Narrative review
Dermatology
Volume 206 - Issue 1

Modern management of acne

Authors:  Victoria Rebecca Harris and Alan J Cooper

Med J Aust 2017; 206 (1): 41-45. || doi: 10.5694/mja16.00516
Published online: 16 January 2017
Given the psychosocial impacts of acne, systemic therapy may be appropriate if topical and general measures have failed
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Summary

  • Acne is a chronic inflammatory disease of the pilosebaceous unit resulting from androgen-induced increased sebum production; altered keratinisation; bacterial colonisation of hair follicles on the face, neck, chest and back by Propionibacterium acnes; and an inflammatory response in the skin. The exact way these processes interact and the order in which they occur in the pathogenesis of acne are still unclear.
  • Scarring that occurs from acne, particularly severe acne, can persist a lifetime and have long lasting psychosocial effects. Depression, social isolation and suicidal ideation are frequent comorbidities in acne.
  • Despite the plethora of topical and systemic treatments available for acne, there is a relative lack of quality evidence for its application. Of the systemic treatments available, oral isotretinoin remains the most effective well established treatment for acne that targets all the aetiological factors.
  • Current guidelines for the treatment of acne are based largely on expert consensus and advocate a combination of topical agents in mild to moderate cases and reserve the use of systemic therapies for moderate to severe or refractory cases of acne. However, given the psychosocial impacts of acne, there is a strong argument for early, effective treatment with systemic therapy when topical and general measures have failed.

Acne vulgaris is an inflammatory skin condition with an estimated global prevalence of 9.4% and is the eighth most prevalent disease in the world.1 Although perceived as a disease of adolescence, it can persist — with women typically more affected than men — beyond the teenage years.2 Acne is increasingly a reason for dermatologic consultation among adult women.3

Risk factors

The factors that contribute to acne, particularly the role of diet, are an area of changing ideas with ongoing research that is of immediate clinical relevance. There exists plausible theoretical research that elements of contemporary Western diets may be associated with acne.4 For example, androgens and hormonal mediators, such as the insulin-like growth factor 1 found in milk, can survive processing and may contribute to the excess sebum production seen in acne.5 A recent large prospective cohort study found that skim milk contains hormonal constituents in quantities that are sufficient to have biological effects in teenage boys.6

The high glycaemic index foods found in the typical adolescent Western diet have also been investigated for their contribution to the development of acne. A recent randomised controlled trial that involved adolescent boys with acne vulgaris found an improvement in acne and insulin sensitivity after a diet with a low glycaemic load.7 However, further research is required to confirm this study and to identify the underlying pathophysiological mechanisms of diet and weight loss in acne.

Hereditary factors have also been attributed to the pathogenesis of acne, with a positive family history observed in severe cases of acne.8 In addition, observations in the study of twins suggest a genetic component of the disease.9 More recently, a large scale genetic study in the United Kingdom compared the genetics of patients with severe acne with that of the subjects in the control group and provided information on predicting who is prone to acne by establishing the loci of possible causative genes.10 This study provides the basis for new research into the genetic basis of acne.

Clinical features

The clinical features of acne include seborrhoea and a spectrum of lesions, including non-inflammatory lesions (comedones), inflammatory lesions (pustules), various degrees of scarring, and in very severe cases, nodules and cysts.11 The distribution of acne follows the areas of greatest density of pilosebaceous units, such as the face, neck, chest and back.12 Acne typically affects adolescents around adrenarche (aged 9–17 years) as this coincides with an increase in sebum production of sebaceous glands (Box 1, Box 2 and Box 3).13

Impact on quality of life

In addition to the physical symptoms of inflammation, scarring and disfigurement, there are also long lasting psychosocial effects. Patients with acne may experience tremendous impairment to quality of life that is comparable with that experienced by patients with chronic illnesses, such as asthma, epilepsy, diabetes, back pain or arthritis.14 Irrespective of the degree of severity of acne, patients are at an increased risk of anxiety and depression compared with the non-affected population.15 Additionally, the emotional components of the disease might not be immediately recognised or volunteered by the patient. It is therefore important for clinicians to be aware of the established psychological sequelae of acne and be alert for and elicit a spectrum of psychological symptoms and signs as clinically appropriate.

