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The efficacy and safety of topical diquafosol ophthalmic solution for
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the treatment of dry eye: A systematic review of randomized clinical
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trials
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Di Wu1,4, PhD, Wang Qi Chen2, Ryan Li3, Yan Wang4, MD, PhD
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Tianjin Medical University. 22 Qixiangtai Rd, Heping, Tianjin, China, 300070
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University of California, Berkeley, College of Chemistry. 419 Latimer Hall, Berkeley, CA
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94720
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University of Toronto, Faculty of Arts and Science. Sidney Smith Hall, 100 St. George Street
Toronto, Ontario, Canada M5S 3G3
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Tianjin Eye Hospital & Eye Institute, Tianjin Key Lab of Ophthalmology and Visual Science,
Tianjin Medical University. No 4. Gansu Rd, Heping District, Tianjin, China, 300020
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Corresponding author: Yan Wang, MD, PhD. Tianjin Eye Hospital & Eye Institute, Tianjin Key
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Lab of Ophthalmology and Visual Science, Tianjin Medical University. No 4. Gansu Rd, Heping
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District, Tianjin, China, 300020 Tel: 86-22-27305083. Email: wangyan7143@vip.sina.com
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None of the authors has a financial interest related to this study.
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Keywords: diquafosol, dry eye, keratoconjunctivitis sicca, randomized clinical trials, systematic
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review
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Purpose: To evaluate the efficacy and safety of topical diquafosol ophthalmic solution treatment
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for dry eye.
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Methods: Randomized clinical trials (RCTs) from MEDLINE, EMBASE and Cochrane Central
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Register of Controlled Trials (CENTRAL) were identified to evaluate the efficacy and safety of
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topical administration of diquafosol for dry eye patients. Data evaluation was based on endpoints
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including Schirmer’s test, tear film break-up time test (TFBUT), ocular surface staining score,
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subjective symptom score and adverse events.
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Results: A total of 8 RCTs involving 1516 patients were selected abiding pre-specified criteria.
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Significant improvement of Schirmer’s test values and TFBUT were reported in 40% (2/5) and
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80% (4/5) studies, respectively. Ocular surface staining scores significantly decreased in 100%
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(Fluorescein corneal staining: 6/6; Rose Bengal corneal and conjunctival staining: 4/4) RCTs.
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Symptoms significantly improved in 75% (6/8) RCTs in dry eye patients. No severe adverse
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events were reported with the concentrations of diquafosol from 0.5% - 5%. Heterogeneity in
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study design prevented meta-analysis from statistical integration and summarization.
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Conclusions: Topical diquafosol appears to be a safe therapeutic option for the treatment of dry
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eye. The high variability of the selected RCTs compromised the strength of evidence and limits
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the determination of efficacy. However, the topical administration of diquafosol appears to be
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beneficial in improving the integrity of the epithelial cell layer of ocular surface and mucin
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secretion in dry eye patients. This review indicates a need for standardized criteria and methods
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for evaluation to assess the efficacy of diquafosol in the future clinical trials.
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INTRODUCTION
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Dry eye or keratoconjunctivitis sicca (KCS) is a multifactorial disease characterized by
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increased osmolarity of the tear film and inflammation of the ocular surface.1 Based on
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population-based epidemiologic studies, The International Dry Eye Workshop (2007) reported
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the prevalence of dry eye to be a range of approximately 5%-35% at various ages.2-9
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Furthermore, the burden of dry eye also may include the impact on daily activities, social and
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physical functioning, and quality of life.10
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The pathogenesis of dry eye is a cyclic amplification of the damage and discomfort
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associated with the disease. The cascade of inflammatory events in dry eye caused by tear
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hyperosmolarity and tear film instability elicits apoptotic death of surface epithelial cells,
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including the goblet cells (GCs).11-13 GCs secrete gel-forming mucin that plays an essential role
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in maintaining the integrity of the tear film.14,15 The reduction of GCs leads to a corresponding
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reduction of mucin, which exacerbates tear film instability and ocular surface hyperosmolarity,
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triggering the progression of dry eye into a vicious cycle. Therefore, increasing mucin secretion
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is an important therapeutic target in dry eye syndrome in an effort to break from this cycle.
