JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTiCS
`Voiurrse 26, Number 2,
`2010
`© Mary Ann Liebert, inc.
`DO!: 10.1089/jop.2Q09.0091
`
`for the Prevention of Dry Eye
`
`Topical Cyclosporine 0.05%
`Disease Progression
`
`Sanjay N. Rao
`
`Abstract
`Purpose: To assess the prognosis of dry eye in patients treated with cyclosporine 0.05% or artificial tears by
`using the International Task Force (ITF) guidelines.
`
`Methods: This was a single-center, investigator-masked, prospective, randomized, longitudinal trial. Dry eye
`patients received twice-daily treatment with either cyclosporine 0.05% (Restasis®; Allergan, Inc., Irvine, CA;
`n = 36) or artificial tears (Refresh Endura®; Allergan, Inc., Irvine, CA; n = 22) for 12 months. Disease severity was
`determined at baseline and month 12 according to the consensus guidelines developed by the ITF. Dry eye signs
`and symptoms were evaluated at baseline and months 4,8, and 12.
`severity level 2
`the disease
`
`Results: Baseline sign and symptom scores and the proportion of patients with
`3 were comparable in both groups (P >
`0.05). At month 12,34 of 36 cyclosporine patients (94%) and 15 of 22 ar­
`tificial tear patients (68%) experienced improvements or no change in
`their disease
`
`severity (P = 0.007) while
`2 of 36 cyclosporine patients (6%) and 7 of 22 artificial tears
`patients (32%) had disease progression (P < 0.01).
`Cyclosporine 0.05% improved Schirmer test scores, tear breakup time, and Ocular Surface Disease Index scores
`throughout the study, with significant (P < 0.01) differences compared with artificial tears being observed at
`months 8 and 12.
`Conclusions: Treatment with cyclosporine 0.05% may slow or prevent disease progression in patients with dry
`eye at severity levels 2 or 3.
`
`or
`
`introduction
`
`pAHENTS
`
`4,
`
`from 1 to
`into 4 levels (Table 1), with increasing severity
`DRY EYE disease suffer from ocular im- and developed consensus treatment guidelines. The level of
`WITH
`_L tation often accompanied by vision
`impairment, which disease severity was considered the most important factor in
`limits important daily activities and negatively impacts determining the appropriate
`
`range of therapeutic options.9
`quality of life (QoL).1-3 The prevalence of dry eye disease
`is While counseling, education,
`and preserved artificial tears
`estimated to be from 5% to >30%.^ The largest US cross- were recommended for the management of patients diag-
`sectional survey studies, the Women's Health Study (WHS) nosed at severity level 1, unpreserved artificial tears, topical
`and the Physician Health Study (PHS), indicated that the
`cyclosporine, and/or corticosteroids were recommended for
`prevalence of dry eye disease among women and men aged patients at severity level 2. Punctal plugs, oral tetracyclines,
`over 50 years is 7.8% and 4.3%, respectively. Using this prev-
`systemic immunomodulators, and surgery were reserved
`
`alence data, ~4.9 million Americans aged over 50 years are
`for the management of dry eye patients diagnosed at se­
`estimated to be affected by dry eye disease.6,7
`verity levels 3 and 4.9
`The diagnosis and treatment of dry eye is challenging.
`A key recommendation of the ITF panel was the use of
`8
`The Wilmer Eye Institute at Johns Hopkins University re- topical anti-inflammatory therapy in patients with clini-
`cently invited the International Task Force (ITF) of 17 dry
`cally apparent ocular surface inflammation.' This recom-
`eye experts to create guidelines for the diagnosis and treat- mendation stemmed from the recent evidence indicating
`ment of dry eye disease by using
`a Delphi
`
`consensus that inflammation plays a major role in the disease etiology tech-
`
`nique.' The ITF panel categorized dry eye disease severity and may be a
`unifying mechanism that underlies dry
`eye
`
`Lakeside Eye Group, Chicago, Illinois.
`
`157
`
`0308
`
` EXHIBIT 1004 (PART 3 of 3)
`
`

`

`158
`
`
`
`
`
`TABLE 1. CRITERIA USED TO DETERMINE THE LEVELS OF DRY
`
`EYE SEVERITY ACCORDING TO
`
`ITF GUIDELINES8
`
`RAO
`
`Symptoms
`
`Signs
`
`Staining
`
`Level 1 Mild to moderate Mild/moderate conjunctival
`signs
`Tear film signs, visual signs
`Corneal filamentary keratitis
`Corneal erosions, conjunctival
`scarnng
`
`Level 2 Moderate to severe
`Level 3 Severe
`Level 4 Severe
`
`None
`
`Mild punctate corneal and conjunctival staining
`Central corneal staining
`Severe corneal staining
`
`Disease severity is categorized into 4 levels based on the severity of symptoms and signs. At least one sign and one symptom
`of each category should be present to qualify for the corresponding
`level assignment.
