Dr. AnitaGanger, G16342, Dr. Noopur Gupta Parakh, Dr.Vanathi M, Dr. (Mrs ) Radhika Tandon
Abstract
Purpose:
To evaluate the effectiveness of topical Rebamipide eye drops on signs and symptoms of vernal keratoconjunctivitis using 5-5-5 scoring system.
Materials and methods:
In this retrospective study, records of vernal keratoconjunctivitis (VKC) patients on topical Rebamipide 2%, from outpatient department of our tertiary centre, were analyzed. The patient’s demographic and ophthalmic examination details including anteriorandposterior segment evaluation, baseline tear film breakup time (TBUT) and Schirmer’s test readings were noted. VKC and dry eye grading as per 5-5-5 scoring system and Ocular surface disease index (OSDI) were noted at baseline (before starting Rebamipide)and 6 weeks post 2% topical Rebamipide therapy.
Results:
Among 31 patients (61 eyes), the mean age of patients, age of onset and duration of disease was 11.87±3.44, 7.74 ±3.69 and 3.98±3.53 years respectively. The mean of baseline logmar visual acuity values was 0.307±0.304 and 0.418±0.526 in right eye (RE) and left eye (LE) respectively. The average K values were 43.19±1.97/44.24 ± 2.38 in RE and 43.01±1.47/44.09± 1.44in LE. The median 5-5-5 score in RE and LE at presentation6 weeks follow up was 224/121(p <0.001) and 221/110 (p <0.001) respectively. The median OSDI score in RE and LE at presentation/6 weeks follow up was 41.7/27.8 (p <0.005) and 46.9/31.3 (p <0.005) respectively. Patients with mild VKC group had not shown significant improvement with Rebamipide in terms of 5-5-5 and OSDI score, while a significant change was seen in the moderate and severe group with maximum effect noted in the severe group (p= 0.001).
Conclusion:
Topical Rebamipide can be used as a promising treatment modality for reducing the signs and symptoms of VKC, especially in patients with moderate and severe diseaseand can be used as a steroid sparing agent in steroid responders.
Introduction
Vernal keratoconjunctivitis (VKC)is anallergic inflammatory disease of palpebral and bulbar conjunctiva with a chronic course. Itmanifests more frequently in first and second decade in young males.1Patients usually present with symptoms like itching, redness, photophobia, ocular discomfort, foreign body sensation and lacrimation. To treat mild VKC; antihistamines, mast-cell stabilizers and lubricating eye drops are the frequently used drugs. Whereas in moderate/severe VKC topical steroidsuse is documented, though risk of steroid-induced ocular complications reduces its safety range, especially in children.2 To combat this, although topical tacrolimus 0.01% solution is reported to be an effectivesubstitutefor VKC patients, but necessity of long term therapy for therapeutic effects and cost factor are still the important issues to deal with.3The severity of VKC and indications for therapeutic topicaldrugs,should be determined by effective severity scores, instead of mere symptomatic assessment. One such scoring system, 5-5-5 exacerbation grading scale was developed in 2009, for the assessment of clinical severity in patients with allergic conjunctivitis diseases, which was found to be valuable clinical tool in assessing the usefulness of various topical medications.4
Use of Rebamipide, as a therapeutic agent for gastritis and gastric ulcers is well known, due to its gastric mucus (mucin) augmentation property.3Furthermore, the use of Rebamipide in ophthalmology as a dry eye medication started with the likelihood of its effect on the ocular surface mucin.6, 7, 8The Rebamipide increases the mucin production in goblet cells and epithelial cells of cultured conjunctival9, 10 and cornea respectively.11Further studies reported,reduction in symptoms of dry eyes with Rebamipide use, due to increased secretion of secreted type as well as membrane associated mucins .9,11,12
In present study, the effect of topical 2% Rebamipidewas assessed on signs and symptoms of VKC using 5-5-5 scoring system and Ocular surface disease index score at 6 weekspost therapy. Though, usefulness of Rebamipide in VKC has been reported in few studies on the basis of subjective symptomatology or by assessing reduction in size of giant papillae.13,14To the best of our knowledge, effect of Rebamipide in VKC patients has never been assessed objectively by using 5-5-5 scoring system.
