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Nutrition in Clinical Care

Efficacy of polyunsaturated fatty acids for dry eye syndrome: a meta-analysis of randomized controlled trials Wei Zhu, Yan Wu, Guigang Li, Juan Wang, and Xinyu Li Dry eye syndrome (DES) is a common ocular disease that significantly affects the quality of life. Polyunsaturated fatty acids (PUFAs) have been used to treat DES; however, randomized controlled trials (RCTs) of PUFA therapy yield discordant results. The objective of this study was to clarify the effects of PUFAs on DES through meta-analysis of all relevant RCTs. To do so, a comprehensive search of PubMed, Embase, the Cochrane Library, ISI Web of Science, and unpublished data was conducted. The changes in clinical and laboratory examinations, symptomatic scores, and rates of relevant symptoms were analyzed. Nine RCTs were included in the current meta-analysis. Compared with placebo, PUFA supplementation was not related to changes in tear film break-up time (weighted mean difference [WMD], 0.33; 95% confidence interval [CI], −0.05 to 0.72), Schirmer's test score (WMD, 0.32; 95%CI, −0.23 to 0.86), or lissamine green staining score (WMD, −0.77; 95%CI, −1.66 to 0.12). However, significant reductions were detected in the symptom score on the ocular surface disease index (WMD, −2.26; 95%CI, −4.44 to −0.08) and in the rate of cells positive for human leukocyte antigen DR (WMD, −5.80; 95%CI, −8.62 to −2.97). This comprehensive meta-analysis supports the use of PUFA supplementation as a potential effective therapy for DES. © 2014 International Life Sciences Institute

INTRODUCTION Dry eye syndrome (DES), or keratoconjunctivitis sicca, is one of the most common ocular diseases. It is a multifactorial disorder that includes the following risk factors: aging, autoimmune disease, menopausal status, medication use, and corneal dysfunction.1–3 The worldwide prevalence of DES ranges from 7.8% to 22%, depending on the source and the diagnostic criteria.2 DES contributes to ocular discomfort, visual disturbance, and potential damage to the ocular surface, all of which significantly affect the quality of life. The lack of certain components in tears leads to a decreased tear quality,

which induces DES. Additionally, decreased tear production and increased tear film evaporation can stimulate development of the disease. Therapeutically, topical artificial tears, which lubricate the ocular surface, are the principal treatment of DES. Other treatments, such as lifestyle modification, alternative therapies, and surgery to close the tear drains, also help to alleviate the symptoms of DES.4–6 The 2007 Report of the International Dry Eye WorkShop7 recommended distinct treatments based on the severity of DES. Depending on the signs and symptoms of DES, four levels of disease severity were stratified, with the treatments for each level of severity presented separately. Although the treatment options are abundant,

Affiliations: W Zhu is with the Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China, and the Department of Ophthalmology, Changshu No. 2, People’s Hospital, Changshu, China. Y Wu is with the Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China, and the Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou, China. G Li, J Wang, and X Li are with the Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. Correspondence: X Li, Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 0195 Liberation Ave, Wuhan, Hubei 430030, China. E-mail: [email protected]. Phone: +86-027-83663456. Key words: dry eye syndrome, meta-analysis, polyunsaturated fatty acids 662

doi:10.1111/nure.12145 Nutrition Reviews® Vol. 72(10):662–671

no treatments are currently available to address the underlying causes of the disease. In general, additional effort is required to find more effective treatments for DES. Ocular inflammation is recognized as one of the main features of DES. Severe ocular surface inflammation leads to epithelial damage and cell death, which in turn exacerbates the inflammatory reaction. Accordingly, control of inflammation in the ocular surface is an important approach to the treatment of DES. Several antiinflammatory drugs, such as steroids or cyclosporine A, have been used to treat DES, but their value is limited because of insufficient efficacy and noticeable side effects in some patients.8,9 Supplementation with polyunsaturated fatty acids (PUFAs), which are usually classified as n-3 or n-6 PUFAs, has been used in the treatment of several diseases (e.g., atherosclerosis and Crohn disease) 10,11 to reduce inflammation. In addition to their anti-inflammatory properties, PUFAs can improve the lipid layer component of the tear film and normalize the functions of both the lacrimal gland and the meibomian gland.12 Thus, PUFA supplementation has been recommended as a potentially important treatment modality for DES. With regard to clinical studies on dietary PUFAs, the Women’s Health Study included 32,470 women aged 45–84 years and provided information on diet and incidence of DES.13 The results demonstrated that dietary intake of n-3 fatty acids was associated with a decreased incidence of DES. These findings are consistent with anecdotal clinical observations and the postulated biological mechanisms. Additionally, several case-control studies and randomized controlled trials (RCTs) were conducted to study the therapeutic efficacy of PUFAs in DES. The conclusions of those studies, however, were contradictory. Meta-analysis is an effective tool to pool existing, homogeneous studies together to estimate an outcome of interest. Several previous meta-analyses were performed to determine the effects of PUFA supplementation in hypertriglyceridemia, cardiovascular disease, and pregnancy.14,15 In this study, a meta-analysis was performed to evaluate the efficacy of PUFA supplementation in DES.