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Diquafosol, a pharmacological agent under investigation, has been known as a purinergic
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P2Y2 receptor agonist that promotes fluid transfer and mucin secretion by activating P2Y2
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receptors expressed on ocular surface.16,17-20 Previous studies have shown that the stimulation of
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water and mucin secretion by diquafosol is related to the activation of phospholipase C via G
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proteins caused by the combination of diquafolsol and P2Y2 receptor, which consequently
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increases the concentration of calcium ion within conjunctival epithelial cells and in GCs.19,21
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There is evidence demonstrating the improvement of aqueous tear secretion in animal
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models22-24, but no consensus on the efficacy of diquafosol as a clinical therapy for dry eye has
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been established. Diquafosol ophthalmic solution was approved in Japan in April 2010 as a novel
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therapeutic option for dry eye, but it has not yet been accepted by United States Food and Drug
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Administration (FDA).25 So far, several randomized clinical trials (RCTs) have been performed
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concerning diquafosol and dry eye. To our knowledge, there has been no reported systematic
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review or meta-analysis to provide recommendations to evaluate the treatment effects of
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diquafosol for dry eye. This present report aimed to systematically review the results of RCTs on
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safety and efficacy of diquafosol ophthalmic solution in different dry eye types.
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MATERIALS AND METHODS
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This review was conducted following the Preferred Reporting Items for Systematic
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Reviews and Meta-Analyses (PRISMA).26 A previously written protocol can be found in the
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Appendix 1.
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Eligibility Criteria
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Types of Studies: RCTs studying the effect of diquafosol administration as an ophthalmic
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solution for dry eye disease.
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Types of Participants: Male or female participants of any age ≥18 with either subjective or
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objective diagnosis of dry eye were considered.
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Types of Intervention: Topical diquafosol administration as an ophthalmic solution of any
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vehicles, dose and regiments were included.
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Types of Outcome: Clinical outcomes including symptom score, ocular surface staining score,
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TFBUT, Schirmer’s test, and adverse events.
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Literature Search
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The Cochrane highly sensitive search strategy was applied to MEDLINE (1966-2014),
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EMBASE (1980-2014), and Cochrane Central Register of Controlled Trials (CENTRAL, the
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Cochrane Library, Issue 9, 2014) database, with language restriction to English, Chinese, and
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French. The initial electronic database search was conducted on July 21st 2014, using the
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following terms to search all databases and registers: diquafosol; diquafosol tetrasodium;
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diquafosol sodium; P2Y2 agonist, P2Y2; dry eye; Sjögren syndrome; keratoconjunctivitis;
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keratoconjunctivitis sicca. The search strategy is available in the Appendix 2. In addition, all
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references of included studies and those of published relevant reviews27, 28 were hand searched.
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Study Selection
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The study selection process was independently completed by two authors (Wu, D; Chen,
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W). All titles and abstracts identified from the search strategy were scanned and reports that were
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apparently neither about diquafosol, nor randomized, nor desired associated clinical outcomes
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were excluded. Full texts of potentially eligible studies were obtained and verified inclusion
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using a prior constructed eligibility form. Disagreements were resolved by discussion.
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Data Extraction
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A data extraction sheet based on “Checklist of items to consider in data collection or data
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extraction” from Cochrane Handbook, pilot-tested it on 3 randomly selected included studies and
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refined accordingly.29 Any unclear or absence of information was confirmed with original
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investigators.
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Risk of Bias in Individual Studies
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Risk of Bias was assessed based on the ‘Risk of bias’ tool described in Handbook (Version
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5.1.0).30 The bias was defined as high risk, low risk, or unclear provided by criteria defined in
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the Cochrane Handbook for evaluating risk of bias.
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Summary Measures
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The primary outcome of this systematic review was the evaluation of the efficacy of topical
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diquafosol treatment on dry eye by tear function tests (Schirmer’s test and TFBUT test).
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Secondary outcomes of this study included: ocular surface staining score (fluorescein or Rose
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Bengal staining), subjective symptom score; and safety parameters (ocular and systemic adverse
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events).
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RESULT
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Due to the presence of between-study heterogeneity induced by the variation of
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comparison, follow-up time points, and diquafosol concentrations for evaluating different
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outcome measures, it is inappropriate to report these outcomes in conjunction with
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meta-analysis. As an alternative, data yielded from included RCTs were subjected to descriptive
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analysis.
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Study Selection
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Of 375 potentially relevant citations identified from electronic databases and hand searches,
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31 articles were retrieved for full-text review after adjusting for duplicates and titles and
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abstracts screening. A total of 8 RCTs were included in this systematic review.31-38 Details of the
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selection process are given in Figure1.
