Recurrent Oral Ulcers: current and future therapeutic approaches
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Polytechnical University of Marche, Department of Clinical Specialistic and Dental Sciences, Italy
Oral ulcers are a common complaint consisting in focal defects in the oral mucosa. Clinically, oral ulcers can be classified in: acute ulcers, if lasts less than 2 weeks; chronic ulcers, if lasts for 2 weeks or longer; and recurrent oral ulcers (ROU), characterized by recurring episodes with intermittent healing. ROU comprise a wide and heterogeneous group of conditions sharing the clinical feature of intermittent oral lesions (Figure 1).
The main causes of ROU are typical recurrent lesions, such as recurrent aphthous stomatitis (RAS), Behçet's Disease (BD), and recurrent herpes stomatitis. There are also several clinical conditions in which patients may report ROU, but only if these conditions undergo periods of remission, such as trauma, adverse drug reactions, and nutrition deficiencies. The aim of this oral communication is to investigate therapeutic protocols of RAS and BD, since there are the only two diseases for which there is a significant amount of clinical studies.
RAS is a common oral condition characterized by shallow, rounded, painful ulcers, with inflammatory halos that recur at intervals of a few days or up to 3 months. RAS is conventionally classified by clinical features in: minor aphthae (MiRAS), major aphthae (MjRAS), and herpetiform ulcerations (HeRAS). MiRAS is the most common form (80%), characterized by round, small (<10 mm), and superficial ulcers that disappear in 10-14 days without leaving scars. MjRAS is less common (10-15%), but clinically more aggressive. In this form, the ulcers are larger (>10 mm) and persist for a long period, leaving scars. HeRAS is the less common form (5-10%), consisting in small and multiple ulcers that resemble ulcers of Herpes simplex virus. Indeed, the first use of the term aphthai in relation to oral disorders is credited to Hippocrates, although it is likely that he used it in describing the lesions of thrush. Only in 1888 a German physician, von Mikulicz-Radecki, described MiRAS as a nosological entity (Mikulicz aphthae). Regarding the other two morphological forms of RAS, as well as BD, clinical descriptions were published by several authors in 20th century (Figure 2).
BD is a rare, multisystemic, relapsing, inflammatory disease, included in the group of systemic vasculitis. It is more common in Turkey and East Asia; thus, it is also known as “Silk Road disease”. The classic clinical triad of BD consists of: oral ulcer, genital ulcer, and ocular manifestations. Two different study groups (International Study Group for BD, 1990; International Criteria for BD, 2006) proposed criteria for the diagnosis of the disease. For this presentation, it is important to stress that ROU are present in almost all patients with BD and are clinically similar to RAS. Considering the transitory nature of these lesions, the main therapeutic objectives are: pain management, reduction of frequency of recurrence, and increase wound healing speed, with no/ little side-effects.
In the last decades, more than 60 different pharmaceutical products have been tested. Among these, topical corticosteroids may speed the healing of ulcers and reduce pain. Patient response is variable, depending on the potency of the active ingredient. The main side effect is an increased risk of developing oral candidiasis. Among nonsteroidal drugs, Amlexanox is a topical anti-inflammatory molecule used to treat RAS. Several studies reported to be effective in reducing pain and lesion size, and it is most effective if applied in the “prodromal” phase. Systemic corticosteroids and immunomodulatory drugs, such as Levamisole and Thalidomide, have been used in patients with severe and non-responding ROU to reduce the frequency duration and severity of mucosal lesions. However, serious side effects limit their use. Antimicrobial agents that have been tested in patients with RAS include antibiotics and antiseptics (e.g. chlorhexidine). Topical use of sub-antimicrobial dose of tetracyclines (e.g. minocycline, doxycycline) seems to have anti-collagenase activity and immunomodulatory effect, showing potential benefits in RAS. Chlorhexidine 0.2% oral rinse is one of the most commonly prescribed agents in patients with a complaint of ROU. Among the “barrier effect” drugs, Sucralfate and Rebamipide are known agents that have been successfully used in the treatment of peptic ulcer disease. For this reason, these drugs seem to provide a protective barrier on the surface of oral ulcers. Low-level laser therapy (LLLT) is a low intensity light therapy that is applied to treat RAS because of its potential beneficial effects, including pain relief and wound healing. Currently, several clinical trials about different types of lasers (e.g. Nd:YAG, Er:YAG, InGaAlP, GaAlAs, etc.) are reported in the use for treatment of RAS, suggesting therapeutic utility of LLLT. Specific subsets of patients with RAS have vitamin deficiencies, suggesting a role of these molecules in the pathogenesis of oral ulcers. Daily vitamin B12 supplementation seems to be effective for patients with RAS, regardless of the serum vitamin B12 level. On the contrary, daily multivitamin supplementation in patients with RAS did not result in a reduction in the number or duration of oral ulcer episodes. Recent studies suggest a potential therapeutic role of a daily omega-3 regimen in the management of RAS. Natural herbal medicine has been widely used as therapy for RAS in many countries for centuries. Today, herbal medicine is becoming increasingly popular and accepted worldwide, and several studies were conducted in patients with RAS. However, the results are still too uncertain to draw firm conclusions about the efficacy of herbal products to treat ROU. Among other therapeutic strategies, the use of a mouthguard for preventing RAS development and the use of ozone applications on oral ulcers have been proposed.
