Treatment of Sjögren s Syndrome Associated Dry Eye

Treatment of Sjögren’s Syndrome–Associated Dry Eye An Evidence-Based Review Esen Karamursel Akpek, MD,1 Kristina B. Lindsley, MS,2 Rohit S. Adyanthaya...
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Treatment of Sjögren’s Syndrome–Associated Dry Eye An Evidence-Based Review Esen Karamursel Akpek, MD,1 Kristina B. Lindsley, MS,2 Rohit S. Adyanthaya, MD,1 Ramya Swamy, BS,1 Alan N. Baer, MD,3 Peter J. McDonnell, MD1 Background: Outcomes-based review of reported treatment options for patients with dry eye secondary to Sjögren’s syndrome (SS). Clinical Relevance: Dry eye affects many individuals worldwide. Significant proportion of patients with dry eye has underlying SS, a progressive autoimmune condition. The few suggested guidelines for the treatment of dry eye are mostly based on severity of symptoms and/or clinical findings rather than on outcomes analysis, and do not differentiate SS from other causes of dry eye. Methods and Literature Review: A search strategy was developed to identify prospective, interventional studies of treatments for SS-associated dry eye from electronic databases. Eligible references were restricted to English-language articles published after 1975. These sources were augmented by hand searches of reference lists from accessed articles. Study selection, data extraction, and grading of evidence were completed independently by ⱖ4 review authors. Results: The searches identified 3559 references as of August 10, 2010. After duplicate review of the titles and abstracts, 245 full-text papers were assessed, 62 of which were relevant for inclusion in the review. Conclusions: In the current literature on SS-associated dry eye, there is a paucity of rigorous clinical trials to support therapy recommendations. Nonetheless, the recommended treatments include topical lubricants, topical anti-inflammatory therapy, and tear-conserving strategies. The efficacy of oral secretagogues seems greater in the treatment of oral dryness than ocular dryness. Although oral hydroxychloroquine is commonly prescribed to patients with SS to alleviate fatigue and arthralgias, the literature lacks strong evidence for the efficacy of this treatment for dry eye. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2011;118:1242–1252 © 2011 by the American Academy of Ophthalmology.

Dry eye syndrome is a common disorder, the symptoms of which are reported by an estimated 25% of patients in general ophthalmology clinics.1 More than 9 million Americans suffer from a moderate to severe form of dry eye.2,3 Recently, an international group, the Definition and Classification Subcommittee of the International Dry Eye Work Shop, redefined dry eye syndrome as “a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.”4 The etiopathogenetic classification suggested by the Dry Eye Work Shop distinguishes 2 main types of dry eye: An aqueous deficiency state and an evaporative state. Aqueous deficiency state is further divided into 2 main groups: Sjögren’s syndrome (SS)–related dry eye and non-SS–related dry eye. Sjögren’s syndrome is an autoimmune disease of the exocrine glands and is a major cause of dry eye. The syndrome may present as a primary disorder or as secondary to other well-defined autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, systemic

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© 2011 by the American Academy of Ophthalmology Published by Elsevier Inc.

sclerosis, and polymyositis.4 The frequency with which dry eye is associated with SS is not fully known. In our recent retrospective study, 25.9% of 220 patients with dry eye had an underlying rheumatic condition, 10.9% patients with primary SS.5 Various therapies are available for the treatment of dry eye to lubricate the ocular surface, increase the secretion of or conserve tears, or target the associated ocular surface inflammation. Currently there are only 2 published treatment algorithms, based primarily on grading the severity of symptoms and signs rather than on outcomes of therapy.4,6 One problem in assessing treatment outcomes is that most available publications on the treatment of dry eye group all causes of dry eye together as a single entity, although they might include different clinical entities with different pathogeneses, natural histories, severities, and outcomes. Dry eye in SS is believed to be progressive and more severe than other causes and may thus require more aggressive treatment. The objective of this review was to compile and summarize the current evidence from clinical studies on the treatment options for dry eye due to SS. ISSN 0161-6420/11/$–see front matter doi:10.1016/j.ophtha.2010.12.016

Akpek et al 䡠 Treatment of Sjögren’s Syndrome–Associated Dry Eye Table 1. Search Strategy for Treatment of Sjögren’s Syndrome Associated Dry Eye: PubMed Searched on August 10, 2010 C Sjögren’s Syndrome-Associated Dry Eye

A Dry Eye

B Sjögren’s Syndrome

1 Dry Eye Syndromes/therapy*[MeSH Terms] 2 “dry eye”[ti] 3 “dry eyes”[ti]

1 Sjögren*[tiab] 2 Gougerot-Sjögren*[tiab] 3 “sicca syndrome”[tiab]

1 2 3 4 5 6 7

1 OR 2 OR 3

1 OR 2 OR 3

1 OR 2 OR 3 OR 4 OR 5 OR 6 OR 7

eye[tiab] eyes[tiab] ocular[tiab] conjunctiva*[tiab] keratoconjunctiviti*[tiab] sicca[tiab] xerophthalmi*[tiab]

D Humans Only 1 Animal[mh] 2 Human[mh]

1 NOT 2

Final search: (A OR (B AND C)) NOT D Exclusions Conference abstract or not peer reviewed article Published before 1976 Non-English language

