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1 CLINICAL SCIENCE Effect of Oral Linoleic and g-linolenic Acid on Meibomian Gland Dysfunction Antonio Pinna, MD, Paola Piccinini, MD, and Francesco Carta, MD Purpose: To assess the effect of oral linoleic and g-linolenic acid, 2 v-6 essential fatty acids, on meibomian gland dysfunction (MGD). Methods: Fifty-seven patients with MGD (27 men and 30 women) were randomly divided into 3 groups of 19. Group A received tablets containing linoleic acid (28.5 mg) and g-linolenic acid (15 mg) once daily. Group B performed eyelid hygiene once daily. Group C received both treatments. Initially and after 60 and 180 days of therapy, all patients completed a self-evaluation questionnaire on ocular surface disorders and underwent slit-lamp examination. The following signs were evaluated: eyelid edema, eyelid margin hyperemia, meibomian secretion appearance, meibomian gland obstruction, foam collection in the tear meniscus, conjunctival hyperemia, conjunctival papillae, and corneal staining. Results: Statistically significant improvement in symptoms occurred in all groups. After 180-day therapy, group A showed significant reduction in secretion turbidity (P = 0.02) and meibomian gland obstruction (P = ), whereas group B had significant reduction in eyelid edema (P = 0.02), corneal staining (P = 0.01), secretion turbidity (P = 0.01), and meibomian gland obstruction (P = ). Group C had significant reduction in eyelid edema (P = 0.003), foam collection in the tear meniscus (P = 0.02), corneal staining (P = 0.02), secretion turbidity (P = ), and meibomian gland obstruction (P = ). Conclusions: Therapy with linoleic and g-linolenic acid tablets along with eyelid hygiene improves symptoms and reduces eyelid margin inflammation in MGD more than either v-6 fatty acids or eyelid hygiene alone. Key Words: meibomian gland dysfunction, therapy, linoleic acid, g-linolenic acid, v-6 fatty acids (Cornea 2007;26: ) Meibomian gland dysfunction (MGD), a major form of blepharitis, is an extremely common, yet often overlooked, chronic disease of the posterior eyelids. 1,2 The pathogenetic mechanisms responsible for MGD are not fully understood. MGD is most often caused by an obstruction of the meibomian glands secondary to hyperkeratinization of the duct epithelium and plugging with a solidified secretion. These changes lead to alterations in the tear film lipid layer with increased evaporation and tear osmolarity, resulting in dry eye signs and symptoms. 3,4 Evidence indicates that meibomian gland secretion in patients with MGD has an increased or decreased melting point and altered excreta viscosity, with the production of toxic and tear film destabilizing components such as fatty acids. 5,6 Long-term treatment is aimed at controlling symptoms through eyelid hygiene. 1,7,8 Systemic antibiotics and topical antibiotic/steroid combinations are used in the short term in patients with a significant amount of inflammation. 1 The v-6 fatty acids, along with v-3 fatty acids, are essential fatty acids required in human nutrition. The v-3 fatty acids are obtained from cold-water fish. Linoleic acid and its derivative g-linolenic acid are 2 v-6 fatty acids obtained from plant sources, including unprocessed, unheated oils, such as corn, sunflower seed, safflower, soy, sesame, cottonseed, black currant seed, and borage oils. Animal sources of v-6 fatty acids, although in smaller amounts than in plants, are lean meats, organ meats, and breast milk. Administration of linoleic and g-linolenic acid as dietary supplements has been reported to have a beneficial effect in the treatment of chronic inflammatory disorders, such as rheumatoid arthritis. 9 Recently, systemic v-6 fatty acids have been shown to reduce ocular surface inflammation and improve dry eye symptoms in patients with Sjögren syndrome and keratoconjunctivitis sicca. 