A Randomized, Double-Masked, Placebo-Controlled Clinical Trial of Two Forms of Omega-3 Supplements for Treating Dry Eye Disease.

PURPOSE To assess the efficacy of 2 forms of oral long-chain omega-3 (ω-3) essential fatty acid (EFA) supplements, phospholipid (krill oil) and triacylglyceride (fish oil), for treating dry eye disease (DED). DESIGN Randomized, double-masked, placebo-controlled clinical trial. PARTICIPANTS This study was conducted at a single site and involved 60 participants with mild to moderate DED who were randomized (1:1:1) to 1 of 3 groups: placebo (olive oil), krill oil, or fish oil supplements. METHODS Participants received 1 of the 3 interventions: placebo (olive oil 1500 mg/day), krill oil (945 mg/day eicosapentaenoic acid [EPA], + 510 mg/day docosahexaenoic acid [DHA]), or fish oil (1000 mg/day EPA + 500 mg/day DHA) for 90 days, with monthly study visits. MAIN OUTCOME MEASURES Primary outcome measures were mean change in (1) tear osmolarity and (2) DED symptoms (Ocular Surface Disease Index [OSDI] score) between days 1 and 90. Secondary outcomes included mean change in key clinical signs (tear stability, tear production, ocular surface staining, bulbar and limbal redness, tear volume, anterior blepharitis, meibomian gland capping) and tear inflammatory cytokine levels. RESULTS In total, 54 participants completed the study. At day 90, tear osmolarity was reduced from baseline with both krill oil (mean ± standard error of the mean: -18.6±4.5 mOsmol/l; n = 18; P < 0.001) and fish oil (-19.8±3.9 mOsmol/l; n = 19; P < 0.001) supplements, compared with placebo (-1.5±4.4 mOsmol/l; n = 17). OSDI score was significantly reduced at day 90 relative to baseline in the krill oil group only, compared with placebo (-18.6±2.4 vs. -10.5±3.3; P = 0.02). At day 90, there were also relative improvements in tear breakup time and ocular bulbar redness, compared with placebo, for both forms of ω-3 EFAs. Basal tear levels of the proinflammatory cytokine interleukin 17A were significantly reduced in the krill oil group, compared with placebo, at day 90 (-27.1±10.9 vs. 46.5±30.4 pg/ml; P = 0.02). CONCLUSIONS A moderate daily dose of both forms of long-chain ω-3 EFAs, for 3 months, resulted in reduced tear osmolarity and increased tear stability in people with DED. Omega-3 EFAs in a predominantly phospholipid form (krill oil) may confer additional therapeutic benefit, with improvements in DED symptoms and lower basal tear levels of interleukin 17A, relative to placebo.

[1]  Prachi Kumar,et al.  A randomized controlled trial of omega-3 fatty acids in dry eye syndrome. , 2013, International journal of ophthalmology.

[2]  Dong Wang,et al.  A randomized, double-masked study to evaluate the effect of omega-3 fatty acids supplementation in meibomian gland dysfunction , 2013, Clinical interventions in aging.

[3]  G. Duchateau,et al.  Age dependent incorporation of 14C-DHA into rat brain and body tissues after dosing various 14C-DHA-esters. , 2010, Prostaglandins, leukotrienes, and essential fatty acids.

[4]  J. O’Shea,et al.  Th17 cells: a new fate for differentiating helper T cells , 2008, Immunologic research.

[5]  K. Kenyon,et al.  Tear film osmolarity and ocular surface disease in two rabbit models for keratoconjunctivitis sicca. , 1988, Investigative ophthalmology & visual science.

[6]  De-Quan Li,et al.  Epithelial-immune cell interaction in dry eye. , 2008, Cornea.

[7]  Angus McFadyen,et al.  Tear film osmolarity: determination of a referent for dry eye diagnosis. , 2006, Investigative ophthalmology & visual science.

[8]  L. Downie.  Automated Tear Film Surface Quality Breakup Time as a Novel Clinical Marker for Tear Hyperosmolarity in Dry Eye Disease. , 2015, Investigative ophthalmology & visual science.

[9]  S. Pflugfelder,et al.  New testing options for diagnosing and grading dry eye disease. , 2014, American journal of ophthalmology.

