Clinical review
`
`Acne vulgaris
`Guy F Webster
`
`Acne may be common, but it causes considerable distress and doctors should treat it effectively,
`not trivialise it
`
`Acne vulgaris is common and affects nearly all adoles›
`cents and adults at some time in their lives. Although
`overall health is not impaired, acne is not a trivial
`disease; it can produce cutaneous and emotional scars
`that last a lifetime.1 2 Numerous psychological prob›
`lems stem from acne, even resulting in decreased
`employability in adulthood.3 Fortunately, acne is
`eminently treatable, and this review provides an outline
`of current treatments.
`
`Sources and selection criteria
`A literature review augmented my extensive experi›
`ence of
`the topic. I used Entrez PubMed for all
`literature searches.
`
`Summary points
`
`Acne is a multifactorial disease which, although
`not life threatening, has profound effects on
`patients
`
`The microcomedo is the primary lesion in acne
`
`Reduction of comedones and Propionibacterium
`acnes is the main aim of treatment
`
`Most effective acne regimens treat inflammatory
`and comedonal acne lesions with a combination
`of antibacterial and retinoid drugs
`
`Department of
`Dermatology,
`Jefferson Medical
`College,
`Philadelphia,
`PA 19107, USA
`Guy F Webster
`professor
`Guy.Webster@
`mail.tju.edu
`
`BMJ 2002;325:475–9
`
`Pathogenesis
`Acne has a complex aetiology, involving abnormal
`keratinisation, hormonal function, bacterial growth,
`and immune hypersensitivity. 1 2 The disease is limited
`to pilosebaceous follicles of the head and upper trunk
`because the sebaceous glands in these regions are par›
`ticularly active. The primary acne lesion is
`the
`“blackhead” (microcomedo), an impaction and disten›
`sion of
`the follicle with improperly desquamated
`keratinocytes and sebum. The stimulus for comedo›
`genesis is uncertain.
`At puberty, when androgens stimulate the produc›
`tion of sebum, pre›existing comedones become filled
`with lipid and may enlarge to become visible.
`Subsequently, some patients also begin to show signs
`of inflammation. Comedones that become inflamed
`are nearly always clinically invisible before the pimple
`develops.
`the host
`the result of
`Inflammatory acne is
`response to the follicular inhabitant Propionibacterium
`acnes,1 4 which is a member of the normal flora and is a
`harmless commensal,
`largely incapable of
`tissue
`invasion or serious infection. The organism metabo›
`lises sebaceous triglycerides, consuming the glycerol
`fraction and discarding free fatty acids. As a
`consequence of growth and metabolism, P acnes
`produces neutrophil chemoattractants. P acnes also
`activates complement and is generally inflammatory
`when brought into contact with the immune system .
`
`Assessment of disease severity and
`impact on patient
`The first step in treating acne is to determine the sever›
`ity of the disease. In diabetes and hypertension (for
`example), severity of disease and response to treatment
`can both be measured quantitatively; but
`such
`measurements have only limited benefits in acne.
`Moreover, the severity of acne is often overestimated by
`the patient and minimised by the doctor. Teenagers in
`particular are stigmatised by fairly trivial acne. In their
`eyes, severe acne can mean ruination. Thus, simple
`pimple counts are only partly useful; it is of little benefit
`to clear 95 of 100 lesions if the patient is left with
`several disfiguring nodules.
`Grading schemes that rely solely on lesion counts
`are of greater use in clinical studies than in clinical
`practice. It is better to focus on the most severe lesions
`present, because adequate treatment for them covers
`all lesser lesions. Acne can be classified into four main
`types: purely comedonal—that is, non›inflammatory
`acne—mild papular, scarring papular, and nodular or
`scarring acne.
`
`Dispelling popular misconceptions
`Child patients
`(and usually their parents) hold
`common misconceptions about acne that need
`tackling before treatment begins. Firstly, they often
`blame themselves for the disease. However, acne does
`
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`

`Clinical review
`
`not come from bad behaviour nor is it a disease of
`poor hygiene. Patients (and parents) need to realise
`that acne has nothing to do with lack of cleanliness.