Materials and Methodology
In this retrospective study, patients having vernal keratoconjunctivitiswere recruited from outpatient department of a tertiary care centre in Northern India.The study was conducted in accordance with the tenets of the Declaration of Helsinki. Retrospectively followup data of consecutive VKC patients on topical 2% Rebamipidewas reviewed from January 2016 to June 2016. Demographic and ophthalmic examination details of all the recruited patients, including age, gender, anteriorandposterior segment ocular evaluation, baselinetear film breakup time (TBUT) and Schirmer’s test readings were noted.Diagnosis and grading of VKC and dry eye was done using 5-5-5 scoring system4 and Ocular surface disease index (OSDI)questionnaire15 respectively. The clinical examination details and scoring values were noted from clinical records at baseline visit (before starting Rebamipide) and at 6 weeks of 2% topical Rebamipide therapy. The patients, who underwent any ocular surgery, who were on previous long term topical medications, had history of contact lens use, blepharitis, meibomitis, and in whom VKC grading with 5-5-5 scoring system was not done or documented in the records were excluded from the study.
TBUT andSchirmer’s test measurement (without topical anesthesia) were noted from records on each visit. Tear break-up time (TBUT) was measured with the help of conventional strip method by assessing the first appearance of a dry spot in the tear film after normal blinking. The Schirmer’s test values were noted after placing aSchirmer’s test strip (without using anesthesia) at the junction of medial two third and lateral one third of lower lids of both eyes for five minutes as per standard procedure.
Outcome measures were assessed by evaluating VKC severity with the help of 5-5-5 grading scale (table 1).4 Classification was divided in to three grade groups, namely; 100-point, 10-point and 1-point groups and each group included five different findings. Each finding represented 100, 10 and 1 points in 100-point, 10-point and 1-point groups respectively. Based on number of clinical findings in each grade group; severe, moderate and mild VKC was diagnosed if more than two findings,only one finding and no finding were observed in 100-point group respectively.
The OSDI questionnaire values were noted from the records of all 31 patient’s records. The 12 questionsincluded in this questionnaire were graded from 0-4 scale values, in which 0,1,2,3 and 4 indicated none of the time, some of the time, half of the time, most of the time, and all of the time respectively. For total Score calculation sum of scores was multiplied by 25 and the consequential value was divided by the number of questions answered. Higher values of total score between 33-100 points indicated greater disability attributed to dry eyes.
Statistical Analysis
Data analysis was completed using Stata (version 13.0, Stata Corp., College Station, TX, USA).
Categorical variables were analysed by chi square and for non parametric values Wilcoxon signed Rank test was used. P value <0.05 was taken as significant.
Results:
The records of a total of 31 patients (61 eyes) were analyzed retrospectively. The mean age of patients was 11.87±3.44 years. Out of the total of 31 patients.24 (77.4%) were males. The age of onset and duration of disease was 7.74 ±3.69 and 3.98±3.53 years respectively. The mean of baseline logmar visual acuity values in right eye (RE) and left eye (LE) was 0.307±0.304 and 0.418±0.526 respectively.
Of total 31 patients, 25 patients had VKC alone. Whereas Giant papillary conjunctivitis (GPC), VKC with limbal stem cell deficiency (LSCD), VKC with keratoconus and VKC with healed keratitiswas noted in 2, 2, 1 and 1 patients respectively. The average K values were 43.19±1.97/ 44.24 ± 2.38 and 43.01±1.47/ 44.09± 1.44in RE and LE respectively.
Mean values of Schirmer test’s and TBUT test, prior to the commencement of Rebamipide therapy and after 6 weekswere compared. Pre and post treatment Schirmer test values, in right eyes were 16.48mm and 19.29mm respectively. Corresponding values in left eyes were 16.84 mm and 19.39 mm respectively (p value <0.05).
In terms of TBUT pre/post Rebamipidemean values noted in RE and LE were 12.58/15.19 seconds and 12.35/15.09 seconds respectively (p value <0.05).