A variety of topical and systemic treatments have been proposed, such as mouthrinses, gels, pastes, and lasers, but few studies have demonstrated efficacy in the management of ROU. For this reason, several systematic reviews have been conducted with the aim to determine the clinical effectiveness and safety of topical and systemic interventions in the treatment of oral ulcers in RAS and BD.
In 2012, Brocklehurst et al. conducted a Cochrane review to determine the clinical effectiveness of systemic interventions in RAS (Brocklehurst et al., 2012). A total of 25 trials were included (22 placebo controlled and 8 head-to-head comparisons trials) and the drug tested were grouped into “immunomodulatory/anti-inflammatory” and “uncertain” groups. The results showed high risk of bias in most studies, mainly due to poor methodological rigour, and no single systemic treatment was proved to be effective in RAS. In 2014, Taylor et al. conducted a Cochrane review to determine the clinical effectiveness and safety of topical and systemic treatments for ROU associated with BD (Taylor et al., 2014). A total of 15 trials were included, grouped into two categories: topical and systemic treatments. The results showed high risk of bias in most studies, and quality of the evidence ranged from moderate to very low. For these reasons, there was insufficient evidence to support or refute the use of any included treatment. In 2016, Han et al. conducted a systematic review to evaluate the clinical effectiveness and security of LLLT in patients with RAS (Han et al., 2016). A total of 10 trials were included, in which comparison between LLLT and placebo or conventional drug therapy were performed. The results showed that, although LLLT seems to be a promising effective treatment for RAS, the complexity of treatment protocols choosing (e.g. wavelength, power density, pulse structure, treatment timing, etc.) has led to insufficient evidence to support or refute this new treatment. Finally, in 2016, Li et al. conducted a systematic review to evaluate the efficacy and safety of topical treatment with natural herbal medicines in patients with RAS (Li et al., 2016). A total of 13 trials were included, in which 12 different types of herbal medicine (8 traditional Chinese and 4 Iranian products) in different pharmaceutical formulations (gargles, powders, tablets, etc.) were used. The methodological quality of the studies was very poor, due to lack of well-designed randomized clinical trials. Furthermore, the heterogeneity of the studies was large, due to several types of treatment, dosage, formula, application method, and experiment duration. For these reasons, there is no evidence regarding the efficacy of the topical herbal medicines in RAS.
In conclusion, a definitive treatment protocol for RAS remains inconclusive, and there is no therapy to prevent the recurrence of oral ulcers (Figure 3). Topical therapy is considered for patients who experience multiple episodes of RAS and/or present with symptoms that affect the quality of life. Amlexanox paste or topical steroids preparations are the first line of treatment for RAS. Other topical agents may be chlorhexidine and antimicrobial mouthwash. Systemic therapy is currently debated and should be reserved only for severe and non-responding ROU. Regarding the future perspectives in treatment of ROU, well-designed and high-quality randomized clinical trials are strongly required. Furthermore, new pathophysiological aspects of ROU must be more deeply studied, such as the role of microbiota or genetic predisposition, through the use of high-throughput sequencing technologies. The use of biologic drugs, such as anti-TNF-alpha agents, needs to be further studied in randomized clinical trials in patients with non-responding ROU. Finally, new pharmaceutical formulation must be developed, with the aim to optimize local drug delivery for oral mucosa.
References
1. Brocklehurst, P., Tickle, M., Glenny, A.M., Lewis, M.A., Pemberton, M.N., Taylor, J., Walsh, T., Riley, P., and Yates, J.M. (2012). Systemic interventions for recurrent aphthous stomatitis (mouth ulcers). Cochrane Database Syst Rev, CD005411.
2. Taylor, J., Glenny, A.M., Walsh, T., Brocklehurst, P., Riley, P., Gorodkin, R., and Pemberton, M.N. (2014). Interventions for the management of oral ulcers in Behcet's disease. Cochrane Database Syst Rev, CD011018.
3. Han, M., Fang, H., Li, Q.L., Cao, Y., Xia, R., and Zhang, Z.H. (2016). Effectiveness of Laser Therapy in the Management of Recurrent Aphthous Stomatitis: A Systematic Review. Scientifica (Cairo) 2016, 9062430.
4. Li, C.L., Huang, H.L., Wang, W.C., and Hua, H. (2016). Efficacy and safety of topical herbal medicine treatment on recurrent aphthous stomatitis: a systemic review. Drug Des Devel Ther 10, 107-115.
Keywords:
Recurrent oral ulcers,
Recurrent aphthous stomatitis (RAS),
Behçet's disease (BD),
Topical treatments,
systemic treatments
Conference:
5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine., Ancona, Italy, 19 Oct - 20 Oct, 2018.
Presentation Type:
oral presentation
Topic:
Oral Diseases
Citation:
Mascitti
M and
Santarelli
A
(2019). Recurrent Oral Ulcers: current and future therapeutic approaches.
Front. Physiol.
Conference Abstract:
5th National and 1st International Symposium of Italian Society of Oral Pathology and Medicine..
doi: 10.3389/conf.fphys.2019.27.00093
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Received:
27 Nov 2018;
Published Online:
09 Dec 2019.
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Correspondence:
Dr. Marco Mascitti, Polytechnical University of Marche, Department of Clinical Specialistic and Dental Sciences, Ancona, Italy, marcomascitti86@hotmail.it