10,11 This study was designed to investigate whether oral linoleic and g-linolenic acid may have a beneficial effect on MGD signs and symptoms. Received for publication August 26, 2005; revision received July 7, 2006; accepted November 8, From the Institute of Ophthalmology, University of Sassari, Sassari, Italy. Presented as a Scientific Poster at the 35th European Contact Lens Society of Ophthalmologists (ECLSO) Congress/12th Medical Contact Lens and Ocular Surface Association (MCLOSA) Meeting, June 23 26, 2005, London, UK. The authors state that they have no proprietary interest in the products named in this article. Reprints: Antonio Pinna, Institute of Ophthalmology, University of Sassari, Viale San Pietro 43 A, Sassari, Italy ( apinna@uniss.it). Copyright Ó 2007 by Lippincott Williams & Wilkins MATERIALS AND METHODS This research was conducted by medically qualified personnel in strict accordance with the guidelines of the University of Sassari School of Medicine Institutional Review Board and in accordance with the Tenets of the Declaration of Helsinki. Fifty-seven patients (30 women and 27 men; average age, years; range, years) diagnosed with MGD according to McCulley classification (group 4, seborrheic with 260 Cornea Volume 26, Number 3, April 2007

2 Cornea Volume 26, Number 3, April 2007 Effect of Oral Linoleic and g-linolenic Acid on MGD meibomian seborrhea; group 5, seborrheic with secondary meibomitis) were selected consecutively. 2 At day 0 (baseline), all patients completed a validated questionnaire on ocular surface disorders, consisting of 11 questions describing the severity and the nature of their irritation symptoms (Table 1). 12 The patients underwent slitlamp examination and Schirmer I test. The following clinical signs were evaluated and recorded: eyelid edema (yes/no), eyelid margin hyperemia (0/+/++/+++), meibomian secretion appearance (turbid/clear), meibomian gland obstruction (yes/no), foam collection in the tear meniscus (yes/no), conjunctival hyperemia (0/+/++/+++), conjunctival papillae (0/+/++/+++), and corneal staining with fluorescein (yes/no). Eyelid edema was defined as swelling of the skin around the palpebral margins. Exclusion criteria were infectious keratoconjunctivitis or inflammatory diseases unrelated to MGD, Schirmer I test,10 mm/5 min, concomitant ocular pathologies, previous ocular surgery, alterations of the lachrymal drainage system, concomitant topical ophthalmic medications, topical ophthalmic steroids taken during the 4 weeks previous to the study, treatment with systemic drugs affecting tearing, pregnancy, diabetes or other systemic, neurologic, or dermatologic disorders affecting the health of the ocular surface. The patients were randomly divided into 3 treatment groups of 19. Group A received tablets containing linoleic acid (28.5 mg) and g-linolenic acid (15 mg; Medilar tablets; Fidia Oftal Bausch & Lomb Pharmaceuticals, Catania, Italy) once daily. Group B performed eyelid hygiene (warm eyelid compresses, eyelid massage, and eyelid margin scrubbing) once daily. Group C received both treatments. All patients were instructed to follow their usual diet. After 60 and 180 days of therapy, all patients were reexamined by a masked evaluator and asked to complete the symptom questionnaire again. The individual total score, obtained by summing the scores of each symptom, was considered. For each group of patients, the arithmetic means of the questionnaire scores at baseline and after 60 and 180 days of therapy were calculated. Student t test was used to compare changes in the scores from baseline within each group. For statistical reasons, throughout the study, we evaluated the worse eye of each patient at baseline, defined as the eye with the higher degree of clinical signs. In the event of equality, the right eye was considered. The x 2 or Fisher exact test was used, when appropriate, to evaluate changes in clinical signs from baseline. P, 0.05 was