- Email: [email protected]
Anti-inflammatory Therapy of Dry Eye
Clinical Practice EDWARD J. HOLLAND, MD, SECTION EDITOR
Anti-inflammatory Therapy of Dry Eye STEPHEN C. PFLUGFELDER, MD
ABSTRACT As tear secretion and tear clearance decrease in the dry eye, an inflammatory response is initiated on the ocular surface that appears to involve both soluble and cellular mediators. Although the traditional approach to treating dry eye is to hydrate and lubricate the ocular surface with artificial tears, symptoms and/or sight-threatening corneal disease may persist in some patients on such aqueous enhancement therapies. In these patients, treatment with anti-inflammatory agents, such as cyclosporin A, corticosteroids, tetracyclines, or autologous serum, may be considered. Results of studies investigating the use of these agents are discussed. During treatment, patients should be conscientiously monitored for adverse effects. KEY WORDS anti-inflammatory therapy for dry eye, autologous serum, corticosteroids, cyclosporin A, dry eye, inflammatory disease, tetracyclines The Ocular Surface; 2003;1:31–36 ©2003 Ethis Communications, Inc.
I. DRY EYE: A CHRONIC INFLAMMATORY CONDITION
t is now recognized that the ocular surface and tear-secreting glands function as an integrated unit to refresh the tear supply and to clear used tears from the ocular surface.1 Disease or dysfunction of this functional unit results in an unstable and unrefreshed tear film that causes ocular irritation and epithelial disease termed keratoconjunctivitis sicca (KCS). Dysfunction of this integrated unit may develop from age, a decrease in
I
Accepted for publication August 2002. From the Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX Supported by NEI Grant EY11915, an unrestricted grant from Research to Prevent Blindness, The Oshman Foundation and The William Stamps Farish Fund. Correspondence and single copy reprint requests to: Stephen C. Pflugfelder, MD, 6565 Fannin, NC-307,Houston, Texas 77030. PHONE 713-798-4732; FAX 713-798-1457; E-MAIL: [email protected]. Dr. Plugfelder is a consultant for Allergan, Inc., and he receives funds for basic research from Allergan. ©2002 Ethis Communications, Inc. All rights reserved.
supportive factors (such as androgen hormones), systemic inflammatory diseases (such as rheumatoid arthritis), ocular surface diseases or surgeries that disrupt the trigeminal afferent sensory nerves (e.g., herpes zoster ophthalmicus or LASIK), and systemic diseases or medications that disrupt the efferent secretomotor cholinergic nerves that regulate tear secretion and blinking.2–5 As tear secretion and tear clearance decrease, an inflammatory response is initiated on the ocular surface that appears to involve both soluble and cellular mediators (Figure 1). Increased expression of immune activation and cellular adhesion molecules (e.g, HLA-DR antigen and ICAM-1) by the conjunctival epithelium and infiltrating inflammatory cells has been observed in all types of dry eye.6,7 These factors are upregulated by exposure to certain pro-inflammatory cytokines, such as IL-1, IL-6 and TNFα, that have been detected at increased concentrations in the tear fluid and conjunctival epithelium of patients with dry eye.8–10 These factors may directly or indirectly stimulate infiltration of the ocular surface with inflammatory cells. IL-1 and TNF-α are also potent stimulators of matrix metalloproteinase (MMP) enzyme production by epithelial and inflammatory cells on the ocular surface.11 Significantly increased levels of MMP-9 and the enzyme that activates it, MMP-3, have been detected in the tear fluid of patients with dry eye.12–15 These proteases are capable of degrading the corneal epithelial basement membrane and activating latent inflammatory factors in the tear fluid, such as pro-IL-1 beta, pro-TNF-α ,and substance P.16 Accelerated apoptosis of the ocular surface epithelium is another component of the inflammatory cascade of dry eye. A significantly increased number of apoptotic conjunctival epithelial cells were observed in dogs with spontaneous KCS.17 In an experimental murine model of dry eye, a marked increase in epithelial apoptosis was observed within 2 weeks after dryness was induced.18 The expression of pro-apoptotic markers (Fas, Fas ligand, APO 2.7, CD40, CD40 ligand) by the conjunctival epithelium in human patients with KCS was found to be significantly higher than in normal eyes.19 It is possible that one of the initiating events in this inflammatory cascade is the development of hyperosmolar tear film that occurs in dry eye. Exposure of cells to a hyperosmolar environment activates stress kinases, such as c-jun n-terminal kinase (JNK), that are potent cellular regulators of inflammation and apoptosis.20,21
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ANTI-INFLAMMATORY THERAPY OF DRY EYE / Stephen C. Pflugfelder, MD CONTENTS I. Dry eye: a chronic inflammatory condition II. Anti-inflammatory therapy of dry eye: a paradigm shift III. Anti-inflammatory agents used for therapy of dry eye A. Cyclosporin A B. Corticosteroids C. Tetracyclines D. Autologous serum IV. Recommendations for use of anti-inflammatory therapy for dry eye
From a patient’s perspective, neural sensitization and chronic ocular discomfort are major consequences of this chronic ocular surface inflammation. II. ANTI-INFLAMMATORY THERAPY OF DRY EYE: A PARADIGM SHIFT
The traditional approach to treating dry eye is to hydrate and lubricate the ocular surface with artificial tears, which contain water, electrolytes, and polymers, such as polyvinyl alcohol or methylcellulose. Artificial tears have been reported to decrease ocular irritation and blurred vision and to reduce the severity of ocular surface dye staining.22–24 Artificial tears have no direct anti-inflammatory effects, although they may secondarily decrease inflammation through their ability to lower tear osmolarity and to dilute the concentrations of noxious and inflammatory factors and flush them from the ocular surface. In contrast, anti-inflammatory therapies that target one or more of the components of the inflammatory response to dry eye (Table 1) have been reported to have efficacy in treating the signs and symptoms of dry eye. Anti-inflammatory therapies may be considered for patients who have corneal disease or continue to have symptoms on aqueous enhancement therapies. III. ANTI-INFLAMMATORY AGENTS USED FOR THERAPY OF DRY EYE A. Cyclosporin A
Figure 1. Proposed mechanism of ocular surface inflammation in dry eye disease.
