Treatment of Acne Vulgaris

Home , Adapalene, Azelaic acid, Benzoyl peroxide, Clindamycin, Erythromycin, Isotretinoin

CLINICAL REVIEW CLINICIAN’S CORNER

Aamir Haider, MD, PharmD Context Management of acne vulgaris by nondermatologists is increasing. Current James C. Shaw, MD, FRCPC understanding of the different presentations of acne allows for individualized treatments and improved outcomes. HE MANAGEMENT OF ACNE VUL- Objective To review the best evidence available for individualized treatment of acne. garis by nondermatologists is Data Sources Search of MEDLINE, EMBASE, and the Cochrane database to search increasing.1In this article we at- for all English-language articles on acne treatment from 1966 to 2004. tempt to answer the question: Twhat treatments in acne vulgaris have Study Selection Well-designed randomized controlled trials, meta-analyses, and proven efficacy and how are these treat- other systematic reviews are the focus of this article. ments best administered and individu- Data Extraction Acne literature is characterized by a lack of standardization with alized to optimize results and mini- respect to outcome measures and methods used to grade disease severity. mize complications? We considered the Data Synthesis Main outcome measures of 29 randomized double-blind trials that efficacy and safety of topical retinoids, were evaluated included reductions in inflammatory, noninflammatory, and total acne topical antimicrobials, systemic anti- lesion counts. Topical retinoids reduce the number of comedones and inflammatory biotics, hormonal treatments for lesions in the range of 40% to 70%. These agents are the mainstay of therapy in patients with comedones only. Other agents, including topical antimicrobials, oral anti- women, and oral isotretinoin. biotics, hormonal therapy (in women), and isotretinoin all yield high response rates. METHODS Patients with mild to moderate severity inflammatory acne with papules and pustules should be treated with topical antibiotics combined with retinoids. Oral antibiotics are A librarian-assisted literature search was first-line therapy in patients with moderate to severe inflammatory acne while oral isotreti- performed for English-language ran- noin is indicated for severe nodular acne, treatment failures, scarring, frequent re- domized clinical trials. We used lapses, or in cases of severe psychological distress. Long-term topical or oral antibiotic MEDLINE and EMBASE to identify all therapy should be avoided when feasible to minimize occurrence of bacterial resis- therapeutic clinical trials, meta- tance. Isotretinoin is a powerful teratogen mandating strict precautions for use among analyses, and systematic analyses con- women of childbearing age. cerning acne vulgaris from 1966 to 2004. Conclusions Acne responses to treatment vary considerably. Frequently more than We further cross-referenced bibliogra- 1 treatment modality is used concomitantly. Best results are seen when treatments phies of identified articles. This search are individualized on the basis of clinical presentation. strategy identified 248 articles. We then JAMA. 2004;292:726-735 www.jama.com evaluated titles and abstracts, and excluded studies that were not blinded, palene, clindamycin, erythromycin, A recent methodological literature re- were not randomized, had sample sizes tetracycline, azelaic acid, benzoyl perox- view of acne therapy trials over the last of fewer than 50, did not provide ad- ide, minocycline, doxycycline, trimetho- 50 years found that methods of grad- equate information with respect to ob- prim-sulfamethoxazole, flutamide, spi- ing acne severity and methods of assess- jective outcomes measures, contained no ronolactone, cyproterone-acetate, oral ing outcome measures are highly incon- original data, pertained to treatments contraceptives, isotretinoin, clinical trials, that are not available, did not involve hu- Author Affiliations: Division of Dermatology, Uni- review, therapy, treatment, and random- versity of Toronto, Toronto, Ontario. mans, or were therapeutic failures. We ized controlled trials. Financial Disclosure: Dr Shaw has received hono- used the following search words: acne We identified 29 randomized double- raria from Galderma and from Berlex and owns shares vulgaris, acne, tretinoin, tazarotene, ada- in Allergan Pharmaceuticals. blind trials, which comprise the focus Corresponding Author: James C. Shaw, MD, FRCPC, of this article. Where possible, data con- University Health Network, Toronto Western Hospi- tal, 399 Bathurst St, East Wing 8-517, Toronto, On- See also Patient Page. cerning responses to treatment were put tario, Canada M5T 2S8 ([email protected]). in terms of percent reduction of inflam- Section Editor: Michael S. Lauer, MD, Contributing CME available online at matory lesions, noninflammatory le- Editor. We encourage authors to submit papers for www.jama.com consideration as a Clinical Review. Please contact sions (comedones), and total lesions. Michael S. Lauer, MD, at [email protected].

