Description of the condition
Acne vulgaris is a common, chronic inflammatory disease of pilosebaceous units. It is characterised by increased sebum production and the formation of comedones, erythematous papules, pustules and nodules, which may lead to scarring (Archer 2012).
For an explanation of the terminology used throughout the text, please refer to the glossary in Table 1.
|Acne inversa||A chronic disease of the apocrine glands occurring mainly in the axillae and the groin regions. It is caused by poral occlusion with secondary bacterial infection, evolving into abscesses which eventually rupture. The chronic phase is characterised by ulcers, sinus tracts, fistulas, fibrosis and scarring|
|Acne vulgaris||Chronic acne involving mainly the face, chest and shoulders, which is common in adolescents, and characterised by the intermittent formation of discrete papular and/or pustular lesions, sometimes resulting in scarring|
|Alpha-hydroxy acids||Organic acids, such as glycolic, lactic, citric and mandelic acid, containing a hydroxyl group bonded to the carbon atom adjacent to the carboxylic acid group. They are used in skin care preparations for their exfoliating properties|
|Androgens||A steroid hormone, such as testosterone or androsterone, which controls the development and maintenance of masculine characteristics. They stimulate sebaceous glands to grow and produce sebum, and therefore cause acne|
|Azelaic acid||Azelaic acid is a natural material that kills bacteria in the skin and decreases the production of keratin. It is used to treat and prevent mild and moderate acne that is caused by bacteria|
|Bacterial resistance||The ability of bacteria to resist the effects of an antibiotic|
|Benzoyl peroxide||An organic compound in the peroxide family used for acne treatment. It works as a peeling agent. It increases skin turnover, clearing pores and reducing the bacterial count (specifically P. acnes) as well as acting directly as an antimicrobial agent|
|Clindamycin||A lincosamide antibiotic, commonly used for topical treatment of acne|
|Colonisation||The presence of bacteria on a body surface (like on the skin, mouth, intestines or airway) without causing disease in the person|
|Comedone||A blocked pore in the form of a yellow or black bump or plug on the skin|
|Comedolytic||The term used to describe a product or medication that inhibits the formation of comedones. Comedolytic products work by helping the skin to shed more effectively, keeping the pores from becoming plugged|
|Corticosteroids||Any of a class of steroid hormones formed in the cortex of the adrenal gland or chemically similar synthesised hormones that have anti-inflammatory properties|
|Cyst||A closed sac, having a distinct membrane compared to the nearby tissue, which may contain air, fluids or semi-solid material|
|Cytokines||A diverse group of soluble molecules important for cell signalling in the generation of an immune response, where they act as intercellular mediators or signalling molecules|
|Drug-induced acne||Acne caused or exacerbated by several types of drugs, such as antiepileptics, halogens and steroids|
|Differentiation||The process by which a less specialised cell becomes a more specialised cell|
|Eczema||An acute or chronic non-contagious inflammation of the skin, often caused by allergy and characterised by itching, scaling and blistering|
|Erythema||Blanching reddening of the skin due to local vasodilatation|
|Erythromycin||A macrolide antibiotic, commonly used for topical treatment of acne|
|Chloracne||An acneiform eruption due to exposure to chlorine compounds|
|Hypercolonisation||Abnormal increase in the number of bacteria otherwise normally present on a body surface without causing disease in the person|
|Infantile acne||Acne which presents at the age of two to six months and persists until the age of three to four years|
|Keratinisation||The process of keratin production in order to form an epidermal barrier in stratified squamous epithelial tissue|
|Microcomedones||Microscopic comedones, not visible to the naked eye|
|Nodule||A deep skin-seated dome-shaped solid lump|
|Occupational acne||Acne causes by exposure to extraneous agents or adverse conditions in a working environment. The agents and conditions that most commonly cause problems are: oils, tars or excessive humidity|
|Papule||Small, solid, raised lesion, usually dome-shaped|
|Pilosebaceous unit||The hair follicle and sebaceous gland|
