Topical azelaic acid, salicylic acid, nicotinamide, and sulphur for acne
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To assess the effects of topical treatments (azelaic acid, salicylic acid, nicotinamide, and sulphur) for acne.
Background
Please see the glossary in Table 1 for an explanation of medical terms used throughout the text.
| Medical term | Explanation |
| Acne conglobata | A severe form of acne presenting with numerous comedones and large abscessesa |
| Acne fulminans | A severe form of cystic acne presenting with highly inflammatory nodules and plaquesa |
| Acne mechanica | A form of acne caused by the pressure of tight clothing or frictionb |
| Acne vulgaris | A common chronic skin disorder of sebaceous follicles, mainly affecting the face, chest, and backa |
| Chemokine | A group of small cytokines that act as chemical messengers to induce chemotaxis in leukocytesc |
| Comedone | A clogged hair follicle in the skin. It can present as a blackhead or whiteheada |
| Cytokine | A small protein released by cells that function as molecular messengers between cellsc |
| Erythema | Redness of the skin, caused by vascular congestion or increased perfusionb |
| Excoriated acne | Compulsive squeezing and scratching of acne lesions with resultant scabs and scarsa |
| Halogen acne | A form of acne caused by iodides, bromides, and halogensb |
| Hyperkeratosis | Thickening of the outer layer of skin often associated with a quantitative abnormality of keratinb |
| Keratinocytes | The predominant cell type in the epidermis, forming a touch protective layera |
| Microcomedones | Early and small plugging of the follicle with excess keratin and sebumb |
| Nodule | A solid mass in the skin, more than 0.5 cm in diameterb |
| Papule | A circumscribed palpable elevation, less than 0.5 cm in diameterb |
| Pilosebaceous unit | A structure consisting of a hair follicle, sebaceous gland, and an arrector pili muscleb |
| Propionibacterium acnes | Gram‐positive bacterium related to acne developmentb |
| Pustule | A visible accumulation of free pusb |
| Scar | Skin areas of fibrous tissue replacing normal skin after injuryb |
| Sebum | The oily, waxy substance produced by sebaceous glandsb |
| Stratum corneum | The outermost layer of the epidermis, where cells have lost nuclei and cytoplasmic organellesb |
| Toll‐like receptor | A class of proteins that recognise conserved products unique to microbial metabolism in immune responsec |
aAndrews' Diseases of the Skin: Clinical Dermatology, 11th Edition, 2011, Elsevier Inc.
bRook's Textbook of Dermatology, Eighth Edition, 2010, Blackwell Publishing Ltd.
cImmunology, Sixth Edition, 2001, Harcourt Asia Pte Ltd.
Description of the condition
Acne is the most common inflammatory disorder of the hair follicles with their associated sebaceous glands (known as pilosebaceous units). This results in non‐inflammatory lesions known as comedones (whiteheads or blackheads) and inflammatory lesions including papules, pustules, or nodules. Acne primarily affects sebaceous gland‐rich areas, such as the face, shoulders, back, and upper chest (Katsambas 2008). It has several clinical subtypes, such as acne vulgaris, acne conglobata, acne fulminans, acne mechanica, halogen acne, and excoriated acne.
Acne vulgaris is the most common type of acne, which mainly affects adolescents and young adults. Prevalence in young people aged 12 to 24 years is as high as 85% (Bhate 2013). There appears to be no gender or ethnic discrimination, although it tends to occur earlier and to be more persistent in women than in men. The onset of acne vulgaris is approximately 11 years of age in girls and 12 years of age in boys, with the peak age for clinical acne vulgaris being 18 years in both sexes. Acne often regresses at around age 30 as adrenal androgens decrease, but the intensity and duration varies for each individual. Recently, several reports have suggested increased prevalence of an adult form of acne vulgaris (Khunger 2012; Rademaker 2014). Adult acne mainly affects women and the prevalence in adult women is estimated to be 14% (Williams 2006). In addition, although uncommon, childhood acne can also be found and it can be classified according to the age of onset (neonatal, infantile, mid‐childhood, and prepubertal) (Antoniou 2009; Krakowski 2007).
