Combination Therapy with Adapalenebenzoyl Peroxide And

Home , Lymecycline

BJD THERAPEUTICS British Journal of Dermatology Combination therapy with adapalene–benzoyl peroxide and oral lymecycline in the treatment of moderate to severe acne vulgaris: a multicentre, randomized, double-blind controlled study B. Dreńo, R. Kaufmann,* S. Talarico, V. Torres Lozada, M.A. Rodrı´guez-Castellanos,§ M. Go´mez-Flores,– J. De Maubeuge,** M. Berg, P. Foley, A. Sysa-Jedrzejowska,§§ N. Kerrouche,–– F. Paliargues–– and V. Bettoli*** Hoˆpital Hotel Dieu, Department of Dermato-Oncology, Place Alexis-Ricordeau, 44093 Nantes Cedex 1, France *Department of Dermatology, Goethe-University Hospital, Frankfurt am Main, Germany UNIFESP – Universidade Federal de Saõ Paulo, Saõ Paulo, Brazil Department of Dermatology, Jua´rez Hospital, Mexico City, Mexico §Instituto Dermatolo´gico de Jalisco, Zapopan, Mexico –University Hospital ‘Dr Jose´ Eleuterio Gonza´lez’, Monterrey, Mexico **CHU Saint-Pierre, Universite´ Libre de Bruxelles, Brussels, Belgium Department of Dermatology So¨rmland, Ma¨lar Hospital, Eskilstuna, Sweden Skin and Cancer Foundation Inc., Carlton, and the University of Melbourne, Parkville, Victoria, Australia §§Department of Dermatology, Central Clinical Hospital of Medical University of Lodz, Poland ––Galderma R&D, Sophia-Antipolis, France ***Clinica Dermatologica, Azienda Ospedaliera Arcispedale S. Anna Universita` di Ferrara, Ferrara, Italy

Summary

Correspondence Background Oral antibiotics in association with a topical retinoid with or without Brigitte Dreńo. benzoyl peroxide (BPO) are the recommended first-line option in the treatment E-mail: [email protected] of moderate to severe acne vulgaris. Objectives To evaluate the efficacy and safety of oral lymecycline 300 mg with Accepted for publication 5 April 2011 adapalene 0Æ1%–BPO 2Æ5% (A ⁄BPO) fixed-dose gel in comparison with oral lymecycline 300 mg with a vehicle gel in subjects with moderate to severe acne Funding sources vulgaris. This study was supported by Galderma. Methods A total of 378 subjects were randomized in a double-blind, controlled trial to receive once-daily lymecycline with either A ⁄BPO or vehicle for Conflicts of interest 12 weeks. Evaluations included percentage changes from baseline in lesion All investigators received fees for conducting this study. N.K. and F.P. are current employees of counts, success rate (subjects ‘clear’ or ‘almost clear’), skin tolerability, adverse Galderma R&D. events and patients’ satisfaction. Results The median percentage reduction from baseline in total lesion counts at DOI 10.1111/j.1365-2133.2011.10374.x week 12 was significantly higher (P <0Æ001) in the lymecycline with A ⁄BPO group ()74Æ1%) than in the lymecycline with vehicle group ()56Æ8%). The success rate was significantly higher (47Æ6% vs. 33Æ7%, P =0Æ002) in subjects treated with lymecycline and A ⁄BPO. Both inflammatory and noninflammatory lesions were significantly reduced at week 12 (both P <0Æ001) with a rapid onset of action from week 2 for noninflammatory lesions (P<0Æ001) and week 4 for inflammatory lesions (P=0Æ005). The A ⁄BPO and lymecycline combination was well tolerated. The proportion of satisfied and very satisfied subjects was similar in both groups, but the number in the A ⁄BPO group who were ‘very satisfied’ was significantly greater (P=0Æ031). Conclusion These results demonstrate the clinical benefit of combining A ⁄BPO with lymecycline in the treatment of moderate to severe acne vulgaris.

