Supplements Management and Pharmacoeconomics of Dry Eye Disease: The Role of Cyclosporine
Management of Dry Eye
• Topical corticosteroids. Although effective, these agents are generally recommended only for short-term use because prolonged use may result in AEs including ocular infection, glaucoma, and cataracts.
• Oral tetracyclines. Based on limited evidence, oral tetracyclines have been used off-label to treat DED, primarily DED associated with ocular rosacea.
• Topical cyclosporine. Topical cyclosporine is currently the only pharmacologic treatment that is FDA approved specifically for DED. Although its onset of action is relatively slow, it is safe for long-term use and appears to be disease-modifying rather than merely palliative. The most common AE is transient burning or stinging. Because blood levels are negligible even after long-term use, the risk of systemic toxicity is minimal.
Topical NSAIDs have been used off-label in DED; however, their use is controversial because they can promote corneal melting in patients with a compromised ocular surface. Some experts feel that they have no role in DED therapy.
Treatment selection is guided primarily by DED severity. ITF guidelines, published in 2006, proposed a DED severity classification based on clinical signs and symptoms. The ITF also developed a treatment algorithm according to severity grading and the presence or absence of lid margin disease. In 2007 the DEWS Management and Therapy Subcommittee published treatment recommendations based on a modified form of the ITF severity classification.
Author Affiliations: From Georgetown and George Washington Universities, and OcuSense, Inc, Washington, DC.
Funding Sources: The research and manuscript were funded by Allergan, Inc.
Author Disclosures: The author reports being a consultant for Alcon, Allergan, Novagali Pharma, OcuSense, Inc, and SARcode; and being a major stock shareholder for OcuSense, Inc.
Authorship Information: Concept and design, drafting of the manuscript, and critical revision of the manuscript for important intellectual content.
Address Correspondence to: Michael A. Lemp, MD, 4000 Cathedral Avenue, NW #828B, Washington, DC 20016. E-mail: email@example.com.
1. American Academy of Ophthalmology. Preferred practice pattern: dry eye syndrome. http://www.aao.org/education/guidelines/ppp/upload/Dry_Eye_Syndrome-2.pdf. Published 2003. Accessed February 13, 2008.
2. Management and therapy of dry eye disease: report of the Management and Therapy Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf.
2007;5:163-178. http://www.tearfilm.org/dewsreport/. Published April 2007. Accessed February 13, 2008.
3. Blehm C,Vishnu S, Khattak A, Mitra S,Yee RW. Computer vision syndrome: a review. Surv Ophthalmol. 2005;50:253-262.
4. Wolkoff P, Nojgaard JK,Troiano P, Piccoli B. Eye complaints in the office environment: precorneal tear film integrity influenced by eye blinking efficiency. Occup Environ Med. 2005;62:4-12.
5. Perry HD. Dry eye disease: pathophysiology, classification, and diagnosis. Am J Manag Care. 2008;14:S79-S87.
6. Gilbard JP. The diagnosis and management of dry eyes. Otolaryngol Clin North Am. 2005;38:871-885.
7. Craig JP, Blades K, Patel S. Tear lipid layer structure and stability following expression of the meibomian glands. Ophthalmic Physiol Opt. 1995;15:569-574.
8. Korb DR, Greiner JV. Increase in tear film lipid layer thickness following treatment of meibomian gland dysfunction. Adv Exp Med Biol. 1994;350:293-298.
9. Asbell PA. Increasing importance of dry eye syndrome and the ideal artificial tear: consensus views from a roundtable discussion. Curr Med Res Opin. 2006;22:2149-2157.
10. McDonald M. Latest trends in dry eye treatments (advertorial). Cornea Society News. 2007 Spring;3:7-8.
11. Guttman C. Dry eye patients take pick as new treatments flood market. Eurotimes, Eye to Eye Supplement. May 2003. http://www.escrs.org/eurotimes/May2003/dryeye.asp. Accessed February 13, 2008.
12. Soothe XP emollient (lubricant) eye drops FAQs. Bausch & Lomb, 2008. http://www.bausch.com/en_US/consumer/visioncare/faq/soothe_eyedrops_faqs.aspx.
Accessed February 13, 2008.
