Interventions for treating oral lichen planus: corticosteroid therapies
Abstract
Background
Oral lichen planus (OLP) is a relatively common chronic T cell‐mediated disease, which can cause significant pain, particularly in its erosive or ulcerative forms. As pain is the indication for treatment of OLP, pain resolution is the primary outcome for this review. This review is an update of a version last published in 2011, but focuses on the evidence for corticosteroid treatment only. A second review considering non‐corticosteroid treatments is in progress.
Objectives
To assess the effects and safety of corticosteroids, in any formulation, for treating people with symptoms of oral lichen planus.
Search methods
Cochrane Oral Health's Information Specialist searched the following databases to 25 February 2019: Cochrane Oral Health's Trials Register, CENTRAL (2019, Issue 1), MEDLINE Ovid, and Embase Ovid. ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. There were no restrictions on language or date of publication.
Selection criteria
We considered randomised controlled clinical trials (RCTs) of any local or systemic corticosteroid treatment compared with a placebo, a calcineurin inhibitor, another corticosteroid, any other local or systemic (or both) drug, or the same corticosteroid plus an adjunctive treatment.
Data collection and analysis
Three review authors independently scanned the titles and abstracts of all reports identified, and assessed risk of bias using the Cochrane tool and extracted data from included studies. For dichotomous outcomes, we expressed the estimates of effects of an intervention as risk ratios (RR), with 95% confidence intervals (CI). For continuous outcomes, we used mean differences (MD) and 95% CI. The statistical unit of analysis was the participant. We conducted meta‐analyses only with studies of similar comparisons reporting the same outcome measures. We assessed the overall certainty of the evidence using GRADE.
Main results
We included 35 studies (1474 participants) in this review. We assessed seven studies at low risk of bias overall, 11 at unclear and the remaining 17 studies at high risk of bias. We present results for our main outcomes, pain and clinical resolution measured at the end of the treatment course (between one week and six months), and adverse effects. The limited evidence available for comparisons between different corticosteroids, and corticosteroids versus alternative or adjunctive treatments is presented in the full review.
Corticosteroids versus placebo
Three studies evaluated the effectiveness and safety of topical corticosteroids in an adhesive base compared to placebo. We were able to combine two studies in meta‐analyses, one evaluating clobetasol propionate and the other flucinonide. We found low‐certainty evidence that pain may be more likely to be resolved when using a topical corticosteroid rather than a placebo (RR 1.91, 95% CI 1.08 to 3.36; 2 studies, 72 participants; I² = 0%). The results for clinical effect of treatment and adverse effects were inconclusive (clinical resolution: RR 6.00, 95% CI 0.76 to 47.58; 2 studies, 72 participants; I² = 0%; very low‐certainty evidence; adverse effects RR 1.48, 95% 0.48 to 4.56; 3 studies, 88 participants, I² = 0%, very low‐certainty evidence).
Corticosteroids versus calcineurin inhibitors
Three studies compared topical clobetasol propionate versus topical tacrolimus. We found very low‐certainty evidence regarding any difference between tacrolimus and clobetasol for the outcomes pain resolution (RR 0.45, 95% CI 0.24 to 0.88; 2 studies, 100 participants; I² = 80%), clinical resolution (RR 0.61, 95% CI 0.38 to 0.99; 2 studies, 52 participants; I² = 95%) and adverse effects (RR 0.05, 95% CI 0.00 to 0.83; 2 studies, 100 participants; very low‐certainty evidence) .
One study (39 participants) compared topical clobetasol and ciclosporin, and provided only very low‐certainty evidence regarding the rate of clinical resolution with clobetasol (RR 3.16, 95% CI 1.00 to 9.93), pain resolution (RR 2.11, 95% CI 0.76 to 5.86) and adverse effects (RR 6.32, 95% CI 0.84 to 47.69).
Two studies (60 participants) that compared triamcinolone and tacrolimus found uncertain evidence regarding the rate of clinical resolution (RR 0.86, 95% CI 0.55 to 1.35; very low‐certainty evidence) and that there may be a lower rate of adverse effects in the triamcinolone group (RR 0.47, 95% CI 0.22 to 0.99; low‐certainty evidence). These studies did not report on pain resolution.
Authors' conclusions
Corticosteroids have been first line for the treatment of OLP. This review found that these drugs, delivered topically as adhesive gels or similar preparations, may be more effective than placebo for reducing the pain of symptomatic OLP; however, with the small number of studies and participants, our confidence in the reliability of this finding is low. The results for clinical response were inconclusive, and we are uncertain about adverse effects. Very low‐certainty evidence suggests that calcineurin inhibitors, specifically tacrolimus, may be more effective at resolving pain than corticosteroids, although there is some uncertainty about adverse effects and clinical response to tacrolimus showed conflicting results.
PICOs
Plain language summary
Corticosteroids for treating oral lichen planus
Review question
Are corticosteroids effective and safe for the treatment of oral lichen planus that is causing pain?
Background
Oral lichen planus is a common condition that can cause long‐term, painful areas on the lining of the mouth. Usual treatment is with drugs known as corticosteroids applied directly to the painful areas (topically), or taken internally (systemically). Treatment aims to reduce pain and improve healing of the mouth, but there is no cure for the disease.
Study characteristics
The evidence in this review is up‐to‐date as of 25 February 2019. We included 35 randomised controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) with 1474 participants, which tested several different corticosteroids, mostly delivered topically (on the skin). Corticosteroids were compared with one of the following: a placebo (a treatment that resembled the corticosteroid but had no active ingredient); a medicine from a category called calcineurin inhibitors; another medicine type; another corticosteroid or mode of delivery; the same corticosteroid plus an extra treatment; or an alternative treatment. Treatments were given for between one week and six months, with side effects measured throughout the treatment, and pain and healing measured at the end of treatment.
Key results
Results from two studies showed that topical corticosteroids (e.g. clobetasol propionate, flucinonide, betamethasone and triamcinolone acetonide), when applied to the mouth in a sticky cream, may be effective in reducing and stopping pain. We do not have the evidence that topical corticosteroids can eliminate the oral lichen planus lesions, and we are uncertain about side effects.
We found no consistent evidence that any particular corticosteroid was better than any other.
Three studies using another topical medicine called tacrolimus (a calcineurin inhibitor) found that this medicine may be more effective than corticosteroids, but may be more likely to cause mild side effects.
Available evidence comparing corticosteroids with other treatments is very limited.
Reliability of the evidence
The reliability of most of the evidence is very low, so we cannot be sure about the findings and future research may lead us to different conclusions.
Conclusion
The available evidence suggests that topical corticosteroids may be effective for treating painful oral lichen planus, but our confidence in these findings is limited as there were only a small number of studies and participants. There is some evidence that tacrolimus may be more effective than a corticosteroid, but evidence on negative side effects is inconclusive.
Authors' conclusions
Summary of findings
| Corticosteroids compared to placebo for treating symptomatic, biopsy‐confirmed oral lichen planus | ||||||
| Population: people with oral lichen planus Setting: university dental clinics Intervention: topical corticosteroids Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with corticosteroids | |||||
| Pain resolution** measured via VAS (1‐10cm) and 5‐grade score Follow‐up: 8‐9 weeks | 306 per 1000 | 584 per 1000 | RR 1.91 (1.08 to 3.36) | 72 | ⊕⊕⊝⊝ | 1 RCT evaluated clobetasol propionate and the other flucinonide. |
| Clinical resolution*** measured via Thongparsom and 5‐grade score Follow‐up: 8‐9 weeks | 50 per 1000b | 300 per 1000 (38 to 2379) | RR 6.00 (0.76 to 47.58) | 72 | ⊕⊝⊝⊝ | 1 RCT evaluated clobetasol propionate and the other flucinonide. |
| Adverse effects**** Follow‐up: 3‐9 weeks | 89 per 1000 | 132 per 1000 | RR 1.48 (0.48 to 4.56) | 88 | ⊕⊝⊝⊝ | RCTs evaluated clobetasol propionate, flucinonide (no adverse effects noted) and triamcinolone acetonide. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ** Subjective assessment by participants at the end of treatment ***Assessment by clinicians at the end of treatment ****Reported by participants throughout the study CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; VAS: visual analogue scale. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to risk of bias (one study judged at unclear risk). | ||||||
| Corticosteroids compared to calcineurin inhibitors for treating symptomatic, biopsy‐confirmed oral lichen planus | |||||||
| Population: people with oral lichen planus Setting: university dental clinics Intervention: topical corticosteroids Comparison: topical calcineurin inhibitors | |||||||
| Outcomes | Treatment comparison | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with calcineurin inhibitors | Risk with corticosteroids | ||||||
| Pain resolution** measured via VAS and 4‐grade scale Follow‐up: 3‐8 weeks | clobetasol vs ciclosporin | 200 per 1000 | 422 per 1000 | RR 2.11 (0.76 to 5.86) | 39 | ⊕⊝⊝⊝ | — |
| clobetasol vs tacrolimus | 440 per 1000 | 198 per 1000 | RR 0.45 (0.24 to 0.88) | 100 | ⊕⊝⊝⊝ | — | |
| triamcinolone vs tacrolimus | — | — | — | — | — | No data for this outcome | |
| Clinical resolution*** measured via Thongprasom and 4‐grade scale Follow‐up: 3‐8 weeks | clobestol vs ciclosporin | 150 per 1000 | 474 per 1000 | RR 3.16 (1.00 to 9.93) | 39 | ⊕⊝⊝⊝ | — |
| clobetasol vs tacrolimus | 654 per 1000 | 399 per 1000 | RR 0.61 (0.38 to 0.99) | 52 | ⊕⊝⊝⊝ | — | |
| triamcinolone vs tacrolimus | 467 per 1000 | 401 per 1000 | RR 0.86 (0.55 to 1.35) | 60 | ⊕⊝⊝⊝ | — | |
| Adverse effects**** Follow‐up: 3‐8 weeks | clobetasol vs ciclosporin | 50 per 1000 | 316 per 1000 | RR 6.32 (0.84 to 47.69) | 39 | ⊕⊝⊝⊝ | — |
| clobetasol vs tacrolimus | 180 per 1000 | 9 per 1000 | RR 0.05 (0.00 to 0.83) | 100 | ⊕⊝⊝⊝ | — | |
| triamcinolone vs tacrolimus | 516 per 1000 | 243 per 1000 | RR 0.47 (0.22 to 0.99) | 58 | ⊕⊕⊝⊝ | — | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). **Subjective assessment by participants at the end of treatment ***Assessment by clinicians at the end of treatment **** Reported by participants throughout the duration of the study CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; VAS: visual analogue scale. | |||||||
| GRADE Working Group grades of evidence | |||||||
| aDowngraded three levels as very small single study at unclear risk of bias, with large CI that includes the possibility of either intervention being superior. | |||||||
Background
Description of the condition
Oral lichen planus (OLP) is a chronic disorder of the oral cavity that rarely undergoes spontaneous remission. Despite the lack of good epidemiological data, OLP is thought to be relatively common, affecting approximately 1% to 2% of the population, mainly middle‐aged adults (Alrashdan 2016). Women are slightly more likely than men to have this condition. The most commonly affected sites are the buccal mucosa bilaterally, the borders and dorsum of the tongue, and the gingiva. The palate (either hard or soft), the lips and the floor of the mouth are rarely involved.
Typical OLP clinical features are represented by bilaterally located white papules that enlarge and coalesce to form reticulations, the so‐called Wickham's striae (Carrozzo 1999), which are rarely symptomatic. In contrast, erythematous and erosive or ulcerative lesions can cause varying degrees of discomfort. Symptomatic OLP is relatively frequent and can significantly impair quality of life (López‐Jornet 2010; Tadakamadla 2015).
Moreover, the disease has a fluctuating course with apparent spontaneous exacerbations and improvements in disease activity within an individual patient.
Current evidence suggests that people with OLP have an increased risk of developing oral squamous cell carcinoma (SCC) (Eisen 2002; Gonzalez‐Moles 2008), and this has to be considered when planning therapeutic interventions (Aghbari 2017). However, this topic will not be addressed in this review.
