Description of the condition
Recurrent aphthous stomatitis (RAS) is the most common form of oral ulceration with a prevalence in the general population ranging between 5% and 60% (Jurge 2006). It is characterised by recurrent oral mucosal ulceration in an otherwise healthy individual (Porter 1998). The peak age of onset is between 10 and 19 years of age (Ship 2000), and it can persist into adulthood and throughout the patient's lifespan, with no age, gender or cultural preference (Ship 2000).
According to Bagan 1991, there are three recognised forms of RAS.
- Minor aphthae - typically round and less than 10 mm in diameter. These are generally pale in colour with an erythematous border and commonly affect non-keratinised mucosa including the labial and buccal mucosa, the borders of the tongue, and the floor of the mouth. Minor aphthae can occur in isolation but multiple presentations are also common. Healing is spontaneous and usually takes 7 to 10 days. Episodes of ulceration are usually followed by an ulcer-free period lasting a few days to several weeks before the next episode occurs (Thornhill 2007). Minor aphthae account for 80% of patients with RAS (Thornhill 2007).
- Major aphthae are similar to minor aphthae but are larger, usually exceeding 10mm in diameter and deeper. Consequently healing can take longer (20 to 30 days) and may result in scarring (Bagan 1991).
- Herpetiform ulcers are less than 1 mm in diameter and often occur in multiples from 1 to 100. There is a tendency for adjacent ulcers to merge to form a large affected area. Healing takes place within 15 days and can result in scarring (Bagan 1991).
The aetiopathogenesis of RAS is multifactorial (Jurge 2006). Some patients have a genetic predisposition, with at least 40% of patients having a positive family history (Sircus 1957). In a review of the literature, Jurge 2006 suggests that a bacterial or viral aetiology is unlikely and that the immunopathogenesis of the disease is most likely to involve a cell-mediated immune response mechanism involving the generation of T-cells, interleukins and tumour necrosis factor (TNF) (Natah 1998; Sun 2000). However, a lymphocyte-mediated mechanism in addition to immune complexes have also been proposed (Jurge 2006), and cross-reactivity between streptococci and the oral mucosa has been demonstrated (Lehner 1991). Local factors can predispose patients to RAS and physical trauma can initiate ulcers in susceptible people (Wray 1981), but RAS is uncommon in patients who smoke tobacco (Salonen 1990). Reduced iron storage has also been reported in 37% of patients (Porter 1993), and psychological illness has also been postulated but this has not been substantiated (Miller 1977).
Patients with systemic diseases are also prone to oral ulceration but these manifestations may be secondary to their medical condition and so they should be considered separately. These can include, but are not limited to, coeliac disease, vitamin B12 deficiency, iron deficiency anaemia, human immunodeficiency virus infection/acquired immunodeficiency syndrome (HIV/AIDS), cyclic neutropenia, Reiter's syndrome, Behçet's Disease (Baccaglini 2011).
For clarity, if there is no associated systemic disease, this will be described as 'RAS'. When the ulceration may be associated with an underlying systemic disease, then this will be described as 'RAS type ulceration'.
Description of the intervention
Treatment is primarily aimed at pain relief and the promotion of healing to reduce the duration of the disease or reduce the rate of recurrence. A variety of topical and systemic therapies have been utilised (Porter 1998), but few studies have demonstrated efficacy. Empirically, effective treatments include the use of corticosteroids, immunosuppressants and topical barriers (Eisen 2001). Mycophenolate mofetil, pentoxyphylline, colchicine, dapsone and thalidomide have also been used but with some caution due to the potential for adverse effects. The cause of RAS is not known therefore the aims of treatment are primarily pain relief and the reduction of inflammation (Scully 2006).Topical interventions can include mouthrinses, pastes, gels, sprays, injections, laser and locally dissolving tablets. Many treatments are available for patients to buy without prescription.
