Effect of Oral Pilocarpine in Treating Severe Dry Eye in Patients With Sjögren Syndrome. Tetsuya Kawakita, Shigeto Shimmura, and Kazuo Tsubota

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1 ORIGINAL CLINICAL STUDY Effect of Oral Pilocarpine in Treating Severe Dry Eye in Patients With Sjögren Syndrome Tetsuya Kawakita, Shigeto Shimmura, and Kazuo Tsubota Purpose: The aim of this study is to evaluate the efficacy and safety of oral pilocarpine in treating severe dry eye unresponsive to conventional conservative treatment in patients with Sjögren syndrome. Design: A prospective study. Methods: Oral doses of pilocarpine were administered for at least 3 months to patients with Sjögren syndrome complicated by established dry eye of great severity unresponsive to conventional conservative treatment. Results: Subjective eye symptoms (dry eye sensation and eye pain), fluorescein staining scores, rose Bengal staining scores, and tear film breakup time measurements improved significantly after 1 month and 3 months of oral treatment with pilocarpine, whereas no significant improvement was noted in Schirmer I testing. Conclusions: Oral administration of pilocarpine was useful in treating severe dry eye unresponsive to conventional conservative treatment in patients with Sjögren syndrome from the standpoint of efficacy and safety. Thus, we conclude that oral pilocarpine is effective as a new option in treating severe dry eye. Key Words: dry eye, pilocarpine, Sjögren syndrome, oral administration (Asia Pac J Ophthalmol 2015;4: 101Y105) Dry eye is a chronic disease of the tear fluid and the conjunctival and corneal epithelium triggered by various factors and accompanied by eye discomfort and abnormal visual function. This disease has a material effect on the patient s activities of daily living as well. Its pathologic traits may be exhibited by a vicious circle of conjunctival and corneal epithelium disorder, which results from inflammation on the eye surface caused by increased osmotic pressure in the tear fluid due to decreased lacrimation and tear fluid evaporation, and the increased severity of such disorder due to further environmental degradation of the eye surface with the progress of tear film destabilization at the affected site. 1 The dry eye treatment currently available in Japan is classified into 2 categories: supplementation, secretion, or retention of tears and their evaporation and outflow prevention. Pharmacotherapy, which is playing a key role in dry eye treatment, includes artificial tears intended to supplement tears (mainly water layer) tentatively and sodium hyaluronate ophthalmic solution intended to retain tears stably on the conjunctival and corneal epithelium. Furthermore, rebamipide, From the Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan. Received for publication August 7, 2013; accepted January 14, Supported by Kissei, Tokyo, Japan. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the study. The authors have no other funding or conflicts of interest to declare. Reprints: Tetsuya Kawakita, Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan kawakita@a2.keio.jp. Copyright * 2015 by Asia Pacific Academy of Ophthalmology ISSN: DOI: /APO diquafosol sodium, and other agents that stimulate the secretion of water and mucin from the conjunctiva have recently appeared on the market as new drugs for dry eye and will promise to become useful. Nevertheless, the incidence of dry eyeyinduced corneal disorder tends to increase, and in daily medical practice, there are not a few patients with, among others, severe dry eye that is difficult to control satisfactorily with conventional ocular instillation treatment or conservative treatment (eg, punctal occlusion with plugs). Pilocarpine, an alkaloid obtained from the leaves of plants found in South America, is a parasympathetic stimulant mainly with a stimulatory effect on muscarinic M3 receptors, 2 and ophthalmic solutions containing this alkaloid as the active ingredient have long been used to treat glaucoma. In Japan, pilocarpine hydrochloride for oral administration (hereafter referred to as oral pilocarpine ) was approved for an indication for the improvement in symptoms of oral dryness due to radiotherapy for the head and neck in September 2005 and an additional indication for the improvement in symptoms of oral dryness in patients with Sjögren syndrome in October In Japan, therefore, this agent is used widely as a sialagogue. Outside Japan, on the other hand, oral pilocarpine has been approved for an indication for improvement in dry eye in Sjögren syndrome and has been ascertained to be effective for dry eye. 3Y6 Also in Japan, its efficacy for dry eye has been reported. 