Management of acne
`
`John Kraft MD, Anatoli Freiman MD
`
`A cne vulgaris has a substantial impact on a patient’s
`
`quality of life, affecting both self-esteem and psychoso-
`cial development.1 Patients and physicians are faced
`with many over-the-counter and prescription acne treatments,
`and choosing the most effective therapy can be confusing.
`In this article, we outline a practical approach to managing
`acne. We focus on the assessment of acne, use of topical
`treatments and the role of systemic therapy in treating acne.
`Acne is an inflammatory disorder of pilosebaceous units
`and is prevalent in adolescence. The characteristic lesions are
`open (black) and closed (white) comedones, inflammatory
`papules, pustules, nodules and cysts, which may lead to scar-
`ring and pigmentary changes (Figures 1 to 4). The pathogene-
`sis of acne is multifactorial and includes abnormal follicular
`keratinization, increased production of sebum secondary to
`hyperandrogenism, proliferation of Propionibacterium aches
`and inflammation.2,3
`Lesions occur primarily on the face, neck, upper back and
`chest? When assessing the severity of the acne, one needs to
`consider the distribution (back, chest, upper arms), type and
`number of lesions (comedones, papules, pustules, nodules) and
`the presence or absence of scarring (Table 1)),3
`Different variants of acne exist, including acne conglobata,
`acne fulminans, acne mechanica, excoriated acne, chloracne,
`drug-induced acne (e.g., from anabolic steroids, corticos-
`teroids, isoniazid, lithium, phenytoin), neonatal and infantile
`acne, and occupational acne. These variations have a similar
`clinical and histologic appearance to acne vulgaris, but they
`are distinguishable by clinical setting, severity and associated
`symptoms. The common differential diagnosis of acne
`includes folliculitis, keratosis pilaris, perioral dermatitis, seb-
`orrheic dermatitis and rosacea.
`
`Is there an underlying cause?
`
`The diagnosis of acne vulgaris is primarily clinical? History
`and physical examination can help determine if there is an
`underlying cause of the acne, such as an exacerbating medica-
`tion or endocrinologic abnormality causing hyperandro-
`genism (e.g., polycystic ovarian syndrome). Other dermato-
`logic manifestations of androgen excess include seborrhea,
`hirsutism and androgenetic alopecia. Endocrinologic testing is
`not ordered routinely for women with regular menstrual
`~" cycles)~ Older women, especially those with new-onset acne
`and other signs of androgen excess (e.g., hirsutism, andro-
`genic alopecia, menstzual irregularities, infertility), should be
`= tested for androgen excess with measurements of total and
`free serum testosterone, dihydroepiandrosterone, and luteiniz-
`
`Key points
`¯ Effective therapies for acne target one or more pathways
`in the pathogenesis of done, and combination therapy
`gives better results than monotherapy.
`¯ Topical therapies are the standard of care for mild to
`moderate ache.
`¯ Systemic therapies are usually reserved for moderate or
`severe done, with a response to oral antibiotics taking up
`to six weeks.
`¯ Hormonal therapies provide effective second-line
`treatment in women with done, regardless of the presence
`or absence of androgen excess.
`
`ing and follicle-stimulating hormone levels.’ Pelvic ultra-
`sonography may show the presence of polycystic ovaries.’ In
`prepubertal children with acne, signs of hyperandrogenism
`include early-onset accelerated growth, pubic or axillary hair,
`body odour, genital maturation and advanced bone age.
`Treatment for acne vulgaris should aim to reduce severity
`and recurrences of skin lesions as well as to improve appear-
`ance. The approach depends on the severity of the acne, the
`treatment preferences and age of the patient, and adherence and
`response to previous therapy (Table 2)?,6 Various acne tzeat-
`ments target different steps in the pathogenesis of acne, from
`counteracting androgens and decreasing sebum production to
`preventing follicular occlusion, reducing P. aches proliferation
`and decreasing inflammation.
`Many research studies on acne therapies are small trials
`comparing the active drug with placebo or larger studies com-
`paring different formulations of the same drag.