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Study Characteristics
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All 8 studies (see Table 1) selected for the review were RCTs published in English. Seven
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of which were full text31-37 and one was conference abstract38. A total of four trials were
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performed in Japan,31,33,34,36 three in America,32,37,38 and one in Korea.35 Two studies were
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conducted following two trials each.33, 37 One study included a RCT and a non-RCT.33 Only the
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RCT was enrolled in this review. The other study with two trials evaluated the safety of
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diquafosol and its efficacy separately.37
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The included studies involved 1516 patients with dry eye. Mean age was 59.87 (range: 36.7
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- 65.3) years old, and 73.0% were female. All studies included provided specified criteria of dry
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eye diagnosis. Four studies evaluated diquafosol efficacy in specific dry eye populations 33,35-37
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(see Table 2).
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Of the 8 included studies, one study recruited 32 patients and tested topical diquafosol in 1
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randomly selected eye, and the other eye was assigned as control.36 Three studies enrolled 286,
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150 and 17 patients respectively, and only one eye from each patient was selected into study.
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31,33,35
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that recruited 286 and 158 patients remained unclear in the number of eyes included in trials.34,38
No explicit explanation relating to the selection of two eyes was documented. Two studies
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In the remaining 2 studies (three trials), 527 and 60 enrolled patients were grouped respectively
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and randomly to receive either topical diquafosol in both eyes, or placebo in both eyes.32,37
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Different concentrations of diquafosol were evaluated in the 8 studies included in this
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systematic review with a range from 0.5% to 5%. Detailed information of regimen can be found
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in Table 1.
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Risk of Bias Within Studies
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The outcome of ‘Risk of Bias’ assessment is summarized in Figure 2. In terms of selection
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bias, four of the eight RCTs specified the methods of random sequence generation.33-36 Two
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studies provided the method of allocation concealment.33,36 Regarding performance biases
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(blinding of participants and personnel), four of the eight included studies were double
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masked,31,32,34,37 and two were open-label,33,35 which were judged as high risk in both
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performance bias and detection bias. Among the eight included RCTs, six were judged as low
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risk of attrition bias because the dropouts patients’ number were reported clearly and the
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percentages were believed unlikely to affect the outcome.31-36 Six RCTs included in this
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systematic review were judged to be free from reporting bias, as all of the studies’ pre-specified
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outcomes were addressed in result.31,33-37 One study didn’t report the result of TFBUT, which
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was addressed as an endpoint for efficacy assessment in methodologies.32 For the only one
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conference abstract enrolled in this review, there was no sufficient information to assess the risk
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of bias within study.
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Outcome of Efficacy
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Schirmer I/II Test
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Schirmer’s test is a method of assessment indicative of volume tear fluid secretion. In the
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result of the included studies, two out of five studies showed significant improvement.32,35 (Table
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3) Hwang35 reported improvement in both monotherapy and in combination (diquafosol/ sodium
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hyaluronate) throughout a three months period from 1.12 to 3.27mm(/5min). Tauber32 reported
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of the subjects with intermediate or high tear volume in diquafosol (1%, 2%) treatment group
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was significantly higher than placebo group at six weeks. The other three studied showed no
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significant improvement compared with baseline values.33,36,37 No significant improvement
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reported from Schirmer II test assessed.37
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TFBUT
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TFBUT is indicative of tear film stability. Of the included studies, five assessed TFBUT.31,
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33-36
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improvement compared with baseline or control values (Table 3) with a range from 0.9-3.9s, and
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one study showed improvement but is not statistically significant31.
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Ocular surface staining
All five studies reported improvement. Four out of five studies32-35 reported a significant
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Ocular surface staining was used to evaluate the integrity of the superficial cell layers of the
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ocular surface.39 Six of the included studies31,32,34-36,38 evaluated fluorescein corneal (FC)
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staining and four31,34-36 evaluated Rose Bengal (RB) corneal and conjunctival staining. FC
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staining results all reported statistically significant amelioration from -0.35 to -2.12. RB staining
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results all showed statistically significant improvement from -0.21 to -3.06.
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Subjective ocular symptoms
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All 8 studies included in this review evaluated subjective ocular symptoms, including one
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evaluated ocular surface disease index score (OSDI).35 A significant alleviation of at least one
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ocular symptom was reported by six studies.31-36 Diquafosol eye drop treatment showed
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significant improvement of dry eye sensation or ocular dryness in four out of five trials
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evaluating this symptom31, 33, 36, 37 and foreign body sensation in three out of six trials32, 36, 37. No
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mitigation was observed in eye discharge (evaluated in 4 studies31, 33, 34, 36), ocular discomfort
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(evaluated in 3 studies31, 34, 36) and tearing (evaluated in 2 studies31,33).
