Guidelines of Care for Acne Vulgaris Management

Technical Report
 2

Acne Vulgaris

Table of Contents Page No.

Introduction ................................................................................................ 3

Clinical questions ....................................................................................... 3

Method of evaluation of evidence .............................................................. 4

Grading and classification systems............................................................ 7

Microbiological and endocrine testing ...................................................... 12

Topical agents.......................................................................................... 18

Systemic agents....................................................................................... 30

Hormonal agents...................................................................................... 36

Isotretinoin ............................................................................................... 42

Miscellaneous therapies .......................................................................... 49

Complementary/alternative therapies ...................................................... 53

Dietary restriction ..................................................................................... 58

Graded References.................................................................................. 60
 3

Introduction

Approximately 40-50 million people in the United States have acne vulgaris. It is the
most common skin disease, especially in adolescents and young adults. Acne affects
more than 85% of teenagers. There is no mortality associated with acne disease, but
there is often significant physical and psychological morbidity such as permanent
scarring, poor self-image, depression and anxiety. The direct cost of acne is estimated to
exceed $1 billion per year, with $100 million spent on over-the-counter acne products in
the United States.
Acne is a multifactorial disease affecting the pilosebaceous follicles of the skin. Some
factors that play an important role in the pathogenesis of acne are follicular
hyperkeratinization, microbial colonization, sebum production inflammation following
chemotaxis and the release of various pro-inflammatory mediators. Appropriate
evaluation and management of acne vulgaris are important. At present there are many
topical and systemic therapeutic options available for the treatment of acne because of
the multifactorial etiology of acne vulgaris. Various therapies are discussed in the
“Guidelines of care for acne vulgaris management” (J Am Acad Dermatol. 2007
Apr;56(4):651-63).

Clinical Questions

This is a comprehensive search of the peer-reviewed biomedical literature and analysis

of the evidence regarding therapies for acne as a basis for the development of the
American Academy of Dermatology (AAD) clinical guidelines of care for the treatment of
acne.
Specific Clinical Questions addressed in the acne guidelines are the following:

I. What systems are most commonly used for the grading and classification of adult
acne and acne vulgaris in adolescents (11 to 21 years) to adults?

II. What is the role of microbiological and endocrine testing in evaluating patients
with adult acne and acne vulgaris in adolescents to adults?

III. What is the effectiveness and what are the potential side effects of the following
topical agents in the treatment of adult acne and acne vulgaris in adolescents to
adults including:
a) retinoids and retinoid-like drugs
b) benzoyl peroxide
c) topical antibiotics
d) salicylic/azelaic acids
e) sulfur and resorcinol
f) aluminum chloride
g) zinc
h) combinations of topical agents

IV. What is the effectiveness and what are the potential side effects of the following
systemic antibacterial agents in the treatment of adult acne and acne vulgaris in
adolescents to adults including:
a) tetracyclines: doxycycline, minocycline
b) macrolides: erythromycin
 4

c) clindamycin
d) trimethoprim
e) ampicillin/amoxicillin

V. What is the effectiveness and what are the potential side effects of hormonal
agents in the treatment of adult acne and acne vulgaris in adolescents to adults
including:
a) contraceptive agents, especially oral preparations
b) spironolactone
c) antiandrogens
d) oral corticosteroids

VI. What is the effectiveness and what are the potential side effects of isotretinoin in
the treatment of adult acne and acne vulgaris in adolescents to adults?

VII. What is the effectiveness and what are the potential side effects of miscellaneous
therapies in the treatment of adult acne and acne vulgaris in adolescents to
adults including:
a) chemical peels
b) comedo removal
c) intralesional steroids

VIII. What is the effectiveness and what are the potential side effects of
complementary/alternative therapies in the treatment of adult acne and acne
vulgaris in adolescents to adults including:
a) herbal agents
b) homeopathy
c) psychological approaches
d) massage therapy
e) hypnosis/biofeedback

IX. What is the effectiveness of dietary restriction in the treatment of adult acne and
acne vulgaris in adolescents to adults?