`The black tip of a comedo is oxidised sebum,2 not dirt,
`and it cannot be removed by scrubbing. Vigorous
`washing may actually make things worse.
`Secondly, despite parental admonitions, diet has
`never been shown to have much effect on acne. Thirdly,
`patients need to understand that topical treatments
`work by preventing new lesions, not shrinking ones
`that have already formed. Thus, the treatment should
`be applied faithfully to all skin that may be affected, not
`just to visible lesions.
`
`Treatment regimens should be simple
`Many doctors seem tempted to use as many as five or
`six treatments. I believe, however, that most acne can be
`treated effectively with two drugs, or at most three, at
`any one time. Failure to respond to a regimen within
`four to eight weeks should prompt a substantial
`change in drugs, not merely the addition of another
`product. Besides adding expense with little benefit,
`complex regimens are usually more irritating and
`present problems with compliance.
`
`Comedonal acne
`Non›inflammatory acne is the mildest form of disease
`but can be the hardest to treat. Comedones are usually
`firmly seated in the follicle, and, if untreated, they can›
`not often be expressed without some degree of
`violence. Tretinoin, isotretinoin, adapalene, and tazaro›
`tene are topical retinoids which, if applied daily, inhibit
`formation of comedones and usually clear even severe
`comedonal acne within a few months.5 The only major
`drawback is irritation, which is greatest after a few
`weeks, but the irritation usually requires no more than
`simple moisturising. Because their skin is inherently
`irritable, patients with atopic diseases may not tolerate
`topical retinoids, even if they apply a moisturiser.
`Azelaic acid is a dicarboxylic acid with modest antibac›
`terial and comedolytic effects. It is the least irritating
`preparation. The side effect of hypopigmentation may
`be desirable in some patients: in dark skinned patients,
`inflammation results in hyperpigmentation, which
`could otherwise remain for weeks or months.
`
`Box 1: Typical treatment regimens for acne
`
`Comedonal acne
`• Topical tretinoin, adapalene, or tazarotene applied daily
`• Salicylic acid
`• Azelaic acid
`Mild papulopustular acne
`• Benzoyl peroxide
`• Topical gel preparations of benzoyl peroxide with either clindamycin or
`erythromycin
`• Oral doxycycline or minocycline 75›100 mg twice daily plus topical
`retinoid
`
`Severe papulopustular or nodular acne
`• Oral doxycycline or minocycline plus topical retinoid
`• Isotretinoin 1 mg/kg a day
`
`Box 2: Solutions for acne that is resistant to
`treatment
`• Investigate compliance
`• Increase frequency of topical therapy
`• Begin or increase oral antibiotic dosage
`• Search for hormonal derangement
`• Begin oral isotretinoin therapy
`
`Inflammatory acne
`Topical treatment
`Mild papulopustular acne rarely results in scarring and
`typically is responsive to aggressive, twice daily, topical
`treatment. Usually,
`two drugs are prescribed—an
`antibacterial and a comedolytic. Benzoyl peroxide 2.5›
`10% is extremely effective against P acnes. Its major dis›
`advantage is irritation, which can be minimised by
`using lower concentrations in a cream vehicle. Topical
`erythromycin and clindamycin are available as
`alcoholic solutions, lotions, creams, and gels, all of
`which are about equally effective.6 A combination of
`clindamycin and benzoyl peroxide in gel form is supe›
`rior to a topical antibiotic alone.7 Azelaic acid 20%
`cream is also an effective alternative to topical
`macrolide preparations.8 9
`During the past two decades many reports have
`documented the acquisition of antibiotic resistance by
`P acnes during treatment of acne. 7 10 11 The problem is
`most often seen with topical clindamycin and erythro›
`mycin, and I now find neither of these drugs useful
`unless combined with benzoyl peroxide. When resist›
`ance is suspected, culture and susceptibility testing are
`not needed. Failure to respond to topical treatment
`within four to eight weeks should automatically
`prompt a change in treatment. Other options for
`include oral
`antibiotics
`and
`resistant P acnes
`isotretinoin.
