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`Clin Ophthalmol. 2008 Dec; 2(4): 829–836.
`Published online 2008 Dec.
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`PMCID: PMC2699789
`
`Treatment of chronic dry eye: focus on cyclosporine
`George D Kymionis, Dimitrios I Bouzoukis, Vassilios F Diakonis, and Charalambos Siganos
`
`Department of Ophthalmology, Vardinoyannion Eye Institute of Crete, University of Crete, Greece
`Correspondence: George D Kymionis, Vardinoyannion Eye Institute of Crete, University Of Crete, Medical School, Department of
`Ophthalmology, 71110 Heraklion, Crete, Greece, Tel +30 2810 371800, Fax +30 2810 394653, Email
`rg.cou.dem@sinoimyk
`
`Copyright © 2008 Dove Medical Press Limited. All rights reserved
`
`This article has been cited by other articles in PMC.
`
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`
`Abstract
`To review the current treatment of chronic dry eye syndrome, focusing on cyclosporine A (CsA), a
`systematic literature search was performed using PubMed databases in two steps. The first step was
`oriented to articles published for dry eye. The second step was focused on the use of CsA in dry eye. A
`manual literature search was also undertaken based on citations in the published articles. The
`knowledge on the pathogenesis of dry eye syndrome has changed dramatically during the last few
`years. Inflammation and the interruption of the inflammatory cascade seem to be the main focus of the
`ophthalmologic community in the treatment of dry eye, giving the anti-inflammatory therapy a new
`critical role. The infiltration of T-cells in the conjuctiva tissue and the presence of cytokines and
`proteasis in the tear fluid were the main reason introducing the use of immunomodulator agents such as
`corticosteroids, cyclosporine, and doxycicline in order to treat dry eye syndrome. CsA emulsion is
`approved by the FDA for the treatment of dry eye, while clinical trials of this agent have demonstrated
`efficacy and safety of CsA. CsA seems to be a promising treatment against dry eye disease. New agents
`focused on the inflammatory pathogenesis of this syndrome in combination with CsA may be the future
`in the quest of treating dry eye. More studies are needed to determine the efficacy, safety, timing, and
`relative cost/effect of CsA.
`Keywords: dry eye, cyclosporine A, inflammation, immunomodulator agents
`
`Introduction
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`Epidemiology
`Dry eye is a frequent disease. Among dry eye patients over the age of 65 in the US, 25% reported using
`artificial tears on a frequent basis and 73% visited an eye care professional during the previous year for
`this condition (Shein et al 1997).
`
`It is estimated that approximately 7.1 million people over the age of 40 in the US experience symptoms
`of ocular irritation due to dry eye syndrome (Pflugfelder 2004), while more than 6% of the population
`over the age of 40 and more than 15% of the population over the age of 65 suffer from dry eye
`(Bjerrum 1997; Schein et all 1997; McCarty et all 1998).
`
`The estimated global sales of artificial tears exceeded US$540 million annually in 2002 (Harmon and
`Murphy 2003), whereas the total annual healthcare cost of 1,000 dry eye syndrome sufferers managed
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`https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2699789/
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`MYLAN - EXHIBIT 1070
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
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`by ophthalmologists ranged from US$0.27 million (95% CI: $0.20; US$0.38 million) in France to
`US$1.10 million (95% CI: US$0.70; US$1.50 million) in the UK. A large proportion of dry eye
`patients is either self-treated or managed by their general practitioner (Clegg et al 2006).
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`Diagnosis of dry eye
`Clinically there is a plethora of irritation symptoms associated with dry eye such as ocular burning,
`stinging, scratchiness, soreness, photophobia, blurred vision and foreign body sensation. Tear film
`stability can be assessed with the fluorescein tear break-up time test, measuring the interval in seconds
`between a complete blink and the first appearing dry spot or discontinuity in the precorneal film.
`Aqueous tear production is measured more commonly with Shirmer test, calculating the length in
`millimeters that a folded filter paper strip placed in the lower lid wets during a 5-minute test period.