7,8 In our own experience, oral pilocarpine, when used in the patients with dry eye who had presented at our outpatient department, especially those with Sjögren syndrome or any other disease complicated by severe dry eye unresponsive to conventional conservative treatment (eg, ophthalmic solutions), produced a distinct improvement on symptoms. This finding suggests that oral pilocarpine might become a new therapeutic agent in treating severe dry eye. The present study was thus undertaken to demonstrate the possibility of oral pilocarpine as a new therapeutic agent for dry eye in patients with Sjögren syndrome complicated by severe dry eye unresponsive to conventional conservative treatment. MATERIALS AND METHODS Patients The subjects were patients with dry eye who had presented at our outpatient department and had an established diagnosis of dry eye consistent with the Definition and Diagnosis of Dry Eye 2006 in Japan. 9 The dry eye occurred as a complication of Sjögren syndrome and was too severe to be controlled with conventional conservative treatment. Their ages were 20 years or older at the time informed consent was obtained, and no restrictions were imposed with respect to sex. On the other hand, excluded from the study were patients (with serious ischemic heart disease, such as myocardial infarction or angina pectoris) in whom oral pilocarpine was contraindicated, patients with bronchial asthma or chronic obstructive pulmonary disease, patients with gastrointestinal or bladder neck obstruction, patients with epilepsy, patients with Parkinson disease or parkinsonism, patients with iritis, Asia-Pacific Journal of Ophthalmology & Volume 4, Number 2, March/April

2 Kawakita et al Asia-Pacific Journal of Ophthalmology & Volume 4, Number 2, March/April 2015 patients with a history of hypersensitivity to any ingredient of this agent, patients from whom informed consent was not obtained concerning an ophthalmologic examination, and other patients who were, in the judgment of the investigator, unfit for entry into the study. Before the study, approval was obtained from the institutional review board of Keio University Hospital. Before the entry of potential study participants into the study, the investigator gave them full and adequate verbal and written information in a subject information and informed consent form and obtained their consent to participate voluntarily in the study. Methods Patients received an oral dosage of, in principle, 2.5 mg of pilocarpine 3 times a day after each meal. In patients with severe symptoms of dry eye, however, an oral dosage of 5 mg 3 times a day was also allowed. The duration of administration was set, in principle, at 3 months, but further treatment was allowed when it was, in the judgment of the investigator, clinically appropriate and the patient wished to continue treatment. This study was performed in a nonblind trial without control group. During the study period, the patients were forbidden to use the drugs considered to influence the evaluation of efficacy and safety of pilocarpine [pilocarpine ophthalmic solutions, parasympathetic stimulants, parasympatholytic agents, agents indicated for oral dryness or reduced saliva due to Sjögren syndrome, tricyclic antidepressant drugs, and antihistamines (topical preparations other than nasal drops)]. With regard to antihistamines, their short-term use within 7 days was permitted for the treatment of adverse events or the like after the initiation of treatment with the study drug, but their use for 3 days immediately before the clinic visit was forbidden. In addition, concomitant therapy information (name and duration of therapy) was also collected when therapy that might affect the drug effect evaluation (eg, contact lenses, punctal occlusion with plugs, surgical punctal occlusion, ocular surgical procedure, ocular autoserum instillation, or dry eye protection glasses) was given during the study period. Efficacy was evaluated before the treatment with oral pilocarpine (baseline) and after 1 month and 3 months of the treatment by examining each patient for subjective eye symptoms (dry eye sensation and eye pain) and objective findings [fluorescein staining, rose Bengal staining, Schirmer I test, and tear film breakup time (BUT) scores], and the changes of scores from baseline were determined. With regard to subjective eye symptoms (dry eye sensation and eye pain), the patients recorded their subjective impressions of dry eye sensation and eye pain on a face scale of 0 ( no bother ) to 5 ( extreme discomfort ) (Fig. 1) based on the Wong-Baker face pain scale. 