13. Di Pascuale MA, Goto E,Tseng SC. Sequential changes of lipid tear film after the instillation of a single drop of a new emulsion eye drop in dry eye patients. Ophthalmology. 2004;111:783-791.
14. Foulks GN. Clinical evaluation of the efficacy of PEG/PG lubricant eye drops with gelling agent (HPguar) for the relief of the signs and symptoms of dry eye disease: a review. Drugs Today (Barc). 2007;43:887-896.
15. Gifford P, Evans BJ, Morris J. A clinical evaluation of Systane. Cont Lens Anterior Eye. 2006;29:31-40.
16. Prabhasawat P, Tesavibul N, Kasetsuwan N. Performance profile of sodium hyaluronate in patients with lipid tear deficiency: randomised, double-blind,
controlled, exploratory study. Br J Ophthalmol. 2007;91:47-50.
17. Moon JW, Lee HJ, Shin KC,Wee WR, Lee JH, Kim MK. Short term effects of topical cyclosporine and viscoelastic on the ocular surfaces in patients with dry eye. Korean J Ophthalmol. 2007;21:189-194.
18. Aragona P, Papa V, Micali A, Santocono M, Milazzo G. Long term treatment with sodium hyaluronate-containing artificial tears reduces ocular surface damage in
patients with dry eye. Br J Ophthalmol. 2002;86:181-184.
19. Brignole F, Pisella PJ, Dupas B, Baeyens V, Baudouin C. Efficacy and safety of 0.18% sodium hyaluronate in patients with moderate dry eye syndrome and superficial
keratitis. Graefes Arch Clin Exp Ophthalmol. 2005;243:531-538.
20.Vehige JG, Simmons PA. Ocular lubrication vs. viscosity of ophthalmic products. Contact Lens Spectrum; December 2004. http://www.clspectrum.com/article.aspx?article=12720. Accessed February 18, 2008.
21. Harvey B. Five days in Denver (conference report). Optician. 2007 Jan 12;233:15-16. http://www.optician online.net/assets/getAsset.aspx?ItemID=2143. Accessed February 18, 2008.
22. Sall KN, Cohen SM, Christensen MT, Stein JM. An evaluation of the efficacy of a cyclosporine-based dry eye therapy when used with marketed artificial tears as
supportive therapy in dry eye. Eye Contact Lens. 2006;32:21-26.
23. Christensen MT, Cohen S, Rinehart J, et al. Clinical evaluation of an HP-guar gellable lubricant eye drop for the relief of dryness of the eye. Curr Eye Res.
24. Ousler GW, Michaelson C, Christensen MT. An evaluation of tear film breakup time extension and ocular protection index scores among three marketed lubricant
eye drops. Cornea. 2007;26:949-952.
25. Korb DR, Scaffidi RC, Greiner JV, et al. The effect of two novel lubricant eye drops on tear film lipid layer thickness in subjects with dry eye symptoms. Optom
Vis Sci. 2005;82:594-601.
26. Scaffidi RC, Korb DR. Comparison of the efficacy of two lipid emulsion eyedrops in increasing tear film lipid layer thickness. Eye Contact Lens. 2007;33:38-44.
27. Geerling G, MacLennan S, Hartwig D. Autologous serum eye drops for ocular surface disorders. Br J Ophthalmol. 2004;88:1467-1474.
28. Noble BA, Loh RS, MacLennan S, et al. Comparison of autologous serum eye drops with conventional therapy in a randomised controlled crossover trial for ocular
surface disease. Br J Ophthalmol. 2004;88:647-652.
29. Tananuvat N, Daniell M, Sullivan LJ, et al. Controlled study of the use of autologous serum in dry eye patients. Cornea. 2001;20:802-806.
30. Kojima T, Ishida R, Dogru M, et al. The effect of autologous serum eyedrops in the treatment of severe dry eye disease: a prospective randomized case-control
study. Am J Ophthalmol. 2005;139:242-246.
31. Noda-Tsuruya T, Asano-Kato N,Toda I, Tsubota K. Autologous serum eye drops for dry eye after LASIK. J Refract Surg. 2006;22:61-66.
