COMPLETE HOW TO TREAT QUIZZES ONLINE ( to earn CPD or PDP points.

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1 HowtoTreat PULL-OUT SECTION COMPLETE HOW TO TREAT QUIZZES ONLINE ( to earn CPD or PDP points. inside Aetiology and pathogenesis Clinical manifestations Diagnosis Management The authors DR BENJAMIN DANIEL, dermatology research fellow, St George Hospital and school of medicine, University of NSW, Sydney, NSW. PROFESSOR DEDEE MURRELL, professor and head of dermatology, St George Hospital and school of medicine, University of NSW, Sydney; executive vicepresident, International Society of Dermatology; and chair, World Congress task force, American Academy of Dermatology. Background and epidemiology ACNE is the most common skin condition, affecting most people at some time during their life. Despite the multiple treatments available, many patients are often undertreated, resulting in long-term scars and psychological distress. This article outlines some important treatment options that should be considered when treating a patient with acne. vulgaris is a very common skin condition in adolescents. About 85% of adolescents experience acne, with studies indicating a larger proportion of girls affected than boys. Girls tend to develop acne before boys. However, boys tend to have more persistent and severe acne compared with girls. The earlier onset of acne in girls is probably due to the earlier age of onset of puberty. In some patients acne improves in their mid-to-late 20s. However, severe cases usually take longer to improve. Importantly, up to 50% of patients will have acne that persists in adulthood. cont d page 33

2 Aetiology and pathogenesis ALTHOUGH acne is the most common skin condition worldwide, it is poorly understood by patients and some health professionals. Misconceptions about triggers, prevention and treatments often lead to a delay in appropriate therapy and worsening of the acne and/or related scarring. Sebaceous glands are present all over the body, except for the palms and soles, with a large number located on the face and scalp. It is the pilosebaceous unit, comprised of a sebaceous gland and a hair follicle, that is affected in acne. The main role of the sebaceous glands is to produce sebum. Studies have shown that patients with acne have larger sebaceous glands and produce more sebum than those without acne. Fetal and neonatal sebaceous gland development is dependent on maternal androgens and endogenous fetal steroids. Four main factors contribute to the pathogenesis of acne (see box, right). They are: Excess sebum production secondary to androgen secretion. Follicular hyperkeratinisation and occlusion. Colonisation by and proliferation of Proprionibacterium acnes. Inflammation. Hormones Hormones play a significant role in the pathogenesis of acne. often begins at puberty, coinciding with a surge in sex hormone levels. The important role of androgens can also be seen in the flare of acne that occurs before and during menstruation, due to increased production of ovarian androgens. During puberty there are dynamic changes secondary to these hormones, such as skeletal growth, sexual maturation and menses. The increase in androgen levels also results in an increase in sebaceous gland activity and increased sebum production. The levels of androgens in women with acne are generally higher than in those without acne. Although these androgen levels can be within the normal range, hyperandrogenic states should be considered in women with acne who also have other signs of androgenisation (such as hirsutism and irregular menses), as other conditions such as polycystic ovary syndrome or adrenal or ovarian tumours may be present. The sebaceous gland produces androgens such as testosterone from the precursor dehydroepiandrosterone sulfate (DHEAS). Testosterone is converted there to 5-alphadihydrotestosterone (DHT). Both testosterone and DHT are potent androgens responsible for the development of acne. Oestrogens also play a role in acne. Some women with acne can have lower levels of serum oestrogen than other women with acne. Also, just before the beginning of the menstrual cycle, oestrogen levels fall, which correlates with premenstrual worsening of acne. Oestrogens reduce acne by suppressing gonadal androgen production via negative feedback on the hypothalamic pituitary gonadal axis. The role of progesterone in acne Figure 1: Nodulocystic acne on the chest. Stress increases levels of endogenous corticosteroids, which can worsen acne. is unclear. There is evidence that progesterone worsens acne by promoting sebum secretion and follicular keratinocyte proliferation. Medroxyprogesterone acetate is a progestin that can significantly worsen acne. Diet The association between diet and acne is of concern and interest to many patients. Diet has been implicated as a major reason for the variation in prevalence of acne in different societies. One study found the prevalence of acne in Turkish teenagers was 60.7%, and there was a direct relationship between dietary fat and sugar intake and the risk of developing acne. 1 In a Chinese study, 46.8% of 19-year-olds had acne, which is significantly less than in a Caucasian population. 2 In Australia the prevalence of acne in year olds was 93.3%. 3 Randomised controlled trials have shown the benefit of low-glycaemicindex (low-gi) diets in reducing the severity of acne. 4 The typical Western diet contains large amounts of carbohydrates and high-gi foods, which in some people may result in hyperinsulinaemia, insulin resistance and eventually diabetes. It is hypothesised that this excess insulin stimulates insulin-like growth factor-1 (IGF- 1) to act on the skin directly, and to stimulate androgen production in the adrenal glands, ovaries and testes, resulting in increased amounts of sebum, and hence worsening acne. Reducing insulin levels in a patient with insulin resistance, hyperinsulinaemia or polycystic ovary syndrome can improve their acne. 5 Studies have found that women with acne usually have higher levels of free testosterone, IGF-1 and DHT than controls, albeit often in the normal range. There is a correlation between the serum levels of these hormones and the severity of acne. A randomised controlled trial has demonstrated that a low-gi diet reduced the levels of testosterone and DHEAS, as well as the number of acne lesions. Over the years there has been conflicting information about the role of milk in acne. However, the Nurses Health Study II found a direct relationship between the intake of milk and increasing teenage acne. Interestingly, skim milk produced more acne, suggesting the fat content has a negligible effect. 