Annals and Essences of Dentistry

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1 /aedj A POTENT REGIMEN FOR ORAL LICHEN PLANUS: A REVIEW 1 Tejaswi Katne 2 Anantha Venkata Srikar Muppirala 3 Rama Raju Devaraju 4 Ramlal Gantala 1 Post graduate student 2 Post graduate student 3 Professor and Head 4 Professor 1-4 Department of Oral Medicine and Radiology S.V.S Institute of Dental Sciences Telangana India ABSTRACT: Background:Oral lichen planus (OLP) is a chronic inflammatory disease that affects oral mucosa. Substantial fluctuation is seen between the patients in response to various treatments posing difficulty for the physician in management of the disease. Aim: To assess efficacy of any form of intervention used to manage oral lichen planus. Materials and methods: All the published randomised control trials from 2000 to 2016 in the management of OLP, comparing active interventions with or without placebo irrespective of age, gender were selected from Cochrane central register of controlled trials, CENTRAL, EMBASE and MEDLINE were included in the study, and SWOT analysis was performed. Results and conclusion: Thirty two randomised control trials using different drug interventions were included in this systematic review. The superiority of corticosteroids in remission of clinical signs of OLP is evident, though with few side effects. Future research with consistent parameters and newer formulations, directed towards personalised medicine are required in a quest of the potent regime to treat this condition. KEYWORDS: Lichen planus, drug therapy, topical steroids. INTRODUCTION Oral lichen planus is a chronic inflammatory T-cell mediated autoimmune disease with unclear aetiology. 1 The conception in pathogenesis of Oral lichen planus has been continuously changing from earlier era to recent times from initial concept of inflammation to immunological mediated reaction then followed by the idea of autoimmune mediated reaction to present genetic concept. Accordingly the treatment strategies have been continuously kept on changing to the present day. 2 Various treatment regimens have been tried to improve the lesions and to reduce the pain but a cure for OLP has not been found because of lack of an apparent cause and its recalcitrant nature. Purpose of the present systematic review was to evaluate the efficacy and safety of interventions in the treatment of OLP. Materials and methods All the published randomised control trials from 2000 to 2016 in the management of lichen planus comparing active interventions with or without placebo, irrespective of age, gender having symptomatic OLP and histopathological confirmation were included and selected from Cochrane central register of controlled trials CENTRAL, EMBASE, MEDLINE, Cochrane oral health trials register using key words lichen planus, oral lichen planus, randomised control trials oral lichen planus, steroids oral lichen planus, drug therapy oral lichen planus and SWOT analysis was performed. Study characteristics All the included studies in this systematic review were randomised control trials. The total number of participants included in the trials was 2073, with a mean of 65 subjects 7c per study. All the studies included were performed in a secondary care except for one (yoke 2006), which was a multi-centre study. Diagnosis of oral lichen planus was confirmed clinically and histopathologically in all except in one study (Malhotra 2008). Results and discussion A randomised cross over study on 48 subjects was done by Buajeeb (2000) to compare the efficacy of Flucinolone acetonide gel 0.1% in two base forms ( carbopol 1% and 0.5%) and Flucinolone acetonide in oral base 0.5% for 4 weeks and concluded that both drugs provided similar efficacy in the treatment but there was no statistical significance. 3 Study on 48 subjects using fluticasone propionate spray (50µg aqueous solution) and beta methasone sodium phosphate mouth rinse (0.5 mg tab in 10 ml of water) for 6 weeks with intervening washout with 0.15% benzydamine hydrochloride was carried out by Hegarty (2002) and concluded that both are effective in the management but fluticasone spray is easily accepted by the patients and recurrence is noticed in 4 subjects within the treatment period. 4 Efficacy and compliance of new lipid microspheres loaded with 0.025% of Clobetasol propionate (Formulation A) with commonly used formulation (a sort of dispersion of a lipophilic ointment in a hydrophilic phase) with the same amount of drug. (Formulation B) on 50 subjects for 2 months was evaluated by Campisi (2004) and concluded that Formulation A was effective and superior in terms of