Sources and Methods of Literature Search We developed an electronic search strategy to identify reports of studies related to the treatment of SSassociated dry eye (Tables 1 and 2). The searches were limited to English-language articles published in peerreviewed journals after 1975. The electronic searches were conducted in PubMed and the Cochrane Collaboration’s database on August 10, 2010. The electronic search was supplemented by a hand search of reference lists of all papers identified and all major review articles related to SS or dry eye. At least 2 authors, including 1 clinician (EKA, RSA, RS) and 1 methodologist (KBL), independently reviewed the titles and abstracts identified by the electronic searches for inclusion in the review. An abstract was excluded from the review if it (1) was not relevant to the treatment of dry eye or SSassociated dry eye; (2) was a report of a laboratory or animal study; (3) was not a prospective, comparative study (i.e., case report, case series, or retrospective cohort); (4) was a metaanalysis or review; (5) lacked original data (i.e., editorial or letter); (6) did not include dry eye related outcomes; or (7) excluded patients with SS from the study. For all abstracts that were not excluded, full text copies of the articles were obtained and assessed independently by 4 of the authors, including 1 methodologist (KBL), 2 ophthalmologists (EKA, PJM), and 1 rheumatologist (ANB). Based on the full-text assessments, studies were either included in the review or excluded from the Table 2. Search Strategy for Treatment of Sjögren’s Syndrome Associated Dry Eye: Cochrane Central Register of Controlled Trials Searched on August 10, 2010 A Dry Eye

B Sjögren’s Syndrome

“dry eye” OR “dry eyes” in Title, Abstract or Keywords

Sjögren* OR Gougerot-Sjögren* OR “sicca syndrome” in Title, Abstract or Keywords

Final search: A OR B Exclusions Conference abstract or not peer reviewed article Published before 1976 Non-English language

review. A study at this stage was excluded if it (1) did not include patients with SS; (2) did not report data for patients with SS separately; (3) was not a prospective study or included ⬍10 patients with SS; or (4) did not report objective outcomes related to dry eye. Evidence for treatment options was assessed and graded by 4 of the authors (EKA, KBL, PJM, ANB) independently. Discrepancies were resolved at a meeting by discussion until consensus was achieved. The overall strength of evidence (I, II, and III) and ratings for clinical recommendations (A, B, C, and I) for interventions were graded as outlined in the journal guidelines. In summary, level I indicates that the data provided strong evidence for the recommendation, the study design addressed the issue in question, and the study was performed in the population of interest and in a manner that ensured accurate and reliable data, using appropriate statistical methods. This level includes well-conducted, randomized, controlled clinical trials and meta-analyses. Level II indicates that the data provided substantial evidence for the recommendation, but the evidence lacked some components of level I. Examples include nonrandomized, comparative trials with sufficient numbers of observational studies, including control groups, wellconducted cross-sectional studies and literature reviews, and even large, consecutive case series. Level III indicates a weaker body of evidence that does not meet the criteria for levels I and II; this generally includes expert opinions, small noncomparative case series, and individual case reports. In the ratings for clinical recommendations, A indicates that the recommendation is very important or crucial to a good clinical outcome; B, that the recommendation is moderately important to clinical outcome; C, that the recommendation may be but is not definitely related to clinical outcome; and I, that data on outcomes are insufficient.

Results There were 3559 references identified by the searches conducted on August 10, 2010 (Fig 1). After duplicate review of the titles and abstracts, 3314 references were excluded: 2822 were not relevant to the treatment of dry eye, or specifically SS-associated dry eye; 61 were reports of lab-

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Figure 1. Flowchart of reference review for treatment of Sjögren’s syndrome–associated dry eye.

oratory or animal studies; 111 were not prospective studies; 121 were reviews or meta-analyses; 117 did not report original data; 45 did not report outcomes related to dry eye; and 37 excluded patients with SS. Of the remaining 245 references, 62 were included in the review and 183 were excluded. The reasons for exclusion were as follows: the study did not include patients with SS (94 papers); data for patients with SS were not reported separately (61 papers); the study was not a prospective or included ⬍10 patients (22 papers); or the study did not report objective outcomes related to dry eye (6 papers).

Summary of Evidence Topical Lubricants. Although a large number of ocular lubricants are regularly used in treating dry eye, only 4 reports investigated the effects of these specifically for the treatment of SS-associated dry eye.7–10 Sodium hyaluronate is a viscoelastic substitute commonly used in intraocular surgery to protect the corneal endothelium. In a formulation osmolarity study,7 40 patients with SS were enrolled. Group 1 patients received hypotonic (150 mOsm/L) 0.4% hyaluronate drops (Ialurex, Fidia Oftal, Catania, Italy), and group 2 patients received isotonic 0.4% hyaluronate drops (Dropstar TG, Farmigea, Pisa, Italy) instilled 6 times daily for 90 days. Both groups had significant improvement in tear film breakup time (TBUT)

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scores, corneal and conjunctival staining, as well as impression cytology after 2 weeks of treatment as compared with baseline. Patients who received the hypotonic solution did better and had a normal cytology by day 30. There was no change in Schirmer test results in either group. In a multicenter, randomized, crossover trial,8 39 women with primary or secondary SS received treatment with either 0.1% (w/v) sodium hyaluronate solution (HA, Fermavisc, Vitrolife UK Ltd., Edinburgh, UK) or 1.4% (w/v) polyvinyl alcohol (Refresh, Allergan, Inc., Irvine, Ca). After 4 weeks, patients switched to the other solution for an additional 4 weeks. No significant differences were observed for Schirmer score, tear clearance rate, tear function index, or TBUT in either treatment group. Conjunctival staining scores were lower for patients receiving the sodium hyaluronate treatment. One study9 evaluated the treatment of SS-associated dry eye with 2 types of hydroxypropyl cellulose formulations in 2 consecutive series. In the first series, 29 patients with primary SS were randomized to receive either 5 mg hydroxypropyl cellulose inserts (Lacrisert, MSD, Lyngby, Denmark) plus saline drops or placebo inserts plus saline drops. After 3 weeks of treatment, patients were switched to the other treatment modality. The TBUT and conjunctival staining scores significantly improved after the hydroxypropyl cellulose inserts compared with the placebo inserts. In the second series, patients were randomized to receive either

