From new findings in acne pathogenesis to new approaches in treatment

Transcription

1 DOI: /jdv JEADV REVIEW ARTICLE From new findings in acne pathogenesis to new approaches in treatment H. P. M. Gollnick* Department of Dermatology & Venereology, Otto-von-Guericke University Magdeburg, Magdeburg, Germany *Correspondence: H. P. M. Gollnick. Abstract Acne is a chronic disease of the pilosebaceous unit which is most common during adolescence. Four factors are believed to play a key role in the development of acne lesions: excess sebum production, disturbed keratinization within the follicle, colonization of the pilosebaceous duct by Propionibacterium acnes, and the release of inflammatory mediators into the skin. Consequently, in order to effectively and rapidly reduce acne lesions, treatments need to address as many of these underlying factors as possible. Currently, about half of patients have poor adherence to acne treatments. To overcome this limitation, treatments need to be developed which are well tolerated by patients, and easy for them to use, handle and apply. Topical monotherapies for acne such as retinoids and antimicrobials by themselves have a restricted range of actions against the pathogenic factors of acne. Instead, the Global Alliance to Improve Outcomes in Acne Group recommends combination therapy with a topical retinoid and an antimicrobial agent as the preferred approach for almost all acne patients. The principal advantage of such combinations is that they target more of the underlying pathogenic factors of acne than individual monotherapies and this results in faster and more complete clearing of acne lesions. Fixed-dose combinations are also more convenient than applying two medications separately, which leads to improved adherence with the regimen. By normalizing desquamation, the retinoid component of these combinations allows entry of the antimicrobial agent into the pilosebaceous unit resulting in faster clearance of P. acnes. In conclusion, topical retinoid/antimicrobial fixed-dose combinations represent a rational approach for the treatment of acne. They should be considered as the cornerstone of acne management and should be used much more in the future. Received: 09 March 2015; Accepted: 14 April 2015 Conflict of interest HG has been, over the last decade, a speaker at several symposia sponsored by Meda, Galderma, Roche-Posay, Intendis, GSK, Hermal-Almiral. He was invited to attend advisory boards of Galderma, Meda, Novartis, Intendis, Hermal-Almirall. Funding source This supplement was funded by Meda Pharma GmbH & Co. KG. Introduction Acne is a disease of the pilosebaceous unit which usually presents on areas of the body with the highest density of these units such as the face, neck, upper chest, shoulders and back. 1 The disease is now considered to be a chronic and relapsing inflammatory condition which varies in severity and which may require long-term treatment. 2 Acne is most prevalent during the teenage years affecting over 80% of adolescents. 3 A recent cross-sectional study of 1277 schoolchildren from Lithuania showed that the age of onset of acne is becoming earlier with 42% of those aged 7 9 years and 76% of those aged years having acne. 4 This earlier onset of acne may be due to puberty occurring at an earlier age, 5 although the disease is also apparent in pre-pubertal individuals. Acne is also becoming more prevalent in adulthood with 64% of those in their 20s and 43% of those in their 30s suffering from the condition and with higher prevalence rates in adult women than men. 5,6 The increasing prevalence of acne, together with the physical, psychological and social impact of the disease, 1 means that there has never been a greater need for effective and well tolerated treatments. In this article, I discuss the latest understanding of acne pathogenesis and examine how this informs our understanding of the medical needs of acne treatments. I also review the main classes of topical treatment for acne and argue that fixed-dose combination therapies represent a rational approach for treating the disease. In subsequent articles in this supplement, Prof