METHODS

trials.gov), TrialsCentral (http://www.trialscentral.org), and Current Controlled Trials (http://www.controlledtrials.com) were searched to identify unpublished studies. The reference lists of the relevant articles were reviewed for additional publications. The text words “dry eye,” “dry eye syndrome,” “ophthalmoxerosis,” “xerophthalmia,” “xeroma,” or “keratoconjunctivitis sicca” were used in combination with “fatty acid” in the literature search. No language or other restrictions were set in the literature search. Corresponding authors were contacted if the required data were absent from the article. The articles retrieved were considered eligible when they met the following inclusion criteria: 1) they adopted a randomized, double-blind, placebo-controlled methodological design; 2) they evaluated the efficacy of PUFAs in the treatment of DES; and 3) they reported at least one of the outcomes of interest. Studies were excluded if they met one of the following exclusion criteria: 1) PUFAs were combined with any other anti-inflammatory agent; and 2) no suitable data could be extracted for quantitative analyses. Data extraction was conducted by two reviewers (WZ and YW) independently, and the extracted data were rechecked after the first extraction. Any incongruity was analyzed by the third reviewer (XL) and resolved through discussion. The following data were extracted from each study: name of first author, country, sample size, source and type of PUFAs, detailed definitions of the case and control groups, tear film break-up time, Schirmer’s test, lissamine green staining score, corneal fluorescent staining, symptom score on the ocular surface disease index, rate of cells positive for human leukocyte antigen DR (HLA-DR), and fluorescence intensity of HLA-DR cells. Assessment of methodological quality Two reviewers (WZ and XL) assessed the methodological quality independently, and any incongruity was discussed and resolved. The methodological quality of the trials included was assessed using elements of the Cochrane Collaboration’s tool for assessing risk of bias.17 A total of 7 domains were reported for each study: random sequence generation, allocation concealment, blinding of participants, blinding of outcome assessment, follow-up, selective reporting, and other bias.

Search strategy, inclusion criteria, and data extraction Statistical methods for meta-analysis This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and MetaAnalyses (PRISMA) guidelines.16 Relevant published studies were identified by searching PubMed, Embase, the Cochrane Library, and ISI Web of Science through March 2013. Additionally, ClinicalTrials (http://www.clinical Nutrition Reviews® Vol. 72(10):662–671

A fixed-effects model was employed to conduct a metaanalysis of all relevant RCTs unless the heterogeneity was significant. For dichotomous variables, the risk ratios (RRs) were measured with 95% confidence intervals (CIs), while for continuous variables, the weighted mean 663

Figure 1 Flow diagram of the inclusion and exclusion criteria for screening of relevant studies. A total of 622 studies were identified, and 9 randomized controlled trials were included in the meta-analysis. Abbreviations: PUFAs, polyunsaturated fatty acids; RCT, randomized controlled trial. difference (WMD) was measured along with the 95%CI.A P value of 50%. Potential publication bias was assessed by both visual evaluation of funnel plots and Egger’s test. Review Manager software (RevMan, version 5.1; The Nordic Cochrane Centre, The Cochrane Collaboration) and STATA (version 11.0; StataCorp) were used to conduct the meta-analysis. RevMan 5.1 was used for the forest plots and STATA 11.0 for Egger’s test and meta-regression. To explore the source of heterogeneity, each included study was removed one by one to detect its contribution to heterogeneity. Additionally, meta-regression was conducted to evaluate the source of heterogeneity. Sensitivity analysis was conducted by employing the random-effects model and then detecting the efficacy of PUFA supplementation in DES. The results were considered robust when the results did not change significantly. RESULTS Literature search The flow diagram of the literature search is presented in Figure 1. A total of 911 records were identified from the 664