Clinical appearance alone, particularly when showing the 'classic' reticular form, may sometimes allow a definitive diagnosis. However, given the chronic course of the disease, the sometimes pleomorphic clinical manifestations, and the common long‐term treatment and monitoring of people with OLP, biopsy is a prudent – yet still controversial – clinical practice. Inappropriate diagnosis is a notable cause of therapy failure, so histopathological confirmation of OLP is helpful before starting an active treatment. Histopathology can be subjective and non‐specific (Van der Meij 2003), but it can be useful to exclude dysplasia and SCC. When exclusive gingival or predominantly erosive or ulcerative lesions are present, immunological tests are warranted to achieve a proper diagnosis.
OLP is probably a T cell‐mediated immunological reaction to an induced antigenic change in the oral mucosa in predisposed people. An early event in OLP is the genetically driven enhanced production of Th1 cytokines, particularly tumour necrosis factor‐alpha (TNF‐α) and interferon‐gamma (IFN‐γ) (Carrozzo 2004). Studies of T cell receptor variable region genes have highlighted that OLP is likely to be the common outcome of a limited combination of extrinsic antigens, altered self‐antigens or super antigens (Thomas 1997). In a minority of people, aetiological factors can be identified and they are usually drugs, dental materials and infectious agents, especially hepatitis C virus infection (Lodi 2005a; Lodi 2010).
Description of the intervention
Various treatment regimens have been employed to treat ulcerative lesions, and, more importantly, to reduce the associated pain, though a definitive cure for OLP has not yet been achieved (Lodi 2005b). The primary goal of treatment of symptomatic OLP is the reduction and preferably elimination of pain associated with the lesions.
How the intervention might work
Because OLP is considered a T cell‐mediated disease associated with a Th1 imbalance of cytokine production, most of the therapeutic interventions have aimed to target the inflammatory pathway underlying OLP. In particular, local suppression of T cells and a reduction in the release of cytokines such as TNF‐α and IFN‐γ are highly regarded in OLP management. As a result, the mainstay medications in OLP management are anti‐inflammatory drugs. The most commonly used anti‐inflammatory medication is glucocorticosteroids, commonly called corticosteroids. Around 1950, topical glucocorticosteroids (TGCs) were employed to treat skin inflammatory disease; the use of TGCs for mouth diseases, including OLP, started around a decade later (Zegarelli 1960). TGCs have a multiplicity of actions: anti‐inflammatory, immunomodulatory, vasoconstrictor, and they can inhibit the activity of several cytokines following inactivation of specific transcription factors such as activator protein 1 (AP‐1) and nuclear factor kappa B (NFκB) (Ahluwalia 1998). Specifically, the analgesic effect of corticosteroids is likely related to their effect on the inflammatory pathway underlying OLP and its beneficial effect on mucosal healing and integrity.
Why it is important to do this review
Symptomatic OLP is a relatively common, painful oral disorder that can significantly impair quality of life (Tadakamadla 2015). Because of its chronic nature and lack of an apparent cause, a definitive cure is very difficult to achieve. Current treatments aim to reduce pain and to heal erosive and ulcerative lesions. Most published reviews on the topic suggest the use of topical drugs, mainly TGCs (Al‐Hashimi 2007; Carrozzo 1999; Carrozzo 2009; Cribier 1998; Eisen 2005; Lodi 2005b); however, the previous version of this Cochrane Review provided only weak evidence for the superiority of any interventions over placebo for palliation of symptomatic OLP (Other published versions of this review). As we were aware of an increasing number of randomised controlled trials (RCTs) evaluating corticosteroids, we updated the review, focusing on these interventions. A further review on non‐corticosteroids is also being produced.
Objectives
To assess the effects and safety of corticosteroids, in any formulation, for treating people with symptoms of oral lichen planus.
Methods
Criteria for considering studies for this review
Types of studies
We included RCTs. We excluded quasi‐randomised trials (where treatment assignment was by alternating sequence, date of birth, registration number or some other such non‐random method).
Types of participants
We included participants satisfying the following criteria.
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Having a clinical and histological diagnosis of OLP.
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Having painful symptoms associated with OLP.
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Not concurrently receiving any other treatment for OLP or treatment likely to modify their OLP (e.g. systemic steroids, antifungals or immunosuppressants).
For people being treated for both skin and OLP, we extracted only the OLP data; if this was not possible, we excluded the study.
Types of interventions
Any local or systemic corticosteroid treatment compared with a placebo, a calcineurin inhibitor, another corticosteroid, any other local or systemic treatment, or the same corticosteroid plus an adjunctive treatment.
Types of outcome measures
Primary outcomes
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Pain (score and resolution) as assessed by participants (measured at the end of the treatment course).
Secondary outcomes
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Clinical response (score and resolution of the disease) in terms of changes in the extension and severity (degree of erosion, erythema and reticulation) as assessed by clinicians (measured at the end of the treatment course).
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Adverse effects, including clinical candidiasis or other toxic and side effects (measured at any time point).
Search methods for identification of studies
Electronic searches
Cochrane Oral Health's Information Specialist conducted systematic searches in the following databases. The search was inclusive of RCTs and controlled clinical trials, but the latter were filtered out during the selection process. There were no language, publication year or publication status restrictions.
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Cochrane Oral Health's Trials Register (searched 25 February 2019; Appendix 1).
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Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 1) in the Cochrane Library (searched 25 February 2019; Appendix 2).
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MEDLINE Ovid (1946 to 25 February 2019; Appendix 3).
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Embase Ovid (1980 to 25 February 2019; Appendix 4).
Subject strategies were modelled on the search strategy designed for MEDLINE Ovid. Where appropriate, they were combined with subject strategy adaptations of the highly sensitive search strategy designed by Cochrane for identifying RCTs and controlled clinical trials as described in Chapter 6 of the Cochrane Handbook for Systematic Reviews of Interventions (Lefebvre 2011).
Searching other resources
The following trial registries were searched for ongoing studies:
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov; searched 25 February 2019; Appendix 5);
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World Health Organization International Clinical Trials Registry Platform (apps.who.int/trialsearch; searched 25 February 2019; Appendix 6).
We also checked the reference lists of identified publications for relevant studies, and contacted authors to identify missing and unreported trials.
We checked that none of the included studies in this review were retracted due to error or fraud.
We did not perform a separate search for adverse effects of interventions used; we considered adverse effects described in included studies only.
Data collection and analysis
Selection of studies
Three review authors independently scanned titles and abstracts (when available) of all reports identified. The search was designed to be sensitive and include controlled clinical trials, these were filtered out early in the selection process if they were not randomised. For studies appearing to meet the inclusion criteria, or when there was insufficient information in the title and abstract to make a clear decision, we obtained the full reports and all review authors independently assessed them to establish if they met inclusion criteria. We resolved disagreements by discussion. We recorded studies that we rejected at this or subsequent stages in the Characteristics of excluded studies table, along with the reasons for exclusion.
Data extraction and management
At least two review authors extracted data from all studies meeting the inclusion criteria, using a specially designed form. We recorded the characteristics of the trial participants, interventions and outcomes in the Characteristics of included studies table. The studies measured the effects of treatment on pain and clinical presentation using scales and scoring systems, which were often significantly different and difficult to compare. In order to increase the amount of comparable data, we decided to record the number of participants who did not receive benefit in terms of symptoms (pain) and clinical signs.
Assessment of risk of bias in included studies
All review authors independently assessed the risk of bias of the included trials. All review authors independently assessed the full‐text papers, unblinded, and resolved disagreements through discussion and consensus. We used the recommended tool for assessing risk of bias in studies included in Cochrane Reviews (Higgins 2011). It is a two‐part tool, addressing seven specific domains as follows:
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random sequence generation (selection bias);
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allocation concealment (selection bias);
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blinding of participants and personnel (performance bias);
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blinding of outcome assessment (detection bias);
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incomplete outcome data (attrition bias);
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selective reporting (reporting bias);
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other bias.
Each domain in the tool includes one or more specific entries in a 'Risk of bias' table. Within each entry, the first part of the tool describes what was reported to have happened in the study, in sufficient detail to support a judgement about the risk of bias. The second part of the tool assigns a judgement relating to the risk of bias for that entry. This is achieved by assigning a judgement of 'low', 'high' or 'unclear' risk of bias.
After taking into account the additional information provided by trial authors, we categorised trials as:
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overall low risk of bias if low risk of bias for all key domains;
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overall unclear risk of bias if unclear risk of bias for one or more key domains; or
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overall high risk of bias if high risk of bias for one or more key domains.
We completed a 'Risk of bias' table for each included study (see Characteristics of included studies table), and presented the results graphically by study and by domain across all studies.
Measures of treatment effect
For dichotomous outcomes, we expressed the estimates of effects of an intervention as risk ratios (RR) or odds ratios (OR) if paired, together with 95% confidence intervals (CIs). For continuous outcomes, we used mean differences (MD) and standard deviation (SD) for each group in order to express the estimate of effect as MD with 95% CI. If studies reported continuous outcomes on different scales, we planned to use standardised mean difference (SMD) to pool these data in meta‐analyses. For paired data (split‐mouth studies), we used the generic inverse variance method (Higgins 2011).
Unit of analysis issues
The statistical unit of analysis was the participant.
For studies with more than two control arms, we selected the one we considered most appropriate to compare.
We intended to analyse split‐mouth and cross‐over trials. Where the intraclass correlation was not provided for cross‐over and split‐mouth trials, we estimated this as 0.5.
Dealing with missing data
We contacted trialists to ask them to supply missing information and to clarify points.
Assessment of heterogeneity
We assessed the significance of any discrepancies in the estimates of the treatment effects from the different trials by means of Cochrane's test for heterogeneity and the I² statistic, which describes the percentage total variation across studies that is due to heterogeneity rather than chance. We considered heterogeneity to be statistically significant if the P value was less than 0.1. A rough guide to the interpretation of the I² statistic given in the Cochrane Handbook for Systematic Reviews of Interventions is: 0% to 40% might not be important, 30% to 60% may represent moderate heterogeneity, 50% to 90% may represent substantial heterogeneity and 75% to 100% is considerable heterogeneity (Higgins 2011).
Assessment of reporting biases
We attempted to minimise reporting biases by conducting a thorough search of multiple sources including trial registries, and efforts to identify unpublished trials and non‐English language publications.
Data synthesis
Where studies comparing similar interventions reported the same outcome measures, we combined the data in meta‐analyses. We combined RRs for dichotomous data, and MDs for continuous data, using fixed‐effect models unless there were more than three studies being combined. We dichotomised four‐ or five‐step rating scales as appropriate. If studies reported continuous outcomes on different scales, we planned to use SMD to pool these data in meta‐analyses.
Subgroup analysis and investigation of heterogeneity
If there were sufficient studies, we planned to assess clinical heterogeneity by examining the characteristics of participants included in the studies.
Sensitivity analysis
If there were sufficient studies, we planned to undertake sensitivity analyses to examine the effect of the study risk of bias assessment on the overall estimates of effect.
'Summary of findings' table
We created 'Summary of findings' tables for the comparisons of treatments considered 'first choice' and routinely adopted in clinical practice, and presented summary information for primary outcomes, in particular pain resolution, clinical resolution and adverse effects. At least two review authors (of GL, MM, MC, VM) independently assessed the certainty of evidence using GRADE criteria (Schünemann 2017), which considers a body of RCT evidence to provide high‐certainty evidence unless 'downgraded' by one, two or three levels (to moderate, low or very low certainty, respectively) on the basis of problems in study design, imprecision, inconsistency, indirectness or publication bias.
Results
Description of studies
See Characteristics of included studies table.
Results of the search
We identified 1030 records and rejected 943 on the basis of title or abstract. We considered 87 articles in full text and excluded 36 of these (we also excluded 11 studies that had been included in the previous version of the review as these will be part of our sister review on non‐corticosteroids). Two studies are awaiting classification and we found 12 ongoing studies. Therefore, we included 37 articles (35 RCTs) in this review. See Figure 1.
Study flow diagram of searches for this update.
Included studies
For a summary of the characteristics of each of the included studies, see the Characteristics of included studies tables.
