acne

This report reflects the best data available at the time the report was prepared, but caution should beexercised in interpreting the data; the results of future studies may require alteration of the conclusionsor recommendations set forth in this report.

Acne: 1991-2001

Diane Thiboutot, MD Hershey, Pennsylvania

OVERVIEWThe goal of this presentation is to update practi-

tioners on developments in the pathogenesis andtreatment of acne from 1991 to 2001.

PATHOGENESISThe pathogenesis of acne centers on the interac-

tion of follicular hyperkeratinization, action of Pro-pionibacterium acnes, sebum production, and in-flammation.

Follicular hyperkeratinizationThe cause of follicular hyperkeratinization is still

unknown. Follicular deficiency of linoleic acid hasbeen implicated. Recent studies suggest that inter-leukin 1 and androgens may be involved in thisprocess.

Proliferation of follicular keratinocytesKnaggs H, Holland K, Morris C, Wood E, Cunliffe W. Quantification of

cellular proliferation in acne using the monoclonal antibody Ki-67. J Invest Dermatol 1994;102:89-92.

Keratinocyte proliferation was assessed in normalfollicles and acne follicles by using the antibodyKi-67. Cellular proliferation was greater in normalfollicles from acne-affected areas compared with ar-eas not affected by acne. Proliferation was alsogreater in comedones compared with normal folli-cles. The authors conclude that normal follicles fromskin affected with acne may be “acne-prone” com-pared with normal follicles from areas of skin notaffected by acne.

Role of cytokines: Interleukin 1Guy R, Green M, Kealey T. Modeling of acne in vitro. J Invest Dermatol

1996;106:176-82.

Using a model of human infrainfundibular seg-ments to study the process of follicular hyperkerati-nization, these authors found that the addition ofinterleukin 1 (IL-1) to the infrainfundibular segmentscaused hyperkeratinization similar to that seen incomedones. This effect could be blocked by addi-tion of IL-1 receptor antagonist. These authors sug-gest that changes in sebum secretion or compositioncould lead to the release of IL-1 by follicular kera-tinocytes, which in turn may stimulate comedogen-esis.

Role of androgensThiboutot D, Harris G, Iles V, Cimis G, Gilliland K, Hagari S. Activity of

the type 1 5�-reductase exhibits regional differences in isolatedsebaceous glands and whole skin. J Invest Dermatol 1995;105:209-14.

Activity of the type 1 5�-reductase was shown topredominate in human sebaceous glands and epi-dermis. This enzyme is responsible for the conver-sion of testosterone to the more potent androgen,dihydrotestosterone (DHT). DHT in turn is thoughtto mediate androgen-dependent skin diseases suchas acne, hirsutism, and androgenetic alopecia. Inthis study, activity of the type 1 5�-reductase wasgreatest in sebaceous glands isolated from acne-prone regions of the skin compared with nonacne-prone regions. These data suggest that regional dif-ferences in the local production of DHT maycontribute to androgen-mediated skin diseases andthat specific inhibition of the type 1 5�-reductasemay be beneficial in the treatment of these condi-tions.

Thiboutot D, Knaggs H, Gilliland K, Hagari S. Activity of the type 15�-reductase is greater in the follicular infrainfundibulum com-pared to the epidermis. Br J Dermatol 1997;136:166-71.

Androgen metabolism in infrainfundibular seg-ments of follicles and in epidermal keratinocyteswas studied to explore the potential role of andro-

From the Division of Dermatology, Pennsylvania State College ofMedicine.

Reprint requests: Diane M. Thiboutot, MD, Pennsylvania State Col-lege of Medicine, Division of Dermatology, 500 University Dr, UPC2, Suite 4300, Hershey, PA 17033.

J Am Acad Dermatol 2002;47:109-17.Copyright © 2002 by the American Academy of Dermatology, Inc.0190-9622/2002/$35.00 � 0 16/1/123483doi:10.1067/mjd.2002.123483

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gens in follicular hyperkeratinization. Activity of thetype 1 5�-reductase was noted in infrainfundibularsegments, suggesting that these keratinocytes arecapable of converting testosterone to DHT. Enzymeactivity was greater in the infrainfundibular keratin-ocytes, suggesting that these cells have a greatercapacity to produce androgens compared with theepidermis. Additional studies are needed to docu-ment a role for androgens in follicular hyperkerati-nization.

Propionibacterium acnesBacterial resistance. Before 1976, resistance of

Propionibacterium acnes to antibiotics was not anissue. During the past several years, investigatorshave documented resistance to erythromycin andtetracyclines and the emergence of resistance to mi-nocycline. How this resistance affects the use ofantibiotics for acne is a matter of discussion.

Eady EA, Jones CE, Tipper JL, Cove JH, Cunliffe WJ, Laytom AM. Anti-biotic resistant propionibacteria in acne: need for policies tomodify antibiotic usage. Br Med J 1993;306:555-6.

In 1992, 468 patients with acne were screened forresistant strains of P acnes. Among these, 178 pa-tients carried resistant strains of P acnes. Resistanceto erythromycin was most common (124 patients);most of these strains were cross-resistant to clinda-mycin. Sixty-one patients carried strains that wereresistant to tetracycline and cross-resistant to doxy-cycline but not to minocycline. Thirty patients car-ried strains resistant to trimethoprim. Twenty-sevenpatients had 2 or more strains with different antibi-otic resistance. In 1992 no strains resistant to mino-cycline were noted. Recommendations: (1) Do notuse oral antibiotics when topical agents will suffice.(2) Treat for no longer than is necessary. (3) Iffurther treatment is needed, reuse the same drugwhenever possible. Use intervening courses of top-ical benzoyl peroxide to eliminate resistant strains.(4) Avoid concomitant topical and oral treatmentwith chemically dissimilar antibiotics to prevent thedevelopment of resistance to both.

