BACKGROUNDPeople with chronic plaque psoriasis often have lesions on the scalp. Hair makes the scalp difficult to treat and the adjacent facial skin is particularly sensitive to topical treatments.OBJECTIVESTo assess the efficacy and safety of topical treatments for scalp psoriasis.SEARCH METHODSWe searched the following databases up to August 2015: the Cochrane Skin Group Specialised Register, CENTRAL (2015, Issue 7), MEDLINE (from 1946), EMBASE (from 1974) and LILACS (from 1982). We also searched five trials registers, screened abstracts of six psoriasis-specific conferences and checked the reference lists of included studies for further references to relevant randomised controlled trials.SELECTION CRITERIARandomised controlled trials (RCTs) with a parallel-group, cross-over or within-patient design of topical treatments for people of all ages with scalp psoriasis.DATA COLLECTION AND ANALYSISTwo authors independently carried out study selection, data extraction and 'Risk of bias' assessment. Disagreements were settled by reference to a third author.To assess the quality of evidence, we focused on the following outcomes: 'clearance' or 'response' as assessed by the investigator global assessment (IGA), improvement in quality of life, adverse events requiring withdrawal of treatment and 'response' as assessed by the patient global assessment (PGA).We expressed the results of the single studies as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes, and mean differences (MD) with 95% CI for continuous outcomes. If studies were sufficiently homogeneous, we meta-analysed the data by using the random-effects model. Where it was not possible to calculate a point estimate for a single study, we described the data qualitatively. We also presented the number needed to treat to benefit (NNTB).We categorised topical corticosteroids according to the German classification of corticosteroid potency as mild, moderate, high and very high.MAIN RESULTSWe included 59 RCTs with a total of 11,561 participants. Thirty studies were either conducted or sponsored by the manufacturer of the study medication. The risk of bias varied considerably among the included studies. For instance, most authors did not state the randomisation method and few addressed allocation concealment. Most findings were limited to short-term treatments, since most studies were conducted for less than six months. Only one trial investigated long-term therapy (12 months). Although we found a wide variety of different interventions, we limited the grading of the quality of evidence to three major comparisons: steroid versus vitamin D, two-compound combination of steroid and vitamin D versus steroid monotherapy and versus vitamin D.In terms of clearance, as assessed by the IGA, steroids were better than vitamin D (RR 1.82; 95% CI 1.52 to 2.18; four studies, 2180 participants, NNTB = 8; 95% CI 7 to 11; moderate quality evidence). Statistically, the two-compound combination was superior to steroid monotherapy, however the additional benefit was small (RR 1.22; 95% CI 1.08 to 1.36; four studies, 2474 participants, NNTB = 17; 95% CI 11 to 41; moderate quality evidence). The two-compound combination was more effective than vitamin D alone (RR 2.28; 95% CI 1.87 to 2.78; four studies, 2008 participants, NNTB = 6; 95% CI 5 to 7; high quality evidence).In terms of treatment response, as assessed by the IGA, corticosteroids were more effective than vitamin D (RR 2.09; 95% CI 1.80 to 2.41; three studies, 1827 participants; NNTB = 4; 95% CI 4 to 5; high quality evidence). The two-compound combination was better than steroid monotherapy, but the additional benefit was small (RR 1.15; 95% CI 1.06 to 1.25; three studies, 2444 participants, NNTB = 13; 95% CI 9 to 24; moderate quality evidence). It was also more effective than vitamin D alone (RR 2.31; 95% CI 1.75 to 3.04; four studies, 2222 participants, NNTB = 3; 95% CI 3 to 4; moderate quality evidence).Reporting of quality of life data was poor and data were insufficient to be included for meta-analysis.Steroids caused fewer withdrawals due to adverse events than vitamin D (RR 0.22; 95% CI 0.11 to 0.42; four studies, 2291 participants; moderate quality evidence). The two-compound combination and steroid monotherapy did not differ in the number of adverse events leading withdrawal (RR 0.88; 95% CI 0.42 to 1.88; three studies, 2433 participants; moderate quality evidence). The two-compound combination led to fewer withdrawals due to adverse events than vitamin D (RR 0.19; 95% CI 0.11 to 0.36; three studies, 1970 participants; high quality evidence). No study reported the type of adverse event requiring withdrawal.In terms of treatment response, as assessed by the PGA, steroids were more effective than vitamin D (RR 1.48; 95% CI 1.28 to 1.72; three studies, 1827 participants; NNTB = 5; 95% CI 5 to 7; moderate quality evidence). Statistically, the two-compound combination was better than steroid monotherapy, however the benefit was not clinically important (RR 1.13; 95% CI 1.06 to 1.20; two studies, 2226 participants; NNTB = 13; 95% CI 9 to 26; high quality evidence). The two-compound combination was more effective than vitamin D (RR 1.76; 95% CI 1.46 to 2.12; four studies, 2222 participants; NNTB = 4; 95% CI 3 to 6; moderate quality evidence).Common adverse events with these three interventions were local irritation, skin pain and folliculitis. Systemic adverse events were rare and probably not drug-related.In addition to the results of the major three comparisons we found that the two-compound combination, steroids and vitamin D monotherapy were more effective than the vehicle. Steroids of moderate, high and very high potency tended to be similarly effective and well tolerated. There are inherent limitations in this review concerning the evaluation of salicylic acid, tar, dithranol or other topical treatments.AUTHORS' CONCLUSIONSThe two-compound combination as well as corticosteroid monotherapy were more effective and safer than vitamin D monotherapy. Given the similar safety profile and only slim benefit of the two-compound combination over the steroid alone, monotherapy with generic topical steroids may be fully acceptable for short-term therapy.Future RCTs should investigate how specific therapies improve the participants' quality of life. Long-term assessments are needed (i.e. 6 to 12 months).