`There are two ways to perform this test: a) Shirmer test I is performed without topical anesthesia, which
`evaluates better the ability of the ocular gland to respond to ocular surface stimulation; b) Shirmer test
`II (or Basic Secretion test) which is performed after topical anesthesia, evaluating better the basal tear
`secretion. Meibonian gland disease is diagnosed by biomicroscopic recognition of pathological signs
`such as ductal orifice metaplasia, reduced expressibility of meibonian gland secretions, increased
`viscosity of the expressed secretion and dropout of glandular acini. Conjunctival goblet cell density and
`epithelial morphology can be directly evaluated by cytology. The most practical clinical method for
`assessing the severity of dry eye is the ocular surface dye staining. Fluorescein, rose Bengal and
`lissamine green are use as diagnostic dyes for evaluating the staining. Fluorescein staining occurs when
`the epithelial barrier is disrupted, due to the loss of the epithelial cells, is well tolerated by patients and
`evaluates better corneal staining. Rose Bengal and lissamine green stain the conjunctiva more brightly
`than the cornea. Rose Bengal stains devitalized epithelial cells or cells without protective mucus layer,
`but cause transient irritation after installation. Lissamine green dyes degenerated or dead cells and
`produces less irritation than rose Bengal (Plufelder 2006).
`
`However, many times symptoms and signs are not always specific and are often underestimated by the
`patient or under diagnosed by ophthalmologist (Schein et al 1997; Afonso et al 1999; Lin et al 2003).
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`Definitions and classifications of dry eye
`In 1995 the National Eye Institute workshops, defined dry eye as “a disorder of the tear film due to tear
`deficiency or excessive evaporation that causes damage to the interpalpebral ocular surface and is
`associated with symptoms of discomfort” (Lemp 1995). In the Definition and Classification
`Subcommittee of the international Dry Eye Workshop in 2007, a new contemporary definition of dry
`eye disease was reported, supported within a comprehensive classification framework. In accordance
`with the committee, dry eye was defined as a multifactorial disease of the tears and ocular surface that
`results in symptoms of discomfort, visual disturbance, and tears 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. The committee recommended a three part classification system. The first part was
`etiopathogenic, illustrating the multiple causes of dry eye. In this group dry eye was divided in two
`principal categories: aqueous deficient (Sjogren or non-Sjogren related) and evaporative (intrinsic or
`extrinsic causes); the second was mechanistic, showing the way each cause may act through a common
`pathway (tear hyperosmolarity and tear film instability); the third part was based on the severity of the
`disease (four groups correlated to visual symptoms, conjuctival injection, conjunctival staining, corneal
`staining, corneal/tears signs, lid/meibonian glands, tear break-up time, and Shirmer test), providing a
`rational basis for therapy (DEW 2007).
`
`In 2006 in a Delphi panel approach to treatment recommendations by 17 international specialists on dry
`eye syndrome, a new term was proposed for dry eye disease: dysfunctional tear syndrome (DTS). In our
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`study the most commonly used diagnostic test reported by more than half of the panelists for evaluating
`probable dry eye were fluorescein staining (100%), tear break up time (94%), Shirmer test (71%), and
`rose Bengal staining (65%). Panelists agreed on three particular relevant symptoms and historical
`elements to be considered: ocular discomfort (itch, scratch, burn, foreign body sensation, and/or
`photophobia), tear substitute requirements, and visual disturbance. There was a consensus that most
`cases of DTS have an inflammatory basis that either triggers or maintains the inflammation. However,
`there was an agreement on the difficulty in clearly identifying inflammation in most patients and
`consequently the panel agreed to subclassify the disease as either DTS with clinically apparent
`inflammation or DTS without clinically evident inflammation (Behrens et al 2006).
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`Pathogenesis
`The ocular surface and the lacrimal gland are considered, studied, and treated as an integrated
`functional unit interconnected by neural sensory/autonomic reflex arcs. Sensory afferent nerves, which
`enervate the ocular surface, traffic along the ophthalmic branch of the trigeminal nerve to the Pont area
`of the central nervous system. After received inputs from cortical areas (emotional central nervous
`centers), efferent nerves, consisting of parasympathetic fibers traveling in the facial nerve and of
`sympathetic fibers from the paraspinal sympathetic chain, lead to the main and the accessory lacrimal
`gland (Pflugfelder et all 2000).
