SURVEY OF OPHTHALMOLOGY VOLUME 45 • SUPPLEMENT 2 • MARCH 2001
`
`The Treatment of Dry Eye
`Margarita Calonge, MD
`
`Instituto Universitario de Oftalmobiologia Aplicada (IOBA), University of Valladolid, Valladolid, Spain
`
`Abstract. The most widely used therapy for dry eye disease is tear replacement by topical artificial tears.
`Punctal occlusion to prevent the drainage of natural or artificial tears is the most common non-
`pharmacological treatment. These and other traditional therapies for dry eye disease are only palliative,
`however, as they replace or conserve the tears without necessarily correcting the underlying disease pro-
`cess. As our understanding of the pathology of dry eye disease improves, new treatment strategies are
`being developed. Topical anti-inflammatory and immunomodulatory agents, such as cyclosporin A, are
`under investigation in the treatment of dry eye, as it is anticipated that they will correct the vicious cycle
`Surv Ophthalmol
`of inflammation and cell damage on the ocular surface and lacrimal glands.
`(
`45(Suppl 2)
`:S227–39, 2001. © 2001 by Elsevier Science Inc. All rights reserved.)
`
`Key words.
`anti-inflammatory agents
`disease • keratoconjunctivitis sicca
`steroids
`syndrome •
`
`cyclosporin A • dry eye
`• blepharitis
`artificial tears
`•
`•
`• punctal occlusion •
`sexual hormones
`• Sjögren’s
`
`Traditional therapies for dry eye are palliative, in
`that their purpose is to replace or conserve the pa-
`tient’s tears without correcting the underlying dis-
`ease process. As our understanding of the pathology
`of dry eye disease improves, we will be able to de-
`velop new strategies to treat the condition. An im-
`portant factor in the success of dry eye therapy is
`that the patient is fully informed as to the nature of
`his or her dry eye disease and the goals of the clini-
`cian’s choice of therapy, so as to encourage compli-
`ance with the treatment regimen.30,58,83
`Currently, the choice of therapy for dry eye dis-
`ease may be determined by the severity of the condi-
`tion. Mild cases of dry eye, in which there are no
`signs of damage to the conjunctiva or cornea, may
`be successfully managed with artificial tears applied
`up to four times per day. In moderate cases of dry
`eye, examination will reveal mild damage to the cor-
`nea, such as superficial punctate keratopathy (SPK)
`limited to certain zones. In these cases, more fre-
`quent treatment will be required, e.g., use of unpre-
`
`served artificial tears up to 12 times per day and an
`unpreserved lubricating ointment at bedtime. Se-
`vere dry eye can be characterized by keratinization
`of the conjunctiva and moderate to severe corneal
`damage, including SPK, filaments, epithelial defects,
`and a subsequently higher risk of secondary infec-
`tions. In addition to frequent instillation of unpre-
`served artificial tears and lubricating ointment at
`night, severe cases of dry eye will require other treat-
`ment strategies, such as tear-conserving therapies.
`This review describes the current treatment options
`for dry eye and discusses future developments.
`
`Tear Substitution: Artificial Tear
`Substitutes and Lubricants
`Tear replacement by topical artificial tears and lu-
`bricants is currently the most widely used therapy for
`dry eye, and a variety of components are used to for-
`mulate a considerable number of commercially
`available preparations (Table 1).30,58,59,73,76,83 The goal
`of using tear substitutes is to increase humidity at the
`
`© 2001 by Elsevier Science Inc.
`All rights reserved.
