`Volume 26. Number 2, 2616
`@ Mary Ann Lichen, inc.
`Dill; tOJOSQIEopEOQEOGQi
`
`Topical Cyclosperine Caddie tor the Prevention of thry Eye
`Eiseese 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 (lTll) 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% (RestasisQ; Allergen, inc, Irvine, CA;
`a = 36) or artificial tears (Refresh Eudora”; Allergan, Inc, Irvine, CA; 71 = 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.
`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 cyclosporine 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 cyciosporine patients (6%) and 7 of 22 artificial tears patients (32%) had disease progression (P < 0.01).
`Cyclosporine (3.05% 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
`
`“EMS WW“ DRY EYE disease 511559? from Willa! m"
`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{l%."~5 The largest US cross-
`sectional survey studies, the Women’s Health Study (Wt-IS)
`and the Physician Health Study (Pl-18), indicated that the
`prevalence of dry eye disease among women and men aged
`over 50 years is 7.8% and 4.3%, respectively. Using this prev-
`alence data, ~49 million Americans aged over 50 years are
`estimated to be affected by dry eye disease.‘t7
`The diagnosis and treatment of dry eye is challtu‘tging.8
`The Wilmer Eye Institute at johns Hopkins University re—
`cently invited the International Task Force (lTF) of 17 dry
`eye experts to create guidelines for the diagnosis and treat~
`merit of dry eye disease by using a Delphi consensus tech—
`nique.9 The ITF panel categorized dry eye disease severity
`
`into 4 levels (Table I), 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 optimist.9
`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 immunomodulators, 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 l'l‘F panel was the use of
`topical antininflammatory therapy in patients with clini—
`cally apparent ocular surface inflarriuuition.9 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
`
`I “lakeside Eye Group, Chicago,
`
`
`
`157
`
`TEVA - EXHIBIT 1004 (PART 3 OF 4)
`
`0347
`
`TEVA - EXHIBIT 1004 (PART 3 OF 4)
`
`
`
`158
`
`RAG
`
`TABLE 1. CRITERIA Usro ro Dmnuma ins Levers or Day Err Smarrr Acconomc ro ITF Gmorrrurs"
`
`Symptoms
`
`Signs
`
`Staining
`
`Level 1 Mild to moderate
`
`Level 2 Moderate to severe
`Level 3
`Severe
`Level 4
`Severe
`
`Mild/moderate conjunctival
`signs
`Tear film signs, visual signs
`Corneal filamentary keratitis
`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.
`
`diseased”2 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.13
`Ophthalmic cyclosporine 0.05% emulsion (RestasisQ;
`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.14 In T lym-
`phocytes, cyclosporine binds to cyclophilin A and inhibits
`calcineurin—catalyzed dephosphorylation of the nuclear
`factor for T—cell activationm“ Cyclosporine thereby inhibits
`lL-Z transcription, which upon secretion stimulates T-cell di-
`vision by a self~propagating autocrine and paracrine loop}6
`In humans, topical administration of cyclosporine (3.05% has
`been shown to decrease the number of activated T cells and
`
`expression of inflammatory markers in the conjunctiva of
`dry eye patients.1218 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 FTP guidelines.13 Physicians participating in
`that study successfully implemented the ITF guidelines for
`diagnosis and treatment of dry eye patients.13 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 it 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
`l).9 Primary exclusion criteria were prior use of topical cyclo—
`sporine 0.05% within the last year, topical or systemic use of
`anti-mflammatory or antiwallergy 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 0.65% therapy
`to halt or slow disease progression relative to control at
`month 12 based on the ITF severity categorization (Table
`l). 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 HF
`consensus guidelines at baseline and month 12 (Table l).9
`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
`(OSDI) at baseline (month 0) and after receiving the study
`treatments at months 4, S, 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, 0 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 05131, a validated iZ—item
`questionnaire, on a scale of 0 to 100 with 0 representing
`asymptomatic and 100 representing severe debilitating dry
`eye disease?“
`
`0348
`
`0348
`
`
`
`CVCLGSPORlNE AGABNST DRY EYE PEGGRESSION
`
`159
`
`Goblet oeii density
`
`The density of goblet cells in hulhar 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—Schiff Papanicolaou stain.
`Goblet cells were counted in 5 (400 X 400 mm) representa—
`tive microscopic fields on each filter.21
`
`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 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, 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 patients discontin~
`need 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, 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 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 [94%] patients vs.
`15 of 22 {68%} patients, respectively; P = 0.007).
`
`Schirmer test scores
`
`The mean baseline Schirmer test score was 7.7 i 0.6 mm
`in patients randomized to artificial tears and 7.9 t 1.2 mm
`
`TABLE 2. Parrams’ Drsrosmorv AND DISEASE CHARACTERISTICS
`
`Patients (n)
`Enrolled in study
`Discontinued study
`Completed study
`Mean agec 1‘. SD, years
`Range
`Gender“, in (‘34:)
`Female
`
`Dry eye severity at baseline,c n (%)
`Level 2
`level 3
`
`Artificial Tear
`
`Cyclosporine 0.05%
`
`33
`11“
`22
`48.2 i 6.3
`39—59
`
`16 (73)
`
`15(68)
`7 (32)
`
`41
`5b
`36
`47.5 i 5.9“
`30—57
`
`25 ((39)e
`
`24 (67)
`12 (33)
`
`INine 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%.
`Vl'wo patients discontinued the study because of discomfort upon instillation.
`Three patients were lost to follow—up or moved.
