Abstract

This is a short summary of the complete version of the S3 European Acne guideline, please see online appendix for full text (Document S1. Long Version) and detailed methods report (DOI: 10.1111/jdv.13783). Expiry date: 31 December 2020 In order to grade the recommendation a "standardized guideline" language was used: Recommendations are based on available evidence and expert consensus. Available evidence and expert voting lead to classification of strength of recommendation. Adapalene + BPO (f.c.) or BPO + Clindamycin (f.c.) e Azelaic acid or BPO or Topical Retinoid d or Topical Clindamycin + Tretinoin (f.c.) e,f or Systemic Antibiotic e,g,h + Adapalene i Systemic Antibiotic e,h + Adapalene i or Systemic Antibiotic e,h + Azelaic acid j or Systemic Antibiotic e,h + Adapalene + BPO (f.c.) Systemic Antibiotic e,h + Azelaic Acid or Systemic Antibiotic e,h + Adapalene + BPO (f.c.) Azelaic acid or BPO Blue Light or Oral Zinc or Systemic Antibiotic e,g,h + Azelaic Acid j or Systemic Antibiotic e,g,h + Adapalene + BPO (f.c.) k or Systemic Antibiotic e,g,h + BPO l or Topical Erythromycin + Isotretinoin (f.c.) e or Topical Erythromycin + Tretinoin (f.c.) e Systemic Antibiotic e,h + Adapalene i,k or Systemic Antibiotics e,h + BPO k Hormonal Anti-androgens + Systemic Antibiotic e,h + Topicals (apart from antibiotics) or Hormonal Anti-androgens + Topical Treatment (apart from antibiotics) Hormonal Anti-androgens + Systemic Antibiotic e,h + Topicals (apart from antibiotics) or Hormonal Anti-androgens + Topical Treatment (apart from antibiotics) Recommendations for comedonal acne a High strength of recommendation None Medium strength of recommendation Topical retinoids b can be recommended for the treatment of comedonal acne. Low strength of recommendation Azelaic acid can be considered for the treatment of comedonal acne. BPO can be considered for the treatment of comedonal acne. Open recommendation A recommendation for or against treatment of comedonal acne with visible light as monotherapy, lasers with visible wavelengths and lasers with infrared wavelengths, with intense pulsed light (IPL) and photodynamic therapy (PDT) cannot be made at the present time. Negative recommendation Topical antibiotics are not recommended for the treatment of comedonal acne. Hormonal anti-androgens, systemic antibiotics and/or systemic isotretinoin are not recommended for the treatment of comedonal acne. Artificial ultraviolet (UV) radiation is not recommended for the treatment of comedonal acne. Only one trial looks specifically at patients with comedonal acne. As a source of indirect evidence, trials including patients with papulopustular acne were used and the percentage in the reduction of non-inflammatory lesions was considered as the relevant outcome parameter. Because of the general lack of direct evidence for the treatment of comedonal acne, the strength of recommendation was downgraded for all considered treatment options, starting with medium strength of recommendation as a maximum. Due to the usually mild to moderate severity of comedonal acne, generally, a topical therapy is recommended. The best efficacy was shown for topical retinoids, BPO and azelaic acid. The tolerability of topical retinoids and BPO is comparable; there is a trend towards azelaic acid having a better safety/tolerability profile than BPO and a comparable profile to adapalene (indirect evidence, see Table 11 in long version). The fixed-dose combination of adapalene with BPO shows a trend towards better efficacy against non-inflammatory lesions (NIL) when compared to BPO and a comparable efficacy when compared to adapalene (see Table 4 in long version). However, there is also a trend towards inferiority of the fixed combination with respect to the safety/tolerability profile (indirect evidence, see Table 12 in long version). The fixed-dose combinations of clindamycin with BPO showed a trend towards better efficacy against NIL vs. clindamycin and comparable efficacy vs. BPO (see Table 5 in long version). With respect to the safety/tolerability profile, the combination is comparable to its single components (indirect evidence, see Table 12 in long version). Few and only indirect data on patient preference are available. They indicate patient preference for adapalene over other topical retinoids. Additional pathophysiological considerations favour the use of topical retinoids (reduction of microcomedones). Recommendations for mild to moderate papulopustular acne a High strength of recommendation The fixed-dose combination adapalene and BPO is strongly recommended for the treatment of mild to moderate papulopustular acne. The fixed-dose combination BPO and clindamycin b is strongly recommended for the treatment of mild to moderate papulopustular acne. Medium strength of recommendation Azelaic acid can be recommended for the treatment of mild to moderate papulopustular acne. BPO can be recommended for the treatment of mild to moderate papulopustular acne. A combination of a systemic antibiotic b,c,d with adapalene g can be recommended for the treatment of moderate papulopustular acne. f The fixed-dose combination clindamycin and tretinoin b can be recommended for the treatment of mild to moderate papulopustular acne. Topical retinoids g can be recommended for the treatment of mild to moderate papulopustular acne. Low strength of recommendation Blue light monotherapy can be considered for the treatment of mild to moderate papulopustular acne. Oral zinc can be considered for the treatment of mild to moderate papulopustular acne. Systemic antibiotic b,c,d in combination with azelaic acid h can be considered for the treatment of mild to moderate papulopustular acne. A combination of a systemic antibiotic b,c,d with adapalene in fixed-dose combination with BPO i can be considered for the treatment of moderate