2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp383–390 383 384 Adapalene-BPO gel with oral lymecycline in acne vulgaris, B. Dre´no et al.

The combination of a topical retinoid and an antimicrobial conducted in 2009 at 32 investigational centres in nine coun- agent is considered to be the preferred approach for almost all tries worldwide (France, Italy, Belgium, Sweden, Germany, patients with acne vulgaris except the most severe cases.1 Poland, Mexico, Brazil and Australia). Enrolled subjects were Among various fixed-dose combinations, the once-daily gel of any race or either sex, aged between 12 and 35 years, with containing the topical retinoid adapalene 0Æ1% and the anti- moderate or severe acne vulgaris as defined by the Investiga- microbial benzoyl peroxide 2Æ5% (A ⁄BPO) has shown its tor’s Global Assessment (IGA; score of 3 or 4 on a scale from benefit in several double-blind, randomized and controlled 0 to 5). Eligible subjects were required to have a minimum of trials. Compared with the adapalene and BPO monotherapies, 20 inflammatory lesions, between 30 and 120 noninflamma- A ⁄BPO when applied once daily for 12 weeks significantly tory lesions, and no more than three nodulocystic lesions on reduced the number of both inflammatory and noninflamma- the face excluding the nose area. Subjects with acne conglobata, tory lesions in subjects with moderate acne, with a rapid onset acne fulminans (secondary acne) or other dermatological of action and a good safety profile.2–4 The effect of A ⁄BPO conditions which could interfere with treatment or evaluation was sustained for 4 months, and it was also safe as a long- were excluded. All female subjects of childbearing potential term treatment for up to 12 months.5 had to have a negative urine pregnancy test before and during Tetracyclines are a historically conventional treatment of the study. The study protocol was approved by the local ethics acne vulgaris and more particularly in papulopustular acne not committees and the study was conducted in accordance with amenable to topical therapy. Tetracyclines function by inhibit- Good Clinical Practice. All subjects provided written informed ing bacterial multiplication and growth and also possess anti- consent before entering the study. inflammatory properties.6 Second-generation tetracyclines such as lymecycline, minocycline and doxycycline are preferred Treatment administered because of improved oral absorption, enhanced tissue penetra- tion and slower elimination than first-generation tetra- Subjects were randomized in a 1 : 1 ratio by a designated stat- cyclines.7 Furthermore, the efficacy of lymecycline has been istician (using a computed randomization list that generated demonstrated to be similar to that of minocycline in multicen- treatment numbers in a block size of four) to receive either tre, double-blind, randomized and controlled studies, with oral lymecycline with A ⁄BPO gel (Epiduo; Galderma SA, fewer treatment-related adverse events (AEs), and to be more Lausanne, Switzerland) or lymecycline (Tetralysal; Galderma) cost-effective.8,9 Thus, lymecycline may be regarded as a suit- with a vehicle gel. Oral lymecycline 300 mg was to be taken able first-line oral treatment for acne vulgaris. once daily in the morning, and A ⁄BPO or its vehicle was to While isotretinoin is reserved for the most severe cases of be topically applied on the whole face, once daily in the even- acne, few options are available for the treatment of moderate ing for 12 weeks. The randomization list and the electronic to severe acne. Combination therapy including agents of dis- file were secured in a locked cabinet and in an electronic file tinct and complementary modes of action may enhance treat- with restricted access to only the designated personnel directly ment efficacy and is recommended in several international responsible for labelling and handling the study medications, consensus guidelines.1,7,10 A previous clinical trial clearly until the study database was locked and ready to be unblinded demonstrated that lymecycline 300 mg daily plus adapalene for statistical analyses. The investigators could not access the gel 0Æ1% combination treatment resulted in a significantly randomization list. greater mean decrease in the number of inflammatory, non- In addition, use of the provided gentle skin cleanser at least inflammatory and total lesions than lymecycline plus vehicle prior to applying the study medication, and moisturizing in the treatment of moderate to moderately severe acne vulga- lotion in the morning for symptomatic relief of skin dry- ris.11 More recently, a double-blind, randomized, controlled ness ⁄irritation was encouraged. A sun-protection factor (SPF) study demonstrated the superior efficacy of a combination 50 sunscreen was also provided and recommended for used in treatment using oral doxycycline 100 mg and A ⁄BPO com- case of outdoor activities. Integrity of the blinding was pared with doxycycline and vehicle in the treatment of severe ensured by packaging the topical medication in identical tubes acne vulgaris.12 The aim of the present study was to evaluate and requiring a third party other than the investigator ⁄evalua- the efficacy and safety of oral lymecycline with A ⁄BPO gel tor to dispense the medications. compared with oral lymecycline with vehicle in the treatment of moderate to severe acne vulgaris. Study assessments and outcomes

