Acne vulgaris (hereinafter acne ) is one of the most common inflammatory skin diseases observed worldwide, with a peak prevalence between 15 and 20 years of age in all ethnic groups.1-3 It was considered as a transient disease in adolescence, but it is now recognized that acne occurs earlier 4.5 and for a longer duration, 6.7 with the possibility of persisting well into adulthood if not treated effectively. The reason for this change remains unclear; could be the result of a Western diet (e.g., increased glycemic intake), earlier onset of puberty, genetic drift, or other environmental factors.
The burden of acne is substantial.8 The visible nature of the condition makes it a cosmetically unacceptable problem, resulting in a multi-million pound acne cosmetics industry and a substantial burden on health services. Acne affects adolescents at a time when they are undergoing both physical and social changes and can have a profound negative effect on mood and psychosocial well-being. The combined effects of acne and the resulting scarring or pigmentation (hyperpigmentation is the most common pigmentary change), or both, can result in low self-esteem, depression, and anxiety.
The pathogenesis of acne involves sebum production, hyperkeratinization in the intrafollicular duct of the pilosebaceous follicle, colonization by Cutibacterium acnes , and a loss of strain diversity and immune complex reactions leading to inflammation. Inflammation is key to pathogenesis as shown in the subclinical inflammation found histologically in acne-prone skin.9
In adrenarche , increased adrenal dehydroepiandrosterone production is the trigger for increases in sebum mediated by androgen production and an increase in keratinocytes in susceptible follicles.10 Early adrenarche in girls is a recognized risk factor for acne more severe.2 Increased sebum excretion is associated with more severe acne11 and more inflammatory lesions.12
Acne most commonly occurs on the face (in 92% of cases) but could also affect the back (61%) and chest (45%).13
The clinical features of acne are seborrhea, inflamed lesions known as papules, pustules (≤5 mm in diameter) and nodules (>5 mm in diameter), open comedones known as blackheads, and closed comedones known as whiteheads.
Comedonal acne may be detected in some children before any overt signs of puberty, and the early development of comedonal acne in girls and midfacial presentation in all genders could be a predictor of more severe disease in later life.1,2
The clinical presentation can vary from mild facial comedonal lesions, with or without sparse inflammatory lesions, to an aggressive, generalized, fulminant inflammatory disease with associated systemic disorders. Inflammatory macules are flat, regressing lesions that may persist for many weeks, contributing to the overall erythematous appearance of acne-affected skin.
A common consequence of acne is scarring ; It may present as atrophic scarring due to tissue loss or, conversely, as elevated hypertrophic or keloid scarring due to excess tissue development. Hyperpigmentation is commonly seen, particularly in darker skin tones, and may persist for many months to years in some individuals.14 Most individuals have a mixture of comedonal and inflammatory lesions, and other clinical sequelae.
| Acne assessment to inform treatment |
Effective treatment of acne in adolescents depends on many factors, including severity, exacerbating factors, physical and psychological comorbidities, skin tone, impact of the disease, patient preference, and the presence of clinical sequelae. These factors must be considered when selecting and prescribing treatments.
Accurate assessment of acne severity is notoriously challenging. Many grading systems have been adopted, but few are validated.17 The affected site, extent of acne, number of lesions, and degree of seborrhea, inflammation, and clinical and psychological sequelae contribute and should be considered in any assessment of severity. .
Appearance-related concerns are frequently reported especially during adolescence.18 The use of quality of life measures (HRQoL) and patient-reported outcome measures (PROMs) can capture the impact of acne and response to treatment.
There is no universally standardized or validated tool for use in adolescents, but several disease-specific measures are available and could be useful in a clinical setting.