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sistent.2 There are more than 25 methods microspere gel, or 0.05% cream.6-9 Taz- intrafollicular P acnes.17 Our discus- of assessing acne severity and more than arotene 0.1% gel had proven efficacy in sion focuses on 5 well-designed, ran- 19 methods for counting lesions. Our lit- an RCT showing 52% total acne reduc- domized, double-blind trials assessing erature review verifies the lack of stan- tion of total lesions compared with 33% the effectiveness of topical antibiotics dardized of methodology. Neverthe- with vehicle.10 Tretinoin was com- in acne. Newer formulations have been less, analysis of acne therapy data does pared with tazarotene in a 12-week RCT studied most rigorously. allow conclusions to be drawn that can with 169 patients.11 Tazarotene 0.1% gel Original placebo-controlled RCTs direct therapeutic decisions. produced reductions in acne severity of with clindamycin and erythromycin In addition to the randomized con- 36% vs 26% with tretinoin 0.1% gel showed a 46% to 70% reduction in in- trolled trials (RCTs), we reviewed se- (P=.02). In another comparison trial, flammatory lesions18-21 (Table 1). In an- lected articles that included data col- tazarotene 0.1% gel was more effec- other RCT, an erythromycin–4%-zinc lected or analyzed after the trial, tive than tretinoin 0.025% gel in re- combination reduced inflammatory le- including meta-analyses and other sys- ducing noninflammatory lesion counts sions by 85% vs a 46% reduction using tematic reviews. We also mention se- (55% vs 42%; P=.042) and equally ef- 2% erythromycin alone (PϽ.001).22 Re- lected non-RCTs when they represent fective in reducing inflammatory le- cent interest has centered around com- best evidence concerning established sions.12 In a multicenter RCT, ada- binations of topical antimicrobials with therapies that have not yet been stud- palene 0.1% cream demonstrated a 38% benzoyl peroxide or retinoids. Support ied in well-designed RCTs. reduction in total lesion counts vs 20% for combining erythromycin or clinda- with vehicle.13 In a 12-week RCT with mycin with benzoyl peroxide includes Pathophysiology 145 patients tazarotene 0.1% gel was a randomized, 10-week, multicenter, The origin of acne vulgaris is complex significantly better than adapalene single-blind trial that enrolled 492 pa- and incompletely understood. At least 0.1% gel in terms of mean reductions tients in which treatment with the com- 4 pathophysiologic events take place in overall disease severity (44% vs 24%; bination products used twice daily was within acne-infected hair follicles: PϽ.001), noninflammatory lesion more effective than benzoyl peroxide (1) androgen-mediated stimulation of count (71% vs 48%; PϽ.0001), and in- alone.23 Additionally, a review of 3 clini- sebaceous gland activity, (2) abnormal flammatory lesion count (70% vs 55%; cal studies involving 1259 patients con- keratinization leading to follicular P=.0002).14 Alternate-day application cluded that the combination of clinda- plugging (comedo formation), (3) pro- of tazarotene 0.1% gel was equally ef- mycin 1% benzoyl–peroxide 5% was liferation of the bacterium Propioni- fective to daily adapalene 0.1% gel in a more effective than either drug used bacterium acnes within the follicle, and 15-week RCT15 (Table 1). alone in reducing lesions and suppress- (4) inflammation. In addition to these Tretinoin, is available as a gel (0.01% ing P acnes.24 In 2 RCTs 334 patients 4 basic mechanisms, genetic factors,3 and 0.025%), cream (0.025%, 0.05%, were treated once nightly with either a stress,4 and possibly diet may influence and 0.1%), and liquid (0.05%). Cuta- combination clindamycin–benzoyl per- the development and severity of acne.5 neous erythema, peeling, and edema oxide gel, benzoyl peroxide alone, clin- with tretinoin are dose-related adverse damycin alone, or vehicle25 (Table 1). Af- TREATMENT OF effects. Adapalene 0.1% is available as ter 11 weeks, 66% of patients in the ACNE VULGARIS a cream, gel, and solution, all with simi- clindamycin and benzoyl peroxide group Topical Retinoids lar efficacy.16 Tazarotene is available as experienced a good or excellent re- Retinoids, first shown in the 1970s to 0.1% cream or gel formulations. sponse compared with 41% in the ben- be of value for treating acne, are de- In summary, all topical retinoids ef- zoyl peroxide group, 36% in the clin- rivatives of vitamin A that prevent com- fectively reduce the number of com- damycin group, and 10% in the vehicle edone formation by normalizing des- edones and inflammatory lesions in the group. A similar 16-week trial showed quamation of follicular epithelium. The range of 40% to 70% (Table 1). Ada- a 53% lesion reduction with clindamy- 3 main topical retinoids are tretinoin, palene is less likely to cause skin irri- cin 1% benzoyl–peroxide 5% vs 28% adapalene, and tazarotene. tation and is better tolerated than treti- with clindamycin alone (P=.013).26 Tretinoin has long been considered noin or tazarotene, but tazarotene Combining topical antibiotics with the gold standard with which new prod- appears to be most efficacious. topical retinoids is also effective. Ada- ucts are compared. A meta-analysis of palene gel 0.1% plus clindamycin 1% 5 multicenter randomized investigator- Topical Antimicrobials was studied in a 12-week RCT involv- blinded trials involving 900 patients6 Currently available topical antimicro- ing 249 patients with mild to moder- confirmed that total lesion counts re- bials include clindamycin, erythromy- ate acne. A significantly greater reduc- duced by 53% with tretinoin 0.05% gel cin, tetracycline, and benzoyl perox- tion in total (PϽ.001), inflammatory and 57% with adapalene 0.1% gel ide. Azelaic acid may also be considered (P=.004), and noninflammatory le- (TABLE 1). Adapalene gel causes less ir- within this group because it has dem- sions (PϽ.001) was seen in the clinda- ritation than tretinoin 0.05% gel, 0.1% onstrated antibacterial activity against mycin-plus-adapalene group than in the

