Recent therapeutic developments for acne

Abstract

Current therapeutic concepts of acne vulgaris have to consider that acne is now understood as a primary inflammatory and chronic disease aggravated by genetic, microbial and environmental factors. Recent developments still focus on topical fixed combinations of substances with complementary effects in order to optimize efficacy without promoting bacterial resistance, which is a major concern resulting from inadequate use of antibiotics. New innovative therapeutic targets of acne pathophysiology are rare. Easy, convenient application and patient education are the basis to ensure patient adherence, which has been identified as a vital factor of therapeutic success of this chronic disease. The implementation of the European evidence-based S3 guidelines represents a major advancement in supporting therapeutic decisions based on literature review instead of expert opinion alone and traded therapy concepts.

Keywords::

• acne
• adherence
• alternative treatment
• antimicrobials
• fixed combinations
• guidelines
• isotretinoin
• physical therapy
• retinoids
• therapy

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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/expertdermatol; (4) view/print certificate.

Release date: 5 February 2013; Expiration date: 5 February 2014

Learning objectives

Upon completion of this activity, participants will be able to:

• • Assess the management of mild comedonal acne

• • Evaluate the management of moderate papulopustular acne

• • Assess the treatment of recalcitrant moderate acne

• • Evaluate the treatment of severe cystic acne

Financial & competing interests disclosure

EDITOR

Elisa Manzotti

Publisher, Future Science Group, London, UK.

Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.

CME AUTHOR

Charles Vega

Associate Professor and Residency Director, Department of Family Medicine, University of California, CA, USA.

Disclosure: Charles P Vega, MD, FAAFP, has disclosed no relevant financial relationships.

AUTHORS AND CREDENTIALS

Anja Thielitz

Department of Dermatology and Venereology, Otto-von-Guericke University Magdeburg, Germany.

Disclosure: Anja Thielitz has disclosed the following relevant financial relationships: Received speaker’s honoraria from Galderma and LaRochePosay.

Harald Gollnick

Professor, Department of Dermatology and Venereology, Otto-von-Guericke University Magdeburg, Germany.

Disclosure: Harald Gollnick has disclosed the following relevant financial relationships: Received speaker’s honoraria from Bayer-Intendis, Galderma, Almirall, GlaxoSmithKline and is honorary advisor of Galderma, Meda, Merz and Bayer-Intendis.

Acne is one of the most common diseases with a point prevalence of up to 100% among adolescents and often persists into adulthood, with detrimental effects on self-esteem [1,2]. Sixty percent of all acne cases are so-called ‘physiologic acne’, the other 40% are those that need continuous help by a specialist to prevent physical or psychological scarring. Acne is still the most frequent primary diagnosis for visits to dermatologists [3].

The conception of acne has been refined towards a ‘chronic disease’ and rather represents a condition that continuously changes in its clinical appearance than an acute, self-limited disease of teenagers. This means the strategy of acne treatment is not only an acute intervention, but also maintenance [4]. The self-reported prevalence of acne in American women between the age of 20 and 29 years was 50.9%, and between 40 and 49 years was 26.3% [5]. A clinical evaluation in a German working cohort revealed a prevalence of acne of 10.9% at 21–30 years and 2.3% at 41–50 years [6]. However, the definition of late-type acne (persisting/relapsing/first onset) above the age of 20–23 years, when the usual cessation takes place, is still lacking.

Advances in the pathophysiology of acne

Acne is currently understood as a chronic inflammatory disease of the pilosebaceous unit, characterized by androgen-induced increased sebum production, follicular hyperkeratinisation, inflammation and altered adaptive immune response [7,8]. Bacterial colonization by Propionibacterium acnes definitely aggravates the course of the disease in various manners, but its role as a prerequisite of the induction of acne is disputable [9,10].

Sebaceous glands may act as important regulators in the early inflammatory events of acne because they possess the enzyme machinery for the production of hormones (i.e., 5α-dihydrotestosterone, vitamin D, corticotropin-releasing hormone) and proinflammatory cytokines (IL-1α, TNF-α, IL-6 and IL-8), express a variety of receptors including those for sex steroids, retinoic acid (isotypes α, γ) and retinoid-X receptors (isotypes α, β, γ), peroxisome proliferator-activated receptors, liver-X receptors, histamine, prostaglandins, corticotropin-releasing hormone, neuropeptides, growth hormone, IGF-1 and melanocortin-1, and thereby function as independent endocrine organs [11]. They are also an important part of the innate immune system, expressing Toll-like receptors 2, 4, 6 and CD14, or producing a variety of antimicrobial peptides like human β-defensins, cathelicidin or antibacterial lipids, such as sapienic acid or other monounsaturated fatty acids [11].

Immune-mediated inflammatory processes precede follicular hyperkeratinisation and involve CD4⁺ lymphocytes (possibly triggered by a specific immune response against P. acnes antigen), macrophages and IL-1α [12].

According to a current hypothesis, the interaction of innate and specific adaptive immunity in primary acne pathogenesis might, in acne-prone individuals, generate an imbalance between proinflammatory and anti-inflammatory pathways that predispose individual susceptibility against androgens, microbial or exogenous factors, thus potentiating the disease [10].

Recently detected genetic polymorphisms against IL-1α, IGF-1, TNF-α and its Type-II receptor, Toll-like receptor 2 and androgen receptor might explain the familial predisposition for this disease [13,14], with a heritability of 78.47 ± 2.05% in first-degree relatives and 75.05 ± 3.18% in second-degree relatives of adolescents [15].

The role of environmental and dietary factors in the development of acne is discussed in all old textbooks, but was abandoned at the end of the 1960s by the study of Fulton et al. [16]. Cordain et al. recently showed the complete absence of acne in non-westernised hunter–gatherer societies like the Kitavan (Papua New Guinea) and the Aché (Paraguay) population [17].

