JQURNAL OF OCULAR PHARMAGOLGGY AND THERAPEUTECS
`Volume 23. Number 2, 2010
`@ Mary Ann Liehert, inc.
`Dill: ‘i0.‘it)39;'§op.20§i9.009i
`
`Topical Cyciosporine asst/G tor the Prevention oi Dry Eye
`Eisease 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 (lTl-7) guidelines.
`Methods: This was a single-center, investigator-masl<ed, prospective, randomized, longitudinal trial. Dry eye
`patients received twice—daily treatment with either cyclosporine 0.05% (Restasis®; Allergen, Inc, Irvine, CA;
`22 = 36) or artificial tears (Refresh Endura®; Allergan, Inc, Irvine, CA; 21 = 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 -i, 8, and 12.
`Results: Baseline sign and symptom scores and the proportion of patients with the disease severity level 2 or
`3 were comparable in both groups (P > 0.05). At month 12, 34 of 36 cyciesporine patients (94%) and 15 of 22 ar-
`tificial tear patients (68%) experienced improvements or no change in their disease severity (P = 0.00?) 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 Schirrner 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.
`
`introduction
`
`ATIENTS wrrn net are disease suffer from ocular irri-
`
`tation often accompanied by vision impairment, which
`limits important daily activities and negatively impacts
`quality of life (QoL).“-’"’ The prevalence of dry eye disease is
`estimated to be from 5% to >3{i%."~5 The largest US cross-
`sectional survey studies, the Women's Health Study (‘Wt-IS)
`and the Physician Health Study (ens), indicated that the
`prevalence of dry eye disease among women and men aged
`over 50 years is 718% and 4.3%, respectively. Using this prev-
`alence data, ~4.9 million Americans aged over 50 years are
`estimated to be affected by dry eye disease.”
`The diagnosis and treatment of dry eye is challenging.”
`The Wilmer Eye Institute at johns Hopkins University re-
`cently invited the International Task Force (ITF) of 17 dry
`eye experts to create guidelines for the diagnosis and treat-
`ment ot dry eye disease by using a Delphi consensus tech-
`nique.-" The ITF panel categorized dry eye disease severity
`
`into 4 levels (Table 1), with increasing severity from 1 to 4,
`and developed consensus treatment guidelines. The level of
`disease severity was considered the most important factor in
`determining the appropriate range of therapeutic optional’
`While counseling, education, and preserved artificial tears
`were recommended for the management of patients diag-
`nosed at severity level 1, unpreserved artificial tears, topical
`cyclosporine, and/or corticosteroids were recommended for
`patients at severity level 2. Punctal plugs, oral tetracyclines,
`systemic immunornodulators, and surgery were reserved
`for the management of dry eye patients diagnosed at se-
`verity levels 3 and 4.9
`A key recommendation of the ITF panel was the use of
`topical anti.-intlammatory therapy in patients with clini-
`cally apparent ocular surface iriflammation? This recom-
`mendation stemmed from the recent evidence indicating
`that inflammation plays a major role in the disease etiology
`and may be a unifying mechanism that underlies dry eye
`
`"""liié;il;l§§éE§l§£;fEiEEl§£;iiii;l{"""“""
`
`
`
`157'
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`EXHIBIT 1004 (Part 3 of 4)
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`158
`
`RAG
`
`TABLE 1. Ciurarua Uses in Dsrrruunvs THE Lsvars or Dar Err Ssvrmrr Acconomc ro ITF Gmnrcmrsi
`
`Symptoms
`
`Signs
`
`Staining
`
`Level 1 Mild to moderate
`
`Level 2 Moderate to severe
`Level 3
`Severe
`Level 4
`Severe
`
`Mild/moderate conjuznctival
`signs
`Tear film signs, visual signs
`Corneal filamentary keratitls
`Corneal erosions, conjunctival
`scarring
`
`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.
`
`disease.“"” Therefore, it was suggested that the chronic use
`of safe anti-inflammatory therapies that normalize tear film
`composition early in the disease process may have the po-
`tential to slow, prevent, or reverse dry eye progression.”