`
`both
`
`that the chronic use
`
`disease.'®"12 Therefore, it was
`Patients were randomly assigned in a 3:2 ratio to twice-
`suggested
`daily treatment with either cyclosporine 0.05% or artificial
`
`therapies that normalize
`tear film
`of safe anti-inflammatory
`composition early in
`
`the disease process may have the po­
`tears (Refresh Endura®; Allergan, Inc., Irvine, CA) in
`tential to slow, prevent, or reverse dry eye progression.13
`eyes for 12 months. The randomization ratio was an empir­
`Ophthalmic cyclosporine 0.05% emulsion (Restasis®;
`in­
`ical estimation due to lack of adequate epidemiological
`Allergan, Inc., Irvine, CA) is the only anti-inflammatory
`formation to conduct power calculations prior to initiating
`medication approved by the Food and Drug Administration
`the study. Randomization was performed by a statistical
`to increase tear production in dry eye patients.14 In T lym­
`program and was overseen by the research coordinator.
`phocytes, cyclosporine binds
`
`cyclophilin A and inhibits
`Patients were enrolled in the study and initiated therapy
`to
`calcineurin-catalyzed dephosphorylation of the nuclear
`after screening and randomization on the same day at
`factor for T-cell activation.15-16 Cyclosporine
`thereby inhibits
`the baseline visit
`(month 0). All patients were allowed to
`IL-2 transcription, which upon secretion stimulates T-cell di­
`utilize rescue artificial tears as
`
`needed if discomfort was
`vision by a self-propagating autocrine and paracrine loop.16 experienced. The primary objective of this study was to
`In humans, topical administration of cyclosporine 0.05% has
`assess the potential of topical cyclosporine 0.05% therapy
`been shown to decrease the number of activated T cells and
`to halt or slow disease progression relative to control at
`expression of inflammatory markers in the conjunctiva of
`month 12 based on
`
`the ITF severity categorization (Table
`dry eye patients.®8 These findings suggest that topical cy­
`1). The secondary outcome variables were the changes in
`closporine 0.05% targets the underlying
`inflammatory pro­
`dry eye signs and symptoms. The study was conducted
`cesses in dry eye disease. Therefore, chronic treatment with
`in compliance with regulations of the Health Insurance
`cyclosporine 0.05% may offer the potential to alter the course
`Portability and Accountability Act and the Declaration of
`of dry eye disease.
`Helsinki.
`Wilson and Stulting recently evaluated the clinical appli­
`cability of the ITF guidelines.'3 Physicians participating in
`Disease severity and dry eye signs
`that study successfully implemented the
`ITF guidelines
`for
`and symptoms
`diagnosis and treatment of dry eye patients.13 Using
`
`the ITF
`Disease severity was assessed according to the ITF
`guidelines, this study was designed to assess
`the prognosis
`consensus guidelines at baseline and month 12 (Table I).9
`of dry eye disease in patients treated with cyclosporine
`Patients were evaluated for signs and symptoms of dry eye
`0.05% or artificial tears.
`by Schirmer test with anesthesia, tear breakup time (TBUT),
`ocular surface staining, and Ocular Surface Disease Index
`Methods
`(OSDI) at baseline (month 0) and after receiving the study
`treatments at months 4,8, and 12. In each study visit, TBUT
`Study design
`was evaluated first, followed by ocular surface staining and
`This was a single-center, investigator-masked, random­
`Schirmer test, respectively. The TBUT was measured using
`ized, prospective, longitudinal clinical
`fluorescein dye. Ocular surface damage was assessed by the trial. The study was
`
`approved by the Western institutional review board in
`Oxford method using sodium fluorescein to stain the cornea
`Olympia, WA, and was registered with ClinicalTrials.gov
`and lissamine green to stain the nasal and temporal bulbar
`18
`(identifier # NCT00567983). Inclusion criteria were of age
`conjunctiva.19 The scoring scale for ocular staining was 0 to 5
`years or older, diagnosis of dry eye without lid margin dis­
`in cornea, 0 to 5 in temporal conjunctiva, and 0 to 5 in nasal
`ease or altered tear distribution and clearance, and a disease
`conjunctiva, with 0 representing no staining and 5 repre-
`severity of level 2 or 3 as defined by the ITF guidelines (Table senting severe staining. These individual scores were then
`I).9 Primary exclusion criteria were prior use of topical cyclo-
`summed for the total Oxford score, which ranged from 0 to
`sporine 0.05% within the last year, topical or systemic use of
`15. The change from baseline was calculated by subtract-
`
`ing the baseline score from the months 4, 8, and 12 scores.