6 Milk contains many hormones including progesterone, 5-alphapregnanedione and 5-alphaandrostenedione, which are precursors of testosterone. The pilosebaceous unit contains enzymes that can convert these hormones into testosterone and DHT and hence stimulate the development of acne. Milk also contains growth hormones, especially IGF- 1, which stimulates androgen synthesis and sebum production. 7 Although studies in the literature have not found a direct correlation between chocolate and acne, it is possible that the resultant hyperinsulinaemia, the increased serum fatty acids, and the milk in chocolate all contribute to increased levels of IGF-1, androgens and sebum production, leading to acne. Stress, genetics and medications Stress, genetics and medications also contribute to the development of acne. Stress increases levels of endogenous corticosteroids, which can worsen acne. Although acne has a strong genetic component, the specific susceptibility genes have not been identified. Sebaceous glands vary in their response to androgens in different patients. In one study, eight prepubertal boys of parents who had acne had topical testosterone applied to their forehead. In three boys the topical testosterone had no effect of on the skin, while in a different three boys sebum excretion rates increased 15-fold. Hence, when seeing patients with acne, it is important to realise that the sebaceous gland activity varies and that some patients may require more intense treatment than others. Exogenous corticosteroids, lithium and vitamin B12 are common culprits in acne. Anabolic steroids have also been implicated in the worsening of acne. affecting young teenage boys or men in their fifth decade should raise the suspicion of an exogenous comedogenic cause. There has been a rise in the prevalence of acne due to protein shakes, which are promoted in many gyms to bulk up muscle. In recent years the formulations of these protein shakes have changed from soy-based to casein and whey (see the previous discussion on the association between milk and acne), resulting in worsening of acne. Therefore, during history-taking, patients need to be asked if they are taking exogenous androgens such as anabolic steroids or protein shakes, as they are unlikely to volunteer this information. Girls should be asked about any Depo-Provera use. Micro-organisms and inflammation Three main micro-organisms are associated with acne: Propionibacterium acnes, Staphylococcus epidermidis and Malassezia furfur. P. acnes is an anaerobic bacterium found in low numbers in the sebaceous glands of normal skin. Desquamated epithelium and excess sebum produces a milieu that promotes the proliferation of P. acnes. These micro-organisms are trapped in the follicular ducts by keratinocyte plugs, and secrete enzymes that result in tissue damage. Once the trapped, micro-organisms die and more enzymes are released, leading to an immune response and inflammation. T cells, cytokines and macrophages are commonly found within these inflammatory lesions. Moisturisers and some cosmetic products increase the lipid content of the skin, making it a breeding ground for bacteria. Patients should be advised to select non-comedogenic cosmetics (usually written on the packaging), as these products have been tested in acne-prone patients and found not to promote acne. Matrix metalloproteinases (MMPs) are also involved in the pathogenesis of acne. MMPs such as collagenases and gelatinases are produced in sebum and are seen in proliferative skin diseases (when the epidermis tends to grow more rapidly). The amount of MMPs in sebum is reduced by isotretinoin and tetracyclines. Follicular hyperkeratinisation and occlusion Follicular hyperkeratinisation is a key element in the pathogenesis of acne. With hyperkeratinisation, the epithelial cells of the follicle (keratinocytes) proliferate, become cohesive and do not shed normally onto the skin s surface. Sebaceous glands produce excess sebum which, along with desquamated epithelial cells, further contributes to sebaceous follicle obstruction, resulting in the formation of a microcomedone. This microcomedone can develop into a comedone or inflammatory lesion, depending on the presence of bacteria. IGF-1 stimulates both sebum synthesis in sebocytes and the proliferation of keratinocytes, thus contributing to the development of a comedone. cont d next page 9 March 2012 Australian Doctor 33

3 HOW TO TREAT Clinical manifestations ACNE predominantly affects the face, chest, and back. It is characterised by inflammatory and noninflammatory lesions (comedones). Comedones are a result of both abnormal follicular epithelial desquamation that blocks the follicular ducts, and of excess sebum production. They are typically categorised as open (blackheads) or closed comedones (whiteheads). Patients tend to present with a mixture of open and closed comedones. With the proliferation of P. acnes, these comedones evolve into inflammatory lesions, with associated erythema. Inflammatory lesions are classified as superficial or deep. Superficial inflammatory lesions are papules and pustules; deep lesions are deep pustules, nodules and cysts (figure 1, page 33). Comedones tend to appear on the facial T-zone (the forehead, nose, cheeks and chin) which corresponds to areas of high sebaceous gland activity. In many patients these areas look shiny because of excess sebum. Scarring is usually secondary to inflammatory