`Ophthalmic cyclosporine 0.05% emulsion (Restasisfg
`Allergen, Inc, Irvine, CA) is the only anti-inflammatory
`medication approved by the Food and Drug Administration
`to increase tear production in dry eye patients.“ in T lym-
`phocytes, cyclosporine binds to cyclophilin A and inhibits
`calcineurin—catalyzed dephosphorylation of the nuclear
`factor for T-cell activation.‘53‘ Cyclosporine thereby inhibits
`IL-2 transcription, which upon secretion stimulates T-cell di-
`vision by a selhpropagating autocrine and paracrine loop.“
`In humans, topical administration of cyclosporine 0.05% has
`been shown to decrease the number of activated T cells and
`
`expression of inflammatory markers in the conjunctiva of
`dry eye patients."i“‘ These findings suggest that topical cy-
`closporine 0.05% targets the underlying inflammatory pro-
`cesses in dry eye disease. Therefore, chronic treatment with
`cyclosporine 0.05% may offer the potential to alter the course
`of dry eye disease.
`Wilson and Stulting recently evaluated the clinical appli-
`cability of the ITF guidelines.“ Physicians participating in
`that study successfully implemented the ITF guidelines for
`diagnosis and treatment of dry eye patients.“ Using the ITF
`guidelines, this study was designed to assess the prognosis
`of dry eye disease in patients treated with cyclosporine
`0.05% or artificial tears.
`
`Methods
`
`Study design
`
`This was a single-center, investigator-masked, random-
`ized, prospective, longitudinal clinical trial. The study was
`approved by the Western institutional review board in
`Olympia, WA, and was registered with ClinicalTrials.gov
`(identifier # NCT00567983). Inclusion criteria were of age 18
`years or older, diagnosis of dry eye without lid margin dis-
`ease or altered tear distribution and clearance, and a disease
`severity of level 2 or 3 as defined by the ITF guidelines (Table
`1)? Primary exclusion. criteria were prior use of topical cyclo-
`sporine 0.05% within the last year, topical or systemic use of
`anti-inflammatory or anti—allergy medications, active ocular
`infection or inflammatory disease, or uncontrolled systemic
`disease that can exacerbate dry eye disease. Patients who
`wore contact lenses were also excluded from the study. All
`participating patients signed a written consent form before
`initiation of the study—spccific procedures.
`
`Patients were randomly assigned in a 3:2 ratio to twice-
`daily treatment with either cyclosporine 0.05% or artificial
`tears (Refresh Endura®; Allergan, Inc., Irvine, CA) in both
`eyes for 12 months. The randomization ratio was an empir-
`ical estimation due to lack of adequate epidemiological in~
`formation to conduct power calculations prior to initiating
`the study. Randomization was performed by a statistical
`program and was overseen by the research coordinator.
`Patients were enrolled in the study and initiated therapy
`after screening and randomization on the same day at
`the baseline visit (month 0). All patients were allowed to
`utilize rescue artificial tears as needed if discomfort was
`
`experienced. The primary objective of this study was to
`assess the potential of topical cyclosporine 0.05% therapy
`to halt or slow disease progression relative to control at
`month 12 based on the ITF severity categorization (Table
`1). The secondary outcome variables were the changes in
`dry eye signs and symptoms. The study was conducted
`in compliance with regulations of the Health Insurance
`Portability and Accountability Act and the Declaration of
`Helsinki.
`
`Disease severity and dry eye signs
`and symptoms
`
`Disease severity was assessed according to the ITF
`consensus guidelines at baseline and month 12 (Table 1).’
`Patients were evaluated for signs and symptoms of dry eye
`by Schirmer test with anesthesia, tear breakup time (TBUT),
`ocular surface staining, and Ocular Surface Disease Index
`((35331) at baseline (month 0) and after receiving the study
`treatments at months 4, 8, and 12. In each study visit, TBUT
`was evaluated first, followed by ocular surface staining and
`Schirmer test, respectively. The TBUT was measured using
`fluorescein dye. Ocular surface damage was assessed by the
`Oxford method using sodium fluorescein to stain the cornea
`and lissamine green to stain the nasal and temporal bulbar
`conjunctiva.” The scoring scale for ocular staining was 0 to 5
`in cornea, O to 5 in temporal conjunctiva, and 0 to 5 in nasal
`conjunctiva, with 0 representing no staining and 5 repre-
`senting severe staining. These individual scores were then
`summed for the total Oxford score, which ranged from 0 to
`15. The change from baseline was calculated by subtract-
`ing the baseline score from the months 4, 8, and 12 scores.