A ‘western’ diet, typically rich in high glycemic load food, is considered to cause chronic hyperinsulinemia, potentially provoking a growth factor response via IGF-1 receptor, thereby potentiating hyperseborrhea and androgen signaling [18]. Two randomized controlled studies have provided evidence for minor beneficial therapeutic effects of low-glycemic load diets in acne after 10–12 weeks [19,20]. Another controlled study failed to show significant differences in the effect a of low and high glycemic index nutrition in schoolboys after an intervention period of 8 weeks [21], suggesting that at least 10 weeks, or better 3 months, of strict nutrition control might be necessary to improve acne. Epidemiological evidence suggests that milk consumption might have an acne-aggravating effect [22,23], but interventional studies to support this association are lacking. The historic and current evidence about the relation between diet and acne has been extensively reviewed by Bowe et al. [24].

Hyperactivated, nutrient-sensitive kinase mTOR complex 1 (mTORC1) signaling, in combination with the nuclear shift of the nutrient-sensitive transcription factor FoxO1, controlled by insulin/IGF-1 signaling via activation of phosphoinositol-3 kinase and Akt kinase, are currently hypothesized to be the major molecular targets to mediate food-induced acne promotion [18,25,26].

Despite these advances in pathophysiology, the knowledge about the molecular sequence of events triggering acne is still incomplete. The need for better treatments affecting the course of the disease is the subject of ongoing research in laboratories of universities and industry.

In the last 30 years, the groups of compounds used for acne therapy remained relatively constant, and consist mainly of topical and systemic antimicrobials and retinoids [27]. However, key experiments with new and old compounds acting in the different pathogenetic steps are reported from time to time without a real breakthrough. Only a constant improvement has been achieved with regard to the development of new fixed combinations or delivery systems with better efficacy and tolerability.

Evidence-based acne therapy guidelines

Clinical experience and evidence of various studies have shown that parallel targeting of major pathogenetic factors, depending on clinical type and severity either by mono- or combination therapy, represents the most effective approach to treat acne. Consensus recommendations based on literature review and expert opinions have previously been published [28,29] and have paved the way for critical evaluation of personal experiences, as well as traded therapy concepts, resulting in the publication of the first European evidence-based (S3) guidelines for the treatment of acne [30], which was developed by systematic analysis of the literature and a structured consensus process. When using this guideline, one has to be aware that only the most relevant treatments available in Europe were included in the review process.

To make severity-adjusted therapeutic decisions easier for clinicians, the following simplified clinical classification has been introduced: comedonal acne; mild-to-moderate papulopustular acne; severe papulopustular acne, moderate nodular acne; severe nodular acne; and conglobate acne. Additional factors that should influence therapeutic decisions are the course of inflammation and scarring, persistent or late-onset disease, hyperseborrhoea, androgenic triggers, truncal acne and/or psychologic sequelae, that is, in patients with a severe impact on their quality of life (QoL), a more aggressive therapy may be justified.

In mild-to-moderate comedonal acne, a topical (mono-)therapy is recommended, consisting preferably of retinoids (adapalene > tretinoin, isotretinoin), followed by azelaic acid or benzoyl peroxide (BPO). The use of fixed combinations does not significantly increase efficacy against noninflammatory lesions, but might reduce tolerability. The general lack of direct evidence for the treatment of comedonal acne accounts for the inability of giving high strength recommendations for this disease subtype.

The combination of single retinoids or antimicrobials with complementary mode of action significantly enhances efficacy against inflammatory lesions and leads to a faster onset of clinical improvement, which can be optimized by fixed combinations enhancing patient compliance and adherence. In mild-to-moderate papulopustular acne, fixed-dose combinations of BPO plus adapalene and BPO plus clindamycin (C) are recommended as superior treatment of choice. An alternative option that can be considered is monotherapy with azelaic acid, BPO or topical retinoids, which all showed comparable efficacy. Owing to the risk of the development of antibiotic resistance, topical monotherapy with antibiotics is no longer recommended.

In more refractory or widespread, but still moderate, cases, a combination of a systemic antibiotic with a topical (nonantibiotic) agent (i.e., adapalene ± BPO) should always be preferred, whereas systemic monotherapies with antibiotics, antiandrogens or isotretinoin should be avoided for this acne severity grade.

For severe papulopustular and moderate nodular acne, a systemic treatment with isotretinoin is recommended due to very good efficacy seen in clinical practice, although the available evidence on safety and tolerability was considered insufficient to be used as a basis to formulate treatment recommendations [30]. A good alternative recommended for the treatment of severe papulopustular acne is systemic antibiotics in combination with adapalene, the fixed-dose combination of adapalene/BPO or in combination with azelaic acid.

In conglobate acne, systemic isotretinoin shows superior to comparable efficacy compared with systemic antibiotics in combination with topical treatments, although the lack of published studies for this subtype of acne makes it difficult to support conclusions that are based on clinical evidence rather than expert opinion [30]. Double-blind studies are not possible because of the visible adverse drug profile of isotretinoin. Other systemic acne treatments include hormonal therapies (antiandrogens, combined oral contraceptives, glucocorticoids), which may be used in more severe acne grades in addition with other topical or systemic treatments (‘low strength of recommendation’ or expert opinion).

Topical retinoids & retinoid-based fixed combination therapies

Topical retinoids act against comedones and microcomedones and also have direct immunomodulatory and anti-inflammatory effects without inducing bacterial resistance, which renders them uniquely suitable as adjunctive treatment in all combination therapies of acne, as well as a useful tool to prevent relapses during maintenance therapy of this chronic disease. The efficacy and safety of topical retinoids used in acne therapy, including tretinoin (all trans-retinoic acid), isotretinoin (13-cis retinoic acid), adapalene and tazarotene have been reviewed elsewhere [27,29,31] and are beyond the scope of this article, which focuses on recent advances.