|Polycystic ovarian syndrome||A condition caused by the imbalance of female sex hormones. It is associated with absence of ovulation resulting in irregular menstrual cycles and infertility, insulin resistance causing obesity, as well as high levels of masculinising hormones causing excessive hair growth and acne|
|Pustule||A visible collection of pus|
|Reactive oxygen species||Chemically reactive molecules containing oxygen. Increased levels of reactive oxygen species may result in significant damage to cell structures, which is called an oxidative stress|
|Resorcinol||A dihydroxy benzene compound used in many acne treatment products. It helps prevent comedones by removing buildup of dead skin cells|
|Retinoids||A class of chemical compound related chemically to vitamin A, topically used for acne treatment due to the way they regulate the epithelial cell growth|
|Rosacea||A chronic dermatitis of the face, especially of the nose and cheeks, characterised by a red or rosy coloration, caused by dilation of capillaries, and the appearance of acne-like pimples|
|Sebaceous glands||Glands that produce sebum and deliver it to the surface of the skin. They are larger and greater in number on the face and upper parts of the trunk, which makes these the acne-prone areas|
|Sebum||An oily substance produced by the sebaceous glands of the skin. Its main function is to protect and waterproof the hair and skin. Oily skin and acne are the result of excessive sebum production|
|Scar||The fibrous tissue replacing normal tissues destroyed by injury, disease or surgery|
|Sodium sulphacetamide||A sulphonamid antibiotic used topically for fighting bacteria on the skin in the treatment of acne, dandruff and seborrhoeic dermatitis|
|Tetracycline||A broad-spectrum antibiotic synthesised from chlortetracycline or derived from certain micro-organisms of the genus Streptomyces|
|Topical therapy||A medication in the form of a cream, foam, gel, lotion or ointment, which is applied to body surfaces in order to treat ailments|
Acne vulgaris affects nearly all adolescents and adults at some time in their lives (Webster 2002). It is estimated that up to 40 to 50 million individuals in the USA have acne, with an 85% prevalence in those aged 12 to 24 years (Bhate 2013; White 1998). Moderate to severe acne constitutes 15% to 20% of all cases (Bhate 2013; Dréno 2010; Law 2010; Wei 2010). Girls are likely to suffer from acne earlier than boys (Archer 2012), but boys appear to be more susceptible to the disease (Halvorsen 2011). Acne may decrease with age, but 64% of people aged 20 to 29 years and 43% of people aged 30 to 39 years may still have visible acne (Bhate 2013; Schäfer 2001). Globally, acne is the second most disabling skin disease after eczema (Murray 2012).
Multiple factors are involved in the development of acne. An increased level of androgens at puberty, greater sebum production and abnormal hyperproliferation of keratinocytes leads to the development of small microscopic lesions called microcomedones. In this lipid-rich and anaerobic environment Propionibacterium acnes (P. acnes), which is present in normal follicles, proliferates abnormally. Conventionally, it is believed that abnormal colonisation of P. acnes initiates the production of inflammatory and chemotactic mediators, which drives the inflammatory processes (Brown 1998; Burkhart 1999; Cunliffe 2000; Gollnick 2003). There is also evidence suggesting the involvement of inflammation at all the stages of acne development (Jeremy 2003; Tanghetti 2013), and the exact sequence of events and the interaction between these events and other possible factors (genes, diet, smoking, sunlight, etc.) remains unclear (Williams 2012).
Diagnosis and outcome measures
Clinical diagnosis of acne is usually straightforward. The condition tends to affect the face (99%), the back (60%) and the chest (15%) (Archer 2012), where the lesions are comedones (whiteheads and blackheads), which are non-inflamed lesions (Simpson 2008). Inflammatory lesions such as papules, pustules, nodules and cysts may develop after the non-inflamed lesions (Layton 2010). Papules and pustules are superficial lesions 5 mm or less in diameter, but they may evolve into deep pustules or nodules in more severe forms of the disease. In conglobate acne, suppurative nodules can extend deeply and over larger areas, forming exudative sinus tracts and tissue destruction, resulting in extensive and disfiguring scarring.