Akpek et al 䡠 Treatment of Sjögren’s Syndrome–Associated Dry Eye hydroxypropyl cellulose inserts plus tear substitute (oxypropyl methylcellulose drops [oculoguttae viscosae, DAK, Copenhagen, Denmark]) or placebo inserts plus tear substitute. After 3 weeks of treatment, patients were switched to the other therapy. No differences in objective parameters were found between the 2 groups. Complaints of partially dissolved inserts being expelled shortly after insertion were reported frequently in both groups. Sucralfate (aluminum sucrose sulfate) is a gastric mucosal protectant. A 2% ophthalmic solution of sodium sucrose sulfate was tested in a double-masked, crossover trial.10 The trial included 30 patients with SS who were allocated to 1-month treatment periods using the 2% solution or placebo ⱖ5 times a day, and then switched to the other treatment. A significant improvement was noted in the conjunctival staining scores in the treated group compared with the placebo group. Topical Anti-Inflammatory Therapy. There is increasing evidence that inflammation may be an important factor in the pathogenesis of SS-associated dry eye. Inflammatory cell infiltration, predominantly by T lymphocytes, has been seen in the conjunctival tissues and lacrimal glands of patients with SS.11–13 Seven studies reported the effects of topical anti-inflammatory therapy for the treatment of SSassociated dry eye.14 –20 Corticosteroids. In a prospective study14 of 53 patients with SS, the long-term recurrence rate of dry eye symptoms and signs after short-term pulse topical preservative-free methylprednisolone therapy was evaluated. Therapy started at 4 times a day for the first 2 weeks and tapered off every 2 weeks until complete discontinuation. Improvement in subjective symptoms and corneal staining scores occurred as early as 2 weeks. Significantly improved TBUT and Schirmer test results were observed at the end of the treatment period. Impression cytology revealed a significantly increased number of conjunctival goblet cells. After the first pulse therapy, mean drug-free remission time was 56.6 weeks; 11 patients (20.8%) had a recurrence of symptoms and signs. After the second pulse therapy, mean drug-free remission time was 72.4 weeks; only 1 patient had a recurrence. No serious complications, including intraocular pressure elevation and cataract formation, occurred during the entire follow-up period. Cyclosporine. Cyclosporine (CsA) is a neutral, hydrophobic, cyclic undecapeptide metabolite of the fungus Tolypocladium inflatum. Its major clinical effect is disruption of expression of interleukin-2 by helper T cells, preventing T-cell proliferation.21 Four published studies evaluated the use of topical CsA at various concentrations to treat SS-associated dry eye.15–18 In a randomized, double-masked, placebo-controlled trial,15 30 patients (60 eyes) underwent a 2-month treatment with 2% topical CsA, versus vehicle (olive oil) as placebo. There was a significant improvement in TBUT and conjunctival staining score in the treatment group (compared with control) at the end of the study period. Schirmer test results were unaffected in both groups. Another randomized trial compared 1% CsA drops to placebo over a period of 3 months.16 Twenty-five patients were included in each group. Subjective symptoms im-

proved in both groups. The CsA group had a statistically better improvement in Schirmer test scores at 3 months and conjunctival staining at 1 month (P⬍0.05). A third randomized trial was a crossover study that compared 2% CsA drops with placebo over the course of 2 treatment periods of 8 weeks each.17 Among the 15 patients with SS, 8 weeks of treatment with topical CsA did not improve TBUT or cumulative conjunctival staining scores. One patient had improved Schirmer test scores after CsA use compared with none after placebo. No significant symptom relief was observed. In a nested case-control study,18 a random sample of 32 patients was selected from a trial cohort of patients with moderate to severe dry eye for conjunctival biopsy after a twice-daily regimen for 6 months using 0.05% or 0.1% CsA eye drops versus placebo drops. Among the selected patients, 12 had SS and 20 did not. A significant decrease in the number of CD11a- and CD3-positive cells (i.e., activated lymphocytes) was observed in the specimens of SS patients treated with 0.05% CsA compared with placebo. Comparisons with the 0.01% CsA group were not made as only 1 SS patient was treated with 0.01% CsA. Nonsteroidal Anti-Inflammatory Drugs. Two randomized clinical trials investigated the effectiveness of topical nonsteroidal anti-inflammatory drugs for the treatment of SS-associated dry eye. A prospective, open-label, randomized study19 compared the efficacy of diclofenac sodium 0.1% drops (Voltaren Ophtha, Ciba Vision, Duluth GA) versus sodium chloride 5% ophthalmic solution in the treatment of filamentary keratitis in 32 patients. Half of the patients received diclofenac sodium and half received the saline 4 times a day for 28 days. Overall, patients in the diclofenac group showed a significantly greater improvement in itching, ocular pain, and foreign-body sensation on days 7 and 14 compared with the patients in the saline group. However, no significant difference in symptomatology between the groups was noted by day 28. Although the number of corneal filaments on days 14 or 21 was lower in the diclofenac group, compared with the saline group there was no significant difference between groups by day 28. In a controlled, single-masked, parallel-group study,20 the effects of 2 nonsteroidal anti-inflammatory drugs on corneal sensitivity and ocular surface health were studied in 20 patients with SS. Patients were randomly divided into 2 groups: Group 1 was treated with 0.1% indomethacin drops (Indocollirios, Bausch & Lomb Oftal, Catania, Italy) and group 2 with 0.1% diclofenac drops (Voltaren Oftas, Novartis Farma, Hettlingen, Switzerland), 3 times a day for 1 month. Although the ocular discomfort score was significantly reduced in both groups (with better results in group 2) starting on day 15, corneal staining showed significant worsening in the diclofenac group compared with the indomethacin group 7 days posttreatment. The authors concluded that although topical nonsteroidal anti-inflammatory drugs can be useful in resolving discomfort symptoms, caution should be exercised because of corneal epithelial problems.