Cyclosporin is a fungal-derived peptide that prevents activation and nuclear translocation of cytoplasmic transcription factors that are required for T-cell activation and inflammatory cytokine production.25 Cyclosporin also inhibits an initiating event in mitochondrial-mediated pathways of apoptosis by blocking the opening of the mitochondrial permeability transition pore (MPTP).26 The potential of cyclosporin A (CsA) for treating dry eyeassociated 32
ocular surface disease was initially recognized in dogs that spontaneously developed KCS.27 The therapeutic efficacy of CsA for human KCS was then documented in several small single-center, randomized, doublemasked clinical trials.28,29 CsA emulsion for treatment of KCS has been subsequently evaluated in several large multicenter, randomized, doublemasked FDA clinical trials. A phase 2 FDA clinical trial of four doses of CsA (0.05%, 0.1%, 0.2%, or 0.4%) administered twice daily to both eyes of 129 patients for 12 weeks was compared to treatment with vehicle in 33 patients.30 CsA was found to significantly decrease conjunctival rose bengal staining, superficial punctate keratitis, and ocular irritation (sandy or gritty feeling, dryness, and itching) in a subset of 90 patients with moderate-to-severe KCS. There was no clear dose-response; CsA 0.1% produced the most consistent improvement in objective end points, while CsA 0.05% gave the most consistent improvement in patient symptoms. Two independent phase 3 FDA clinical trials compared twice-daily treatment with 0.05% or 0.1% CsA or vehicle in 877 patients with moderate-to-severe dry eye disease.31 One of these clinical trials showed that CsA 0.05% significantly improved irritation symptoms and corneal fluorescein staining compared to vehicle; however, this treatment effect
was not duplicated in the second trial. Based on these study results, the FDA requested that a third confirmatory trial be performed, and that trial is scheduled for completion by the first quarter of 2003. When the results of these two trials were combined for statistical analysis, patients treated with CsA, 0.05% or 0.1%, showed significantly (P < 0.05) greater improvement in two objective signs of dry eye disease (corneal fluorescein staining and categorized Schirmer values)
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Table 1. Anti-Inflammatory Agents with Reported Efficacy for Dry Eye Disease Agent
Indications
Mechanism of Action
Cyclosporin A
Dr y eye Keratoconjunctivitis sicca
Inhibits epithelial apoptosis and T cell activation
Cor ticosteroids
Keratoconjunctivitis sicca Delayed tear clearance
Inhibits MMP, inflammator y cytokine/chemokine and adhesion molecule production
Tetracyclines
Ocular rosacea Keratoconjunctivitis sicca
Inhibit MMP and IL-1 production
Autologous serum
Keratoconjunctivitis sicca
Soluble protease and inflammatory cytokine inhibitors
MMP = matrix metalloproteinase, IL-1 = interleukin-1
than those treated with vehicle. CsA 0.05% treatment also produced significantly greater improvements (P < 0.05) in three subjective measures of dry eye disease (blurred vision, need for concomitant artificial tears, and the global response to treatment). No dose-response effect was noted. Both doses of CsA exhibited an excellent safety profile with no significant ocular or systemic adverse events, except for burning symptoms after instillation in 17% of patients. Burning was noted with the same frequency in patients receiving the vehicle. The clinical improvements in these clinical trials have been accompanied by decreased expression of immune activation markers (i.e., HLA-DR), apoptosis markers (i.e., Fas) and inflammatory cytokines, such as IL-6, by the conjunctival epithelial cells.32,33 The numbers of CD3-, CD4-, and CD8-positive T lymphocytes in the conjunctiva decreased in cyclosporine-treated eyes, while vehicle-treated eyes showed increases in the numbers of cells expressing these markers. Following treatment with 0.05% cyclosporine, there was a significant decrease in the number of cells expressing the lymphocyte activation markers CD11a and HLA-DR, indicating less activation of lymphocytes compared with eyes treated with vehicle. This agent has also been reported to heal paracentral sterile corneal ulcers associated with Sjogrens syndrome.35 Until CsA is approved by the FDA, it can be obtained in a variety of concentrations (0.05 to 2%) from a number of formulation pharmacies in the USA. The relative efficacy of these different formulations has not been compared. B. Corticosteroids
Corticosteroids are potent inhibitors of many inflammatory pathways. Activated corticosteroid receptors in the cell nucleus bind to DNA and regulate gene expression. They also interfere with transcriptional regulators (e.g., AP-1 and NF-κB) of pro-inflammatory genes.36,37 Among their multiple biological activities, corticosteroids inhibit inflammatory cytokine and chemokine production, decrease the synthesis of matrix metalloproteinases and lipid mediators of inflammation (e.g., prostaglandins), decrease expression of cell adhesion molecules (e.g., ICAM-1), and