As a chronic disease psoriasis often requires long-term treatment. Successful continuation of therapy during a maintenance phase is therefore important. A systematic review was performed on the efficacy of psoriasis drugs during maintenance treatment in patients who had achieved sufficient treatment success during the induction period. Maintenance therapy is defined as treatment during the period after successful induction therapy. Inclusion criteria were prospective studies with systemic therapies recommended by the 2009 European psoriasis guidelines (plus ustekinumab), and a study population that had achieved a defined treatment response criterion after induction therapy within a period of ≥ 6 months. Maintenance studies on conventional treatments were identified for ciclosporin (CSA) only (no studies investigating acitretin, methotrexate or ustekinumab were found). Compared with placebo, CSA was shown to be effective in maintenance therapy, yet CSA 1·5 mg kg(-1) seems to be insufficient to maintain disease control. Based on the evidence, it is uncertain whether there is any difference between daily or intermittent treatment. For biologics, maintenance data were available for adalimumab, etanercept and infliximab. No differences in 75% improvement in Psoriasis Area and Severity Index (PASI 75) response were identified between adalimumab 40 mg once and twice a month. Continuous infliximab treatment was shown to be superior to as-needed treatment. For etanercept, only observational postrandomized controlled trial data were available, indicating a maintained PASI 75 response in approximately three-quarters of patients during long-term treatment. Only limited evidence is available for a conclusion on how patients with an adequate response should be optimally treated during the maintenance period. A clear ranking of the available treatments is not yet possible.

BackgroundActinic keratosis (AK) is a frequent health condition attributable to chronic exposure to ultraviolet radiation. Several treatment options are available and evidence based guidelines are missing.ObjectivesThe goal of these evidence- and consensus-based guidelines was the development of treatment recommendations appropriate for different subgroups of patients presenting with AK. A secondary aim of these guidelines was the implementation of knowledge relating to the clinical background of AK, including consensus-based recommendations for the histopathological definition, diagnosis and the assessment of patients.MethodsThe guidelines development followed a pre-defined and structured process. For the underlying systematic literature review of interventions for AK, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was adapted. All recommendations were consented during a consensus conference using a formal consensus methodology. Strength of recommendations was expressed based on the GRADE approach. If expert opinion without external evidence was incorporated into the reasoning for making a certain recommendation, the rationale was provided. The Guidelines underwent open public review and approval by the commissioning societies.ResultsVarious interventions for the treatment of AK have been assessed for their efficacy. The consenting procedure led to a treatment algorithm as shown in the guidelines document. Based on expert consensus, the present guidelines present recommendations on the classification of patients, diagnosis and histopathological definition of AK. Details on the methods and results of the systematic literature review and guideline development process have been published separately.ConclusionsInternational guidelines are intended to be adapted to national or regional circumstances (regulatory approval, availability and reimbursement of treatments).

Psoriasis as a chronic inflammatory disease often requires effective long-term treatment; a comprehensive systematic evaluation of efficacy and safety of systemic long-term treatments in patients with moderate-to-severe psoriasis is lacking. Twenty-five randomized clinical trials were included. Results were pooled and quality of evidence was assessed using GRADE (Grading of Recommendations Assessment, Development and Evaluation). With respect to PASI 75 (psoriasis area and severity index), pooled risk ratios for infliximab (13.07, 95% confidence interval (Cl): 8.60-19.87), secukinumab (11.97, 95% Cl: 8.83-16.23), ustekinumab (11.39, 95% Cl: 8.94 14.51), adalimumab (8.92, 95% Cl: 6.33-12.57), etanercept (8.39, 95% Cl: 6.74-10.45), and apremilast (5.83, 95% Cl: 2.58-13.17) show superiority of biologics and apremilast in long-term therapy compared with placebo. With respect to the addressed safety parameters, no differences were seen between adalimumab, etanercept, or infliximab versus placebo. No placebo-controlled data on conventional treatments was identified. Head-to-head studies showed superior efficacy of secukinumab and infliximab versus etanercept and of infliximab versus methotrexate. A clear ranking is limited by the lack of long-term head-to-head trials. From the available evidence, infliximab, secukinumab, and ustekinumab are the most efficacious long-term treatments. Data on conventionals are insufficient. Further head-to-head comparisons and studies on safety and patient-related outcomes are needed to draw more reliable conclusions.