`The symptoms of ocular irritation and their impact on vi-
`sual functioning was assessed by OSDI, a validated 12-item
`questionnaire, on a scale of 0 to 100 with 0 representing
`asymptomatic and 100 representing severe debilitating dry
`eye disease?“
`
`0348
`
`0348
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`

`
`CVCLOSPORENE AGABNST DRY EYE PROGRESSION
`
`159
`
`Goblet oeii density
`
`The density of goblet cells in hulbar conjunctiva was
`evaluated at baseline and month 12. Impression cytology
`was performed in both eyes after evaluation of TBUT, oc-
`ular staining, and Schirrner test. Goblet cells were collected
`on cellulose acetate filters (HAWP 304 F0; Millipore Corp,
`Billerica, MA). The filters were fixated in glacial acetic acid,
`formaldehyde, and 70% ethanol and subsequently stained
`with a modified periodic acid-—Schif§ Papanicolaou stain.
`Goblet cells were counted in 5 (400 X 400 mm) representa-
`tive microscopic fields on each filter.“
`
`Statistical analyses
`
`Patients who completed 12 months of treatment were
`included in the analyses. The results were presented as
`mean 1 SD. lntergroup 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 hetween—group comparisons
`and Wilcoxon signed rank tests for within—group cornpari~
`sons). A P value < 0.05 was considered a statistically signifi-
`cant difference. Statview software (SAS Institute, Cary, NC)
`was used for all analyses.
`
`Results
`
`Patient disposition and disease characteristics
`
`Of 74 patients enrolled between February 2006 and
`Ianuary 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-
`thirds of dry eye patients in both groups were diagnosed
`at severity level 2, while one—third of patients was diag-
`nosed at severity level 3 (Table 2). There were no significant
`
`between—group differences in the mean age (P = 0.667) or
`distribution of gender (P = 0.800).
`Sixteen patients discontinued the study. The number of
`discontinuations was significantly higher among patients
`treated with artificial tears compared with those treated with
`cyclosporine 0.05% (11 vs. 5; P = 0.028; Table 2). Of 11 discon-
`tinuations in the artificial tear group, 9 patienb discontin—
`ued the study because of discomfort upon instillation, and
`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
`disease severity of level 3. Of the 5 discontinuations in the cy-
`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.
`
`Disease severity
`
`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, thmefore, were
`categorized as progressing to a higher disease severity level
`(7 of 22 [32%} patients vs. 2 of 36 {(5%}, 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 01°22 08%} 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 12,
`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 [94l%] patients vs.
`15 of 22 [68%} patients, respectively; P = 0.007).
`
`Sciiirmer test scores
`
`The mean baseline Schirmer test score was 7.7 i 0.6 mm
`in patients randomized to artificial tears and 7.9 : 1.2 mm
`
`TABLE 2. Prcrrarrrs’ DrsrosmoN AND Drssass Cnasacrsursrrcs
`
`Patients (rt)
`Enrolled in study
`Discontinued study
`Completed study
`Mean age‘ 1: SD, years
`Range
`Gender‘, n (915)
`Female
`
`Dry eye severity at baseline,‘ 1: (%)
`Level 2
`Level 3
`
`Artificial Tear
`
`Cyciosporine 0.05%
`
`33
`11“
`22
`48.2 3 6.3
`39-59
`
`16 (73)
`
`15 (68)
`7 (32)
`
`41
`5”
`36
`47.5 : 5.9‘
`30-5?
`
`25 039)‘
`
`24 (67)
`12 (33)
`
`‘Nine patients discontinued the study because of discomfort upon instillation. Two
`patients were lost to follow—up or moved. P = 0.028 compared to patients who received
`cyclosporine 0.05%.
`"Two patients discontinued the study because of discomfort upon instillation.
`Three patients were lost to follow—up or moved.
`‘For patients who completed 12~rnonth study.
`‘P = 0.667 compared to the mean age of patients who received artificial tears.