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Table 1. Clinical Trials in Topical Acne Therapy Length of Reduction in Lesions, % No. of Treatment, Source Patients Study Type wk Type of Acne* Treatment Inflammatory Noninflammatory Total Topical Retinoids Cunliffe et al,6 900 Meta-analysis 12 Mild to moderate Adapalene 0.1% gel 52 58 57 1998 facial acne Tretinoin 0.025% gel 51 52 53 Shalita et al,10 446 Randomized, 12 Mild to moderate Tazarotene 0.1% gel 42 55 52 1999 double-blind, facial acne Tazarotene 0.05% gel 39 45 44 placebo- Vehicle 30 35 33 controlled, multicenter Leyden et al,11 169 Randomized, 12 Mild to moderate Tazarotene 0.1% gel 56 60 ... 2002 double-blind, facial acne Tretinoin 0.1% gel 46 38 multicenter Webster 143 Randomized, 12 Mild to moderate Tazarotene 0.1% gel 54 55 ... et al,12 double-blind, facial acne Tretinoin 0.025% gel 44 42 2001 multicenter Lucky et al,13 237 Randomized, 12 Mild to moderate Adapalene 0.1% cream 36 38 38 2001 double-blind, facial acne Vehicle 19 20 20 multicenter Webster 145 Randomized, 12 Mild to moderate Tazarotene 0.1% gel 70 71 ... et al,14 double-blind, facial acne Adapalene 0.1% gel 55 48 2002 multicenter Leyden et al,15 164 Randomized, 15 Mild to moderate Adapalene 0.1% gel 54 58 ... 2001 double-blind, facial acne Tazarotene 0.1% gel† 57 55 multicenter Topical Antimicrobials Becker et al,18 358 Randomized, 8 Mild to moderate Clindamycin phosphate 66 ...... 1981 double-blind, acne Clindamycin hydrochloride 63 placebo- Vehicle 42 controlled, multicenter Dobson and 253 Randomized, 12 Mild to moderate Erythromycin 1.5% solution 70 26 40 Belknap,19 double-blind, acne Vehicle 5 55 30 1980 multicenter, placebo- controlled Lesher et al,20 225 Randomized, 12 Mild to moderate Erythromycin 2% 46 ...... 1985 double-blind, acne Vehicle 19 multicenter, placebo- controlled Jones and 156 Randomized, 12 Moderate to Erythromycin 2% 51 ...... Crumley,21 double-blind severe facial Vehicle 33 1981 acne Habbema 122 Randomized, 12 Moderate to Erythromycin–4%-zinc solution 85 68 ... et al,22 double-blind, severe facial Erythromycin 2% lotion 46 49 1989 multicenter acne Lookingbill 334 Randomized, 11 Mild to moderate Clindamycin–1%/BP 5% gel 61 36 ... et al,25 double-blind, facial acne Clindamycin–1% gel 35 9 1997 placebo- BP 5% gel 39 30 controlled, Vehicle 5 0 multicenter Cunliffe et al,26 79 Randomized, 16 Mild to moderate Clindamycin–1% plus/BP 5% gel ...... 53 2002 double-blind facial acne Clindamycin–1% 28 Oral and Topical Treatments Katsambas 92 Randomized, 12 Moderate acne Azelaic acid 20% 72 56 ... et al,33 double-blind, Placebo 47 0 1989 placebo- controlled Hjorth and 333 Randomized, 20 Moderate to Azelaic acid 20% 83 ...... Graupe,34 261 double-blind, severe acne; Oral tetracycline 86 1999 multicenter 24 Moderate to Azelaic acid 20% 79 severe acne Oral tetracycline 79 Abbreviation: BP, benzoyl peroxide; ellipses, data were not reported in the trial. *For an example of acne severity, see the Figure. †Therapy is taken on alternate days.

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clindamycin-plus-vehicle group.27 cline vs 67% with erythromycin and a likely than tetracycline to cause pho- Other trials with clindamycin- reduction in noninflammatory lesion tosensitivity.46 Doxycycline can be taken tretinoin and erythromycin-tretinoin counts by 34% with tetracycline vs 22% with food. Tetracyclines should not be have shown similar results.28-32 with erythromycin (TABLE 2). In an- taken immediately before sleep be- Azelaic acid 20%, in an RCT that en- other comparison trial topical clinda- cause the pills may lodge in the esopha- rolled patients with moderate acne re- mycin 1% showed a 72% reduction vs gus and cause ulceration. sulted in a 72% reduction of inflam- a 57% reduction using oral tetracycline Minocycline is prescribed in a dosage matory lesions vs 47% with placebo.33 and a 12% reduction with placebo.41 range of 50 to 100 mg twice daily. Ad- Two RCTs compared oral tetracycline Doxycycline was recently studied in verse effects include vertigo, dizziness, with topical azelaic acid 20%.34 Reduc- a RCT in which 51 patients received ataxia, and rarely a bluish discoloration tions in inflammatory lesion counts either a submicrobicidal dose (20 mg of the skin.46 Minocycline has also been were 83% for azelaic acid and 86% for twice daily) for 6 months or placebo. reported to be associated with drug in- oral tetracycline in one study and 79% Mean reduction in total lesions was 52% duced lupus, autoimmune hepatitis, and for both drugs in another (Table 1). The with doxycycline vs 18% with placebo a hypersensitivity syndrome.47 The rela- efficacy of azelaic acid in mild to mod- (PϽ.01; Table 2).42 Even low doses of tive risk of developing a lupuslike syn- erate acne matches that of tretinoin doxycycline may be effective by inhibi- drome with minocycline is 8.5 (95% con- 0.05%, benzoyl peroxide 5%, or topi- tion of collagenases including matrix fidence interval [CI], 2.1-35.0) compared cal erythromycin 2%.17 metalloproteinases.39 