The Acne Outcomes Research Network (ACORN) initiative has identified several quality of life measures to assess HRQoL. Acne-Q and Comp-AQ, which are two PROMs used to measure facial and torso acne, were found to be validated to a sufficient standard for ACORN to suggest their consideration as measures for acne-associated quality of life.19
ACORN suggests that the Acne-Specific Quality of Life Questionnaire and the Acne Symptom and Impact Scale could also be considered for additional content validity.19 Alternatives used in clinical trials include the Cardiff Acne Disability Index and the Evaluation of the Psychological and Social Effects of Acne.
| MANAGEMENT OF ADOLESCENT ACNE |
International evidence and expert-based guidelines are available to inform treatment selection for acne in adolescents and adults.20–24 The goals of treatment are to alleviate the clinical signs and symptoms of acne, improve psychosocial well-being, and prevent clinical sequelae. and psychological. A delay in effective acne treatment is more likely to produce clinically relevant scarring and pigmentation, hence early treatment aimed at treating the underlying inflammatory processes is advocated.16, 25, 26
| General Tips |
Adolescents with acne should be provided with information to enable them to understand the reasons for their acne, treatment options, and likely outcomes.
Skin care advice is recommended, including using a non-alkaline cleansing product (syndet), avoiding oil-based products and comedogenic products, and refraining from picking and scratching. It is important to explain to people of childbearing potential that many treatment options for acne, including some topical treatments, are contraindicated in pregnancy and that effective contraception or selecting an alternative treatment is required.
| Role of diet |
Debate persists over whether and how diet might play a role in acne, and most guidelines do not recommend specific dietary treatment. However, it would be useful to evaluate dietary intake, especially with respect to high glycemic load in the diet, milk intake, and nutritional supplements such as whey protein, all of which have been shown to be associated with acne.27–31
Insulin-like growth factor 1 ( IGF-1) can potentially stimulate androgen production and induce sebocyte and keratinocyte proliferation. Because diets containing high glycemic loads could increase IGF-1, reducing dietary glycemic load or opting for low glycemic index diets could result in improvement of acne. However, a 2015 Cochrane systematic review found insufficient evidence to support a low-glycemic index diet for the treatment of acne32 and concluded that more evidence is required.
Milk consumption has also been implicated in acne because milk can increase insulin and IGF-1 concentrations and contains dihydrotestosterone precursors, in the form of bovine IGF-1.33,34 A meta-analysis including 14 observational studies found a positive association between acne and intake of whole milk, low-fat milk, and skim milk.35 Findings indicated that acne had stronger associations with intake of low-fat milk and skim milk.35 After they have been established dietary habits, people can be advised whether their diet could be implicated in contributing to their acne.36
| Topical medications |
International guidelines are very similar in their recommendations for topical treatment. Most recommend that adolescents with acne should be offered a 12-week course of first-line treatment options.19, 22 These treatments should be implemented after taking into account the severity of the acne and taking into account personal preferences, after discussing the advantages and disadvantages of each treatment option.
Treatment principles include the use of combination treatments of topical retinoids or antimicrobial agents, or both, avoiding antibiotics as monotherapy.
Several fixed combinations of topical products are available that can be selected as first-line therapy for acne. If fixed combinations of topical products are contraindicated or not tolerated as first-line treatment, alternative treatments may be used, including monotherapy with topical benzoyl peroxide, a topical retinoid, or azelaic acid.
Skin irritation is commonly associated with the application of topical treatments, such as benzoyl peroxide or retinoids, and can be mitigated by beginning with alternate-day application or short-contact therapy (e.g., washing off the topical product afterward). 1 or 2 h), and combining topical treatments with dermocosmetic preparations.
Weak evidence and expert opinions suggest that this combination may improve tolerability and help improve adherence to topical therapy.37,38
| Oral antibiotics |
Second-generation tetracyclines are considered appropriate oral antibiotics for people with moderate to severe acne along with a fixed combination of topical products containing benzoyl peroxide and a non-antibiotic antimicrobial agent. For people who cannot tolerate or have contraindications to the recommended tetracyclines, a macrolide (e.g., erythromycin) or trimethoprim may be administered as an alternative oral antibiotic along with topical therapy.
