Effects of Diquafosol Ophthalmic Solution on Quality of Life in Dry Eye Assessed Using the Dry Eye–Related Quality-Of-Life

CLINICAL SCIENCE

Effects of Diquafosol Ophthalmic Solution on Quality of Life in Dry Eye Assessed Using the Dry Eye–Related Quality-of-Life Score Questionnaire: Effectiveness in Patients While Reading and Using Visual Display Terminals

Tsugiaki Utsunomiya, MD, PhD,* Atsushi Kawahara, MD, PhD,† Kazuomi Hanada, MD, PhD,‡ and Akitoshi Yoshida, MD, PhD*

Conclusions: Purpose: Diquafosol ophthalmic solution was effective in Diquafosol ophthalmic solution improves objective patients with dry eye, especially those with foreign body sensation fi ndings in the ocular surface and subjective symptoms in patients and problems when reading and using visual display terminals. with dry eye. The Dry Eye-Related Quality-of-Life Score (DEQS) questionnaire was developed to assess dry eye symptoms and their Key Words: dry eye, diquafosol sodium, quality of life, question- effects on quality of life. However, because little research using the naire, visual display terminal DEQS has been reported, we evaluated the effects of diquafosol – ophthalmic solution on ocular surface findings and quality of life (Cornea 2017;36:908 914) using the DEQS in patients with dry eye. Methods: Sixty-threepatientswithdryeyewereassignedto ry eye is a chronic disorder characterized by deficient the control group (artificial tears) or diquafosol group. Both Dtear quantity and/or quality, unstable tear film, ocular groups instilled 1 drop of the solution in both eyes 6 times daily surface damage, ocular irritation, dryness, fatigue, and and were evaluated after 2 weeks; the diquafosol group also was fluctuating visual disturbances. The prevalence rates of dry instructed to be examined at 1 and 3 months. We evaluated eye are high in many countries1–3 and have been predicted to the subjective symptoms using the DEQS, fluorescein staining increase further with increased use of visual display terminals score, tear film breakup time (BUT), Schirmer testing, and (VDTs).4–6 Dry eye is a public health problem because the lower tear meniscus height with anterior-segment optical symptoms reduce work productivity7,8 and impair patients’ coherence tomography. quality of life (QOL).9,10 It is important to improve objective findings and subjective symptoms when treating dry eye. Results: In the diquafosol group, the fluorescein staining score, 11 fi The Ocular Surface Disease Index and the Impact of BUT, tear meniscus height, and DEQS scores improved signi - Dry Eye on Everyday Life12 are well-known specific dry eye cantly compared with before treatment in contrast to the control questionnaires. Although the Ocular Surface Disease Index is group. Furthermore, in the diquafosol group, the staining score and fi easy to use, it does not fully cover the effect of dry eye on the BUT improved signi cantly compared with the control group. activities of daily living. Although the Impact of Dry Eye on Analysis of each DEQS item indicated that diquafosol ophthalmic Everyday Life includes questions about the effects on the solution relieved foreign body sensation and problems when QOL, it takes a long time to complete. Recently, the Dry Eye- reading and using visual display terminals compared with the Related Quality-of-Life Score (DEQS), a new Japanese control group. questionnaire on the symptoms attributed to dry eye and their effect on QOL, was developed.13 The DEQS can be used easily in routine clinical practice to evaluate the multifaceted 14 Received for publication December 20, 2016; revision received March 27, effects of dry eye on the activities of daily living. The 2017; accepted March 28, 2017. Published online ahead of print May 23, DEQS questionnaire has good reliability, validity, specificity, 2017. and responsiveness.13 From the *Department of Ophthalmology, Asahikawa Medical University, Although artificial tears, hyaluronic acid, corticosteroid Asahikawa, Japan; †Takayanagi Clinic, Kushiro, Japan; and ‡Department of Medicine and Engineering Combined Research Institute, Asahikawa eye drops, and immunosuppressant eye drops, are used to Medical University, Asahikawa, Japan. treat dry eye, new drugs are being developed. Diquafosol T. Utsunomiya is supported by JSPS KAKENHI Grant number JP16K20295. ophthalmic solutions, which contain diquafosol sodium, The remaining authors have no funding or conflicts of interest to disclose. a P2Y2 receptor agonist, have become available recently as Reprints: Tsugiaki Utsunomiya, MD, Department of Ophthalmology, Asahi- kawa Medical University, 2-1-1 Midorigaoka Higashi, Asahikawa 078- prescription drugs. On the ocular surface, the P2Y2 receptor 8510, Japan (e-mail: [email protected]). is expressed in the cornea, conjunctiva, and meibomian Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. glands15 and is activated by adenosine triphosphate or uridine