Doxycycline is fre- with 1.7 (95% CI, 0.4-8.1) for other Adverse effects of topical antibiotics quently dosed at 100 mg/d for acne treat- tetracyclines.48 include erythema, peeling, dryness, and ment although best evidence for those Antibiotic-resistant strains of P acnes burning.35 Benzoyl peroxide can also doses comes from small studies.43 have increased steadily since the 1970s cause an irritant dermatitis and bleach The efficacy of minocycline was as- and are now found in more than 50% hair, clothes, and bed linens. A recent sessed in a Cochrane review,43 which of cases in Europe and the United King- consensus has recommended that topi- concluded that minocycline is an effec- dom.49 Resistance of P acnes to oral an- cal antibiotics should not be used alone tive therapy for moderate acne, but its tibiotics is associated with treatment fail- due to the potential for bacterial resis- efficacy compared with other acne thera- ures.50 The effect of resistance to P acnes tance and relatively slow onset of ac- pies could not be reliably determined with topical antimicrobial use is un- tion.35 Antimicrobial resistance with due to methodological flaws in the com- clear.51 Resistance to tetracyclines is less benzoyl peroxide or azelaic acid has not parative trials. In a 3-month double- common than to erythromycin49 and is been reported. Combining antibiotics blind RCT, minocycline was some- least with minocycline.52 with benzoyl peroxide is the most com- what more effective in reducing Recommendations for reducing an- mon practice. A minimum of 6 to 8 inflammatory lesion counts compared tibiotic resistance in acne have been weeks of treatment is recommended.35 with zinc gluconate (67% vs 50%; published recently and include using PϽ.001).44 Antimicrobial effects against combined topical therapy—such as reti- Oral Antibiotics P acnes are greater with minocycline than noids, benzoyl peroxide, or both when Systemic antibiotics used in acne vul- with doxycycline or tetracycline,45 and using topical antibiotics—and avoid- garis have both antimicrobial and anti- higher lipid solubility favors its bioavail- ing long-term use of topical or oral an- inflammatory properties. They reduce P ability in pilosebaceous units. tibiotics when feasible.35 acnes within follicles, thereby inhibit- Oral tetracycline is usually pre- ing production of bacterial-induced in- scribed at a dosage of 500 mg twice a Hormonal Therapy flammatory cytokines.36 Tetracycline and day. The absorption of tetracycline is Hormonal treatments for acne are tol- erythromycin suppress leukocyte che- reduced by food and dairy products; erated in women only. These treat- motaxis37 and bacterial lipase activity38 therefore, it must be taken on an empty ments, which decrease androgen ex- while minocycline and doxycycline in- stomach. Adverse effects include gas- pression, are based on the requirement hibit cytokines and matrix metallopro- trointestinal tract dyspepsia, vaginal for androgens in the pathophysiologic teinases thought to contribute to inflam- candidiasis in women, and a small risk development of acne.53-54 A direct re- mation and tissue breakdown.39 The of photosensitivity. In children younger lationship between levels of circulat- main systemic antibiotics used in acne than 10 years, tetracycline can cause ing androgens and acne severity has not vulgaris are tetracycline, doxycycline, enamel hypoplasia and a yellowish dis- been established although prior stud- minocycline, and erythromycin. coloration of the forming teeth.46 Doxy- ies suggest some degree of hyperan- Relatively few RCTs have studied the cycline has traditionally been used at drogenemia in women with acne.55-57 use of oral antibiotics in treating acne. a dose of 50 to 100 mg twice daily. Suc- Antiandrogenic compounds in- A 12-week RCT involving 200 pa- cess with 20 mg/d may change clinical clude oral contraceptives (OCs) and tients40 showed a reduction in inflam- practice over time.42 Doxycycline causes androgen-receptor blockers such as flu- matory lesions by 64% with tetracy- gastrointestinal tract upset and is more tamide, spironolactone, and cyproter-

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one acetate. Several OCs are now ap- crease in steroid hormone binding duction with placebo.58,59 Two RCTs proved for use in acne. All contain 35 globulin. After 6 months, 2 multi- studying the efficacy of 20 µg of EE plus µg of estrogen or less. None of the an- center RCTs involving 507 women with 100 µg of levonorgestrel (Alesse [Wy- drogen-receptor blockers are approved moderate acne found that triphasic norg- eth, Madison, NJ]) showed total acne im- by the US Food and Drug Administra- estimate and ethinyl estradiol (EE, Or- provement of 23% to 40% compared tion for use in the treatment of acne. thotri-cyclin [Ortho-McNeil Pharma- with 9% to 23% with placebo (Table Oral contraceptives suppress ovar- ceutical Inc, Raritan, NJ]) had decreased 2).60,61 A recent RCT involving 128 ian androgens and reduce bioavailable inflammatory lesions by approxi- women showed an acne-lesion count re- testosterone by an estrogen-mediated in- mately 50% compared with a 30% reduction of 63% using the combination