The drawback of low cutaneous tolerability of topical tretinoin is continuously improved by new delivery systems to facilitate controlled release, including tretinoin trapped with copolymer microspheres (Retin-A Micro^® gel 0.1% or 0.04%, Ortho-Neutrogena, USA), prepolyolprepolymer-2 gel or cream (Avita^® 0.025%, Bertek pharmaceuticals, USA) or micronized tretinoin (Atralin^® Gel 0.05%, Valeant Pharmaceuticals, NI, USA). Another advantage of microsphere and micronized formulation is marked protection against tretinoin photodegradation and oxidation by BPO [32,33], which was also confirmed clinically in a study showing that simultaneous application of tretinoin microsphere 0.04% with BPO in the morning does not reduce efficacy compared with a morning/evening regimen [34]. The micronized formulation of tretinoin (0.05%) showed better cutaneous tolerability than tretinoin microsphere (0.1%) gel without compromising efficacy in a population of young adolescents [35]. A Tretinoin Microsphere Gel 0.04% (TGM) pump was superior compared with vehicle in the reduction of noninflammatory lesions in preadolescent patients aged 9–11 with acne vulgaris with similar tolerability [36]. The same TGM 0.04% pump demonstrated significantly improved tolerance than adapalene/BPO 0.1%/2.5% gel in a split-face comparison involving 170 persons [37].

In a recent investigator-blinded, randomized, parallel-design study comparing tretinoin microsphere gel 0.04% (TMG Pump) to tazarotene cream 0.05% in mild-to-moderate facial acne vulgaris, both substances showed similar efficacy with more rapid improvement and better tolerability in the TMG group [38].

Adapalene, a synthetic third-generation topical retinoid, is available as 0.1% gel, cream, solution and recently as lotion and as 0.3% gel (Differin^®, Galderma, Watford, UK). The efficacy and safety of the newly developed adapalene 0.1% lotion was investigated and compared with its vehicle in two placebo-controlled, multicenter, randomized double-blind clinical studies involving 2141 subjects, and it demonstrated superior efficacy in IGA assessments and total, inflammatory and noninflammatory lesion count reductions [39]. The lotion formulation was well tolerated and, according to patient surveys, easily spreadable, easily absorbed and pleasant to use.

Topical tazarotene is approved for acne treatment only in the USA (Tazorac^®, Allergan Inc.). A 16-week study evaluated once-daily tazarotene 0.1% cream and adapalene 0.3% gel in patients with moderate-to-severe acne, and found that tazarotene 0.1% cream was slightly more effective in many efficacy parameters and was more effective than adapalene 0.3% gel in reducing postinflammatory hyperpigmentation [40].

The fact that many subjects experience an acne history of several years underlines the necessity for a safe and effective maintenance therapy regimen, which is supported by several studies demonstrating the efficacy of a topical retinoids for this strategy [27]. Adapalene has been studied most intensely with regard to maintenance regimens, and the available evidence comprises four controlled studies (one on microcomedones) and two uncontrolled studies [27,29,30].

Combination therapies have been developed to target two or more causative elements of the complex disease and enhance treatment efficacy. A fixed combination is optimal to enhance patient adherence due to easy and reduced application modus and also avoids substance incompatibilities due to application errors (e.g., oxidation by using incompatible single agents) [27]. Recently introduced retinoid-based fixed combinations with high-quality clinical efficacy evidence include fixed combinations of tretinoin 0.025% and clindamycin phosphate 1.2% (Ziana^®, Medicis Pharmaceutical Corporation, Scottsdale; AZ and Veltin^® Gel, Stiefel Laboratories Inc., NC, USA), the latter being approved by the US FDA in July 2010, and adapalene 0.1% and BPO 2.5% (Epiduo™, Tactuo™, Galderma), representing the only fixed-dose combination product available that combines a topical retinoid with BPO.

In three 12-week trials in patients aged ≥12 years with moderate acne, success rates were significantly higher with adapalene 0.1%/BPO 2.5% gel than with adapalene 0.1% gel or BPO 2.5% gel alone, and combination therapy had an earlier onset of action demonstrating a real synergy of the single compounds [41], which has also been shown histologically in an ex vivo analysis [42]. Feldman et al. analyzed several clinical trials on adapalene 0.1%/BPO 2.5% and found that its benefit increases with higher lesion counts at the beginning of the study [43], which might indicate that this combination is suitable for more severe forms of acne, although clinical studies designed to investigate these particular subgroups are lacking. Another 4-week, open-label, single-center study including 30 healthy adults showed that the fixed-dose combination gel containing adapalene 0.1% and BPO 2.5% effectively inhibited both antibiotic-susceptible and antibiotic-resistant P. acnes, and eradicated some resistant strains entirely in some individual subjects [44]. These results provide further evidence to support the combination of 0.1% gel or BPO 2.5% gel with systemic antibiotics in more severe forms of acne.

Studies investigating such combinations showed that the fixed topical adapalene 0.1%/benzoyl peroxide 2.5% gel in combination with oral lymecycline [45] was more effective than oral lymecycline alone in patients with moderate-to-severe acne, and in combination with oral doxycycline hyclate [46] it was more effective than oral doxycycline hyclate alone in patients with severe acne. In responders to this therapy, an additional 6-month maintenance therapy with adapalene 0.1%/BPO 2.5% gel maintained results in comparison to vehicle and demonstrated even further improvement, thereby representing the first study to demonstrate the efficacy of this product in a maintenance regimen [47].

In three randomized, 12-week, double-blind studies involving more than 4500 patients, the combination of clindamycin phosphate 1.2% and tretinoin 0.025% gel (Ziana^®) was well tolerated and significantly more effective than clindamycin 1.2% gel, tretinoin 0.025% gel, or vehicle gel at reducing inflammatory, noninflammatory and total lesion counts (p < 0.001) [27,31]. The novel formulation of clindamycin phosphate 1.2% and tretinoin 0.025% solubilized in an aqueous-based gel (Veltin^®) was investigated in three studies including a total of 2219 subjects with mild-to-moderate acne vulgaris aged 12 years and older, treated once daily for 12 weeks. The results were consistent and demonstrated that the combination gel is more effective than clindamycin or tretinoin monotherapy, with a safety and tolerability profile similar to that of tretinoin [48].

