SEARCH

SEARCH BY CITATION

I Introduction

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

Nasty/Rzany

I.1 Notes on use of guidelines

An evidence-based guideline has been defined as ‘a systematically developed statement that assists clinicians and patients in making decisions about appropriate treatment for a specific condition’.1 A guideline will never encompass therapy specifications for all medical decision-making situations. Deviation from the recommendations may, therefore, be justified in specific situations.

This is not a textbook on acne, nor a complete, all-inclusive reference on all aspects important to the treatment of acne. The presentation on safety in particular is limited to the information available in the included clinical trials and does not represent all the available and necessary information for the treatment of patients. Additional consultation of specific sources of information on the particular intervention prescribed (e.g. product information sheet) is necessary. Furthermore, all patients should be informed about the specific risks associated with any given topical and/or systemic therapy.

Readers must carefully check the information in this guideline and determine whether the recommendations contained therein (e.g. regarding dose, dosing regimens, contraindications, or drug interactions) are complete, correct, and up-to-date. The authors and publishers can take no responsibility for dosage or treatment decisions.

I.1. Objectives of the guidelines

Improvement in the care of acne patients

The idea behind this guideline is that recommendations based on a systematic review of the literature and a structured consensus process will improve the quality of acne therapy in general. Personal experiences and traded therapy concepts should be critically evaluated and replaced, if applicable, with the consented therapeutic recommendations. In particular, a correct choice of therapy should be facilitated by presenting the suitable therapy options in a therapy algorithm, taking into account the type of acne and the severity of the disease.

Reduction of serious conditions and scarring

As a result of the detailed description of systemic therapies for patients with severe acne, reservations about these interventions should be overcome to ensure that patients receive the optimal therapy. With the timely introduction of sufficient therapies, the development of serious post-acne conditions and severe scarring should be reduced.

Promotion of adherence

Good therapeutic adherence is key to treatment success. Adherence is facilitated by knowledge of the product being used, for example treatment duration, the expected onset of effect, the sequence of the healing process, the maximal achievable average effect, expected adverse events and the benefit to quality of life.

Reduction of antibiotic resistance

The use of topical and systemic antibiotics should be optimized by using appropriate combinations for a predefined duration, to reduce the development of antibiotic resistance.

I.3 Target population

Health care professionals

This guideline has been developed to help health care professionals provide optimal therapy to patients with mild, moderate or severe acne. The primary target groups are dermatologists and other professionals involved in the treatment of acne, such as paediatricians and general practitioners. The target group may vary with respect to national differences in the distribution of services provided by specialists or general practitioners.

Patients

The recommendations of the guideline refer to patients who suffer from acne. These are mainly adolescents treated in outpatient clinics. The appropriate therapy option is presented according to the type of acne that is present. The primary focus is the induction therapy of facial acne (see Chapter 1.6). Non-primary target groups are patients with special forms of acne, such as, occupational acne, chloracne, acne aestivalis, acne neonatorum, acne inverse (hidradenitis suppurativa).

I.4. Pharmacoeconomic considerations

European guidelines are intended for adaptation to national conditions. It is beyond the scope of this guideline to take into consideration the specific costs and reimbursement situations in every European country. Differences in prices, reimbursement systems, willingness and ability to pay for medication among patients and the availability of generics are too large. Therefore, pharmacoeconomic considerations will have to be taken into account when guidelines are developed at national and local levels.

The personal financial and health insurance situation of a patient may necessitate amendments to the prioritization of treatment recommendations. However, if financial resources allow, the suggested ranking in the therapeutic algorithm should be pursued.

I.5 Considerations with respect to vehicle for topical treatments

The skin type and stage of disease has to be taken into consideration when choosing the vehicle for topical treatments. The efficacy and safety/tolerability of topical treatments are largely influenced by the choice of vehicle.

I.6 Considerations with respect to body area

The face is the primary region of interest for the treatment of acne. Appearance, scarring, quality of life and social stigmatization are important considerations when dealing with facial dermatological diseases.

The recommendations of this guideline apply primarily to the treatment of facial acne. More widespread involvement will certainly favour earlier use of a systemic treatment due to the efficacy and practicability of such treatments.

I.7 Clinical features and variants

Layton/Finlay

Acne (synonym ‘acne vulgaris’) is a polymorphic, inflammatory skin disease most commonly affecting the face (99% of cases). Less frequently it also affects the back (60%) and chest (15%).2 Seborrhoea is a frequent feature.3

The clinical picture embraces a spectrum of signs, ranging from mild comedonal acne, with or without sparse inflammatory lesions (IL), to aggressive fulminate disease with deep-seated inflammation, nodules and in some cases associated systemic symptoms.

I.7.1 Comedonal acne

Clinically non-inflamed lesions develop from the subclinical microcomedo which is evident on histological examination early in acne development.2 Non-inflamed lesions encompass both open (blackheads) and closed comedones (whiteheads). Comedones frequently have a mid-facial distribution in childhood and, when evident early in the course of the disease, this pattern is indicative of poor prognosis.4 Closed comedones are often inconspicuous with no visible follicular opening.

I.7.2 Papulopustular acne

Most patients have a mixture of non-inflammatory (NIL) and inflammatory lesions.5 Inflammatory lesions arise from the microcomedo or from non-inflammatory clinically apparent lesions and may be either superficial or deep.6 Superficial inflammatory lesions include papules and pustules (5 mm or less in diameter). These may evolve into deep pustules or nodules in more severe disease. Inflammatory macules represent regressing lesions that may persist for many weeks and contribute markedly to the general inflammatory appearance.5

I.7.3 Nodular/conglobate acne

Small nodules are defined as firm, inflamed lesions >5 mm diameter, painful by palpation. Nodules are defined as larger than 5 mm, large nodules are >1 cm in size. They may extend deeply and over large areas, frequently resulting in painful lesions, exudative sinus tracts and tissue destruction. Conglobate acne is a rare but severe form of acne found most commonly in adult males with few or no systemic symptoms. Lesions usually occur on the trunk and upper limbs and frequently extend to the buttocks. In contrast to ordinary acne, facial lesions are less common. The condition often presents in the second to third decade of life and may persist into the sixth decade. Conglobate acne is characterized by multiple grouped comedones amidst inflammatory papules, tender, suppurative nodules which commonly coalesce to form sinus tracts. Extensive and disfiguring scarring is frequently a feature.

I.7.4 Other acne variants

There are several severe and unusual variants or complications of acne as well as other similar diseases. These include acne fulminans, gram-negative folliculitis, rosacea fulminans, vasculitis, mechanical acne, oil/tar acne, chloracne, acne in neonates and infants and late onset, persistent acne, sometimes associated with genetic or iatrogenic endocrinopathies. The current guidelines do not lend themselves to comprehensive management of all these variants.

II Assessment, comparability of treatment outcomes

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

Finlay/Layton

II.1 Acne grading

Acne can be largely assessed from two perspectives: objective disease activity (based on measurement of visible signs) and quality of life impact. There are other aspects of measurement, such as sebum excretion rate, scarring development or economic impact.

There are inherent difficulties in objectively measuring acne. Over 25 different methods have been described7 but there is no consensus as to which should be used. Most methods are non-validated and consequently the results of separate trials cannot be directly compared. There are detailed reviews on this subject by Barratt et al.,8 Witkowski et al.,9 Thiboutot et al.,10 and Gollnick et al.11

Proper lighting, appropriate patient positioning and prior facial skin preparation (gentle shaving for men, removal of make-up for women) are helpful in facilitating accurate assessment. Palpation in addition to visual inspection may also help define lesions more accurately.

II.1.1 Acne grading systems
II.1.1.1 Sign-based methods

Many methods for measuring acne have been described, ranging from global assessments to lesion counting.7,9 Despite a range of methods being used to measure acne in the 1960’s and 1970’s, it was the Leeds technique12 that dominated acne measurement for the next two decades. The Leeds technique included two methods; the grading technique and the counting technique. The grading technique allocated patients a grade from 0 to 10, with seven subgroups between 0 and 2. Photographic guides illustrating each grade are given, but the importance of palpating lesions is also stressed. The experience on which this system was based stemmed from the pre-isotretinoin era, and acne of the severity described by grades above 2 is now rarely seen. The counting technique involves the direct counting of non-inflamed and inflamed lesions, including superficial papules and pustules, deep inflamed lesions and macules. The revised Leeds acne grading system13 includes numerical grading systems for the back and chest as well as for the face.

The Echelle de Cotation des Lesions d’Acne (ECLA) or ‘Acne Lesion Score Scale’ system has demonstrated good reliability.14 However, ECLA scores do not correlate with quality of life scores and the use of both disease and quality of life scores is suggested.15

II.1.1.2 Global assessment techniques

Global assessment scales incorporate the entirety of the clinical presentation into a single category of severity. Each category is defined by either a photographic repertoire with corresponding numeric scale or descriptive text. Grading is a subjective task, based on observing dominant lesions, evaluating the presence or absence of inflammation, which is particularly difficult to capture, and estimating the extent of involvement. Global methods are much more practically suited to clinical practice. In clinical investigations, they should be combined with lesion counts as a co-primary endpoint of efficacy.16 A simple photographic standard-based grading method using a 0–8 scale has been successfully employed in a number of clinical trials.17

In 2005, the US FDA proposed an IGA (investigator global assessment) that represented a static quantitative evaluation of overall acne severity. To accomplish this, they devised an ordinal scale with five severity grades, each defined by distinct and clinically relevant morphological descriptions that they hoped would minimize inter-observer variability. Indeed, the more detailed descriptive text has resulted in this system being considered to provide even greater reliability than previous global assessments.16

A very simple classification of acne severity was described in the 2003 report from the Global Alliance for better outcome of acne treatment.11 This basic classification was designed to be used in a routine clinic, and its purpose was to map treatment advice onto common clinical presentations. For each acne descriptor a first-choice therapy is advised, with alternatives for female patients and maintenance therapy. There are five simple descriptors: mild comedonal, mild papulopustular, moderate papulopustular, moderate nodular and severe nodular/conglobate. A series of eight photographs span and overlap these five descriptors. Different facial views and different magnifications are used, reducing the comparability of the images.

To give treatment recommendations based on disease activity, the EU Guidelines group has considered how best to classify acne patients. It has used the following simple clinical classification:

  • 1
     Comedonal acne
  • 2
     Mild–moderate papulopustular acne
  • 3
     Severe papulopustular acne, moderate nodular acne
  • 4
     Severe nodular acne, conglobate acne

Other already existing systems are very difficult to compare with one another. The group has tried to map the existing systems to the guidelines’ clinical classification. However, in many cases the systems do not include corresponding categories and often it has to be considered an approximated narrowing rather than a precise mapping (Table 1).

Table 1.   Comparison of different acne assessment scales. This is an attempt to approximately map the various published acne classifications to the simple four group classification used in these guidelines
PublicationComedonal acneMild–moderate papulopustular acneSevere papulopustular acne, moderate nodular acneSevere nodular acne, conglobate acne
  1. IL: inflammatory lesions; NIL: non-inflammatory lesions.

Pillsbury 1956181–42–42–4
Michaelsson 1977190–3020–3020 to >30
Cook 1979170–12–468
Wilson 19802002–46–88
Allen 1982210–22–668
Burke (Leeds) 198450.50.75–22–33–8
Pochi 199116MildMild/moderateModerateSevere
O’Brien (Leeds) 1988 (face)131–34–78–1011–12, nodulocystic
Dreno 199914F1R1–5F1Is1–4F1Is4–5, F1Ip 1–4F1Ip 4–5
Lehmann 20027MildMild/moderateSevereSevere
Gollnick 200311Mild comedonalMild papular–pustular, moderate papular–pustularModerate nodularSevere nodular/conglobate
Layton 201022MildModerateSevere
Tan 200723Mild: 0–5 papules–pustulesModerate: 6–20 papules–pustulesSevere: 21–50 papules–pustules, very severe: >50 IL severe
FDA’s IGA for acne vulgaris (2005)241 Almost clear: rare NIL with no more than 1 papule2 Mild: some NIL but no more than a few papule/pustule3 Moderate: many NIL, some IL no more than 1 nodul 4 Severe: up to many noninflammatory and inflammatory lesions, but no more than a few nodular lesions
II.1.1.3 Quality of life methods

Simpson and Cunliffe25‘consider the use of quality of life and psychosocial questionnaires essential to adequately understanding just how the disease is affecting the patient, and to better understand the progress of the disease’. The impact of acne on quality of life can be measured using general health measures, dermatology-specific measures or acne-specific measures. In order for quality of life measures to be used more frequently in the routine clinical work, they need to be easy to use, the scores need to be meaningful and they need to be readily accessible. Clinicians must be convinced that the information gained from using them is of benefit in guiding them to make optimum clinical decisions for their patients, and they need to become aware that the use of these measures may help to justify their clinical decisions. Quality of life measures can influence the choice of therapy. In patients with a severe impact on their quality of life, a more aggressive therapy may be justified.

II.2 Prognostic factors that should influence treatment choice

II.2.1 Prognostic factors of disease severity

A number of prognostic factors relating to more severe disease should be considered when assessing and managing acne. These are outlined and evidenced in review papers published by Holland and Jeremy 200526 and Dreno et al. 200827 and include family history, course of inflammation, persistent or late-onset disease, hyperseborrhoea, androgenic triggers, truncal acne and/or psychological sequelae. Previous infantile acne may also correlate with resurgence of acne at puberty and early age of onset with mid-facial comedones, early and more severe seborrhoea and earlier presentation relative to menarche are all factors that should alert the clinician to increased likelihood of more severe acne.

II.2.2 The influence of the assessment of scarring/potential for scarring on disease management

Scarring usually follows deep-seated inflammatory lesions, but may also occur as a result of more superficial inflamed lesions in scar-prone patients. Acne scarring, albeit mild, has been identified in up to 90% of patients attending a dermatology clinic.28 Scars may show increased collagen (hypertrophic and keloid scars) or be associated with collagen loss. The presence of scarring should support aggressive management and therapy should be commenced early in the disease process.

III Methods

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

(For further details please see the methods report at http://www.acne-guidelines.com.)

Nast/Rzany

III.1 Nomination of expert group/patient involvement

All experts were officially nominated by the European Dermatology Forum (EDF) or the European Academy of Dermatology and Venereology. They were selected according to their clinical expertise, publication record and/or experience in the field of evidence-based medicine and guideline development. None of the experts received any financial incentive other than reimbursement of travel costs.

Participation of patients was difficult to realize, since no patient organization exists. Attempts to invite patients currently treated by the involved experts did not succeed. Patients were invited to participate in the external review. Patient preference was considered as an important outcome and trials looking at patient preferences were included.

III.2 Selection of included medications/interventions

There is a vast array of treatment options available for acne. The options are further extended by the availability of different vehicles and formulations. When choosing a treatment, different skin types, ethnic groups and subtypes of acne must also be considered.

The authors of this guideline selected the most relevant treatments in Europe to be included in the guideline. The fact that a certain treatment was not selected as a topic for this guideline, does not mean that it may not be a good treatment for acne. Additional treatment options may be considered for a later update.

Fixed-dose combinations were considered as long as they were licensed in a European country (e.g. adapalene + benzoyl peroxide (BPO), clindamycin + BPO, erythromycin + tretinoin, erythromycin + isotretinoin, erythromycin + zinc).

Treatment options consisting of more than two topical components were not included because of the likeliness of reduced patient adherence and/or because of a limitation in the feasibility of discussing all possible combinations and sequences.

III.3 Generation of evidence for efficacy, safety and patient preference

III.3.1 Literature search and evaluation of trials

An extensive search of existing guidelines and systematic reviews was performed at the beginning of the project. The search was performed in Medline, Embase, and Cochrane (for search strategies see the methods report at http://www.acne-guidelines.com). The date of the systematic searches was March 10th 2010 for topical and systemic interventions and April 13th 2010 for laser and light therapies. The results were checked for the inclusion criteria and trial quality using a standardized literature evaluation form. Existing systematic reviews (e.g. Cochrane) and other guidelines served as an additional basis for the body of evidence in this guideline. Pooling of the trials was not attempted due to the lack of common outcome measures and endpoints and the unavailability of some primary data (for details of search strategies, standardized evaluation form and references of included reviews see methods report at http://www.acne-guidelines.com).

III.3.2 Extrapolation of evidence for specific acne types

The aim of this guideline is to give recommendations for specific clinical conditions, e.g. the severity of acne, and not to assess the different medications one by one without respect to clinical stage. However, most trials did not look in detail at subtypes but include patients with ‘acne vulgaris’ in general. Therefore, for some recommendations, ‘indirect evidence’ was generated from looking at suitable outcome parameters:

  • 1
     The percentage ‘reduction of non-inflammatory lesions’ was the efficacy parameter considered for comedonal acne.
  • 2
     Efficacy in papulopustular acne was assessed by ‘reduction in inflammatory lesions’, ‘reduction in total lesion count’ and other acne grading scales.
  • 3
     The generation of evidence for nodular/conglobate acne was particularly difficult, since very few trials included nodular/conglobate acne. Consequently, treatment recommendations also took into account indirect data from trials of severe papulopustular acne.

The evidence from clinical trials almost always focuses on facial acne. Trials that examined acne at other locations (e.g. back), were considered as indirect evidence and the level of evidence was downgraded accordingly.

III.3.3 Minimal clinically important difference in assessing the efficacy of two therapeutic options for acne

Very little attention has been given during clinical trials to the question of a minimal clinically important difference from the perspective of the patient. It would be helpful to know the extent of reduction in the number of acne lesions required for patients to consider that there has been a clinically important improvement. One study has been identified that empirically validated a non-inferiority margin of 10–15% for facial acne lesion counts as appropriate.356

The consensus view of the authors of this guideline is that a treatment should achieve at least a 10% greater reduction in the number of lesions to demonstrate superior efficacy. Hence, for the evaluation of superior or comparable efficacy throughout the evidence generation process, a 10% difference in efficacy (lesion reduction) was considered relevant.