lesions, especially the deep nodules and cysts. Scars occur due to either collagen excess or loss. Hypertrophic scars and keloids are due to collagen excess, usually affecting the trunk (figure 2). Ice-pick scars, atrophic macules and perifollicular elastolysis are caused by a deficiency of collagen Figure 2: Severe scarring and keloids on the back. and elastin. Post-inflammatory hyperpigmentation is another common consequence of acne, especially in darker-skinned individuals. This pigment change is made worse when patients pick or scratch their acne. There is usually a strong family history of acne and this should be elucidated when seeing a patient. Parents of an adolescent should be asked if they (or their partner) had acne as a teenager and if they required systemic treatment. The risk of developing acne more than doubles if there is a positive family history. Also, a family history of diabetes, insulin resistance or polycystic ovary syndrome is important, as it may indicate a possible hormonal basis for the acne. A sexual history and menstruation history is required to elucidate menstrual irregularities and infertility, and is important if considering systemic therapies that are contraindicated in pregnancy, such as anti-androgens, retinoids and tetracyclines. The size and fitness of the patient should be considered when treating them. Excessive weight, virilisation and hirsutism indicate an underlying endocrinopathy. Females with acne around the chin or mandible tend to have a hormonal basis for their acne and to respond to hormonal therapies. Concurrent acanthosis nigricans (figures 3 and 4) and alopecia (male or female pattern) also point to a hormonal cause. Quality of life Although acne does not have a direct impact on health, it does affect the patient s self-esteem, and quality of life. Adolescence itself is often already a time of emotional difficulty, without papules, pustules and cysts erupting on the face. The effects of acne on quality of life should not be ignored, as there is a strong association of acne with anxiety, depression and suicide. The psychological impact of acne can become a chronic issue affecting the patient s work, schooling and relationships. Withdrawal from social activities and spending less time with friends and family may be a reflection of the intense psychological impact of the acne. Bullying, taunts and social ridicule because of acne can often go unreported by the patient and therefore be unrecognised by family and friends, especially if the adolescent feels embarrassed and becomes reclusive. This can be a downward spiral, as stress worsens acne by the release of adrenal androgens. Therefore, it is important to address the psychological impact early on in the disease and to offer acne treatments specific to the severity of the acne. Doctors need to be aware that the psychological impact does not correlate with the severity of the acne. In clinical practice patients with mild disease may often be the most affected, while those with severe disease may be oblivious to the severity and the scarring. Studies have shown the perception of severity of acne correlates with emotions such as anger, sadness, shame and loneliness. If appropriate, patients should be encouraged to seek psychological assistance even if the acne does not seem severe to the doctor. The impact acne has on a patient s quality of life is comparable to chronic diseases such as diabetes, cystic fibrosis or even cancer. Suicide has been reported in acne patients. As suicide in boys aged years is usually unrelated to acne, the causation of suicide in males in this age group with acne is unclear, as this is also the age when boys are treated for acne. Given the impact on psychological health, all patients with acne should be made aware of counselling and psychological services if they need them. Diagnosis Investigations ACNE is usually diagnosed clinically, although very rarely a skin punch biopsy is useful to exclude other skin conditions. Given the role of hormones in the pathogenesis of acne, it is important to screen all patients for endocrinopathies. An oral glucose tolerance test (OGTT) can be used to diagnose insulin resistance, hyperinsulinaemia and diabetes. Serum oestradiol, progesterone, 17-hydroxyprogesterone, testosterone, prolactin, LH, FSH, DHEAS and sex-hormone-binding globulin (SHBG) should be measured. In women these tests should be performed in the first two weeks of the menstrual cycle. Baseline blood tests including LFTs and fasting lipid levels are required before starting oral systemic therapies. A summary of investigations is provided in the box, right. Investigations* FBC Electrolytes Renal and LFTs LH FSH Testosterone Dehydroepiandrosterone sulfate (DHEAS) Oestradiol 17-Hydroxyprogesterone Progesterone Oral glucose tolerance test (OGTT) If considering isotretinoin: fasting lipid profile; beta human chorionic gonadotropin (beta-hcg) (if female) *Including those for the underlying causes of acne, such as an hyper-androgenic state and insulin resistance Figure 3: Acanthosis nigricans on the hands at the knuckles. Differential diagnosis Rosacea may mimic acne, with erythema, papules and pustules on the face. It is sometimes difficult to distinguish between the two and they often coexist. Patients with rosacea often complain of flushing, telangiectasia, inflammation surrounding the eyes and rhinophyma. There are no comedones in rosacea. This chronic condition is characterised by episodes, possibly precipitated by gastrointestinal disease or infections. Rosacea typically affects older patients. Perioral dermatitis is different to acne in that it may start off with itch and dry skin and progress to an acneiform eruption after steroid treatment, or it may appear de novo as an acneiform eruption, limited to this location. Comedones are absent. Other differential diagnoses of acne are: Eczema. Eczema herpeticum. Folliculitis. Seborrhoeic dermatitis. Warts. Sarcoidosis. Chloracne. Drug-induced acneiform reactions. Management A SUMMARY of acne treatments is provided