Aphthous ulcers (recurrent)

Abstract

Introduction

Most people with recurrent aphthous ulcers develop a few ulcers less than 10 mm in diameter that heal after 7 to 10 days without scarring. The causes are unknown but local physical trauma may trigger ulcers in susceptible people. In 10% of sufferers, lesions are more than 10 mm in diameter and can cause scarring.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical question: What are the effects of selected topical treatments for recurrent idiopathic aphthous ulcers? We searched: Medline, Embase, The Cochrane Library, and other important databases up to December 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found nine studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review we present information relating to the effectiveness and safety of the following interventions: analgesics (local), corticosteroids (topical), tetracycline antibiotic mouthwash, and topical antiseptic agents (chlorhexidine and similar agents).

Key Points

Recurrent aphthous ulcers are the most common cause of recurrent oral ulceration in otherwise-healthy individuals.

Most people with recurrent aphthous ulcers develop a few ulcers less than 10 mm in diameter that heal after 7 to 10 days without scarring.

• In 10% of sufferers, lesions are more than 10 mm in diameter and can cause scarring.

• The majority of aphthous ulcers are idiopathic, although factors such as local physical trauma may trigger ulcers in susceptible people.

Chlorhexidine mouth rinses may reduce the severity and pain of ulceration, although studies have reported inconclusive results about whether the incidence of new ulcers is reduced.

Topical corticosteroids may reduce the number of new ulcers, reduce pain, and increase healing of ulcers without causing notable adverse effects.

We don't know whether local analgesics or tetracycline mouthwash work, as evidence was weak.

Clinical context

General background

Recurrent aphthous ulcers are the most common cause of recurrent oral ulceration. They are painful and usually occur in recurrent bouts at intervals of a few days to a few months. Up to 66% of young adults give a history consistent with recurrent aphthous ulceration. The frequency of recurrent aphthous ulceration lessens with advancing age.

Focus of the review

This update focuses on the evidence base for selected topical treatments used for idiopathic recurrent aphthous ulceration. Topical treatments, in general terms, are safer than systemic interventions and are considered as a first-line treatment for recurrent aphthous ulceration.

Comments on evidence

This systematic review highlighted inconclusive evidence-based results with regard to the best topical intervention for recurrent aphthous ulceration. Consideration needs to be given that, in clinical practice, different topical treatments may appear to be effective in individual patients despite the paucity of evidence to substantiate the treatment’s efficacy. Hence, the lack of evidence may simply reflect either the absence of studies for certain therapies or inadequate study design and/or implementation combined with the multifactorial nature of recurrent aphthous ulceration.

Search and appraisal summary

The updated literature search for this review was carried out from the date of the last search, August 2006 to December 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 153 studies. After deduplication and removal of conference abstracts, 109 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 100 studies and the further review of nine full publications. Of the nine full articles evaluated, two RCTs were added at this update.

Additional information

In future updates, we would like to consider other topical interventions such as barrier techniques (i.e., inactive preparations that put a lining on ulcers), topical immunosuppressant agents (e.g., tacrolimus), topical calcineurin inhibitors, and homeopathic topical treatments.

About this condition

Definition

Recurrent aphthous ulcers (RAU) are superficial, rounded, painful mouth ulcers usually occurring in recurrent bouts at intervals of a few days to a few months in otherwise-well people. They are the most common cause of recurrent oral ulceration and may be classified as minor (<10 mm), major (>10 mm) or herpetiform aphthous ulcers.

Incidence/ Prevalence

The point prevalence of recurrent aphthous ulcers in Swedish adults has been reported as 2%. Prevalence may be 5% to 10% in some groups of children. Up to 66% of young adults give a history consistent with recurrent aphthous ulceration. Frequency of RAU lessens with advancing age.

Aetiology/ Risk factors

The majority of aphthous ulcers are idiopathic with no known cause identified, although, factors such as local physical trauma may trigger ulcers in susceptible people. Recurrent aphthous ulcers are uncommon on keratinised oral mucosal surfaces or with people who smoke tobacco. Aphthous-like ulcers may develop secondary to systemic diseases such as Behçet’s disease, coeliac disease, inflammatory bowel disease, and haematinic deficiencies, or to drugs such as non-steroidal anti-inflammatory drugs (NSAIDS). Only idiopathic RAU are considered in this review.