Classification of acne severity at the time of diagnosis is important because guidelines for subsequent treatment are based on the severity of disease (Nast 2012; Strauss 2007; Thiboutot 2009). Acne can be assessed and subsequently classified from two perspectives: as objective disease activity based on measurement of the visible signs of acne by an investigator, or as a patient assessment of the impact on their quality of life (Nast 2012). More than 25 acne assessment scales have been described and they are inconsistently used across different trials (Lehmann 2002). This does not allow a direct comparison of the results of separate trials (Nast 2012; Zarchi 2012). Additionally, grading is a subjective measure that may vary from one dermatologist to another (Ramli 2012). In clinical trials, assessment of the severity of acne before and after the intervention is essential to determine the therapeutic effect (Zarchi 2012). Grading and lesion counting appear to be most frequently used for this purpose (Zarchi 2012), as is described in the revised Leeds acne grading system, which includes numerical grading systems for the back and chest as well as for the face (Lehmann 2002).
Description of the intervention
Treatments for acne target the pathophysiological processes and a wide range of topical and systemic treatments are currently available (Katsambas 2004). Topical therapies, including benzoyl peroxide, tretinoin, antibiotics and salicylic acid, can be used for non-inflammatory comedones or mild to moderate inflammatory acne (Strauss 2007; Thiboutot 2009). The underlying mechanism can be action primarily against comedones (retinoids and salicylic acid) or against inflammatory lesions (antibacterials and antibiotics).
Benzoyl peroxide is an oxidising agent that is bactericidal for P. acnes. Besides its primary bactericidal effect on P. acnes, it also has mild anti-inflammatory, as well as comedolytic activity (Patel 2010; Strauss 2007). Treatment of acne vulgaris with benzoyl peroxide alone or in combination with other topical treatments (antibiotics, retinoid, salicylic acid or zinc) at concentrations of 2% to 5% is the standard of care for mild to moderate acne (Bojar 1994; Dutil 2010; Gollnick 2003; Lookingbill 1997; Strauss 2007). The most common fixed-combination products containing benzoyl peroxide are clindamycin with benzoyl peroxide, erythromycin with benzoyl peroxide and adapalene with benzoyl peroxide (Layton 2009; Taylor 2004). Besides benzoyl peroxide, other potentially efficient over-the-counter agents for acne treatment include azelaic acid, alpha-hydroxy acids, resorcinol, sulphur and zinc, but evidence of their effectiveness from randomised controlled clinical trials and studies comparing their efficacy with other topical treatments is still lacking.
There is also an increasingly wide range of non-drug-based approaches that have been developed for treating acne, among which low-concentration chemical peels with glycolic, salicylic or trichloroacetic acid are beneficial for the reduction of comedones (Kempiak 2008; Rendon 2010). In addition, comedo extractions, light electrocautery, electrofulguration and cryotherapy present other therapeutic options for comedonal acne. In addition, acne can be treated by photodynamic therapy, utilising topical 5-aminolevulinic acid together with various light sources (e.g. blue, red, intense pulsed) or lasers (e.g. pulsed dye, 635 nm red diode), as well as methyl aminolevulinate plus red light. Blue or intense pulsed light alone and lasers such as the pulsed dye, the 1320 nm neodymium:YAG and especially the 1450 nm diode may be of therapeutic benefit for inflammatory acne (Rai 2013). For deep, inflamed nodules and cysts, intralesional injections of corticosteroids, such as triamcinolone acetate, are beneficial (Levine 1983; Strauss 2007).
Commercially available over-the-counter preparations of benzoyl peroxide include gels, creams, lotions, soaps and washes, ranging from 2.5% to 10% in concentration (Strauss 2007; Zaenglein 2006). The choice of vehicle depends largely on skin type and the person's preference (Brown 1998). Irritant dermatitis (erythema, scaling, burning and itching) is the primary limitation of benzoyl peroxide for some people; this primarily occurs within the first few days of treatment but generally subsides with continued use (Gollnick 2003; Sagransky 2009). However, when in contact with hair, clothing and other fabrics benzoyl peroxide can cause bleaching (Bojar 1995; Sagransky 2009).
How the intervention might work
Benzoyl peroxide acts through three fundamental mechanisms: it is bactericidal to P. acnes, it has mild comedolytic and anti-inflammatory properties (Dutil 2010; Patel 2010; Strauss 2007), and it is lipophilic, concentrating inside the sebaceous follicles to produce benzoic acid and reactive oxygen species. By oxidising bacterial proteins, benzoyl peroxide can inhibit protein and nucleotide synthesis, and mitochondrial activity (Dutil 2010; Fakhouri 2009; Krakowski 2008). The response to benzoyl peroxide appears to be rapid; it has been shown that significant reductions in surface and follicular micro-organisms may be obtained after 48 hours treatment with 5% benzoyl peroxide in aqueous gel (Bojar 1995), and clinical improvement has been noted as early as five days after beginning treatment (James 2005). A novel finding is the report of a significant reduction in P. acnes within 20 hours of a single application of 5% benzoyl peroxide in solution, which implies that the vehicle in topical therapy is important (Ramirez 2006).