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`Over recent years, inflammation has been shown to be the key in the pathogenesis of this syndrome, as
`it seems to be the cause and the consequence of dry eye. Regardless of the triggering factor, a vicious
`cycle of inflammation may be developed on the ocular surface in patients with dry eye. A glandular
`dysfunction creating tear deficiency or instability could irritate the surface of the eye and promote
`inflammation, which increases further the tear deficiency (Jones et all 1998). The results are antigen
`presentation and cytokine secretion by the epithelial cells of the lacrimal gland which promote the
`activation of the T-cells lymphocytes. Finally, the T-cells secrete pro-inflammatory cytokines,
`increasing further the level of inflammation (Meggs 1993; Mircheff et al 1998; Gao et al 1998).
`Consequently, the tears will contain cytokines. The ocular surface reacts, promoting inflammatory
`response which consists of inflammatory cell infiltration, epithelial activation, increased concentrations
`of cytokines and other inflammatory factors, and increased activity of matrix-degrading enzymes
`(Baudouin et al 1997; Tishler et al 1998; Afonso et al 1999; Pflugfelder 1999; Pflugfelder 2000; Sobrin
`et al 2000). This knowledge concerning the inflammation pathogenic mechanism in dry eye syndrome
`alters also the therapeutic approach against this syndrome which is now based on anti-inflammatory
`agents.
`
`Therapy
`The therapy of dry eye depends on its severity. Based on the most recent concept, the armamentarium
`used to control dry eye comprises a large range of therapeutic strategies.
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`Modification of the environmental conditions that increase tear evaporation (eg, low humidity),
`avoiding the use of systemic medications with anticholinergic side effects (eg, antihistamines),
`occlusion of the lacrimal canaliculi (punctal occlusion), stimulation of tears production (oral
`secretagogues pilocarpine), and minimization of corneal exposure (tarsorrhaphy, gas permeable contact
`lenses). Although these treatment options are very useful, all of them are considered to be symptomatic
`therapeutic approaches and not pathogenic.
`
`Artificial tears
`Artificial tears provide temporal improvement in eye irritation and blurred vision symptoms, visual
`contrast sensitivity, tear break up time, and ocular surface dye staining. (Gifford et al 2006; Ousler et al
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`2007). Artificial tears contain polymers such as cellulose esters, polyvinyl alcohol, and povidone, which
`determine their viscosity, shear properties, retention time, and adhesion to the ocular surface. Gels have
`longer retention times than artificial tear solutions (Bron et al 1998; Wilson et al 1998).
`
`Anti-inflammatory therapy
`Anti-inflammatory therapy is considered to be the first “causative therapeutic approach” in the
`treatment of dry eye, since its objective is to interrupt the inflammatory cascade. Topical
`corticosteroids, tetracyclines, and cyclosporine A (CsA) are the drugs used in the anti-inflammatory
`therapy of dry eye.
`
`Corticosteroids
`Topical corticosteroids can be used in order to decrease ocular surface inflammation inhibiting MMPs
`(matrix metalloproteinasis), inflammatory cytokines and adhesion molecule production. They
`demonstrate satisfactory results as pulse therapy. In a retrospective study which included Sjogren
`syndrome patients with keratoconjunctivitis sicca (KCS), the administration of 1% solution of
`methylprednisolone (3 times a day for 2 weeks) relieved symptoms in all patients (Marsh and
`Pflugfelder 1999). Corticosteroids should not be administered for long-term use owing to the side
`effects they can provoke (steroid response increasing of IOP, cataractogenesis). Corticosteroids with
`minimal potential to raise IOP (fluorometholone and loteprendol etabonate) could be considered a safer
`approach. A randomized, double-masked, placebo-controlled study of loteprednol etabonate and its
`vehicle was conducted on 64 patients with delayed tear clearance and KCS. After 2 and 4 weeks of
`treatment, there was no change in IOP in the corticosteroid-treated group. Patients with the most severe
`inflammatory signs at entry showed a significantly greater decrease in central corneal fluorescein
`staining scores while a significant decrease in inferior bulbar conjunctival hyperemia was demonstrated
`after 2 weeks (Plugfelder et al 2004).
