JEADV SUPPLEMENT ARTICLE

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1 DOI: /jdv JEADV SUPPLEMENT ARTICLE Safety and efficacy of adapalene 0.1% / benzoyl peroxide 2.5% in the long-term treatment of predominantly moderate acne with or without concomitant medication results from the non-interventional cohort study ELANG H.P.M. Gollnick, 1, * M. Friedrich, 2 M. Peschen, 3 R. Pettker, 4 A. Pier, 5 V. Streit, 6 P. J ostingmeyer, 7 D. Porombka, 8 I. Rojo Pulido 8,A.J ackel 8 1 Department of Venerology and Dermatology, Otto-von-Guericke University, Magdeburg, Germany 2 Dermatologist in Private Practice, Oranienburg, Germany 3 Dermatologist in Private Practice, Freiburg, Germany 4 Dermatologist in Private Practice, Berlin, Germany 5 Dermatologist in Private Practice, Lippstadt, Germany 6 Dermatologist in Private Practice, Buchholz in der Nordheide, Germany 7 Med:Unit GmbH, Köln, Germany 8 Galderma Laboratorium GmbH, Düsseldorf, Germany *Correspondence: H.P.M. Gollnick. Harald.Gollnick@med.ovgu.de Abstract Background Acne is a chronic inflammatory disease requiring long-term treatment. The fixed-dose combination adapalene 0.1%/benzoyl peroxide 2.5% (adapalene-bpo) is indicated for the once-daily topical treatment of Acne vulgaris when comedones, papules and pustules are present. Objective The main objectives of this non-interventional study were to assess long-term efficacy and safety of adapalene-bpo in moderate to severe acne with and without concomitant medication. Methods Patients with moderate to severe acne received adapalene-bpo alone or in combination with concomitant medication over a course of 9 months. The primary efficacy endpoint was changes in acne severity according to the Leeds Revised Acne Grading System; secondary endpoints included treatment success assessed by the patient and safety. Results In total, 5131 patients were eligible for efficacy and 5141 for safety evaluation. The majority of patients (78.8%) received adapalene-bpo alone. About 21.2% received adapalene-bpo in combination with another agent, mostly topical antibiotics (8.8%) or systemic antibiotics (8.7%). Mean (SD) acne severity improved from at baseline to at month 3, and further to at month 9 (both P < ). The degree of improvement correlated significantly with the severity at baseline. After 3 and 9 months of treatment, the facial skin was cleared completely (no more visible acne lesions) in 420 (8.2%) and 1326 patients (25.8%), respectively. A therapeutic effect was noted by the patients after a median time of 3 weeks (range: from 1 day to 12 weeks). No serious adverse events were reported. Facial skin irritations, mostly mild to moderate, occurred in 49.5% of patients and led to discontinuation in only 1.7% of cases. Conclusion In consistence with previous clinical findings, the use of adapalene-bpo in daily practice routine is safe and effective in the long-term management of patients with moderate to severe acne. Received: 3 April 2015; Accepted: 7 April 2015 Conflicts of interest Prof. Gollnick has participated in acne-relevant clinical and experimental studies, symposia and advisory boards of Galderma, Stiefel/GSK, Intendis, Meda, Merz, Hoffmann-LaRoche, Novartis, Schering, Pierre Fabre, IMTM and Vichy. Dr. Friedrich has participated in acne-relevant clinical studies and advisory boards of Galderma. Dr. Peschen has participated in acne-relevant clinical studies and advisory boards of Galderma. Dr. Pettker has participated in acne-relevant clinical studies of Galderma. Pier has participated in acne-relevant clinical studies of Galderma. Dr. Streit has participated in acne-relevant clinical studies and advisory boards of Galderma. Dr. J ostingmeyer is employed by med:unit GmbH, Cologne, Germany, an agency contracted by Galderma Laboratorium GmbH. Dr. Porombka, Dr. Rojo Pulido and Dr. J ackel are employed by Galderma Laboratorium GmbH, D usseldorf, Germany.

