Comparative Efficacy of Dexamethasone, Doxycycline, Nystatin and Promethazine With Triamcinolone in Orabase as Symptomatic Treatment of Oral Lichen Planus, A Randomized Controlled Trial

Introduction Oral lichen planus (OLP) is a chronic inflammatory mucocutaneous autoimmune disease mainly affecting stratum basal of the epithelium. It is T-cell mediated immunological disease that mostly occurs bilaterally on buccal mucosa while tongue and gingiva are other commonly involved sites while palatal mucosa and floor of the mouth are rarely affected (Roopashree MR, 2010, Torrente-Castells et al., 2010, Alves et al, 2010). The prevalence of OLP in general population is 0.1-4% (Sugerman et al., 2002) mainly affecting the middle-aged and elderly people (Ingafou et al., 2006) and female: male ratio 2:1 (Shen et al., 2012).

It has six clinical forms: keratotic, reticular, papular, plaquelike white patches, erosive, atrophic, and bullous (Shen et al., 2012). Reticular and erosive form are most common (Alves et al, 2010). Keratotic reticular, papular, plaque like white patches often present with no complaints (Oczko et al, 2011), while erosive, atrophic, and ulcerative lesions are a painful or present with a burning sensation, and thus make eating, speaking, and swallowing difficult (Thongprasom et al., 2007). Histologically, a subepithelial infiltration in the form of dense band of lymphocytes, increased numbers of intraepithelial lymphocytes and the liquefaction degeneration of basal keratinocytes is seen in OLP (Payeras et al., 2013).

Several predisposing factors have been identified which may cause or progress OLP which include immunity, infection, genetics, stress and endocrine. Recent researches showed an increased activity of prolidase and oxidative stress in OLP patients, causing disturbance in the antioxidant defense system (Batu et al, 2016, Ergun et al, 2011). Although the exact cause is still not clear, facts show that an immunological process is involved in OLP which is activated by an unknown antigen that change the basal keratinocytes of the oral mucosa and these alterations cause the cell immune response to attack the keratinocytes. (Ismail et al., 2007, Payeras et al., 2013). This antigen may be intrinsic or extrinsic, or both. Evidence shows that bacteria can be one of the etiologic factors of OLP. An association has already been found between OLP and infection, such as Ebstein Barr virus, Hepatitis C virus, Helicobacter pylori and Candida Albicans. A study also pointed out the allergy to various antigens coming in direct contact with oral cavity to contribute to the etiology of OLP. (D. Wray, 2000) As the etiology is not known therefore there is no definitive treatment for OLP and the mainstay of therapy for improving the life of these patients is symptomatic topical treatment. Topical treatments which have been tried for the symptomatic OLP include topical corticosteroids (TCSs), including betamethasone, clobetasol, dexamethasone and triamcinolone; topical calcineurin inhibitors (TCIs) such as pimecrolimus, tacrolimus or ciclosporin; retinoids such as tretinoin; photochemotherapy; amitryptaline; thalidomide; amlexanox and traditional medicines such as curcumin, selenium-ACE combined with itraconazole, glycyrrhiza glabra and aloe vera.

In a study both tacrolimus 0.1% ointment and pimecrolimus 1% cream were found equally effective for the treatment of OLP (Vohra et al., 2016). Similarly another study showed that Clobetasol propionate (0.05%) was found more effective than triamcinolone acetonate (0.1%) and tacrolimus orabase (0.03%) for the management of OLP. This study also found that triamcinolone 0.1% is superior to tacrolimus 0.03% in terms of effectiveness for the treatment of OLP.(Sivaraman et al., 2016) According to another study both triamcinolone and curcumin paste were found almost equally effective in reducing the pain and improving the appearance of OLP lesions (Kia et al., 2015). In another study it was concluded that combination of Selenium-ACE, corticosteroid and antifungal is a better treatment regimen for the treatment of erosive ulcerative OLP than a capsule of 100 mg Itraconazole plus dexamethsone mouthwash or dexamethasone alone (Belal, 2015). In another similar study cocktail of clobetasol, ketoconazole and amitryptiline was found more efficacious than diluted dexamethasone, nystatin and Diphenhydramine elixir (Javadzadeh et al, 2008). In a comparative study tacrolimus 0.1% cream was found more effective than 0.05% clobetasol propionate cream in reducing pain and healing of OLP lesions (Hettiarachchi et al., 2016). Both thalidomide and dexamethasone were found almost equally effective in another trail (Wu et al., 2010). In a trail of comperison between amlexanox paste and dexamethasone paste both were found equally effective at the end of 7 days in terms of reduction in clinical signs (erosion) and symptoms like pain and burning sensation (Fu et al., 2012). Some herbal medicines have also been tried like Glycyrrhiza glabra and Aloe vera, in a trail to compare the efficacy of 1% Glycyrrhiza glabra In orabase with 0.1% Triamcinolone Acetonide both were found almost equally effective in reducing the pain and improving the appearance of OLP lesions (Najafi et al., 2016) and in another trail both Aloe Vera Mouthwash and Triamcinolone Acetonide were found almost equally effective in reducing the pain and in reducing the size of OLP lesions (Mansourian et al., 2011) So steroids remained the mainstay of treatment for OLP but evidence points towards the involvement of bacterial and fungal infections in the pathogenesis of OLP as according to a recent study disbiosis was found in the buccal surface mucosa of patients of OLP, as certain bacterial species were found in greater no in buccal mucosa of OLP patients so they concluded that an association exists between bacterial disbiosis of buccal mucosa and OLP (He et al., 2017). Similar studies showed that antibiotics relieved symptoms of OLP effectively (Backman & Jontell, 2007; Carbone et al, 1999). OLP is a disease which reduces the individual's resistance and changes the candida albican's role from commensalism to parasitism which is among the normal flora of oral cavity or candida may secondarily infect the OLP lesions and exacerbate the signs and symptoms (santosh gowdru shivanandappa, 2012). In a study 62% of OLP patients were found allergic to different allergens which come in contact with mucosa in daily life so they found that association exists between OLP and allergy (D. Wray, 2000). According to another study mast cell hyperplasia was seen in OLP patients which suggests their role in pathogenesis of OLP (Ankle R et al, 2007) The most used therapy is TCSs however its effectiveness is limited due to opportunistic oral infections in patients with OLP. Adjunct antibiotic therapies have been used to aid in symptomatic relief and improved response has been observed as compared to TCSs alone. however none of the combined therapies have used antifungal as an additive in their local applications, as candida is one of the opportunistic organisms that colonizes affected sites. Role of allergy mechanisms have also been discussed.

Rationale Evidence of involvement of bacterial and fungal infections and allergy in the pathogenesis of OLP suggests the need for the use of antibiotic, anti fungal and antihistamine for the topical treatment of OLP and there is a gap in literature. That's why current trail is being done to evaluate the efficacy of topical doxycycline, nyastatin and promethazine along with dexamethasone for the symptomatic relief of OLP.