considered to be statistically significant. RESULTS Six patients (5 women and 1 man; 2 in group A, 2 in group B, and 2 in group C) used soft contact lenses on a dailywear basis. Thirteen patients (7 women and 6 men; 3 in group A, 5 in group B, and 5 in group C) had systemic hypertension under treatment with oral angiotensin-converting enzyme (ACE) inhibitors. Four women (2 in group B and 2 in group C) suffered from hypothyroidism treated with oral thyroxin. Two patients (1 in group B and 1 in group C) dropped out of the study at day 60, and 6 others (3 in group A, 1 in group B, and 2 in group C) were lost at follow-up at day 180. In total, 49 (86%) of 57 patients (16 in group A, 17 in group B, and 16 in group C) completed the study. None reported any particular diet change. TABLE 1. Symptom Questionnaire Never Seldom Sometimes Often Always (0) (1) (2) (3) (4) A Have you experienced any of the following during the last week? 1 Light sensitivity... h h h h h 2 Foreign body sensation... h h h h h 3 Burning or stinging... h h h h h 4 Vision fluctuating with blinking... h h h h h 5 Vision improving with lubricating eye drops... h h h h h 6 Eye-watering... h h h h h 7 Pain or burning in the middle of night or on awakening... h h h h h B Have your eye problems limited you in performing any of the following during the last week? 8 Reading or driving a car for a long period... h h h h h 9 Watching TV or working on a computer for an extended period h h h h h C Have your eyes felt uncomfortable in any of the following situations during the last week? 10 Windy conditions... h h h h h 11 Places with low humidity (e.g., air conditioned or heated buildings, airplanes)... h h h h h Modified from Macri et al. 12 In sections A, B, and C, the score for each row ranged from 0 to 4 (total score ranging from 0 to 44). q 2007 Lippincott Williams & Wilkins 261

3 Pinna et al Cornea Volume 26, Number 3, April 2007 Statistically significant improvement in symptoms occurred in all groups after 60 and 180 days of therapy (P, 0.01). All patients had Schirmer I test.10 mm/5 min. After 60 and 180 days of therapy, reduction in eyelid margin hyperemia, conjunctival hyperemia, and conjunctival papillae was found in all patients; however, results were not statistically significant. Changes from baseline in eyelid edema, meibomian secretion appearance, meibomian gland obstruction, foam collection in the tear meniscus, and corneal staining with fluorescein are shown in Tables 2 and 3. After 180 days of therapy, group A showed a significant reduction in secretion turbidity (P = 0.02) and meibomian gland obstruction (P = ), whereas group B had a significant reduction in eyelid edema (P = 0.02), corneal staining (P = 0.01), secretion turbidity (P = 0.01), and meibomian gland obstruction (P = ). Group C had significant reduction in eyelid edema (P = 0.003), foam collection in the tear meniscus (P = 0.02), corneal staining (P = 0.02), secretion turbidity (P = ), and meibomian gland obstruction (P = ). The x 2 test for independence, calculated using as variables the treatment groups and the clinical changes from baseline (improved, worsened, or unchanged) after 180 days of therapy, revealed no significant relationship between group membership and each of the clinical parameters analyzed (P. 0.05), thus showing that the 3 groups were statistically independent. Consequently, therapy with linoleic and g-linolenic acid tablets along with eyelid hygiene was found to be more effective than either v-6 fatty acids or eyelid hygiene alone (P, 0.05). DISCUSSION MGD is a common chronic cause of ocular irritation. Although MGD rarely threatens sight, it is a troublesome and symptomatic condition. Many patients move fruitlessly from doctor to doctor, seeking a more satisfying solution to the problem. The mainstay of long-term treatment is eyelid hygiene. 