on the next page. Topical treatments Many treatments are available for acne, depending on the patient s skin type and the severity of disease. In general, topical treatments remove the sebum and reduce the desquamation of follicular epithelium but do not alter sebum production. These include the retinoids (tretinoin, isotretinoin, adapalene, tazarotene), benzoyl peroxide, salicyclic acid, and azelaic acid. Topical retinoids are vitamin A derivatives proven to be effective in reducing the number and size of comedones by about 40-70%. The most effective topical retinoid is tazarotene, although it is sometimes too strong and irritating. Adverse effects such as erythema, skin irritation and peeling are noted less often when adapalene is used. In Australia, benzoyl peroxide comes in 2.5%, 4%, 5% and 10% creams or gels. It has a strong antibacterial effect, with a mild keratolytic action. Cutaneous irritation and contact dermatitis are common adverse effects. Topical antibiotics include clindamycin, erythromycin, metronidazole and azelaic acid. The last of these has some antimicrobial effect against P. acnes and should be used with caution in darkerskinned individuals, as there is an increased risk of hypopigmentation. Monotherapy with a topical retinoid or antimicrobial is not as effective as combining the two agents. Topical antibiotics are not as effective as topical tretinoin or benzoyl peroxide in penetrating the lipid-rich environment in which P. acnes lives. A combination of benzoyl peroxide and topical antibiotic is ideal to suppress P. acnes growth and reduce comedonal development. This combination also reduces the 34 Australian Doctor 9 March

4 Treatments for acne Medications available for the treatment of acne Figure 4: Acanthosis nigricans of the flexural crease. Lifestyle changes TOPICAL Treat underlying cause such as insulin resistance Avoid precipitants, drugs that induce acne Non-comedogenic cosmetics Avoid oily skin; do not moisturise Retinoids Adapalene (Differin) 0.1% cream or gel Isotretinoin (Isotrex) 0.05% gel Tazarotene (Zorac) 0.0.5%, 0.1% cream Tretinoin (Stieva-A, Retin-A, Retrieve) 0.025%, 0.05%, 0.1 % cream; 0.01% gel Education: do not squeeze or pick acne Non-hormonal Topical antibiotics Systemic antibiotics (doxycycline, minocycline, erythromycin, amoxycillin) Topical retinoid (tretinoin, adapalene, tazarotene) Systemic retinoids Note: Antibiotic with retinoid gives a better efficacy than one therapy alone Antibacterials Benzoyl peroxide (Brevoxyl, Clean and Clear Continuous Control Cleanser, Clearasil Ultra Treatment, Oxy, Oxy Vanishing, Benzac AC, Panoxyl) 2.5%, 4%, Clindamycin (Zindaclin, Clindatech, Dalacin) 1% gel, liquid, lotion Erythromycin (Eryacne) 2% gel Metronidazole gel Combination Benzoyl peroxide 5% and clindamycin 1% (Duac Once Daily) gel Benzoyl peroxide 2.5% and adapalene 0.1% (Epiduo) gel Other agents Hormonal Azelaic acid (Finacea, Azclear) 15%, 20%, gel, lotion; 5%,10%, cream and gel Oral contraceptives Spironolactone Cyproterone risk of antibiotic resistance, as benzoyl peroxide also has non-specific antibacterial effects via free radical formation. Topical agents are available in creams, liquids and gels. Gels are typically prescribed in more humid environments or for patients with very oily skin, while creams are used in colder weather or for patients with sensitive skin. Tricks to improve compliance are to tell patients not to put these irritating products on immediately after washing their face and to use milder facial cleansers. Some patients need to use a noncomedogenic moisturiser to tolerate the topical therapy. If unsure, it is better to start with one product at a time and make it stronger later by adding another treatment or changing to a gel. Systemic treatments Antibiotics Systemic antibiotics (eg, minocycline, tetracycline, doxycycline, erythromycin) are used for their antibacterial and anti-inflammatory effects. These bacteriostatic drugs are prescribed in moderate inflammatory acne and work by reducing the amount of intrafollicular P. acnes, preventing inflammatory cytokine production and inhibiting MMPs. Adverse effects include: Abdominal discomfort. Photosensitivity. Urticaria. Vestibular abnormalities such as vertigo, dizziness and ataxia. Tetracyclines can induce skin pigmentation and should not be used in children, as they can stain the teeth and result in enamel hypoplasia. Penicillins and cephalosporins are not effective in eradicating P. acnes. Antibioticresistant P. acnes has become more common recently probably due to monotherapy. This can be avoided by using combinations of topical and/or oral medications. Minocycline has a higher chance of inducing blue black skin pigmentation than the other antibiotics. Photodynamic therapy SYSTEMIC Antibacterials Minocycline Tetracycline Doxycycline Erythromycin Retinoids Acitretin (not for premenopausal women, due to persistence) Isotretinoin Hormonal therapies (females only) Oral contraceptive pill (containing 50μg of ethinyloestradiol) Cyproterone Spironolactone Source: Australian Medicines Handbook. Australian Medicines Handbook Pty Ltd, Adelaide, Hormonal manipulation using anti-androgens and oestrogen therapy is useful in treating acne. Hormonal treatment Hormonal manipulation using antiandrogens and oestrogen therapy is useful in treating acne. Because of the anti-androgen activity, they should only be used in women. All patients started on anti-androgen treatment should be using adequate contraception and/or demonstrate evidence of sterilisation, as antiandrogens have significant adverse effects on a male fetus. Exogenous oestrogens are beneficial in treating acne. The oral contraceptive pill has been used for many years in women for this purpose. At least four months of treatment is required before noticeable improvement is seen, and relapse after cessation is common. Although the exact mechanism of action is unknown, oestrogen seems to increase the amount of SHBG, thus decreasing the amount of circulating free testosterone. A Cochrane review found that the