How the intervention might work
As the aetiopathogenesis of aphthous ulceration is not fully understood, the precise mode of action of topical interventions is unclear. Topical interventions range from inert barriers to active treatments. Providing a barrier for the ulcer (for example a mucoadhesive paste) should allow the breach in the mucosa to temporarily be protected and therefore noxious stimulants are less likely to sensitise nerve endings. This in theory should provide pain relief. The addition of active compounds to the barrier can potentially give an immunomodulatory effect. Due to the nature of the mucosal layer, there is great variability in the penetration of active compounds through the mucosal barrier, and as such there is great variability as to the efficacy of such topical treatments.
Why it is important to do this review
All three clinical types of RAS are associated with varying degrees of morbidity, including pain and difficulties in function. RAS is a chronic episodic oral mucosal condition which can impact upon the experiences of daily life, such as physical health and functioning (Riordain 2011). Given, its high prevalence, the prevention of RAS or the reduction of the pain or longevity of the disease are important goals in oral medicine. This review will focus on the use of topical interventions in the management of RAS and complements the Cochrane systematic review of systemic interventions for the management of RAS by the same author team (Brocklehurst 2012).
The objectives of this review are to determine the clinical effectiveness and safety of topical interventions in the reduction of pain associated with recurrent aphthous stomatitis, a reduction in episode duration, a reduction in episode frequency and improved quality of life.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) investigating the effects of topical interventions for the management of recurrent aphthous ulcers. We will also include RCTs of a cross-over design, provided that the trial included a suitable washout period and no carry-over effects were evident. Split-mouth studies will also be included if it is apparent that there is no risk of contamination of the intervention from one part of the mouth to another. This will be more likely for the topical interventions which are a physical barrier.
Types of participants
Participants with a previous or current history of recurrent aphthous stomatitis (RAS), diagnosed either clinically or histopathologically. We will exclude participants with the following conditions:
- Behçet's disease;
- Reiter's syndrome;
- recurrent erythema multiforme or any viral infection.
In addition, we will exclude patients with coeliac disease, Crohn's disease, ulcerative colitis, anaemia and haematinic deficiency (vitamin B12, folic acid and iron), when sufficient detail is provided in the trial. This will ensure that patients entering into a trial are for primary lesions, not lesions that are secondary to a medical condition. We will also exclude participants taking medications associated with oral ulceration e.g. nicorandil, diclofenac.
Types of interventions
Active treatment will include any preventive, palliative or curative interventions administered topically (i.e. where the primary mode of action is topical, acknowledging that some of the topical interventions may also have systemic effect). Controls will be either no active treatment or the administration of a placebo, but head to head trials of different interventions will also be included, if identified.
Types of outcome measures
Primary outcome measures assessed will be:
- pain associated with RAS;
- episode duration associated with RAS;
- episode frequency associated with RAS;
- safety of the intervention including adverse effects.
Any patient reported outcomes that measure improvements in the patients' quality of life and reduction in morbidity (e.g. function).
Search methods for identification of studies
For the identification of studies included or considered for this review, we will develop detailed search strategies for each database searched. These were based on the search strategy developed for MEDLINE (OVID) but revised appropriately for each database (Appendix 1). We will combine this search strategy with the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials in MEDLINE: sensitivity maximising version as referenced in Chapter 18.104.22.168 and detailed in box 6.4.c of theCochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will link the search of EMBASE to the Cochrane Oral Health Group filter for identifying RCTs.
The following electronic databases will be searched:
- the Cochrane Oral Health Group's Trials Register (to present);
- the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, current issue);
- MEDLINE via OVID (1946 to present);
- EMBASE via OVID (1980 to present);
- CINAHL via EBSCO (1980 to present);
- AMED via OVID (1985 to present).
Searching other resources
We will screen the bibliographies of included papers and relevant review articles will be checked for studies not identified by the search strategies above. We will search the US National Institutes of Health Trials Register (http://clinicaltrials.gov/) for ongoing trials.
Any non-English trials that are identified will be translated through The Cochrane Collaboration.