10 Adverse events were investigated throughout the entire treatment period, and of the adverse events that had occurred after the initiation of treatment with oral pilocarpine, those whose causal relationship to the relevant drug could not be ruled out were considered adverse reactions. All the data are expressed as mean T SD. Statistical analysis was performed using the paired t test for intraocular pressure data and Wilcoxon signed-rank test for other data. All statistical tests were conducted with a 2-sided significance level of RESULTS Demographic Characteristics of the Study Population Demographic characteristics of the study population are given in Table 1. The ages of the 15 patients (28 eyes in all) were averaged as 69.5 T 11.5 years, and all the patients were female. The underlying illness was Sjögren syndrome in all 15 patients, 13 (86.7%) of whom received a daily dosage of 7.5 mg oral pilocarpine (2.5 mg 3 times a day). Sodium hyaluronate ophthalmic solution was used concomitantly in 14 patients. Subjective Eye Symptoms Dry Eye Sensation Dry eye sensation scores significantly declined from 2.5 T 0.8 at baseline through 1.8 T 0.7 at month 1 (P G ) up to 1.7 T 0.5 at month 3 (P = ; Table 2). Eye Pain Eye pain scores significantly declined from 1.7 T 0.7 at baseline through 1.4 T 0.6atmonth1(P = ) up to 1.0 T 0.6 at month 3 (P G ; Table 2). Objective Findings Fluorescein Staining Fluorescein staining scores declined from 2.1 T 1.3 at baseline through 1.8 T 1.5 at month 1 (no significant difference, P = ) significantly up to 1.7 T 1.5 at month 3 (P = ; Table 2). Rose Bengal Staining Rose Bengal staining scores significantly declined from 3.3 T 1.7 at baseline through 2.8 T 1.8 at month 1 (P = ) up to 2.3 T 2.0 at month 3 (P G ; Table 2). Schirmer I Test Lacrimation volumes, as measured by the Schirmer I test, increased after treatment initiation, as shown by 3.9 T 2.2 mm at FIGURE 1. Six-grade evaluation of subjective eye symptoms (dry eye sensation, eye pain). Each of the patient s subjective impression of dry eye sensation and eye pain was classified into 6 grades by reference to the face scale referred to as the Wong-Baker scale * 2015 Asia Pacific Academy of Ophthalmology

3 Asia-Pacific Journal of Ophthalmology & Volume 4, Number 2, March/April 2015 Pilocarpine in Severe Dry Eye in Sjögren Patients TABLE 1. Demographic Characteristics of the Study Population Age, mean T SD, y 69.5 T 11.5 Sex, male/female 0/15 Underlying or Sjögren syndrome present illness Intraocular pressure, 13.4 T 2.9 mean T SD, mm Hg Dry eye sensation, 2.5 T 0.8 Eye pain, 1.7 T 0.7 Fluorescein staining, 2.1 T 1.3 Rose Bengal staining, 3.3 T 1.7 Schirmer I test, 3.9 T 2.2 mean T SD, mm Tear film breakup 2.6 T 1.3 time, mean T SD, s Dosage of pilocarpine 2.5 mg 3 times a day, 13 patients 5 mg 3 times a day, 2 patients Concomitant drugs Sodium hyaluronate ophthalmic solution 0.1%, 2 patients Sodium hyaluronate ophthalmic solution 0.3%, 12 patients baseline, 5.1 T 5.1 mm at month 1 (no significant difference, P = ), and 4.5 T 2.9 mm at month 3 (no significant difference, P = ; Table 2). Breakup Time The BUT scores significantly increased from 2.6 T 1.3 seconds at baseline through 3.0 T 1.6 seconds at month 1 (P = ) up to 3.3 T 1.7 seconds at month 3 (P = ; Table 2). Stratified Analysis Using the Strata Based on Dry Eye Sensation Scores The study patients were stratified into 2 groupsvless than 3 (16 eyes in all) and greater than or equal to 3 (11 eyes in all)vaccording to the dry eye sensation score. Both groups had significantly declined eye pain scores and rose Bengal staining scores at month 3. The group with greater than of equal to 3 score only had significantly declined dry eye sensation score, fluorescein staining scores at month 3, and significantly increased BUT at month 3. However, both groups did not show significant change in Schirmer I test (Figs. 2Y4). Adverse Reaction Adverse reactions were reported from 6 (40.0%) of 15 patients included in the safety evaluation. These reactions consisted of stomach discomfort in 5 patients and sweating in 4 patients, and occurred within 1 week of treatment with oral pilocarpine. All of them were mild in intensity and resolved while the treatment was ongoing. The intraocular pressure was 13.4 T 2.9 mm Hg at baseline and 13.4 T 2.5 mm Hg at month 3, showing no significant change (P = 0.774). DISCUSSION Dry eye, if mild in intensity, can be controlled with conventional ocular instillation treatment, punctal occlusion with plugs, or other conservative treatments. In daily medical practice, however, there are not a few patients with severe dry eye that is difficult to control satisfactorily with such treatments. Some kind of treatment modality is desired in such patients. Pilocarpine, an alkaloid obtained from the leaves of plants found in South America, is a parasympathetic stimulant mainly with a stimulatory effect on muscarinic M3 receptors. 