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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 1  |  Page : 49-56

Evaluation of oral rebamipide as a potential therapy for Sjögren syndrome-related dry eye and mouth


1 Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
2 Department of Ocular Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India
3 Department of Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

Date of Submission09-Sep-2020
Date of Acceptance18-Dec-2020
Date of Web Publication23-Mar-2021

Correspondence Address:
Dr. Radhika Tandon
Room 490, 4th Floor, Dr Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_254_20

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  Abstract 


Background: Efficacy and safety of orally administered rebamipide was assessed in treating dry eye disease (DED) and xerostomia in Sjögren syndrome (SS) patients.
Methods: Patients of SS with bilateral DED and xerostomia were offered a choice between either oral rebamipide (100 mg BID) with topical 0.5% carboxymethylcellulose (CMC) (R + CMC group) or CMC alone (CMC group), for 3 months, in a quasi-experimental study. Outcome measures were tear-film break-up time (TBUT) and xerostomia symptoms (XS), Schirmer's test (ST), Lissamine green staining grade (LGSG) and goblet cell density (GCD), Saxon salivary secretion test (SSST), and Ocular Surface Disease Index (OSDI).
Results: Twenty patients were enrolled in each group. Those who preferred oral rebamipide had worse ST (P = 0.04), LGSG (P = 0.04), SSST (P = 0.006), and GCD (P = 0.009). At 1, 2, and 3 months, the mean increase in TBUT were, respectively, 3.4, 2.9, and 3.45 s in R + CMC, higher than CMC (P < 0.001). Improvement in ST was significantly higher in R + CMC (from 6.75 ± 0.43 to 12.6 ± 1.23 mm) than CMC (P < 0.001). The improvement in OSDI, LGSG, and XS was higher in R + CMC group (all P < 0.001), while that in SSTT (P = 0.6) and GCD (P = 0.7) was similar. No serious adverse events were seen.
Conclusion: The dry eye and mouth showed improvement with oral rebamipide, proving its dual therapeutic action in SS.

Keywords: Dry eye, dry mouth, oral drug, rebamipide, sjögren's syndrome


How to cite this article:
Mutha V, Gupta Y, Gupta N, Vanathi M, Sen S, Kumar U, Tandon R. Evaluation of oral rebamipide as a potential therapy for Sjögren syndrome-related dry eye and mouth. Indian J Rheumatol 2021;16:49-56

How to cite this URL:
Mutha V, Gupta Y, Gupta N, Vanathi M, Sen S, Kumar U, Tandon R. Evaluation of oral rebamipide as a potential therapy for Sjögren syndrome-related dry eye and mouth. Indian J Rheumatol [serial online] 2021 [cited 2021 Apr 16];16:49-56. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/1/49/311309




  Introduction Top


Sjögren's syndrome (SS) is a chronic autoimmune exocrinopathy consequent to autoantibodies against multiple self-antigens including those found in lacrimal and salivary glands.[1] These glands are infiltrated by activated T-cells, which attack the ductular and acinar cells,[2] resulting in hyposecretion of tears and saliva, leading to dry eye disease (DED) and dry mouth (xerostomia) in majority of patients at presentation. SS-related DED is aqueous-tear deficient DED and is generally severe with an incidence of one in ten patients.[1] Inflammation and tear film hyperosmolarity lead to tear film instability, which results in chronic damage to the ocular surface.[2]

DED and xerostomia are the major distressing symptoms in SS that interfere with the quality of life of patients.[3] Various treatment modalities for SS-associated DED include topical lubricants, topical steroids, immunomodulators (e.g., cyclosporine A), and autologous serum. The therapy is often patient specific. Low levels of mucin proteins (e.g., MUCA5) and other glycoproteins have been detected in the tear films of patients with SS.[4],[5] This led to trials of mucin secretagogues for DED such as diquafosol (INS 365) and rebamipide.[6] Treatment for xerostomia in SS includes pilocarpine, cevimeline, and more recently, oral rebamipide.[7]

Rebamipide, a quinolone derivative, stimulates mucin glycoprotein synthesis and has anti-inflammatory and immunomodulatory properties.[8],[9],[10] For SS-related DED, randomized controlled trials (RCTs) have demonstrated the efficacy and safety of topical 2% rebamipide drops.[6],[8] Currently, RCTs also support the role of oral rebamipide in the improvement of xerostomia symptoms (XS)[7] and increasing salivary secretion in patients with SS.[3] However, the dual role of rebamipide on tears and salivary secretion has not been studied in SS patients.