Nowadays, the development of fixed-concentration combinations of agents is the basis of topical treatment of acne. Combinations of benzoyl peroxide with topical antibiotics or retinoids exert a synergistic effect, allowing several pathogenic factors to be targeted by a single product, which makes them an ideal choice from the point of efficacy, tolerability, compliance and decreased bacterial resistance (Gamble 2012).
Resistance to P. acnes, which commonly develops during monotherapy with topical antibiotics, has not been reported with benzoyl peroxide because of its direct toxicity to P. acnes, which is due to its ability to inhibit bacterial protein and nucleotide synthesis, metabolic pathways and mitochondrial activity (Dutil 2010). This mechanism allows benzoyl peroxide to be used as a long-term therapy for acne, either as monotherapy or in combination with topical antibiotics, without the hazard of the development of bacterial resistance. However, any relationship between skin colonisation with antibiotic-resistant P. acnes and treatment outcomes remains unclear.
Besides topical antibiotics, topical retinoids (adapalene and tazarotene) are frequently used as combination therapy with benzoyl peroxide. Retinoids regulate the differentiation and proliferation of keratinocytes, and have an anti-inflammatory effect (Chivot 2005; Williams 2012). However, because benzoyl peroxide oxidises retinoids if applied simultaneously, it has been suggested that it should be used in the morning and the retinoid at night to minimise any possible interaction (Gollnick 2003; Kraft 2011). However, modern formulations allow the stable combination of topical retinoids and benzoyl peroxide (Tan 2009).
Why it is important to do this review
Effective treatment of this condition is important. Acne is a common skin disease in adolescence, which can cause psychological harm to an individual and the possibility of long-term scarring. It is also an economic burden.
More than half of people with acne may experience shame, embarrassment, anxiety, lack of confidence and impaired social contact (Bach 1993; Cunliffe 1986; Jowett 1985). Severe acne may increase anger and anxiety (Layton 2010). Acne itself induces stress, which may also exacerbate the condition (Archer 2012). Furthermore, acne episodes impose a financial burden on healthcare providers as well as the person themselves: an acne episode costs a total of USD 690 on average, ranging from USD 360 to USD 870 (Gamble 2012; Yentzer 2010). The average cost of a 30-day supply of a topical treatment depends on the drugs, but ranges from USD 21 to more than USD 100, while generic benzoyl peroxide costs USD 21 to USD 60 per 30-day course of treatment (Gamble 2012; Krakowski 2008). The annual direct cost of acne management is over USD 2.5 billion and among skin diseases it ranks second only to the cost of treating skin ulcers and wounds (Bickers 2006).
Multiple treatments for acne have been developed, among which topical benzoyl peroxide has been recommended for the first-line treatment of mild or moderate acne.
Evidence from two recently published systematic reviews assessing the use of benzoyl peroxide for treating acne was insufficient to inform clinical practice (Mohd Nor 2012; Seidler 2010). One compared the efficacy of 5% benzoyl peroxide, clindamycin with a range of concentrations between 1% and 1.2%, 5% benzoyl peroxide with salicylic acid and a combination of benzoyl peroxide with clindamycin (Seidler 2010). The other focused only on benzoyl peroxide-containing products but restricted the length of follow-up to at least six weeks (Mohd Nor 2012). Neither review gave details about the search strategies they used, nor was it clear whether their outcomes of interest were defined a priori. Further, there was no third author in either review to act as an arbiter if there was a dispute when extracting data from the studies or evaluating study quality.
A comprehensive and transparent assessment of the efficacy and safety of topical benzoyl peroxide treatment for acne is important and this is what we plan to do in our Cochrane review. We will not apply any restriction on the concentration of benzoyl peroxide or the length of follow-up. We hope to provide sufficient evidence to inform physicians when treating people with this skin condition.