Am J Ophthalmol 2003 Oct 136(4) 593-602.pdf

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The Comparison of Efficacies of TopicalCorticosteroids and Nonsteroidal Anti-

inflammatory Drops on Dry Eye Patients: A

Clinical and Immunocytochemical Study

AVNI MURAT AVUNDUK, MD, MUSTAFA CIHAT AVUNDUK, MD,

EMILY D. VARNELL, BS, AND HERBERT E. KAUFMAN, MD

●

PURPOSE: To investigate whether conjunctival inflam-mation represents a primary event in the pathogenesis ofkeratoconjunctivitis sicca or whether it is a secondary

inflammatory reaction caused by enhanced mechanicalirritation as a result of surface dryness and whether

anti-inflammatory drops (corticosteroids and nonsteroi-dal anti-inflammatory) have therapeutic effects and are

similar.● DESIGN: Single-masked, randomized, prospective clin-

ical trial.● METHODS: Thirty-two keratoconjuctivitis patients

with or without Sjogren syndrome were included in the

study. The patients were randomized to three groups.Group 1 patients received a topical artificial tear substi-

tute (ATS); group 2 received ATS plus nonsteroidalanti-inflammatory drops (NSAID); and group 3 received

ATS plus topical corticosteroidal drops. The eye symp-tom severity scores, Schirmer test values, rose bengal and

fluorescein staining scores were evaluated before treat-ment and 15 and 30 days after start of treatment.

Impression cytology specimens were stained using immu-nohistochemical methods to detect the percentages of

human leukocyte antigen II (HLA-DR) positive, Apo2.7 positive, and periodic acid–Schiff positive cells. Sta-

tistical analyses were performed within and betweengroups.

●

RESULTS: Group 3 patients had significantly lowersymptom severity scores, fluorescein and rose bengalstaining, and HLA-DR positive cells on days 15 and 30

compared with patients in other groups. They also had asignificantly higher number of periodic acid–Schiff posi-

tive (goblet) cells in their impression cytology specimenson days 15 and 30 compared with the other patients. On

day 30, group 3 patients had significant differencescompared with their baseline measurements in terms of

above-mentioned parameters. However, we did not detecta significant effect of any treatment schedule on the

Shirmer test value and the numbers of Apo 2.7 cells in

impression cytology specimens.● CONCLUSIONS: Topical corticosteroids had a clearly

beneficial effect both on the subjective and objectiveclinical parameters of moderate-to-severe dry eye pa-

tients. These effects were associated with the reductionof inflammation markers of conjunctival epithelial cells.

(Am J Ophthalmol 2003;136:593– 602. © 2003 byElsevier Inc. All rights reserved.)

ALTHOUGH THE IMMUNOPATHOLOGIC ANALYSIS OF

the lacrimal gland has received considerable atten-tion, less work has been done on pathologic

changes occurring in the ocular surface of patients withkeratoconjunctivitis sicca (KCS). However, a strong ex-

pression of human leukocyte antigen II (HLA-DR) anti-gens has been found in conjunctival epithelial cells of dry

eye patients.1 A strong relationship also has been proposedbetween inflammatory pathways and apoptosis, which

directly affects epithelial turnover.2 Overexpression of apoptotic markers was shown in impression cytology spec-

imens from patients with KCS.3,4 The above findingssupport the immunopathogenesis of KCS. However, it is

not clear that this inflammatory reaction represents aprimary phenomenon. Conversely, it may result from

chronic surface dryness and an increased friction between

Accepted for publication March 14, 2003.InternetAdvance publication at ajo.com April 24, 2003.From the Louisiana State University, School of Medicine, LSU Eye

Center, New Orleans, Louisiana (A.M.A., E.D.V., H.E.K.); and SelcukUniversity, School of Medicine, Department of Pathology, Konya,Turkey (M.C.A.).

This study was supported in part by US Public Health Service GrantEY02377 (H.E.K.) from the National Eye Institute, National Institutes of Health, Bethesda, Maryland, and an unrestricted departmental grant fromResearch to Prevent Blindness, Inc., New York, New York.