III.3.4 Qualitative assessment of evidence

Many different grading systems for assessing the quality of evidence are available in the field of guideline development. For this guideline, the authors used the grading system adopted for the European Psoriasis Guidelines with some adaptations taken from the GRADE system.29–31

III.3.4.1 Grade of evidence (quality of individual trial)

The available literature was evaluated with respect to the methodological quality of each single trial. A grade of evidence was given to every individual trial included:

  • (A)
     Randomized, double-blind clinical trial of high quality [e.g. sample-size calculation, flow chart of patient inclusion, intention-to-treat (ITT) analysis, sufficient sample size].
  • (B)
     Randomized clinical trial of lesser quality (e.g. only single-blind, limited sample size: at least 15 patients per arm).
  • (C)
     Comparative trial with severe methodological limitations (e.g. not blinded, very small sample size, no randomization).
III.3.4.2 Level of evidence (quality of body of evidence to answer a specific question)

When looking at a specific question (e.g. efficacy of BPO relative to adapalene) the available evidence was summarized by aligning a level of evidence (LE) using the following criteria:

  • 1
    Further research is very unlikely to change our confidence in the estimate of effect. At least two trials are available that were assigned a grade of evidence A and the results are predominantly consistent with the results of additional grade B or C studies.
  • 2
    Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. At least three trials are available that were assigned a grade of evidence B and the results are predominantly consistent with respect to additional grade C trials.
  • 3
    Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Conflicting evidence or limited amount of trials, mostly with a grade of evidence of B or C.
  • 4
    Any estimate of effect is very uncertain. Little or no systematic empirical evidence; included trials are extremely limited in number and/or quality.
III.3.4.3 Consensus process

All recommendations were agreed in a consensus conference of the authors using formal consensus methodology (nominal group technique). The consensus conference was moderated by Prof. Dr. med. Berthold Rzany MSc, who is a certified moderator for the German Association of Scientific Medical Societies (AWMF). All members of the author committee were entitled to vote in the consensus conference.

In general, a high consensus (>90%) was aimed for. In the absence of a consensus, this was noted in the text and reasons for the difference in views were given. All consensus statements are highlighted in a grey box throughout the text.

To weigh the different recommendations, the group assigned a ‘strength of recommendation’ grade (see box below). The strength of recommendation considered all aspects of the treatment decision, such as efficacy, safety, patient preference and the reliability of the existing body of evidence (level of evidence).

Strength of recommendation

To grade the recommendation a ‘standardized guidelines’ language was used:

  • 1
     Is strongly recommended.
  • 2
     Can be recommended.
  • 3
     Can be considered.
  • 4
     Is not recommended.
  • 5
     May not be used under any circumstances.
  • 6
     A recommendation for or against treatment X cannot be made at the present time.
III.3.5 Peer review/piloting

An extensive external review was performed. National dermatological societies [European Dermatology Forum (EDF) members], other specialties [paediatrics, gynaecologists, general practitioners as organized in the European Union of Medical Specialists (UEMS)] and patients (patient internet platforms) were invited to participate. Access was open and it was possible for anybody to comment via the internet (using the platform http://www.crocodoc.com). The expert group piloted the guidelines within their own practices and performed a trial implementation within their clinics. (For further details see the methods report at http://www.acne-guidelines.com.).

III.3.6 Implementation, evaluation, updating

Implementation will be pursued at a national level by local medical societies. Materials such as an online version, a short version and a therapeutic algorithm will be supplied.

Strategies for evaluation (e.g. assessment of awareness, treatment adhesion and patient changes) are in preparation and will mostly be pursued at a national level.

Guidelines need to be continually updated to reflect the increasing amount of medical information available. This guideline will not be valid after 31.12.2015. In case of important changes in the meantime (e.g., new licensed drugs, withdrawal of drug licensing, new important information) an update will be issued earlier. The guidelines committee under the coordination of the division of evidence-based medicine (dEBM) will access the necessity for an update by means of a Delphi vote.

IV Epidemiology and pathophysiology

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

IV.1 Epidemiology

Degitz/Ochsendorf

Acne is one of the most frequent skin diseases. Epidemiological studies in Western industrialized countries estimated the prevalence of acne in adolescents to be between 50% and 95%, depending on the method of lesion counting. If mild manifestations were excluded and only moderate or severe manifestations were considered, the frequency was still 20–35%.32–35 Acne is a disease primarily of adolescence. It is triggered in children by the initiation of androgen production by the adrenal glands and gonads, and it usually subsides after the end of growth. However, to some degree, acne may persist beyond adolescence in a significant proportion of individuals, particularly women.36 Even after the disease has ended, acne scars and dyspigmentation are not uncommon permanent negative outcomes.10 Genetic factors have been recognized; there is a high concordance among identical twins,37 and there is also a tendency towards severe acne in patients with a positive family history for acne.38 So far little is known about specific hereditary mechanisms. It is probable that several genes are involved in predisposing an individual to acne. These include the genes for cytochrome P450-1A1 and steroid-21-hydroxylase.39 Racial and ethnic factors may also contribute to differences in the prevalence, severity, clinical presentation and sequelae of acne.40,41 Environmental factors also appear to be of relevance to the prevalence of acne; populations with a natural lifestyle seem not to develop acne.42 In particular, diet has recently gained attention, with epidemiological43 and investigative studies44 indicating a correlation between acne and Western diet.

IV.2 Pathophysiology

Dréno/Gollnick

Acne is an androgen-dependent disorder of pilosebaceous follicles (or pilosebaceous unit). There are four primary pathogenic factors, which interact to produce acne lesions: (1) sebum production by the sebaceous gland, (2) alteration in the keratinization process, (3) Propionibacterium acnes follicular colonization, and (4) release of inflammatory mediators.

Patients with seborrhoea and acne have a significantly greater number of lobules per gland compared with unaffected individuals (the so-called genetically prone ‘Anlage’). Inflammatory responses occur prior to the hyperproliferation of keratinocytes. Interleukin-1α up-regulation contributes to the development of comedones independent of the colonization with P. acnes. A relative linoleic acid deficiency has also been described.

Sebaceous lipids are regulated by peroxisome proliferator-activated receptors which act in concert with retinoid X receptors to regulate epidermal growth and differentiation as well as lipid metabolism. Sterol response element-binding proteins mediate the increase in sebaceous lipid formation induced by insulin-like growth factor-1. Substance P receptors, neuropeptidases, α-melanocyte stimulating hormone, insulin-like growth factor (IGF)-1R and corticotrophin-releasing hormone (CRH)-R1 are also involved in regulating sebocyte activity as are the ectopeptidases, such as dipeptidylpeptidase IV and animopeptidase N. The sebaceous gland also acts as an endocrine organ in response to changes in androgens and other hormones. Oxidized squalene can stimulate hyperproliferative behaviour of keratinocytes, and lipoperoxides produce leukotriene B4, a powerful chemoattractant.

Acne produces chemotactic factors and promotes the synthesis of tumour necrosis factor-α and interleukin-1β. Cytokine induction by P. acnes occurs through Toll-like receptor 2 activation via activation of nuclear factor-κB and activator protein 1 (AP-1) transcription factor. Activation of AP-1 induces matrix metalloproteinase genes, the products of which degrade and alter the dermal matrix.

The improved understanding of acne development on a molecular level suggests that acne is a disease that involves both innate and adaptive immune systems and inflammatory events.

V Therapeutic options

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

5.1 Summary of therapeutic recommendations

Recommendations are based on available evidence and expert consensus. Available evidence and expert voting lead to classification of strength of recommendation (Table 2).

Table 2.   Summary of therapeutic recommendations*,†
 Comedonal acneMild-to-moderate papulopustular acneSevere papulopustular/moderate nodular acneSevere nodular/conglobate acne§
  1. *Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first line therapy (e.g. financial resources/reimbursement limitations, legal restrictions, availability, drug licensing).

  2. †In case of more widespread disease/moderate severity, initiation of a systemic treatment can be recommended.

  3. ‡Adapalene to be preferred over tretinoin/isotretinoin (see Chapter 9.1).

  4. §Systemic treatment with corticosteroids can be considered.

  5. ¶Doxycycline and lymecycline (see Chapter 9.2).

  6. **Low strength of recommendation.

  7. ††Indirect evidence from a study also including chorhexidin, recommendation additionally based on expert opinion.

  8. ‡‡Indirect evidence from nodular and conglobate acne and expert opinion.

  9. §§Indirect evidence from severe papularpustular acne.

  10. ¶¶Only studies found on systemic AB + adapalene, isotretinoin and tretinoin can be considered for combination treatment based on expert opinion.

  11. f.c.: fixed combination.

High strength of recommendationAdapalene + BPO (f.c.) or BPO + clindamycin (f.c.)Isotretinoin*Isotretinoin*
Medium strength of recommendationTopical retinoid‡Azelaic acid or BPO or topical retinoid‡ or systemic antibiotic† + adapalene¶¶Systemic antibiotics¶ + adapalene¶¶ or systemic antibiotics¶ + azelaic acid‡‡ or systemic antibiotics + adapalene + BPO (f.c.)Systemic antibiotics¶ + azelaic acid
Low strength of recommendationAzelaic acid or BPOBlue light or oral zinc or topical erythromycin + isotretinoin (f.c.) or topical erythromycin + tretinoin (f.c.) or systemic antibiotic†,¶ + BPO†† or systemic antibiotic †,¶ + azelaic acid¶¶ or systemic antibiotics †,¶ + adapalene + BPO (f.c.)§§Systemic antibiotics¶ + BPO††Systemic antibiotics¶ + BPO†† or systemic antibiotics¶ + adapalene§§,¶¶ or systemic antibiotics¶ + adapalene + BPO (f.c.)§§
Alternatives for female patientsHormonal antiandrogens + topical treatment or hormonal antiandrogens + systemic antibiotics**Hormonal antiandrogens + systemic antibiotics**

VI Treatment of comedonal acne

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

VI.1 Recommendations for comedonal acne*

  1. *Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first line therapy (e.g. financial resources/reimbursement limitations, legal restrictions, availability, drug licensing).

  2. †Adapalene (see chapter 9.1).

High strength of recommendation
None
Medium strength of recommendation
Topical retinoids† can be recommended for the treatment of comedonal acne
Low strength of recommendation
BPO can be considered for the treatment of comedonal acne
Azelaic acid can be considered for the treatment of comedonal acne
Negative recommendation
Topical antibiotics are not recommended for the treatment of comedonal acne
Hormonal antiandrogens, 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
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

VI.2 Reasoning

General comment: Only one trial looks specifically at patients with comedonal acne. As a source of indirect evidence, trials including patients with papulopustular acne were used and the percentage in the reduction of non-inflammatory lesions was considered as the relevant outcome parameter. Because of the general lack of direct evidence for the treatment of comedonal acne, the strength of recommendation was downgraded for all considered treatment options, starting with medium strength of recommendation as a maximum.

Choice of topical vs. systemic treatment

Due to the usually mild-to-moderate severity of comedonal acne, a topical therapy is generally recommended.

VI.2.1 Efficacy

Superior efficacy was defined as a difference of ≥10% in the reduction of non-inflammatory lesions in head-to-head comparisons (see also Chapter 3.3.3.).

VI.2.1.1 Topical monotherapy vs. placebo

Superior efficacy against NIL compared with placebo is demonstrated by: azelaic acid45–47 (LE 1), BPO48–60 (LE 1), and the topical retinoids49–51,60–75 (LE 1) (Table 3).

Table 3.   Efficacy: comedonal acne – topical therapy vs. topical therapy Thumbnail image of

Among the topical antibiotics, clindamycin57,58,72,76–79 (LE 1) and tetracycline80,81 (LE 1) show superior efficacy against NIL compared with placebo. Topical erythromycin59,66,82–85 (LE 1) shows only a trend towards superior efficacy against NIL compared with placebo (Table 4).

Table 4.   Efficacy: comedonal acne – antibiotics vs. placebo/BPO/azelaic acid/top. retinoids Thumbnail image of
VI.2.1.2 Topical monotherapy vs. topical monotherapy

The efficacy of adapalene and isotretinoin on NIL is comparable to the efficacy of BPO (adapalene50,51,60,86–88 LE 1, isotretinoin49 LE 3; Table 3).

Tretinoin shows a trend for comparable-to-superior efficacy on NIL compared with BPO89–91 LE 4; Table 3) and superior efficacy compared with azelaic acid (LE 4).

Benzoyl peroxide shows superior efficacy on NIL compared with topical antibiotics (clindamycin54–58,92,93 LE 1, tetracycline94 LE 3, erythromycin59 LE 4; Table 4).

Benzoyl peroxide shows superior efficacy against NIL compared with azelaic acid86,95 (LE 3), although there is some conflicting evidence (Table 3).

There are very little data comparing the efficacy of adapalene, topical isotretinoin or topical antibiotics with azelaic acid45,86,95 (no evidence or LE 4, Tables 3 and 4).

More evidence is available for a comparison of tretinoin and clindamycin, and shows comparable-to-superior efficacy for tretinoin72,96 (LE 3). The evidence also shows erythromycin to have comparable efficacy to isotretinoin66 (LE 3, Table 4).

Study results on the comparative efficacies of the topical retinoids against NIL are partly conflicting. The efficacy of adapalene against NIL is comparable, if not superior, to the efficacy of tretinoin97–106 (LE 1). Isotretinoin, however, shows comparable efficacy to adapalene107 (LE 4), and superior efficacy compared with tretinoin108 (LE 4, Table 3).

VI.2.1.3 Topical combination therapies

The combination of BPO and clindamycin shows comparable efficacy against NIL to monotherapy with BPO54–58,93,109–112 (LE 1) and superior efficacy compared with clindamycin monotherapy54–58,93,110 (LE 1, Table 5).

Table 5.   Efficacy: comedonal acne – top. combination therapy vs. top. therapy/combinations Thumbnail image of

The combination of BPO and adapalene shows a comparable-to-superior efficacy compared with BPO50,51,60,88 (LE 3) or adapalene alone50,51,60,88 (LE 3, Table 5).

Erythromycin plus isotretinoin shows comparable efficacy to both erythromycin66 (LE 3) and isotretinoin alone66 (LE 3, Table 5).

There were no trials comparing the efficacy of the fixed combination of tretinoin and erythromycin against its components.

The combination of BPO and clindamycin and the combination of BPO and adapalene have comparable efficacy against NIL113 (LE 4, Table 5).

Since this trial was published after the deadline of literature search, it was not officially included in the assessment, and since the safety/tolerability profile was inferior, the guidelines group did not deem it necessary to update the guideline and to change its conclusions.114,115

VI.2.1.4 Laser and light sources

Although there are some studies of the treatment of NIL with laser and light sources, the published evidence is still very scarce. A standardized treatment protocol and widespread clinical experience are still lacking.

VI.2.2 Tolerability/safety

Only one trial looked specifically at comedonal acne. It showed a superior safety/tolerability profile for azelaic acid compared with tretinoin (LE 4).45

As a source of further indirect evidence, trials in patients with papulopustular acne were considered to evaluate the safety and tolerability profile of the included treatments. For a summary of the data, see Chapter 7.2.2 Tolerability/safety.

VI.2.3 Patient preference/practicability

There is only indirect evidence from trials in patients with papulopustular acne that shows a preference among the topical retinoids for adapalene.116,117

VI.2.4 Other considerations

Animal experiments, in the rhino mouse model in particular, have shown for decades that retinoids have a strong anti-comedonal efficacy. Clinical trials on the microcomedo, the natural precursor of comedones, have shown that retinoids significantly reduce microcomedo counts. In addition, in vitro data provide pathophysiological support for the use of topical retinoids for comedonal acne.118,119

VI.3 Summary

No high strength recommendation was given because of the general lack of direct evidence for the treatment of comedonal acne.

Due to the generally mild-to-moderate severity of comedonal acne, a topical therapy is recommended.

The best efficacy was found for azelaic acid, BPO and topical retinoids.

The use of a fixed-dose combination of BPO + clindamycin does not lead to a clinically relevant increase in the efficacy against NIL.

The fixed-dose combination of BPO + adapalene shows a trend towards better efficacy against NIL when compared to its components as a monotherapy. However, there is also a trend towards inferiority with respect to the tolerability profile.

The tolerability of topical retinoids and BPO is comparable; there is a trend towards azelaic acid having a better tolerability/safety profile.

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.

There is a lack of standard protocols, experience and clinical trials for the treatment of comedonal acne with laser and light sources.

VII Treatment of papulopustular acne

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

VII.1 Recommendations

VII.1.1 Mild-to-moderate papulopustular acne*
  1. *Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first line therapy (e.g. financial resources/reimbursement limit, legal restrictions, availability, drug licensing).

  2. †Limited to a treatment period of 3 months.

  3. ‡Adapalene (see Chapter 9.1).

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 clindamycin and BPO 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
Topical retinoids can be recommended for the treatment of mild to moderate papulopustular acne‡
In case of more widespread disease, a combination of a systemic antibiotic with adapalene can be recommended for the treatment of moderate papulopustular.
Low strength of recommendation
Blue light monotherapy can be considered for the treatment of mild to moderate papulopustular acne
The fixed-dose combination of erythromycin and tretinoin can be considered for the treatment of mild to moderate papulopustular acne
The fixed-dose combination of isotretinoin and erythromycin 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
In case of more widespread disease, a combination of a systemic antibiotic with either BPO or with adapalene in fixed combination with BPO can be considered for the treatment of moderate papulopustular
Negative recommendation
Topical antibiotics as monotherapy are not recommended for the treatment of mild to moderate papulopustular acne
Treatment of mild to moderate papulopustular acne with 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
Open recommendation
Due to a lack of sufficient evidence, it is currently not possible to make a recommendation for or against treatment with red light, IPL, Laser or PDT in the treatment of mild to moderate papulopustular acne
VII.1.2 Severe papulopustular/moderate nodular acne
  1. *Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first line therapy (e. g. financial resources/reimbursement limit, legal restrictions, availability, drug licensing).

  2. †Doxycycline or lymecycline, limited to a treatment period of 3 months.

  3. ‡Adapalene (see Chapter 9.1).

  4. §Hormonal anti-androgens for female patients.

  5. ¶Only studies found on systemic AB + adaplene, Isotretinoin and tretinoin can be considered for combination treatment based on expert opinion.

High strength of recommendation
Oral isotretinoin monotherapy is strongly recommended for the treatment of severe papulopustular acne
Medium strength of recommendation
Systemic antibiotics can be recommended for the treatment of severe papulopustular acne in combination with adapalene,¶ with the fixed-dose combination of adapalene/BPO or in combination with azelaic acid†,‡
Low strength of recommendation
Oral anti-androgens in combination with oral antibiotics can be considered for the treatment of severe papulopustular acne†,§
Oral anti-androgens in combination with topical treatment can be considered for the treatment of severe papulopustular acne§
Systemic antibiotics in combination with BPO can be considered for the treatment of severe papulopustular/moderate nodular acne
Negative recommendation
Single or combined topical monotherapy is not recommended for the treatment of severe papulopustular acne
Oral antibiotics as monotherapy are not recommended for the treatment of severe papulopustular acne
Oral anti-androgens as monotherapy are not recommended for the treatment of severe papulopustular acne
Visible light as monotherapy is not recommended for the treatment of severe papulopustular acne
Artificial UV radiation sources are not recommended as a treatment of severe papulopustular 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 and laser in severe papulopustular acne
Although PDT is effective in the treatment of severe papularpustular/moderate nodular acne, it cannot yet be recommended due to a lack of standard treatment regimens that ensure a favourable profile of acute adverse reaction

VII.2 Reasoning

Choice of topical vs. systemic treatment

There are limited data comparing topical treatments with systemic treatments. Most of the available trials compare topical treatment with systemic treatment plus antibiotics. The general impression of a systemic treatment being more effective than a topical treatment could not be confirmed from the included trials. When looking at all comparisons between any topical therapy and systemic antibiotic treatments, five trials showed superiority of topical treatment, ten showed comparable efficacy and only three showed superior efficacy of systemic treatment.

