Efficacy of rebamipide 2% ophthalmic solution in the treatment of dry eyes

Abstract

AIM:

The aim of this study is to evaluate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status in patients with dry eyes.

MATERIALS AND METHODS:

A prospective study was carried out on forty eyes of patients having signs and symptoms of dry eye. Two percent rebamipide ophthalmic solution was applied four times a day for a period of 4 weeks. Patients were evaluated on the basis of dry eye-related symptom score, tear film break-up time (TFBUT), tear meniscus height, fluorescein ocular surface staining score (FOSS), and the Schirmer's test at the end of 2, 4, 6, and 12 weeks and their values were compared with the baseline.

RESULTS:

Significant improvement was noted in the mean dry eye-related symptom score, TBUT, and the FOSS values from the baseline at the end of 2, 4, 8, and 12 weeks. The values of tear meniscus height and Schirmer's test were improved at the end of 8 weeks but were not statistically significant.

CONCLUSION:

Nearly 2% rebamipide ophthalmic solution provided relief in the symptoms of patients having dry eyes. It also prevented further ocular surface damage and aided in stabilizing the tear film.

Introduction

Dry eye disease was earlier defined as, the reduction of the aqueous phase of tear film. In 1995, the definition was modified to include medical and ocular diseases that reduce tear production and/or increase tear evaporation.[1] It causes damage to the interpalpebral ocular surface giving rise to the symptoms of ocular discomfort.

Literatures have recognized the various risk factors for the development of dry eye. These include female gender, hormonal changes, systemic autoimmune disease (most prominently Sjogren syndrome), decreased corneal sensation, refractive surgery, blinking abnormalities, drug effects, viral infections such as HIV, diabetes mellitus, Vitamin A deficiency, and graft-versus-host disease. In addition to the risk factors listed above, environmental, workplace stress (arid atmosphere, constant wind currents) or recreational stress (prolonged use of video display screens), and presence of contact lenses also add to the development of dry eye disease.[2]

The management of dry eyes continues to challenge the clinicians. Usually, the treatment is aimed at providing symptomatic relief. The choice of therapy for dry eye disease may be determined by the severity of the condition. In mild cases, artificial tears may be applied. In moderate cases, more frequent treatment will be required. Artificial tear eyedrops can also be supplemented with anti-inflammatory eyedrops, corticosteroids, topical or systemic omega 3 fatty acids, tetracycline, and autologous serum. In cases of severe dry eye, in addition to frequent instillation of unpreserved artificial tears, other tear conserving therapies are often required. These include occlusion of punctum and prevention of the evaporation of moisture from the eye with the use of room humidifiers, usage of tight-fitting goggles, moisture chamber spectacles, or tear feeding spectacles.[3,4] Hydrophilic bandage contact lenses are often used in cases of corneal ulceration or following corneal surgery.[4,5,6] Surgical modalities of treatment include the use of punctual plugs and tarsorrhaphy to reduce the exposed area of the cornea, thus reducing the evaporation of tears.

Rebamipide is a novel ophthalmic suspension which was initially used in treating gastric ulcers due to its mucin secretagogue activity. It is an amino acid analog of 2 (1H)-quinolinone. There have been very limited studies to see the effect of this new drug in cases with dry eye disease, and to the best of our knowledge, there is no study done till now in India. There is a poor correlation between the symptoms and signs of dry eye. Thus, it is particularly important to perform an assessment of efficacy using subjective measures (symptoms) as well as objective measures (signs). This study was done to evaluate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status in patients with dry eyes using both subjective measures (symptoms) as well as objective measures (signs).

Materials and Methods

A prospective randomized study was carried out on twenty patients (forty eyes) over a period of 3 months, after taking permission from the ethics committee. An informed consent was taken from the patients prior to recruitment. All the therapeutic decisions were taken by the treating doctor. Patient confidentiality was maintained, and they had the right to opt out of the study at any point of time. A detailed history of disease and prior treatment was taken. We included patients above the age of 20 years who had mild-to-severe symptoms and/or Schirmer's test value, without anesthesia of ≤10 mm/5 min; or tear film break-up time (TFBUT) ≤10 s; or fluorescein staining score of ≥4 (van Bijsterveld system) and Rose Bengal score of ≥4 were included in the study dry eye who were resistant to/not responding to the prototype dry eye treatment, namely, topical artificial tears, cyclosporine, and steroids (immunosuppressants). The following patients were excluded from the study as follows: (1) Patients with a systemic illness like Sjogren's syndrome, (2) patients discontinuing the treatment, and (3) loss to follow-up cases.

All the patients were instructed to instill rebamipide 2% (Eyesec, Akumentis Healthcare Ltd.) eyedrop four times a day for a period of 12 weeks. These patients were asked to fill the dry eye symptom questionnaire which was developed by Schein et al.[7] It comprises of six questions based on six symptoms (dryness, gritty or sandy sensation, burning sensation, redness, crusting or discharge on the lashes, and having eyelids stuck shut in the morning). Patients were asked to grade the symptoms as under the categories of mild, moderate, and severe [Annexure 1 ^{(415.5KB, tif)} ].

