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Treatment of Sjögren’s Syndrome-Associated Dry Eye: An Evidence-Based Review

Treatment of Sjögren’s Syndrome-Associated Dry Eye: An Evidence-Based Review Rohit S.Adyanthaya, M.D., Ramya Swamy B.S., Esen Karamursel Akpek, M.D. From The Ocular Surface Diseases and Dry Eye Clinic, The Wilmer Eye Institute, Baltimore, Maryland.

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Treatment of Sjögren’s Syndrome-Associated Dry Eye: An Evidence-Based Review

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  1. Treatment of Sjögren’s Syndrome-Associated Dry Eye: An Evidence-Based Review Rohit S.Adyanthaya, M.D., Ramya Swamy B.S., Esen Karamursel Akpek, M.D. From The Ocular Surface Diseases and Dry Eye Clinic, The Wilmer Eye Institute, Baltimore, Maryland. Financial Disclosure: Dr. Akpek has received research grants from Allergan Inc.

  2. Purpose Dry eye affects many individuals worldwide. A significant proportion of patients with dry eye have underlying Sjögren’s syndrome(SS), which is an autoimmune condition. Although there are a few suggested guidelines for treating individuals with dry eye, these are mostly based on the severity and grade of symptoms and/or clinical findings and do not differentiate SS from other causes of dry eye syndrome. Thus, we decided to review the literature pertaining to the various treatment options for individuals with dry eye secondary to SS and propose a treatment algorithm.

  3. Methods • An electronic search of English language articles published from 1964 to October 2008 was conducted in Pub Med and the Cochrane Collaboration’s database. Based on the keyword search of SS, dry eye, SS and dry eye, 13,351 abstracts were initially accessed and reviewed. Publications that did not state whether or not the participating subjects had SS were excluded. From these, a total of 472 papers were reviewed and 42 of them were found to be relevant and included in this study. The overall strength of evidence (levels I, II, and III) and ratings for clinical recommendations (levels A, B, and C) for any intervention were graded as below : • Evidence was graded from Levels I, II, and III where Level I indicated that the data provided strong evidence in support of the recommendations and level III indicated a weaker body of evidence that did not meet the criteria for levels I and II. • Clinical recommendations were graded from A to C where A indicated that the recommendations were considered very important or crucial to a good clinical outcome while C indicated that the recommendation may be relevant but could not be definitely related to clinical outcome.

  4. Topical Lubricants • There is evidence to recommend the use of hypotonic (150 mOsm/l) 0.4% sodium hyaluronate eye drops as first line treatment (A,I) to improve symptoms as well as signs of dry eye syndrome associated with SS. Remarkably, the improvement in impression cytology can be achieved as early as 30 days. The Schirmer’s levels do not seem to improve with short-term treatment. In addition, 0.5% hydroxypropyl methylcellulose has shown some efficacy in the treatment that has not responded to traditional lubricants (B,II). Aragona, P., et al. "Sodium Hyaluronate Eye Drops of Different Osmolarity for the Treatment of Dry Eye in Sjögren's Syndrome Patients." British Journal of Ophthalmology 86.8 (2002): 879. • DeLuise VP, and Peterson WS. "The use of Topical Healon Tears in the Management of Refractory Dry-Eye Syndrome." Ann Ophthalmol. 1984 Sep;16(9):823-4. 16.9 (1984): 823-4. • Toda I, Shinozaki N, and Tsubota K. "Hydroxypropyl Methylcellulose for the Treatment of Severe Dry Eye Associated with Sjögren's Syndrome." Cornea. 1996 Mar;15(2):120-8. 15.2 (1996): 120-8.