Data collection and analysis
Selection of studies
Three review authors (Paul Brocklehurst (PB), Anne-Marie Glenny (AMG) and Jennifer Taylor (JT)) will independently screen the titles and abstracts obtained from the initial electronic searches. Reports from the studies that fulfil the inclusion criteria will be obtained. When there are insufficient data in the study title to determine whether a study fulfils the inclusion criteria, the full report will be obtained and assessed independently by the same review authors. Disagreement will be resolved by discussion.
Data extraction and management
At least two review authors (JT, AMG, Tanya Walsh (TW), PB, Philip Riley (PR), Julian Yates (JY)) will independently extract data from each included study using a tool developed for the review. All studies meeting the inclusion criteria will undergo data extraction and an assessment of risk of bias will be made using a pre-standardised data extraction form. Studies rejected at this and subsequent stages will be recorded in the table of excluded studies. Differences will be resolved by discussion. If a single publication reports two or more separate studies, then the data from each study will be extracted separately. If the findings of a single study are spread across two or more publications, then the publications will be extracted as one. For each study with more than one control or comparison group for the intervention, the results will be extracted for each intervention arm.
For each trial the following data will be recorded.
- Year of publication, country of origin and source of study funding.
- Details of the participants including demographic characteristics and criteria for inclusion.
- Details on the type of intervention and comparisons.
- Details on the study design.
- Details on the outcomes reported, including method and timings of assessments, and adverse outcomes.
Assessment of risk of bias in included studies
All review authors will assess the risk of bias in included studies using The Cochrane Collaboration's tool for assessing risk of bias. The domains that will be assessed for each included study will be:
- sequence generation;
- allocation concealment;
- completeness of outcome data;
- selective outcome reporting;
- risk of other potential sources of bias.
We will tabulate a description of the above domains for each included trial, along with a judgement of on the risk of bias (low, high or unclear), based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011):
- low risk of bias (adequate concealment of the allocation (e.g. sequentially numbered, sealed, opaque envelopes or centralised or pharmacy-controlled randomisation));
- unclear risk of bias (unclear about whether the allocation was adequately concealed (e.g. where the method of concealment is not described or not described in sufficient detail to allow a definite judgement));
- high risk of bias (inadequate allocation concealment (e.g. open random number lists or quasi-randomisation such as alternate days, date of birth, or case record number)).
We will provide a summary assessment of the risk of bias for the primary outcome across the studies (Higgins 2011). For each study, we will assess according to the following rationale:
- low risk when there is a low risk of bias across all six key domains;
- unclear risk of bias when there is an unclear risk of bias in one or more of the six key domains;
- high risk of bias when there is a high risk of bias in one or more of the six key domains.
Measures of treatment effect
For dichotomous outcomes (e.g. pain or adverse effects: yes/no), we will express the estimate of effect of an intervention as risk ratios (RRs) together with 95% confidence intervals (CIs). For continuous outcomes (e.g. pain on a visual analogue scale), we will use mean differences (MDs) and 95% CIs to summarise the data; in the event that different studies measure outcomes using different scales, we will express the estimate of effect of an intervention as standardised mean differences (SMDs) and 95% CIs.
Unit of analysis issues
Where cluster randomised trials are included, we will undertake data analysis, whenever feasible, at the same level as the randomisation, or at the individual level accounting for the clustering.
Analysis of cross-over studies should take into account the two-period nature of the data using, for example, a paired t-test. We will enter log RRs or MDs/SMDs and standard errors into Review Manager software (Review Manager 2013), using the generic inverse variance method (Higgins 2011).
Dealing with missing data
We will contact trial authors for missing data if the report was published from the year 2000 or onwards. We consider it unfeasible to obtain data for trials published prior to this cut-off date. We will use methods as outlined in the Cochrane Handbook for Systematic Reviews of Interventions to estimate missing standard deviations (Higgins 2011).