`
`How well do topical treatments work?
`
`Topical therapy is the standard of care for mild to moderate
`acne? Retinoids and antimicrobials such as benzoyl peroxide
`and antibiotics are the mainstay of topical acne therapy. Such
`treatments are active at application sites, and they can prevent
`new lesions? The main side effect is local irritation. Gels,
`pledgets (medication-soaked pads), washes and solutions tend
`to be drying and are helpful for oily skin. Lotions, creams and
`oint~nents are beneficial for dry, easily irritated skin. Most top-
`ical preparations require at least six to eight weeks before an
`improvement is seen; they may be used for years as needed?
`
`From the Division of Dermatology, University of Toronto, Toronto, Ont.
`
`CMAJ20ll. DOI:10.1503/cmaj.090374
`
`E430 CMAJ ¯ APRIL 19, 2011 . 183(7)
`© 2011 Canadian Medical Association or its licensors
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`Almirall EXHIBIT 2024
`Amneal v. Almirall
`IPR2018-00608
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`Retinoids
`The main target of acne treatment is the microcomedone. Topi-
`cal retinoid therapy acts on follicular keratinocytes to prevent
`excessive comification and follicular blockage? It may also
`reduce the release of proinflaxrkrnatory cytokines. Such therapy
`decreases the number of comedones and inflammatory lesions
`by 40% to 70%.2 The most common side effect is irritation with
`erythema and scaling. Patients should be instructed to apply
`very small amounts initially. Optimal response occurs after 12
`weeks.7 Continuous maintenance therapy can prevent flares2
`The most commonly available topical retinoids are
`tretinoin, adapalene and tazarotene. A meta-analysis of five
`multicentre randomized investigator-blind trials involving
`900 patients showed adapalene 0.1% gel to be as effective as,
`but less irritating than, tzetinoin 0.025% gel.° Different con-
`centrations of retinoids affect tolerability. One commonly
`used approach is to start with the lowest concentration and
`increase as tolerated.
`
`Antim icrobials
`Topical antimicrobials, including benzoyl peroxide and antibi-
`otics, are effective in treating inflammatory disease.3,4 Benzoyl
`peroxide is a bactericidal agent that prevents the resistance of
`P. aches to antibiotic therapy9 and has moderate comedolytic
`and anti-inflammatory properties. It is available in various top-
`ical preparations, ranging in strength from 2.5% to 10.0%.
`Any strength can be used initially, although it may be more
`prudent to start with a lower concentration; stronger prepara-
`tions are more irritating and not necessarily more effective.I°
`Benzoyl peroxide kills P. aches by releasing oxygen within
`the follicle. It can be fast-acting, with a response as early as
`five days? The main drawback is that it is a potent bleaching
`
`Figure 1: Grade I (mild) acne showing comedones with few
`inflammatory papules and pustules,
`
`Figure 3: Grade III (moderately severe) acne showing numer-
`ous large painful nodules and pustules as well as some
`inflamed nodules.
`
`Figure 2: Grade II (moderate) acne showing papules and pustules,
`
`Figure 4: Grade IV (severe) acne showing many large inflamed
`nodules and pustules as well as scarring.
`
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`agent? Patients should be warned that fabrics that come in
`contact with benzoyl peroxide, including towels, bed sheets
`and clothing, may be bleached.
`Topical erythromycin and clindamycin are generally well-
`tolerated and have been shown to reduce inflammatory lesions
`by 46% to 70% in several randomized controlled trials?
`Monotherapy with topical antibiotics should not be used rou-
`tinely beause P. aches may become resistant within one month
`after daily treatment has begun.6 Some argue that this resis-
`tance is not relevant because the antibiotics (e.g., clindamycin,
`tetracyclines, erythromycin) also have intrinsic anti-inflamma-
`tory and antimicrobial effects.11 However, antibiotic-resistant
`Staphylococcus epidermidis and Staphylococcus aureus may
`also develop with monotheraw; resistance can be avoided
`when a topical antibiotic is combined with benzoyl peroxide.1~ When should systemic therapy be started?
