Treatment of adult female acne: a new challenge

Transcription

1 DOI: /jdv JEADV REVIEW ARTICLE Treatment of adult female acne: a new challenge B. Dreno* Department of Dermato-Cancerology, University of Nantes, Nantes, France *Correspondence: B. Dreno. brigitte.dreno@wanadoo.fr Abstract Acne is affecting an increasing number of adult females and so can no longer be considered as a disease of adolescence. The disease has a greater negative impact on the quality of life of adult females than their younger counterparts. Adult female acne may persist from adolescence or may have its first occurrence once adulthood has been reached. The clinical presentation and pathogenesis of adult female acne may be somewhat different to that of adolescent acne and this may require a different treatment approach. Genetic and hormonal factors are thought to play key roles in the pathogenesis of adult female acne and the disease is characterized by a chronic evolution with frequent relapses requiring long-term maintenance therapy. Fixed-dose retinoid/antimicrobial combinations may be of interest for the treatment of adult female acne given that subgroup analysis of clinical trials has indicated that they are effective against both inflammatory and non-inflammatory lesions in these patients. These treatments may also be of interest, given the chronic course of the disease in adult females, the high likelihood of the presence of antibiotic-resistant P. acnes and the poor adherence of patients to other long-term therapies. Oral hormonal treatment or isotretinoin may be required in patients with severe acne or disease that is refractory to other treatments. Additional clinical studies of acne treatments specifically conducted in adult female patients are required to increase the evidence base on which future treatment recommendations can be based. Received: 09 March 2015; Accepted: 14 April 2015 Funding source This supplement was funded by Meda Pharma GmbH & Co. KG. Conflict of interest BD has served as a consultant for Meda, Galderma, Fabre. Introduction Although acne is traditionally considered to be a disease which affects teenagers, recent research has shown that acne is affecting an increasing number of adults, particularly females. 1 This skin condition can have a substantial negative psychosocial and emotional impact on affected adults with older female patients reporting a greater impact of acne on their quality of life than younger patients. 2,3 Acne is characterized by the presence of inflammatory and non-inflammatory lesions and can lead to some degree of facial scarring in up to 20% of those affected with the likelihood of scarring increasing as the disease persists. 4,5 The aim of this article is to discuss the pathophysiological and clinical evidence which indicates that adult female acne should be considered as a specific acne subtype distinct from adolescent acne and to review topical and oral treatment options which may be particularly suitable for treating acne in adult females. Prevalence Acne is a common disease in adult females. The overall prevalence rates of adult female acne have been reported in different studies to range from 14% to 54%. 6 9 These variations in prevalence rates are likely to be due to differences in the design of the studies, with self-reported prevalence rates being higher than those from clinical studies. The results of several age-stratified surveys have shown that a substantial proportion of women experience acne in adulthood, with the prevalence generally declining with increasing age Representative results from one survey which documented the self-reported prevalence of acne in 540 adult females are shown in Fig. 1. Of particular note, over a quarter of the women included in this survey had acne beyond the age of 40 as did 15% of those aged over Two surveys have shown that adult women in different age categories have a significantly higher prevalence of acne than adult men. 10,11 In one of these surveys, a greater proportion of women than men reported that their acne worsened in adulthood (13.3% vs. 3.6%). 11 One survey of 3305 French adult women aged years reported that 49% of those with acne had sequelae such as scars and/or pigmented macules. 6 The prevalence of adult female acne is rising. 13 One investigation into adult acne reported an increasing rate of referrals of