stimulate lymphocyte apoptosis.38–43 Side chain substitutions on the corticosteroid ring structure alter their potency, free radical scavenging effects, and membrane stabilizing properties.44 Corticosteroids have been reported to improve both signs and symptoms of dry eye in several clinical studies. In a retrospective clinical series, topical administration of a 1% solution of nonpreserved methylprednisolone, given 3–4 times daily for 2 weeks to patients with Sjogrens syndrome KCS, provided moderate or complete relief of symptoms in all patients.45 In addition, there was a decrease in corneal fluorescein staining and complete resolution of filamentary keratitis. This therapy was effective even for patients suffering from severe KCS who had no improvement from maximum aqueous enhancement therapies. A prospective, randomized clinical trial compared the severity of ocular irritation symptoms and corneal fluorescein staining in two groups of patients, one treated with topical nonpreserved methylprednisolone for 2 weeks, followed by punctal occlusion (Group 1) with a group that received punctal occlusion alone (Group 2).46 After 2 months, 80% of patients in Group 1 and 33% of patients in Group 2 had complete relief of ocular irritation symptoms. Corneal fluorescein staining was negative in 80% of eyes in Group 1 and 60% of eyes in Group 2 after 2 months. No steroid-related complications were observed in this study. A separate retrospective review of patients with delayed tear clearance who were treated with topical nonpreserved 1% methylprednisolone reported an improvement in irritation symptoms in 83% and ocular surface dye staining in 80% of treated patients.47 This symptomatic response was accompanied by improvement in fluorescein tear clearance. A masked, placebo-controlled trial would be useful to further clarify the benefits and risks of corticosteroid therapy for dry eye. C. Tetracyclines
Tetracyclines are compounds that have traditionally been used as antibiotics. More recently, they have been observed to have numerous anti-inflammatory properties,
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including the abilities to decrease the production and activity of inflammatory cytokines, to decrease nitric oxide production, and to inhibit matrix metalloproteinase production and activation.11,38,48–50 With regard to the ocular surface, tetracyclines have been observed to decrease production of IL-1 and matrix metalloproteinases by human corneal epithelial cells.11,15,38 The significant clinical improvement in the severity of the inflammatory gingival disease periodontitis has been attributed to these nonantimicrobial activities of tetracyclines.51,52 Systemically administered tetracycline antibiotics have long been recognized as effective therapies for inflammatory diseases of the ocular surface. The semisynthetic tetracycline, doxycycline, has been reported to improve irritation symptoms, increase tear film stability, and decrease the severity of ocular surface disease in patients with ocular rosacea.53–55 Doxycycline has also been reported to be effective for treating recurrent corneal epithelial erosions and phlyctenular keratoconjunctivitis.40,56,57
3. 4.
5.
6.
7.
8. 9.
D. Autologous Serum
Serum contains a number of anti-inflammatory factors that have the potential to inhibit mediators of the ocular surface that are involved with the inflammatory cascade of dry eye. These include inhibitors of inflammatory cytokines (e.g., IL-1 RA and soluble TNF-α receptors) and matrix metalloproteinases (e.g, TIMPs) inhibitors.58–60 Autologous serum drops (diluted 1% with saline) have been reported to improve ocular irritation symptoms and conjunctival and corneal dye staining in Sjogrens syndrome associated KCS in several small clinical trials.61–63
10.
11. 12. 13.
14.
IV. RECOMMENDATIONS FOR USE OF ANTI-INFLAMMATORY THERAPY FOR DRY EYE
Anti-inflammatory therapies should be considered for patients with severe KCS that is causing intolerable irritation, blurred vision, or sight-threatening corneal complications (e.g., thinning, filamentary keratitis) despite maximum hydration and lubrication therapy. Because of their potential to raise intraocular pressure, cause posterior subcapsular cataracts,and increase the risk for infection, topical corticosteroids should be used in short pulses (1–4 weeks), followed by cessation or change to a low dose (once or twice daily) of an agent that carries less risk for glaucoma or cataract formation (e.g., loteprednol etabonate or fluorometholone). Patients on corticosteroids should be closely observed for steroid-related side effects. Cyclosporin and oral tetracyclines have excellent safety profiles and can be safely used for extended periods. The gastrointestinal side effects of doxycyline can be diminished by using lower doses (40–50 mg/day).
15.
16. 17.
18.
19.
20.
