Dry eye disease (also called keratoconjunctivitis sicca) is a common condition, with a prevalence ranging from 8–34%, depending on the criteria used.1 It becomes more common with increasing age and affects more women than men. Artificial tears and ocular lubricants are considered the mainstay of treatment and there is a very wide range of these products available. In England in 2014, over 6.4 million prescription items for artificial tears, ocular lubricants and astringents were dispensed in the community at a cost to the NHS of over £27 million.2 In this article we review the management of dry eye disease, focusing on artificial tears and ocular lubricants.
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About dry eye
The tear film, which covers the cornea and exposed conjunctiva, is composed of three layers: a mucin layer that sits on the epithelial surface; a middle aqueous layer; and an outer lipid layer that plays a role in preventing tear evaporation.3 Dry eye has been defined as a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.4
There are two main types of dry eye: aqueous insufficiency (due to reduced aqueous secretion from lacrimal glands) and evaporative (due to a deficient lipid layer).
Aqueous insufficiency is divided into two main groups: Sjögren's syndrome-related dry eye and non-Sjögren's syndrome-related dry eye (which includes the use of systemic medication). Dry eye in Sjögren's syndrome (an autoimmune disease) is often severe and requires more aggressive treatment.5
Evaporative dry eye is most commonly a result of meibomian gland dysfunction.4 External causes include allergy, topical medication use (including preservative content) and contact lens wear.
Risk factors associated with dry eye include: female sex; older age; postmenopausal oestrogen therapy; computer use; contact lens wear; a diet low in omega-3 essential fatty acids or a high ratio of omega-6 to omega-3 fatty acids; refractive eye surgery; bone marrow transplantation; hepatitis C; some systemic and ocular medications; and vitamin A deficiency.6 A study of UK women, in whom the prevalence of dry eye disease was found to be 10%, found an association with cataract surgery and also with pain syndromes, raising the possibility that altered pain perception and psychological and somatisation factors have an influence on dry eye disease and symptomatology.7
Patients with dry eyes may complain of ocular discomfort, light sensitivity and watery eyes, and the condition can adversely affect quality of life.1 In severe cases, the inflammation associated with dry eye syndrome could potentially result in irreparable damage to the corneal surface.6 However, symptoms can be a relatively poor indicator of disease severity3,8 and there is no gold-standard test for determining the severity of dry eye disease.8
Tests used to diagnose dry eye disease and to assess efficacy of treatments in clinical trials include:
measurement of tear film break-up time (the interval between the individual's last complete blink and the break-up of the tear film) using fluorescein (shortened in dry eye disease);
evaluation of tear quantity with Schirmer's test (using a strip of filter paper placed under the lower eyelid);
assessment of corneal and conjunctival epithelium integrity using stains and dyes;
A validated questionnaire, the Ocular Surface Disease Index (OSDI: 12 items graded on a scale of 0–4; see Box), was developed by researchers at Allergan. It is used to assess recent symptoms and is thought to correlate moderately well with disease severity.8,12
Ocular Surface Disease Index12
Have you experienced any of the following during the last week?
Eyes that are sensitive to light
Eyes that feel gritty
Painful or sore eyes
Have problems with your eyes limited you in performing any of the following during the last week?
Driving at night
Working with a computer or bank machine (ATM)
Have your eyes felt uncomfortable in any of the following situations during the last week?
Places or areas with low humidity (very dry)
Areas that are air conditioned
An OSDI score of ≥30 is necessary for a diagnosis of severe disease.8
Management of dry eye disease
The main goals of treatment of dry eye disease include relief of symptoms and improved quality of life. There are no UK national guidelines on the management of the condition. The National Institute for Health and Care Excellence (NICE) Clinical Knowledge Summaries' (CKS) recommendations on dry eye disease are adapted for UK primary care from US guidelines and the report of an international workshop.13 For initial management of the condition CKS recommends the following:13
reviewing the response to any treatments that have been tried;
making changes to the environment at home or work that increases evaporation of tears (e.g. computer use, air humidity);
considering whether preservatives in topical eye medications might be a cause;
reviewing any systemic medication that can induce or aggravate eye symptoms (e.g. antihistamines, beta-blockers, oestrogen therapy, tricyclic antidepressants, selective serotonin reuptake inhibitors, isotretinoin);9
identifying underlying medical and surgical conditions associated with dry eye syndrome (e.g. allergic conjunctivitis; blepharitis; Sjögren's syndrome; previous ocular or eyelid surgery; radiation therapy).13
Artificial tears and ocular lubricants have traditionally been the mainstay of the management of dry eye disease. There is a large range of products available for treating dry eye listed in the British National Formulary. Many are classed as medical devices, which are subject to a different regulatory process from licensed medicinal products.14,15
Are topical therapies effective?
The regular use of artifical tears or lubricating drops has been found to increase tear break-up time by a small amount (a mean of 1.4 seconds, from a baseline of 4.7 seconds),10 and reduce signs of corneal damage as measured with rose Bengal staining (from a median rose Bengal score of 4.4 to 2.4 after 1 month's treatment).10,11 However, no significantly meaningful differences between products has been found.10,11,16 The absence of good comparative evidence is hampered by the lack of standard definitions for disease severity and outcome measures, by differences in study design and duration of follow-up, and a limited number of comparative trials.11,16
NICE CKS recommends the following treatment where practical advice alone is insufficient:13
For mild or moderate symptoms: artificial tears.
For severe symptoms: preservative-free artificial tears, perhaps with an ocular lubricant ointment to use at night.
For people with visible strands of mucus: consider acetylcysteine drops (limited evidence).
