Dry eye, Feature, Insight's Continuing Professional Development – NEW in 2022!, Report, Therapies

Understanding new treatment protocols for severe dry eye

 

At the completion of this CPD activity, optometrists will have developed their knowledge of treatment options for severe dry eye disease. Including:

  • Understand the use of anti-inflammatory agents in the treatment of extreme dry eye
  • Understand the benefits and contraindications for treatment of dry eye with topical ciclosporin and lifitegrast
  • Understand the benefits, indications and contraindications of amniotic membrane therapy for dry eye

NOTE: Optomery Australia members can enter their details at the bottom of this article to have it automatically added to their Learning Plan.

DR MARGARET LAM addresses the complicit role of inflammation in the most extreme dry eye cases and explores the use of anti-inflammatory agents to break the cycle, reduce symptoms and restore eye health for patients.

Margaret Lam
BOptom UNSW OA CCLSA OSO IAO GAICD
Optometrist, Head of Professional Services, George & Matilda
Adjunct Senior Lecturer, School of Optometry & Vision Science, Faculty of Medicine and Health, UNSW
National President, Cornea & Contact Lens Society of Australia
National Deputy President, Optometry Australia
State Director, Optometry NSW/ACT

Pathophysiology of dry eye disease

Dry eye (keratoconjunctivitis sicca) is a multifactorial ocular surface disease, accompanied by ocular symptoms, and characterised by clinical signs including a loss of tear film homeostasis. These ocular signs include tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities. Collectively, these changes all play aetiological roles in the pathophysiology of dry eye disease.

In 2017 the definition of dry eye was established by the Tear Film and Ocular Surface Society’s International Dry Eye Workshop II (DEWS II). Our understanding of dry eye focuses on tear film hyperosmolarity as a core mechanism, precipitating a compounding inflammatory cascade that damages the ocular surface.1,2

Today we understand that dry eye disease, beyond a condition that is caused simply by insufficient tear production, is a complex ocular surface disorder in which the tear film is unstable and no longer provides sufficient nourishment or protection to the ocular surface – which thus becomes inflamed and damaged.3

Inflammation has a complicit role in the pathophysiology of dry eye disease, promoting symptoms of irritation and ocular surface damage. Anti-inflammatory agents are thus appropriate treatments in the management of dry eye disease. The purpose of these treatments is to inhibit inflammation, re-establish the appropriate production of a healthy tear film and to reduce signs and symptoms of the disease.4

This article looks at the role of three new treatments for dry eye patients: topical pharmaceutical agents ciclosporin and lifitegrast, and amniotic membrane therapy with bandage contact lenses.

Ciclosporin

Prescribing anti-inflammatory agents, such as ciclosporin, that target specific inflammatory pathways to break the inflammatory cycle, is a therapeutic strategy worth considering for severe dry eye disease.5

Ciclosporin inhibits calcineurin, which creates a multi-step immune response that prevents the transcription and release of pro-inflammatory cytokines and dampens the message from pro-inflammatory cellular messenger proteins.6 Ciclosporin also inhibits cellular apoptosis of the conjunctival epithelial cells, potentially increasing tear film production, hence its benefits in the management of patients that exhibit dry eye disease.7

Dosage guide to ciclosporin

There are currently two commercially-available formulations for topical ciclosporin for patients with severe keratitis with dry eye disease that can be prescribed by optometrists in Australia.

  • Cequa ciclosporin (0.09mg/mL 0.09%), prescribed one drop instilled twice a day, (ideally twelve hours apart). Cequa is not listed on Pharmaceutical Benefits Scheme (PBS).
  • Ikervis ciclosporin (0.1mg/mL 0.1%) prescribed as one drop instilled once a day. Ikervis is listed on the PBS if the patient meets criteria for approval.

Nanomicellar technology vs nanoemulsion delivery

By itself, ciclosporin is poorly absorbed on the ocular surface. The two commercially-available ciclocporin brands differ from one another by how they deliver the drug so that it can be absorbed.8

Cequa’s ciclosporin incorporates ‘nanomicellar technology’ to increase its penetration in ocular tissues. The nanomicelles are composed of polymers that create a hydrophilic outer layer compatible with the tear film which allows it to transport through the tear film onto the ocular surface.

Table 1: This table outlines a proposed treatment algorithm for when to consider ciclosporin among the existing prescribing options for dry eye.15

NOTE: For a clearer view of Table 1, click here.

