SYMPOSIUM: DERMATOLOGY
`
`Treatment of acne vulgaris
`
`Rebecca Nguyen
`
`John Su
`
`Abstract
`Acne vulgaris is a disorder of the pilosebaceous unit, characterized by
`comedones, inflammatory lesions and scars on the face and trunk. It pres-
`ents a significant financial burden to the community and its psychosocial
`impact can be severe, life-altering and even life-threatening. Effective
`treatment can reduce the burden of disease but poorly considered
`therapy can be ineffective, costly and may also worsen non-compliance.
`In the management of acne, it is important to identify triggers, such as
`drugs, endocrinopathies and topical agents. Comedonal acne can
`respond well to topical retinoids. Mild to moderately inflammatory acne
`is usually initially treated with combination topical therapy, sometimes
`adding an oral antibiotic. Anti-androgen therapy can be helpful in females
`with seborrhoea and premenstrual flaring of acne. Isotretinoin remains
`a very effective treatment for potentially scarring and refractory acne,
`but new possible adverse effects have been recently described. Treatment
`regimens should accommodate individual patient considerations, duly
`noting limitations and potential adverse effects of all therapeutic options.
`
`Keywords acne vulgaris; acneiform eruptions; depression; follicular
`occlusion; inflammatory bowel disease; isotretinoin; oral contraceptive
`pill; topical antibiotics; topical retinoids
`
`Introduction
`
`Acne vulgaris is a disorder of the pilosebaceous unit resulting in the
`formation of comedones, inflammatory papules, pustules, nodules,
`cysts and scars. It affects the face and trunk, most commonly pre-
`senting in puberty. In a cross-sectional study of 16-year-olds, acne
`prevalence was 94.4% for males and 92% for females, with 14%
`having moderate to severe acne. The prevalence of acne after 25 years
`of age is 10% and after 40, 1% in men and 5% in women. In the UK in
`1992, there were 3.5 million general practice consultations for acne
`reflecting a significant health burden on the National Health Service.
`
`Epidemiology
`
`Several twin studies suggest familial clustering and a genetic
`predisposition to acne. Environmental factors can affect the
`severity of disease. Recent studies suggest that increased milk
`consumption is weakly associated with increased acne severity. It
`
`is unlikely to be related to the fat content of milk. However, the
`roles of hormones and IGF-1 in milk products require clarification.
`More convincingly, high glycaemic diet has been linked to
`increased acne lesion counts, increased free androgen index and
`impaired insulin sensitivity, but larger, randomized studies are
`lacking. There is no conclusive evidence that chocolate intake is
`related to acne. The effects of omega-3 fatty acids, antioxidants,
`dietary fibre, vitamin A and zinc require further study. Two studies
`have shown stress during exam periods can exacerbate acne
`severity but have no increase in sebum production. No correlation
`between exercise and truncal acne has been demonstrated.
`
`Pathogenesis
`
`There are four processes in the pathogenesis of acne:
`1. Increased sebum production;
`2. Perifollicular hyperkeratinization and follicular obstruction;
`3. Colonization with Propionibacterium acnes;
`4. Release of enzymes which induce humoral and cell mediated
`inflammations.
`Sebum production depends on local androgen levels and androgen
`sensitivity. Two subtypes of 5-alpha-reductase convert testosterone
`to the more active dihydrotestosterone (DHT): type 1 isozyme is
`expressed in the scalp, chest and sebaceous glands, whereas type 2
`isozyme is expressed in genitourinary tissue, dermal papillae and
`hair follicles. DHT stimulates sebum production by sebocytes.
`Androgens,
`lipids, bacteria and cytokines induce hyper-
`keratinization and hyperproliferation of keratinocytes. This
`results in follicular obstruction forming microcomedones.
`Propionibacterium acnes,
`a
`gram positive
`anaerobic
`commensal, (a) produces lipases, proteases and hydrolases
`contributing to inflammation and tissue destruction, (b) expresses
`stress proteins responsible for comedonal rupture and (c) possibly
`binds toll-like receptors on keratinocytes to increase production
`and release of pro-inflammatory cytokines like Interleukin (IL)-1.