Topical antimicrobials & their fixed combinations

Topical antimicrobials are an essential part of the therapeutic armamentarium for mild-to-moderate acne vulgaris and represent an alternative for patients who cannot take systemic antibiotics.

Topical antibiotics were most commonly used, but the worldwide concern about antibiotic resistance resulted in changing their role in the topical treatment of acne. Clindamycin, erythromycin, tetracycline or nadifloxacin are bacteriostatic for P. acnes, and have also been demonstrated to have anti-inflammatory activities [49].

Their use as monotherapy is no longer recommended [29,30], and they should be applied preferentially in combination with BPO – an approach that also reduces the emergence of P. acnes strains that are resistant or less sensitive to antibiotics. The combination of a topical retinoid plus an antimicrobial is a rational choice because of the complementary modes of action that increase speed of response and enhance efficacy against comedones and inflammatory lesions.

BPO is a lipophilic, nonantibiotic antimicrobial agent with mild comedolytic effects. It penetrates in the pilosebacous follicle, where it propagates free radicals to oxidize proteins in the bacterial cell membrane inducing bactericide effects against P. acnes and thus far has not been detected to induce bacterial resistance. BPO has been shown to be equally effective at concentrations of 2.5, 5 and 10% [50]. However, a concentration-dependent irritant dermatitis can occur with higher concentrations. The drawback of the irritative and bleaching potential of BPO has been reduced by new formulations, such as BPO emollient foam, which was effective in a short-contact approach used on the trunk [51]. A solubilized 5% BPO gel has been developed to enhance the bioavailability, follicular penetration, and efficacy of BPO, which was recently demonstrated to be superior to 5% BPO/1% clindamycin in a split-face investigator-blind study involving 65 patients [52].

The combination of BPO with chemical structures that contain a tertiary amine within their structure, such as clindamycin and erythromycin, increases the generation of BPO radicals and thereby creates a real biologic synergism [53] contributing to their complementary effects on acne pathogenesis. At the moment, three fixed combination products of clindamycin and BPO are on the market: two containing clindamycin 1% and BPO 5% (Duac^®, Stiefel Laboratories, NC, USA and Benzaclin^®, SanofiAventis, NJ, USA) and an optimized formulation of clindamycin phosphate 1.2%/BPO 2.5% aqueous gel (Acanya^®, Valeant Pharmaceuticals) developed without the use of surfactants or alcohol. A recent meta-analysis of 16 randomized, controlled trials in 5737 subjects compared the efficacy of fixed combinations containing clindamycin–BPO and concluded that clindamycin phosphate 1.2%–BPO 2.5% gel was comparable to clindamycin–BPO 5% in reducing lesion counts and may have an advantage in treating noninflammatory lesions. All combinations were superior to the single agents alone in treating inflammatory lesions over 10–12 weeks and clindamycin phosphate 1.2%–BPO 2.5% gel had a greater absolute reduction in lesion count for both inflammatory and noninflammatory lesions than did clindamycin–BPO 5% [54]. Another randomized, double-blind, active and vehicle-controlled Phase III study recently showed that a clindamycin phosphate 1.2%–BPO 3% fixed-dose combination gel provides superior efficacy with regard to Investigator’s Static Global Assessment score and inflammatory and total lesion counts compared with the individual active ingredients and vehicle, while maintaining a highly favorable safety and tolerability profile that is similar to BPO 3% alone [55].

A study comparing the efficacy, tolerability and safety of clindamycin 1%–BPO 5% (C/BPO) gel with hydrating excipients and adapalene 0.1%–BPO 2.5% gel concluded that both combinations have similar efficacy in treating inflammatory and noninflammatory acne lesions, however, C/BPO achieved better overall treatment success in less time, coupled with a significantly better tolerability profile and a notably better safety profile [56].

The decision for the appropriate combination treatment should not only take into account clinical efficacy, but also prevention or clearance of bacterial resistance. Recently, the fixed combination of a retinoid with an antibiotic (clindamycin phosphate 1.2%/tretinoin 0.025% gel) was less potent than clindamycin phosphate 1%/BPO 5% gel in reduction of P. acnes counts and eradication of clindamycin-resistant and erythromycin-resistant P. acnes strains [57] in subjects treated for 16 weeks. However, the addition of a 4% BPO wash to the combination of clindamycin phosphate 1.2%/tretinoin 0.025% gel was safe and well tolerated in participants with mild-to-moderate acne vulgaris, showing only slightly more local tolerability reactions at week 1 improving thereafter [58].

Other topical treatments

Azelaic acid 20% in a cream formulation has been established as an efficacious and safe topical drug for almost two decades. Azelaic acid 15% gel is approved for the treatment of rosacea in the USA, but also has approval for the treatment of acne vulgaris in Europe and recently proved efficacious in the treatment of postinflammatory hyperpigmentation in acne patients after 16 weeks of treatment [59], which is related to its antityrosinase activity. New investigations on the mode of action revealed that azelaic acid significantly reduced the ultraviolet B light-induced IL-1β, IL-6 and TNF-α mRNA expression and protein secretion by affecting nuclear translocation of nuclear factor kB p65 subunit and phosphorylation of the p38 mitogen and stress-activated protein kinase and by peroxisome proliferator-activated receptor-γ activation in keratinocytes, which has a crucial role in the control of inflammation in acne [50]. Azelaic acid is currently recommended as second-line option for the treatment of mild-to-moderate papulopustular acne and comedonal acne, or also in combination with systemic antibiotics for severe acne forms as alternative treatment for isotretinoin [30].

