Treatment challenges in adult female acne and future directions

madman

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Abstract

Introduction:
Acne is a chronic, inflammatory, and immune-mediated disease of the pilosebaceous unit, highly prevalent in adolescents. However, an increasing number of adults over 25 years old with facial acne, particularly women, have been observed. It is considered a different disease when compared to acne vulgaris. The face is the mainly involved area with inflammatory lesions and more sensitive skin, pointing out the need for a holistic approach.

Areas covered: We performed a comprehensive literature search on the PubMed database, up to January 2021, regarding adult female acne. We synthesized data about pathogenesis; differences compared to acne vulgaris; and treatment, with a focus on the management challenges and perspectives.

Expert opinion: it is essential to value the negative impact on the quality of life of adult female acne, independently of severity. The disease has prolonged evolution, and the patient might be resilient once the improvement, regardless of the treatment option, will just be noticeable after three months. Aggravating factors should be clearly discussed, such as the need of changing many habits, especially lesions manipulation. The therapeutic regimen includes make-up and tailored skincare (considering proneness to sensitivity), while anti-acne drugs should be chosen in accordance with a desire to be pregnant, presence of pregnancy, or breastfeeding.




1. Introduction

Acne of the adult female (AFA) has been observed in the past 30 years in opposite to acne juvenile that is recognized for centuries. It is well known that acne vulgaris is a chronic inflammatory and immune-mediated disease of the pilosebaceous unit with noninflammatory (comedones) and inflammatory (papules, pustules, nodules) lesions compounding the clinical picture. Regarding the severity, acne may be mild, moderate, or severe, with the possibility of spontaneous resolution, but with the risk of scars and postinflammatory hyperpigmentation. Lesions are localized in the seborrheic areas on the face and trunk. There is some controversy regarding the distribution of lesions in adult female acne (AFA), i.e., similar to acne vulgaris or predominantly in the lower one-third of the face. With respect to age, it is considered when occurs in patients over 25 years old and there are differences with regard to therapeutic decisions in women ages 25 to 44 from those over 45 years, in perimenopause [1].


*This review represents a guide for an appropriated diagnosis, identification of possible triggers, aggravating factors, and therapeutic challenges for choosing the best topical and/or systemic drugs, as well adjuvant measures and procedures.




4. Topical treatment


Considering that AFA commonly presents mild or moderate lesions, the topical treatment may be able to control the disease. The most used, in monotherapy or combined products, are:


Azelaic acid (15% gel or foam or 20% cream): anti-microbial, anti-inflammatory, depigmenting, and mild comedolytic action; also useful for post-inflammatory hyperpigmentation.

Retinoids, such as adapalene gel (0.1%, 0.3%), tretinoin (0.025%, 0.05% cream) and trifarotene (0.005%, just approved in USA): comedolytic and anti-inflammatory activity, as modulators of TLR.

Benzoyl peroxide (BP) gel (2.5%, 4%, 5%, 8% and 10%): antimicrobial, anti-inflammatory and comedolytic properties.


Antibiotics: the only one still recommended is clindamycin, as it is less associated with bacterial resistance; the mechanism of action is the anti-inflammatory activity; however, it never should be used as monotherapy and combined with oral antibiotics. Considering that acne is not an infectious disease, new options targeting the skin microbiome are under development to replace the antibiotics [40].


*Fixed combinations have been demonstrated by high certainty evidence, and are: BP (2.5%) plus adapalene (0.1%, the most used); and clindamycin (1% or 1.2%) plus tretinoin (0.025%) or adapalene (0.1%) or BP (5%) [62-65].





5. Systemic treatment:

5.1 Antibiotics


5.2 Isotretinoin

Isotretinoin, the single systemic intervention which can be used as monotherapy for acne is the first-line drug for severe or moderate nodulocystic and alternative therapy for severe or moderate papulopustular acne which relapses rapidly after the first therapeutic approach has a tendency for scarring or compromises significantly QoL [82-84]. Isotretinoin improves more Qol than any other intervention [95].