`IL-1 is thought to stimulate hyperkeratinization, cell adhesion,
`follicular obstruction and further inflammation. Other cytokines
`like TNF,
`IL-2 and IL-6 are released and the corticotropin
`releasing hormone (CRH) system is stimulated. CRH, CRH
`binding protein (CRHBP) and CRH receptor are expressed in
`human sebocytes in vitro. CRH up-regulates 3-beta hydroxyste-
`roid dehydrogenase, which converts dehydroepiandrosterone
`(DHEA) to testosterone, and stimulates sebocyte lipogenesis and
`differentiation. CRHBP reduces the ability of CRH to dissolute
`into the systemic circulation,
`therefore increasing its local
`epidermal effect. CRH receptor-2 has increased expression in
`acne and may mediate increased sebum production. Melnik et al.
`suggested that a relative deficiency of the nuclear transcription
`factor Fox01 might underlie all pathogenic pathways of acne.
`
`History
`
`Rebecca Nguyen MB BS is a Dermatology resident in the Department of
`Dermatology, at Box Hill Hospital, Victoria, Australia. Conflicts of
`interest: none.
`
`John Su MB BS M Epi FRACP FACD is Head of Dermatology, Eastern Health,
`level 2, 5 Arnold St, Box Hill, 3128 Victoria, Australia, in the Department
`of Paediatrics, University of Melbourne, and the Department of Medi-
`cine, Monash University, Victoria, Australia. Conflicts of interest: none.
`
`Important points in the history include the age of onset, distri-
`bution and nature of lesions (comedones, inflammation and the
`scars), disease progression, possible triggers and relieving
`factors. Extreme seborrhoea, a positive family history or early
`disease onset, and rapidly progressive, extensive, persistent, or
`scarring disease may warrant more aggressive therapy.
`Symptoms of hyperandrogenism include premenstrual flaring of
`acne, seborrhoea, hirsutism, deepening of the voice, increased
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`libido, clitoral enlargement, menstrual changes and precocious
`puberty. The presence of these symptoms may require further
`investigation and consideration of anti-androgen therapy in females.
`Past treatment responses and side effects will affect the choice
`of future therapy. An accurate quantification of past medication
`usage may reflect the patient’s tendency to compliance. The
`potential for child-bearing is important to note as many acne
`treatments are teratogenic. Concerns have been raised about
`possible links between isotretinoin and depression, inflammatory
`bowel disease and night vision impairment; so relevant risk
`factors should be sought. A social history will help clarify the
`affordability of treatments, patient motivation and disease burden.
`Drugs, cosmetics and topical agents can cause an acneiform
`eruption characterized by monomorphous pustules and papules
`without comedones. Common drugs include steroids, bromides,
`iodides, lithium, phenytoin, epidermal growth factor receptor inhib-
`itors, isoniazid, high dose vitamin B, olanzapine and amineptine.
`
`Examination
`
`Acne most commonly affects the face, especially the T-zone, and
`trunk. Non-inflammatory lesions include open, “black” come-
`dones (papules with central darkened impaction) and closed,
`“white” comedones (flat, pale papules). Inflammatory lesions
`include papules, pustules and nodules (Figure 1). Secondary
`infection (e.g. Staphylococcal aureus) may rarely
`bacterial
`increase crusting and inflammation.
`There are five main types of scars. Ice-pick scars are narrow,
`tapering deeply into the dermis. Rolling scars are wide and
`shallow. Boxcar scars are well demarcated, punched out
`depressions (Figure 2). Hypertrophic and keloid scars are raised,
`the latter extending beyond the area of original inflammation.
`Perifollicular elastolysis presents as truncal follicular atrophy.
`Despite inter-observer and intra-observer variability, grading
`the severity of acne can be useful for monitoring response to
`therapy. The Leeds-Cunliffe technique is a facial photo-numeric
`scale that assigns a number from a manual to the patient’s
`presentation. Serial photography is also helpful.
`Psychological assessment is pertinent for those with severe
`scarring, acne excoriee and dysmorphophobia.
`
`Figure 1 Comedones, papules and pustules in mixed comedonal and
`inflammatory acne.
`
`Figure 2 Common acne scars.