A new aqueous gel formulation of dapsone 5% (Aczone^®, QLT Inc., Vancouver, Canada) was approved by the FDA in 2005. It was recently shown in a randomized study involving 171 subjects that combination therapy with tazarotene cream 0.1% was more effective than tazarotene monotherapy for treatment of comedonal acne, suggesting that anti-inflammatory agents such as dapsone might effectively treat early stages of acne (both comedonal and noncomedonal) when used in combination with a retinoid [61]. A previous 12-week, randomized, double-blind study investigating the efficacy of dapsone gel 5% in combination with adapalene gel 0.1%, BPO gel 4% or moisturizer for the treatment of acne vulgaris revealed that patients treated with dapsone gel combined with adapalene showed a significantly better response in reducing in non-inflammatory and total acne lesion count than those who received the dapsone moisturizer combination, confirming that retinoid combination therapy can enhance the efficacy of dapsone and is well tolerated [62]. However, the established single acne agents were not investigated as comparators.

Oral antibiotics

Systemic antibiotics are recommended in the management of moderate-to-severe inflammatory acne, after failure of topical treatment and in acne covering large parts of the body surface [27]. Substances reported to be effective in acne therapy are tetracycline, doxycycline, minocycline, lymecycline, trimethoprim-sulfomethoxazole, clindamycin, roxithromycin and azithromycin, but particularly minocycline and docycycline, with their potent anti-inflammatory effects on neutrophil chemotaxis or inhibitory effects on cytokines and matrix metalloproteinases. For this reason they are routinely used as the first-line oral antibiotic therapy in acne [27]. There is insufficient evidence to support one tetracycline rather than another in terms of efficacy [63–65], although minocycline shows less resistance toward P. acnes than first-generation tetracyclines and doxycycline do, as well as higher lipid solubility [65]. The pharmacokinetic and pharmocodynamic properties of tetracyclines have been recently reviewed and showed that rapid absorption (immediate release formulation) increases the occurrence of acute vestibular adverse events, whereas slower absorption (extended release) improves tolerability [63].

Minocycline seems to be almost unique within the group in causing potentially irreversible slate-grey hyperpigmentation of the skin and is associated with a higher risk to induce to lupus-like syndrome [64,66], limiting its recommended use as a first-line antibiotic [66]. Recently reported adverse events associated with the use of oral antibiotics are an increased risk of pharyngitis with an odds ratio of 3.53 (95% CI: 1.14–10.95) in patients receiving oral antibiotics for acne versus those who are not receiving oral antibiotics [67], and the association of tetracycline-class antibiotics, particularly doxycycline, with the development of inflammatory bowel disease [68], which was also discussed to be associated with acne itself [69]. The clinical relevance and importance of these findings needs to be evaluated by further studies.

Current treatment guidelines recommend the combination of oral antibiotics with retinoids, azelaic acid, BPO or a combination of retinoid/BPO for moderate-to-severe forms of acne [29,30]. To limit the emergence of resistant strains, the use of antibiotics should be restricted, and with regard to indication and duration, topical and systemic antibiotic therapy should always be combined with broad-spectrum antibacterial agents (e.g., BPO), and the combination of topical antibiotic and systemic antibiotic therapy as well as antibiotic monotherapy should be avoided.

Hormonal therapy & spironolactone

Hormones and growth factors, including androgens, estrogens, growth hormone and insulin-like growth factor, play an important role in the development of acne. Hormonal therapy represents an alternative or additional treatment regimen, especially in late-type female acne, polycystic ovary syndrome, other signs of hyperandrogenism, such as seborrhoea, androgenetic alopecia or hirsutism in combination with acne (SAHA syndrome) and in case of parallel wishes of contraception or as a requirement for a systemic isotretinoin treatment [27,70]. It can be combined with topical therapy or systemic antibiotics in moderate-to-severe acne forms, but is not a primary monotherapy for uncomplicated acne [30].

The combinations of ethinyl estradiol with cyproterone acetate, chlormadinone acetate, dienogest desogestrel and drospirenone have shown the strongest antiacne activity [70]. Several epidemiologic studies raised the question of whether drospirenone is associated with a higher risk of thrombembolism compared with other oral contraceptives, which could not be confirmed in a recent meta-analysis [71]. However, the FDA has recently completed its review of observational studies regarding the risk of blood clots in women taking drospirenone-containing birth control pills, and concluded that these may be associated with a higher risk for blood clots than other progestin-containing pills [72].

Gestagens or estrogens as monotherapy, spironolactone, flutamide, gonadotropin-releasing hormone agonists and inhibitors of peripheral androgen metabolism are not recommended according to the current stand of knowledge [70]. Low-dose prednisolone is to only be administered at late-onset congenital adrenal hyperplasia and dopamine agonists at hyperprolactinemia.

A recent Cochrane systematic review investigating the effectiveness of spironolactone versus placebo or in combination with steroids for hirsutism and/or acne found that there is some evidence that spironolactone is not an efficient treatment of acne vulgaris [73].

Oral isotretinoin

Oral isotretinoin exhibits activity against all major etiologic factors involved in the pathogenesis of acne. It significantly reduces size and sebum production of sebaceous glands by inducing apoptosis in sebocytes via TNF-related, apoptosis-inducing ligand [74] and neutrophil gelatinase-associated lipocalin, normalizes follicular keratinization and prevents the development of microcomedones and comedones, indirectly inhibits P. acnes growth by changing the follicular milieu and upregulation of antimicrobial factors and exerts direct immunologic and anti-inflammatory activity [75]. It might also affect growth hormone physiology and nutrient-associated signaling, because IGF-1 and IGF-binding protein 3 levels decreased significantly after treatment [76].

The clinical experience with systemic isotretinoin now comprises three decades. Although being a safe and potent substance in the hands of experienced dermatologists, its use has experienced a drawback since the directive towards the harmonization of the Summary of Product Characteristics, launched by the European Medicines Agency in 2003, changed its indication from a first-line to a second-line medication [27]. However, the published data and expert opinion, 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, especially when other complicating prognostic factors are present. The rationale behind this recommendation is that quick reduction of inflammation in acne may prevent the occurrence of clinical and psychological scarring and improve QoL, whereas delay of isotretinion due to legal restrictions implies a significant ethical problem.