Effective agents to decrease resistanceCoates P, Adams CA, Cunliffe WJ, et al. Does oral isotretinoin prevent

Propionibacterium acnes resistance? Dermatology 1997;195(Suppl 1):4-9; discussion 38-40.

Pilot data are presented to suggest that isotreti-noin may be effective in reducing the number ofantibiotic-resistant P acnes organisms.

Eady EA, Bojar RA, Jones CE, et al. The effects of acne treatment witha combination of benzoyl peroxide and erythromycin on skincarriage of erythromycin-resistant propionibacteria. Br J Derma-tol 1996;134:107-13.

In a double-blind study, 37 patients with mild tomoderate acne were treated with 5% benzoyl per-

oxide/3% erythromycin for 6 weeks. This resulted ina 3 log reduction in total P acnes and significantlyreduced the number of erythromycin-resistantstrains. In contrast, erythromycin alone only pro-duced a 1.5-log reduction in total P acnes countsand did not reduce the number of resistant strainsafter the same amount of time. In an open study of21 patients with erythromycin-resistant strains of Pacnes, the total counts and counts of resistant strainswere reduced by 2.5 log after 6 weeks.

Sebum productionAcne in prepubescent children (role of de-

hydroepiandrosterone sulfate)Lucky AW, Biro FM, Huster GA, et al. Acne vulgaris in premenarchal

girls. An early sign of puberty associated with rising levels ofdehydroepiandrosterone. Arch Dermatol 1994;130:308-14.

The relationships of pubertal maturation, sex ste-roid hormone levels, and the presence of acne wereexamined in 626 premenarchal females (mean age,9.97 � 0.62 years). Girls were evaluated for acneprevalence and severity. Pubertal maturation andserum hormone levels were determined in 181 girls.Overall, 77.8% of girls had some acne: 48.3% hadcomedonal acne, 2.2% had only inflammatory acne,and 27.3% had both types. The level of serum de-hydroepiandrosterone sulfate (DHEAS) was signifi-cantly higher in prepubertal girls with comedonalacne compared with girls without acne. The level ofDHEAS was also significantly higher in the girls withinflammatory acne compared with those withoutinflammatory acne. Serum DHEAS is significantlyand specifically associated with the development ofacne in young girls.

Stewart ME, Downing DT, Cook JS, Hansen JR, Strauss JS. Sebaceousgland activity and serum dehydroepiandrosterone sulfate lev-els in boys and girls. Arch Dermatol 1992;128:1345-8.

Sebum composition, serum levels of DHEAS, andpubertal stage were examined in 111 boys and girlsaged 2 to 15 years. Sebum composition was evalu-ated by measuring the ratio of wax esters to choles-terol � cholesterol esters, a ratio known to increasewith increasing sebaceous gland activity. The sebumratio and serum DHEAS level began to rise in chil-dren aged 7 to 10 years, before signs of puberty inmany. The production of sebum, as assessed by thesebum ratio, correlated significantly with serum lev-els of DHEAS, indicating that adrenal androgens area major determinant of sebaceous gland activity dur-ing the prepubertal period.

Role of 5�-reductase type 1Thiboutot D, Harris G, Iles V, Cimis G, Gilliland K, Hagari S. Activity of

the type 1 5�-reductase exhibits regional differences in isolatedsebaceous glands and whole skin. J Invest Dermatol 1995;105:209-14.

Activity of the type 1 5�-reductase was shown to

110 Thiboutot J AM ACAD DERMATOL

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predominate in human sebaceous glands and epi-dermis. This enzyme is responsible for the conver-sion of testosterone to the more potent androgen,DHT. DHT in turn is thought to mediate androgen-dependent skin diseases such as acne, hirsutism,and androgenetic alopecia. In this study, activity ofthe type 1 5�-reductase was greatest in sebaceousglands isolated from acne-prone regions of the skincompared with nonacne-prone regions. These datasuggest that regional differences in the local produc-tion of DHT may contribute to androgen-mediatedskin diseases and that specific inhibition of the type1 5�-reductase may be beneficial in the treatment ofthese conditions.

Thiboutot D, Gilliland K, Light J, Lookingbill D. Androgen metabo-lism in sebaceous glands from subjects with and without acne.Arch Dermatol 1999;135:1041-8.

The activity of the androgen-metabolizing en-zymes, 5�-reductase (converts testosterone to DHT)and 17�-hydroxysteroid dehydrogenase (intercon-verts androstenedione and testosterone), was mea-sured in sebaceous glands isolated from facial skinof males and females with mild to moderate acne.Serum levels of DHEAS, testosterone, DHT, and an-drostenedione were determined in these patients.The mean serum levels of androgens were signifi-cantly higher in females with acne compared withthose without acne, yet values were within the nor-mal range. The mean activity of 5�-reductase type 1was higher in sebaceous glands from women withacne compared with those without acne, althoughthis difference did not achieve statistical signifi-cance. These data suggest that as a group, womenwith acne have higher serum androgen levels andpossibly an increased capacity to produce potentandrogens within the sebaceous glands via the type1 5�-reductase.