  5. Topical Anti-inflammatory Therapy • There is sufficient evidence both clinically and histopathologically demonstrating the effectiveness of topical cyclosporine (A,I) as well as its safety over long-term use. • Although the studies evaluating 1% topical methyprednisolone were open label and retrospective in nature, the effect was robust (B,II). If used short-term, the side effects do not seem to be serious. • Various NSAIDS have also been effective in terms of patient symptoms however, deleterious effects on corneal epithelium must be carefully watched for. • 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 Apr;107(4):631-9. • 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 May;107(5):967-74. • Power WJ, et al. "Effect of Topical Cyclosporin A on Conjunctival T Cells in Patients with Secondary Sjögren's Syndrome." Cornea. 12.6 (1993): 507-11. • Gündüz K, and Ozdemir O. "Topical Cyclosporin Treatment of Keratoconjunctivitis Sicca in Secondary Sjögren's Syndrome." Acta Ophthalmol (Copenh) 72.4 (1994): 438-42. • Marsh P, and Pflugfelder SC. "Topical Nonpreserved Methylprednisolone Therapy for Keratoconjunctivitis Sicca in Sjögren Syndrome." Ophthalmology. 106.4 (1999): 811-6. • Hong S, et al. "Recurrence After Topical NonpreservedMethylprednisolone Therapy for Keratoconjunctivitis Sicca in Sjögren's Syndrome." J OculPharmacolTher 23.1 (2007): 78-82. • Avisar R, et al. "Diclofenac Sodium, 0.1% (VoltarenOphtha), Versus Sodium Chloride, 5%, in the Treatment of Filamentary Keratitis." Cornea. 2000 Mar;19(2):145-7 19.2 (2000): 145-7. • Avunduk AM, et al. "The Comparison of Efficacies of Topical Corticosteroids and Nonsteroidal Anti-Inflammatory Drops on Dry Eye Patients: A Clinical and Immunocytochemical Study." Am J Ophthalmol. 136.4 (2003): 593-602. • Aragona P, et al. "Effects of the Topical Treatment with NSAIDs on Corneal Sensitivity and Ocular Surface of Sjögren's Syndrome Patients." Eye. 19.5 (2005): 535-9.

  6. Secretogogues • Pilocarpine and Cevemeline are oral muscarinic cholinergic parasympathomimetic agonists that bind to M3 receptors causing stimulation of exocrine glands. The use of 5mg of pilocarpine qid or 30mg of cevimeline tid seemed to be effective to treat dry eye as well as dry mouth symptoms secondary to SS (A,I). • Diquafosol tetrasodium is a novel dinucleotide P2Y2 receptor agonist that promotes nonglandular secretion of fluid, mucin and possibly lipid production in the meibomian glands. The evidence regarding topical diquafosol 2% is still unclear requiring further clinical trials in patients with SS (C,III). • Vivino FB, et al. "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. P92-01 Study Group." Arch Intern Med. 1999 Jan 25;159(2):174-81 159.2 (1999): 174-81. • Tsifetaki N, 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 62.12 (2003): 1204-7. • Papas AS, et al. "Successful Treatment of Dry Mouth and Dry Eye Symptoms in Sjögren's Syndrome Patients with Oral Pilocarpine: A Randomized, Placebo-Controlled, Dose-Adjustment Study." J ClinRheumatol. 10.4 (2004): 169-177. • Aragona P, et al. "Conjunctival Epithelium Improvement After Systemic Pilocarpine in Patients with Sjogren's Syndrome." Br J Ophthalmol 90.2 (2006): 166-70. • Petrone D, et al. "A Double-Blind, Randomized, Placebo-Controlled Study of Cevimeline in Sjögren's Syndrome Patients with Xerostomia and Keratoconjunctivitis Sicca." Arthritis Rheum 46.3 (2002): 748-54. • Fife RS, et al. "Cevimeline for the Treatment of Xerostomia in Patients with Sjögren Syndrome: A Randomized Trial." Arch Intern Med. 162.11 (2002): 1293-300. • Ono M, et al. "Therapeutic Effect of Cevimeline on Dry Eye in Patients with Sjögren's Syndrome: A Randomized, Double-Blind Clinical Study." Am J Ophthalmol. 138.1 (2004): 6-17. • Tauber J, et al. "Double-Masked, Placebo-Controlled Safety and Efficacy Trial of Diquafosol Tetrasodium (INS365) Ophthalmic Solution for the Treatment of Dry Eye." Cornea 23.8 (2004): 784-92.