2 symptom remission and compliance and recurrence was noticed in five patients receiving Formulation B. 5 Effectiveness of Clobetasol (0.025%) and cyclosporine (1.5%) was compared on 40 subjects by Conrotto (2006) in terms of long term remission of symptoms and cost effectiveness for 2 months and stated that Clobetasol is more effective than cyclosporine in inducing clinical improvement and gives less stable results with higher incidence of side effects in a follow up of 2 months. Cyclosporine is cost effective (five times higher than that of Clobetasol). 6 A study on 139 subjects was done by Yoke (2006) to compare the effectiveness of cyclosporine solution with triamcinolone acetonide in oral base for 8 weeks. Pain, burning sensation, area of reticulation erythema, ulceration were all worse in patients receiving cyclosporine by the end of 4 th week and concluded that topical cyclosporine is no more effective than steroid. 7 Topical tacrolimus (0.1%) was compared with triamcinolone acetonide (0.1%)in hypromellose 20% ointment by Laeijendecker(2006) on 40 subjects (20 in each group) for 6 weeks and results were in favour of topical tacrolimus(0.1%) which induced a better initial therapeutic response than triamcinolone but relapses occurred within 3-9 weeks of cessation of treatment. 8 Effectiveness of isotretinoin 0.18% with most frequently used isotretinoin 0.05% concentration was evaluated on 70 subjects for 3 months by Scardina (2006) and concluded that isotretinoin 0.18% was superior and effective in disappearance of dysplastic phenomena than 0.05%. 9 Study was conducted on 13 subjects by Thongprasom (2007) to compare the effectiveness of cyclosporine solution with triamcinolone acetonide 0.1% in orabase for 8 weeks and concluded that topical cyclosporine was not effective than triamcinolone acetonide and more side effects were noticed in patients receiving cyclosporine. 10 Efficacy of curcuminoids capsules (2000mg/day) for 7 weeks and prednisone 60mg/day for 1 st week on 33 subjects were evaluated by Chainani Wu (2007) which stated that curcuminoids at this dose were well tolerated but this study ended early for futility. 11 Efficacy of 1% pimecrolimus for 4 weeks on 12 subjects was done by Passeron (2007) and concluded that pimecrolimus seems to be effective and well tolerated treatment but with minimal side effects and relapse of the treatment was seen in 1 month follow up. 12 Forty subjects were evaluated to compare the efficacy and safety of pimecrolimus 1% cream with triamcinolone acetonide 0.1% for 2 months by Gorouhi (2007) drawing to a conclusion that both the drugs were effective in the management but with minimal side effects noticed with pimecrolimus in 2 months of follow up. 13 Effect of Clobetasol propionate with and without topical anti-fungal drug for 6 weeks on 35 subjects was carried by Lodi (2007) which stated that addition of miconazole significantly have not affected the signs and symptoms except in preventing iatrogenic candidiasis. 14 Study on 49 subjects was done to evaluate the efficacy and safety of betamethasone (5 mg) oral mini pulse therapy with triamcinolone acetonide 0.1% paste for 6 months by Malhotra (2008) and concluded that both are equally effective but response is earlier with betamethasone oral mini pulse therapy and relapse of the treatment was seen in half of the patients with more side effects. 15 In a study conducted by Radfar (2008), the effectiveness of Clobetasol (0.05%) and tacrolimus (0.1%) was evaluated. Regimen was used for 6 weeks on 30 subjects divided in 2 groups and summarized that the latter is superior and is more effective than Clobetasol. 16 Thirty two subjects were evaluated by Corrocher (2008) to compare the efficacy of tacrolimus 0.1% and Clobetasol 0.05% for 4 weeks and result was in favour of tacrolimus with low symptom scores and is more effective than Clobetasol. 17 Efficacy of Aloe Vera with placebo for 8 weeks on 54 subjects was carried out by Choonhakaran (2008) which stated that Aloe Vera is more effective than placebo and can be considered as a safe alternative treatment with no side effects. 