32. Behrens A, Doyle JJ, Stern L, et al. Dysfunctional tear syndrome: a Delphi approach to treatment recommendations. Cornea. 2006;25:900-907.
33. Taban M, Chen B, Perry JD. Update on punctal plugs. Compr Ophthalmol Update. 2006;7:205-212; discussion 213-214.
34. American Optometric Association. Optometric clinical practice guideline: care of the patient with ocular surface disorders. http://www.aoa.org/documents/CPG-10.pdf. 2002, updates April and June 2003. Accessed February 13, 2008.
35. Lindsay RG. Therapeutic use of silicone hydrogel lenses for the management of dry eye. In The Practice; March 2007. http://www.siliconehydrogels.org/in_the_practice/mar_07.asp. Accessed February 18, 2008.
36. Diller R, Sant S. A case report and review of filamentary keratitis. Optometry. 2005;76:30-36.
37. Albietz J, Sanfilippo P,Troutbeck R, Lenton LM. Management of filamentary keratitis associated with aqueous- deficient dry eye. Optom Vis Sci. 2003;80:420-430.
38. Rosenthal P, Croteau A. Fluid-ventilated, gas-permeable scleral contact lens is an effective option for managing severe ocular surface disease and many corneal
disorders that would otherwise require penetrating keratoplasty. Eye Contact Lens. 2005;31:130-134.
39. Jacobs DS, Rosenthal P. Boston Scleral Lens prosthetic device for treatment of severe dry eye in chronic graft-versus-host disease. Cornea. 2007;26:1195-1199.
40. Rosenthal P, Cotter J. The Boston Scleral Lens in the management of severe ocular surface disease. Ophthalmol Clin North Am. 2003;16:89-93.
41. Cosar CB, Cohen EJ, Rapuano CJ, et al. Tarsorrhaphy: clinical experience from a cornea practice. Cornea. 2001;20:787-791.
42. Salagen (pilocarpine) product information. MGI Pharma; September 2003. http://www.mgipharma.com/ pdfs/salagen_pi.pdf. Accessed February 18, 2008.
43. Evoxac (cevimeline) product information. Daiichi Sankyo; April 2005. http://www.evoxac.com/prescrib ing_info.htm. Accessed February 18, 2008.
44. Nelson JD, Friedlaender M,Yeatts RP, et al; and MGI PHARMA Sjögren’s Syndrome Study Group. Oral pilocarpine for symptomatic relief of keratoconjunctivitis
sicca in patients with Sjögren’s syndrome. Adv Exp Med Biol. 1998;438:979-983.
45. Papas AS, Fernandez MM, Castano RA, Gallagher SC, Trivedi M, Shrotriya RC. Oral pilocarpine for symptomatic relief of dry mouth and dry eyes in patients with Sjögren’s syndrome. Adv Exp Med Biol. 1998;438:973-978.
46.Vivino FB, Al-Hashimi I, Khan Z, et al, for the P92-01 Study Group. Pilocarpine tablets for the treatment of dry mouth and dry eye symptoms in patients with
Sjögren syndrome: a randomized, placebo-controlled, fixed-dose, multicenter trial. Arch Intern Med. 1999;159:174-181.
47. Tsifetaki N, Kitsos G, Paschides CA, et al. Oral pilocarpine for the treatment of ocular symptoms in patients with Sjögren’s syndrome: a randomised 12 week controlled study. Ann Rheum Dis. 2003;62:1204-1207.
48. Petrone D, Condemi JJ, Fife R, Gluck O, Cohen S, Dalgin P. A double-blind, randomized, placebo-controlled study of cevimeline in Sjögren’s syndrome
patients with xerostomia and keratoconjunctivitis sicca. Arthritis Rheum. 2002;46:748-754.
49. Ono M,Takamura E, Shinozaki K, et al. Therapeutic effect of cevimeline on dry eye in patients with Sjögren’s syndrome: a randomized, double-blind clinical
study. Am J Ophthalmol. 2004;138:6-17.
50. Avunduk AM, Avunduk MC, Varnell ED, Kaufman HE. The comparison of efficacies of topical corticosteroids and nonsteroidal anti-inflammatory drops on dry eye
patients: a clinical and immunocytochemical study. Am J Ophthalmol. 2003;136:593-602.