Previously, Tandon et al. determined good ocular bioavailability oral administration of rebamipide (100 mg twice daily) in patients of dyspepsia,[11] indicating its potential value for treating SS-associated DED. The current study investigates the hypothesis that oral rebamipide may have dual therapeutic action on dry eye and mouth both in SS patients.


  Methods Top


Design

A prospective interventional patient preference trial with a quasi-experimental design was used, including pre- and posttesting in the intervention group (n1 = 20) and comparison group (n2 = 20). The study was performed in compliance with the Declaration of Helsinki. The study was conducted according to Good Clinical Practice Guidelines and the study protocol was reviewed and approved by the Institute Ethics Committee. Clearance for using oral rebamipide for SS-related dry eye as a new indication was obtained from the Drug Controller General of India.

Participants

After obtaining written informed consent, 40 patients of diagnosed SS with dry mouth and bilateral DED (referred from the rheumatology clinic of a tertiary care hospital) were enrolled in the study. The inclusion criteria were patients aged 18–65 years with SS and bilateral DED and xerostomia willing to participation and follow-up. Exclusion criteria were as follows: those with punctal plugs, with severe eyelid disease, any prior ocular surgery or treatment affecting tear film, contact lens-users, pregnant/lactating females, those on any prescribed/over-the-counter topical ophthalmic drugs, those on drugs that are known to affect the tear film (e.g., β-blockers, anticholinergics, antihistaminics, oral contraceptives, and steroids), and those on oral rebamipide for gastric mucosal disorders.

Diagnosis of SS was based on the Revised International Classification criteria for SS (2002).[12] The diagnosis of DED was based on the consensus definition by the Dry Eye Workshop in 2007.[2] Tear-film break-up time (TBUT) values of the worse eye or the right eye (if right eye and left eye values were equal), were used for analysis.

Sample size calculation and patient recruitment

As there were no previous data available in the literature for oral rebamipide for dry eyes and dry mouth in patients with SS, a sample size of 20 in each group was selected. Recruitment of individuals was done simultaneously into intervention and comparison groups and recruitment continued to ensure a total number of 20 eligible patients in each group. All patients were explained about the available therapy for dry eye and dry mouth in patients with SS and also informed about the study objectives indicating the potential benefits and possible adverse effects of rebamipide and the available literature on the role of rebamipide for dry eyes and dry mouth. The patients were explained that it was a preliminary study and in view of lack of adequate data, they were given an option to choose rebamipide, thereby minimizing selection and performance bias. The patients who opted for rebamipide were recruited in the intervention group, those who were not willing to try rebamipide were included as controls.

Twenty patients were in the intervention group (“R + CMC” group) and 20 were treated as comparative controls (“CMC” group). All patients in the intervention group were given oral rebamipide 100 mg twice daily (Rebagen, Macleods pharmaceutical limited) for 3 months[11] in addition to topical tear supplements (0.5% CMC) QID for 3 months. Those in the comparison group were given 0.5% CMC only (qid). Drug compliance was ensured with patient counseling and regular follow-ups. After 3 months of treatment with R + CMC or only CMC, rebamipide was discontinued and only CMC was continued for another 3 months in both the groups.

Data collection and measures

Patient evaluation

After a thorough history, a baseline clinical evaluation (age, gender, duration of disease, associations of SS, and previous treatment details) and comprehensive ocular and systemic examinations were done. Subjective parameters included Ocular Surface Disease Index (OSDI) score and XS grading. The objective parameters were best-corrected visual acuity (BCVA), Schirmer's test (ST), TBUT, goblet cell density (GCD), Lissamine green staining grade (LGSG), and Saxon salivary secretion test (SSST).