`
`Oral treatment
`Acne that is resistant to topical treatment or that mani›
`fests as scarring or nodular lesions typically requires
`oral antibiotics.8 9 Many of the antibiotics useful in acne
`also have an anti›inflammatory activity, which is nearly
`as important as their effect on the P acnes itself. Oral
`erythromycin used to be a common treatment for
`acne, but the rise of resistance has greatly reduced its
`utility.8 9 11
`Many doctors prefer to start with tetracycline at 1 g
`a day in divided dose. I often find this insufficient and
`usually begin with doxycycline or minocycline at
`75›200 mg a day. Lower doses of doxycycline and
`minocycline—for example, 20 mg or 50 mg—are avail›
`able and are useful
`for maintenance treatment.
`Acquired resistance to minocycline and doxycycline is
`less common than to erythromycin but
`is still a
`concern, and use of these drugs should be limited to
`those patients who truly need them. Patients are
`instructed to take the drug with food—this minimises
`stomach complaints and maximises compliance, albeit
`with a slight decrease in absorption. Patients should be
`warned that they may get sunburnt more easily. Rarely,
`a hypersensitivity syndrome ranging from urticaria to
`drug induced lupus can be caused by minocycline.12
`Onset of symptoms, especially early in minocycline
`
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`
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`

`Clinical review
`
`DRKARILOUNATMAA/SPL
`
`Propionibacterium acnes
`
`steroid; oral contraception; cyproterone acetate; or
`spironolactone.14
`
`Isotretinoin
`Isotretinoin revolutionised the treatment of severe
`acne about 20 years ago. It is a synthetic retinoid that
`inhibits differentiation of sebaceous glands, corrects
`the keratinisation defect in the follicle, and also has
`some anti›inflammatory activity. Its major indication is
`severe nodular acne, but it is commonly used for severe
`acne that is resistant to oral antibiotics as well.
`Side effects of isotretinoin are mostly dose related
`and are not always trivial.15 Most patients complain of
`dry skin, lips, and eyes. In dry seasons, it is common to
`see epistaxis and mild flares of atopic dermatitis due to
`the drug. About a third of patients show raised triglyc›
`eride levels during the first month of
`treatment.
`Usually, modifying the diet or reducing the dosage
`keeps the triglyceride level from rising too high. Thin›
`ning of hair is uncommon but can be particularly dis›
`tressing. Rarely, patients complain of myalgias while
`taking isotretinoin and show substantial rises in levels
`of muscle derived aminotransferase. Typically these
`patients are engaging in vigorous exercise. Because
`
`Box 3: Adverse effects of oral isotretinoin
`
`treatment, should prompt evaluation. In the vast
`majority of patients, oral antibiotics may be continued
`for months or years with little concern—the safety
`record of these drugs in acne goes back decades.
`If minocycline or doxycycline cannot be used, alter›
`natives include co›trimoxazole and ciprofloxacin. Risk
`of acquiring resistance to these drugs after long term
`use has not been studied, but it is clearly a concern, and
`use of these drugs should be minimised. In general,
`cephalosporins and penicillins are not very effective in
`treating acne. The increased cost of some of these
`newer drugs may make using isotretinoin an attractive
`option if long term treatment is anticipated.
`Because all acne begins with follicular impaction, a
`topical comedolytic such as tretinoin, tazarotene, or
`adapalene should be added to oral antibiotic regimens,
`and most patients greatly benefit from such addition.
`Even with combination therapy, the physician should
`not expect to see maximal improvement in under at
`least six to eight weeks. When the patient’s acne has
`been controlled to a satisfactory level, maintenance
`treatment may be begun. Topical treatment with retin›
`oids or benzoyl peroxide is often sufficient for long
`term control.