References 1. Stern ME, Beuerman RW, Fox RI, et al. The pathology of dry eye: The interaction between ocular surface and lacrimal glands. Cornea 1998; 17:584–9 2. Krenzer KL, Dana MR, Ullman MD, et al. Effect of androgen
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deficiency on the human meibomian gland and ocular surface. J Clin Endocrinol Metab 2000;85:4874–82 Heigle TJ, Pflugfelder SC. Aqueous tear production in patients with neurotrophic keratitis. Cornea 1996; 15:135–8 Battat L, Macri A, Dursun D, Pflugfelder SC. Effects of laser in situ keratomileusis on tear production, clearance and the ocular surface. Ophthalmology 2001; 108:1230–5 Bacman S, Berra A, Sterin-Borda L, Borda E. Muscarinic acetylcholine receptor antibodies as a new marker of dry eye Sjogren syndrome. Invest Ophthalmol Vis Sci 2001;42:321–7 Brignole F, Pisella PJ, Goldschild M, et al. Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eyes. Invest Ophthalmol Vis Sci. 2000; 41: 1356–63 Stern ME, Gao J, Schwalb TA, et al. Conjunctival T-cell subpopulations in Sjogren’s and non-Sjogren’s patients with dry eye. Invest Ophthalmol Vis Sci 2002;43:2609–14 Dinarello CA. Proinflammatory cytokines. Chest 2000; 118:503–8 Groves RW, Mizutani H, Kieffer D, Kupper TS. Inflammatory skin disease in transgenic mice that express high levels of IL-1α in basal epidermis. Proc Ntl Acad Sci USA 1995; 92:11874–8 Cheng J, Turksen K, Yu QC, et al. Cachexia and graft-vs-hostdisease type skin changes in keratin-promoter-driven TNF-α transgenic mice. Genes Dev 1992; 6:1444–56 Li DQ, Lokeshwar BL, Solomon A, et al. Regulation of MMP-9 in human corneal epithelial cells. Exp Eye Res 2001; 73:449–59 Sack RA, Beaton A, Sathe S, et al. Towards a closed eye model of the pre-ocular tear layer. Prog Retin Eye Res 2000;19:649–68 Smith VA, Rishmawi H, Hussein H, Easty DL. Tear film MMP accumulation and corneal disease. Br J Ophthalmol 2001;85:147–53 Afonso AA, Sobrin L, Monroy DC, et al. Tear fluid gelatinase B activity correlates with IL-1α concentration and fluorescein clearance in ocular rosacea. Invest Ophthalmol Vis Sci 1999;40:2506–12 Sobrin L, Liu Z, Monroy DC, et al. Regulation of stromelysin (MMP-3) activity in human tear fluid and corneal epithelial culture supernatant. Invest Ophthalmol Vis Sci 2000; 41:1703–9 Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001;17:463–516 Gao J, Schwalb TA, Addeo JV, et al. The role of apoptosis in the pathogenesis of canine keratoconjunctivitis sicca: the effect of topical Cyclosporin A therapy. Cornea 1998;17:654–63 Yeh S, Xiu JS, Farley W, et al. Apoptosis of ocular surface cells in experimentally induced dry eye. Invest Ophthalmol Vis Sci 2002 (in press) Brignole F, De Saint-Jean M, Goldschild M, et al. Expression of Fas-Fas ligand antigens and apoptotic marker APO2.7 by the human conjunctival epithelium. Positive correlation with class II HLA DR expression in inflammatory ocular surface disorders. Exp Eye Res 1998; 67: 687–97 Caffrey DR, O’Neill LA, Shields DC. The evolution of the MAP kinase pathways: coduplication of interacting proteins leads to new signaling cascades. J Mol Evol 1999; 49:567–82 Rosette C, Karin M. Ultraviolet light and osmotic stress: activation of the JNK cascade through multiple growth factor and cytokine receptors. Science 1996;274:1194–7
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ANTI-INFLAMMATORY THERAPY OF DRY EYE / Stephen C. Pflugfelder, MD 22. Nelson JD, Farris RL. Sodium hyaluronate and polyvinyl alcohol artificial tear preparations. A comparison in patients with keratoconjunctivitis sicca. Arch Ophthalmol 1988;106:484–7 23. Toda I, Shinozaki N, Tsubota K. Hydroxypropyl methylcellulose for the treatment of severe dry eye associated with Sjogren’s syndrome. Cornea 1996;15:120–8 24. Liu Z, Pflugfelder SC. Corneal surface regularity and the effect of artificial tears in aqueous tear deficiency. Ophthalmology 1999; 106:939–43 25. Matsuda S, Koyasu S. Mechanisms of action of cyclosporin. Immunopharmacology 2000;47:119–25 26. Halestrap AP, McStay GP, Clarke SJ. The permeability transition pore complex: another view. Biochimie 2002;84:153–66 27. Kaswan RL, Salisbury MA, Ward DA. Spontaneous canine keratoconjunctivitis sicca. A useful model for human keratoconjunctivitis sicca: treatment with cyclosporin eye drops. Arch Ophthalmol 1989;107:1210–6 28. Gunduz K, Ozdemir O. Topical cyclosporin treatment of keratoconjunctivitis sicca in secondary Sjogren’s syndrome. Acta Ophthalmol 1994;72:438–2 29. Laibovitz RA, Solch S, Andrianao J, et al. Pilot trial of cyclosporin 1% ophthalmic ointment in the treatment of keratoconjunctivitis sicca. Cornea 1993;12:315–23 30. Stevenson D, Tauber J, Reis BL. Efficacy and safety of cyclosporin A ophthalmic emulsion in the treatment of moderate-to-severe dry eye disease: A dose-ranging, randomized trial. The Cyclosporin A Phase 2 Study Group. Ophthalmology 2000;107:967–74 31. Sall K, Stevenson OD, Mundorf TK, Reis BL. Two multicenter, randomized studies of the efficacy and safety of cyclosporin ophthalmic emulsion in moderate to severe dry eye disease. Ophthalmology 2000;107:631–9 32. Brignole F, Pisella PJ, De Saint Jean M, et al. Flow cytometric analysis of inflammatory markers in KCS: 6-month treatment with topical cyclosporin A. Invest Ophthalmol Vis Sci 2001;42:90–5 33. Turner K, Pflugfelder SC, Ji Z, et al. Interleukin-6 levels in the conjunctival epithelium of patients with dry eye disease treated with cyclosporine ophthalmic emulsion. Cornea 200019:492–6 34. Kunert KS, Tisdale AS, Stern ME, et al. Analysis of topical cyclosporine treatment of patients with dry eye syndrome: effect on conjunctival lymphocytes. Arch Ophthalmol 2000;118:1489–96 35. Kervick GN, Pflugfelder SC, Haimovici R, et al. Paracentral rheumatoid corneal ulceration. Clinical features and cyclosporine therapy. Ophthalmology 1992; 99:80–8 36. Almawi WY, Melemedjian OK. Negative regulation of nuclear factor-kappaB activation and function by glucocorticoids. J Mol Endocrinol 2002;28:69–78 37. Adcock IM. Glucocorticoid-regulated transcription factors. Pulm Pharmacol Ther 2001;14:211–9 38. Solomon A, Rosenblatt M, Li DQ, et al. Doxycycline inhibition of interleukin-1 in the corneal epithelium. Invest Ophthalmol Vis Sci 2000; 41:2544–57 39. Hashimoto S, Gon Y, Matsumoto K,et al. Inhalant corticosteroids inhibit hyperosmolarity-induced, and cooling and rewarming-induced interleukin-8 and RANTES production by human bronchial epithelial cells. Am J Respir Crit Care Med