Efficacy assessment: The primary measures were

  1. TBUT: For the TBUT, after explaining the procedure to the patient, 2% fluorescein strip wetted with artificial tears was instilled in the inferior fornix, and the patient was asked to blink twice, TBUT was calculated as the time gap between the last blink and appearance of the first dry spot on the cornea when seen in cobalt blue filter light through slit lamp biomicroscope
  2. SSST: Salivary secretion assessment was done using Saxon test.[13] The patient was asked to chew on a folded sterile sponge for 2 min. Saliva production is quantified by weighing the sponge before and after chewing, in grams.


The secondary measures were:

  1. OSDI score: Calculated based on OSDI questionnaire[14] filled by patients, with total score divided by the total number of questions answered multiplied by 25
  2. GCD: For the conjunctival GCS, the eye was anesthetized with 1% topical proparacaine. Cut sections of cellulose acetate filter paper were placed on the superotemporal area of the bulbar conjunctiva of both eyes 2–4 mm from the limbus and transferred to rubber stopped glass vial with a fixative solution containing 95% ethyl alcohol. Then, the filter paper was placed on the perforated metal cachet and stained with periodic acid-Schiff stain and GCD was measured as a number of goblet cells per high-power field (hpf), i.e., per × 400 magnified field of the microscope. A mean of the two measures was taken
  3. Schirmer's test was done using the Whatman filter paper # 41. The filter paper was put in the cul-de-sac at the junction of medial two-third and lateral one-third of the lower lid. The amount of wetting of filter paper in 5 min was measured in millimeters
  4. LGSG: For the Lissamine green staining, after explaining the procedure to the patient 1% Lissamine green strip wetted with artificial tears was put in the inferior cul-de-sac and staining of ocular surface was assessed using Oxford staging[15] performed under diffuse illumination on slit-lamp biomicroscope
  5. Xerostomia symptom score: XS were graded based on questioning the patients regarding oral discomfort and impediment of daily living as described by Sugai et al.,[7] on a four grade scale: none, mild, moderate, and severe.


Safety assessment

The safety variables were as follows: the occurrence of any adverse event (ocular or systemic) determined after careful clinical evaluation including external eye evaluation, slit-lamp biomicroscopy, fundus evaluation, vision assessment, intraocular pressure measurement, and systemic examination for features of SS.

Follow-up schedule

The subjects were followed up at monthly intervals during the intervention period (baseline to 3 months) and an additional 3 months thereafter, i.e., upto 6 months from recruitment. GCD was evaluated using impression cytology at 3 and 6 months after the intervention. All other measures were repeated at 1st, 2nd, 3rd, 4th, 5th, and 6th month. Adverse drug effects (ADE) were assessed with history and clinical examination at each follow-up visit.

Data analysis

Data were entered using Microsoft Excel sheet®. Data were analyzed using the Statistical Package for the Social Science (SPSS) version 25.0 (IBM Corp, Armonk, NY, USA). Descriptive statistics using continuous data were analyzed using means and standard deviation (for parametric data) and median and interquartile range (IQR) for nonparametric data. The categorical data was analysed using frequencies and percentage. The normality of the data was checked using histogram and Shapiro–Wilk normality test. An outcome variable was compared between the groups at the baseline and postintervention. For within-group differences, if data were assumed normally distributed data, parametric tests such as Paired t-test and repeated measures analysis of variance (ANOVA) were utilized to evaluate the null hypothesis that there is no change in patient's parameters measured before, during, and after the intervention. But if data were assumed nonnormal distributed data, nonparametric tests such Mann–Whitney U-test and Wilcoxon signed-rank test were utilized. Apart from that, McNemar Test was used to determine the association of two categorical-related variables. For between group difference, parametric tests such as independent t-test and nonparametric tests such Mann–Whitney U and Friedman tests were utilized. Chi-square test and Fisher exact were used to test the association between two categorical variables. Logistic regression was used to assess the initial preference of rebamipide versus no rebamipide. A one-way repeated measure ANOVA was conducted (n = 40). The missing value in the longitudinal analysis was analyzed using the last observation carried forward method.