1 The patient should be told that MGD is a chronic condition and that eyelid hygiene should become part of the patient s daily routine. In this study, we showed that therapy with linoleic and g-linolenic acid tablets along with eyelid hygiene improves symptoms and reduces eyelid margin inflammation in MGD more than either v-6 fatty acids or eyelid hygiene alone. Evidence indicates that the administration of linoleic and g-linolenic acid as dietary supplements reduces the levels of inflammatory arachidonic acid oxidation products, with the formation of less active prostanoids. 13 Linoleic acid from dietary sources is converted into a derivative fatty acid, g-linolenic acid, which does not accumulate in significant amounts in cell membranes, even when it is provided in the diet. g-linolenic acid is converted into dihomo-g-linolenic acid, a substrate for the enzymes cyclooxygenase and 15-lipoxigenase, which catalyze the production of prostaglandin E1 (PGE1) and 15-hydroxydihomo-g-linolenic acid (15-OH-DGLA), respectively (Fig. 1). Dihomo-g-linolenic acid can also be converted into arachidonic acid, a substrate for the enzymes cyclooxygenase and 5-lipoxigenase, which catalyze the production of prostaglandin E2 (PGE2) and leukotrienes, respectively. PGE1 possesses several anti-inflammatory properties, including inhibition of superoxide, tumor necrosis factor, interleukin-1b, and interleukin Furthermore, 15-OH-DGLA inhibits 5-lipoxygenase, thus reducing the production of arachidonic acid derived eicosanoids with proinflammatory properties, such as leukotrienes B4 and C4. 15,16 On the other hand, PGE2 is inflammatory and increases platelet stickiness and blood clotting. If arachidonic acid and its derivative PGE2 are overproduced or imbalanced with PGE1 and prostaglandin E3 (PGE3), an anti-inflammatory agent derived from v-3 fatty acids, they can increase inflammation. The overconsumption of land-based meats and the underconsumption of unprocessed oils and cold-water fish can lead to an overproduction of proinflammatory PGE2 and an underproduction of anti-inflammatory PGE1 and PGE3. The goal is to consume v-6 fatty acids in a balance with v-3 fatty acids, TABLE 2. Eyelid Edema, Meibomian Gland Obstruction, and Meibomian Secretion Turbidity at Baseline (T0) and After 60 (T60) and 180 Days (T180) of Therapy With Oral Linoleic and g-linolenic Acids (Group A), Eyelid Hygiene (Group B), or Both (Group C) Patients With Eyelid Edema/Total No. Patients (%) Category and Group T0 T60 T180 T0 vs. T60 (P) T0 vs. T180 (P) Eyelid edema Group A 3/19 (16%) 1/19 (5%) 1/16 (6%) Group B 9/19 (47%) 2/18 (11%) 2/17 (12%) Group C 8/19 (42%) 3/18 (17%) 0/16 (0) Meibomian gland obstruction Group A 19/19 (100%) 9/19 (47%) 6/16 (38%) Group B 19/19 (100%) 11/18 (61%) 8/17 (47%) Group C 19/19 (100%) 6/18 (33%) 5/16 (31%) Meibomian secretion turbidity Group A 10/19 (53%) 1/19 (5%) 2/16 (13%) Group B 13/19 (68%) 9/18 (50%) 4/17 (24%) Group C 15/19 (79%) 2/18 (11%) 2/16 (13%) P, 0.05 is considered statistically significant (significant values are underlined). 262 q 2007 Lippincott Williams & Wilkins

4 Cornea Volume 26, Number 3, April 2007 Effect of Oral Linoleic and g-linolenic Acid on MGD TABLE 3. Foam Collection in the Tear Meniscus and Corneal Staining With Fluorescein at Baseline (T0) and After 60 (T60) and 180 Days (T180) of Therapy With Oral Linoleic and g-linolenic Acids (Group A), Eyelid Hygiene (Group B), or Both (Group C) Patients With Foam in Tears/Total No. Patients (%) Category and Group T0 T60 T180 T0 vs. T60 (P) T0 vs. T180 (P) Foam collection in the tear meniscus Group A 2/19 (11%) 1/19 (5%) 1/16 (6%) Group B 5/19 (26%) 7/18 (39%) 2/17 (12%) Group C 8/19 (42%) 1/18 (6%) 1/16 (6%) Corneal staining with fluorescein Group A 4/19 (21%) 2/19 (11%) 0/16 (0) Group B 10/19 (53%) 3/18 (17%) 2/17 (12%) Group C 6/19 (32%) 1/18 (6%) 0/16 (0%) P, 0.05 is considered statistically significant (significant values are underlined). with a suggested optimal ratio of ;4:1. Daily consumption of v- 6 fatty acids by many people may be excessive, because of their presence in common vegetable oils and processed foods. In the Mediterranean diet, there is a balanced ratio of v-6/v-3 fatty acids (;4:1), whereas in the American and Northern European diets, there is an unhealthy overabundance of v-6 fatty acids, with ratios ranging from 15:1 to 18:1. 