pill was effective in decreasing the number and size of both inflammatory and non-inflammatory lesions. There was insufficient evidence to suggest one particular formulation or a certain dose of progestin was more effective than another. However, the dose of ethinyl oestradiol is related to the effectiveness of the combined pill for the treatment of acne. Formulations containing 50μg daily dose of ethinyl oestradiol were more effective in reducing sebum production than those with <35μg. Combined pills containing dienogest or drospirenone can be used in acne, as these progestogens have antiandrogenic effects. Desogestrel-containing formulations should be avoided, as they do not seem to be as effective for acne. Some dermatologists prescribe cyproterone acetate, an anti-androgen shown to be effective in reducing acne lesion size and count. Contraception is essential in this situation, as this drug will affect the development of a male fetus. Doses range from 2mg to 100mg daily, usually in combination with ethinyl oestradiol in a combined pill. It is an androgen-receptor blocker and also inhibits production of FSH and LH by negative feedback on the pituitary, hence lowering ovarian-derived serum androgen levels. 8 Spironolactone is an effective treatment for female patients with acne. It blocks androgen receptors and reduces androgen synthesis leading to a reduction in sebum production. Optimal response is achieved at doses of mg/day. At this dose acne improves by at least 50%. Though effective, its use is limited to women because of the anti-androgenic effects. Commonly reported adverse effects include irregular menses and hyperkalaemia. Retinoids Oral isotretinoin is a retinoid used to treat severe acne, especially if cysts, nodules and scars have developed or are likely to develop. In Australia it can only be prescribed by dermatologists, and patients need ongoing monitoring for adverse events or changes in blood parameters. Patients are weighed before treatment to gauge the appropriate daily dose, cumulative dose and expected length of treatment. Doses range from 0.1mg/kg/day to 1.0mg/kg/day, depending on the severity of acne, the presence or risk of scarring and the sensitivity of the skin. Isotretinoin works on all four of the major factors in the pathophysiology of acne by reducing sebum production, follicular keratinisation, inflammation and the level of P. acnes colonisation. The reduction in sebaceous gland size and activity is dose dependent and also depends on the duration of treatment. Patients are advised beforehand that treatment with isotretinoin is to prevent further permanent scarring from acne rather than heal the alreadyformed scars. About 60% of patients remain acne-free after just one course of isotretinoin. The duration of treatment varies depending on patient weight and acne severity but is for at least five months. The acne continues to improve even after completion of the course. Therefore a second course may not be required and is recommended only if the acne is worsening after two months of completing the first course. Isotretinoin is contraindicated in pregnancy and should not be prescribed in those planning pregnancy. Patients must be counselled about the teratogenicity of isotretinoin and the need to use adequate contraception (described below). Often this needs to be explained multiple times to ensure the patient understands the gravity of congenital malformations and birth abnormalities. This discussion should also be clearly documented in the patient s medical record. Pregnancy and fetal associated adverse effects include significant neurological and cardiovascular and other abnormalities, such as hydrocephalus, microcephalus, cleft palate, cardiac septal defects and miscarriage. Before prescribing isotretinoin, all females of childbearing potential should use two forms of contraception, due to the drug s teratogenicity; they should be on hormonal contraception either oral (combined pill), injectable or implantable, plus use a barrier method. Pregnancy must be excluded by two negative serum beta human chorionic gonadotropin (beta-hcg) tests at least two cont d next page 9 March 2012 Australian Doctor 35

5 HOW TO TREAT from previous page weeks apart before starting isotretinoin. Documented informed consent should be obtained and it should be recorded in the patient s notes that they are using two acceptable forms of contraception and understand the implications of pregnancy while on teratogenic medications. The progesterone only pill may not be as effective as the combined pill for patients on isotretinoin and it can worsen acne. Dermatologists work closely with GPs to ensure the patient is on appropriate contraception. Women who have had a hysterectomy are exempt from taking contraception but must provide evidence of surgery. At subsequent appointments it is not uncommon for some dermatologists not to renew a prescription of isotretinoin without a negative serum pregnancy test. Age, religious or familial beliefs should not be a reason not to counsel the patient or not provide adequate contraception. Female patients are required to sign a form indicating they are not pregnant, have been taking adequate contraception and understand the risk of pregnancy while on isotretinoin. Patients are advised that termination is required for those who become pregnant while on isotretinion. Contraception must be taken for at least one month after stopping isotretinoin. Males started on isotretinoin do not need to use contraception but are advised not to give their isotretinoin to any women. Isotretinoin is contraindicated in patients with hyperlipidaemia, hepatic failure and hypervitaminosis A. Adverse effects of isotretinoin on the patient include: Dry skin and mucous membranes. Musculoskeletal symptoms such as arthralgia and myalgia. Abnormal blood tests (elevated blood lipid levels and LFTs). Some patients experience an initial worsening of the acne, especially in the first few weeks of treatment. This will resolve and may require a reduction in the dose. Most