Treatment%20of%20Sj

1

• Treatment of Sjögrens
• 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 Sjögrens 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
  Collaborations 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 Schirmers
  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
  Sep16(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 Mar15(2)120-8. 15.2
  (1996) 120-8.

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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
  Apr107(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 May107(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 Mar19(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 25159(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
  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.

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. "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.

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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.

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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.

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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.