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Ophthalmology Volume 118, Number 7, July 2011 Other Topical Therapies. Autologous Serum. Tears contain essential components for maintaining the ocular surface, such as epidermal growth factor, vitamin A, fibronectin, and other cytokines. Because these components are also found in serum, the application of autologous serum is thought to offer advantages over artificial tears, which lack such essential components. In a prospective, crossover trial,22 16 patients (6 with SS) were randomized to receive autologous serum tears for 3 months followed by conventional treatment for 3 months or conventional treatment for 3 months followed by autologous serum tears for 3 months. Conventional therapy included intensive preservative-free artificial tears and punctal occlusion. Clinical assessments including Schirmer test, conjunctival and corneal staining, impression cytology, and subjective comfort scores were performed at intervals during the study. At the end of the study, impression cytology improved in 4 SS patients, was unchanged in 1 SS patient, and worsened in 1 SS patient after serum treatment compared with conventional treatment. However, Schirmer test and conjunctival and corneal staining did not show significant improvement in either SS or non-SS patients. Subjective comfort scores were not reported separately for SS patients. None of the patients had adverse reactions to serum treatment or developed secondary infections during the course of the study. Another trial23 also showed potential benefits for the treatment of SS-associated dry eye with autologous serum tears. The effects of autologous serum tears were evaluated in 15 patients with dry eye syndrome of whom 8 had primary SS (pSS). Subjective improvements in symptoms as well as a decrease in conjunctival staining were noted in all pSS patients. In a crossover phase of the study, 6 patients were switched to placebo drops. All 6 patients notified study investigators within 96 hours of using the placebo that the drops were not as soothing or long lasting compared with the previous use of autologous serum drops. It was not reported how many of these patients had SS. In a nonrandomized clinical trial comparing 2 types of topical serum,24 7 SS patients were treated with autologous serum and 10 SS patients were treated with umbilical cord serum for 2 months. At the end of the treatment period, both groups showed significant improvements in symptom scores, TBUT, corneal staining score, grade of squamous metaplasia, and goblet cell density. The group receiving umbilical cord serum showed greater improvement in symptom scores and corneal staining scores at 1 and 2 months after treatment compared with the group receiving autologous serum. Goblet cell density scores were significantly higher in the umbilical cord serum group compared with autologous serum group at 2 months as well. Secretagogues. Exocrine gland secretion, including lacrimation, is mainly controlled by acetylcholine acting through muscarinic receptors. Patients with SS have been shown to have serum autoantibodies that bind to M3 receptors. Lymphocytic cell infiltration and glandular destruction are thought to be the main mechanism of dryness associated with SS, but the M3 receptor-binding antibodies might also play a role in the pathogenesis. There were 7 reports inves-

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tigating secretagogues for the treatment of SS-associated dry eye identified in this review. Pilocarpine. Pilocarpine is a muscarinic cholinergic parasympathomimetic agonist that binds to M3 receptors and stimulates exocrine glands. Pilocarpine (Salagen tablets, Novartis Pharmaceuticals, Basel, Switzerland) is currently available in 5- and 7.5-mg tablets for oral use. Most patients require 20 mg/d in divided doses for a therapeutic response. In a multicenter, placebo-controlled, fixed-dose trial,25 373 patients with primary or secondary SS and clinically significant dry mouth and dry eyes were randomized to receive 10 or 20 mg/d of pilocarpine or placebo tablets for 12 weeks. For global improvement of dry eye symptoms, a significant benefit was observed in the 20-mg pilocarpine group versus the placebo group. The 10-mg pilocarpine group had no better symptomatic relief of oral or ocular symptoms than the placebo group. Additionally, a greater proportion of patients taking 20-mg pilocarpine tablets showed clinically significant improvement (compared with those taking placebo) in the ability to focus their eyes while reading and reduced severity of blurred vision. Excessive sweating was the most commonly reported side effect, occurring in ⬎40% of patients. Another 12-week, single-center, randomized, controlled study was performed in 85 patients with SS.26 Patients were randomly assigned to receive 5 mg of oral pilocarpine twice a day (n ⫽ 29), artificial tears (n ⫽ 28), or inferior punctal occlusion (n ⫽ 28). Changes in ocular symptoms from baseline were assessed on a 100-mm visual analog scale. Patients taking oral pilocarpine had significant improvement in subjective global assessment of dry eye compared with patients receiving artificial tears or inferior punctal occlusion as well as greater improvement in conjunctival staining. Schirmer test results showed no differences between treatment groups. In a multicenter, randomized, placebo-controlled, doseadjustment study involving 256 patients with SS,27 the safety and efficacy of oral pilocarpine (20 or 30 mg/d) for relief of dry mouth and dry eye symptoms was assessed over 12 weeks. There was significant symptomatic improvement of dry eye at 12 weeks with pilocarpine 20 mg/d. Of note, the use of artificial tears also decreased significantly in the pilocarpine group at the end of the study period. Cevimeline. Cevimeline hydrochloride is an orally administered derivative of acetylcholine that binds to M3 receptors in exocrine glands and increases exocrine gland secretion. Cevimeline (Evoxac, Daiichi Pharmaceutical Corp, Montvale, NJ) 30-mg tablets are typically taken 3 times daily. Four randomized trials investigated the use of cevimeline for the treatment of SS-associated dry eye. In a multicenter, double-blind, randomized, parallelgroup study,28 197 patients were randomly assigned to receive 15 or 30 mg of cevimeline or placebo 3 times daily. At the end of the 12-week study, 31% of patients in the 15-mg cevimeline group and 39% in the 30-mg group reported improvement in global assessment of “overall dryness” (mouth and eyes), compared with 24% of the placebo group. The difference between the placebo and 30-mg group was significant. There was a significantly greater improvement in Schirmer test results in the 30-mg cevimeline group than in the placebo group. Of note, 82% of patients reported