Among all other systemic anti-acne therapies, isotretinoin is the only one that acts against all pathogenic mechanisms [96]. Isotretinoin normalize follicular hyperkeratinization by increasing the production of cytokeratin 7, 13, and 19, laminin B1 and interleukin 1 (IL-1); while promotes a decrease in the release of cytokeratin 1, 10 and 14, filaggrin and metalloproteinases. The corneal lawyer changes favor cellular proliferation and shedding, with renewal within the follicular units and reduced comedogenesis [97]. There is local immune regulation, with a decrease in inflammation, chiefly by down-regulation of gene expression related to TLR-2 and 4 and T helper cells [98,99]. Isotretinoin inactivates the androgen nuclear receptor in sebaceous glands and increases cell apoptosis, explaining the potent Sebo-suppressive effect [100]. Finally, the microenvironment within the pilosebaceous follicle changes, regarding sebum quantity and composition, and becomes unfavorable to the hypercolonization by C. acnes [101,102].


5.3 Hormonal treatment

5.3.1 Inhibitors of androgen synthesis

5.3.2 Blockers of androgen receptor

5.3.2.1 Spironolactone
5.3.2.2 Cyproterone acetate


5.3.3 Associations


6. Adjuvant measures


7. Future Directions

There are two important new options for the treatment of acne, which will be useful, in particular, for AFA: clascoterone (topical androgen blocker) and new oral nonsteroidal anti-androgen.

7.1 Clascoterone

7.2 Nonsteroidal anti-androgens




8. Conclusions

AFA is a distinct disease in the "Acne spectrum". As adult women with acne usually are in pregnancy and breastfeeding age, limitations are imposed to treatment. It is frequent the need for contraception, which is an advantage if the women agree and there is no contraindication, as it also has a beneficial effect for disease control. As much as possible, systemic therapy is the choice, and anti-androgens, particularly spironolactone, are the first option in association with topical agents, such as azelaic acid, used twice a day. This is the best topical regimen. Other topical anti-acne drugs can cause irritative dermatitis, as adult women with inflammatory lesions have more sensitive skin and hyperseborrhoea is not always present.

Oral isotretinoin should be considered for moderate or severe acne to accelerate the improvement and can be associated with spironolactone.

As the disease has a prolonged evolution the maintenance treatment is recommended. It is mandatory to add skincare, including photoprotection and make-up in the management schedule. Attention to psychological, habits, lifestyle, lesions manipulation, risk of scars, and hyperpigmentation is also essential. Finally, a good patient-doctor relationship with empathy is the key to therapeutic success and positive impact on quality of life.





9. Expert opinion:


Considering the literature review and the author’s opinion, it is relevant to highlight the following key messages:


• It is essential to consider the negative impact on the quality of life of AFA, independently of severity and the doctor should value the patients’ suffering and demonstrate an interest in her disease. Even when acne severity is mild, this harm might not be misjudged.

• Patients need to understand that the disease has prolonged evolution, and resilience is necessary once the improvement, regardless of the therapeutic option, will be noticeable after three months.

• Aggravating factors should be clearly discussed; the need of changing lifestyle and habits such as lesions’ manipulation, self-treatment, smoking, stress, and insomnia.

• Well-designed observational studies are still needed to well-elucidate clinical pictures of AFA: age groups between 25 and 45 years old and perimenopausal women; facial involvement, following the adolescent pattern, or classical presentation with mild or moderate inflammatory lesions in the lower third of the face.

• Therapeutic regimen, always including skincare and make-up, may be chosen according to desire to be pregnant or presence of pregnancy or breastfeeding.

• More data from well-designed randomized controlled trials involving exclusively AFA is still necessary to support spironolactone indication, especially regarding the best dosing regimen for acne clearance without side effects. Also, there is a lack of high-certainty evidence regarding the use of isotretinoin to manage AFA and the superiority of COC’s containing antiandrogenic progestin when compared to other anti-acne therapies. Another clinical research gap is the true benefit of associated systemic therapies: efficacy and safety of spironolactone plus isotretinoin (important antibiotic-sparing approach for more severe AFA) and COCs plus spironolactone compared with isolated use of these drugs and oral antibiotics have not yet been analyzed in randomized controlled trials.