2 2 Gollnick Ochsendorf discusses the key properties of clindamycin 1% (as clindamycin phosphate 1.2%)/tretinoin 0.025% (Clin-RA) a novel fixed-dose combination for the treatment of acne. Prof Brigitte Dreno concludes by examining the topic of adult female acne and the specific challenges of treating these patients. The articles in this supplement are based on a symposium held at the 23 rd Congress of the European Academy of Dermatology and Venereology on 10 th October Acne pathogenesis Acne is a multifactorial disease which originates in the pilosebaceous unit. It involves the interplay of four main factors: excess sebum production, disturbed keratinization within the follicle, colonization of the pilosebaceous duct by the oxygen-tolerant, anaerobic bacterium Propionibacterium acnes, and the release of inflammatory mediators into the skin (Fig. 1). 7 A summary of the steps involved in the pathogenesis of acne is shown in Fig. 2. The exact sequence of events which leads to the development of acne lesions is currently not fully understood. However, the first step in the process is believed to be the formation of the microcomedo, which is the precursor to comedones, papules and pustules. 7 This is driven by increased production of sebum due to stimulation of the sebaceous glands and follicular corneocytes, in particular by androgens, usually around the time of puberty. 8 Acne-prone individuals have a higher amount of lobules per sebaceous gland and the overall size of the follicles is increased. 9 Androgens such as dihydrotestosterone (DHT) and testosterone have been shown to stimulate the proliferation of sebocytes from the face, but not the leg, and this differential response may Figure 1 Four key factors involved in acne pathogenesis. Figure 2 Summary of steps involved in the pathogenesis of acne. DC, dendritic cell; FFA, free fatty acid; IL, interleukin; PMN, polymorphonuclear cells; TNF, tumour necrosis factor. account for the specific localization of acne lesions on the body. 10 Recent work suggests that the formation of sebocytes is regulated by several molecular pathways (e.g. Lef-1, Blimp1, Wnt, C-myc) and that sebocyte activity is controlled via a range of cellular pathways and hormones in addition to androgens including, for example, peroxisome proliferator-activated receptors, substance P receptors, a-melanocyte-stimulating hormone, insulin-like growth factor, corticotropin-releasing hormone, vitamin D and ectopeptidases At the same time as sebum production is increased, there is also increased proliferation and reduced shedding of intra-follicular keratinocytes causing the pilosebaceous unit to become obstructed. 14 As sebum and keratinocyte debris accumulate in the microcomedo, larger, clinically visible closed or open comedones develop. Colonization of the infra-infundibulum of follicles by P. acnes and the release of inflammatory mediators into the surrounding perifollicular dermis together with attraction of immunocompetent cells leads to the development of inflammatory lesions. P. acnes stimulates inflammation and an immune response through a variety of mechanisms. 15 Pro-inflammatory agents released by P. acnes include lipases, which degrade triglycerides, and proteases, which damage the follicular wall and trigger inflammation, as well as chemotactic factors, which firstly recruit CD4-lymphocytes, and later neutrophils and monocytes to the affected area. In addition, P. acnes activates markers of the innate immune system such as Toll-like receptor 2 (TLR-2) on monocytes and this induces the production of pro-inflammatory cytokines such as interleukin (IL)-8 which subsequently leads to

3 Acne pathogenesis and new treatments 3 the recruitment of neutrophils into the pilosebaceous unit. 16,17 P. acnes interacts with other innate immunity molecules such as antimicrobial peptides and protease-activated receptors. 15 Up-regulation of the production of other pro-inflammatory cytokines such as IL-1a, IL-1b and IL-17, and activation of the inflammasome of peripheral neutrophils by P. acnes may be of further importance. 15,18 Finally, P. acnes itself may act as a superantigen activating cells to proliferate and to accumulate. 19 P. acnes acts on keratinocyte differentiation and contributes to the development of comedones. 15 P. acnes induces the expression of TLR-2 on keratinocytes and the secretion of pro-inflammatory cytokines and matrix metalloproteinase The secretion of this latter molecule enhances follicular rupture, as does invasion of CD4 cells, which further spreads inflammation through the dermis. 15 P. acnes also induces follicular keratinocytes to release IL-1a leading to keratinocyte proliferation and comedone formation. 21 Recent research has shown that P. acnes may be present in the infundibulum of sebaceous follicles in large macrocolonies or biofilms, 22 and these biofilms may affect the responsiveness of P. acnes to antibiotics. 23 P. acnes biofilms secrete a glycocalyx polymer to adhere to the follicular wall and this polymer may also be present in sebum where it increases the adhesiveness of the disturbed shedding keratinocytes leading to the formation of follicular plugs. 