2 Adult female acne 15 Figure 1 Prevalence of adult female acne (n = 540). 11 patients aged over 25 years over the previous decade. The mean age at which acne patients were referred increased from 20.5 years in 1984 to 26.5 years in This increasing prevalence of adult female acne has been postulated to be related to factors such as the stress of modern life and sleep deprivation. 15 The prevalence of adult female acne is different among different ethnic groups. A study into 2895 women of different ethnicities showed that acne was more prevalent in women of darker skin types (African American, 37%; Hispanic, 32%) than those with lighter skin types (Asian, 30%; Caucasian, 24%; Continental Indian, 23%). 16 In Asian women, inflammatory acne was more prevalent than non-inflammatory acne (20% vs. 10%), whereas in Caucasians, non-inflammatory acne was more prevalent (14% vs. 10%). The prevalence of these two subtypes of acne was similar in the other racial groups. 16 Clinical presentation There are two main subtypes of adult female acne. Persistent acne is acne which continues from adolescence into adulthood sometimes with periods of remission. This is the most common subtype of adult female acne being present in approximately 80% of cases. 1,17,18 Late-onset acne occurs in approximately 20% of women with adult female acne and this subtype has its first onset long after puberty, most often between the age of 21 and 25 years. 1,17,18 Women with late-onset acne have significantly fewer comedones and a lower proportion of comedones than women with early-onset acne. 19 Furthermore, adults with lateonset acne often have larger pores than individuals of the same age without acne. 18 The clinical presentation of adult female acne is typically considered to be different to that of adolescent acne. Adult acne usually presents gradually and is mild-to-moderate in severity in contrast to adolescent acne which may develop rapidly and present as severe disease. 1,17 Adult female acne has traditionally been viewed as presenting with two main clinical profiles. 17 One profile consists of hyperseborrhoea and predominant diffuse noninflammatory lesions; these are mostly small closed comedones with open comedones being rare. The other profile consists of predominant inflammatory lesions. These can be either mild-tomoderate superficial inflammatory lesions or deep-seated, longlasting nodules and cysts on the lower third of the face, jaw-line and neck (i.e. chin acne ). This traditional view of the clinical presentation of adult female acne has recently been challenged by an observational, prospective, international study in 374 adult females with acne. 20 The results showed that 90% of women had acne involving multiple areas of the face (cheeks, forehead, mandibles, temples) and they had a range of acne severity similar to that observed in adolescents. Most women had both inflammatory and non-inflammatory acne lesions, with just 6.4% having only inflammatory lesions and 17.1% having only comedonal acne. 20 In addition, only 11.2% had acne localized specifically to the mandibular area. Whilst the face is the most common site of disease presentation, extrafacial areas such as the upper back, chest and shoulders may be affected in up to 50% of adult female patients. 20,21 Pathogenesis Similar to adolescent acne, the pathogenesis of adult female acne involves the interplay of excess sebum production, abnormal keratinization within the follicle and bacterial colonization of the pilosebaceous duct by Propionibacterium acnes. 22 However, the influence of these different factors may be somewhat different in adult female acne compared with adolescent acne and this will ultimately necessitate a slightly different treatment approach. Studies have shown that genetic factors play a strong role in the pathogenesis of adult female acne. Indeed, it has been shown that a history of acne can be identified in at least one first degree relative of 67% of adult females with acne aged 25 years or older. 21 And another study comparing 204 adults with persistent acne with 144 non-acne controls showed that relatives of patients with persistent adult acne had a significantly greater risk of adult acne than relatives of people without acne (odds ratio: 3.93; 95% confidence interval: ; P < 0.001). 23 Hormonal factors are also likely to play a role in the pathogenesis of adult female acne. Studies have shown that 39 85% of adult women with acne have worsening of their acne in the days before menstruation. 6,11,14,24 26 The rate of premenstrual acne flares is significantly higher in older women (aged over 30 years, 53%) compared to younger adults (20 33 years, 39%; P = 0.03). 26 The high frequency of seborrhoea in adult female acne also suggests that hormonal factors in association with genetic factors may be involved. 21 However, studies of ovarian