Method

Evidence evaluated for this report was obtained primarily from a search of MEDLINE
and EMBASE databases spanning the years 1966 to 2006.
The available evidence was evaluated using a unified system called the Strength of
Recommendation Taxonomy (SORT) developed by editors of the US family medicine
and primary care journals (i.e., American Family Physician, Family Medicine, Journal of
Family Practice and BMJ-USA). This strategy was supported by a decision of the Clinical
Guidelines Task Force in 2005 with some minor modifications for a consistent approach
to rating the strength of the evidence of scientific studies.1 Evidence was graded using a
three-point scale based on the quality of methodology as follows:

I Good quality patient-oriented evidence

II Limited quality patient-oriented evidence
 5

III Other evidence including consensus guidelines, extrapolations

from bench research, opinion or case studies
 6

Clinical recommendations were developed based on evidence tabled in the guideline

and explained further in the technical report. These are ranked as follows:

A. Recommendation based on consistent and good-quality patient-oriented evidence

B. Recommendation based on inconsistent or limited quality patient-oriented evidence
C. Recommendation based on consensus, opinion or case studies

For each intervention within the Clinical Questions, an effort was made to identify and
present the best evidence regarding its use in the treatment of acne. Studies of clinical
measurements of outcome were considered for analysis whether or not the clinical
outcome was the primary outcome measured.

Disclosure of Significant Relationships with Relevant Commercial

Companies/Organizations

The Academy must ensure balance, independence, objectivity and scientific rigor in its
evidence-based guidelines of care. The Board of Directors requires that all participating
members of the guidelines of care associated work groups must comply with regulations
governing disclosure.

All participants are expected to disclose in the document “Authors’ Conflict of Interest
Disclosure Statement” any significant financial interest or other relationship with the
manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services
discussed by them. The intent of this disclosure is not to prevent anyone with a
significant financial or other relationship from participating, but rather to provide readers
of the guidelines with information on which to make their own judgments. It remains for
the reader to determine whether any work member’s interests or relationships may
influence the discussion. Following are the Work Group members that developed the
acne guidelines along with their affiliation and disclosure of potential conflict of interest:”

John Strauss, MD, Chair Acne Work Group – the Department of Dermatology, Roy J.
and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa
Dr. Strauss was a consultant and investigator for Roche Laboratories receiving
honoraria and grants, and a consultant for Medicis receiving honoraria.

Karl R. Beutner, MD, PhD, Chair Clinical Guidelines Task Force – Anacor
Pharmaceuticals, Inc., Palo Alto, California
Dr. Beutner was an employee of Anacor receiving salary and stock options and a
stockholder of Dow Pharmaceutical Sciences receiving stock.
Daniel Krowchuk, MD – the Departments of Pediatrics and Dermatology, Wake Forest
University School of Medicine, Brenner Children’s Hospital, Winston-Salem, North
Carolina
Dr. Krowchuk had no relevant conflicts of interest to disclose.
James J. Leyden, MD – the Department of Dermatology, University of Pennsylvania
Hospital, Philadelphia, Pennsylvania
Dr. Leyden was a consultant for Stiefel and SkinMedica, receiving honoraria; served on
the Advisory Board and was a consultant for Galderma and Obaj, receiving honoraria;
was on the Advisory Board and was a consultant and investigator for Connetics,
Collagenex, Allergan, and Medicis, receiving honoraria.
 7