Neonatal acne and Malassezia speciesNiamba P, Weill FX, Sarlangue J, Labreze C, Couprie B, Taieb A. Is

common neonatal cephalic pustulosis (neonatal acne) trig-gered by Malassezia sympodialis? Arch Dermatol1998;134:995-8.

Nineteen patients with neonatal acne and 19 con-trol subjects younger than 45 days were studied.Cultures from pustules and contralateral uninvolvedskin were obtained from patients, and cultures fromhealthy site-matched skin were obtained from con-trol subjects. Among 14 patients from whom ade-quate samples were taken, 4 had positive results forMalassezia species. Cultures from 6 of 16 contralat-eral swabs were also positive. All cultures indicatedthe presence of Malassezia sympodialis. Among the19 control subjects, 6 had cultures positive forMalassezia species: 4 for M furfur and 2 for Msympodialis. The severity of the papulosis correlated

with isolation of M sympodialis. Common neonatalcephalic pustulosis is a well-recognized entity,which was, in the past, improperly named neonatalacne. The hypothesis that it represents an inflamma-tory reaction against Malassezia species is stronglysuggested by this study.

THERAPYNew therapies and dosage forms

Topical retinoids. Tretinoin interacts with cyto-plasmic retinoic acid-binding proteins and each sub-class of retinoic acid receptor (RAR �, �, and �).New retinoids such as tazarotene and agents withretinoid activity such as adapalene interact with RAR� and RAR � but not with RAR �. This receptorselectivity may impart differences in efficacy andside effect profiles.

Adapalene (Differin)Shalita AR, Weiss JS, Chalker DK, et al. A comparison of the efficacy

and safety of adapalene gel 0.1% and tretinoin gel 0.025% in thetreatment of acne vulgaris: a multicenter trial. J Am Acad Der-matol 1996;34:482-5.

In a multicenter study of 323 patients with acne,the safety and efficacy of adapalene gel and tretinoin0.025% gel were compared. Evaluations were per-formed at baseline and weeks 2, 4, 8, and 12. Ada-palene gel 0.1% produced greater reductions in non-inflammatory (P � .02), inflammatory (P � .06), andtotal lesions (P � .01) at 12 weeks. There weresignificantly fewer incidents and less severity of er-ythema, scaling, dryness, and burning throughoutthe study in the adapalene group (P � .05). Of noteis that tretinoin therapy is not often initiated with the0.025% gel formulation, because it is most oftenprescribed once patients have become accustomedto tretinoin.

Tazarotene (Tazorac)Shalita AR, Chalker DK, Griffith RF, Herbert AA, Hickman JG, Maloney

JM, et al. Tazarotene gel is safe and effective in the treatment ofacne vulgaris: a multicenter, double-blind, vehicle-controlledstudy. Cutis 1999;63:349-54.

The safety and efficacy of tazarotene 0.1% and0.05% gels were compared with vehicle gel in a12-week randomized double-blind study of 446 pa-tients with mild to moderate facial acne. Treatmentwith tazarotene 0.1% gel resulted in significantlygreater reductions in noninflammatory and total le-sion counts at all follow-up visits and significantlygreater reductions in inflammatory lesion counts atweek 12 compared with vehicle gel. Tazarotene0.05% gel resulted in significantly greater reductionsin noninflammatory and total lesion counts thanvehicle gel at weeks 8 and 12. At week 12, treatmentsuccess rates were 68% and 51% for tazarotene 0.1%

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and tazarotene 0.05%, respectively (40% reductionfor vehicle gel).

Tretinoin dosage forms. Novel delivery sys-tems (microspheres and polyolprepolymer-2) havebeen developed to minimize the adverse effects as-sociated with topical tretinoin.

Tretinoin microspheres (Retin A micro)Webster G. Topical tretinoin in acne therapy. J Am Acad Dermatol

1998;39:S38-S44.

Data on the safety and efficacy of 0.1% tretinoingel microspheres compared with vehicle gel arepresented in this review. Tretinoin gel microspheres,applied once daily, were significantly more effectivethan vehicle in reducing acne lesion counts in 2studies, each involving approximately 70 patientswho were treated for 12 weeks. The mean percentreduction in noninflammatory lesions was 49% and32% for studies 1 and 2 compared with vehicle (22%and 3%, respectively). For inflammatory lesions,counts were reduced by the active drug by 37% and29% in studies 1 and 2 compared with reductions of18% and 24% in the vehicle groups. Data from adouble-blind, randomized, half-face study compar-ing 0.1% tretinoin gel microspheres with 0.1% treti-noin cream are presented and indicate improvedtolerance with the microsphere preparation.

Tretinoin/polyolprepolymer polymer (Avita)Lucky A, Cullen S, Funicella T, Jarratt M, Jones T, Reddick M. Double-

blind, vehicle-controlled, multicenter comparison of two0.025% tretinoin creams in patients with acne vulgaris. J AmAcad Dermatol 1998;38(Suppl):S24-S30.

The safety and efficacy of tretinoin cream 0.025%in a vehicle containing polyolprepolymer-2 (Avita,Penederm, Inc, Foster City, Calif) and commerciallyavailable tretinoin 0.025% cream (Retin-A, OrthoDermatologics, Raritan, NJ) were compared in 271patients with mild to moderate acne. Patients weretreated for 12 weeks. The efficacy and safety of bothformulations were comparable, and each formula-tion was statistically significantly better than vehiclecreams.

