JOURNAL OF EVIDENCE BASED MEDICINE AND HEALTHCARE

Table of Contents

2019 Month : December Volume : 6 Issue : 52 Page : 3275-3279

Topical Rebamipide Treatment for Dry Eye Syndrome in Thyroid Ophthalmopathy..

Prasanta Kumar Nanda1, Bishnu Prasad Rath2, Jayaram Meher3

1. Professor and HOD, Department of Ophthalmology, SCB Medical College, Cuttack, Odisha.
2. Postgraduate Resident, Department of Ophthalmology, SCB Medical College, Cuttack, Odisha.
3. Postgraduate Resident, Department of Ophthalmology, SCB Medical College, Cuttack, Odisha.

Corresponding Author:
Dr. Bishnu Prasad Rath,
1B/58, Sector-8,
Dr. D. B. Tonpe Road, CDA,
Cuttack- 753014, Odisha, India.
E-mail: rathbishnuprasad@gmail.com
DOI: 10.18410/jebmh/2019/686

ABSTRACT
BACKGROUND
Thyroid eye disease (TED) is prevalent in patients with thyroid abnormality and usually in hyperthyroid state. Dry eye disease in TED is multifactorial with a significant component being the inflammatory processes due to involvement of the lacrimal gland, goblet cells in the conjunctival microvilli etc. The effect of Rebamipide tablet on the gastric mucosa for healing of gastric ulcer has already been proved by many studies. Rebamipide acts on the goblet cells, microvilli functions and decrease the inflammatory process.

METHODS
42 eyes of 33 patients having thyroid eye disease were included in the study. They were evaluated with TBUT and Schirmer test using Whatman-41 stripes and using dry eye scoring system. They were diagnosed as dry eye if TBUT < 10 secs and Schirmer <5 mm/ 5 mins and dry eye score >6. These eyes were treated with eye drop Rebamipide 2% and reassessed at 8 wks. and 16 wks.

RESULTS
38 and 39 eyes showed significant improvement of dry eye state as evaluated by means of TBUT (>10 secs) and Schirmer’s test (> 5 mm/ 5 mins) and decrease in the dry eye score at 8 weeks and 16 weeks of follow up respectively. No serious adverse events were reported during follow up.

CONCLUSIONS
Topical Rebamipide significantly improved the dry eye condition in patients of thyroid eye disease.

KEYWORDS
Thyroid Eye Disease, Dry Eye Disease, Rebamipide, TBUT, Schirmer’s Test, OSDI

How to cite this article

Nanda PK, Rath BP, Meher J. Topical rebamipide treatment for dry eye syndrome in thyroid ophthalmopathy. J. Evid. Based Med. Healthc. 2019; 6(52), 3275-3279. DOI: 10.18410/jebmh/2019/686

BACKGROUND

Thyroid Ophthalmopathy / Thyroid eye disease is a group of disorders affecting the eye in patients having thyroid abnormalities mostly in hyperthyroid states (Graves’s disease) but can be seen in patients with hypothyroid and euthyroid states.1 The main pathophysiology behind the development of TED is the autoantibody against the thyroid gland also act on the fibroblasts of ocular tissue.

Due to antibodies against the ocular fibroblasts, it initiates an inflammation cascade by secretion of inflammatory mediators like IL-6, IL-8, prostaglandins and GAGs. These agents cause tissue oedema of the orbital fat, extra ocular muscles, interstitial tissue and lacrimal glands. They present with epibulbar hyperaemia, swelling, tear insufficiency and instability, signs due to lid retraction, proptosis, corneal signs due to lid retraction, lack of lubrication and optic nerve compression signs.

The tear film stability is due to the action of both membrane-associated mucin present on the corneal and conjunctival microvilli and secretory mucin secreted by conjunctival goblet cells.2,3 In TED there is decrease in both the membrane associated and secretory mucin due to the inflammatory process. TED also affects the tear secretion by affecting the lacrimal glands leading to tear insufficiency. There is also increase evaporation due to lid retraction, lid lag and proptosis. All these mechanisms may lead to development of dry eye in TED. The dry eye condition should be addressed to prevent symptoms arising from dry eye and prevent complication arising from this.

The quality of life on the basis of symptoms of patients of dry eye disease is evaluated using many different questionnaires. Among them the Ocular Surface Disease Index (OSDI) is frequently used to assess the severity of DED. The diagnosis of both symptomatic and asymptomatic DED patients can be made using tear film break up time (TBUT) and Schirmer test.

Rebamipide is a novel quinolinone derivative which act as a secretagogue for mucin and also has cytoprotective, anti-inflammatory action.4 It up regulates the gene expression of MUC1, MUC4, MUC16, thus increases membrane associated mucin. It increases the secretory mucin level in the damaged eye by increasing secretion of mucin from goblet cells and by increasing the no of goblet cells. It attenuates the production of inflammatory cytokines like IL-6, IL-8.5 It restores the microvilli present on the apical surface of corneal and conjunctival epithelium.