Materials and methods Efficacy and safety assessments were performed at baseline and at weeks 2, 4, 8 and 12. Efficacy variables were the percentage change from baseline in inflammatory, noninflammatory and Study design total lesion counts (sum of inflammatory and noninflammatory This double-blind, randomized, controlled, parallel group trial lesions), the total lesion improvement assessed by the Kligman (EudraCT number: 2008-006792-68) was performed to com- score (poor, fair, good, excellent), and the success rate pare the efficacy and safety of lymecycline 300 mg in combin- defined as the percentage of subjects with an IGA score of 0 ation with either A ⁄BPO or its vehicle. The study was (clear) or 1 (almost clear) at each postbaseline visit.

2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp383–390 Adapalene-BPO gel with oral lymecycline in acne vulgaris, B. Dre´no et al. 385

Safety was assessed at each visit through evaluations of the All efficacy variables were analysed by using the Cochran– incidence of AEs and local tolerability. Erythema, scaling, dry- Mantel–Haenszel statistics, stratified by centre after ridit trans- ness and stinging ⁄burning were rated on a scale of 0 (none) formation with row mean difference statistics, testing the null to 3 (severe). hypothesis. Tests were two sided and considered as statistically In addition, the subject’s satisfaction was assessed using a significant at the a level of 0Æ05. Descriptive statistics were questionnaire at the last visit. used in the analyses of AEs, local tolerability and satisfaction questionnaire. Statistical analyses Results The primary endpoint was median percentage change from baseline in total lesion counts at week 12 in the intent-to-treat Subject disposition and baseline characteristics (ITT) population composed of all enrolled and randomized subjects. The last-observation-carried-forward method was A total of 378 subjects were randomized and included in the used to impute efficacy missing values. ITT population (Fig. 1): 191 received lymecycline with For confirmation, the primary analysis was performed on A ⁄BPO and 187 received lymecycline with vehicle. Overall, the per-protocol (PP) population composed of all enrolled and 93Æ2% of subjects completed the study. The early discontinua- randomized subjects, except subjects considered not evaluable tion rate was low (6Æ8%) and similar between the two groups. due to major deviations from the protocol. The main reasons for study discontinuation in both groups From a previous study, results showed a standard deviation were ‘subject’s request’ and ‘lost to follow-up’. Only three around 33% and a difference of 12% at week 12, in terms of subjects (1Æ6%) in the lymecycline with A ⁄BPO group discon- percentage change from baseline in total lesion counts tinued due to an AE. The PP population was composed of 334 between adapalene 0Æ1% and its vehicle, both combined with subjects: 170 (89Æ0%) in the lymecycline with A ⁄BPO group lymecycline 300 mg. We assumed that results of the current and 164 (87Æ7%) in the lymecycline with vehicle group. study should be at least equivalent to those of the aforemen- Baseline demographics and clinical characteristics of the ITT tioned study. To reach this objective with 90% power, 159 population are summarized in Table 1. Demographics were subjects per group were needed. Accounting for subjects similar between the two groups in terms of age, sex and eth- excluded due to major deviations, a total of 360 subjects were nicity. Slightly more male subjects (55Æ3% of the total popula- to be enrolled. tion) than female subjects were enrolled. The majority were

Fig 1. Subject disposition. A ⁄BPO, adapalene 0Æ1%–benzoyl peroxide 2Æ5%; ITT, intent-to treat; PP, per-protocol.