Akpek et al 䡠 Treatment of Sjögren’s Syndrome–Associated Dry Eye side effects, including increased sweating, abdominal pain, headaches, and nausea. In another multicenter, double-blind, randomized, placebocontrolled trial,29 75 patients with SS were randomized to receive 30 or 60 mg of cevimeline or placebo 3 times daily for 6 weeks. At the end of the study period, 18 patients in the 30-mg cevimeline group (72%) versus 7 patients in the placebo group (30%) had responses of “better” in assessing improvement of dry eye. In the 60-mg cevimeline group, 14 patients (52%) reported a response of “better,” but this was not significant. No differences were observed in Schirmer test results or decreased daily use of artificial tears. A third study, a multicenter, prospective, double-blind clinical trial30 involving 60 patients, randomly assigned participants to 1 of 3 groups: 20 or 30 mg of cevimeline or placebo, 3 times daily for 4 weeks. Compared with the placebo group, significant differences in subjective symptoms, ocular surface staining, and TBUT were seen in the 20-mg cevimeline group. The authors concluded that cevimeline might increase goblet cell secretions. No difference in side effects was found among the 3 groups. A prospective randomized, double-blind, placebo-controlled, crossover study31 evaluated the effects of oral cevimeline in 50 patients with SS. Patients received cevimeline 30 mg or matched placebo 3 times per day over 10 weeks followed by a 4-week washout period before treatment crossover. Participants were assessed by a symptom questionnaire for ocular sicca. Although there was a significant improvement in the subjective and objective rating of xerostomia, no improvement in salivary flow rates or dry eye symptoms was noted. Systemic Immunosuppressive/Immunomodulatory Therapy. About one third of patients with SS have extraglandular manifestations mediated by immune complexes and vasculitis, giving rise to nonvisceral (skin, arthralgia, and myalgia) and visceral (lung, heart, kidney, gastrointestinal, endocrine, and central and peripheral nervous system) findings that are generally managed by rheumatologists. Also, lymphoma occurs in approximately 5% of patients with primary SS, and the risk increases with disease duration.32 Most of the lymphomas are marginal zone B-cell lymphomas, arising in diverse extranodal and nodal sites and generally not associated with viruses.33 About 20% of deaths among patients with primary SS are attributable to lymphoma.34 Various immunosuppressive and immunomodulatory agents have been used to treat patients with primarily nonglandular involvement, as well as lymphoma. Their effects of treating the sicca component of the disease were assessed in only a small proportion of these studies, and 16 were included in this review. Hydroxychloroquine. Hydroxychloroquine is an oral immunomodulator used at a dose of 6 to 7 mg/kg per day in the treatment of various autoimmune diseases. The exact mechanism of action is not fully understood but has been attributed to interference with macrophage processing of antigens interfering with T-cell activation35 and possibly preventing epitope spreading for autoantibodies. T-cell– derived cytokines are required for B cells to switch from immunoglobulin (Ig)M to IgG synthesis, which explains the

beneficial effects of hydroxychloroquine in SS with hypergammaglobulinemia.36 Hydroxychloroquine is believed to improve salivary gland function,35 and it may prevent neoplastic transformation by modulating lymphoproliferation.36 Further, a decreased erythrocyte sedimentation rate has been noted,36 as well as decreased salivary and serum interleukin (IL)-6, serum gamma globulin, and C-reactive protein.37 Hydroxychloroquine generally has a good safety record, with ⬍1 in 1000 patients experiencing macular problems.38 In a 2-year, double-blind, crossover trial,36 hydroxychloroquine 200 mg twice daily by mouth was used in the treatment of 19 patients with primary SS. Existing symptomatic treatment, including topical artificial tears, was continued during the study. The study assessed symptoms of dryness and sandy feeling as well as tear lysozyme and lactoferrin concentrations, Schirmer test, TBUT, and conjunctival staining. No differences were found between the treated and untreated groups. In a 12-week prospective study,39 32 women with SS were observed after discontinuing treatment with hydroxychloroquine after at least 2 years of use. Both signs (TBUT, corneal and conjunctival staining) and symptoms (gritty sensation and burning sensation) worsened significantly after withdrawal of treatment. Furthermore, levels of tear fluid B-cell–activating factor belonging to the tumor necrosis factor family increased with withdrawal. Rituximab. Rituximab is a chimeric (murine and human) monoclonal antibody directed against the CD20 molecule, a tetraspan membrane protein found only on the surface of mature B cells. The mechanism by which rituximab causes B-cell death is not fully understood, but is likely to be a combination of antibody-dependent cellmediated cytotoxicity, complement-mediated lysis, growth inhibition, and apoptosis.40 The drug is typically administered as intravenous infusions (375 mg/m2) once weekly for 4 weeks. Although overall positive results have been reported for systemic complications and fatigue, effects on sicca are disappointing.41– 43 A randomized clinical trial demonstrated no effect in Schirmer test scores and TBUT at weeks 5 and 48, although there was a significant decrease in conjunctival staining scores after 2 infusions of rituximab.44 There were 2 additional case series that studied rituximab for the treatment of SS-associated dry eye. One study45 involving 15 patients with severe SS with autoantibodies and disease duration ⬍4 years reported a significant improvement in conjunctival staining of the ocular surface, although Schirmer test scores and TBUT did not change. The second study46 failed to demonstrate improvements in objective measures of ocular dryness. Anti-Tumor Necrosis Factor Agents. In a pilot study, systemic infliximab significantly improved dry eye symptoms and Schirmer scores47 in 16 patients with sustained improvement at 1 year of follow-up.48 However, 3 subsequent prospective trials using the anti-tumor necrosis factor agents, infliximab49 and etanercept,50,51 failed to demonstrate any objective improvement in the sicca component of SS syndrome. D-Penicillamine. In a prospective, open-label study,52 D-penicillamine was used (first 3 months, 250 mg/d;