`
`Signs of possible hyperandrogenism include, (1) late onset,
`severe acne, (2) marked seborrhoea, (3) acanthosis nigricans
`(HAIR-AN syndrome), (4) dysmenorrhoea and infertility (poly-
`cystic ovary syndrome), (5) dyslipidaemia and diabetes (HAIR-AN,
`PCOS) and (6) Cushingoid habitus (Cushing’s syndrome).
`Androgen secreting tumours may present with precocious puberty,
`prominent male external genitalia, deepening of voice, pubic hair
`growth and a testicular or ovarian mass. 33% of the non-classical
`forms of congenital adrenal hyperplasia present with prepubescent
`acne, precocious puberty, rapid growth and amenorrhoea.
`
`Acne variants
`
`Acne infantum
`Infantile acne presents at 3e6 months with facial acne from
`transient high levels of DHEA in infancy produced by trans-
`placental stimulation of the adrenal gland. Although therapeutic
`agents resemble those used in adult acne, tetracyclines and anti-
`androgens should not be used.
`
`Acne cosmetica
`Comedogenic cosmetics can cause adult-onset acne. Common
`culprits are moisturizers (lanolin alcohol and myristyl acetate),
`facial
`sunscreens (isopropyl myristate and octyl palmitate),
`cleansers (isopropyl palmitate and lanolin) and face powders (cocoa
`butter). Resolution usually occurs with cessation of cosmetics.
`
`Acne excoriee
`Compulsive scratching can complicate mild acne, notably in
`young adult females with psychological morbidity. Excoriations
`can be a few millimetres in diameter and may weep, crust or
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`scar. It presents in 2% of dermatology acne patients. Treatments,
`including antidepressants, antipsychotics and mood stabilizers,
`show variable success.
`
`Acne agminata
`Acne agminata presents as a papulopustular eruption that affects
`the cheeks, periorbital region, eyelids and occasionally limbs. It
`lasts 2e6 weeks and often resolves with scarring. Histology
`shows sterile dermal granulomata with central caseous necrosis.
`It is unrelated to mycobacterium infection, but of unknown
`cause.
`
`Severe variants
`
`Acne conglobata
`Acne conglobata presents as severe nodulocystic acne, with
`nodules and abscesses on the trunk and buttocks, less commonly
`on the face. It shares the pathogenesis of follicular occlusion and
`rupture with dissecting cellulitis, hidradenitis suppurativa and
`pilonidal sinus. Management involves systemic and intralesional
`steroids,
`antibiotics,
`cautious
`surgical
`debridement
`and
`isotretinoin.
`
`Acne fulminans
`Sudden rupture of microcomedones with widespread necrosis can
`result in painful, sterile, haemorrhagic nodules and plaques,
`leading to truncal and facial ulcers and severe scarring. Usually
`occurring in males, acne fulminans can be associated with
`
`leukocytosis, raised inflammatory markers, hepatosplenomegaly,
`raised liver enzymes, arthropathy, erythema nodosum and
`osteolysis. Histology shows dermal abscesses, epidermal necrosis
`and a mixed granulocytic and lymphocytic infiltrate. Treatment
`includes warm compresses, surgical debridement, topical, intra-
`lesional and systemic steroids, isotretinoin and antibiotics.
`
`Pyoderma gangrenosum and acne
`There are reports of pyoderma gangrenosum with acne that do
`not fit the criteria of SAPHO or PAPA syndrome (Figure 3). They
`may represent incomplete syndrome variants or have an alter-
`native underlying immunopathology.
`
`Solid facial oedema
`This is a rare condition presenting with persistent, symmetrical,
`non-pitting, painful oedema of the glabellar, periorbital and nasal
`regions on a background of acne. Treatment includes surgical
`debridement, oral and topical steroids, antibiotics and isotretinoin.
