018; 12: 1921 
19. Zhou, XQWei, RLJC. Topical cyclosporine A in the treatment of dry eye: a systematic review and metaanalysis. 2014; 33: 760-767