Inquiries to Avni Murat Avunduk, MD, KTU Lojmanlari No: 31/1761080, Trabzon, Turkey; fax: (90) 462-3252270; e-mail: [email protected]

© 2003 BY ELSEVIER INC. ALL RIGHTS RESERVED.0002-9394/03/$30.00 593doi:10.1016/S0002-9394(03)00326-X



palpebral and bulbar conjunctiva because of tear defi-ciency.

Evidence of inflammatory processes in the pathogenesisof KCS led to the development of cyclosporine A (CsA) as

a first attempt to treat this condition therapeutically. Theproposed mechanisms of CsA are twofold: immunomodu-

lation and anti-inflammation. Immunomodulatory activity

of CsA is achieved by its selective inhibition of the signaltransduction cascade of inflammatory cytokines such asinterleukin 2 and an eventual prevention of the autoim-

mune response.5 The anti-inflammatory effect of CsA isthrough its inhibition of phosphatases.6 Topical CsA

treatment of dry eye patients has been reported to beclinically effective7,8 and to reduce the numbers of acti-

vated lymphocytes and immune-related markers within theconjunctiva.9,10 The ef ficacy of topical CsA in dry eye

patients suggested that other immunosuppressive or anti-inflammatory drops would have a similar or greater bene-

ficial effect in KCS patients.

The aims of this study are twofold: (1) to investigatewhether conjunctival inflammation represents a primaryevent in the pathogenesis of KCS or whether it is a

secondary inflammatory reaction caused by enhanced me-chanical irritation as a result of surface dryness; and (2) to

investigate whether other anti-inflammatory drops (corti-costeroids and nonsteroidal anti-inflammatory) have sim-

ilar therapeutic effects.

METHODS

THE STUDY WAS COMMENCED AS A SINGLE-SITE, PROSPEC-tive, randomized, and single-masked clinical trial. In-

formed consent was obtained from all patients, and theresearch was begun after obtaining approval from the

Institutional Review Board of the Louisiana State Univer-sity Health Sciences Center. The research was carried out

according to the tenets of the Declaration of Helsinki. Allstudy medications were dispensed in coded bottles. The

examiner (A.M.A.) was masked as to the medication usedby the patients. Thirty-two KCS patients with or without

Sjogren syndrome were included in the study. All patientswere at least 21 years of age. Inclusion criteria for patients

included Schirmer test (without anesthesia) of 7 mm in 5minutes or less in at least one eye; mild superficial punctate

keratitis defined as a corneal punctate fluorescein score of 1 in either eye (scale 0 [none]–3 [severe]); and one or

more moderate dry eye related symptom including itching,burning, blurred vision, foreign body sensation, dryness,

photophobia, and soreness or pain.Patients were excluded from the study if they had eye

injury, infection, nondry eye ocular inflammation, trauma,or surgery within the previous 6 months; received concur-

rent treatment that could interfere with the interpretationof the study results (systemic corticosteroids, immunosup-

pressive therapy, and so on); had an uncontrolled disease

or significant illness; or were pregnant or lactating. Post-menopausal patients who were on hormonal replacement

therapy were also excluded. Before initialization of thestudy, the patients were instructed not to use any topical or

systemic medication for at least 1 week.On day 0, Schirmer test, tear breakup time, fluorescein

and rose bengal staining examinations were performed on

both eyes of all patients. The Schirmer test was performedafter corneal staining, because it may affect the stainingpattern of the cornea with either fluorescein or rose bengal.