Lucky A, Cullen S, Jarratt M, Quigley J. Comparative efficacy andsafety of two 0.025% tretinoin gels: results from a multicenter,double-blind, parallel study. J Am Acad Dermatol 1998;38:S17-S23.

The safety and efficacy of tretinoin gel 0.025% ina vehicle containing polyolprepolymer-2 (Avita,Penederm, Inc) and commercially available tretinoin0.025% gel (Retin-A, Ortho Dermatologics) werecompared in 215 patients with mild to moderateacne. Patients were treated for 12 weeks. The effi-cacy of both formulations was comparable, and eachwas statistically significantly better than vehicle gels.

Significantly less peeling and drying than the com-mercially available tretinoin gel was noted at day 84of the study. Of note is that tretinoin therapy is notoften initiated with the 0.025% gel formulation be-cause it is most often prescribed once patients havebecome accustomed to tretinoin.

Topical antibioticsAzelaic acid (Azelex). Azelaic acid has been

widely used in Europe for several years. It wasapproved for use in the United States in 1996. Thisdrug is a dicarboxylic acid with both comedolyticand antibacterial activity. It is available as a 20%cream.

Graupe K, Cunliffe W, Gollnick H, Zaumseil R. Efficacy and safety oftopical azelaic acid (20% cream): an overview of results fromEuropean clinical trials and experimental reports. Cutis 1996;57:13-9.

The authors review pertinent clinical studies ofthe efficacy of azelaic acid 20% cream as mono-therapy in the treatment of acne vulgaris in compar-ison with vehicle, tretinoin cream 0.05%, benzoylperoxide 5% gel, 2% erythromycin gel, oral tetracy-cline, and oral isotretinoin. Data regarding combina-tion therapy of azelaic acid with minocycline andazelaic acid maintenance therapy are also presented.Studies of the safety and tolerability of azelaic acidare summarized, as are studies of the safety andefficacy of azelaic acid in the treatment of rosacea.

Clindamycin/benzoyl peroxideLookingbill DP, Chalker DK, Lindholm JS, et al. Treatment of acne

with a combination clindamycin/benzoyl peroxide gel com-pared with clindamycin gel, benzoyl peroxide gel and vehiclegel: combined results of two double-blind investigations. J AmAcad Dermatol 1997;37:590-5.

In two double-blind, randomized, parallel, vehi-cle-controlled trials, patients were treated oncenightly with a combination clindamycin/benzoylperoxide gel, benzoyl peroxide, clindamycin, or ve-hicle gel. Evaluations included acne lesion countsand assessment of global responses and irritant ef-fects. A total of 334 patients completed the study. All3 active preparations were significantly better thanvehicle. The combination gel was significantly supe-rior to the 2 individual agents in global improvementand reduction of inflammatory lesions. The authorsconclude that topical clindamycin/benzoyl peroxidegel is well-tolerated and superior to either individualagent.

Hormonal therapiesOral contraceptives. New progestins have

been developed that have low intrinsic androgenicactivity. These progestins include desogestrel, norg-estimate, and gestodene (not available in the United


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States). Each of these has been combined with ethi-nyl estradiol in an oral contraceptive. Ortho TriCy-clen has been approved by the Food and DrugAdministration (FDA) for treatment of acne. It con-tains norgestimate in combination with 35 �g ofethinyl estradiol. Newer preparations containinglower doses of estrogen (20 �g) are also beingevaluated for efficacy in the treatment of acne.Lucky A, Henderson T, Olson W, Robisch D, Lebwohl M, Swinyer L.

Effectiveness of norgestimate and ethinyl estradiol in treatingmoderate acne vulgaris. J Am Acad Dermatol 1997;37:746-54.

Redmond GP, Olson WH, Lippman JS, Kafrissen ME, Jones TM,Jorizzo JL. Norgestimate and ethinyl estradiol in the treatmentof acne vulgaris: a randomized, placebo-controlled trial. ObstetGynecol 1997;89:615-22.

Two randomized, double-blind, placebo-con-trolled trials of a norgestimate and ethinyl estradiolcombination oral contraceptive in the treatment ofmoderate acne in women were performed. Each trialincluded approximately 250 women who weretreated for 6 months and were evaluated for thepresence of acne and adverse effects. In each study,the improvement in acne was significantly greater inthe active group than in the placebo group, with a50% to 60% improvement in inflammatory lesions.The drug was well tolerated. Decreases in serumfree testosterone levels and an increase in sex hor-mone binding globulin were noted in the activegroup.

Thorneycroft I, Stanczk F, Bradshaw K, Ballagh S, Nichols M, Weber M.Effect of low-dose oral contraceptives on androgenic markersand acne. Contraception 1999;60:255-62.

A multicenter, open-label, randomized trial wasperformed to compare androgen profiles and clini-cal outcomes associated with 2 oral contraceptivescontaining the same amounts of ethinyl estradiol (20�g) but different progestins: levonorgestrel (LNG),100 �g (Alesse), and norethindrone acetate (NETA),1000 �g (Loestrin). Thirty women received 3 cyclesof treatment with LNG and 28 women receivedNETA. These results showed that LNG reduced ad-renal, ovarian, and peripheral androgen levels.NETA reduced peripheral and adrenal androgens.Despite a 2.2-fold greater relative increase in sexhormone binding globulin with NETA than withLNG, bioavailable testosterone was reduced by thesame amount with NETA and LNG. Both treatmentsimproved acne and were well-tolerated. Althoughthese 2 progestins affected secondary markers dif-ferently, both produced an equivalent decrease inbioavailable testosterone.