`anti-inflammatory or anti-allergy medications, active ocular
`infection or inflammatory disease, or uncontrolled systemic
`The symptoms of ocular irritation and their impact on vi­
`disease that can exacerbate dry eye disease. Patients who
`sual functioning was assessed by OSDI, a validated 12-item
`wore contact lenses were also
`the study. All
`excluded
`from
`questionnaire, on a scale of 0 to 100 with 0 representing
`form before
`participating patients signed a written consent
`asymptomatic and 100 representing severe debilitating dry
`initiation of the study-specific procedures.
`eye disease.20
`
`0309
`
`

`

`CYCLOSPORINE AGAINST DRY EYE PROGRESSION
`
`159
`
`the
`
`
`
`mean or
`
`age
`
`(P =
`
`Goblet cell density
`between-group differences
`in
`distribution of gender
`
`(P = 0.800).
`The density of goblet cells in bulbar conjunctiva was
`Sixteen patients discontinued the study. The number of
`evaluated at baseline and month 12. Impression cytology
`discontinuations was significantly higher among patients
`was performed in both eyes after evaluation of TBUT, oc­
`treated with artificial tears compared with those treated with
`ular staining, and Schirmer test. Goblet cells were collected
`cyclosporine 0.05% (11 vs. 5; P = 0.028; Table 2). Of 11 discon­
`on cellulose acetate filters (HAWP 304 FO; Millipore
`Corp.,
`tinuations in
`the artificial tear group, 9 patients discontin­
`glacial acetic acid,
`Billerica, MA). The filters were fixated in
`ued the study because of discomfort upon instillation, and
`formaldehyde, and 70% ethanol and subsequently stained
`with a modified periodic acid-Schiff Papanicolaou stain. 2 patients were lost to follow-up or moved. Seven of these
`patients had a disease severity of level 2, and 4 patients had a
`Goblet cells were counted in
`5
`
`(400 X 400 mm) representa­
`disease severity of level 3. Of the 5 discontinuations in the cy­
`tive microscopic fields on each filter.21
`closporine group, 2 patients discontinued the study because
`of discomfort upon instillation while 3 were lost to follow-up
`or moved. Three of these patients had a disease severity of
`level 2, and 2 patients had a disease severity of level 3.
`
`Statistical analyses
`Patients who completed 12 months of treatment were
`included in the analyses. The results were presented as
`mean ± SD. Intergroup comparisons of categorical variables
`were performed using
`the chi-square or Fisher's exact test.
`Continuous variables were analyzed using nonparametric
`tests (Mann-Whitney tests
`
`for between-group comparisons
`and Wilcoxon signed rank tests for within-group compari­
`sons). A P value < 0.05 was considered a statistically signifi­
`cant difference. Statview software (SAS Institute, Gary, NC)
`was used for ail analyses.
`
`Disease seventy
`At month 12, significantly more patients treated with artifi­
`cial tears had more severe signs and symptoms of disease than
`did those treated with cyclosporine 0.05% and, therefore, were
`categorized as progressing to a higher disease severity level
`(7 of 22 [32%] patients vs. 2 of 36 [6%], respectively; P < 0.007;
`Fig. 1). In contrast, a greater percentage of patients treated with
`cyclosporine 0.05% had less severe signs and symptoms of
`disease and were categorized as improving to a lower disease
`severity level (14 of 36
`[39%] patients vs. 4 of 22 [18%] patients,
`respectively). This difference, however, was not statistically
`significant (P = 0.098). When combined with those who did
`not have a change
`in
`the
`
`disease severity levels at month
`significantly more patients treated with cyclosporine 0.05%
`had either improvements or no change in disease severity than
`did those treated with artificial tears (34 of 36 [94%] patients vs.
`15 of 22 [68%] patients, respectively; P = 0.007).
`
`Results
`Patient disposition and disease characteristics
`Of 74 patients enrolled between February 2006 and
`January 2007,58 patients completed the 12-month study and
`were included in the analyses (Table 2). Forty-one patients
`were female and 17 patients were male. The distribution
`of patients with disease severity of level 2 or 3 was similar
`in both treatment groups at baseline. Approximately two-
`Schirmer test scores
`thirds of dry eye patients in both groups were diagnosed
`at severity level 2, while one-third of patients was diag­
`0.6 mm
`The mean baseline Schirmer test score was 7.7 ±
`nosed at severity level 3 (Table 2). There were no significant
`in patients randomized to artificial tears and 7.9 ± 1.2 mm
`
`12,
`
`TABLE 2.
