Drs Alison Layton (left) and Rebecca Mawson discuss current guidance on the use of topical, oral, systemic, and hormonal therapies in the management of acne
- Acne requires early diagnosis and prompt aggressive management
- Not all cases of acne are the same—a diagnosis should be made and disease severity graded. This helps to target treatment and measure any improvements
- Acne needs to be managed with a treatment regimen that targets pathogenic and clinical factors; treatment should be escalated using evidence-based practice
- Acne is a chronic illness with a remitting and relapsing course that may need long-term maintenance therapy
- Major psychological sequelae can result from acne—it is the clinician’s role to identify patients at risk of scarring and refer early to prevent future sequelae
- The majority of treatments prevent future acne formation, and improvement may therefore take a number of weeks
- Medical adherence is a major issue with topical therapy
- Oral antibiotics should not be used alone as a result of bacterial resistance—they should be combined with BPO
- Patients’ and healthcare professionals’ understanding of how to use topical therapies should be improved
- Support and review are necessary to improve compliance.
Acne is a disease of the pilosebaceous unit leading to a polymorphic condition with variable presentations. The peak incidence is between 13 and 16 years in both sexes; 70% of acne cases will resolve after 5 years, but in some individuals it may persist into the 20s and 30s with significant impact on social wellbeing. Acne is often viewed as a ‘rite of passage’ for teenagers and is therefore frequently disregarded by patients, parents, and practitioners.
Burden of disease
Acne is one of the most common inflammatory dermatoses seen in primary and secondary care and as such, results in a significant burden in numerous ways:
- All acne sub-types can have a significant psychosocial impact, with reduced self-esteem and impaired social functioning, which may include difficulties with relationships and lower socioeconomic achievement. 1 The psychological and social impact of acne is similar to other systemic diseases such as diabetes and epilepsy 2
- Physical scarring is a common sequel to acne, seen in up to 90% of cases 3
- Many factors effect health-seeking behaviour and often the severity of acne may not correlate to the patient’s perception of disease. Approximately 3% of GP consultations involve patients with acne aged between 13–25 years 4
- In 2000, UK GPs wrote 2.6 million acne prescriptions, which included 0.7 million prescriptions for topical antibiotics and 1 million for oral tetracyclines 1
- The BNF has over 30 different acne treatments—making a rational choice is difficult because of a limited evidence base 5
- In the USA, treatment of acne is estimated to exceed $1 billion. 6 There are no current data for cost in the UK.
Acne presents with a mixture of open and closed comedones, macules, papules, pustules, nodules, cysts, and scarring, all in varying degrees. 7 Acne can affect both the face and trunk. Early presentation with mid-facial comedones is a poor prognostic risk.
Scarring is a common sequel to acne as a result of:
- tissue loss:
- Atrophic scars
- tissue increase:
- Hypertrophic scars
- Keloid scars.
The pathogenesis of acne is complex and centres around the pilosebaceous unit. Factors involved in the pathophysiology include:6
- an androgen-dependent increase in sebum production
- abnormal follicular differentiation with hyperkeratinisation within the intrafollicular duct
- colonisation with gram-positive anaerobic Propionibacterium acnes
- early peri-follicular inflammation prior to any microbial colonisation
- later inflammation as a result of P. acnes colonisation; this is characterised by a cell-mediated immune response.
It is likely that genetic or immunological variation between patients with acne leads to worse responses and subsequent disfigurement. 8
A number of suggested guidelines and algorithms for the treatment of acne are now available. Developing evidence-based guidance is fraught with the challenges of non-standardised outcome measures, inadequately powered trials, commercially sponsored studies that do not necessarily compare one agent with another in head-to-head trials, and a paucity of much-needed high-quality studies to answer many of the pertinent questions.