Table 2. Clinical Trials in Oral Acne Therapy Length of Reduction in Lesions, % No. of Treatment, Source Patients Study Type wk Type of Acne Treatment Inflammatory Noninflammatory Total Antibiotics Gammon et 200 Randomized, 8 Moderate to Oral erythromycin 67 22 ... al,40 1986 double-blind, severe acne Oral tetracycline* 64 34 multicenter Braathen,41 87 Randomized, 8 Moderate to Oral tetracycline, 500 mg twice 57 ...... 1984 double-blind severe acne per d Clindamycin 1% 72 Placebo 12 Skidmore 51 Randomized, 24 Moderate facial Oral doxycycline, 20 mg twice 50 54 52 et al,42 double-blind acne per day 11 18 2003 placebo- Placebo 30 controlled, MC Dreno et al,44 332 Randomized, 12 Moderate acne Oral minocycline, 100 mg/d 67 ...... 2001 double-blind Zinc gluconate, 30 mg/d 50 multicenter Oral Contraceptives Lucky et al,58 257 Randomized, 24 Moderate acne Ethinyl estradiol, 35 µg plus 62 ... 53 1997 double-blind in women norgestimate, 180 µg, 215 placebo- µg, or 250 µg of controlled, Placebo 39 27 multicenter Redmond 250 Randomized, 24 Moderate acne Ethinyl estradiol, 35 µg plus 51 ... 46 et al,59 double-blind in women norgestimate, 180 µg, 215 1997 placebo- µg, or 250 µg of controlled, Placebo 35 34 multicenter Thiboutot 350 Randomized, 24 Moderate acne Ethinyl estradiol, 20 µg plus 47 25 40 et al,60 double-blind in women levonorgestrel 100 µg 2001 placebo- Placebo 33 14 23 controlled, multicenter Leyden et al,61 371 Randomized, 24 Moderate acne Ethinyl estradiol, 20 µg 32 13 23 2002 double-blind, in women pluslevonorgestrel, 100 µg placebo- Placebo 22 4 9 controlled Van Vloten 128 Randomized, 36 Mild to moderate Ethinyl estradiol, 30 µg plus 74 50 63 et al,62 double-blind, acne in drospirenone, 3 mg 2002 multicenter women Ethinyl estradiol, 35 µg plus 75 60 59 cyproterone acetate, 2 mg Isotretinoin Jones et al,81 76 Randomized, 16 Moderate to Isotretinoin, 0.1 mg/kg per d 80 ...... 1983 double-blind severe acne Isotretinoin, 0.5 mg/kg per d 80 Isotretinoin, 1.0 mg/kg per d 89 Strauss et al,82 150 Randomized, 20 Severe acne Isotretinoin, 0.1 mg/kg per d 79 ...... 1984 double-blind Isotretinoin, 0.5 mg/kg per d 79 multicenter Isotretinoin, 1.0 mg/kg per d 89 Strauss et al,83 600 Randomized, 20 Severe nodular Isotretinoin, 1.0 mg/kg per d 90 ...... 2001 double-blind acne Micronized isotretinoin, 87 multicenter 0.4 mg/kg per d Ellipses indicate that data were not reported in the trial. *Variable doses used.

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drugs of 35 µg of EE plus 3 mg of used in doses of 50 to 100 mg/d in found that retreatment was required in drospirenone (Yasmin [Berlex, Mon- women with hirsutism (not available in 42% of patients receiving 0.1 mg/kg per treal, Quebec]) and a 59% reduction us- the United States). Flutamide, a non- day and only 10% of patients receiving ing 35 µg of EE plus 2 mg of cyproter- steroidal androgen-receptor blocker 1 mg/kg per day (Table 2).82 A new mi- one acetate (Diane-35 [Berlex]).62 commonly used in prostate cancer is cronized formulation of isotretinoin (0.4 Neither Alesse nor Yasmin is marketed used in women with hirsutism and acne mg/kg per day) was equivalent in effi- for acne although both are used exten- at doses of 250 to 500 mg/d. cacy and safety to standard isotretinoin sively for that indication. Best evidence for the use of spirono- (1 mg/kg per day).83,84 Outside of the United States, the OC lactone in acne comes from 4 studies in A 10-year follow-up of 88 patients containing 35 µg of EE plus 2 mg of cy- which spironolactone alone or as an ad- who received isotretinoin in an initial proterone acetate is the combination to junct in doses of 50 to 200 mg/d showed dose of 0.5 or 1 mg/kg per day showed which newer OCs have usually been 50% to 70% improvement of acne.73-76 that 23% required a second course of compared for acne treatment. The pro- A randomized comparison study of 53 isotretinoin,85 usually within 3 years of gestin, cyproterone is an effective an- participants showed a 50% improve- stopping therapy. The daily and cumu- drogen-receptor blocker when used at ment in acne and seborrhea among those lative dosage was an important factor in higher doses in men with prostate can- who received a combination of 100 mg/d determining relapse rate. Patients re- cer63 and in women with acne, hirsut- of spironolactone with an OC vs an 80% ceiving 0.5 mg/kg per day had a relapse ism, and polycystic ovary syndrome.64 improvement among those who re- rate of 39% vs 22% in those taking 1 Best evidence for the use of this combi- ceived 250 mg of flutamide with an mg/kg per day (PϽ.05). A cumulative nation for acne comes from open stud- OC.77 Together with OCs, cyproterone dosage of less than 120 mg/kg had a sig- ies or comparison trials with newer OCs acetate 50 to 100 mg/d is also effective nificantly higher relapse rate than those containing levonorgestrel, drospire- in treating acne.78,79 Cyproterone ac- given a larger dose (82% vs 30%, respec- none, and desogestrel. At least 60% im- etate is, however, most commonly used tively; PϽ.01). A recent chart review of provement was demonstrated with all in the low-dose formulation (2 mg) as 179 patients who had received 1 course the above OCs.62,65,66 In Europe, the an- part of an oral contraceptive. of isotretinoin revealed that at the 3-year tiandrogen–progestin chlormadinone follow up, 35% had no recurrence; 16% has been combined with EE in an oral Isotretinoin required topical therapy; 27% required contraceptive (Belara [Grunenthal, Isotretinoin, a naturally occurring me- the use of oral antibiotics, and 23% re- Aachen, Germany]) and has been shown tabolite of vitamin A, inhibits seba- quired more isotretinoin.86 to be superior to an OC containing le- ceous gland differentiation and prolif- Adverse effects of isotretinoin in- vonorgestrel in treating acne.67 eration, reduces sebaceous gland size, clude dry lips, dry