  Results Top


Participant characteristics

A total of 40 patients with SS, bilateral DED, and dry mouth were enrolled in the study: 20 received oral rebamipide plus topical CMC (R + CMC) and 20 received only topical CMC 0.5% (CMC). One patient could not follow-up for the 6th month testing. Two patients could not be evaluated for dry mouth parameters, as they underwent root canal surgery during the study. The patient characteristics across the treatment groups were comparable [Table 1]. The mean age of participants was 44 ± 11 years with a female-to-male ratio of 1.66:1 (11 female subjects in R + CMC and 14 female subjects in the CMC group). The median (IQR) duration of diagnosed SS before the study was 1.5 (10.25) years (3[8] and 1 [10.75] year in R + CMC and CMC groups, respectively).
Table 1: Baseline characteristics of participants in the two groups

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Patient preference for oral rebamipide

Those who chose oral rebamipide along with CMC had significantly lower ST (P = 0.04), greater OSDIs (P < 0.001), worse LSSG (0.04) and lesser GCD (P = 0.009), and lower SSTT (P = 0.006). The XS were same in the two groups (P = 0.97). However, the preference for choosing treatment with oral rebamipide was not significantly associated with baseline values of TBUT (P = 0.79), OSDI (P = 0.09), ST (P = 0.43), goblet cell density (P = 0.54), SSST (P = 0.15), duration of disease (P = 0.86), or xerostomia symptom severity (P = 0.88).

Changes in dry eye objective signs in 3 months

TBUT, ST, and Lissamine green staining grades were tested in all 40 subjects [Table 2]. The values of TBUT improved significantly in the rebamipide group at all time points [Figure 1]: months 1, 2, and 3. At 1, 2, and 3 months, mean increases in TBUT were, respectively, 3.4, 2.9, and 3.45 s in R + CMC, while they were 0.7, 1.2, 0.5 in the CMC group. The improvement from baseline to 3 months was significantly more in the R + CMC group than in CMC only group (P < 0.001). ST values improved significantly more in 3 months in the R + CMC group than in CMC only group (P < 0.001). Lissamine staining grade also improved from baseline (14 in grade 1, 5 in grade 2, and 1 in grade 3) to 3 months (10 in grade 0, 9 in grade 1, and 1 in grade 2) significantly in R + CMC group (P < 0.001) than in CMC only group (12 in grade 0, 4 in grade 1, and 4 in grade 2 at baseline; 9 in grade 0, 9 in grade 1, and 2 in grade 2 at 3 months).
Table 2: Changes in the qualitative parameters from baseline to the end of the 3rd month in the intervention (R+carboxymethylcellulose) and comparison (carboxymethylcellulose) groups

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Figure 1: Changes in tear film break-up time with time in the two groups from baseline to months 1, 2, 3, 4, 5, and 6

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Changes in dry eye subjective parameter

From baseline to 3 months, OSDI changed from 50.39 ± 13.16 to 31.77 ± 12.47 in the oral rebamipide group and from 32.06 ± 13.15 to 31.33 ± 13.13 in CMC only group. The improvement was significantly more in the oral rebamipide group than CMC only group (P < 0.001).

Changes in dry mouth objective sign

From baseline to 3 months, SSTT changed from 2.40 ± 0.33 to 2.60 ± 0.34 in rebamipide versus from 2.62 ± 0.56 to 2.66 ± 0.54 in CMC only group. At 1, 2, and 3 months, the mean increase in salivary secretion were, respectively, 0.22, 0.2, 0.23 in R + CMC group and -0.13, 0.34, 0.12 in CMC group. The improvement from baseline was similar in the two groups (P = 0.63)

Changes in dry mouth subjective symptom

XS improvement in the group treated on oral rebamipide [Figure 2] was significant (P < 0.001). In the rebamipide group, two subjects improved markedly, nine improved, six improved slightly, one was unchanged, and none worsened. In CMC only group, the symptoms were unchanged after 3 months.
Figure 2: Changes in the xerostomia symptoms (patient's impression) in the two groups

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Changes in goblet cell density