`
`PATIENTS' DISPOSITION AND DISEASE CHARACTERISTICS
`
`Artificial Tear
`
`Cyclosporine 0.05%
`
`33
`11s
`22
`48.2 ± 6.3
`39-59
`
`16 (73)
`
`15(68)
`7(32)
`
`41
`5B
`36
`47.5 ± 5.9"
`30-57
`
`25 (69)e
`
`24 (67)
`12(33)
`
`Patients («)
`Enrolled in study
`Discontinued study
`Completed study
`Mean age1 ± SD, years
`Range
`Gender^ n (%)
`Female
`Dry eye severity at baseline/ n (%)
`Level 2
`Levels
`•Nine patients discontinued the study because of discomfort upon instillation. Two
`P
`
`patients were lost to follow-up or moved. =
`0.028 compared
`
`
`patients to who received
`cyclosporine 0.05%.
`
`Three patients were lost to follow-up or moved.
`'For patients who completed 12-month study.
`dP - 0.667 compared to the mean age of patients who received artificial tears.
`*P = 0.800 compared
`to
`the
`
`artificial tear group.
`
`Two patients discontinued the study because of discomfort upon instillation.
`
`0310
`
`

`

`ISO
`
`RAO
`
`55
`
`50
`
`E3 Aftificial Tear (n =
`22)
`g CycSosporine 0.05%
`(n =
`
`38)
`
`39
`
`18
`
`m
`
`B
`
`•s
`
`a.
`
`60
`
`r»
`
`J
`
`40
`
`20 -
`
`0
`
`No Change
`Worsened
`improved
`Change in Dry Eye Severity Levels
`
`Patients treated with cyclosporine were
`
`eye severity at month 12 compared with
`
`FIG. 1. Changes in dry
`0.05%
`
`baseline.
`the
`
`International Task Force (TTF) consensus
`
`months. Disease was assessed according severity
`
`to
`or artificial
`tears for 12
`guidelines at baseline and month 12. The changes in disease severity levels were categorized as worsened, no change, or im­
`proved when a patient had a, respectively, higher, same, or lower disease severity level at month 12 compared with baseline.
`*P < 0.007 compared with the treatment with artificial tears.
`
`randomized to cyclosporine 0.05% (P = 0.550). The mean
`in patients randomized to cyclosporine 0.05% (P = 0.625).
`Patients treated with artificial tears did not have a significant
`TBUT of patients treated with artificial tears slightly de­
`change in
`
`their Schirmer test scores throughout
`
`the study,
`creased throughout the study, whereas patients treated with
`cyclosporine 0.05% had increasingly longer mean TBUT
`whereas those
`
`treated with cyclosporine 0.05% had
`increas­
`ingly higher mean Schirmer test scores at each follow-up
`at each follow-up visit (Fig. 3). The mean TBUT of patients
`visit. The mean Schirmer test
`scores of patients treated with
`treated with cyclosporine 0.05% was significantly longer
`cyclosporine 0.05% were
`
`greater those of
`than
`than those of patients treated with
`
`
`tears artificial months
`significantly
`8 (6.2 ± 1.4 s
`
`vs. 4.6 ± 0.6 s; P =
`0.001) and
`12 ± 1.1 s vs.
`
`(6.5
`
`patients treated with artificial tears at month 8 (9.1 ± 1.0 mm
`vs. 7.5 ± 1.1 mm; P <
`
`0.001) and month 12 (9.8 ± 1.0 mm
`vs.
`4.6 ± 0.7 s; P <
`0.001).
`7.6 ± 1.1; P <
`
`
`0.001; Fig. 2).
`
`at
`
`Ocular surface staining scores
`0.05%
`At baseline, patients randomized to cyclosporine
`
`or artificial tears had similar mean Oxford staining scores
`
`TBUT
`The mean baseline TBUT was 5.0 ± 0.8 s in patients
`randomized to artificial tears and 4.9 ± 0.8 s in patients
`
`14-j
`
`12 -
`
`J
`
`1 0 -
`
`1 4
`
`7.9
`
`7.7
`
`8.2
`
`7.6
`
`• Cyclosporine 0.05%
`© Artificial Tear (n =
`
`(n -
`22)
`
`9.1*
`
`7.5
`
`9.8*
`
`7.6
`
`S
`5
`|5 4-
`
`4.9
`5.0
`
`5.1
`
`4.7
`
`6.2*
`
`J6'5"
`
`T
`
`4.6
`
`4.6
`
`0
`
`0
`
`4
`Time (months)
`
`8
`
`12
`
`36)
`
`0
`
`0
`
`(/> = 36)
`• Cyclosporine 0.05%
`© Artificial Tear (n = 22)
`
`4
`Time (months)
`
`8
`
`12
`
`Patients were
`FIG. 2. Schirmer test scores.