We used the previously described scoring system for rosebengal and fluorescein staining.11 We also obtained symp-

tom severity scores from patients12 who were instructed tograde their symptoms averaging the symptom severities for

both eyes. The results of the Schirmer test and rose bengaland fluorescein staining scores were evaluated separately

from right and left eyes.Impression cytology specimens were obtained from the

right eyes of all patients on day 0, day 15, and day 30 to

avoid statistical comparison between different eyes indifferent periods. For this purpose, Whatman nitrocellulosefilter paper (cat no: 7195004, Whatman Int. Ltd., Maid-

stone, UK) was used. The paper was cut into strips of approximately 6 15 mm, which were pressed against the

temporal bulbar conjunctiva for 5 seconds and removed.Patients were randomized to three groups according to a

computerized list generated by the LSU Eye Center bio-statistician. Group 1 patients were treated with a preser-

vative-free topical artificial tear substitute (ATS; Refresh,Allergan Inc., Irvine, California, USA) four times a day in

both eyes. Group 1 patients did not receive any medication

besides Refresh. Groups 2 patients were treated withtopical nonsteroidal anti-inflammatory drug (NSAID) eye

drops, flurbiprofen (Ocufen, Allergan Inc. Irvine, Califor-nia, USA) four times a day plus ATS four to eight times a

day in both eyes. Group 3 patients were treated withtopical corticosteroidal drops (TSD) FML (Allergan Inc.,

Irvine, California, USA) four times a day plus ATS four toeight times a day in both eyes. The patients were in-

structed to discuss their medications only with the studycoordinator and not with the examiner.

The impression cytology sample strips were cut intothree pieces: one piece was used for periodic acid–Schiff

(PAS) staining; one was used for HLA-DR (MonoclonalMouse Anti Human HLA-DR, Alpha-Chain Clone TAL

1B5 Code No. M0746 Lot068 DAKO); and the other forApo 2.7 (Monoclonal Antibody Apo 2.7 Cat. No: 2087

Immunotech) staining. The strip samples were placedseparately cell side down on gelatin-coated slides. The

slides, with adherent nitrocellulose strips, were air driedthoroughly at room temperature, placed in 100% metha-

nol, and washed repeatedly with methanol until thenitrocellulose totally dissolved. The slides were then

wrapped in waxed papers and mailed to the laboratory insuitable containers. The immunohistochemistry tech-

niques reported by Bales and Durfeen13 were used.

AMERICAN JOURNAL OF OPHTHALMOLOGY594 OCTOBER 2003



Negative and positive control slides were run with eachsample. The staining pattern of goblet cells of colon

mucous epithelium was used as control to PAS staining.Similarly, the staining pattern of human tonsil specimen

was used as control to HLA-DR and the staining pattern of the basal cell layers of squamous epithelium was used as

control to Apo 2.7 staining. The slides were viewed andphotographed using a Zeiss Photomicroscope III (Zeiss,

Oberkochen, Germany). To standardize data collection,

four fields on each sample were viewed using a 25objective and photographed. Cell counts were carried out

on coded slides to avoid bias. In masked fashion, twoexaminers quantified the pattern of staining photographi-

cally (Figures 1 and 2). Percentages of reactive cells weredetermined by counting at least 200 cells in each speci-

men. Damaged cells were not considered.Statistical analyses were performed using SPSS for

Windows (Version 6.0 and 10.0, SPSS Inc., Chicago,Illinois, USA). The first comparison between and within

groups on different examination days was analyzed using atwo-way analysis of variance (ANOVA) test. Examination

days and groups were chosen as independent variables orfactors, and the other parameters were chosen as depen-

dent variables. Within groups, changes from baseline wereevaluated with a one-way ANOVA test (day was the

independent variable) using the Tukey post-hoc test. Thecomparisons between groups on different examination

points were also analyzed with a one-way ANOVA testusing the Tukey post-hoc test (group was an independent

variable). P .05 was considered significant for all effects.The null hypothesis was that there was no difference

among the treatment groups with regard to changes frombaseline values. The alternate hypothesis was that there

was a change.

Power was calculated to detect an among-group differ-ence in change from baseline in symptom severity scores

on day 30. The power of the study was calculated accord-ing to the given formula.14 For a sample size of 11 patients,

the power to calculate 1 grade difference was 0.64.