18 Efficacy of pimecrolimus 1% cream (Elidel) with vehicle for 30 days on 20 subjects was evaluated by Volz (2008) drawing to a conclusion that pimecrolimus is more effective and no severe adverse reactions were reported in one month follow up. 19 Thirty subjects were evaluated to know the efficacy of Ignatia with placebo for 4 months by Mousavi (2009) which stated that Ignatia has beneficial effects. 20 One hundred and twenty four subjects were included in a study by Nolan (2009) to evaluate the efficacy of 0.2% hyaluronic acid and placebo for 28 days and concluded that 0.2% hyaluronic acid was effective in reducing size of the lesion and providing efficacy for up to 4 hrs after administration and can be useful addition to the treatment option for oral lichen planus. 21 Carbone (2009) conducted a randomized, doubleblind, placebo-controlled trial to compare the efficacy and safety of two different formulations of Clobetasol, in the topical management of OLP and to evaluate the remission from signs and symptoms. Thirty-five patients were divided into two groups: the first received clobetasol propionate 0.025% and the second was given clobetasol propionate 0.05%. In all, 14 of the 15 clobetasol 0.025% patients (93%) and 13 of the 15 clobetasol 0.05% patients (87%), had symptoms improvement after 2 months of therapy (P = in both groups). Also, 13 of the 15 clobetasol 0.025% patients (87%) and 11 of the 15 clobetasol 0.05% patients (73%) had clinical improvement after 2 months of therapy (P < 0.05 in both groups). No statistical differences were found in comparing the two different formulations. 22 8c

3 The efficacy of intralesional injection of 0.5ml BCG-PSN and 10mg triamcinolone acetonide was evaluated by Xiong (2009), in 56 patients for 2 weeks. The intralesional BCG-PSN injection is equally effective and can be a promising therapeutic alternative for erosive OLP, especially for those insensitive, or even resistant, to glucocorticoids. 23 Wu (2010) conducted a study on 69 subjects to evaluate short term efficacy and safety of thalidomide (1%) and dexamethasone (0.043%) for 3 weeks. In conclusion, thalidomide appears as effective as dexamethasone with recurrence seen in 3 month follow up and adverse effects at 1 year. 24 The efficacy of aloe vera was evaluated by Salazar- Sanchez (2010) in a study on 64 subjects, in comparison with placebo for 12 weeks and concluded that aloe vera improves total quality of life scores with no adverse effects. 25 In a 4 week study on 46 subjects by Mansourian (2011), compared the therapeutic effects of aloe vera mouth wash with triamcinolone acetonide (0.1%) for and concluded that aloe vera mouth wash is an effective substitute for triamcinolone acetonide. 26 Sawaarn (2011) assessed in 30 subjects, the efficacy of systemic lycopene 8mg/day against placebo for 8 weeks. The study concluded that lycopene is very effective in reducing the oxidative stress, which may have a role in the disease pathogenesis. 27 Mc Caughey (2011) conducted a study on 21 subjects to assess the efficacy of topical pimecrolimus 1% with placebo for 6 weeks. Pimecrolimus 1% was found superior to vehicle in reducing symptoms but with no side effects. 28 Fu (2012) in a study on 38 subjects evaluated the efficacy of amlexanox paste with dexamethasone paste for 7 days. Here, the topical application of amlexanox appeared as effective as dexamethasone with no serious side effects. 29 Sonthalia (2012) piloted an 8 week study on 40 subjects, to relate the efficacy of clobetasol propionate 0.05% with tacrolimus 0.1%. The results disclosed that the latter is effective and can be considered as first line of therapy with no adverse effects. 30 An 8 week study on 40 subjects was conducted by Lee (2013), to compare the efficacy between intralesional injection (0.5 ml) and mouth rinse of triamcinolone acetonide (0.4%). It concluded that efficacies of both the treatments were similar but rate of adverse effects was significantly lower for intralesional injection of triamcinolone acetonide than mouth rinse. 31 Mu guard (5ml) was found effective in reducing pain and ulceration associated with oral mucositis in comparison to saline bicarbonate, in a study by Velez (2014), conducted on 20 subjects. 