24 There is now evidence that distinct subpopulations of P. acnes are associated with moderate-to-severe acne and these are different to those found in healthy skin. 25 Medical needs of acne treatments Acne treatments fall into three broad categories: (i) intervention treatments which aim to eliminate the visible inflammatory and non-inflammatory lesions that characterize the acute presentation of the disease; (ii) maintenance treatments which try to minimize the likelihood of disease relapse; and (iii) adjunctive procedures which focus on improving the appearance of the sequelae of the disease such as scars and post-inflammatory hyperpigmentation (Fig. 3). For the purpose of this article, I will focus on the medical needs for intervention treatments. According to the Global Alliance to Improve Outcomes in Acne Group, the multifactorial nature of the pathogenesis of acne means that in order to be effective, an acne treatment intervention needs to address as many of the causative factors as possible. 7 The treatment should aim to rapidly and effectively reduce acne lesions and to prevent scarring. 26 Ideally, treatments need to have minimal side-effects and acceptable tolerability, as well as being easy for patients to use, handle and apply. 26 Acne treatments also need to meet patient preferences. A conjoint analysis showed that patients prefer gel formulations rather than lotions or creams, and prefer products which can be kept at room temperature rather than being stored in the fridge. This study also showed that patients prefer treatments which they can apply once- rather than twice-daily, and prefer to use their (a) (b) (c) Figure 3 General acne management. OTC, over-the-counter; PDT, photodynamic therapy. fingers for treatment application rather than pads or roller balls. 27 The selection of the most appropriate treatment for an individual patient is also guided factors such as their skin type, their specific type of acne and its severity, and whether they have any co-morbidities. It is also important to take psychosocial factors into consideration as well as determining whether the treatment will fit into the patient s lifestyle. A major global problem with current acne treatments is poor adherence and so there is a need to develop new therapies which encourage better adherence. A study of 3339 patients from the Americas, Europe and Asia showed that 50% had poor adherence. 28 Factors which were associated with poor adherence included young age, side-effects, lack of clinical improvement, lack of patient satisfaction with the treatment and lack of knowledge about acne treatment. 28 Topical acne monotherapies There are two main classes of topical monotherapies for acne treatment: retinoids and antimicrobial agents such as antibiotics and benzoyl peroxide (BPO). These are discussed in detail in the sections below. Retinoids According to the Global Alliance to Improve Outcomes in Acne Group, topical retinoid-based treatment should be the foundation in acne therapy for almost all acne patients except those with the most severe disease. 7 This is due to the mode of action of this class of treatment. Topical retinoids are both comedolytic and anti-comedogenic. 7 They help to normalize the disturbed

4 4 Gollnick differentiation and hyperproliferation of the follicular epithelium, and in so doing, prevent the formation of microcomedones thereby decreasing the formation of both inflammatory and non-inflammatory acne lesions. 7,29,30 By normalizing differentiation and desquamation, topical retinoids also facilitate the entry of other topically applied agents such as antibiotics and BPO into the deeper parts of the pilosebaceous unit. 31 Topical retinoids also have direct and indirect anti-inflammatory effects. 32 For example, tretinoin has been shown to inhibit the expression of TLR-2 on monocytes by 41%. 33 This will decrease the inflammatory cytokine response that the activation of these receptors by P. acnes initiates. Other anti-inflammatory effects of tretinoin include enhancing phagocytic function; suppression of the production of pro-inflammatory cytokines such as IL-6, IL-12, interferon-ɣ and tumour necrosis factor-a by cells such as macrophages and keratinocytes; and a reduction in other pro-inflammatory mediators such as prostaglandins, transcription factor AP-1 and vascular cell adhesion molecule Retinoids are also effective for the treatment of post-inflammatory hyperpigmentation which is particularly important for acne patients from darker racial ethnic groups. For example, a double-blind study which randomized 74 acne patients with post-inflammatory hyperpigmentation to 18 weeks of retinoid or vehicle showed that the retinoid was associated with significantly greater reductions in overall disease severity and in the intensity and area of hyperpigmentation. 