Characteristics of the trials
Design
Twenty‐nine trials used a two‐arm parallel design; four used a three‐arm parallel design (Hesen 2017; Siponen 2017; Sivaraman 2016; Thomas 2017), though we used only two arms from Hesen 2017 and Thomas 2017; one used a two‐arm cross‐over design (Hegarty 2002); and one used a split‐mouth design (Amanat 2014).
The total number of participants included in the trials was 1474, with the number per study ranging from 20 to 139.
Setting
Seven studies were conducted in Iran (Amanat 2014; Amirchaghmaghi 2016; Bakhtiari 2017; Ghabanchi 2009; Gorouhi 2007; Kia 2015; Pakfetrat 2015), six in Italy (Arduino 2018; Campisi 2004; Carbone 2009; Conrotto 2006; Corrocher 2008; Lodi 2007), five in China (Fu 2012; Liu 2013; Wei 2003; Xiong 2009; Xu 2002), four in India (Arunkumar 2015; Malhotra 2008; Sivaraman 2016; Thomas 2017), four in Egypt (Ezzatt 2019; Hashem 2019; Hesen 2017; Mostafa 2017), two in the Netherlands (Laeijendecker 2006; Voute 1993), one in the US (Chainani‐Wu 2007), one in Sweden (Rodstrom 1994), one in the UK (Hegarty 2002), one in Brazil (Dillenburg 2014), one in Sri Lanka (Hettiarachchi 2017), one in Finland (Siponen 2017), and one was an Asian multicentre study (Singapore, South Korea, India, Thailand) (Yoke 2006). All the studies were conducted in university clinics or hospitals.
Funding
Companies provided drugs to four trials (Conrotto 2006; Gorouhi 2007; Voute 1993; Yoke 2006); one trial received support for the multicentric co‐ordination and study drug from the sponsor (Yoke 2006); two received support from the principal investigator (Arduino 2018; Ezzatt 2019); and 10 received support from institutional funding bodies (Amanat 2014; Amirchaghmaghi 2016; Chainani‐Wu 2007; Dillenburg 2014; Ghabanchi 2009; Hettiarachchi 2017; Lodi 2007; Pakfetrat 2015; Siponen 2017; Xiong 2009).
Characteristics of the interventions
See Table 1.
| Comparison | Delivery method | Interventions | Study |
| Corticosteroids vs placebo | Topical | Fluocinonide 0.025% in 40% hypromellose ointment in white soft paraffin vs placebo | |
| Topical | Triamcinolone acetonide ointment 0.1% vs placebo | ||
| Topical | Clobetasol propionate 0.025% in 4% hydroxyethyl cellulose gel vs placeboa | ||
| Corticosteroids vs calcineurin inhibitors | Topical | Triamcinolone acetonide 0.1% paste vs pimecrolimus 1% paste | |
| Topical | Clobetasol propionate 0.025% in 4% hydroxyethyl cellulose gel vs ciclosporin 1.5% in 4% hydroxyethyl cellulose gela | ||
| Topical | Clobetasol propionate 0.05% ointment vs tacrolimus 0.1% ointment | ||
| Topical | Betamethasone 0.1% gel vs pimecrolimus 1% gel | ||
| Topical | Clobetasol propionate 0.05% cream vs tacrolimus 0.1% cream | ||
| Topical | Clobetasol propionate 0.05% vs tacrolimus 0.03% | ||
| Topical | Triamcinolone 0.1% paste vs pimecrolimus 1% cream | ||
| Topical | Triamcinolone acetonide 0.1% in Orabase vs pimecrolimus 1% cream | ||
| Topical | Triamcinolone acetonide 0.1% in hypromellose 20% ointment vs tacrolimus 1% ointment | ||
| Topical | Triamcinolone acetonide ointment 0.1% vs tacrolimus 0.1% ointment | ||
| Topical | Triamcinolone acetonide 0.1% vs tacrolimus 0.03% | ||
| Topical | Triamcinolone acetonide 0.1% in Orabase vs ciclosporin solution 0.1% | ||
| Corticosteroid A vs corticosteroid B | Topical | Clobetasol propionate in microspheres 0.025% vs clobetasol propionate 0.025% in a dispersion of a lipophilic ointment in a hydrophilic phase | |
| Topical | Clobetasol priopionate 0.05% in 4% hydroxyethyl cellulose vs clobetasol priopionate 0.025% in 4% hydroxyethyl cellulosea | ||
| Topical | Clobetasol propionate 0.05% ointment in Orabase vs triamcinolone acetonide 0.1% ointment in Orabase | ||
| Topical | Clobetasol propionate 0.05% vs triamcinolone acetonide 0.1% | ||
| Injected locally | Betamethasone dipropionate 5 mg + betamethasone disodium phosphate 2 mg/mL intralesional injection vs triamcinolone acetonide 8 mg, intralesional injection | ||
| Systemic | Betamethasone 5 mg daily orally vs triamcinolone acetonide 0.1% paste | ||
| Topical | Prednisolone 5 mg mucoadhesive tablet vs triamcinolone acetonide 0.1% paste | ||
| Topical | Fluticasone spray 50 μg vs betamethasone sodium phosphate 500 μg oral rinses | ||
| Corticosteroids vs other treatments | Topical | Triamcinolone acetonide paste 0.1% vs curcumin paste 5% | |
| Topical | Triamcinolone acetonide paste 0.1% vs Curenext Oral Gel containing curcuma longa extracts 10 mg | ||
| Topical | Dexamethasone mouthwash 0.5 mg oral rinses vs photodynamic therapy mediated by methylene blue | ||
| Topical | Triamcinolone acetonide 0.1% paste vs hyaluronic acid preparation 0.2% paste | ||
| Topical | Triamcinolone acetonide 0.1% in Orabase vs photodynamic therapy mediated by methylene blue | ||
| Topical | Triamcinolone acetonide ointment 0.1% in Orabase vs cryotherapy | ||
| Topical | Clobetasol propionate gel 0.05% vs laser diodeb | ||
| Injected locally | Triamcinolone acetonide 10 mg intralesional injection vs Bacillus Calmette‐Guerin polysaccharide nucleic acid, 0.5 mL intralesional injection | ||
| Topical | Dexamethasone paste 0.043% vs amlexanox paste 250 mg | ||
| Adjunctive treatment to corticosteroids | Topical | Clobetasol propionate gel 0.05% + miconazole 2% gel vs clobetasol propionate gel 0.05% + placebo gel | |
| Topical | Dexamethasone paste and mycostatin paste alternatively vs dexamethasone paste | ||
| Topical | Dexamethasone mouthwash 0.5 mg oral rinses + curcumin 250 mg tablets vs dexamethasone mouthwash 0.5 mg oral rinses + placebob | ||
| Topical | Triamcinolone acetonide 0.1% oral paste + glucosamine sulphate 1500 mg vs triamcinolone acetonide 0.1% oral paste | ||
| Systemic | Prednisone 60 mg + curcuminoids 2000 mg daily vs prednisone 60 mg + placebo | ||
| Systemic | Herbal topical and decoction + prednisone 5–10 mg 3 times daily chlorphenamine 4 mg 3 times daily, vitamin C 0.1 g 3 times daily vs prednisone 5–10 mg 3 times daily, chlorphenamine 4 mg 3 times daily, vitamin C 0.1g 3 times daily |
aParticipants in both groups also received antifungals: miconazole gel plus 0.12% chlorhexidine mouthrinse.
bParticipants in both groups also took antifungals: nystatin 100,000 UI/mL oral rinse.
Three trials compared a corticosteroid drug (flucinonide, triamcinolone acetonide and clobetasol propionate in different adhesive bases) with placebo (Arduino 2018; Siponen 2017; Voute 1993).
Eleven studies compared a corticosteroid with a calcineurin inhibitor; they compared: clobetasol propionate with ciclosporin (Conrotto 2006); clobetasol propionate with tacrolimus (Corrocher 2008; Hettiarachchi 2017; Sivaraman 2016); triamcinolone acetonide with pimecrolimus (Arunkumar 2015; Gorouhi 2007; Pakfetrat 2015); triamcinolone acetonide with tacrolimus (Laeijendecker 2006; Siponen 2017; Sivaraman 2016); and triamcinolone acetonide with ciclosporin (Yoke 2006); and betamethasone gel with pimecrolimus gel (Ezzatt 2019).
Eight studies compared two corticosteroids or the same corticosteroid in different modalities: one compared two different formulations of clobetasol propionate (Campisi 2004); one compared two ointments with different concentrations (Carbone 2009); two compared different preparations of betamethasone with triamcinolone acetonide (Liu 2013; Malhotra 2008); two compared clobetasol propionate with triamcinolone acetonide (Rodstrom 1994; Sivaraman 2016); one compared prednisolone with triamcinolone acetonide (Ghabanchi 2009); one compared fluticasone propionate with betamethasone sodium phosphate (Hegarty 2002).
Nine trials compared corticosteroids with other treatments; two compared triamcinolone acetonide with curcumin (Kia 2015; Thomas 2017), two compared topical corticosteroids with photodynamic therapy (Bakhtiari 2017; Mostafa 2017); one compared triamcinolone acetonide with cryotherapy (Amanat 2014), one compared clobetasol propionate with laser diode (Dillenburg 2014), one compared triamcinolone acetonide with bacillus Calmette‐Guerin polysaccharide nucleic acid (Xiong 2009), one compared dexamethasone with amlexanox (Fu 2012), and one compared triamcinolone acetonide gel with hyaluronic acid gel (Hashem 2019).
Five trials tested a treatment adjunctive to the corticosteroid (i.e. both groups received the same corticosteroid) (Amirchaghmaghi 2016; Chainani‐Wu 2007; Hesen 2017; Lodi 2007; Wei 2003). Two studies tested antimycotic drugs as adjunctive treatment (Lodi 2007; Wei 2003), and two tested curcumin (Chainani‐Wu 2007; Dillenburg 2014). One study compared three‐stage treatment integrating Western and Chinese medicine, with a two‐stage Western medicine approach (Xu 2002).
Due to the limited availability of commercial preparations to be used in the oral mucosa, most of the studies employed ad hoc or galenical preparations.
The treatment courses varied from one week to six months, with the majority lasting one to two months.
Characteristics of the outcomes
There were three main outcomes reported in the trials included in this review: pain (score and resolution), clinical response (score and resolution) and adverse effects of treatment. The outcomes were measured between one week and six months.
Pain
Twenty‐seven studies used visual analogue scales (VAS) to measure pain. This is a validated tool used by participants to assess their own pain on a 0‐mm to 100‐mm or 0‐cm to 10‐cm scale, where the lower the value, the lower the pain. Three studies adopted rating scales (Corrocher 2008; Thomas 2017; Voute 1993). We dichotomised Likert scales into complete resolution versus partial or no resolution. Five studies did not measure pain (Ghabanchi 2009; Laeijendecker 2006; Sivaraman 2016; Wei 2003; Xu 2002).
Conrotto?
Clinical response
All studies measured clinical response to treatment. Four measured the size of the affected area (Fu 2012; Liu 2013; Lodi 2007; Xiong 2009). Seventeen studies used the Thongprasom clinical score or a modification of it (Amanat 2014; Amirchaghmaghi 2016; Arduino 2018; Arunkumar 2015; Bakhtiari 2017; Campisi 2004; Carbone 2009; Conrotto 2006; Dillenburg 2014; Gorouhi 2007; Hegarty 2002; Hesen 2017; Hettiarachchi 2017; Kia 2015; Mostafa 2017; Pakfetrat 2015; Yoke 2006). Three studies used the modified oral mucositis index (Chainani‐Wu 2007; Hashem 2019; Thomas 2017). Eight studies used a four‐ or five‐grade rating scale (Corrocher 2008; Ezzatt 2019; Ghabanchi 2009; Laeijendecker 2006; Rodstrom 1994; Voute 1993; Wei 2003; Xu 2002). Malhotra 2008 used a semi‐quantitative scoring system and Siponen 2017 measured changes in clinical scores (modified from Setterfield) from baseline to week three. Sivaraman 2016 provided a dichotomous outcome only: complete resolution.