`‘P = 0.800 compared to the artificial tear group.
`
`0349
`
`0349
`
`

`
`150
`
`HAG
`
`E3
`
`PercentageofPatients
`
`450
`
`
`MO .T.,,..
`
`§ Artificial Tear in = 22)
`
`a Cyoiosporine 0.05% (n = 30)
`
`39
`
`
`
`worsened
`
`No Change
`
`improved
`
`Change in Dry Eye Severity Levels
`
`FIG. 1. Changes in dry eye severity at month 12 compared with baseline. Patients were treated with cyclosporine 0.05%
`or artificial tears for 12 months. Disease severity was assessed according to the international Task Force (KTF) consensus
`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.
`
`in patients randomized to cyclosporine 0.05% (P = 0.625).
`Patients treated with artificial tears did not have a significant
`change in their Schirmer test scores throughout the study,
`whereas those treated with cyclosporine 0.05% had increas-
`ingly higher mean Schirmer test scores at each follow—up
`visit. The mean Schirmer test scores of patients treated with
`cyclosporine 0.05% were significantly greater than those of
`patients treated with artificial tears at month 8 (9.1 1 1.0 mm
`vs. 7.5 2*: 1.1 mm; P < 0.001) and month 12 (9.8 1 1.0 mm vs.
`7.6 i 1.1; P < 0.001; Fig. 2).
`
`TBUT
`
`The mean baseline TBUT was 5.0 i 0.8 s in patients
`randomized to artificial tears and 4.9 i 0.8 s in patients
`
`randomized to cyclosporine 0.05% (P = 0.550). The mean
`TBUT of patients treated with artificial tears slightly de—
`creased throughout the study, whereas patients treated with
`cyclosporine 0.05% had increasingly longer mean TBUT
`at each follow—up visit (Fig. 3). The mean TBUT of patients
`treated with cyclosporine 0.05% was significantly longer
`than those of patients treated with artificial tears at months
`8 (6.2 i 1.4 s vs. 4.6 i 0.6 s; P = 0.001) and 12 (6.5 : 1.1 s vs.
`4.6 1 0.7 5,‘ P < 0.001).
`
`Ocular surface staining scores
`
`At baseline, patients randomized to cyclosporine 0.05%
`or artificial tears had similar mean Oxford staining scores
`
`_\ -335
`
`..A N?
`
`.4 Q
`
`4
`
`9 Cyolospodne 0.05% (n = 36)
`9 Artificial Tear (n = 22)
`
` MeanTBUT(s)
`
`
`
`*9 Cyciosporine 0.05% (n = 36)
`it Artificial Tear (n = 22)
`
` 0
`
`8
`
`12
`
`4
`
` 0
`
`8
`
`12
`
`4
`
`
`
`MeanSchinnerTestScores(mm)
`
`
`
`
`
`Time (months)
`
`Turns (months)
`
`FIG. 2. Schirmer test scores. Patients were treated with cy~
`ciosporine 0.05% or artificial tears for 12 months. Schirrner I
`test was performed with anesthesia at indicated study vis-
`its. ‘P < 0.001 compared with patients treated with artificial.
`tears.
`
`FIG. 3. TBUT. Patients were treated with cyclosporine
`0.05% or artificial tears for 12 months. Tear breakup time
`Tear breakup time (TBUT). was measured with flnorescein
`dye at indicated study visits. ‘P 5 0.001 compared with
`patients treated with artificial tears.
`
`0350
`
`0350
`
`

`
`CVCLGSPGRINE AGMNST DRY EYE PRGGRESSWN
`
`101
`
`TABLE 3. MEAN QCUZLAR SURFACE Srammo Scones
`
`Art1:ficialtear(n = 22)
`
`Cyclosporine 0.05% (it = 36)
`
`P
`
`Baseline
`Month 4
`Month s
`Month 12
`
`7.86 t 1.13 (NA)
`7.73 : 0.99 (-0.12 I 0.64)
`7.53 4: 1.01 («(3.25 2 0.94)
`7.54 t 0.91 (-0.32 t 0.94)
`
`8.44 t 0.94 (NA)
`8.31 t 0.95 (-0.13 : 0.35)
`7.73 e 0.93 (-0.64 : 0.53)
`7.28 i 1.28 (-1.19 : 1.36)
`
`0.056 (NA)
`0.035 (0.787)
`0.575 (0.087)
`0.223 (0.011)
`
`Patients were treated with cyclosporine 0.05% or artificial tears for 12 months. Ocular surface
`damage was assessed at indicated times by the Oxford method. The mean changes from baseline
`and corresponding P values are indicated in brackets.’ The change from baseline was calculated by
`subtracting the baseline score from the month 4, 3, 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.