database search (601 from PubMed, 272 from Embase, 13 from the Cochrane Library, and 147 from Web of Science). In addition, 21 records were obtained from the reference lists of the relevant articles. After removing 111 duplicate articles, 511 articles were assessed for eligibility. Review of the abstracts showed 17 records to be possibly eligible for inclusion in the meta-analysis. After assessing the full text of these records, 8 articles were excluded for the following reasons: study design not an RCT (n = 4), article contained duplicate data (n = 2), article contained no qualified data (n = 2), and PUFA supplementation was combined with another anti-inflammatory agent (n = 1). Unpublished data from ClinicalTrials (n = 13), TrialsCentral (n = 7), and Current Controlled Trials (n = 9) were also assessed. After duplicate data were removed, no suitable and available unpublished data could be included in the meta-analysis. In all, 9 articles were selected for the quantitative synthesis.18–26 Study characteristics The 9 articles, published between 2002 and 2011, reported data for 716 subjects. Seven of the included studies were conducted in Europe, and the other 2 were conducted in the United States. The causes of DES varied in each study, and studies in the current meta-analysis included patients with both Sjögren’s syndrome and xerophthalmia. Except for 1 study, female patients were more common in the Nutrition Reviews® Vol. 72(10):662–671

included studies. The sources of PUFAs were fish oil, sea buckthorn, evening primrose oil, flax seed, and borage oil. Four articles did not mention the source of the PUFAs. Examination of the supplements provided to the case groups showed that each study used different subtypes of PUFAs. Two articles reported the effect of n-3 PUFAs on DES, 3 articles reported the effects of n-6 PUFAs on DES, and 4 articles reported the effect of both n-3 and n-6 PUFAs on DES. Details about the supplements provided to case and control groups are listed in Table 1. Data quality The risk-of-bias assessment for each trial included in the meta-analysis is summarized in Table 2. Randomized, double-blinded, placebo-controlled designs were reported by all studies. Three studies reported the random sequence generation method (2 trials with random number tables and 1 trial with computergenerated random sequences). The other 6 did not mention the details of the random sequence generation methods. Allocation concealment was clearly adequate in 3 trials. All of the included studies reported the blinding of participants, while only 3 trials reported the blinding of outcome assessment. The follow-up periods reported in the studies varied, and the follow-up rate of all the trials was over 80%. Six of the included studies were free of selective reporting, while the status of selective reporting was unclear in 3 studies. No other risks of bias were detected in the included trials. Clinical and laboratory examinations The most common and important data from each trial were extracted and pooled together in this meta-analysis. Focus was placed on the following outcomes: tear film break-up time, results of Schirmer’s test, lissamine green staining score, intensity of corneal fluorescent staining, score of symptoms on the ocular surface disease index, rate of cells positive for HLA-DR, and fluorescence intensity of HLA-DR cells. The change from the baseline was recorded for the analyses. The forest plots of all the outcomes are shown in Figures 2–4. No significant differences were detected in either the tear film break-up time (WMD, 0.33; 95%CI, −0.05 to 0.72) or the Schirmer’s test (WMD, 0.32; 95%CI, −0.23 to 0.86) when the PUFA-supplemented group was compared with the control group (Figure 2). In addition, the meta-analysis of 3 studies demonstrated that PUFA supplementation was not effective in the reduction of either the lissamine green staining score (WMD, −0.77; 95%CI, −1.66 to 0.12) or the intensity of corneal fluorescent staining (WMD, 1.01; 95%CI, 0.75 to 1.35) (Figure 3). However, a significantly decreased score of Nutrition Reviews® Vol. 72(10):662–671