2 16 Gollnick et al. Introduction Acne vulgaris is a complex inflammatory skin disorder induced by multiple functional abnormalities of the pilosebaceous unit, including follicular hyperkeratinization, increased sebum production, bacterial proliferation and inflammation. 1 There is consensus among dermatologists that acne is a chronic disease with important ramifications. 2 Consistent with the definition of chronicity, 3 acne is characterized by a prolonged course, a pattern of recurrence or relapse, manifestation as acute outbreaks or slow onset and a psychological and social impact that affects patients quality of life. 2 Inflammation is a major pathogenic factor of acne. Recent data prove persistence of inflammatory mediators throughout acne lesion progression from pre-lesional formation to post-lesional resolution and scarring. 4,5 Caused by follicular hyperkeratinization, acne lesions first develop in the pilosebaceous unit as microcomedones. These subclinical lesions evolve into closed or open comedones and/or inflammatory lesions. Propionibacterium acnes (P. acnes) has been shown to trigger inflammatory cytokine release in acne via activation of Toll-Like Receptor 2 (TLR2). 6 This observation turned TLR2 into an attractive target for therapeutic intervention in the very early steps of the inflammatory cascade by preventing inflammatory cytokine release. Such anti-inflammatory activity has been described for the retinoids adapalene 7 and tretinoin. 8 In particular, adapalene has been shown to modulate specifically the expression of TLR2 in keratinocytes, and therefore adapalene blocks the early inflammatory reactions around the pilosebaceous follicle. 9,10 Its proven anti-inflammatory characteristics together with its good tolerability profile led to the recommendation to give preference to adapalene over first generation retinoids, e.g. tretinoin and isotretinoin. 11 To target multiple pathophysiologic factors of acne, topical agents with complementary mechanisms, such as antimicrobials and retinoids, are often combined. Topical retinoid-based combination therapy, first recommended in 2003 by the Global Alliance to Improve Outcomes in Acne 12 in a therapeutic algorithm, has become a standard first-line therapeutic approach because this regimen attacks three of four major pathogenic factors of acne: abnormal keratinization and loss of desquamation in the infundibulum, P. acnes hypercolonization and primary and secondary inflammatory events. 2 BPO is the most potent bactericidal agent, being more effective and acting faster than topical antibiotics against P. acnes with, no evidence of antimicrobial resistance. 13 To date, adapalene 0.1%/benzoyl peroxide 2.5% (adapalene- BPO) is the only available treatment option that combines a retinoid with the antimicrobial agent BPO in a fixed-dose formulation. It was developed for the once-daily treatment of acne. Due to its well-known features, BPO does not exert selective pressure on bacteria, which is commonly associated with the use of topical and systemic antibiotics. The fixed-dose combination adapalene-bpo is efficient and intended for short-term and long-term usage at the same time. 5,12 Based on favourable safety and efficacy data from several clinical studies, the European Guidelines for the Treatment of Acne strongly recommend adapalene-bpo for patients with mild to moderate inflammatory lesions. 18 Addressing the early onset of acne, 19 the beneficial effect was also shown in a setting with pre-adolescent patients aged 9 11 years. 20 Moreover, several studies have demonstrated the effective treatment of severe acne cases with a combination of adapalene-bpo together with temporarily used oral antibiotics 21,22 resulting in the recommendation to use this regimen of topical and systemic agents in severe popular acne as well as in nodular acne. 11 Due to its chronic character, long-term management of acne patients is essential to prevent relapse and to maintain the improvement achieved in initial short-term therapy. Long-term efficacy over 12 months has been demonstrated in a controlled study investigating patients with mild to moderate acne. 13 Furthermore, maintenance therapy with adapalene-bpo over 6 and 12 months after oral isotretinoin treatment prevented relapse in a large percentage of patients with severe 23 and those with moderate to severe acne. 24 In order to confirm data from controlled clinical trials, the ELANG study investigated safety and efficacy of adapalene-bpo in a real-world non-interventional setting, including patients of all ages with moderate to severe inflammatory acne who applied adapalene-bpo alone or in combination with other drugs. Investigational results concerning quality of life and patient adherence associated with this long-term topical treatment were reported in a separate publication. Materials and methods Study design The long-term efficacy and safety of adapalene-bpo in patients with moderate to severe inflammatory acne was evaluated in a multicentre, open-label, prospective non-interventional observational cohort study conducted at 189 centres in Germany between June 2012 and September Observation time per patient was approximately 9 months. Safety and efficacy data were assessed at baseline and after 3 and 9 months, respectively. In case the patient returned for an unscheduled visit within the 9-month observation period, this visit was documented in addition. Patients were free to withdraw from the study at any time and for any reason. This non-interventional observational study [according to 4 (23) AMG (Medicinal Products Act)] was conducted in accordance with the joint recommendations for the planning, conducting and analysing of observational studies compiled by the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI) (edition of July 7, 2010). This study