Contraindications for oral tetracyclines include pregnancy and age under 8 years. However, because tetracyclines deposit in bones and teeth and can cause staining and hypoplasia of tooth enamel, these antibiotics are often not used until permanent teeth are developed (around age 12).
Trimethoprim is not licensed for use in acne and has been associated with Steven-Johnson syndrome and toxic epidermal necrosis in rare cases; therefore, it is not recommended as a first-line treatment.
Oral antibiotics may be associated with side effects, such as gastrointestinal upset; However, a major concern is that its use could lead to antimicrobial resistance. For this reason, judicious use of antibiotics should always be adopted and, where possible, non-antibiotic therapies should be considered when initially selecting a treatment. However, when antibiotics are required, monotherapy with a topical or oral antibiotic, or a combination of a topical and oral antibiotic, should be avoided.
In treatment review, consideration should be given to whether antibiotic-based therapies can be replaced by effective non-antibiotic treatments as a means of reducing the likelihood of antimicrobial resistance.
| Hormonal treatment for acne |
International guidelines are inconsistent in their recommendations for the use of combination oral contraceptives as a treatment for acne. The NICE guidelines for acne suggest that the evidence for the effectiveness of the combined pill in treating acne is weak.20 Therefore, these guidelines do not recommend it as a treatment option for acne, except for co-cyprindiol (cyproterone). acetate-ethinyl estradiol), which is recommended as a second-line treatment for patients with acne and polycystic ovary syndrome.20
However, other guidelines, including those produced by the European Dermatology Forum21 and the American Academy of Dermatology,22 recommend the use of a combined oral contraceptive for acne in women, if the individual requires a contraceptive or has menstrual problems that could be improved or regulate with him.
Evidence-based pediatric acne guidelines suggest that a combination of low-estrogen oral contraceptives may be helpful, but it is recommended to avoid their use within 2 years of the onset of menstruation or in girls with acne under 14 years of age, unless clinically justified, because some concerns remain about potential osteopenia or decreased bone mineral density.23
A 2012 Cochrane systematic review suggested that all combined oral contraceptives showed some effectiveness in treating acne due to their estrogenic effects; however, data were scarce on differences in effectiveness of combined contraceptives containing variable progestins.39
In a meta-analysis of 32 randomized controlled trials, 40 antibiotics were superior to oral contraceptives in reducing acne lesions at 3 months, but were equivalent at 6 months.
The delay in onset of action resulting in benefit from oral contraceptive treatment, which may be 3 to 6 months, emphasizes the need to consider the use of combined oral contraceptives as part of a regimen along with the agents topicals and antibiotics rather than as monotherapy.40
There is concern about interactions between combined oral contraceptives and antibiotics when used together to treat acne, as they could reduce the effectiveness of the contraceptive. However, pharmacokinetic studies have shown that serum estrogen concentrations are affected by tetracyclines and that the failure rate of combined oral contraceptives used with tetracyclines is no greater than the failure rate when used alone.41 The The only antibiotic that has so far been shown to reduce the effectiveness of the combined contraceptive pill is rifampicin.42
A combined oral contraceptive pill should be used in preference to the progesterone-only pill if a person receiving treatment for acne wishes to use hormonal contraceptive treatment.
Cyproterone acetate is a very effective antiandrogen therapy and has been used as part of a combination pill (i.e., along with ethinyl estradiol), but has also been used alone or in addition to the combination pill to increase antiandrogenic properties. Concerns have been raised following a reported association between long-term high-dose cyproterone acetate use and meningioma.43
Other antiandrogens have been recommended to treat acne in women and girls, including spironolactone and metformin, as discussed later in this review.
| Oral isotretinoin treatment |
Oral isotretinoin is a highly effective treatment for acne, but has sparked controversy due to reported safety concerns. For many teens, a single course of isotretinoin will clear their acne, and some do not require any additional treatment.