symptoms on the ocular surface disease index was detected in the PUFA-supplemented group compared with the control group (WMD, −2.26; 95%CI, −4.44 to −0.08) (Figure 4A). The expression levels of the inflammatory marker HLA-DR were also analyzed. Supplementation with PUFAs significantly decreased the rate of HLA-DR expressing conjunctival epithelium cells in DES patients (WMD, −5.80; 95%CI, −8.62 to −2.97). The fluorescence intensity of HLA-DR-positive cells was also significantly decreased in the PUFA-supplemented group compared with the control group (WMD, −12.70; 95%CI, −15.79 to −9.61) (Figure 4B,C). Statistical heterogeneity was detected in 2 of the outcomes analyzed above: lissamine green staining score (I2 = 79%; P = 0.0087) and score of symptoms on the ocular surface disease index (I2 = 66%; P = 0.02). After 1 of the included studies was removed from the metaanalysis (Barabino et al.21 for lissamine green staining score and Larmo et al.20 for score of symptoms on the ocular surface disease index, respectively), the heterogeneity was not significant. After removing the 2 studies from each outcome respectively, the result of the metaanalysis did not change significantly. A meta-regression was also employed to search for the source of heterogeneity in the score of symptoms on the ocular surface disease index, and no significant results were detected. Symptomatic outcomes A number of different symptoms were reported, and the following symptoms were analyzed: photophobia, dryness, foreign body sensation, burning, stinging, reflex lacrimation, eyestrain, and redness. All the results of meta-analysis are shown in Table 3. Compared with the control group, the PUFA-supplemented group showed significantly decreased symptoms of sensations of burning (RR, 0.57; 95%CI, 0.40 to 0.80) and reflex lacrimation (RR, 0.64; 95%CI, 0.44 to 0.93). No significant heterogeneity was detected in any outcome. The summary of the main results for the meta-analysis of symptomatic outcomes is presented in Table 3. Sensitivity analysis and publication bias After a random-effects model was obtained, no outcome was significantly changed except the symptom of reflex lacrimation. The increase observed for reflex lacrimation in the PUFA-supplemented group was not detected (RR, 0.59; 95%CI, 0.29 to 1.23) in a random-effects model. Publication bias was assessed by both funnel plot and Egger’s liner regression test. Both methods demonstrated no evidence of publication bias. 665

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Xerophthalmia

Xerophthalmia

Primary SS

Primary SS and xerophthalmia

Primary SS and xerophthalmia SS and xerophthalmia

Finland

Italy

Sweden

France

Brazil

Larmo et al. (2010)20

Barabino et al. (2003)21

Theander et al. (2002)22 Creuzot et al. (2006)23

France

Cases: 67/70

Cases: 25 Controls: 13 Cases: 90 Controls: 91

Cases: 39 Controls: 48 Cases: 36 Controls: 35

Cases: 13 Controls: 13

Cases: 52 Controls: 48

Cases: 21 Controls: 15 Cases: 20 Controls: 20

No. of patients

85/15

17/9

Cases: 45 ± 18 Controls: 46 ± 17

Cases: 63.4 ± 8.2 Controls: 54.3 ± 11.3

133/4

166/15

Cases: 61.3 ± 12.15 Controls: 61.79 + 11.74 Cases: 61 ± 11.75 Controls: 59.7 ± 11.95

380

NA

68/3

79/8

37/3

Cases: 36.9 ± 7.9 Controls: 36.3 ± 5.5

Cases: 64 (50–68) Controls: 56 (50–71) Cases: 59.7 ± 14.7 Controls: 61.1 ± 11.1

20/16

Gender (F/M)

61 (29–84)

Mean age (y)

Fish oil and borage oil

Drugs that contains PUFAs

Flax seed

Evening primrose oil Drugs that contains PUFAs

Drugs that contains PUFAs

Sea buckthorn

Drugs that contains PUFAs

Source of PUFAs Fish oil

n-3 and n-6

n-3 and n-6

n-3

n-3 and n-6

n-6

n-6

n-3 and n-6

n-6

n-3

n-3 or n-6

GLA 800 mg or 1,600 mg daily n-3 (196 mg DHA & 14 mg EPA) n-6 (41 mg GLA & 63 mg LA) Flaxseed oil, 1 g or 2 g daily, in capsules n-3 (196 mg DHA & 14 mg EPA) n-6 (41 mg GLA & 63 mg LA) Fish oil (n-3 source; 855 mg, containing 427.5 mg EPA & 285 mg DHA) Borage oil (Borago officinalis; n-6 source; average value: 15 mg)

LA (28.5 mg) and GLA (15 mg), twice daily

1 g sea buckthorn, twice daily

450 mg EPA, 300 mg DHA, 1,000 mg flaxseed oil 112 mg LA and 15 mg GLA

Supplementation, cases

Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; GLA, gamma linolenic acid; LA, linoleic acid; NA, not available; PUFAs, polyunsaturated fatty acids; SS, Sjögren’s syndrome.