51. Pflugfelder SC, Maskin SL, Anderson B, 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. Am J Ophthalmol. 2004;138:444-457.
52. Lee HK, Ryu IH, Seo KY, Hong S, Kim HC, Kim EK. Topical 0.1% prednisolone lowers nerve growth factor expression in keratoconjunctivitis sicca patients. Ophthalmology. 2006;113:198-205.
53. Sainz De La Maza Serra M, Simon Castellvi C, Kabbani O. Nonpreserved topical steroids and lacrimal punctal occlusion for severe keratoconjunctivitis sicca. Arch
Soc Esp Oftalmol. 2000;75:751-756. [English abstract; article in Spanish]
54. Lotemax (loteprednol etabonate ophthalmic suspension) product information. Bausch & Lomb; April 2006. http://www.bausch.com/en_US/downloads/ecp/pharma/general/lotemaxinsert.pdf. Accessed February 19, 2008.
55. Oracea (doxycycline) product information. CollaGenex Pharmaceuticals; June 2007. http://www.oracea.com/PDF/ORA-0214_Full_PI_m2.pdf. Accessed March 26, 2008.
56. Seal DV,Wright P, Ficker L, Hagan K,Troski M, Menday P. Placebo controlled trial of fusidic acid gel and oxytetracycline for recurrent blepharitis and rosacea. Br J Ophthalmol. 1995;79:42-45.
57. Bartholomew RS, Reid BJ, Cheesbrough MJ, Macdonald M, Galloway NR. Oxytetracycline in the treatment of ocular rosacea: a double-blind trial. Br J Ophthalmol. 1982;66:386-388.
58. Zengin N,Tol H, Gunduz K, Okudan S, Balevi S, Endogru H. Meibomian gland dysfunction and tear film abnormalities in rosacea. Cornea. 1995;14:144-146.
59. Restasis (cyclosporine ophthalmic emulsion) product information. Allergan, Inc, February 2004. http://www.restasisprofessional.com/_prescribe/prescribe_home.htm. Accessed February 19, 2008.
60.Turner K, Pflugfelder SC, Ji Z, Fener WJ, Stern M, Reis BL. Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporine ophthalmic emulsion. Cornea. 2000;19:492-496.
61. Kunert KS, Tisdale AS, Stern ME, Smith JA, Gipson IK. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol. 2000;118:1489-1496.
62. Brignole F, Pisella PJ, De Saint Jean M, Goldschild M, Goguel A, Baudouin C. Flow cytometric analysis of inflammatory markers in KCS: 6-month treatment with
topical cyclosporin A. Invest Ophthalmol Vis Sci. 2001;42:90-95.
63. Baudouin C, Brignole F, Pisella PJ, De Saint Jean MS, Goguel A. Flow cytometric analysis of the inflammatory marker HLA DR in dry eye syndrome: results from 12 months of randomized treatment with topical cyclosporin A. Adv Exp Med Biol. 2002;506(Pt B):761-769.
64. Kunert KS, Tisdale AS, Gipson IK. Goblet cell numbers and epithelial proliferation in the conjunctiva of patients with dry eye syndrome treated with cyclosporine. Arch Ophthalmol. 2002;120:330-337. Erratum in: Arch Ophthalmol. 2002;120:1099.
65. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporine ophthalmic emulsion in moderate to
severe dry eye disease. CsA Phase 3 Study Group. Ophthalmology. 2000;107:631-639. Erratum in: Ophthalmology. 2000;107:1220.
66. Barber LD, Pflugfelder SC,Tauber J, Foulks GN. Phase III safety evaluation of cyclosporine 0.1% ophthalmic emulsion administered twice daily to dry eye disease
patients for up to 3 years. Ophthalmology. 2005;112:1790-1794.
67. Small DS, Acheampong A, Reis B, et al. Blood concentrations of cyclosporin A during long-term treatment with cyclosporin A ophthalmic emulsions in patients
with moderate to severe dry eye disease. J Ocul Pharmacol Ther. 2002;18:411-418.