3 Efficacy and safety of long-term adapalene-bpo 17 was reviewed and approved by federal state law established Ethics Committees Counselling and has therefore been performed in accordance with the ethical standards laid down in the Declaration of Helsinki passed in 1964 and its later amendments. No diagnostic or therapeutic measures, exceeding the already necessary scope were required, and treatment routine was not altered by this non-interventional, observational study. All patients (respectively their legal guardians) provided their written informed consent prior to entering the study. Participants Patients with moderate to severe inflammatory facial acne, equivalent to grade 4 12 according to the Leeds Revised Acne Grading System defined for the face (grade 0 3: mild, grade 4 7: moderate, grade 8 10: moderately severe, grade 11 12: very severe), 25 were selected from dermatology practices if that topical acne therapy with adapalene-bpo alone or in combination with other drugs was indicated. A further requirement was that the decision on whether to treat the patient with adapalene-bpo was made independently from this study. Criteria for non-selection were pregnancy or breastfeeding, hypersensitivity to the medication or any of the ingredients. Patients were selected at the discretion of the investigator. To minimize bias, the physician was obliged to include and to document consecutively the first appropriate patients fitting the selection criteria defined in the study protocol. The participating investigator exclusively determined treatment regimen, dose and duration of the adapalene-bpo treatment. In line with the common clinical acne treatment practice, an interim documentation was scheduled 3 months after the start of initial treatment. In order to examine long-term effects, the full observation time per patient was 9 months. Safety and efficacy assessments Safety and tolerability were assessed by evaluating local skin irritations and adverse drug reactions (ADR) which are defined as adverse events (AE) with a suspected causal relationship with one or more applied drugs (as assessed by a health care professional). At each follow-up visit, the most common skin irritations such as erythema, dryness, desquamation, burning/stinging and pruritus were rated by the investigator on a 4-step scale (none, mild, moderate, severe). ADRs were documented additionally at each follow-up visit. Furthermore, overall tolerability was rated on a 4-step scale (very good, good, satisfactory, poor) at the interim and the final visit. Efficacy variables were changes in severity of facial acne according to the Leeds Revised Acne Grading System (primary endpoint), physician s assessment of efficacy (very good, good, satisfactory, poor) at each visit, patient s assessment of therapeutic efficiency (completely resolved, marked improvement, moderate improvement, mild improvement, no change, worsened) after 3 months, and time to onset of action observed by the patient. Statistical analyses All data analyses were carried out according to a pre-established analysis plan. The sample size was chosen in order to gain a large patient collective that would allow the discovery of rare adverse drug reactions. The collected data were analysed with epidemiological methods, using the SPSS (IBM Deutschland GmbH, Ehningen, Germany) for Windows programme package. For continuous variables, statistic parameters including arithmetic mean, standard deviation and range were calculated. Frequency distributions for discrete variables were provided as percentage in relation to the total sample. Free text answers were transferred post hoc into adequate coding schemes and analysed as frequency distribution. Evaluation of parameters measuring the clinical course were performed by intra-individual difference analysis (first vs. last examination) using the Wilcoxon signedrank test. Difference was calculated per patient and subsequently averaged. Patients with missing data for one or both variables were not imputed. In case patients had not returned after their unscheduled visit, assessment was based on data obtained from the unscheduled visit (LOCF). For post hoc analyses of variables affecting efficacy, subgroups were compared using Mann Whitney U-Test. Correlations were calculated using Spearman correlation. All tests were two-sided, and significance was declared at the 0.05 level. Results Patient disposition