34 The main drawback to the majority of topical retinoids is that they are associated with a range of cutaneous side-effects in up to 75% of patients including erythema, scaling, dryness, burning and pruritus. 35 However, certain newer retinoid formulations are associated with substantially less skin irritation. 36,37 Retinoids may also cause acne flaring defined as a transient increase in pustule formation via expulsion of comedones during the first few weeks of treatment. This phenomenon occurs in up to 20% of patients treated with older topical retinoid formulations. 38 Certain formulations of topical retinoids are inactivated by sunlight or BPO which affects the convenience of how the treatment can be used. 39 Topical retinoids are still contraindicated in pregnancy, and women of childbearing age must use effective contraception whilst on treatment. 1 Antibiotics The principal mechanism of action of topical antibiotics is to target P. acnes. 7,40 Some topical antibiotics such as clindamycin also have some anti-comedogenic activity as well as direct and indirect anti-inflammatory effects. 41,42 Clindamycin leads to a decrease in cytotoxic and chemotactic pro-inflammatory substances by directly inhibiting the growth of P. acnes. It also inhibits the production of pro-inflammatory cytokines (e.g. IL-1b, IL-6, interferon-ɣ, tumour necrosis factor-a) in cells such as keratinocytes, monocytes and macrophages. 42 Other reported anti-inflammatory mechanisms of action of clindamycin include a decrease in the level of follicular free fatty acids, a reduction in leucocyte chemotaxis, an inhibition of the respiratory burst in macrophages and an enhancement of phagocytosis. 42 Antibiotics have also been reported to increase the production of ceramides by follicular corneocytes. 41 Antibiotics are commonly prescribed to treat acne due to their inexpensive cost and lack of local side-effects. However, antibiotics are no longer recommended as monotherapy in consensus papers from the Global Alliance to Improve Outcomes in Acne Group and the S3 guideline of the European Dermatology Forum due to the growing worldwide problem of antibiotic resistance. 7,13,43 Studies have shown that up to 94% of acne patients have propionibacteria on their skin that are resistant to at least one antibiotic, with the rates of resistance varying according to the antibiotic studied and the geographic region, and with multidrug resistance also being common Evidence suggests that topical antibiotics not only increase the levels of antibiotic-resistant propionibacteria, but also lead to an increase in the prevalence and density of other antibiotic-resistant bacteria such as staphylococci. 47 An analysis of clinical studies of topical erythromycin in acne patients has shown a gradual decrease in its efficacy over time, which is considered to be related to the development of antibiotic-resistant propionibacteria. 48 In contrast, the efficacy of clindamycin has remained quite stable since its widespread introduction in the mid-1970s. 48 Given the growing concerns about antibiotic resistance, the Global Alliance has issued a set of recommendations to limit the development of antibiotic resistance during acne treatment. 7,43 One of their key recommendations is to treat patients with a combination of a topical retinoid and an antimicrobial agent rather than using an antibiotic alone (see section below on fixed-dose combination therapy). Benzoyl peroxide Another topical antimicrobial agent that is used to treat acne is BPO. The primary mode of action of BPO is to destroy P. acnes. It also has anti-inflammatory properties, but only weak activity against comedones (<20%). 40,49 The main advantage of BPO compared with topical antibiotics is that BPO is not associated with the development of bacterial resistance. 40,49 Drawbacks to the use of BPO include side-effects such as cutaneous irritation or dryness, and patients may find the treatment unacceptable as it can cause bleaching of hair, clothes and bed linens. 40,49 BPO may also cause allergic contact dermatitis in some acne patients. 49 In the future, new galenic formulations and lower concentrations may overcome some of these problems. Fixed-dose combination therapies: the future of topical acne treatment Fixed-dose combination topical therapies need to be used to treat more and more acne patients. The Global Alliance to Improve Outcomes in Acne Group recommends combination