BrignoleBaudouin et al. (2011)26

SS and xerophthalmia

Primary SS

Italy

France

Xerophthalmia

USA

Wojtowicz et al. (2011)18 Aragona et al. (2005)19

Pinheiro et al. (2007)24 CreuzotGarcher et al. (2011)25

Disease

Country

Reference

Medium-chain triglycerides, 575 mg

Placebo capsules (basal oleic acid)

Basal oleic acid

Basal oleic acid

Fructose (2,383.3 mg), monohydrate citric acid (50 mg), aspartame (12.5 mg), silicon dioxide (6 mg), bigrade aroma (45 mg), citrus aroma (131 mg) Placebo oil (placebo capsules contained triacylglycerols of medium-chain fatty acids isolated from coconut and palm kernel), twice daily Specially made tablets containing a low quantity of sugar, same dose as cases Mainly corn oil and no GLA

Supplementation, control group Wheat germ oil

Table 1 Characteristics of the 9 randomized controlled trials included in the review that investigated the effects of PUFAs in dry eye syndrome.

3 mo

6 mo

6 mo

6 mo

6 mo

1.5 mo

3 mo

1 mo

Length of follow-up 3 mo

Table 2 Quality of the 9 studies included in the meta-analysis, as assessed by the Cochrane Collaboration tool. Reference Random Allocation Blinding of Blinding of Follow-up Free of Free of sequence concealment participants outcome ≥80% selective other bias generation assessment reporting ? ? + ? + + + Wojtowicz et al. (2011)18 + ? + + + + + Aragona et al. (2005)19 ? + + ? + ? − Larmo et al. (2010)20 + ? + ? + + − Barabino et al. (2003)21 ? + + ? + ? ? Theander et al. (2002)22 Creuzot et al. (2006)23 ? ? + + + ? + ? ? + ? + + + Pinheiro et al. (2007)24 ? ? + ? + + + Creuzot-Garcher et al. (2011)25 + + + + + + Brignole-Baudouin et al. (2011)26 +

Symbols: +, adequate (low risk of bias); ?, unclear (unknown risk of bias); −, inadequate (high risk of bias).

DISCUSSION This meta-analysis contains 9 RCTs that investigated the efficacy of PUFA supplementation for DES. The results of this meta-analysis suggest that PUFA supplementation provides no benefit to DES patients with regard to tear volume or the stability of the ocular surface. Nevertheless, PUFA supplementation was shown to improve the symptom score on the ocular surface disease index and to relieve burning and reflex lacrimation symptoms in DES

patients. Moreover, PUFA supplementation reduced inflammatory responses in the ocular surface. Considering the statistical heterogeneity of several outcomes, some of the results should be considered with great caution. Overall, the sensitivity analysis and the assessment of publication bias provide strong evidence supporting PUFA supplementation as a potentially effective treatment for DES. PUFAs are essential fatty acids with two main subclasses (n-3 and n-6 PUFAs). The n-3 PUFA group

Figure 2 Forest plot of the effects of PUFAs on tear film break-up time and Schirmer's test in dry eye syndrome. When the heterogeneity was not significant, a fixed-effects model was obtained; otherwise, a random-effects model was chosen. (A) The PUFA supplement was not related to the changes of either the tear film break-up time (WMD, 0.33; 95%CI, −0.05 to 0.72) or (B) the Schirmer’s test (WMD, 0.32; 95%CI, −0.23 to 0.86). Abbreviations: CI, confidence interval; IV, inverse variance; PUFAs, polyunsaturated fatty acids; SD, standard deviation; WMD, weighted mean difference. Nutrition Reviews® Vol. 72(10):662–671

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Figure 3 Forest plot of the effects of PUFAs on lissamine green staining and corneal fluorescent staining in dry eye syndrome. No significant result was detected in either the (A) lissamine green staining score (WMD, −0.77; 95%CI, −1.66 to 0.12) or (B) corneal fluorescent staining (RR, 1.01; 95%CI, 0.75 to 1.35). Abbreviations: CI, confidence interval; IV, inverse variance; M-H, Mantel-Haenszel; PUFAs, polyunsaturated fatty acids; RR, risk ratio; WMD, weighted mean difference.

Figure 4 Forest plot of the effects of PUFAs on ocular surface disease index score, the rate of HLA-DR-positive cells, and fluorescence intensity of HLA-DR cells in dry eye syndrome. (A) Significant reduction in symptom score on the ocular surface disease index was detected in the PUFA-supplemented group compared with the control group (WMD, −2.26; 95%CI, −4.44 to −0.08). (B–C) The rate of HLA-DR-positive cells and the fluorescence intensity were both reduced in the PUFA-supplemented group. Abbreviations: CI, confidence interval; IV, inverse variance; PUFAs, polyunsaturated fatty acids; WMD, weighted mean difference. 668