SpironolactoneShaw J. Low-dose adjunctive spironolactone in the treatment of

acne in women: a retrospective analysis of 85 consecutivelytreated patients. J Am Acad Dermatol 2000;43:498-2.

Records were reviewed from 85 women treatedwith spironolactone, 50 to 100 mg/d, administeredeither as a single agent or as an adjunct to standardtherapies. The maximum length of treatment was 24months. Clearing of acne occurred in 33% of womentreated with low-dose spironolactone: 33% hadmarked improvement, 27.4% showed partial im-provement, and 7% showed no improvement. Thedata are further broken down according to concom-itant therapies. The treatment was well-tolerated,with 57.5% of women reporting no adverse effects.Menstrual irregularities were reported in 17.5% ofwomen; and symptoms of lethargy, fatigue, dizzi-ness, or headache (central nervous system symp-toms) were reported in 16.3%. Less common symp-toms included breast tenderness, diuretic effect,postural hypotension, and nausea. Slight elevationsin serum potassium levels (range, 4.8-5.3 mEq/L)were identified in 13.7% of the 73 patients exam-ined. This was not considered to be clinically signif-icant. The following benefits were noted in somepatients: improvement in premenstrual syndrome,decreased facial oiliness, decreased metrorrhagia,reduced endometriosis pain, and increased libido.These data suggest that (1) most adverse effects ofspironolactone are dose-dependent; (2) menstrualirregularities, the most common side effect, can bereduced significantly by using lower doses of spi-ronolactone; (3) central nervous system symptomscan occur in up to 16% of patients but appear to beunrelated to dose; (4) hyperkalemia is measurablebut clinically insignificant in the absence of cardiacor renal disease; and (5) reductions in blood pres-sure are slight but can (rarely) be associated withorthostatic symptoms. Of note is that spironolactoneis not approved by the FDA for the treatment ofacne.

Phototherapy for acne. The recent literaturecontains reports of the efficacy of visible light andphotodynamic therapy in the treatment of acne.

Papageorgiou P, Katsambas A, Chu A. Phototherapy with blue (415nm) and red (660 nm) light in the treatment of acne vulgaris. Br JDermatol 2000;142:973-8.

One hundred seventeen patients with mild tomoderate acne were randomly assigned to receivetreatment with blue light, mixed blue and red light,cool white light, and 5% benzoyl peroxide. Dailyirradiation with light was performed for 15 minutes.After 12 weeks, a mean improvement of 76% ininflammatory lesions was achieved with the blue-red phototherapy. This was significantly superior tothe other treatment groups. The authors concludethat phototherapy with blue-red light, probably by


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combining antibacterial and antiinflammatory ac-tion, is an effective treatment for acne.

Hongcharu W, Taylor CR, Chang Y, Aghassi D, Suthamjariya K, Ander-son RR. Topical ALA-photodynamic therapy for the treatment ofacne vulgaris. J Invest Dermatol 2000;115:183-92.

Topical aminolevulinic acid (ALA) is converted toa potent photosensitizer in hair follicles and seba-ceous glands. Twenty-two subjects with acne on theback were treated in 3 sites with topical ALA plus redlight, ALA alone, light alone; one site was left un-treated as a control. Eleven patients were treatedonce and 11 patients were treated twice. Sebumexcretion rate and autofluorescence from follicularbacteria were measured before treatment and at 2, 3,10, and 20 weeks after treatment. Clinical and statis-tically significant clearance of inflammatory acnewas associated with ALA plus red light for at least 20weeks after multiple treatments and 10 weeks after asingle treatment. Adverse effects included transienthyperpigmentation, superficial exfoliation, and crust-ing, which cleared without scarring. ALA plus redlight caused phototoxicity to sebaceous follicles,prolonged suppression of sebaceous gland function,and an apparent decrease in follicular bacteria afterphotodynamic therapy.

Update on current therapiesTopical tretinoin and pregnancy

Buchan P, Eckhoff C, Caron D, Nau H, Shroot B, Schaefer H. Repeatedtopical administration of all-trans-retinoic acid and plasma lev-els of retinoic acids in humans. J Am Acad Dermatol 1994;30:428-34.

Plasma retinoid levels were measured in healthysubjects before, during, and after 14 days of topicaltretinoin application (2 g) to the face, neck, andupper chest. Diurnal and nutritional factors influ-enced plasma levels of endogenous retinoids to agreater extent than topical administration of all-trans-retinoic acid in doses used for acne therapy.

Shapiro L, Pastuszak A, Curto G, Koren G. Safety of first-trimesterexposure to topical tretinoin: prospective cohort study. Lancet1997;350:1143-4.

A survey study of 94 first-trimester exposures totopical tretinoin compared with 133 controlsshowed no differences in pregnancy outcome. Theincidence of major malformations did not differ.Major defects in tretinoin-exposed babies includedone bicuspid aortic valve and one case of dysplastickidneys. Neither defect is associated with retinoidembryopathy. Defects in the control group consistedof congenital hip dislocation and imperforate anus.Results failed to show an increased risk of congenitalmalformations for users of topical tretinoin.

Jick SS, Terris BZ, Jick H. First trimester topical tretinoin and congen-ital disorders. Lancet 1993;341:1181-2.