`
`Hormonal treatment
`Women with masculinisation have a higher incidence
`of acne, but it is wrong to assume that any woman with
`acne has a hormonal derangement. In fact, androgen
`levels do not correlate with acne severity among
`people with acne.13 Acne resistant
`to treatment,
`especially in a woman with irregular menses, should be
`investigated with, at least, measurements of total and
`free testosterone as well as dehydroepiandrosterone
`sulphate. If these levels are raised, four approaches may
`be taken: suppression with low dose oral cortico›
`
`Common
`• Dry skin
`• Hyperlipidaemia
`• Initial flare of acne
`Uncommon
`• Alopecia
`• Myalgia
`• Pseudotumour cerebri
`• Visual
`• Depression (link not confirmed)
`
`DRZARA/BIPP/SPL
`
`Acne vulgaris in an adolescent
`
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`

`Clinical review
`
`Additional resources
`
`Webster GF. Acne vulgaris and rosacea. In: Rakel RA,
`ed. Conn’s current therapy. Philadelphia, PA: W B
`Saunders, 2002.
`Plewig G, Kligman AM. Acne morphogenesis and
`treatment. Berlin: Springer, 1975.
`www.skincarephysicians.com/acnenet/ (a sensible and
`accessible website endorsed by the American Academy
`of Dermatology)
`
`doctors rarely request measurement of creatine kinase,
`drug related hepatitis is often incorrectly diagnosed.
`Restriction of exercise and reduction of dose usually
`correct the problem. Depression is a rare adverse effect
`of isotretinoin, but a convincing link to the drug has
`not been documented.16 Decreased night vision may be
`measured but is rarely noticed by the patient. Finally,
`patients with severely inflamed lesions, especially those
`on the back and chest, may have a severe flare of
`disease accompanied by systemic complaints similar to
`those seen in acne fulminans. Prednisone 20›40 mg a
`day, along with low starting doses of isotretinoin, is
`indicated in such patients.
`The most important side effect of isotretinoin is
`teratogenicity.15 Two means of birth control, one either
`hormonal or surgical, are required for all
`fertile
`women taking the drug and should be continued for
`one menstrual period after treatment is stopped. After
`a course of isotretinoin, fertility and fetal development
`are normal once circulating isotretinoin levels return
`to normal.15 There are no known deleterious effects on
`male fertility.
`Patients should be monitored routinely. Pretreat›
`ment tests should include a lipid profile aspartate
`aminotransferase, complete blood count, and in the
`case of women, two negative pregnancy tests. At one
`month these tests should be repeated. If the results are
`normal and the dose of isotretinoin is not increased,
`only the pregnancy test needs be repeated each month.
`The correct dosage of isotretinoin is controversial,
`and there is a point at which greater efficacy is
`outweighed by an increase in side effects. I prefer to use
`
`1 mg/kg a day. Lower dosages often require longer
`than the standard four or five months of treatment and
`have a higher long term failure rate.
`
`Acne and pregnancy
`Erythromycin, topical or oral, is safe in pregnancy,
`although oral erythromycin is often poorly tolerated in
`patients whose lower oesophageal sphincter is already
`relaxed by pregnancy. Benzoyl peroxide rapidly
`decomposes into benzoic acid and hydrogen peroxide
`and is also safe. Topical tretinoin in pregnancy is theo›
`retically safe as circulating vitamin A blood levels do
`not change with topical tretinoin treatment. However,
`many doctors avoid its use until after childbirth. No
`increase in fetal abnormalities has been seen in women
`using topical tretinoin while pregnant.17
`
`Contributors: GFW is the sole contributor.
`Competing interests: GFW is a consultant to Ortho, Medicis,
`Dermik, Allergan, and Roche.
`
`1 Webster GF. Inflammation in acne vulgaris. J Am Acad Derm 1995;33:
`247›53.