The ciclosporin molecules gain entrance into corneal and conjunctival cells, and once inside the tear film’s aqueous layer, the nanomicelles break up to release ciclosporin into the ocular tissues.9

Ikervis’ ciclosporin uses a positively charged oil-in-water nanoemulsion delivery system. The corneal epithelial cells are negatively charged, and the positive charge of Ikervis’ oil-in-water emulsion prolongs its time on the ocular surface and allows corneal and conjunctival penetration.10

The cationic emulsion itself in Ikervis has been shown to contribute to tear film stability and provide beneficial moisturising and lubricating effects.11,12  In combination with ciclosporin, the emulsion suppresses the secretion and expression of pro-inflammatory cytokines.14 

In addition to contributing to tear film stability, the nanodroplets contain cetalkonium chloride (CKC) which act as its cationic surfactant, further increasing its time on the ocular surface.14

When and why to prescribe ciclosporin

Ciclosporin is indicated for patients whose symptoms do not improve despite the use of ocular lubricants. In our practice, once a patient shows no improvement despite artificial tear film supplements, our current prescribing algorithm considers pharmacological agents such as topical corticosteroids, to inhibit the expression of inflammatory mediators; restore the secretion of a healthy tear film; and finally, to reduce signs and symptoms of the disease.13 

Very early in their normal treatment protocol, many eyecare practitioners prescribe a short pulse of a two-to-four week course of topical corticosteroids to attempt to reduce the inflammatory reaction and obtain symptomatic improvement.

Normally, it would be appropriate to taper topical corticosteroid therapy after a short period of corticosteroid use when there is improvement of ocular symptoms. Even though it is milder, long-term corticosteroid use has been shown to have a causative link with glaucoma, cataracts, and other steroid-related adverse effects.

Should dry eye symptoms persist beyond the initial course of corticosteroids, it would be appropriate to consider prescribing topical ciclosporin therapy. Ciclosporin could also be prescribed with the straight-forward intention of alleviating symptoms of dry eye disease while avoiding the potential adverse effects of topical corticosteroid therapy.

For many reasons, the prescription of ciclosporin could be more widely-adopted than it currently is: for the potential improvement in symptomatic relief for patients, reduction in corneal fluorescein staining; and clinically based symptoms recorded in dry eye surveys such as patient scores Ocular Surface Disease Index (OSDI); Tear Break Up Time (TBUT); Schirmer Tear Test and other clinical signs of dry eye disease.

Contraindications to ciclosporin

Ciclosporin should not be used in patients who are allergic to ciclosporin, or any other ingredients in the prescribed ciclosporin medium. Ciclosporin is also contraindicated in patients with active or suspected ocular or peri-ocular infection, or patients with ocular or peri-ocular malignancies or premalignant conditions.

Due to its actions as an immunosuppressive agent, ciclosporin should be prescribed with caution to patients who have a potential for eye injury and those with active infections. For patients who wear contact lenses, the use of ciclosporin should be closely monitored. Although safety and efficacy has not been established in patients below the age of 18,16 topical ciclosporin has shown no difference in safety and effectiveness in the elderly.

Lifitegrast (Xiidra)

Lifitegrast 5% (commercial name: ‘Xiidra’) is another effective pharmacological therapeutic agent for patients with severe dry eye. This has been a new addition to optometrists to be able to prescribe Lifitegrast since Optometry Board Approval on December 10, 2021.

Lifitegrast mechanism of action

In dry eye, the hyperosmolarity of the tear film causes the ocular surface to over-express a molecule known as intercellular adhesion molecule (ICAM-1).

ICAM-1 molecules have binding sites for T-cells, also known as T-lymphocytes. On the cellular surface, T-lymphocytes have proteins known as LFA-1 integrin. When LFA-1 integrin and ICAM-1 interact, T-cells activate and migrate to conjunctival and lacrimal glands, releasing cytokines, which are proteins that increase the inflammatory response and increase dry eye signs and symptoms.

Essentially, at the cellular level, Lifitegrast blocks T-cell adhesion to ICAM-1 and disrupts the dry eye inflammatory cascade.17,18,19

Lifitegrast prescribing guide

Lifitegrast 5% ophthalmic solution comes in individual vials and is prescribed one drop instilled twice a day, ideally 12 hours apart.

Adverse effects of Lifitegrast

Lifitegrast adverse effects include ocular irritation, discomfort, blurriness on instillation, conjunctival hyperaemia, discharge, itchy eyes, sinusitis and dysgeusia (distortion of taste sensation). Wheezing, difficulty breathing or swelling on the tongue is possible with Lifitegrast but rare.20

Lifitegrast contraindications

Xiidra is contraindicated in patients with known hypersensitivity to lifitegrast or to any of the other ingredients in the formulation. It has not been tested for children under 17 years of age.

Amniotic membrane therapy (AMT)

Amniotic membrane therapy applied with a bandage contact lens is still fairly new to Australia, but has been well established over the last few decades, particularly in the USA, as a very effective dry eye treatment option that should be considered for moderate-to-advanced dry eye, and particularly for patients that show recalcitrant dry eye disease despite other treatments.