            We wanted to evaluate the efficacy of 2% topical Rebamipide ophthalmic solution for treatment of dry eye disease in patients of thyroid eye disease.

METHODS

 

Patients with thyroid eye disease were evaluated for dry eye disease and diagnosed cases were included in the study. The patients were explained about the study in their understandable language. Consents were obtained from the patients. Patients with other ocular comorbidities, who fail to follow up, and who fail to adhere to the study were excluded from the study. It was a tertiary care hospital based prospective study conducted between April 2019 - October 2019. 42 number of eyes of 33 number of patients having thyroid ophthalmopathy and dry eye disease were included in the study. Age range of patients was 30-70 years. Patients with thyroid ophthalmopathy and dry eye disease were started with commercially available 2% Rebamipide ophthalmic suspension four times a day in the affected eye for 16 weeks and were evaluated at 8 weeks interval. The patients who were using any artificial tear preparation previously were allowed to use the same along with Rebamipide. The signs evaluated were tear film break up time and Schirmer’s test (Whatman-41 stripes).

TBUT was measured by means of sodium fluorescent stripes. The stipes were wetted with the tear film without any prior eye drop or procedure in the eye. The corneal surface was observed using blue filter of the slit lamp. The time calculated till appearance of 1st break in tear film. Those who had TBUT less than 10 secs were included in the study. Schirmer’s test was performed using Whatman-41 stripes. On seated position the stripes were placed in lower lid after folding at appropriate place. The length of wet stripe was noted after 5 mins. The value below 5 mm were included in our study.

 

OSDI Questionnaire-

 

Have You Experienced Any of The Following During the Last Week-

 

 

All of

the Time

Most of

the Time

Half of

the Time

Some of the Time

None of

the Time

1

Eyes that are

sensitive to light?

4

3

2

1

0

2

Eyes that feel gritty?

4

3

2

1

0

3

Painful or sore eyes?

4

3

2

1

0

4

Blurred vision?

4

3

2

1

0

5

Poor vision?

4

3

2

1

0

Table 1a

 

Have Problems with Your Eyes Limited you Performing any of the Following During the Last Week-

 

 

All of

the Time

Most of

the Time

Half of

the Time

Some of the

Time

None of

the Time

 

6

Reading?

4

3

2

1

0

N/A

7

Driving at night?

4

3

2

1

0

N/A

8

Working with a

computer or a

bank machine (ATM)?

4

3

2

1

0

N/A

9

Watching TV?

4

3

2

1

0

N/A

Table 1b

 

Have Your Eyes Felt Uncomfortable in Any of the Following Situations During the Last Week-

 

 

All of

the Time

Most of

the Time

Half of

the Time

Some of the Time

None

of

the Time

 

10

Windy conditions?

4

3

2

1

0

N/A

11

Places or areas with low humidity (very dry)?

4

3

2

1

0

N/A

12

Areas that are air conditioned?

4

3

2

1

0

N/A

Table 1c

 

The symptoms were evaluated on basis of Ocular surface disease index (OSDI) score, a 12-questionnaire system. The 12 items were graded on a scale of 0 to 4, where 0 indicates none of the time, 1; some of the time, 2; half of the time, 3; most of the time, 4; all the time. The total score was then calculated on the basis of a formula: OSDI = [(sum of scores of all the questions answered) × 100] / [(total number of questions answered) × 4]. So, it is a scale of disability from 0-100, with higher the score showing greater the disability. Score above 5 was taken as abnormal and were accordingly graded into normal, mild, moderate and severe dry eye disease.

 

RESULTS

The distribution of age and sex in the studied patients were shown by the charts below. There were 20 males and 13 females in our study. The highest percentage of patients in the age group of 30-39 yrs. (39.3%).

Chart 2. Age Distribution

The TBUT finding in seconds at the baseline level were compared with the TBUT at 8th and 16th week by means of number of eyes showing improvement from the baseline score. There is significant improvement in the TBUT values at both 8th week (p=0.000) and in 16th week (p=0.000).

 

No. of Eyes Showing Improvement at 8th wk.

%

No. of Eyes Showing Improvement at 16th wk.

%

23

54.76%

38

90.48%

Table 2. No. of Subjects Showing Improvement in TBUT

 

Mean Baseline TBUT

Mean TBUT at

8th Wk.

Mean TBUT at

16th Wk.

5.5714±1.63

6.857±1.68

9.5952±1.30

Table 3. Improvement in Mean TBUT in Seconds

Chart 3. Mean TBUT Graph Showing Improvement

The mean TBUT values at both 8th (6.857±1.68) and 16th (9.5952±1.30) week were also compared with the base line value (5.5714±1.63) showing a significant increase in the TBUT score at 16th week.