2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp383–390 386 Adapalene-BPO gel with oral lymecycline in acne vulgaris, B. Dre´no et al.

Table 1 Baseline demographic and clinical characteristics (intent-to-treat population)

A ⁄BPO + lymecycline Vehicle + lymecycline Total (n=191) (n=187) (n=378) Gender, n (%) Male 100 (52Æ4) 109 (58Æ3) 209 (55Æ3) Female 91 (47Æ6) 78 (41Æ7) 169 (44Æ7) Age (years), mean ± SD (min–max) 18Æ6±4Æ7 (12–35) 19Æ1±4Æ6 (12–34) 18Æ9±4Æ6 (12–35) Race, n (%) Caucasian 126 (66Æ0) 118 (63Æ1) 244 (64Æ6) Black 3 (1Æ6) 6 (3Æ2) 9 (2Æ4) Asian 3 (1Æ6) 5 (2Æ7) 8 (2Æ1) Hispanic 54 (28Æ3) 53 (28Æ3) 107 (28Æ3) Other 5 (2Æ6) 5 (2Æ7) 10 (2Æ6) Investigator Global Assessment 3: Moderate 153 (80Æ1) 162 (86Æ6) 315 (83Æ3) 4: Severe 38 (19Æ9) 25 (13Æ4) 63 (16Æ7) Inﬂammatory lesion count, mean ± SD 37Æ9±19Æ538Æ4±16Æ338Æ1±18Æ0 Noninﬂammatory lesion count, mean ± SD 72Æ4±29Æ567Æ4±27Æ370Æ0±28Æ5 Total lesion count, mean ± SD 110Æ3±36Æ1 105Æ8±34Æ2 108Æ1±35Æ2

A ⁄BPO, adapalene 0Æ1%–benzoyl peroxide 2Æ5%. caucasian (64Æ6%) or Hispanic (28Æ3%) and had been suffer- from week 2 ()19Æ6% vs. )11Æ5%) and a maximal difference ing from acne for 4Æ5 years on average. Overall, the two obtained at week 12 ()71Æ7% vs. )52Æ5%) (Fig. 2d). groups had comparable IGA severity scores and similarly high The success rate (subjects ‘clear’ or ‘almost clear’) at week numbers of inflammatory, noninflammatory and total lesions 12 was significantly higher in the lymecycline with A ⁄BPO at baseline. group than in the lymecycline with vehicle group (47Æ6% vs. 33Æ7%, P=0Æ002) with results diverging from week 8 (Fig. 3). Efficacy evaluation Figure 4 illustrates the effect of lymecycline and A ⁄BPO The median percentage change from baseline in lesion counts combination treatment on a subject with moderate acne. (total, inflammatory and noninflammatory) at weeks 2, 4, 8 and 12 are illustrated in Figure 2. The superiority of lymecy- Safety evaluation cline with A ⁄BPO compared with lymecycline with vehicle in the reduction of total lesion counts was shown at each visit The frequency of treatment-related AEs was comparable (Fig. 2a). At week 12, the median percentage change from between the two groups [16 subjects (8Æ4%) and 24 events in baseline in total lesion counts was )74Æ1% in the lymecycline the lymecycline with A ⁄BPO group; 15 subjects (8Æ0%) and with A ⁄BPO group vs. )56Æ8% in the lymecycline with vehicle 20 events in the lymecycline with vehicle group]. Most related group (P<0Æ001). A statistically significant difference AEs were mild or moderate in intensity. The most common between the two groups was shown as early as the first visit related AE was headache, with the same frequency in the ()25Æ6% vs. )18Æ2%, at week 2, P<0Æ001) demonstrating a lymecycline with A ⁄BPO group (2Æ1% of subjects) and in the more rapid onset of action of the combination treatment. lymecycline with vehicle group (2Æ1%). Related dermatological Similar results were seen in the PP analysis. AEs were also reported in a similarly low frequency in both The percentage of subjects with an excellent improvement treatment groups (4Æ2% and 1Æ6% of subjects, respectively). in total lesion count reduction (i.e. more than 75% reduction) Overall, a good local tolerability [mean score < 1 (mild) at was significantly higher at each visit in the lymecycline with each visit] was obtained for both treatment groups (Fig. 5). A ⁄BPO group than in the lymecycline with vehicle group, Slightly higher mean tolerability scores were shown at week 2 reaching 47Æ6% vs. 26Æ7% (P <0Æ001) at week 12 (Fig. 2b). in the lymecycline with A ⁄BPO group compared with the Although both study treatments showed a rapid and high lymecycline with vehicle group, but the signs and symptoms efficacy in reducing inflammatory lesions (Fig. 2c), a signifi- were transient, and the scores decreased rapidly and became cant difference in favour of lymecycline with A ⁄BPO was similar to those of vehicle with lymecycline from week 4. demonstrated starting at week 4 (P=0Æ005), with a maximal effect at the last visit ()81Æ7% vs. )71Æ0%, P<0Æ001). Subject satisfaction The superiority of lymecycline with A ⁄BPO over lymecycline with vehicle in reducing noninflammatory lesions was Most patients in the lymecycline with A ⁄BPO group (71Æ3%) shown at each visit (P<0Æ001), with a faster onset of action and in the lymecycline with vehicle group (71Æ6%) were