`treated
`closporine 0.05% or artificial tears for
`12 months.
`test was performed with anesthesia at indicated study vis­
`its. *P < 0.001 compared with
`
`patients with artificial treated
`
`tears.
`
`with
`cy­
`FIG. 3. TBUT. Patients were treated with cyclosporine
`Schirmer
`I
`0.05% or artificial tears for 12 months. Tear breakup time
`Tear breakup time (TBUT). was measured with
`fluorescein
`dye at indicated study visits. *P =£ 0.001 compared with
`patients treated with artificial tears.
`
`0311
`
`

`

`CYCLOSPORINE AGAINST DRY EYE PROGRESSION
`
`161
`
`
`
`TABLE 3. MEAN OCULAR SURFACE STAINING SCORES
`
`
`
`Artificial tear (n - 22)
`
`Cyclosporine 0.05% (n - 36)
`
`P
`
`Baseline
`Month 4
`Months
`Month 12
`
`7.86 ± 1.13 (NA)
`7.73 ± 0.99 (-0.12 ±
`7.53 ± 1.01 (-0.25 ±
`7.54 ± 0.91 (-0.32 ±
`
`8.44 ± 0.94 (NA)
`8.31 ± 0.95 (-0.13 £
`0.64)
`7.78 ± 0.93 (-0.64 ±
`0.94)
`7.28 ± 1.28 (-1.19 ±
`0.94)
`
`0.056 (NA)
`0.35)
`0.036 (0.787)
`0.63)
`0.576 (0.087)
`1.36)
`0.223 (0.011)
`
`Patients were treated with cydosparine 0.05% or artificial tears for 12 months. Ocular surface
`damage was assessed at indicated times by the Oxford method. The mean changes tern baseline
`and corresponding P values ate indicated in brackets.9 The change from baseline was calculated by
`subtracting
`the baseline score from the month 4,8, or 12 scores.
`NA = not applicable.
`The changes form baseline were paired comparisons. If a data point was missing, the
`baseline was also excluded from that calculation.
`
`density
`Goblet cell
`(8.4 ± 0.9 vs. 7.9 ± 1.1; P = 0.056; Table 3). At month 4, patients
`treated with cyclosporine 0.05% had significantly higher
`tears or cy-
`
`artificial
`to
`At baseline, patients randomized
`mean staining scores than those treated with artificial tears
`closporine 0.05% had similar mean goblet cell density in
`(8.3 ± 1.0 vs. 7.7 ± 1.0; P <
`0.036). There was no
`between-
`bulbar conjunctiva (95.8 ±
`
`12.5 cells 93.6 ± 9.4 cells, re­and
`
`group difference in ocular staining at months 8 and 12
`spectively; P - 0.446; Fig. 5). By month 12, goblet cell density
`(Table 3). Nonetheless, the mean improvement from baseline
`was significantly higher in patients treated with cydo­
`in the ocular staining scores of patients
`
`treated with cyclo­
`sparine 0.05% than
`those treated with artificial tears
`(116.8
`sporine 0.05% was significantly greater than of those treated
`± 14.8 cells vs. 92.7 ±
`11.0 cells; P < 0.001).
`1.4
`vs.
`with artificial tears at month
`12
`
`(1.2 ± 0.3 ± 0.9, re­
`spectively; P =
`
`0.011; Table 3). These findings indicate that
`cyclosporine 0.05% improved ocular surface staining signif­
`icantly more than did artificial tears at month 12 compared
`with baseline.
`
`Safety
`study medications
`the
`No adverse events attributable to
`were reported other
`
`than discomfort upon instillation dur­
`ing the study.
`
`OSDI Scores
`Discussion
`or
`cyclosporine
`tears
`artificial
`to
`Patients randomized
`tears and the
`
`the
`
`Dry eye is a multifactorial disorder of
`0.05% had similar OSDI scores at baseline (19.1 ± 1.9
`and 18.9 ± 2.9, respectively; P = 0.571). The mean OSDI ocular surface that results in tear film instability and symp-
`scores of patients treated with artificial tears remained
`toms of discomfort and visual disturbance.22 Traditionally,
`unchanged
`throughout
`the
`study
`(Fig.
`
`4). Patients treatment of dry
`
`treated eye
`has been
`palliative
`and
`with cyclosporine
`0.05%, however, had increasingly
`lower on over-the-counter artificial eyedrops and lubricating oint-
`
`
`OSDI scores at each study visit, with the scores at months ments,23 The vast majority of patients seek new therapies
`8 and 12 being significantly
`lower
`
`than those of patients after using
`several over-the-counter products
`over years.23
`treated with artificial tears (17.4 ± 3.4 vs. 19.6 ± 1.6 at However, it is not known if dry eye severity progresses
`month 8; P -
`0.011 and 14.9 ± 4.2 vs. 19.7 ± 2.0 at month through the course of disease during the years. Recently
`
`12; P <
`0.001).