skin, dry eyes, de- Safety profiles are reasonable for OCs suppresses sebum production, and nor- creased night vision, headache, epi- containing 35 µg of EE or less. Cardio- malizes follicular epithelial desquama- staxis, and backache. Less common vascular risks are not significantly in- tion. Isotretinoin is indicated in severe adverse effects include benign intracra- creased in nonsmokers,68 and breast nodular acne and acne unresponsive to nial hypertension, so therapy must be cancer risks have not been shown to be other therapies. It is used at a dosage of stopped if a patient experiences persis- increased overall.69 The risk of deep- 0.5 to 1 mg/kg per day with a cumula- tent headaches. Isotretinoin can also be vein thrombosis increases from 1 per tive dosage of 120 to 150 mg/kg over a associated with a mild to moderate el- 10000 woman-years to 3.4 per 10000 4- to 6-month treatment period. evation in liver enzymes and in serum woman-years during the first year and Isotretinoin was first shown to be ef- lipid indices, especially triglycerides.87 It decreases therafter.70 Contraindica- fective in a nonrandomized clinical trial is generally well accepted that baseline tions to using OCs in an otherwise at an average dose of 2 mg/kg per day cholesterol, fasting triglycerides, and liver healthy woman include smoking, mi- for 4 months in 14 patients with severe function tests be done. Follow-up tests graine headaches with aura, and hy- acne.80 Complete clearing occurred in 13 are recommended at weeks 4 and 8. If pertension.71 of 14 patients and all 14 had prolonged these test results are normal, further test- Androgen-receptor blockers used in remissions. A dose-response RCT in- ing at week 12 may not be necessary. acne include spironolactone, flu- volving 76 patients showed that at 4 Isotretinoin is a proven teratogen, and tamide, and cyproterone acetate. Spi- months, total acne lesions were re- its use necessitates adequate contra- ronolactone is well established as an duced by 80% with a treatment of 0.1 ception during and 6 weeks after aldosterone-blocking agent at doses of mg/kg per day or 0.5 mg/kg per day and therapy, as well as baseline and monthly 25 mg/d in patients with heart failure.72 by 89% with 1.0 mg/kg per day.81 A sig- pregnancy tests. Major malformations Higher doses (50-100 mg/d) are required nificantly greater treatment failure rate occur in 40% of infants exposed to for androgen-receptor blockade. Cyprot- (45%) was observed with the lowest dose isotretinoin in the first trimester.88 It is erone acetate, in addition to being used (0.1 mg/kg per day dosage). A related strongly recommended that patients as the progestin in the OC Diane-35, is dose-comparison trial in 150 patients have 2 negative pregnancy tests be-

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tient as well as what can be measured. Figure. Severity and Type of Acne Since morbidity in acne is primarily emotional (psychological), different de- A Comedonal Acne B Mild to Moderate Inflammatory Acne grees of success may satisfy different in- dividuals. Acne severity fluctuates over time and treatments often need to change accordingly.

Comedones Only For this treatment, topical retinoids are the mainstay of treatment. Choices include tretinoin, adapalene, and tazarotene (FIGURE, A). Treatment response expectations are in the range of a 40% to 70% reduction in number of comedones within 12 weeks.6,11,14 Creams and lower concentrations of retinoids C Moderate to Severe D Severe Papulonodular are less irritating but may take longer Inflammatory Acne Inflammatory Acne for a response than higher concentrations and gels. Short-contact therapy, starting with 30 seconds and building up to 1 hour or more followed by wash- ing, was demonstrated effective and safe in a study with tazarotene gel91 and could be considered with all topical retinoids. Application should be to the en- tire area of involvement. Maintenance treatment is usually required.

Inflammatory Acne (Papules and Pustules), Mild to fore starting isotretinoin and regular be informed about depressive symp- Moderate Severity monthly pregnancy tests thereafter. toms, and screening for depression Topical antibiotics are the treatment of Current prescribing regulations in the should be an essential part of each visit. choice for these patients (Figure, B). United States require physicians to iden- Choices include benzoyl peroxide, az- tify on each prescription that patients CASE-BASED CLINICAL elaic acid, clindamycin, erythromy- have met the above qualifications and APPLICATIONS cin, and dual agents combining ben- have signed a consent form. Further Diagnosis zoyl peroxide with either erythromycin measures are being discussed to man- The diagnosis of acne vulgaris is usu- or clindamycin. Current recommenda- date a single, centralized registration ally uncomplicated. Differential diag- tions favor combining topical antimi- and tracking system for all health care noses mainly include rosacea, perioral crobial products with topical reti- professionals involved with isotreti- dermatitis, bacterial folliculitis, and noids if they can be tolerated by noin. A recent evidence-based review drug-induced acneiform eruptions. The patients.27,35,92 Benzoyl peroxide, 2% to examined the issue of an increasing presence of comedones confirms the di- 10%, is an inexpensive and effective an- number of reported cases of depres- agnosis of acne vulgaris. timicrobial that is not associated with sion and suicide associated with isotreti- Evidence-based