3 16 Dreno Table 1 Treatment recommendations for acne and alternatives for females Global Alliance Acne Treatment Algorithm 22 Mild comedonal Mild mixed and papular/pustular Moderate mixed and papular/pustular Moderate nodular Severe nodular conglobate 1st Choice Topical retinoid Topical retinoid + topical antimicrobial Oral antibiotic + topical retinoid BPO Alternatives for females Oral anti-androgen + topical retinoid/azelaic acid topical antimicrobial European Dermatology Forum 29 Oral antibiotic + topical retinoid + BPO Oral anti-androgen + topical retinoid/ oral antibiotic alternative antimicrobial Oral isotretinoin High dose oral antiandrogen + topical retinoid alternative topical antimicrobial Comedonal acne Mild-to-moderate papulopustular acne Severe papulopustular/ moderate nodular acne Severe nodular/ conglobate acne High strength of recommendation Adapalene + BPO BPO + clindamycin Isotretinoin Alternatives for females Hormonal anti-androgens + topical treatment Or Hormonal anti-androgens + systemic antibiotics Isotretinoin Hormonal anti-androgens + systemic antibiotics and adrenal androgenic hormone levels in the serum of adult females with acne have not shown any clear patterns of abnormalities. 18 Whilst several significant increases in androgen levels have been detected in women with adult-onset acne and hirsutism compared with healthy controls (e.g. luteinizing hormone, follicle-stimulating hormone, testosterone, dihydroepiandrosterone sulphate [DHEA-S]), only the level of DHEA-S was shown to be mildly to moderately elevated in women with adult-onset acne without hirsutism compared with controls (266 vs. 201 ɥg/ dl, respectively; P = 0.03). 27 The lack of androgen hormone abnormalities in adult female acne suggests that hormonal receptors expressed by both sebocytes and keratinocytes may be more sensitive to low levels of androgens in these patients and/ or there may be an increased local metabolism of androgens by enzymes. 17,18,28 Another key factor in the pathogenesis of adult female acne is chronic activation of cutaneous innate immunity which may be driven by the long duration of acne and higher levels of antibiotic-resistant P. acnes selected by previous long-term use of topical and systemic antibiotics. 14,17 Treatment of adult female acne The principal recommendations from the Global Alliance to Improve Outcomes in Acne Group and the European Dermatology Forum for the treatment of female acne are shown in Table 1 and discussed in more detail in the sections below. 22,29 Adult female acne is characterized by a chronic evolution with frequent relapses requiring long-term maintenance therapy. 1 One study of 200 adults with acne aged over 25 years showed that 82% relapsed after multiple courses of oral antibiotics and 32% relapsed after one or more course of oral isotretinoin. 14 Other factors need to be taken into consideration when selecting a treatment for adult females such as the slow response to therapy of this group of patients, their childbearing potential, the increased likelihood of skin irritation and the high psychosocial impact of the disease. 30 Treatment choice is also guided by the severity of acne, response to prior treatments, patient preferences and cost. The use of moisturisers and gentle, non-soap cleansers with a ph close to that of the skin is recommended as part of the therapeutic regimen for adult females with acne. 30 Topical treatments Topical retinoid monotherapy is recommended in adult females with mild comedonal acne. 22,29 However, it is important to recognize that older patients may be more susceptible to the skin irritation that these agents may cause suggesting that formulations which are less irritating may be beneficial. 18,31 Fixed-dose combinations such as retinoid/antimicrobial combinations are recommended in adult females with mild-to-moderate papulopustular acne. 22,29 However, to date, there have not been any clinical trials with topical treatments which have only included adult females with acne. Clindamycin 1% (as clindamycin phosphate 1.2%)/tretinoin 0.025% (Clin-RA) is a new fixed-dose topical combination treatment which was shown in a pooled analysis of three pivotal 12-week studies involving over 4500 acne patients to be safe and