`
`Differential diagnosis
`
`Chloracne
`Aromatic halogenic hydrocarbons found in coal tar derivatives,
`cutting oils, fungicides, insecticides and wood preservatives can
`cause chloracne through dioxin exposure. Chloracne presents as
`sterile, polymorphous, large comedones and cysts involving the
`retroauricular and malar areas, but also the axillae and groin. It is
`associated with xerosis, variable hypertrichosis, pigmentation
`
`Syndromes associated with acne
`
`Syndrome
`Apert syndrome
`(acrocephalosyndactyly
`type 1)
`
`Aetiology
`Autosomal dominant
`New missense in FGFR2
`with androgen sensitivity
`
`Behcet syndrome
`
`Skin signs
`Acne (severe, widespread:
`buttocks, forearms)
`Seborrhoea
`Hyperhidrosis
`Nail dystrophy
`Hypopigmentation
`
`Aphthous and genital ulcers
`Pustulosis
`Acne
`Folliculitis
`Erythema nodosum
`Pathergy
`
`Other signs
`Early epiphyseal
`closure
`Craniofacial deformity,
`Hypertelorism, Proptosis,
`Prognathism,
`Dental disorders
`
`Uveitis
`Iritis
`Vasculitis
`Arthritis
`
`PAPA syndrome
`
`Autosomal dominant
`CD2BP1 gene mutation
`
`Pyoderma gangrenosum
`Acne conglobata
`
`Pyogenic arthritis
`
`SAPHO syndrome
`
`Acne fulminans and conglobata
`Palmoplantar pustulosis
`Hidradenitis suppurativa
`Psoriasis
`
`Synovitis
`Hyperostosis
`Osteitis
`
`Treatment
`Isotretinoin
`
`Immunomodifiers:
`Steroids
`Colchicine
`Dapsone
`Interferon alpha
`Azathioprine
`TNF inhibitors
`Thalidomide
`
`Tetracyclines
`Isotretinoin
`Immunomodifiers
`TNF/IL-1 inhibitors
`
`Nonsteroidal
`antiinflammatories
`Steroids
`Oral antibiotics
`Topical retinoids
`Isotretinoin
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`Pityrosporum folliculitis
`Malasezzia can cause a pruritic, monomorphic, papulopustular
`folliculitis on the trunk, arms and face. Diagnosis is supported by
`KOH examination showing the yeast. It is often associated with
`immunocompromise. It does not respond to antibiotics or reti-
`noids and is treated with topical or oral antifungals.
`
`Seborrhoeic dermatitis
`Malasezzia is also associated with seborrhoeic dermatitis leading
`to red, sharply demarcated lesions with greasy scale affecting the
`eyebrow, nasolabial and retroauricular folds, chest and scalp.
`
`Perioral dermatitis
`Papules, pustules and erythema in the perioral, paranasal or
`periorbital areas, sparing the lip border, characterize perioral
`dermatitis. Possible triggers include potent
`topical steroids,
`chemicals (cosmetics,
`toothpaste),
`local
`infection, hormonal
`changes, sunlight and rarely foods.
`
`Rosacea
`Rosacea presents with facial vasodilation, flushing, oedema,
`papules, pustules and rhinophyma. Ocular dryness, grittiness and
`inflammation may occur. Pyoderma faciale is a severe variant
`occurring in young females. Treatment includes topical metronida-
`zole, azelaic acid, oral tetracyclines and in selected cases, low dose
`isotretinoin. Telangiectasia responds well to vascular laser therapy.
`
`Lupus erythematosus
`Lupus is an autoimmune disorder occurring more commonly in
`20e40-year-old females. Mucocutaneous features include malar
`erythema (without pustules), photosensitivity, discoid plaques,
`scarring, livedo reticularis, alopecia and mucosal ulcers.
`
`Dysmorphophobia
`Dysmorphophobia is a psychiatric condition described in DSM-IV
`characterized by excessive preoccupation with minimal ‘defects’
`causing functional impairment in multiple domains. Its preva-
`lence in dermatology populations is as high as 14%. It shows
`
`Figure 3 Acne and pyoderma gangrenosum complicating IBD.
`
`and palmoplantar hyperhidrosis. There may be neuropathy,
`impotence, hyperlipidaemia and liver and eye disease. Skin
`changes are persistent and resistant to oral isotretinoin. Topical
`retinoids, oral antibiotics and gentle cautery can help, but
`prevention of exposure to dioxins is critical.
`
`Gram-negative folliculitis
`With long-term oral antibiotic treatment, gram-negative follicu-
`litis can develop, presenting as a persistent, papulopustular,
`acneiform eruption resistant to conventional therapies. Common
`bacteria cultured are Escherichia coli, Klebsiella and Proteus
`species. Ampicillin and trimethoprim can help, but isotretinoin is
`more effective.