literature in acne antimicrobial resistance.93 The dual- noin.89 Epidemiological evidence for an treatment is growing, and there is suf- agent products combining topical an- association between isotretinoin and de- ficient evidence to justify specific treat- tibiotics (clindamycin, erythromycin) pression is currently lacking.89 Further- ments for most clinical presentations. with benzoyl peroxide are more effec- more, there is a 24.7% and 13.3% preva- Successful outcomes frequently re- tive than antibiotics alone.23-25,93 Best re- lence of anxiety and depression, quire nuance in management and a sults require 8 to 12 weeks and main- respectively, in patients with acne.90 Un- thorough understanding of all treat- tenance therapy is usually required. til well-designed studies are con- ment modalities. Good outcomes are Reasonable response expectations are ducted, patients and their relatives must based on what is perceived by the pa- in the range of 30% to 80%.17-20,25,26

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Moderate to Severe ceptives do not preclude using stan- tantly.97 Another well-tolerated treat- Inflammatory Acne dard therapies if indicated. Approved ment is 250 mg/d flutamide . Its potential Oral antibiotics including the tetracy- OCs for use for acne include Orthotri- adverse effects include gastrointestinal clines (minocycline, doxycycline, tetra- cyclin (in the United States and tract upset and, at higher doses, hepa- cycline) are the first-line choices (Fig- Canada), Estrostep (in the United States totoxicity. Periodic liver function tests ure, C). Erythromycin is recommended [Pfizer, New York, NY), and Diane-35 are recommended with any dose of flu- less often because of its association with (Canada). The results of RCTs and tamide. Similar to spironolactone is 50 resistant P acnes.94 Trimethoprim- other best evidence, expected improve- to 100 mg/d of cyproterone acetate. sulfamethoxizole has been reported to ment with OCs alone is from 40% to Hepatotoxicity has been reported rarely be successful, but there is an unaccept- greater than 70% (TABLE 3). in men receiving cyproterone acetate for ably high risk of severe adverse events. For those who do not respond to OCs, prostate cancer98 and in women receiv- Response expectations with oral antibi- androgen-receptor blockers, alone or as ing OCs containing cyproterone ac- otics are in the range of 64% to 86%.34,40 adjuncts to OCs, have response expec- etate.99 Hormonal treatments for acne All oral antibiotics require a mini- tation in the range of 50% to 80%. A treatment are usually prolonged, de- mum of 6 to 8 weeks of treatment. treatment dosage of 50 to 100 mg/d of pending on response and tolerance. There are no strict regulations on du- Spironolactone is well tolerated, with ad- ration of use, but the recent increase in verse effects including diuretic effect, Laboratory Studies the prevalence of resistant organisms breast tenderness, and menstrual irregu- For women with regular menstrual has resulted in current recommenda- larities if OCs are not used concomi- cycles, serum-androgen measurements tions to encourage using antibiotics for shorter periods and to avoid the long- term use of antibiotics for mainte- Table 3. Most Common Adverse Effects of Systemic Acne Medications nance therapy.35 Drug Approximate Frequency Oral Antibiotics Severe Papulonodular Acne Dyspepsia, % 30 Oral isotretinoin is indicated for severe Photosensitivity Rare (highest: doxycycline) papulonodular acne (Figure, D), treat- Benign intracranial hypertension Rare ment failures, scarring, or frequently re- Hypersensitivity reaction Rare Lupuslike syndrome* lapsing acne or in cases where psycho- Tetracyclines as a group 14.2 Cases per 100 000 prescriptions logical distress is severe. Isotretinoin is Minocycline 52.8 Cases per 100 000 prescriptions used as a single-drug therapy except for Isotretinoin, % women for whom concomitant OCs are Mucocutaneous (cheilitis) 95 strongly recommended. Best responses Tetratogenicity 25-40 of exposed fetuses are seen with daily doses of 1 mg/kg per Hypertriglyceridemia 25 day for a period of 20 weeks or a total Elevation of liver transaminases 15 accumulative dose of 120 mg/kg.85 Hypercholesterolemia 7 A rare adverse effect of isotretinoin is Oral contraceptives, % Dysmenorrhea 10 called acne fulminans, characterized by Nausea 2-10 extensive erosive lesions, fever, arthral- Breast tenderness 6 gias, and leukocytosis. Treatment re- Headache 5 quires systemic corticosteroids. In a re- Depressed mood 3-30 cent report of 25 cases of acne fulminans, Venous thromboembolism†70 3.4 per 10 000 woman-years† best responses were seen with 0.5 to 1.0 Highest during first year of use mg/kg of prednisone daily for 4 to 6 Spironolactone, %‡ weeks, with isotretinoin resumed on Diuretic effect 30 week 4, starting with 0.5 mg/kg per day Dysmenorrhea 20 and increasing gradually.95 Dysphoria 20 Breast tenderness 18 Women With Acne Flutamide§ Hepatotoxicity, % 1 (doses Ͼ500 mg) Hormonal treatments with OCs or an- Cyproterone acetate࿣ drogen-receptor blockers have been Hepatotoxicity Rare (doses of 50-100 mg) shown to be helpful and are reviewed *Sturkenboom et al.48 96 †Lidegaard et al.70 elsewhere. For a woman with acne ‡Shaw et al.97 who desires birth control, OCs are an §Lin et al.98 ࿣Rudiger et al99 and Legro.100 excellent initial choice. Oral contra-