Conflict of interest: the authors declare that they have no conflicts of interest. We read the article by Meng et al.1 in Clinical and Experimental Dermatology with interest. We agree that a systematic assessment of the evidence with respect to efficacy and safety of ustekinumab is valuable to guide physicians in the treatment of patients with psoriasis. However, we are concerned about one major error in the review by Meng et al.1 The authors reported that they included nine randomized controlled trials (RCTs) with a total of 11 381 patients, but the included patients were not derived from 9 independent RCT populations; these 9 publications provided data from only 5 placebo‐controlled RCT populations covering 2467 patients (see Table 1 of that paper1). Although multiple counting of study populations does not influence the conclusion of the review, the calculated confidence interval of the pooled effect estimates became smaller due to the (false) inclusion of a higher number of patients. Moreover, the review gives the impression that ustekinumab is supported by more evidence than it actually is (Table 1).

Anja Jacobs Alexander Nast Stefanie Rosumeck Ricardo Niklas Werner This document is the methods report to the ‘Update of the evidence and consensus-based European S3-Guidelines of systemic treatment of psoriasis vulgaris’. The first edition of these guidelines has been published in the Journal of the European Academy of Dermatology and Venereology.1 Please use the following reference when citing these guidelines: Nast A, Gisondi P, Ormerod AD, Saiag P, Smith C, Spuls PI, Arenberger P, Bachelez H, Barker J, Dauden E, de Jong E, Feist E, Jacobs A, Jobling R, Kemeny L, Maccarone M, Mrowietz U, Papp KA, Paul C, Reich K, Rosumeck S, Talme T, Thio HB, van de Kerkhof P, Werner RN, Yawalkar N. European S3-Guidelines on the systemic treatment of psoriasis vulgaris - Update 2015 - Short version - EDF in cooperation with EADV and IPC. J Eur Acad Dermatol Venereol 2015; 29: 2277–2294. The guidelines were developed taking into account the quality criteria for guidelines as suggested by the Appraisal of Guidelines Research and Evaluation (AGREE II) Instrument.2 For the planning and elaboration of the underlying systematic literature review of interventions for psoriasis vulgaris, the methodology suggested by the Cochrane Handbook for Systematic Reviews of Interventions3 and the GRADE working group4 was adapted. These evidence- and consensus-based guidelines contain recommendations that were developed to assist clinicians in the care of patients in specific clinical conditions. The recommendations are based on the best available evidence and their development followed a pre-specified, standardized process. Nevertheless, guidelines do not replace the clinicians' knowledge and skills, since guidelines never encompass therapy specifications for all medical decision-making situations, deviation from the recommendations may be justified or inevitable in specific situations. Safety aspects that were considered within these guidelines do not represent a comprehensive assessment of all available safety information for the included interventions. They are limited to those aspects chosen for evaluation and the information available in the included clinical trials. Readers must carefully check the information in these guidelines and determine whether the recommendations (e.g. regarding dose, dosing regimens, contraindications or drug interactions) are complete, correct, up-to-date and appropriate. European guidelines are intended to be adapted to national or regional circumstances (regulatory approval and availability of treatments, health care provider and insurance systems). Thus, the national medical societies associated with the European Dermatology Forum (EDF) and the European Association for Dermatology and Venereology (EADV) will be responsible for the adoption and implementation of the guidelines on a national level. Aim was the update of the guidelines' version of 2009.5 The primary goal of these guidelines was to assist health care professionals in the choice of the optimal systemic treatment for their psoriasis patients with the specific circumstances of the individual patient. These guidelines are targeted at all health care professionals involved in the treatment of patients with psoriasis, primarily dermatologists and general practitioners (GP). For the development of these evidence and consensus-based guidelines, the available evidence of the efficacy and safety of the systemic treatments for psoriasis was summarized. Based on the evidence, recommendations were formulated and consented by an expert panel in a structured consensus process. The Division of Evidence based Medicine (dEBM) from the Department of Dermatology, Venereology and Allergology, Charité – Universitätsmedizin Berlin, Germany coordinated the guidelines development process including the organization of the guidelines process, development of methodology and the conduction of a systematic review of the literature on the systemic treatment of psoriasis vulgaris. Members of the dEBM participated in or moderated the consensus conference, but were not entitled to vote on recommendations. Members of the expert group were dermatologists and a rheumatologist. They were officially nominated by the European Dermatology Forum (EDF), the European Association for Dermatology and Venereology (EADV) and the International Psoriasis Council (IPC). The expert group members were selected by virtue of their clinical experience and/or research expertise in the field of psoriasis vulgaris and their previous work on the first version of the European S3-Guidelines on the systemic treatment of psoriasis vulgaris in 2009. An international patient organization to nominate representatives for patients affected by psoriasis vulgaris could not be identified, and thus patient participation was difficult to realize. Patient representatives from the UK and Italy each participated in the guidelines development process as a part of the expert group. These representatives had the same voting rights as the other members of the expert group and participated in the process of the internal review too. Furthermore one chapter, namely ‘Severity assessment/Quality of life – Patients perspective’ which is integrated in the main chapter ‘introduction to psoriasis vulgaris’ was written by the patient