This article amalgamates advice from:
- a recent European Dermatology Forum S3 evidence-based update 9
- the Global Alliance guidance to improve outcomes in acne 7
- the Prodigy Summary on acne 10
- the NICE referral guidance for acne. 11
This article has been designed to enable improvements in primary care by selecting key elements from the guidance above, embracing available evidence-based information, alongside expert opinion. The guidance within this paper is not an all-inclusive coverage of acne treatment, but aims to clarify important aspects relating to primary care. Secondary care management, such as oral retinoid therapy and the use of physical therapies in acne are not included.
Why are acne guidelines important?
Within primary care, acne management is of inconsistent quality, and community practitioners have a variable depth of knowledge. This is partly because of the vast and variable management regimens available and the paucity of dermatology exposure provided within medical training. Implementation of guidelines in primary care will facilitate effective acne management early in the course of the disease thereby avoiding physical and psychological scarring. This will improve the psychosocial wellbeing of patients, reduce the referrals to secondary care, and make overall prescribing for this chronic disease more cost effective. In addition, rationalising antibiotic prescription will reduce the emergence of bacterial antibiotic resistance. 12
Diagnosis and assessment
With over 25 different grading systems, there is no consensus in the way that acne should be graded. 6 Future technological advances may allow computer analysis and more sophisticated grading scales to be developed. 6 For the purpose of this article, acne is described as mild, moderate, and severe—there are obvious limitations to this approach, primarily in the variation of inflammatory and non-inflammatory elements within grades.
Early diagnosis and careful clinical assessment of acne can help to deliver best practice in a number of ways. Some patients will be destined to develop more severe disease and/or respond less well to treatment. It is important that primary care clinicians recognise poor prognostic factors: 13
- Early age of onset for acne in both sexes and in girls relatively earlier menarche and higher levels of dehydroepiandrosterone
- Early presentation with mid-facial lesions, predominantly comedones
- Marked seborrhoea
- Truncal acne
- Strong family history of acne and/or scarring
- Development of scarring
- Psychological issues as a result of acne.
A careful history and examination will identify at-risk individuals. Assessment and recognition of specific lesions and the degree of seborrhoea will inform management and selection of therapies that target the specific clinical presentation as well as aetiological factors. Acne is associated with an increased likelihood of psychiatric morbidity so it is important to assess mental status. 14 Early intervention and counselling may reduce mental health decline and the isolation associated with acne. 10
There are subtle variations in the treatment of acne between the current published guidance documents. This paper aims to clarify and simplify the available guidance for the GP, offering a practical guide that encompasses evidence-based information alongside expert opinion.
The microcomedo is central to the development of both inflammatory and non-inflammatory lesions and management should consider this. The key is to target multiple implicated pathogenic factors using simple well-tolerated regimens that are practical for the patient, cost effective, and efficacious. Acne is now recognised as a chronic disease and patients should be given realistic expectations about the improvement expected from treatment: they may need long-term maintenance therapy. 9
|Table 1: The impact of topical agents in acne aetiology16|
|Inflammation||Comedogenesis||Reduction in P. acnes|
|Antibiotics (not to be used as monotherapy)|
|+++||+/-||++||Dependent on whether P. acne strains are resistant|
|Fixed combination therapy|
Adapalene plus BPO (Epiduo®)
Tretinoin plus erythromycin (Aknemycin Plus®)
Isotretinoin plus erythromycin (Isotrex®)
Adapalene plus BPO (Epiduo®)
It is essential that topical therapies are applied correctly and regularly. Initial application may cause irritation, therefore short contact (e.g. 30 minutes followed by washing off), with gradual increasing increments in application or alternate day applications will help to aid tolerability. 15 Products must be applied to all acne-prone areas rather than just specific lesions to prevent follicle development. The efficacy of the different types of topical agents on acne aetiology is shown in Table 1 (see above) 16 and available topical therapies for acne management are shown in Table 2).
