Usefulness of a New Therapy Using Rebamipide Eyedrops in ... - Core

Allergology International. 2014;63:75-81 DOI: 10.2332! allergolint.13-OA-0605

ORIGINAL ARTICLE

Usefulness of a New Therapy Using Rebamipide Eyedrops in Patients with VKC! AKC Refractory to Conventional Anti-Allergic Treatments Mayumi Ueta1,2, Chie Sotozono1, Ayaka Koga1,2, Norihiko Yokoi1 and Shigeru Kinoshita1 ABSTRACT Background: Rebamipide, a gastroprotective drug, has been reported to suppress gastric mucosal inflammation. In Japan, rebamipide eyedrops have recently been approved for the treatment of dry eye disease. Some patients with allergic conjunctival diseases such as vernal keratoconjunctivitis (VKC) or atopic keratoconjunctivitis (AKC) manifest dry eye with decreased tear break-up time only. We report patients with VKC! AKC refractory to anti-allergic treatments who responded to the combination of rebamipide eyedrops and conventional anti-allergic treatments with anti-allergic- and!or immunosuppressive!steroid eyedrops. Methods: Four patients with allergic conjunctival diseases with giant papillae (VKC or AKC) instilled rebamipide eyedrops three or four times a day for varying periods. All had dry eye with decreased tear break-up time. We evaluated changes in the size of their giant papillae using Image J software. Results: We observed attenuation of the giant papillae in all 4 patients. In 2 patients with severe disease, whose giant papillae had become larger despite the administration of tacrolimus and steroids, the addition of rebamipide contributed to their attenuation. In 2 patients with mild disease, the giant papillae had become larger or remained the same size despite the administration of anti-allergy drugs; the addition of rebamipide eyedrops also resulted in the attenuation of their giant papillae. Conclusions: Our findings suggest that rebamipide eyedrops might attenuate giant papillae in patients with allergic conjunctival diseases and that these eyedrops may be useful for the treatment of not only dry eye but also of allergic conjunctival diseases.

KEY WORDS allergic conjunctivitis, atopy, dry eye with decreased tear break-up time, giant papilla, rebamipide

Rebamipide eyedrops have been approved in Japan for the treatment of dry eye disease. They up-regulate the production and secretion of mucin.1 Kinoshita et al.2,3 reported that the administration of 2% rebamipide was well-tolerated and effectively improved objective signs and the subjective symptoms of dry eye. Rebamipide, a gastroprotective drug, increases

gastric mucus production4,5 and suppresses gastric mucosal inflammation6,7 Naito et al.8 reported that rebamipide was dominantly distributed in mucosal tissues. Elsewhere we showed that it suppressed polyI: C-induced inflammatory cytokines in human conjunctival epithelial cells9 and Kimura et al.10 documented that rebamipide protects corneal epithelial cells from the TNFα-induced disruption of barrier function by maintaining the distribution and expression of ZO-1 as well as the organization of the actin cytoskeleton.

1Department of Ophthalmology, Kyoto Prefectural University of Medicine and 2Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan. Authors’ Contributions: MU, CS, AK, NY, and SK contributed materials for the research. MU wrote the manuscript and reviewed it. All the authors approved the final manuscript. Conflict of interest: SK received research funding from Otsuka Pharmaceutical. The rest of the authors have no conflict of inter-

est. Correspondence: Mayumi Ueta, Department of Ophthalmology, Kyoto Prefectural University of Medicine, Hirokoji, Kawaramachi, Kamigyo-ku, Kyoto 602−0841, Japan. Email: [email protected]−m.ac.jp Received 19 July 2013. Accepted for publication 29 September 2013. !2014 Japanese Society of Allergology

INTRODUCTION

Allergology International Vol 63, No1, 2014 www.jsaweb.jp!

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Ueta M et al. It also suppressed the TNFα-induced expression of interleukin-6 and interleukin-8 at the mRNA- and protein level and inhibited the TNFα-induced degradation of IκBα.11 Some patients with allergic conjunctival diseases manifest dry eye with only decreased tear break-up time (BUT).12,13 We prescribed rebamipide eyedrops to patients with allergic conjunctival diseases with giant papillae who presented with dry eye. We now report patients with VKC! AKC refractory to conventional treatment with anti-allergic- and! or immunosuppressive! steroid eyedrops who responded to the combination of rebamipide eyedrops and conventional anti-allergic treatments.