representatives. Patient reported outcomes such as DLQI scores were considered as a relevant outcome and studies reporting on these endpoints were included into the systematic literature review. Patients were invited to take part in the external review and to comment the drafted guidelines document. A steering group of the guidelines project was composed by members of the expert group who have experiences in the field of guidelines development. The steering group was responsible for the selection of interventions, outcomes and relevant patient subgroups in the evidence assessment process. A full list of the guidelines steering group and expert group members is supplied at the beginning of this document on page 2. The guidelines project has kindly been supported by the EDF. The financial support did not influence the guidelines development. The expert group did not receive financial incentives or reimbursement for the participation in the guidelines development. Assessment and synthesis of the evidence were done independently from industrial interest. Key questions to be answered and outcomes were chosen in accordance to consensus of the members from the steering group. Recommendations on the systemic treatment of psoriasis vulgaris were exclusively based on the consensus of the members from the expert group in the consensus conference, according to the clinical expertise and evidence assessment. A declaration of potential conflicts of interest (COI) adapted from the International Committee of Medical Journal Editors6 was required for the participation in the guidelines development. At the beginning of the formalized consensus conference, each member was asked to update his or her declaration. COI were discussed. The expert group did not see any substantial conflicts of interest and there were no further comments or remarks. COI of each person involved in the guidelines development are presented in Appendix 4.1. The selection of key questions to be answered by guidelines is according to the previous version of the guidelines.1, 5 The following steps in the preparation of the systematic literature review were performed via electronic mail contacts and decided with the members of the expert group. The following treatment options were selected as relevant treatments for psoriasis vulgaris and included in the evaluation: Although fumaric acid esters are licensed only in Germany, it is known that they are used in several other European countries as off-label medication (e.g. UK7) for psoriasis vulgaris and they are therefore included in the evidence-based assessment. The biological agent efalizumab8 lost its marked authorization for psoriasis. Alefacept is licensed in Switzerland and the US only, but is currently not being distributed any more. Both medications were therefore excluded from the guidelines. Furthermore, the expert panel decided to exclude phototherapy due to the high number of studies for which the evidence work up was not feasible during this update (time and costs). Combinations of more than two treatment options were not considered. Studies on combination therapies were included if they compared the combination with the included systemic monotherapy to evaluate the benefit of the combination in comparison to the monotherapy. The fact that certain treatments were not included does not necessarily imply that it may not be an appropriate treatment for psoriasis vulgaris. The evaluation of the treatment options was based on efficacy, patient reported as well as safety outcomes. Beside these parameters, other outcomes were selected that seem to be of high importance to the patient.9, 10 According to the GRADE methodology, expert group members were asked to rate outcomes with respect to their relevance for clinical decisions concerning the choice of a treatment for psoriasis vulgaris on a scale from 1 to 9 with 1 representing irrelevant and 9 representing critical outcomes. Mean values of the ratings from the experts served to rank the importance of the selected outcomes when grading the available evidence. A mean score of 7–9 rated an outcome as critical for a decision, 4–6 rated an outcome as important but not critical for decision making, and a mean score of 1–3 indicated that the respective outcome was of limited importance.11 Only critical and important outcomes were considered in the evidence assessment. Table 1 shows the selected outcomes and assigned rating of importance. For reasons of feasibility and to ensure comparability, for the induction therapy the outcomes had to be reported at week 16 after the start of treatment or whatever was closest to that time point, however, not earlier than week 8.12 For long-term therapy, the results had to be reported for week 24 or whatever was closest thereafter. To be included into the systematic review, studies had to report at least one of the selected outcomes. Outcomes had to be reported as events per patients in case of dichotomous outcomes (the number of events and the number of patients at the time of assessment had to be reported) or as mean change in case of continuous outcomes (the mean and standard deviation had to be reported). Eligible studies for inclusion were initial RCTs (including placebo controlled or head-to-head trials) reporting on participants with a clinical diagnosis of psoriasis vulgaris independent of the publication type. A minimal number of 10 evaluated participants per study arm was required and a minimal treatment duration of 8 weeks. Publication language was not restricted. At least 80% of the study participants need to fulfil the above mentioned population criteria. As these guidelines are an update of the previous version,1, 5 there was no systematic search for existing guidelines and systematic reviews on systemic treatments of psoriasis vulgaris. A systematic literature search was performed to update the previous guidelines using the databases Cochrane Library, Medline, Medline In-Process and Embase on September 12th 2013. Start date was the particular inception date of each database. Automatic e-mail alerts by all four databases with new hits for the entire search strategy were received monthly up to October 12th 2014. Detailed electronic search strategies for the different databases are presented in the Appendix (see chapter 4.2). Titles and abstracts of the search were individually checked for eligibility by two independent