68. Avisar R, Robinson A, Appel I, et al. Diclofenac sodium, 0.1% (Voltaren Ophtha), versus sodium chloride, 5%, in the treatment of filamentary keratitis. Cornea.
69. Schechter BA. Ketorolac during the induction phase of cyclosporin-A therapy. J Ocul Pharmacol Ther. 2006;22:150-154.
70. Aragona P, Stilo A, Ferreri F, Mobrici M. Effects of the topical treatment with NSAIDs on corneal sensitivity and ocular surface of Sjögren’s syndrome patients.
71. Aragona P, Di Pietro R. Is it safe to use topical NSAIDs for corneal sensitivity in Sjögren’s syndrome patients? Expert Opin Drug Saf. 2007;6:33-43.
72. Pinna A, Piccinini P, Carta F. Effect of oral linoleic and gamma-linolenic acid on meibomian gland dysfunction. Cornea. 2007;26:260-264.
73. TheraTears Nutrition. Advanced Vision Research, Inc. http://www.theratears.com/nutrition.aspx. Accessed February 21, 2008.
74. BioTears. Biosyntrx. http://www.biosyntrx.com/Supplement.php?item_id=1. Accessed February 21, 2008.
75. Miljanovic B,Trivedi KA, Dana MR, Gilbard JP, Buring JE, Schaumberg DA. 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.
76. Singh M, Singh M, Papas A. The effect of an omega-3 supplement on dry mouth and dry eye in Sjögren’s patients. Abstract #87. IXth International Symposium
on Sjögren’s Syndrome; April 27-29, 2006; Washington, DC. http://www.sjogrens.org/research/ISSS/isss_poster_abstracts_day2.pdf. Accessed February 18, 2008.
77. Oxholm P, Manthorpe R, Prause JU, Horrobin D. Patients with primary Sjögren’s syndrome treated for two months with evening primrose oil. Scand J Rheumatol. 1986;15:103-108.
78. Theander E, Horrobin DF, Jacobsson LT, Manthorpe R. Gammalinolenic acid treatment of fatigue associated with primary Sjögren’s syndrome. Scand J Rheumatol.
79. Barabino S, Rolando M, Camicione P, et al. Systemic linoleic and gamma-linolenic acid therapy in dry eye syndrome with an inflammatory component. Cornea.
80. Aragona P, Bucolo C, Spinella R, Giuffrida S, Ferreri G. Systemic omega-6 essential fatty acid treatment and pge1 tear content in Sjögren’s syndrome patients.
Invest Ophthalmol Vis Sci. 2005;46:4474-4479.
81. Macri A, Giuffrida S, Amico V, Iester M, Traverso CE. Effect of linoleic acid and gamma-linolenic acid on tear production, tear clearance and on the ocular surface
after photorefractive keratectomy. Graefes Arch Clin Exp Ophthalmol. 2003;241:561-566.
82. Absolon MJ, Brown CA. Acetylcysteine in keratoconjunctivitis sicca. Br J Ophthalmol. 1968;52:310-316.
83. Calonge M. The treatment of dry eye. Surv Ophthalmol. 2001;45:S227-S239.
84. Anzaar F, Foster CS, Ekong AS. Dry eye syndrome. eMedicine. http://www.emedicine.com/oph/topic 597.htm. Updated August 25, 2006. Accessed February 13, 2008.
85. Murphy PT, Sivakumaran M, Fahy G, Hutchinson RM. Successful use of topical retinoic acid in severe dry eye due to chronic graft-versus-host disease. Bone Marrow Transplant. 1996;18:641-642.
86. Tseng SC, Maumenee AE, Stark WJ, et al. Topical retinoid treatment for various dry-eye disorders. Ophthalmology. 1985;92:717-727. Erratum in: Ophthalmology. 1989;96:730.
87. Herbort CP, Zografos L, Zwingli M, Schoeneich M. Topical retinoic acid in dysplastic and metaplastic keratinization of corneoconjunctival epithelium. Graefes
Arch Clin Exp Ophthalmol. 1988;226:22-26.
88. Roberts CW, Carniglia PE, Brazzo BG. Comparison of topical cyclosporine, punctal occlusion, and a combination for the treatment of dry eye. Cornea. 2007;26:805-