5 Acne pathogenesis and new treatments 5 Table 1 Pathogenic targets of topical acne treatments. Topical treatment Sebum production Keratinization Bacterial colonization Inflammation Retinoids ++ + Antibiotics ++ + BPO ++ (+) Retinoid/antimicrobial combination , no effect; +, mild effect; ++, strong effect. BPO, benzoyl peroxide. therapy with a topical retinoid and an antimicrobial agent as the preferred approach for almost all acne patients. 7 In the latest S3 guidelines from the European Dermatology Forum, fixed-dose combinations have a high strength of recommendation for the treatment of patients with mild-to-moderate papulopustular acne. 13 The principal benefit of fixed-dose combinations of retinoids and antimicrobials is that the complementary mechanisms of action of these monotherapies enables three out of the four major pathogenic factors of acne to be targeted, namely follicular plugging, P. acnes colonization, and inflammation (Table 1). 7 Monotherapies themselves are unable to counter as many of the different areas of the pathophysiology of acne. This effective targeting of the pathogenic factors of acne translates into more rapid and effective clearance of both inflammatory and non-inflammatory acne lesions than either monotherapy alone. 7 Another key advantage of fixed-dose combinations is that they offer patients greater convenience compared with having to apply two separate medications at different times of the day. This translates into improved treatment adherence and clinical outcomes as demonstrated in a 12-week study which randomized 26 patients with mild-to-moderate acne to once-daily application with a fixed-dose combination gel containing clindamycin and tretinoin or to separate daily applications of clindamycin gel and tretinoin cream. The median adherence was greater in the fixed-dose combination group compared with the group that applied the medications separately (88% vs 61%) as was the mean percentage reduction in total lesions at the end of the study (51% vs 32%, respectively, Fig. 4). 50 A further benefit of retinoid/antibiotic fixed-dose combinations is that the retinoid normalizes desquamation which permits the antibiotic to accumulate to a higher concentration in the pilosebaceous unit where colonization with P. acnes occurs. 7,51 Consequently, topical retinoid/antibiotic combinations eliminate P. acnes faster and more effectively than antibiotic monotherapy, and ultimately, this may lower the potential for the emergence of antibiotic-resistant bacteria. 52 Fixed-dose combinations which combine two agents with similar modes of action such as two antimicrobial agents are generally regarded as suboptimal. 31 This is because these combinations do not contain a retinoid, and so are unable to target microcomedones and comedones as antimicrobials are only (a) (b) Figure 4 Comparison of (a) adherence and (b) clinical outcomes with fixed-dose retinoid/antibiotic combination vs. separate application of medications. C, clindamycin phosphate; T, tretinoin. mildly comedolytic. Consequently, clinical studies of such combinations have shown that they are less effective against noninflammatory acne lesions. 53

6 6 Gollnick Conclusions Acne is a prevalent and chronic skin disease with a high psychosocial impact. Given that the pathogenesis of the disease is multifactorial, effective acne treatments need to target as many of the causative factors as possible. Topical antibiotics should no longer be used as a monotherapy for acne since antibiotic resistance has been shown to be a significant and growing global problem, and since this monotherapy only targets a limited range of the causative factors for acne. The latest understanding of the multifactorial pathophysiology of acne means that fixed-dose combination therapy with retinoids and antimicrobials is a rational and effective strategy for managing acne as most of the multiple pathogenic factors are targeted, resulting in faster and more complete clearance of acne lesions compared with monotherapies. Fixed-dose combinations also offer patients the benefit of improved convenience, which can increase adherence with the therapeutic regimen. Accordingly, combination treatment with topical retinoids and antimicrobials should now be considered as the cornerstone of acne management. Acknowledgements Editorial assistance in the preparation of this manuscript was provided by David Harrison, Medscript Communications, funded by Meda Pharma GmbH & Co. KG. References 1 Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet 2012; 379: Gollnick HP, Finlay AY, Shear N. Can we define acne as a chronic disease? If so, how and when? Am J Clin Dermatol 2008; 9: Rademaker M, Garioch JJ, Simpson NB. Acne in schoolchildren: no longer a concern for dermatologists. BMJ 1989; 298: Karciauskiene J, Valiukeviciene S, Gollnick H, Stang A. The prevalence and risk factors of adolescent acne among schoolchildren in Lithuania: a cross-sectional study. J Eur Acad Dermatol Venereol 2014; 28: Bhate K, Williams HC. Epidemiology of acne vulgaris. Br J Dermatol 2013; 168: Collier CN, Harper JC, Cafardi JA et al. 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