assessors (AJ, SR). Full texts of potentially relevant studies were similarly checked for eligibility by two independent assessors (AJ, SR). In the case of disagreement during the screening of abstracts and full texts, a third assessor (AN) was involved and the conflict solved by discussion (Fig. 1). Data collection of the literature search results was done independently by two assessors (AJ, SR), using a standardized data extraction form (Microsoft® Excel worksheet, Table 2). All relevant outcome data were then transferred in a Review Manager file.13 Risk ratios with 95% CI for dichotomous data and mean differences with 95% CI for continuous data were calculated for each study comparison. In case of continuous data with missing standard derivation (SD), SD was calculated from standard error or confidence interval if available. No other SD imputation methods were performed and results from comparisons without any measure of variance were not considered for meta-analysis. The effect estimates of the individual studies were pooled in meta-analysis using the random effects model (Review Manager 5.2). We included numerous multi-arm studies in our analyses. If multiple comparisons of one study were included into one meta-analysis, we split the shared group into two or three groups with smaller sample size to avoid double-counting of the participants that would create a unit-of-analysis error. Studies with no events in both arms were excluded from the meta-analysis, because they do not provide any information of either the direction or magnitude of the relative treatment effect3. Limited placebo controlled data were available for long-term treatment. Most of the long-term studies ‘loose’ their placebo group after the induction period. Only three long-term studies were identified that provide placebo controlled data for week 24. To include long-term data from studies without a long-term placebo group, long-term placebo data from the three studies were pooled to calculate the ‘placebo response’. Based on the original size of the ‘lost’ placebo arms, placebo values for long-time studies with lost placebo groups were imputed using the pooled placebo response. Placebo data were available for PASI75, PASI90 and PGA ‘clear/almost clear’. Identified placebo data at week 24 are provided in Table 3. The method used to calculate the mean time until onset of action (TOA 25 PASI 75 [w] and TOA 25% mean PASI [w]) is described elsewhere.9 A drug was assessed to have a slightly faster onset of action than its comparator if the difference of time was > 0.5 weeks; a faster onset of action was described by a difference of > 1 week. The quality of the included studies was assessed by using the Cochrane Risk of bias tool.3 The available evidence and its quality were summarized according to the system recommended by the GRADE (Grading of Recommendations Assessment, Development and Evaluation) working group4 for each available outcome in each comparison. Using the GRADE profiler,14 GRADE evidence profiles were developed for each available treatment comparison, based on the rated outcomes (see chapters 3.3.1). The quality of the evidence for each key question was categorized into one of four categories, from ‘very low’ to ‘high’.15 Table 4 summarizes the different quality levels of evidence and the approach used to grade the quality of evidence as suggested by the GRADE working group.15 The following criteria, as presented by the GRADE working group were applied to decrease or increase the quality ratings for each key question, intervention and outcome: The Cochrane risk of bias tool3 was used to assess limitations to the study quality on a study level. The following domains were assessed: random sequence generation, allocation concealment, incomplete outcome data, selective reporting, blinding of participants and personnel, blinding of outcome assessment and other sources of bias. Overall study quality depended on the limitations of the contributing studies. A downgrading of 1 (‘serious limitations’) or 2 points (‘very serious limitations’) was possible.16 In addition to these criteria quality was downgraded by two points in case of imputed placebo group data. Overall quality of evidence was downgraded by 1 point (‘important inconsistency’), when the study results were heterogeneous with respect to the direction or the size of the effect. The main criteria for downgrading were: widely varying point estimates across the studies, minimal or no overlap of the confidence intervals (CI), large I² (I² is a statistical test quantifying the variation in the point estimate between the studies).17 Inconsistency could not be assessed in case of only one contributing study and no downgrading was performed. When differences between the effect size in the populations recruited for the study participation and the patient subgroup to make a recommendation for were expected (due to significant and important differences in the studied populations to the target population), overall study quality was downgraded by 1 (‘some’) or 2 points (‘major uncertainty about the directness’).18 Here, study quality was downgraded, when the study inclusion criteria or the patient characteristics at baseline did not match exclusively one of the predefined patient subgroups (e.g. study population consist of patients with mild psoriasis). The main criterion for determining the precision of the pooled effect size is the width and position of the 95% confidence interval (CI)19: the overall study quality was downgraded for imprecision if the CI was very wide, crossed the threshold of minimal important difference (defined as the line of no effect ± 0.25) or if the CI crossed the line of no effect and the threshold of minimal important difference. For continuous outcomes such as the mean reduction in PASI, the minimal important difference was calculated as the line of no effect ± 0.5*SD of the control group. For outcome data calculated in secondary analysis (i.e. TOA) the quality of evidence was downgraded twice, because no measure of variance was available and the degree of imprecision therefore not estimable. When publication bias was expected to influence the size or direction of the effect, study quality was downgraded by 1 point.20 Due to the low number of contributing trials for each comparison, no formal testing (e.g. visual characterization of funnel plots) could be performed. Rating