`developed FTP guidelines provide a clinical standard for
`
`largely
`
`24 ^
`
`20 -
`
`S 16 -
`8
`CO
`tJ 12 -
`<0
`0
`
`1
`
`19.1
`
`18.9
`
`19.6
`
`18.5
`
`I
`
`19.6
`
`I
`
`17.4*
`
`I19"7
`
`14.9"
`
`{n -
`® Artificial Tear
`• Cyclosporine 0.05%
`
`(n =
`
`36)
`
`22)
`
`0
`
`0
`
`4
`Time (months)
`
`8
`
`12
`
`Ocular Surface Disease Index (OSDI) scores.
`FIG. 4.
`Patients were treated with
`cyclosporine
`0.05% or
`tears for 12 months. Dry eye signs and symptoms were
`assessed by the
`self-reported OSDI questionnaire
`cated study visits. *P < 0.011 and **P < 0.001 compared
`with patients treated with
`artificial
`tears
`
`at and
`12, respectively.
`
`artificial
`
`at
`
`indi­
`
`months
`
`0312
`
`

`

`162
`
`RAO
`
`140
`
`120
`
`—
`
`O
`« 100
`
`s 1
`
`•5
`
`80 -
`
`60
`? 40 4
`
`I 20 -
`
`0
`
`Baseiine
`
`Month 12
`
`s
`
`symptoms,
`and
`alleviating dry eye signs
`
`to
`In addition
`topical cyciosporine 0.05% therapy appears to be capable
`of slowing
`the
`
`of rate disease progression. Reassessment
`
`patients at the end
`of the
`study
`
`(month period 12) indicated
`
`that a greater number of cyciosporine patients compared
`with the artificial tear
`
`patients (94% vs. 68%) had improve­
`ments or no change in
`their disease
`
`severity status, and far
`fewer (6% vs. 32%) experienced disease progression. These
`findings suggest
`the progressive
`
`of nature dry eye disease
`
`and indicate that dry
`
`eye patients may benefit
`
`from cycio­
`sporine 0.05% therapy by achieving disease stabilization or a
`slower rate of progression. A recent retrospective study pro­
`vided evidence that cyciosporine 0.05% therapy may change
`the course of dry eye disease. In that study, 8 chronic dry eye
`patients diagnosed
`at severity level 2 or 3 were free of signs
`and symptoms
`of dry
`eye
`disease
`for a
`after completing a 6- to 72-month course of cyciosporine
`0.05% therapy.28
`FIG. 5. Conjunctival goblet cell density at baseline and
`In some patients, dry eye is a difficult-to-treat disease that
`month 12. Patients were treated with
`cyciosporine
`0.05% or
`requires long-term anti-inflammatory therapy. The safety
`artificial tears for 12 months. Conjunctival goblet cells were
`profile of a topical anti-inflammatory agent and its suitability
`collected by impression cytology and counted following
`for long-term use is, therefore, a key factor in successful
`staining with modified periodic acid-Schiff Papanicolaou at
`management of dry eye disease. Topical corticosteroids have
`with
`baseline and month
`12. *P <
`
`0.001 compared artificial
`been effective in alleviating the
`signs and symptoms of dry
`tears at month 12.
`eye following short-term use
`weeks).29-30 Prolonged
`(2-4
`ministration of topical corticosteroids is complicated by
`the
`.
`.
`, .
`
`
`based
`events including elevation of intraocular
`the on disease se- associated
`categorization of dry eye patients
`adverSe
`verity and thereby allow longitudinal studies to evaluate the ^ defects
`fieids of vision,
`cat.
`in visual
`
`acuit and
`progression of dry eye disease. This study not only sought to £ract
`formation,
`of ocular infections.**
`increased
`and
`assess the progression of dry eye disease m patients treated Topical
`however, appears
`to
`
`be for
`safe
`Cydosporine
`with artificial tears, but
`also
`evaluated
`
`the cycio­
`impact
`of
`a long-term use.
`Several
`clinical
`studies
`demonstrated
`course
`of
`dry
`eye
`sporine 0.05% therapy in
`modulating
`the
`
`cyciosporine 0.05% was well tolerated for up to 3 years with
`disease.
`
`
`most adverse events being transient in nature and mild to
`Treatment of dry eye patients with cyciosporine 0.05%
`in severity.24-2532
`moderate
`improved Schirmer test scores, TBUT, conjunctival goblet
`The present study had a number of limitations. The
`cell density, ocular surface staining
`scores, and OSDI scores
`sample size was small, as this was a pilot study to assess the
`throughout the study. Treatment with artificial tears was not
`feasibility of the study design.