To date, there are various grading systems for severity assessment but with no consensus (Lehmann 2002; Ramli 2012). According to the predominant types of lesions, study authors can classify acne vulgaris as comedonal, papulopustular, and nodular acne (Ramli 2012). However, when the predominant lesion type is difficult to determine, it may be considered as polymorphic acne (Kharfi 2001). Study authors may also classify acne vulgaris as mild, moderate, and severe based on the severity of lesions (O'Brien 1998). Mild acne refers to either non‐inflammatory comedonal lesions or inflammatory papulopustular lesions, or both non‐inflammatory comedonal lesions and a few inflammatory papulopustular lesions. When there are more inflammatory papulopustular lesions and even sometimes nodular lesions, and some slight scarring, then this is considered to be moderate acne. Severe acne is diagnosed when there are widespread inflammatory papulopustular lesions, or nodules, and scarring.
The mechanism that causes the disease is unknown, but it is widely accepted that increased sebum excretion induced by androgens, follicular hyperkeratinisation, Propionibacterium acnes (P. acnes), and bacterial hypercolonisation, as well as inflammation, are the major pathogenetic factors for acne (Friedlander 2010). A keratinous plug forms at the follicular infundibulum resulting from hyperkeratosis in the follicle, initiating the formation of microcomedones. Within these microcomedones is an anaerobic lipid‐rich environment suitable for the growth of P. acnes. The P. acnes then hydrolyse triglycerides into glycerol and free fatty acids, which can initiate the inflammatory response. The cell surface toll‐like receptors, which play critical roles in the immune response against micro‐organisms, are involved in this bacteria‐mediated inflammatory response by triggering the release of proinflammatory cytokines (Kim 2005).
Although acne vulgaris is not life‐threatening and usually regresses in the third decade, it may cause serious psychological distress, as well as pain, and may considerably compromise the quality of life of the individual. Embarrassment, shame, and lack of confidence are important consequences resulting from acne vulgaris. Furthermore, scarring and embarrassment from acne begins at approximately the same age that adolescents are undergoing significant emotional and physical changes which, if combined, can be devastating. Indeed, there have been reports suggesting that severe acne can result in permanent physical scarring and even suicidal ideation (Dunn 2011; Misery 2011).
Description of the intervention
Treatment options for acne are often targeted at the factors implicated in acne development, such as sebaceous hypersecretion, abnormal keratinisation, P. acnes bacteria colonisation, and the inflammation process. The choice of treatments depends on the type and extent of acne (Gollnick 2003). Topical therapy is a standard treatment applied to mild and moderate acne. The current mainstay of topical therapy for acne vulgaris includes retinoids and antimicrobials, such as benzoyl peroxide and antibiotics (Akhavan 2003; Titus 2012; Well 2013). However, other topical medications such as azelaic acid, salicylic acid, topical nicotinamide, and sulphur, have also been used effectively for acne vulgaris.
How the intervention might work
Azelaic acid
As an ingredient found in many whole grain cereals and animal products, azelaic acid is a well‐known aliphatic dicarboxylic acid and it has been used for several decades in the treatment of acne. Azelaic acid 20% cream monotherapy or in combination therapy with glycolic acid (Graupe 1996; Spellman 1998), azelaic acid 20% (Iraji 2007) or 15% gel (Thiboutot 2008), azelaic acid 5% gel in combination with clindamycin 2% (Pazoki‐Toroudi 2011), or erythromycin 2% (Pazoki‐Toroudi 2010) have been found to be effective treatments for acne. Azelaic acid 20% cream can reduce the number of both non‐inflammatory and inflammatory lesions and has an effect comparable to the other approved standard treatments, including benzoyl peroxide and erythromycin, as well as tretinoin, but it is better tolerated by people with fewer side effects (Spellman 1998).