Oral isotretinoin may be considered for people 12 years of age or older who have a severe form of acne resistant to adequate courses of standard therapy with systemic antibiotics and topical therapy. These severe forms may include nodulocystic acne, acne conglobata, acne fulminans, and acne at risk of permanent scarring.
The patient’s psychological well-being should be considered before considering oral isotretinoin as a treatment for acne, and referral to mental health services may be required before starting treatment.
Cases of mental health problems developing during and after isotretinoin treatment have been reported, and positive withdrawal and challenge responses resulting in depression have been published.44, 45 However, a meta-analysis46 found no association between isotretinoin and increased risk. of depression, and other studies47, 48 have suggested that depressive symptoms generally decrease after completing treatment.
Large population studies have also shown that rates of depression and suicide are lower in patients with acne treated with isotretinoin than in patients with acne treated with oral antibiotics or the general population.49–51 Despite these findings, they need to be explained to patients of the potential neuropsychiatric problems associated with isotretinoin treatment and regulatory advice should be followed, while ensuring that the person receiving treatment and their family are informed.19
Psychological and physical well-being should be monitored during treatment, including symptoms or signs of depression, and advice given on the importance of seeking help if mental health is affected or worsens while on treatment with oral isotretinoin.
Patients who may become pregnant should be informed that isotretinoin can cause serious harm to the fetus if taken during pregnancy, and a pregnancy prevention program should be closely followed.
Dosing of isotretinoin is difficult due to the lipophilic nature of the drug, such that ingesting enough fat with the drug can increase absorption by six-fold compared to ingesting the drug without food.52 One review has shown that most of previous studies examining dosage are challenged for not controlling for this factor.53
Many guidelines recommend that oral isotretinoin be started for the treatment of acne at a standard daily dose of 0.5–1 mg/kg per day, 20–24 but a reduced daily dose of isotretinoin may be considered for persons at increased risk of , or who experiences, adverse events. When giving isotretinoin as a course of treatment for acne, some guidelines currently recommend a total cumulative dose of 120–150 mg/kg.
However, in clinical practice, if the response has been adequate and no new acne lesions have occurred, treatment is frequently discontinued based on clinical response and once acne has been clear for 2-3 months. .54,55 Further research is required to clarify optimal dosing regimens.53
Studies suggest that routine laboratory tests, including a complete blood count, are not required when prescribing oral isotretinoin.56, 57 Mild increases in triglycerides are seen in about a quarter of patients receiving oral isotretinoin, but concentrations are said to be higher. clinically relevant serious illnesses are infrequent.56, 57
Once the patient is on a stable dose, subsequent changes in lipid concentrations are rare. A reasonable approach is to monitor triglycerides and liver enzymes at baseline and 2 months into treatment, with more frequent monitoring if the dose is increased or if clinically indicated.57
| Maintenance treatment |
Some adolescents with acne may need maintenance therapy after successful clearance to prevent relapse and ensure long-term control. Maintenance treatment should be considered and reviewed periodically. The fixed combination with topical adapalene and benzoyl peroxide is the treatment of choice for maintenance; however, if not tolerated or contraindicated, other topical treatments may be considered, including monotherapy with adapalene, azelaic acid, or benzoyl peroxide.20
| New acne treatments |
Spironolactone has been used unlicensed by dermatologists as an antiandrogen therapy in the treatment of acne for many years, but strong evidence is lacking to support its effectiveness and it is unclear whether some age groups might benefit more than others.58 A cohort study has suggested that spironolactone could have similar efficacy to oral tetracyclines used to treat acne.59
A small retrospective study of 80 adolescent women aged 14 to 20 years showed that 64 (80%) experienced improvement in their acne with 100 mg/day of spironolactone, with 18 (22.5%) having clear skin after 7 months and without experiencing serious adverse effects.60 A large study (ISRCTN12892056) funded by the UK National Institute for Health and Care Research has been completed to establish differences in the effectiveness of spironolactone among women with acne, and will provide evidence of the effectiveness of treatment and ideas about whether acne in teenage girls responds as well as acne in older women.61
Metformin has also been investigated as a new repurposed acne medication.62 Studies have shown benefit in patients with polycystic ovary syndrome, although there is substantial heterogeneity among study reports due to different acne rating scales, doses of metformin and duration of treatment.