RESULTS

A TOTAL OF 32 PATIENTS WERE ENROLLED IN THE STUDY.Four patients were discontinued for administrative reasons.Eight patients in group 1, nine patients in group 2, and 11

patients in group 3 concluded the whole study period. None of the above discontinued patients reported adverse

effects that could be related to the medications used in this

study.Group 1 contained five female and three male patients

(mean age, 51.2 12.4 SD). Five female and four malepatients constituted group 2 (mean age, 46.67 8.66 SD).

Group 3 comprised seven female and four male patients(mean age, 57.6 12.4 SD).

At the beginning of the study (day 0), no significantdifference was detected between groups in terms of any

parameters studied.We did not observe any complication that could be

linked to the study medications during treatment period.Significant differences between groups, days, and mean

effect were observed in terms of symptom severity scores(mean effect, P .01; groups, P .01; days, P .09;

two-way ANOVA). Group 3 patients had significantly lesssymptom severity scores both on days 15 and 30 compared

with groups 1 and 2 patients (P .02 and P .03 for day15 comparisons, and P .03 and P .03 for day 30

comparisons). When comparisons were made between the

FIGURE 1. An impression cytology specimen from a patient

with pretreatment period. The monoclonal antibody (anti hu-

man HLA-DR) stains cell membranes in a granular manner, as

evidenced by this photomicrograph. Arrows indicate the cells

stained positively (bar 25 ).

FIGURE 2. An impression cytology specimen stained with

antihuman Apo 2.7 after treatment with nonsteroidal anti-

inflammatory drops plus artificial tear substitute. Apo 2.7 is a

specific apoptosis marker, and anti-Apo 2.7 antibody stains cell

membranes of reactive cells. Arrows indicate positive cells (bar

25 ).

DRY EYE TREATMENT WITH CORTICOSTEROIDS AND NSAIDVOL. 136, NO. 4 595



treatment days in particular groups, no significant differ-

ence was found in groups 1 and 2 patients. However, asignificantly less symptom severity score was detected on

day 30 compared with day 0 in group 3 patients (P .02).Comparison between days 0 and 15 also gave a significant

result (P .03). Other comparisons within and betweengroups did not differ significantly (Figure 3).

Similarly, when rose bengal staining of right eyes wascompared between groups, significant differences were

obtained in terms of main effect (P .03) and groupcomparison (P .04), but no significant difference was

observed in terms of day comparison (P .07) (two-wayANOVA). Although there was no significant difference

observed between groups on day 15, group 3 patients hadsignificantly lower rose bengal staining scores compared

with group 2 patients on day 30 (P .046), but compar-ison between groups 2 and 3 did not show a significant

difference. In group 3 patients, the mean rose bengalstaining score on day 30 was significantly lower than that

of day 0 (P .01), and the mean score on day 15 was alsolower than that on day 0 (P .02). However, comparison

between days 15 and 30 was not significantly different.

There was a significant difference between days 0 and 15 in

group 2 patients (P .007). However, other comparisonswithin and between groups did not give any significant

difference (Figure 4). Left eye comparisons between groupsgave similar results.

Comparison between groups in terms of fluoresceinstaining patterns of right eyes was significantly different in

terms of groups (P .019), but no significant differencewas observed in terms of days (P .074) or main effect (P .092). Group 3 patients had a significantly lowerfluorescein staining score compared with group 2 patients

on day 30 (P .017). In group 2 patients, the fluoresceinstaining score was significantly lower on day 15 compared

with day 0 (P .017). Similarly, comparisons betweendays 0 to 15 and 0 to 30 gave significant results in group 3

patients (P .018 and 0.016, respectively). Other com-parisons within and between groups did not differ signifi-

cantly (Figure 5). Comparison between left eyes amongfluorescein staining pattern gave similar results.

In impression cytology examinations, comparison be-tween groups in terms of PAS staining gave a significant

result among group comparison (P .003) and main effect

FIGURE 3. Change from baseline in symptom severity scores. *Significantly different from baseline value (all P .000 both for

days 15 and 30; P .003 on day 15 for ATSTSD treated group, and P .002 on day 30 of ATSTSD treated group). ATS

artificial tear substitute; NSAIDs nonsteroidal anti-inflammatory drops; TSD topical corticosteroidal drops.