Owing to the risk of the development of antibiotic resistance, topical monotherapy with antibiotics is generally not recommended. 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 treatment is used. In addition, better adherence and patient satisfaction is anticipated. Efficacy can be further enhanced by adding a topical therapy (see below).

VII.2.1 Efficacy

Superior efficacy was defined as a difference of ≥10 in head-to-head comparisons (see also Chapter 3.3.3.).

VII.2.1.1 Topical monotherapy vs. placebo

Superior efficacy against IL, compared with placebo, is observed with topical antibiotics (erythromycin59,66,82–85,120–125 LE 1, clindamycin58,72,76–79,126–133 LE 1, tetracycline80,81,134 LE 1, nadifloxacin135 LE 4), azelaic acid45–47 (LE 1), BPO48–56,58–60,136–140 (LE 1) and topical retinoids (adapalene50,51,60–64 LE 1, isotretinoin49,65,66,141 LE 1, tretinoin67–75,133,142,143 LE 1).

VII.2.1.2 Topical monotherapy vs. topical monotherapy

The efficacy of azelaic acid against inflammatory lesions is comparable to the efficacy of BPO86,95,144 (LE 2, Table 6).

Table 6.   Efficacy: papulopustular acne – top. therapy vs. top. therapy Thumbnail image of

The efficacy of adapalene against IL is comparable to the efficacy of azelaic acid86 (LE 4); there are no trials comparing isotretinoin or tretinoin with azelaic acid (Table 6).

The efficacy of BPO is comparable to the efficacy of adapalene50,51,60,86–88 (LE 2); there is conflicting evidence for BPO compared with tretinoin89–91,145 (LE 4) and there is one trial indicating superior efficacy of BPO over isotretinoin49 (LE 3, Table 6).

The efficacy of adapalene is comparable to the efficacy of tretinoin97–106,146 (LE 2) and isotretinoin107 (LE 4). The efficacy of tretinoin is comparable to efficacy of isotretinoin108 (LE 4).

Monotherapy with topical antibiotics is not recommended due to the risk of antibacterial resistance, and so is not further considered within this section; please see tables for individual trial results.

VII.2.1.3 Topical monotherapy vs. topical fixed-combinations (BPO/clindamycin, BPO/adapalene, tretinoin/isotretinoin, erythromycin/zinc)

The combination of adapalene and BPO against IL shows superior efficacy compared with adapalene alone50,51,60,88 (LE 1) and has comparable-to-superior efficacy compared with BPO alone50,51,60,88 (LE 3, Table 7).

Table 7.   Efficacy: papulopustular acne – top. combination therapy vs. top. therapy/combinations Thumbnail image of

The combination of clindamycin and BPO shows superior efficacy against IL compared with BPO alone54–56,58,93, 109,111,112,136,147 (LE 1) or clindamycin alone54–56,58,93,136,147 (LE 1, Table 7).

The combination of adapalene and BPO against IL shows comparable efficacy to the combination of clindamycin and BPO113 (LE 4, Table 7).

The combination of erythromycin and isotretinoin against IL shows a superior efficacy compared with isotretinoin alone66 (LE 3) and is comparable to erythromycin alone66 (LE 3, Table 7).

There were no trials comparing the combination of erythromycin and tretinoin to its individual components.

There is insufficient evidence for the additional benefit of adding topical zinc to topical erythromycin.148,149 (LE 3, Table 7).

VII.2.1.4 Topical monotherapy vs. systemic monotherapy

There are no trials comparing topical retinoids with systemic treatments.

Systemic treatment is generally considered to be more efficacious than a topical treatment, however, this could not be confirmed from the included trials. Of all comparisons between any topical therapy and systemic antibiotic treatments, three trials showed superiority of topical monotherapy,150–152 ten showed comparable efficacy80,127,128,153–159 and only three showed superior efficacy for systemic therapy81,160,161 (Table 8). However, the definition of acne severity grades, inclusion criteria and trial methodology were not always comparable.

Table 8.   Efficacy: papulopustular acne – top. therapy vs. sys. therapy Thumbnail image of

Evidence would suggest that efficacy is not increased by switching from a topical treatment to a systemic antibiotic treatment. Instead, a topical-systemic combination treatment should be considered.

VII.2.1.5 Systemic monotherapy vs. combination of topical therapy and systemic therapy

All included trials combining a topical treatment with a systemic antibiotic treatment showed at least a trend towards increased efficacy with combination therapy.

The combination of systemic doxycycline with topical adapalene showed a trend towards superior efficacy compared with doxycycline alone162 (LE 4). Adapalene combined with BPO and systemic doxycycline showed superior efficacy compared with doxycycline alone115 (LE 3, Table 9).

Table 9.   Efficacy: papulopustular acne – sys. therapy vs. sys. monotherapy/sys.–top. combination Thumbnail image of

The combination of lymecycline and adapalene shows superior efficacy compared with lymecycline monotherapy163 (LE 4, Table 9).

VII.2.1.6 Systemic monotherapy vs. other systemic monotherapy

There are no trials comparing systemic isotretinoin and monotherapy with systemic antibiotics.

Systemic isotretinoin shows a comparable efficacy against IL to minocycline plus azelaic acid164 (LE 4). However, isotretinoin showed a more rapid onset of action (Table 9).

Systemic isotretinoin shows superior efficacy compared with tetracycline plus adapalene165 (LE 4, Table 9).

Minocycline166 (LE 3) and tetracycline167 (LE 3) both show superior efficacy compared with zinc.

From the available data, it is very difficult to draw conclusions on the differences in efficacy between the anti-androgens.

Ethinylestradiol and cyproteronacetate (EE-CPA) show superior efficacy compared with ethinylestradiol and levonorgestrel (EE-LG)168–170 (LE 2).

EE-CPA shows comparable efficacy to ethinylestradiol and desogestrel (EE-DG)171–174 (LE 4).

Ethinylestradiol and chlormadinon (EE-CM) show superior efficacy compared with EE-LG175 (LE 4).

Ethinylestradiol and drospirenone (EE-DR) show comparable efficacy to ethinylestradiol and norgestimate (EE-NG)176 (LE 3).

EE-DG shows comparable efficacy to EE-LG177–179 (LE 3). This, however, can be influenced by the dosage used.

The evidence comparing oral contraceptives with systemic antibiotic therapy is scarce and conflicting: minocycline shows comparable efficacy to EE-CPA180 (LE 4), whereas EE-CPA shows superior efficacy compared with tetracycline181 (LE 3). Combining EE-CPA and tetracycline shows no superior efficacy compared with EE-CPA alone181 (LE 3, Table 10).

Table 10.   Efficacy: papulopustular acne – contraceptives vs. systemic antibiotic Thumbnail image of
VII.2.1.7 Laser and light sources

Blue light has superior efficacy against IL/total lesion (TL) compared with placebo182,183 (LE 3).

There is conflicting evidence regarding the efficacy of red light compared with placebo.

There is insufficient evidence regarding the efficacy of all other light and laser interventions compared with placebo.

A standardized treatment protocol and widespread clinical experience are still lacking.

VII.2.2 Tolerability/safety

To determine whether or not a safety and tolerability profile was ‘superior’, the number of drop-outs due to adverse events and the frequency and relevance and severity of the side effects were taken into consideration. In addition, an individual global assessment was performed.

VII.2.2.1 Topical monotherapy

The data on azelaic acid (15% or 20%) show a trend towards a superior tolerability/safety profile compared with BPO (5%)86,95,144 (LE 3), topical adapalene86 (LE 4) and tretinoin45 (LE 4). There is no evidence for a comparison with isotretinoin (Table 11).

Table 11.   Safety/tolerability: papulopustular acne Thumbnail image of

Benzoyl peroxide has a comparable tolerability/safety profile to topical retinoids (adapalene50,51,86–88 LE 4, isotretinoin49 LE 4 and tretinoin89–91,145 LE 4). Lower concentrations of BPO show a trend towards a better tolerability/safety profile (Table 11).

Among the topical retinoids, adapalene (LE 4) shows the best tolerability/safety profile followed by isotretinoin (LE 4) and tretinoin (LE 4) (Table 11).

Data on the safety and tolerabilities of combination therapies with topical antibiotics are not described, since topical antibiotics are not recommended as monotherapy.

VII.2.2.2 Topical combination therapies

The combination of BPO and clindamycin shows a similar tolerability/safety profile during the treatment of IL compared to monotherapy with BPO54–56,58,93,109,111,112,136,147 (LE 1) and an inferior profile to monotherapy with clindamycin alone (LE 3, Table 12).

Table 12.   Safety/tolerability: papulopustular acne – top. combinations vs. monotherapy or combination therapy Thumbnail image of

Benzoyl peroxide alone shows a superior safety/tolerability profile compared with a combination of BPO and adapalene50,51,88 (LE 3), whereas adapalene has a comparable-to-superior safety/tolerability profile50,51,88 (LE 4, Table 12).

The combination of erythromycin and isotretinoin shows a similar tolerability/safety profile to erythromycin or isotretinoin alone66 (LE 4, Table 12).

The combination of BPO and clindamycin shows a superior safety/tolerability profile compared with the combination of BPO and adapalene113 (LE 4).

VII.2.2.3 Topical monotherapy vs. systemic monotherapy

Topical treatments usually result in local side effects whereas systemic treatments cause, among others, mostly gastrointestinal effects. It is therefore difficult to accurately compare topical and systemic treatments in terms of safety/tolerability.

In trials comparing topical and systemic treatments drop-out rates due to drug-related adverse events are higher in the topical treatment groups than in the systemic treatment groups (top. 24 patients vs. syst. 11 patients/11 trials,127,128,151–154,157–160,184,185 assuming a similar distribution of patients in systemic and topical arms). In six of the trials no information on drop-outs was provided.80,81,150,155,156,161

No reasonable conclusion seems justified with the available evidence, however, no immediate superiority of either systemic or topical treatment is apparent.

VII.2.2.4 Systemic antibiotics vs. systemic antibiotics

From the included trials, no clear conclusion can be drawn as to which antibiotic treatment has the best safety/tolerability profile.

Smith and Leyden186 performed a systemic review analysing case reports on adverse events with minocycline and doxycycline between 1966 and 2003. As a result, they suggest that adverse events may be less likely with doxycycline than with minocycline. More severe adverse events seem to appear during treatments with minocycline. Doxycycline, however, leads to photosensitivity, which is not seen with minocycline.

The 2003 Cochrane review from Garner et al.187 provided no further clear evidence on the safety profile of minocycline and doxycycline and underlines the ongoing debate and need for further evidence.

Treatment with anti-androgens

From the included trials, no clear comparison of the safety/tolerability profiles of anti-androgens with other systemic treatments can be made. An assessment to compare the safety profile of the different anti-androgens is out of the scope of these guidelines. For the use of anti-androgens, relevant safety aspects such as the risk of thrombosis have to be considered.

Systemic treatments with isotretinoin

From the included trials, no clear comparison of the safety/tolerability profiles of isotretinoin with other systemic treatments can be made. (For a discussion of isotretinoin depression, see Chapter 9.5.) (Table 13).

Table 13.   Safety/tolerability: papulopustular acne – sys. therapy vs. sys. monotherapy/sys.–top. combination Thumbnail image of
VII.2.3 Patient preference/practicability

Split-face trials show a patient preference for adapalene over tretinoin188,189 (LE 3).

VII.2.4 Other considerations

For further discussion on the use of isotretinoin as a first line treatment for severe papulopustular acne, see Chapter 9.3.

The expert group feels strongly that the effectiveness seen in clinical practice is highest with systemic isotretinoin, although this can only be partly supported by published evidence. However, the dose response rates, the relapse rates after treatment and the pharmacoeconomic calculations strongly favour systemic isotretinoin.

VII.3 Summary

The best efficacy against IL was found to be achieved with the fixed-dose combinations of BPO plus adapalene and BPO plus clindamycin, when compared with topical monotherapies.

Monotherapy with azelaic acid, BPO or topical retinoids all showed comparable efficacy when compared with each other.

Systemic monotherapy with antibiotics shows no superiority to topical treatments, therefore combining systemic therapy with a topical agent should always be preferred.

For severe cases, a 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.

VIII Treatment nodular/conglobate acne

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

VIII.1 Recommendations*,†

  1. *Limitations can apply that may necessitate the use of a treatment with a lower strength of recommendation as a first line therapy (e.g. financial resources/reimbursement limit, legal restrictions, availability, drug licensing).

  2. †Expert opinion: for the initial treatment phase with isotretinoin a combination with oral corticosteroids treatment can be considered in conglobate acne.

  3. ‡Doxycycline or lymecycline limited to a treatment period of 3 months.

  4. §Hormonal anti-androgens for female patients.

High strength of recommendation
Oral isotretinoin is strongly recommended as a monotherapy for the treatment of conglobate acne
Medium strength of recommendation
Systemic antibiotics can be recommended for the treatment of conglobate acne in combination with azelaic acid
Low strength of recommendation
Oral anti-androgens in combination with oral antibiotics can be considered for the treatment of conglobate acne‡,§
Systemic antibiotics in combination with adapalene, BPO or the adapalene-BPO fixed-dose combination can be considered for the treatment of nodular/conglobate acne
Negative recommendation
Topical monotherapy is not recommended for the treatment of conglobate acne.
Oral antibiotics are not recommended as monotherapy for the treatment of conglobate acne
Oral anti-androgens are not recommended as monotherapy for the treatment of conglobate acne
Artificial UV radiation sources are not recommended for the treatment of conglobate acne
Visible light as monotherapy is not recommended for the treatment of conglobate acne
Open recommendation
Due to lack of sufficient evidence, it is currently not possible to make a recommendation for or against treatment with IPL, or laser in conglobate acne
Although PDT is effective in the treatment of moderate 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

VIII.2 Reasoning

General comment: Very few of the included trials (described below) 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.

VIII.2.1 Efficacy

Superior efficacy was defined as a difference of ≥ 10 in head-to-head comparisons (see also Chapter 3.3.3).

VIII.2.1.1 Systemic monotherapy vs. placebo

Systemic isotretinoin has superior efficacy compared with placebo190 (LE 4*).

*There is only one trial comparing systemic isotretinoin with placebo in nodular/conglobate acne resulting only in LE 4. However, there are multiple trials comparing different dosage without a placebo group and following expert opinion, there is no doubt about its superior efficacy.

VIII.2.1.2 Topical monotherapy vs. systemic monotherapy

Systemic treatment with tetracycline has superior efficacy against noduls/cycsts (NO/CY) compared with topical clindamycin153 (LE 3).

Systemic treatment with tetracycline has a comparable efficacy against NO/CY to azelaic acid155 (LE 3).

VIII.2.1.3 Systemic monotherapy vs. systemic monotherapy

There are eight trials comparing different dosage regimens of systemic isotretinoin. Most of these used 0.5 mg/kg bodyweight as one comparator. With this dosage, the mean reduction of NO/CY was around 70%.191–198

Systemic isotretinoin shows superior efficacy against NO/CY compared with systemic minocycline199 (LE 4) or systemic tetracycline200 (LE 3, Table 14).

Table 14.   Efficacy: nodular/conglobate acne Thumbnail image of

Systemic isotretinoin shows comparable efficacy to systemic minocycline combined with topical azelaic acid164 (LE 4, Table 14).

Systemic isotretinoin shows comparable efficacy against deep IL (indirect evidence) to systemic tetracycline in combination with topical adapalene165 (LE 4).

The addition of topical clindamycin and topical adapalene to systemic isotretinoin does not provide superior efficacy compared with isotretinoin monotherapy201 (LE 4, Table 14).

VIII.2.1.4 Laser and light sources

Due to there being insufficient evidence, it is not currently possible to make a recommendation for or against treatment with IPL, laser or PDT in conglobate acne.

VIII.2.2 Tolerability/safety

See also Chapter 7.2.2 on the tolerability/safety of papulopustular acne treatments.

From the trials specifically investigating conglobate acne, very little information is available to compare the different treatment options. Almost all patients suffer from xerosis and cheilitis during treatment with isotretinoin, whereas systemic antibiotics more commonly cause gastrointestinal adverse events (LE 4).

VIII.2.3 Patient preference/practicability

There is no evidence on the treatment preferences of patients suffering from conglobate acne.

VIII.2.4 Other considerations

For comment on EMEA directive see also Chapter 9.3.

VIII.3 Summary

Systemic isotretinoin shows superior/comparable efficacy in the treatment of conglobate acne compared with systemic antibiotics in combination with topical treatments. The expert group considers that greatest effectiveness in the treatment of conglobate acne in clinical practice is seen with systemic isotretinoin, although this can only be partly supported by published evidence, because of the lack 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.

There are insufficient data on the efficacy of other treatment options for conglobate acne.

There is a lack of standard protocols, experience and clinical trial data for the treatment of papulopustular acne with laser and light sources other than blue light.

IX General considerations

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

IX.1 Choice of type of topical retinoid

Adapalene should be selected in preference to tretinoin and isotretinoin.

IX.1.1 Reasoning/summary

All topical retinoids show comparable efficacy against IL (see Chapter 7.2.1.2), whereas against NIL the evidence is conflicting (see Chapter 6.2.1.2).

Among the topical retinoids, adapalene shows the best tolerability/safety profile followed by isotretinoin and tretinoin (see Chapter 7.2.2).

Patient preference favours adapalene over tretinoin (see Chapter 7.2.3).

IX.2 Choice of type of systemic antibiotic

Doxycycline and lymecycline should be selected in preference to minocycline and tetracycline.

IX.2.1 Reasoning

General comment: In addition to the literature included in the guidelines, the Cochrane review on the efficacy and safety of minocycline187 and the systematic review by Simonart et al.202 were taken into consideration.