2000;162(3 Pt 1):1075–80 40. Dursun D, Kim MC, Solomon A, Pflugfelder SC. Treatment of recalcitrant recurrent corneal epithelial erosions with inhibitors of matrix metalloproteinases-9, doxycyclne and corticosteroids. Am J Ophthalmol 2001;132:8–13 41. Liden J, Rafter I, Truss M, et al. Glucocorticoid effects on NFkappaB binding in the transcription of the ICAM-1 gene. Biochem Biophys Res Commun 2000 Jul 14;273:1008–14 42. Aksoy MO, Li X, Borenstein M, et al. Effects of topical corticosteroids on inflammatory mediator-induced eicosanoid release by human airway epithelial cells. J Allergy Clin Immunol 1999;103:1081–91 43. Brunner T, Arnold D, Wasem C, et al. Regulation of cell death and survival in intestinal intraepithelial lymphocytes. Cell Death Differ 2001;8:706–14 44. Yoshida T, Tanaka M, Sotomatsu A, Okamoto K. Effect of methylprednisolone-pulse therapy on superoxide production of neutrophils. Neurol Res 1999;21:509–12 45. Marsh P, Pflugfelder SC. Topical non-preserved methylprednisolone therapy for keratoconjunctivitis sicca in Sjogren’s syndrome. Ophthalmology 1999;106:811–6 46. Sainz de la Maza Serra M, Simon Castellvi C, Kabbani O. Nonpreserved topical steroids and lacrimal punctual occlusion for severe keratoconjunctivitis sicca. Arch Soc Esp Oftalmol 2000;75:751–6 47. Prabhasawat P, Tseng SC. Frequent association of delayed tear clearance in ocular irritation. Br J Ophthalmol 1998;82:666–75 48. Amin AR, Attur MG, Thakker GD, et al. A novel mechanism of action of tetracyclines: effects on nitric oxide synthases. Proc Natl Acad Sci U S A 1996;93:14014–9 49. Hanemaaijer R, Sorsa T, Konttinen YT,et al. Matrix metalloproteinase-8 is expressed in rheumatoid synovial fibroblasts and endothelial cells. Regulation by tumor necrosis factor-alpha and doxycycline. J Biol Chem 1997;272:31504–9 50. Shlopov BV, Smith GN Jr, Cole AA, Hasty KA. Differential patterns of response to doxycycline and transforming growth factor beta1 in the downregulation of collagenases in osteoarthritic and normal human chondrocytes. Arthritis Rheum 1999;42:719–27 51. Novak MJ, Johns LP, Miller RC, Bradshaw MH. Adjunctive benefits of subantimicrobial dose doxycycline in the management of severe, generalized, chronic periodontitis. J Periodontol 2002;73:762–9 52. Eickholz P, Kim TS, Burklin T, et al. Non-surgical periodontal therapy with adjunctive topical doxycycline: a double-blind randomized controlled multicenter study. J Clin Periodontol 2002;29:108–17 53. Frucht-Pery J, Sagi E, Hemo I, Ever-Hadani P. Efficacy of doxycycline and tetracycline in ocular rosacea. Am J Ophthalmol 1993;116:88–92 54. Zengin N, Tol H, Gunduz K, et al. Meibomian gland dysfunction and tear film abnormalities in rosacea. Cornea 1995;14:144–6 55. Akpek EK, Merchant A, Pinar V, Foster CS. Ocular rosacea: patient characteristics and follow-up. Ophthalmology 1997;104:1863–7 56. Hope-Ross MW, Chell PB, Kervick GN, et al. Oral tetracy-
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ance in stable angina pectoris in relation to angiographic findings. Thromb Haemost 2001;86:636–9 61. Fox RI, Chan R, Michelson JB, et al. Beneficial effect of artificial tears made with autologous serum in patients with keratoconjunctivitis sicca. Arthritis Rheum 1984; 27:459–61 62. Kono I, Kono K, Narushima K, et al. Beneficial effect of the local application of plasma fibronectin and autologous serum in patients with keratoconjunctivitis sicca of Sjogren’s syndrome. Ryumachi 1986; 26:339–43 63. Tsubota K, Goto E, Fujita H, et al. Treatment of dry eye by autologous seum application in Sjogren’s syndrome. Br J Ophthalmol 1999;83:390–5
For more information, please contact: Ms Karen Chee, Event Manager FIRST SERI–ARVO MEETING ON RESEARCH IN VISION AND OPHTHALMOLOGY Singapore Eye Research Institute 11, Third Hospital Avenue, Singapore 168751, Republic of Singapore Tel: 65-63228311 Fax: 65-63231903 or 65-62262886 Email: [email protected] or [email protected]
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Anti-inflammatory Therapy of Dry Eye STEPHEN C. PFLUGFELDER, MD
ABSTRACT As tear secretion and tear clearance decrease in the dry eye, an inflammatory response is initiated on the ocular surface that appears to involve both soluble and cellular mediators. Although the traditional approach to treating dry eye is to hydrate and lubricate the ocular surface with artificial tears, symptoms and/or sight-threatening corneal disease may persist in some patients on such aqueous enhancement therapies. In these patients, treatment with anti-inflammatory agents, such as cyclosporin A, corticosteroids, tetracyclines, or autologous serum, may be considered. Results of studies investigating the use of these agents are discussed. During treatment, patients should be conscientiously monitored for adverse effects. KEY WORDS anti-inflammatory therapy for dry eye, autologous serum, corticosteroids, cyclosporin A, dry eye, inflammatory disease, tetracyclines The Ocular Surface; 2003;1:31–36 ©2003 Ethis Communications, Inc.