`
`(8.4 i 0.9 vs. 7.9 :1: 1.1; P = 0.056; Table 3). At month 4, patients
`treated with cyclosporine 0.05% had significantly higher
`mean staining scores than those treated with artificial tears
`(8.3 t 1.0 vs. 7.7 1 1.0; P < 0.036). There was no between-
`group difference in ocular staining at months 8 and 12.
`(Table 3). Nonetheless, the mean improvement from baseline
`in the ocular staining scores of patients treated with cyclo-
`sporine 0.05% was significantly greater than of those treated
`with artificial tears at month 12 (1.2 1 1.4 vs. 0.3 : 09, 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.
`
`(3301 Scores
`
`Goblet cell density
`
`At baseline, patients randomized to artificial tears or cy-
`closporine 0.05% had similar mean goblet cell density in
`bulbar conjunctiva (95.8 2 12.5 cells and 93.6 2 9.4 cells, re-
`spectively; P = 0.446; Fig. 5). By month 12, goblet cell density
`was significantly higher in patients treated with cyclo-
`sporine 0.05% than those treated with artificial tears (116.8
`2 14.8 cells vs. 92.7 t 11.0 cells; P < 0.001).
`
`Safety
`
`No adverse events attributable to the study medications
`were reported other than discomfort upon instillation dur-
`ing the study.
`
`Discussion
`
`Patients randomized to artificial tears or cyclosporine
`0.05% had similar OSDI scores at baseline (19.1 i 1.9
`and 18.9 2: 2.9, respectively; P = 0.571). The mean OSDl
`scores of patients treated with artificial tears remained
`unchanged throughout the study (Fig. 4). Patients treated
`with cyclosporine 0.05%, however, had increasingly lower
`OSDI scores at each study visit, with the scores at months
`8 and 12 being significantly lower than those of patients
`treated with artificial tears (17.4 4: 3.4 vs. 19.6 t 1.6 at
`month 8; P = 0.011 and 14.9 t 4.2 vs. 19.7 1 2.0 at month
`12,- P < 0.001).
`
`Dry eye is a multifactorial disorder of the tears and the
`ocular surface that results in tear film instability and symp-
`toms of discomfort and visual disturbance.” Traditionally,
`treatment of dry eye has been palliative and largely based
`on over-the-counter artificial eyedrops and lubricating oint-
`II'i€!i‘llIS.73 The vast majority of patients seek new therapies
`after using several over-the-counter products over years.”
`However, it is not known it dry eye severity progresses
`through the course of disease during the years. Recently
`developed ITF guidelines provide a clinical standard for
`
`24
`
`FIG. 4. Ocular Surface Disease Index (05131) scores.
`Patients were treated with cyclosporine 0.05% or artificial
`tears for 12 months. Dry eye signs and symptoms were
`assessed by the self-reported OSDI questionnaire at indi-
`cated study visits.
`‘P < 0.011 and “P < 0.001 compared
`with patients treated with artificial tears at months 8 and
`12, respectively.
`
`20
`
`16 12
`
`19.7
`
`5 Artificial Tear (fl = 22)
`
`4
`
`9 Cyclosporine 0.05% (n = 36)
`
`
`
`
`
`Mean0SDlScores
`
` 0
`
`8
`
`12
`
`4
`
`Time (months)
`
`0351
`
`0351
`
`

`
`102
`
`RAG
`
`In addition to alleviating dry eye signs and symptoms,
`topical cyclosporine 0.05% therapy appears to be capable
`of slowing the rate of disease progression. Reassessment of
`patients at the end of the study period (month 12) indicated
`that a greater number of cyclosporine 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 nature of dry eye disease
`and indicate that dry eye patients may benefit from cyclo-
`sporine 0.05% therapy by achieving disease stabilization or a
`slower rate of progression. A recent retrospective study pro-
`vided evidence that cyclosporine 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 minimum of 1 year
`after completing a 6- to 72-month course of cyclosporine
`0.05% therapy.”