`
`Tetracyclines
`Tetracyclines have also a variety of anti-inflammatory properties such as inhibition of MMPs and
`interleukine-I (IL-I) production (Amin et al 1996; Shlopov et al 1999). Orally administrated they
`decrease ocular surface symptoms in patients with ocular rosacea (Frucht-Pery et al 1993; Akpek et al
`1997) and in patients with recurrent corneal epithelial erosions (Hope-Ross et al 1994).
`
`The best tolerated tetracycline is doxycycline, which is effective in doses of 20–50 mg orally twice a
`day for a treatment up to 4 weeks (Plugfelder 2004).
`
`Cyclosporine A
`Today CsA seems to represent a very promising treatment against dry eye syndrome since it is the first
`agent focused on the pathogenesis of this disease. It can be used for long term without presentation of
`the adverse effects characterizing the other anti-inflammatory agents.
`
`Methodology
`A systematic literature review was performed using PubMed databases in two steps. The first step was
`oriented to articles published for dry eye. The second step was focused on the use of CsA in dry eye.
`The search strategy was not limited by year of publication. A manual literature search was also
`undertaken based on citations in the published articles.
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`Results
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`Cyclosporine A is a fungal-derived peptide that inhibits T-cell activation and consequently inhibits the
`inflammatory cytokine production (selective inhibition of IL-I). In addition, CsA inhibits apoptosis by
`blocking the opening of the mitochondrial permeability transition pore (MPTP) (Matsuda and Koyasu
`2000) and by increasing the density of conjuctival goblet cells (Kunert et al 2002).
`
`®
`In the US, CsA is commercially distributed as Restasis . This ophthalmic emulsion (0.05%
`cyclosporine [Allergan, Inc. Irvine, CA, USA]) is preservative free packaged in unit-dose vials.
`Restasis has been a prescription drug in the US since April 2003 when it was approved by the FDA for
`patients whose tear production is presumed to be suppressed due to ocular inflammation associated with
`KCS.
`
`CsA was used for years routinely as an oral immunosuppressor for organ transplantation. Its action is
`non toxic and reversible after the treatment. In ophthalmology prior to dry eye treatment, CsA was used
`also for the treatment of severe posterior segment inflammations, when administered systemically (iv)
`or orally (Masuda et al 1989). Systemically CsA was also used for the treatment of peripheral ulcerative
`keratitis associated with Wegener’s granulomatosis, in severe Graves’s ophthalmopathy, and for the
`prevention of the recurrence of graft rejection after keratoplasty (Prummel et al 1989; Nussenblatt et al
`1991; Georganas et al 1996; Reinhard et al 1997).
`
`All these indications were the result of CsA’s pharmacokinetics, since extraocular and intraocular
`tissues can be reached by this agent through the systemic pathway after oral administration. In fact,
`after oral daily administration of 5 mg/kg daily, the concentration of CsA was measured to be 25–75
`μg/mL in human tears (BenEzra et al 1990); systemic administration may be accompanied by severe
`side effects such as nephrotoxity and hypertension (Mihatsch et al 1998). As a result topical ocular
`delivery was proposed as a good alternative. Despite its poor intraocular penetration, topical CsA has
`been successfully used in dry eye syndrome. Another pharmacokinetic limitation was that CsA could
`not be prepared in a formulation based on aqueous ophthalmic vehicles because of both its
`hydrophobicity and its low aqueous solubility. Therefore, the agent was dissolved in vegetable oils
`(Lallemand et al 2003).
`
`The potential of CsA for treating dry eye syndrome and its clinical expression KCS was initially tested
`in 1989 in dogs affected with spontaneous canine KCS. Tear production was increased. CsA caused
`marked regression of chronic corneal neovascularization and granulation even in eyes in which
`lacrimation failed to improve. Additional benefits of topical cyclosporine were: reduced mucopurulent
`conjunctivitis, rapid healing of non-healing corneal ulcers, and reduced dependence on frequent topical
`treatments of KCS (Kaswan et al 1989). The experimental results were verified by other similar studies
`in dogs (Morgan and Abrams 1991; Olivero et al 1991; Izci et al 2002). Furthermore, experiments in a
`mutant mouse model used for primary Sjogren’s syndrome has demonstrated the anti-inflammatory
`effect of both topical and orally administrated CsA on the lacrimal gland (Tsubota et al 1998), whereas
`other experiments in mice suggested that CsA accelerates tear secretion by releasing neurotransmitters
`from sensory nerve endings, which interact with the parasympathetic nerves (Yoshida et al 1999).