and baseline characteristics In total, 6036 patients were included into this non-interventional study, of which 895 were lost to follow-up. Of 5141 patients administered adapalene-bpo at least once and were included in the safety set. Of those, 10 patients were excluded from efficacy analyses due to protocol violation (n = 9) and missing followup data on efficacy (n = 1). Thus, 5131 patients from 178 centres were included in the efficacy evaluation (Fig. 1). A total of 1378 patients discontinued adapalene-bpo prior to the end of the 9-month observation period. Of those, a majority of 525 patients gave acne resolution as the reason for earlier discontinuation. An additional unscheduled visit within the 9-month observation period was documented for 141 patients (2.7%). Reasons for this additional visit included additional routine check-up by the investigator, efficacy, local skin irritations and new prescription. Baseline characteristics are summarized in Table 1. Gender distribution was 56.5% male, 42.8% female, (0.7% unknown) in this study subpopulation. Median age of the study population was 18.0 years (range 10 74). Median age at onset of acne was 14 years (range: 1 70). The majority of patients (86.3%) suffered from moderate facial acne at baseline,

4 18 Gollnick et al. Table 1 Baseline demographics (n = 5131). Parameter n (%) Gender Male 2898 (56.5%) Female 2195 (42.8%) Unknown 38 (0.7%) Age, median (range) 18.0 years (10 74) Age at onset of acne, median (range) 14.0 years (1 70) Smoker 928 (18.1%) Figure 1 Patient flow in the ELANG study. corresponding to Leeds grades 4 7. Chest and back were affected in 43.1%. About 1880 patients (36.6%) received previous acne treatment, predominantly topical antibiotics (17.9%). Almost half of the patients (49.2%) had a positive family history of acne and one third (33.9%) presented with facial, mostly atrophic scars. Concomitant medication administered for other diseases than acne was documented for 5.9% of patients, whereby dermal agents (1.4%; for example for eczema or warts) were most frequently prescribed. Treatment regimen For most patients (94.2%) the prescribed dosage of adapalene- BPO was once per day. The majority of patients (78.8%) received adapalene-bpo alone while 21.2% received adapalene- BPO in combination with another agent (Fig. 2), in most cases either topical antibiotics (8.8%), mostly erythromycin, or systemic antibiotics (8.7%). Patients receiving oral antibiotics had more severe acne. The subgroup of patients with affected chest or/and back had been administered oral antibiotics approximately twice as often as the subgroup with only facial manifestation (12.4% vs. 5.6%). Treatment changes were reported at interim and final visits. About 10% of patients discontinued treatment with adapalene-bpo upon acne improvement. About 12.8% and 9.2% of patients receiving combination therapy at baseline and interim visit switched, from combination therapy to maintenance therapy with adapalene-bpo alone at interim and final visit respectively. The percentage of patients with a new prescription of oral antibiotics was highest at study start (8.7%) and decreased steadily during the course of the study (4.1% at interim visit and 2.4% at final visit). Efficacy Over the course of the study, facial acne severity according to the Leeds Revised Acne Grading System improved from Phototype I 228 (4.4%) II 2340 (45.6%) III 1857 (36.2%) IV 491 (9.6%) V 89 (1.7%) VI 10 (0.2%) Not documented 116 (2.3%) Known family history of acne 2526 (49.2%) Facial scarring 1739 (33.9%) Severity of facial acne according to the Leeds revised acne grading system (25.6%) (27.0%) (21.2%) (12.5%) (8.3%) (2.5%) (1.3%) (0.2) 12 3 (0.1%) Not documented 73 (1.4%) Previous treatment 1880 (36.6%) Systemic antibiotics 363 (7.1%) Oral isotretinoin 70 (1.4%) Topical retinoids 257 (5.0%) BPO 652 (12.7%) Topical antibiotics 919 (17.9%) Azelaic acid 290 (5.7%) Antiandrogenous contraception 85 (1.7%) Others 112 (2.2%) at baseline to at the interim visit, and further to at the final visit (both P < ) (Fig. 3). Stratification by facial Leeds grade at baseline showed significant improvement at all baseline Leeds grades (Fig. 4a), whereby a significant correlation was found between improvement and baseline Leeds grade: The more severe the acne at baseline, the greater the improvement (Fig. 4b). After applying adapalene-bpo for a median time of 3 months, the facial skin was completely cleared (no more visible acne lesions) in 420 patients (8.2%). After applying adapalene-bpo for a median