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Outcome of Safety
Of the 8 studies included, 5 of which evaluated the safety and adverse events of topical
administration of diquafosol and reported no serious adverse events.31,32,34,36,37
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DISCUSSION
This systematic review combines evidence and findings across studies to evaluate efficacy
and safety of diquafosol with a more holistic view than permitted in a single study.
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Considering clinical safety of diquafosol, the evaluation demonstrated no serious ocular or
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systemic adverse effect was found. Furthermore, the occurrence of adverse events does not
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increase with the increase of the concentration of diquafosol (0.5%-5%). Therefore, as a
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secretion stimulating treatment for dry eye, diquafosol is clinically safe.
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Another consideration, based on the result of clinical tests evaluated in the included RCT, is
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the efficacy of diquafosol. Ocular surface damage can be evaluated by vital staining, a hallmark
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of dry eye disease.40 From the included RCTs, significant improvement were found in all studies
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that evaluated ocular surface staining. This result is congruent with evidence found in a rat dry
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eye model.24 In accordance with the pathology of dry eye and mechanism of diquafosol, the
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staining scores are indicative of either the improvement of aqueous tear production or mucin
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secretion. Aqueous tear production can be evaluated clinically using Schirmer’s test. The result
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from the included RCT is inconsistent and inconclusive of improvement in aqueous tear
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secretion. On the other hand, mucin production, evaluated by TFBUT, was reported to improve
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by the majority of the included studies (4/5). From these trends, one can see a possible
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correlation between the function of diquafosol and the improvement of mucine secretion as well
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as the mitigation of ocular surface damage, while aqueous tear production does not seem to have
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a strong association with diquafosol efficacy.
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Even though there are discernable trends in the result, the evidence is not sufficiently robust
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to determine the efficacy of diquafosol primarily due to the high heterogeneous nature of the
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included studies. Firstly, the participants of the selected studies have high variability in patient
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selection criteria. For example, among the selected studies, some studies includes while other
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excludes patients with Sjögren syndrome. In another case, while most of the studies require
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Schirmer’s test value less than 5, one study only includes patients with short TFBUT and
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Schirmer’s test value greater than 5.33 Furthermoer, the interventions of the selected study have
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variation in dosage, combination of therapy (e.g. sodium hayaluronate + diquafosol), and
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concentration. The comparators of the selected studies also have a high variation including
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placebo, artificial tears and sodium hayaluronate. The outcomes of the studies have variation in
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time point, test, scales, and reporting formats. The study design has variability as well; some
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include double-mask, no blinding and washout/no washout period.
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Aside from heterogeneity, among the RCTs evaluating topical diquafosol treatment in
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patients with dry eye, there remain several other concerns that inhibit us to formulate
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conclusions adopting an evidence-based approach to dry eye. First, the randomized trial did not
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evaluate a sufficient number of patients. The only 3 studies with a larger number of participants
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(286-527) are sponsored by pharmaceutical companies, of which only one study includes
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patients over 300 participants. Furthermore, among the included study, only two designed a
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follow up period of more than 3 months. In the report of the International Dry Eye Workshop
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(2007), the Diagnostic Methodology Subcommittee regarded dry eye as a chronic, symptomatic
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ocular surface disease.41 Therefore, it is logical to assume that a longer follow-up period is
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necessary.
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This systematic review has several limitations on a study and review level including the
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quality of the studies varied. Concerning randomization, limitations include inability to assess
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the quality of the selected studies due to unclear reports of the randomization method. Regarding
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the review process, no unpublished data was selected and the language of the searched studies
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was restricted to English, Chinese, and French.
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In summary, the safety of diquafosol is established based on the included study. Although
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there is a possible correlation between diquafosol and mucin secretion and between diquafosol
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and surface damage assuagement, the high heterogeneity of the selected study limits the
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determination of the efficacy of diquafosol on dry eye. For future trials, this review indicates a
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need for a neutral organization to perform a multi-centered, large sample sized, long term
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evaluation of the efficacy of diquafosol. Some aspects to consider for future trials include
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concentration of diquafosol [varied] and the duration of efficacy of diquafosol post treatment.
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Further suggestions include a standardized comparator in evaluation of any particular drug for
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dry eye.
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Figure 1. Flow diagram of systematic process for report identification.
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Figure 2. Risk of bias summary in included studies. Green (+) = low risk; Red (-) = high risk;
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Yellow (?) = unclear.
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Supplemental Digital Content：
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Appendix 1: Protocol of the present systematic review
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Appendix 2: Search Strategy
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