2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp383–390 Adapalene-BPO gel with oral lymecycline in acne vulgaris, B. Dre´no et al. 387

A/BPO + lymecycline Vehicle + lymecycline

(a) Change in total lesions (%) (b) Excellent improvement in total lesions (%)

P < 0·001

P < 0·001 P < 0·001

P < 0·001

P < 0·001 P < 0·001 P < 0·001

P < 0·001

P = 0·005

P = 0·002 P < 0·001

P < 0·001 P < 0·001

Fig 2. Lesion counts (intent-to-treat–last-observation-carried-forward analysis). (a) Median percentage change from baseline in total lesion counts; (b) percentage of subjects with an excellent improvement in total lesion counts according to the Kligman scale; (c) median percentage change from baseline in inflammatory lesion counts; (d) median percentage change from baseline in noninflammatory lesion counts. A ⁄BPO, adapalene 0Æ1%–benzoyl peroxide 2Æ5%. satisfied or very satisfied with the effectiveness of the treat- contraindications to this treatment or who poorly tolerate its ment (Fig. 6a). However, more patients (37Æ0%) in the lyme- problematic side-effect profile, combination therapy is both cycline with A ⁄BPO group were very satisfied with treatment the logical and recommended first alternative. effectiveness than in the lymecycline with vehicle group This worldwide, randomized, controlled study was designed (25Æ6%). to determine the clinical benefit of a combination therapy Similar results were observed for the overall satisfaction, using topical A ⁄BPO gel and oral lymecycline 300 mg once with a significantly higher proportion of subjects in the lyme- daily in the treatment of subjects with moderate to severe acne cycline with A ⁄BPO group expressed to be overall ‘very satis- vulgaris. Results of this study showed that the addition of fied’ with the treatment compared with the vehicle with A ⁄BPO to lymecycline (300 mg once daily) significantly lymecycline group (38Æ9% vs. 26Æ1%, P=0Æ031) (Fig. 6b). improved the outcome of acne vulgaris in terms of reduction of both inflammatory and noninflammatory lesions and Discussion increase of treatment success, with a rapid onset of action. Both treatments were well tolerated and subjects were satisfied For the treatment of all but the most severe recalcitrant acne in both treatment groups; however, significantly more subjects vulgaris, combination therapy of a topical retinoid and an oral were very satisfied when treated with lymecycline and A ⁄BPO. antibiotic, along with BPO, has been recommended as first- The efficacy and safety of A ⁄BPO alone in the treatment of line therapy.1 Although oral isotretinoin remains an effective moderate acne vulgaris compared with its monotherapies has systemic treatment for severe acne (nodulocystic or after been demonstrated in several previous studies.2–4 The treat- treatment failure with antibiotics), for patients with ment is also safe and well tolerated, and thus could be used