32 Efficacy of topical curcumin and triamcinolone was evaluated in 50 subjects by Sied Javad Kia (2015). The 4 week study concluded that curcumin is effective because of its desirable anti-inflammatory effects and insignificant side effects. 33 Siva Raman (2016) compare the effectiveness of topical triamcinolone acetonide (0.1%), clobetasol (0.05%) and tacrolimus Orabase (0.03%) in the management. thirty subjects were included in this study which concluded that clobetasol propionate has higher efficacy when compared to triamcinolone acetonide and tacrolimus with no side effects. It was also inferred that triamcinolone acetonide 0.1% has better effects than tacrolimus 0.03%. 34 Numerous therapies have been considered. All the above included trials have used different interventions, comparisons, dosages, vehicles, time of application and different ways of measuring the common outcomes such as pain and clinical symptoms. Of the 32 included trials eleven trials compared an active intervention with placebo. Two active treatments were compared in thirteen trials and in eight studies same intervention was compared in different concentrations. Seven studies same intervention was compared at different concentrations. Twelve trials out of 32 have compared eight different active treatments with placebo. Not all the trials using steroids showed evidence that these treatments were better than placebo in reducing pain and lesional size of oral lichen planus. Studies conducted by Choonhakaran (2008) 18 and Salazar-Sanchez (2010) 25 have shown that aloe Vera gel may be associated with a reducing pain in OLP patients. Three trials of pimecrolimus have shown that it is better than placebo. Of them, the study by Volz (2008) 19 had a very short period of follow up and another study by McCaughy (2011) 28 had no post treatment follow up. Nolan (2009) 21 has shown weak evidence of trials using hyaluronic acid and Mousavi (2009) 20 using Ignatia. These both trials may be effective in reducing pain and clinical signs of OLP. Sawaarn (2011) 27 have conducted trial on lycopene which showed significant reduction in pain compared to placebo. Velez (2014) 32 saw significant reductions in MuGuard treated group despite of several limitations of the trial such as short span of study, head to head comparisons with steroids and Calcineurin inhibitors in management of OLP which makes it debatable. Six trials out of 32 have compared with different steroid treatments. Study by Campisi (2004) 5 showed microspheres while another trial by Malhotra (2008) 15 showed betamethasone to be effective in reducing pain. Study by Hegarty (2002) 4 has shown lesional surface area reduction favouring spray. However all the three trials were at high risk and no statistical difference was seen in other three studies. Seven trials out of 32 have compared steroids with Calcineurin inhibitors, each evaluating a different pair of intervention. Study by Corrocher (2008) 17 and Sonthalia (2012) 30 favoured tacrolimus in terms of pain reduction. Corrocher (2008) 17 was the only study with significant difference. Study by Laeijendecker (2006) 8 favoured Calcineurin in terms of clinical improvement. However studies conducted by Thongprasom 10, Radfar 16, Gorouhi 13, Sonthalia 30 have found no statistical difference in clinical response between steroid and Calcineurin inhibitor. Seven trials comparing two active interventions (excluding steroids and Calcineurin inhibitors) didn t show evidence that any of these interventions may be effective 9c

4 in reducing pain and clinical signs of OLP, except for two trials i.e. Buajeeb (2000) 3 and Scardina (2006) 9. Although several trials have been conducted with various medicaments, studies on personalised medicine are scarce. Future research should be focussed on identifying the defective protein and treatment is directed towards it. We are identifying the single nucleotide polymorphism (SNP) thus providing the matching medication. SNPs like rs , rs , rs6323, rs etc were identified in few cases of OLP. The efficacy of Clobetasol propionate, cyclosporine, curcumin and tretinoin drugs were evaluated against these protiens. Cyclosporine in these samples showed poor efficacy, while other were superior which is backing with the literature. Further insilico studies with phase are needed to direct management further competently. CONCLUSION OLP is an autoimmune mucocutaneous disorder, where the management is still empirical. With this systematic review, an attempt