SYSTEMIC ANTIOXIDANTS IN MANAGEMENT OF ORAL SUBMUCOUS FIBROSIS: A SYSTEMATIC REVIEW OF RANDOMISED CONTROL TRIALS AND META–ANALYSIS. Dr. Kondajji

Dr. Kondajji Ramchandra Vijayalakshmi 1 , * Dr. Ankit Srivastava 2 and Dr. Mubeen Khan 3 . 1. Associate Professor (M.D.S), Room No.1, Department of Oral Medicine & Radiology, Govt. Dental College & Research Institute, [Affiliated to Rajiv Gandhi University of Health Sciences (RGUHS)], Bangalore–560002. 2. Post Graduate Student, Room No.1, Department of Oral Medicine & Radiology, Govt. Dental College & Research Institute [Affiliated to Rajiv Gandhi University of Health Sciences (RGUHS)], Bangalore-560002. 3. Professor & Head (M.D.S), Room No. 1, Department of Oral Medicine & Radiology, Govt. Dental College & Research Institute, [Affiliated to Rajiv Gandhi University of Health Sciences (RGUHS)], Bangalore–560002. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History

Management of OSMF aims to reduce the symptoms and prevent the risk of malignant transformation. The current protocol for the management of OSMF can be divided into 3 broad groups: pharmacological, physical and surgical modalities. [4] Pharmacological management includes usage of Vitamins and Antioxidants, antiinflammatory drugs (principally corticosteroids), proteolytic agents (such as hyaluronidase) and anti -cytokines. Antioxidants act through their antiinflammatory, antimutagenic and anticarcinogenic properties. Moreover, Antioxidants stabilize and deactivate the free radicals which are induced by the ingredients of the betel nut. Various studies have shown that antioxidants are highly effective in controlling the signs and symptoms of OSMF and have been the mainstay of a conservative approach for management of OSMF. [4] [5] Several narrative and systematic reviews on management of OSMF have highlighted the beneficial role of various antioxidants like natural extracts, micronutrients, vitamins, nutritional supplements. [5][6] [7] Nonetheless, no systematic review or metaanalysis has yet given evidence of efficacy of systemic Antioxidants in management of OSMF. Thus, this systematic review aimed to critically summarize and evaluate results of clinical studies investigating systemic antioxidants to improve signs and symptoms of OSMF.

Material and methods:-
Review design:-The present systematic review was carried out by three investigators with an aim to systematically retrieve and analyse clinical studies investigating antioxidants in the management of clinical signs and symptoms of OSMF. The 3 rd investigator performed an electronic search. Thus identified titles / abstracts through the search engines were independently screened by first and second investigators according to set inclusion and exclusion criteria for selection of abstracts. Full text articles of the selected abstracts were retrieved by the third investigator and further retrieval of titles / abstracts was done by crossreferencing of fulltext articles. The fulltext articles were assessed for eligibility by the first and second investigators and the selected studies are assessed for the quality of their reporting.
Search strategy:-An electronic data base search was performed in PubMed and Science Direct for last 20 years from a time period of January 1995 to March 2015. The MESH keywords were ANTIOXIDANTS, MICRONUTRIENTS, VITAMINS, NUTRITIONAL SUPPLEMENTS combined with OSMF with Boolean term -AND‖. A total of 1189 title / abstracts identified through the search engines and the 9 title / abstracts identified through manual search were independently screened according to set inclusion and exclusion criteria for selection of Titles / abstracts (Table.1). The investigators were not blinded to journal names or authors. Screening yielded total of 41 title / abstracts out of which 12 full text articles could be retrieved. 3 full text articles were excluded because of repetition. Finally 9 full text articles were selected and assessed for eligibility through PICO guidelines. Agreement concerning study inclusion or exclusion was achieved by thorough discussion among the investigators. Further 6 fulltext articles were selected which fulfilled the PICO guidelines. These fulltext articles are qualitatively analysed with consort

assessment of eligibility (With PICO guidelines)[8]-
The 9 fulltext articles were evaluated with participants, interventions, comparators, outcomes (PICO) guidelines as follows-

Participants-
Studies with human participants, who were diagnosed as having OSMF clinically or histologically or both.

Type of interventions-
Systemic Antioxidants as a single entity or in combination, at any dosage and over any time period.

Comparators (Control)-
Negative (placebo treatment), positive (other intervention; i.e other treatment modalities or antioxidant administered in any other mode).