2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp383–390 388 Adapalene-BPO gel with oral lymecycline in acne vulgaris, B. Dre´no et al.

Recently, it was also demonstrated that A ⁄BPO provides higher efficacy when more lesions are presented at baseline.15 Although there are limits to applying results of a randomized controlled trial to the general population as they may differ from those in practice, our large sample size including both patients with moderate and severe acne can presumably indicate pertinence of our results for patients in the clinical set- ting. Another limitation that exists for every study that uses a vehicle as a comparator is that side-effects could have poten- tially affected the blinding of both subjects and investigators. However, even though signs and symptoms of local tolerability were more marked in the A ⁄BPO group, it is of note that they were also present in a great majority of patients in the other group. Combination of A ⁄BPO and oral antibiotics includes three active agents with different properties and modes of action, and is in line with the international consensus recommenda- Fig 3. Success rate. The success rate was defined as the percentage of tions on the treatment of all but the most severe forms of subjects ‘clear’ or ‘almost clear’ according to the Investigator’s Global acne.1,10 This triple combination would presumably be supe- Assessment. A ⁄BPO, adapalene 0Æ1%–benzoyl peroxide 2Æ5%. rior in efficacy compared with its individual components and the combination of two components. Indeed, A ⁄BPO has been (a) shown to be superior to its monotherapies in a pooled data analysis of almost 4000 patients, with a 10% and 13Æ1% add- itional benefit in terms of IGA success rate after 12 weeks when compared with BPO and adapalene, respectively (33Æ1% vs. 23Æ1% and 20%, both P<0Æ001).14 We demonstrated in the present study that compared with the oral antibiotic alone, the combination treatment led to a significantly greater reduction in all lesion counts, high IGA success rate and subject’s satisfaction after 12 weeks of treatment. We hypothesize that the IGA success rate of lymecycline with A ⁄BPO (47Æ6%) could surpass the efficacy of each of its individual components by approximately 14% (when compared with 33Æ7% for lymecycline and 33Æ1% for A ⁄BPO). This emphasizes the benefit of adding lymecycline to A ⁄BPO in acne combination therapy. (b) In addition to its superior efficacy at week 12, the combination of A ⁄BPO and oral antibiotics also presents several advantages. Firstly, addition of A ⁄BPO to antibiotics led to a more rapid onset of action and a greater level of satisfaction among subjects. Both are of clinical interest in this chronic pathology, as lack of improvement and lack of patient satisfaction with treatment were shown to be independently corre- lated with poor adherence behaviour as recently reported in a large-scale observational study.16 Secondly, despite their efficacy in the treatment of inflammatory acne lesions, oral antibiotics are not recommended as monotherapy or to be used for a prolonged period, due to the risk of developing antibiotic-resistant bacterial strains.10,17,18 The use of BPO and ⁄or retinoid in association with oral antibiotics to reduce the resistant population of Propionibacterium acnes has been widely Fig 4. Patient before (a) and 12 weeks after (b) treatment with advocated, as both agents minimize the development of anti- adapalene 0Æ1%–benzoyl peroxide 2Æ5% gel + lymecycline. microbial resistance.18,19 A ⁄BPO has been used in association with doxycycline13 and for a prolonged period and as a maintenance therapy.5,13 The lymecycline (the present study) for enhanced efficacy among great efficacy of A ⁄BPO could be explained by the synergistic patients with acne. Lymecycline is an efficacious, safe and cost- effect of adapalene and BPO when used in association.14 effective choice of oral antibiotic for the treatment of acne.8