Data from 215 women exposed to topical treti-noin during the first trimester of pregnancy werecompared with data from 430 matched, nonexposedcontrol subjects. Of note is that these women wereidentified as having a prescription filled for tretinoin,but it is not known whether or how much tretinoinwas used. The prevalence of major anomaliesamong babies born to exposed mothers was 1.9%compared with 2.6% among babies born to nonex-posed mothers. The relative risk estimate of havinga baby with a major congenital anomaly for exposedversus nonexposed women was 0.7 (95% confi-dence interval � 0.2-2.3), suggesting that from anepidemiologic standpoint, first-trimester exposure totretinoin did not increase the risk of major congen-ital anomalies.

IsotretinoinMechanism of action

Tsukada M, Schroder M, Roos T, Chandraratna R, Reichert U, Merk H,et al. 13-Cis retinoic acid exerts its specific activity on humansebocytes through selective intracellular isomerization to all-trans retinoic acid and binding to retinoic acid receptors. J In-vest Dermatol 2000;115:321-7.

Isotretinoin does not bind to retinoid receptors,and hence, it is thought to act as a prodrug in thetreatment of acne. In this study, the metabolism of13-cis-retinoic acid was studied in an immortalizedhuman sebocyte cell line (SZ95 cells). Rapid isomer-ization of 13-cis-retinoic acid to all-trans-retinoicacid was demonstrated by using high-performanceliquid chromatography. This rapid isomerizationwas a sebocyte-specific event because no significantisomerization of 13-cis-retinoic acid to all-trans- reti-noic acid occurred in immortalized keratinocytes(HaCaT cells). These data support the hypothesisthat 13-cis-retinoic acid exerts its action in acne byisomerization to all-trans-retinoic acid, which theninteracts with known retinoid receptors.

Long-term safety and efficacyLayton AM, Knaggs H, Taylor H, Cunliffe WJ. Isotretinoin for acne

vulgaris—10 years later: a safe and successful treatment. Br JDermatol 1993;129:292-6.

Eighty-eight patients were treated with isotreti-noin for acne. Most patients required 4 months oftherapy to produce at least 85% improvement. Pa-tients were seen again after 10 years. Sixty-one pa-tients were clear of their disease. Of the others, 16%required treatment with conventional antibiotics and23% required a second course of isotretinoin. Ofthose who experienced relapse, 96% did so withinthe first 3 years. Those patients receiving 0.5 mg/kgper day or a cumulative dose of �120 mg/kg had asignificantly higher relapse rate compared with


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those receiving a higher dose. Long-term biochem-ical or systemic adverse effects were not noted.

Barth JH, MacDonald-Hull SP, Mark J, Jones RG, Cunliffe WJ. Isotreti-noin therapy for acne vulgaris: a re-evaluation of the need formeasurements of plasma lipids and liver function tests. Br J Der-matol 1993;129:704-7.

Plasma lipid profiles and liver function test resultsof 209 patients treated with isotretinoin were re-viewed. Of these subjects, 113 were treated with 1mg/kg per day, and 96 were treated with 0.5 mg/kgper day. There were no significant changes in liverfunction test results during 16 weeks of treatment.There were significant elevations in plasma choles-terol and triglyceride levels at 8 and 16 weeks forboth dosage regimens. All individuals with elevatedcholesterol levels during therapy had elevated cho-lesterol levels at baseline. There were no furtherelevations in plasma triglyceride levels after 8weeks. These authors conclude that it is prudent tomonitor for elevations in liver enzyme levels andplasma lipid levels at baseline and for elevations inplasma triglyceride levels at 4 weeks.

Need for repeat coursesStainforth JM, Layton AM, Taylor JP, Cunliffe WJ. Isotretinoin for the

treatment of acne vulgaris: which factors may predict the needfor more than one course? Br J Dermatol 1993;129:297-301.

Two hundred ninety-nine patients treated withisotretinoin were followed up for an average 5 yearsafter treatment: 22.7% required repeat courses ofisotretinoin; 17% had 2 courses, 5% had 3 courses,and 1% had 4 to 5 courses. Factors contributing tothe need for additional courses were lower doseregimens (0.1-0.5 mg/kg per day), the presence ofsevere acne, being a female older than 25 years atthe start of therapy, and having a prolonged historyof acne.

Effects on bone in acne regimensMargolis DJ, Attie M, Leyden J. Effects of isotretinoin on bone min-

eralization during routine therapy with isotretinoin for acne vul-garis. Arch Dermatol 1996;132:769-74.

Twenty patients were treated with isotretinoin,0.89 mg/kg per day (range, 0.77-0.98 mg/kg perday), for 20 weeks. Markers of bone turnover andcalcium homeostasis were assayed at baseline andvarious time intervals over the 20 weeks. Bone min-eral density of the lumbar spine and hip was deter-mined by dual-energy x-ray absorptiometry at base-line and 20 weeks. No alterations were noted inserum measurements of osteocalcin, calcium, 25-dihydroxyvitamin D, intact parathyroid hormone, orurinary hydroxyproline or calcium. A significant de-crease in serum 1,25-dihydroxyvitamin D was notedafter isotretinoin therapy. No changes were noted inbone mineralization of the lumbar spine or hip.

Kindmark A, Rollman O, Mallin H, Petren-Mallimin M, Ljunghall S,Melhus H. Oral isotretinoin therapy in severe acne induces tran-sient suppression of biochemical markers of bone turnover andcalcium homeostasis. Acta Derm Venereol 1998;78:266-9.