`cFor patients who completed 12~month study.
`“P = 0.667 compared to the mean age of patients who received artificial tears.
`el" = 0.800 compared to the artificial tear group.
`
`0349
`
`0349
`
`
`
`150
`
`HA9
`
`PercentageofPatients
`
`1’3‘3 .".1
`
`
`MO«4.14....».L««...«««.«fi«1.4.«1"...my..." “fen..
`
`fi Artificial Tear (n = 22)
`
`E Cyoiosponne 0.05% (n e 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 (HF) 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 Schiriner 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 i 1.0 mm
`vs. 7.5 2*: 1.1 mm; P < 0.001) and month 12 (9.8 i 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 1' 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 t 1.1 5 vs.
`4.6 i 0.7 S; P < 0.001).
`
`Ocular surface staining scores
`
`At baseline, patients randomized to cyclosporine 0.05%
`or artificial tears had similar mean Oxford staining scores
`
`-—L as
`
`.A N
`
`.A O
`
`4
`
`a Cyclosporine 0.05% (n = as;
`0 Artificial Tear (n = 22)
`
` MeanTBUT(s)
`
`
`
`it Cyclosporine 0.05% (n = 36)
`it Artificial Tear (n = 22)
`
` 0
`
`8
`
`12
`
`4
`
` 0
`
`8
`
`12
`
`4
`
`
`
`MeanSohinnerTestScores(mm)
`
`
`
`
`
`Time (months)
`
`Turns (months)
`
`FIG. 2. Schinner test scores. Patients were treated with cyv
`closporine 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. TBUI‘. Patients were treated with cyclosporine
`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 1: 0.001 compared with
`patients treated with artificial tears.
`
`0350
`
`0350
`
`
`
`CVCLGSPGRINE AGAlNST BRY EYE PEGGRESSiON
`
`151
`
`TABLE 3. MEAN (ileum Sunsnce Srammo Scones
`
`Artificial tear (n = 22)
`
`Cyclosporine 0.05% (n == 36)
`
`P
`
`Baseline
`Month 4
`Month 8
`Month 12
`
`7.86 t 1.13 (NA)
`7.73 t 0.99 (-0.12 i 0.64)
`7.53 i 1.01 (43.25 t 0.94)
`7.54 t 0.91 (“0.32 i 0.94)
`
`8.44 i 0.94 (NA)
`8.31 I 0.95 (—0.13 t 0.35)
`7.78 t 0.93 (“0.64 t 0.63)
`7.28 i 1.28 ("1.19 i 1.36)
`
`0.056 (NA)
`0.035 (0.787)
`0.5760108?)
`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.9 The change from baseline was calculated by
`subtracting the baseline score from the month 4, 8. or 12 scores.
`NA = not applicable.
`atThe 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. 29 :t 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 t 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 :t 1.4 vs. 0.3 i 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.
`
`0310! 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 t 12.5 cells and 93.6 i 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
`1 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 3: 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 i 3.4 vs. 19.6 1- 1.6 at
`month 8; P = 0.011 and 14.9 i 4.2 vs. 19.7 i 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 ot discomfort and visual disturbance.22 Traditionally,
`treatment of dry eye has been palliative and largely based
`on over—the-counter artificial eyedrops and lubricating oint-
`ments.” The vast majority of patients seek new therapies
`after using several oventhe—counter products over years?3
`However, it is not known it dry eye severity progresses
`through the course of disease during the years. Recently
`developed l'l'F guidelines provide a clinical standard for
`
`24
`
`FIG. 4. Ocular Surface Disease Index (03131) 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 03131 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
`
`9 Artificial Tear (n = 22)
`
`4
`
`9 Cyclosporine 0.05% (n = 38)
`
`
`
`
`
`Mean0801Scores
`
` 0
`
`8
`
`12
`
`4
`
`Time (months)
`
`0351
`
`0351
`
`
`
`102
`
`RAG
`
`§ Artificial Tear (n = 22)
`E Cyclosporine 0.05% (n = 36)
`
`140
`
`120 »
`
`ll:
`g
`§ 100
`
`nO
`
`<5
`5
`.3
`E
`3
`E
`an
`
`o§
`
`95's
`
`93.6
`
`92.7
`
`l
`
`l
`
`
`
`80
`
`so
`
`l
`i
`40 i
`i
`
`
`
`Baseline
`
`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—Scth 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 0391 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 eyed“:25 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.26 Other studies
`have shown that treatment with cyclosporine 0.05% also in—
`creased conjunctival goblet cell density in patients with dry
`eye diseasezw’
`Physicians participating in a study to develop treat—
`ment regimens based on the l'TF 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 (is, unpreserved tears and topical cyclosporine
`0.05%);13 Hence, the use of l'l‘F guidelines resulted in greater
`focus on treatment of the disease at early stages. This shift
`in the patterns of anti—inflammatory therapy use stems
`from the notion that early interruption of inflammatory
`cycles may be instrumental in preventing disease progres-
`sion.’3 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
`
`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.23
`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—41 weeks).7330 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”:51
`Topical cyclosporine 0.05%, 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 seveirityfi‘md2
`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 proinflammatory characteristicsmw
`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 flisolosure Statements
`
`This study was supported by an unrestricted grant from
`Allergen, Inc, lrvine, CA. The author has no proprietary in~
`terest in any material or method mentioned in this study
`
`0352
`
`0352
`
`
`
`CYCLOSPGRlNE AGAlNST DRY EYE PROGRESSBON
`
`163
`
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