Interventions for the management of oral ulcers in Behçet's disease

  • Protocol
  • Intervention



This is the protocol for a review and there is no abstract. The objectives are as follows:

The objectives of this review are to determine the clinical effectiveness and safety of interventions in the pain, episode duration and episode frequency of oral ulcers and any change in the quality of life for patients with aphthous-type ulceration associated with Behçet's disease.


Description of the condition

Behçet's disease is a chronic, relapsing, multisystem, inflammatory vasculitis (Chams-Davatchi 2010). It affects both the large and small vessels (including veins and arteries) (Mat 2013). It is characterised by a multitude of systemic signs and symptoms. Oral and genital ulcerations, skin lesions, uveitis, and inflammatory vascular involvement of the central nervous system and gastrointestinal tract are common (Dalvi 2012). Although the aetiology of Behçet’s disease is unknown it is thought to involve a genetic predisposition combined with environmental factors (Yazici 2012).

The genetic risk factor most strongly associated with Behçet's disease is the human leukocyte antigen (HLA)-B51 allele. HLA-B51 occurs in around 60% of Behçet's disease patients (Gul 2007; Kose 2012; Yazici 1980).

Behçet's disease is more frequent in the countries along the 'Silk Road', an ancient trading route, where the prevalence of HLA-B51 is relatively high compared with the other parts of the globe (Yurdakul 2010). The prevalence is high in Turkey (> 1/1000).

Behçet's disease most commonly presents in the third decade. The disease is rare in individuals older than age 50 years and during childhood. Although both sexes are equally affected, it is thought that the disease has a more severe course amongst men aged less than 25 (Yazici 1984).


Previously, the International Guidelines for the Classification of Behçet's Disease were generally accepted as a diagnostic tool (ISG 1990).

The criteria included recurrent oral 'aphthae' (at least three episodes within 12 consecutive months) plus two of the following: recurrent, genital ulcers; uveitis or retinal vasculitis; skin lesions that are classified as erythema nodosum (EN)-like lesions, acneiform lesions, pustulosis, or pseudofolliculitis; and a positive pathergy test.

More recently a large group involving 32 countries attempted to establish new international guidelines (IGBD). Following a prospective, international, multicentre diagnostic accuracy study, data from over 2556 Behçet's patients were reviewed from 27 different countries. A new diagnostic scoring system was developed. As in the previous diagnostic criteria, oral lesions scored highly along with ocular and genital lesions. In fact 98% of Behçet's patients had oral aphthous ulceration as a feature (Davatchi 2004).

Oral ulceration in Behçet's disease

The oral ulceration that occurs in Behçet's disease resembles recurrent aphthous stomatitis (RAS). In the oral medicine and dental literature RAS is now commonly used as a term to indicate a primary condition where ulceration is not in association with a systemic disease such as Behçet's. Where a relevant systemic disease is present, the term RAS-type ulceration would be used instead. In the general medical literature however, this division of nomenclature is not widely used and, in appearance and natural history, the oral ulceration in Behçet's is indistinguishable from RAS. It remains unclear whether the ulceration in RAS and RAS-type ulceration shares a common pathogenesis.

Recurrent aphthous stomatitis is the most common form of oral ulceration with prevalence in the general population ranging between 5% and 60% (Jurge 2006).

RAS-type ulceration in association with a systemic disease is common. Systemic diseases featuring oral ulceration 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, systemic lupus erythematosus (SLE) and Behçet's disease (Baccaglini 2011).

The frequency of RAS-type ulceration in Behçet's disease is 97% to 100% (Yurdakul 2008).

According to Bagan 1991, there are three recognised forms of RAS (and hence also RAS-type ulceration).

  1. 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).

  2. Major aphthae are similar to minor aphthae but are larger, usually exceeding 10 mm in diameter and deeper. Consequently healing can take longer (20 to 30 days) and may result in scarring (Bagan 1991).

  3. 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.

In Behçet's disease, minor aphthae-type lesions are the most commonly seen type, whereas major and herpetiform types are rare (Hamuryudan 1998; Melikoglu 2005; Yurdakul 2001.).

Description of the intervention

The cause of RAS is not known; therefore the aims of treatment are primarily pain relief and the reduction of inflammation (Scully 2006). The cause of oral ulceration in Behçet's disease is also poorly understood and therefore treatment of the oral ulceration 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).Topical interventions can include mouthrinses, pastes, gels, sprays, injections, laser and locally dissolving tablets. Many of the topical treatments are available without prescription. Systemic immunomodulators such as mycophenolate mofetil, pentoxyphylline, colchicine, dapsone and thalidomide have also been used but with some caution due to the potential for adverse effects.

How the intervention might work

As the aetiopathogenesis of aphthous-type ulceration in Behçet's disease is not fully understood, the precise mechanisms by which the various topical and systemic treatments may affect the disease process are unclear.

Topical interventions for oral ulceration 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.

Systemic interventions include immunomodulators (colchicine, azathioprine, cyclosporin, thalidomide), corticosteroids, biological agents (interferon, anti-TNF agents - infliximab, etanercept, adalimumab) and other drugs such as dapsone and daclizumab. As previously stated, the precise mode of action of these interventions is often unclear.

Many of the systemic treatments used in Behçet's disease are given for life threatening systemic complications, and not primarily for the oral ulceration. Nevertheless, these systemic treatments may also improve the severity and frequency of episodes of aphthous-type ulceration in these patients.

Why it is important to do this review

All three clinical types of RAS and RAS-type ulceration are associated with varying degrees of morbidity, including pain and difficulties in function. RAS (and RAS-type ulceration) is a chronic episodic oral mucosal condition which can impact upon the experiences of daily life, such as physical health and functioning (Riordain 2011).