`
`zinc, resorcinol, sulfur and aluminum chloride is also either
`limited or negative.
`There is no clear evidence that acne vulgaris is related to
`poor hygiene or that frequent face washing lessens acne.
`Patients should be instructed to wash their face gently with
`warm water and mild soap twice daily; rough scrubbing can
`cause new lesions because of follicular rupture. The only
`antibacterial soaps that may be effective are those containing
`benzoyl peroxide.19
`Patients should ensure that their facial products, includ-
`ing sunscreens, are noncomedogenic. They should also
`avoid oil-based makeup. Some topical acne products contain
`a sunscreen.
`
`Patients with mild acne can be treated with topical therapies;
`however, those with moderate to severe acne will require sys-
`temic therapy. Oral antibiotic treatment, hormonal therapies
`and isotreretinoin are the mainstay systemic therapies for
`acne.
`
`Combination therapy
`Combination therapy, for example with retinoids and antibi-
`otics, is more effective than either agent used alone.13 However,
`the agents should be applied at separate times, unless they are
`known to be compatible? Benzoyl peroxide may oxidize a
`retinoid such as tretinoin if it is applied simultaneously.14 A 12-
`Antibiotics
`week randomized controlled trial involving 249 patients with
`mild to moderate ache showed treatment with adapalene gel When topical agents are insufficient or not tolerated, or in
`0.1% and clindamycin 1.0% to be superior to that with clin-
`cases of moderate to severe acne, especially when the chest,
`damycin 1.0¼ used alone. If inflammatory lesions axe present,
`back and shoulders are involved, systemic antibiotics are
`topical antibiotics containing benzoyl peroxide should be corn-
`often considered the next line of treatment (Table 3)?°’~1 How-
`bined with a topical retinoid (e.g., topical antibiotic with ben-
`ever, regular use of a combination of topical antibiotics and
`benzoyl peroxide may be similarly effective, as shown in a
`zoyl peroxide in the morning and retinoid at night). A review of
`three clinical studies with 1259 patients showed that a combi-
`randomized controlled trial of five antimicrobial regimens)2
`nation of clindamycin 1% and benzoyl peroxide 5% was more
`Response to oral antibiotics is usually seen after at least six
`effective than either drug used alone in reducing lesions and
`weeks of therapy? If control is maintained for several months,
`suppressing P. aches.1~
`the antibiotic may be discontinued gradually and only the top-
`ical theraW continued. Systemic antibiotics should not be
`used to treat mild acne because of the risk of increasing resis-
`tance?3,~ The additional use of nonantibiotic topical agents in
`combination with oral antibiotics should be considered? Topi-
`cal retinoids with oral antibiotics may give a faster response
`and be more effective than either drug used alone?
`Treatment with tetracyclines and erythromycin reduces P.