2 As the action mechanism, Aragona et al 5 reported that oral pilocarpine causes goblet cells to increase, thereby stimulating mucin production, and that such an action of pilocarpine provided stability in the tear film, which produced the improvement of conjunctival and corneal epithelium disorder, resulting in an improvement in subjective eye symptoms and objective findings. Oral pilocarpine, which is indicated for the improvement in symptoms of oral dryness due to radiotherapy for the head and neck and the improvement in symptoms of oral dryness in patients with Sjögren syndrome, is commonly used in Japan as a therapeutic agent in the treatment of oral dryness. 11,12 Outside Japan, indications for the improvement in dry eye in Sjögren syndrome have also been approved, and this agent is used to treat dry eye as well. In our own experience, oral pilocarpine, when used in the patients with dry eye, especially in those with Sjögren syndrome or any other disease complicated by severe dry eye unresponsive to conventional conservative treatment (eg, ophthalmic solutions), TABLE 2. Time Course of Changes in Subjective Eye Symptoms and Objective Findings No. Eyes Baseline Month 1 Month 3 Dry eye sensation, score T T 0.7* (P G ) 1.7 T 0.5* (P = ) Eye pain, score T T 0.6 (P = ) 1.0 T 0.6* (P G ) Fluorescein staining, score T T1.5 (P = ) 1.7 T 1.5 (P = ) Rose Bengal staining, score T T 1.8 (P = ) 2.3 T 2.0* (P G ) Schirmer I test, mm T T 5.1 (P = ) 4.5 T 2.9 (P = ) Tear film breakup time, s T T 1.6 (P = ) 3.3 T 1.7* (P = ) The values were expressed as mean T SD and were compared with the pretreatment value (Wilcoxon signed-rank test). *P G P G No significant difference P G Schirmer I test, 26 eyes (only month 3). * 2015 Asia Pacific Academy of Ophthalmology 103

4 Kawakita et al Asia-Pacific Journal of Ophthalmology & Volume 4, Number 2, March/April 2015 FIGURE 2. Time course of changes in subjective eye symptoms. Graphs demonstrated the time course change of subjective dry eye sensation (A) and eye pain, as assessed on the face scale (B), showed a significant improvement in both dry eye sensation and eye pain after 1 month and 3 months of treatment compared with baseline. produced a distinct improvement on symptoms. This finding suggests that oral pilocarpine might become a new therapeutic agent in treating severe dry eye. In that case, patients received oral pilocarpine 5 mg 3 times a day, the clinical dose available in Japan, but many dropouts were experienced owing to the occurrence of gastrointestinal disorders or sweating. In the present study, therefore, oral pilocarpine was administered, in principle, at 2.5 mg 3 times a day with safety in mind, and the dosage was increased up to 5 mg 3 times a day according to the intensity of symptoms. After 1 month and 3 months of treatment with oral pilocarpine, a significant improvement was noted in subjective eye symptoms (dry eye sensation and eye pain). Fluorescein staining, rose Bengal staining, and BUT scores also showed a significant improvement at months 1 and 3. In contrast, no significant changes were seen in the Schirmer I test. Kono et al 7 administered oral pilocarpine 10 mg/d (5 mg twice a day) to 15 patients (30 eyes in all) with dry eye accompanied by symptoms of oral dryness and have reported that although there was a significant improvement in subjective eye symptoms, BUT scores, fluorescein staining scores, and rose Bengal staining scores after 4 weeks and 8 weeks of treatment, Schirmer I test results showed no significant changes. The results of the present study, like the findings obtained by Kono et al, 7 indicate that although subjective eye symptoms and other findings showed a significant improvement, no significant change was found in the Schirmer I test. The 1 reason that Schirmer I test results did not show significant changes might be the lack of number of subjects. Stomach discomfort and sweating, adverse reactions considered due to a parasympathetic acceleration effect, were reported from 6 (40.0%) of 15 patients in the present study. In a phase II dose-response study of pilocarpine conducted in Japan in patients with Sjögren syndrome, the incidence of adverse reactions (clinical symptoms) has been reported to be 52.0% (39 of 75 patients) in the placebo group, 58.7% (44 of 75 patients) in the pilocarpine 7.5 mg/d (2.5 mg 3 times a day) group, and 75.0% (54 of 72 patients) in the pilocarpine 15 mg/d (5 mg 3 times a day) group. 