`Similar conclusions were also demonstrated in studies with rabbits (Toshida et al 1998).
`
`The use of CsA delivered as ointment or oil suspension was then studied for treatment of humans KCS.
`Topical CsA 2% in olive oil was investigated for its possible immunoregulatory role on the dry eye
`state in patients with secondary Sjogren’s syndrome. Thirty eyes of 15 patients were randomized to
`undergo treatment with topical cyclosporine in olive oil, while another group of 15 patients (30 eyes)
`received a placebo (which was the sterile olive oil used as a vehicle for the cyclosporine). There was a
`significant increase in the break-up time and a significant decrease in rose Bengal staining score
`between the cyclosporine and control groups at the end of the 2-month study period (Gunduz and
`Ozdemir 1994). Laibovitz et al (1993) conducted a study in which patients with KCS underwent 6
`weeks of treatment with either cyclosporine 1% ophthalmic ointment or placebo, followed by 6 weeks
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`of the alternative treatment. Cyclosporine ointment was associated with initial mild to moderate
`redness, itching, and burning that returned to baseline levels within 1–2 weeks. Rose Bengal results and
`results of 4 subjective (patient diary) efficacy parameters favored cyclosporine: foreign body sensation,
`overall symptoms, hours of symptom control per day, and overall effectiveness. No systemic adverse
`events or laboratory abnormalities occurred. Subsequently, CsA for treating KCS in patients with dry
`eye was evaluated in large multi-center randomized double-masked FDA clinical trials. An FDA phase
`2, randomized, multicenter, double masked, parallel-group, dose-response clinical trial compared 4
`different dose of CsA (CsA ophthalmic emulsion 0.05%, 0.1%, 0.2%, 0.4%) administrated twice daily
`into both eyes of 129 patients and 33 patients treated with a vehicle for 12 weeks, followed by a 4-week
`post-treatment observation period. In a subset of 90 patients with moderate to severe KCS, CsA was
`found to decrease rose Bengal staining, superficial punctuate keratitis, and symptoms of ocular
`discomfort. Although there was no clear dose-response relationship, CsA 0.1% seemed to produce the
`most consistent improvements in subjective and objective end points, whereas CsA 0.05%
`demonstrated the most consistent improvement in patients’ symptoms. All treatments were well
`tolerated by patients (Stevenson et al 2000).
`
`In the FDA phase 3 study group, 2 independent multicenter, randomized, double-masked, parallel
`group, 6-month, vehicle control clinical trials compared the efficacy and safety of CsA in 877 patients
`with defined moderate to severe dry eye disease. The patients were treated twice daily with either CsA
`0.05% or 0.1%, or vehicle (292 to 293 patients in each group). The results of these two trials were
`combined for analysis. There was no dose-response effect. A treatment effect was observed after first
`month of treatment and increased over the 6-month follow-up period. Patients treated with CsA (0.05%
`or 0.1%) showed significantly greater improvements than vehicle in 2 objective signs (corneal
`fluorescein staining and categorized Shirmer values). CsA 0.05% treatment also demonstrated
`significantly greater improvements in three subjective measures of dry eye (blurred vision, need for
`concomitant artificial tears, and physician’s evaluation of global response to treatment). After 6 months
`of treatment there was a statistically significant improvement from baseline within both groups in
`Shirmer tear test obtained with anesthesia, whereas in those obtained without anesthesia there was a
`statistically significant improvement from baselines within all treatment groups but no statistically
`significant differences among the groups. The most common treatment-related adverse effect was
`burning eye sensation (15% for CsA 0.05% group and 17% for CsA 0.1% group). Patients receiving the
`vehicle had a lower frequency of burning eye sensation (7%). Other common adverse events (reported
`by >3% of patients) were stinging eye, eye discharge, foreign body sensation, conjunctival hyperemia,
`visual disturbance, and eye pain (Sall et al 2000).