`In some patients, dry eye is a difficult-to-treat disease that
`requires long-term anti-inflammatory therapy. The safety
`profile of a topical anti-inflammatory agent and its suitability
`for long-term use is, therefore, a key factor in successful
`management of dry eye disease. Topical corticosteroids have
`been effective in alleviating the signs and symptoms of dry
`eye following short-term use (2-4 weel<s).7*“-3° Prolonged ad-
`ministration of topical corticosteroids is complicated by the
`associated adverse events including elevation of intraocular
`pressure, defects in visual acuity and fields of vision, cat-
`aract formation, and increased risk of ocular infections.29r5l
`Topical cyclosporine 0.05"/o, however, appears to be safe for
`a long—term use. Several clinical studies demonstrated that
`cyclosporine 0.05% was well tolerated for up to 3 years with
`most adverse events being transient in nature and mild to
`moderate in severity.“«2532
`The present study had a number of limitations. The
`sample size was small, as this was a pilot study to assess the
`feasibility of the study design. It should also be noted that
`the differences between the treatment groups reported in
`this study can be applied only to the use of Refresh Enduram
`as the artificial tears. Other artificial tears may have variable
`efficacies in alleviating the signs and symptoms of dry eye.
`Strategies to treat dry eye disease are evolving as our
`understanding of dry eye as a tear volume insufficiency
`condition is changing to a disease of abnormal tear film
`composition with prointlammatory characteristics.‘°'33"”“
`The findings of the current study are the first evidence in-
`dicating that dry eye can be progressive in patients treated
`with artificial tears alone, whereas topical anti-inflamma-
`tory therapy with cyclosporine 0.05% may slow or prevent
`the disease progression in patients with dry eye at severity
`level 2 or 3. Large-scale, controlled studies are warranted to
`confirm these findings.
`
`Acknowledgment
`
`Hadi Moini, PhD, of Pacific Communications provided
`editorial assistance for this manuscript.
`
`Author Disclosure Statements
`
`This study was supported by an unrestricted grant from
`Allergen, Inc., Irvine, CA. The author has no proprietary in-
`terest in any material or method mentioned in this study
`
`0352
`
`§ Artificial Tear (n = 22)
`E Cyclosporine 0.05% (n = 35)
`
`Mg
`
`953
`
`93.6
`
`92.7
`
`120 ~
`
`CI:
`3
`.9
`§ 100
`O
`<5
`5
`.3
`E
`
`80
`
`so
`
`l
`
`E
`
`l
`
`
`
`40 ~:
`i
`
`
`
`Baseline
`
`d3
`
`:
`in
`
`o§
`
`FIG. 5. Conjunctival goblet cell density at baseline and
`month 12. Patients were treated with cyclosporine 0.05% or
`artificial tears for 12 months. Conjunctival goblet cells were
`collected by impression cytology and counted following
`staining with modified periodic acid—Schiff Papanicolaou at
`baseline and month 12. "’P < 0.001 compared with artificial
`tears at month 12.
`
`categorization of dry eye patients based on the disease se-
`verity and thereby allow longitudinal studies to evaluate the
`progression of dry eye disease. This study not only sought to
`assess the progression of dry eye disease in patients treated
`with artificial tears, but also evaluated the impact of cyclo-
`sporine 0.05% therapy in modulating the course of dry eye
`disease.