IX.2.2 Efficacy

Doxycycline, lymecycline, minocycline and tetracycline all seem to have a comparable efficacy against IL (see Chapter 7.2.2.4).

There is a trend towards comparable-to-superior efficacy for tetracycline compared with clindamycin203,204 and erythromycin205–207 (LE 4).

IX.2.3 Tolerability/safety

From the included trials, no clear results can be drawn as to which antibiotic treatment has the best safety/tolerability profile.

The 2003 Cochrane review from Garner et al.187 provides no further clear evidence on the safety profiles of minocycline and doxycycline. The review showed no significant difference in the number of dropouts due to adverse events when comparing minocycline with doxycycline, lymecycline or tetracycline. Overall, an adverse drug reaction (ADR) was experienced by 11.1% of the 1230 patients receiving minocycline, 13.1% of the 415 patients receiving tetracycline or oxytetracycline and 6.1% of the 177 patients receiving doxycycline.

Two analyses of reported ADRs have shown lower incidence rates and lower severity of ADRs with doxycycline compared with minocycline.186,208

The most frequent ADRs for doxycycline are manageable (sun protection for photosensitivity and water intake for oesophagitis), whereas the most relevant side effects of monocycline (hypersensitivity, hepatic dysfunction, lupus like syndrome) are not easily managed.209

The phototoxicity of doxycycline is dependent on dosage and the amount of sun light.210,211

There is little information on the frequency of ADRs with lymecycline. Its phototoxicity has been reported to be lower than with doxycycline and its safety profile is comparable to that of tetracycline.209,212

IX.2.4 Patient preference/practicability

Doxycycline, lymecycline and minocycline have superior practicability compared with tetracycline due to their requirement for less frequent administration. The Cochrane review by Garner et al. included one trial showing a patient preference for minocycline over tetracycline.187

IX.2.5 Other considerations

The use of systemic clindamycin for the treatment of acne is generally not recommended as this treatment option should be kept for severe infections.

IX.2.6 Summary

The efficacies of doxycycline, lymecycline, minocycline and tetracycline are comparable.

Tetracycline has a lower practicability and patient preference compared with doxycycline, lymecycline and minocycline.

More severe drug reactions are experienced during treatment with minocycline compared with doxycycline, lymecycline and tetracycline.

IX.3 Considerations on isotretinoin and dosage

The evidence on the best dosage, including cumulative dosage, is rare and partly conflicting. In most trials, higher dosages have lead to better response rates whilst having less favourable safety/tolerability profiles. Attempts to determine the cumulative dose necessary to obtain an optimal treatment response and low relapse rate have not yet yielded sufficient evidence for a strong recommendation. The following recommendation is based more on expert opinion, than on existing published trials.

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 can be recommended
The duration of the therapy should be at least 6 months
In case of insufficient response, the treatment period can be prolonged

IX.4 Oral isotretinoin considerations with respect to EMEA directive

Bettoli/Layton/Ochsendorf

The current European Directive for prescribing oral isotretinoin differs from the recommendations given in this guideline with respect to indication.

The EU directive states: “oral isotretinoin should only be used in severe acne, nodular and conglobate acne, that has or is not responding to appropriate antibiotics and topical therapy.”213 The inference of this being that it should now not be used at all as first line therapy.

After almost three decades of experience with oral isotretinoin, the published data and opinion of many experts, including the authors of the EU Acne Guidelines, support systemic isotretinoin being considered as the first-choice treatment for severe papulopustular, moderate nodular, and severe nodular/conglobate acne.11,214–216 Acne treatment guidelines written some years ago pointed out that oral isotretinoin should be used ‘sooner rather than later’.217 It is well known that a quick reduction of inflammation in acne may prevent the occurrence of clinical and psychological scarring and also significantly improves quality of life and reduces the risk of depression.218,219 Delaying the use of oral isotretinoin, which the group considers to be the most effective treatment for severe acne, poses a significant ethical problem. Although comparative trials are missing, clinical experience confirms that the relapse rates after treatment with isotretinoin are the lowest among all the available therapies.

Unfortunately the European Directive, although not supported by convincing evidence-based data, reach a different conclusion. Theoretically, in EU countries clinicians are free to prescribe drugs, such as oral isotretinoin, according to their professional experience. However, in the event of any medical problems, they could be deemed liable if they have failed to follow recommended prescribing practice.220

For many reasons, systemic isotretinoin must be considered the first-choice treatment for severe acne: clinical effectiveness, prevention of scarring and quick improvement of a patient’s quality of life.

The EMEA recommendations include the following points:

  • 1
     To start at the dosage of 0.5 mg/kg daily.
  • 2
     Not recommended for patients under 12 years of age.
  • 3
     To monitor laboratory parameters, primarily liver enzymes and lipids, before treatment, 1 month after starting and every 3 months thereafter.
  • 4
     To avoid laser treatment, peeling and wax epilation for at least 6 months after stopping therapy.

The European Guidelines group agrees with these recommendations of the EMEA, although expert opinion suggests that being less than 12 years old (point 2) does not necessarily contraindicate the use of isotretinoin and we did not identify any evidence to support the avoidance of wax epilation and peeling for at least 6 months after isotretinoin treatment (point 4).220

IX.5 Consideration on isotretinoin and the risk of depression

Nast

A systematic literature search to investigate the risk of depression during treatment with isotretinoin was not conducted. To specifically assess this issue at an evidence-based level, the data presented in the included trials were supplemented with the systematic review by Marqueling et al.221 They reported that rates of depression among isotretinoin users ranged from 1% to 11% across trials, with similar rates in oral antibiotic control groups. Overall, trials comparing depression before and after treatment did not show a statistically significant increase in depression diagnoses or depressive symptoms. Some, in fact, demonstrated a trend towards fewer or less severe depressive symptoms after isotretinoin therapy. This decrease was particularly evident in patients with pre-treatment scores in the moderate or clinical depression range. No correlation between isotretinoin use and suicidal behaviour was reported, although only one retrospective trial presented data on this topic. The current literature does not support a causative association between isotretinoin use and depression; however, there are important limitations to many of the trials. The available data on suicidal behaviour during isotretinoin treatment are insufficient to establish a meaningful causative association. Prior symptoms of depression should be part of the medical history of any patient before the initiation of isotretinoin and during the course of the treatment. Patients should be informed about a possible risk of depression and suicidal behaviour.

IX.6 Risk of antibiotic resistance

Simonart/Ochsendorf/Oprica

The first relevant changes in P. acnes antibiotic sensitivity were found in the USA shortly after the introduction of the topical formulations of erythromycin and clindamycin. The molecular basis of resistance, via mutations in genes encoding 23S and 16S rRNA, are widely distributed.222 However, the development of strains with still unidentified mutations suggests that new mechanisms of resistance are evolving in P. acnes.222 Combined resistance to clindamycin and erythromycin is much more common (highest prevalence 91% in Spain) than resistance to the tetracyclines (highest prevalence 26% in the UK).223 Use of topical antibiotics can lead to resistance largely confined to the skin of treated sites, whereas oral antibiotics can lead to resistance in commensal flora at all body sites.224 Resistance is more common in patients with moderate-to-severe acne and in countries with high outpatient antibiotic sales.225 Resistance is disseminated primarily by person-to-person contact, and so the spread of resistant strains by the treating physicians and by family and friends occurs frequently.10,222,223 Although some data suggest that resistant isolates disappear after antibiotic treatment is stopped,226 other data suggest that resistance persists and can be reactivated rapidly.227

There have been an increasing number of reports of systemic infections caused by resistant P. acnes in non-acne patients, e.g. post-surgery.225 In addition, a transmission of factors conferring resistance to bacteria other than P. acnes is described.82,228 Although antibiotic use in acne patients has been shown to be associated with an increased risk of upper respiratory tract infection, the true clinical importance of these findings requires further investigation.

It has been argued that the most likely effect of resistance is to reduce the clinical efficacy of antibiotic-based treatment regimens to a level below that which would occur in patients with fully susceptible flora.223,229 Some trials have suggested a clear association between P. acnes resistance to the appropriate antibiotic and poor therapeutic response.223,229 There is a gradual decrease in the efficacy of topical erythromycin in clinical trials of therapeutic intervention for acne, which is probably related to the development of antibiotic-resistant propionibacteria.230 In contrast, there is so far no evidence that the efficacy of oral tetracycline or topical clindamycin has decreased in the last few decades.165,202,230

Studies on P. acnes resistance have highlighted the need for treatment guidelines to restrict the use of antibiotics to limit the emergence of resistant strains. As a consequence, the use of systemic antibiotics should be limited (both indication and duration) and topical antibiotic monotherapy should be avoided. Other recommendations include stricter cross-infection control measures when assessing acne in the clinic and combining any topical/systemic antibiotic therapy with broad-spectrum antibacterial agents, such as BPO.10,27,223

X Maintenance therapy

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

Dréno/Gollnick

This chapter is based on expert opinion and a narrative literature review only. These recommendations were not generated by systematic literature search with formalized consensus conference.

Acne lesions typically recur for years, and so acne is nowadays considered to be a chronic disease.12 It has been shown that microcomedones significantly decrease during therapy but rebound almost immediately after discontinuation of a topical retinoid. Hence, the strategy for treating acne today includes an induction phase followed by a maintenance phase, and is further supported by adjunctive treatments and/or cosmetic treatments. Therefore, a maintenance therapy to reduce the potential for recurrence of visible lesions should be considered as a part of routine acne treatment. However, it is important to emphasize the lack of definitions surrounding the topic. One possible definition is: ‘Maintenance therapy can be defined as the regular use of appropriate therapeutic agents to ensure that acne remains in remission’.

Since 1973 it has clearly been shown that, after a controlled intervention phase with oral antibiotic and topical tretinoin, patients continuing to receive the topical retinoid in a controlled maintenance phase experience a significantly lower relapse rate.231

Several controlled trials have now been performed with topical retinoids to show the value of maintenance treatment, with a topical retinoid decreasing the number and preventing the development of microcomedones in different severity grades of acne.

To date, adapalene regimens have been most extensively studied as maintenance treatments for acne in four controlled trials (one on micro comedones) and two uncontrolled trials.

One clinical trial evaluating tazarotene and one involving maintenance treatment with tretinoin after oral tetracycline and tretinoin topical treatment have also been published. In all except one trial (Bettoli et al.232 after oral isotretinoin therapy), topical retinoid monotherapy was been evaluated after an initial 12 weeks of combination therapy comprising a topical retinoid plus an oral or topical antibiotic. The majority of trials has lasted 3–4 months (up to 12 months) and shows a significant trend towards continuing improvement with topical retinoid maintenance therapy and relapse when patients stop treatment. This suggests that a longer duration of maintenance therapy is likely to be beneficial.

Two open studies with long-term use of adapalene have been conducted,233,234 providing additional evidence supporting the concept of maintenance therapy.235

Topical azelaic acid is an alternative to topical retinoids for acne maintenance therapy. Its efficacy and favourable safety profile are advantageous for long-term therapy.236

To minimize antibiotic resistance, long-term therapy with antibiotics is not recommended as an alternative to topical retinoids. If an antimicrobial effect is desired, the addition of BPO to topical retinoid therapy is preferred.

In future studies, it would be useful to present data on the proportion of patients who were able to maintain a defined level of improvement (e.g., 50% from baseline). Other issues that should be addressed include creating a standardized definition of successful maintenance, determining the most appropriate patient populations for maintenance therapy and identifying the ideal length of observation of patients.

For a successful long-term treatment, any acne maintenance therapy must be tolerable, appropriate for the patient’s lifestyle and convenient. The natural history of acne suggests that maintenance therapy should continue over a period of months to years depending upon the patient’s age. Ongoing research will help to define the optimal duration of therapy and, perhaps, refine patient selection. Some patients with significant inflammation may need to be treated with a combination of topical retinoid and antimicrobial agents. This should be further studied.

Education about the pathophysiology of acne can enhance patient adherence to maintenance therapy. However, the psychosocial benefits of clearer skin may be the most compelling reason for consistent maintenance therapy. Finally, it may also be helpful to explain to patients that acne is often a chronic disease that requires acute and maintenance therapy for sustained remission.