Outcomes-
The primary outcomes assessed were-maximal mouth opening, burning sensation, palpable fibrous bands, tongue movements. Secondary outcomes assessed were the adverse effects of the antioxidants used and Change or improvement of nutritional status by laboratory investigations and clinical evaluation.

Data extraction and synthesis-
Data of the 9 fulltext articles was extracted and recorded in a format designed for this purpose. The data extracted from all the studies were combined and the subjects who were administered systemic antioxidants alone or in combination with other treatment modalities were considered into interventional group. Subjects who were administered placebo, intralesional corticosteroids or topical antioxidants were considered in control group. The data of the 9 fulltext articles were assessed for eligibility according to PICO guidelines. However, only 6 studies could be included in the systematic review after assessment of eligibility (  [17]. The extracted data resulted in 207 subjects using systemic antioxidants these subjects were considered to be in interventional group in the systematic review and meta -analysis. 203 subjects were considered in the control / comparator group. Out of which, 82 were included in the placebo group, 121 controls were in the other treatment modalities group like intralesional corticosteroids or topical antioxidants.

Quality assessment of selected studies-
The quality of reporting of RCTs was carried out by using the 2010 CONSORT criteria as modified by Fricton, et al. 1 st and 2 nd investigators independently evaluated the method of randomization and blinding using points 8,9,10,11,15,16 of CONSORT guidelines 2010 as they are the indicators of risk of systemic bias (Table 3 showing the details). In case of disagreement between the investigators, differences were discussed and a decision was made by consensus. The overall score of the studies gave an average of 6.83 which varied from a minimum of six to a maximum of 8 (scoring shown in Table 4). [18] Statistical analysis:-The extracted data of the selected studies are tabulated. Metaanalysis could be achieved only for one primary outcome i.e mouth opening as the method of its assessment was uniform in all the included studies. Due to heterogeneity of data and methods of assessment the rest of the primary outcomes could not be taken for metaanalysis. The primary measures of effect between treatment and control groups for mouth opening were calculated as the standardized mean differences (SMDs) with a 95% confidence interval. A random and fixed effects model was used to calculate a pooled estimate effect. Cochrane's Q test, a statistic based on the chisquared test was used to assess the existence of heterogeneity among the interventional and control groups for mouth opening.

Results:-Study characteristics:-
The electronic searches yielded a total of 1889 articles and manual search yielded total of 9 articles. Following a meticulous search strategy according to prisma guidelines (FIGURE.1), finally 9 full text articles were selected and assessed for eligibility through PICO guidelines. Further 6 fulltext articles were selected which fulfilled the PICO guidelines. These fulltext articles were qualitatively analysed with CONSORT guidelines 2010 as modified by Fricton et al. The extracted data was quantitatively assessed for the outcomes. The data analysis yielded complete information for only one of our primary outcomes i.e mouth opening. Metaanalysis could be achieved only for mouth opening as the methodology used for its assessment was same in all the included studies. All the other primary outcomes could not be taken for metaanalysis due to heterogeneous in complete data and different methodology used for their assessment.
Characteristics of outcomes:-Mouth opening:-All the 6 included studies assessed change in mouth opening as one of their treatment outcomes. All the studies measured mouth opening using interincisal distance in dentulous patients and for edentulous patients, the opening between the upper and lower ridges was recorded (Table.2). . Q test of heterogeneity was 122.9207, df = 4 with a significant p value of 0.0001. Hence, here emphasis should be placed on random effects model as test for heterogeneity is significant. (Fig.2) A third forest plot was drawn combining all the interventional groups and control groups (placebo & other treatment modalities) which depicted that systemic antioxidants as a single entity or in combination with other treatment modalities i.e intralesional steroids significantly improve mouth opening v/s controls i.e topical antioxidants and intralesional steroids considering the random effects model. (SMD = -1.226; 95% CI = -1.459 to -0.993); for fixed effects and SMD = -1.235; 95% CI = -2.263 to -0.206; for random effects). Q test of heterogeneity was 130.8958, df = 7 with a significant p value of 0.0001. Hence, here emphasis should be placed on random effects model as test for heterogeneity is significant. (Fig.2)