A meta-analysis of available studies reported that metformin may be considered as a stand-alone or adjuvant therapy in patients with PCOS, pending further clinical trials.63 A separate randomized open-label study supports metformin as an adjunctive therapy in conjunction with a Tetracycline and topical benzoyl peroxide for treatment of moderate to severe acne.64
Other novel treatments that have been approved so far include a new formulation that is a fourth-generation retinoid cream—trifarotene 50 μg/g. Trifarotene is the first retinoid produced in more than 20 years and has been approved in several countries and regions (e.g., US and EU) for the treatment of facial and trunk acne.
Trifarotene selectively targets the retinoic acid receptor γ (RAR-γ), which limits systemic exposure65. Studies have shown that treatment with trifarotene can reduce inflammatory lesions as early as 1 week and further studies are being considered to evaluate whether trifarotene can reduce acne-induced pigmentation in the longer term. 65
A new, higher-strength combination consisting of adapalene (0.3%) and benzoyl peroxide (2.5%) was shown to be safe and effective for the treatment of acne from the age of 12 and, compared to vehicle, appears to be more likely to reduce scar development over a 24-week study period.66
Over an extended period of 48 weeks, the reduction in acne and scarring was maintained, showing the long-term effectiveness of this new combination treatment.66,67 Additional improvement in atrophic scarring occurred with 48 weeks of active treatment compared to Delayed treatment, in which the only vehicle was used for the first 24 weeks, highlighted the importance of early intervention in acne.66,67
Topical foam containing 4% minocycline has been approved by the US Food and Drug Administration (FDA), after clinical trials demonstrated its effectiveness in moderate to severe acne in the pediatric population aged 9 years and older. further. The lipophilic nature of the product allows it to preferentially enter the pilosebaceous follicles.
The formulation consists of micronized particles in a glyceride vehicle. This lipophilic formulation means that the concentration is 850 times higher in the skin than would be seen with systemic absorption, and blood concentrations of minocycline have been shown to be almost undetectable.68 Therefore, the treatment acts locally without the potential of severe systemic adverse events, which is a concern with oral minocycline, and the product is well tolerated.
Because skin concentrations are notably high, the potential for antimicrobial resistance is substantially reduced. The concept of mutant selection suggests that extremely high concentrations of minocycline in the skin will overwhelm the microbes in the skin, so antimicrobial resistance does not occur.68
Oral sarecycline is an oral tetracycline approved by the FDA in 2018, and is used specifically for the treatment of moderate to severe, inflammatory, non-nodular acne on the face and trunk in people with acne aged 9 years and older. Sarecycline has an anti-inflammatory action and, in vitro, has a narrow spectrum of activity, with reduced activity against Gram-negative organisms and the intestinal microbiome.69
The minimum inhibitory concentration required to kill pathogens is much higher than that of the aforementioned tetracyclines, and sarecycline can kill C. acnes at lower concentrations very effectively.69 Because this evidence is driven by in vitro data , it is uncertain whether the effect on the microbiome is clinically significant and further studies are needed.