Annexure 1

Schein questionnaire

The patients underwent routine ophthalmological examination which included visual acuity, slit lamp examination, Schirmer's test (without anesthesia), tear film break up time (TBUT), corneal surface staining with fluorescein dye, and Rose Bengal stain. Tear production was measured by the Schirmer's test. Schirmer's test strip was placed over the lower lid margin into the tear lake at the junction of the middle and lateral one-third of the eye lids for 5 min. The strip was then removed, and the amount of wetting in millimeters was recorded as the Schirmer's test score.

Tear film stability was estimated based on TBUT. A fluorescein-impregnated strip (Bell Pharma) wetted with nonpreservative saline solution was placed in the lower conjunctival sac. The examination was done under a slit lamp with the use of a cobalt blue filter. The time between the last blink and the appearance of the first black spot on the stained tear film was noted.

The ocular surface was examined by Fluorescein staining of the cornea (van Bijsterveld system) [Annexure 2 ^{(463.4KB, tif)} ]. A fluorescein impregnated strip wetted with nonpreservative saline solution was placed in the lower conjunctival sac of anesthetised eye. Corneal fluorescein staining was recorded in the temporal bulbar conjunctiva, nasal bulbar conjunctiva, and cornea and each graded on a scale of 0–3 points, with 0 being no stain, 1 indicating few separated spots of staining, 2 indicating many separated spots of staining, and 3 indicating confluent staining. The total score was from 0 to 9 points [Annexure 2 ^{(463.4KB, tif)} ].

Annexure 2

Fluorescein staining of the cornea : Van Bijsterveld system

Rose Bengal staining was done to stain damaged conjunctival and corneal cells and thereby identifying damage to the eye. A Rose Bengal impregnated strip wetted with nonpreservative saline solution was placed in the inferior fornix of the anesthetized eye. The patient was asked to blink twice and measurement was done after approximately 3–5 min. Grading was done on a scale of 0–9 points, 0–3 being mild, 3–6 being moderate, and 6–9 being severe.

The eyedrop was instilled four times a day for a period of 12 weeks. Dry eye-related symptom score, tear film break-up time (TBUT), fluorescein ocular surface staining score (FOSS), Rose Bengal score, and Schirmer's test without anesthesia were measured at the end of 1, 4, 8, and 12 weeks and their values were compared with baseline values which was taken as the control group. Efficacy was evaluated by comparing pretreatment/baseline score to posttreatment scores.

Statistical analysis

Data were entered in Microsoft Excel and analyzed using SPSS 24 Trial Version. We calculated the means and standard deviations and medians and interquartile ranges for continuous variables. We calculated the proportions for categorical variables. We used t-test for parametric data and Mann–Whitney test for nonparametric data. The proportions were compared using the Chi-square test or the Fischer's exact test (for low expected cell counts). P < 0.05 was considered to be statistically significant.

Results

A total of 20 patients of age group of 20 years and above were enrolled in this study. A comprehensive summary of the test results is depicted in Figure 1. Patients who had severe symptoms showed a clinical as well as statistically significant improvement at the end of 12 weeks. There were 32.5% patients with severe symptoms at the start of the study, but there were none with severe symptoms at the end of 12 weeks (P < 0.01). However, in those with mild symptoms, there was no improvement. There were 27.5% cases with mild symptoms at the start of the study and at the end of 12 weeks. In those patients with moderate symptoms, there was an improvement. There were 40% cases at the start of the study whereas there were just 5% cases at the end of 12 weeks [Table 1 and Figure 2].

Figure 1.

Symptoms score, TFBUT, Schirmer's score, fluorescein ocular staining score and Rose Bengal score from baseline up to 12 weeks

Table 1.

Pre and post treatment values of symptoms and tests for dry eye

Figure 2.

Symptoms score

Rose Bengal staining values did not show any significant change in the values at the end of 12 weeks. There were 75% cases with score between 0 and 3 at the beginning of the study as opposed to 92.5% cases at the end of 12 weeks. Cases with score between to 9 were 2.5% at the start and none at the end of 12 weeks [Table 1].

Fluorescein staining showed some improvement in values at the end of 12 weeks. 45% of cases with a high fluorescein score showed statistically significant decrease in score to 12.5% at the end of 12 weeks. This improvement was statistically significant (P < 0.01) [Table 1 and Figure 3].

Figure 3.

Schirmer's score value

Schirmer's test scores did not show any improvement which was clinically or statistically significant. 92.5% patients had Schirmer's score <10 mm which at the end of 12 weeks was seen in 82.5% patients. Thus, there was no significant improvement in the Schirmer's values [Table 1 and Figure 4].

Figure 4.

Fluorescein ocular staining score values

TFBUT scores showed minimal improvement at the end of 12 weeks. Nearly 90% patients had TFBUT <10 s which was 72.5% at the end of 12 weeks [Table 1].

