Abstract
Acne is one of the most prevalent skin conditions affecting teenagers. It is a disease of the pilosebaceous unit. Blockage of sebaceous glands and colonisation with Proionobacterium acnes leads to acne. Grading the severity of acne helps to determine the appropriate treatment. Treatment of acne should be started as early as possible to minimise the risk of scarring and adverse psychological effects. It should be tailored to the individual patient, the type of acne, its severity, the patient's ability to use the treatment, and the psychological state. Topical agents are the mainstay for treatment of mild acne. Moderate acne is treated with oral antibiotics. Resistance to antibiotics may be reduced by subsequent use of non‐antibiotic topical medications. Severe acne is treated with isotretinoin, and this can lead to permanent remission. With better education and care given by medical profession, acne treatment could be significantly improved.
Keywords: acne vulgaris, propionobacterium acnes, acne grading, acne treatment, acne psychological effects
Acne is one of the most prevalent skin conditions, affecting more than 85% of teenagers.1,2,3 It typically starts at puberty and resolves slowly as the person reaches 20, although some people continue to have acne into their 40s and 50s.4,5,6,7,8 It is seldom life threatening and is often dismissed as a self limiting condition. Little attention is given to it in either undergraduate or postgraduate education.9 Despite its apparent cosmetic nature, its effects can go far deeper than the surface of the skin, and can place a heavy emotional and psychological burden on patients that may be far worse than the physical impact. The change in the skin's appearance may give rise to a changed body image that in turn is known to lead to anger, fear, shame, anxiety, depression, embarrassment, and bullying and stigmatisation within peer groups.10,11,12 Lack of confidence, social withdrawal, feelings of insecurity and inferiority, limited employment opportunities, functional and interpersonal difficulties at work, and suicidal tendencies have also been reported and attributed to the effects of acne.9,13,14,15,16,17,18,19,20,21 The reduction in quality of life has been estimated to be as great as that associated with epilepsy, asthma, diabetes, or arthritis.22
Aetiopathogenesis
Acne is a multifactorial disease: genetic factors,23 stress,24 androgens,25 and excess sweating all influence its development and/or severity.26 Corticosteroids, oral contraceptives, iodides, bromides, lithium, and chemicals such as dioxins are known to induce acne eruptions, as are endocrine disorders such as Cushing's syndrome and polycystic ovary syndrome. It is often found that acne is worse in current smokers,27 but despite popular myth, diet, lack of exercise, lack of hygiene, greasy hair hanging over the face, and masturbation do not have any effect.28,29
Acne is a disease of the pilosebaceous units in the skin. A changed keratinisation pattern in the hair follicle leads to blockage of sebum secretion.30 It is probable that hyperresponsiveness to the stimulation of sebocytes and follicular keratinocytes by androgens leads to the hyperplasia of sebaceous glands and seborrhea that characterise acne.31,32 The enlarged follicular lumen attributable to inspissated keratin and lipid debris forms a closed comedone (whitehead). When the follicle has a portal of entry at the skin, the semisolid mass protrudes forming a plug, producing an open comedone (blackhead).7,33
Propionobacterium acnes colonises the follicular duct and proliferates, breaking down the sebum to triglycerides, irritants that probably contribute to the development of inflammation. When the follicular epithelium is invaded by lymphocytes it ruptures, releasing sebum, micro‐organisms, and keratin into the dermis.34 Neutrophils, lymphocytes, and foreign body giant cells accumulate and produce the erythematous papules, pustules, and nodular swelling characteristic of inflammatory acne.
Clinical features
The clinical features of acne are a cluster of signs related to distended, inflamed, or scarred pilosebaceous units. Lesional polymorphism is the main feature, and is most commonly seen on the face, back, and the chest. Seborrhoea is the most frequently occurring feature. Distended pilosebaceous units can take the form of open or closed comedones, and the types of inflamed lesions exhibited are pustules, papules, nodules, and cysts. In more severe cases, multiple inflammatory papules and nodules fuse to form draining sinuses, which lead to chronic scarring and, rarely, malignant changes.35 Post‐inflammatory lesions may also occur and are represented by macular pigmentation and scars (hypertrophic, keloids, ice pick scars, depressed fibrotic and atrophic macules, perifollicular elastolysis).36 Post‐inflammatory hyperpigmentation is commonly seen in pigmented skin.