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Table 3 Summary of the incidence of clinical symptoms in the PUFA-supplemented groups compared with the control groups. Symptom No. of studies No. of participants Overall effect Study heterogeneity P value RR 95%CI P value I2, % Photophobia 2 188 0.97 0.76–1.24 0.79 0.00 0.78 Dryness 3 288 0.84 0.68–1.05 0.13 26.00 0.26 Foreign body sensation 3 288 1.15 0.87–1.53 0.33 0.00 0.55 3 288 0.57 0.40–0.80 0.00 14.00 0.31 Burninga Stinging 2 221 0.89 0.57–1.38 0.60 0.00 0.40 2 167 0.64 0.44–0.93 0.02 41.00 0.19 Reflex lacrimationa Eyestrain 1 67 0.91 0.52–1.57 0.72 – – Redness 1 100 1.06 0.67–1.67 0.80 – – Abbreviations: CI, confidence interval; RR, risk ratio. a Difference between groups was significant.

includes alpha-linolenic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), while the n-6 PUFA group includes linoleic acid, gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid, and arachidonic acid. These intermediate products are processed by cyclooxygenase and lipoxygenase. In addition to having other important functions, they produce both pro- and anti-inflammatory effects. The efficacy of PUFAs supplements was studied in cancer prevention,27 allergic disease,28 and diabetes.29 In several studies, PUFA supplementation resulted in positive outcomes and showed potential as a therapeutic or preventive intervention. Recently, PUFA supplementation has been applied to the treatment of DES in animal models. Viau et al.30 conducted an in vivo study to examine the effect of PUFAs on DES in a rat model. Female Lewis rats were fed diets containing GLA, EPA, and DHA or combinations thereof, and 2 months later, a DES phenotype was induced in those rats. The symptoms of DES were partly prevented by PUFA supplementation, although the overexpression of MHC II in the conjunctival epithelium induced by DES was significantly reduced only in the combined GLA + EPA + DHA treatment group. These results indicate that oral PUFA supplementation is beneficial in DES. Notably, there is a potentially important increase in therapeutic efficacy with the combined administration of n-3 and n-6 PUFAs. There are also several clinical studies that focused on the effects of PUFAs on DES patients. A cross-sectional study with data from the Women’s Health Study assessed the relationship between fatty acid intake and selfreported DES. The results indicated that the prevalence of DES was lower in women with a higher intake of n-3 PUFAs. Furthermore, a higher ratio of n-6/n-3 PUFA consumption was associated with more than twice the risk of DES.13 Even though the Women’s Health Study was a self-reported cross-sectional study, its large sample size and well-controlled analysis provided valuable data for studying the effects of PUFA in DES. The results of the Women’s Health Study are worth considering, but more clinical trials are needed. Kokke et al.31 conducted an RCT Nutrition Reviews® Vol. 72(10):662–671

to explore the efficacy of n-6 PUFAs on contact-lensassociated DES. They reported that oral n-6 PUFA intake improved dryness scores and lens discomfort at 3 and 6 months. However, no significant improvements were identified in tear quality, tear stability, or ocular surface damage.31 The results of this meta-analysis are quite similar to those of Kokke et al.,31 which showed significant improvement in burning and reflex lacrimation symptoms and in the symptom score on the ocular surface disease index. PUFAs are more likely to reduce the inflammatory responses rather than improve tear quality/ stability in DES patients. While 1 study claimed that PUFAs contributed to tear formation and excretion,32 no improvement in tear quality or stability was detected in the present meta-analysis. Additionally, Järvinen et al.33 conducted an RCT to explore fatty acids in the tear films of the PUFA-supplemented group. No significant difference in tear film fatty acids was detected at 1 month or 2 months in the PUFA-supplemented group when compared with the placebo group. Even though improvement in tear film osmolarity was reported in 1 study,2 there is still no direct evidence for an effect of fatty acids on tear composition or tear film quality/stability. This meta-analysis indicates that the rate of reflex lacrimation was reduced in the PUFA-treated group, although significance was not observed in the sensitivity analysis. This finding suggests there still might be unclear effects of PUFA supplementation on reflex lacrimation symptoms. Healthy corneal nerves are vital to the normal function of the ocular surface,12 while DES leads to increasing ocular surface sensitivity. The dysfunction of the corneal nerves is associated with reflex lacrimation symptoms. He and Bazan34 mentioned that n-3 PUFAs were beneficial to corneal nerve regeneration and, accordingly, it can be hypothesized that PUFAs would prevent serious corneal nerve damage, thus improving DES symptoms such as decreased or absent reflex lacrimation. This hypothesis indicates additional areas of potential DES research, both in vitro and in vivo. The duration of PUFA treatment for DES varied from 1 to 6 months in the studies included in the meta669