2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp383–390 Adapalene-BPO gel with oral lymecycline in acne vulgaris, B. Dre´no et al. 389

(a) (b)

Fig 5. Local tolerability. Skin tolerability was assessed according to the following scoring scale: none = 0, mild = 1, moderate = 2 and severe = 3. Mean scores were calculated at each visit: (a) stinging ⁄burning, (b) erythema, (c) dryness and (d) scaling. The dashed lines indicate the mild value level (score = 1). A ⁄BPO, adapalene 0Æ1%–benzoyl peroxide 2Æ5%.

Like minocycline and doxycycline, it has a better pharmacoki- mune disorders and DRESS syndrome in the first week of netic profile compared with the first-generation tetracyclines. treatment.20 Minocycline and doxycycline are also known to However, minocycline has an increased risk of severe adverse induce hyperpigmentation,21 which is not reported with lyme- effects compared with other tetracyclines, including autoim- cycline. Furthermore, lymecycline has been shown to be less

Fig 6. Subject satisfaction. Satisfaction was rated by the subjects as ‘very satisfied’, ‘satisfied’, ‘somewhat satisfied’ or ‘not satisfied.’ A ⁄BPO, adapalene 0Æ1%–benzoyl peroxide 2Æ5%.

2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp383–390 390 Adapalene-BPO gel with oral lymecycline in acne vulgaris, B. Dreńo et al. phototoxic than doxycycline.22 Thus, lymecycline may be more 6 Webster G, Del Rosso JQ. Anti-inflammatory activity of tetracy- appropriate in patients with acne exposed to ultraviolet rays. clines. Dermatol Clin 2007; 25:133–5. In conclusion, the combination of A ⁄BPO and oral lymecy- 7 Dreńo B, Bettoli V, Ochsendorf F et al. European Expert Group on Oral Antibiotics in Acne. European recommendations on the use of cline provided a greater efficacy in terms of lesion counts, suc- oral antibiotics for acne. Eur J Dermatol 2004; 14:391–9. cess rate and onset of action compared with lymecycline with 8 Bossuyt L, Bosschaert J, Richert B et al. Lymecycline in the treat- vehicle in subjects with moderate to severe acne vulgaris. ment of acne: an efficacious, safe and cost-effective alternative to minocycline. Eur J Dermatol 2003; 13:130–5. What’s already known about this topic? 9 Grosshans E, Belaı¨ch S, Meynadier J et al. A comparison of the efficacy and safety of lymecycline and minocycline in patients with • A once-daily, fixed-dose combination gel of adapalene moderately severe acne vulgaris. Eur J Dermatol 1998; 8:161–6. and benzoyl peroxide (A ⁄BPO) is an efficacious and 10 Gollnick H, Cunliffe W, Berson D et al. Global Alliance to Improve Outcomes in Acne. Management of acne: a report from a Global safe treatment for moderate acne. However, few Alliance to Improve Outcomes in Acne. J Am Acad Dermatol 2003; options are available for treatment of more severe acne. 49(1 Suppl.):S1–37. 11 Cunliffe WJ, Meynadier J, Alirezai M et al. Is combined oral and topical therapy better than oral therapy alone in patients with What does this study add? moderate to moderately severe acne vulgaris? A comparison of the efficacy and safety of lymecycline plus adapalene gel 0Æ1%, versus • The combination of A ⁄BPO and oral lymecycline led to lymecycline plus gel vehicle. J Am Acad Dermatol 2003; 49(3 Suppl.): a significantly higher treatment success and greater S218–26. reduction of lesion counts in treatment of moderate to 12 Stein Gold S, Cruz A, Eichenfield L et al. Effective and safe combin- severe acne with a more rapid onset of action, com- ation therapy for severe acne vulgaris: a randomized, vehicle-con- Æ pared with lymecycline and vehicle. trolled, double-blind study of adapalene 0 1%–benzoyl peroxide 2Æ5% fixed-dose combination gel with doxycycline hyclate 100 mg. Cutis 2010; 85:94–104. 