Pathogenesis

Acne is a multifactorial, inflammatory disease of the pilosebaceous unit. It involves the interplay of four distinct processes:16

  • excess sebum production caused by increased androgen production;

  • altered keratinisation within the follicle and ductal occlusion;

  • proliferation and colonisation of the pilosebaceous duct by Propionibacterium acnes (P. acnes); and

  • release of inflammatory mediators into the skin.

The exact sequence of events and how they are interconnected remain unknown; however, recent research suggests that these factors are more interrelated than previously understood.17

Treatment

The mainstays of an acne treatment regimen should include general measures, such as face hygiene with soap-free face wash, use of oil-free moisturisers to minimise the side effects of topical treatments, and avoidance of triggers. Examples of reported triggers of acne include makeup, sunscreens and medications, such as corticosteroids and anabolic steroids.18 The aim of pharmacological treatment of acne is to maximally suppress the aetiological factors, clear the acne and minimise scarring. The role of combining topical agents is to target more of the pathogenic factors of acne and promote a more effective clearance of acne.19 The main topical treatments include keratinolytics (sulphur, salicyclic acid), antiseptics (benzoyl peroxide), retinoids and antibiotics. These agents are available in a variety of strengths and vehicles; therefore, a tolerable regimen can usually be found for most skin types.

While there is a plethora of topical options available, there is a paucity of quality studies comparing relative efficacy among the different topical agents. Current guidelines are instead reliant on expert consensus for treatment rather than on evidence-based treatment and include the Global Alliance to Improve Outcomes in Acne,20 the European Dermatology Forum,21 and the guidelines of care from the American Academy of Dermatology.11

Another factor that contributes to the difficulty of treating acne is the lack of a singular global assessment standard in clinical practice or research.22 An assessment of acne severity is multifactorial and dependent on physical assessment (eg, lesion type, number, size, distribution and location)23 in addition to an assessment on the impact of acne on the quality of life of the individual (eg, the Dermatology Life Quality Index).24

Benzoyl peroxide (BPO)

BPO is an effective bactericidal agent that causes peeling of the skin and is beneficial for acne with mild and transient irritation. It is also conveniently available for patients as an over-the-counter treatment. It is currently the strongest antimicrobial agent that has no known association with development of resistance.25 The current therapeutic guidelines in Australia recommend BPO 5% as initial therapy for mild to moderate acne.26 It can be used in combination with topical antibiotics or a topical retinoid. However, the side effects of BPO can make its use intolerable; they include cutaneous irritation or dryness, which can be minimised by application to dry skin to reduce irritation; contact urticaria; contact dermatitis; and bleaching of clothes and bed linen. If irritation occurs, then lower strengths and less frequent application may be suggested to ensure compliance.

Topical retinoids

Topical retinoids, including tretinoin, adapalene, isotretinoin and tazarotene, work by reducing obstruction within the follicle through action on abnormal keratinisation and are also anti-inflammatory.12 The Australian therapeutic guidelines recommend either adapalene 0.1% in cream or gel topically, or tretinoin 0.025% in cream topically for 6 weeks and then review.26 Side effects for topical retinoids include local irritation and photosensitivity and should be discontinued in rare cases of severe cutaneous irritation. The gradual introduction of retinoids in combination with a low irritant, pH balanced, soap-free cleanser may avoid irritation.

The current Australian therapeutic guidelines warn that topical retinoids are teratogenic and state that they should be avoided in women who are planning to become pregnant, are pregnant or breastfeeding.26 The regulatory concern of the teratogenic potential of topical tretinoin is contrary to previous human percutaneous absorption studies. A human study that examined the percutaneous absorption of tretinoin in various formulations indicated that it was minimally absorbed and did not affect the endogenous levels of the drug or its metabolites in the subjects studied.27 There has also been a study that examined the incidence of major congenital anomalies for 215 exposed women versus 430 non-exposed age-matched women, and concluded that topical tretinoin is not associated with increased risk for major congenital disorders.28

Antibiotics

Topical

The primary topical antibiotics used for acne are clindamycin and erythromycin and they have similar efficacy. However, there is growing concern about P. acnes resistance, particularly with erythromycin.16 Therefore, the current Australian therapeutic guidelines suggest the use of a combination of BPO and topical retinoid gel (benzoyl peroxide/adapalene 2.5%/0.1%) or clindamycin gel (benzoyl peroxide/clindamycin 5%/1%).26 Antibiotic topical monotherapy is to be avoided; nevertheless, clindamycin alone can be used if the patient’s skin is prone to irritation with other acne treatments.