[10]  S. Pflugfelder,et al.  Topical cyclosporine inhibits conjunctival epithelial apoptosis in experimental murine keratoconjunctivitis sicca. , 2005, Cornea.

[11]  L. Downie,et al.  A Pragmatic Approach to the Management of Dry Eye Disease: Evidence into Practice , 2015, Optometry and vision science : official publication of the American Academy of Optometry.

[12]  S. Pflugfelder,et al.  Topical nonpreserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjögren syndrome. , 1999, Ophthalmology.

[13]  Christophe Baudouin,et al.  Tear osmolarity in the diagnosis and management of dry eye disease. , 2011, American journal of ophthalmology.

[14]  H. Hashemi,et al.  Short-term consumption of oral omega-3 and dry eye syndrome. , 2013, Ophthalmology.

[15]  Tian-yu Chen,et al.  Endogenous n-3 polyunsaturated fatty acids protect against imiquimod-induced psoriasis-like inflammation via the IL-17/IL-23 axis , 2014, Molecular medicine reports.

[16]  J. Chodosh,et al.  A randomized, double-masked, placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunctivitis sicca in patients with delayed tear clearance. , 2004, American journal of ophthalmology.

[17]  A. Simopoulos,et al.  The importance of the ratio of omega-6/omega-3 essential fatty acids. , 2002, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[18]  S. Matsuda,et al.  Mechanisms of action of cyclosporine. , 2000, Immunopharmacology.

[19]  De-Quan Li,et al.  IL-17 disrupts corneal barrier following desiccating stress , 2009, Mucosal Immunology.

[20]  M. Pinazo-Durán,et al.  Effects of a nutraceutical formulation based on the combination of antioxidants and ω-3 essential fatty acids in the expression of inflammation and immune response mediators in tears from patients with dry eye disorders , 2013, Clinical interventions in aging.

[21]  S. Yeh,et al.  Apoptosis of ocular surface cells in experimentally induced dry eye. , 2003, Investigative ophthalmology & visual science.

[22]  L. Downie,et al.  A Pragmatic Approach to Dry Eye Diagnosis: Evidence into Practice , 2015, Optometry and vision science : official publication of the American Academy of Optometry.

[23]  P. J. Murphy,et al.  The Effect of Instilled Fluorescein Solution Volume on the Values and Repeatability of TBUT Measurements , 2005, Cornea.

[24]  A. Vingrys,et al.  Accuracy of Laboratory Assays in Ophthalmic Practice. , 2015, JAMA ophthalmology.

[25]  P. Asbell,et al.  Minimal clinically important difference for the ocular surface disease index. , 2010, Archives of ophthalmology.

[26]  J. McCulley,et al.  Pilot, Prospective, Randomized, Double-masked, Placebo-controlled Clinical Trial of an Omega-3 Supplement for Dry Eye , 2011, Cornea.

[27]  R. Gibson,et al.  Dietary polyunsaturated fatty acids and inflammatory mediator production. , 2000, The American journal of clinical nutrition.

[28]  A. Bron,et al.  Amélioration de la symptomatologie chez des patients atteints de sécheresse oculaire et traités oralement par des acides gras polyinsaturés , 2006 .

[29]  R. Bustos,et al.  Oxidative stability of carotenoid pigments and polyunsaturated fatty acids in microparticulate diets containing krill oil for nutrition of marine fish larvae , 2003 .

[30]  James E. Evans,et al.  Correlations between nutrient intake and the polar lipid profiles of meibomian gland secretions in women with Sjögren's syndrome. , 2000, Advances in experimental medicine and biology.

[31]  Jennifer I. Lim,et al.  A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. , 2001, Archives of ophthalmology.

[32]  M. Viitanen,et al.  Oral sea buckthorn oil attenuates tear film osmolarity and symptoms in individuals with dry eye. , 2010, The Journal of nutrition.

[33]  D. Moher,et al.  CONSORT 2010 Statement: updated guidelines for reporting parallel group randomised trials , 2010, BMC medicine.

[34]  T. Strasser,et al.  Supplementation with n‐3 fatty acids from fish oil in chronic inflammatory bowel disease—a randomized, placebo‐controlled, double‐blind cross‐over trial , 1989, Journal of internal medicine. Supplement.