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Ophthalmology Volume 118, Number 7, July 2011 next 3 months, 500 mg/d) to investigate clinical and immunologic parameters in 19 patients with SS with a mean disease duration of 3.8 years. Laboratory values showed a decrease in erythrocyte sedimentation rate (P⬍0.05) and in IgA, IgM, and rheumatoid factor levels and an increase in hemoglobin. Clinically, saliva flow was improved, but no significant changes were noted in Schirmer test scores, TBUT, or subjective symptoms of dryness. Five patients had to discontinue treatment because of side effects, including severe loss of taste, nausea, anorexia, malaise, and diplopia, all of which were reversible. Mycophenolic Acid. Mycophenolic acid is a selective inhibitor of inosine monophosphate dehydrogenase, and thus inhibits the de novo pathway of nucleotide synthesis. Its antiproliferative effect occurs through inhibition of T and B lymphocytes, because proliferation of these cells is more dependent than other eukaryotic cells on de novo purine synthesis.53 Mycophenolate mofetil was used in a single-center, prospective, open-label, pilot trial with 11 patients with SS,54 for an observation period of 6 months. Treatment was initiated with 360 mg/d and increased weekly by 360 mg, up to a maximum stable dose of 1440 mg/d. There was a significant reduction in artificial tear use and improvement in patient symptoms, but no significant increase in Schirmer test results. Interferon Alpha-2. Interferon alpha-2 was compared with hydroxychloroquine (control) in an open-label study of 20 patients with SS.55 Lacrimal and salivary functions improved by 67% and 61%, respectively, for the interferon alpha-2 group, and by 15% and 18% for the control group (P⬍0.01). Immunologic parameters did not change over time in either group. In 3 patients, a decrease in the biopsy score was observed in the interferon alpha-2 group, whereas no changes were seen in the control group. Tolerability was acceptable in both groups. Oral Cyclosporine. Oral cyclosporine was also used in a double-blind study as an immunomodulator in 20 patients with systemic findings from SS.56,57 At the end of a 1-year treatment, there were no improvements in oral or ocular sicca findings as determined with saliva flow or Schirmer test, respectively. Systemic Corticosteroids. A single study investigated systemic prednisone for the treatment of SS-associated dry eye in a randomized, double-masked trial with 3 arms.58 Eight patients with SS received 30 mg of prednisone on alternate days, 8 received 20 mg piroxicam daily, and 8 were assigned to the placebo group. After 6 months of treatment, neither Schirmer scores nor conjunctival staining were altered for any group. Other Systemic Treatments. Bromhexine. Bromhexine is a synthetic derivative of vasicine, an alkaloid from the leaves of the Adhatoda vasica. The drug is used as a mucolytic agent, which consequently increases sputum. In 2 consecutive, randomized, double-blind, crossover trials,59 29 patients with SS were assigned to treatment with bromhexine or placebo. Each crossover trial was composed of two 2-week periods. In the first trial bromhexine 24 mg/d was given by mouth; in the second, the dose was increased to 48 mg/d. After each treatment period, the Schirmer test, TBUT, conjunctival staining score, and the time taken for the patient to eat a dry biscuit were recorded, as well as the

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patient’s estimate of moistness in the eyes and mouth. In the second (higher dose) trial, values on the Schirmer test were significantly higher after bromhexine than after placebo and the TBUT was also increased after bromhexine, which suggested that the drug has a dose-dependent effect on lacrimal gland secretion in SS. Neither dose had an effect on salivary gland function. In a prospective study,60 30 patients with SS were treated with 32 mg/d bromhexine and 6 patients were placed on placebo and then switched to bromhexine. After 3 weeks of treatment 70% of patients treated with bromhexine showed increases in tear secretion and lysozyme content. In another prospective study61 of 14 patients with SS, Schirmer levels and tear lysozyme levels did not improve after 2 weeks of 16 mg bromhexine 4 times daily. Discouraging results were also seen in another study in which lacrimal and salivary gland secretions increased in only 25% of the patients; however, safety was evident over 24 months.62 In a nonrandomized trial,63 38 patients with SS were treated with either bromhexine 24 or 48 mg/d. After 6 months of treatment, dry eye symptoms were improved and tear lysozyme levels were significantly increased in a dose-dependent manner, although Schirmer test scores remained unchanged for both groups. A bromhexine metabolite, NA-872, used 15 mg 3 times daily over a period of 3 weeks, did not improve Schirmer test scores, conjunctival staining, TBUT, corneal sensitivity or oral sicca symptoms.64 – 66 Bromhexine also failed to induce significant changes in the tear protein composition. Treatment with another bromhexine metabolite, ambroxol (Mucosolvan), did not improve Schirmer score, TBUT, or tear lysozyme in a randomized crossover trial of 36 patients with SS.67 Similarly, another study68 showed no objective ocular improvements with ambroxol treatment; however, patients reported symptomatic relief. Sex Steroid Hormones. One study69 examined the relationship between levels of sex hormones and SS symptoms. Twenty-three postmenopausal women with primary SS and subnormal dehydroepiandrosterone levels were included in a 9-month, randomized, controlled, double-blind, crossover study. Dry mouth symptoms correlated with low testosterone and androstenedione levels, and dry eye with low estrogen levels, and most strongly with low estrone levels. Presence of anti–SS-A and/or anti–SS-B was independently associated with low estradiol levels. Dry mouth symptoms decreased with dehydroepiandrosterone therapy, but no significant improvement was seen in symptoms of dry eye. An earlier clinical trial70 also demonstrated no significant differences for objective or subjective ocular dryness measurements with dehydroepiandrosterone treatment. Doxycycline. In an evaluation of the effect of matrix metalloproteases (doxycycline) in 22 patients with SS,71 the therapy did not produce improvement in either subjective or objective ocular symptoms. Reverse Transcriptase Inhibitors. One study72 investigated treatment with reverse transcriptase inhibitors for SS-associated dry eye in 17 patients. In a randomized trial of lamivudine versus placebo, no objective outcomes for dry eye were improved after 12 weeks of treatment for either group.