METHODS This study was a case report on the VKC! AKC patients with giant papillae intractable for a conventional anti-allergic treatment undergoing topical combined therapy using rebamipide eyedrops. Our study included 4 patients with allergic conjunctival diseases with giant papillae (VKC or AKC) and dry eye with decreased tear break-up time, which we treated with rebamipide in 2012. They were 3 males and 1 females; their age ranged from 10 - 48 years (mean 29.5). They were instructed to instill rebamipide eyedrops three or four times a day for varying periods. We started the administration of rebamipide eyedrops when the patients have dry eyes, and the size of giant papillae had increased despite the more than 2-week administration of tacrolimus and steroids (severe cases), or had become larger or remained the same despite the use of anti-allergy drugs (mild cases). We observed attenuation of the giant papillae in all 4 patients with VKC or AKC. We evalutated changes in the size of their giant papillae and in the area of involvement. The study protocol was approved by the ethical review board of Kyoto Prefectural University of Medicine; all patients provided written informed consent. We marked the papillae on photographs of the ocular surface and calculated their size using Image J software (Fig. 1). We show their total- and average size. Data were expressed as the mean ± SE and evaluated by Student’s t-test using Microsoft Excel software.

RESULTS CASE 1 47-year-old man with left AKC. He previously had undergone penetrating keratoplasty for limbal stem cell deficiency. He was on topical tacrolimus (0.1%, 2! day), fluorometholone (0.1％! day), and systemic prednisolone (10 mg! day) for more than a year before starting therapy with rebamipide eyedrops. We prescribed rebamipide eyedrops to him when the size of his giant papillae and the area of involvement continued to increase; his left BUT was 0 sec at that time.

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Fig. 1 We measured the size of the giant papillae on photographs of the ocular surface obtained before and at the indicated times during rebamipide treatment using Image J software.

Two weeks of rebamipide treatment yielded no attenuation although the discharge and itching were reduced. After 6 weeks the giant papillae were smaller and his subjective symptoms were milder and the prednisolone dose was reduced to 5 mg! day. After 13 weeks of rebamipide therapy his papillae were almost flat. Prednisolone was stopped 17 weeks after the start of rebamipide administration and at the last follow-up, performed about one year later, his giant papillae were silent (data not shown). Figure 2 shows the pictures of his left upper eyelid, drug history and graphs showing the size of total- and the each area of


New Therapy Using Rebamipide for VKC! AKC

2% rebamipide (4/day) 0w 0.1% tacrolimus (2/day) & 0.1% fluorometholone (4/day)

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0.5% moxifloxacin (4/day) & clarithromycin (400 mg/ day) (systemic)

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Fig. 2 Case 1 - A patient with atopic keratoconjunctivitis. The size of total- and each area of the giant papillae at 0-, 2-, and 6 weeks after starting rebamipide treatment are shown. Data are expressed as the mean ± SE and evaluated by Student’s t-test using Microsoft Excel software (*p < 0.05).

the giant papillae at 0-, 2-, and 6 weeks after starting rebamipide treatment.

CASE 2 13-year-old boy with right VKC. The topical administration of tacrolimus (0.1%, 2! day) and betamethasone (0.1%, 4! day) had been ineffective and he suffered severe VKC with massive superficial punctate keratopath and visual impairment. Therefore, we


added systemically prednisolone (10 mg! day) for 3 weeks and then replaced betamethasone with fluorometholone (0.1%, 4! day for 3 weeks). However, despite these treatments his VKC again became severe and rebamipide therapy was started; his right BUT was 2 sec at that time. After 3 weeks his giant papillae were smaller and the severity of his symptoms was decreased. After 6 weeks the giant papillae were almost flat; their flattening continued until week

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2% rebamipide (3/day) 0w 0.1% tacrolimus (2/day)

0.1% fluorometholone (4/day)

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0.3% gatifloxacin (4/day)

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Fig. 3 Case 2 - A patient with vernal conjunctivitis. The size of total- and each area of the giant papillae at 0-, 3-, and 6 weeks after starting rebamipide treatment are shown. Data are expressed as the mean ± SE and evaluated by Student’s t-test using Microsoft Excel software (***p < 0.005).

14. Figure 3 shows the pictures of his left upper eyelid, drug history and graphs showing the size of totaland the each area of the giant papillae at 0-, 3-, and 6 weeks after the start of rebamipide instillation.

CASE 3 When we first saw this 10-year-old girl with VKC she

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was on topical fluorometholone (0.1%, 4! day) and olopatadine (0.1%, 4! day). We added rebamipide eyedrops (4! day); her right BUT was 2 sec at that time. Although she arbitrarily stopped fluorometholone instillation after one week, after 2 weeks of rebamipide treatment her giant papillae became smaller and the severity of discharge and itching was lessened. After


New Therapy Using Rebamipide for VKC! AKC

2% rebamipide (4/day)

0.1% fluorometholone(4/day)

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0.1% olopatadine (4/day)

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Total area of giant papillas


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12 **

60

10 (mm2/papilla)

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50 40 30 20

6 4 2

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Fig. 4 Case 3 - A patient with vernal conjunctivitis. The size of total- and each area of the giant papillae at 0-, 2-, and 4 weeks after starting rebamipide treatment are shown. Data are expressed as the mean ± SE and evaluated by Student’s t-test using Microsoft Excel software (**p < 0.01).