`
`Management
`
`Comedonal acne
`
`Topical retinoid
`
`Mixed comedonal lesions
`and papulopustules
`Retinoid þ topical antibiotic
`
`Papules and pustules
`Oral antibiotic þ
`topical retinoid
`
`Severe inflammatory
`nodulocystic
`Previous treatments þ/
`antiandrogen
`
`Benzoyl peroxide
`
`Retinoid þ benzoyl peroxide
`
`Azelaic acid
`
`Benzoyl peroxide þ topical antibiotic
`
`Salicylic acid
`
`Retinoid þ benzoyl peroxide þ
`topical antibiotic
`
`Azelaic acid þ benzoyl peroxide
`Azelaic acid þ topical antibiotic
`
`Oral antibiotic þ
`benzoyl peroxide
`Oral antibiotic þ
`topical retinoid þ
`benzoyl peroxide
`(more severe)
`
`Oral isotretinoin þ
`oral contraceptive
`
`Possibly with associated
`early short-term use
`of steroids
`
`Associated with
`hormonal symptoms
`Anti-androgens
`(oral contraceptive or
`spironolactone) þ/
`topical comedolytic
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`good response to selective serotonin reuptake inhibitors and
`cognitive behavioural therapy.
`
`Investigations
`
`Generally patients with acne do not require further investigation
`apart from those required for starting treatment. However, if
`there is clinical suspicion of hyperandrogenism syndromes,
`further studies are warranted.
`Laboratory investigations include serum luteinizing hormone:
`follicle stimulating hormone ratio, testosterone (total/free), sex
`hormone binding globulin, dehydroepiandrosterone sulphate
`(DHEAS), prolactin, cortisol and 17-alpha hydroxyprogesterone.
`Adrenal tumours are suspected if DHEAS is greater than 8000 ng/
`ml. Ovarian or testicular tumours are suspected if total testos-
`terone is greater than 200 mg/dL.
`There may be a place for thyroid function tests, lipids, glucose
`tolerance/insulin resistance tests and dexamethasone suppres-
`sion tests (the latter for Cushing’s). Other tests include bone age
`measurements for those with prepubertal acne to distinguish
`precocious puberty. Radiological examination is required if sus-
`pecting visceral tumours or polycystic ovaries.
`
`Treatment of mild and moderate acne
`
`Facial washing with ordinary soaps can increase bacteria and
`should be avoided. In a recent trial, facial cleansers showed no
`efficacy in improving acne lesion counts.
`
`Topical therapies
`The desired vehicle for topical agents depends on the skin type.
`Usually creams are used in dry or sensitive skin, gels or solutions for
`those with seborrhoeic skin. Lotions can be used in most skin types.
`
`Topical
`
`retinoids are
`comedolytic agents which reduce
`abnormal mitosis of keratinocytes, hyperkeratinization and
`inflammation. They are first line therapy for comedonal and
`inflammatory acne. As local adverse effects include erythema,
`dryness, peeling and photosensitivity, we suggest
`limiting
`application time (in the first week) to 3 h before rinsing off. They
`are spread thinly and evenly in facial zones affected by acne. If
`tolerated, they can be left on overnight, daily or second daily.
`Commonly available agents are tretinoin,
`tazarotene and
`adapalene.
`Tazarotene 0.1% gel reduces comedones more quickly than
`tretinoin 0.025e0.1% and adapalene 0.1e0.3% gels. Adapalene
`0.1% gel
`is equally as effective as tretinoin 0.05% cream,
`tretinoin microsphere 0.1% gel and isotretinoin 0.05% gel.
`Adapalene 0.1% is associated with less erythema, dryness and
`burning than tazarotene 0.1% gel, tretinoin 0.025e0.1% gel,
`tretinoin 0.05% cream and isotretinoin 0.05% gel. Adapalene
`0.3% is more effective than adapalene 0.1%.
`Contraception is advised as retinoids are potentially terato-
`genic and are contraindicated in pregnancy.
`
`Benzoyl peroxide: it is an antibacterial agent that reduces lesion
`counts in mild to moderate acne. It has a 1 in 450 risk of allergic
`contact dermatitis, bleaches clothing and irritates the skin if used
`in excess. It can be applied in the morning, being less photo-
`sensitizing than topical retinoids.