of the adverse effects are dose dependent and can be improved by decreasing the dose. Concerns about depression as a potential side effect have been augmented by the media and internet. Patients are often reluctant to start isotretinoin due to concerns it causes depression and suicide. According to the literature to date, there is no direct association between isotretinoin and suicide. In fact, severe acne warranting isotretinoin, especially in adolescents, of itself leads to low self-esteem, social isolation and depression. The psychological impact is attributable to the underlying disease rather than the introduction of a new medication. One study showed that the number of suicides of patients on isotretinoin in the US between 1982 and 2000 was less than the expected suicide rate for the same age group. However, further research is required to determine if there is any association between isotretinoin and mood changes, given there are a number of case reports suggesting anxiety, depression and psychosis may worsen soon after starting isotretinoin treatment. In practice it is recommended that patients with Figure 5: Scarring on the face. Precautions with use of isotretinoin Reproductive-age females must be taking a hormonal contraceptive (combined oral, injectable or implantable) for at least one month before starting isotretinoin. Women must remain on two forms of appropriate contraception (hormonal plus barrier) for the duration of treatment and for at least one month after cessation of isotretinoin. Women must not be pregnant, and should have two negative serum betahcg tests before and regularly during therapy. Patients must be counselled about the risk of pregnancy while on isotretinoin and males reminded not to share their treatment with female relatives/friends. Blood tests, including LFTs and fasting lipids, must be performed at baseline and during treatment. It is recommended that patients with pre-existing mental health issues be identified and regularly reviewed by psychiatrists and GPs before and during treatment. pre-existing mental health issues be identified and regularly reviewed by psychiatrists and GPs before and during treatment. Some reports have indicated nightblindness as a side effect that can persist after stopping the drug. Pilots or patients who drive at night for an occupation should therefore not be prescribed isotretinoin. If they are using the medication, they require ongoing eye examinations by an ophthalmologist. Because patients usually research medications on the internet before the appointment, providing adequate literature and material is useful. Before starting isotretinoin, patients are often given a DVD about acne, isotretinoin and common adverse effects. A pack containing moisturisers, facial cleansers and lip balm is also available for patients. By providing resources to patients, the medical profession will assist patients in their knowledge about treatments, without relying solely on the internet or word of mouth. The box above summarises pertinent issues in the use of systemic isotretinoin. Acitretin is an oral retinoid not commonly prescribed for acne, given its prolonged teratogenic effects. It is recommended that premenopausal women do not use this medication, as teratogenicity can last years after stopping the drug. Photodynamic therapy Photodynamic therapy (PDT) is a non-invasive procedure commonly used in dermatology to treat skin cancers such as Bowen s disease, basal cell carcinomas and actinic keratoses. The procedure begins by applying a photosensitising agent to the lesions. A special light is then shone on these lesions. When a certain wavelength of light shines on the photosensitiser, reactive oxygen species are produced, resulting in chemical destruction of the lesions. The major advantage of PDT is that selected lesions are targeted so that normal skin is spared from being damaged. The uptake of the photosensitising agent is higher in reproducing cells such as malignant cells. Different photosensitising agents are available in PDT. Some common examples are aminolevulinic acid (ALA), methyl aminolevulinate and porfimer sodium. Both laser and non-laser light can be used in PDT. Commonly reported side effects include burning, stinging, redness and skin peeling. PDT in acne works by reducing the proliferation and activity of P. acnes. It also selectively injures the sebaceous glands, reducing both sebum excretion and follicular keratinisation. Randomised controlled trials have shown just one treatment with PDT can significantly reduce the number of inflammatory lesions for 10 weeks. Patients who had four treatments had reduction for at least 20 weeks. All the trials and case series have shown a reduction of at least 50% in acne with PDT. PDT is most effective when used for inflammatory acne, especially on the face and the back. PDT is usually somewhat painful when delivered and the treatment is relatively expensive. Treatment of acne depending on severity Before starting treatment, one should assess the severity of acne and determine the psychological impact on the patient. Treatment consists of: Avoiding precipitants. Making lifestyle changes. Treating underlying conditions. Using topical and/or systemic agents specific against acne. Because acne is a multifactorial disease, its treatment should be multipronged, sometimes using concomitant therapies and lifestyle changes to obtain optimal results. If an underlying disease such as polycystic ovary syndrome or insulin resistance is diagnosed, appropriate therapy should be instituted. Insulinsensitising agents such as metformin are commonly prescribed and are helpful in improving acne in such patients. Ongoing review by an endocrinologist and dietitian is recommended. Avoiding potential triggers such as oily moisturisers, cosmetic agents and anabolic steroids is key in preventing outbreaks. Patients should only use the moisturisers and cosmetic products labelled non-comedogenic. Though elimination of dairy products may not result in improvement, it is often worthwhile for the patient to modify their diet, given the evidence supporting a relationship cont d page 38 References 1. Koku Aksu AE, et al. : prevalence and relationship with dietary habits in Eskisehir, Turkey. Journal of the European Academy of Dermatology and Venereology 2011; online. 