Discussion:-
Antioxidants provide a noninvasive conservative approach for management of OSMF. Various studies have proved that antioxidants when used as a standard or adjunct are effective in controlling the signs and symptoms of OSMF. This systematic review aimed to assess the evidence of systemic antioxidants in management of signs and symptoms of OSMF and to compare the systemic antioxidants with other treatment modalities in improving the signs and symptoms of OSMF. This systematic review included only randomized controlled trials, as non randomized trials tend to show frequent -false -positive‖ results than randomized trials. . This attributes to lack of credible evidence and high variability in between the studies as depicted significant test of heterogeneity (p = 0.0001 < 0.05) to estimate the effect of intervention. However, it can be inferred that systemic antioxidants as a single entity or in combination with intralesional corticosteroids does not seem to be better than other treatment modalities i.e intralesional corticosteroids and topical antioxidants in improving mouth opening patients with OSMF.
Meta-analysis of the combined data of all the interventional groups (n = 207) and control groups (n = 203; placebo & other treatment modalities) which depicted that systemic antioxidants as a single entity or in combination with other treatment modalities i.e intralesional steroids significantly improve mouth opening v/s controls i.e topical antioxidants and intralesional steroids (SMD = -1.235; 95% CI = -2.263 to -0.206). However, this data also depicted high variability in between the studies as depicted by significant test of heterogeneity (and p = 0.0001 < 0.05).

Limitations:-
The meta-analysis and systematic review reported here combines data across studies in order to estimate treatment effects with more precision than is possible in a single study. The main limitation of this meta -analysis, as with any overview is that the antioxidant used and the outcome definitions are not the same across studies. Only one primary outcome could be assessed i.e mouth opening, rest of primary and secondary outcomes could not be assessed due to lack of consensus among researchers invalidation of other signs and symptoms of OSMF. Although, only two studies mention about the adverse effects of the systemic antioxidant used. This leads us to an observation that systemic antioxidants are relatively safe for the treatment of OSMF. Moreover, the lack of assessment of nutritional status by laboratory investigation or clinical evaluation further highlights the lack of clear markers in serum and saliva which can reliably estimate the overall status of the subjects suffering from OSMF. At the study and review level our review did not include any grey literature and studies published in other languages were not considered in the review. Only 12 fulltext article could be retrieved due to constrained resources available to the investigators. Although, randomization of the selected studies was adequate the quality of randomization varied and none of the studies could be given high scores according to CONSORT guidelines as modified by Friction et al.

Implications for practice:-
Although the investigators in all the trials concluded that the results indicated that antioxidants were safe, appeared to be effective in reducing symptoms and might prove beneficial in the therapeutic management of oral submucous fibrosis, the uncertain reliability of the limited amount of available data would not appear to support these contentions. Moreover, the meta-analysis carried out for mouth opening suggests that systemic antioxidants are not as effective when compared with other interventions but it does indicate a certain beneficial role of systemic antioxidants being used as an adjuvant with other medical intervention. Additionally other antioxidants like Oxitard and Spirulina have proved to be effective in alleviating the signs and symptoms of OSMF.

Implications for research:-
OSMF has proven to be a significant global burden, especially in the South Asian countries where prevalence of this debilitating disease is relatively more. But treatment of OSMF has been clearly inadequate owing to its multifactorial pathogenesis and evaluation of the merits and disadvantages of individual drugs has been difficult because of empirical nature of the approach.
This systematic review opines that future research trials should be reported strictly adhering to the CONSORT guideline to ensure high quality research especially in terms of randomization and blinding of the subjects for better results. Further the effect of drug on progression of the OSMF can be assessed by using various classifications present in literature based on signs and symptoms of OSMF. However, this systematic review stresses the need of consensus among investigators for the various clinical criteria used to assess OSMF so that significant evidence of a particular treatment modality like antioxidant could be achieved in future review designs. Table 1:-Showing inclusion and exclusion criteria used for screening of title / abstracts INCLUSION CRITERIA-1.

Conflicts of interest -NONE
Randomised clinical trials which mention the use of antioxidants for management of OSMF on human subjects.

2.
Randomised clinical trials in the management of OSMF which include a group intervened with systemic antioxidants by random allocation.

3.
Randomised clinical trials in which effect of systemic antioxidants on signs and symptoms of OSMF could be clearly / separately identified. EXCLUSION CRITERIA-1.
Publications written in languages other than English.

2.
Review articles on management of OSMF.

3.
Non-randomised studies on management of OSMF.