`
`Topical antibacterials: topical erythromycin and clindamycin
`both suppress P. acnes growth and reduce lesion counts
`compared with placebo. However, an increasing incidence of
`P. acnes erythromycin resistance (47% in the UK), has resulted in
`reduced efficacy of erythromycin. Topical clindamycin, regard-
`less of vehicle or formulation type, has shown to be effective in
`reducing lesion counts and no significant decrease in efficacy has
`yet been demonstrated despite increasing bacterial resistance
`(45% in the UK). Side effects include erythema, dryness and
`a burning sensation.
`
`Combined topical treatment: in multiple trials, topical combi-
`nation therapies are more effective than monotherapy as they
`target multiple pathogenic mechanisms. Increasing tetracycline
`resistance has further compromised the response to mono-anti-
`microbial therapy. Clindamycin or erythromycin combined with
`benzoyl peroxide, tretinoin or adapalene show greater efficacy
`than monotherapy. Benzoyl peroxide and topical retinoids in
`combination are also more effective than monotherapy.
`Less commonly used, topical salicylic acid and azelaic acid
`reduce lesion counts, with less irritation than retinoids. Dapsone
`5% gel also reduces lesion counts. Comparative studies with
`other topical
`treatments are lacking. Side effects of
`topical
`dapsone include dryness, rash and photosensitivity. Phase IV
`clinical trials have showed no evidence of haemolytic anaemia in
`G6PD deficient individuals using dapsone 5% gel.
`
`Oral antibiotics
`Clinical
`response has been demonstrated to doxycycline
`50e200 mg per 24 h, trimethoprimesulfamethoxazole 80/400
`mg per 12e24 h and minocycline 50 mg per 12e24 h. These
`antibiotics
`all have
`antimicrobial
`and antiinflammatory
`activity. No significant difference in efficacy between minocy-
`cline and other tetracyclines has been shown. Although less
`photosensitizing than other tetracyclines, minocycline has an
`increased risk of pigmentation,
`lupus-like syndrome and
`hepatitis. It is also more costly, thus it is not recommended as
`first line treatment.
`Antibiotics are best used together with a topical retinoid or
`benzoyl peroxide due to their limited effect on comedogenesis
`and
`increasing
`antimicrobial
`resistance. Antibiotics
`can
`compromise the efficacy of the oral contraceptive pill. Tetracy-
`clines are teratogenic and thus contraindicated in pregnancy.
`
`Hormonal therapy
`Oral contraceptive pill (OCP): a Cochrane review demonstrated
`that the combined oral contraceptive pill (COC) compared with
`placebo significantly reduced inflammatory and non-inflamma-
`tory lesion counts and severity of acne. It reduces androgen
`synthesis and increases binding of androgens in the blood, thus
`reducing free testosterone levels. It also inhibits 5-alpha-reduc-
`tase activity, reducing conversion of testosterone to the more
`androgenic DHT.
`The choice between antibiotics and oral contraception for
`acne treatment is dictated by clinical indications and contrain-
`dications. Clinical response to the OCP may be delayed by 4
`months. Clinical features suggesting a role for the OCP include
`premenstrual, cyclical acne, hyperandrogenism syndromes and
`hyperseborrhoea. Contraindications include a family history of
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`breast or ovarian cancer, hypertension, venous thrombosis,
`smoking, other cardiac risk factors and religious objection.
`There is limited evidence that COCs containing cyproterone
`acetate (CPA) or chlormadinone acetate improve acne more
`effectively than levonorgestrel containing COCs. However, there
`is evidence of a higher risk of venous thrombosis in CPA con-
`taining pills compared with non-CPA containing pills. In the UK,
`but not the USA, a CPA containing pill, Dianette, is licensed for
`severe acne refractory to oral antibiotic therapy. Other OCPs,
`prescribed for dual contraceptive and acne benefit with
`progestins,
`include
`norethindrone,
`norgestimate
`and
`drosperinone.
`A trial using the same progesterone with differing doses of
`ethinyl estradiol in the COC found no difference in lesion counts.