Akpek et al 䡠 Treatment of Sjögren’s Syndrome–Associated Dry Eye Other Systemic Treatments. There were 5 other systemic treatments investigated by 1 study each. Studies of treatment with oral N-acetylcysteine,73 oral methotrexate,74 and intramuscular injections of nandrolone decanoate (decadurabolin)75 reported symptomatic improvements for patients with SS, but no objective outcomes for dry eye were significantly affected by treatment. Treatment with oral thalidomide did not show any subjective or objective dry eye improvements in 1 study76; furthermore, the use of thalidomide resulted in severe adverse effects which led to the termination of the study. Finally, treatment with enteric lactoferrin by mouth for 1 month showed encouraging results for objective dry eye outcomes.77 The study included 10 SS patients; 7 SS patients who did not consent served as the control group and underwent the same examinations as the treatment group throughout the study period. Mean corneal sensitivity, TBUT, central tear film lipid layer thickness, vital staining scores, squamous metaplasia grades, and goblet cell densities were significantly improved during the treatment period, but Schirmer test results were not changed. Interventional Treatments. Various surgical measures have been used for the therapy of dry eye in patients with SS. Punctal occlusion with plug insertion is the most commonly used technique and was reported by 2 studies included in this review. Punctal Plugs. In a prospective study78 to evaluate the efficacy of a thermosensitive punctum plug (SmartPlug), 22 patients with primary SS who had plug insertions were followed for 1 year. At the end of the study period, significant improvements were seen in the Schirmer I test scores (P ⫽ 0.006) and TBUT (P⬍0.0001). In another study,79 uniocular occlusion by plugs in the upper and lower puncta was performed in 20 patients, with the fellow eye serving as control. The minimal duration of plugging was 6 weeks and the maximum 20 weeks; 7 patients were lost to follow-up. In the occluded eye, a significant improvement occurred in both symptoms and conjunctival staining. However, Schirmer test scores did not change. Spontaneous plug loss was the most common complication. Other Treatment Methods. Dietary Supplements. Gamma linolenic acid and its precursor linoleic acid are essential fatty acids found in certain plant seed oils. Their administration has been reported to have beneficial effects in the treatment of chronic inflammatory disorders, such as rheumatoid arthritis, demonstrating significant improvements in several clinical cases.80 In a prospective, double-masked, randomized study81 a combination of gamma linolenic acid 15 mg and linoleic acid 112 mg administered twice daily for 1 month was compared with placebo in a group of 40 patients with SS. There was a significant improvement in the tear prostaglandin E levels, as well as patients’ symptoms scores and corneal staining in the treated group. Another study82 also demonstrated beneficial effects of efamol (73% cis-linoleic acid, 9% gamma linolenic acid, and 18% saturated and monounsaturated fatty acids) 1500 mg twice daily. Increase in Schirmer test scores (P⬍0.03) but no change in the TBUT, corneal sensitivity, conjunctival staining, or tear

Table 3. Summary of Evidence for the Treatment of Sjögren’s Syndrome Associated-Dry Eye Treatment Modality Topical lubricants Systemic secretagogues Topical steroids Topical cyclosporine Topical nonsteroidal antiinflammatories Punctal occlusion Serum tears Systemic dietary supplements Systemic immunomodulatory treatments

Strength of Evidence

Clinical Recommendation

II II III II Insufficient

A B B A Not recommended

II II Insufficient

B B Not recommended

Insufficient

Not recommended

lysozyme or nuclear chromatin in conjunctival epithelial cells was noted. However, a similar study83 found no difference between the efamol-treated versus placebo-treated group in terms of Schirmer test scores, TBUT, and conjunctival staining over a period of 2 months in a group of 28 patients. A final study84 evaluated 90 patients with pSS over a 6-month period in a double-blind, placebo-controlled, randomized trial with high dose gamma linolenic acid (extracted from evening primrose oil) or corn oil. The primary outcome parameter was fatigue; secondary end points were eye dryness, mouth dryness, and muscle and joint pain. No significant improvement was found in fatigue assessed by visual analogue scale or in the time needed for sleeping/ resting during a 24-hour period between the treatment and placebo groups. Likewise, no differences in dry eye (Schirmer test, van Bijsterveld score, and use of artificial tears), dry mouth (unstimulated whole sialometry), or pain (use of analgesics) were noted. Only mild side effects were observed.

Clinical Recommendations The published evidence on the treatment of SS-related dry eye syndrome is reviewed in Table 3. Unfortunately, the current literature includes almost exclusively short-term studies with small sample sizes. Some of these studies demonstrate improvement of ocular symptoms and/or objective signs of dry eye, but there is no strong evidence that any of the suggested treatments alter the natural course of SS-related ocular sicca. A number of topical artificial tears are being used widely by clinical practitioners. However, an overwhelming majority of these are available over the counter and thus far only a few of them have been studied in the treatment of SSassociated dry eye. All published studies demonstrate an improvement over baseline using artificial tear substitutes. Hypotonic (150 mOsm/L) 0.4% sodium hyaluronate eye drops seem to improve symptoms of dry eye syndrome as well as ocular surface staining associated with SS (A, II).