XII References

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information
  • 1
    Field M, Lohr KN. Institute of Medicine Committee to Advise the Public Health Service on Clinical Practice Guidelines. Clinical Practice Guidelines: Directions for a New Program. National Academy Press, Washington, DC, 1990.
  • 2
    Cunliffe WJ. The Acnes. Martin Dunitz Ltd, London, 1989.
  • 3
    Cunliffe WJ, Shuster S. Pathogenesis of acne. Lancet 1969; 1: 685687.
  • 4
    Lucky AW, Biro FM, Huster GA, Leach AD, Morrison JA, Ratterman J. Acne vulgaris in premenarchal girls. An early sign of puberty associated with rising levels of dehydroepiandrosterone. Arch Dermatol 1994; 130: 308314.
  • 5
    Burke BM, Cunliffe WJ. The assessment of acne vulgaris – the Leeds technique. Br J Dermatol 1984; 111: 8392.
  • 6
    Orentreich N, Durr NP. The natural evolution of comedones into inflammatory papules and pustules. J Invest Dermatol 1974; 62: 316320.
  • 7
    Lehmann HP, Robinson KA, Andrews JS, Holloway V, Goodman SN. Acne therapy: a methodologic review. J Am Acad Dermatol 2002; 47: 231240.
  • 8
    Barratt H, Hamilton F, Car J, Lyons C, Layton A, Majeed A. Outcome measures in acne vulgaris: systematic review. Br J Dermatol 2009; 160: 132136.
  • 9
    Witkowski JA, Parish LC. The assessment of acne: an evaluation of grading and lesion counting in the measurement of acne. Clin Dermatol 2004; 22: 394397.
  • 10
    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: S1S50.
  • 11
    Gollnick H, Cunliffe WJ, Berson D et al. Management of acne: a report from a Global Alliance to Improve Outcomes in Acne. J Am Acad Dermatol 2003; 49: S1S37.
  • 12
    Gollnick HPM, Finlay AY, Shear N. Can we define acne as a chronic disease? If so, how and when? Am J Clin Dermatol 2008; 9: 279284.
  • 13
    O’brien SC, Lewis JB, Cunliffe WJ. The Leeds revised acne grading system. J Dermatolog Treat 1998; 9: 215220.
  • 14
    Dreno B, Bodokh I, Chivot M et al. [ECLA grading: a system of acne classification for every day dermatological practice]. Ann Dermatol Venereol 1999; 126: 136141.
  • 15
    Dreno B, Alirezai M, Auffret N et al. [Clinical and psychological correlation in acne: use of the ECLA and CADI scales]. Ann Dermatol Venereol 2007; 134: 451455.
  • 16
    Pochi PE, Shalita AR, Strauss JS et al. Report of the Consensus Conference on Acne Classification. Washington, D.C., March 24 and 25, 1990. J Am Acad Dermatol 1991; 24: 495500.
  • 17
    Cook CH, Centner RL, Michaels SE. An acne grading method using photographic standards. Arch Dermatol 1979; 115: 571575.
  • 18
    Pillsbury DM, Shelley WB, Kligman AM. Acne, acneform eruptions and rosacea. In Pillsbury DM, Shelley WB, Kligman AM, eds. Dermatology. Saunders, Philadelphia, 1956: 80048027.
  • 19
    Michaelsson G, Juhlin L, Vahlquist A. Effects of oral zinc and vitamin A in acne. Arch Dermatol 1977; 113: 3136.
  • 20
    Wilson RG. Office application of a new acne grading system. Cutis 1980; 25: 6264.
  • 21
    Allen BS, Smith JG Jr. Various parameters for grading acne vulgaris. Arch Dermatol 1982; 118: 2325.
  • 22
    Layton AM. Disorders of the sebaceous glands. In Burns T, Breathnach S, Cosx N, Griffiths C, eds. Rook’s Textbook of Dermatology, 8th edn. Wiley-Blackwell, Oxford, 2010: 3839.
  • 23
    Tan JK, Tang J, Fung K et al. Development and validation of a comprehensive acne severity scale. J Cutan Med Surg 2007; 11: 211216.
  • 24
    U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER). Guidance for industry. Acne vulgaris: developing drugs for treatment. 2005. URL http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM071292.pdf (last accessed: 4 May 2011).
  • 25
    Simpson NB, Cunliffe WJ. Disorders of the sebaceous glands. In Burns T, Breathnach S, Cosx N, Griffiths C, eds. Rook’s Textbook of Dermatology, 7th edn. Blackwell Science, Oxford, 2004: 43.
  • 26
    Holland DB, Jeremy AH. The role of inflammation in the pathogenesis of acne and acne scarring. Semin Cutan Med Surg 2005; 24: 7983.
  • 27
    Dreno B, Bettoli V, Ochsendorf F et al. An expert view on the treatment of acne with systemic antibiotics and/or oral isotretinoin in the light of the new European recommendations. Eur J Dermatol 2006; 16: 565571.
  • 28
    Layton AM, Henderson CA, Cunliffe WJ. A clinical evaluation of acne scarring and its incidence. Clin Exp Dermatol 1994; 19: 303308.
  • 29
    Pathirana D, Nast A, Ormerod AD et al. On the development of the European S3 guidelines on the systemic treatment of psoriasis vulgaris: structure and challenges. J Eur Acad Dermatol Venereol 2010; 24: 14581467.
  • 30
    Pathirana D, Ormerod AD, Saiag P et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009; 23(Suppl 2): 170.
  • 31
    GRADE working group. URL http://www.gradeworkinggroup.org/ (last accessed: 2 November 2010).
  • 32
    Amado JM, Matos ME, Abreu AM et al. The prevalence of acne in the north of Portugal. J Eur Acad Dermatol Venereol 2006; 20: 12871295.
  • 33
    Kilkenny M, Merlin K, Plunkett A, Marks R. The prevalence of common skin conditions in Australian school students: 3. acne vulgaris. Br J Dermatol 1998; 139: 840845.
  • 34
    Nijsten T, Rombouts S, Lambert J. Acne is prevalent but use of its treatments is infrequent among adolescents from the general population. J Eur Acad Dermatol Venereol 2007; 21: 163168.
  • 35
    Smithard A, Glazebrook C, Williams HC. Acne prevalence, knowledge about acne and psychological morbidity in mid-adolescence: a community-based study. Br J Dermatol 2001; 145: 274279.
  • 36
    Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999; 41: 577580.
  • 37
    Friedman GD. Twin studies of disease heritability based on medical records: application to acne vulgaris. Acta Genet Med Gemellol (Roma). 1984; 33: 487495.
  • 38
    Dreno B, Poli F. Epidemiology of acne. Dermatology 2003; 206: 710.
  • 39
    Herane MI, Ando I. Acne in infancy and acne genetics. Dermatology 2003; 206: 2428.
  • 40
    Perkins A, Cheng C, Hillebrand G, Miyamoto K, Kimball A. Comparison of the epidemiology of acne vulgaris among Caucasian, Asian, Continental Indian and African American women. J Eur Acad Dermatol Venereol 2010; 25: 10541060.
  • 41
    Cheng CE, Irwin B, Mauriello D, Liang L, Pappert A, Kimball AB. Self-reported acne severity, treatment, and belief patterns across multiple racial and ethnic groups in adolescent students. Pediatr Dermatol 2010; 27: 446452.
  • 42
    Cordain L, Lindeberg S, Hurtado M, Hill K, Eaton SB, Brand-Miller J. Acne vulgaris: a disease of Western civilization. Arch Dermatol 2002; 138: 15841590.
  • 43
    Adebamowo CA, Spiegelman D, Danby FW, Frazier AL, Willett WC, Holmes MD. High school dietary dairy intake and teenage acne. J Am Acad Dermatol 2005; 52: 207214.
  • 44
    Smith RN, Mann NJ, Braue A, Makelainen H, Varigos GA. A low-glycemic-load diet improves symptoms in acne vulgaris patients: a randomized controlled trial. Am J Clin Nutr 2007; 86: 107115.
  • 45
    Katsambas A, Graupe K, Stratigos J. Clinical studies of 20% azelaic acid cream in the treatment of acne vulgaris. Comparison with vehicle and topical tretinoin. Acta Derm Venereol Suppl (Stockh) 1989; 143: 3539.
  • 46
    Iraji F, Sadeghinia A, Shahmoradi Z, Siadat AH, Jooya A. Efficacy of topical azelaic acid gel in the treatment of mild-moderate acne vulgaris. Indian J Dermatol Venereol Leprol 2007; 73: 9496.
  • 47
    Cunliffe WJ, Holland KT. Clinical and laboratory studies on treatment with 20% azelaic acid cream for acne. Acta Derm Venereol Suppl (Stockh) 1989; 143: 3134.
  • 48
    Sklar JL, Jacobson C, Rizer R, Gans EH. Evaluation of Triaz 10% Gel and Benzamycin in acne vulgaris. J Dermatolog Treat 1996; 7: 147152.
  • 49
    Hughes BR, Norris JF, Cunliffe WJ. A double-blind evaluation of topical isotretinoin 0.05%, benzoyl peroxide gel 5% and placebo in patients with acne. Clin Exp Dermatol 1992; 17: 165168.
  • 50
    Thiboutot DM, Weiss J, Bucko A et al. Adapalene-benzoyl peroxide, a fixed-dose combination for the treatment of acne vulgaris: results of a multicenter, randomized double-blind, controlled study. J Am Acad Dermatol 2007; 57: 791799.
  • 51
    Gold LS, Tan J, Cruz-Santana A et al. A North American study of adapalene-benzoyl peroxide combination gel in the treatment of acne. Cutis 2009; 84: 110116.
  • 52
    Papageorgiou PP, Chu AC. Chloroxylenol and zinc oxide containing cream (Nels cream) vs. 5% benzoyl peroxide cream in the treatment of acne vulgaris. A double-blind, randomized, controlled trial. Clin Exp Dermatol 2000; 25: 1620.
  • 53
    Hunt MJ, Barnetson RS. A comparative study of gluconolactone versus benzoyl peroxide in the treatment of acne. Australas J Dermatol 1992; 33: 131134.
  • 54
    Webster G, Rich P, Gold MH, Mraz S, Calvarese B, Chen D. Efficacy and tolerability of a fixed combination of clindamycin phosphate (1.2%) and low concentration benzoyl peroxide (2.5%) aqueous gel in moderate or severe acne subpopulations. J Drugs Dermatol 2009; 8: 736743.
  • 55
    Thiboutot D, Zaenglein A, Weiss J, Webster G, Calvarese B, Chen D. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for the once-daily treatment of moderate to severe acne vulgaris: assessment of efficacy and safety in 2813 patients. J Am Acad Dermatol 2008; 59: 792800.
  • 56
    Lookingbill DP, Chalker DK, Lindholm JS et al. Treatment of acne with a combination clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol 1997; 37: 590595.
  • 57
    Tschen EH, Katz HI, Jones TM et al. A combination benzoyl peroxide and clindamycin topical gel compared with benzoyl peroxide, clindamycin phosphate, and vehicle in the treatment of acne vulgaris. Cutis 2001; 67: 165169.
  • 58
    Fagundes DS, Fraser JM, Klauda HC. New therapy update – a unique combination formulation in the treatment of inflammatory acne. Cutis 2003; 72: 1619.
  • 59
    Burke B, Eady EA, Cunliffe WJ. Benzoyl peroxide versus topical erythromycin in the treatment of acne vulgaris. Br J Dermatol 1983; 108: 199204.
  • 60
    Gollnick HP, Draelos Z, Glenn MJ et al. Adapalene-benzoyl peroxide, a unique fixed-dose combination topical gel for the treatment of acne vulgaris: a transatlantic, randomized, double-blind, controlled study in 1670 patients. Br J Dermatol 2009; 161: 11801189.
  • 61
    Thiboutot D, Pariser DM, Egan N et al. Adapalene gel 0.3% for the treatment of acne vulgaris: a multicenter, randomized, double-blind, controlled, phase III trial. J Am Acad Dermatol 2006; 54: 242250.
  • 62
    Pariser DM, Thiboutot DM, Clark SD, Jones TM, Liu Y, Graeber M. The efficacy and safety of adapalene gel 0.3% in the treatment of acne vulgaris: a randomized, multicenter, investigator-blinded, controlled comparison study versus adapalene gel 0.1% and vehicle. Cutis 2005; 76: 145151.
  • 63
    Lucky A, Jorizzo JL, Rodriguez D et al. Efficacy and tolerance of adapalene cream 0.1% compared with its cream vehicle for the treatment of acne vulgaris. Cutis 2001; 68: 3440.
  • 64
    Kawashima M, Harada S, Loesche C, Miyachi Y. Adapalene gel 0.1% is effective and safe for Japanese patients with acne vulgaris: a randomized, multicenter, investigator-blinded, controlled study. J Dermatol Sci 2008; 49: 241248.
  • 65
    Chalker DK, Lesher JL Jr, Smith JG Jr et al. Efficacy of topical isotretinoin 0.05% gel in acne vulgaris: results of a multicenter, double-blind investigation. J Am Acad Dermatol 1987; 17: 251254.
  • 66
    Glass D, Boorman GC, Stables GI, Cunliffe WJ, Goode K. A placebo-controlled clinical trial to compare a gel containing a combination of isotretinoin (0.05%) and erythromycin (2%) with gels containing isotretinoin (0.05%) or erythromycin (2%) alone in the topical treatment of acne vulgaris. Dermatology 1999; 199: 242247.
  • 67
    Berger R, Barba A, Fleischer A et al. A double-blinded, randomized, vehicle-controlled, multicenter, parallel-group study to assess the safety and efficacy of tretinoin gel microsphere 0.04% in the treatment of acne vulgaris in adults. Cutis 2007; 80: 152157.
  • 68
    Christiansen J, Holm P, Reymann F. The retinoic acid derivative Ro 11-1430 in acne vulgaris. A controlled multicenter trial against retinoic acid. Dermatologica 1977; 154: 219227.
  • 69
    Krishnan G. Comparison of two concentrations of tretinoin solution in the topical treatment of acne vulgaris. Practitioner 1976; 216: 106109.
  • 70
    Lucky AW, Cullen SI, Jarratt MT, Quigley JW. Comparative efficacy and safety of two 0.025% tretinoin gels: results from a multicenter double-blind, parallel study. J Am Acad Dermatol 1998; 38: S17S23.
  • 71
    Lucky AW, Cullen SI, Funicella T, Jarratt MT, Jones T, Reddick ME. Double-blind, vehicle-controlled, multicenter comparison of two 0.025% tretinoin creams in patients with acne vulgaris. J Am Acad Dermatol 1998; 38: S24S30.
  • 72
    Leyden JJ, Krochmal L, Yaroshinsky A. Two randomized, double-blind, controlled trials of 2219 subjects to compare the combination clindamycin/tretinoin hydrogel with each agent alone and vehicle for the treatment of acne vulgaris. J Am Acad Dermatol 2006; 54: 7381.
  • 73
    Pedace FJ, Stoughton R. Topical retinoic acid in acne vulgaris. Br J Dermatol 1971; 84: 465469.
  • 74
    Nighland M, Grossman R. Tretinoin microsphere gel in facial acne vulgaris: a meta-analysis. J Drugs Dermatol 2008; 7: s2s8.
  • 75
    Webster G, Cargill DI, Quiring J, Vogelson CT, Slade HB. A combined analysis of 2 randomized clinical studies of tretinoin gel 0.05% for the treatment of acne. Cutis 2009; 83: 146154.
  • 76
    Kuhlman DS, Callen JP. A comparison of clindamycin phosphate 1 percent topical lotion and placebo in the treatment of acne vulgaris. Cutis 1986; 38: 203206.
  • 77
    Lucchina LC, Kollias N, Gillies R et al. Fluorescence photography in the evaluation of acne. J Am Acad Dermatol 1996; 35: 5863.
  • 78
    Rizer RL, Sklar JL, Whiting D, Bucko A, Shavin J, Jarratt M. Clindamycin phosphate 1% gel in acne vulgaris. Adv Ther 2001; 18: 244252.
  • 79
    Shalita AR, Myers JA, Krochmal L, Yaroshinsky A. The safety and efficacy of clindamycin phosphate foam 1% versus clindamycin phosphate topical gel 1% for the treatment of acne vulgaris. J Drugs Dermatol 2005; 4: 4856.
  • 80
    Blaney DJ, Cook CH. Topical use of tetracycline in the treatment of acne: a double-blind study comparing topical and oral tetracycline therapy and placebo. Arch Dermatol 1976; 112: 971973.
  • 81
    Smith JG Jr, Chalker DK, Wehr RF. The effectiveness of topical and oral tetracycline for acne. South Med J 1976; 69: 695697.
  • 82
    Mills O Jr, Thornsberry C, Cardin CW, Smiles KA, Leyden JJ. Bacterial resistance and therapeutic outcome following three months of topical acne therapy with 2% erythromycin gel versus its vehicle. Acta Derm Venereol 2002; 82: 260265.
  • 83
    Dobson RL, Belknap BS. Topical erythromycin solution in acne. Results of a multiclinic trial. J Am Acad Dermatol 1980; 3: 478482.
  • 84
    Llorca M, Hernandez-Gill A, Ramos M et al. Erythromycin laurilsulfate in the topical treatment of acne vulgaris. Curr Ther Res 1982; 32: 1420.
  • 85
    Pochi PE, Bagatell FK, Ellis CN et al. Erythromycin 2 percent gel in the treatment of acne vulgaris. Cutis 1988; 41: 132136.
  • 86
    Stinco G, Bragadin G, Trotter D, Pillon B, Patrone P. Relationship between sebostatic activity, tolerability and efficacy of three topical drugs to treat mild to moderate acne. J Eur Acad Dermatol Venereol 2007; 21: 320325.
  • 87
    do Nascimento LV, Guedes AC, Magalhaes GM, de Faria FA, Guerra RM, de C Almeida F. Single-blind and comparative clinical study of the efficacy and safety of benzoyl peroxide 4% gel (BID) and adapalene 0.1% Gel (QD) in the treatment of acne vulgaris for 11 weeks. J Dermatolog Treat 2003; 14: 166171.
  • 88
    Korkut C, Piskin S. Benzoyl peroxide, adapalene, and their combination in the treatment of acne vulgaris. J Dermatol 2005; 32: 169173.
  • 89
    Bucknall JH, Murdoch PN. Comparison of tretinoin solution and benzoyl peroxide lotion in the treatment of acne vulgaris. Curr Med Res Opin 1977; 5: 266268.
  • 90
    Handojo I. The combined use of topical benzoyl peroxide and tretinoin in the treatment of acne vulgaris. Int J Dermatol 1979; 18: 489496.
  • 91
    Lyons RE. Comparative effectiveness of benzoyl peroxide and tretinoin in acne vulgaris. Int J Dermatol 1978; 17: 246251.
  • 92
    Swinyer LJ, Baker MD, Swinyer TA, Mills OH Jr. A comparative study of benzoyl peroxide and clindamycin phosphate for treating acne vulgaris. Br J Dermatol 1988; 119: 615622.
  • 93
    Tucker SB, Tausend R, Cochran R, Flannigan SA. Comparison of topical clindamycin phosphate, benzoyl peroxide, and a combination of the two for the treatment of acne vulgaris. Br J Dermatol 1984; 110: 487492.
  • 94
    Norris JF, Hughes BR, Basey AJ, Cunliffe WJ. A comparison of the effectiveness of topical tetracycline, benzoyl-peroxide gel and oral oxytetracycline in the treatment of acne. Clin Exp Dermatol 1991; 16: 3133.
  • 95
    Gollnick HP, Graupe K, Zaumseil RP. [Azelaic acid 15% gel in the treatment of acne vulgaris. Combined results of two double-blind clinical comparative studies]. J Dtsch Dermatol Ges 2004; 2: 841847.
  • 96
    Rietschel RL, Duncan SH. Clindamycin phosphate used in combination with tretinoin in the treatment of acne. Int J Dermatol 1983; 22: 4143.
  • 97
    Thiboutot D, Gold MH, Jarratt MT et al. Randomized controlled trial of the tolerability, safety, and efficacy of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis 2001; 68: 1019.