2. Shen Y, et al. Prevalence of acne vulgaris in Chinese adolescents and adults: a community-based study of 17,345 subjects in six cities. Acta Dermato- Venereologica 2012; 92: Kilkenny M, et al. The prevalence of common skin conditions in Australian school students: 3. vulgaris. British Journal of Dermatology 1998; 139: Smith RN, et al. A low-glycemicload diet improves symptoms in acne vulgaris patients: a randomized controlled trial. American Journal of Clinical Nutrition 2007; 86: Kidson WJ. Insulin levels in polycystic ovary syndrome: a valuable tool. Medical Journal of Australia 2007; 186:269; author reply: Adebamowo CA, et al. High school dietary dairy intake and teenage acne. Journal of the American Academy of Dermatology 2005; 52: Danby FW. Nutrition and acne. Clinical Dermatology 2010; 28: Katsambas AD, Dessinioti C. Hormonal therapy for acne: why not as first line therapy? Facts and controversies. Clinical Dermatology 2010; 28: Further reading Davidovici BB. The role of diet in acne: facts and controversies. Clinics in Dermatology 2010; 28: Gottlieb A. Safety of minocycline for acne. Lancet 1997; 349:374. Green J, Sinclair RD. Perceptions of acne vulgaris in final year medical student written examination answers. Australasian Journal of Dermatology 2001; 42: Haider A, Shaw JC. Treatment of acne vulgaris. Journal of the American Medical Association 2004; 292: Melnik B, Schmitz G. Role of insulin, insulin-like growth factor- 1, hyperglycaemic food and milk consumption in the pathogenesis of acne vulgaris. Experimental Dermatology 2009; 18: Mills OH, Klingman AM. detergicans. Archives of Dermatology 1975; 111: Ramakrishna J, et al. Long-term minocycline use for acne in healthy adolescents can cause severe autoimmune hepatitis. Journal of Clinical Gastroenterology 2009; 43: Online resources DermNet NZ: dermnetnz.org Conflict of interest Professor Murrell is an investigator and consultant for several of the companies who have developed treatments for acne, including Roche, GSK (formerly Stiefel) and Galderma. 36 Australian Doctor 9 March

6 HOW TO TREAT from page 36 between hormones in milk and acne. Patients are often teased because of their acne, as a lot of people think acne is caused by lack of cleanliness. Contrary to common belief, acne is not a result of poor hygiene, and patients should be advised against washing their face excessively. Severe scarring (figure 5, page 36), post-inflammatory hyperpigmentation and infection commonly occur after the use of over-the-counter exfoliative treatments, abrasives and facial scrubs, so use of these products should be discouraged. In fact, some cleaning products are comedogenic and should be avoided. Localised trauma by picking, squeezing and bursting acne induces inflammation, making the acne more visible and worsening the cosmetic outcome. Comedonal acne, which usually affects adolescents, is characterised by small papules on the forehead (figure 6) and face due to excess sebum. At this stage of disease there is no P. acnes growth, hence it is referred to as non-inflammatory acne. The aim of treatment is to prevent further comedones and inhibit microbial proliferation by Figure 6: Comedones on the forehead. using topical agents such as tretinoin, adapalene or salicyclic acid. Patients require at least six months of treatment. Comedonal extraction is a method to remove comedones and instantaneously induce better-looking skin. However, this is a time-consuming procedure that often is not successful and so needs to be repeated monthly. Common risks of manual extraction of comedones includes infection, How to Treat Quiz 9 March 2012 scarring and bleeding. In inflammatory acne there are pustules, nodules and cysts often on the face, back and chest. Treatment consists of a topical retinoid with either topical or systemic antibiotic. Oral antibiotics alone are not sufficient to manage acne and can increase resistance. Systemic isotretinoin and referral to a dermatologist is essential if scarring is present or likely. Mild inflammatory acne is characterised by comedones, papules and pustules. Because there is a proliferation of P. acnes, patients require a topical antibiotic in combination with a retinoid or benzoyl peroxide. The retinoids have both comedolytic and anti-inflammatory actions on the acne. Patients generally start to respond within 2-4 weeks of treatment. A lower strength of benzoyl peroxide can be used if irritation occurs. Therapy should not be tapered until no new comedones are evident. Moderate and severe inflammatory acne are treated similarly with the combination of topical retinoids and systemic antibiotics. unresponsive to this regimen typically requires oral isotretinoin. In most cases patients respond to oral isotretinoin after at least four weeks of treatment. Treatment of scarring Both patients and their parents should be educated about scar prevention and compliance with medications. Existing scarring can be treated with varying degrees of success by cosmetic dermatologists using laser therapy, ablative therapies, micro-needling, dermal fillers and surgery. INSTRUCTIONS Complete this quiz online and fill in the GP evaluation form to earn 2 CPD or PDP points. We no longer accept quizzes by post or fax. The mark required to obtain points is 80%. Please note that some questions have more than one correct answer. ONLINE ONLY for immediate feedback Summary GIVEN the medical, cosmetic and social ramifications, a holistic approach is needed when managing a patient with acne. The goals of therapy are to eradicate existing lesions, prevent the development of new lesions and minimise long-term scarring and psychological trauma. GPs, endocrinologists, gynaecologists, dermatologists and psychiatrists are just a few of the health practitioners who may be involved in the care of patients with acne. With appropriate patient education and compliance with appropriate treatment, acne can be managed successfully. 