`Effects of other oestrogen-containing contraceptives such as
`vaginal rings and transdermal patches have not been studied.
`
`Spironolactone: Spironolactone is an aldosterone antagonist
`which has anti-androgen effects. When given 50e200 mg per
`24 h it appears to reduce sebum production and acne severity but
`studies are limited. Adverse effects, including hyperkalaemia,
`teratogenicity, gynaecomastia in men and menstrual dysfunction
`in women, limit its usage.
`
`Flutamide: a nonsteroidal anti-androgen agent used for the
`treatment of hirsutism, appears to improve acne. However,
`hepatotoxicity limits its usage.
`
`Oral corticosteroids: by reducing testosterone levels and
`inflammation, can be used for short periods in conjunction with
`other agents like isotretinoin for the treatment of severe acne.
`Steroids can induce steroid acne and its extensive side effect
`profile limits its role.
`
`Treatment of severe acne
`
`Oral isotretinoin
`Isotretinoin is used to treat not only severe, cystic and scarring
`acne vulgaris but also refractory disease. It reduces sebaceous
`gland size and secretory activity, comedone formation and
`follicular colonization of P. acnes.
`Although 0.5e1 mg/kg/day as a single or divided dose has
`been recommended, we suggest a lower starting dose (0.3e0.5
`mg/kg/day) to minimize adverse effects. Severe cystic acne may
`benefit from a lower starting dose and initial adjuvant oral
`corticosteroids, weaned over the first 2e3 weeks. Most resolve
`within 20 weeks of isotretinoin therapy but refractory cases
`require longer treatment.
`Isotretinoin is a vitamin A derivative. Its side effect pattern
`resembles hypervitaminosis A syndrome and is dose dependent,
`resolving with drug cessation. Before initiating treatment, we
`suggest (1) discussing possible side effects in detail, (2) identi-
`fying and addressing potential contraindications, (3) discussing
`appropriate contraceptive measures due to the teratogenic risk,
`(4) screening full blood count, liver function tests, fasting lipids
`and in females, serum pregnancy test and (5) obtaining written
`consent. Generally, tests are repeated after 1 month of treatment.
`The commonest side effect is dryness of skin, lips, nose and
`mucous membranes, which can lead to cheilitis and decreased
`tolerance of contact lenses without lubrication. Patients should
`
`avoid vitamin A supplementation, topical retinoids and drying
`topical agents.
`It
`is contraindicated in hypervitaminosis A
`syndrome.
`Liver enzymes should be monitored and hepatotoxins avoi-
`ded. Isotretinoin may cause reversible hypertriglyceridaemia and
`hypercholesterolaemia requiring dietary measures.
`Teratogenic effects include life-threatening foetal abnormali-
`ties, facial dysmorphia, cleft palate, central nervous system,
`external ear, cardiovascular and thymus gland abnormalities and
`an increased risk of miscarriage.
`In the UK,
`females are
`prescribed isotretinoin monthly through the Pregnancy Preven-
`tion Program. Pregnancy tests are conducted before, during and 5
`weeks post-cessation of therapy. If sexually active, at least two
`forms of reliable contraception must be used, from 1 month
`before initiation until 1 month after cessation of
`therapy.
`Progesterone only pills are not considered appropriate and the
`COC should be used.
`There are conflicting reports regarding the association
`between isotretinoin and subsequent depression. Some studies
`have suggested a small but significant increase in the risk of
`depression. Psychosocial assessment and clinical review is
`important. For at risk patients, psychological or psychiatric
`referral before instituting treatment may be necessary.
`Less common adverse effects include headaches, myalgias,
`alopecia, nose bleeds, pancreatitis, skeletal hyperostosis and
`extraosseous calcifications. Other ocular effects are cataracts,
`optic neuritis and photosensitivity. Potential aeroplane pilots
`should be warned about possible lasting impaired night vision
`identifiable with Goldmann-Weekers Dark Adaptation and Elec-
`troretinogram studies. Other photosensitizing drugs should be
`avoided. Tetracyclines should be avoided given the risk of
`pseudotumour cerebri.
`There is a probable causal association between isotretinoin
`and inflammatory bowel disease (IBD). However, the association
`is not established. Further studies are required to exclude
`possible confounding variables. Though the risk of IBD is esti-
`mated at less than 1:10 000, the physician should counsel and
`screen the patient before beginning treatment.