up the quality of evidence due to the mentioned reasons is generally recommended only to be applied to results from observational studies or non-randomized trials.21 As the systematic literature search was restricted to randomized controlled trials, no upgrading of the overall study quality was performed. The quality of the evidence was evaluated by two assessors (AJ, SR) after discussion of each aspect. Comments to justify the ratings are supplied in case of downgrading. For each comparison of interventions, a short text summarizing the available evidence and a GRADE summary of findings table is presented in the guidelines. Data are presented as risk ratios (dichotomous outcomes)22 or mean differences (continuous outcomes).23 The summary of finding tables served as the basis for developing the treatment recommendations. The recommendations for subchapters are not based on systematically assessed literature and represent expert opinions. Although topicals and UV are not the focus of the guideline, the group decided on mentioning them for these subpopulation, where they are highly relevant as first line treatments. Prior the consensus conference, the draft of the guideline including the results of the systematic literature review was circulated in the expert group. Using the Delphi technique a first voting on the drafts of recommendations on drugs and on therapies in special patient populations was performed and alternative suggestions were collected where required. During the consensus conference performed on October 9th and 10th in Amsterdam, The Netherlands, the formal consensus methodology of the nominal group technique was used to agree upon the recommendations.24 All expert group members were entitled to vote on the recommendations. The nominal group technique was moderated by Alexander Nast, MD, certified moderator for the German Association of Scientific Medical Societies (AWMF). To simplify the identification of consented recommendations, all consented recommendations are highlighted throughout the guidelines document (grey boxes). To avoid ambiguity, a standardized language was used to classify the direction and strength of each recommendation. Based on the GRADE approach, five strengths of recommendations were differentiated: strong recommendations for or against the use of an intervention, weak recommendations for or against the use of an intervention, and no recommendation.25 The strength of a recommendation based on the quality of the evidence (high/moderate/low/very low), the balance of expected undesirable and desirable outcomes and consideration of costs as well as of values and preferences.25, 26 The strength of recommendation was expressed by the wording and symbols (Table 5). For each recommendation, the strength of consensus in terms of percentage of agreement was measured and documented. Three levels of consensus were defined and distinguished. A ‘strong consensus’ defined as an agreement of at least 95% of the members of the expert group was generally aimed at. In cases where only lower values of agreement were achieved, these were defined as ‘consensus’ (75–94% agreement) or ‘weak consensus’ (50–74% agreement). The sections ‘Instructions for use’ and ‘Lab control’ of each medication were discussed and consented as a whole within the expert group, at which no strength of recommendation was provided in the guidelines text. Before publication, the guidelines draft underwent an extensive internal and external review. Internal review was accomplished at the beginning of the guidelines development to confirm the selection of key questions (kick-off conference), prior to the consensus conference for a preliminary review of the results from the systematic literature review, after the consensus conference to confirm the completed recommendations, and after the external review to confirm changes before publication. The EDF disseminated the draft to its members for external review. The external review was performed in cooperation with the EADV, UEMS and IPC. In addition, any other interested individual was free to participate in the external review, as the guidelines draft was accessible online for open comments from 27th January 2015 through 23rd February 2015 (using the platform www.crocodoc.com). Each comment was categorized as ‘editorial change’, ‘forwarded to authors for consideration’ or ‘rejected (including reasoning)’. This document with all responses is available at the dEBM. As a result of the comments and suggestions of the external review the expert group re-voted on three issues using a modified Delphi technique. These were namely (i) blood count monitoring in therapy with fumaric acid esters, (ii) instruction for use for woman of childbearing age after etanercept therapy and (iii) the definition of ‘second line’ in the footnote of the treatment recommendation of ustekinumab. For the results of re-voting, see final version of guidelines text. During the phase of external review, the members of the expert panel piloted the drafted guidelines within their own practices and were encouraged to comment on the practicability and results during the second internal review. European guidelines are intended to be adapted to the national circumstances of each health system. European guidelines are intended to be adapted to national or regional circumstances (regulatory approval and availability of treatments, health care provider and insurance systems). Thus, the national medical societies associated to the EDF will be responsible for the adaption and implementation of the guidelines on a national level. The guidelines publication and this methods report will be published online (http://www.euroderm.org/index.php/edf-guidelines). Evaluation strategies with respect to the awareness of the treatment necessity among patients and physicians, the treatment adhesion and treatment success should be pursued at a national level. Due to the increasing amount of publications, guidelines need to be continually updated to reflect the recent state of evidence. After December 31st, 2019, these guidelines will expire. Should important changes occur in the meantime (such as new available interventions, new important evidence or withdrawal of drug licensing) the information may expire earlier. In these cases, an update issue of the guidelines is needed earlier. The EDF will be responsible to initiate an update.