Assessment of heterogeneity
We will assess the significance of any discrepancies in the estimates of the treatment effects from the different trials by means of Cochran's test for heterogeneity; heterogeneity will be considered significant if P value < 0.1 (Higgins 2011). We will also use the I
Assessment of reporting biases
If there are a sufficient number of trials (more than 10) included in any meta-analysis, we will assess publication bias according to the recommendations on testing for funnel plot asymmetry as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
We will perform meta-analysis of studies assessing the same comparisons and outcomes. We will combine RRs for dichotomous outcomes, and MDs (or SMDs if different scales are used) for continuous outcomes, using a random-effects model where there are four or more studies, or a fixed-effect model if there are less than four studies. We will include data from cross-over studies in any meta-analysis using the generic inverse variance method described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), combining them with parallel studies using the methods described in Elbourne 2002. We will present data from studies not included in meta-analyses in an additional table.
Subgroup analysis and investigation of heterogeneity
As appropriate, we will pursue subgroup analysis according to the three classifications of RAS highlighted above: minor, major and herpetiform.
If the number of studies allows, we will undertake a sensitivity analysis for each intervention and outcome limiting the analysis to studies at overall low risk of bias.
Presentation of main results
We will develop a 'Summary of findings' table for the main outcomes of this review using the GRADEPro software (GRADEpro 2008). We will assess the quality of the body of evidence with reference to the overall risk of bias of the included studies, the directness of the evidence, the inconsistency of the results, the precision of the estimates, the risk of publication bias and the magnitude of the effect. We will categorise quality of the body of evidence of each of the main outcomes as high, moderate, low or very low.
The review authors would like to thank all the previous contributors to the original protocol, particularly Paolo Prolo and Zbys Fedorowicz.
Appendix 1. MEDLINE (OVID) search strategy
- Stomatitis, aphthous/
- (recur$ or reoccur$ or severe).ti,ab.
- 1 and 2
- ((recur$ or reoccur$ or severe) adj10 ((aphthous or apthous or mouth$ or oral$) adj3 (ulcer$ or lesion$ or stomatitis))).ti,ab.
- (aphthae or apthae).ti,ab.
- "canker sore$".ti,ab.
- "herpetiform ulcer$".ti,ab.
- "periadenitis mucosa necrotica recurrens".ti,ab.
Contributions of authors
Development of protocol based on the latest Cochrane guidance: Jennifer Taylor (JT), Philip Riley (PR), Paul Brocklehurst (PB), Mike Lewis (ML), Mike Pemberton (MP), Anne-Marie Glenny (AMG), Tanya Walsh (TW), Martin Tickle (MT).
Identification of studies: JT, PB, AMG.
Data extraction: JT, PB, AMG, TW, Julian Yates (JY), PR.
Assessment of risk of bias: JT, PB, AMG, TW, JY, PR.
Data input/synthesis: JT, PB, AMG, TW, JY, PR.
Writing of conclusions: JT, PB, MT, TW, ML, MP, AMG, JY, PR.
Declarations of interest
There are no financial conflicts of interest and the review authors declare that they do not have any associations with any parties who may have vested interests in the results of this review.
Sources of support
- MAHSC, UK.The Cochrane Oral Health Group is supported by the Manchester Academic Health Sciences Centre (MAHSC) and the NIHR Manchester Biomedical Research Centre.
- The University of Manchester, UK.
- Central Manchester University Hospitals NHS Foundation Trust, UK.
- National Institute for Health Research (NIHR), UK.CRG funding acknowledgement:
The NIHR is the largest single funder of the Cochrane Oral Health Group.Disclaimer:
The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.
- Cochrane Oral Health Group Global Alliance, UK.All reviews in the Cochrane Oral Health Group are supported by Global Alliance member organisations (British Association of Oral Surgeons, UK; British Orthodontic Society, UK; British Society of Paediatric Dentistry, UK; British Society of Periodontology, UK; Canadian Dental Hygienists Association, Canada; National Center for Dental Hygiene Research & Practice, USA; Mayo Clinic, USA; New York University College of Dentistry, USA; and Royal College of Surgeons of Edinburgh, UK) providing funding for the editorial process (http://ohg.cochrane.org/).