Amniotic membrane and its mechanism of action

Amniotic membrane is an avascular foetal membrane, the overlying layer is the chorion and the amnion tissue that makes up the amniotic membrane is harvested from the amnion, on the innermost layer deeper than the chorion. The amniotic membrane is obtained during elective caesarean sections. Donors are screened for transmissible diseases, and the amniotic membrane is gamma-irradiated to ensure safety and sterility.21

Figure 2: Patient with grade 0.5 corneal staining after 10-day treatment with Amniotek-C dry amniotic membrane therapy applied with a bandage contact lens. The patient reports almost full cessation of dry eye associated pain after the amniotic membrane therapy.

Amniotic membrane therapy works in multiple ways in dry eye disease. Firstly, amniotic membranes applied with an overlying bandage contact lens act as a physical barrier to protect the corneal epithelium as it heals and reduces the discomfort from eyelids over a damaged ocular surface.

Secondly, the basement membrane of the amniotic membrane promotes epithelial healing through cellular migration, adhesion and differentiation, and prevents cellular apoptosis.

Thirdly, amniotic membrane also encourages a reduction of inflammation through down-regulation of inflammatory cytokines, and the amniotic membrane that contains foetal hyaluronic acid may inhibit fibroblast growth to reduce corneal scarring.

Finally, amniotic membranes may potentially also contain inherent antimicrobial properties to prevent the risk of infection.22

Indications for AMT

Amniotic membrane therapy can be used in any condition that requires promotion of ocular surface healing, as well as conditions that can create corneal scarring and are not responding to existing treatments. These include various types of keratitis, corneal ulcers, neurotrophic keratopathy, and chemical burns.23

Considerations with AMT

Amniotic membrane therapy is within the scope of optometrists and ophthalmologists to prescribe in Australia. The only amniotic membrane therapy accessible to prescribing eyecare practitioners in Australia applied as a sutureless therapy is by Amniotek-C and distributed by Designs For Vision with access strictly under approval through application to the Therapeutic Goods Administration (TGA)’s Special Access Scheme.

As with any bandage contact lens therapy, an appropriate broad spectrum prophylactic topical antibiotic eye drop, such as a fluoroquinolone based antibiotic four times daily, is necessary for the duration of the treatment.

Currently, there is some discussion between experts around if amniotic therapy is more effective with corneal debridement vs no corneal debridement.

Currently, corneal debridement with amniotic membrane therapy is not within the scope of optometric practice so any optometric practitioners should consider the application of the amniotic membrane without debriding the cornea. Depending on the condition being treated, corneal debridement may not be required to obtain excellent results from amniotic membrane therapy.

After seven to 10 days of treatment, the amniotic membrane dissolves and the bandage contact lens is removed in office.

Potential adverse effects of AMT

Temporary blurring of vision is caused while the amniotic membrane is in place covering the cornea. Mild irritation or a foreign body sensation is possible during the amniotic membrane therapy.

Summary

Prescribing topical ciclosporin or lifitegrast should be considered as an appropriate long term therapy to potentially break the complicit inflammatory cascade in dry eye disease. These therapeutic agents have no association with any significant systemic immunosuppressive adverse effects, nor do they have the more serious adverse ocular effects that are associated with long term topical corticosteroid use.

If symptoms of dry eye persist for a patient, or if there are patients that exhibit recurrence of dry eye symptoms, there is increasing support to consider topical ciclosporin or lifitegrast as a safer long term therapy than topical corticosteroids.

For those patients that are seeking relief from their dry eye symptoms and are keen to reduce their pharmaceutical therapy with moderate to severe dry eye signs, amniotic membrane therapy is quickly proving to be a very effective non-invasive treatment option.

As optometrists, we should consider expanding our armamentarium and prescribe these interventions for patients that are experiencing persistent and ongoing symptoms of dry eye disease. 

References 

1. Nelson JD, Craig JP, Akpek EK, et al. TFOS DEWS II introduction. Ocul Surf. 2017; 15 (3): 269–75.

2. Jones L, Downie LE, Korb D, et al. TFOS DEWS II management and therapy report. Ocul Surf. 2017; 15 (3): 575–628.

3. Baudouin C, Aragona P, Messmer EM, et al. Role of hyper- osmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. Ocul Surf. 2013; 11 (4): 246–258.

4. Hessen M, Akpek EK. Dry eye: an inflammatory ocular disease. J Ophthalmic Vis Res. 2014; 9 (2): 240–250.

5. Baudouin C, Irkec M, Messmer EM, et al. Clinical impact of inflammation in dry eye disease: proceedings of the ODISSEY group meeting. Acta Ophthalmol (Copenh). 2017. doi:10.1111/ aos.13436.