Topical retinoids are the mainstay for comedonal acne treatment. They also have some impact on inflammatory lesions and enhance the efficacy of other topical therapies. Novel retinoids such as adapalene have been shown to have a better tolerability profile while achieving similar efficacy to older topical retinoids like tretinoin. 9
Non-antibiotic antimicrobials, including benzoyl peroxide (BPO) and azelaic acid, should be used in preference to topical antibiotics because of bacterial resistance. Benzoyl peroxide has multiple mechanisms of action. It is the most effective agent for targeting P. acnes and will reduce both sensitive and resistant strains by more than 95% in 5 days. 7 It is particularly useful for targeting inflammatory acne although a reduction in non-inflammatory lesions has also been noted in many clinical trials. 7 There is no evidence that increasing the concentration of BPO improves outcome, therefore the lowest concentration available at the most reasonable cost can be considered as an appropriate way forward. 17 The main issue with BPO relates to irritation, bleaching, 5 and in rare cases, contact hypersensitivity.
Benzoyl peroxide should:
- always be used alongside antibiotics to both prevent and clear resistant strains of P. acnes 1
- be considered between antibiotic courses for a minimum of 5–7 days to clear resistant bacterial organisms. 12
Azelaic acid is an alternative antimicrobial therapy and has been shown to have beneficial effects on non-inflammatory and inflammatory lesions and can also reduce post-inflammatory hyperpigmentation. 18
Although topical antibiotics are effective in inflammatory acne, they have very little impact, if any, on comedonal lesions. The main issue with topical antibiotics relates to their ability to promote bacterial resistance to antibiotics and therefore they should not be used as a monotherapy.1 Combining topical antibiotics with BPO will negate this risk.
|Table 2: Available topical therapies for management of acne5|
Benzoyl peroxide: 2.5%, 4%, 5%, 10%
Azelaic acid: 15%, 20%
Adapalene 0.1% (Differin®)
Isotretinoin 0.05% (Isotrex®)
Tretinoin 0.025% (Retin-A®)
|Topical antibiotics (not to be used as monotherapy)||
Clindamycin 1% (Dalacin T®; Zindaclin®)
Erythromycin 2% (Stiemycin®)
Adapalene 0.1% plus benzoyl peroxide 2.5% (Epiduo®)
Benzoyl peroxide 5% plus clindamycin 1% (Duac®)
Tretinoin 0.025% plus erythromycin 4% (Aknemycin Plus®)
Isotretinoin 0.05% plus erythromycin 2% (Isotrexin®)
Benzoyl peroxide 10% plus potassium hydroxyquinoline sulphate 0.5% (Quinoderm®)
Erythromycin 40 mg/ml and zinc acetate 12 mg/ml on constitution (Zineryt®)
Oral antibiotics in acne must only be used when indicated and they should never be used as monotherapy because of the increasing emergence of antibiotic resistance. Oral antibiotics are indicated for patients with extensive disease, which includes truncal acne and moderate to severe papulopustular acne. Antibiotics commonly used for acne are shown in Table 3. Doxycycline and lymecycline should be selected in preference to minocycline and oxytetracycline because they have a superior side-effect profile and result in better patient adherence to therapy. 9 Benzoyl peroxide should be used alongside antibiotics to reduce the likelihood of bacterial resistance emerging. 12
Hormonal therapies can be a useful option in the management of acne. All combined oral contraceptives (COC) have the potential to reduce acne through their oestrogenic effects. 19 One ethinylestradiol/cyproterone acetate preparation has a licence for the treatment of severe acne, but is not licensed as a contraceptive agent in the UK. Third-generation COCs contain less androgenic progesterone (e.g. gestodene and desogestrel), but have an increased risk of venous thromboembolism (VTE) compared with second-generation pills containing progesterone (e.g. levonorgestrel). 20
The risk of a VTE is highest for first-time users and during the first year a woman uses the combined pill. 20 Careful selection and counselling of patients is required when prescribing a COC for acne, and healthcare professionals should be mindful of the adverse effect profile.