`2 Kligman AM. An overview of acne. J Invest Derm 1974;62:268›87.
`3 Cunliffe WJ. Acne and unemployment. Br J Derm 1984;115:386.
`4 Leyden JJ. The evolving role of Propionibacterium acnes in acne. Semin
`Cutan Med Surg 2001;20:139›43.
`5 Shalita AR. The integral role of topical and oral retinoids in the early
`treatment of acne. J Eur Acad Dermatol Venereol 2001;15(suppl 3):43›9.
`6 Leyden JJ, Shalita AR, Saatjian GD, Sefton J. Erythromycin 2% gel in
`comparison with clindamycin phosphate 1% solution in acne vulgaris.
`J Am Acad Derm 1987;16:822›7.
`7 Eady EA, Farmery MR, Ross JI, Cove JH, Cunliffe WJ. Effects of benzoyl
`peroxide and erythromycin alone and in combination against antibiotic›
`sensitive and ›resistant skin bacteria from acne patients. Br J Dermatol
`1994;131:331›6.
`8 Sykes N, Webster GF. Therapeutic advances in the treatment of acne vul›
`garis. Drugs 1994;48:59›70.
`9 Webster GF. Acne and rosacea. Med Clin North Am 1998;82:1145›54.
`10 Eady EA. Bacterial resistance in acne. Dermatology 1998;196(1):59›66.
`11 Leyden JJ, McGinley KJ, Cavalieri S, Webster GF, Mills OH, Kligman AM.
`Propionibacterium acnes resistance to antibiotics in acne patients. J Am
`Acad Derm 1983;8:41›5.
`12 Schlienger RG, Bircher AL, Meier CR. Minocycline›induced lupus. A sys›
`tematic review. Dermatology 2000;200:223›31.
`13 Levell MJ, Cawood ML, Burke B, Cunliffe WJ. Acne is not associated with
`abnormal plasma androgens. Br J Derm 1989;120:649›54.
`14 Thiboutot D. New treatments and therapeutic strategies for acne. Arch
`Fam Med 2000;9:179›87.
`15 McClane J. Analysis of common side effects of isotretinoin. J Am Acad
`Dermatol 2001;45:S188›94.
`16 Jacobs DG, Deutsch NL, Brewer M. Suicide, depression, and isotretinoin:
`is there a causal link? J Am Acad Dermatol 2001;45:S168›75.
`17 Jick SS, Terris BZ, Jick H. First trimester topical tretinoin and congenital
`disorders. Lancet 1993:341:1181›2.
`
`Commentary: A UK primary care perspective on treating acne
`Tom Poyner, Bill Cunliffe
`
`Queens Park
`Medical Centre,
`Stockton›on›Tees
`TS18 2AW
`Tom Poyner
`general practitioner
`Clinical Trial Unit,
`Department of
`Dermatology,
`General Infirmary,
`Leeds LS1 3EX
`Bill Cunliffe
`professor
`
`478
`
`In the United States, many patients with skin disease
`are treated predominantly by dermatologists. In the
`United Kingdom, patients often turn first
`to
`community pharmacists and then to their general
`practitioner. Acne can be managed in primary care
`provided that the general practitioner has adequate
`training and experience, but this is not always the case.
`Dermatology remains an area with high levels of
`referral
`to specialist
`services, and this demand
`outweighs capacity.1
`No national UK guidelines exist for treating acne,
`although some trusts and health boards have local
`
`ones. The BNF (British National Formulary) and the
`MeReC Bulletin provide some information,2 and the
`National Institute for Clinical Excellence provides
`advice on referral to secondary care.3 Also, increasing
`numbers of general practitioners are developing a spe›
`cial interest in dermatology.
`The principles of treatment suggested by Professor
`Webster are logical. A holistic approach is important
`with topical treatment for mild disease, a combination
`of oral and topical treatment for more troublesome
`disease, and oral isotretinoin for severe disease and
`when other treatment fails.