6. Santen Oy. IKERVIS 1 mg/mL eye drops, emulsion: EU summary of product characteristics. 2017.

7. Donnenfeld E, Pflugfelder SC. Topical ophthalmic cyclos- porine: pharmacology and clinical uses. Surv Ophthalmol. 2009; 54 (3): 321–338.

8. Lallemand F, Schmitt M, Bourges J-L, et al. Cyclosporine A delivery to the eye: a comprehensive review of academic and industrial efforts. Eur J Pharm Biopharm. 2017; 117: 14–28.

9. Mandal A, Bisht R, Rupenthal ID, et al. Polymeric micelles for ocular drug delivery: from structural frameworks to recent preclinical studies. J Control Release. 2017; 248: 96-116.

10. Lallemand F, Schmitt M, Bourges J-L, et al. Cyclosporine A delivery to the eye: a comprehensive review of academic and industrial efforts. Eur J Pharm Biopharm. 2017; 117: 14–28.

11. Lyseng-Williamson KA. Cationorm (cationic emulsion eye drops) in dry eye disease: a guide to its use. Drugs Ther Perspect. 2016; 32 (8): 317–22.

12. Daull P, Lallemand F, Garrigue JS. Benefits of cetalkonium chloride cationic oil-in-water nanoemulsions for topical ophthalmic drug delivery. J Pharm Pharmacol. 2014; 66 (4): 531–41.

13. Santen Oy. IKERVIS 1 mg/mL eye drops, emulsion. EU summary of product characteristics [Internet]. European Medicines Agency; 2017 [cited 2022 March 1]. Available from: https://www.ema.europa.eu/en/documents/product-information/ikervis-epar-product-information_en.pdf.

14. European Medicines Agency. Ikervis (ciclosporin). EU summary of the assessment report [Internet]. European Medicines Agency; 2015 [cited 2022 March 1]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/ikervis.

15. Pharmaceutical Benefits Scheme (PBS); CICLOSPORIN Eye drops 0.1%, single dose units 0.4 mL, Ikervis, Seqirus (Australia) Pty Ltd Public Summary Document — March 2021 PBAC Meeting [Internet]. Australian Department of Health; 2021 [cited 2022 March 1] .Available from: https://www.pbs.gov.au/industry/listing/elements/pbac-meetings/psd/2021-03/files/ciclosporin-psd-march-2021.pdf

16. Schachter S, Johnston, J, Kabat, A, Shen Lee B. Raising the bar for dry eye disease therapy [Internet]. Review of Optometry; 2020 [cited 2022 March 1] Available from: https://www.reviewofoptometry.com/CMSDocuments/2020/10/SunPharma.pdf

17. Murphy CJ, Bentley E, Miller PE, et al. The pharmacologic assessment of a novel lymphocyte function-associated antigen-1 antagonist (SAR 1118) for the treatment of keratoconjunctivitis sicca in dogs. Invest Ophthalmol Vis Sci. 2011; 52: 3174-80.

18. Sun Y, Zhang R, Gadek TR, et al. Corneal inflammation is inhibited by the LFA-1 antagonist, lifitegrast (SAR 1118). J Ocular Pharmacol. 2013; 29: 395-402.

19. Zhong M, Gadek TR, Bui M, et al. Discovery and development of potent LFA-1/ICAM-1 antagonist SAR 1118 as an ophthalmic solution for treating dry eye. ACS Medicinal Chemistry Letters. 2012;3:203-6.

20. Novartis Pharmaceuticals Corporation. Patient Information XIIDRA (ZYE-druh) (lifitegrast ophthalmic solution) 5% for topical ophthalmic use [Internet]. East Hanover, NJ: Novartis Pharmaceuticals 2020 [cited 2022 March 1] Available from: https://www.novartis.us/sites/www.novartis.us/files/xiidra_ppi.pdf.

21. Malhotra C, Jain AK. Human amniotic membrane transplantation: Different modalities of its use in ophthalmology. World J Transplant. 2014; 4 (2): 111-121. doi:10.5500/wjt.v4.i2.111

22. Mcgaughy AG, Gupta PK. In-Office Use of Amniotic Membrane. [Internet] American Academy of Ophthalmology Feb 2015 [cited 2022 March 1] Available from: https://www.aao.org/eyenet/article/in-office-use-of-amniotic-membrane.

23. Ijiri S et al. Evaluation of Visual Acuity and Color Vision in Normal Human Eyes with a Sutureless Temporary Amniotic Membrane Patch. Am J Ophthalmol. 2007; 144 (6): 938-942.

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