Eleven patients with nodulocystic acne weretreated with isotretinoin (mean maintenance dose,0.88 mg/kg per day; range, 0.66-1 mg) for 6 months.Biochemical markers of bone turnover were exam-ined at baseline and after 1, 5, and 14 days oftherapy. Bone mineral density (dual-energy x-rayabsorptiometry) of the lumbar spine was determinedat baseline and after 6 months of treatment. Tran-sient fluctuations in markers of bone turnover werenoted at 5 days. These values normalized by day 14.No significant radiologic changes or effects on bonemineral density were noted.

Leachman SA, Insogna KL, Katz L, Ellison A, Milstone LM. Bone den-sities in patients receiving isotretinoin for cystic acne. Arch Der-matol 1999;135:961-5.

Bone density and calcium metabolism were mea-sured in 18 men treated with isotretinoin for cysticacne (1 mg/kg per day for 6 months) and in 14control subjects. Bone density was measured at thelumbar spine, femoral neck, and Ward’s triangle (aregion of the femoral head). Bone density was vari-able in men with cystic acne, even at baseline. Nochanges in calcium metabolism as a result of treat-ment were noted. Changes in bone density werenoted at Ward’s triangle (mean decrease of 4.4%,P � .03) in treated patients. No significant changesin bone density were noted in the other 2 regions.The clinical significance of this change in bone den-sity has not yet been determined.

Modified guidelines for useCunliffe W, van de Kerkhof P, Caputo R, Cavicchini S, Cooper A, Fyr-

and O, et al. Roaccutane treatment guidelines: results of an in-ternational survey. Dermatology 1997;194:351-7.

An international group of 12 experts on acnetreatment met to formally review the survey of theirlast 100 patients with acne treated with oral isotreti-noin to identify the types of patients treated andhow their treatment was managed. Of the 1000 pa-tients reviewed, 55% were treated on the basis ofhistorical guidelines, and 45% were treated accord-ing to criteria that consisted of failure to respond toconventional oral antibiotic and topical therapy,scarring acne, acne causing psychologic distress,and acne that quickly relapses during or after con-ventional therapy. A discussion on dosing regimensand adverse effects is presented.

Intermittent isotretinoinGoulden V, Clark SM, McGeown C, Cunliffe WJ. Treatment of acne with

intermittent isotretinoin. Br J Dermatol 1998;137:106-8.


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Eighty patients with acne unresponsive to or re-lapsing rapidly after 3 or more courses of antibioticswere recruited. Patients were treated with isotreti-noin 0.5 mg/kg per day for 1 week every 4 weeks fora total of 6 months. Seventy-five patients completedthe study. Both total acne grade and lesion countswere significantly reduced at the end of treatment.The acne resolved in 68 (88%) of patients. The re-sponse was maintained in 68 patients who re-sponded, but 26 patients had relapses after 1 year.Higher relapse rate correlated to acne severity, trun-cal acne, and increased sebum excretion rate. Inter-mittent administration of moderate-dose isotretinoinmay be a cost-effective alternative to administrationof full doses in adults with facial acne, mild acne(fewer than 20 inflamed lesions), and a low sebumexcretion rate.

Issues of depression/suicideLamberg L. Acne drug depression warnings highlight need for ex-

pert care. JAMA 1998;8:1057.

Lamberg presents statistics for the rates of suicidereported before 1998 in patients taking isotretinoin(12 suicides/8 million treated patients) in the contextof the incidence of major depression in the acne agegroup of 15 to 24 years (6.1%). A brief discussion ofthe psychologic risks and benefits of isotretinointherapy is included.

Jick S, Kremers H, Vasilakis-Scaramozza C. Isotretinoin use and risk ofdepression, psychotic symptoms, suicide and attempted sui-cide. Arch Dermatol 2000;136:1231-6.

A population-based cohort study of 7195 isotreti-noin users and 13,700 oral antibiotic users from 2health databases was performed. The prevalencerates of neurotic and psychotic disorders, suicide,and attempted suicide were compared betweenisotretinoin and antibiotic users and within thegroup of isotretinoin users (before and after treat-ment). Relative risk estimates comparing isotretinoinuse and oral antibiotic use with nonexposure toeither drug for newly diagnosed depression or psy-chosis were approximately 1.0. Relative risks wereapproximately 1.0 before and after isotretinoin use.The relative risk estimate for attempted suicide was0.9 when current isotretinoin exposure was com-pared with nonexposure. The authors conclude thatthis study provides no evidence that use of isotreti-noin is associated with an increased risk for depres-sion, suicide, or other psychiatric disorders.

Wysowski DK, Pitts M, Beitz J. An analysis of reports of depression andsuicide in patients treated with isotretinoin. J Am Acad Derma-tol 2001;45:515-9.

An analysis was made of the reports of depres-sion, suicidal ideation, suicide attempt, and suicide

in US isotretinoin users voluntarily submitted to themanufacturer and the FDA from 1982 to May 2000and entered in the FDA’s Adverse Event ReportingSystem database. There were 37 reports of suicide;110 reports of patients hospitalized for depression,suicidal ideation or suicide attempt; and 284 reportsof depression without hospitalization. With institu-tion of the depression warning in 1998, there was aninflux of reports of depression received from anincreased percentage of patients and patients’ fami-lies. Isotretinoin ranks in the top 10 drugs for whichreports of depression and suicide attempt have beenreceived. Case reports of patients both with andwithout recurrence of depressive symptoms duringrepeat courses of isotretinoin are presented. Theauthors comment that additional studies are neededto determine whether isotretinoin causes depres-sion.