I. DRY EYE: A CHRONIC INFLAMMATORY CONDITION
t is now recognized that the ocular surface and tear-secreting glands function as an integrated unit to refresh the tear supply and to clear used tears from the ocular surface.1 Disease or dysfunction of this functional unit results in an unstable and unrefreshed tear film that causes ocular irritation and epithelial disease termed keratoconjunctivitis sicca (KCS). Dysfunction of this integrated unit may develop from age, a decrease in
I
Accepted for publication August 2002. From the Ocular Surface Center, Department of Ophthalmology, Baylor College of Medicine, Houston, TX Supported by NEI Grant EY11915, an unrestricted grant from Research to Prevent Blindness, The Oshman Foundation and The William Stamps Farish Fund. Correspondence and single copy reprint requests to: Stephen C. Pflugfelder, MD, 6565 Fannin, NC-307,Houston, Texas 77030. PHONE 713-798-4732; FAX 713-798-1457; E-MAIL: [email protected]. Dr. Plugfelder is a consultant for Allergan, Inc., and he receives funds for basic research from Allergan. ©2002 Ethis Communications, Inc. All rights reserved.
supportive factors (such as androgen hormones), systemic inflammatory diseases (such as rheumatoid arthritis), ocular surface diseases or surgeries that disrupt the trigeminal afferent sensory nerves (e.g., herpes zoster ophthalmicus or LASIK), and systemic diseases or medications that disrupt the efferent secretomotor cholinergic nerves that regulate tear secretion and blinking.2–5 As tear secretion and tear clearance decrease, an inflammatory response is initiated on the ocular surface that appears to involve both soluble and cellular mediators (Figure 1). Increased expression of immune activation and cellular adhesion molecules (e.g, HLA-DR antigen and ICAM-1) by the conjunctival epithelium and infiltrating inflammatory cells has been observed in all types of dry eye.6,7 These factors are upregulated by exposure to certain pro-inflammatory cytokines, such as IL-1, IL-6 and TNFα, that have been detected at increased concentrations in the tear fluid and conjunctival epithelium of patients with dry eye.8–10 These factors may directly or indirectly stimulate infiltration of the ocular surface with inflammatory cells. IL-1 and TNF-α are also potent stimulators of matrix metalloproteinase (MMP) enzyme production by epithelial and inflammatory cells on the ocular surface.11 Significantly increased levels of MMP-9 and the enzyme that activates it, MMP-3, have been detected in the tear fluid of patients with dry eye.12–15 These proteases are capable of degrading the corneal epithelial basement membrane and activating latent inflammatory factors in the tear fluid, such as pro-IL-1 beta, pro-TNF-α ,and substance P.16 Accelerated apoptosis of the ocular surface epithelium is another component of the inflammatory cascade of dry eye. A significantly increased number of apoptotic conjunctival epithelial cells were observed in dogs with spontaneous KCS.17 In an experimental murine model of dry eye, a marked increase in epithelial apoptosis was observed within 2 weeks after dryness was induced.18 The expression of pro-apoptotic markers (Fas, Fas ligand, APO 2.7, CD40, CD40 ligand) by the conjunctival epithelium in human patients with KCS was found to be significantly higher than in normal eyes.19 It is possible that one of the initiating events in this inflammatory cascade is the development of hyperosmolar tear film that occurs in dry eye. Exposure of cells to a hyperosmolar environment activates stress kinases, such as c-jun n-terminal kinase (JNK), that are potent cellular regulators of inflammation and apoptosis.20,21
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ANTI-INFLAMMATORY THERAPY OF DRY EYE / Stephen C. Pflugfelder, MD CONTENTS I. Dry eye: a chronic inflammatory condition II. Anti-inflammatory therapy of dry eye: a paradigm shift III. Anti-inflammatory agents used for therapy of dry eye A. Cyclosporin A B. Corticosteroids C. Tetracyclines D. Autologous serum IV. Recommendations for use of anti-inflammatory therapy for dry eye
From a patient’s perspective, neural sensitization and chronic ocular discomfort are major consequences of this chronic ocular surface inflammation. II. ANTI-INFLAMMATORY THERAPY OF DRY EYE: A PARADIGM SHIFT
The traditional approach to treating dry eye is to hydrate and lubricate the ocular surface with artificial tears, which contain water, electrolytes, and polymers, such as polyvinyl alcohol or methylcellulose. Artificial tears have been reported to decrease ocular irritation and blurred vision and to reduce the severity of ocular surface dye staining.22–24 Artificial tears have no direct anti-inflammatory effects, although they may secondarily decrease inflammation through their ability to lower tear osmolarity and to dilute the concentrations of noxious and inflammatory factors and flush them from the ocular surface. In contrast, anti-inflammatory therapies that target one or more of the components of the inflammatory response to dry eye (Table 1) have been reported to have efficacy in treating the signs and symptoms of dry eye. Anti-inflammatory therapies may be considered for patients who have corneal disease or continue to have symptoms on aqueous enhancement therapies. III. ANTI-INFLAMMATORY AGENTS USED FOR THERAPY OF DRY EYE A. Cyclosporin A
Figure 1. Proposed mechanism of ocular surface inflammation in dry eye disease.