papulopustular acne. A combination of a systemic antibiotic b,c,d with BPO j can be considered for the treatment of moderate papulopustular acne. The fixed-dose combination of erythromycin and isotretinoin b can be considered for the treatment of mild to moderate papulopustular acne. The fixed-dose combination of erythromycin and tretinoin b can be considered for the treatment of mild to moderate papulopustular acne. Open recommendation Due to a lack of sufficient evidence, a recommendation for or against treatment of mild to moderate papulopustular acne with red light, IPL, Laser or PDT cannot be made at the present time. Negative recommendation Topical antibiotics as monotherapy are not recommended for the treatment of mild to moderate papulopustular acne. Artificial UV radiation is not recommended for the treatment of mild to moderate papulopustular acne. The fixed-dose combination of erythromycin and zinc is not recommended for the treatment of mild to moderate papulopustular acne. Systemic therapy with anti-androgens, antibiotics, and/or isotretinoin is not recommended for the treatment of mild to moderate papulopustular acne. Recommendations for severe papulopustular/moderate nodular acne a High strength of recommendation Oral isotretinoin monotherapy is strongly recommended for the treatment of severe papulopustular/moderate nodular acne. Medium strength of recommendation Systemic antibiotics b,c in combination with adapalene d, with the fixed-dose combination of adapalene and BPO, or in combination with azelaic acid e can be recommended for the treatment of severe papulopustular/moderate nodular acne. Low strength of recommendation Systemic antibiotics b,c in combination with BPO e can be considered for the treatment of severe papulopustular/moderate nodular acne. For females: Hormonal anti-androgens in combination with systemic antibiotic b,c and topicals (apart from antibiotics) can be considered for the treatment of severe papulopustular/moderate nodular acne. For females: Hormonal anti-androgens in combination with a topical treatment (apart from antibiotics) can be considered for the treatment of severe papulopustular/moderate nodular acne. Open recommendation Due to a lack of sufficient evidence, a recommendation for or against treatment of severe papulopustular/moderate nodular acne with red light, IPL, laser or PDT cannot be made at the present time. Although PDT is effective in the treatment of severe papulopustular/moderate nodular acne, a recommendation for or against its use cannot be made at the present time due to a lack of standard treatment regimens that ensure a favourable profile of acute adverse reaction. Negative recommendation Single or combined topical monotherapy is not recommended for the treatment of severe papulopustular/moderate nodular acne. Oral antibiotics as monotherapy are not recommended for the treatment of severe papulopustular/moderate nodular acne. Oral anti-androgens as monotherapy are not recommended for the treatment of severe papulopustular/moderate nodular acne. Visible light as monotherapy is not recommended for the treatment of severe papulopustular/moderate nodular acne. Artificial UV radiation sources are not recommended as a treatment of severe papulopustular/moderate nodular acne. Monotherapy with azelaic acid, BPO or topical retinoids showed superior efficacy when compared with vehicle. Adapalene, azelaic acid and BPO showed comparable efficacy when compared with each other. When comparing the topical retinoids (adapalene, isotretinoin and tretinoin) directly against each other, no relevant difference with respect to efficacy was seen. Some conflicting evidence to the comparability of the efficacy of the treatment options above arises, when looking at the other head to head comparisons indicating superiority of BPO over isotretinoin and tretinoin over azelaic acid. With respect to the fixed combinations, BPO/clindamycin shows superiority over both single components. The three fixed combinations of adapalene/BPO, clindamycin/tretinoin as well as erythromycin/isotretinoin show superiority to one of the components but not to both of the components when compared individually. Head to head comparisons of the fixed combinations of adapalene/BPO vs. BPO/clindamycin as well as head to head comparisons of clindamycin/tretinoin vs. BPO/clindamycin show comparable efficacy. Due to the serious concerns regarding the risk of developing antibiotic resistance, topical monotherapy with antibiotics is generally not recommended. The potential risk of developing antibiotic resistance was taken into consideration by the expert group. It led to a medium strength of recommendation for the fixed combination of clindamycin/tretinoin despite comparable efficacy and safety when compared to the fixed combination of BPO/clindamycin. The differentiation between clindamycin/tretinoin (medium strength of recommendation) and erythromycin/isotretinoin (low strength of recommendation) was based on evidence showing the lack of development of antibiotic resistance after 16 weeks of treatment with clindamycin/tretinoin as well as indirect evidence on stronger development of antibiotic resistance to erythromycin and expert opinion on better follicular penetration and galenic of the clindamycin/tretinoin f.c. formulation. Monotherapy with azelaic acid, BPO or topical retinoids showed comparable efficacy when compared with each other. For severe cases, systemic treatment with isotretinoin is recommended based on the very good efficacy seen in clinical practice. The available evidence on safety and tolerability is extremely scarce and was considered insufficient to be used as a primary basis to formulate treatment recommendations. The lack of standardized protocols, experience and clinical trial data mean there is insufficient evidence to