The median 5-5-5 score in RE at presentation and at 6 weeks post Rebamipide therapy was 224 and 121 respectively (p <0.001). Whereas in LE median valuesat presentation and at 6 weeks were 221 and 110 respectively (p <0.001). Before starting Rebamipide, mild, moderate and severe VKC was noted bilaterally in 3, 7 and 21patients. At 6 weeks post Rebamipide 2% therapy, number of right and left eyes with mild, moderate and severe VKC was changed to 8,15,8 and 9,15, 7 respectively (p value <0.001).
For dry eye evaluation, the median OSDI score in RE and LE at presentation/6 weeks post Rebamipide therapy was 41.7/27.8 and 46.9/31.3respectively (p < 0.005).Prior to the commencement of Rebamipide, OSDI score was significant (>33) in 22 patients. After 6 weeks of Rebamipide therapy significant score was noted in 13 patients only (p value <0.005)
Patients with mild VKC group did not show much change at follow up in terms of both 5-5-5 scoreand OSDI score, while a significant change was seen in the moderate and severe group with maximum effect noted in the severe group (p= 0.001).
Discussion
Rebamipide has been commonly used for the treatment of dry eyes owing to production of mucin from the goblet cells and epithelial cells of conjunctiva and cornea respectively. Recent studies have proven its efficacy and safety for dry eye patients.16,17
The ocular surface mucins mainly are of two types: membrane associated and secreted type.17 First type of mucin (membrane associated) including MUC1, MUC4 and MUC16are released from the epithelial cells of both conjunctiva and cornea, which improves the lubrication of corneal surface and can act as barrier to various pathogens and foreign bodies.18, 19 Whereas goblet cells of conjunctiva produce the second type mucin known as secreted mucin (MUC5AC) and this increases the tear film stability.18,19
Rebamipide has shown its affectivity by enhancement of the expression of proteins in corneal epithelial cell, by upregulating the gene expression of membrane associated mucins20 and by increasing the amount of secreted mucin in the tear fluid.11
Although use of Rebamipide in dry eye patients is well established now, however for VKC its usefulness has been sparsely reported in one or two studies only and that too on the basis of assessment of improvement in subjective symptomatology or by assessing reduction in size of giant papillae.13, 14
Therefore, in current study effectiveness of 2% topicalRebamipide was assessed in treating VKC patients by comparing baseline values of 5-5-5 scoring with values at 6 weeks of Rebamipide therapy. Other parameters observed in our study were Schirmer test values, TBUT values and OSDI score. All the studied parameters were found to be improved after 6 weeks of topical Rebamipide use in VKC patients.
It is noteworthy that magnitude of symptoms reported by the patients and objective measurement by the ophthalmologist such as 5-5-5 scoring, there is often a difference. Hence, in present study benefits of Rebamipide in VKC have been evaluated by the scoring systemand results demonstrated significant improvement in 5-5-5 score, especially in the moderate and severe group.
In context to recent case series of four patients by Ueta M et al,13 in which authors acknowledgedattenuation of giant papillae by using topical Rebamipide inpatients with allergic conjunctival disease and concluded that these eye drops may be useful for the treatment of such patients. Similarly, our study also demonstrated improvement in objective signs (5-5-5 scoring) of VKC after Rebamipide use.
Another study done by Munish D et al, 14 reported significant improvement in symptomatolgy, values of Schirmer and TBUT testing after rebamipide use in VKC patients and these results corroborated well with our study, in which both 5-5-5 scoring and OSDI score showed significant improvement after 6 weeks of Rebamipide therapy (p value < 0.001 and < 0.005 respectively).
Dysguesia as a side effect of topical Rebamipide was observed in 2 out of 31 patients;however it was mild and resolved without treatment. Additional side effect in the form of eye irritation was complained by three patients, which could be tackled by prescribing lubricating eye drops in conjuction with Rebamipide therapy.