Azelaic acid is able to competitively antagonise the activity of mitochondrial oxidoreductases and 5‐alpha‐reductase. The mechanism of action of azelaic acid in acne treatment may relate to its inhibitory effects on mitochondrial oxidoreductase and DNA synthesis (Fitton 1991). It has a predominant antibacterial activity on P. acnes by inhibiting protein synthesis and has a modest comedolytic effect by inhibiting the proliferation and differentiation of human keratinocytes, as well as an anti‐inflammatory action by inhibiting the generation of pro‐inflammatory oxygen derivatives in neutrophils. It can also reduce sebum production on the forehead, chin, and cheek through its inhibitory effect on the conversion from testosterone to 5‐dehydrotestosterone (Passi 1989).
Adverse effects of azelaic acid are mild and transient. About 5% to 10% of people report a burning or stinging sensation, tightness of the skin, and erythema in the treated area but this usually only lasts for a few weeks (Graupe 1996). It can cause hypopigmentation, so its use should be monitored in people with dark skin. Azelaic acid is categorised as a US Food and Drug Administration (FDA) pregnancy category B drug: it has minimal systemic absorption when used topically, therefore use in pregnancy and lactation should not be a cause for concern (Bozzo 2011), although the excretion of azelaic acid into milk has been demonstrated and caution is advised in nursing mothers (Akhavan 2003).
Salicylic acid
Salicylic acid is often incorrectly recognised as a beta‐hydroxy acid but is actually an O‐hydroxybenzoic acid (Kempiak 2008), and has been used for many years for the treatment of acne vulgaris. Salicylic acid is a component of most over‐the‐counter acne preparations. Its concentration varies from 0.5% to 3.0% (Babayeva 2011; Zander 1992) and it is available in washes (Choi 2010), creams (Zheng 2013), and lotions (Babayeva 2011). Salicylic acid monotherapy (Strauss 2007) or combination therapy with benzoyl peroxide (Akarsu 2012; Seidler 2010) or clindamycin phosphate (NilFroushzadeh 2009; Touitou 2008) can improve acne lesions. Salicylic acid 20% or 30% peels (Kempiak 2008) or salicylic 20% mandelic acid 10% peels (Garg 2009) are also frequently used for the treatment of acne vulgaris. Previous studies have shown that topical salicylic acid has mild to moderate activity against both non‐inflammatory lesions and inflammatory lesions in acne vulgaris (Akarsu 2012; Degitz 2008; Thiboutot 2009). It is approved for use in children with acne.
Salicylic acid possesses keratolytic and comedolytic activities. It can break down the follicular keratotic plugs through dissolving the intercellular cement holding the stratum corneum cells and promoting the desquamation of follicular epithelium. It also has anti‐inflammatory capabilities, affecting the arachidonic acid cascade (Lee 2003).
When used at concentrations of 2% or higher, salicylic acid can cause local skin peeling and discomfort to some degree (Akarsu 2012; Boutli 2003). Salicylic acid is considered a pregnancy category C drug by the FDA (Kempiak 2008). There are no studies conducted in lactating women on topical use of salicylic acid and little is known about the excretion of salicylic acid in breast milk, therefore salicylate avoidance is advised during lactation (Akhavan 2003; Bozzo 2011).
Topical nicotinamide
Nicotinamide serves as the pyridine‐3‐carboxylic acid amide form of niacin, a component of the vitamin B complex. Topical nicotinamide 4% has been shown to be effective for mild to moderate acne (Khodaeiani 2013; Shahmoradi 2013). Nicotinamide 5% gel has been found to be as effective as clindamycin 2% gel for the treatment of mild to moderate acne vulgaris (Shahmoradi 2013). Nicotinamide 4% linoleic acid‐rich phosphatidylcholine produced global clinical improvements in acne (Morganti 2011).