Discussion

In 2007, the International Dry Eye Workshop updated the original definition and classified dry eye 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 of the ocular surface.” It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.[8,9] Rebamipide ophthalmic suspension (Eyesec) was recently approved for the treatment of dry eye in India. It was initially synthesized and developed by Otsuka Pharmaceutical Company, Limited (Tokyo, Japan). Discovery of its ability to increase gastric mucin led to investigations of its effect on ocular surface mucin and the subsequent development for use in dry eye patients. Investigations have confirmed that rebamipide increases corneal and conjunctival mucin-like substances. Rebamipide upregulates the gene expression of MUC1, MUC4, and MUC16 which are expressed on the apical surface of the conjunctival and corneal epithelia.[10] Rebamipide also has anti-inflammatory properties. Rebamipide could suppress poly I: C-induced cytokine production and the expression of mRNAs for CXCL10, CXCL11, regulated on activation, normal T-cell expressed and secreted, monocyte chemotactic protein-1, and interleukin-6 (IL-6) in human conjunctival epithelial cells. Rebamipide inhibited IL-6 and IL-8 production induced by tumor necrosis factor alpha.[11] These findings suggested that the mechanism responsible for the inhibition was the inhibition of nuclear factor-κB activation. The tight junctions that exist between the corneal epithelial cells serve an important function as a barrier for deeper corneal tissue. Rebamipide ophthalmic solution has been shown to increase goblet cell count in normal rabbits as observed by impression cytology.[12] Studies show that it also helps in improving the tear status in patients having aqueous deficiency dry eyes.[13] Due to its ability to modify epithelial cell function, improve tear stability, and suppress inflammation in the absence of any known major side effects, rebamipide can also be used in treating other ocular surface disorders such as lagophthalmos, lid wiper epitheliopathy, and persistent corneal erosion.

In this observational case series study, we have evaluated the effect of 2% rebamipide ophthalmic suspension in patients with dry eye at baseline and at 2, 4, 8, and 12 weeks visit to elucidate the therapeutic effects of rebamipide ophthalmic suspension in clinical practice and shown relevant factors for the changes of subjective signs and objective symptoms of dry eye. There was statistically significant improvement in symptoms and fluorescein staining at the end of 12 weeks. There were 32.5% patients with severe symptoms at the start of the study; however, there were none with severe symptoms at the end of 12 weeks (P < 0.01). Forty-five percent of cases with a high fluorescein score showed statistically significant decrease in score to 12.5% at the end of 12 weeks (P < 0.01). TFBUT scores showed minimal improvement at the end of 12 weeks. However, there was no improvement in Schirmer's score and Rose Bengal staining score. Kinoshita et al.[14] reported improvement of fluorescein corneal staining score, lissamine green conjunctival staining score and TFBUT. They found no significant difference for Schirmer's score values. Another study by Igarashi et al.,[15] in which the ocular surface disease index questionnaire was used for evaluating the symptoms, showed significant improvement in symptoms in patients who were not showing improvement with the prototype treatment of artificial tears and immunosuppressants. This is in correlation to our study.

In India, artificial tears are the first-line agents and immunosuppressants (Cyclosporine A [CsA] and steroids) are the second-line agents. CsA is a fungal-derived peptide that has an anti-inflammatory and immunomodulatory mode of action. It inhibits T-cell activation and consequently inhibits the inflammatory cytokine production (selective inhibition of IL-I). In addition, CsA inhibits apoptosis by blocking the opening of the mitochondrial permeability transition pore (Matsuda and Koyasu 2000) and by increasing the density of conjunctival goblet cells.[16] However, CsA causes more stinging and irritation which was seen to be much less with rebamipide. Rebamipide has a multifactorial action, namely, anti-inflammatory, mucin secretagogue, tear film stability, and conjunctival healing, increasing the goblet cell counts. The only side effect observed was bitter taste or dysgeusia (10% patients). The most frequently observed adverse event in the Kinoshita et al. Phase III study was dysgeusia (bitter taste); but this was only observed in 9.7% of the 2% rebamipide group.[14] The only disadvantage is that rebamipide 2% is costly; therefore, rural population has to resort to cheaper alternatives. In addition, there can be poor patient compliance as it requires frequent instillation (four times a day) for a long duration. Since there is a poor correlation between the symptoms and signs of dry eye, it is particularly important to perform an assessment of efficacy using subjective measures (symptoms) as well as objective measures (signs).[17] In our study, 2% rebamipide four times a day significantly improves symptoms and fluorescein ocular staining score.

Conclusion

This study was done to evaluate the efficacy of 2% rebamipide ophthalmic solution on the tear functions and ocular surface status in patients with dry eyes using both subjective measures (symptoms) as well as objective measures (signs).

In our study, rebamipide 2% improved symptoms and signs (FOSS) in patients who were refractory to the conventional treatment (artificial tears and immunosuppressants, i.e., cyclosporine and steroids). Thus, it can be used as an alternative to the second-line agents in patients who are refractory to the existing line of treatment and improve the quality of life of such patients.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.