`
`It should also be noted
`effective in
`improving
`
`the signs and symptoms
`of dry eye
`the differences between the treatment groups reported in
`disease. Similar to these
`findings, several other studies dem­
`this study can be applied only
`to the use of Refresh Endura*
`onstrated that cyciosporine 0.05% significantly increased
`as the artificial tears. Other artificial tears may have variable
`tear production, decreased
`
`of the intensity ocular staining,
`
`efficacies in alleviating the signs and symptoms of dry eye.
`and decreased the severity of symptoms in patients with
`Strategies to treat dry eye disease are evolving as our
`to severe dry eye.24-25 A recent prospective study
`moderate
`understanding of dry eye as a tear volume insufficiency
`indicated that cyciosporine 0.05% therapy significantly im­
`condition is changing to a disease of abnormal tear film
`at
`all
`stages
`of
`dry
`proved signs and
`symptoms
`in
`patients
`composition with proinflammatory characteristics.10-53-34
`eye disease: mild, moderate, and severe.26 Other studies
`The findings of the current study
`
`are the first evidence
`in­
`have shown
`
`that treatment with cyciosporine 0.05% also in­
`dicating that dry
`
`
`can eye be progressive
`in patients
`treated
`creased conjunctival goblet
`cell
`
`density in patients with dry
`with artificial tears alone, whereas topical anti-inflamma­
`eye disease.21-27
`tory therapy with
`cyciosporine
`0.05% may
`
`slow prevent
`Physicians participating in a study to develop treat­
`the disease progression in patients with dry eye at severity
`ment regimens based on the ITF consensus guidelines
`level 2 or 3. Large-scale, controlled studies are warranted to
`for newly diagnosed dry eye patients chose to treat over
`confirm these
`findings.
`level
`2
`40% of patients at severity
`level 1 with the severity
`
`treatments (ie, unpreserved
`
`and tears topical cyciosporine
`
`Acknowledgment
`0.05%).13 Hence, the use of ITF guidelines resulted in greater
`
`
`at focus on treatment of the disease early stages. This shift
`Hadi Moini, PhD, of Pacific Communications provided
`in the patterns of anti-inflammatory therapy use stems
`editorial assistance
`this manuscript.
`for
`from the notion that early interruption of inflammatory
`cycles may be instrumental
`in
`preventing disease progres­
`sion.13 The impact of dry eye in limiting daily activities and
`causing discomfort is known to become clinically more sig­
`nificant as the disease progresses
`from mild to moderate in
`severity.2
`
`S Artificial Tear (n = 22)
`• Cyciosporine 0.05% (n =
`
`36)
`116,8*
`
`95.8
`
`93.6
`
`92.7
`
`of
`
`minimum
`
`ad­
`
`that
`
`or
`
`Author Disclosure Statements
`This study was supported by an unrestricted grant from
`Allergan, Inc., Irvine, CA. The author has no proprietary in­
`terest in any material or method mentioned in this study.
`
`0313
`
`

`

`CYCLOSPORINE AGAINST
`
`
`
`DRY EYE PROGRESSION
`
`163
`
`of
`
`Ophthalmology.
`
`al. Evaluation of
`
`
`eye disease. Arch.
`
`of
`
`References
`20, Schiffman, R.M., Christianson, M.D., Jacobsen, G., et al.
`Reliability and validity of the Ocular Surface Disease Index.
`1. Ishida, R.» Kojima, X, Dogru, M., et al. The application of a new
`Arch. Ophthalmol. 118:615-621,2000.
`continuous functional visual acuity measurement system in
`21. Pflugfelder, S.C., De Paiva, C.S., Villarreal, A.L., et al. Effects of
`dry eye syndromes. Am.
`j. Ophthalmol. 139:253-258,2005.
`sequential artificial
`tear and cyclosporine emulsion therapy on
`2. Mertzanis, P., Abetz, L., Rajagopalan, K., et al. The
`conjunctival goblet cell density
`
`and transforming growth
`fac-
`
`relative burden of dry eye in patients' lives: comparisons to a
`tor-beta2 production. Cornea. 27:64-69,2008.
`U.S. normative sample. Invest. Ophthalmol. Vis. Sci. 46:46-50,
`22. The definition and classification of dry eye disease: report of the
`2005.
`Definition and Classification Subcommittee of the International
`3. Miljanovic, B., Dana, R., Sullivan, D. A., et al. Impact of dry
`eye
`Dry Eye Workshop (2007). Ocul. Surf. 5:75-92,2007.