At baseline, the median (IQR) GCD was 1 (0–2) and 2 (1–3) in R + CMC and CMC groups, respectively. At 3 months, the median (IQR) GCD was 0 (0–2) and 2 (1–2.75). GCD was, thus, seen to be preserved at 3 months in R + CMC (P = 0.32) and CMC (P = 0.10) groups [Figure 3].
Figure 3: Representative images of conjunctival impression cytology pre- and postintervention (3 months oral rebamipide therapy) used for analyzing goblet cell density in 400 x magnified field, periodic acid-Schiff stain

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Effects after stopping oral rebamipide

Dry eye and mouth parameters worsened after stopping oral rebamipide in R + CMC, that is from 3rd to 6th month. The change was significantly more in TBUT (P = 0.004), OSDI (P = 0.002), and SSTT (P = 0.041). However, ST (P = 0.5), XS (P = 0.40), and LGSG grades (P = 0.7) were similar at 6th month as those in 3rd month. The mean differences between 6th and 3rd month values in R + CMC group were: −0.85 s for TBUT, −1.65 mm for ST, 6.86 for OSDI, and − 0.05 for ST [Table 2]. The GCD was preserved at 6th month in R + CMC (P = 0.5) and CMC (P = 0.32) groups.

Adverse drug effects

In this study, oral rebamipide was found to be safe, with no serious adverse drug reactions (ADRs) in any patient. Mild gastric upset and nausea were noted in four subjects in the intervention group, which was managed adequately. There were no ocular or oral ADEs.


  Discussion Top


There is currently no therapy that directly addresses the pathophysiology of SS, rather they achieve only symptomatic treatment of dry eye and dry mouth. Pilocarpine hydrochloride and cevimeline have been used as a common treatment for DED and xerostomia, but trials have shown therapeutic failure and ADRs due to the muscarinic action, such as nausea, vomiting, and excessive perspiration are quite troublesome.[16] Therefore, there is a need to explore safer and more effective therapeutic options. Rebamipide poses a good option as a single alternative potential drug for DED and xerostomia. A single efficacious option will also reduce the number of drugs required by a patient of SS on a daily basis.

Secretagogues (e.g., rebamipide, diquafosol tetrasodium, and ecabet sodium) are a host of potential drugs for the management of DED. Rebamipide, first used as a gastroprotective drug, increases gastric mucus production and suppresses mucosal inflammation.[17],[18],[19],[20]It is widely used today for gastritis and gastric ulcerative diseases. In 2008, Kohashi et al.[21] demonstrated that oral rebamipide (4 weeks) prevented auto-immune lesions, improved salivary and lacrimal secretion, reduced TUNEL + apoptotic duct cells (in salivary and lacrimal glands), and inhibited the levels of autoantibodies, IgM, and IgG1 in serum in murine models of SS. Tanaka et al.[22] have recently reported its role in the promotion of rabbit lacrimal duct epithelial cell in vivo survival. Rebamipide has anti-inflammatory role in human conjunctival epithelial cells,[23] human corneal fibroblasts,[24] and improves the barrier function in human corneal epithelial cells.[25] Its topical use increases facilitate lacrimal stent intubation.[26] It corrects the imbalance between immune and regulatory cells in mice models of SS.[16] The systemic absorption of topical preparation is not yet known. To our best knowledge, this is the first study evaluating the effectiveness of oral rebamipide for both DED and dry mouth.

The rationale for using oral rebamipide in the current study is its reported safety and efficacy in improving salivary secretion and symptoms of dry mouth in cases of SS.[7] In SS, the ductular and acinar cells of lacrimal and salivary glands are infiltrated and damaged by T-cells,[2] resulting in hyposecretion of tears and saliva. The proposed hypothesis for the response of DED and dry mouth to rebamipide was that rebamipide has anti-inflammatory role, reduces auto-immune lesions, and reduces apoptosis in ductular cells of the two glands.[21] There is evidence of adequate ocular bioavailability of its levels in tear film after oral administration.[11] In a study by Tandon et al.,[11] significant tear film levels were demonstrated after oral administration of rebamipide for 3 months in 100% (n = 27) patients (P < 0.001).