  • 98
    Tu P, Li GQ, Zhu XJ, Zheng J, Wong WZ. A comparison of adapalene gel 0.1% vs. tretinoin gel 0.025% in the treatment of acne vulgaris in China. J Eur Acad Dermatol Venereol 2001; 15(Suppl 3): 3136.
  • 99
    Pierard-Franchimont C, Henry F, Fraiture AL, Fumal I, Pierard GE. Split-face clinical and bio-instrumental comparison of 0.1% adapalene and 0.05% tretinoin in facial acne. Dermatology 1999; 198: 218222.
  • 100
    Cunliffe WJ, Danby FW, Dunlap F, Gold MH, Gratton D, Greenspan A. Randomised, controlled trial of the efficacy and safety of adapalene gel 0.1% and tretinoin cream 0.05% in patients with acne vulgaris. Eur J Dermatol 2002; 12: 350354.
  • 101
    Cunliffe WJ, Caputo R, Dreno B et al. Efficacy and safety comparison of adapalene (CD271) gel and tretinoin gel in the topical treatment of acne vulgaris. A European multicentre trial. J Dermatolog Treat 1997; 8: 173178.
  • 102
    Ellis CN, Millikan LE, Smith EB et al. Comparison of adapalene 0.1% solution and tretinoin 0.025% gel in the topical treatment of acne vulgaris. Br J Dermatol 1998; 139(Suppl 52): 4147.
  • 103
    Grosshans E, Marks R, Mascaro JM et al. Evaluation of clinical efficacy and safety of adapalene 0.1% gel versus tretinoin 0.025% gel in the treatment of acne vulgaris, with particular reference to the onset of action and impact on quality of life. Br J Dermatol 1998; 139(Suppl 52): 2633.
  • 104
    Shalita A, Weiss JS, Chalker DK et al. A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial. J Am Acad Dermatol 1996; 34: 482485.
  • 105
    Verschoore M, Langner A, Wolska H, Jablonska S, Czernielewski J, Schaefer H. Efficacy and safety of CD 271 alcoholic gels in the topical treatment of acne vulgaris. Br J Dermatol 1991; 124: 368371.
  • 106
    Nyirady J, Grossman RM, Nighland M et al. A comparative trial of two retinoids commonly used in the treatment of acne vulgaris. J Dermatolog Treat 2001; 12: 149157.
  • 107
    Ioannides D, Rigopoulos D, Katsambas A. Topical adapalene gel 0.1% vs. isotretinoin gel 0.05% in the treatment of acne vulgaris: a randomized open-label clinical trial. Br J Dermatol 2002; 147: 523527.
  • 108
    Dominguez J, Hojyo MT, Celayo JL, Dominguez-Soto L, Teixeira F. Topical isotretinoin vs. topical retinoic acid in the treatment of acne vulgaris. Int J Dermatol 1998; 37: 5455.
  • 109
    Leyden JJ, Hickman JG, Jarratt MT, Stewart DM, Levy SF. The efficacy and safety of a combination benzoyl peroxide/clindamycin topical gel compared with benzoyl peroxide alone and a benzoyl peroxide/erythromycin combination product. J Cutan Med Surg 2001; 5: 3742.
  • 110
    Cunliffe WJ, Holland KT, Bojar R, Levy SF. A randomized, double-blind comparison of a clindamycin phosphate/benzoyl peroxide gel formulation and a matching clindamycin gel with respect to microbiologic activity and clinical efficacy in the topical treatment of acne vulgaris. Clin Ther 2002; 24: 11171133.
  • 111
    Kircik L, Green L, Thiboutot D et al. Comparing a novel solubilized benzoyl peroxide gel with benzoyl peroxide/clindamycin: final data from a multicenter, investigator-blind, randomized study. J Drugs Dermatol 2009; 8: 812818.
  • 112
    Tanghetti E, Kircik L, Wilson D, Dhawan S. Solubilized benzoyl peroxide versus benzoyl peroxide/clindamycin in the treatment of moderate acne. J Drugs Dermatol 2008; 7: 534538.
  • 113
    Zouboulis CC, Fischer TC, Wohlrab J, Barnard J, Alio AB. Study of the efficacy, tolerability, and safety of 2 fixed-dose combination gels in the management of acne vulgaris. Cutis 2009; 84: 223229.
  • 114
    Tan J, Gollnick HP, Loesche C, Ma YM, Gold LS. Synergistic efficacy of adapalene 0.1%-benzoyl peroxide 2.5% in the treatment of 3855 acne vulgaris patients. J Dermatolog Treat 2010; 22: 197205.
  • 115
    Gold LS, Cruz A, Eichenfield L et al. Effective and safe combination therapy for severe acne vulgaris: a randomized, vehicle-controlled, double-blind study of adapalene 0.1%-benzoyl peroxide 2.5% fixed-dose combination gel with doxycycline hyclate 100 mg. Cutis 2010; 85: 94104.
  • 116
    Kellett N, West F, Finlay AY. Conjoint analysis: a novel, rigorous tool for determining patient preferences for topical antibiotic treatment for acne. A randomised controlled trial. Br J Dermatol 2006; 154: 524532.
  • 117
    Henderson TA, Olson WH, Leach AD. A single-blind, randomized comparison of erythromycin pledgets and clindamycin lotion in the treatment of mild to moderate facial acne vulgaris. Adv Ther 1995; 12: 172177.
  • 118
    Thielitz A, Helmdach M, Röpke EM, Gollnick H. Lipid analysis of follicular casts from cyanoacrylate strips as a new method for studying therapeutic effects of antiacne agents. Br J Dermatol 2001; 145: 1927.
  • 119
    Thielitz A, Sidou F, Gollnick H. Control of microcomedone formation throughout a maintenance treatment with adapalene gel, 0.1%. J Eur Acad Dermatol Venereol 2007; 21: 747753.
  • 120
    Bernstein JE, Shalita AR. Topically applied erythromycin in inflammatory acne vulgaris. J Am Acad Dermatol 1980; 2: 318321.
  • 121
    Hellgren L, Vincent J. Topical erythromycin for acne vulgaris. Dermatologica 1980; 161: 409414.
  • 122
    Jones EL, Crumley AF. Topical erythromycin vs blank vehicle in a multiclinic acne study. Arch Dermatol 1981; 117: 551553.
  • 123
    Lesher JL Jr, Chalker DK, Smith JG Jr et al. An evaluation of a 2% erythromycin ointment in the topical therapy of acne vulgaris. J Am Acad Dermatol 1985; 12: 526531.
  • 124
    Prince RA, Busch DA, Hepler CD, Feldick HG. Clinical trial of topical erythromycin in inflammatory acne. Drug Intell Clin Pharm 1981; 15: 372376.
  • 125
    Rivkin L, Rapaport M. Clinical evaluation of a new erythromycin solution for acne vulgaris. Cutis 1980; 25: 552555.
  • 126
    Alirezai M, Gerlach B, Horvath A, Forsea D, Briantais P, Guyomar M. Results of a randomised, multicentre study comparing a new water-based gel of clindamycin 1% versus clindamycin 1% topical solution in the treatment of acne vulgaris. Eur J Dermatol 2005; 15: 274278.
  • 127
    Braathen LR. Topical clindamycin versus oral tetracycline and placebo in acne vulgaris. Scand J Infect Dis Suppl 1984; 43: 7175.
  • 128
    Gratton D, Raymond GP, Guertin-Larochelle S et al. Topical clindamycin versus systemic tetracycline in the treatment of acne. Results of a multiclinic trial. J Am Acad Dermatol 1982; 7: 5053.
  • 129
    Becker LE, Bergstresser PR, Whiting DA et al. Topical clindamycin therapy for acne vulgaris. A cooperative clinical study. Arch Dermatol 1981; 117: 482485.
  • 130
    Ellis CN, Gammon WR, Stone DZ, Heezen-Wehner JL. A comparison of Cleocin T Solution, Cleocin T Gel, and placebo in the treatment of acne vulgaris. Cutis 1988; 42: 245247.
  • 131
    McKenzie MW, Beck DC, Popovich NG. Topical clindamycin formulations for the treatment of acne vulgaris. An evaluation. Arch Dermatol 1981; 117: 630634.
  • 132
    Petersen MJ, Krusinski PA, Krueger GG. Evaluation of 1% clindamycin phosphate lotion in the treatment of acne. Curr Ther Res 1986; 40: 232238.
  • 133
    Leyden JJ, Wortzman M. A novel gel formulation of clindamycin phosphate-tretinoin is not associated with acne flaring. Cutis 2008; 82: 151156.
  • 134
    Anderson RL, Cook CH, Smith DE. The effect of oral and topical tetracycline on acne severity and on surface lipid composition. J Invest Dermatol 1976; 66: 172177.
  • 135
    Kurokawa I, Akamatsu H, Nishijima S, Asada Y, Kawabata S. Clinical and bacteriologic evaluation of OPC-7251 in patients with acne: a double-blind group comparison study versus cream base. J Am Acad Dermatol 1991; 25: 674681.
  • 136
    Ellis CN, Leyden J, Katz HI et al. Therapeutic studies with a new combination benzoyl peroxide/clindamycin topical gel in acne vulgaris. Cutis 2001; 67: 1320.
  • 137
    Ede M. A double-blind, comparative study of benzoyl peroxide, benzoyl peroxide-chlorhydroxyquinoline, benzoyl peroxide-chlorhydroxyquinoline-hydrocortisone, and placebo lotions in acne. Curr Ther Res Clin Exp 1973; 15: 624629.
  • 138
    Jaffe GV, Grimshaw JJ, Constad D. Benzoyl peroxide in the treatment of acne vulgaris: a double-blind, multi-centre comparative study of ‘Quinoderm’ cream and ‘Quinoderm’ cream with hydrocortisone versus their base vehicle alone and a benzoyl peroxide only gel preparation. Curr Med Res Opin 1989; 11: 453462.
  • 139
    Mills OH Jr, Kligman AM, Pochi P, Comite H. Comparing 2.5%, 5%, and 10% benzoyl peroxide on inflammatory acne vulgaris. Int J Dermatol 1986; 25: 664667.
  • 140
    Smith EB, Padilla RS, McCabe JM, Becker LE. Benzoyl peroxide lotion (20 percent) in acne. Cutis 1980; 25: 9092.
  • 141
    Langner A, Boorman GC, Stapor V. Isotretinoin cream 0.05% and 0.1% in the treatment of acne vulgaris. J Dermatol Treat 1994; 5: 177180.
  • 142
    Webster GF. Safety and efficacy of Tretin-X compared with Retin-A in patients with mild-to-severe acne vulgaris. Skinmed 2006; 5: 114118.
  • 143
    Mills OH Jr, Kligman AM. Treatment of acne vulgaris with topically applied erythromycin and tretinoin. Acta Derm Venereol 1978; 58: 555557.
  • 144
    Cavicchini S, Caputo R. Long-term treatment of acne with 20% azelaic acid cream. Acta Derm Venereol Suppl (Stockh) 1989; 143: 4044.
  • 145
    Handojo I. Retinoic acid cream (Airol cream) and benzoyl-peroxide in the treatment of acne vulgaris. Southeast Asian J Trop Med Public Health 1979; 10: 548551.
  • 146
    Zhu XJ, Tu P, Zhen J, Duan YQ. Adapalene gel 0.1%: effective and well tolerated in the topical treatment of acne vulgaris in Chinese patients. Cutis 2001; 68: 5559.
  • 147
    Leyden JJ, Berger RS, Dunlap FE, Ellis CN, Connolly MA, Levy SF. Comparison of the efficacy and safety of a combination topical gel formulation of benzoyl peroxide and clindamycin with benzoyl peroxide, clindamycin and vehicle gel in the treatments of acne vulgaris. Am J Clin Dermatol 2001; 2: 3339.
  • 148
    Bojar RA, Eady EA, Jones CE, Cunliffe WJ, Holland KT. Inhibition of erythromycin-resistant propionibacteria on the skin of acne patients by topical erythromycin with and without zinc. Br J Dermatol 1994; 130: 329336.
  • 149
    Habbema L, Koopmans B, Menke HE, Doornweerd S, De Boulle K. A 4% erythromycin and zinc combination (Zineryt) versus 2% erythromycin (Eryderm) in acne vulgaris: a randomized, double-blind comparative study. Br J Dermatol 1989; 121: 497502.
  • 150
    Stoughton RB, Cornell RC, Gange RW, Walter JF. Double-blind comparison of topical 1 percent clindamycin phosphate (Cleocin T) and oral tetracycline 500 mg/day in the treatment of acne vulgaris. Cutis 1980; 26: 424425, 429.
  • 151
    Rapaport M, Puhvel SM, Reisner RM. Evaluation of topical erythromycin and oral tetracycline in acne vulgaris. Cutis 1982; 30: 122126, 130, 132–125.
  • 152
    Sheehan-Dare RA, Papworth-Smith J, Cunliffe WJ. A double-blind comparison of topical clindamycin and oral minocycline in the treatment of acne vulgaris. Acta Derm Venereol 1990; 70: 534537.
  • 153
    Katsambas A, Towarky AA, Stratigos J. Topical clindamycin phosphate compared with oral tetracycline in the treatment of acne vulgaris. Br J Dermatol 1987; 116: 387391.
  • 154
    Borglund E, Hagermark O, Nord CE. Impact of topical clindamycin and systemic tetracycline on the skin and colon microflora in patients with acne vulgaris. Scand J Infect Dis Suppl 1984; 43: 7681.
  • 155
    Hjorth N, Graupe K. Azelaic acid for the treatment of acne. A clinical comparison with oral tetracycline. Acta Derm Venereol Suppl (Stockh) 1989; 143: 4548.
  • 156
    Drake LA. Comparative efficacy and tolerance of Cleocin T topical gel (clindamycin phosphate topical gel) versus oral minocycline in the treatment of acne vulgaris. unpublished. 1980.
  • 157
    Peacock CE, Price C, Ryan BE, Mitchell AD. Topical clindamycin (Dalacin T(TM)) compared to oral minocycline (Minocin 50(TM)) in treatment of acne vulgaris. A randomized observer-blind controlled trial in three university student health centres. Clin Trials J 1990; 27: 219228.
  • 158
    Ozolins M, Eady EA, Avery A et al. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne. Health Technol Assess 2005; 9: iii212.
  • 159
    Ozolins M, Eady EA, Avery AJ et al. Comparison of five antimicrobial regimens for treatment of mild to moderate inflammatory facial acne vulgaris in the community: randomised controlled trial. Lancet 2004; 364: 21882195.
  • 160
    Bladon PT, Burke BM, Cunliffe WJ, Forster RA, Holland KT, King K. Topical azelaic acid and the treatment of acne: a clinical and laboratory comparison with oral tetracycline. Br J Dermatol 1986; 114: 493499.
  • 161
    Mareledwane NG. A randomized, open-label, comparative study of oral doxycycline 100 mg vs. 5% topical benzoyl peroxide in the treatment of mild to moderate acne vulgaris. Int J Dermatol 2006; 45: 14381439.
  • 162
    Thiboutot DM, Shalita AR, Yamauchi PS, Dawson C, Arsonnaud S, Kang S. Combination therapy with adapalene gel 0.1% and doxycycline for severe acne vulgaris: a multicenter, investigator-blind, randomized, controlled study. Skinmed 2005; 4: 138146.
  • 163
    Cunliffe WJ, Meynadier J, Alirezai M et al. Is combined oral and topical therapy better than oral therapy alone in patients with moderate to moderately severe acne vulgaris? A comparison of the efficacy and safety of lymecycline plus adapalene gel 0.1%, versus lymecycline plus gel vehicle. J Am Acad Dermatol 2003; 49: S218S226.
  • 164
    Gollnick HP, Graupe K, Zaumseil RP. Comparison of combined azelaic acid cream plus oral minocycline with oral isotretinoin in severe acne. Eur J Dermatol 2001; 11: 538544.
  • 165
    Oprica C, Emtestam L, Hagstromer L, Nord CE. Clinical and microbiological comparisons of isotretinoin vs. tetracycline in acne vulgaris. Acta Derm Venereol 2007; 87: 246254.
  • 166
    Dreno B, Moyse D, Alirezai M et al. Multicenter randomized comparative double-blind controlled clinical trial of the safety and efficacy of zinc gluconate versus minocycline hydrochloride in the treatment of inflammatory acne vulgaris. Dermatology 2001; 203: 135140.
  • 167
    Cunliffe WJ, Burke B, Dodman B, Gould DJ. A double-blind trial of a zinc sulphate/citrate complex and tetracycline in the treatment of acne vulgaris. Br J Dermatol 1979; 101: 321325.
  • 168
    Carlborg L. Cyproterone acetate versus levonorgestrel combined with ethinyl estradiol in the treatment of acne. Results of a multicenter study. Acta Obstet Gynecol Scand Suppl 1986; 134: 2932.
  • 169
    Lachnit-Fixson U, Kaufmann J. [Therapy of androgenization symptoms: double blind study of an antiandrogen preparation (SH B 209 AB) against neogynon (author’s transl)]. Med Klin 1977; 72: 19221926.
  • 170
    Wishart JM. An open study of Triphasil and Diane 50 in the treatment of acne. Australas J Dermatol 1991; 32: 5154.
  • 171
    Vartiainen M, de Gezelle H, Broekmeulen CJ. Comparison of the effect on acne with a combiphasic desogestrel-containing oral contraceptive and a preparation containing cyproterone acetate. Eur J Contracept Reprod Health Care 2001; 6: 4653.
  • 172
    Charoenvisal C, Thaipisuttikul Y, Pinjaroen S et al. Effects on acne of two oral contraceptives containing desogestrel and cyproterone acetate. Int J Fertil Menopausal Stud 1996; 41: 423429.
  • 173
    Dieben TO, Vromans L, Theeuwes A, Bennink HJ. The effects of CTR-24, a biphasic oral contraceptive combination, compared to Diane-35 in women with acne. Contraception 1994; 50: 373382.
  • 174
    Erkkola R, Hirvonen E, Luikku J, Lumme R, Mannikko H, Aydinlik S. Ovulation inhibitors containing cyproterone acetate or desogestrel in the treatment of hyperandrogenic symptoms. Acta Obstet Gynecol Scand 1990; 69: 6165.
  • 175
    Worret I, Arp W, Zahradnik HP, Andreas JO, Binder N. Acne resolution rates: results of a single-blind, randomized, controlled, parallel phase III trial with EE/CMA (Belara) and EE/LNG (Microgynon). Dermatology 2001; 203: 3844.
  • 176
    Thorneycroft H, Gollnick H, Schellschmidt I. Superiority of a combined contraceptive containing drospirenone to a triphasic preparation containing norgestimate in acne treatment. Cutis 2004; 74: 123130.
  • 177
    Winkler UH, Ferguson H, Mulders JA. Cycle control, quality of life and acne with two low-dose oral contraceptives containing 20 microg ethinylestradiol. Contraception 2004; 69: 469476.
  • 178
    Rosen MP, Breitkopf DM, Nagamani M. A randomized controlled trial of second- versus third-generation oral contraceptives in the treatment of acne vulgaris. Am J Obstet Gynecol 2003; 188: 11581160.
  • 179
    Palatsi R, Hirvensalo E, Liukko P et al. Serum total and unbound testosterone and sex hormone binding globulin (SHBG) in female acne patients treated with two different oral contraceptives. Acta Derm Venereol 1984; 64: 517523.
  • 180
    Monk BE, Almeyda JA, Caldwell IW et al. Efficacy of low-dose cyproterone acetate compared with minocycline in the treatment of acne vulgaris. Clin Exp Dermatol 1987; 12: 319322.
  • 181
    Greenwood R, Brummitt L, Burke B, Cunliffe WJ. Acne: double blind clinical and laboratory trial of tetracycline, oestrogen-cyproterone acetate, and combined treatment. Br Med J (Clin Res Ed) 1985; 291: 12311235.
  • 182
    Papageorgiou P, Katsambas A, Chu A. Phototherapy with blue (415 nm) and red (660 nm) light in the treatment of acne vulgaris. Br J Dermatol 2000; 142: 973978.
  • 183