`
`0039-6257/01/$–see front matter
`PII S0039-6257(00)00205-8
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`S227
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`INNOPHARMA v. SENJU
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`Surv Ophthalmol 45 (Suppl 2) March 2001
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`CALONGE
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`ocular surface and to improve lubrication, with sub-
`sequent secondary benefits. For example, a recent
`study demonstrated that artificial tears smooth the
`corneal surface of dry eye patients, an effect that
`may contribute to improved vision.63 Moreover, the
`intraoperative and postoperative use of carmellose
`artificial tears has been shown to help restore the oc-
`ular surface after refractive surgery.60
`The use of artificial tears has obvious limitations,
`however. Natural tears have a complex composition
`of water, salts, hydrocarbons, proteins, and lipids,
`which artificial tears cannot completely substitute. In
`addition, the integrity of the three-layered lipid,
`aqueous, and mucin structure, vital to the effective
`functioning of the tear film, cannot be reproduced
`by these artificial components.58,76,83
`Furthermore, artificial tears are delivered inter-
`mittently, rather than continuously as are natural
`tears. To try to overcome this problem, formulations
`contain additional ingredients to increase their con-
`tact time with the ocular surface. These ingredients
`are designed to have mucoadhesive properties; that
`is, they adhere to and simulate the mucous layer of
`the tear film.79 Fig. 1 shows the mucoadhesive forces
`between the mucous layer and various polymers
`commonly used in ocular lubricants.18,48,82,100 Many
`of these mucoadhesive components are formulated
`as viscous gels,14,15,79,97 which can tend to cause irrita-
`tion, blur vision, make the eyelid sticky, and create a
`sensation of heavy eyelids.
`More than 20 years ago, sustained-release artificial
`tear inserts (hydroxypropylcellulose rods) were de-
`veloped. These release their viscous coating on con-
`tact with the ocular surface, and need to be used in
`addition to other artificial tears to initiate the dissolv-
`ing process. However, their high cost, the difficulty in
`handling them, and the intense foreign body sensa-
`tion they create have discouraged their use.59 Related
`to this system is a new preservative-free lyophilisate
`drug delivery system, in which hydroxypropylmethyl-
`cellulose detaches from a polymeric carrier upon
`contact with the tear film. Although the tolerability
`of this system appears to be satisfactory, its clinical ef-
`ficacy remains to be demonstrated.22
`It seems, however, that problems associated with
`highly viscous materials can be overcome by differ-
`ent formulation strategies, such as bipolymeric sys-
`tems that allow less viscosity while retaining mucoad-
`hesive properties.79 Alternatively, formulations can
`simply use less viscous materials.14,15,97 A slightly dif-
`ferent approach aims to increase the preocular resi-
`dence time by the use of topical chitosan, a mucoad-
`hesive polymer. This chitinous material has been
`found in ocular mucus2 and is presently being tested
`in ophthalmology.27 Artificial tear formulations
`based on soluble derivatives of chitosan would be in-
`
`teresting,2 as, in addition to its bioadhesive charac-
`teristics, chitosan has been shown to have lubricat-
`ing properties.61
`Almost no attempt has been made to find a substi-
`tute for the mucus layer of the tear film, in spite of
`the fact that this layer is frequently altered in dry eye
`disorders. Some unfortunate patients with kerato-
`conjunctivitis sicca (KCS) have a highly viscous and
`stringy mucus that form plaques and filaments on
`the ocular surface, and these are a major source of
`irritation and pain.59 The application of mucolytic
`solutions can be of help, and although a 10% acetyl-
`cysteine ophthalmic solution in an artificial tear-base
`has been proposed,20 major drawbacks are that it has
`to be kept refrigerated and remains stable for only
`60 days, which precludes its commercialization.