12 According to the previously mentioned report from Kono et al, 7 sweating was observed in 9 (60%) of FIGURE 3. Time course of changes in objective findings. Graphs demonstrated time course change in fluorescein staining scores (C) and in rose Bengal staining scores (D). Fluorescein staining scores declined at month 1 and 3 (no significant difference) * 2015 Asia Pacific Academy of Ophthalmology

5 Asia-Pacific Journal of Ophthalmology & Volume 4, Number 2, March/April 2015 Pilocarpine in Severe Dry Eye in Sjögren Patients FIGURE 4. Time course of changes in objective findings. Graphs demonstrated time course change in Schirmer I test (E) and tear film breakup time (F). Schirmer I test showed no significant difference at month 1 and 3 in both dry eye sensation scores (Q3 and G3). 15 patients, and 5 (33%) of 15 patients responded to the survey to the effect that no adverse reactions had occurred. 7 The incidence of adverse reactions observed in the present study is similar to that reported from the pilocarpine 7.5 mg/d group in the previously mentioned phase II dose-response study in patients with Sjögren syndrome. This indicates that setting the dose at half the standard dose (5 mg) for oral dryness will make it possible to keep down the incidence of adverse reactions. Furthermore, all of the adverse reactions encountered in the present study were mild in intensity and resolved while treatment was ongoing. In addition to the viewpoint of treatment continuity, a low dosage of 7.5 mg/d is considered to be highly useful. The present study was conducted in a limited number of subjects for a short period of 3 months. To demonstrate the usefulness in treating dry eye, which requires long-term therapy, it may be necessary to carry out a study in a larger number of subjects for a longer period, and a study to establish a control group may be necessary. Nevertheless, the administration of oral pilocarpine, especially its low dosage (7.5 mg/d), intended to treat severe dry eye resistant to conventional treatment (eg, ophthalmic solution) in patients with Sjögren syndrome was highly useful from the standpoint of efficacy and safety. This treatment modality is thus concluded to be effective as a new option in treating severe dry eye. REFERENCES 1. Lemp MA, Baudouin C, Baum J, et al. The definition and classification of dry eye disease: report of the Definition and Classification Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf. 2007;5:75Y Wynn RL. Oral pilocarpine (Salagen)Va recently approved salivary stimulant. Gen Dent. 1996;44:26,29Y Tsifetaki N, Kitsos G, Paschides CA, 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. 2003;62:1204Y Papas AS, Sherrer YS, Charney M, 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. 2004;10:169Y Aragona P, Di Pietro R, Spinella R, et al. Conjunctival epithelium improvement after systemic pilocarpine in patients with Sjogren s syndrome. Br J Ophthalmol. 2006;90:166Y Kumar A, Singla V, Khokhar S, et al. Efficacy of oral pilocarpine in patients with Sjögren s syndrome. Indian J Rheumatol. 2006;1:93Y Kono T, Shiraishi A, Yamaguchi M, et al. Effect of peroral pilocarpine for dry eye. Jpn J Clin Ophthalmol. 2011;65:617Y Miyamoto T, Eguchi H, Mitamura Y. Ocular findings following discontinuation of oral pilocarpine in patients with dry eye. Jpn J Clin Ophthalmol. 2012;66:67Y Uchino Y, Uchino M, Dogru M, et al. Changes in dry eye diagnostic status following implementation of revised Japanese dry eye diagnostic criteria. Jpn J Ophthalmol. 2012;56:8Y Wong DL, Baker CM. Pain in children: comparison of assessment scales. Pediatr Nurs. 1988;14:9Y Konno A, Nishio M, Origasa H. Oral Pilocarpine for Radiation-induced XerostomiaVa randomized, double-blind, placebo-controlled trial. Jpn Pharmacol Ther. 2007;35:131Y Sugai S, Koike T, Miyasaka N, et al. Dose-finding study of oral pilocarpine for the treatment of xerostomia associated with Sjögren s Syndrome. Jpn Pharmacol Ther. 2007;35:141Y153. * 2015 Asia Pacific Academy of Ophthalmology 105