The mechanisms of action are mainly due to its potent anti‐inflammatory effect (Shalita 1995) and inhibition of sebum production (Draelos 2006). Nicotinamide exerts its anti‐inflammatory effects by inhibiting P. acnes‐induced chemokine IL‐8 production in keratinocytes through interfering with NF‐kappa B by inhibiting PARP‐1 and mitogen‐activated protein kinases (MAPK) pathways (Grange 2009).
Only mild stinging or burning at the application site has been observed during topical treatment with nicotinamide (Shalita 1995). It is thought to be safe in pregnancy, although topical nicotinamide has not been formally assigned to a pregnancy category by the FDA. Nicotinamide is excreted in breast milk, but no data regarding topical nicotinamide use in women who are pregnant or lactating are available.
Sulphur
Topical sulphur‐containing preparations at concentrations of 1% to 10% have been utilised in the treatment of acne for many decades, even though they may be both comedogenic and comedolytic (Mills 1972). Sulphur can be used in the form of lotions, foam, creams, ointments, and soaps. When used together with benzoyl peroxide or sodium sulfacetamide, sulphur shows a better therapeutic effect on acne vulgaris. Sodium sulfacetamide 10% with sulphur 5% emollient foam (Del Rosso 2009), sodium sulfacetamide with sulphur lotion (Breneman 1993), benzoyl peroxide 10%, and sulphur in the range 2% to 5% cream have all been found to be effective acne treatments (Danto 1966; Wilkinson 1966).
The mechanism of action may be due to sulphur's keratolytic action and consequent inhibitory effect on the proliferation of P. acnes. It is thought that sulphur interacts with cysteine in keratinocytes resulting in the production of hydrogen sulphide, which has a keratolytic effect by rupturing the disulphide bonds of cysteine molecules in keratin (Pace 1965).
Rare adverse effects have been found during use of topical sulphur; commonly reported adverse effects include dryness and itching of the skin (Breneman 1993; Gupta 2004; Tarimci 1997). Sulphur has been classified as a FDA pregnancy category C drug. Little is known about the excretion of sulphur in breast milk, therefore caution is advised in breastfeeding mothers (Akhavan 2003).
Why it is important to do this review
The Global Burden of Disease (GBD) 2010 project measured disease burden using disability‐adjusted life years (DALYs) metrics (Hay 2014). Of the 15 dermatologic conditions analysed in the GBD 2010 study, acne vulgaris was the skin disease with the second highest percentage of total 2010 DALYs (Hay 2014). Thus, the global burden of acne is very high (Hay 2014). A recent report, however, has demonstrated that the limited number of reviews and protocols published in the Cochrane Database of Systematic Reviews (CDSR) does not reflect disease disability estimates for acne and that this topic is underrepresented (Karimkhani 2014). Cochrane reviews on oral treatments including minocycline (Garner 2012) and contraceptive pills (Arowojolu 2012) for acne have been conducted. Topical treatments including retinoids, benzoyl peroxide (Yang 2014), and antibiotics for acne are or will be dealt with in other Cochrane reviews.
We know of several systematic reviews on these four topical treatments for acne (Gamble 2012; Haider 2004; Lehmann 2001; Purdy 2011; Seidler 2010). Three of these reviews demonstrated that use of topical azelaic acid shows benefits for mild and moderate acne and is comparable to topical retinoid or benzoyl peroxide (Gamble 2012; Haider 2004; Purdy 2011). However, there is only limited evidence to demonstrate that topical salicylic acid (Gamble 2012), nicotinamide (Purdy 2011), and sulphur (Gamble 2012; Lehmann 2001) may be beneficial for acne treatment. A review on salicylic acid did not include adequate intervention arms and did not assess side effects of the treatments (Seidler 2010). In summary, most of the up‐to‐date evidence on these medications is from summary reviews (Gamble 2012; Haider 2004; Purdy 2011), and the only two systematic reviews identified are either out of date (Lehmann 2001), or without clear assessment of the quality of evidence (Seidler 2010).
Given the various limitations of previous reviews and the new evidence from recent studies on the use of azelaic and salicylic acids, nicotinamide and sulphur, we feel it is important to systematically assess their benefits and harms for the treatment of acne vulgaris using Cochrane methodology.