`syndrome on vision-related quality of life. Am. /. Ophthalmol.
`23. The Gallup Organization,
`Inc. The 2008 Gallup Study of Dry Eye
`143:409-415,2007.
`Sufferers. Princeton, NJ: Multi-Sponsor Surveys, Inc.; 2008.
`4. Lin, P.Y., Tsai, S.Y., Cheng, C.Y., et al. Prevalence of dry eye
`24. Sail, K., Stevenson, O.D., Mundorf, T.K., et al. Two multicenter,
`among an
`
`
`elderly Chinese population in Taiwan: the Shihpai
`randomized studies
`
`of the efficacy and
`
`safety cyclosporine of
`
`Eye Study. Ophthalmology. 110:1096-1101,2003.
`ophthalmic emulsion in moderate to severe dry eye disease.
`5. McCarty, C.A., Bansal, A.K., Livingston, P.M., et al. The epi­
`CsA Phase 3 Study Group. Ophthalmology. 107:631-639,2000.
`Ophthalmology.
`demiology of dry eye in Melbourne, Australia.
`25. Stevenson, D., Tauber, J., and Reis, B.L. Efficacy and safety
`105:1114-1119,1998.
`cyclosporin A ophthalmic
`
`
`in emulsion the treatment of mod­
`6. Schaumberg, D.A., Sullivan, D.A., Buring, J.E., et al. Prevalence
`erate-to-severe dry eye disease: a dose-ranging, randomized
`of dry eye syndrome among US women. Am. j. Ophthalmol
`tried. The Cyclosporin A Phase
`2 Study
`Group.
`136:318-326,2003.
`107:967-974,2000.
`7. Miljanovic, B.M. et al. Association for research in vision and
`26. Perry, H.D., Solomon, R., Donnenfeld, E.D., et
`ophthalmology. Invest. Ophthalmol. Vis.
`48:E-abstract 4293,
`Sci.
`topical cyclosporine
`for
`
`the treatment of dry
`2007.
`Ophthalmol 126:1046-1050,2008.
`8. Methodologies to diagnose and monitor dry eye disease:
`27. Kimert, K.S., Tisdale, A.S., and Gipson, I.K. Goblet cell numbers
`report of the Diagnostic Methodology Subcommittee of the
`and epithelial proliferation
`in
`the
`
`conjunctiva patients with
`International Dry Eye Workshop
`(2007). Ocul. Surf. 5:108-152,
`
`
`Arch. cyclosporine. Ophthalmol.
`dry eye syndrome treated with
`2007.
`120:330-337,2002.
`tear syn­
`9. Behrens, A., Doyle, J.J., Stem, L., et al; Dysfunctional
`28. Wilson, S.E., and Perry, H.D. Long-term resolution of chronic
`drome study group. Dysfunctional tear syndrome: a Delphi
`dry eye symptoms and signs after topical cyclosporine treat­
`approach to treatment recommendations. Cornea. 25:900-907,
`ment. Ophthalmology. 114:76-79,2007.
`2006.
`29. Marsh, P., and Pflugfelder, S.C. Topical nonpreserved methyl-
`
`Am.
`therapy
`eye.
`10. Pflugfelder, S.C. Antiinflammatory
`prednisolone
`therapy
`for keratoconjunctivitis sicca in
`Sjogren
`Ophthalmol. 137:337-342,2004.
`*
`syndrome. Ophthalmology. 106:811-816,1999.
`11. Stem, M.E., Beuerman, R.W., Fox, R.I., et al. The pathology of
`30. Pflugfelder, S.C., Maskin, S.L., Anderson, B., et al. A randomized,
`dry eye: the interaction between the ocular surface and lacrimal
`double-masked, placebo-controlled, multicenter
`comparison
`glands. Cornea. 17:584-589,1998.
`loteprednol etabonate ophthalmic suspension, 0.5%, and pla-
`unifying
`for
`the
`origin
`of
`a
`12. Wilson, S.E. Inflammation:
`cebo for treatment of keratoconjunctivitis
`sicca
`in
`with
`dry eye syndrome. Manag. Care. 12:14-19,2003.
`delayed tear clearance. Am. J. Ophthalmol. 138:444-457,2004.
`of R.D. Agreement physician treat-
`
`
`13. Wilson, S.E., and Stulting,
`31. Lotemax [package insert]. Tampa, FL: Bausch & Lomb, Inc.;
`ment practices with
`the
`international
`task
`force
`guidelines
`for
`2006.
`treatment of dry eye disease. Cornea. 26:284-289,
`diagnosis and
`Phase HI safety
`
`al.
`J., et
`32. Barber, L.D., Pflugfelder, S.C., Tauber,
`2007.
`ev