The time until a patient achieves a relevant improvement during the treatment of a skin disease is important for selecting a therapy, but has been largely neglected in reviews and guidelines. The aim of this systematic review was to determine the time until the onset of action (TOA) of topical acne treatments. The primary outcome was the TOA defined as the time until a 25% reduction in the mean number of inflammatory lesions had been achieved. A systematic literature search in Medline and Embase was carried out. Clinical trials that evaluated head-to-head comparisons of treatments in patients suffering from mild-to-moderate papulopustular acne were included. Abstract and full-text screening and data extraction were done independently by two investigators. With respect to inflammatory lesions, different concentrations of benzoyl peroxide (BPO) or adapalene did not seem to influence the TOA. BPO seemed to act more quickly than isotretinoin and tretinoin. Adapalene showed a shorter TOA than isotretinoin. Conflicting results were seen when comparing adapalene with tretinoin, with a tendency for adapalene to be faster. Clindamycin/BPO seemed to act more quickly than adapalene. Inconsistent results were seen for the comparison of clindamycin/BPO and BPO alone with a slight indication of a shorter TOA for clindamycin/BPO. Adapalene/BPO and clindamycin/BPO showed comparable TOA. When interpreting the data, the different study designs and the limited study quality need to be taken into account. Further research is needed to identify treatments that offer an early onset of action and possibly help to optimize patients' adherence. TOA should be considered as an additional outcome in acne trials.

Background Management of anticoagulation and anti-platelet drugs during cutaneous surgery is still a challenge for many dermatologists and standards of care with respect to stopping, continuing or bridging vary widely. Methods We performed a systematic review (Medline, Cochrane Library, until August 27th, 2013) of studies assessing the risk of complications due to anticoagulation during cutaneous surgery. Primary outcomes were mild-moderate and severe postsurgical bleeding. The secondary outcomes were excessive and uncontrollable intraoperative bleeding and other postsurgical complications as wound dehiscence, erythema, wound infection. Results 1.287 publications were identified and 10 studies were included into the review. The frequencies of bleeding in the control groups in general were low (about 1%). In patients on aspirin, increased risks were seen neither with respect to mild-moderate postoperative bleeding (RR 1.1, CI 0.5-2.3), nor with respect to severe bleeding (RR 0.9, CI 0.2-4.6). The studies with patients on warfarin showed a risk for mild-moderate bleeding that was three times as high as in controls (RR 3.2, CI 1.4-7.1) and for severe bleeding that was 15 times higher (RR 14.8, CI 2.7-80.4). In general the study sizes were small and the methodological quality low. Conclusion The risk of bleeding due to a medication with aspirin seems to be negligible. With warfarin, the risk is increased; an exact estimate of the risk increase is difficult to give, because of the lack of sufficient high quality studies. A two-fold increase appears likely, the 15-fold increase is most likely due to statistical reasons arising from the rareness of the event in the small number of included patients. Stopping, bridging or continuing a medication should always be an individual decision. In accordance with guidelines from internal medicine for most patients it will be recommendable to continue with the medication.

Stillen gilt als die optimale Ernährungsform für gesunde reif geborene Säuglinge und ist mit einer Vielzahl an Vorteilen für Gesundheit und Entwicklung verbunden. Jedoch führen Stillprobleme häufig zu einem frühzeitigen Abbruch der Stillbeziehung. Um eine optimale Betreuung von stillenden Frauen zu gewährleisten, sind einheitliche Handlungsempfehlungen für die Therapie der stillassoziierten Brusterkrankungen notwendig. Auf Initiative der Nationalen Stillkommission wurde eine evidenz- und konsensbasierte Leitlinie zur Therapie wunder Brustwarzen, der verstärkten initialen Brustdrüsenschwellung, der Mastitis puerperalis und des Milchstaus entwickelt. Die Leitlinienentwicklung folgte methodisch den Kriterien der Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF). Die Empfehlungen wurden basierend auf systematischen Recherchen und Bewertungen der Literatur und unter Berücksichtigung praktischer Erfahrungen in einer interdisziplinär zusammengesetzten Expertengruppe abgeleitet. Zusätzlich wurden Klinische Konsensuspunkte als Expertenmeinung zu Fragestellungen formuliert, zu denen keine wissenschaftlichen Untersuchungen möglich sind oder angestrebt werden. Im vorliegenden Artikel werden die Empfehlungen der S3-Leitlinie zusammenfassend präsentiert.