4 Adult female acne 17 (a) (b) Figure 2 Effect of Clin-RA and its components on adult male and female acne: (a) inflammatory lesions; (b) non-inflammatory lesions. *P < 0.03 vs. Clin-RA; **P < 0.02 vs. Clin-RA. Adult defined as age 18 years. Clin-RA, clindamycin phosphate 1.2%/ tretinoin 0.025%. effective in the treatment of acne when comedones, papules and pustules are present. 32 A subgroup analysis of the pooled results including only adult patients aged 18 years or older (1194 females and 438 males) showed that the median percentage reduction in inflammatory lesions with Clin-RA from baseline to week 12 was numerically greater in adult females compared with males (72.4% vs. 66.7%) as was the median percentage reduction in non-inflammatory lesions (55.2% vs. 53.3%; Fig. 2). Taking into consideration only the adult females, Clin-RA was shown to be significantly more effective at reducing inflammatory lesions than clindamycin, tretinoin and vehicle (72.4% vs. 63.3%, 57.7% and 55.7% respectively; P < 0.03). Clin-RA was also significantly more effective at reducing non-inflammatory lesions than clindamycin in adult females (55.2% vs. 43.8% respectively; P < 0.02). In addition to its efficacy against inflammatory and noninflammatory lesions in adult females with acne, Clin-RA may be a useful treatment option in this acne subgroup since it is not associated with an increase in antibiotic-resistant P. acnes counts and has even been shown to be effective at clearing clindamycin resistant P. acnes These considerations are important given that resistant P. acnes strains are common in adult females since these patients have often been treated with several previous courses of topical and systemic antibiotic therapy. Given that adult females often have a slow response to treatment, adherence to the therapeutic regimen is of particular importance. In this regard, it is noteworthy that patient adherence to a fixed-dose combination gel containing clindamycin and tretinoin was higher than when patients applied the treatments separately. 36 Oral treatments Adult females with chronic deep-seated inflammatory lesions may require systemic treatment. Long-term oral antibiotic monotherapy is not recommended due to the growing problem of antibiotic resistance. 22,29 Furthermore, around 80% of adult females with acne are refractory to this type of treatment. 14 Oral contraceptives may be the first hormonal therapy used to treat adult female acne when peripheral hyperandrogenemia is noted specifically with flare-ups before menstruation. The third generation progestins (e.g. desogestrel) have the lowest androgenic activity and so are preferred to progestins with intrinsic androgenic activity which may cause worsening of acne. 18 Since hormonal therapy targets excess sebum production, they are usually combined with treatments which are directed against the other pathogenic factors of acne. 30 Due to thromboembolic risk, it is important to check whether the patient has any history of thrombosis, pulmonary embolism, phlebitis or any other coagulation abnormalities before initiating treatment. Anti-androgens (e.g. cyproterone and spironolactone) may be added to contraceptive therapy if there is no improvement in acne after 3 6 cycles. 18 Spironolactone which has anti androgenic activity (due to inhibition of 5-alpha reductase) is typically reserved for adult females with acne that is refractory to conventional treatment. Low doses of spironolactone are generally used to improve the tolerability of this treatment ( mg daily). If patients are using spironolactone as monotherapy, then adequate contraception needs to be used to avoid exposure to the drug during pregnancy since this can lead to male fetal abnormalities. 37 The therapeutic response usually occurs within 2 months of starting therapy. One study of 14 adult females with acne who had failed to respond to isotretinoin showed that low-dose spironolactone mg/ day may be a useful therapeutic alternative. A clinical response