Oral

Despite the growing concerns surrounding antimicrobial resistance, initial treatment for moderate to severe acne is an oral antibiotic — for both antimicrobial and anti-inflammatory effects — in combination with topical retinoid and benzoyl peroxide.29 To prevent recurrence when oral antibiotics are ceased, it is important to establish a tolerable long term topical treatment when commencing oral antibiotics. Doxycycline (50–100 mg orally once daily for 6 weeks) is the first agent of choice, and if it is not tolerated, then minocycline (50–100 mg orally once daily for 6 weeks), and if tetracyclines are contraindicated (eg, pregnancy), then erythromycin (250–500 mg daily for 6 weeks).26

Side effects of antibiotic treatment are a concern for both patients and clinicians and, therefore, the choice of antimicrobial agent may vary among dermatologists based on preference and experience. For example, photosensitivity caused by doxycycline may be intolerable or impractical as a first line treatment for some patients. Rare serious effects exist within both tetracycline and macrolide antibiotic classes. Minocycline, for example, has been associated with drug reaction with eosinophilia and systemic symptoms,30 vestibular disturbances, benign intracranial hypertension, and pigment deposition in the teeth, skin and mucous membranes.31 Macrolides are not without serious adverse effects either, with reports of cardiac conduction abnormalities and hepatotoxicity.32

The efficacy of antibiotic therapy should be reviewed after 6 weeks and if no improvement is observed, a change in antibiotic should be considered. The prolonged use of antibiotics is questionable in light of resistance concerns from the long term use of low dose antibiotics.33

Antiadrenergics

Combined oral contraceptive pill (COCP)

Hormonal therapies are useful adjunctive treatment options. A recent Cochrane review reaffirmed the efficacy of COCP for treatment of inflammatory and non-inflammatory acne, but found few differences in efficacy between the different types of COCP that are currently available.34 The Australian guidelines, however, suggest that the COCP most likely to improve acne is one that contains cyproterone acetate.26 The benefit from COCP is slow and may not be apparent for 3 months, so a 6 month trial is recommended.

Spironolactone

Spironolactone is a diuretic and anti-androgen drug that works by blocking androgen receptors when administered at increased doses. Spironolactone is useful to treat acne in female patients when COCP is contraindicated, not tolerated or desired, or insufficient as monotherapy.35 It can be used in male patients, but may have the adverse effect of feminisation, as seen in a recent Japanese trial that involved 23 men treated initially with 200 mg spironolactone daily for 8 weeks, but ceased in men prematurely due to the side effect of gynaecomastia.36 The common adverse effects of treatment are irregular menstrual bleeding, diuresis, breast tenderness, fatigue, headache and dizziness.37 Pregnancy should be excluded before commencing therapy, as there is a risk of defective virilisation of the male fetus. Hyperkalaemia is a concerning side effect; however, it is rare in young healthy females and it was recently stated in the American guidelines for the treatment of acne that testing potassium in young healthy females on spironolactone is unnecessary.11

Oral retinoids

Since isotretinoin (13-cis retinoic acid) was introduced in 1982, it has been the most effective treatment for acne and the only treatment that offers remission.

