Transcript Treatment of Sjögren’s Syndrome-Associated Dry Eye: An Evidence-Based Review Rohit S.Adyanthaya, M.D.,

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.
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.
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.
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).
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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.
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.
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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 doseranging, 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 Nonpreserved Methylprednisolone Therapy for Keratoconjunctivitis Sicca in Sjögren's Syndrome." J Ocul Pharmacol
Ther 23.1 (2007): 78-82.
Avisar R, et al. "Diclofenac Sodium, 0.1% (Voltaren Ophtha), 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.
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).
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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, FixedDose, Multicenter Trial. P92-01 Study Group." Arch Intern Med. 1999 Jan 25;159(2):174-81 159.2 (1999): 174-81.
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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 Clin
Rheumatol. 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.
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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.
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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. "Lacrimal Punctum 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 Craniofac Surg 15.1
(2004): 6-10.
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.
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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.
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.
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.