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Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cornea Volume 36, Number 8, August 2017 Effects of Diquafosol Ophthalmic Solution triphosphate and promotes fluid secretion from the conjunc- solution (Diquas ophthalmic solution 3%, Santen) (diquafosol tival epithelial cells and mucin secretion from conjunctival group) on the basis of the date of dry eye diagnosis. The goblet cells by the activation.16–18 Through activation of the patients were instructed to instill a drop of ophthalmic P2Y2 receptor, diquafosol ophthalmic solution hydrates the solution in both eyes 6 times daily. Follow-up visits were ocular surface, stabilizes the tear film, and helps relieve dry performed at 2 weeks (both groups) and 1 and 3 months eye. Diquafosol ophthalmic solution effectively improves the (diquafosol group). At each visit, the subjective symptoms objective findings on the ocular surface and subjective using the DEQS, fluorescein staining score, BUT, Schirmer symptoms in patients with dry eye.19–31 Only Shigeyasu testing, and lower tear meniscus height (TMH) with anterior- et al30 reported the effect of diquafosol ophthalmic solution segment optical coherence tomography were evaluated. on QOL using the DEQS, although that study included soft contact lens wearers with dry eye. Using the DEQS, the present study investigated the effects of diquafosol ophthal- Analysis of Subjective Symptoms by the mic solution on the ocular surface and QOL of patients with DEQS Score dry eye. The symptoms and effects of dry eye on the activities of daily life were evaluated using the DEQS questionnaire,13 METHODS which comprises 6 items about bothersome ocular symptoms and 9 items related to the impact on daily living. The DEQS This study adhered to the tenets of the Declaration of questionnaire adopts 2-step scales: first, the frequency of Helsinki. The ethics committee of Sapporo Tokushukai symptoms and disability and, second, their severity. The Hospital approved the study protocol. All subjects provided frequency was scored on a 5-point Likert scale ranging from informed consent after they received a detailed explanation of 0 to 4, with 0 indicating no symptoms and 4 indicating the the study. highest frequency. The severity was scored on a 4-point Likert scale ranging from 1 to 4, with a larger number Subjects indicating greater severity. When the frequency scale score is This study was conducted at the Department of 0, the severity scale score also is 0. We used the severity Ophthalmology in Sapporo Tokushukai Hospital. The Japanese score. The summary score was calculated as follows:

sum of the severity score for all questions answered · 25 summary score ¼ total number of questions answered diagnostic criteria for dry eye, revised in 2006, were used to The summary score ranges from 0 to 100, with a higher establish the diagnosis32 based on the presence of 2 or more score representing greater disability. of the following 3 items: the presence of symptoms associated with dry eye including ocular discomfort such as foreign body sensation, dry sensation, pain, ocular Evaluation of Ocular Surface and fatigue, and so on; a Schirmer test (without anesthesia) resultof5mmorlessoratearfilm breakup time (BUT) of 5 Tear Function fl seconds or less; and a fluorescein staining score 3 or more The uorescein staining test with a blue-free barrier fi points (of 9 points). The exclusion criteria were previous lter was used to evaluate corneal and conjunctival epithelial ocular trauma and active ocular disease other than dry eye. For patients diagnosed with dry eye from June 2013 to January 2014, 3% diquafosol ophthalmic solution was TABLE 1. Baseline Patient Characteristics prescribed. For patients diagnosed from February 2014 to Control Diquafosol P at April 2014, preservative-free artificial tears were pre- Parameter Group Group Baseline scribed. The patients were instructed to instill a drop in Case, n 24 39 both eyes 6 times daily and to return after 2 weeks. Sixty- Age, yr 52.1 6 15.4 58.8 6 14.6 0.087 three patients who returned after 2 weeks were enrolled. Sex (male:female) 3:21 15:24 0.043 This study included 39 patients who received 3% diquafosol Fluorescein score 2.27 6 1.38 2.28 6 2.05 0.973 ophthalmic solution and 24 patients who received (point) preservative-free artificial tears. BUT, s 3.04 6 2.04 2.45 6 1.86 0.096 Schirmer value, mm 16.6 6 11.8 14.7 6 9.8 0.372 Protocol Schirmer value 6:18 9:30 0.862 (#5:.5) The patients were assigned to either preservative-free 6 6 artificial tear (Soft Santear ophthalmic solution; Santen, TMH, mm 0.22 0.07 0.24 0.09 0.135 DEQS (point) 29.8 6 21.4 30.9 6 15.1 0.581 Osaka, Japan) (control group) or 3% diquafosol ophthalmic

Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Utsunomiya et al Cornea Volume 36, Number 8, August 2017 damage.33 Staining was semiquantitatively recorded as 0 to vertically across the central cornea.35 The TMH was measured 3 in the nasal and temporal bulbar conjunctiva and the by the caliper tools built into the CASIA instrument. cornea, and the sum of the scores (9 points maximally) was used as the representative value.34 The Schirmer test was performed using standardized filter paper strips (Alcon, Fort Statistical Analysis Worth, TX) placed in the lateral canthus without topical Data are expressed as mean 6 SD. Statistical analysis anesthesia, away from the cornea, for 5 minutes with the was performed using GraphPad Prism version 6.0 for Mac eyes closed. Readings were recorded in millimeters as the (GraphPad Software, San Diego, CA). The Mann–Whitney length of the wet paper. test (fluorescein staining score and DEQS) and the unpaired t test (BUT, Schirmer test, and TMH) were used to compare the variables between the diquafosol and the artificial tear Measurement of Tear Meniscus groups. Variables within subgroups were compared using To obtain noninvasive and objective measurements of the the Wilcoxon rank-sum test (fluorescein staining score and tear film meniscus dimensions, the commercial swept-source DEQS) and the paired t test (BUT, Schirmer test, and TMH) Anterior segment optical coherence tomography (CASIA; with the Bonferroni correction. The adjusted P values are Tomey Corp, Nagoya, Japan) was used. Before Schirmer shownintablesandfigures. P , 0.05 was considered testing, the images of the lower tear meniscus were taken statistically significant.

FIGURE 1. Ocular surface findings and DEQS score. A–C, In the diquafosol group, the staining score, BUT, and TMH improved significantly from baseline. D, The Schirmer test score did not improve significantly from baseline. E, In the diquafosol group, the DEQS score improved significantly from 30.9 6 15.1 points to 21.6 6 17.5 points after 2 weeks, to 15.9 6 12.4 points after 1 month, and to 16.0 6 12.5 points after 3 months. In the control group, the DEQS score improved from 29.8 6 21.4 points to 24.9 6 20.3 points after 2 weeks, but the difference did not reach statistical significance. Although the DEQS score in the diquafosol group improved more than in the control group, the difference was not significant.