Minocycline. Adverse effects associated with theuse of minocycline include systemic lupus erythem-atosus; serum sickness-like reactions; autoimmunehepatitis; pseudotumor cerebri; pigmentation ofskin, sclera, mucous membranes, and alveolar bone;pneumonitis; and eosinophilia.

Chiu A, Chuenkongkaew W, Cornblath W, Trobe J, Digre K, Dotan S,et al. Minocycline treatment and pseudotumor cerebri syn-drome. Am J Ophthalmol 1998;126:116-21.

A retrospective study of 12 patients from 5 neuro-ophthalmic referral centers, in whom pseudotumorcerebri developed after administration of standarddoses of minocycline for acne, was performed. Sev-enty-five percent of cases of pseudotumor devel-oped within 8 weeks. Two cases developed after ayear. One patient was asymptomatic. No recur-rences were noted after 1 year. Three patients (25%)had residual visual field loss after 1 year. Withdrawalof minocycline and treatment for increased intracra-nial pressure led to resolution of the pseudotumorcerebri syndrome, but visual field loss may persist.

Goulden V, Cunliffe WJ. Safety of long-term high-dose minocyclinein the treatment of acne. Br J Dermatol 1996;134:693-5.

Seven hundred patients treated with minocyclinefor acne were studied. Two hundred patients weremonitored for adverse effects and laboratory abnor-malities; tests included complete blood count, deter-mination of blood urea nitrogen and electrolyte lev-els, and liver function tests. Adverse effects wererecorded in 13.6%. Pigmentation was the only ad-verse effect found to be significantly increased inpatients taking higher doses of minocycline as com-pared with those taking lower doses. All patientswith pigmentation had taken more than 70 g. Nosignificant abnormalities were found in any of the


JULY 2002

hematologic or biochemical profiles. Authors con-clude that minocycline is safe for long-term treat-ment of acne in doses up to 200 mg/d. The meanduration of treatment was 10.5 months. Dosesranged from 100 to 200 mg/d.

Gough A, Chapman S, Wagstaff K, Emery P, Elias E. Minocycline in-duced autoimmune hepatitis and systemic lupus erythemato-sus-like syndrome. Br Med J 1996;312:169-72.

Eleven cases of minocycline-induced systemic lu-pus erythematosus and 16 cases of hepatitis werereported to the Committee on Safety of Medicines inthe United Kingdom. An additional 7 cases are pre-sented. Two patients being treated for acne died,and one needed a liver transplant. The authors stressthe need for early recognition of minocycline reac-tions.

Sitbon O, Bidel N, Dusspopt C, Azariam R, Braud ML, Lebargy F, et al.Minocycline pneumonitis and eosinophilia. Arch Intern Med1994;154:1633-40.

Data are presented on 8 cases of minocycline-induced pneumonitis and eosinophilia in patientsbeing treated for acne (n � 4), genital infection (n �3), and Lyme disease (n � 1). The mean duration oftreatment was 13 � 5 days. The mean total dose was2060 � 540 mg. Patients presented with dyspnea,fever, dry cough, hemoptysis, chest pain, fatigue, orrash. Seven of 8 had eosinophilia.

Sturkenboom MC, Meier CR, Jick H, Stricker BH. Minocycline andlupuslike syndrome in acne patients. Arch Intern Med 1999;159:493-7.

A case-controlled study was conducted in a co-hort of 27,688 patients with acne, aged 15 to 29years, in general practitioners’ offices in the UnitedKingdom. Lupus-like syndrome was defined as theoccurrence of polyarthritis or polyarthralgia of un-known origin with negative rheumatoid factor orlatex agglutination test results, positive or unmea-sured antinuclear antibody level, elevated or unmea-

sured erythrocyte sedimentation rate, and absenceor unmeasured antinative DNA antibody levels. Cur-rent use of minocycline was associated with an 8.5-fold greater risk of developing lupus-like syndrome.

Acne scarringAlster T, McMeekin T. Improvement of facial acne scars by the 585

nm flashlamp-pumped pulsed dye laser. J Am Acad Dermatol1996;35:79-81.

Hypertrophic and erythematous facial acne scarswere treated with the flashlamp-pumped pulsed dyelaser in 22 patients. Scars on the opposite side of theface were used as a control. Scars were evaluated byphotography, grading of erythema with reflectancespectroscopy, and skin texture analysis. Significantclinical improvement was observed in laser-irradi-ated acne scars compared with untreated scars after1 or 2 laser treatments. Erythema measurements andskin texture analyses of laser-treated scars approxi-mated those obtained in adjacent normal skin.

Walia S, Alster T. Prolonged clinical and histologic effects from CO2

laser resurfacing of atrophic acne scars. Dermatol Surg 1999;25:926-30.

Sixty patients with moderate to severe atrophicfacial acne scars were evaluated in the immediatepostoperative period and during long-term fol-low-up (12-18 months) after laser resurfacing. Nine-teen patients received regional cheek treatment, and41 patients received full-face resurfacing with ahigh-energy pulsed carbon dioxide laser. Clinicaland histologic analyses of scars were performed atbaseline and at 1, 6, 12, and 18 months after resur-facing. Significant immediate and prolonged clinicalimprovement in skin tone, texture, and appearanceof carbon dioxide laser-irradiated scars was seen inall patients. On average, scars were improved by75% at 18 months compared with 67% improved at 6months. Histologically continued collagenesis anddermal remodeling were observed for up to 18months after surgery.


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