5 Efficacy and safety of long-term adapalene-bpo 19 Figure 2 Product prescribed in combination with adapalene-bpo. Figure 3 Mean changes in facial acne severity according to the Revised Leeds Acne Grading System. time of 9 months, the number of patients without any visible acne lesions trebled to 1326 (25.8%). A therapeutic effect was noted by the patients after a median time of 3 weeks (range <1 week 12 weeks). Overall, acne improvement was similar between the groups treated with adapalene-bpo alone and in combination with oral antibiotics. For the majority of patients (83.1%), physicians assessed efficacy of adapalene-bpo as good or very good. Safety For most patients (90.2%), overall tolerability was assessed as good or very good. No serious adverse events were reported during the course of the study. In total, local skin irritations were documented in 49.5% of patients. Dryness (30.7%), erythema (24.3%) and desquamation (22.4%) were reported most frequently. The majority of skin irritations (71.7%) were mild and resolved when adapalene-bpo was discontinued. In addition to local skin irritations, a total of 42 ADRs were documented in 40 patients (Table 2). Three patients (0.1%) experienced suspected allergic reactions to benzoyl peroxide, localized at the application site. Local skin irritations led to discontinuation in only 85 patients (1.7%) and only 0.4% of the patients had an unscheduled visit because of local skin irritation. A significant correlation was found between Leeds grade at baseline and tolerability assessed by the physician at both, interim (r = 0.847; P = 0.008; Spearman) and final visit (r = 0.964; P < 0.001; Spearman): In general, patients with lower acne severity grade tolerated the topical fixed-dose-combination better. Overall, tolerability was rated as good for male and female patients. However, when stratified by gender, differences in the subjective rating were observed during the first 3 months, but not over the long-term period of 9 months. At the interim visit, tolerability on the 4-step scale (very good, good, satisfactory, poor) was slightly better rated for male patients than for female patients. Discussion Here, we present for the first time data of a non-interventional study that was designed to explore the long-term efficacy and safety of adapalene-bpo in patients with predominantly moderate inflammatory acne, using this topical agent alone or in combination with other drugs under daily routine conditions in the private dermatologist outpatient clinics. Such non-interventional studies are designed to collect and evaluate clinical data on current treatment standards in daily practice rather than comparing efficacy profiles of different treatment regimens in interventional, randomized, comparative clinical trials, e.g. fixeddose combinations alone or in combination with systemic antibiotics. Adapalene-BPO is known for its rapid onset of therapeutic efficiency 15 with no limitation of treatment duration. Acne is considered to be a chronic disease 26 and therefore demands an effective and safe treatment option that can be used for a longterm course. In this study, we observed both, a significant improvement within the short-term application of three months as well as during long-term application. The number of patients without any visible acne lesions increased threefold in the whole patient collective after 9 months. In total, an almost 4 grade improvement

6 20 Gollnick et al. (a) (b) Figure 4 Improvement in Leeds grade (baseline vs. final visit), stratified by acne severity at baseline. Mean improvement (a) and correlation between Leeds grade at baseline and improvement in Leeds grade (b). Data from Leeds grades 11 and 12 were pooled due to the low number of patients. Table 2 Adverse drug reactions reported during the course of the study. ADR n (%) Poor tolerability 14 (0.3%) Eczema 8 (0.2%) Inflammation 4 (0.1%) BPO allergy 3 (0.1%) Peeling 2 (0.0%) Fissures 2 (0.0%) Skin-related tension 2 (0.0%) Aching skin 1 (0.0%) Headache 1 (0.0%) Lid oedema 1 (0.0%) Oozing erosions 1 (0.0%) Pustules 1 (0.0%) Sebostasis 1 (0.0%) Xerosis 1 (0.0%) Safety set (n = 5141). in mean acne severity according to the Leeds Revised Acne Grading System from at baseline to was found at the final visit, indicating an ongoing acne improvement after successful initial therapy. Thus, the long-term application led to further improvement of the facial clearance already achieved by short-term therapy. Generally, acne improvement was observed across all grades of severity. Stratification by Leeds grade at baseline revealed that improvement was greater in cases of more severe acne compared to moderate cases. The relative benefit of adapalene-bpo with a higher lesion count at baseline has already been demonstrated over 3 months in a previous short-term observational study that included patients with mild to moderate acne, 27 thus confirming data generated from clinical trials. 28 The present long-term study also effectively demonstrates this correlation over 9 months of treatment, and in a sample that includes patients with moderate as well as severe acne. This effect may be due to the complementary mechanisms of the topical retinoid adapalene and the antimicrobial BPO in combination, which allows simultaneous targeting of multiple pathogenic factors of acne, 2 whereby BPO eliminates P. acnes and adapalene down-regulates the cell surface receptor 9 used by P. acnes for the induction of inflammatory cytokine production. 15 Adapalene also alters the follicular microclimate, thus enhancing the penetration of BPO. 12 The synergistic action of an adapalene-bpo combination has been demonstrated in several clinical settings. 29