Its efficacy is due to the fact that it targets all four known components involved in the development of acne.38

A widely accepted standard dosing of isotretinoin in severe cases of acne is a starting dose of 0.5 mg/kg/day for the first 4 weeks, increase to 1 mg/kg/day, then continuation until a cumulative dose of 120–150 mg/kg is reached and tolerated by the patient.39 For very severe cases that involve large areas of inflammatory lesions, a course of prednisone 20–40 mg a day and starting at lower doses of isotretinoin to prevent severe flares may also be warranted (Box 4 and Box 5).40

Considerably higher doses of isotretinoin than those used historically, including up to 220 mg/kg, were examined in a recent prospective interventional study and it was found that there was a significantly decreased risk of relapse and that rash was the only adverse effect in patients.41 Conversely, a low dose isotretinoin (0.3–0.4 mg/kg/day) treatment has also been found to be a safe and effective management of patients with early recurrent disease.42

Use of oral isotretinoin is tightly regulated because of its well known teratogenic effects and is available in many countries only through specialist care.43 A recent population-based study of incidence rates of pregnancy, abortions and birth deformities incurred by women on isotretinoin found that the incidence of major malformations while on isotretinoin was 11%, which is lower than what was previously reported.44

Depression and suicide have been reported and well publicised in patients taking isotretinoin.45 However, a causal relationship between isotretinoin and suicidal thoughts or depression has never been established.46 Conversely, there have been studies that showed reduced anxiety and depression in patients with cystic acne after a successful treatment with oral isotretinoin.47

Adjuvant and newer procedures for acne and acne scarring

Scarring is an unwanted complication of acne that should be treated seriously (Box 6). The psychological effects of acne can be long lasting, and the association between acne and depression and anxiety is independent of the disease severity.48 As a consequence, newer treatment modalities and adjuvant therapies for acne and scarring, while costly, are a growing market in both medical and cosmetic practices. Examples of these adjuvant modalities include chemical peels, light, laser and radiofrequency.

Salicylic acid (a β-hydroxy acid) and glycolic acid (an α-hydroxy acid) are two chemical peels currently available as an adjuvant treatment for acne affecting the face.49 Chemical peels improve acne by minimising the abnormal pattern of keratinisation by causing desquamation, which reduces corneocyte cohesion and keratinocyte blockage, and allowing the promotion of normal epidermal differentiation.50 A downside to this is that it requires multiple treatments to be efficacious, which is costly and can have side effects of redness and irritation to the skin. Therefore, chemical peels do not replace the existing topical and systemic treatment available for acne.11

Lasers and light-based devices for acne have been increasingly used over the past few years. Light therapy, in the form of blue light and blue and red light, can treat active acne causing the destruction of the propionibacteria through targeting the porphyrins produced by these bacteria.51 Evidence exists that light therapy is a safe and efficacious treatment of acne.52

Radiofrequency and photodynamic therapy are examples of other new therapies for the treatment of acne and scarring. While there has been a recent plethora of research on the efficacy of the different modalities, there is still a lack of long term follow-up to prove their efficacy in the treatment of acne.53

Conclusion

Acne is a chronic disease prevalent in the adolescent population and, without appropriate treatment, it may cause potentially serious psychological damage and physical scarring. In order to effectively and rapidly reduce acne lesions, a combination therapy that targets as many of the underlying factors as possible should be considered. The emergence of P. acnes resistance requires a combination topical therapy and a low therapeutic threshold to introduce oral isotretinoin, which is a highly effective, well established treatment of acne and the only therapy that targets all of the aetiological factors of this disease.

Box 1 – Clinical photograph of a 16-year-old male patient with severe nodulocystic acne affecting the chest

Box 2 – Clinical photograph of a 16-year-old male patient with severe nodulocystic acne affecting the face

Box3 – Clinical photograph of a 16-year-old male patient with severe nodulocystic acne affecting the back

Box 4 – Clinical photograph of a 14-year-old male patient with severe nodulocystic acne and scarring of the face and chest before treatment

Box 5 – Clinical photograph of an 18-year-old male patient following treatment of isotretinoin at 135mg/kg cumulative dose

Box 6 – Clinical photograph of an 18-year-old male patient with extensive hypertrophic scarring over the shoulders

Authors

  • Victoria Rebecca Harris
  • Alan J Cooper
  • 1. Royal North Shore Hospital, Sydney, NSW

Correspondence: alanjco@tpg.com.au

Competing interests

Alan Cooper was a member of the Roaccutane Advisory Board, a group of Australian dermatologists brought together by Roche Products Pty Ltd. The preparation of this document was not supported in any way by Roche Products Pty Ltd.

References

Provenance: Commissioned; externally peer reviewed.

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