`Lipids are usually formulated as ointments, and
`there are some preservative-free formulations on the
`market that can provide relief for patients experi-
`encing symptoms during the night and upon awak-
`ening.59 Lipids have also been proposed as eyedrops,90
`but there is no conclusive evidence of their utility.116
`A new petrolatum ointment containing calcium car-
`bonate placed on the lower lid skin has recently
`been shown to be helpful in dry eye patients.124
`One of the most important drawbacks of many of
`the commercially available artificial tear substitutes and
`lubricants is the fact that they must contain preserva-
`tives, stabilizers, and other additives. These compo-
`nents supply stability and retard germ contamination
`and growth, thus ensuring the long shelf-life required
`for commercialization. The most common preserva-
`tives currently used in artificial tear preparations are
`quartenary ammonium compounds (benzalkonium
`chloride, benzododecinium bromide, cetrimide,
`polyquad), alcohols (chlorobutanol), and other com-
`pounds (chlorhexidine, sorbic acid, potassium sor-
`bate, boric acid, biguanides, etc).73,118 Mercurial
`agent thimerosal, much used in the past, has been
`abandoned because of its high potential to provoke
`not only toxic but also allergic reactions.117,118
`Even though the concentration of preservatives in
`artificial tear preparations is generally low, their pro-
`longed presence on an already compromised ocular
`surface, such as that of a dry eye, can cause serious ia-
`trogenic effects, worsening the ocular surface dis-
`ease.6,7,16,21,64,118,130 Especially toxic to the ocular sur-
`face cells is the cationic detergent benzalkonium
`chloride, which emulsifies cell wall lipids, subse-
`quently breaking intercellular unions.6,9,16,21,64,118,130
`This risk may be increased in patients with therapeuti-
`cally blocked tear ducts, since the agent persists
`longer in the tear sac, relatively undiluted by lacrimal
`fluid.65,136 Patients who require the application of tear
`substitutes more than four times daily on a long-term
`basis to maintain comfort should avoid such prepara-
`
`Page 2 of 13
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`THE TREATMENT OF DRY EYE
`
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`
`•Little clinical experience with
`•Cause blurred vision
`
`lipid eyedrops
`
`•High viscosity and, therefore,
`
`•Contribute to re-build the
`
`•Useful adjunct to other
`
`used at night
`artificial tears when
`
`lipid layer
`
`high retention
`
`•Not commercially available as a
`
`topical agent
`
`mucus in severe dry eye
`resulting from very dense
`
`•Useful for complications
`
`•Little clinical experience
`
`•Beneficial in mucin layer
`
`deficiency
`
`•Short retention time on ocular
`
`•Little clinical experience
`
`•Does not mix well with other
`
`ophthalmic products
`
`surface
`
`•Beneficial in corneal wound
`
`•Good retention time on
`
`ocular surface
`
`healing
`
`•Water soluble, does not cause
`and mucin layer deficiencies
`
`•Beneficial in lipid, aqueous,
`
`blurring of vision
`
`•Often uncomfortable to patients
`•Tend to blur vision
`
`•Good retention time on
`
`ocular surface
`
`•Hypromellose can cause crusting
`
`•Only of benefit in aqueous tear
`
`deficiency
`
`blepharitis
`of eyelids, mimicking
`
`•Viscosity not influenced by
`
`•Good retention time on
`
`ocular surface
`
`•Mix well with other
`
`ophthalmic products
`
`blinking
`
`•Formulated as drops
`•Organic substances
`
`and ointments
`
`hypromellose
`another lubricant such as
`•Can be co-formulated with
`•Breaks down mucin molecules
`
`alcohol
`co-formulated with polyvinyl
`•Superior wetting ability when
`•Co-formulated with electrolytes
`•Synthetic polymer
`
`•Viscous formulation
`•Mucopolysaccharides
`
`•Low viscosity but optimal
`•Synthetic polymer
`minimizing drag
`thickness of the tear film while
`eye movement, maximizing
`shears thin during blinking or
`•High viscosity when eye is static,
`•Synthetic polymers
`
`concentration of 1.4%
`wetting characteristics at a
`
`(hydroxypropylcellulose rods)
`artificial tear inserts
`
`•Available as sustained-release
`
`electrolytes, as hypotonic
`
`•Sometimes co-formulated with
`
`•Large increase in viscosity
`•Increase the viscosity of tears
`•Viscoelastic polysaccharides
`
`moderately increased
`when concentration is
`
`Lipids (e.g. petrolatum [paraffin, vaseline,
`
`mineral oil] lanolin, lecithin)
`
`Acetylcysteine
`
`Povidone (polyvinyl pyrrolidone)
`
`Sodium hyaluronate
`
`Polyvinyl alcohol
`
`Carbomers (polyacrylic acid)
`
`carboxymethylcellulose [carmellose])
`hydroxyethylcellulose, methylcellulose,
`
`Cellulose ethers (e.g., hypromellose,
`
`Disadvantages
`
`Advantages
`
`Properties
`
`Component
`
`TABLE 1: Properties of Some Components Used in Artificial Tear Substitutes73,76
`
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`CALONGE
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`Fig. 1. Rank order of mucoadhesive force between the mucous layer and various polymers found in ocular lubricants
`(data from references18,48,82,100). The clinical significance of these in vitro data is unknown.