Objectives
To assess the effects of topical treatments (azelaic acid, salicylic acid, nicotinamide, and sulphur) for acne.
Methods
Criteria for considering studies for this review
Types of studies
We will consider all relevant randomised controlled trials (RCTs).
Randomised trials with a cross‐over design are eligible. We will exclude cluster‐randomised trials and quasi‐randomised trials (e.g. trials that allocate by using date of birth, case record number, or alternation).
Types of participants
We will include participants with acne vulgaris who have been diagnosed based on clinical definition, regardless of age, gender, acne severity, and previous treatments. Studies will also be eligible where participants are diagnosed as having papulopustular, inflammatory, juvenile, or polymorphic acne.
Except for neonatal and infantile acne, we will exclude trials in which participants have had a diagnosis of other subtypes of acne variants or acneiform eruptions as listed in Table 2.
| Acne vulgaris | |
| Acne variants: | Neonatal acne |
| Infantile acne | |
| Acne conglobata | |
| Acne fulminans | |
| SAPHO syndrome | |
| PAPA syndrome | |
| Acne excoriee des jeunes filles | |
| Acne mechanica | |
| Acne with solid facial oedema | |
| Acne with associated endocrinology abnormalities | |
| Acneiform eruptions: | Steroid folliculitis |
| Drug‐induced acne | |
| Epidermal growth factor receptor inhibitor associated eruption | |
| Occupational acne and chloracne | |
| Gram‐negative folliculitis | |
| Radiation acne | |
| Tropical acne | |
| Acne aestivalis | |
| Pseudoacne of the nasal crease | |
| Apert syndrome |
aFitzpatrick's Dermatology in General Medicine, Eighth edition, 2012, The McGraw‐Hill Companies, Inc.
Types of interventions
Topical azelaic acid, salicylic acid, nicotinamide, and sulphur with any treatment regimen, duration, dose, and delivery mode, compared with:
-
any topical treatments;
-
placebo;
-
no treatment.
The concomitant use of other topical or oral medications for acne vulgaris must be the same in both intervention arms.
Types of outcome measures
Primary outcomes
-
Participants' global self assessment of acne improvement (e.g. measured by a four‐point scale: excellent, good, fair, and poor).
-
Withdrawal for any reason.
Secondary outcomes
-
Change in lesion counts (total or inflamed and non‐inflamed separately).
-
Physicians' global evaluation of acne improvement.
-
Minor adverse events.
-
Quality of life (QoL).
Timing
If possible, we will assess treatment effects by grouping the outcomes into short term (up to four weeks), medium term (from four to eight weeks) and long term (over eight weeks). Where there is more than one follow‐up point within the same time period, we will use the latest one.
Search methods for identification of studies
We aim to identify all relevant randomised controlled trials (RCTs) regardless of language or publication status (published, unpublished, in press, or in progress).
Electronic searches
We will search the following databases for relevant trials:
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the Cochrane Skin Group Specialised Register;
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the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library;
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MEDLINE via OVID (from 1946);
-
EMBASE via OVID (from 1974); and
-
LILACS (Latin American and Caribbean Health Science Information database, from 1982).
We have devised a draft search strategy for RCTs for MEDLINE (OVID), which is displayed in Appendix 1. This will be used as the basis for search strategies for the other databases listed.
Trials registers
We will search the following trials registers:
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the metaRegister of Controlled Trials (www.controlled‐trials.com);
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the US National Institutes of Health Ongoing Trials Register (www.clinicaltrials.gov);
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the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au);
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the World Health Organization International Clinical Trials Registry platform (www.who.int/trialsearch);
-
the EU Clinical Trials Register (www.clinicaltrialsregister.eu/).
Searching other resources
References from included studies
We will check the bibliographies of included studies for further references to relevant trials.
Adverse effects
We will not perform a separate search for adverse effects of the target interventions. However, we will examine data on adverse effects from the included studies we identify.