  7. Surgical Therapy • There have been studies (B,II) demonstrating that the use of bilateral punctual plugs following the maximal use of topical lubricants helped improved both subjective and objective symptoms up to 6 months following insertion. The downside to this treatment however, was the high rates of spontaneous loss of plugs. • A case report (C,II) discussed the effects of minor salivary gland autotransplant for dry eyes. There was improvement in tear production as well as subjective symptoms following the surgery. • Balaram M, Schaumberg DA, and Dana MR. "Efficacy and Tolerability Outcomes After Punctal Occlusion with Silicone Plugs in Dry Eye Syndrome." Am J Ophthalmol. 131.1 (2001): 30-6. • Mansour K, et al. "LacrimalPunctum Occlusion in the Treatment of Severe Keratoconjunctivitis Sicca Caused by Sjögren Syndrome: A Uniocular Evaluation." Cornea. 26.2 (2007): 147-50. • Sakamoto A, Kitagawa K, and Tatami A. "Efficacy and Retention Rate of Two Types of Silicone Punctal Plugs in Patients with and without Sjögren Syndrome." Cornea. 23.3 (2004): 249-54. • Güerrissi JO, and Belmonte J. "Surgical Treatment of Dry Eye Syndrome: Conjunctival Graft of the Minor Salivary Gland." J CraniofacSurg 15.1 (2004): 6-10.

  8. Other • Autologous serum: There are several studies (A,I), (B,II) that demonstrate the subjective improvement following the use of autologous serum. However, there is not much objective evidence to suggest that the treatment is beneficial. In addition, the process of obtaining and storing the serum is labor intensive. Therefore, this particular therapy may be recommended for individuals as an alternative to artificial lubricants and secretogogues. • Systemic immunomodulatory therapy: In an observational case series of four patients with extremely severe acute dry eye syndrome who were profoundly disabled by pain and photophobia despite aggressive conventional therapy, were treated with systemic immunomodulatory therapy . Various systemic immunosuppressive agents were used to control inflammation of the lacrimal glands including prednisone, methotrexate, cyclosporine, and infliximab. There was a rapid resolution of signs and symptoms of keratoconjunctivitis sicca in all four patients. • Kojima, Takashi, et al. "The Effect of Autologous Serum Eyedrops in the Treatment of Severe Dry Eye Disease: A Prospective Randomized Case-Control Study." American Journal of Ophthalmology 139.2 (2005): 242-6. • Noble BA, Loh RS, MacLennan S, Pesudovs K, Reynolds A, Bridges LR, Burr J, Stewart O, Quereshi S. "Comparison of Autologous Serum Eye Drops with Conventional Therapy in a Randomised Controlled Crossover Trial for Ocular Surface Disease." British Journal of Ophthalmology 88.5 (2004): 647-52. • Tananuvat N, et al. "Controlled Study of the use of Autologous Serum in Dry Eye Patients." Cornea. 20.8 (2001): 802-6. • Tsubota K, et al. "Treatment of Dry Eye by Autologous Serum Application in Sjögren's Syndrome." Br J Ophthalmol. 83.4 (1999): 390-5. • Cordero-Coma M, et al. "Systemic Immunomodulatory Therapy in Severe Dry Eye Secondary to Inflammation." Ocul Immunol Inflamm. 15.2 (2007): 99-104.

  9. Conclusions • Lubricants that have been shown to be most effective include hypotonic sodium hyaluronate (A,I). • There is sufficient evidence both clinically and histopathologically demonstrating the effectiveness of cyclosporine (A,I) as well as its safety over long-term use. • Punctal plugs are effective and may be used in conjunction with lubricants but they do have a high rates of spontaneous loss. • Steroids are effective, but have ocular and other side effects. They should be used therefore be used with caution among individuals with moderate to severe disease and among individuals who have failed other forms of therapy.

  10. Conclusions • Secretogogues such as Pilocarpine, Cevimeline and Diquafosol are effective in the treatment of dry eye associated with SS in individuals who have failed topical lubricants and punctual occlusion. This line of therapy is also likely to be most effective among individuals with symptoms of dry eyes and dry mouth. • There are very few studies on the effectiveness of immunomodulators. Additional studies are necessary before recommendations can be made. • Other therapies such as autologous serum and selective estrogen receptor modulator have been shown to be effective in the treatment of dry eyes secondary to SS. These may be recommended to certain patients if they have failed all other types of therapy.

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