• First therapeutic options are: gentle cleanser, light moisturizer (with niacinamide, ceramides) once a day, at night; tinted sunscreen in the morning and lunchtime; 15% azelaic acid gel minutes before sunscreen in the morning and moisturizer at night; spironolactone associated or not to COCs and, in severe or refractory cases, already presenting scars, a low daily dose of oral isotretinoin until complete clearance of lesions may be added, always associated with highly effective contraception methods. For the retentional form, 0.05% tretinoin for three months is recommended, and if poor or no response, low daily dose of oral isotretinoin constitutes the best option. Topical antibiotics should be avoided, even when in combinations. Oral antibiotics are rarely indicated, as they are less effective for AFA if compared to adolescent acne and should be used at a maximum of three months, which is a very short time for this disease that has prolonged evolution. In addition, many cycles of oral antibiotics may increase the risk of bacterial resistance.

• Finally, AFA is an increasingly prevalent disease, affecting the quality of life and should be specifically treated as early as possible to prevent psychological sequels and scarring. It also may be the first sign of hyperandrogenism, when associated with hirsutism, even mild, and menstrual irregularities. The early diagnose of this condition is fundamental to prevent the evolution of metabolic syndrome and its serious consequences.
 

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madman

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Table 1. Adult female acne (AFA) pathogenesis [33-35]
Screenshot (4605).png
 

madman

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Article highlights

• Adult female acne (AFA) has been demonstrating an increasing prevalence all over the world. It is an impacting disease for adult women, in their social, and professional life. Quality of life and patients’ suffering should be valued.

• In accordance with the available data from a more recent international observational study, lesions may have a different distribution from adolescent acne in about 10 % of the cases, when there is a predominance of mild to moderate inflammatory papules along with mandibular and perioral areas of the face, in a “surgical mask-like” pattern. The presence of comedones and inflammatory papules, with a full-face involvement, is the most common clinical picture in AFA; and more than 50% of the affected women have truncal lesions.

• The pathogenesis is similar to acne vulgaris, but additional factors trigger and aggravate the disease's chronic evolution, including a high level of stress, sleep deprivation, picking habits, sensitive skin, pollution, and diet. It seems that peripheral production of androgens, at the sebaceous gland level, is responsible for its prolonged duration.

• It is important to treat AFA as early and as effectively as possible to avoid scars and psychological sequelae, taking into account the desire to be pregnant. The majority of patients have normal androgen levels in the serum. However, other signals of hyperandrogenism, mainly hirsutism, and menstrual irregularities, should be addressed and hormonal investigation, as well as transvaginal ultrasound, requested.

• There are many topical but only three different systemic drugs (antibiotics, antiandrogens, and isotretinoin) available for treatment, usually in combination for inflammatory acne.

• For mild acne, topical treatment, always combined with adjuvant measures (gentle cleanser, moisturizer, sunscreen, and dermo-cosmetics), may be sufficient for disease control, in a prolonged period of time. For this reason, topical antibiotics should be avoided.

• Oral hormones represent the most important drugs for AFA, especially spironolactone and contraceptives, containing Ethinyl estradiol and cyproterone acetate, drospirenone or chlormadinone as progestins

• Oral isotretinoin might be considered in severe and refractory disease as it is highly effective and safe for acne vulgaris. Off-label low daily doses and variable duration of the treatment is the best approach, always associated with contraception methods, starting one month before the treatment up to one month after drug interruption, This regimen promotes fewer mucocutaneous side effects, same efficacy, and better adherence. Lab tests (lipid profile, transaminases, Gama-GT, total blood count) should be requested at baseline and repeated after two months, as well as beta-HCG monthly. Serious adverse events, including depression and inflammatory bowel disease, are rare and individual and do not justify excessive warning and concern.

• Topical clascoterone (androgen blocker) and new anti-inflammatory substances, as well as a new use of oral non-steroidal anti-androgen, such as bicalutamide, are interesting perspectives for AFA control.
 

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