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RESULTS Analysis of DEQS Items We analyzed each DEQS item 2 weeks after pre- Subjects scription (Table 2). The scores of 4 of 6 symptoms (Table 2), The baseline characteristics of the subjects are shown in fi foreign body sensation, dry eye sensation, painful/sore eyes, Table 1. No signi cant differences in age, DEQS scores, or and ocular fatigue, improved significantly in the diquafosol the ocular surface findings were seen between the diquafosol fi fi group; only the ocular fatigue score improved signi cantly in and control groups. The control group had signi cantly (P = the control group. The scores for heavy sensation in the 0.043) more women than the diquafosol group. Two subjects eyelids and redness in the eyes did not improve significantly in the diquafosol group discontinued using the solution in either group. The score for foreign body sensation because of discomfort from ocular discharge 1 month after improved significantly in the diquafosol group more than in prescription. Eleven subjects in the diquafosol group did not the control group. There was no significant difference return for the scheduled 3-month evaluation after prescription. between the groups in the other 5 symptoms. No severe adverse events developed in this study. All subjects Regarding the 9 factors studied for their impact on daily responded to the DEQS questionnaire easily over a few- living (Table 3), diquafosol ophthalmic solution significantly minutes while awaiting examination. improved the scores of 4: difficulty opening eyes, blurred vision when watching something, problems with eyes when watching television or looking at a computer or cell phone, Changes Within Subgroups: Objective Ocular and feeling depressed because of eye symptoms, whereas Surface Findings preservative-free artificial tears significantly improved the fi The diquafosol group had signi cant improvement in score for feeling depressed because of ocular symptoms. the corneal and conjunctival staining score, BUT, and TMH but not the Schirmer test score. The staining score improved significantly from 2.3 6 2.1 points to 1.6 6 1.7 points after 2 TABLE 2. Analysis of Each Item in DEQS (Ocular Symptoms) weeks, to 1.7 6 1.8 points after 1 month, and to 1.7 6 1.9 fi Bothersome P points after 3 months (Fig. 1). The BUT improved signi - Ocular Control Diquafosol P (Comparison cantly from 2.4 6 1.9 seconds to 3.4 6 1.8 seconds after 2 Symptoms Group Group (at Time) of D) weeks, to 3.3 6 1.9 seconds after 1 month, and to 3.3 6 1.8 Foreign body seconds after 3 months (Fig. 1). The TMH increased sensation fi 6 6 signi cantly from 0.24 0.09 mm to 0.28 0.10 mm after 0 wk 1.17 6 1.27 1.74 6 1.33 0.099 6 2 weeks and to 0.28 0.09 mm after 1 month. Although the 2 wk 1.50 6 1.22 1.28 6 1.23 0.547 0.012 6 TMH increased to 0.27 0.10 mm after 3 months, the P (compared 0.172 0.034 increase did not reach statistical significance (Fig. 1). The with 0 wk) Schirmer test score did not improve significantly from 14.9 6 Dry sensation 9.8 mm at baseline to 14.0 6 8.6 mm after 2 weeks, to 15.4 6 in the eyes 9.2 mm after 1 month, and to 17.5 6 10.0 mm after 3 months 0 wk 1.58 6 1.41 1.90 6 1.17 0.298 (Fig. 1). There was no significant improvement in any 2 wk 1.33 6 1.31 1.18 6 1.23 0.664 0.134 measurement in the control group (Fig. 1). P (compared 0.292 0.002 with 0 wk) Painful or Changes Within Subgroups: Dry Eye sore eyes 6 6 Symptoms and Effects on Daily Living 0 wk 1.43 1.41 1.67 1.55 0.595 2 wk 1.00 6 1.22 0.97 6 1.14 0.999 0.526 In the diquafosol group, the DEQS score improved fi 6 6 P (compared 0.085 0.015 signi cantly from 30.9 15.1 points to 21.6 17.5 points with 0 wk) 6 after 2 weeks, to 15.9 12.4 points after 1 month, and to Ocular fatigue 6 16.0 12.5 points after 3 months (Fig. 1). In the control 0 wk 2.42 6 1.18 2.21 6 1.26 0.575 6 group, the DEQS score improved from 29.8 21.4 points to 2 wk 1.71 6 1.20 1.45 6 1.27 0.405 0.618 6 24.9 20.3 points after 2 weeks, a change that did not reach P (compared 0.008 ,0.0001 statistical significance (Fig. 1). with 0 wk) Heavy sensation in eyelids Comparison of the Diquafosol and 0 wk 1.38 6 1.58 0.85 6 1.09 0.22 Control Groups 2 wk 1.13 6 1.30 0.80 6 1.15 0.223 0.895 The diquafosol group had a significant improvement in P (compared 0.380 0.824 the corneal and conjunctival staining score and BUT but not with 0 wk) in the DEQS score, TMH, or Schirmer test score compared Redness in eyes with the control group (Fig. 1). Although the DEQS score and 0 wk 1.08 6 1.18 1.31 6 1.26 0.508 TMH in the diquafosol group improved more than those in 2 wk 0.67 6 1.05 1.11 6 1.23 0.141 0.759 the control group, the differences did not reach P (compared 0.063 0.281 statistical significance. with 0 wk)