The recommended dose to start isotretinoin therapy is now 0.3–0.5 mg/kg for severe papulopustular acne/moderate nodular acne and 0.5 mg/kg for conglobate acne [29]. The duration of the therapy should be at least 6 months and can be prolonged in case, of insufficient response. Side effects of isotretinoin include those of the mucocutaneous, musculoskeletal and ophthalmic systems, as well as headaches [77]. A recently published case–control study reported that increasing the dose of isotretinoin was associated with an elevated risk of ulcerative colitis [78]. Although the study failed to demonstrate a causal association and the absolute risk of developing ulcerative colitis after taking isotretinoin is quite low, clinicians prescribing isotretinoin as well as prospective patients should be aware of this possible association.

Isotretinoin therapy has also been associated with suicidal ideation, mood alterations and depression [79] However, a causal relationship has not been established, and the link between isotretinoin use and psychiatric events remains controversial [79]. Acne itself is significantly associated with suicidal ideation and a high degree of social impairment in adolescents [80]. Psychological adverse effects that have been associated with therapies for acne may reflect the burden of substantial acne rather than the effects of medication. This was also confirmed in a retrospective Swedish cohort study, where an increased risk of attempted suicide observed up to 6 months after the end of treatment with isotretinoin was not attributable to the medication because the risk of attempted suicide was already rising before treatment [81]; therefore, an additional risk due to the isotretinoin treatment could not be established. According to currently available evidence, the prescription of oral isotretinoin should not be discouraged in severe acne patients who will normally experience both physical and psychological improvement of their disease [27]. As patients with a history of suicide attempts before treatment made new attempts to a lesser extent than did patients who started such behavior in connection with treatment, patients with severe acne should not automatically be refused isotretinoin treatment because of a history of attempted suicide, and prospective studies reported an improvement of depressive symptoms under isotretinoin therapy [82]. To rule out the few cases with adverse psychopathologic reactions, careful history-taking, probably supported by standardized tools [77] and information of patients and their relatives about the problem, as well as assessment of psychiatric symptoms at each visit should be done and, if necessary, referral to a psychiatrist and discontinuation of isotretinoin should be considered.

The most severe safety issue concerning oral isotretinoin is teratogenicity. Therefore, women of childbearing potential must be treated whilst adhering to the pregnancy-prevention program (PPP) implemented in the UK and other countries, and the iPLEDGE program in the USA, which requires mandatory registration of all patients receiving the drug [27]. A recent review aimed at identifying the compliance with the PPP in Europe reported that isotretinoin was prescribed in full accordance with PPP in only 6–26% of cases, and that pregnancy incidence was seen in 0.2–1.0 per 1000 women of childbearing age using isotretinoin [83]. With regard to these legal issues, the use of propagated ‘off-label’ low-dose isotretinoin or intermittent regimens [84], which are also undoubtedly clinically effective and well tolerated in the control of moderate acne, should be critically seen with regard to possible extension of its use to ‘off-label’ indications, as well as therapy duration. An open question of these regimens yet to be resolved is the optimal cumulative threshold dose to prevent relapses.

Physicochemical adjunctive treatments of acne

Popular adjunctive therapies in acne include light and laser therapy, photodynamic therapy (PDT), chemical peels and comedo extraction and might offer advantages with regard to the reduction of the risk of bacterial resistance, nonsystemic administration and control of patient adherence. Those treatments, however, have to be evaluated under the aspect if used as interventional of acute acne or as an adjunctive in post-acne situations. Particularly, blue light and PDT show promise as they directly target pathogenetic factors of acne and may potentially complement current conventional therapy. In general, light-based treatments target P. acnes levels and/or disruption of sebaceous gland function, and may also have anti-inflammatory effects via action on inflammatory cytokines. Red light phototherapy is less effective for the eradication of P. acnes than blue light phototherapy, but efficacy of red light phototherapy can be markedly enhanced by the addition of 5-aminolevulinic acid [30]. According to reviewed evidence, blue light monotherapy reduces the counts of inflammatory lesions by 36–62.5% and can be considered for the treatment of mild-to-moderate papulopustular acne, whereas the evidence regarding the efficacy of red light compared with placebo is still conflicting [29]. Narrowband light therapies are typically well tolerated and conveniently administered; but their mode of action, primarily against P. acnes, requires repeated application, which argues for its use in combination with other medical treatments with anticomedogenic and comedolytic effects [29].

Visible light as monotherapy is not recommended for the treatment of comedonal, severe papulopustular and conglobate acne [30]. Although PDT is effective in the treatment of severe papulopustular/moderate nodular acne, it cannot yet be recommended due to a lack of standard treatment regimens that ensure a favorable profile of acute adverse reaction, including pain, erythema, severe folliculitis and desquamation. Furthermore, destruction of pilosebaceous units and scarring have been reported after selective phototermolysis (Indocyanine green and diode laser) treatment for acne [85], raising concerns about the long-term effects of PDT with regard to the maintenance of endocrine and immunological functions of sebaceous glands. According to an article reviewing PDT practicability, a topical short-contact (90 min or less) 5-aminolevulinic acid or methylaminolaevulinate using a noncoherent light source at 2- to 4-week intervals for a total of two to four treatments produces the greatest clinical effect and shows a good side-effect profile, resulting in acne remission for at least 3 months up to a year [86]. Indocyanine green and indole-3-acetic acid are new photosensitizers with comparable efficacy in mild-to-moderate acne vulgaris, which reduce mainly inflammatory and, to a lesser extent, noninflammatory lesions and sebum secretion [87].

Artificial UV radiation sources are not recommended for the treatment of any type of acne. In summary, the evidence of existing studies of variable quality is not sufficiently robust to recommend any device be used as interventional monotherapy in acne [30].

The level of good-quality evidence for the efficacy of superficial peels in the literature is scarce. According to clinical impression, using superficial chemical peels in combination with other physical treatments might contribute to achieving a faster response, improving patient satisfaction and maintaining a good skin texture by reducing the appearance of new acne lesions in mild and moderate acne [88].

Despite a favorable risk–benefit ratio for use in acne, more rigorous clinical trials are needed to demonstrate if they can have a synergistic effect with topical or systemic acne drugs.