(P .012), but no significant difference could be observed

between day comparisons. On day 15, group 3 patients hada significantly greater number of PAS cells compared

with both groups 1 and 2 patients (P .034 and P .028,respectively). Similar results were obtained on day 30

comparisons. On day 30, the mean percentage of PAS

cells in group 3 patients was significantly higher than in

both groups 1 and 2 patients (P .000 and P .001,respectively). In group 3 patients, the mean percentage of

PAS cell was significantly higher on day 30 than both ondays 0 and 15 patients (P .01, P .02). Other

comparisons within and between groups were not signifi-cant (Figure 6).

Human leukocyte antigen (HLA) staining comparisonbetween groups also revealed significant differences in terms

of group comparison (P .046), but no significant differencecould be detected in terms of either days or main effect. On

day 15, group 3 patients had significantly lower HLA cells

compared with both groups 1 and 2 patients (P .032 and P

.042, respectively). On day 30, group 3 patients had asignificantly less HLA-DR cells compared with groups 1

and 2 (P .024 and P .033, respectively). In group 3patients, mean HLA-DR cells on day 30 were significantly

lower than that in both groups 1 and 2 on days 0 and 15 ( P

.042 and P .038, respectively). Other comparisons

within and between groups did not reveal any significantdifference (Figure 7).

No significant differences at any examination point (Figure8) were found with Schirmer test values and the percentage

of Apo 2.7 cells in impression cytology specimens.

DISCUSSION

THE MOST IMPORTANT RESULTS OF THIS STUDY WERE

that treatment with TSD significantly improved the ocular

FIGURE 4. Change from baseline in rose bengal staining of right eye. *Significantly different from baseline value (P .007 on day

15 of ATSNSAIDs group; P .02 on day 15 of ATSTSD group; P .01 on day 30 of ATSTSD group). ATS artificial

tear substitute; NSAIDs nonsteroidal anti-inflammatory drops; TSD topical corticosteroidal drops.




signs and symptoms of moderate-to-severe dry eye patients,and these improvements were associated with reduction of

HLA-DR cells and an increase of PAS cells in con-junctival impression cytology specimens. However, ATS

alone or ATS plus NSAID did not change these parame-ters. Keratoconjunctivitis sicca is an autoimmune disease

that involves not only the lacrimal gland but also thewhole ocular surface. Increased conjunctival inflammation

has been reported before in KCS patients.1,15 Brignole andcoworkers found that conjunctival cells from patients with

dry eye with moderate-to-severe KCS, with or withoutSjogren Syndrome, overexpressed inflammatory markers.16

However, whether inflammation is a primary phenomenonin KCS or is the consequence of repetitive abrasion of the

corneal surface after tear film deficiency is not clear. Itcauses chronic inflammation, lymphocytic infiltrates, and

apoptosis of ocular epithelial cells that could hypotheti-

cally result from chronic ocular surface dryness and epi-thelial cell degeneration caused by increased friction

between ocular surfaces.10 Our results presented here aresomewhat contradictory to this hypothesis. This study

provides evidence that conjunctival inflammation plays aprimary role in the pathogenesis of KCS, because treat-

ment with ATS and ATS plus NSAID drops did notchange HLA-DR expression in conjunctival cells, but

treatment with corticosteroids significantly reduced thesemarkers in conjunctival epithelial cells.

Our study provides evidence that TSD treatment im-proved clinical signs and symptoms, but topical ATS plus

NSAID and ATS alone had no effect on these subjectiveand objective clinical parameters. The beneficial effect of

corticosteroidal drops in the treatment of KCS has beenreported before. Marsh and Pflugfelder17 treated 21 severe

KCS patients with Sjogren syndrome with nonpreserved

FIGURE 5. Change from baseline in fluorescein staining of right eye. *Significantly different from baseline value (P .017 on day

15 of ATSNSAIDs group; P .018 on day 15 of ATSTSD group; P .016 on day 30 of ATSTSD group). ATS artificial

tear substitute; NSAIDs nonsteroidal anti-inflammatory drops; TSD topical corticosteroidal drops.




topical methylprednisolone and observed impressive im-

provement in clinical parameters. However, they advo-cated using this treatment as “pulse therapy” because they

observed significant side effects of corticosteroids afterlong-term therapy. We did not observe any TSD-related

complication during the study period, but using corticoste-roids was relatively weak compared with methypred-

nisolone, and the duration of the therapy was short. Thus,it is possible to see corticosteroidal side effects in the

longer therapy with TSD. Sainz de la Maza Serra and hiscoworkers treated 15 severe KCS patients with unpre-

served TSD before punctual occlusion and compared theclinical results with the patients who did not receive any

pretreatment before punctual occlusion.18 They reportedthat 2 weeks of therapy with unpreserved TSD signi ficantly

improved clinical parameters in severe KCS. Treating thepatients with ocular surface inflammation with nonpre-

served methylprednisolone drops was reported to avertdelayed tear clearance.19 In our study, the clinical im-

provement observed after TSD plus ATS treatment wasassociated with reduction of the number of HLA-DR

cells and an increase of goblet cell numbers in the

impression cytology specimens. HLA-DR is a major im-

mune-related marker normally expressed by immunocom-ponent cells, that has been shown to be upregulated in

epithelial cells in cases of autoimmune and inflammatorydisorders, and in KCS, conjunctival cells overexpress this

marker.15 Part of the beneficial effect of TSD on dry eyepatients might be a result of the reduction in HLA-DR

conjunctival cells. The decreasing effect of corticosteroidson HLA-DR expression of human epithelial cells has been

reported before.16 The mechanism of this reduction mayinvolve several possibilities. As HLA-DR expression in

epithelial cells is stimulated by various cytokines, such asinterferon- (I-) and tumor necrosis factor- (TNF-),

which could be synthesized in the ocular surface and byinfiltrating lymphocytes, TSD might downregulate

HLA-DR expression by decreasing these cytokine produc-tions. The reductive effects of corticosteroids on TNF-

and I- are well known.17 Conversely, because corticoste-roids decrease intercellular adhesion molecule-1

(ICAM-1) activation,18,19 TSD may display its beneficialeffect on the ICAM-1 system. ICAM-1 plays an important

role in cell-to-cell interactions and cell migration of

FIGURE 6. Change from baseline in PAS cells. *Significantly different from baseline value (P .01). ATS artificial tear

substitute; NSAID nonsteroidal anti-inflammatory drops; PAS periodic acid–Schiff; TSD topical corticosteroidal drops.




lymphocytes into the surrounding tissues such as theconujunctival epithelium and substantia propria.20 We

failed to find any effect of NSAID on HLA-DR expressionof the conjunctival cells. However, this finding did not

seem to be surprising, especially considering the abovepossible mechanisms of effect, because NSAID have no

effect on cytokine production.21 The decrease of HLA-DR cells in conjunctival epithelial cells of dry eye

patients (Sjogren and non-Sjogren) had been reportedbefore after topical CsA treatment.9,10 Fukagawa and

associates speculated that chronic stimulation from envi-ronmental challenges (contact lens, low humidity, wind,

and so on) on the ocular surface interferes with theneuronal transmission to the lacrimal glands, resulting in

the activation of vigilant traf ficking lymphocytes and sub-sequent production of proinflammatory cytokines, promoting

the autoimmune response.22 Therefore, CsA and TSD ther-apy are rational approaches for treating immune-based in-

flammation in KCS.Another important finding of the current study is an

increase of goblet cell numbers in impression cytology

specimens of dry eye patients after treatment with TSD, asevidenced by a significant increase of PAS cells. Such an

effect was demonstrated previously following treatment of non-Sjogren syndrome patients with CsA ophthalmic

emulsion.23 The authors speculated that reducing inflam-mation with topical CsA treatment might have a prolifer-

ating effect on goblet cells. It is logical to think the samemechanism may be valid for TSD treatment.