was made to establish various therapeutic modalities in OLP, taking into consideration only randomized control trials, using evidence based medicine analysis. Literature confirms the frequent use of topical corticosteroids, which remains the main stay in this condition, few indicated use of calcineurin inhibitors for treatment & symptomatic relief. The evidence of the trials suggests the superiority of corticosteroids in alleviating pain and remission of clinical signs of OLP with few side effects. Further studies on large scale, future research with consistent parameters and newer formulations, also the research directed towards personalised medicine are required in a quest of the potent regime to treat this condition. References: 1. Scully C, Eisen D, Carrozzo M. Management of oral lichen planus. Am J Clin Dermatol. 2000;1: Gupta S, Jawanda MK. 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5 20. Mousavi F, Sherafati S, Mojaver YN. Ignatia in the treatment of oral lichen planus. Homeopathy. 2009;98: Nolan A, Badminton J, Maguire J, Seymour AR. The efficacy of topical hyaluronic acid in the management of oral lichen planus. J Oral Pathol Med. 2009;38: Carbone M, Arduino GP, Carrozzo M, Caiazzo G, Broccoletti R, Conrotto D, et al. Topical clobetasol in the treatment of atrophic-erosive oral lichen planus: a randomized controlled trial to compare two preparations with different concentrations. J Oral Pathol Med. 2009;38: Xiong C, Li Q, Lin M, Li X, Meng W, Wu Y, et al. The efficacy of topical intralesional BCG-PSN injection in the treatment of erosive oral lichen planus: a randomized controlled trial. J Oral Pathol Med. 2009;38: Wu Y, Zhou G, Zeng H, Xiong C, Lin M, Zhou H, et al. A randomized double-blind, positive-control trial of topical thalidomide in erosive oral lichen planus. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2010;110: Salazar-Sanchez N, Lopez-Jornet P, Camacho- Alonso F, Sanchez-Siles M. Efficacy of topical Aloe Vera in patients with oral lichen planus: a randomized double-blind study. J Oral Pathol Med. 2010;39: Mansourian A, Momen-Heravi F, Saheb-Jamee M, Esfehani M, Khalilzadeh O, Momen-Beitollahi J. Comparison of Aloe vera mouthwash with triamcinolone acetonide 0.1% on oral lichen planus: a randomized double-blinded clinical trial. Am J Med Sci. 2011;342(6): Sawaarn N, Shashikanth MC, Sawaarn S, Jirge V, Chaitanya CSKN, Pinakapani R. Lycopene in the management of oral lichen planus: A placebo controlled study. IJDR. 2011;22(5): McCaughey C, Machan M, Bennett R, Zone JJ, Hull CM. Pimecrolimus 1% cream for oral erosive lichen planus: a 6-week randomized, double-blind, vehiclecontrolled study with a 6-week open-label extension to assess efficacy and safety. J Eur Acad Dermatol Venereol. 2011;25: Fu J, Zhu X, Dan H, Zhou Y, Liu C, Wang F, et al. Amlexanox is as effective as dexamethasone in topical treatment of erosive oral lichen planus: a shortterm pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2012;113: Sonthalia S, Singal A. Comparative efficacy of tacrolimus 0.1% ointment and clobetasol propionate 0.05% ointment in oral lichen planus: a randomized double-blind trial. Int J Dermatol. 2012;51: Lee YC, Shin SY, Kim SW, Eun YG. Intralesional injection versus mouth rinse of triamcinolone acetonide in oral lichen planus: a randomized controlled study. Otolaryngol Head Neck Surg. 2013;148: Velez I, Spielholz NI, Siegel MA, Gonzalez T, MuGuard, an oral muco adhesive hydrogel, reduces the signs and symptoms of oral mucositis in patients with lichen planus: a double-blind, randomized, placebo-controlled pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2014;118: Kia SJ, Shirazian S, Mansourian A, Khodadadi FL, Ashnagar S. Comparative Efficacy of Topical Curcumin and Triamcinolone for Oral Lichen Planus: A Randomized, Controlled Clinical Trial. J Dent (Tehran). 2015;12(11): Siva Raman S, Santham K, Nelson A, Laliytha B, Azhalvel P, Deepak JH. A randomized triple-blind clinical trial to compare the effectiveness of topical triamcinolone acetonate (0.1%), clobetasol propionate (0.05%), and tacrolimus Orabase (0.03%) in the management of oral lichen planus. J Pharm Bio all Sci. 2016;8:S86-9. Corresponding Author Dr. Tejaswi Katne Post Graduate student Department of Oral Medicine and Radiology S.V.S Institute of Dental sciences Telangana, India Ph No Id: tejaswikatne@gmail.com 11c