Anne W. Lucky, MD – the Division of Pediatric Dermatology, Cincinnati Children's

Hospital Medical Center and the University of Cincinnati School of Medicine, Cincinnati,
Ohio
Dr. Lucky was an investigator for Connetics, Dow, Galderma, Healthpoint, Johnson &
Johnson, QLT, and Stiefel, receiving grants, and an investigator and consultant for
Berlex receiving grants and honoraria.
Alan R. Shalita, MD – the Department of Dermatology, State University of New York
Downstate Medical Center, Brooklyn, New York
Dr. Shalita was a consultant, investigator, stockholder, and speaker for Allergan,
receiving grants and honoraria; a consultant for Bradley/Doak receiving honoraria;
served on the Advisory Board and was a consultant for Collagenex, receiving honoraria;
was a consultant and investigator for Connetics receiving grants and honoraria; an
Advisory Board member, consultant, investigator, and speaker for Galderma receiving
grants and honoraria; a consultant, speaker, and stockholder for Medicis receiving
honoraria; an Advisory Board member for Ranbaxy receiving honoraria; and a
consultant, investigator, and speaker for Stiefel, receiving grants and honoraria.
Elaine C. Siegfried, MD – the Department of Dermatology, St. Louis University School of
Medicine, St. Louis, Missouri
Dr. Siegfried was an investigator for Atrix receiving salary.

Diane M. Thiboutot, MD – the Department of Dermatology, Pennsylvania State

University College of Medicine, Milton S. Hershey Medical Center, Hershey,
Pennsylvania
Dr. Thiboutot served on the Advisory Board and was an investigator and speaker for
Allergan and Galderma, receiving honoraria; was on the Advisory Board and was a
consultant and investigator for Collagenex receiving honoraria; was on the Advisory
Board and was an investigator for Connetics, Dermik, and QLT, receiving honoraria; and
was a consultant, investigator, and speaker for Intendis, receiving honoraria.

Abby S. Van Voorhees, MD – the Department of Dermatology, University of

Pennsylvania Hospital, Philadelphia, Pennsylvania
Dr. Van Voorhees served on the Advisory Board and was an investigator and speaker
for Amgen, receiving grants and honoraria; was an investigator for Astellas, Bristol
Myers Squibb, and GlaxoSmithKline, receiving grants; was an Advisory Board member
and investigator for Genentech and Warner Chilcott, receiving grants and honoraria; was
on the Advisory Board for Centocor receiving honoraria; was a speaker for Connetics
receiving honoraria; and was a stockholder of Merck, owning stock and stock options.

Carol Sieck, RN, MSN – the American Academy of Dermatology, Schaumburg, Illinois
C. Sieck had no relevant conflicts of interest to disclose.

Reva Bhushan, PhD - the American Academy of Dermatology, Schaumburg, Illinois

Dr. Bhushan had no relevant conflicts of interest to disclose.
 8

I. Grading and classification systems of adult acne and acne vulgaris in

adolescents (11 to 21 years) to adults

Many acne grading and classification systems have been proposed but at present there
is not any one system universally accepted for assessing and grading acne severity. The
grading and classification of acne is essential for the initial evaluation as a base of
comparison during treatment and as a method to assess clinical trials. Acne severity is
generally considered the most important patient characteristic used in determining
individual treatment profiles. There are several grading/classification systems; most
include lesion counting combined with some type of global severity assessment. Global
evaluation takes into account the total impact of the disease. Grading systems are
mainly used in clinical studies for the evaluation of acne treatment. Comparing
therapeutic efficacy in different studies because of the lack of a validated classification
system becomes difficult. It is important to standardize a specific and reproducible
method to grade the severity of acne.
 9

Table 1. Acne Grading/Classification Systems

Level
Author/Date/
of Evi- Type of scale Method of Assessment Conclusions
study design
dence

Lehmann et al., J Am Acad
II Dermatol 2002; 47: 231-40.2
Methodological review of
literature and
recommendations.
Review of acne The target population for the review 250 papers were reviewed. There were more than
clinical trials to was all patients with acne who did not 25 different methods of assessment of acne
provide clinicians the have complicating co-morbidities such severity and 19 methods of counting lesions. There
background needed as endocrinopathies. were many different ways the outcomes were
to interpret current expressed. There was no standard approach to
and future clinical The search was an expert-advised describing side effects, and no standard follow-up
trials, and scientists a structured literature synthesis. times.
basis for further
The authors made recommendations for the
studies.
scientists for future clinical trials.