Grading of acne
Grading the severity of acne helps to determine the appropriate treatment. Many grading systems exist, but the Leeds revised acne grading system (a numerical pictorial grading system) seems to be the most accurate, reproducible, and rapid (fig 1).31
Figure 1 Photographs illustrating different grades of acne (adapted from O'Brien).37 (A) Mild acne (grade 2). Comedones, a few small papules and a few pustules. (B) Moderate acne (grade 7). Numerous comedones and small inflammatory papules, numerous pustules. (C) Severe acne (grade 12). Numerous comedones, deeper papules and pustules, deep and large lesions, presence of cysts and abscesses.
As well as assessing the clinical aspects, it is also important to assess the psychological impact using tools such as the APSEA questionnaire (fig 2)38 or the Cardiff acne disability index.39
Figure 2 APSEA assessment of psychological and social effects of acne.
Management of acne
Management should comprise safe treatment, reduction of the psychological burden through emotional and social support, and clarifying popular misconceptions about the disease.
Treatment should start as early as possible to minimise the risks of scarring or adverse psychological effects. It should be aimed at reducing non‐inflammatory lesions that may be precursors to inflammatory lesions, improving existing inflammation, and lowering the P acnes population. Treatment must be tailored to the individual patient, the type of acne, its severity, the patient's ability to use the treatment, and their psychological state.24 It is very important to emphasise to the patient from the outset that the treatment of acne is a long term affair. Advice on the use of cosmetics, moisturisers, sunscreens, and hair gels may be appropriate, as some formulations are greasy and could exacerbate existing acne or even cause acne‐type lesions.40
Treatment of mild acne
Topical preparations are the mainstay therapy, and their main action is the prevention of new lesions. Their effect is slow and treatment should be maintained to prevent recurrence. Topical agents are active only where and when they are applied, and should therefore be applied daily to all areas of the skin prone to acne.1 Maintenance therapy is crucial to prevent recurrence.
The topical agents available are benzoyl peroxide, antibiotics, azelaic acid, or retinoids.
Benzoyl peroxide is bactericidal for P acnes and improves both inflammatory and non‐inflammatory lesions.41 It is an oxidising agent that works by introducing oxygen into follicles, which then kills P acnes. Because of this mechanism of action, P acnes never develops resistance to benzoyl peroxide, however there can be adverse side effects such as irritant dermatitis and bleaching of hair, clothes, and linen.42,43
Topical antibiotics such as clindamycin, tetracycline, and erythromycin are bacteriostatic for P acnes and are effective for mild to moderate inflammatory acne.41,44
Topical retinoids such as tretinoin and adapalene correct abnormalities in follicular keratinocytes. They are effective in both the treatment of inflammatory lesions and in the prevention of the formation of comedones.1,42,45 They may also reduce inflammation by interfering with the interaction between toll‐like receptor 2 and external products of P acnes on the surface of antigen presenting cells.46 In addition, topical retinoids improve the penetration of other topical medications and may also help to improve the hyperpigmentation that is left in dark skin types after the resolution of inflammatory lesions.47 The maximum therapeutic response to topical retinoids occurs over about 12 weeks. They may produce local irritation, increased sensitivity to sunlight, and exacerbation of inflammatory lesions.48
Combined agents such as erythromycin/zinc, erythromycin/tretinoin, erythromycin/isotretinoin, erythromycin/benzoyl peroxide, and clindamycin/benzoyl peroxide are increasingly being used and are useful in reducing the development of antibacterial resistance in P acnes.