`
`A multicentered, non-randomized, open label extension study of the two previous phase 3 clinical trials,
`evaluated the safety and efficacy of CsA 0.1% ophthalmic emulsion over 1–3 years in moderate to
`severe dry eye disease patients. In 412 patients previously dosed for 6–12 months with CsA 0.05% or
`0.1%, CsA 0.1% was instilled twice daily for up to 3 consecutive 12-month periods. For the duration of
`almost all the 20-month treatment, improvements in objective and subjective measures of dry eye were
`modest. The changes in corneal staining and Shirmer scores were not statistically significant.
`Treatment-related adverse effects were found in 22% of patients. The most common were burning eye,
`stinging eye, and conjunctival hyperemia, but only 2 patients reported these symptoms as severe. In a
`survey of patients receiving CsA during a 12-month treatment period, most patients reported that during
`the first clinical trial preceding this study, their symptoms began to resolve after the first 3 months.
`Although 85% of respondents continued to use artificial tears, their frequency decreased from 7.6 times
`per day to 3.8 times per day. 95.2% of respondents said that they would continue taking CsA after the
`study and 98% would recommend it to other patients. A 2 line loss of visual acuity was found in 13% of
`patients, whereas only 5% showed a gain of 2 lines (Barber et al 2005).
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`The use of CsA for the treatment of dry eye was also tested in a variety of situations correlated with this
`syndrome. It is well known that LASIK, despite its positive attributes in keratorefractive surgery, can
`induce dry eye syndrome in some patients (Aras et al 2000; Battat et al 2001; Toda et al 2001;
`Nassaralla et al 2003). Dry eye in patients that underwent LASIK seems to be a result of multifactorial
`processes such as decreased corneal sensation or alteration ocular surface and lacrimal gland function
`(Heigle and Plugfelder 1996; Linna et al 2000; Stern et al 2000). As a result, dry eye is considered to be
`almost a contraindication for LASIK surgery. A prospective clinical trial evaluated the safety and
`efficacy of CsA 0.05% versus artificial tears in dry eye patients, from 1 month before to 3 months after
`having LASIK. There were no statistically significant differences between baselines or between the two
`groups in response to ocular surface disease index questionnaire or best spectacle-corrected visual
`acuity. Treatment with CsA provided greater refractive predictability than artificial tears 3 and 6
`months after surgery (Salib et al 2006).
`
`Rao and Rao (2006) assessed the efficacy of cyclosporine in patients with dry eye associated with draft
`versus host disease after stem cells transplantation. After completing a 3-month run-in period of using
`only artificial tears to control dry eye symptoms in both eyes, patients who failed to achieve adequate
`relief were instructed to instill topical cyclosporine twice a day. Dry eye signs improved significantly
`with cyclosporine treatment.
`
`Based on its anti-inflammatory action, topical CsA could also be used in a variety of other ocular
`surface disease such as vernal keratoconjutivitis (Pucci et al 2002), atopic keratoconjutivitis (Akpek et
`al 2004), ligneous conjutivitis (Rubin et al 1991), conjuctival linchen planus (Levell et al 1992), and
`superior limbic keratoconjutivitis (Perry et al 2003).
`
`The concomitant use of cyclosporine with artificial tears has also been analyzed. Sal et al (2006)
`evaluated the efficacy of marked artificial tears in relieving the signs and symptoms of dry eye when
`used as a supportive therapy to a cyclosporine-based ophthalmic emulsion in a 6-month randomized
`investigator masked parallel study of 61 patients. The patients were divided in 3 groups; in the first two
`cyclosporine was combined with a preservative-free carboxymethylcellulose 0.5% agent (Refresh
`®
`®
`Plus , Allergan, Irvine, CA, USA) and with a hydroxypropylguar gellable lubricant eye drop (Systane ,
`Alcon laboratories, Inc., Fort Worth, TX, USA), whereas in the third group only Systane was used.
`Results indicated that the choice of concomitant therapy had significant effects on outcome measures.
`The combination of Restasis-Systane was statistically significantly better in reducing the signs and
`symptoms of dry eye than the combination of Restasis-Refresh. In addition, Systane used alone was
`statistically significantly better than Restasis-Refresh for 3 ocular symptom frequency scales (burning,
`dryness, and scratchiness) and 6 Likert acceptability questions. Finally, Restasis-Systane, compared
`with Systane alone, was not statistically different for any of the signs and symptoms measured except
`for the frequency of ocular blurring (Sal et al 2006).