A recent Cochrane review (Brocklehurst 2012) evaluated the evidence for the systemic interventions for RAS and an ongoing review by the same author group is evaluating the topical interventions for RAS (Taylor 2013). Both of these reviews have specifically excluded trials of interventions for oral ulcers in systemic disease. This therefore excludes trials involving Behçet's patients.

There is therefore a population of patients in whom oral ulcers are the most common presenting feature and for whom we have no formal evaluation of the evidence base on which to guide our clinical treatments for them. An evaluation of the evidence for interventions for oral ulcers in this group of patients is therefore essential.


The objectives of this review are to determine the clinical effectiveness and safety of interventions in the pain, episode duration and episode frequency of oral ulcers and any change in the quality of life for patients with aphthous-type ulceration associated with Behçet's disease.


Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) investigating the effects of interventions for the management of recurrent aphthous ulcers in Behçet's disease will be included. We will also include RCTs of a cross-over design, provided that the trial includes a suitable washout period and no carry-over effects are 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 any topical interventions which are a physical barrier rather than a mouthwash for example.)

Studies looking at interventions for the management of Behçet's disease which also report on oral ulcers as an outcome measure will also be included. The oral outcome measures should be pre-specified in the methodology.

Types of participants

Participants with Behçet's disease with a history of recurrent aphthous-type ulcers diagnosed clinically will be included. Where additional systemic diseases are reported in studies, these will be noted.

Types of interventions

Active treatment will include any preventive, palliative or curative interventions administered systemically or topically. 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 outcomes
  1. Pain associated with oral ulcers.

  2. Episode duration associated with oral ulcers.

  3. Episode frequency associated with oral ulcers.

  4. Safety of the intervention including adverse effects.

Secondary outcomes

Any patient-reported outcomes that measure a change in the patients' quality of life or change in morbidity (e.g. function) or both.

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 will be 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 and detailed in box 6.4.c of the Cochrane 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.

Electronic searches

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).

There will be no restrictions on language or date of publication in the searches of the electronic databases.

Searching other resources

Unpublished trials

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 following databases for ongoing trials:

Data collection and analysis

Selection of studies

Two review authors (Jennifer Taylor (JT) and Anne-Marie Glenny (AMG)) 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), Paul Brocklehurst (PB) and Philip Riley (PR)) 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.

  1. Year of publication, country of origin and source of study funding.

  2. Details of the participants including demographic characteristics and criteria for inclusion.

  3. Details on the type of intervention and comparisons.

  4. Details on the study design.

  5. 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.

  1. Sequence generation.

  2. Allocation concealment.

  3. Blinding.

  4. Completeness of outcome data.

  5. Selective outcome reporting.

  6. 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 the risk of bias (low, high or unclear), based on the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011):

  1. low risk of bias (adequate concealment of the allocation (e.g. sequentially numbered, sealed, opaque envelopes or centralised or pharmacy-controlled randomisation));

  2. 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));

  3. 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 the overall risk of bias according to the following rationale:

  1. low risk when there is a low risk of bias across all six key domains;

  2. unclear risk of bias when there is an unclear risk of bias in one or more of the six key domains;

  3. high risk of bias when there is a high risk of bias in one or more of the six key domains.

If high risk of bias is present in one of the six domains then it will take precedence.

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 (Elbourne 2002). We will enter log RRs or MDs/SMDs and standard errors into Review Manager (RevMan) software (Review Manager 2012), 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 I2 statistic, which describes the percentage total variation across studies that is due to heterogeneity rather than chance, to quantify heterogeneity with I2 over 50% being considered substantial heterogeneity (Higgins 2011).

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).

Data synthesis

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.

Sensitivity analysis

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.


Appendix 1. MEDLINE (OVID) search strategy

1. Behcet syndrome/
2. (Behcet adj2 (syndrome$ or disease)).ti,ab.
3. ("triple-complex syndrome$" or "triple-complex disease$").ti,ab.
4. or/1-3
5. Stomatitis, aphthous/
6. ((aphthous or apthous or mouth$ or oral$) adj3 (ulcer$ or lesion$ or stomatitis)).ti,ab.˜
7. (aphthae or apthae).ti,ab.
8. "canker sore$".ti,ab.
9. "herpetiform ulcer$".ti,ab.
10. "periadenitis mucosa necrotica recurrens".ti,ab.
11. or/5-10
12. 4 and 11

The above subject search will be linked with the Cochrane Highly Sensitive Search Strategy (CHSSS) for identifying randomised trials in MEDLINE: sensitivity maximising version (2008 revision) as referenced in Chapter and detailed in box 6.4.c of theCochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0 [updated March 2011] (Higgins 2011).

1. randomized controlled
2. controlled clinical
3. randomized.ab.
4. placebo.ab.
5. drug therapy.fs.
6. randomly.ab.
7. trial.ab.
8. groups.ab.
9. or/1-8
10. exp animals/ not
11. 9 not 10

Contributions of authors

Development of protocol based on the latest Cochrane guidance: Jennifer Taylor (JT), Philip Riley (PR), Paul Brocklehurst (PB), Mike Pemberton (MP), Anne-Marie Glenny (AMG), Tanya Walsh (TW), and Rachel Gorodkin (RG).

Identification of studies: JT, AMG.

Data extraction: JT, PB, AMG, TW, PR.

Assessment of risk of bias: JT, PB, AMG, TW, PR.

Data input/synthesis: JT, PB, AMG, TW, PR.

Writing of conclusions: JT, PB, TW, MP, AMG, PR, RG.

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

Internal sources

  • 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.

External sources

  • 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 (

  • National Institute for Health Research (NIHR), UK.

    CRG funding acknowledgement:
    The NIHR is the largest single funder of the Cochrane Oral Health Group.

    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.