Adverse effects
Twenty‐one studies reported general adverse effects of treatment (Amirchaghmaghi 2016; Arduino 2018; Campisi 2004; Carbone 2009; Chainani‐Wu 2007; Conrotto 2006; Corrocher 2008; Dillenburg 2014; Ezzatt 2019; Fu 2012; Ghabanchi 2009; Gorouhi 2007; Hegarty 2002; Hettiarachchi 2017; Laeijendecker 2006; Liu 2013; Lodi 2007; Malhotra 2008; Rodstrom 1994; Siponen 2017; Xiong 2009). The remaining studies either did not consider adverse effects at all, or did not report data in an usable form.
Other outcomes not relevant for this review
Other outcomes reported in the studies but not relevant for this review were relapses (Arduino 2018; Carbone 2009; Dillenburg 2014; Liu 2013), quality of life (Gorouhi 2007; Hegarty 2002), anxiety and function (Dillenburg 2014), and cost (Conrotto 2006).
Excluded studies
We divided the content of our previous reviews (Chan 1999; Thongprasom 2011) into two reviews, this one focusing on corticosteroid treatment, and another, currently in progress, on non‐corticosteroid treatments. Therefore, we removed from this update 11 trials of non‐corticosteroid treatments that were included in the previous version of this review (Agha‐Hosseini 2010; Choonhakarn 2008; Eisen 1990; Gaeta 1994; Lundquist 1995; Mousavi 2009; Nolan 2009; Passeron 2007; Salazar‐Sánchez 2010; Swift 2005; Volz 2008). These are listed in the Characteristics of excluded studies table. There we also listed the 47 articles that seemed initially to be relevant but we found did not fulfil inclusion criteria when we studied the full texts.
Studies awaiting classification
Two studies await classification (Fricain 2014; Qu 2016) (see Characteristics of studies awaiting classification tables).
Ongoing studies
We found 12 ongoing studies (2017‐002193‐40; ChiCTR1800016507; CTRI/2018/03/012661; CTRI/2018/08/015185; CTRI/2018/08/015563; Ferri 2018; IRCT20171017036835N2; IRCT20181226042133N1; NCT03386643; NCT03592342; NCT03738176; NCT03793634) (see Characteristics of ongoing studies). Two trials are comparing a corticosteroid drug (clobetasol propionate patches) with placebo; eight trials are comparing a corticosteroid drug with another treatment (systemic and topic curcumin; natural products with Vitamin E; vitamin C and propolis; neem leaves mouthwash; photobiomodulation; vitamin D capsules; probiotic treatment; topical sesame oil and topical chamomile). Finally, two trials are comparing two different corticosteroids (betamethasone versus dexamethasone mouth rinse; mucoadhesive nano‐triamcinolone gel versus conventional triamcinolone gel).
Risk of bias in included studies
Allocation
We considered the method of randomisation adequate in both its components (sequence generation and allocation concealment) in 14 trials (Amirchaghmaghi 2016; Arduino 2018; Carbone 2009; Conrotto 2006; Ezzatt 2019; Gorouhi 2007; Hegarty 2002; Hesen 2017; Hettiarachchi 2017; Lodi 2007; Malhotra 2008; Pakfetrat 2015; Siponen 2017; Yoke 2006); in nine trials, sequence generation was adequate, but allocation concealment unclear (Chainani‐Wu 2007; Corrocher 2008; Dillenburg 2014; Fu 2012; Kia 2015; Laeijendecker 2006; Liu 2013; Sivaraman 2016; Xiong 2009), and in the remaining 12 trials, sequence generation and allocation concealment were both unclear (Amanat 2014; Arunkumar 2015; Bakhtiari 2017; Campisi 2004; Ghabanchi 2009; Hashem 2019; Mostafa 2017; Rodstrom 1994; Thomas 2017; Voute 1993; Wei 2003; Xu 2002).
Blinding
Performance bias
We judged 12 trials at low risk of performance bias as both participants and personnel were blinded (Amirchaghmaghi 2016; Arduino 2018; Carbone 2009; Chainani‐Wu 2007; Corrocher 2008; Ezzatt 2019; Hettiarachchi 2017; Lodi 2007; Rodstrom 1994; Siponen 2017; Voute 1993; Wei 2003).
We judged 14 trials at high risk of performance bias (Amanat 2014; Bakhtiari 2017; Campisi 2004; Dillenburg 2014; Ghabanchi 2009; Gorouhi 2007; Hegarty 2002; Liu 2013; Malhotra 2008; Mostafa 2017; Pakfetrat 2015; Thomas 2017; Xiong 2009; Xu 2002), and nine studies as unclear (Arunkumar 2015; Conrotto 2006; Fu 2012; Hashem 2019; Hesen 2017; Kia 2015; Laeijendecker 2006; Sivaraman 2016; Yoke 2006).
Detection bias
Fourteen studies reported that outcome assessment was blind so we judged these at low risk of detection bias (Amirchaghmaghi 2016; Arduino 2018; Carbone 2009; Chainani‐Wu 2007; Conrotto 2006; Corrocher 2008; Ezzatt 2019; Hettiarachchi 2017; Kia 2015; Lodi 2007; Rodstrom 1994; Siponen 2017; Voute 1993; Wei 2003).
Fifteen studies were at high risk of detection bias (Amanat 2014; Bakhtiari 2017; Campisi 2004; Dillenburg 2014; Ghabanchi 2009; Gorouhi 2007; Hegarty 2002; Hesen 2017; Liu 2013; Malhotra 2008; Mostafa 2017; Pakfetrat 2015; Thomas 2017; Xiong 2009; Xu 2002), and six studies as unclear (Arunkumar 2015; Fu 2012; Hashem 2019; Laeijendecker 2006; Sivaraman 2016; Yoke 2006).
Incomplete outcome data
We judged 31 trials at low risk of attrition bias since all enrolled participants completed the study, or the number of participants lost was not likely to have a clinically relevant impact on the intervention effect estimate, or intention‐to‐treat (ITT) analysis was performed (Amirchaghmaghi 2016; Arduino 2018; Arunkumar 2015; Bakhtiari 2017; Campisi 2004; Carbone 2009; Chainani‐Wu 2007; Conrotto 2006; Corrocher 2008; Ezzatt 2019; Fu 2012; Ghabanchi 2009; Gorouhi 2007; Hashem 2019; Hegarty 2002; Hesen 2017; Hettiarachchi 2017; Kia 2015; Laeijendecker 2006; Liu 2013; Lodi 2007; Malhotra 2008; Mostafa 2017; Rodstrom 1994; Siponen 2017; Sivaraman 2016; Thomas 2017; Voute 1993; Wei 2003; Xu 2002; Yoke 2006).
We judged four trials at high risk of attrition bias since the rate of dropouts was higher than 20% (Amanat 2014; Dillenburg 2014; Pakfetrat 2015), or was very imbalanced between groups (Xiong 2009).
Selective reporting
We judged 26 trials at low risk of bias since all planned outcomes were reported (Amanat 2014; Amirchaghmaghi 2016; Arduino 2018; Arunkumar 2015; Campisi 2004; Carbone 2009; Conrotto 2006; Corrocher 2008; Ezzatt 2019; Fu 2012; Gorouhi 2007; Hashem 2019; Hegarty 2002; Hettiarachchi 2017; Kia 2015; Laeijendecker 2006; Liu 2013; Lodi 2007; Mostafa 2017; Pakfetrat 2015; Siponen 2017; Sivaraman 2016; Thomas 2017; Voute 1993; Wei 2003; Xiong 2009; Xu 2002; Yoke 2006).
Seven studies reported one or more outcomes of interest incompletely or in a way that did not allow quantitative analysis, thus we judged them at high risk of bias (Bakhtiari 2017; Chainani‐Wu 2007; Dillenburg 2014; Ghabanchi 2009; Hesen 2017; Malhotra 2008; Rodstrom 1994).
We assessed the remaining two trials at unclear risk of selective outcome reporting bias as there was insufficient information to make a judgement (Wei 2003; Xu 2002).
Other potential sources of bias
In one study, the two groups had a statistically significant difference in clinical score at baseline (Malhotra 2008).
Overall risk of bias
Seven studies were at overall low risk of bias (Amirchaghmaghi 2016; Arduino 2018; Carbone 2009; Ezzatt 2019; Hettiarachchi 2017; Lodi 2007; Siponen 2017); 11 were at unclear risk of bias overall (Arunkumar 2015; Conrotto 2006; Corrocher 2008; Fu 2012; Hashem 2019; Kia 2015; Laeijendecker 2006; Sivaraman 2016; Voute 1993; Wei 2003; Yoke 2006); and the remaining 17 studies were at high risk of bias (because of no blinding, incomplete outcome data, selective reporting or baseline imbalance) (Amanat 2014; Bakhtiari 2017; Campisi 2004; Chainani‐Wu 2007; Dillenburg 2014; Ghabanchi 2009; Gorouhi 2007; Hegarty 2002; Hesen 2017; Liu 2013; Malhotra 2008; Mostafa 2017; Pakfetrat 2015; Rodstrom 1994; Thomas 2017; Xiong 2009; Xu 2002). Risk of bias assessments are summarised in Figure 2 and Figure 3.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Effects of interventions
See: Summary of findings for the main comparison Corticosteroids compared to placebo for treating oral lichen planus; Summary of findings 2 Corticosteroids versus calcineurin inhibitors for treating oral lichen planus
1. Corticosteroids versus placebo
Three studies compared the effects of a corticosteroid with a placebo. The active treatments were flucinonide (Voute 1993), triamcinolone acetonide (Siponen 2017), and clobetasol propionate (Arduino 2018). All studies employed topical corticosteroids that were characterised by adhesive formulations, allowing longer contact with oral mucosa. In Arduino 2018, both arms received miconazole gel once a day plus 0.12% chlorhexidine mouthrinse twice a day, thus, although not strictly placebo‐controlled, we considered it correct to include it in this comparison.
The effectiveness data of Siponen 2017 were not reported in a way that allowed us to perform quantitative analysis.
Pain score
One study measured pain score on a 0 to 10 scale (Arduino 2018). Clobetasol propionate had a higher rate of pain control than placebo (MD –1.81, 95% CI –3.54 to –0.09; 1 study, 32 participants; low‐certainty evidence; Analysis 1.1).
Pain resolution
Two studies measured pain resolution (Arduino 2018; Voute 1993). Topical corticosteroids were more likely than placebo to resolve pain (RR 1.91, 95% CI 1.08 to 3.36; 2 studies, 72 participants; I² = 0%; low‐certainty evidence; Analysis 1.2).
Clinical score
One study measured clinical score as continuous data, based on Thongprasom's signs (Arduino 2018). There seemed to be little or no difference in clinical score between clobetasol propionate and placebo (MD –0.38, 95% CI –0.89 to 0.14; 1 study, 32 participants; low‐certainty evidence; Analysis 1.3).
Clinical resolution
Two studies comparing a corticosteroid with a placebo considered clinical resolution (Arduino 2018; Voute 1993), but the findings were inconclusive (RR 6.00, 95% CI 0.76 to 47.58; 2 studies, 72 participants; I² = 0%; very low‐certainty evidence; Analysis 1.4).
Adverse effects
Neither flucinonide nor placebo caused any adverse effects in Voute 1993. In Arduino 2018 and Siponen 2017, the number of participants experiencing adverse effects were similar in both arms of the trials. Arduino 2018 reported one case of gastro‐oesophageal reflux in the corticosteroid group (clobetasol propionate) and a severe skin reaction in the placebo group (possibly due to the antimycotic drug). Both participants left the study for this reason. Siponen 2017 reported that 43% of participants taking triamcinolone acetonide and 33% taking placebo experienced local adverse effects. Adverse effects reported with triamcinolone included "smarting sensation" in the mouth and tenderness in the gingiva, while placebo users reported burning and sensitivity to hot food or drink, soreness of the gingiva, and increased salivary flow after applying the paste (RR 1.48, 95% CI 0.48 to 4.56; 3 studies, 88 participants; I² = 0%; very low‐certainty evidence; Analysis 1.5).