`aches within the follicles, thereby inhibiting production of
`bacterial-induced inflammatory cytokines?’ These agents also
`have inherent anti-inflammatory effects, such as suppressing
`
`o
`
`15
`
`Over-the-counter therapy
`Before seeing a physician, patients frequently use over-the-
`counter therapies for their acne. Such treatments may be more
`accessible, cosmetically elegant, less expensive and less irri-
`tating than prescription therapies.17 However, there is insuffi-
`cient evidence to evaluate and compare the efficacy of over-
`the-counter formulations)
`The most popuDx over-the-counter products, such as Proactiv,
`contain benzoyl peroxide but at lower concentrations than most
`prescription-strength products. Proactiv, a system of cleansing
`products in which benzoyl peroxide 2.5% is the active ingredi-
`ent, is claimed to enhmace compliance by providing a cosmeti-
`cally elegant product that also minimizes irritation. The makers
`of Proactiv also market Gentle Formula, which replaces benzoyl
`peroxide with salicylic acid for people with allergy or intoler-
`mace. There have been few studies assessing the efficacy of the
`Proactiv system. In one open-label study of 23 patients with mild
`to moderate acne, inflammatory lesions were reduced by 39% in
`patients using a combination of butenifme (an allylamine) and
`benzoyl peroxide compm:ed with 34% in those using Proactiv.18
`Salicylic acid 2% wash is moderately effective but less
`potent than a topical retinoid in acne therapy. Although it has
`been used for many years, well-designed trials of its safety
`and efficacy are lacking. The evidence for the use of topical
`
`Table 1: Grading severity of ache2’3
`
`Grade
`
`Severity
`
`Clinical findings
`
`I
`
`II
`
`III
`
`Mild
`
`Moderate
`
`Moderately
`severe
`
`IV
`
`Severe
`
`Open and closed comedones
`with few inflammatory papules
`and pustules
`Papules and pustules, mainly on
`face
`Numerous papules and pustules,
`and occasional inflamed nodules,
`also on chest and back
`Many large, painful nodules and
`pustules
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`leukocyte chemotaxis and bacterial lipase activity. Minocy-
`cline and doxycycline also inhibit cytokines and matrix met-
`alloproteinases that are thought to promote inflammation and
`tissue breakdown.26 Although P. acnes has a resistance rate to
`telxacyclines of 20% to 60%, it is uncertain if this is signifi-
`cant in the treatment of acne.27’~8
`Oral antibiotics have been shown to be effective in reducing
`the number of inflammatory lesions (52% to 67% reduction),
`but fiais is based on limited evidence2 Higher doses can be tried
`if a patient seeks better control. Doxycycline and minocycline
`are considered more effective than tetxacyclineY Eryfilromycin
`is reserved for patients in whom telxacyclines are contxaindi-
`cated (e.g., pregnant women and children under nine years of
`age), alfilough the development of resistance to eryfilromycin is
`more common than with the other antibiotics. ~
`
`Hormonal therapies
`Hormonal agents provide effective second-line treatment in
`women with acne regardless of underlying hormonal abnor-
`malities2° It is not necessary to demonstrate androgen excess
`to achieve a benefit from antiandrogen therapy. Clinical
`observation suggests that deep-seated nodules on the lower
`face and neck are especially responsive to hormonal therapy¢
`
`Table 2: Approach to therapy for ache vulgaris3’6
`
`Severity;
`clinical findings
`
`Mild
`
`Comedonal
`
`Papularlpustular
`
`Moderate
`
`Treatment options
`
`First line
`
`Second line
`
`Topical retinoid
`
`Topical retinoid
`Topical antimicrobial
`¯ benzoyl peroxide
`¯ clindamycin
`¯ erythromycin
`Combination products
`
`Alternative topical retinoid
`S a l i cyli c a c i d w a s h e s
`Alternative topical retinoid
`plus alternative topical
`antimicrobial
`Salicylic acid washes
`
`Clinical trials have shown that estrogen-containing oral
`contraceptives can be helpful;313~ the various formulations are
`thought to decrease levels of free testosterone by increasing
`sex-hormone-binding globulin and are considered equally
`effective. The choice of combined oral contraceptive should
`be based on a patient’s tolerance and potential side effects. It is
`not known whefiler other estxogen-containing contraceptives
`(e.g., vaginal rings, txansdermal patches) are effective. Contxa-
`ceptives containing only progesterone may worsen acne.4
`A randomized controlled trial with 128 women showed a
`reduction in acne lesions of 63% with 35 gg ethinylestradiol
`and 3 mg drospirenone and a 59% reduction with 35 gg
`efilinyleslxadiol and 2 mg cyproterone acetate24 Antiandrogen
`filerapy is usually needed for at least fiaree to six monfils to see
`significant improvement.