BACKGROUNDDoctors are more likely to implement guidelines in their everyday practice if the recommendations contained in them are understandable. So far, there has been little standardization in the wording of guideline recommendations. It would be important to know how certain terms are understood by guideline users. In this study, doctors were asked in a survey about what they considered to be the level of obligation carried by various formulations that are commonly used in guidelines to recommend particular courses of action.METHODSAn online survey of physicians (mostly dermatologists) was carried out in which they were asked to rate, on a visual analog scale, what they perceived to be the level of obligation of various common formulations for guideline recommendations.RESULTSThe terms "muss" (must) and "darf nicht" (must not) were interpreted as being maximally binding. The two closely related German words "soll" (shall) and "sollte" (should) were considered highly binding, as were negative formulations such as "wird nicht empfohlen" (is not recommended). The perceived level of obligation of "soll" did not differ from that of "sollte" to any detectable extent, nor was there any detectable distinction between the various negative formulations studied. Formulations with the words "wird empfohlen" (is recommended), "kann empfohlen werden" (can be recommended), or other "kann" (can) expressions were considered to be only mildly or moderately binding. In general, there was marked variation in the perceived level of obligation of formulations located in the low and middle ranges.CONCLUSIONThese findings suggest that guideline users do not necessarily perceive recommendation strengths as the guideline authors intended. It might be better if positive recommendations came in only two different strengths, while a single recommendation strength might suffice for negative ones. Further studies should shed more light on this question.

Breastfeeding is widely acknowledged to be the best and most complete form of nutrition for healthy infants born at term and is associated with numerous benefits in terms of infants' health, growth, immunity and development. However, breastfeeding problems often result in early weaning. Standardized treatment recommendations for breastfeeding-related diseases are necessary to optimize the care offered to breastfeeding women. Evidence and consensus based guidelines for the treatment of puerperal mastitis, sore nipples, engorgement and blocked ducts were developed on the initiative of the National Breastfeeding Committee. These guidelines were developed in accordance with the criteria set up by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF), the Association of Scientific Medical Societies in Germany. The recommendations were drawn up by an interdisciplinary group of experts and were based on a systematic search and evaluation of the literature but also took clinical experience into account. Additionally good clinical practice (GCP) in terms of expert opinion was formulated in cases where scientific investigations could not be performed or were not aimed for. This article presents a summary of the recommendations of the S3-guidelines.

Breastfeeding is widely acknowledged to be the best and most complete form of nutrition for healthy infants born at term and is associated with numerous benefits in terms of infants' health, growth, immunity and development. However, breastfeeding problems often result in early weaning. Standardized treatment recommendations for breastfeeding-related diseases are necessary to optimize the care offered to breastfeeding women. Evidence and consensus based guidelines for the treatment of puerperal mastitis, sore nipples, engorgement and blocked ducts were developed on the initiative of the National Breastfeeding Committee. These guidelines were developed in accordance with the criteria set up by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF), the Association of Scientific Medical Societies in Germany. The recommendations were drawn up by an interdisciplinary group of experts and were based on a systematic search and evaluation of the literature but also took clinical experience into account. Additionally good clinical practice (GCP) in terms of expert opinion was formulated in cases where scientific investigations could not be performed or were not aimed for. This article presents a summary of the recommendations of the S3-guidelines.

Background A recent study has shown that the perceived meaning of wordings in recommendations such as “should” or “must” can vary among guideline users. In addition to the wordings, many guidelines use graphic symbols such as arrows or smileys to support their recommendations. Objectives To determine whether such symbols influence the perceived meaning of the recommendations or may help to reduce variation in the perception of the meaning between different guidelines’ users. Methods With the help of an online-survey, using a visual analogue scale (0–100), participating physicians from different specialties were asked to express their perceived levels of obligation when confronted with different guidelines recommendations in combination with different symbols. Results 269 physicians participated, the addition of a “single arrow” or “double arrow” to the recommendation did not lead to relevant changes in the perceived obligation expressed by the recommendation (median: soll/shall: 83 vs. 87; “sollte/should”: 77 vs. 78). In comparison to the prior study, variations in the interpretation of typical guideline wordings were not reduced if symbols were used additionally. Discussion In this study, the impact of symbols on the understanding of a guidelines recommendation was limited. Important methodological limitations apply but this study questions the impact of symbols to clarify a recommendation’s message. However, visual aids are likely to be very important for users to help to identify recommendations within larger text document and therefore make guidelines easier to use and implement.

Breastfeeding is widely acknowledged to be the best and most complete form of nutrition for healthy infants born at term and is associated with numerous benefits in terms of infants' health, growth, immunity and development. However, breastfeeding problems often result in early weaning. Standardized treatment recommendations for breastfeeding-related diseases are necessary to optimize the care offered to breastfeeding women. Evidence and consensus based guidelines for the treatment of puerperal mastitis, sore nipples, engorgement and blocked ducts were developed on the initiative of the National Breastfeeding Committee. These guidelines were developed in accordance with the criteria set up by the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften (AWMF), the Association of Scientific Medical Societies in Germany. The recommendations were drawn up by an interdisciplinary group of experts and were based on a systematic search and evaluation of the literature but also took clinical experience into account. Additionally good clinical practice (GCP) in terms of expert opinion was formulated in cases where scientific investigations could not be performed or were not aimed for. This article presents a summary of the recommendations of the S3-guidelines.