4 weeks her giant papillae were yet smaller and flatter. She subsequently was treated elsewhere. Figure 4 shows the pictures of his left upper eyelid, drug history and graphs showing the size of total- and the each area of her giant papillae at 0-, 2-, and 4 weeks after the start of rebamipide therapy.

CASE 4 This 48-year-old man presented with bilateral AKC. He had suffered several episodes of herpetic keratitis


in the right or left eye. He was treated with olopatadine (0.1%, 4! day) without topical steroids to prevent the recurrence of herpetic keratitis. Rebamipide treatment was added when his giant papillae became bigger and the area of involvement increased; his right and left BUT was 2 sec at that time. After 6 weeks his discharge and itching were reduced and his giant papillae were smaller as was the area of involvement. Figure 5 shows the pictures of his both upper eyelid, drug history and graphs showing the size of total- and

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right

left 2% rebamipide (3/day) 0w

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35

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0.1% olopatadine (2/day) & 0.1% sodiumhyaluronate (2/day)

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left Each area of papillas P = 0.08

2.5 2 1.5 1

1 0.5

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Fig. 5 Case 4 - A patient with atopic keratoconjunctivitis. The size of total- and each area of the giant papillae at 0- and 6 weeks after starting rebamipide treatment are shown. Data are expressed as the mean ± SE and evaluated by Student’s t-test using Microsoft Excel software (**p < 0.01).

the each area of the giant papillae at 0- and 6 weeks after the start of rebamipide treatment.

DISCUSSION Our findings suggest that rebamipide eyedrops might contribute to the reduction of giant papillae in patients with AKC and VKC. Rebamipide has been used to treat gastritis and

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gastric ulcers; it suppresses gastric mucosal inflammation4,5 and increases gastric mucus production.2,3 We posited that rebamipide eyedrops may also exert anti-inflammatory effects on the ocular surface. Elsewhere we reported that rebamipide suppressed the polyI: C-induced production of CXCL10, CXCL11, RANTES, MCP-1, and IL-6 in human conjunctival epithelial cells, and that its topical administration sup-


New Therapy Using Rebamipide for VKC! AKC pressed conjunctival allergic eosinophil infiltration in our murine allergic conjunctivitis model.6 Others found that rebamipide protects corneal epithelial cells from the TNFα-induced disruption of barrier function11 and that it suppressed the TNFα-induced expression of interleukin-6 and interleukin-8 at the mRNA- and protein level.7 We administered rebamipide eyedrops to 4 patients with allergic conjunctival diseases with giant papillae and found that it helped to decrease their size and area of involvement. In two patients (cases 1 and 2) whose giant papillae worsened despite the administration of immunosuppressants and steroids, the addition of rebamipide eye drops exerted antiinflammatory effects. In the other patients with less severe disease (cases 3 and 4), the administration of rebamipide eyedrops with anti-allergy drugs also produced anti-inflammatory effects. Based on our observations we suggest that the anti-inflammatory effects of rebamipide eyedrops may help to combat human ocular surface inflammation. On the other hand, in a patient with giant papillary conjunctivitis induced by soft contact lenses, the administration of rebamipide eyedrops failed to reduce the size of the giant papillae (data not shown). Therefore, we think that rebamipide might not be effective in patients with giant papillary conjunctivitis. On the other hand, we also encountered a patient whose giant papillae became smaller and the discharge and itching were alleviated by the sole treatment with rebamipide eyedrops (Supplementary Fig. 1). This suggests that even the sole administration of rebamipide eyedrops may reduce mild giant papillae. To confirm the effectiveness of rebamipide eyedrops in the treatment of various allergic conjunctival diseases, more investigations are needed. In conclusion, our experience suggests that the combination of rebamipide eyedrops and conventional anti-allergic treatments with anti-allergic- and! or immunosuppressive! steroid eyedrops may represent a new effective therapy for VKC! AKC refractory to the usual anti-allergic treatments and that rebamipide eyedrops-may also be effective in the treatment of not only dry eye but also allergic conjunctival diseases.

ACKNOWLEDGEMENTS This work was supported in part by grants-in-aid for scientific research from the Japanese Ministry of Health, Labour and Welfare, the Japanese Ministry of Education, Culture, Sports, Science and Technology, a research grant from the Kyoto Foundation for the Promotion of Medical Science, and the Intramural Re-


search Fund of Kyoto Prefectural University of Medicine.

SUPPLEMENTARY MATERIALS Supplementary Figure 1 is available online.

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