17 As a result, supplements containing linoleic and g-linolenic acid should be avoided in patients consuming an unbalanced diet with excessive intake of v-6 fatty acids. PGE1 has been shown to have an anti-inflammatory effect in animal models of ocular inflammation and arthritis FIGURE 1. Metabolism of linoleic acid. COX, cyclooxygenase; 15-LOX, 15-lipoxygenase; 5-LOX, 5-lipoxygenase; PG, prostaglandin; 15-OH-DGLA, 15-hydroxy-dihomo-g-linolenic acid; LT, leukotrienes (LTB4, LTC4, LTD4, LTE4). Furthermore, several studies have shown that oral linoleic and g-linolenic acid have a beneficial effect in the treatment of human rheumatoid arthritis. 9,21 Likewise, Barabino et al 10 have shown that systemic therapy with linoleic and g-linolenic acid reduces ocular surface inflammation and improves dry eye symptoms in patients with keratoconjunctivitis sicca. These authors suggested that the clinical efficacy of oral g-linolenic acid in keratoconjunctivitis sicca may be caused by elevation of local PGE1. This hypothesis has recently been confirmed by Aragona et al, 11 who showed that oral v-6 administration increases the PGE1 levels in tears of patients with Sjögren syndrome. To the best of our knowledge, we are unaware of any other reported study about the efficacy of v-6 fatty acids in the treatment of MGD. Meibomian gland secretion consists largely of neutral sterol and wax esters, with lesser amounts of polar lipids, diesters, triesters, triglycerides, free fatty acids, and free sterols. 22 Studies have found statistically significant differences in each component of meibomian secretion in patients with MGD compared with controls. 5,6,23 Interestingly, cholesterol esters are always present in patients with MGD, whereas healthy individuals fall into 2 groups: one with and one without cholesterol esters in their meibomian secretion. 24 This finding suggests that cholesterol esters may be necessary for the development of MGD. Reports have shown considerable variation in lipid composition among healthy individuals. However, there is little doubt that the lipid composition in healthy patients varies greatly from that found in patients with MGD. There is an increased or decreased melting point and altered excreta viscosity in the lipid composition of patients with MGD, with the production of toxic and tear film destabilizing components such as fatty acids. In our study, we evaluated subjective symptoms and objective external eye signs to provide a complete picture of the possible role of linoleic and g-linolenic acid therapy in MGD. Results suggest that oral v-6 fatty acids may have a dual effect in the treatment of MGD. On the one hand, as in rheumatoid arthritis and keratoconjunctivitis sicca, they may have an anti-inflammatory effect and contribute to reducing eyelid edema, eyelid margin hyperemia, and conjunctival hyperemia. On the other hand, they may modify the lipid composition of meibomian secretion, which appears less q 2007 Lippincott Williams & Wilkins 263