`
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`

`Clinical review
`
`As the microcomedo is a precursor of many acne
`lesions it is reasonable to introduce a topical retinoid
`(or retinoid›like drug, such as adapalene). Such drugs
`reverse formation of comedones. Retinoids should be
`used early on and continued throughout much of the
`treatment programme. In contrast to the United States,
`the topical retinoid tazarotene is not licensed for acne.
`A topical retinoid can be used in the evening and an
`antimicrobial agent in the morning. It is important to
`emphasise the benefit of benzoyl peroxide, which may
`reverse the increasing problems of resistance to Propi›
`onibacterium acnes. Benzoyl peroxide can be used in
`combination with oral and topical antibiotics or during
`“antibiotic holidays” (breaks from antibiotic use).
`We agree that when an oral antibiotic is needed,
`oxytetracycline is the first choice. More expensive
`preparations are not proved to be more effective. As a
`second line drug, minocycline is worth trying. General
`practitioners should be aware of the possible side
`effects, especially drug induced lupus.4 General practi›
`tioners in the United Kingdom prescribe minocycline
`in a dose of 100 mg a day but American dermatologists
`regularly prescribe 200 mg a day. Generic trimetho›
`prim is both effective and inexpensive.
`Patients should be warned to expect little improve›
`ment in the first month, but thereafter they should
`expect about 20% improvement a month. After
`successful control of the disease, maintenance treat›
`ment with topical agents is essential. Oral antibiotics
`should be reintroduced if the acne occurs.
`Women with acne who need the contraceptive pill
`for gynaecological reasons are often prescribed cypro›
`terone acetate and oestrogen (Dianette) and topical
`treatment. Oral
`isotretinoin is highly effective at
`treating acne, but in the United Kingdom it can be pre›
`scribed only in secondary care because of
`its
`teratogenicity and the risk of adverse psychiatric
`events. In the United States the prescribing of oral
`isotretinoin and contraceptive advice is very proscrip›
`tive. UK guidelines are expected soon. The idea of
`
`prescribing oral isotretinoin in the community is a
`matter of debate. If general practitioners with a special
`interest
`in dermatology were able to prescribe
`isotretinoin it may reduce the waiting time for second›
`ary care. However, any small changes in the threshold
`for prescribing isotretinoin could have serious financial
`implications for the NHS.5
`
`1 Associate Parliamentary Group on Skin. Report on the enquiry into primary
`care dermatology care services. London: APGS, 2002:1.
`2 National Prescribing Centre. The treatment of acne vulgaris: an update.
`MeReC Bulletin 1999;10(8):29›32.
`3 National Institute for Clinical Excellence. Referral Advice. A guide to
`to specialist services. London: NICE,
`appropriate referral
`from general
`2001:7›8.
`4 Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Minocycline induced
`autoimmune hepatitis and systemic lupus erythematosus›like syndrome.
`BMJ 1996;312:169›72.
`5 Williams HC. Health care needs assessment: dermatology. Oxford: Radcliffe
`Medical Press, 1997:34›6.
`
`Corrections and clarifications
`
`Randomised trial of endoscopy with testing for
`Helicobacter pylori compared with non›invasive H pylori
`testing alone in the management of dyspepsia
`In this paper by K E L McColl and colleagues
`(27 April, pp 999›1002), we inadvertently
`published the wrong date for when we finally
`accepted the paper for publication. The correct
`acceptance date was 20 December 2001 [not
`2 February 2002].
`A time for global health
`In this editorial by Richard Smith (13 July,
`pp 54›5), we managed to mangle a currency
`conversion. In the second sentence of the third
`paragraph, $119bn is £76bn (exchange rate at time
`of writing this correction), not £158bn, which is
`patently wrong, even with the recent shifting
`exchange rates. We should also have followed our
`policy, in place since 1 January 2002, of including a
`conversion to euros (which would be &121bn).
`
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