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are not necessary. For those with rapid and tretinoin microsphere gel 0.1% for the treatment 25. Lookingbill DP, Chalker DK, Lindholm JS, et al. of acne vulgaris. Cutis. 2001;68(suppl 4):20-24. Treatment of acne with a combination clindaymycin/ onset of hyperandrogenism and viril- 8. Thiboutot D, Gold MH, Jarratt MT, et al. Random- benzoyl peroxide gel compared with clindamycin gel, ization, an androgen-secreting ovarian ized controlled trial of the tolerability, safety and ef- benzoyl peroxide gel and vehicle gel: combined re- ficacy of adapalene gel 0.1% and tretinoin micro- sults of two double blind investigations. J Am Acad or adrenal tumor can be excluded with sphere gel 0.1% for the treatment of acne vulgaris. Dermatol. 1997;37:590-595. a normal total testosterone and dehy- Cutis. 2001;68(suppl 4):10-19. 26. Cunliffe WJ, Holland KT, Bojar R, et al. A ran- droepiandosterone sulfate levels, respec- 9. Cunliffe WJ, Danby FW, Dunlap F, et al. Ran- domized double blind comparison of clindamycin phos- domised controlled trial of the efficacy and safety of phate/benzoyl peroxide gel formulation and a match- tively. Irregular menses, hirsutism, obe- adapalene gel 0.1% and tretinoin cream 0.05% in pa- ing clindamycin gel with respect to microbiologic sity, or a family history of type 2 diabetes tients with acne vulgaris. Eur J Dermatol. 2002;12: activity and clinical efficacy in the topical treatment 350-354. of acne vulgaris. Clin Ther. 2002;24:1117-1133. suggest a possible endocrinopathy, such 10. Shalita AR, Chalker DK, Griffith RF, et al. Tazaro- 27. Wolf JE Jr, Kaplan D, Kraus SJ, et al. Efficacy and as polycystic ovary syndrome. Further tene gel is safe and effective in the treatment of acne tolerability of combined topical treatment of acne vul- studies may be indicated, which could vulgaris: a multicenter, double blind, vehicle con- garis with adapalene and clindamycin: a multicenter, trolled study. Cutis. 1999;63:349-354. randomized investigator blinded study. J Am Acad Der- include measurement of gonadotro- 11. Leyden JL, Tanghetti EA, Miller B, et al. Once daily matol. 2003;49:S211-S217. pins, free testosterone, 17-hydroxy pro- tazarotene 0.1% gel versus once daily tretinoin 0.1% 28. Richter JR, Bousema MT, De Boulle KLVM, et al. microsponge gel for the treatment of facial acne vul- Efficacy of a fixed clindamycin phosphate 1.2%, treti- gesterone, prolactin, and androstenedi- garis: a double blind randomized trial. Cutis. 2002; noin 0.025% gel formulation (Velac) in the topical con- one.57,100 Unfortunately, there is no 69(suppl 2):12-19. trol of facial acne lesions. J Dermatol Treat. 1998;9: 12. Webster GF, Berson D, Stein LF, et al. Efficacy and 81-90. widely accepted best laboratory test in tolerability of once daily tazarotene 0.1% gel versus 29. Richter JR, Forstrom LR, Kiistala UO,Jung EG. Ef- 101 this setting. once daily tretinoin 0.025% gel in the treatment of ficacy of the fixed 1.2% clindamycin phosphate, facial acne vulgaris: a randomized trial. Cutis. 2001; 0.025% tretinoin gel formulation (Velac) and a pro- 67(suppl 6):4-9. prietary 0.025% tretinoin gel formulation (Aberela) Conclusion 13. Lucky A, Jorizzo JL, Rodriguez D, et al. Efficacy in the topical control of facial acne. J Eur Acad Der- Current treatments in acne target one and tolerance of adapalene cream 0.1% compared with matol Venereol. 1998;11:227-233. its cream vehicle for the treatment of acne vulgaris. 30. Rietschel RL, Duncan SH. Clindamycin phos- or more of the known mechanisms in- Cutis. 2001;68:34-40. phate used in combination with tretinoin in the treat- volved in the disease. Combining more 14. Webster GF, Guenther L, Poulin YP, et al. A mul- ment of acne. Int J Dermatol. 1983;22:41-43. ticenter, double-blind, randomized comparison study 31. Mills OH Jr, Kligman AM. Treatment of acne vul- than 1 treatment frequently yields op- of the efficacy and tolerability of once daily tazaro- garis with topically applied erythromycin and treti- timal responses. Patients may require tene 0.1% gel and adapalene 0.1% gel for the treat- noin. Acta Derm Venereol. 1978;58:555-557. adjustment of therapies depending on ment of facial acne vulgaris. Cutis. 2002;69(suppl 2): 32. Korting HC, Braun-Falco O. Efficacy and toler- 4-11. ability of combined topical treatment of acne vul- their degree of improvement and level 15. Leyden J, Lowe N, Kakita L, Draelos Z. Compari- garis with tretinoin and erythromycin in general prac- of tolerance to the treatments. son of treatment of acne vulgaris with alternate-day tice. Drugs Exp Clin Res. 1989;15:447-451. applications of tazarotene 0.1% gel and once-daily 33. Katsambas A, Graupe K, Stratigos J. Clinical stud- Author Contributions: Drs Shaw and Haider had full applications of adapalene 0.1% gel: a randomized trial. ies of 20% azelaic acid cream in the treatment of acne access to all of the data in the study and take respon- Cutis. 2001;67:10-16. vulgaris: comparison with vehicle and topical treti- sibility for the integrity of the data and the accuracy 16. Ellis CN, Millikan LE, Smith EB, et al. Comparison noin. Acta Derm Venereol Suppl (Stockh). 1989;143 of the data analysis. of adapalene 0.1% solution and tretinoin 0.025% gel (suppl):35-39. Study concept and design: Shaw, Haider. in the topical treatment of acne vulgaris. Br J Derma- 34. Hjorth N, Graupe K. Azelaic acid for the treat- Acquisition of data: Shaw, Haider. tol. 1998;139(suppl 52):41-47. ment of acne: a clinical comparison with oral tetracy- Drafting of the manuscript: Shaw, Haider. 17. Graupe K, Cunliffe WJ, Gollnick HP, Zaumseil RP. cline. 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