5 Pinna et al Cornea Volume 26, Number 3, April 2007 turbid and dense after treatment. These changes may increase the efficacy of eyelid hygiene. In conclusion, our results suggest that therapy with oral linoleic and g-linolenic acid along with eyelid hygiene improves symptoms and reduces eyelid margin inflammation in MGD more than either v-6 fatty acids or eyelid hygiene alone. The v-6 fatty acids, such as linoleic and g-linolenic acid, may help normalize the melting point of the meibomian secretion and reduce eyelid margin inflammation. Although we are greatly encouraged by the improvement in symptoms and clinical signs, further large-scale studies of the long-term effects are necessary before considering extended use of v-6 fatty acids in patients with MGD. ACKNOWLEDGMENT The authors thank Professor Giuliana Solinas, Institute of Hygiene and Preventive Medicine, University of Sassari, Sassari, Italy, for essential statistical assistance. REFERENCES 1. Driver P, Lemp MA. Seborrhea and meibomian gland dysfunction. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. St. Louis, MO: Mosby-Year Book; 1997: McCulley JP, Dougherty JM, Denau DG. Classification of chronic blepharitis. Ophthalmology. 1982;89: Tiffany JM. The role of meibomian secretion in the tears. Trans Ophthalmol Soc U K. 1985;104: Mathers WD. Ocular evaporation in meibomian gland dysfunction and dry eye. Ophthalmology. 1993;100: Shine WE, McCulley JP. Role of wax ester fatty alcohols in chronic blepharitis. Invest Ophthalmol Vis Sci. 1993;34: Shine WE, McCulley JP. Polar lipids in human meibomian gland secretions. Curr Eye Res. 2003;26: Olson MC, Korb DR, Greiner JV. Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction. Eye Contact Lens. 2003;29: Nagymihalyi A, Dikstein S, Tiffany JM. The influence of eyelid temperature on the delivery of meibomian oil. Exp Eye Res. 2004;78: Calder PC, Zurier RB. Polyunsatered fatty acids and rheumatoid arthritis. Curr Opin Clin Nutr Metab Care. 2001;4: Barabino S, Rolando M, Camicione P, et al. Systemic linoleic and gammalinolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea. 2003;22: Aragona P, Bucolo C, Spinella R, et al. Systemic omega-6 essential fatty acid treatment and PGE1 tear content in Sjögren s syndrome patients. Invest Ophthalmol Vis Sci. 2005;46: Macri A, Rolando M, Pfugfelder S. A standardized visual scale for evaluation of tear fluorescein clearance. Ophthalmology. 2000;107: Wu D, Meydani M, Leka LS, et al. Effect of dietary supplementation with black currant seed oil on the immune response of healthy subjects. Am J Clin Nutr. 1999;70: Devchand PR, Keller H, Peters JM, et al. The PPAR-leukotriene B4 pathway to inflammation control. Nature. 1996;384: Johnson MM, Swan DD, Surette ME, et al. Dietary supplementation with gamma-linolenic acid alters fatty acid content and eicosanoid production in healthy humans. J Nutr. 1997;127: Levin G, Duffin KL, Obukowicz MG, et al. Differential metabolism of dihomo-gamma-linolenic acid and arachidonic acid by cyclo-oxigenase-1 and cyclo-oxigenase-2: implications for cellular synthesis of prostaglandin E1 and prostaglandin E2. Biochem J. 2002;365: Simopoulos AP. The Mediterranean diets: what is so special about the diet of Greece? The scientific evidence. J Nutr. 2001;131:3065(S) 3073(S). 18. Zurier RB. Prostaglandins. Their potential in clinical medicine. Postgrad Med. 1980;68: Hoyng PF, Verbey N, Thong L, et al. Topical prostaglandins inhibit trauma-induced inflammation in the rabbit eye. Invest Ophthalmol Vis Sci. 1986;27: Zurier RB, Quagliata F. Effect of prostaglandin E1 on adjuvant arthritis. Nature. 1971;234; Belch JJF, Muir A. Evening primrose oil and borage oil in rheumatologic conditions. Am J Clin Nutr. 2000;71(suppl): Nicolaides N, Kaitaranta JK, Rawdah TN, et al. Meibomian gland studies: comparison of steer and human lipids. Invest Ophthalmol Vis Sci. 1981; 20: Dougherty JM, Osgood JK, McCulley JP. The role of wax and sterol ester fatty acids in chronic blepharitis. Invest Ophthalmol Vis Sci. 1991;32: Shine WE, McCulley JP. The role of cholesterol in chronic blepharitis. Invest Ophthalmol Vis Sci. 1991;32: q 2007 Lippincott Williams & Wilkins

OCULAR SURFACE DISEASE SYNDROMES WAYNE ISAEFF, MD LOMA LINDA UNIVERSITY DEPARTMENT OF OPHTHALMOLOGY

OCULAR SURFACE DISEASE SYNDROMES WAYNE ISAEFF, MD LOMA LINDA UNIVERSITY DEPARTMENT OF OPHTHALMOLOGY SURFACE DISEASE DRY EYE DYSFUNCTIONAL TEARS SYND ALLERGIC DISORDERS MEIBOMIAN GLAND PROBLEMS OCULAR IMMUNE