    Tzung TY, Wu KH, Huang ML. Blue light phototherapy in the treatment of acne. Photodermatol Photoimmunol Photomed 2004; 20: 266269.
  • 184
    Feucht CL, Allen BS, Chalker DK, Smith JG Jr. Topical erythromycin with zinc in acne. A double-blind controlled study. J Am Acad Dermatol 1980; 3: 483491.
  • 185
    Stainforth J, Macdonald-Hull S, Papworth-Smith JW et al. A single-blind comparison of topical erythromycin/zinc lotion and oral minocycline in the treatment of acne vulgaris. J Dermatolog Treat 1993; 4: 119122.
  • 186
    Smith K, Leyden JJ. Safety of doxycycline and minocycline: a systematic review. Clin Ther 2005; 27: 13291342.
  • 187
    Garner SE, Eady EA, Popescu C, Newton J, Li WA. Minocycline for acne vulgaris: efficacy and safety. Cochrane Database Syst Rev(Online). 2003; 1: CD002086.
  • 188
    Dunlap FE, Mills OH, Tuley MR, Baker MD, Plott RT. Adapalene 0.1% gel for the treatment of acne vulgaris: its superiority compared to tretinoin 0.025% cream in skin tolerance and patient preference. Br J Dermatol 1998; 139(Suppl 52): 1722.
  • 189
    Egan N, Loesche MC, Baker MM. Randomized, controlled, bilateral (split-face) comparison trial of the tolerability and patient preference of adapalene gel 0.1% and tretinoin microsphere gel 0.1% for the treatment of acne vulgaris. Cutis 2001; 68: 2024.
  • 190
    Peck GL, Olsen TG, Butkus D et al. Isotretinoin versus placebo in the treatment of cystic acne. A randomized double-blind study. J Am Acad Dermatol 1982; 6: 735745.
  • 191
    Strauss JS, Leyden JJ, Lucky AW et al. A randomized trial of the efficacy of a new micronized formulation versus a standard formulation of isotretinoin in patients with severe recalcitrant nodular acne. J Am Acad Dermatol 2001; 45: 187195.
  • 192
    Strauss JS, Rapini RP, Shalita AR et al. Isotretinoin therapy for acne: results of a multicenter dose-response study. J Am Acad Dermatol 1984; 10: 490496.
  • 193
    Jones DH, King K, Miller AJ, Cunliffe WJ. A dose-response study of I3-cis-retinoic acid in acne vulgaris. Br J Dermatol 1983; 108: 333343.
  • 194
    King K, Jones DH, Daltrey DC, Cunliffe WJ. A double-blind study of the effects of 13-cis-retinoic acid on acne, sebum excretion rate and microbial population. Br J Dermatol 1982; 107: 583590.
  • 195
    van der Meeren HL, van der Schroeff JG, Stijnen T, van Duren JA, van der Dries HA, van Voorst Vader PC. Dose-response relationship in isotretinoin therapy for conglobate acne. Dermatologica 1983; 167: 299303.
  • 196
    Al Mishari MA. A study of isotretinoin (Roaccutan) in nodulocystic acne. Clin Trials J 1986; 23: 15.
  • 197
    Mandekou-Lefaki I, Delli F, Teknetzis A, Euthimiadou R, Karakatsanis G. Low-dose schema of isotretinoin in acne vulgaris. Int J Clin Pharmacol Res 2003; 23: 4146.
  • 198
    Plewig G, Gollnick H, Meigel W, Wokalek H. [13-cis retinoic acid in the oral therapy of acne conglobata. Results of a multi-center study]. Hautarzt 1981; 32: 634646.
  • 199
    Pigatto PD, Finzi AF, Altomare GF, Polenghi MM, Vergani C, Vigotti G. Isotretinoin versus minocycline in cystic acne: a study of lipid metabolism. Dermatologica 1986; 172: 154159.
  • 200
    Lester RS, Schachter GD, Light MJ. Isotretinoin and tetracycline in the management of severe nodulocystic acne. Int J Dermatol 1985; 24: 252257.
  • 201
    Dhir R, Gehi NP, Agarwal R, More YE. Oral isotretinoin is as effective as a combination of oral isotretinoin and topical anti-acne agents in nodulocystic acne. Indian J Dermatol Venereol Leprol 2008; 74: 187.
  • 202
    Simonart T, Dramaix M, De Maertelaer V. Efficacy of tetracyclines in the treatment of acne vulgaris: a review. Br J Dermatol 2008; 158: 208216.
  • 203
    Panzer JD, Poche W, Meek TJ, Derbes VJ, Atkinson W. Acne treatment: a comparative efficacy trial of clindamycin and tetracycline. Cutis 1977; 19: 109111.
  • 204
    Poulos ET, Tedesco FJ. Acne vulgaris: double-blind trial comparing tetracycline and clindamycin. Arch Dermatol 1976; 112: 974976.
  • 205
    Al-Mishari MA. Clinical and bacteriological evaluation of tetracycline and erythromycin in acne vulgaris. Clin Ther 1987; 9: 273280.
  • 206
    Brandt H, Attila P, Ahokas T et al. Erythromycin acistrate – an alternative oral treatment for acne. J Dermatolog Treat 1994; 5: 35.
  • 207
    Gammon WR, Meyer C, Lantis S, Shenefelt P, Reizner G, Cripps DJ. Comparative efficacy of oral erythromycin versus oral tetracycline in the treatment of acne vulgaris. A double-blind study. J Am Acad Dermatol 1986; 14: 183186.
  • 208
    Association Mieux prescrire (Editeur scientifique). Moins d’effets indésirables avec la doxycycline qu’avec la minocycline. Rev Prescrire 2009; 29: 354.
  • 209
    Ochsendorf F. Minocycline in acne vulgaris: benefits and risks. Am J Clin Dermatol 2010; 11: 327341.
  • 210
    Layton AM, Cunliffe WJ. Phototoxic eruptions due to doxycycline – a dose-related phenomenon. Clin Exp Dermatol 1993; 18: 425427.
  • 211
    Lim DS, Murphy GM. High-level ultraviolet A photoprotection is needed to prevent doxycycline phototoxicity: lessons learned in East Timor. Br J Dermatol 2003; 149: 213214.
  • 212
    Bjellerup M, Ljunggren B. Differences in phototoxic potency should be considered when tetracyclines are prescribed during summer-time. A study on doxycycline and lymecycline in human volunteers, using an objective method for recording erythema. Br J Dermatol 1994; 130: 356360.
  • 213
    European Directive for systemic isotretinoin prescription. EMEA – Committee for Proprietary Medicinal Products (CPMP). [WWW document]. URL http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Isotretinoin_29/WC500010882.pdf (last accessed: 6 January 2012), 2003.
  • 214
    Ganceviciene R, Zouboulis CC. Isotretinoin: state of the art treatment for acne vulgaris. J Dtsch Dermatol Ges 2010; 8(Suppl 1): S47S59.
  • 215
    Layton AM, Cunliffe WJ. Guidelines for optimal use of isotretinoin in acne. J Am Acad Dermatol 1992; 27: S2S7.
  • 216
    Strauss JS, Krowchuk DP, Leyden JJ et al. Guidelines of care for acne vulgaris management. J Am Acad Dermatol 2007; 56: 651663.
  • 217
    Cunliffe WJ, van de Kerkhof PC, Caputo R et al. Roaccutane treatment guidelines: results of an international survey. Dermatology 1997; 194: 351357.
  • 218
    Layton AM. Optimal management of acne to prevent scarring and psychological sequelae. Am J Clin Dermatol 2001; 2: 135141.
  • 219
    Rubinow DR, Peck GL, Squillace KM, Gantt GG. Reduced anxiety and depression in cystic acne patients after successful treatment with oral isotretinoin. J Am Acad Dermatol 1987; 17: 2532.
  • 220
    Layton AM, Dreno B, Gollnick HPM, Zouboulis CC. A review of the European Directive for prescribing systemic isotretinoin for acne vulgaris. J Eur Acad Dermatol Venereol 2006; 20: 773776.
  • 221
    Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with isotretinoin: a systematic review. Semin Cutan Med Surg 2007; 26: 210220.
  • 222
    Ross JI, Snelling AM, Eady EA et al. Phenotypic and genotypic characterization of antibiotic-resistant Propionibacterium acnes isolated from acne patients attending dermatology clinics in Europe, the U.S.A., Japan and Australia. Br J Dermatol 2001; 144: 339346.
  • 223
    Ross JI, Snelling AM, Carnegie E et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol 2003; 148: 467478.
  • 224
    Eady EA, Cove JH. Topical antibiotic therapy: current status and future prospects. Drugs Exp Clin Res 1990; 16: 423433.
  • 225
    Oprica C, Nord CE, Bacteria ESGoARiA. European surveillance study on the antibiotic susceptibility of Propionibacterium acnes. Clin Microbiol Infect 2005; 11: 204213.
  • 226
    Nord CE, Oprica C. Antibiotic resistance in Propionibacterium acnes. Microbiological and clinical aspects. Anaerobe 2006; 12: 207210.
  • 227
    Eady EA. Bacterial resistance in acne. Dermatology 1998; 196: 5966.
  • 228
    Levy RM, Huang EY, Roling D, Leyden JJ, Margolis DJ. Effect of antibiotics on the oropharyngeal flora in patients with acne. Arch Dermatol 2003; 139: 467471.
  • 229
    Eady EA, Cove JH, Holland KT, Cunliffe WJ. Erythromycin resistant propionibacteria in antibiotic treated acne patients: association with therapeutic failure. Br J Dermatol 1989; 121: 5157.
  • 230
    Simonart T, Dramaix M. Treatment of acne with topical antibiotics: lessons from clinical studies. Br J Dermatol 2005; 153: 395403.
  • 231
    Cunliffe WJ, Forster RA, Greenwood ND et al. Tetracycline and acne vulgaris: a clinical and laboratory investigation. Br Med J 1973; 4: 332335.
  • 232
    Bettoli V, Mantovani L, Borghi A. Adapalene 0.1% Cream after Oral Isotretinoin: Evaluation of the Acne Recurrence Incidence. 15th Annual EADV Congress. Rhodes. Medimond International Proceedings, Bologna, Italy, 2006.
  • 233
    Thiboutot DM, Shalita AR, Yamauchi PS et al. Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a randomized, controlled, investigator-blind follow-up of a recent combination study. Arch Dermatol 2006; 142: 597602.
  • 234
    Zhang JZ, Li LF, Tu YT, Zheng J. A successful maintenance approach in inflammatory acne with adapalene gel 0.1% after an initial treatment in combination with clindamycin topical solution 1% or after monotherapy with clindamycin topical solution 1%. J Dermatolog Treat 2004; 15: 372378.
  • 235
    Alirezai M, George SA, Coutts I et al. Daily treatment with adapalene gel 0.1% maintains initial improvement of acne vulgaris previously treated with oral lymecycline. Eur J Dermatol 2007; 17: 4551.
  • 236
    Graupe K, Cunliffe WJ, Gollnick HP, Zaumseil RP. Efficacy and safety of topical azelaic acid (20 percent cream): an overview of results from European clinical trials and experimental reports. Cutis 1996; 57: 2035.
  • 237
    Goltz RW, Coryell GM, Schnieders JR, Neidert GL. A comparison of Cleocin T 1 percent solution and Cleocin T 1 percent lotion in the treatment of acne vulgaris. Cutis 1985; 36: 265268.
  • 238
    Parker F. A comparison of clindamycin 1% solution versus clindamycin 1% gel in the treatment of acne vulgaris. Int J Dermatol 1987; 26: 121122.
  • 239
    Leyden JJ, Shalita AR, Saatjian GD, Sefton J. Erythromycin 2% gel in comparison with clindamycin phosphate 1% solution in acne vulgaris. J Am Acad Dermatol 1987; 16: 822827.
  • 240
    Mills OH, Berger RS, Kligman AM, McElroy JA, Di Matteo J. A comparative study of Erycette(TM) vs Cleocin-T(TM). Adv Ther 1992; 9: 1420.
  • 241
    Thomas DR, Raimer S, Smith EB. Comparison of topical erythromycin 1.5 percent solution versus topical clindamycin phosphate 1.0 percent solution in the treatment of acne vulgaris. Cutis 1982; 29: 624625, 628–632.
  • 242
    Shahlita AR, Smith EB, Bauer E. Topical erythromycin v clindamycin therapy for acne. A multicenter, double-blind comparison. Arch Dermatol 1984; 120: 351355.
  • 243
    Plewig G, Holland KT, Nenoff P. Clinical and bacteriological evaluation of nadifloxacin 1% cream in patients with acne vulgaris: a double-blind, phase III comparison study versus erythromycin 2% cream. Eur J Dermatol 2006; 16: 4855.
  • 244
    Patel VB, Misra AN, Marfatia YS. Preparation and comparative clinical evaluation of liposomal gel of benzoyl peroxide for acne. Drug Dev Ind Pharm 2001; 27: 863869.
  • 245
    Cunliffe WJ, Holland KT. The effect of benzoyl peroxide on acne. Acta Derm Venereol 1981; 61: 267269.
  • 246
    Fyrand O, Jakobsen HB. Water-based versus alcohol-based benzoyl peroxide preparations in the treatment of acne vulgaris. Dermatologica 1986; 172: 263267.
  • 247
    Patel VB, Misra A, Marfatia YS. Topical liposomal gel of tretinoin for the treatment of acne: research and clinical implications. Pharm Dev Technol 2000; 5: 455464.
  • 248
    Schafer-Korting M, Korting HC, Ponce-Poschl E. Liposomal tretinoin for uncomplicated acne vulgaris. Clin Investig 1994; 72: 10861091.
  • 249
    Berger R, Rizer R, Barba A et al. Tretinoin gel microspheres 0.04% versus 0.1% in adolescents and adults with mild to moderate acne vulgaris: a 12-week, multicenter, randomized, double-blind, parallel-group, phase IV trial. Clin Ther 2007; 29: 10861097.
  • 250
    Thiboutot D, Jarratt M, Rich P, Rist T, Rodriguez D, Levy S. A randomized, parallel, vehicle-controlled comparison of two erythromycin/benzoyl peroxide preparations for acne vulgaris. Clin Ther 2002; 24: 773785.
  • 251
    Schachner L, Eaglstein W, Kittles C, Mertz P. Topical erythromycin and zinc therapy for acne. J Am Acad Dermatol 1990; 22: 253260.
  • 252
    Dhawan SS. Comparison of 2 clindamycin 1%-benzoyl peroxide 5% topical gels used once daily in the management of acne vulgaris. Cutis 2009; 83: 265272.
  • 253
    Kircik L. Community-based trial results of combination clindamycin 1%--benzoyl peroxide 5% topical gel plus tretinoin microsphere gel 0.04% or 0.1% or adapalene gel 0.1% in the treatment of moderate to severe acne. Cutis 2007; 80: 1014.
  • 254
    Kircik LH. Comparative efficacy and safety results of two topical combination acne regimens. J Drugs Dermatol 2009; 8: 624630.
  • 255
    Cunliffe WJ, Fernandez C, Bojar R, Kanis R, West F. An observer-blind parallel-group, randomized, multicentre clinical and microbiological study of a topical clindamycin/zinc gel and a topical clindamycin lotion in patients with mild/moderate acne. J Dermatolog Treat 2005; 16: 213218.
  • 256
    Del Rosso J. Study results of benzoyl peroxide 5%/clindamycin. J Drugs Dermatol 2007; 6: 616622.
  • 257
    Shalita AR, Rafal ES, Anderson DN, Yavel R, Landow S, Lee WL. Compared efficacy and safety of tretinoin 0.1% microsphere gel alone and in combination with benzoyl peroxide 6% cleanser for the treatment of acne vulgaris. Cutis 2003; 72: 167172.
  • 258
    Wolf JE Jr, Kaplan D, Kraus SJ et al. Efficacy and tolerability of combined topical treatment of acne vulgaris with adapalene and clindamycin: a multicenter, randomized, investigator-blinded study. J Am Acad Dermatol 2003; 49: S211S217.
  • 259
    NilFroushzadeh MA, Siadat AH, Baradaran EH, Moradi S. Clindamycin lotion alone versus combination lotion of clindamycin phosphate plus tretinoin versus combination lotion of clindamycin phosphate plus salicylic acid in the topical treatment of mild to moderate acne vulgaris: a randomized control trial. Indian J Dermatol Venereol Leprol 2009; 75: 279282.
  • 260
    Cambazard F. Clinical efficacy of Velac, a new tretinoin and clindamycin phosphate gel in acne vulgaris. J Eur Acad Dermatol Venereol 1998; 11(Suppl 1): S20S27; discussion S28-29.
  • 261
    Zouboulis CC, Derumeaux L, Decroix J, Maciejewska-Udziela B, Cambazard F, Stuhlert A. A multicentre, single-blind, randomized comparison of a fixed clindamycin phosphate/tretinoin gel formulation (Velac) applied once daily and a clindamycin lotion formulation (Dalacin T) applied twice daily in the topical treatment of acne vulgaris. Br J Dermatol 2000; 143: 498505.
  • 262
    Richter JR, Forstrom LR, Kiistala UO, Jung EG. Efficacy of the fixed 1.2% clindamycin phosphate, 0.025% tretinoin gel formulation (Velac) and a proprietary 0.025% tretinoin gel formulation (Aberela) in the topical control of facial acne. J Eur Acad Dermatol Venereol 1998; 11: 227233.
  • 263
    Ko HC, Song M, Seo SH, Oh CK, Kwon KS, Kim MB. Prospective, open-label, comparative study of clindamycin 1%/benzoyl peroxide 5% gel with adapalene 0.1% gel in Asian acne patients: efficacy and tolerability. J Eur Acad Dermatol Venereol 2009; 23: 245250.
  • 264
    Langner A, Chu A, Goulden V, Ambroziak M. A randomized, single-blind comparison of topical clindamycin + benzoyl peroxide and adapalene in the treatment of mild to moderate facial acne vulgaris. Br J Dermatol 2008; 158: 122129.
  • 265
    Gupta AK, Lynde CW, Kunynetz RA, Amin S, Choi K, Goldstein E. A randomized, double-blind, multicenter, parallel group study to compare relative efficacies of the topical gels 3% erythromycin/5% benzoyl peroxide and 0.025% tretinoin/erythromycin 4% in the treatment of moderate acne vulgaris of the face. J Cutan Med Surg 2003; 7: 3137.
  • 266
    Marazzi P, Boorman GC, Donald AE, Davies HD. Clinical evaluation of double strength isotrexin versus benzamycin in the topical treatment of mild to moderate acne vulgaris. J Dermatolog Treat 2002; 13: 111117.
  • 267
    Chu A, Huber FJ, Plott RT. The comparative efficacy of benzoyl peroxide 5%/erythromycin 3% gel and erythromycin 4%/zinc 1.2% solution in the treatment of acne vulgaris. Br J Dermatol 1997; 136: 235238.
  • 268
    Packman AM, Brown RH, Dunlap FE, Kraus SJ, Webster GF. Treatment of acne vulgaris: combination of 3% erythromycin and 5% benzoyl peroxide in a gel compared to clindamycin phosphate lotion. Int J Dermatol 1996; 35: 209211.
  • 269
    Schachner L, Pestana A, Kittles C. A clinical trial comparing the safety and efficacy of a topical erythromycin-zinc formulation with a topical clindamycin formulation. J Am Acad Dermatol 1990; 22: 489495.
  • 270
    Bowman S, Gold M, Nasir A, Vamvakias G. Comparison of clindamycin/benzoyl peroxide, tretinoin plus clindamycin, and the combination of clindamycin/benzoyl peroxide and tretinoin plus clindamycin in the treatment of acne vulgaris: a randomized, blinded study. J Drugs Dermatol 2005; 4: 611618.
  • 271
    Langner A, Sheehan-Dare R, Layton A. A randomized, single-blind comparison of topical clindamycin + benzoyl peroxide (Duac) and erythromycin + zinc acetate (Zineryt) in the treatment of mild to moderate facial acne vulgaris. J Eur Acad Dermatol Venereol 2007; 21: 311319.