1. Which THREE statements are correct? a) The pathogenesis of acne includes excess sebum production secondary to androgens, and follicular hyperkeratinisation and occlusion b) The pathogenesis of acne includes proliferation of Proprionibacterium acnes, and associated inflammation c) The serum levels of androgens in women with acne are usually above the normal range d) with hirsutism and irregular menses may indicate the presence of polycystic ovary syndrome (PCOS), or adrenal or ovarian tumours 2. Which TWO statements are correct? a) Women with acne tend to have higher levels of serum oestrogen than other women b) Oestrogens suppress gonadal androgen production and increase levels of sexhormone-binding globulin c) The premenstrual flare in acne may be due to the rise in oestrogen levels at that time of the cycle d) Progesterone may worsen acne by promoting sebum secretion and follicular keratinocyte proliferation 3. Which TWO statements are correct? a) Reducing insulin levels in a patient with insulin resistance, hyperinsulinaemia or PCOS can improve their acne b) A low-glycaemic-load diet reduces the levels of testosterone and dehydroepiandrosterone sulfate (DHEAS), and the number of acne lesions c) There is an inverse relationship between milk consumption and teenage acne d) It is the fat content of milk that predisposes to acne 4. Which TWO statements are correct? a) Milk contains hormones that are precursors of testosterone b) Patients with a family history of acne may have an increased response of the pilosebaceous unit to a given exposure to testosterone c) Protein shakes consumed for musclebuilding that do not contain added anabolic steroids do not predispose to acne d) Chronic exposure to corticosteroids suppresses inflammation, and reduces the severity of acne 5. Which TWO statements are correct? a) P. acnes is not found in the sebaceous glands of normal skin b) The scarring of acne is caused by inflammatory lesions, especially deep nodules and cysts, and is due to either collagen excess or loss c) Post-inflammatory hyperpigmentation associated with acne is particularly common in fair-skinned individuals d) A family history of diabetes, insulin resistance or PCOS may indicate an hormonal basis for the acne 6. Which TWO statements are correct? a) Females with acne around the chin or mandible tend to have a hormonal basis for their acne b) The psychological impact on the patient correlates with the severity of the acne c) The perception of severity of acne correlates with emotions such as anger, sadness, shame and loneliness d) Hormonal tests in women with acne should be performed in the second half of the menstrual cycle 7. Which TWO statements are correct? a) A 75g oral glucose tolerance test with insulin levels at zero, one, and two hours can be used to diagnose insulin resistance, hyperinsulinaemia and diabetes as causes of acne b) Topical antibiotics or antiseptics reduce sebum production c) Topical benzoyl peroxide has a strong keratolytic effect but is not antibacterial d) Topical azelaic acid may cause hypopigmentation in darker-skinned individuals 8. Which TWO statements are correct? a) Monotherapy with a topical retinoid or antimicrobial is as effective as combining the two agents b) A combination of benzoyl peroxide and topical antibiotic is ideal to suppress P. acnes growth and reduce comedonal development c) Systemic tetracyclines or erythromycin have bacteriostatic and anti-inflammatory effects in acne d) Penicillins and cephalosporins are effective in eradicating P. acnes 9. Which TWO statements are correct? a) Antibiotic resistant P. acnes can be avoided by using combinations of topical and/or oral medications b) Anti-androgens can be used for acne in both sexes c) Oestrogen treatment for acne with the combined oral contraceptive pill takes at least four months to have a noticeable effect d) Pills containing dienogest or drospirenone should be avoided in women with acne 10. Which TWO statements are correct? a) Cyproterone acetate and spironolactone are antiandrogens used for the treatment of female acne b) After successful treatment of acne with systemic isotretinoin, the acne usually recurs on stopping treatment c) Women on isotretinoin must use both hormonal contraception plus a barrier method d) The progesterone-only pill can be used as contraception in women on systemic isotretinoin CPD QUIZ UPDATE The RACGP requires that a brief GP evaluation form be completed with every quiz to obtain category 2 CPD or PDP points for the triennium. You can complete this online along with the quiz at Because this is a requirement, we are no longer able to accept the quiz by post or fax. However, we have included the quiz questions here for those who like to prepare the answers before completing the quiz online. HOW TO TREAT Editor: Dr Giovanna Zingarelli Co-ordinator: Julian McAllan Quiz: Dr Giovanna Zingarelli NEXT WEEK The next How to Treat explores the latest developments in diagnosing and treating the many diverse types of neuroendocrine tumours. The authors are Dr Michael Hofman, nuclear medicine physician, centre for cancer imaging, Peter MacCallum Cancer Centre, and clinical senior lecturer, University of Melbourne; Associate Professor Michael Michael, medical oncologist, head of upper GI tumour stream; Peter MacCallum Cancer Centre, and co-chair, neuroendocrine service, and associate professor of medicine, University of Melbourne ; Mr Benjamin Thomson, hepatobiliary surgeon, Peter MacCallum Cancer Centre, and head of upper GI tumour stream, Royal Melbourne Hospital; and Professor Rodney Hicks, department of medicine and radiology, University of Melbourne, and director, centre for cancer imaging; co-chair, neuroendocrine service and translational research group; and head, molecular imaging and targeted therapeutics laboratory, Peter MacCallum Cancer Centre, Melbourne. 38 Australian Doctor 9 March