Cyclosporin is a fungal-derived peptide that prevents activation and nuclear translocation of cytoplasmic transcription factors that are required for T-cell activation and inflammatory cytokine production.25 Cyclosporin also inhibits an initiating event in mitochondrial-mediated pathways of apoptosis by blocking the opening of the mitochondrial permeability transition pore (MPTP).26 The potential of cyclosporin A (CsA) for treating dry eyeassociated 32
ocular surface disease was initially recognized in dogs that spontaneously developed KCS.27 The therapeutic efficacy of CsA for human KCS was then documented in several small single-center, randomized, doublemasked clinical trials.28,29 CsA emulsion for treatment of KCS has been subsequently evaluated in several large multicenter, randomized, doublemasked FDA clinical trials. A phase 2 FDA clinical trial of four doses of CsA (0.05%, 0.1%, 0.2%, or 0.4%) administered twice daily to both eyes of 129 patients for 12 weeks was compared to treatment with vehicle in 33 patients.30 CsA was found to significantly decrease conjunctival rose bengal staining, superficial punctate keratitis, and ocular irritation (sandy or gritty feeling, dryness, and itching) in a subset of 90 patients with moderate-to-severe KCS. There was no clear dose-response; CsA 0.1% produced the most consistent improvement in objective end points, while CsA 0.05% gave the most consistent improvement in patient symptoms. Two independent phase 3 FDA clinical trials compared twice-daily treatment with 0.05% or 0.1% CsA or vehicle in 877 patients with moderate-to-severe dry eye disease.31 One of these clinical trials showed that CsA 0.05% significantly improved irritation symptoms and corneal fluorescein staining compared to vehicle; however, this treatment effect
was not duplicated in the second trial. Based on these study results, the FDA requested that a third confirmatory trial be performed, and that trial is scheduled for completion by the first quarter of 2003. When the results of these two trials were combined for statistical analysis, patients treated with CsA, 0.05% or 0.1%, showed significantly (P < 0.05) greater improvement in two objective signs of dry eye disease (corneal fluorescein staining and categorized Schirmer values)
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Table 1. Anti-Inflammatory Agents with Reported Efficacy for Dry Eye Disease Agent
Indications
Mechanism of Action
Cyclosporin A
Dr y eye Keratoconjunctivitis sicca
Inhibits epithelial apoptosis and T cell activation
Cor ticosteroids
Keratoconjunctivitis sicca Delayed tear clearance
Inhibits MMP, inflammator y cytokine/chemokine and adhesion molecule production
Tetracyclines
Ocular rosacea Keratoconjunctivitis sicca
Inhibit MMP and IL-1 production
Autologous serum
Keratoconjunctivitis sicca
Soluble protease and inflammatory cytokine inhibitors
MMP = matrix metalloproteinase, IL-1 = interleukin-1
than those treated with vehicle. CsA 0.05% treatment also produced significantly greater improvements (P < 0.05) in three subjective measures of dry eye disease (blurred vision, need for concomitant artificial tears, and the global response to treatment). No dose-response effect was noted. Both doses of CsA exhibited an excellent safety profile with no significant ocular or systemic adverse events, except for burning symptoms after instillation in 17% of patients. Burning was noted with the same frequency in patients receiving the vehicle. The clinical improvements in these clinical trials have been accompanied by decreased expression of immune activation markers (i.e., HLA-DR), apoptosis markers (i.e., Fas) and inflammatory cytokines, such as IL-6, by the conjunctival epithelial cells.32,33 The numbers of CD3-, CD4-, and CD8-positive T lymphocytes in the conjunctiva decreased in cyclosporine-treated eyes, while vehicle-treated eyes showed increases in the numbers of cells expressing these markers. Following treatment with 0.05% cyclosporine, there was a significant decrease in the number of cells expressing the lymphocyte activation markers CD11a and HLA-DR, indicating less activation of lymphocytes compared with eyes treated with vehicle. This agent has also been reported to heal paracentral sterile corneal ulcers associated with Sjogrens syndrome.35 Until CsA is approved by the FDA, it can be obtained in a variety of concentrations (0.05 to 2%) from a number of formulation pharmacies in the USA. The relative efficacy of these different formulations has not been compared. B. Corticosteroids
Corticosteroids are potent inhibitors of many inflammatory pathways. Activated corticosteroid receptors in the cell nucleus bind to DNA and regulate gene expression. They also interfere with transcriptional regulators (e.g., AP-1 and NF-κB) of pro-inflammatory genes.36,37 Among their multiple biological activities, corticosteroids inhibit inflammatory cytokine and chemokine production, decrease the synthesis of matrix metalloproteinases and lipid mediators of inflammation (e.g., prostaglandins), decrease expression of cell adhesion molecules (e.g., ICAM-1), and