`
`tions and use only unpreserved (usually unit-dose)
`formulations.9
`The introduction of preservative-free solutions
`can be considered the single most important contri-
`bution in the formulation of tear substitutes. Two
`drawbacks exist, however, with these single unit-
`dose tears. First, they are more expensive than pre-
`served preparations. Second, they can induce lack
`of compliance, because patients must carry numer-
`ous vials to maintain adequate dosage over 24 hours
`or more. One of the possible solutions could be the
`so-called “ABAK bottle,” which has an eyedrop dis-
`penser system that contains an adsorbent to retain
`benzalkonium chloride before instillation. Although
`an artificial tear based on this technology has been
`commercialized in some countries, the clinical effi-
`cacy of this system has not yet been well docu-
`mented.85
`Other common additives used in artificial tear
`preparations are buffers, which have the purpose of
`maintaining the pH of human natural tears (7.4) as
`closely as possible when they are applied to the ocu-
`lar surface.73 This is important, as it has been widely
`demonstrated that the pH of the tear film should be
`kept constant to maintain the normal function of
`the epithelial cells in the ocular surface.17 It has also
`been shown that pH decreases after instillation of
`eyedrops, and then rapidly becomes more alkaline
`before normalizing after about 2 minutes.135 Since
`the chemical buffering capacity of natural tears de-
`pends mostly on bicarbonates,73 this and also other
`components (phosphates, acetates, citrates, borates,
`sodium hydroxide) are frequently added to artificial
`tears in an attempt to make them slightly alkaline,
`
`and the more alkaline solutions seem to be more
`comfortable than neutral or acidic preparations.50
`It is important to keep in mind that the neutraliza-
`tion process of tears depends not just on their chem-
`ical buffering capacity, but also largely on the tear
`turnover rate.135 Therefore it can be altered when
`tear clearance is delayed, such as in dry eye states
`and after therapeutic blocking of the tear drainage
`system.136
`In addition, hypotonic electrolyte-based formula-
`tions have been developed based on the recognition
`of the importance of tear osmolarity and electrolytes
`in maintaining the ocular surface.37,39,40,59,128 In fact,
`tear film osmolarity and tear electrolyte (sodium, po-
`tassium, calcium, magnesium, bicarbonate) levels
`have been shown to be increased in dry eye states
`caused by meibomian gland disease and/or lacrimal
`gland disease.37 One of these electrolytes, bicarbon-
`ate, seems to be an essential component in the re-
`covery of the damaged corneal epithelial barrier and
`in the maintenance of normal ultrastructure.128 One
`artificial tear formulation, not just hypotonic but
`also with a unique electrolyte-based composition,
`seems to increase corneal glycogen and conjunctival
`goblet cell density in a rabbit model of KCS39,40 and
`to decrease rose bengal staining and tear film osmo-
`larity in dry eye patients.40
`Finally, surgical approaches aimed at substituting
`the absent natural tears with natural saliva by autolo-
`gous transplantation of salivary glands has been pro-
`posed as an alternative for desperate dry eye condi-
`tions.36,71,72,74 The quality and effects of
`this
`condensed saliva secretion on the ocular surface has
`yet to be evaluated.35
`
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`THE TREATMENT OF DRY EYE
`
`Tear Preservation
`
`OCCLUSION OF THE TEAR DRAINAGE SYSTEM
`Occlusion of the lacrimal puncta or canaliculi pre-
`vents the drainage of natural and artificial tears and
`is currently the most common nonpharmacological
`therapy for dry eye disease.59,74
`Canalicular or punctal occlusion has been
`claimed to improve the quantity and the quality of
`the aqueous component of the tear film, relieving
`symptoms and signs of dry eye, making patients
`more comfortable and reducing the need for artifi-
`cial tears.74,133 Controversy remains, however, about
`many of those claims, as some authors have reported
`disadvantages to these techniques. For instance, a
`study suggested that punctal occlusion can decrease
`tear production, clearance, and ocular surface sensa-
`tion.136 It is believed that many of the problems that
`can be caused by occlusion of tear film drainage are
`derived from delayed tear clearance and turnover,
`and it has to be kept in mind that this delay is al-
`ready present in dry eye states.65 Delayed tear clear-
`ance can result in increased concentration of proin-
`flammatory cytokines in the tear film, causing
`desensitization of the corneal surface and promot-
`ing inflammation.65,84,136 It is also possible, as already
`mentioned, that delayed tear clearance can result in
`increased toxicity of preservatives present in other
`ocular medications that the dry eye patient might
`need.