Effectiveness of immunosuppressive drugs like cyclosporine and tacrolimus, for the treatment of allergic conjunctivitis had been extensively studied earlier. Double masked placebo trial done by Pucci et al in patients having allergic conjunctivitis, reported 40% reduction insubjective and objective scores with 2% cyclosporine. 21Another study done by Smedtet al, documented similar effectiveness of 2%cyclosporine eye drops and topical dexamethasone in their 4 weeks study.22
Previous studies on topical tacrolimus use in VKC, reported the improvement in conjunctival papillary reaction with higher concentration of tacrolimus (0.1%).23, 24However in Shoughy et al study least improvement was noted in conjunctival papillary hypertrophy with 0.001% tacrolimus. This study demonstrated efficacy and safety of 0.01% tacrolimus solution as a steroid-sparing agent in the management of refractory VKC, but recurrence of symptoms was noted in almost all patients on discontinuation of therapy.25
Study done by Labcharoenwongs et al compared cyclosporine and tacrolimus and concluded that twice daily application of tacrolimus ointment or cyclosporine eye drops four times daily resulted in similar improvement in VKC symptoms. Ocular signs observed objectively and improved more with tacrolimus although not statistically significant. Authors reported annoying burning sensation and ocular pain with cyclosporine eye drops and transient burning with 0.1% tacrolimus.26
Although most of the studies showing benefits of immunosuppressive agent in VKC, a randomized controlled trial done by Daniell et al, reported no benefit of topical cyclosporin A 0.05% over placebo as a steroid sparing agent in allergic eye disease.27
A common problem with tacrolimus as well as cyclosporine use is the difficulty to find a nonirritating vehicle for eyedrop preparation.25Moreover, treatment with topical tacrolimus can increase the risk of infections attributed to modulated ocular surface’s local immune response. So possibility of recurrence of herpes simplex virus keratitis should be kept in mind in long term tacrolimus therapy.28, 29Fortunately, risk of malignancyand fungal superimposed infection due to a topical treatment with tacrolimus and cyclosporine ophthalmic preparation respectively has not been proven in literature.30-33However risk should be still considered.
In view of certain above mentioned limitations and cost effectiveness, another steroid sparing alternative should be developed and searched for by doing further studies. Hence present study assessed the effectiveness of topical 2% Rebamipide eye drops by comparing objective 5-5-5 scoring values pre and post 6 weeks of therapy.
To summarize, taking immunosuppressive medication’s side effects in to consideration, we can say topical Rebamipide can be used as a promising treatment modality for reducing the signs and symptoms of VKC, especially in patients with moderate and severe disease and can be used as a steroid sparing agent in steroid responders.
References:
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| Table 1.5-5-5 grading scale for VKC patients | |||
| Grade of clinical sign
|
100-point grade | 10-point grade | 1-point grade |
|
Clinical sign |
Active giant papilla | Blepharitis | Papillae at upper palpebral conjunctiva |
| Gelatinous infiltrates of the
limbus |
Papillary proliferation with velvety
Appearance |
Follicular lesion at lower palpebral
Conjunctiva |
|
| Exfoliative epithelial keratopathy Horner-Trantas spots
pathy |
Horner-Trantas spots | Hyperemia of palpebral conjunctiva | |
| Shield Ulcer | Edema of bulbar lconjunctiva | Hyperemia of bulbarconjunctiva | |
| Papillary proliferation at
lower palpebral conjunctiva |
Superficial punctate keratopathy- Lacrimal effusion ‡ | Lacrimal effusion | |
| Score | 100 points × number of
Score positive sign |
10 points × number of positive
Signs |
1 point × number of positive
Signs |
| Range | 0-500 points | 0-50 points | 0-5 points |
| Table 2. Comparison of mean Shirmer test and TBUT test values, before and after using 2% topical rebamipide for 6 weeks | |||||
| Baseline mean values | Mean values after 6 weeks of Rebamipide Therapy | p value
|
|||
| RE | LE | RE | LE | ||
| Values of Schirmer tests (in millimeters) | 16.48 | 16.84 | 19.29 | 19.39 | <0.05 |
| Values of TBUT test (in seconds) | 12.58 | 12.35 | 15.19 | 15.09 | <0.05 |
| Table 3. Comparison of median values of 5-5-5 score and OSDI score, before and after using 2% topical rebamipide for 6 weeks | |||||
| Baseline median values | Median values after 6 weeks of Rebamipide Therapy | p value
|
|||
| RE | LE | RE | LE | ||
| 5-5-5 Score (points) | 224 | 221 | 121 | 110 | <0.05 |
| OSDI Score (points) | 41.7 | 46.9 | 27.8 | 31.3 | <0.05 |