Most of these topical preparations are available in a variety of strengths and delivery systems. Drying agents (gels, washes, and solutions) are particularly suited to oily skin, whereas creams, lotions, and ointments are more suited to patients with dry, easily irritated skin.1
Treatment of moderate acne
Oral antibiotics are the standard treatment for moderate acne and for cases where topical combinations are not tolerated or are ineffective.25 They have been shown to reduce the number of P acnes.49 In addition to interfering with the growth and metabolism of propionobacteria, antibiotics have an anti‐inflammatory activity by reducing and inhibiting cytokine production, affecting macrophage functions, and inhibiting neutrophil chemotaxis.50 The main systemic antibiotics used are erythromycin and different types of tetracyclines. They have a long history of verified efficacy in the management of inflammatory acne.49 Erythromycin (macrolide) should be reserved for cases where tetracyclines are not tolerated or are contraindicated: for example in pregnancy, when breast feeding, and in children below the age of 8–12 years.51
First generation tetracyclines (tetracycline hydrochloride, oxytetracycline) or second generation tetracyclines (doxycycline, lymecycline, or minocycline) should be considered as first line oral antibiotic therapy. Tetracycline is inexpensive and is often effective in previously untreated cases, however gastrointestinal side effects and the need to take it on an empty stomach are disadvantageous.
One advantage of the second generation of tetracyclines relates to improved absorption that is unaffected by food. This may improve compliance when second generation tetracyclines are used, particularly for adolescents. Doxycycline is cleared by the liver, allowing this treatment to be used in patients with renal impairment.51 Co‐trimoxazole and trimethoprim have been used as third line agents in the treatment of acne when other systemic antibiotics are contraindicated or there is verified resistance to other agents.51
Table 1 outlines the optimum dose regimen, expense, incidence of bacterial resistance, and potential adverse effects. It is recommended to continue treatment for up to three months. If little response is seen after six weeks, the addition of a topical non‐antibiotic medication or a switch to an alternative oral antibiotic should be considered.52 After control of acne is achieved and maintained for at least two months, a reduction in the dose can be attempted. Eventual withdrawal is the goal, followed by long term topical therapy.
Table 1 Systemic antibiotics for the treatment of acne vulgaris (adapted from Layton)51.
Drug | Dose | Comments regarding use | Incidence of acne resistance | Adverse effects |
---|---|---|---|---|
Oxytetracycline | 500 mg twice daily | Inexpensive, take 30 minutes before food and not with milk | Moderate (20%) | Rare onycholysis, photosensitivity, benign intracranial hypertension |
Erythromycin | 500 mg twice daily | Inexpensive | High (>50%) | Gastrointestinal upset, nausea, diarrhoea all fairly common |
Minocycline | 100–200 mg daily | Expensive | Low (but has increased) | Headache (dose dependent), pigmentary changes, autoimmune hepatitis |
Doxycycline | 100–200 mg daily | Moderate cost | Moderate | Photosensitivity (dose dependent) |
Lymecycline | 300–600 mg daily | Moderate cost | As for tetracycline | Less than with minocycline |
Trimethoprim | 200–300 mg twice daily | Inexpensive | Low (12%) | Rare hepatic/renal toxicity, agranulocytosis. |
Resistance to antibiotics is a problem, and a large contributory factor has been their widespread inappropriate use (such as inadequate potency, inadequate duration of treatment, and/or poor compliance).53,54,55 This may cause therapeutic failure in some patients. However, as a result of a change in prescription policy the level of resistance has recently fallen.55 Guidelines for optimising oral antibiotic use and preventing the emergence of resistant strains is given in box 1.56 If resistance to tetracycline is suspected, switching to minocycline is recommended, as resistance to it is rare.57
Box 1 Recommendations to limit antibacterial resistance of P acnes (adapted from Simpson, Tan, Cunliffe)56,58,59
Avoid antibiotics if non‐antibiotic agents such as benzoyl peroxide or retinoids are effective.
Only continue antibiotics until the doctor and the patient agree there is no further improvement. Prescribe antibiotics for a maximum of six months.
Use the same antibiotics if relapse occurs.
Give antibiotics for a minimum of two months before changing because of poor therapeutic response.
Avoid concomitant use of oral and topical antibiotics with chemically dissimilar properties to decrease development of resistance to both agents
Use short intervening courses (5–7 days) of benzoyl peroxide to reduce/eliminate selected resistant propionobacteria.
Use benzoyl peroxide in combination with topical and oral antibiotics. Use systemic isotretinoin if several antibiotics have been tried without success.