`As a consequence of all the above mentioned fac-
`tors, some patients may experience little, only tem-
`porary, or no relief at all from therapeutic occlusion
`of the tear drainage system. In addition, epiphora
`can occur after occlusion, causing a great deal of dis-
`comfort to the patient. To minimize this risk, most
`authorities advise assessing the result of temporary
`occlusion with absorbable or removable plugs or in-
`serts before proceeding with permanent occlusion.59,74
`More rarely reported complications include rupture
`of the punctal ring, pruritus and discomfort, supu-
`rative canaliculitis, intrusion/extrusion of some
`plugs, and canalicular stenosis.74 Finally, silicone
`punctal plugs have sometimes been associated with
`the formation of pyogenic granulomas.88,132
`In conclusion, the decision to block the tear
`drainage system should be taken with care, as it may
`not be the treatment of choice for every dry eye
`state. Most authors reserve this method for moder-
`ate to severe dry eyes, and only after frequent use of
`unpreserved artificial tears and lubricants remains
`insufficient. The reported specific criteria for punc-
`tal or canalicular occlusion are quite variable,74 but
`most authors agree that the nasolacrimal duct has to
`be permeable before therapeutic blocking; other-
`wise acute dacryocistitis can occur.43 Although occlu-
`
`S231
`
`sion of only one punctum in each eye, usually the in-
`ferior punctum, provides sufficient relief from the
`symptoms of dry eye for many patients, occlusion of
`both inferior and superior puncta may be necessary
`for severe cases.
`
`METHODS OF OCCLUSION
`Many surgical, thermal, and tamponade methods
`of occlusion have been reported (reviewed by Mu-
`rube and Murube74). The following are the most
`used today.
`Surgical methods are not usually performed, as
`they are extremely difficult to reverse with the ex-
`ceptions of “transfer of the punctum to dry dock”
`and the punctum patch.74 The punctum patch,
`which covers the punctum with autologous conjunc-
`tiva, seems to be easy to perform, producing com-
`plete and permanent occlusion, and it can be re-
`moved if occlusion needs to be reversed.75
`Thermal methods (cautery, diathermy, or laser)
`produce canalicular occlusion by destroying and
`shrinking the canaliculi walls.74 Cautery uses an elec-
`trically heated probe to seal the punctum perma-
`nently. The probe can be placed in the vertical por-
`tion of the canaliculus only or through the whole
`length of the canaliculus, thereby reducing the risk
`of healing without occlusion. Diathermy (Hyfreca-
`tor) uses an electrode to deliver a high frequency
`current to the tissues, which produces heat and co-
`agulation. Laser canaliculoplasty uses argon laser to
`cauterize the punctal opening.8 This method offers
`more flexibility than thermal occlusion, as the
`puncta can be either fully or partially occluded. The
`slit-lamp delivery method also allows more precise
`placement of burns than does cautery. Recanaliza-
`tion is, however, more common with this method of
`punctal occlusion.
`Tamponade methods occlude the drainage system
`with a foreign body (Fig. 2). They are by far the most
`popular and commonly performed techniques, as
`they require no surgery and can be easily performed
`as an outpatient procedure. An additional advantage
`is that a large body of clinical experience exists with
`these procedures.43,55,59,62,74,89,133
`Absorbable inserts are used before a more perma-
`nent occlusion is made to assess the patient’s toler-
`ance of punctal occlusion and to avoid subsequent
`epiphora.55,59,74 The manufactured inserts are made
`of hydroxypropyl cellulose or collagen and are in-
`serted into the vertical or the horizontal canaliculus
`after topical anesthesia and punctal dilatation (Fig.