analysis. Although it might be difficult to conduct an RCT with a longer duration of follow-up,it should be noted that the duration of treatment may affect the efficacy of PUFA supplementation. PUFAs, which are now regarded as an effective nutritional supplement, may produce a more significant effect with a longer duration of consumption. Oral intake is a convenient route of PUFA supplementation, but it is not known how well the anti-inflammatory PUFAs are distributed on the ocular surfaces following oral ingestion. A longer duration of PUFAs supplementation might help increase the concentration of antiinflammatory agents on the ocular surfaces.A clinical trial of longer duration would likely provide more powerful evidence of the effects of PUFAs on ocular surfaces. Although several inflammatory markers are highly expressed in the cornea of DES patients, HLA-DR is one of the most important.35 In this meta-analysis, PUFA supplementation significantly decreased the level of HLA-DR expression in the conjunctival epithelium. Increased levels of other inflammatory markers, such as interleukin (IL)-1, IL-6,and tumor necrosis factor α,were also detected in the tear fluid and conjunctival epithelium of DES patients.36,37 In both animal models and patients, the tear film prostaglandin E2 level was associated with the severity of DES.38 Recently,a prospective study was conducted to explore the effects of daily oral intake of antioxidants and PUFAs in DES patients. The data from 66 patients showed that PUFA intake was associated with decreased levels of IL-1β, IL-6, and IL-10. More experimental and clinical data are required for better understanding of the antiinflammatory effects of PUFAs in DES.39 It should be noted that tear film break-up time and Schirmer’s test are both well-accepted major parameters for DES diagnosis and for evaluation of treatment efficacy. In this meta-analysis, however, neither test could detect significant improvement from PUFA supplementation. The therapeutic effects of the PUFAs were detected by the ocular surface disease index and the rate of cells positive for HLA-DR, which are less recognized and less frequently used in clinical practice. In general, the tear film break-up test and Schirmer’s test focus on tear volume and the stability of the tear film, while the ocular surface disease index and the HLA-DR index focus on the severity of symptoms and the inflammatory response. It is hypothesized that PUFA supplementation may provide therapeutic efficacy in DES by improving the symptoms and reducing inflammation. Even though tear volume and the stability of the tear film were not significantly improved, the changes in the ocular surface disease index and the HLA-DR index provide evidence of the efficacy of PUFAs in DES. Apart from simple oral PUFA supplementation, there are other ways to administer PUFAs. Topical n-3 PUFAs were reported to have beneficial effects in DES-induced in 670

mice.40 Compared with the control group, treated mice showed significant decreases in dry eye symptoms and in levels of inflammatory markers. Unlike oral PUFA supplementation, topical application of PUFAs avoids gastrointestinal side effects and can affect the ocular surface directly. Topically applied PUFAs can also be combined with other anti-inflammatory agents, such as cyclosporine A. When combined with cyclosporine A in one study, topically applied PUFAs improved the tear film break-up time better than PUFA supplementation alone.9 Various means of PUFA delivery, along with the combination of PUFAs with different agents, provide a wide range of potential applications for the therapeutic use of PUFAs. This is believed to be the first meta-analysis designed to analyze the efficacy of PUFA supplementation in the treatment of DES. The strengths of the present metaanalysis include the detailed search strategy, the attempt to acquire unpublished data, and the relatively low heterogeneity and publication bias. Nevertheless, there are still several limitations of this analysis. First, the evaluation of bias showed that bias could be identified in most of the studies. Without trials of sufficiently high quality, however, it is difficult to reach a definitive conclusion. Second, although the effects of different PUFA subtypes (n-3 and n-6) PUFAs are not the same, the data obtained were insufficient to conduct a subgroup analysis in this meta-analysis. Inverse effects of n-3 PUFAs and of higher ratios of n-6 to n-3 PUFA intake were reported in the Women’s Health Study. More trials investigating the effects of n-3 or of different n-3/n-6 combinations are required to fully examine the efficacy of PUFAs in DES. Third, the inclusion criteria for DES in this meta-analysis contained both Sjögren’s syndrome and xerophthalmia. Even through several trials used both of these inclusion criteria, the different characteristics of these two disease subtypes may increase the potential for bias. Fourth, all of the included studies had a relatively short duration. The protective effects of the PUFAs might be masked by the short duration of treatment. In the future, clinical trials of a longer duration will be required. In view of the limitations of some of the previous clinical trials, several points should be considered when future studies are designed. The duration of the PUFA treatment should be longer in order to allow detection of any long-term effects of PUFAs on DES symptoms. The differential effects of the PUFAs subtypes should be explored by applying either n-3 or different n-3/n-6 combinations to treat DES. Currently, there are many PUFA supplements on the market, and several head-to-head clinical trials would provide more informative and persuasive evidence to guide the use of the most suitable and effective supplements. The source of the PUFAs, which might influence the efficacy and the economic cost of PUFAs, also should be considered in future study designs. Nutrition Reviews® Vol. 72(10):662–671