The role of adherence in acne therapy

The established term ‘compliance’ implying that the patient is taking medication as ordered and emphasizing the patient’s obedience has been recently substituted by the term ‘adherence’, which, in contrast, premises the patient’s willingness to implement a healthcare plan or therapeutic concept in concert with the physician [29]. Although acne requires prolonged treatment due to its nature as a chronic disease, and medication adherence has a prominent role in the success of therapy, previous small studies suggest that adherence to acne medications is often poor [89]. A recently published study conducted to investigate risk of poor adherence in acne therapy utilized a simple, validated questionnaire (Elaboration d’un outil d’evaluation de l’observance des traitements medicamenteux, ECOB) in a large worldwide cohort of acne patients (n = 3339) from three major geographic regions (America [n = 952], Europe [n = 1196], and Asia [n = 1191]) and revealed an overall adherence rate of 50% – the lowest in Europe compared with Asia and America (poor adherence rates of 58, 48 and 43%, respectively; p < 0.0001) [90]. In addition, adherence was analyzed related to the type of treatment and showed that of the patients taking a combination of both systemic and topical therapy, 60% (n = 944) of patients had poor adherence to at least one treatment (54% systemic vs 44% topical, respectively) as defined in the study protocol, suggesting that simplified treatment regimens are required to increase adherence. Lower rates of poor adherence were observed in patients with topical therapy only (40%) or patients using oral isotretinoin therapy (46%). Other factors identified in this study being correlated with poor adherence were young age (most strongly with <15 years, but also in the age group from 15 to 25 years), side effects, lack of improvement as evaluated by dermatologist, previous systemic therapy, lack of knowledge about acne treatment, consultation with a primary care physician, and lack of patient satisfaction with treatment. Factors promoting adherence were a higher severity grade, use of cosmetics (moisturizers, cleansers), use of either topical therapy alone or isotretinoin, good clinical improvement as evaluated by the dermatologist, patient satisfaction with therapy and knowledge of acne treatment. Another small study including 428 Japanese patients revealed even higher rates of poor adherence to topical medication in 52%, and in 49% of those receiving combination therapy. The likelihood of poor adherence to oral medication was higher, both when administered alone (n = 30; 93% poor adherence) and when given as part of a combination regimen (n = 275; 86%) [91].

Identifying poor adherence helps clinicians to focus their educational efforts to improve adherence and optimize outcomes by means of skilled counseling, consideration of the patient’s perspective, effective means of educating the patient; and simple, effective, tolerable regimens that are compatible with the patient’s lifestyle [29]. It has been shown that simply asking about adherence can identify more than 50% of cases of nonadherence. The use of clinical photographs may help patients to understand discussion of acne lesions. For dermatologists, it is vital to know that information about acne is most often obtained from family physicians, mass media and friends or relatives, and that patients usually expect acne to be treated within a few weeks. Taking the time for initial education of patients, including also the detailed mode of application, can help them cope with medication side effects and develop proper expectations for treatment.

Main reasons declared for missing treatments were being fed up, forgetful and too busy. Strategies to help patients manage their schedules and routines in a manner that will facilitate medication adherence could possibly consist of medication reminders (text messages), self-monitoring with diaries, rewards for adherence, support groups and telephone follow-up. However, in a recent small study conducted in 40 patients with mild-to-moderate acne, electronic reminders in the form of daily and customized text messages were not associated with significant differences in adherence to topical medications and had no significant effect on therapeutic response [92].

Alternative & emerging therapies

With regard to the need to prevent antibiotic resistance, nonantibiotic substances with anti-inflammatory and antibacterial effect would provide a potential benefit in the treatment of acne. The existing experimental and human studies of phytotherapeutics in acne therapy were recently reviewed [93]. Various natural substances and herbs showed anti-inflammatory effect in in vitro or animal studies and some substances were successfully tested in humans. Eleven human studies revealed that Camellia sinensis has 5α-reductase inhibitory and anti-inflammatory activity, and antibacterial effect was shown by oleoresin of Commiphora mukul. However, randomized, large double-blind studies showing comparable or superior efficacy to established treatments are lacking.

Experimental data showed that lauric acid (C12:0), a middle chain-free fatty acid commonly found in natural products, has stronger antimicrobial properties than BPO and effectively decreased the number of P. acnes colonized in mouse ears, thereby relieving P. acnes-induced ear swelling and granulomatous inflammation. The obtained data suggest the potential future use of lauric acid as an alternative treatment for antibiotic therapy of acne vulgaris [94]. The use of the topical antiseptic octenidine dihydrochloride/2-phenoxyethanol decreased inflammatory acne lesions by 50% in a 6-week regimen studied in an open labeled clinical trial involving 30 patients [95], and in the future, might be used as alternative antimicrobial agent in combination therapies of acne.

The superpotent α-melanocyte stimulating hormone analog, afamelanotide, has recently been shown to have anti-inflammatory effects in three patients with mild-to-moderate acne vulgaris as a sustained-release resorbable subcutaneous implant formulation [96].

Cortexolone 17α-propionate 1% cream, a new potent topical antiandrogen, was evaluated in a randomized, double-blind comparative study versus placebo and tretinoin 0.05% cream, and was significantly better than placebo, well tolerated and clinically more effective than the comparator [97].

A double-blind controlled trial demonstrated that efficacy of acupuncture treatment of moderate acne vulgaris was associated with reduction of inflammatory lesions and improvement of the QoL [98].

The use of biologics in acne therapy should be limited to very severe fulminant acne or acne forms as part of systemic inflammatory syndromes (e.g., synovitis-acne-pustulosis hyperostosis-osteomyelitis syndrome) [99], because cases of acne induction by TNF-α antagonists have also been reported [100].

Expert commentary

The management of acne remains complex and new pathophysiological insights request a more multifactorial approach to control the condition, because to date, available therapies are still incapable of providing a cure.