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TABLE 3. Analysis of Each Item in DEQS (Impact on Daily Life) Impact on Daily Life Control Group Diquafosol Group P (at Baseline) P (Comparison of D) Difﬁculty opening eyes 0 wk 0.83 6 1.34 1.05 6 1.17 0.294 2 wk 0.83 6 1.09 0.67 6 1.03 0.541 0.088 P (compared with 0 wk) 0.999 0.015 Blurred vision when watching something 0 wk 1.46 6 1.38 1.37 6 1.13 0.983 2 wk 1.08 6 1.38 0.95 6 0.97 0.997 0.834 P (compared with 0 wk) 0.066 0.005 Sensitivity to bright light 0 wk 1.29 6 1.30 1.00 6 0.89 0.534 2 wk 1.04 6 1.37 0.87 6 0.98 0.999 0.48 P (compared with 0 wk) 0.315 0.459 Problems with eyes when reading 0 wk 0.96 6 1.43 1.54 6 1.17 0.026 2 wk 1.13 6 1.30 1.21 6 1.24 0.799 0.04 P (compared with 0 wk) 0.481 0.075 Problems with eyes when watching television or looking at a computer or cell phone 0 wk 1.25 6 1.42 1.59 6 1.25 0.226 2 wk 1.38 6 1.25 1.05 6 1.15 0.312 0.021 P (compared with 0 wk) 0.615 0.017 Feeling distracted because of eye symptoms 0 wk 0.96 6 1.20 1.08 6 1.23 0.676 2 wk 0.88 6 1.04 0.80 6 1.15 0.585 0.482 P (compared with 0 wk) 0.828 0.072 Eye symptoms affect work 0 wk 0.83 6 1.31 0.74 6 1.14 0.974 2 wk 0.54 6 1.14 0.54 6 1.07 0.944 0.998 P (compared with 0 wk) 0.266 0.296 Not feeling like going out because of eye symptoms 0 wk 0.25 6 0.74 0.08 6 0.35 0.254 2 wk 0.21 6 0.66 0.10 6 0.45 0.318 0.999 P (compared with 0 wk) 0.999 0.999 Feeling depressed because of eye symptoms 0 wk 1.00 6 1.47 0.71 6 1.11 0.659 2 wk 0.54 6 0.98 0.33 6 0.70 0.426 0.981 P (compared with 0 wk) 0.039 0.022

Neither treatment significantly improved the scores of the artificial tears did. Although the diquafosol ophthalmic other 5 items in the impact on daily living category. The solution improved the DEQS score and TMH more than the scores for problems with eyes when reading and when preservative-free artificial tears did, the differences did not watching television or looking at a computer or cell phone reach statistical significance. Analysis of each DEQS item improved significantly more in the diquafosol group than in showed for the first time that diquafosol ophthalmic solution the control group, although the former at baseline differed was especially effective for relieving foreign body sensation significantly between the groups. There was no significant and problems when reading and using a VDT. difference between the diquafosol and control groups in the The diquafosol ophthalmic solution hydrates the ocular other 7 items on the impact on daily living. surface, stabilizes tear film, and benefits treatment of dry eye through activation of the P2Y2 receptor.16–18 Diquafosol ophthalmic solution was reported to improve the BUT and DISCUSSION ocular staining in patients with aqueous-deficient dry eye19–23 We found that the diquafosol ophthalmic solution and to improve the BUT in patients with short tear film BUT- significantly improved the fluorescein staining score, BUT, type of dry eye.26–28 In addition, the 3% diquafosol TMH, and DEQS scores in patients with dry eye. The ophthalmic solution increased the tear fluid on the ocular diquafosol ophthalmic solution significantly improved the surface for up to 30 minutes in normal human eyes,36 whereas staining score and BUT more than the preservative-free the increased tear fluid resulting from instillation of artificial

Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cornea Volume 36, Number 8, August 2017 Effects of Diquafosol Ophthalmic Solution tears returned to baseline 5 minutes after instillation.37 The BAK-free. The improved diquafosol solution might be more diquafosol ophthalmic solution also improved the TMH in effective than this study demonstrated. patients with aqueous-deficient dry eye.22 Therefore, the In summary, the diquafosol ophthalmic solution current findings that diquafosol ophthalmic solution improved improved the subjective symptoms and objective findings the staining score, BUT, and TMH in patients with dry eye such as the fluorescein staining score, BUT, and TMH in agree with previous studies.19–28 patients with dry eye. The DEQS was helpful for assessing The DEQS could be used easily in routine clinical the severity of symptoms attributed to dry eye and their practice to evaluate the multifaceted effects of dry eye on the effects on QOL of patients with dry eye. The diquafosol activities of daily living. The DEQS was helpful for assessing ophthalmic solution especially improved the foreign body the severity of symptoms attributed to dry eye and their sensation and problems when reading and using a VDT and effects on QOL of patients with dry eye. The improved DEQS might be effective in this subgroup of patients. score after instillation of diquafosol ophthalmic solution might be reflected by the improvements in the ocular surface REFERENCES and agreed with previous studies that reported improved 1. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye subjective symptoms. We analyzed the score of each DEQS syndrome. 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Moreover, since December 2015 (after the time of a Japanese phase 2 clinical trial. Ophthalmology. 2012;119:1954– this study), the diquafosol ophthalmic solution has been 1960.

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