`2, left). There, the inserts dissolve slowly at body
`temperature, the hydroxypropyl cellulose inserts
`lasting up to 18 hours and the collagen inserts up to
`2 weeks, although collagen degradation time is quite
`
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`Surv Ophthalmol 45 (Suppl 2) March 2001
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`Fig. 2. Absorbable inserts (left) and non-absorbable intracanalicular and punctal plugs (right) in place.
`
`unpredictable.55,62 Collagen implants typically re-
`duce tear flow through the canaliculus only par-
`tially, by 60–80%; therefore patients who do not
`experience epiphora with these temporary im-
`plants may develop epiphora subsequently with to-
`tal occlusion.89
`Nonabsorbable tamponade can be achieved by in-
`tracanalicular occlusion or by punctal occlusion.
`Punctal plugs made from silicone, HEMA, or teflon
`are inserted into the vertical portion of the canalicu-
`lus with the head of the plug left protruding from
`the punctum (Fig. 2, right).32 Topical anesthesia is
`often used and the punctum must be dilated before
`the plug is inserted. The plug can be easily removed
`with forceps. Rarely, these plugs fall out, particularly
`if the punctum has been over-dilated on insertion.
`Occasionally, the head of the plug can irritate the
`conjunctiva and cornea, resulting in reflex epi-
`phora.133 A recent study has found that a bacterial
`biofilm can form in the holes of punctal plugs, and
`advises their immediate removal if accumulation of
`material is observed in the heads of punctal plugs.109
`The intracanalicular plug is a silicone plug that is in-
`serted past the punctum into the horizontal portion
`of the canaliculus until it becomes lodged just in
`front of the common canaliculus (Fig. 2). Insertion
`of the plugs may not require anesthesia or punctal
`dilatation. The plug can be removed by flushing sa-
`line or inserting a probe through the canaliculus.
`Because the plug does not stick out of the punctum,
`it does not scratch the cornea.74
`
`OTHER METHODS OF TEAR PRESERVATION
`Rather than preserving natural or artificial tears
`by blocking their drainage from the eye, some meth-
`
`ods of tear preservation act to prevent the evapora-
`tion of moisture from the eye.59
`Room humidifiers are a simple, noninvasive way
`of reducing the evaporation of tears. Wearing tight-
`fitting goggles, moisture chamber spectacles, or tear-
`feeding spectacles are also effective, but are some-
`times inconvenient for the patient.59,120
`Hydrophilic bandage contact lenses are often
`used in cases of corneal ulceration or following cor-
`neal surgery.5,26,120 Patients with dry eye disease, how-
`ever, may have difficulty with contact lenses becom-
`ing dry and falling off the eye. In addition, contact
`lenses will exacerbate the already increased risk of
`corneal infection in dry eyes. Although a specific
`type of contact lens has been shown to produce a
`barrier to evaporation in dry eye disease,5 the thera-
`peutic value of contact lenses in dry eye patients is
`minimal.26 Furthermore, prolonged contact lens use
`can ultimately cause dry eye.26
`Tarsorrhaphy can substantially reduce the ex-
`posed area of the cornea, thus reducing the evapora-
`tion of tears. The procedure tends to be reserved for
`patients with persistent corneal epithelial defects in
`severe dry eye disease. The procedure is reversible, if
`necessary.72,74,105
`
`Pharmacological Stimulation of
`Natural Tears
`Drugs known as secretagogues or lacrimomimet-
`ics, such as mucolytics (bromhexine and ambroxol),
`cholinergic agents (carbachol, bethanecol, pilo-
`carpine), or eledoisin have been used to stimulate
`the lacrimal glands to produce tears.4,49,77,81,114,129 In
`general, drugs that can increase cyclic nucleotide
`
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`THE TREATMENT OF DRY EYE
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`(cAMP or cGMP) levels could theoretically increase
`tear secretion.41
`Oral bromhexine and its derivative ambroxol have
`demonstrated variable results in clinical trials and
`have sometimes been associated with side effects,
`such as generalized nausea, sweating and rashes,
`and, therefore, have not achieved widespread use.4,49
`Eledoisin is a natural endekapeptide extracted from
`the salivary glands of the Mediterranean octopus Ele-
`done moscata and has been and still is used in some
`European countries. Its topical use has been docu-
`mented to increase tear volume and tear flow by
`fluorophotometry for up to 2 hours after instillation
`in healthy individuals and even longer in dry eye
`patients.44 Its potential to improve the signs and
`symptoms of dry eye has not been documented,
`however, and perhaps that is why it is not more
`widely used.