2. Corticosteroids versus calcineurin inhibitors
Eleven studies compared a corticosteroid with a calcineurin inhibitor, in particular they compared: clobetasol propionate with ciclosporin (Conrotto 2006), clobetasol propionate with tacrolimus (Corrocher 2008; Hettiarachchi 2017; Sivaraman 2016), triamcinolone acetonide with pimecrolimus (Arunkumar 2015; Gorouhi 2007; Pakfetrat 2015), triamcinolone acetonide with tacrolimus (Laeijendecker 2006; Siponen 2017; Sivaraman 2016), triamcinolone acetonide with ciclosporin (Yoke 2006), and betamethasone 0.1% gel with pimecrolimus 1% gel (Ezzatt 2019).
The effectiveness data of Ezzatt 2019, Pakfetrat 2015, and Siponen 2017 were not reported in a way that allowed us to perform quantitative analysis.
Pain score
Four studies comparing a corticosteroid with a calcineurin inhibitor measured pain by VAS as a continuous value: clobetasol cream versus tacrolimus cream (Hettiarachchi 2017); triamcinolone acetonide in Orabase versus ciclosporin mouthwash (Yoke 2006); and triamcinolone acetonide paste versus pimecrolimus paste (Arunkumar 2015; Gorouhi 2007). None of the studies showed a difference between the two treatments in terms of mean pain values (low‐ to very low‐certainty evidence; Analysis 2.1).
Pain resolution
Three studies comparing a corticosteroid with a calcineurin inhibitor reported pain resolution (Conrotto 2006; Corrocher 2008; Hettiarachchi 2017). Conrotto 2006 found no evidence of a difference between clobetasol propionate and ciclosporin in the same adhesive gel (RR 2.11, 95% CI 0.76 to 5.86; 39 participants; very low‐certainty evidence; Analysis 2.2). Two studies found that people treated with clobetasol propionate reported pain resolution less frequently compared with those treated with topical tacrolimus (RR 0.45, 95% CI 0.24 to 0.88; 100 participants; I² = 80%; very low‐certainty evidence; Analysis 2.2).
Clinical score
Three studies comparing a steroid with a calcineurin inhibitor measured clinical score: Arunkumar 2015 and Gorouhi 2007 compared triamcinolone acetonide paste with pimecrolimus paste and Hettiarachchi 2017 compared clobetasol propionate cream with tacrolimus cream. Neither of the comparisons showed evidence of a difference between the two treatments in terms of clinical score (low to very low‐certainty evidence; Analysis 2.3).
Clinical resolution
Four studies comparing a corticosteroid with a calcineurin inhibitor measured clinical resolution (Analysis 2.4; Conrotto 2006; Corrocher 2008; Laeijendecker 2006; Sivaraman 2016).
Conrotto 2006 found a better rate of clinical resolution among participants treated with clobetasol propionate gel compared with ciclosporin gel (RR 3.16, 95% CI 1.00 to 9.93; 39 participants; very low‐certainty evidence).
Pooled data from Corrocher 2008 and Sivaraman 2016 showed that participants treated with clobetasol reported clinical resolution less frequently compared with those treated with topical tacrolimus (RR 0.61, 95% CI 0.38 to 0.99; 2 studies, 52 participants; I² = 95%; very low‐certainty evidence). The high heterogeneity, also found for pain resolution, was difficult to explain, as the two studies were very similar. The main difference was related to drug dosage. In Corrocher 2008, participants applied them four times a day for four weeks, while in Hettiarachchi 2017, application was only two times a day for three weeks. One possibility was that tacrolimus may benefit more than clobetasol from frequent applications.
Pooled data from Laeijendecker 2006 and Sivaraman 2016 showed no evidence of a difference between triamcinolone acetonide ointment and tacrolimus ointment (RR 0.86, 95% CI 0.55 to 1.35; 2 studies, 60 participants; I² = 83%; very low‐certainty evidence). We do not know why there was such high heterogeneity between the two studies. It is not possible to reliably investigate causes of heterogeneity when there are only two studies.
Adverse effects
Seven studies that compared a topical corticosteroid with a topical calcineurin inhibitor reported adverse effects. One study reported that there were no adverse effects in either group (very low‐certainty evidence) (Hettiarachchi 2017). One study, comparing clobetasol propionate and ciclosporin, showed a higher incidence of adverse effects among participants treated with the corticosteroid (low‐certainty evidence) (Conrotto 2006). All the other studies showed higher incidence of adverse effects in the calcineurin inhibitor group (Corrocher 2008; Gorouhi 2007; Laeijendecker 2006; Siponen 2017; Yoke 2006).
The pooled data of two studies comparing triamcinolone acetonide with tacrolimus showed a higher incidence of adverse effects among participants treated with tacrolimus (RR 0.47, 95% CI 0.22 to 0.99; 2 studies, 58 participants; I² = 0%; very low‐certainty evidence; Analysis 2.5; Laeijendecker 2006; Siponen 2017).
The most frequently reported adverse effects were transient burning or stinging associated with application, and some participants also reported dyspepsia, skin rashes, local swelling and gastrointestinal upsets. Conrotto 2006 reported an increased burning sensation in the tacrolimus group that reduced as the lesions healed.
Notably, one study, conducted in Italy between 1999 and 2002, compared costs, which were considerably less for the corticosteroid (ciclosporin EUR 1.82 per day and clobetasol EUR 0.35 per day (Conrotto 2006).
3. Corticosteroid A versus corticosteroid B
Eight studies compared two corticosteroids or the same corticosteroid with different modalities (Campisi 2004; Carbone 2009; Ghabanchi 2009; Hegarty 2002; Liu 2013; Malhotra 2008; Rodstrom 1994; Sivaraman 2016). In particular, they compared two different formulations of clobetasol (Campisi 2004); two clobetasol ointments with different concentrations (Carbone 2009); betamethasone with triamcinolone (Liu 2013; Malhotra 2008); clobetasol with triamcinolone (Rodstrom 1994; Sivaraman 2016); prednisolone with triamcinolone (Ghabanchi 2009); and fluticasone with betamethasone (Hegarty 2002).
For two studies, data were not suitable for quantitative analysis (Ghabanchi 2009; Hegarty 2002).
Pain score
Three studies comparing different corticosteroids measured pain score (Campisi 2004; Carbone 2009; Liu 2013). Carbone 2009 compared two different concentrations of clobetasol ointment and found no difference between 0.025% and 0.05% formulations (MD –0.26, 95% CI –1.42 to 0.90; 30 participants; low‐certainty evidence). Campisi 2004 compared two different formulations of topical clobetasol propionate and showed that participants treated with 0.025% microspheres of clobetasol reported significantly less pain in comparison with standard ointment at the same concentration (MD 1.83, 95% CI 0.80 to 2.86; 45 participants). Liu 2013 compared two different intralesional corticosteroids (betamethasone and triamcinolone acetonide), and found no evidence in terms of pain reduction between the two groups (MD –0.41, 95% CI –1.47 to 0.65; 59 participants; low‐certainty evidence).
Pain resolution
One study that compared systemic betamethasone and topical triamcinolone acetonide showed no evidence of a difference in pain resolution between the two treatments (RR 1.04, 95% CI 0.60 to 1.80; 49 participants; very low‐certainty evidence; Analysis 3.2) (Malhotra 2008).
Clinical score
Four studies comparing steroids included clinical score (Campisi 2004; Carbone 2009; Liu 2013; Malhotra 2008).
Carbone 2009 compared two different concentrations of clobetasol propionate ointment, and showed no difference between 0.025% and 0.05% formulations (MD 0.47, 95% CI –0.26 to 1.20; 30 participants; low‐certainty evidence; Analysis 3.3). Campisi 2004 compared two different formulations of topical clobetasol, and showed no difference between participants treated with 0.025% microspheres of clobetasol and those treated with standard clobetasol 0.025% (MD 0.00, 95% CI –0.61 to 0.61; 45 participants; Analysis 3.3). Malhotra 2008 compared systemic betamethasone and topical triamcinolone acetonide, showing a better clinical score among participants treated with topical triamcinolone acetonide (MD 1.13, 95% CI 0.09 to 2.17; 46 participants; very low‐certainty evidence; Analysis 3.3). In contrast, Liu 2013 found in favour of intralesional betamethasone over triamcinolone acetonide when measuring clinical improvement at 14 days (MD 9.77, 95% CI 0.81 to 18.73; 59 participants; very low‐certainty evidence).
Clinical resolution
Five studies comparing steroids included clinical resolution (Campisi 2004; Carbone 2009; Liu 2013; Rodstrom 1994; Sivaraman 2016).
Carbone 2009 compared two different concentrations of clobetasol ointment and showed no evidence of a difference between 0.025% and 0.05% formulations (RR 1.14, 95% CI 0.56 to 2.35; 30 participants; very low‐certainty evidence). Campisi 2004 compared two different formulations of topical clobetasol and showed no evidence of a difference between participants treated with 0.025% microspheres of clobetasol and those treated with standard clobetasol 0.025%. Liu 2013 compared two different intralesional corticosteroids (betamethasone and triamcinolone acetonide) and showed a better resolution rate among participants treated with betamethasone (RR 1.40, 95% CI 1.06 to 1.83; 59 participants; low‐certainty evidence). Two studies compared clobetasol propionate ointment with triamcinolone acetonide ointment (Rodstrom 1994; Sivaraman 2016): the pooled data showed that participants treated with clobetasol were more likely to achieve clinical resolution (RR 1.56, 95% CI 1.09 to 2.21; 2 studies, 57 participants; I² = 96%; low‐certainty evidence) (Analysis 3.4). There was very high heterogeneity. In one study, all participants experienced clinical resolution.
Adverse effects
Five studies provided data on adverse effects. In Carbone 2009, there were no adverse effects in either group. In Campisi 2004, the two formulations of clobetasol propionate caused adverse effects with similar frequency. In Malhotra 2008, oral betamethasone caused significantly more adverse effects than triamcinolone oral paste. In Rodstrom 1994, three participants had adverse effects, all from the clobetasol group (they did not complete the study). Liu 2013 reported only one participant with adverse effects in the intralesional betamethasone group (Analysis 3.5). The evidence from these studies was low to very low certainty.
4. Corticosteroids versus other treatments
Nine studies compared one corticosteroid with another treatment: two compared local corticosteroids, namely dexamethasone mouthrinse and triamcinolone acetonide in Orabase, with photodynamic therapy (Bakhtiari 2017; Mostafa 2017); two compared triamcinolone acetonide cream with curcumin paste (Kia 2015; Thomas 2017); one split‐mouth study compared triamcinolone acetonide cream with cryotherapy (Amanat 2014); one compared triamcinolone acetonide cream with local injections with Bacillus Calmette‐Guerin polysaccharide nucleic acid (BCG‐PSN) (Xiong 2009); one compared clobetasol propionate ointment with low‐level laser therapy (LLLT) (Dillenburg 2014); one compared dexamethasone ointment with amlexanox paste (Fu 2012); and one compared triamcinolone acetonide gel with hyaluronic acid gel (Hashem 2019).
Pain score
All nine studies comparing one corticosteroid with another treatment reported pain score. There was very low‐certainty evidence that three local treatments may have achieved better pain control than local corticosteroids, namely LLLT (MD 0.62, 95% CI 0.42 to 0.82; 1 study, 42 participants; Analysis 4.1), photodynamic therapy (MD 4.90, 95% CI 2.98 to 6.82; 1 study, 20 participants; Analysis 4.1) and cryotherapy (MD 1.48, 95% CI 0.58 to 2.38; 1 study, 52 participants; Analysis 4.2). Topical triamcinolone acetonide achieved better pain control than topical curcumin (MD –0.64, 95% CI –1.19 to –0.10; 2 studies, 100 participants; I² = 0%; low‐certainty evidence). For the other treatments, there were no differences (moderate‐ to very low‐certainty evidence).
Pain resolution
Fu 2012 compared dexamethasone ointment with amlexanox paste and found no difference in pain resolution between the two treatments (RR 0.75, 95% CI 0.34 to 1.66, 36 participants; very low‐certainty evidence) (Analysis 4.3).