`
`Discussion
`Although traditional symptomatic treatment still remains the method of choice, a more reasonable
`approach in the treatment of this syndrome would seem to be consider the inflammatory mechanism of
`dry eye. The trend nowadays in patients with slight to mild episodic dry eye seems to be symptomatic
`therapy (eg, artificial tears, punctual occlusion), while in patients who already use artificial tears and
`who continue to have detectable ocular surface disease associated with inflammatory signs, anti-
`inflammatory agents seem to be the treatment of choice.
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`The use of CsA as anti-inflammatory treatment for dry eye has advantages over corticosteroids because
`until now a) it has not demonstrated serious adverse effects; b) its action is reversible after the
`treatment; and c) it has a very low rate of systemic absorption. These pharmacokinetic characteristics
`are critical, since the possibility for long-term therapy in these patients is absolutely necessary for a
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`chronic disease such as dry eye. In fact, the benefits of CsA begin after 1 moth of treatment and a
`therapy of at least 3 months seems to be indispensable.
`
`Also other conditions associated with dry eye could benefit from CsA. For example, refractive surgery
`of the cornea, most particularly LASIK, is almost contraindicated now in patients with dry eye. CsA
`treatment before and after surgery could help these patients obtain a surgical correction of their
`refractive error without the risk of dry eye. Graft versus Host disease cells after stem transplantation
`could also benefit from CsA. Similar results were be found in other pathologies with an inflammatory
`base, such as vernal kerato-conjunctivitis, atopic kerato-conjunctivitis, ligneous conjunctivitis, and
`superior limbic kerato-conjunctivitis.
`
`Plugfelder (2004) reviewed anti inflammatory therapy for chronic dry eye. He stated that dry eye is
`associated with ocular surface inflammation that may further compromise tear secretion and cause
`ocular surface disease and irritation symptoms. Ocular surface inflammation should be assumed in
`patients with an unstable tear film and ocular surface epithelial disease that is detected by staining with
`diagnostic dyes. Of course, there is no diagnostic test available to gauge easily the level of
`inflammation on the ocular surface. As a result, no firm recommendations can be made about the
`optimal timing for initiating anti-inflammatory therapy in patients with dry eye. He concluded that it is
`reasonable to consider anti-inflammatory therapy for patients using artificial tears who continue to have
`clinically detectable ocular surface disease, particularly if inflammatory signs (for example,
`conjunctival redness) and irritation symptoms are present.
`
`The Delphi panel in 2006 proposed treatment recommendation for dry eye on the basis of level of
`severity. They recommended that topical administration of CsA must be given only when the disease is
`in severity level two, characterized by moderate to severe symptoms, tear film signs, mild cornea
`punctuate staining, conjunctival staining, and visual signs.
`
`However, a new treatment must take consider the relationship between cost and effect. Miljanovic et al
`(2007) measured the impact of dry eye syndrome on vision-related quality of life. They asked 190
`participants with clinically diagnosed dry eye or severe symptoms and 399 without dry eye to complete
`a questionnaire, asking how much their everyday activities were limited by symptoms of dry eye and to
`what degree problems with their eyes limited their reading, driving, working at the computer,
`professional activities, and watching television. They concluded that dry eye syndrome is associated
`with a measurable adverse impact on several common and important tasks of daily living, further
`implicating this condition as an important public health problem deserving increased attention and
`resources. Clegg et al (2006) estimated the annual cost associated with the management of dry eye
`patients by ophthalmologists in France, Germany, Italy, Spain, Sweden, and the UK from the
`perspective of the health-care systems in the respective countries. They concluded that dry eye
`syndrome did not appear to impose a direct burden on the health care expenditure of the country
`investigated (Clegg et al 2006). However, among these countries CsA was used only in Germany for
`severe cases associated with Sjogren’s syndrome. CsA costs much more than other medicines and the
`economic impact of this medicine must be seriously considered in relation to its effect on dry eye, given
`that it not only substitutes for but also complements the existing treatments for dry eye.
`
`It is likely that future clinical and epidemiological studies will provide more definitive
`recommendations about the timing, efficacy, safety, and relative costs/benefits of anti-inflammatory
`therapy with CsA for dry eye.
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