recommend the treatment of papulopustular acne with laser and light sources other than blue light. There are limited data comparing topical treatments with a systemic treatment or the additional effect of a combination of a topical plus systemic vs. topical treatment only. Most of the available trials compare a topical antibiotic monotherapy with a systemic antibiotic monotherapy. Issues of practicability between topical and systemic treatments must also be taken into consideration in cases of severe, and often widespread, disease. The consensus within the expert group was that most cases of severe papulopustular acne or moderate nodular acne, will achieve better efficacy when a systemic antibiotic treatment in combination with a topical treatment or if systemic isotretinoin is used. Involvement of the trunk areas plays an important role. In addition, better adherence and patient satisfaction is anticipated for systemic treatments. Recommendations for severe nodular/conglobate acne a High strength of recommendation Oral isotretinoin is strongly recommended as a monotherapy for the treatment of severe nodular/conglobate acne. Medium strength of recommendation Systemic antibiotics b,c in combination with the fixed-dose combination of adapalene and BPO or in combination with azelaic acid can be recommended for the treatment of severe nodular/conglobate acne. Low strength of recommendation Systemic antibiotics b,c in combination with adapalene d,e or BPO e can be considered for the treatment of severe nodular/conglobate acne. For females: Hormonal anti-androgens in combination with systemic antibiotic b,c and topicals (apart from antibiotics) can be considered for the treatment of severe nodular/conglobate acne. For females: Hormonal anti-androgens in combination with a topical treatment can be considered for the treatment of severe nodular/conglobate acne. Open recommendation Due to a lack of sufficient evidence, it is currently not possible to make a recommendation for or against treatment with IPL or laser in severe nodular/conglobate acne. Although PDT is effective in the treatment of severe nodular/conglobate acne, it cannot yet be recommended due to a lack of standard treatment regimens that ensure a favourable profile of acute adverse reaction. Negative recommendation Topical monotherapy is not recommended for the treatment of conglobate acne. Oral antibiotics are not recommended as monotherapy for the treatment of severe nodular/conglobate acne. Oral anti-androgens are not recommended as monotherapy for the treatment of severe nodular/conglobate acne. Artificial UV radiation sources are not recommended for the treatment of severe nodular/conglobate acne. Visible light as monotherapy is not recommended for the treatment of severe nodular/conglobate acne. Very few of the included trials (see long version) looked specifically at patients with nodular or conglobate acne. As a source of indirect evidence, studies of patients with severe papulopustular acne were used and the percentage in the reduction of nodules (NO) and cysts (CY) in these studies was used. In case of use of such indirect evidence, the strength of recommendation was downgraded for the considered treatment options. Systemic isotretinoin shows superior efficacy in the treatment of severe nodular/conglobate acne when compared with systemic antibiotics or topical therapy only. The expert group considered that the greatest effectiveness in the treatment of severe nodular/conglobate acne in clinical practice is seen with systemic isotretinoin. This can only be partly supported by published evidence, due to the scarcity of clinical trials in conglobate acne. In the experts' opinion, safety concerns with isotretinoin are manageable if treatment is properly initiated and monitored. Patient benefit with respect to treatment effect, improvement in quality of life and avoidance of scarring outweigh the side-effects. Adapalene should be selected in preference to tretinoin and isotretinoin. Doxycycline and lymecycline should be selected in preference to minocycline and tetracycline. For severe papulopustular acne/moderate nodular acne, a dosage of systemic isotretinoin of 0.3–0.5 mg/kg can be recommended. For conglobate acne a dosage of systemic isotretinoin of ≥0.5 mg/kg canbe recommended. The duration of the therapy should be at least 6 months. In case of insufficient response, the treatment period can be prolonged. Azelaic Acid or Topical Retinoid b Azelaic Acid or BPO or Topical Retinoid b Adapalene + BPO (f.c.) c or Azelaic Acid or BPO c or Low Dose Systemic Isotretinoin (max. 0.3 mg/kg/day) or Topical Retinoid b Adapalene + BPO (f.c.) c or Azelaic Acid or BPO c or Low Dose Systemic Isotretinoin (max. 0.3 mg/kg/day) or Topical Retinoid b A maintenance treatment, especially for the patients with "particular need for a maintenance treatment" as defined below, is recommended. The low strength of recommendation provided below reflects primarily the lack of good evidence as to which is the best treatment and does not put into question the need for maintenance therapy in general. Available evidence indicates efficacy of azelaic acid, topical retinoids and adapalene/BPO over vehicle during maintenance treatment. Pathophysiological data supports use of azelaic acid, topical retinoids and adapalene based on their demonstrated efficacy on microcomedones. Any use of topical or systemic antibiotics is not recommended on a long-term base/during maintenance therapy. The development of guidelines is a time and resource intensive process and currently no public funding is available for European guidelines. In order to be able to produce high quality guidelines, the EDF uses its membership contributions and asks its cooperative partners for support (see Funding source). Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.