Clinical score
All nine studies comparing one corticosteroid with another treatment reported clinical score. Two treatments obtained a better clinical improvement than local corticosteroids, namely LLLT (MD 0.56, 95% CI 0.50 to 0.62; 42 participants; very low‐certainty evidence; Dillenburg 2014), and photodynamic therapy (MD 1.52, 95% CI 0.17 to 2.87; 20 participants; low‐certainty evidence; Mostafa 2017). For the other treatments, there were no differences (low‐ to very low‐certainty evidence) (Analysis 4.4; Analysis 4.5).
Clinical resolution
Five studies comparing one corticosteroid with another treatment reported clinical resolution (Amanat 2014; Bakhtiari 2017; Dillenburg 2014; Fu 2012; Kia 2015). One treatment, LLLT, achieved a better clinical resolution rate than local corticosteroid (RR 0.46, 95% CI 0.22 to 0.98; 42 participants; very low‐certainty evidence; Analysis 4.6; Dillenburg 2014). For the other treatments, there were no differences (low‐ to very low‐certainty evidence; Analysis 4.6; Analysis 4.7).
Adverse effects
Five studies provided data on adverse effects (Amanat 2014; Dillenburg 2014; Fu 2012; Kia 2015; Xiong 2009). In one study, there were no adverse events in any group (Kia 2015). Cryotherapy caused significantly more adverse events than triamcinolone (Analysis 4.9; Amanat 2014). In the other studies, the two treatments caused the same type of adverse effects with similar frequency (Analysis 4.8). The evidence was from low to very‐low certainty.
5. Adjunctive treatment to corticosteroids
Six studies investigated the putative benefits of treatments adjunctive to corticosteroids. Two studies investigated the effect of antifungals, with the aim of improving OLP or preventing candidosis secondary to local immunosuppression, or both: one compared dexamethasone with and without nystatin (Wei 2003), and the other compared clobetasol propionate gel with and without miconazole gel (Lodi 2007). One study compared dexamethasone mouthwash (0.5%) plus nystatin suspension, with or without curcumin tablets (Amirchaghmaghi 2016). One study compared triamcinolone with or without systemic glucosamine sulphate (Hesen 2017).
One study was designed to assess the effect of adjunctive treatment with curcuminoids (compounds found to have anti‐inflammatory effects and used in Ayurvedic medicine (one of the world's oldest holistic healing systems developed in India)) in people also receiving treatment with oral prednisone (Chainani‐Wu 2007). This study planned to recruit 100 participants but recruitment stopped after a planned interim analysis showed no difference between the adjunctive curcuminoid and placebo groups.
One study compared an unusual three‐stage treatment integrating Western and Chinese medicine, with a two‐stage Western medicine approach. Western‐Chinese included topical application of herbal pulvis, herbal decoction together with oral corticosteroid (prednisone), oral antihistamine (chlorphenamine) and vitamin C using gradually decreasing doses, followed by herbal decoction alone. The comparison group received prednisone, chlorphenamine and vitamin C in fixed dose, followed by a phase of gradually decreasing dosage (Xu 2002).
Pain score
Three studies investigating adjunctive treatment with corticosteroids included pain measured by VAS as a continuous value. There was no benefit of miconazole, curcumin or glucosamine sulphate in terms of pain relief (Analysis 5.1; Amirchaghmaghi 2016; Hesen 2017; Lodi 2007). The evidence was from low to very low certainty.
Pain resolution
None of the studies investigating adjunctive treatment with corticosteroids included pain resolution as a dichotomous outcome.
Clinical score
Three studies investigating adjunctive treatment with corticosteroids included clinical score. Lodi 2007 found no difference in the percentage of oral mucosa affected between the adjunctive antifungal and steroid‐only groups. Amirchaghmaghi 2016 and Hesen 2017 found no difference in terms of Thongprasom score (Thongprasom 1992) between the two groups, with or without adjunctive treatment (Analysis 5.2). The evidence was from low to very low certainty.
Xu 2002 found a benefit favouring the integrated Chinese and Western medicine that just attained statistical significance, although this study was at high risk of bias.
Clinical resolution
Two studies investigating adjunctive treatment with corticosteroids included clinical resolution (Amirchaghmaghi 2016; Wei 2003). Neither study found a difference in the number of participants in each group reporting clinical resolution (Analysis 5.3). The evidence was very‐low certainty.
Adverse effects
Two studies investigating adjunctive treatment with corticosteroids reported adverse effects. One study recorded no adverse effects in either group (Amirchaghmaghi 2016), while the other reported five cases of candidosis among the 15 participants of the group without antifungal compared with no cases in the group with antifungal (Lodi 2007) (Analysis 5.4). The evidence was of low certainty.
Discussion
Summary of main results
The main objective of this review was to evaluate the efficacy of corticosteroids to treat people with symptoms of OLP. We included participants with symptoms only, as presence of pain is the main indication for OLP treatment, and for this reason, pain was the primary outcome of this review, measured as resolution of symptoms or change in pain score. The efficacy of corticosteroid treatments was also evaluated on the basis of resolution of clinical lesions and change in clinical score. We also considered adverse effects of treatments.
We included 35 RCTs in our review. We assessed seven studies at overall low risk of bias, 10 studies at unclear risk and the remaining 18 at high risk.
Three studies compared a topical corticosteroid with a placebo. The corticosteroids used in the studies were flucinonide, triamcinolone acetonide and clobetasol propionate, all in adhesive preparations. Pain resolution was more common among participants treated by topical corticosteroids than those receiving placebo. As reported in summary of findings Table for the main comparison, the certainty of evidence as measured according to GRADE criteria was low. We found no evidence of a difference between topical steroids and placebo when measuring clinical resolution. Adverse effects caused by topical steroids were not significant in terms of frequency or severity. The certainty of the evidence assessed was very low for clinical resolution and adverse effects.
Twelve studies compared a corticosteroid with a calcineurin inhibitor; in particular, clobetasol propionate versus ciclosporin (one study); clobetasol propionate versus tacrolimus (three studies); triamcinolone acetonide versus pimecrolimus (three studies); triamcinolone acetonide versus tacrolimus (three studies); triamcinolone acetonide versus ciclosporin (one study) and betamethasone versus pimecrolimus (one study). We were able to conduct meta‐analyses for studies comparing clobetasol propionate versus tacrolimus (outcomes: pain resolution, clinical resolution and adverse effects) and studies comparing triamcinolone acetonide versus tacrolimus (outcomes: clinical resolution and adverse effects). Pain resolution and clinical resolution were significantly more frequent among participants treated with topical tacrolimus compared with clobetasol propionate, with the certainty of evidence assessed according to GRADE being very low (summary of findings Table 2). Two studies only compared clinical resolution among participants treated with triamcinolone acetonide and tacrolimus, showing conflicting results; the pooled data indicated no significant benefit among participants treated with tacrolimus; however, such results must be carefully interpreted because of the very low certainty of the evidence assessed according to GRADE (summary of findings Table 2). One study showed higher incidence of adverse effects in participants treated with corticosteroids when compared to calcineurin inhibitors, while all the other studies showed higher incidence of adverse effects in the calcineurin inhibitor group (low‐ to very low‐certainty evidence).
The results for calcineurin inhibitors should be also considered with caution and the benefits and adverse effects of this class of medication on OLP will be scrutinised in more in depth scrutinised our the sister review on non‐corticosteroids.
Twenty‐three studies compared either two corticosteroids or the same corticosteroid in different modalities (eight studies), or one corticosteroid with another treatment (nine studies), or treatments adjunctive to corticosteroids (six studies). Although no corticosteroid or formulation has proven to be convincingly superior, single trials suggest that low‐level laser, cryotherapy and photodynamic therapy may be superior to topical corticosteroids (low‐ to very low‐certainty evidence). One single trial at high risk of bias has also reported benefit from integrating traditional Chinese medicine with corticosteroids (very low‐certainty evidence).
Although not negligible (Varoni 2012), systemic absorption of topical corticosteroids throughout oral mucosa is less likely to cause the adverse events characteristic of long‐term use of such drugs, particularly in those due to adrenal suppression. For this reason, topical application is considered the preferable approach for first‐line corticosteroid treatment of OLP.
Overall completeness and applicability of evidence
In this review, we presented the evidence regarding the effects of corticosteroids, mainly used in topical preparations, in treating people affected by symptomatic OLP.
The studies included in the review investigated the efficacy of a large number of systemic and topical corticosteroids, including some of the drugs most frequently used as first‐line treatment, such as clobetasol propionate and triamcinolone acetonide. In this updated version of the review, we identified three placebo‐controlled trials of corticosteroids of different potencies, namely triamcinolone acetonide, flucinonide and clobetasol propionate, for treating symptomatic OLP, which showed some benefit. Interestingly, all three corticosteroids were delivered in adhesive creams. Because of high variability in corticosteroid formulation, concentration or dosage regimen among studies, it is difficult to evaluate and compare them, and to meta‐analyse data. Interestingly, topical corticosteroids seem to be more effective than most other treatment modalities except topical tacrolimus. However, when it comes to clinical response, the benefit of topical tacrolimus over topical corticosteroids is less clear and more better‐conducted trials are clearly warranted. Moreover, topical tacrolimus seems to cause more adverse effects than corticosteroids and there is some concern that this drug could increase the risk of malignant transformation of OLP (Becker 2006; Mattsson 2010).
Thirty of 35 included studies measured pain, which was the primary outcome of this review as it is most often the reason that people seek treatment. Measuring pain in clinical trials of treatments for OLP is difficult due to the fluctuating nature of OLP pain and variations between participants. In addition, pain scores may be influenced by the timing of the evaluation: assessments at different times of the day (e.g. between meals, while eating or while performing oral care) may give rise to different pain scores. Moreover, the impact of pain on physical, emotional and social functions may require multidimensional qualitative tools and health‐related quality of life instruments that are uncommonly used in OLP trials. For our secondary outcomes, 100% of studies measured clinical presentation and 62% measured adverse effects. However, the methods adopted to measure such outcomes were different and often difficult to compare, representing another obstacle to summarising their effects and to meta‐analysing data. Less than half (47%) of the studies included in this review assessed Improvement of clinical signs of OLP using the same clinical criteria score (one devised by Thongprasom 1992). The remaining studies used a variety of assessments. The lack of a widely accepted system for scoring the clinical severity of OLP makes it difficult to compare the effectiveness of drugs within and between individuals, and between different institutions. Therefore, clinical assessment criteria should be established and accepted by clinicians before further RCTs are undertaken.
Due to the chronic nature of OLP and the impact of this condition on quality of life, the use of patient‐reported outcome measures (PROMs) in assessing the treatment of chronic oral mucosal diseases is of great importance (Ní Ríordáin 2015). For this reason, the next update of this review will include PROMs among primary outcome measures.
Because of small sample size in many trials, it is likely that there was a lack of power to detect differences between treatments, if indeed such a difference existed.
The evidence for corticosteroids should have reasonable applicability as the included studies reported data from participants from different countries. In addition, our criteria limited the inclusion in the review, to studies enrolling participants who can benefit from corticosteroid treatment, that is, affected by symptomatic OLP, with the typical clinical features of people attending the majority of oral medicine services.
Quality of the evidence
Seven studies were at overall low risk of bias (Amirchaghmaghi 2016; Arduino 2018; Carbone 2009; Ezzatt 2019; Hettiarachchi 2017; Lodi 2007; Siponen 2017). Seventeen included studies were at high risk of bias: 15 for detection or performance bias (blinding), four for attrition bias, seven for reporting bias and one for 'other potential sources of bias', because of differences between groups in clinical score at baseline (Malhotra 2008).
When assessed using the GRADE method (Atkins 2004), the overall certainty of the evidence from placebo‐controlled studies was low to very low due to the small number of participants and relatively large CIs, risk of bias and high heterogeneity (summary of findings Table for the main comparison). Likewise, for studies comparing topical corticosteroids with topical calcineurin inhibitors, the certainty of the evidence varied from low to very low, mainly due to heterogeneity, risk of bias, small number of participants and large CIs (summary of findings Table 2).
Potential biases in the review process
We have taken steps to minimise the bias in every step of the review. We searched databases and trial registries with no language limitations to identify all the relevant reports. We tried to contact the study authors for missing data through e‐mails. We provided a narrative description of trials with data that did not allow quantitative analysis.