For people with mild or moderate symptoms, treatment with over-the-counter artificial tears alone may be sufficient.17 It is logical to start with a less viscous formulation at first as these are less likely to cause stinging and blurring. Hypromellose-containing drops are the most commonly used products but they provide only temporary relief and so require frequent application. More viscous products (e.g. those containing carbomers or polyvinyl alcohol) need to be used less frequently but may be less well tolerated. Ointments containing paraffins can feel uncomfortable and cause blurring and so are more suitable for use at night.9 Other available products contain carmellose, hydroxypropyl guar, sodium hyaluronate or lipids.
Preservatives in eye drop formulations (e.g. benzalkonium chloride) can cause irritation or allergy. Although in vitro studies have suggested that prolonged contact with preservatives is problematic in dry eye, clinical studies are more mixed.18 This may be because dilution of preservative in the tear film may help to reduce the harmful effect. Preservative-containing preparations may be suitable for patients with mild dry eye and an otherwise healthy ocular surface.19 In more severe dry eye disease the use of preservative-free drops is more important because of reduced dilution in the tear film. Guidelines from the USA and Canada suggest that a preservative-free preparation is preferable for patients using multiple drops on a daily basis (>4 times/day) or those who also use other eye drops in order to reduce total exposure to the preservative.9,19 Preservative-free products are available as single-dose vials (some of which are resealable for use up to 12 hours later) and as multidose units. Preservative-free preparations should be considered if a product causes irritation or if soft contact lenses are worn.13
The ease of use of the product is an important consideration. For people with arthritic hands, single-dose units can be more difficult to use than multidose bottles. An eye drop dispenser or compliance aid (e.g. Opticare, ComplEye) may help some people.18
In the absence of evidence to guide product choice and in an attempt to manage the prescribing of products for which there is a wide choice and price range, many NHS authorities have produced their own guidelines.20-24 In general, these recommend first-line treatment with a generic or low-cost brand of hypromellose (0.3–1%).
The unit cost of artificial tears and ocular lubricants varies widely from around £1 for generic hypromellose to around £10 for some brands of preservative-free sodium-hyaluronate that have a 6-month expiry date while in use. The overall cost of treatment is affected by whether or not a preservative-free product is used, the product expiry once in use, and frequency of use. Some formularies advise that it is only more cost-effective to start with a preparation with a 6-month expiry date if the patient uses the product less often than four times daily.20
When to refer
It may be appropriate to refer patients to an optometrist before an ophthalmologist. An optometrist can assess people with dry eye syndrome and advise on treatment.18 However, access to NHS commissioned optometry services is not comprehensive.13
NICE CKS recommends referring patients with the following:13
moderate to severe eye pain or photophobia; marked redness in one eye; reduced visual acuity (same-day referral);
symptoms uncontrolled despite appropriate treatment for about 4 weeks;
diagnosis that requires specialist assessment;
ulcers or other signs of corneal damage;
associated disease that requires specialist management (e.g. Sjögren's syndrome; eyelid deformities).
NICE CKS also recommends considering referral of patients who require a preservative-free topical eye product for more than 4 weeks. It provides no evidence to support this approach.13
Other treatments for dry eye
Given that there is an inflammatory component to dry eye disease, anti-inflammatory and immodulatory treatments (including topical corticosteroids) have been tried for patients in whom artificial tears and lubricants are ineffective.25 The use of corticosteroids is limited by their adverse effects.
Ciclosporin eye drop emulsion 0.1% (Ikervis) is marketed for treatment of severe keratitis in adults with dry eye disease, which has not improved despite treatment with tear substitutes.26 Compared with vehicle, ciclosporin eye drops have been shown to improve signs of corneal surface damage but not symptoms.27 Within its licensed indication it has been accepted for use by the Scottish Medicines Consortium and NICE.27,28 It must be initiated by an ophthalmologist or a healthcare professional qualified in ophthalmology.26
Other treatments that have been used to treat dry eye disease include autologous eye drops (derived from the patient's own blood serum),29 and the insertion of punctal plugs to block the lacrimal drainage system.30
Supplementation with polyunsaturated fatty acids (omega 3 and 6) has also been tried for anti-inflammatory effect and also because they can improve lacrimal and meibomian gland function. The authors of a systematic review included nine double-blind randomised controlled trials (involving a total of 716 patients) assessing the effects of polyunsaturated fatty acids (from fish oil, buckthorn, evening primrose oil, flax seed, borage oil).31 Supplementation improved OSDI symptom score, relieved burning and eye watering, and reduced inflammatory response on the ocular surface, but had no effect on tear volume or ocular surface stability. Large scale randomised controlled trials are needed to confirm an effect.
Dry eye is a common condition, particularly among older women. It is a multifactorial disease with an inflammatory component that can cause damage to the ocular surface. Symptoms can range from mild and episodic to severe and disabling, but relate poorly to ocular disease severity. Management of dry eye includes practical measures (such as increasing humidity in the environment) and symptomatic treatment with artificial tears and ocular lubricants. There is a very wide range of ocular products available, and a proliferation of products that are classified as medical devices. This wide choice (and wide variation in cost) together with a lack of comparative evidence makes selecting the most appropriate product for a patient difficult. In the absence of comparative evidence of safety or efficacy it makes sense to start with the lowest cost preparations. Given the higher price associated with preservative-free formulations, local guidelines should be agreed to target their use to those groups of patients most likely to benefit. These are likely to include patients using drops more than four times per day and those with more severe dry eye disease.
[R=randomised controlled trial; M=meta-analysis]
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