Sarecycline is prescribed according to weight, with a dosage regimen of 1.5 mg/kg per day, with or without food (avoiding milk, iron and fat), making it more convenient to use than oral tetracyclines. Studies have suggested that side effects associated with sarecycline are fewer than those associated with other tetracyclines, including no evidence of tooth staining in trials, and sarecycline can be used safely for up to 12 months.69
Clascoterone is another novel topical agent, which is a competitive androgen receptor antagonist with a structure similar to spironolactone and dihydrotestosterone, making it highly effective in binding to the receptor.70 Clascoterone does not inhibit 5α-reductase and is metabolized . to cortexolone, therefore limiting any potential for systemic absorption.70
Local inhibition of androgen binding produces downstream effects. For example, clascoterone is the first topical agent with the potential to reduce sebum production and activation of inflammatory pathways. The topical agent has been approved by the FDA for men and non-pregnant women ages 9 and older with moderate to severe facial acne.70
Interest has been increasing in energy-based devices for acne treatment. A 2016 Cochrane systematic review suggested that there was no high-quality evidence for the use of light therapies for the treatment of people with acne; However, at that time, the usefulness of photodynamic therapy with methyl aminolevulinate (using a red light source) or photodynamic therapy with 5-aminolevulinic acid (using a blue light) as standard therapies for people with moderate to severe acne is not well established.71
Since then, more studies have been conducted to support the use of photodynamic therapy, particularly in the context of moderate to severe cases of acne when other treatment options have been unsuccessful or are contraindicated.20 However, photodynamic therapy remains an unapproved treatment for acne and there is no standardized protocol to clarify the best photosensitizer, light source, or treatment regimen to optimize this therapy. Therefore, carefully planned studies using validated outcome measures and comparing the effectiveness of common acne treatments with light therapies would be useful to better inform this new type of therapy.
Overall, these new treatment options have the potential to prevent antimicrobial resistance and offer effective therapies that should reduce the likelihood of physical scarring and pigmentation. For prescription medications, once-daily applications or tablets improve treatment adherence.
| Emerging treatment options |
Novel, more effective treatments associated with reduced side effects are likely to emerge as understanding of the pathophysiology and genetics of acne improves. Treatment goals include sebum production, hyperkeratinization, C acnes colonization , microbiome adjustment, and inflammation. There is also interest in developing new treatments for the clinical sequelae of acne, including persistent erythema, scarring and pigmentation, with hyperpigmentation being a significant problem in people with darker skin tones and lasting for several years in some populations.14, 72
Sebum production in people with acne is generally considered a consequence of androgenic stimuli, but results have shown that other hormones such as α-melanocyte-stimulating hormone and IGF-1 may also play a role. 73 These new findings have opened up a number of possibilities for new treatment targets, such as the control of exogenesis with acetyl coenzyme A carboxylase, the endocannabinoid system, and the presence of proinflammatory mediators (e.g., leukotriene B4).74
Other selective RAR agonists may emerge as an alternative to currently available retinoid therapy, with a better safety profile as a means of limiting adverse events such as irritation, erythema, scaling, and dryness, which could result from topical agents that contain RAR-β and RAR-γ agonists, therefore limiting their use, and as a means of possibly addressing teratogenicity concerns.
Antimicrobial resistance induced by antibiotics is a topic of growing global concern. Therefore, current recommendations in all acne guidelines aim to reduce the use of antibiotics for the treatment of acne and interest is increasing in the use of antimicrobial peptides and agents that modulate C acnes populations , such as probiotic preparations and biofilm matrix degradation gels.
Interest in other novel agents includes those that modify IL-1α, IL-β, TNFα, metalloproteinase secretion, neutrophil migration, and the consequent inflammation observed in people with acne. By controlling inflammatory responses, subsequent scarring and pigmentation should be avoided.
As with other common inflammatory dermatoses, medications that modulate inflammatory responses (e.g., monoclonal antibodies) are of interest for the treatment of acne. Research is being considered with energy-based devices both as a direct mode of treatment, as well as a means of delivering treatment.
| Conclusions |
Acne is a common and complex condition that has a profound impact on adolescents and adults, resulting in a substantial burden worldwide. As understanding of the pathophysiology of acne continues to increase, treatment approaches are emerging that allow clinicians to select therapies early in the course of the disease and help avoid some of the clinical sequelae that may ensue.
Understanding the psychological impact of acne and ensuring that management aligns with patient preferences and knowledge remains paramount to how healthcare professionals achieve the best outcomes for patients.