Agreements and disagreements with other studies or reviews
Most published reviews, both systematic and narrative, on OLP management consider topical corticosteroids to be the most useful agents for the treatment of this disease (e.g. Al‐Hashimi 2007; Carrozzo 2009; Cribier 1998; Le Cleach 2012).
Chamani 2015, a systematic review and meta‐analysis including 10 studies, assessed the efficacy of tacrolimus and clobetasol in the treatment of OLP. Three out of 10 studies directly compared clobetasol with tacrolimus and two found this drug more effective than the topical corticosteroid, which is similar to the findings of our systematic review.
Another systematic review assessed the efficacy of any form of intervention used to medically manage OLP and included 29 clinical trials using corticosteroid as an active intervention (Suresh 2016). Conclusions suggest that betamethasone valerate, fluocinonide and clobetasol propionate are more effective than placebo. Whereas these conclusions are, generally speaking, in agreement with our review, it should be emphasised that the inclusion criteria of the Suresh 2016 review were significantly different from our review and the results were mainly reported in a descriptive way. The review stated that it fulfils the PRISMA checklist (Moher 2009); however, reporting of the data collection process and data items were unclear and no meta‐analysis was attempted (Suresh 2016).
Two systematic reviews compared the efficacy of LLLT in OLP to that of topical corticosteroids (Akram 2018; Al‐Maweri 2018). Both reviews selected the same three RCTs, only one of which was included in our review (Dillenburg 2014). We excluded the other two RCTs: Jajarm 2011 enrolled participants without symptoms, and Kazancioglu 2015 did not use corticosteroids. Akram 2018 also considered two non‐RCTs. The reviews reached different conclusions: Al‐Maweri 2018 stated that LLLT is effective and can be used as an alternative to corticosteroids; Akram 2018 concluded that is unclear whether LLLT is more or as effective as topical corticosteroids in OLP management. Our review concords with the latter, as we found little evidence that LLLT is better than TCs.
Another review has systematically evaluated the efficacy of aloe vera in comparison to triamcinolone acetonide paste in the management of OLP (Ali 2017). It concluded that they showed comparable effectiveness. The review included two RCTs (Mansourian 2011; Reddy 2012). Notably, neither of these studies is included in our review because they enrolled participants without symptoms (Characteristics of excluded studies table).
Study flow diagram of searches for this update.
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
Comparison 1 Corticosteroids versus placebo, Outcome 1 Pain score.
Comparison 1 Corticosteroids versus placebo, Outcome 2 Pain resolution.
Comparison 1 Corticosteroids versus placebo, Outcome 3 Clinical score.
Comparison 1 Corticosteroids versus placebo, Outcome 4 Clinical resolution.
Comparison 1 Corticosteroids versus placebo, Outcome 5 Adverse effects.
Comparison 2 Corticosteroids versus calcineurin inhibitors, Outcome 1 Pain score.
Comparison 2 Corticosteroids versus calcineurin inhibitors, Outcome 2 Pain resolution.
Comparison 2 Corticosteroids versus calcineurin inhibitors, Outcome 3 Clinical score.
Comparison 2 Corticosteroids versus calcineurin inhibitors, Outcome 4 Clinical resolution.
Comparison 2 Corticosteroids versus calcineurin inhibitors, Outcome 5 Adverse effects.
Comparison 3 Corticosteroid A versus corticosteroid B, Outcome 1 Pain score.
Comparison 3 Corticosteroid A versus corticosteroid B, Outcome 2 Pain resolution.
Comparison 3 Corticosteroid A versus corticosteroid B, Outcome 3 Clinical score.
Comparison 3 Corticosteroid A versus corticosteroid B, Outcome 4 Clinical resolution.
Comparison 3 Corticosteroid A versus corticosteroid B, Outcome 5 Adverse effects.
Comparison 4 Corticosteroids versus other treatments, Outcome 1 Pain score.
Comparison 4 Corticosteroids versus other treatments, Outcome 2 Pain score (split‐mouth study).
Comparison 4 Corticosteroids versus other treatments, Outcome 3 Pain resolution.
Comparison 4 Corticosteroids versus other treatments, Outcome 4 Clinical score.
Comparison 4 Corticosteroids versus other treatments, Outcome 5 Clinical score (split‐mouth study).
Comparison 4 Corticosteroids versus other treatments, Outcome 6 Clinical resolution.
Comparison 4 Corticosteroids versus other treatments, Outcome 7 Clinical Resolution (split‐mouth study).
Comparison 4 Corticosteroids versus other treatments, Outcome 8 Adverse effects.
Comparison 4 Corticosteroids versus other treatments, Outcome 9 Adverse events (split‐mouth study).
Comparison 5 Adjunctive treatment to corticosteroids, Outcome 1 Pain (mean score).
Comparison 5 Adjunctive treatment to corticosteroids, Outcome 2 Clinical score.
Comparison 5 Adjunctive treatment to corticosteroids, Outcome 3 Clinical resolution.
Comparison 5 Adjunctive treatment to corticosteroids, Outcome 4 Adverse effects.
| Corticosteroids compared to placebo for treating symptomatic, biopsy‐confirmed oral lichen planus | ||||||
| Population: people with oral lichen planus Setting: university dental clinics Intervention: topical corticosteroids Comparison: placebo | ||||||
| Outcomes | Anticipated absolute effects* (95% CI) | Relative effect | Number of participants | Certainty of the evidence | Comments | |
| Risk with placebo | Risk with corticosteroids | |||||
| Pain resolution** measured via VAS (1‐10cm) and 5‐grade score Follow‐up: 8‐9 weeks | 306 per 1000 | 584 per 1000 | RR 1.91 (1.08 to 3.36) | 72 | ⊕⊕⊝⊝ | 1 RCT evaluated clobetasol propionate and the other flucinonide. |
| Clinical resolution*** measured via Thongparsom and 5‐grade score Follow‐up: 8‐9 weeks | 50 per 1000b | 300 per 1000 (38 to 2379) | RR 6.00 (0.76 to 47.58) | 72 | ⊕⊝⊝⊝ | 1 RCT evaluated clobetasol propionate and the other flucinonide. |
| Adverse effects**** Follow‐up: 3‐9 weeks | 89 per 1000 | 132 per 1000 | RR 1.48 (0.48 to 4.56) | 88 | ⊕⊝⊝⊝ | RCTs evaluated clobetasol propionate, flucinonide (no adverse effects noted) and triamcinolone acetonide. |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). ** Subjective assessment by participants at the end of treatment ***Assessment by clinicians at the end of treatment ****Reported by participants throughout the study CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; VAS: visual analogue scale. | ||||||
| GRADE Working Group grades of evidence | ||||||
| aDowngraded one level due to risk of bias (one study judged at unclear risk). | ||||||
| Corticosteroids compared to calcineurin inhibitors for treating symptomatic, biopsy‐confirmed oral lichen planus | |||||||
| Population: people with oral lichen planus Setting: university dental clinics Intervention: topical corticosteroids Comparison: topical calcineurin inhibitors | |||||||
| Outcomes | Treatment comparison | Anticipated absolute effects* (95% CI) | Relative effect | № of participants | Certainty of the evidence | Comments | |
| Risk with calcineurin inhibitors | Risk with corticosteroids | ||||||
| Pain resolution** measured via VAS and 4‐grade scale Follow‐up: 3‐8 weeks | clobetasol vs ciclosporin | 200 per 1000 | 422 per 1000 | RR 2.11 (0.76 to 5.86) | 39 | ⊕⊝⊝⊝ | — |
| clobetasol vs tacrolimus | 440 per 1000 | 198 per 1000 | RR 0.45 (0.24 to 0.88) | 100 | ⊕⊝⊝⊝ | — | |
| triamcinolone vs tacrolimus | — | — | — | — | — | No data for this outcome | |
| Clinical resolution*** measured via Thongprasom and 4‐grade scale Follow‐up: 3‐8 weeks | clobestol vs ciclosporin | 150 per 1000 | 474 per 1000 | RR 3.16 (1.00 to 9.93) | 39 | ⊕⊝⊝⊝ | — |
| clobetasol vs tacrolimus | 654 per 1000 | 399 per 1000 | RR 0.61 (0.38 to 0.99) | 52 | ⊕⊝⊝⊝ | — | |
| triamcinolone vs tacrolimus | 467 per 1000 | 401 per 1000 | RR 0.86 (0.55 to 1.35) | 60 | ⊕⊝⊝⊝ | — | |
| Adverse effects**** Follow‐up: 3‐8 weeks | clobetasol vs ciclosporin | 50 per 1000 | 316 per 1000 | RR 6.32 (0.84 to 47.69) | 39 | ⊕⊝⊝⊝ | — |
| clobetasol vs tacrolimus | 180 per 1000 | 9 per 1000 | RR 0.05 (0.00 to 0.83) | 100 | ⊕⊝⊝⊝ | — | |
| triamcinolone vs tacrolimus | 516 per 1000 | 243 per 1000 | RR 0.47 (0.22 to 0.99) | 58 | ⊕⊕⊝⊝ | — | |
| *The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). **Subjective assessment by participants at the end of treatment ***Assessment by clinicians at the end of treatment **** Reported by participants throughout the duration of the study CI: confidence interval; RCT: randomised controlled trial; RR: risk ratio; VAS: visual analogue scale. | |||||||
| GRADE Working Group grades of evidence | |||||||
| aDowngraded three levels as very small single study at unclear risk of bias, with large CI that includes the possibility of either intervention being superior. | |||||||
| Comparison | Delivery method | Interventions | Study |
| Corticosteroids vs placebo | Topical | Fluocinonide 0.025% in 40% hypromellose ointment in white soft paraffin vs placebo | |
| Topical | Triamcinolone acetonide ointment 0.1% vs placebo | ||
| Topical | Clobetasol propionate 0.025% in 4% hydroxyethyl cellulose gel vs placeboa | ||
| Corticosteroids vs calcineurin inhibitors | Topical | Triamcinolone acetonide 0.1% paste vs pimecrolimus 1% paste | |
| Topical | Clobetasol propionate 0.025% in 4% hydroxyethyl cellulose gel vs ciclosporin 1.5% in 4% hydroxyethyl cellulose gela | ||
| Topical | Clobetasol propionate 0.05% ointment vs tacrolimus 0.1% ointment | ||
| Topical | Betamethasone 0.1% gel vs pimecrolimus 1% gel | ||
| Topical | Clobetasol propionate 0.05% cream vs tacrolimus 0.1% cream | ||
| Topical | Clobetasol propionate 0.05% vs tacrolimus 0.03% | ||
| Topical | Triamcinolone 0.1% paste vs pimecrolimus 1% cream | ||
| Topical | Triamcinolone acetonide 0.1% in Orabase vs pimecrolimus 1% cream | ||
| Topical | Triamcinolone acetonide 0.1% in hypromellose 20% ointment vs tacrolimus 1% ointment | ||
| Topical | Triamcinolone acetonide ointment 0.1% vs tacrolimus 0.1% ointment | ||
| Topical | Triamcinolone acetonide 0.1% vs tacrolimus 0.03% | ||
| Topical | Triamcinolone acetonide 0.1% in Orabase vs ciclosporin solution 0.1% | ||
| Corticosteroid A vs corticosteroid B | Topical | Clobetasol propionate in microspheres 0.025% vs clobetasol propionate 0.025% in a dispersion of a lipophilic ointment in a hydrophilic phase | |
| Topical | Clobetasol priopionate 0.05% in 4% hydroxyethyl cellulose vs clobetasol priopionate 0.025% in 4% hydroxyethyl cellulosea | ||
| Topical | Clobetasol propionate 0.05% ointment in Orabase vs triamcinolone acetonide 0.1% ointment in Orabase | ||
| Topical | Clobetasol propionate 0.05% vs triamcinolone acetonide 0.1% | ||
| Injected locally | Betamethasone dipropionate 5 mg + betamethasone disodium phosphate 2 mg/mL intralesional injection vs triamcinolone acetonide 8 mg, intralesional injection | ||
| Systemic | Betamethasone 5 mg daily orally vs triamcinolone acetonide 0.1% paste | ||
| Topical | Prednisolone 5 mg mucoadhesive tablet vs triamcinolone acetonide 0.1% paste | ||
| Topical | Fluticasone spray 50 μg vs betamethasone sodium phosphate 500 μg oral rinses | ||
| Corticosteroids vs other treatments | Topical | Triamcinolone acetonide paste 0.1% vs curcumin paste 5% | |
| Topical | Triamcinolone acetonide paste 0.1% vs Curenext Oral Gel containing curcuma longa extracts 10 mg | ||
| Topical | Dexamethasone mouthwash 0.5 mg oral rinses vs photodynamic therapy mediated by methylene blue | ||
| Topical | Triamcinolone acetonide 0.1% paste vs hyaluronic acid preparation 0.2% paste | ||
| Topical | Triamcinolone acetonide 0.1% in Orabase vs photodynamic therapy mediated by methylene blue | ||
| Topical | Triamcinolone acetonide ointment 0.1% in Orabase vs cryotherapy | ||
| Topical | Clobetasol propionate gel 0.05% vs laser diodeb | ||
| Injected locally | Triamcinolone acetonide 10 mg intralesional injection vs Bacillus Calmette‐Guerin polysaccharide nucleic acid, 0.5 mL intralesional injection | ||