`
`Light therapy
`Light therapy appears to reduce P. acnes numbers and disrupt
`sebaceous gland function, possibly on par with topical therapies.
`No studies directly compare light therapy with standard acne
`treatments. A systemic review showed that MAL-photodynamic
`therapy (PDT) had a 68% reduction and aminolevulanic acid
`(ALA)-PDT had a 59% reduction in facial acne compared to
`placebo after 12 weeks. However, ALA-PDT caused more
`erythema, pustular eruptions, exfoliation and hyperpigmentation
`than MAL-PDT. Intense pulsed light assisted PDT was more
`beneficial then intense pulsed light therapy alone. There were no
`significant differences between placebo, pulsed dye laser therapy
`and infrared laser therapy.
`
`Complementary and alternative medicines
`In randomized controlled trials, tea tree oil, gluconolactone and
`glycolic acids (fruit-derived) were less effective than benzoyl
`peroxide 5% lotion but more effective than placebo in reducing
`acne. There is little evidence for the use of alternative medicines
`in the treatment of acne.
`
`PAEDIATRICS AND CHILD HEALTH 21:3
`
`124
`
`Ó 2010 Published by Elsevier Ltd.
`
`6
`
`

`

`SYMPOSIUM: DERMATOLOGY
`
`Assessment of treatment
`
`Complications
`Failing to treat acne can increase scarring. Early treatment is
`paramount for optimizing the outcome. Scarring occurs in 95%
`of cases in both sexes. In a study, 91% had ice-pick scars
`76e84% had macular atrophic scars, 6% had hypertrophic
`scarring and 2% had keloid scarring. Hypopigmentation or
`hyperpigmentation can occur.
`Ice-pick and boxcar scars may benefit from punch-excision,
`punch-elevation, punch-grafting and subcision. For rolling scars,
`subcision, fillers, fraxel and collagen induction therapy may be
`helpful. Hypertrophic or keloid scarring can be treated with
`intralesional steroid or 5-fluorouracil, (rarely combined with
`excision given the unacceptable risks of post-surgical keloid).
`Chemical peels and micro-dermabrasion have largely been
`superseded by other therapies, but play a role in treating mild
`comedonal acne. Vascular laser therapy has been used for
`problematic erythema.
`
`Prognosis
`Non-compliance can lead to treatment failure. Topical regimens
`usually have the worst adherence rates in clinical practice.
`Factors associated with decreased adherence include male
`gender, frequency of dosing, smoking and alcohol consumption.
`Factors associated with increased adherence include satisfaction
`with physician and a high level of embarrassment with acne.
`Compliance can be improved by simplifying medication
`regimens, reinforcing positive patient behaviour and encour-
`aging patient understanding with written patient handouts,
`electronic resources and other forms of media. The physician can
`assure the patient that acne is usually self limiting with less than
`5% having acne at the age of 40 years.
`
`Follow up
`The majority of cases are managed by general practitioners. The
`National Institute for Health and Clinical Excellence referral
`guidelines state those with severe nodulocystic disease or acne
`fulminans should have a dermatological referral within 2 weeks
`for isotretinoin. Those with severe psychological problems or
`dysmorphophobia related to acne should be referred within 2
`months. Routine specialist referral is required for those who 1)
`are at risk of scarring despite primary care therapies, 2) fail 6
`months of topical and oral treatment or 3) have an underlying
`endocrinological cause for acne.
`
`Prevention
`
`Potential vaccination, targeting the cell wall-anchored sialidase
`of P. acnes is being studied. Anti-sialidase antibodies have been
`shown to suppress P. acnes-induced inflammation and neutralize
`P. acnes cytotoxicity in sebocytes. A vaccine is yet to be trialled
`A
`in humans.
`
`FURTHER READING
`Arowojolu AO, Gallo MF, Lopez LM, Grimes DA, Garner SE. Combined oral
`contraceptive pills for treatment of acne. Cochrane Database Syst Rev
`2009. CD004425.
`
`Azoulay L, Blais L, Koren G, et al. Isotretinoin and the risk of depression in
`patients with acne vulgaris: a case-crossover s