`The oral antiandrogen spironolactone can be added if oral
`contraceptives are not effective/Spironolactone is a 5c~-reduc-
`tase inhibitor when administered at higher doses/’ Spironolac-
`tone, used alone or as an adjunct at doses of 50-200 mg/d, has
`been shown to be effective in improving acne, but fiais is based
`on limited evidence.~ However, patients should be warned about
`possible side effects, including hyperkalemia, menstrnal irregu-
`larities and feminization of a male fetus. Antio~drogen filerapy
`alone may be successful, but in less than
`half of women;~ the acne may recur when
`it is discontinued. Combination therapy
`with topical agents or oral antibiotics pro-
`vides substantially more benefit/7
`
`Isotretinoin
`Isotretinoin affects all causative mecha-
`nisms of acne -- it changes abnormal fol-
`liculox keratinization, decreases sebum pro -
`duction by 70%, decreases P. acnes
`colonization and is anti-inflammatory28
`Indications for isotxetinoin include scarring
`disease, severe nodulocystic acne and less
`than 50% improvement with oral antibi-
`otics or hormonal therapies after four
`months.~ Isotretinoin therapy must be
`monitored carefully because adverse
`effects include potent teratogenicity,
`hypertriglyceridemia and pancreatitis,
`hepatoxicity, blood dyscrasias, hyperosto-
`sis, premature epiphyseal closure and night
`blindness. An association with severe skin
`reactions, such as erythema multiforme,
`Stevens-Johnson syndrome and toxic epi-
`dermal necrolysis, has been reported29
`Although a causal relationship has not
`been shown, patients must be warned
`about depression, suicidal thoughts and
`psychosis, and monitored closely.4°
`Before a patient starts oral isotzetinoin
`therapy, baseline blood work is recom-
`mended.~ This testing includes serum
`blood lipid measurements, complete
`blood count and differential, liver
`
`Papular/pustular Oral antibiotics Alternative oral antibiotic
`¯ tetracyclines Alternative topical retinoid
`¯ erythromycin
`Benzoyl peroxide
`¯ trimethoprim-
`sulfamethoxazole
`Topical retinoid
`_+ benzoyl peroxide
`Oral antibiotic
`
`Oral isotretinoin
`
`Nodular
`
`Topical retinoid Alternative oral antibiotic
`_+ benzoyl peroxide Alternative topical retinoid
`
`Severe
`
`Oral isotretinoin
`
`Benzoyl peroxide
`High-dose oral antibiotic
`Topical retinoid (also
`maintenance therapy)
`Benzoyl peroxide
`
`Note: In women with acne, oral contraceptives or androgen receptor blockers (e.g., spironolactone)
`may be used in addition to the above treatment options,
`
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`ing acne.3 One clinical trial showed that topical tea tree oil
`was effective but had a slower onset of action than traditional
`topical agents?3 The Cochrane Collaboration is undertaking a
`systematic review of the effects of treatments in the manage-
`ment of acne that are currently considered complementary or
`altemative.
`
`enzyme tests and blood glucose levels (and a pregnancy test
`for women of child-bearing age).41 These tests should be
`repeated at monthly intervals during treatment. In women of
`childbearing age, two forms of birth control should be used
`during and for one montJ~ after therapy, unless the patient has
`had a hysterectomy or is sexually abstinent.41
`Cutaneous side effects of isotretinoin include dry eyes,
`nose and lips, and dermatitis. Patients should use artificial What physical treatments are available?
`tears, and generous amounts of moisturizer on the nose, lips
`and skin.
`According to a 10-year follow-up study of 88 patients,
`those who had received a cumulative dose of isotreretinoin
`120-150 mg/kg had a substantially lower rate of recurrence
`(30%) than those who received less than 120 mg/kg (82%).42
`An additional course can be prescribed for patients in whom
`the acne recurs after isotretinoin is discontinued,
`
`Physical treatments for acne include comedone extraction,
`chemical peels and microdermabrasion, intralesion cortico-
`steroid injection for acne cysts, and high-intensity, narrow-
`band blue light photodynamic fl~erapy, as well as injectable
`fillers and laser resurfacing for acne scarring. However, there
`is limited evidence in peer-reviewed literature to support such
`treatments.~’~ The results of small pilot studies have supported
`the use of chemical peels,4’ and some evidence suggests that
`corticosteroid injections are helpful for treating large inflam-
`matory lesions?6
`
`What about alternative therapies?