The Schirmer’s test value in terms of mm in 5 mins were compared at 8th and 16th week by means of number of patients showing improvement from baseline value. They so an increase in Schirmer test value both at 8th week (p=0.001) and 16th week (p=0.000). The mean Schirmer value also showed an increase at 16th week.

 

No. of Eyes Showing Improvement at 8th Wk.

%

No. of Eyes Showing Improvement at 16th Wk.

%

23

54.76

39

92.86

Table 4. No. of Subjects Showing Improvement in Schirmer’s Value

 

Mean Baseline Schirmer’s Value

Mean Schirmer’s Value

at 8th Week

Mean Schirmer’s Value

at 16th Week

3.4524±1.76

4.4286±2.29

7.9286±1.56

Table 5. Improvement in Mean Schirmer’s Value

Chart 4. Graph Showing Improvement in Mean Schirmer’s Value

 

 

They showed a significant improvement in symptoms by means of decrease on OSDI score both at 8th and 16th week. The number of patients who were severe group at baseline (20) as per OSDI decreased to 11 at 8th week and to 2 at 16th week. There was an increase in mild and normal cases during the study. The moderate group remained almost same throughout the study as number in the severe group decreased.

 

Time

Normal

Mild

Moderate

Severe

Baseline

2

8

12

20

At 8th week

12

9

10

11

At 16th week

35

3

2

2

Table 6. OSDI Score

DISCUSSION

Rebamipide is a novel quinolinone derivative synthesised and developed by a Japanese company. Initially it was developed to be used for gastric ulcer.6,7,8,9 Its use was 1st established by animal experimental models.10,11,12,13 In 1990, it was marketed in the form of tablet for gastric ulcer.

Many studies were done to know its effect on gastrointestinal mucosa in terms of cytoprotection, wound healing, and anti-inflammatory action.14,15 These action on gastrointestinal mucosa is universal.16,17 Similar to gastric mucosa the eye contains goblet cells on its surface which help in lubrication and tear film stabilisation.2,3,18,19 So, use of Rebamipide on ocular surface diseases specially in dry eye diseases was thought. In vivo results of Rebamipide on goblet cells of conjunctiva,20,21,22,23 microvilli maintenance24,25,26 and its anti-inflammatory properties 20 were encouraging.27,28,29 In 2012 Rebamipide 2% eye suspension was lunched in Japan. Our study showed a significant improvement in dry eye condition with the use of rebamipide 2% ophthalmic suspension in dry eye diseases of TED patients in terms of TBUT. Nakashima H, et al28 in their study on mucin removed rabbit eye model showed effect of rebamipide ophthalmic solution. Rebamipide also subsides the inflammation of lacrimal gland along with the surface epithelium. Our study showed there was significant improvement in the Schirmer test value. Kinosita et al30,31 reported improvement in fluorescent corneal staining score, lisamine green conjunctival staining and TBUT score in DED patients treated with rebamipide ophthalmic suspension at 2 weeks and 52 weeks. But their study showed no significant improvement in Schirmer test value contrary to our study which showed a significant improvement.

Koh et al32 found a significant increase in TBUT with application of rebamipide similar to our study. They also found improved tear stability leading to improved optical quality with rebamipide in patients of dry eye. No specific study was found for rebamipide use in thyroid eye disease with dry eye disease after search of Google scholar and Pubmed. But studies were done on the effects of rebamipide ophthalmic suspension on superior limbic keratopathy (SLK),33 lagophthalmos,34 lid wiper epitheliopathy35 and persistent corneal erosion.36 Takahashi et al reported that thyroid eye disease patients with SLK after using topical rebamipide showed an improvement and complete disappearance of SLK in 84.8% of patients after treatment. They suggested rebamipide as first line of treatment in such patients. We used OSDI scoring system to assess the quality of life of the subjects and to classify them with respect to dry eye. It has a simple 12 questions mainly concentrating on symptoms on last week.

Use of this questionnaire for DED was validated by many studies. Our study showed there is reduction in severe group and increase in normal and mild group during the study period. The moderate group showed almost no change as the severe group subjects became moderate group. Our study showed a positive effect of rebamipide ophthalmic 2% suspension on dry eyes of TED patients. The limitations of our study that it included lesser number of subjects and all signs of DED were not taken into account and also done for a shorter interval. Larger studies should be performed with special importance to TED and for longer period.

CONCLUSIONS

Our study showed a significant improvement in signs of dry eye disease in patients of thyroid eye disease in terms of TBUT and Schirmer’s test at 8th and 16th week of treatment with 2% Rebamipide ophthalmic suspension. There was also improvement in the quality of life of these patients measured by OSDI questionnaire. We suggest use of Rebamipide in patients of TED may be along with other lubricating solutions.

ACKNOWLEDGEMENTS

We are thankful to Prof Dr. Sumita Mohapatra for her insights and support. Special thanks to Kankotree Rath for helping in data compilation.

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