Data collection and analysis
We plan to include at least one 'Summary of Findings' table in our review in which we will summarise the primary outcomes for the most important comparisons. To create 'Summary of Findings' tables, we will use the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and publication bias) to assess the quality of the body of evidence for the primary outcomes, and document all the assessments of the body of evidence using the GRADE tool.
Selection of studies
Two authors (HL and HY) will independently inspect the titles and abstracts of all studies identified for eligibility. For studies that appear to be eligible we will retrieve the full text of reports for reassessment to see whether they meet the inclusion criteria. Where discrepancies arise this will be resolved by discussion between authors (HL and HY) and, as needed, arbitration by a third author (JX or HS).
Data extraction and management
For data collection, we plan to use a data extraction form adapted from a standard one and we will extract data on an intention‐to‐treat (ITT) basis (once‐randomised‐always‐analyse). We will use RevMan 5 for the analysis of data (RevMan 2014).
Two authors (HL and HY) will independently extract data from eligible studies using an ITT approach. We plan to collect both qualitative and quantitative information according to Table 7.3.a, 'Checklist of items to consider in data collection or data extraction', in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), and we will collect characteristics of the included studies in sufficient detail to populate a table of 'Characteristics of included studies'. Where further information is required, we will try to contact the authors for clarification. Any disagreements will be resolved by discussion and, if necessary, judged by a third review author (JX or HS). In the case of data displayed only in graphs or figures, if we are unable to contact study authors, we will make efforts to extract the data but will only include the data if two review authors independently collect the same results.
The authors will not be blind to journals, authors, or their academic affiliations. HL and HY will enter the data into the RevMan 5 software.
Assessment of risk of bias in included studies
Two authors (HL and HS) will independently assess the methodological quality of eligible studies using the 'Risk of bias' tool as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). Any disagreements will be resolved by discussion and, as required, arbitrated by a third author (JX or GL). We will assess the following domains for bias:
-
random sequence generation (selection bias);
-
allocation concealment (selection bias);
-
blinding of participants and personnel (performance bias);
-
blinding of outcome assessment (detection bias);
-
incomplete outcome data (attrition bias);
-
selective reporting (reporting bias);
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other bias.
We will categorise the risk of bias in each domain as either 'low', 'high', or 'unclear'. Where two or more out of seven domains within a trial are rated as 'high' risk of bias, we will consider the trial for a sensitivity analysis.
Measures of treatment effect
Interpretation
If possible, we will compare the pooled estimates with the minimally important difference (MID) values for both primary and secondary outcomes to aid interpretation. We will use the suggested MID from the literature, such as MID estimates for acne lesion counts (Gerlinger 2011) and Acne‐Specific Quality of Life Questionnaire (Acne‐QoL) outcomes (McLeod 2003).
1. Dichotomous data
For binary outcomes, we will calculate the risk ratio (RR) and its 95% confidence interval (CI) to summarise estimates of treatment effect, because the RR is more intuitive than the odds ratio (Boissel 1999), which is often misinterpreted as RR by clinicians (Deeks 2002).
2. Continuous data
2.1 Summary statistic
For continuous outcomes, we will calculate the mean difference (MD) and its 95% CI to summarise data, and use standardised mean difference (SMD) with 95% CI where different measurement scales have been used across studies.
2.2 Skewed data
Data from continuous outcomes are often not normally distributed and the statistics to summarise average (medians) and spread of data (quartiles, minimum and maximum, and ranges) may be used in this case. We will summarise such variables using the summary statistics for skewed data in additional tables rather than in the main analysis, and we will forego analysis of the treatment effect sizes to avoid applying parametric tests to data with skewed distribution. We plan to classify data as skewed when the mean is less than twice the standard deviation, but only when the data are from a scale or outcome measure that has positive values with a minimum value of zero (Altman 1996). Sometimes trials use means to summarise skewed data from very large trials. For this situation, we will enter the data into analysis but a sensitivity analysis will be needed.