7 Efficacy and safety of long-term adapalene-bpo 21 The median time of 3 weeks to achieve a therapeutic effect was slightly longer compared to the 2 weeks observed in a former randomized controlled trial 26 as well as in a 12-week observational study. 27 However, compared to these studies, our study included both patients with severe and moderate acne, whereas only a small portion of patients with a higher acne severity grade got appropriate systemic treatment as recommended by current guidelines. Taken together, this might account for the difference identified in the therapeutic onset. As severe acne patients might not get necessarily systemic treatments in daily practice, it indicates the continued need for stronger topical therapy options. Within the study population also suffering from acne on chest and back, only 12.4% got an additional temporary systemic treatment. This finding indicates a therapeutic gap between guideline recommendations and daily practice. Furthermore, we noticed additional use of topical antibiotics in about 8% which is not recommended by guidelines. In severe acne, the combination of topical acne therapy and short-term administration of oral antibiotics is recommended. 12,18 Adapalene-BPO in combination with oral antibiotics in the initial treatment phase has been shown to be efficacious, especially in patients with severe acne. 21 Hence the concomitant prescription of oral antibiotics for patients with severe acne was in line with treatment guidelines. 18 However, efficacy results did not show the expected additional treatment benefit when compared to patients receiving adapalene-bpo alone. The percentage of patients with prescription of oral antibiotics was highest at study start and decreased steadily during the course of the study. In general, treatment regimen was predominantly changed at the interim or final visit. This approach follows current recommendations in acne management to limit the duration of systemic antibiotic use. 30 Contrary to antibiotics, adapalene-bpo is appropriate for long-term use, as neither adapalene nor BPO is known to enhance the development of antibiotic resistance in bacteria. 30,31 Due to the non-interventional character of this study, the exact dose and duration of oral antibiotic use was not recorded, merely the prescriptions at the respective visits. Therefore, any effects regarding oral treatment cannot be concluded finally. In general, it is well known from previous studies that topical adapalene-bpo complements oral treatments optimally, during initial therapy as well as in maintenance therapy. 21,23 Adapalene-BPO is known to cause predominantly mild local skin irritations, 32 particularly at the beginning of therapy. 15 Although local skin irritations were documented in 50% of the patient population, <2% of patients discontinued treatment because of poor tolerability. Due to the mostly mild nature of local skin irritations which usually resolved spontaneously within two weeks after the start of treatment, tolerability was rated as good or very good for the majority of patients. Usually, the alternating use of adapalene-bpo every second day within the initial two weeks of topical treatment and / or concomitant use of moisturizer are known to attenuate tolerability issues. However, due to the limiting character of the non-interventional study design, this point was not addressed. The study is limited by its non-interventional design, which did not allow a wash-out phase before application of adapalene- BPO was initiated. For ethical reasons, a wash-out phase is not recommended either. The lack of a control group and the use of concomitant acne medication might interfere with the interpretation of outcome data. However, the large number of patients receiving adapalene-bpo alone ensures statistically conclusive data to assume that the observed effects may be attributable to adapalene-bpo. Overall, the study design was chosen to provide a comprehensive profile of the clinical situation of acne patients in a real-world setting. In conclusion, our findings support the advantage of longterm treatment with adapalene-bpo in patients with predominantly moderate acne. Acne severity continued to improve beyond the 3-months treatment duration. In this prospective study, adapalene-bpo was safe in the long-term administration and led to satisfactory results in a large patient collective with predominantly moderate inflammatory acne under real-life clinical practice conditions. Acknowledgement This study was funded by Galderma Laboratorium GmbH. References 1 Pawin H, Beylot C, Chivot M, et al. Physiopathology of acne vulgaris: recent data, new understanding of the treatments. Eur J Dermatol 2004; 14: Thiboutot D, Gollnick H, Bettoli V, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol 2009; 60(Suppl 5): S1 S50. 3 O Halloran J, Miller GC, Britt H. Defining chronic conditions for primary care with ICPC-2. Fam Pract 2004; 21: Harvey A, Huynh TT. Inflammation and acne: putting the pieces together. J Drugs Dermatol 2014; 13: Del Rosso JQ, Kircik LH. 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