`Regarding the parasympathicomimetic agent pilo-
`carpine, a previous study showed that topical appli-
`cation had no effect on the stimulation of tear secre-
`tion from accessory glands in a rabbit model of
`KCS.41 Oral pilocarpine, however, has more recently
`been demonstrated to objectively increase tear pro-
`duction and flow67 and to improve symptoms of dry
`eye and dry mouth in Sjögren’s syndrome patients129
`with an acceptable tolerance, although nausea and
`sweating can still be present.67,129
`P2Y2 nucleotide receptor agonists are under inves-
`tigation as topical secretagogues. P2Y2 receptors
`(formerly designated as P2U) seem to be widely
`present in the epithelial cells of the ocular surface.137
`Stimulation of these receptors by ATP increases mu-
`cin-like glycoprotein secretion in rabbit and human
`conjunctival cells (including goblet cells) through
`the increase of intracellular calcium, a second mes-
`senger with a key role in the regulation of exocrine
`gland secretion.51 A preliminary study has shown an
`acceptable tolerability in healthy subjects,69 but the
`clinical efficacy of this therapeutic strategy for dry
`eye patients remains to be determined.
`Stimulation of tear production, however, is not a
`widespread therapeutic strategy generally offered to
`dry eye patients. The reason seems to be the scarcity
`of prospective studies and clinical trials proving ro-
`bust efficacy of these treatments and their propen-
`sity to cause side effects when taken orally. In addi-
`tion, these agents may not be a realistic alternative
`when the disease process has already caused exten-
`sive damage to the lacrimal gland parenchyma or
`blocked the lacrimal ducts through conjunctival
`scarring. It is also possible that the stimulation of
`previously inflamed lacrimal glands and conjunctiva,
`as is the case in dry eye patients, could deliver pro-
`inflammatory tears to the ocular surface, worsening
`the disease.
`
`Treatment of the Underlying Causes of
`Dry Eye Disease
`The therapies described in the previous section
`only improve the symptoms and signs of dry eye, but
`do not treat the underlying condition. As new con-
`cepts are rapidly emerging in the understanding of
`dry eye, new treatment strategies should now aim to
`address the underlying pathophysiology of dry eye
`disease.
`New findings are demonstrating that a chronic im-
`mune-mediated inflammatory process plays an es-
`sential role in the pathogenesis of dry eye disease
`not only in dogs,34 but also in humans. This evidence
`includes increased expression of immune activation
`molecules (HLA-DR, ICAM-1, CD40, CD40 ligand)
`and apoptosis-related markers (Fas, APO2.7). In-
`creased levels of inflammatory cytokines have also
`been demonstrated, especially interleukin-6 (IL-6),
`in the lacrimal glands, conjunctival epithelium,
`and/or tear fluid of dry eye patients with or without
`Sjögren’s syndrome.12,13,84,107 It is still unknown how
`these findings correlate with the lack of hormonal
`support in some dry eye states and with other find-
`ings, such as chronic irritation or altered innerva-
`tional mechanisms.107
`It is known that healthy individuals produce anti-
`inflammatory androgens and that as long as this hor-
`mone is maintained at normal circulating levels, the
`lacrimal glands and ocular surface remain in a non-
`inflammatory state.107,112 It is believed that when an-
`drogen levels fall, for example, with age or at meno-
`pause, a precipitating stimulus, such as infection or a
`dry environment, can allow an inflammatory im-
`mune response to occur on the ocular surface or in
`the lacrimal glands. T-cells are activated, resulting in
`the release of inflammatory mediators, causing fur-
`ther inflammation and damage to the ocular sur-
`face.107 An understanding of the disease process of
`dry eye predicts that topical anti-inflammatory, im-
`munomodulatory, or hormonal agents may be capa-
`ble of normalizing the disturbed neuro-hormonal
`reflex between the ocular surface and lacrimal
`glands.