`
`Herbal therapies such as tea tree oil, and topical and oral
`ayurvedic compounds seem to be well tolerated; however,
`there are limited data about their efficacy and safety in treat-
`
`Table 3: Oral antibiotic therapy for acne vulgaris2°’2~
`
`Notes
`
`How should children and pregnant women
`be treated?
`
`The treatment of acne in children is similar to that in adults.
`Because topical fl~erapies may be more irritating in children, ini-
`tiation witJ~ low concentrations is preferred. Systemic treatments
`should be reserved for more extensive cases. Eryfllromycin is
`preferred over tetzacyclines for children under nine years of age,
`because tetzacyclines can affect growing cartilage and teeth.
`Although treatment with isotzetinoin has numerous poten-
`tial minor side effects in patients of all ages, an uncommon
`complication in young patients is premature epiphyseal clo-
`sure28 This generally occurs when isotretinoin is administered
`in high doses, tJms limiting long-term therapy.
`Selecting appropriate treatment in pregnant women can be
`challenging because many acne therapies are teratogenic; all
`topical and especially oral retinoids should be avoided.~8 Oral
`therapies such as tetracyclines and antiandrogens are also
`contraindicated in pregnancy. Topical and oral treatment with
`eryflaromycin may be considered.
`
`¯ Inexpensive
`¯ Contraindicated in pregnant women
`or in children under nine years of age
`¯ Chelated by antacids and milk; to be
`taken on empty stomach
`¯ Can be taken with food
`¯ Contraindicated in pregnant women
`or in children under nine years of age
`¯ Adverse reactions: dizziness, pigment
`changes, hepatitis, lupus-like
`reactions
`¯ Can be taken with food
`¯ Acceptable for use in patients with
`renal failure
`¯ Contraindicated in pregnant women
`or in children under nine years of age What’s new in treating acne?
`¯ Adverse reactions: gastrointestinal
`upset; phototoxicity (greatest of all
`tetracyclines)
`¯ Safe in pregnantwomen and
`children
`¯ Adverse reaction: may cause
`gastrointestinal upset
`¯ 42% of patients may show resistance
`to Propionibacterium acnes~8
`¯ Useful in patients resistant to other
`antibiotics
`¯ Adverse reactions: 3%-4% of
`patients experience rash;2~ risk of
`serious skin reactions, such as
`Stevens-Johnson syndrome
`
`Trials are being conducted with currently available fl~erapies,
`in different strengths and combinations. Combining an ally-
`lamine antifungal agent with benzoyl peroxide may prove to
`enhance the effectiveness of benzoyl peroxide in treating acne
`while preventing antibiotic resistance.18 Topical dapsone 5%
`gel is a newer option for treating acne. A large multicentre
`randomized controlled trial in adolescents with acne found
`that when the gel was applied twice daily on the affected
`areas, 40% of the treatment group and 28% of the placebo
`group (p < 0.001) achieved the desired outcome at 12 weeks.47
`The same trial and an additional study found that topical dap-
`sone 5% gel is a safe treatment option in patients with a deft-
`ciency in glucose-6-phosphate dehydrogenase?~
`More studies are needed to resolve tJ~e long-standing con-
`
`Anti biotic, dose
`
`Tetracycline
`250-500 mg twice
`daily
`
`Minocycline
`50-200 mg daily
`
`Doxycycline
`100-200 mg daily
`
`Erythromycin
`500 mg twice daily
`
`Trimethoprim/
`sulfamethoxazole
`80/400 mg or
`160/800 mg four
`times a day
`
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`txoversy about the role of diet and acne. As well, furflaer direct
`treatment comparison and long-term trials are needed to deter-
`mine the optimal sequence of treatment selection as well as to
`establish flae effects on quality of life and long-term efficacy.
`
`This review- was solicited and has been peer reviewed,
`
`Competing interests: None declared.
`
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