13 Poulin Y, Sanchez NP, Bucko A et al. A 6-month maintenance therapy with adapalene–benzoyl peroxide gel prevents relapse and Acknowledgments continuously improves efficacy among severe acne vulgaris patients. Br J Dermatol 2011; 164:1376–82. The authors would like to thank the other TEAM investigators 14 Tan J, Gollnick HP, Loesche C et al. Synergistic efficacy of adapalene for their participation, as well as Thierry Radeau for editorial 0Æ1%–benzoyl peroxide 2Æ5% in the treatment of 3855 acne vulga- assistance. ris patients. J Dermatolog Treat 2011 (in press). 15 Feldman SR, Tan J, Poulin Y et al. The efficacy of adapalene-benzoyl peroxide combination increases with number of acne lesions. References J Am Acad Dermatol 2011; 64:1085–91. 16 Dreńo B, Thiboutot D, Gollnick H et al. Global Alliance to Improve 1 Thiboutot D, Gollnick H, Bettoli V et al. Global Alliance to Improve Outcomes in Acne. Large-scale worldwide observational study of Outcomes in Acne. New insights into the management of acne: an adherence with acne therapy. Int J Dermatol 2010; 49:448–56. update from the Global Alliance to Improve Outcomes in Acne 17 Leyden J, Del Rosso J, Webster G. Clinical considerations in the group. J Am Acad Dermatol 2009; 60(5 Suppl.):S1–50. treatment of acne vulgaris and other inflammatory skin disorders: 2 Thiboutot DM, Weiss J, Bucko A et al. Adapalene-BPO Study Group. focus on antibiotic resistance. Cutis 2007; 79(Suppl. 6):9–25. Adapalene–benzoyl peroxide, a fixed-dose combination for the 18 Del Rosso JQ, Kim G. Optimizing use of oral antibiotics in acne treatment of acne vulgaris: results of a multicenter, randomized vulgaris. Dermatol Clin 2009; 27:33–42. double-blind, controlled study. J Am Acad Dermatol 2007; 57:791–9. 19 Leyden JJ, Wortzman M, Baldwin EK. Antibiotic-resistant Propioni- 3 Gollnick HP, Draelos Z, Glenn MJ et al. Adapalene–BPO Study bacterium acnes suppressed by a benzoyl peroxide cleanser 6%. Cutis Group. Adapalene–benzoyl peroxide, a unique fixed-dose combin- 2008; 82:417–21. ation topical gel for the treatment of acne vulgaris: a transatlantic, 20 Ochsendorf F. Minocycline in acne vulgaris: benefits and risks. Am randomized, double-blind, controlled study in 1670 patients. Br J J Clin Dermatol 2010; 11:327–41. Dermatol 2009; 161:1180–9. 21 Maffeis L, Veraldi S. Minocycline in the treatment of acne: latest 4 Stein Gold L, Tan J, Cruz-Santana A et al. Adapalene–BPO Study findings. G Ital Dermatol Venereol 2010; 145:425–9. Group. A North American study of adapalene–benzoyl peroxide 22 Bjellerup M, Ljunggren B. Differences in phototoxic potency combination gel in the treatment of acne. Cutis 2009; 84:110–16. should be considered when tetracyclines are prescribed during 5 Pariser DM, Westmoreland P, Morris A et al. Long-term safety and summer-time. A study on doxycycline and lymecycline in human efficacy of a unique fixed-dose combination gel of adapalene 0Æ1% volunteers, using an objective method for recording erythema. Br J and benzoyl peroxide 2Æ5% for the treatment of acne vulgaris. Dermatol 1994; 130:356–60. J Drugs Dermatol 2007; 6:899–905.

2011 The Authors BJD 2011 British Association of Dermatologists 2011 165, pp383–390