5 18 Dreno (defined as 50% reduction in total lesions) was detected after an average treatment period of 17 months in 50% of cases with facial lesions and 37.5% of those with acne on the back. 38 A retrospective chart review of 85 women with acne treated with spironolactone mg/day also showed the usefulness of this treatment either as a monotherapy or in combination with other therapies. The patients were treated for up to 2 years with 33% being cleared of their acne and 33% having a marked improvement. 39 A small prospective study of 27 women with severe papular and nodulocystic acne showed that combined therapy with an oral contraceptive and spironolactone 100 mg/day was effective with 85% of patients being clear of lesions or having 75% lesion clearance after 6 months. 40 Isotretinoin may be considered in adult female patients with severe acne and in those with less severe acne that is refractory to standard therapies. 18 The starting dose recommended by the European Directive for Prescribing Systemic Isotretinoin for severe acne is 0.5 mg/kg/day with subsequent adjustments based on efficacy and tolerability, and complete responses seen 4 6 months after treatment initiation. Patients initiating treatment with oral isotretinoin need to have a negative pregnancy test and to use adequate contraception, given that this treatment is a potent teratogen, according to the European recommendations. 18 Positive predictors of therapeutic response to isotretinoin 0.5 mg/kg/day in a study of 32 adult females with acne included a low body mass index, late-onset acne and not being a tobacco user. This regimen given for 6 months was associated with a complete response on the face in 59% of patients, on the trunk in 80% of patients and on both the face and the trunk in 43% of patients. 41 Low doses of mg/day and/or intermittent regimens may be suitable for adult female patients with less severe acne that has not responded to other treatments. 13,18 A study of isotretinoin 0.5 mg/kg/day for 1 week out of every four in 80 patients aged over 25 years with acne that was refractory to antibiotic therapy showed that this intermittent regimen was well tolerated and effective with 88% of patients being cleared of their acne after 6 months. 42 Conclusions Adult female acne affects around 40% of women and the prevalence of the disease in adult women is increasing. Adult female acne is considered to be different to adolescent acne both in terms of its clinical presentation and pathogenesis. These differences necessitate alternative approaches to the treatment of adult female acne. Fixed-dose retinoid/antimicrobial combinations may be of interest for the treatment of adult female acne when comedones, papules and pustules are present, given that subgroup analyses of clinical trials have indicated their efficacy against inflammatory and non-inflammatory lesions in these patients. Fixed-dose combinations may also be of interest for adult female acne taking into account the chronic evolution of the disease, the high likelihood of carriage of antibiotic-resistant P. acnes strains and the poor adherence of patients to other long-term therapies. New retinoid-based formulations which are better tolerated may also be beneficial for adult females, given that these patients may be more susceptible to the skin irritation these agents cause. Adult females presenting with more severe acne or acne that is refractory to standard therapies may require hormonal treatment or isotretinoin. Future clinical studies of acne treatments should be performed in separate populations of adult and adolescent females to provide objective evidence of efficacy and safety in these different acne subtypes. 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 Holzmann R, Shakery K. Postadolescent acne in females. Skin Pharmacol Physiol 2014; 27(Suppl. 1): Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch Dermatol 1998; 134: Tan JK, Li Y, Fung K et al. Divergence of demographic factors associated with clinical severity compared with quality of life impact in acne. J Cutan Med Surg 2008; 12: Williams HC, Dellavalle RP, Garner S. Acne vulgaris. Lancet 2012; 379: Layton AM, Henderson CA, Cunliffe WJ. A clinical evaluation of acne scarring and its incidence. Clin Exp Dermatol 1994; 19: Poli F, Dreno B, Verschoore M. An epidemiological study of acne in female adults: results of a survey conducted in France. J Eur Acad Dermatol Venereol 2001; 15: Stern RS. The prevalence of acne on the basis of physical examination. J Am Acad Dermatol 1992; 26: Goulden V, Stables GI, Cunliffe WJ. Prevalence of facial acne in adults. J Am Acad Dermatol 1999; 41: Plunkett A, Merlin K, Gill D, Zuo Y, Jolley D, Marks R. The frequency of common nonmalignant skin conditions in adults in central Victoria, Australia. Int J Dermatol 1999; 38: Cunliffe WJ, Gould DJ. Prevalence of facial acne vulgaris in late adolescence and in adults. Br Med J 1979; 1: Collier CN, Harper JC, Cafardi JA et al. The prevalence of acne in adults 20 years and older. J Am Acad Dermatol 2008; 58: Perkins AC, Maglione J, Hillebrand GG, Miyamoto K, Kimball AB. Acne vulgaris in women: prevalence across the life span. J Womens Health (Larchmt) 