Current advice from the Faculty of Sexual and Reproductive Healthcare states that no additional contraception is needed during or after a course of non-enzyme-inducing antibiotics (NB rifampicin is an enzyme inducer). 21
|Table 3: Systemic antibiotics for acne16|
|Drug||Dosage||Comments regarding usage||Incidence regarding P. acne resistance||Adverse effects|
|Doxycycline||100–200 mg daily||Moderate||Moderate||Photosensitivity
|Lymecycline||300–600 mg daily||Moderate||Moderate||Fewer than minocycline|
|Oxytetracycline||500 mg bd||Inexpensive; should be taken 30 minutes before food and not with milk||Moderate||Rare onycholysis, photosensitivity, benign intracranial hypertension|
(not advocated as first- or second-line treatment choice)
|100–200 mg daily||Expensive||Moderate and increasing||Headaches due to benign intracranial hypertension (dose dependent), pigmentary changes, autoimmune hepatitis/lupus erythematosus-like syndrome|
|Erythromycin||500 mg bd||Inexpensive; should be taken on an empty stomach||High||Gastrointestinal upset, nausea, and diarrhoea are fairly common|
Acne is recognised as a chronic inflammatory dermatosis with a relapsing and remitting course. Maintenance treatment may be required to sustain remission for months or years depending on the age of the patient. 9 This treatment should be tolerable, have minimal impact on the patient’s lifestyle, and be cost effective. Topical retinoids are recommended for maintenance therapy. 9
Treatment of acne should target as many pathogenic factors as possible in a cost-effective and evidence-based manner. Adopting this approach will improve acne in the majority of cases and early intervention with effective treatment can preclude scarring. A modified summary of a stepped approach for the management of acne as recommended by the European Dermatology Forum is shown in Table 4. 9
|Table 4: A summary of recommendations based on evidence base and expert opinion9,16|
|Comedonal acne||Mild-to-moderate papulopustular acne||Moderate-to-severe papulopustular/ moderate nodular acne||Severe nodular/ conglobate acne*|
|High strength of recommendation||-||Adapalene + BPO (f.c) or BPO + clindamycin (f.c)||Isotretinoin†||Isotretinoin†|
|Medium strength of recommendation||Topical retinoid‡||BPO and/or topical retinoid‡ or azelaic acid or systemic antibiotic§ + adapalene¦||Systemic antibiotics¶ + adapalene¦ + BPO (f.c.)||Systemic antibiotics¶ + BPO|
|Alternatives for females||-||-||Hormonal antiandrogens + topical treatment or hormonal antiandrogens + systemic antibiotics**||Hormonal antiandrogens + systemic antibiotics** + BPO|
|Pregnancy first line15||BPO or topical erythromicin/zinc (f.c) + BPO||BPO or topical erythromicin/zinc (f.c) + BPO||Oral erythromycin + BPO||Oral erythromycin + azelaic acid + BPO|
|Maintenance15||Topical retinoid||Topical retinoid||Topical retinoid + BPO||Topical retinoid + BPO|
|BPO=benzoyl peroxide; f.c=fixed combination
*Systemic treatment with corticosteroids can be considered
†Confounding factors may necessitate the use of a treatment with a lower strength of recommendation as a first-line therapy (e.g. financial resources, reimbursement limitations, legal restrictions, availability, drug licensing)
‡Adapalene to be preferred over tretinoin/isotretinoin as better tolerated
§For more widespread disease/moderate severity, a systemic treatment is recommended
¦Only studies found on systemic antibiotics + adapalene, isotretinoin and tretinoin can be considered for combination treatment based on expert opinion
¶Doxycycline and lymecycline
**Low strength of recommendation
Follow up and referral
There is limited evidence regarding the length of treatment for acne before introducing alternative therapies. Improvements should be seen after 6 weeks and patients should therefore be assessed at this point and on a regular basis thereafter. 22 Careful assessment and recognition of specific subtypes of acne and identification of people with severe disease and poor prognostic risk factors should promote early patient referral for consideration of isotretinoin; this is the only agent able to impact on the major pathogenic factors indicated in acne, however it is licensed as a second-line therapy for acne that has not responded to combination regimens including antimicrobials and topical retinoids. 23
Approximately 20% of patients will show a poor response. The reasons behind this include: 16
- the wrong diagnosis
- inadequate adherence to therapy
- inappropriate assessment of overall acne severity by the prescribing practitioner
- side-effects or intolerance of therapy
- resistance to P. acnes
- unusual underlying conditions (congenital adrenal hyperplasia polycystic ovary syndrome [PCOS]).