CONCLUSION This meta-analysis of 9 RCTs suggests that PUFA supplementation can play a beneficial role in DES treatment, especially for the improvement of dry eye symptoms and ocular inflammation. Even if significant improvement in tear quality and stability or in the indicators of ocular surface damage is not attained, PUFA supplementation still has a potentially useful role in the effective management of DES. Additional large-scale, well-designed RCTs are warranted to expand the base of evidence. Acknowledgments Dr. Zhu and Dr. Wu contributed equally to this manuscript. Declaration of interest. The authors have no relevant interests to declare. REFERENCES 1. Moss SE, Klein R, Klein BE. Prevalence of and risk factors for dry eye syndrome. Arch Ophthalmol. 2000;118:1264–1268. 2. Schaumberg DA, Sullivan DA, Buring JE, et al. Prevalence of dry eye syndrome among US women. Am J Ophthalmol. 2003;136:318–326. 3. Galor A, Feuer W, Lee DJ, et al. Depression, post-traumatic stress disorder, and dry eye syndrome: a study utilizing the national United States Veterans Affairs administrative database. Am J Ophthalmol. 2012;154:340–346. 4. Torpy JM, Lynm C, Golub RM. JAMA patient page. Dry eye. JAMA. 2012;308:632. doi: 10.1001/jama.2012.6221. 5. Lan W, Tong L. Acupuncture has effect on increasing tear break-up time: acupuncture for treating dry eye, a randomized placebo-controlled trial. Acta Ophthalmol. 2012;90:e73. doi: 10.1111/j.1755-3768.2011.02201.x. 6. Reddy P, Grad O, Rajagopalan K. The economic burden of dry eye: a conceptual framework and preliminary assessment. Cornea. 2004;23:751–761. 7. Research in dry eye: report of the Research Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:179–193. 8. Emmungil H, Kalfa M, Zihni FY, et al. Interstitial cystitis: a rare manifestation of primary Sjögren’s syndrome, successfully treated with low dose cyclosporine. Rheumatol Int. 2012;32:1215–1218. 9. Jackson MA, Burrell K, Gaddie IB, et al. Efficacy of a new prescription-only medical food supplement in alleviating signs and symptoms of dry eye, with or without concomitant cyclosporine A. Clin Ophthalmol. 2011;5:1201–1206. 10. Thies F, Garry JM, Yaqoob P, et al. Association of n-3 polyunsaturated fatty acids with stability of atherosclerotic plaques: a randomised controlled trial. Lancet. 2003;361:477–485. 11. Trebble TM, Arden NK, Wootton SA, et al. Fish oil and antioxidants alter the composition and function of circulating mononuclear cells in Crohn disease. Am J Clin Nutr. 2004;80:1137–1144. 12. Cortina MS, Bazan HE. Docosahexaenoic acid, protectins and dry eye. Curr Opin Clin Nutr Metab Care. 2011;14:132–137. 13. Miljanovic B, Trivedi KA, Dana MR, et al. Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women. Am J Clin Nutr. 2005;82:887–893. 14. Jacobson TA. Role of n-3 fatty acids in the treatment of hypertriglyceridemia and cardiovascular disease. Am J Clin Nutr. 2008;87:1981S–1990S. 15. Szajewska H, Horvath A, Koletzko B. Effect of n-3 long-chain polyunsaturated fatty acid supplementation of women with low-risk pregnancies on pregnancy outcomes and growth measures at birth: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2006;83:1337–1344. 16. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6:e1000100. doi: 10.1371/ journal.pmed.1000100. 17. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. doi: 10.1136/ bmj.d5928.

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SUPPORTING INFORMATION Additional Supporting Information may be found in the online version of this article at the publisher’s website: Table S1 The primary non-English articles.

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