Sugai et al.[7] studied Saxon test values and XS, while Abou-Raya et al.[3] studied visual analog scale for sicca syndrome symptoms. The parameters for DED studied in similar trials were as follows: TBUT, Schirmer's, Lissamine green staining grade, fluorescein corneal staining (FCS), and dry eye-related ocular symptoms, although our study used OSDI for subjective dry eye assessment. We measured one additional parameter: goblet cell density, using conjunctival impression cytology, which was found to be preserved with rebamipide treatment in our study. Treatment with cyclosporine-A has been reported to increase the GCD in conjunctival biopsy specimens of SS patients with DED.[27] Previous studies in cultured rat cells showed a significant increase in GCD with topical rebamipide.[28] Simsek et al.[15] recently reported improvement in GCD after 12 weeks of use of topical rebamipide in DED patients. Very limited literature exists on effects on GCD in human SS subjects.

In the current study, oral rebamipide in combination with topical tear supplements, given for 3 months, led to significant improvement compared to baseline in majority of signs and symptoms of DED (namely TBUT, OSDI, LGSG, ST) and dry mouth (namely XS) in patients with SS compared to those treated with teardrops alone. There was sustained significant improvement in ST, Lissamine green staining grades, and XS upto 3 months after stopping the drug; however, TBUT and OSDI showed a gradual return to baseline. Similar studies have also reported improvement in TBUT, FCS, LGSG, and dry-eye-related symptoms with topical rebamipide.[6],[8],[15],[29] The effects of oral rebamipide on DED have been studied in mouse models only.[21] The positive therapeutic effect seen on dry mouth symptoms was also coherent with other studies.[3],[7]

In our study, the significant improvement in ST findings with oral rebamipide therapy given for 3 months is an important finding signifying an increase in aqueous secretion. This has not been reported with the use of topical rebamipide.[6],[8],[30],[31] Three months after cessation of oral rebamipide, the significant improvements in ST were sustained at 6 months. This finding may be of great value to ophthalmologists and physicians managing DED in SS.

On basis of these findings, the authors recommend treatment of sicca symptoms (dry eyes and dry mouth) in SS with oral rebamipide 100 mg twice daily dose for atleast 3 months.[11] The rationale behind this dose was good tear film bioavailability achieved with this dose.[11] In a RCT, Sugai et al.[7] evaluated a different dosage (100 mg TID) of oral rebamipide for treatment of SS-related dry mouth. The dosage of oral rebamipide used for treating gastric mucosal ulcers and recurrent aphthous ulcers in Behcet's syndrome is 100 mg TID.[32],[33] However, to our knowledge, no prior study determines the dosage of oral rebamipide for treating SS-related DED.

Salivary secretion and GCD did not improve significantly in our study. In a double-blinded RCT, Sugai et al.[7] reported improvement in salivary secretion also. Major limitations of our study are small sample size, unequal GCD at baseline between the two groups (due to quasi-experimental model), and the possibility of performance bias, as is known with patient preference trials.[34] It was seen that rebamipide was chosen by severe SS cases, probably because they were not satisfied with previously used medicines. Although functional parameters (tear and salivary secretion) were analyzed, anatomical parameters (e.g., lip biopsy for quantitative grading of salivary glands number) could also have been analyzed.

However, more importantly, this study provides the first clinical evidence to support the beneficial effect of oral rebamipide for the dry eye and dry mouth in SS. The therapeutic role of rebamipide can be validated by a randomized double-blind placebo-controlled RCT with larger sample size. We suggest future trials comparing topical and oral rebamipide while studying sialometry and tear osmolarity. It also raises an important question regarding the most efficient therapy for SS patients, i.e., whether targeting dry eye alone with a topical rebamipide formulation is better or using one arrow targeting cure of both dry eye and dry mouth is to be preferred.


  Acknowledgment Top


We acknowledge Dr. Nikita Mutha, Maharashtra University of Health Sciences, Nashik, India, for providing statistical help in this research. We acknowledge the funds provided by the Indian Council of Medical Research (Grant number: 5/4/6/2/07-NCD-II).

Financial support and sponsorship

Funding for this work was provided by the Indian Council of Medical Research. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Conflicts of interest

There are no conflicts of interest.



 
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