Culture P acnes for antibiotic sensitivities.
Educate patients on the importance of good adherence to the prescribed regimen and the importance of limiting exposure to antibiotics.
Hormonal therapy
This can be very effective in women irrespective of their serum androgen levels. Oral contraceptives may decrease free testosterone level, and the oestrogen component may decrease the production of ovarian androgens by suppressing the secretion of pituitary gonadotrophins. The adverse effects of oral contraceptives include nausea, breakthrough bleeding, weight gain, and breast tenderness. Available scientific evidence does not support the hypothesis that antibiotics lower the contraceptive efficacy of oral contraceptives.60 Anti‐androgen therapy may be of use to treat acne in women, particularly those with deep seated nodules of the lower face and neck.31 A combination of cyproterone acetate and ethinyl oestradiol (Dianette) is often effective, but its effect may be delayed for three to six months.11 Side effects of cyproterone include menstrual abnormalities, breast tenderness, nausea, vomiting, fluid retention, headache, and melasma. Pregnancy should be avoided during therapy with cyproterone, because of potential for feminisation of the male fetus. Spironolactone in doses of 50–100 mg twice daily seems to reduce sebum production and improves acne. It acts as an androgen receptor blocker and inhibits 5‐α reductase. There is a theoretical risk of carcinogenicity and is therefore used only rarely. The starting dose should be around 25–50 mg daily and, provided the patient does not experience breast tenderness or headaches, can be increased to the maximum of 200 mg. It can be combined with the oral contraceptive in sexually active women to avoid the risk of pregnancy and feminisation of the fetus.
Treatment of severe acne
Patients with severe acne that does not clear with combined oral and topical therapy are considered for treatment with oral isotretinoin.1 Isotretinoin is a member of the retinoid class of compounds related to retinol (vitamin A). It is the only treatment that has an effect on all four of the major factors involved in the pathogenesis of acne,31,61,62 and it is the only treatment that may lead to permanent remission.11 It is also more cost effective than oral antibiotics.9 As it is a lipid soluble drug, its absorption is increased when given with food. Dose regimens vary from 0.1 mg/kg/day to 0.2 mg/kg/day. The recommended starting dose is 0.5 mg/kg/day, which is gradually increased according to side effects and clinical response. Box 2 shows indications for the use of isotretinoin.
Minor side effects of isotretinoin, such as dryness and soreness of eyes, skin, oral mucosa, nasal mucosa, muscle aches and pains, hypertriglyceridaemia, and impaired night vision are reversible upon reducing the dose or withdrawal of treatment.63,64 Mucocutaneous drying can be managed by emollients and false tears.65 Retinoid induced hyperlipidaemia occurs more frequently in patients with underlying predisposing factors such as obesity, alcoholism, diabetes, or familial hyperlipidaemia. Pre‐treatment levels are not necessarily predictive of increased levels of triglycerides and cholesterol during retinoid treatment. The high levels can be managed at least partially by an appropriate diet and lipid lowering drugs.
Severe potential side effects such as depression and suicide have been reported to occur within the first two months of treatment,66,67 however this was not seen in population based studies.68,69 The risk of inducing depression should be balanced with the psychological benefit of effective treatment.70 Pseudotumour cerebri and benign intracranial hypertension with papilloedema is a rare complication of isotretinoin therapy and has been reported when combined with oral tetracyclines.
The drug is only to be prescribed by dermatologists and a pregnancy prevention programme should be followed.51 Signed consent should be obtained confirming that the patient knows not to get pregnant during therapy and for four weeks afterwards. A pre‐treatment pregnancy test is required and monthly pregnancy testing throughout treatment is a recommended option. Treatment should be started on the second or third day of menstruation and reliable contraceptives should be used where necessary.
Isotretinoin is metabolised by cytochrome P450 enzymes, and thus it may have potential interaction with other drugs (see table 2).
Table 2 Potential interactions of oral isotretinoin with other drugs (adapted from Layton)51.