`The following are the main anti-inflammatory, im-
`munomodulatory, or hormonal therapeutic agents
`tested or under investigation for the treatment of
`dry eye. Some other putative future developments
`are also mentioned.
`
`CYCLOSPORIN A
`Cyclosporin A is an established immunomodulat-
`ing drug used to prevent rejection after organ or tis-
`sue transplantation and as a treatment for a variety
`of autoimmune diseases.
`In animal models of dry eye, cyclosporin A has
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`CALONGE
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`been shown to be effective in reducing lymphocyte
`infiltration.125 In dogs with spontaneous chronic id-
`iopathic KCS, topical cyclosporin A facilitates apop-
`tosis of lymphocytes in the lacrimal glands and con-
`junctiva, while suppressing apoptosis of lacrimal
`gland and conjunctival epithelial cells, both factors
`contributing to a great improvement in the underly-
`ing inflammation and the clinical aspect of these dis-
`eased dogs.34 Early studies in humans with various
`topical preparations of cyclosporin A have shown
`good results in patients with KCS.45,54,86 Another
`study showed that treatment with systemic cy-
`closporin in kidney transplant recipients signifi-
`cantly
`increased previously normal Schirmer
`scores.80
`The above mentioned clinical experience led to
`the belief that topical cyclosporin A could be a po-
`tential treatment for dry eyes that do not have exten-
`sive lacrimal gland damage by reversing inflamma-
`tory events in the conjunctiva and those parts of the
`lacrimal gland accessible to the conjunctival sac (the
`accessory and palpebral portions). Subsequent re-
`search seems to be confirming this hypothesis. A re-
`cently published clinical trial demonstrated that cy-
`closporin A ophthalmic emulsions at 0.05%, 0.1%,
`0.2%, and 0.4% concentrations were safe and well
`tolerated, improved symptoms and signs, and de-
`creased the effect of the disease in vision-related
`functioning for patients with moderate-to-severe dry
`eyes.108 Subsequently, concentrations of 0.05% and
`0.1% were tested in two multicenter, randomized
`clinical trials in Sjögren’s and non-Sjögren’s types of
`dry eye disease. These two trials corroborated the
`good safety and tolerability profile of these cy-
`closporin A ophthalmic emulsions, also showing a
`significantly greater improvement in dry eye signs
`
`and symptoms compared with vehicle.95 Additional
`studies in cohorts of patients participating in these
`two clinical trials demonstrated a decrease in several
`markers of inflammation after 6 months of treat-
`ment with topical 0.05% cyclosporin A emulsion.53,126
`One study demonstrated a significant decrease in IL-6
`levels in conjunctival cytology specimens,126whereas
`the other showed a decreased expression of HLA-DR
`and CD11a, in addition to increased numbers of
`goblet cells, in conjunctival biopsies (Fig.3).53
`In summary, an increasing body of evidence is
`demonstrating that topical treatment with cy-
`closporin A prevents T-cell activation, reverses in-
`flammation of the ocular surface and lacrimal
`glands, and thus improves symptoms and signs of
`dry eye in Sjögren’s and non-Sjögren’s syndrome
`patients.
`
`TOPICAL CORTICOSTEROIDS
`Recently reported results from a retrospective
`study involving patients with Sjögren’s syndrome
`have indicated the efficacy of short-term treatment
`with topical nonpreserved corticosteroids.66 Al-
`though this therapy helps to diminish the initial in-
`flammation, its chronic use for dry eye, and for al-
`most any other ocular disease, must