Prognosis

Minor recurrent aphthous ulcers typically involve non-keratinised oral mucosa, are less than 10 mm in diameter, and persist over a 7 to 10 day period. Spontaneous healing without scarring is generally followed by a variable ulcer-free period and recurrence of the ulceration. The minor variant accounts for 80% of patients with RAU. Major recurrent aphthous may involve both keratinised and non-keratinised oral mucosa, may exceed 10 mm in diameter, may persist for 20 to 30 days, and heal with scarring. Herpetiform ulcers present as multiple (ranging from 1–100) pinpoint ulcers involving either keratinised or non-keratinised mucosa with the potential for these ulcers to merge into a larger area of ulceration. Most of the trials in this review have focused on the treatment of minor aphthous ulceration.

Aims of intervention

To reduce the severity of the episode and the incidence, duration, and pain of ulceration with minimal adverse effects.

Outcomes

Ulcer severity includes Ulcer Day Index (the sum of the number of ulcers each day over a period, usually 4–8 weeks, which indicates the severity of the episode and reflects the mean prevalence and duration of ulcers), number of ulcer-free days during a specified period, duration of ulceration (mean duration of individual ulcers, which is difficult to determine because of uncertainty in detecting the point of complete resolution), size of ulcer, severity of pain (symptom score based on subjective pain severity recorded in categories on a questionnaire [e.g., from 0–3, ranging from no pain to severe pain] or on a 10 cm visual analogue scale); incidence of new ulcers number of new ulcers appearing within a specified period, usually 4 to 8 weeks; adverse effects. The diameter of lesions is a proxy measure of the clinical severity of an episode of ulceration.

Methods

BMJ Clinical Evidence search and appraisal December 2013. The following databases were used to identify studies for this review: Medline 1966 to December 2013, Embase 1980 to December 2013, and The Cochrane Library, issue 11, 2013. Additional searches were carried in the Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA) database. We also searched for retractions of studies included in this review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts of potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were published RCTs and systematic reviews, at least single-blinded, and containing more than 20 individuals (or 10 in a crossover trial), of whom more than 80% were followed up. There was no minimum follow-up. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Aphthous ulcers (recurrent).

Important outcomes	Occurrence of new ulcers, Ulcer severity
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of selected topical treatments for recurrent idiopathic aphthous ulcers?
1 (18)	Ulcer severity	Benzydamine hydrochloride mouthwash compared with placebo	4	–2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
13 (685)	Ulcer severity	Topical corticosteroids versus placebo	4	–2	0	0	0	Low	Quality points deducted for incomplete reporting of results and uncertainty about methodology
5 (217)	Occurrence of new ulcers	Topical corticosteroids versus placebo	4	–2	0	0	0	Low	Quality points deducted for incomplete reporting of results and uncertainty about methodology
1 (30)	Ulcer severity	Tetracycline antibiotic mouthwash versus placebo	4	–3	0	–2	0	Very low	Quality points deducted for sparse data, incomplete reporting of results, and uncertainty about randomisation; directness points deducted for uncertainty of reporting outcomes and single application of treatment in 1 RCT
3 (70)	Ulcer severity	Chlorhexidine versus placebo	4	–3	–1	–1	0	Very low	Quality points deducted for sparse data, poor follow-up, and incomplete reporting of results; consistency point deducted for conflicting results; directness point deducted for uncertainty about benefit of treatment
3 (70)	Occurrence of new ulcers	Chlorhexidine versus placebo	4	–3	–1	–1	0	Very low	Quality points deducted for sparse data, poor follow-up, and incomplete reporting of results; consistency point deducted for conflicting results; directness point deducted for uncertainty about benefit of treatment
1 (37)	Ulcer severity	Hexetidine compared with placebo	4	–3	0	–1	0	Very low	Quality points deducted for sparse data, poor follow-up, and incomplete reporting of results; directness point deducted for uncertainty about benefit of treatment
1 (37)	Occurrence of new ulcers	Hexetidine compared with placebo	4	–3	0	–1	0	Very low	Quality points deducted for sparse data, poor follow-up, and incomplete reporting of results; directness point deducted for uncertainty about benefit of treatment
1 (96)	Ulcer severity	Proprietary antibacterial rinse compared with control	4	–3	0	–2	0	Very low	Quality points deducted for poor follow-up, incomplete reporting of results, no intention-to-treat analysis, and uncertainty about method of randomisation; directness point deducted for uncertainty about disease severity in population and benefit from treatment
1 (96)	Occurrence of new ulcers	Proprietary antibacterial rinse compared with control	4	–3	0	–2	0	Very low	Quality points deducted for poor follow-up, incomplete reporting of results, no intention-to-treat analysis, and uncertainty about method of randomisation; directness points deducted for uncertainty about disease severity in population and benefit from treatment

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

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