`
`Treatment of dry eye patients with cyclosporine 0.05%
`improved Schirmer test scores, TBUT, conjunctival goblet
`cell density, ocular surface staining scores, and 0591 scores
`throughout the study. Treatment with artificial tears was not
`effective in improving the signs and symptoms of dry eye
`disease. Similar to these findings, several other studies dem-
`onstrated that cyclosporine 0.05% significantly increased
`tear production, decreased the intensity of ocular staining,
`and decreased the severity of symptoms in patients with
`moderate to severe dry eye.2435 A recent prospective study
`indicated that cyclosporine 0.05% therapy significantly im-
`proved signs and symptoms in patients at all stages of dry
`eye disease: mild, moderate, and severe.“ Other studies
`have shown that treatment with cyclosporine 0.05% also in-
`creased conjunctival goblet cell density in patients with dry
`eye disease.m7
`Physicians participating in a study to develop treat-
`ment regimens based on the ITF consensus guidelines
`for newly diagnosed dry eye patients chose to treat over
`40% of patients at severity level 1 with the severity level 2
`treatments (ie, unpreserved tears and topical cyclosporine
`0.05%)? Hence, the use of ITF guidelines resulted in greater
`focus on treatment of the disease at early stages. This shift
`in the patterns of anti—inflarnmatory therapy use stems
`from the notion that early interruption of inflammatory
`cycles may be instrumental in preventing disease progres-
`sion.” 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.”
`
`0352
`
`

`
`CYCLOSPORENE AGAENST DRY EYE PRGGRESSEON
`
`163
`
`References
`
`1.
`
`lshida, R., Kojima, T., Dogru, M, et al. The application of a new
`continuous functional visual acuity measurement system in
`dry eye syndromes. Am. I. Ophthalmol. 139:253-258, 2905.
`Mertzanis,
`P., Al:-etz, L, Rajagopalan, K.,
`et
`al. The
`relative burden of dry eye in patients’ lives: comparisons to a
`U3. nonnative sample. Invest. Ophthalmal. Vis. Sci. 46:46-50,
`2005.
`
`Miljanovic, B., Dana, R... Sullivan, D.A., et al. Impact of dry eye
`syndrome on visionwrelated quality of life. Am. I. Ophthaimol.
`143:409-415, 2007.
`Lin, l’.‘r’., Tsai, S.Y., Cheng, C.Y., et al. Prevalence of dry eye
`among an elderly Chinese population in Taiwan: the Shihpai
`Eye Study. Ophthalmology. 11021096-1191, 2003.
`McCarty, C.A., Bansal, A..l(., Livingston, EM, et al. The epi-
`demiology of dry eye in Melbourne, Australia. Ophthalmology.
`105:1114-1119, 1998.
`Schaumberg, D.A., Sullivan, D.A., Boring, ].E., et al. Prevalence
`of dry eye syndrome among US women. Am. I. Ophthalmol.
`136.518-326, 2003.
`Miljanovic, B.M. et al. Association for research in vision and
`ophthalmology. Invest. Ophthalmol. Vis. Sci. 48:E-abstract 4293,
`20017.
`
`Methodologies to diagnose and monitor dry eye disease:
`report of the Diagnostic Methodology Subcommittee of the
`International Dry Eye WorkShop (2007). Qcul. Sw;£ 5:1(l8-l52,
`2007.
`
`Behrens, A., Doyle, }'.}., Stern, 1..., et al.; Dysfunctional tear syn-
`drome study group. Dysfunctional tear syndrome; a Delphi
`approach to treatment recommendations. Cornea. 5:900-902
`2006.
`
`Pflugfelder, S.C. Antiinflamrnatory therapy for dry eye. Am. I.
`Ophfitalmol. 137337-342, 2004.
`Stem, M.E., Beuerman, R.W., Fox, R.l., et al. The pathology of
`dry eye: the interaction between the ocular surface and lacrimal
`glands. Cameo. 172584-589, 1998.
`Wilson, S.E. Inflammation: a unifying theory for the origin of
`dry eye syndrome. Moving Care. 12:14-19, 2003.
`Wilson, S.E., and Stulting, RD. Agreement of physician treat-
`ment practices with the international task force guidelines for
`diagnosis and treatment of dry eye disease. Cornea. 26:284-289,
`2007.
`
`Restasis® [package insert}. Irvine, CA: Allergen, inc; 2004.
`Matsuda, S., and Koyasu, S. Mechanisms of action of
`cyclosporine. lmmunopharmacalogy. 472119-125, 2000.
`Donnenfeld, E., and Pflugfelder, S.C. Topical ophthalmic
`cyclosporine: pharmacology and clinical uses. Sum Ophthalmol.