3. Ordinal data
Results of participant and doctor evaluations may be presented as short ordinal data. In this situation, we will make efforts to convert this type of data into dichotomous data (e.g. 'improved' or 'not improved'), and we will conduct a sensitivity analysis using different cut off points (e.g. 'greatly improved' or 'not greatly improved') when necessary. We will treat long ordinal data as continuous data.
Unit of analysis issues
We will consider the individual participant to be our unit of analysis. For trials with a cross‐over design, we will extract data from a paired t‐test if available and approximate a paired analysis using the generic inverse variance method. We will pool the randomised cross‐over trials separately from parallel trials.
Where a trial has more than two intervention arms, we will identify the interventions relevant to our review and make efforts to combine arms to create a single pair‐wise comparison. If the combination of groups is impossible, we will directly include the correlated or eligible comparisons and address them in different meta‐analyses as suggested by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).
For 'split‐face' design trials in which different body parts are randomised to different interventions, we will treat them as a specific form of cross‐over trials as suggested by the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). In this case, we will incorporate these trials to approximate a paired analysis using the generic inverse variance method and we will undertake a sensitivity analysis where imputations exist. We will meta‐analyse these trials separately from parallel trials.
Finally, trials in which randomisation occurred at a per person level, but multiple body parts received the same intervention and a separate outcome measure was made for each body part, are similar to cluster‐randomised trials except that each participant is a cluster. We will exclude these trials as previously stated.
Dealing with missing data
1. Overall loss of credibility
Data lose their credibility after a certain degree of loss to follow‐up (Xia 2007; Xia 2009). We plan to make a cut off point to guarantee the quality of the review: should more than 50% of data for any outcome be unaccounted for (except 'withdrawal for any reason' and 'minor adverse events'), we will have to forego these data and exclude them from the analysis.
2. Binary data
Where there is attrition between 0% and 50% for a binary outcome, we will manage data based on the 'once‐randomised‐always‐analyse' principle (ITT principle). We will make 'lost to follow‐up' the worst outcome, that is to say, we will impute participants reported as 'lost to follow‐up' as treatment failures for analysis. This assumption is also applicable to negative outcomes such as adverse events.
3. Continuous data
Where there is attrition between 0% and 50% for a continuous outcome, we will reproduce the completer‐only data and use them within the analysis. In many cases, the measures of variance for continuous data cannot be extracted directly from the report. We will calculate the standard deviation from available data (e.g. 95% confidence interval, standard error, exact P value, and t statistic) according to the method described in Section 7.7 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). When necessary, we will contact the trial authors for further information. If these methods are unsuccessful, we will make use of mean standard deviations from other studies within the same analysis.
Assessment of heterogeneity
We will assess heterogeneity across studies using the Chi² test and the I² statistic. If the I² statistic is equal to or greater than 50%, significant heterogeneity is present, and we will investigate the included studies for their clinical, methodological, and statistical similarities. When necessary, we will also employ prespecified subgroup analyses to explore any unexplained heterogeneity. If the I² statistic is equal to or greater than 80%, we will present the data in a forest plot but not carry out a meta‐analysis.
Assessment of reporting biases
Funnel plots can be used to assess reporting biases but have limited power in the case of small‐study effects (Higgins 2011). Therefore, we will not use funnel plots for primary outcomes where there are 10 or fewer studies in the meta‐analysis. Where possible, we will use funnel plots to assess reporting bias, but we will interpret asymmetry as not necessarily indicating publication bias.
Data synthesis
We will employ a fixed‐effect model for pooled analyses unless the I² statistic measure of heterogeneity is equal to or greater than 30%, in which case we will use the random‐effects model. Where results are estimated for individual studies with low numbers of outcomes (fewer then 10 in total), or where the total sample size is fewer than 30 participants and a risk ratio is used, we will report the proportion of outcomes in each treatment group together with a P value from Fisher's Exact test.