Most individuals with acne can be managed in primary care. NICE advises referral to a specialist service if patients: 11
- have a very severe variant such as fulminating acne with systemic symptoms (acne fulminans)
- have severe acne or painful, deep nodules or cysts (nodulocystic acne) and could benefit from oral isotretinoin
- have severe social or psychological problems, including a morbid fear of deformity (dysmorphophobia)
- are at risk of, or are developing, scarring despite primary care therapies
- have moderate acne that has not responded to treatment, which should include several courses of both topical and systemic treatment over a period of at least 6 months; failure is probably best based on a subjective assessment by the patient
- are suspected of having an underlying endocrinological cause for the acne (such as PCOS) that needs assessment.
Education and adherence to therapy
For some teenagers and young adults, management of acne might be the only time they present in general practice. Some surgeries hold teenage clinics run by practice nurses who give health promotion and advice on sexual health, travel, smoking, drugs, and diet. These clinics would be an ideal forum for identifying patients with acne and providing advice accordingly. Patient education should include dispelling myths about the causes of acne and treatments fallacies. 10
It is important to deal with the exogenous factors involved in acne, such as increasing the use of non-comedogenic, oil- and fragrance-free moisturisers, cleansers, and creams. Topical treatments can often make the skin feel tight and dry and it is useful to combine them with appropriate emollients. The challenge of providing adequate information within the context of short consultation times in general practice is difficult. The Acne Academy website is designed to support acne management and will be useful to patients (www.acneacademy.org).
Cost-effective prescribing is essential in the current economic climate. There is limited evidence of different outcomes within treatment groups for different products. However, it is clear that for the product(s) to be cost effective, it needs to be used correctly and fit in with the patient’s lifestyle to achieve long-term adherence. Cheap simple products prescribed with clear guidance can achieve a reduction in prescribing cost. A single combination therapy is more expensive than using two products separately; however, there is evidence to suggest that some fixed-dose combinations achieve more rapid efficacy than individual ingredients and a synergistic effect can be achieved by combining products, which in turn encourages improved medical adherence. 9
Acne represents one of the commonest inflammatory dermatoses seen within primary and secondary care, but for which successful outcomes can be achieved. The management approach for acne should include consideration of the pathogenic factors and tailoring therapy to target clinical lesions, acne sub-sites, and patient preferences.
Judicious use of antibiotics should be employed in the management of acne to avoid the emergence of antibiotic-resistant P. acnes. Antibiotics should not be used as monotherapy and when employed in an acne regimen should be combined with BPO to avoid the emergence of antibiotic resistant bacterial strains.
View the Guidelines summary on the treatment of acne from the European Dermatology Forum: https://www.guidelines.co.uk/edf/acne
- Acne can usually be managed in primary care but some cases may require referral to specialist care
- GPwSIs could form part of the specialist service
- Local referral pathways would facilitate such an option
- Local formularies should be developed to identify cost-effective therapies and ensure that antibiotics are not used without benzoyl peroxide (to avoid bacterial resistance)
- Tariff prices for dermatology outpatients = Â£112 (new), Â£69 (follow up).
- Coates P, Vyakrnam S, Eady E et al. Prevalence of antibiotic-resistant propionibacteria on the skin of acne patients: 10-year surveillance data and snapshot distribution study. Br J Dermatol 2002; 146 (5): 840–848.
- Mallon E, Newton J, Klassen A. The quality of life in acne: a comparison with general medical conditions using generic questionnaires. Br J Dermatol 1999; 140 (4): 672–676.
- Layton A, Henderson C, Cunliffe W. A clinical evaluation of acne scarring and its incidence. Clin Exp Dermatol 1994; 19 (4): 303–308.