`54:32l-338, 2009.
`Kunert, i(.S., Tisdale, A.S., Stern, M.E., et al. Analysis of topi-
`cal cyclosporine treatment of patients with dry eye syndrome:
`effect on conjunctival lymphocytes. Arch. Ophthalmol. ‘.l18:1489-
`1496, 2000.
`Turner, K., Ptlugfelder, S.C., Ii, 2., et al. Interleukin-6 levels in
`the conjonctival epithelium of patients with dry eye disease
`treated with cyclosporine ophthalmic emulsion. Cornea. 19:492-
`496, 2000.
`Bron, A.)'., Evans, V.E., and Smith, ].A. Grading of corneal and
`conjunctival staining in the context of other dry eye tests.
`Cornea. 22:646-650, 2003.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`15.
`
`16.
`
`1'7.
`
`18.
`
`19.
`
`20.
`
`21.
`
`24.
`
`26.
`
`27.
`
`(3., et al.
`Iacohsen,
`Schittrnan, RM, Christianson, M.D.,
`Reliability and validity of the Qcular Surface Disease index.
`Arch. Ophilmimol. 1l8:615-621, 2006.
`Pflugfelder, S.C., De Paiva, C.S., Villarreal, AL, et al. Effects of
`sequential artificial tear and cyclosporine emulsion therapy on
`coniunctival goblet cell density and transforming growth fac—
`tor-betaz production. Cornea. 27:64-69, 2008.
`. The definition and classification of dry eye disease: report of the
`Definition and Classification Subcommittee of the International
`Dry Eye Worl<Shop (2007). Carl. Surf. 5:75-92, 2067.
`. The Gallup Organization, lnc. The 2008 Gallup Study of Dry Eye
`Sufferers. Princeton, N]: Multi-Sponsor Surveys, Inc; 2008.
`Sail, K, Stevenson, 0.1)., Mundorf, 'l‘.l<., et al. Two multicenter,
`randomized studies of the efficacy and safety of cyclosporine
`ophthalmic emulsion in moderate to severe dry eye disease.
`CsA Phase 3 Study Group. Ophthalmology. 1072631-639, 2000.
`Stevenson, ll, Tauber, I., and Reis, B.L. Efficacy and safety of
`cyclosporin A ophthalmic emulsion in the treatment of mod—
`erate—to—severe dry eye disease: a dose-ranging, randomized
`trial. The Cyclosporin A Phase 2 Study Group. Ophthalmology.
`107:967-974,. 2000.
`Perry, H.D., Solomon, R., Donnenfeld, E.D., et al. Evaluation of
`topical cyclosporine for the treatment of dry eye disease. Arch.
`Clphthalmol. 126:1()46-1050, 2008.
`Kunert, l(.S., Tisdale, A.S., and Gipson, LK. Goblet cell numbers
`and epithelial proliferation in the conjunctiva of patients with
`dry eye syndrome treated with cyclosporine. Arch. Ophthalmol.
`120:330—337, 2902.
`Wilson, $13., and Perry, l-l.D. Long-term resolution of chronic
`dry eye symptoms and signs after topical cyclosporine treat»
`rnent. Qphthalmology. 114:76-79, 2007.
`Marsh, R, and Pflugfelder, S.C,. Topical nonpreserved methyl-
`prednisolone therapy for lteratoconjunctivitis sicca in Sjogren
`syndrome. Ophthalmology. 1062811-816, 1999.
`Pflugfelder, S.C., Maskin, S.L., Anderson, B., et al. A randomized,
`double-masked, placebo-controlled, multicenter comparison of
`loteprednol etahonate ophthalmic suspension, 0.5%, and pla-
`cebo for treatment of keratocorijrinctivitis sicoa in patients with
`delayed tear clearance. Am. I. Ophthalmoi. l38:444l-4i5'.7, 2004.
`Loternax [package insert}. Tampa, FL: Bausch 6: Lomb, Inc;
`2006.
`
`28.
`
`29.
`
`31.
`
`32.
`
`Barber, L.D., Pflugfelder, S.C., Tauber, L, et al. Phase {II safety
`evaluation of cyclosporine 0.1% ophthalmic emulsion adminis-
`tered twice