2012; 21: Kim GK, Michaels BB. Post-adolescent acne in women: more common and more clinical considerations. J Drugs Dermatol 2012; 11: Goulden V, Clark SM, Cunliffe WJ. Post-adolescent acne: a review of clinical features. Br J Dermatol 1997; 136: Albuquerque RG, Rocha MA, Bagatin E, Tufik S, Andersen ML. Could adult female acne be associated with modern life? Arch Dermatol Res 2014; 306: Perkins AC, Cheng CE, Hillebrand GG, Miyamoto K, Kimball AB. Comparison of the epidemiology of acne vulgaris among Caucasian, Asian, Continental Indian and African American women. J Eur Acad Dermatol Venereol 2011; 25: Preneau S, Dreno B. Female acne a different subtype of teenager acne? J Eur Acad Dermatol Venereol 2012; 26:

6 Adult female acne Williams C, Layton AM. Persistent acne in women: implications for the patient and for therapy. Am J Clin Dermatol 2006; 7: Choi CW, Lee DH, Kim HS, Kim BY, Park KC, Youn SW. The clinical features of late onset acne compared with early onset acne in women. J Eur Acad Dermatol Venereol 2011; 25: Dreno B, Thiboutot D, Layton AM, Berson D, Perez M, Kang S. Largescale international study enhances understanding of an emerging acne population: adult females. J Eur Acad Dermatol Venereol 2014; Oct 8. doi: /jdv [Epub ahead of print]. 21 Dumont-Wallon G, Dreno B. Specificity of acne in women older than 25 years. Presse Med 2008; 37: 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:S1 S Goulden V, McGeown CH, Cunliffe WJ. The familial risk of adult acne: a comparison between first-degree relatives of affected and unaffected individuals. Br J Dermatol 1999; 141: Shaw JC, White LE. Persistent acne in adult women. Arch Dermatol 2001; 137: Lucky AW. Quantitative documentation of a premenstrual flare of facial acne in adult women. Arch Dermatol 2004; 140: Stoll S, Shalita AR, Webster GF, Kaplan R, Danesh S, Penstein A. The effect of the menstrual cycle on acne. J Am Acad Dermatol 2001; 45: Seirafi H, Farnaghi F, Vasheghani-Farahani A et al. Assessment of androgens in women with adult-onset acne. Int J Dermatol 2007; 46: Carmina E, Lobo RA. Evidence for increased androsterone metabolism in some normoandrogenic women with acne. J Clin Endocrinol Metab 1993; 76: Nast A, Dreno B, Bettoli V et al. European evidence-based (S3) guidelines for the treatment of acne. J Eur Acad Dermatol Venereol 2012; 26(Suppl. 1): Dreno B, Layton A, Zouboulis CC et al. Adult female acne: a new paradigm. J Eur Acad Dermatol Venereol 2013; 27: Marks R. Acne and its management beyond the age of 35 years. Am J Clin Dermatol 2004; 5: Dreno B, Bettoli V, Ochsendorf F et al. Efficacy and safety of clindamycin phosphate 1.2%/tretinoin 0.025% formulation for the treatment of acne vulgaris: pooled analysis of data from three randomised, double-blind, parallel-group, phase III studies. Eur J Dermatol 2014; 24: 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: Jackson JM, Fu JJ, Almekinder JL. A randomized, investigator-blinded trial to assess the antimicrobial efficacy of a benzoyl peroxide 5%/clindamycin phosphate 1% gel compared with a clindamycin phosphate 1.2%/ tretinoin 0.025% gel in the topical treatment of acne vulgaris. J Drugs Dermatol 2010; 9: Leyden JJ. In vivo antibacterial effects of tretinoin-clindamycin and clindamycin alone on Propionibacterium acnes with varying clindamycin minimum inhibitory. J Drugs Dermatol 2012; 11: Yentzer BA, Ade RA, Fountain JM et al. Simplifying regimens promotes greater adherence and outcomes with topical acne medications: a randomized controlled trial. Cutis 2010; 86: Kim GK, Del Rosso JQ. Oral spironolactone in post-teenage female patients with acne vulgaris: practical considerations for the clinician based on current data and clinical experience. J Clin Aesthet Dermatol 2012; 5: Saint-Jean M, Ballanger F, Nguyen JM, Khammari A, Dreno B. Importance of spironolactone in the treatment of acne in adult women. J Eur Acad Dermatol Venereol 2011; 25: Shaw JC. Low-dose adjunctive spironolactone in the treatment of acne in women: a retrospective analysis of 85 consecutively treated patients. JAm Acad Dermatol 2000; 43: Krunic A, Ciurea A, Scheman A. Efficacy and tolerance of acne treatment using both spironolactone and a combined contraceptive containing drospirenone. J Am Acad Dermatol 2008; 58: Preneau S, Dessinioti C, Nguyen JM, Katsambas A, Dreno B. Predictive markers of response to isotretinoin in female acne. Eur J Dermatol 2013; 23: Goulden V, Clark SM, McGeown C, Cunliffe WJ. Treatment of acne with intermittent isotretinoin. Br J Dermatol 1997; 137: