Nasty/Rzany An evidence-based guideline has been defined as ‘a systematically developed statement that assists clinicians and patients in making decisions about appropriate treatment for a specific condition’.1 A guideline will never encompass therapy specifications for all medical decision-making situations. Deviation from the recommendations may, therefore, be justified in specific situations. This is not a textbook on acne, nor a complete, all-inclusive reference on all aspects important to the treatment of acne. The presentation on safety in particular is limited to the information available in the included clinical trials and does not represent all the available and necessary information for the treatment of patients. Additional consultation of specific sources of information on the particular intervention prescribed (e.g. product information sheet) is necessary. Furthermore, all patients should be informed about the specific risks associated with any given topical and/or systemic therapy. Readers must carefully check the information in this guideline and determine whether the recommendations contained therein (e.g. regarding dose, dosing regimens, contraindications, or drug interactions) are complete, correct, and up-to-date. The authors and publishers can take no responsibility for dosage or treatment decisions. Improvement in the care of acne patients The idea behind this guideline is that recommendations based on a systematic review of the literature and a structured consensus process will improve the quality of acne therapy in general. Personal experiences and traded therapy concepts should be critically evaluated and replaced, if applicable, with the consented therapeutic recommendations. In particular, a correct choice of therapy should be facilitated by presenting the suitable therapy options in a therapy algorithm, taking into account the type of acne and the severity of the disease. Reduction of serious conditions and scarring As a result of the detailed description of systemic therapies for patients with severe acne, reservations about these interventions should be overcome to ensure that patients receive the optimal therapy. With the timely introduction of sufficient therapies, the development of serious post-acne conditions and severe scarring should be reduced. Promotion of adherence Good therapeutic adherence is key to treatment success. Adherence is facilitated by knowledge of the product being used, for example treatment duration, the expected onset of effect, the sequence of the healing process, the maximal achievable average effect, expected adverse events and the benefit to quality of life. Reduction of antibiotic resistance The use of topical and systemic antibiotics should be optimized by using appropriate combinations for a predefined duration, to reduce the development of antibiotic resistance. Health care professionals This guideline has been developed to help health care professionals provide optimal therapy to patients with mild, moderate or severe acne. The primary target groups are dermatologists and other professionals involved in the treatment of acne, such as paediatricians and general practitioners. The target group may vary with respect to national differences in the distribution of services provided by specialists or general practitioners. Patients The recommendations of the guideline refer to patients who suffer from acne. These are mainly adolescents treated in outpatient clinics. The appropriate therapy option is presented according to the type of acne that is present. The primary focus is the induction therapy of facial acne (see Chapter 1.6). Non-primary target groups are patients with special forms of acne, such as, occupational acne, chloracne, acne aestivalis, acne neonatorum, acne inverse (hidradenitis suppurativa). European guidelines are intended for adaptation to national conditions. It is beyond the scope of this guideline to take into consideration the specific costs and reimbursement situations in every European country. Differences in prices, reimbursement systems, willingness and ability to pay for medication among patients and the availability of generics are too large. Therefore, pharmacoeconomic considerations will have to be taken into account when guidelines are developed at national and local levels. The personal financial and health insurance situation of a patient may necessitate amendments to the prioritization of treatment recommendations. However, if financial resources allow, the suggested ranking in the therapeutic algorithm should be pursued. The skin type and stage of disease has to be taken into consideration when choosing the vehicle for topical treatments. The efficacy and safety/tolerability of topical treatments are largely influenced by the choice of vehicle. The face is the primary region of interest for the treatment of acne. Appearance, scarring, quality of life and social stigmatization are important considerations when dealing with facial dermatological diseases. The recommendations of this guideline apply primarily to the treatment of facial acne. More widespread involvement will certainly favour earlier use of a systemic treatment due to the efficacy and practicability of such treatments. Layton/Finlay Acne (synonym ‘acne vulgaris’) is a polymorphic, inflammatory skin disease most commonly affecting the face (99% of cases). Less frequently it also affects the back (60%) and chest (15%).2 Seborrhoea is a frequent feature.3 The clinical picture embraces a spectrum of signs, ranging from mild comedonal acne, with or without sparse inflammatory lesions (IL), to aggressive fulminate disease with deep-seated inflammation, nodules and in some cases associated systemic symptoms. Clinically non-inflamed lesions develop from the subclinical microcomedo which is evident on histological examination early in acne development.2 Non-inflamed lesions encompass both open (blackheads) and closed comedones (whiteheads). Comedones frequently have a mid-facial distribution in childhood and, when evident early in the course of the disease, this pattern is indicative of poor prognosis.4 Closed comedones are often inconspicuous with no visible follicular opening. Most patients have a mixture of non-inflammatory (NIL) and inflammatory lesions.5 Inflammatory lesions arise from the microcomedo or from non-inflammatory clinically apparent lesions and may be either superficial or deep.6 Superficial inflammatory lesions include papules and pustules (5 mm or less in diameter). These may evolve into deep pustules or nodules in more severe disease. Inflammatory macules represent regressing lesions that may persist for many weeks and contribute markedly to the general inflammatory appearance.5 Small nodules are defined as firm, inflamed lesions >5 mm diameter, painful by palpation. Nodules are defined as larger than 5 mm, large nodules are >1 cm in size. They may extend deeply and over large areas, frequently resulting in painful lesions, exudative sinus tracts and tissue destruction. Conglobate acne is a rare but severe form of acne found most commonly in adult males with few or no systemic symptoms. Lesions usually occur on the trunk and upper limbs and frequently extend to the buttocks. In contrast to ordinary acne, facial lesions are less common. The condition often presents in the second to third decade of life and may persist into the sixth decade. Conglobate acne is characterized by multiple grouped comedones amidst inflammatory papules, tender, suppurative nodules which commonly coalesce to form sinus tracts. Extensive and disfiguring scarring is frequently a feature. There are several severe and unusual variants or complications of acne as well as other similar diseases. These include acne fulminans, gram-negative folliculitis, rosacea fulminans, vasculitis, mechanical acne, oil/tar acne, chloracne, acne in neonates and infants and late onset, persistent acne, sometimes associated with genetic or iatrogenic endocrinopathies. The current guidelines do not lend themselves to comprehensive management of all these variants. Finlay/Layton Acne can be largely assessed from two perspectives: objective disease activity (based on measurement of visible signs) and quality of life impact. There are other aspects of measurement, such as sebum excretion rate, scarring development or economic impact. There are inherent difficulties in objectively measuring acne. Over 25 different methods have been described7 but there is no consensus as to which should be used. Most methods are non-validated and consequently the results of separate trials cannot be directly compared. There are detailed reviews on this subject by Barratt et al.,8 Witkowski et al.,9 Thiboutot et al.,10 and Gollnick et al.11 Proper lighting, appropriate patient positioning and prior facial skin preparation (gentle shaving for men, removal of make-up for women) are helpful in facilitating accurate assessment. Palpation in addition to visual inspection may also help define lesions more accurately. Many methods for measuring acne have been described, ranging from global assessments to lesion counting.7, 9 Despite a range of methods being used to measure acne in the 1960’s and 1970’s, it was the Leeds technique12 that dominated acne measurement for the next two decades. The Leeds technique included two methods; the grading technique and the counting technique. The grading technique allocated patients a grade from 0 to 10, with seven subgroups between 0 and 2. Photographic guides illustrating each grade are given, but the importance of palpating lesions is also stressed. The experience on which this system was based stemmed from the pre-isotretinoin era, and acne of the severity described by grades above 2 is now rarely seen. The counting technique involves the direct counting of non-inflamed and inflamed lesions, including superficial papules and pustules, deep inflamed lesions and macules. The revised Leeds acne grading system13 includes numerical grading systems for the back and chest as well as for the face. The Echelle de Cotation des Lesions d’Acne (ECLA) or ‘Acne Lesion Score Scale’ system has demonstrated good reliability.14 However, ECLA scores do not correlate with quality of life scores and the use of both disease and quality of life scores is suggested.15 Global assessment scales incorporate the entirety of the clinical presentation into a single category of severity. Each category is defined by either a photographic repertoire with corresponding numeric scale or descriptive text. Grading is a subjective task, based on observing dominant lesions, evaluating the presence or absence of inflammation, which is particularly difficult to capture, and estimating the extent of involvement. Global methods are much more practically suited to clinical practice. In clinical investigations, they should be combined with lesion counts as a co-primary endpoint of efficacy.16 A simple photographic standard-based grading method using a 0–8 scale has been successfully employed in a number of clinical trials.17 In 2005, the US FDA proposed an IGA (investigator global assessment) that represented a static quantitative evaluation of overall acne severity. To accomplish this, they devised an ordinal scale with five severity grades, each defined by distinct and clinically relevant morphological descriptions that they hoped would minimize inter-observer variability. Indeed, the more detailed descriptive text has resulted in this system being considered to provide even greater reliability than previous global assessments.16 A very simple classification of acne severity was described in the 2003 report from the Global Alliance for better outcome of acne treatment.11 This basic classification was designed to be used in a routine clinic, and its purpose was to map treatment advice onto common clinical presentations. For each acne descriptor a first-choice therapy is advised, with alternatives for female patients and maintenance therapy. There are five simple descriptors: mild comedonal, mild papulopustular, moderate papulopustular, moderate nodular and severe nodular/conglobate. A series of eight photographs span and overlap these five descriptors. Different facial views and different magnifications are used, reducing the comparability of the images. To give treatment recommendations based on disease activity, the EU Guidelines group has considered how best to classify acne patients. It has used the following simple clinical classification: Comedonal acne Mild–moderate papulopustular acne Severe papulopustular acne, moderate nodular acne Severe nodular acne, conglobate acne Other already existing systems are very difficult to compare with one another. The group has tried to map the existing systems to the guidelines’ clinical classification. However, in many cases the systems do not include corresponding categories and often it has to be considered an approximated narrowing rather than a precise mapping (Table 1). Simpson and Cunliffe25‘consider the use of quality of life and psychosocial questionnaires essential to adequately understanding just how the disease is affecting the patient, and to better understand the progress of the disease’. The impact of acne on quality of life can be measured using general health measures, dermatology-specific measures or acne-specific measures. In order for quality of life measures to be used more frequently in the routine clinical work, they need to be easy to use, the scores need to be meaningful and they need to be readily accessible. Clinicians must be convinced that the information gained from using them is of benefit in guiding them to make optimum clinical decisions for their patients, and they need to become aware that the use of these measures may help to justify their clinical decisions. Quality of life measures can influence the choice of therapy. In patients with a severe impact on their quality of life, a more aggressive therapy may be justified. A number of prognostic factors relating to more severe disease should be considered when assessing and managing acne. These are outlined and evidenced in review papers published by Holland and Jeremy 200526 and Dreno et al. 200827 and include family history, course of inflammation, persistent or late-onset disease, hyperseborrhoea, androgenic triggers, truncal acne and/or psychological sequelae. Previous infantile acne may also correlate with resurgence of acne at puberty and early age of onset with mid-facial comedones, early and more severe seborrhoea and earlier presentation relative to menarche are all factors that should alert the clinician to increased likelihood of more severe acne. Scarring usually follows deep-seated inflammatory lesions, but may also occur as a result of more superficial inflamed lesions in scar-prone patients. Acne scarring, albeit mild, has been identified in up to 90% of patients attending a dermatology clinic.28 Scars may show increased collagen (hypertrophic and keloid scars) or be associated with collagen loss. The presence of scarring should support aggressive management and therapy should be commenced early in the disease process. (For further details please see the methods report at http://www.acne-guidelines.com.) Nast/Rzany All experts were officially nominated by the European Dermatology Forum (EDF) or the European Academy of Dermatology and Venereology. They were selected according to their clinical expertise, publication record and/or experience in the field of evidence-based medicine and guideline development. None of the experts received any financial incentive other than reimbursement of travel costs. Participation of patients was difficult to realize, since no patient organization exists. Attempts to invite patients currently treated by the involved experts did not succeed. Patients were invited to participate in the external review. Patient preference was considered as an important outcome and trials looking at patient preferences were included. There is a vast array of treatment options available for acne. The options are further extended by the availability of different vehicles and formulations. When choosing a treatment, different skin types, ethnic groups and subtypes of acne must also be considered. The authors of this guideline selected the most relevant treatments in Europe to be included in the guideline. The fact that a certain treatment was not selected as a topic for this guideline, does not mean that it may not be a good treatment for acne. Additional treatment options may be considered for a later update. Fixed-dose combinations were considered as long as they were licensed in a European country (e.g. adapalene + benzoyl peroxide (BPO), clindamycin + BPO, erythromycin + tretinoin, erythromycin + isotretinoin, erythromycin + zinc). Treatment options consisting of more than two topical components were not included because of the likeliness of reduced patient adherence and/or because of a limitation in the feasibility of discussing all possible combinations and sequences. An extensive search of existing guidelines and systematic reviews was performed at the beginning of the project. The search was performed in Medline, Embase, and Cochrane (for search strategies see the methods report at http://www.acne-guidelines.com). The date of the systematic searches was March 10th 2010 for topical and systemic interventions and April 13th 2010 for laser and light therapies. The results were checked for the inclusion criteria and trial quality using a standardized literature evaluation form. Existing systematic reviews (e.g. Cochrane) and other guidelines served as an additional basis for the body of evidence in this guideline. Pooling of the trials was not attempted due to the lack of common outcome measures and endpoints and the unavailability of some primary data (for details of search strategies, standardized evaluation form and references of included reviews see methods report at http://www.acne-guidelines.com). The aim of this guideline is to give recommendations for specific clinical conditions, e.g. the severity of acne, and not to assess the different medications one by one without respect to clinical stage. However, most trials did not look in detail at subtypes but include patients with ‘acne vulgaris’ in general. Therefore, for some recommendations, ‘indirect evidence’ was generated from looking at suitable outcome parameters: The percentage ‘reduction of non-inflammatory lesions’ was the efficacy parameter considered for comedonal acne. Efficacy in papulopustular acne was assessed by ‘reduction in inflammatory lesions’, ‘reduction in total lesion count’ and other acne grading scales. The generation of evidence for nodular/conglobate acne was particularly difficult, since very few trials included nodular/conglobate acne. Consequently, treatment recommendations also took into account indirect data from trials of severe papulopustular acne. The evidence from clinical trials almost always focuses on facial acne. Trials that examined acne at other locations (e.g. back), were considered as indirect evidence and the level of evidence was downgraded accordingly. Very little attention has been given during clinical trials to the question of a minimal clinically important difference from the perspective of the patient. It would be helpful to know the extent of reduction in the number of acne lesions required for patients to consider that there has been a clinically important improvement. One study has been identified that empirically validated a non-inferiority margin of 10–15% for facial acne lesion counts as appropriate.356 The consensus view of the authors of this guideline is that a treatment should achieve at least a 10% greater reduction in the number of lesions to demonstrate superior efficacy. Hence, for the evaluation of superior or comparable efficacy throughout the evidence generation process, a 10% difference in efficacy (lesion reduction) was considered relevant. Many different grading systems for assessing the quality of evidence are available in the field of guideline development. For this guideline, the authors used the grading system adopted for the European Psoriasis Guidelines with some adaptations taken from the GRADE system.29-31 The available literature was evaluated with respect to the methodological quality of each single trial. A grade of evidence was given to every individual trial included: Randomized, double-blind clinical trial of high quality [e.g. sample-size calculation, flow chart of patient inclusion, intention-to-treat (ITT) analysis, sufficient sample size]. Randomized clinical trial of lesser quality (e.g. only single-blind, limited sample size: at least 15 patients per arm). Comparative trial with severe methodological limitations (e.g. not blinded, very small sample size, no randomization). When looking at a specific question (e.g. efficacy of BPO relative to adapalene) the available evidence was summarized by aligning a level of evidence (LE) using the following criteria: Further research is very unlikely to change our confidence in the estimate of effect. At least two trials are available that were assigned a grade of evidence A and the results are predominantly consistent with the results of additional grade B or C studies. Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. At least three trials are available that were assigned a grade of evidence B and the results are predominantly consistent with respect to additional grade C trials. Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Conflicting evidence or limited amount of trials, mostly with a grade of evidence of B or C. Any estimate of effect is very uncertain. Little or no systematic empirical evidence; included trials are extremely limited in number and/or quality. All recommendations were agreed in a consensus conference of the authors using formal consensus methodology (nominal group technique). The consensus conference was moderated by Prof. Dr. med. Berthold Rzany MSc, who is a certified moderator for the German Association of Scientific Medical Societies (AWMF). All members of the author committee were entitled to vote in the consensus conference. In general, a high consensus (>90%) was aimed for. In the absence of a consensus, this was noted in the text and reasons for the difference in views were given. All consensus statements are highlighted in a grey box throughout the text. To weigh the different recommendations, the group assigned a ‘strength of recommendation’ grade (see box below). The strength of recommendation considered all aspects of the treatment decision, such as efficacy, safety, patient preference and the reliability of the existing body of evidence (level of evidence). Strength of recommendation To grade the recommendation a ‘standardized guidelines’ language was used: Is strongly recommended. Can be recommended. Can be considered. Is not recommended. May not be used under any circumstances. A recommendation for or against treatment X cannot be made at the present time. An extensive external review was performed. National dermatological societies [European Dermatology Forum (EDF) members], other specialties [paediatrics, gynaecologists, general practitioners as organized in the European Union of Medical Specialists (UEMS)] and patients (patient internet platforms) were invited to participate. Access was open and it was possible for anybody to comment via the internet (using the platform http://www.crocodoc.com). The expert group piloted the guidelines within their own practices and performed a trial implementation within their clinics. (For further details see the methods report at http://www.acne-guidelines.com.). Implementation will be pursued at a national level by local medical societies. Materials such as an online version, a short version and a therapeutic algorithm will be supplied. Strategies for evaluation (e.g. assessment of awareness, treatment adhesion and patient changes) are in preparation and will mostly be pursued at a national level. Guidelines need to be continually updated to reflect the increasing amount of medical information available. This guideline will not be valid after 31.12.2015. In case of important changes in the meantime (e.g., new licensed drugs, withdrawal of drug licensing, new important information) an update will be issued earlier. The guidelines committee under the coordination of the division of evidence-based medicine (dEBM) will access the necessity for an update by means of a Delphi vote. Degitz/Ochsendorf Acne is one of the most frequent skin diseases. Epidemiological studies in Western industrialized countries estimated the prevalence of acne in adolescents to be between 50% and 95%, depending on the method of lesion counting. If mild manifestations were excluded and only moderate or severe manifestations were considered, the frequency was still 20–35%.32-35 Acne is a disease primarily of adolescence. It is triggered in children by the initiation of androgen production by the adrenal glands and gonads, and it usually subsides after the end of growth. However, to some degree, acne may persist beyond adolescence in a significant proportion of individuals, particularly women.36 Even after the disease has ended, acne scars and dyspigmentation are not uncommon permanent negative outcomes.10 Genetic factors have been recognized; there is a high concordance among identical twins,37 and there is also a tendency towards severe acne in patients with a positive family history for acne.38 So far little is known about specific hereditary mechanisms. It is probable that several genes are involved in predisposing an individual to acne. These include the genes for cytochrome P450-1A1 and steroid-21-hydroxylase.39 Racial and ethnic factors may also contribute to differences in the prevalence, severity, clinical presentation and sequelae of acne.40, 41 Environmental factors also appear to be of relevance to the prevalence of acne; populations with a natural lifestyle seem not to develop acne.42 In particular, diet has recently gained attention, with epidemiological43 and investigative studies44 indicating a correlation between acne and Western diet. Dréno/Gollnick Acne is an androgen-dependent disorder of pilosebaceous follicles (or pilosebaceous unit). There are four primary pathogenic factors, which interact to produce acne lesions: (1) sebum production by the sebaceous gland, (2) alteration in the keratinization process, (3) Propionibacterium acnes follicular colonization, and (4) release of inflammatory mediators. Patients with seborrhoea and acne have a significantly greater number of lobules per gland compared with unaffected individuals (the so-called genetically prone ‘Anlage’). Inflammatory responses occur prior to the hyperproliferation of keratinocytes. Interleukin-1α up-regulation contributes to the development of comedones independent of the colonization with P. acnes. A relative linoleic acid deficiency has also been described. Sebaceous lipids are regulated by peroxisome proliferator-activated receptors which act in concert with retinoid X receptors to regulate epidermal growth and differentiation as well as lipid metabolism. Sterol response element-binding proteins mediate the increase in sebaceous lipid formation induced by insulin-like growth factor-1. Substance P receptors, neuropeptidases, α-melanocyte stimulating hormone, insulin-like growth factor (IGF)-1R and corticotrophin-releasing hormone (CRH)-R1 are also involved in regulating sebocyte activity as are the ectopeptidases, such as dipeptidylpeptidase IV and animopeptidase N. The sebaceous gland also acts as an endocrine organ in response to changes in androgens and other hormones. Oxidized squalene can stimulate hyperproliferative behaviour of keratinocytes, and lipoperoxides produce leukotriene B4, a powerful chemoattractant. Acne produces chemotactic factors and promotes the synthesis of tumour necrosis factor-α and interleukin-1β. Cytokine induction by P. acnes occurs through Toll-like receptor 2 activation via activation of nuclear factor-κB and activator protein 1 (AP-1) transcription factor. Activation of AP-1 induces matrix metalloproteinase genes, the products of which degrade and alter the dermal matrix. The improved understanding of acne development on a molecular level suggests that acne is a disease that involves both innate and adaptive immune systems and inflammatory events. Recommendations are based on available evidence and expert consensus. Available evidence and expert voting lead to classification of strength of recommendation (Table 2). General comment: Only one trial looks specifically at patients with comedonal acne. As a source of indirect evidence, trials including patients with papulopustular acne were used and the percentage in the reduction of non-inflammatory lesions was considered as the relevant outcome parameter. Because of the general lack of direct evidence for the treatment of comedonal acne, the strength of recommendation was downgraded for all considered treatment options, starting with medium strength of recommendation as a maximum. Choice of topical vs. systemic treatment Due to the usually mild-to-moderate severity of comedonal acne, a topical therapy is generally recommended. Superior efficacy was defined as a difference of ≥10% in the reduction of non-inflammatory lesions in head-to-head comparisons (see also Chapter 3.3.3.). Superior efficacy against NIL compared with placebo is demonstrated by: azelaic acid45-47 (LE 1), BPO48-60 (LE 1), and the topical retinoids49-51, 60-75 (LE 1) (Table 3). Among the topical antibiotics, clindamycin57, 58,