The chronic nature of the disease, at least for a limited life-time period of 5–10 years or even more, requires the definition of long-term therapeutic strategies that are safe and effective and have no negative impact, neither on the individual or on the whole population.

The recently introduced topical fixed combinations combine increased and synergistic efficacy of their single compounds and provide application convenience. Furthermore, the patient’s perspective, their education and QoL represent essential constituents for their adherence, and are increasingly recognized as indispensable factors to achieve long-term therapeutic success, which is reflected in numerous recent trials investigating mainly QoL measures.

In addition, the role of exogenous ‘lifestyle’-associated factors and patient-related ‘risk factors’ identified to influence the course of acne will require, beside prescription of evidence-supported medications, a more individualized, patient-oriented and time-consuming acne consultation in the future to implement management strategies to prevent or minimize the impact of the disease.

Five-year view

Although the effect of low-glycemic index diets in acne has been shown in strictly controlled clinical trials, it is questionable whether this will be translatable to everyday practice, because patient education and adherence is mandatory, especially in strategies aiming at changing the lifestyle [27]. The analysis of milk ingredients potentially aggravating acne will be further addressed in the next years.

Therapeutic strategies will focus more and more on patient-related factors and measures to ensure adherence. The increasing use of nonantibiotic, antimicrobial therapy to overcome bacterial resistance should ideally be amended by either prevention of P. acnes-induced inflammation via vaccination [101], or by targeting P. acnes-aggravated downstream inflammatory cascades, such as oxidative stress [102].

Substances or strategies being on the cusp of emerging as potential acne treatments or currently under clinical investigation are anti-inflammatory agents, such as leukotriene antagonists [103], ectopeptidase inhibitors [104], dietary interventions (e.g., ‘chocolate’ NCT01193764), the topically applied N-methyl-D-aspartate-receptor antagonist Neramexane (ID: EUCTR2011-004998-83-DE), Botulinum Neurotoxin Type A (ANT-1207) (ID: NCT01293552) and Gevokizumab, an anti-IL-1β monoclonal antibody (ID: NCT01498874).

Key issues

• • In comedonal acne, a topical monotherapy is recommended, consisting of retinoids (adapalene > tretinoin, isotretinoin) as first-line therapy, followed by azelaic acid or benzoyl peroxide (BPO).

• • The combination of retinoids or antimicrobials with complementary mode of action significantly increases efficacy against acne lesions and leads to a faster onset of clinical improvement, which can be optimized by fixed combinations enhancing patient adherence.

• • In mild-to-moderate papulopustular acne, fixed-dose combinations of BPO plus adapalene or BPO plus clindamycin are recommended as first-line treatments of choice.

• • The nature of acne as a ‘chronic disease’ requires the definition of maintenance treatment regimens. Most evidence is available for retinoids (±BPO) during maintenance treatment due to their multifactorial antiacne efficacy, without inducing bacterial resistance and their ability to prevent microcomedone formation.

• • To prevent the emergence of resistant strains, antibiotic therapy should always be combined with broad-spectrum antibacterial agents (e.g., BPO) and the combination of topical antibiotic and systemic antibiotic therapy, while antibiotic monotherapy should be avoided.

• • Oral isotretinoin is recommended as first-line treatment with a starting dose of 0.3–0.5 mg/kg for severe papulopustular acne/moderate nodular acne and 0.5 mg/kg for conglobate acne given for at least 6 months.

• • Despite the possible association to depression and suicide, current epidemiologic data do not support the refusal of oral isotretinoin automatically to patients with a history of suicide or depression, which are related to the disease itself. However, patients should be screened before and during treatment for depression for up to 1 year after cessation of treatment.

• • Laser and light treatments are currently not recommended as interventional monotherapy, but provide short-term benefit in patients who tolerate some initial discomfort, while long-term benefits are unknown.

• • Screening for adherence, counseling about measures to reduce side effects, patient education about the course of acne and convenient application of treatments are important factors to ensure patient adherence, which has been identified as a vital factor to ensure therapeutic success.

• • Strict low glycemic load diets might have a moderate beneficial effect in acne vulgaris after 10–12 weeks, but interventional studies to support the association of consumption of dairy products and acne are still lacking.

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Recent therapeutic developments for acne

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Activity Evaluation: Where 1 is strongly disagree and 5 is strongly agree

	1	2	3	4	5
1. The activity supported the learning objectives.
2. The material was organized clearly for learning to occur.
3. The content learned from this activity will impact my practice.
4. The activity was presented objectively and free of commercial bias.

1. You are seeing a 14-year-old male patient with mild comedonal acne. What is the most preferred treatment for this patient?

• □ A Topical antibiotic monotherapy

• □ B Adapalene plus benzoyl peroxide (BPO) in a fixed-dose combination

• □ C Azelaic acid alone

• □ D Adapalene, followed by azelaic acid or BPO

2. Two years later, the patient has developed moderate papulopustular acne. What should you consider regarding his treatment now?

• □ A Fixed-dose therapy should be avoided due to a high rate of side effects

• □ B Topical antibiotic monotherapy is usually sufficient to control symptoms

• □ C Topical retinoids are superior to BPO and azelaic acid

• □ D BPO plus adapalene or BPO plus clindamycin are good choices of treatment

3. The patient’s acne continues at moderate levels, and you consider augmenting his therapy. Which of the following statements regarding treatment for refractory moderate acne is most accurate?

• □ A Oral antibiotics should always be combined with topical antibiotics

• □ B Clindamycin is the most popular oral antibiotic for acne

• □ C Oral antibiotics should be combined with retinoids, azelaic acid, or BPO

• □ D Doxycycline is associated with an unacceptable risk of gray hyperpigmentation of the skin

4. The patient eventually develops severe cystic acne. What should you consider regarding the management of this condition?

• □ A The dose of isoretinoin should be 0.3 to 0.5 mg/kg

• □ B Isoretinoin should be avoided among patients with a history of depression

• □ C Isoretinoin should be avoided among patients with a history of suicide attempt

• □ D Depression screening is unnecessary during treatment with isoretinoin