An interesting result was obtained in terms of apoptoticcell numbers that were investigated by Apo 2.7 expression

in impression cytology specimens. Topical TSD treatmenthad no effect on the numbers of apoptotic cells. The same

result has been reported before with topical CsA treat-ment.10 The authors speculated that increased apoptosis

after CsA treatment might represent a very early normal-ization of epithelial cell differentiation from a severely

affected state. Although this mechanism may operate forTSD treatment, another explanation is also present. Both

corticosteroids and CsA have an inducing effect on apo-ptosis.24,25 Thus, an expected decrease in apoptosis after

treatment with either CsA or TSD (because of reduction

FIGURE 7. Change from baseline in HLA-DR cells. *Significantly different from baseline value (P .042). ATS artificial

tear substitute; NSAID nonsteroidal anti-inflammatory drops; TSD topical corticosteroidal drops.




of immune-based inflammation in conjunctiva of dry eyepatients) and direct stimulation of apoptosis by the drugs

may negate each other.Commercial TSD and NSAID used in the study (Oc-

ufen and FML) contain mercurial preservatives that couldhave confounded surface inflammation; however, this fac-

tor was unlikely to affect the comparison between twogroups because both drops contain preservatives.

The results of the study implied that TSDs were moreeffective than topical NSAIDs or ATS in reducing the

ocular surface inflammation in KCS patients. Topicalsteroids had a clear beneficial effect both on the subjective

and objective clinical parameters of moderate-to-severedry eye patients. These effects were associated with the

reduction of inflammation markers of conjunctival epithe-lial cells. Based on the data provided, it may be speculated

that conjunctival inflammation is a primary event in thepathogenesis of KCS rather than a secondary finding,

because the decreasing surface friction by ATS did notprovide any beneficial effect. We think that TSD might be

a good alternative to topical CsA therapy in the treatmentof dry eye disease. A comparison of the two drugs would

clarify this hypothesis.

REFERENCES

1. Baudouin C, Brignole F, Becquet F, Pisella PJ, Goguel A.Flow cytometry in impression cytology specimens: a newmethod for evaluation of conjunctival inflammation. InvestOphthalmol Vis Sci 1997;8:1458–1464.

2. Sayama K, Yonehara S, Watanabe Y, Miki Y. Expression of Fas antigen on keratocytes in vivo and induction of apoptosisin cultured keratinocytes. J Dermatol 1994;103:330–334.

3. Brignole F, de Saint-Jean M, Goldschild M, Becquet F,Goguel A, Baudouin C. Expression of Fas-Fas ligand antigensand apoptotic marker APO 2.7 by the human conjunctival

epithelium: positive correlation with class II HLA DRexpression in inflammatory ocular surface disorders. Exp EyeRes 1998;67:679 –687.

4. Boucier T, de Saint-Jean M, Brignole F, Goguel A, BaodouinC. Expression of CD 40 and CD 40 ligand in the humanconjunctival epithelium. Invest Ophthalmol Vis Sci 2000;41:120–126.

5. Ryffel B. Current aspects in organ transplantations. SchweizRundsch Med Prax 1989;78:997–1002.

6. Florio T, Perrino PA, Stock PJ. Cyclic 3.5 adenosine mono-phosphate and cyclosporine A inhibit cellular proliferationand serine/threonine protein phosphatase activity in putu-itary cells. Endocrinology 1996;137:4409–4418.

7. Stevenson D, Tauber J, Reis BL. Ef ficacy and safety of cyclosporine A ophthalmic emulsion in the treatment of

FIGURE 8. Change from baseline in Apo 2.7 cells. Any significant difference is not present in any group. ATS artificial tear

substitute; NSAIDs nonsteroidal anti-inflammatory drops; TSD topical corticosteroidal drops.




moderate-to-severe dry eye disease. Ophthalmology 2000;107:967–974.

8. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multi-center, randomized studies of the ef ficacy and safety of cyclosporine ophthalmic emulsion in moderate to severe dryeye disease. CsA phase 3 study group. Ophthalmology2000;107:631–639.

9. Kunert KS, Tisdale AS, Stern ME, Smith JA, Gipson IK.Analysis of topical cyclosporine treatment of patients withdry eye syndrome: effect on conjunctival lymphocytes. ArchOphthalmol 2000;118:1489–1496.

10. Brignole F, Pisella P-J, de Saint Jean M, Goldschild M,Baudouin C. Flow cytometric analysis of inflammatory mark-ers in KCS: 6-month treatment with topical cyclosporin A.Invest Ophthalmol Vis Sci 2001;42:90–95.

11. Lemp MA. Report of NEI/Industry workshop on clinicaltrials in dry eyes. CLAO J 1995;21:221–232.

12. Oden NL, Lilienfeld DE, Lemp MA, Nelson JD, Ederer F.Sensitivity and specificity of a screening questionnaire for dryeye. Adv Exp Med Biol 1998;438:807–820.

13. Bales CE, Durfeen GR. Cytologic techniques. In: Koos LG,editor. Diagnostic cytology and its histopathologic bases,Vol. 2, 4th ed. Philadelphia: Lippincott, 1992:1–10.

14. Dawson-Saunders B, Trapp RG. Basic and clinical biostatis-tics. Upper Saddle River, New Jersey: Prentice Hall, 1994:119 –120.

15. Baudouin C, Haoutat N, Brignole F, Bayle J, Gastaut P.Imunopathological findings in conjunctival cells using im-munofluoresence staining of impression cytology specimens.Br J Ophthalmol 1992;76:545–549.

16. Brignole F, Pisella PJ, Goldschild M, De Saint Jean M,Goguel A, Baudouin C. Flow cytometric analysis of inflam-matory markers in conjunctival epithelial cells of patients

with dry eyes. Invest Ophthalmol Vis Sci 2000;41:1356–1363.

17. Marsh P, Pflugfelder SC. Topical non-preserved methylpred-nisolone therapy of keratoconjunctivitis sicca in Sjogren’ssyndrome. Ophthalmology 1999;106:811–816.

18. Sainz de la Maza Serra SM, Simon Castellvi C, Kabbani O. Nonpreserved topical steroids and punctual occlusion forsevere keratokonjunctivitis sicca. Arch Soc Esp Ophthalmol

2000;75:751–756.19. Prabhasawat P, Tseng SC. Frequent association of delayedtear clearance in ocular irritation. Br J Ophthalmol 1998;82:666 –675.

20. Tsubota K, Fujihara T, Saito K, Takeuchi T. Conjunctivalepithelium expression of HLA-DR in dry eye patients.Ophthalmologica 1999;213:16–19.

21. Schwiebert LM, Schleimer RP, Radka SF, Ono SJ. Modula-tion of MHC class II expression in human cells by dexameth-asone. Cell Immunol 1995;165:12–19.

22. Fukagawa K, Saito H, Tsubota K, et al. RANTES productionin a conjunctival epithelial cell line. Cornea 1997;16:564–570.

23. Penfold PL, Wen L, Madigan MC, King NJ, Provis JM.

Modulation of permeability and adhesion molecule expres-sion by human choroidal endothelial cells. Invest Ophthal-mol Vis Sci 2002;43:3125–3130.

24. Tsubota K, Inoue H, Ando K, Ono M, Yoshino K, Saito I.Adenovirus-mediated gene transfer to the ocular surfaceepithelium. Exp Eye Res 1998;67:531–538.

25. Wakefield D, McCluskey P, Palladinetti P. Distribution of lymphocytes and cell adhesion molecules in iris biopsyspecimens from patients with uveitis. Arch Ophthalmol1992;110:121–125.


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