  • 272
    Christian GL, Krueger GG. Clindamycin vs placebo as adjunctive therapy in moderately severe acne. Arch Dermatol 1975; 111: 9971000.
  • 273
    Plewig G, Petrozzi JW, Berendes U. Double-blind study of doxycycline in acne vulgaris. Arch Dermatol 1970; 101: 435438.
  • 274
    Fleischer AB Jr, Dinehart S, Stough D, Plott RT. Safety and efficacy of a new extended-release formulation of minocycline. Cutis 2006; 78: 2131.
  • 275
    Olafsson JH, Gudgeirsson J, Eggertsdottir GE, Kristjansson F. Doxycycline versus minocycline in the treatment of acne vulgaris: a double-blind study. J Dermatolog Treat 1989; 1: 1517.
  • 276
    Cunliffe WJ, Grosshans E, Belaich S, Meynadier J, Alirezai M, Thomas L. A comparison of the efficacy and safety of lymecycline and minocycline in patients with moderately severe acne vulgaris. Eur J Dermatol 1998; 8: 161166.
  • 277
    Bossuyt L, Bosschaert J, Richert B et al. Lymecycline in the treatment of acne: an efficacious, safe and cost-effective alternative to minocycline. Eur J Dermatol 2003; 13: 130135.
  • 278
    Cullen SI, Cohan RH. Minocycline therapy in acne vulgaris. Cutis 1976; 17: 12081210, 1214.
  • 279
    Ruping KW, Tronnier H. Acne therapy: Results of a multicentre study with minocyline. R Soc Med Serv Int Cong Symp Ser 1985; 95: 109119.
  • 280
    Dreno B, Amblard P, Agache P, Sirot S, Litoux P. Low doses of zinc gluconate for inflammatory acne. Acta Derm Venereol 1989; 69: 541543.
  • 281
    Orris L, Shalita AR, Sibulkin D, London SJ, Gans EH. Oral zinc therapy of acne. Absorption and clinical effect. Arch Dermatol 1978; 114: 10181020.
  • 282
    Weimar VM, Puhl SC, Smith WH, tenBroeke JE. Zinc sulfate in acne vulgaris. Arch Dermatol 1978; 114: 17761778.
  • 283
    Vena GA. Comparison of two different dosing regimens with lymecycline, in association with adapalene, in inflammatory acne. Eur J Inflamm 2005; 3: 8995.
  • 284
    Leyden J, Shalita A, Hordinsky M, Swinyer L, Stanczyk FZ, Weber ME. Efficacy of a low-dose oral contraceptive containing 20 microg of ethinyl estradiol and 100 microg of levonorgestrel for the treatment of moderate acne: a randomized, placebo-controlled trial. J Am Acad Dermatol 2002; 47: 399409.
  • 285
    Thiboutot D, Archer DF, Lemay A, Washenik K, Roberts J, Harrison DD. A randomized, controlled trial of a low-dose contraceptive containing 20 microg of ethinyl estradiol and 100 microg of levonorgestrel for acne treatment. Fertil Steril 2001; 76: 461468.
  • 286
    Lucky AW, Henderson TA, Olson WH, Robisch DM, Lebwohl M, Swinyer LJ. Effectiveness of norgestimate and ethinyl estradiol in treating moderate acne vulgaris. J Am Acad Dermatol 1997; 37: 746754.
  • 287
    Redmond GP, Olson WH, Lippman JS, Kafrissen ME, Jones TM, Jorizzo JL. Norgestimate and ethinyl estradiol in the treatment of acne vulgaris: a randomized, placebo-controlled trial. Obstet Gynecol 1997; 89: 615622.
  • 288
    Plewig G, Cunliffe WJ, Binder N, Hoschen K. Efficacy of an oral contraceptive containing EE 0.03 mg and CMA 2 mg (Belara) in moderate acne resolution: a randomized, double-blind, placebo-controlled Phase III trial. Contraception 2009; 80: 2533.
  • 289
    Koltun W, Lucky AW, Thiboutot D et al. Efficacy and safety of 3 mg drospirenone/20 mcg ethinylestradiol oral contraceptive administered in 24/4 regimen in the treatment of acne vulgaris: a randomized, double-blind, placebo-controlled trial. Contraception 2008; 77: 249256.
  • 290
    Maloney JM, Dietze P Jr, Watson D et al. Treatment of acne using a 3-milligram drospirenone/20-microgram ethinyl estradiol oral contraceptive administered in a 24/4 regimen: a randomized controlled trial. Obstet Gynecol 2008; 112: 773781.
  • 291
    Fugere P, Percival-Smith RK, Lussier-Cacan S, Davignon J, Farquhar D. Cyproterone acetate/ethinyl estradiol in the treatment of acne. A comparative dose-response study of the estrogen component. Contraception 1990; 42: 225234.
  • 292
    Halbe HW, de Melo NR, Bahamondes L et al. Efficacy and acceptability of two monophasic oral contraceptives containing ethinylestradiol and either desogestrel or gestodene. Eur J Contracept Reprod Health Care 1998; 3: 113120.
  • 293
    Koetsawang S, Charoenvisal C, Banharnsupawat L, Singhakovin S, Kaewsuk O, Punnahitanont S. Multicenter trial of two monophasic oral contraceptives containing 30 mcg ethinylestradiol and either desogestrel or gestodene in Thai women. Contraception 1995; 51: 225229.
  • 294
    Mango D, Ricci S, Manna P, Miggiano GA, Serra GB. Clinical and hormonal effects of ethinylestradiol combined with gestodene and desogestrel in young women with acne vulgaris. Contraception 1996; 53: 163170.
  • 295
    Graupe K, Zaumseil RP. Skinoren – a new local therapeutic agent for the treatment of acne vulgaris. In Macher E, Kolde G, Bröcker EB, eds. Jahrbuch der Dermatologie. Biermann, Zülpich, 1991: 159169.
  • 296
    Stoughton RB, Resh W. Topical clindamycin in the control of acne vulgaris. Cutis 1976; 17: 551554.
  • 297
    Padilla RS, McCabe JM, Becker LE. Topical tetracycline hydrochloride vs. topical clindamycin phosphate in the treatment of acne: a comparative study. Int J Dermatol 1981; 20: 445448.
  • 298
    Robledo AA, Lopez BE, del Pino GJ et al. Multicentric comparative study of the efficacy and tolerance of clindamycin phosphate 1% topical solution and tetracycline topical solution for the treatment of acne vulgaris. Curr Ther Res Clin Exp 1988; 43: 2126.
  • 299
    Yong CC. Benzoyl peroxide gel therapy in acne in Singapore. Int J Dermatol 1979; 18: 485488.
  • 300
    Strauss JS, Stranieri AM. Acne treatment with topical erythromycin and zinc: effect of Propionibacterium acnes and free fatty acid composition. J Am Acad Dermatol 1984; 11: 8689.
  • 301
    Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using 5-aminolevulinic acid versus methyl aminolevulinate. J Am Acad Dermatol 2006; 54: 647651.
  • 302
    Skidmore R, Kovach R, Walker C et al. Effects of subantimicrobial-dose doxycycline in the treatment of moderate acne. Arch Dermatol 2003; 139: 459464.
  • 303
    Dubertret L, Alirezai M, Rostain G et al. The use of lymecycline in the treatment of moderate to severe acne vulgaris: a comparison of the efficacy and safety of two dosing regimens. Eur J Dermatol 2003; 13: 4448.
  • 304
    Stewart DM, Torok HM, Weiss JS, Plott RT. Dose-ranging efficacy of new once-daily extended-release minocycline for acne vulgaris. Cutis 2006; 78: 1120.
  • 305
    Hersle K, Gisslen H. Minocycline in acne vulgaris: a double-blind study. Curr Ther Res Clin Exp 1976; 19: 339342.
  • 306
    Lane P, Williamson DM. Treatment of acne vulgaris with tetracycline hydrochloride: a double-blind trial with 51 patients. Br Med J 1969; 2: 7679.
  • 307
    Stewart WD, Maddin S, Nelson AJ, Danto JL. Therapeutic agents in acne vulgaris. I. Tetracycline. Can Med Assoc J 1963; 89: 10961097.
  • 308
    Wong RC, Kang S, Heezen JL, Voorhees JJ, Ellis CN. Oral ibuprofen and tetracycline for the treatment of acne vulgaris. J Am Acad Dermatol 1984; 11: 10761081.
  • 309
    Toossi P, Farshchian M, Malekzad F, Mohtasham N, Kimyai-Asadi A. Subantimicrobial-dose doxycycline in the treatment of moderate facial acne. J Drugs Dermatol 2008; 7: 11491152.
  • 310
    Bleeker J, Hellgren L, Vincent J. Effect of systemic erythromycin stearate on the inflammatory lesions and skin surface fatty acids in acne vulgaris. Dermatologica 1981; 162: 342349.
  • 311
    Bleeker J. Tolerance and efficacy of erythromycin stearate tablets versus enteric-coated erythromycin base capsules in the treatment of patients with acne vulgaris. J Int Med Res 1983; 11: 3841.
  • 312
    Pierard-Franchimont C, Goffin V, Arrese JE et al. Lymecycline and minocycline in inflammatory acne: a randomized, double-blind intent-to-treat study on clinical and in vivo antibacterial efficacy. Skin Pharmacol Appl Skin Physiol 2002; 15: 112119.
  • 313
    Hubbell CG, Hobbs ER, Rist T, White JW Jr. Efficacy of minocycline compared with tetracycline in treatment of acne vulgaris. Arch Dermatol 1982; 118: 989992.
  • 314
    Khanna N. Treatment of acne vulgaris with oral tetracyclines. Indian J Dermatol Venereol Leprol 1993; 29: 7476.
  • 315
    Samuelson JS. An accurate photographic method for grading acne: initial use in a double-blind clinical comparison of minocycline and tetracycline. J Am Acad Dermatol 1985; 12: 461467.
  • 316
    Akman A, Durusoy C, Senturk M, Koc CK, Soyturk D, Alpsoy E. Treatment of acne with intermittent and conventional isotretinoin: a randomized, controlled multicenter study. Arch Dermatol Res 2007; 299: 467473.
  • 317
    Kapadia N. Comparative efficacy and safety and efficacy of systemic 13-cis retinoic acid 20 mg/day vs 40 mg/day in acne vulgaris. J Pak Assoc Dermatolog 2005; 15: 238241.
  • 318
    Hillstrom L, Pettersson L, Hellbe L, Kjellin A, Leczinsky CG, Nordwall C. Comparison of oral treatment with zinc sulphate and placebo in acne vulgaris. Br J Dermatol 1977; 97: 681684.
  • 319
    Göransson K, Liden S, Odsell L. Oral zinc in acne vulgaris: a clinical and methodological study. Acta Derm Venereol 1978; 58: 443448.
  • 320
    Liden S, Goransson K, Odsell L. Clinical evaluation in acne. Acta Derm Venereol Suppl (Stockh) 1980; Suppl. 89: 4752.
  • 321
    Verma KC, Saini AS, Dhamija SK. Oral zinc sulphate therapy in acne vulgaris: a double-blind trial. Acta Derm Venereol 1980; 60: 337340.
  • 322
    Weismann K, Wadskov S, Sondergaard J. Oral zinc sulphate therapy for acne vulgaris. Acta Derm Venereol 1977; 57: 357360.
  • 323
    Harrison PV. A comparison of doxycycline and minocycline in the treatment of acne vulgaris. Clin Exp Dermatol 1988; 13: 242244.
  • 324
    Burton J. A placebo-controlled study to evaluate the efficacy of topical tetracycline and oral tetracycline in the treatment of mild to moderate acne. Dermatology Research Group. J Int Med Res 1990; 18: 94103.
  • 325
    Palombo-Kinne E, Schellschmidt I, Schumacher U, Graser T. Efficacy of a combined oral contraceptive containing 0.030 mg ethinylestradiol/2 mg dienogest for the treatment of papulopustular acne in comparison with placebo and 0.035 mg ethinylestradiol/2 mg cyproterone acetate. Contraception 2009; 79: 282289.
  • 326
    Gruber DM, Sator MO, Joura EA, Kokoschka EM, Heinze G, Huber JC. Topical cyproterone acetate treatment in women with acne: a placebo-controlled trial. Arch Dermatol 1998; 134: 459463.
  • 327
    Katz HI, Kempers S, Akin MD, Dunlap F, Whiting D, Norbart TC. Effect of a desogestrel-containing oral contraceptive on the skin. Eur J Contracept Reprod Health Care 2000; 5: 248255.
  • 328
    Kranzlin HT, Nap MA. The effect of a phasic oral contraceptive containing Desogestrel on seborrhea and acne. Eur J Contracept Reprod Health Care 2006; 11: 613.
  • 329
    Colver GB, Mortimer PS, Dawber RP. Cyproterone acetate and two doses of oestrogen in female acne; a double-blind comparison. Br J Dermatol 1988; 118: 9599.
  • 330
    Miller JA, Wojnarowska FT, Dowd PM et al. Anti-androgen treatment in women with acne: a controlled trial. Br J Dermatol 1986; 114: 705716.
  • 331
    Hongcharu W, Taylor CR, Chang Y, Aghassi D, Suthamjariya K, Anderson RR. Topical ALA-photodynamic therapy for the treatment of acne vulgaris. J Invest Dermatol 2000; 115: 183192.
  • 332
    Horfelt C, Stenquist B, Halldin CB, Ericson MB, Wennberg AM. Single low-dose red light is as efficacious as methyl-aminolevulinate – photodynamic therapy for treatment of acne: clinical assessment and fluorescence monitoring. Acta Derm Venereol 2009; 89: 372378.
  • 333
    Horfelt C, Funk J, Frohm-Nilsson M, Wiegleb Edstrom D, Wennberg AM. Topical methyl aminolaevulinate photodynamic therapy for treatment of facial acne vulgaris: results of a randomized, controlled study. Br J Dermatol 2006; 155: 608613.
  • 334
    Na JI, Suh DH. Red light phototherapy alone is effective for acne vulgaris: randomized, single-blinded clinical trial. Dermatol Surg 2007; 33: 12281233; discussion 1233.
  • 335
    Pollock B, Turner D, Stringer MR et al. Topical aminolaevulinic acid-photodynamic therapy for the treatment of acne vulgaris: a study of clinical efficacy and mechanism of action. Br J Dermatol 2004; 151: 616622.
  • 336
    Gold MH, Rao J, Goldman MP et al. A multicenter clinical evaluation of the treatment of mild to moderate inflammatory acne vulgaris of the face with visible blue light in comparison to topical 1% clindamycin antibiotic solution. J Drugs Dermatol 2005; 4: 6470.
  • 337
    Sami NA, Attia AT, Badawi AM. Phototherapy in the treatment of acne vulgaris. J Drugs Dermatol 2008; 7: 627632.
  • 338
    Haedersdal M, Togsverd-Bo K, Wiegell SR, Wulf HC. Long-pulsed dye laser versus long-pulsed dye laser-assisted photodynamic therapy for acne vulgaris: a randomized controlled trial. J Am Acad Dermatol 2008; 58: 387394.
  • 339
    Jung JY, Choi YS, Yoon MY, Min SU, Suh DH. Comparison of a pulsed dye laser and a combined 585/1,064-nm laser in the treatment of acne vulgaris. Dermatol Surg 2009; 35: 11811187.
  • 340
    Leheta TM. Role of the 585-nm pulsed dye laser in the treatment of acne in comparison with other topical therapeutic modalities. J Cosmet Laser Ther 2009; 11: 118124.
  • 341
    Orringer JS, Kang S, Hamilton T et al. Treatment of acne vulgaris with a pulsed dye laser: a randomized controlled trial. JAMA 2004; 291: 28342839.
  • 342
    Seaton ED, Charakida A, Mouser PE, Grace I, Clement RM, Chu AC. Pulsed-dye laser treatment for inflammatory acne vulgaris: randomised controlled trial. Lancet 2003; 362: 13471352.
  • 343
    Bowes LE, Manstein D, Rox Andersen R. Effects of 532 nm KTP laser exposure on acne and sebaceous glands. Lasers Med Sci 2003; 18: S6S7.
  • 344
    Baugh WP, Kucaba WD. Nonablative phototherapy for acne vulgaris using the KTP 532 nm laser. Dermatol Surg 2005; 31: 12901296.
  • 345
    Oh SH, Ryu DJ, Han EC, Lee KH, Lee JH. A comparative study of topical 5-aminolevulinic acid incubation times in photodynamic therapy with intense pulsed light for the treatment of inflammatory acne. Dermatol Surg 2009; 35: 19181926.
  • 346
    Rojanamatin J, Choawawanich P. Treatment of inflammatory facial acne vulgaris with intense pulsed light and short contact of topical 5-aminolevulinic acid: a pilot study. Dermatol Surg 2006; 32: 991996; discussion 996–997.
  • 347
    Santos MA, Belo VG, Santos G. Effectiveness of photodynamic therapy with topical 5-aminolevulinic acid and intense pulsed light versus intense pulsed light alone in the treatment of acne vulgaris: comparative study. Dermatol Surg 2005; 31: 910915.
  • 348
    Paithankar DY, Ross EV, Saleh BA, Blair MA, Graham BS. Acne treatment with a 1,450 nm wavelength laser and cryogen spray cooling. Lasers Surg Med 2002; 31: 106114.
  • 349
    Uebelhoer NS, Bogle MA, Dover JS, Arndt KA, Rohrer TE. Comparison of stacked pulses versus double-pass treatments of facial acne with a 1,450-nm laser. Dermatol Surg 2007; 33: 552559.
  • 350
    Wang SQ, Counters JT, Flor ME, Zelickson BD. Treatment of inflammatory facial acne with the 1,450 nm diode laser alone versus microdermabrasion plus the 1,450 nm laser: a randomized, split-face trial. Dermatol Surg 2006; 32: 249255; discussion 255.
  • 351
    Orringer JS, Kang S, Maier L et al. A randomized, controlled, split-face clinical trial of 1320-nm Nd:YAG laser therapy in the treatment of acne vulgaris. J Am Acad Dermatol 2007; 56: 432438.
  • 352
    Orringer JS, Sachs DL, Bailey E, Kang S, Hamilton T, Voorhees JJ. Photodynamic therapy for acne vulgaris: a randomized, controlled, split-face clinical trial of topical aminolevulinic acid and pulsed dye laser therapy. J Cosmet Dermatol 2010; 9: 2834.
  • 353
    Wiegell SR, Wulf HC. Photodynamic therapy of acne vulgaris using methyl aminolaevulinate: a blinded, randomized, controlled trial. Br J Dermatol 2006; 154: 969976.
  • 354
    Horfelt C, Stenquist B, Larko O, Faergemann J, Wennberg AM. Photodynamic therapy for acne vulgaris: a pilot study of the dose-response and mechanism of action. Acta Derm Venereol 2007; 87: 325329.
  • 355
    Thorneycroft IH, Stanczyk FZ, Bradshaw KD, Ballagh SA, Nichols M, Weber ME. Effect of low-dose oral contraceptives on androgenic markers and acne. Contraception 1999; 60: 255262.
  • 356
    Gerlinger C, Städtler G, Götzelmann R, Graupe K, Endrikat J. A non-inferiority margin for acne lesion counts. Drug Information J 2008; 42: 607615.

Supporting Information

  1. Top of page
  2. I Introduction
  3. II Assessment, comparability of treatment outcomes
  4. III Methods
  5. IV Epidemiology and pathophysiology
  6. V Therapeutic options
  7. VI Treatment of comedonal acne
  8. VII Treatment of papulopustular acne
  9. VIII Treatment nodular/conglobate acne
  10. IX General considerations
  11. X Maintenance therapy
  12. XII References
  13. Supporting Information

Table S1 Comedonal acne

Table S2 Papulopustular acne

Table S3 Conglobate acne

Table S4 Laser and light treatment

Document S5 Key to tables

Document S6 Guidelines method report

FilenameFormatSizeDescription
JDV_4374_sm_TableS1.xls308KSupporting info item
JDV_4374_sm_TableS2.xls445KSupporting info item
JDV_4374_sm_TableS3.xls46KSupporting info item
JDV_4374_sm_TableS4.xls72KSupporting info item
JDV_4374_sm_DocumentS5.pdf25KSupporting info item
JDV_4374_sm_DocumentS6.pdf234KSupporting info item

Please note: Wiley Blackwell 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.