[35]  T. Kawakita,et al.  Amelioration of ultraviolet-induced photokeratitis in mice treated with astaxanthin eye drops , 2012, Molecular vision.

[36]  A. Tomlinson,et al.  Role of hyperosmolarity in the pathogenesis and management of dry eye disease: proceedings of the OCEAN group meeting. , 2013, The ocular surface.

[37]  J. Buring,et al.  Relation between dietary n-3 and n-6 fatty acids and clinically diagnosed dry eye syndrome in women. , 2005, The American journal of clinical nutrition.

[38]  H. Tony,et al.  Correlation Between Tear Film Osmolarity, Dry Eye Disease, and Rheumatoid Arthritis , 2014, Cornea.

[39]  M. Macsai.  The role of omega-3 dietary supplementation in blepharitis and meibomian gland dysfunction (an AOS thesis). , 2008, Transactions of the American Ophthalmological Society.

[40]  Guigang Li,et al.  Efficacy of polyunsaturated fatty acids for dry eye syndrome: a meta-analysis of randomized controlled trials. , 2014, Nutrition reviews.

[41]  R. Dana,et al.  Impact of dry eye syndrome on vision-related quality of life. , 2007, American journal of ophthalmology.

[42]  R. Schiffman,et al.  Reliability and validity of the Ocular Surface Disease Index. , 2000, Archives of ophthalmology.

[43]  P. Morgan,et al.  Short-Term Physiologic Response in Neophyte Subjects Fitted with Hydrogel and Silicone Hydrogel Contact Lenses , 2004, Optometry and vision science : official publication of the American Academy of Optometry.

[44]  N. Black.  CONSORT , 1996, The Lancet.

[45]  Budbazar Enkhjargal,et al.  Effects of Krill-derived phospholipid-enriched n-3 fatty acids on Ca(2+) regulation system in cerebral arteries from ovariectomized rats. , 2014, Life sciences.

[46]  P. Calder.  Omega-3 Polyunsaturated Fatty Acids , 2013 .

[47]  De-Quan Li,et al.  Hyperosmolarity-Induced Apoptosis in Human Corneal Epithelial Cells Is Mediated by Cytochrome c and MAPK Pathways , 2007, Cornea.

[48]  F. Mantelli,et al.  Systematic review of randomised clinical trials on topical ciclosporin A for the treatment of dry eye disease , 2013, British Journal of Ophthalmology.

[49]  S. Pflugfelder,et al.  T helper cytokines in dry eye disease. , 2013, Experimental eye research.

[50]  M. Collu,et al.  Dietary krill oil increases docosahexaenoic acid and reduces 2-arachidonoylglycerol but not N-acylethanolamine levels in the brain of obese Zucker rats , 2010 .

[51]  P. Jones,et al.  Enhanced increase of omega-3 index in healthy individuals with response to 4-week n-3 fatty acid supplementation from krill oil versus fish oil , 2013, Lipids in Health and Disease.

[52]  N Efron,et al.  Grading scales for contact lens complications , 1998, Ophthalmic & physiological optics : the journal of the British College of Ophthalmic Opticians.

[53]  A. Vingrys,et al.  Tear Interferon-Gamma as a Biomarker for Evaporative Dry Eye Disease. , 2016, Investigative ophthalmology & visual science.

[54]  S. Lane,et al.  Effect of Oral Re-esterified Omega-3 Nutritional Supplementation on Dry Eyes , 2016, Cornea.

[55]  J. Pepose,et al.  Clinical Utility of Objective Tests for Dry Eye Disease: Variability Over Time and Implications for Clinical Trials and Disease Management , 2012, Cornea.

[56]  Christophe Baudouin,et al.  The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). , 2007, The ocular surface.

[57]  L. Sechi,et al.  The vascular response to vasodilators is related to the membrane content of polyunsaturated fatty acids in hypertensive patients , 2015, Journal of hypertension.

[58]  Dean P. Jones,et al.  A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. , 2001, Archives of ophthalmology.

[59]  A. Bron,et al.  Grading Of Corneal and Conjunctival Staining in the Context of Other Dry Eye Tests , 2003, Cornea.