Subgroup analysis and investigation of heterogeneity
In the presence of substantial heterogeneity among studies, we will undertake a subgroup analysis of studies to identify factors accounting for heterogeneity. We plan to take treatment duration into consideration, to see if the treatment effects vary in different subgroups.
Sensitivity analysis
If possible, we will employ sensitivity analyses by excluding low methodological quality trials: those with 'high' risk of bias for two or more of the seven domains as defined in the 'Risk of bias' tables. Where inclusion or exclusion of these low methodological quality trials makes no significant changes to treatment effects, we will keep these trials in the final meta‐analysis.
If trials are reported with randomisation and balanced baseline demographic characteristics in each group, we will include the trials and enter them into a sensitivity analysis.
| Medical term | Explanation |
| Acne conglobata | A severe form of acne presenting with numerous comedones and large abscessesa |
| Acne fulminans | A severe form of cystic acne presenting with highly inflammatory nodules and plaquesa |
| Acne mechanica | A form of acne caused by the pressure of tight clothing or frictionb |
| Acne vulgaris | A common chronic skin disorder of sebaceous follicles, mainly affecting the face, chest, and backa |
| Chemokine | A group of small cytokines that act as chemical messengers to induce chemotaxis in leukocytesc |
| Comedone | A clogged hair follicle in the skin. It can present as a blackhead or whiteheada |
| Cytokine | A small protein released by cells that function as molecular messengers between cellsc |
| Erythema | Redness of the skin, caused by vascular congestion or increased perfusionb |
| Excoriated acne | Compulsive squeezing and scratching of acne lesions with resultant scabs and scarsa |
| Halogen acne | A form of acne caused by iodides, bromides, and halogensb |
| Hyperkeratosis | Thickening of the outer layer of skin often associated with a quantitative abnormality of keratinb |
| Keratinocytes | The predominant cell type in the epidermis, forming a touch protective layera |
| Microcomedones | Early and small plugging of the follicle with excess keratin and sebumb |
| Nodule | A solid mass in the skin, more than 0.5 cm in diameterb |
| Papule | A circumscribed palpable elevation, less than 0.5 cm in diameterb |
| Pilosebaceous unit | A structure consisting of a hair follicle, sebaceous gland, and an arrector pili muscleb |
| Propionibacterium acnes | Gram‐positive bacterium related to acne developmentb |
| Pustule | A visible accumulation of free pusb |
| Scar | Skin areas of fibrous tissue replacing normal skin after injuryb |
| Sebum | The oily, waxy substance produced by sebaceous glandsb |
| Stratum corneum | The outermost layer of the epidermis, where cells have lost nuclei and cytoplasmic organellesb |
| Toll‐like receptor | A class of proteins that recognise conserved products unique to microbial metabolism in immune responsec |
| aAndrews' Diseases of the Skin: Clinical Dermatology, 11th Edition, 2011, Elsevier Inc. bRook's Textbook of Dermatology, Eighth Edition, 2010, Blackwell Publishing Ltd. cImmunology, Sixth Edition, 2001, Harcourt Asia Pte Ltd. | |
| Acne vulgaris | |
| Acne variants: | Neonatal acne |
| Infantile acne | |
| Acne conglobata | |
| Acne fulminans | |
| SAPHO syndrome | |
| PAPA syndrome | |
| Acne excoriee des jeunes filles | |
| Acne mechanica | |
| Acne with solid facial oedema | |
| Acne with associated endocrinology abnormalities | |
| Acneiform eruptions: | Steroid folliculitis |
| Drug‐induced acne | |
| Epidermal growth factor receptor inhibitor associated eruption | |
| Occupational acne and chloracne | |
| Gram‐negative folliculitis | |
| Radiation acne | |
| Tropical acne | |
| Acne aestivalis | |
| Pseudoacne of the nasal crease | |
| Apert syndrome | |
| aFitzpatrick's Dermatology in General Medicine, Eighth edition, 2012, The McGraw‐Hill Companies, Inc. | |