- Purdy S, Langston J, Tait L. Presentation and management of acne in primary care: a retrospective cohort study. Br J Gen Pract 2003; 53 (492): 525–529.
- British National Formulary website. www.bnf.org/bnf/index.htm (accessed 10 May 2012).
- Ramli R, Aamir S, Ahmad F et al. Review. Acne analysis, grading and computational assessment methods: an overview. Skin Res Technol 2012; 18 (1): 1–14.
- Thiboutot D, Gollnick H, Bettoli V et al. New insights into the management of acne: an update from Global Alliance to improve outcomes in acne group. J Am Acad Dermatol 2009; 60 (5 Suppl): S1–S50.
- Seukeran D, Layton A, Cunliffe W et al. Inflammation in acne scarring: a comparison
of the responses in lesions from patients prone and not prone to scar. Br J Dermatol 2004; 150 (1): 72–81.
- European Dermatology Forum. Guidelines on the treatment of acne. Berlin: EDF Guidelines Committee, 2011. Available at: www.euroderm.org/images/stories/guidelines/Guideline-on-the-Treatment-of-Acne.pdf
- Prodigy website. Acne vulgaris. London: NICE, 2011. Available at: prodigy.clarity.co.uk/acne_vulgaris (accessed 10 May 2012).
- National Institute for Health and Care Excellence. Referral advice: a guide to appropriate referral from general to specialist services. London: NICE, 2001.
- Williams H, Dellavalel R, Graner S. Acne vulgaris. Lancet 2012; 379 (9813): 361–372.
- Layton A, Dreno B, Gollnick H, Zouboulis C. A review of the European Directive for prescribing systemic isotretinoin for acne vulgaris. J Eur Acad Venereol 2006; 20 (7): 773–776.
- Sundstrom A, Alfredsson L, Gerden B et al. Association of suicide attempts with acne and treatment with isotretinoin: retrospective Swedish cohort study. BMJ 2010; 341: c5812.
- Cunliffe W, Poncet M, Loesche C, Verschoore M. A comparison of the efficacy and tolerability of adapalene 0.1% gel versus tretinoin 0.025% gel in patients with acne vulgaris: a meta-analysis of five randomized trials. Br J Dermatol 1998; 139 (Suppl 52): 48–56.
- Burns T, Breathnach S, Cox N, Griffiths C. Rook’s textbook of dermatology: 4 Volume Set (7th Edition). Wiley-Blackwell, 2010: 42.38–42.46.
- Fakhouri T, Yentzer B, Feldman S. Advancement in benzoyl peroxide-based acne treatment: methods to increase both efficacy and tolerability. J Drugs Dermatol 2009; 8 (7): 657–661.
- Erica C, Davis M, Valerie D et al. Postinflammatory hyperpigmentation: a review of the epidemiology, clinical features, and treatment options in skin of colour. J Clin Aesthet Dermatol 2010; 3 (7): 20–31.
- Arowojolu A, Gallo M, Lopez L. Combined oral contraceptive pills for treatment of acne. Cochrane Database Syst Rev 2009; 8 (3): CD004425.
- Mayor S. European evaluation concludes third generation pills are associated with a small increase in risk of venous thromboembolism. BMJ 2001; 323: 828.4.
- Faculty of Sexual and Reproductive Healthcare. Drug interactions with hormonal contraception. FSRH: 2011, updated January 2012. Available at: https://www.fsrh.org/documents/ceu-guidance-drug-interactions-with-hormonal-contraception-jan/
- Ozolins M, Eady E, Avery A et al. Randomised controlled multiple treatment comparison to provide a cost-effectiveness rationale for the selection of antimicrobial therapy in acne. Health Technol Assess 2005; 9 (1): iii–212.
- Layton A, Dreno B, Gollnick H, Zouboulis C. A review of the European Directive for prescribing systemic isotretinoin for acne vulgaris. J Eur Acad Dermatol Venereol 2006; 20 (7): 773–776.G