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Ophthalmology Volume 118, Number 7, July 2011 Schirmer levels do not seem to improve with short-term treatment. In addition, 0.5% hydroxypropyl methylcellulose inserts and Carbopol 974P also show some efficacy (B, III). Oral therapy with secretagogues (5 mg of pilocarpine 4 times a day or 30 mg of cevimeline 3 times a day) seems to relieve dry eye as well as dry mouth symptoms secondary to SS (B, II). The overall use of the secretagogues is, however, limited by common although not serious side effects such as excessive sweating and diarrhea. The mechanism of action in improving the dry eye, particularly the results of impression cytology, is not clear, but might occur by increasing mucus secretion by conjunctival goblet cells, rather than increasing the aqueous layer of the tear film. Although the studies evaluating 1% topical methylprednisolone were open label and retrospective, the effect was robust (B, III). If used short term, the side effects do not seem to be serious. There is sufficient evidence, both clinical and histopathologic, to demonstrate the effectiveness of topical cyclosporine (A, II) and its safety for long-term use.33 Of note, the treatment was not uniform and various different doses and formulations of CsA have been used in published studies. Topical nonsteroidal anti-inflammatory medications also have been effective in treating patient symptoms, but deleterious effects on the corneal epithelium are considerable and can quickly progress to corneal melting.34 Systemic manifestations of SS such as fatigue, synovitis, arthralgia, cryoglobulinemia-related vasculitis, and neurologic, renal, and pulmonary involvement all seem to respond favorably to immunomodulatory treatment. The effect on primary SS-associated non-Hodgkin’s lymphoma also seems beneficial. However, evidence in treating sicca syndrome owing to SS is insufficient. Recent studies suggest beneficial effects for the sicca symptoms in SS patients if treated early in their disease course. Punctal plug insertion is a common treatment for SSrelated dry eye syndrome. Regrettably, there are no prospective, randomized trials on outcomes. However, all published studies demonstrated significant improvements over baseline (A, II). Replacement of plugs in about one third of patients is a significant issue, possibly requiring permanent surgical closure. Several studies demonstrate subjective symptom improvement after the use of serum tears (B, II), but there is a paucity of objective evidence that the treatment is beneficial in patients with SS. Dietary supplements are likewise currently in widespread use, but randomized, controlled, clinical trials demonstrating efficacy in SS population are lacking.

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Ophthalmology Volume 118, Number 7, July 2011 61. Tapper-Jones LM, Aldred MJ, Cadogan SJ, et al. Sjögren’s syndrome treated with bromhexine: a reassessment. Br Med J 1980;280:1356. 62. Nahir AM, Scharf Y, Ben-Aryeh H, et al. Effect of prolonged bromhexine therapy on Sjögren’s syndrome. Isr J Med Sci 1981;17:403– 6. 63. Kawashima K. Effect of bromhexine on Sjögren’s syndrome accompanied by rheumatoid arthritis. Nippon Ika Daigaku Zasshi 1988;55:191–200. 64. Manthorpe R, Frost-Larsen K, Isager H, Prause JU. Lack of lacrimal gland improvement by NA-872 in Sjögren’s syndrome. Acta Ophthalmol (Copenh) 1981;59:428 –9. 65. Manthorpe R, Frost-Larsen K, Høj L, et al. Bromhexine treatment of Sjögren’s syndrome: effect on lacrimal and salivary secretion, and on proteins in tear fluid and saliva. Scand J Rheumatol 1981;10:177– 80. 66. Prause JU, Frost-Larsen K, Høj L, et al. Lacrimal and salivary secretion in Sjögren’s syndrome: the effect of systemic treatment with bromhexine. Acta Ophthalmol (Copenh) 1984;62: 489 –97. 67. Manthorpe R, Petersen SH, Prause JU. Mucosolvan in the treatment of patients with primary Sjögren’s syndrome: results from a double-blind cross-over investigation. Acta Ophthalmol (Copenh) 1984;62:537– 41. 68. Ichikawa Y, Tokunaga M, Shimizu H, et al. Clinical trial of ambroxol (Mucosolvan) in Sjögren’s syndrome. Tokai J Exp Clin Med 1988;13:165–9. 69. Forsblad-d’Elia H, Carlsten H, Labrie F, et al. Low serum levels of sex steroids are associated with disease characteristics in primary Sjögren’s syndrome: supplementation with dehydroepiandrosterone restores the concentrations. J Clin Endocrinol Metab 2009;94:2044 –51. 70. Pillemer SR, Brennan MT, Sankar V, et al. Pilot clinical trial of dehydroepiandrosterone (DHEA) versus placebo for Sjögren’s syndrome. Arthritis Rheum 2004;51:601– 4. 71. Seitsalo H, Niemelä RK, Marinescu-Gava M, et al. Effectiveness of low-dose doxycycline (LDD) on clinical symptoms of Sjögren’s syndrome: a randomized, double-blind, placebo controlled cross-over study. J Negat Results Biomed [serial online] 2007;31:11. Available at: http://www.jnrbm.com/ content/pdf/1477-5751-6-11.pdf. Accessed November 13, 2010.

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Footnotes and Financial Disclosures Originally received: September 24, 2009. Final revision: November 29, 2010. Accepted: December 14, 2010. Available online: April 3, 2011.

Pfizer Inc. (New York, NY), and Inspire Pharmaceuticals Inc. (Durham, NC). Peter J. McDonnell – consultant – Allergan, Inc.; Alcon Laboratories. Manuscript no. 2010-1326.

1

The Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland.

2

Center for Clinical Trials, The Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

3

Division of Rheumatology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland. Financial Disclosure(s): The authors have made the following disclosures: Esen Karamursel Akpek – research grants – Allergan, Inc. (Irvine, CA),

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Dr Akpek was supported in part by a William and Mary Greve Scholarship from Research to Prevent Blindness. Dr Baer was supported in part by the Jerome L. Greene Sjögren Syndrome Foundation. This research was supported in part by an unrestricted departmental research grant from Research to Prevent Blindness. Correspondence: Dr Esen Karamursel Akpek, Director, Ocular Surface Diseases and Dry Eye Clinic, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Maumenee #317, Baltimore, MD 212879238. E-mail: [email protected].

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