Drug | Effect |
---|---|
Alcohol | Heavy intake of alcohol reduces efficacy of oral isotretinoin and may increase risk of hepatotoxicity |
Imidazole | Antifungal may increase blood levels of isotretinoin |
Highly acidic drugs | Salicylic acid and indomethacin have a high affinity for albumin and may displace isotretinoin from leaving sites, leading to increase of drug concentration in the plasma. |
Carbamazepine | Plasma level decrease when concurrent isotretinoin is taken |
Oral tetracycline | Both isotretinoin and tetracycline can lead to raised intracranial pressure, |
Vitamin A | Addictive toxic effects |
Physical, rather than pharmacological, forms of therapy that result in rapid relief of acne include the removal of comedones and the direct injection of corticosteroids into inflamed cysts.71 Other modalities that are currently being evaluated include the application of topical ALA (amino‐levulinic acid) followed by exposure to broadband UV light, and the N‐Lite laser.72
Atrophic scarring can be treated with laser resurfacing,73,74 dermal collagen injection, or antilogous fat implants. Hypertrophic scarring can be treated by chemical peels, microdermabrasion,71 topical corticosteroid cream, intralesional triamcinolone injection, excision, cryotherapy,75 or application of silicone gels.
Box 2 Indication for the use of oral isotretinoin
Ideally reserved for
Severe acne
Or in carefully selected cases with a combination of the following:
Moderate acne unresponsive to conventional therapy
Moderate acne relapsing after conventional therapy
Acne scarring
Psychological effects resulting from acne and scarring
Unusual form of acne
Key references
James WD. Acne. N Engl J Med 2005;352.
Webster GF. Acne vulgaris. BMJ 2002;325:475–8.
O'Brien SC, Lewis JB, Cunliffe WJ. The Leeds revised acne grading system. J Dermatolog Treat 1998;9:215–20.
Layton A. Systemic therapy of acne vulgaris. Br J Hosp Med 2004;65:80–5.
Cunliffe WJ, Gollnick HPM. Acne diagnosis and management. London: Martin Dunitz, 2001.
Conclusions
Acne is an extremely common skin condition, and despite not directly endangering life it can have a devastating physical and psychological effect on the lives of vulnerable adolescents. Effective and safe treatments for acne are available, yet many do not consider it a problem worth treating. Treatment of acne should be started early to prevent scarring, and the most effective agent with the minimum risk of adverse effects should be chosen.48 There is widespread misjudgment of the condition in both the medical profession and the public. Dispelling misconceptions about acne, its causes, and availability and efficacy of treatment must start from medical school to prevent the continuing perpetration of misinformation throughout the community.76 The failure of patients to take medicine in a way that would lead to therapeutic benefit is an important problem.77 Health education should ensure that patients have accurate information of the causes of acne and also that they have realistic expectations about the time frame and probable results of treatment. Better education and care given by medical staff and other professionals to patients is central to concordance, because it will allow them to treat themselves more effectively.78
Multiple choice questions; answers at the end of the references
-
Acne is caused by
Propionobacterium acnes
Excessive intake of fatty food
Poor hygiene
Corticosteroids
-
Comedones are produced by
Changed keratinisation in hair follicle
Inspissation of keratin
Distension of pilosebaceous unit
Colonisation by propionobacterium.
-
Severe acne consist of
Numeous comedones
Small superficial papules
Cysts
Abscess
-
Treatment of acne should be aimed at reducing
non‐inflammatory lesions
inflammatory lesions
P acne population
Psychological burden
-
Oral isotretinoin
is the only treatment that may lead to permanent remission of acne.
is not effective against all major factors involved in the pathogenesis of acne.
induced mucosal dryness is not reversible on cessation of treatment.
induced suicidal tendency should be balanced with the psychological benefit of treatment.
Acknowledgements
Dr A Narayan, consultant physician, Fairfield General Hospital, Manchester.
Answers
1. (A) and (D) are true, (B) and (C) have no influence on acne. 2. (A), (B), and (C) are correct, (D) probably contributes to the development of inflammation. 3. (A), (C), and (D) are correct. The papules and pustules in severe acne are deeper and larger. 4. All are right. 5. (A) and D) are true, (B) effective against all major factors, (C) mucosal dryness is reversible on cessation of treatment.
Footnotes
Funding: none.
Competing interests: none declared.
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