| Topical | Dexamethasone paste 0.043% vs amlexanox paste 250 mg | ||
| Adjunctive treatment to corticosteroids | Topical | Clobetasol propionate gel 0.05% + miconazole 2% gel vs clobetasol propionate gel 0.05% + placebo gel | |
| Topical | Dexamethasone paste and mycostatin paste alternatively vs dexamethasone paste | ||
| Topical | Dexamethasone mouthwash 0.5 mg oral rinses + curcumin 250 mg tablets vs dexamethasone mouthwash 0.5 mg oral rinses + placebob | ||
| Topical | Triamcinolone acetonide 0.1% oral paste + glucosamine sulphate 1500 mg vs triamcinolone acetonide 0.1% oral paste | ||
| Systemic | Prednisone 60 mg + curcuminoids 2000 mg daily vs prednisone 60 mg + placebo | ||
| Systemic | Herbal topical and decoction + prednisone 5–10 mg 3 times daily chlorphenamine 4 mg 3 times daily, vitamin C 0.1 g 3 times daily vs prednisone 5–10 mg 3 times daily, chlorphenamine 4 mg 3 times daily, vitamin C 0.1g 3 times daily | ||
| aParticipants in both groups also received antifungals: miconazole gel plus 0.12% chlorhexidine mouthrinse. | |||
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain score Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.1 Clobetasol vs placebo | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Pain resolution Show forest plot | 2 | 72 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.91 [1.08, 3.36] |
| 2.1 Flucinonide vs placebo | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.17 [1.03, 4.55] |
| 2.2 Clobetasol vs placebo | 1 | 32 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.6 [0.67, 3.84] |
| 3 Clinical score Show forest plot | 1 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1 Clobetasol vs placebo | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Clinical resolution Show forest plot | 2 | 72 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.0 [0.76, 47.58] |
| 4.1 Flucinonide vs placebo | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 9.0 [0.52, 156.91] |
| 4.2 Clobetasol vs placebo | 1 | 32 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.0 [0.13, 68.57] |
| 5 Adverse effects Show forest plot | 3 | 88 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.48 [0.48, 4.56] |
| 5.1 Flucinonide vs placebo | 1 | 40 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] |
| 5.2 Triamcinolone vs placebo | 1 | 16 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.29 [0.37, 4.53] |
| 5.3 Clobetasol vs placebo | 1 | 32 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.0 [0.20, 19.91] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain score Show forest plot | 4 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1 Clobetasol vs tacrolimus | 1 | 68 | Mean Difference (IV, Fixed, 95% CI) | 0.08 [‐0.33, 0.49] |
| 1.2 Triamcinolone vs pimecrolimus | 2 | 70 | Mean Difference (IV, Fixed, 95% CI) | ‐0.05 [‐2.97, 2.87] |
| 1.3 Triamcinolone vs ciclosporin | 1 | 139 | Mean Difference (IV, Fixed, 95% CI) | ‐0.23 [‐1.02, 0.56] |
| 2 Pain resolution Show forest plot | 3 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 2.1 Clobetasol vs ciclosporin | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 2.11 [0.76, 5.86] |
| 2.2 Clobetasol vs tacrolimus | 2 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.45 [0.24, 0.88] |
| 3 Clinical score Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1 Clobetasol vs tacrolimus | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Triamcinolone vs pimecrolimus | 2 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Clinical resolution Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 Clobetasol vs ciclosporin | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 3.16 [1.00, 9.93] |
| 4.2 Clobetasol vs tacrolimus | 2 | 52 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.61 [0.38, 0.99] |
| 4.3 Triamcinolone vs tacrolimus | 2 | 60 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.86 [0.55, 1.35] |
| 5 Adverse effects Show forest plot | 7 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 5.1 Clobetasol vs ciclosporin | 1 | 39 | Risk Ratio (M‐H, Fixed, 95% CI) | 6.32 [0.84, 47.69] |
| 5.2 Clobetasol vs tacrolimus | 2 | 100 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.05 [0.00, 0.83] |
| 5.3 Triamcinolone vs ciclosporin | 1 | 139 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.15 [0.05, 0.49] |
| 5.4 Triamcinolone vs pimecrolimus | 1 | 35 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.21 [0.01, 4.10] |
| 5.5 Triamcinolone vs tacrolimus | 2 | 58 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.47 [0.22, 0.99] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain score Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.1 Clobetasol ointment (0.025%) vs clobetasol ointment (0.05%) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Clobetasol ointment (0.025%) vs clobetasol microspheres (0.025%) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Intralesional betamethasone (1.4mg) vs intralesional triamcinolone acetonide (8mg) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Pain resolution Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 2.1 Betamethasone (5 mg) vs triamcinolone paste (0.1%) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Clinical score Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 3.1 Clobetasol ointment (0.025%) vs clobetasol ointment (0.05%) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Clobetasol (0.025%) ointment vs clobetasol microspheres (0.025%) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.3 Betamethasone (5 mg) vs triamcinolone (0.1%) | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Clinical resolution Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Subtotals only | |
| 4.1 Clobetasol ointment (0.025%) vs clobetasol ointment (0.05%) | 1 | 30 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.14 [0.56, 2.35] |
| 4.2 Clobetasol ointment (0.025%) vs clobetasol microspheres (0.025%) | 1 | 45 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.04 [0.80, 1.36] |
| 4.3 Clobetasol ointment (0.05%) vs triamcinolone (0.1%) ointment | 2 | 57 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.56 [1.09, 2.21] |
| 4.4 Intralesional betamethasone (1.4 mg) vs intralesional triamcinolone acetonide (8 mg) | 1 | 59 | Risk Ratio (M‐H, Fixed, 95% CI) | 1.40 [1.06, 1.83] |
| 5 Adverse effects Show forest plot | 5 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 5.1 Clobetasol ointment (0.025%) vs clobetasol ointment (0.05%) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.2 Clobetasol ointment (0.025%) vs clobetasol microspheres (0.025%) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.3 Clobetasol ointment (0.05%) vs triamcinolone (0.1%) ointment | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.4 Betamethasone (5 mg) vs triamcinolone (0.1%) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5.5 Intralesional betamethasone (1.4 mg) vs intralesional triamcinolone acetonide (8 mg) | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain score Show forest plot | 7 | Mean Difference (IV, Fixed, 95% CI) | Subtotals only | |
| 1.1 Triamcinolone vs curcumin topical | 2 | 100 | Mean Difference (IV, Fixed, 95% CI) | ‐0.64 [‐1.19, ‐0.10] |
| 1.2 Triamcinolone vs BCG‐PSN | 1 | 53 | Mean Difference (IV, Fixed, 95% CI) | 0.59 [‐0.15, 1.33] |
| 1.3 Clobetasol ointment (0.05%) vs low‐level laser therapy | 1 | 42 | Mean Difference (IV, Fixed, 95% CI) | 0.62 [0.42, 0.82] |
| 1.4 Dexamethasone ointment vs amlexanox paste | 1 | 36 | Mean Difference (IV, Fixed, 95% CI) | 0.05 [‐0.78, 0.88] |
| 1.5 Triamcinolone vs PDT | 1 | 20 | Mean Difference (IV, Fixed, 95% CI) | 4.9 [2.98, 6.82] |
| 1.6 Triamcinolone vs hyaluronic acid | 1 | 40 | Mean Difference (IV, Fixed, 95% CI) | ‐0.12 [‐0.65, 0.41] |
| 2 Pain score (split‐mouth study) Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | Subtotals only | |
| 2.1 Triamcinolone vs cryotherapy | 1 | Mean Difference (Fixed, 95% CI) | 1.48 [0.58, 2.38] | |
| 3 Pain resolution Show forest plot | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1 Dexamethasone ointment vs amlexanox paste | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Clinical score Show forest plot | 8 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 4.1 Triamcinolone vs hyaluronic acid | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.2 Triamcinolone vs curcumin topical | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.3 Triamcinolone vs curcumin topical | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.4 Triamcinolone vs BCG‐PSN | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.5 Clobetasol ointment (0.05%) vs low‐level laser therapy | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.6 Dexamethasone ointment vs amlexanox paste | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.7 Dexamethasone mouthwash + nystatin vs PDT | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.8 Triamcinolone vs PDT | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 5 Clinical score (split‐mouth study) Show forest plot | 1 | Mean Difference (Fixed, 95% CI) | 0.11 [‐0.46, 0.68] | |
| 5.1 Triamcinolone vs cryotherapy | 1 | Mean Difference (Fixed, 95% CI) | 0.11 [‐0.46, 0.68] | |
| 6 Clinical resolution Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 6.1 Triamcinolone paste vs curcumin paste | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.2 Clobetasol ointment (0.05%) vs low‐level laser therapy | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.3 Dexamethasone ointment vs amlexanox paste | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 6.4 Dexamethasone mouthwash + nystatin vs PDT | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 7 Clinical Resolution (split‐mouth study) Show forest plot | 1 | 26 | Odds Ratio (Fixed, 95% CI) | 0.64 [0.17, 2.44] |
| 8 Adverse effects Show forest plot | 4 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 8.1 Triamcinolone paste vs curcumin paste | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.2 Triamcinolone vs BCG‐PSN | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.3 Clobetasol ointment (0.05%) vs low‐level laser therapy | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 8.4 Dexamethasone ointment vs amlexanox paste | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 9 Adverse events (split‐mouth study) Show forest plot | 1 | 30 | Odds Ratio (Fixed, 95% CI) | 0.01 [0.00, 0.16] |
| Outcome or subgroup title | No. of studies | No. of participants | Statistical method | Effect size |
| 1 Pain (mean score) Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 1.1 Clobetasol + miconazole vs clobetasol + placebo | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.2 Dexamethasone + nystatin + curcumin vs dexamethasone + nystatin + placebo | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 1.3 Triamcinolone vs triamcinolone + glucosamine sulphate | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2 Clinical score Show forest plot | 3 | Mean Difference (IV, Fixed, 95% CI) | Totals not selected | |
| 2.1 Clobetasol + miconazole vs clobetasol + placebo | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.2 Dexamethasone + nystatin + curcumin vs dexamethasone + nystatin + placebo | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 2.3 Triamcinolone vs triamcinolone + glucosamine sulphate | 1 | Mean Difference (IV, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3 Clinical resolution Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 3.1 Dexamethasone + mycostatin vs dexamethasone alone | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 3.2 Dexamethasone + nystatin + curcumin vs dexamethasone + nystatin + placebo | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4 Adverse effects Show forest plot | 2 | Risk Ratio (M‐H, Fixed, 95% CI) | Totals not selected | |
| 4.1 Clobetasol + miconazole vs clobetasol + placebo | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
| 4.2 Dexamethasone + nystatin + curcumin vs dexamethasone + nystatin + placebo | 1 | Risk Ratio (M‐H, Fixed, 95% CI) | 0.0 [0.0, 0.0] | |