stimulate lymphocyte apoptosis.38–43 Side chain substitutions on the corticosteroid ring structure alter their potency, free radical scavenging effects, and membrane stabilizing properties.44 Corticosteroids have been reported to improve both signs and symptoms of dry eye in several clinical studies. In a retrospective clinical series, topical administration of a 1% solution of nonpreserved methylprednisolone, given 3–4 times daily for 2 weeks to patients with Sjogrens syndrome KCS, provided moderate or complete relief of symptoms in all patients.45 In addition, there was a decrease in corneal fluorescein staining and complete resolution of filamentary keratitis. This therapy was effective even for patients suffering from severe KCS who had no improvement from maximum aqueous enhancement therapies. A prospective, randomized clinical trial compared the severity of ocular irritation symptoms and corneal fluorescein staining in two groups of patients, one treated with topical nonpreserved methylprednisolone for 2 weeks, followed by punctal occlusion (Group 1) with a group that received punctal occlusion alone (Group 2).46 After 2 months, 80% of patients in Group 1 and 33% of patients in Group 2 had complete relief of ocular irritation symptoms. Corneal fluorescein staining was negative in 80% of eyes in Group 1 and 60% of eyes in Group 2 after 2 months. No steroid-related complications were observed in this study. A separate retrospective review of patients with delayed tear clearance who were treated with topical nonpreserved 1% methylprednisolone reported an improvement in irritation symptoms in 83% and ocular surface dye staining in 80% of treated patients.47 This symptomatic response was accompanied by improvement in fluorescein tear clearance. A masked, placebo-controlled trial would be useful to further clarify the benefits and risks of corticosteroid therapy for dry eye. C. Tetracyclines
Tetracyclines are compounds that have traditionally been used as antibiotics. More recently, they have been observed to have numerous anti-inflammatory properties,
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including the abilities to decrease the production and activity of inflammatory cytokines, to decrease nitric oxide production, and to inhibit matrix metalloproteinase production and activation.11,38,48–50 With regard to the ocular surface, tetracyclines have been observed to decrease production of IL-1 and matrix metalloproteinases by human corneal epithelial cells.11,15,38 The significant clinical improvement in the severity of the inflammatory gingival disease periodontitis has been attributed to these nonantimicrobial activities of tetracyclines.51,52 Systemically administered tetracycline antibiotics have long been recognized as effective therapies for inflammatory diseases of the ocular surface. The semisynthetic tetracycline, doxycycline, has been reported to improve irritation symptoms, increase tear film stability, and decrease the severity of ocular surface disease in patients with ocular rosacea.53–55 Doxycycline has also been reported to be effective for treating recurrent corneal epithelial erosions and phlyctenular keratoconjunctivitis.40,56,57
3. 4.
5.
6.
7.
8. 9.
D. Autologous Serum
Serum contains a number of anti-inflammatory factors that have the potential to inhibit mediators of the ocular surface that are involved with the inflammatory cascade of dry eye. These include inhibitors of inflammatory cytokines (e.g., IL-1 RA and soluble TNF-α receptors) and matrix metalloproteinases (e.g, TIMPs) inhibitors.58–60 Autologous serum drops (diluted 1% with saline) have been reported to improve ocular irritation symptoms and conjunctival and corneal dye staining in Sjogrens syndrome associated KCS in several small clinical trials.61–63
10.
11. 12. 13.
14.
IV. RECOMMENDATIONS FOR USE OF ANTI-INFLAMMATORY THERAPY FOR DRY EYE
Anti-inflammatory therapies should be considered for patients with severe KCS that is causing intolerable irritation, blurred vision, or sight-threatening corneal complications (e.g., thinning, filamentary keratitis) despite maximum hydration and lubrication therapy. Because of their potential to raise intraocular pressure, cause posterior subcapsular cataracts,and increase the risk for infection, topical corticosteroids should be used in short pulses (1–4 weeks), followed by cessation or change to a low dose (once or twice daily) of an agent that carries less risk for glaucoma or cataract formation (e.g., loteprednol etabonate or fluorometholone). Patients on corticosteroids should be closely observed for steroid-related side effects. Cyclosporin and oral tetracyclines have excellent safety profiles and can be safely used for extended periods. The gastrointestinal side effects of doxycyline can be diminished by using lower doses (40–50 mg/day).
15.
16. 17.
18.
19.
20.
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For more information, please contact: Ms Karen Chee, Event Manager FIRST SERI–ARVO MEETING ON RESEARCH IN VISION AND OPHTHALMOLOGY Singapore Eye Research Institute 11, Third Hospital Avenue, Singapore 168751, Republic of Singapore Tel: 65-63228311 Fax: 65-63231903 or 65-62262886 Email: [email protected] or [email protected]
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