Pochi et al.,
II J Am Acad Dermatol 1991;
24: 495-500.3
AAD Consensus conference
on acne classification.
Global evaluation of Includes a total evaluation of lesions
lesions. and complications; categorizes
inflammatory lesions as mild, moderate
or severe.
Panel recommendations:
Dividing acne into 4 grades of severity was overly
simplistic.
It is the opinion of the consensus panel that acne
grading can be accomplished by the use of a
pattern-diagnosis system, which includes a global
(total) evaluation of lesions and their complications.
A strictly quantitative definition of acne severity
cannot be established because of the variable
expression of the disease.
The clinical diagnosis of acne severity should be
based on persistent or recurrent inflammatory
nodules, papulopustular disease, ongoing scarring,
drainage from lesions or the presence of sinus
tracks and psychological factors.
The consensus panel recommendations did not
include non-inflammatory lesions.
 10

Level
Author/Date/
of Evi- Type of scale Method of Assessment Conclusions
study design
dence

Doshi et al., Int J Dermatol
1997; 36: 416-8.4
II
This paper proposed a new
grading system called Global
Acne Grading System
(GAGS).
Global Acne Grading The GAGS considers 6 locations on the
System (GAGS) face and chest/upper back, with factor
for each location based on surface
area, distribution and density of
pilosebaceous units. Each of the six
locations is graded separately on a 0-4
scale. The global score is a summation
of each factor.
This system is accurate and reproducible. Grading
with the GAGS system takes under 1 minute in an
office setting.
The authors suggest that time saved in grading can
be spent on counseling patients.
Includes both inflammatory and non-inflammatory
lesions.
Patients with numerous lesions confined to only 1
or 2 locations may end up with a lower total score
and less severe classification than observed
clinically.

Level
Author/Date/
of Evi-
study design
dence
Allen and Smith, Arch
Dermatol 1982; 118: 23-5.5
II
Randomized, double-blinded,
placebo-controlled trial to
evaluate grading of acne
severity.
Cook et al., Arch Dermatol
II 1979; 115: 571-5.7
Double-blinded, placebo-
controlled trial to determine a
method of grading of acne
severity.
11
Type of scale Method of Assessment Conclusions
Acne severity and Study 1. Physicians and research The authors concluded that acne grading scales
comedo grading scale technician evaluated 190 subjects - and papule counts are equally reproducible
including lesion male college students with acne at methods of grading inflammatory acne. The
counts. baseline and every two weeks comedo grading scale and comedo count are
independently for 12 weeks. All equally reproducible.
subjects at each visit received a
This study does not include the back and chest. It
severity grade, papule count, pustule
uses half of the face for comedo and papule
count and comedo grade. Comedo
counts; both sides of the face for pustule counts
counts were not performed in this
and severity grades.
study.
Study 2. Physicians and research
technician evaluated 141 male college
students with acne at baseline and
every two weeks independently for 10
weeks. All subjects at each visit
received a severity grade, papule
count, pustule count and comedo
grade. Comedo count was also done.
Severity scale ranges from 0 (no or few
comedones) to 8 (all of facial area
involved with large, prominent
nodules). This study used the acne
grading scale devised by Cook et al.7
Photographs of all the subjects were
also used for evaluations.
Acne severity grading Double-blinded, controlled clinical trial. The overall severity grade based on the 0 to 8
scale. Ranges from 0 (no or few comedones) scale with the photographic reference standards
to 8 (all of facial area involved with showed to be useful, reliable and sensitive.
large, prominent nodules).
The photograph creates a permanent record.
Uses photographic reference
This method includes both inflammatory and non-
standards; photographs taken at each
inflammatory lesions.
visit become part of patient’s clinical
record.
 12

Level
Author/Date/
of Evi- Type of scale Method of Assessment Conclusions
study design
dence

Lewis-Jones and Finlay,
II Br J Dermatol 1995; 132:
942-9.11
The aim of the study was to
create and validate a simple
questionnaire to measure the
quality of life in children with
skin disease.
Children’s This study was conducted on 169 The CDLQI is based on the Dermatology Life
Dermatology Life children aged 3-16 years in a pediatric Quality Index (DLQI).
Quality Index dermatology clinic for 1 year.
CDLQI provides a new technique for comparative
(CDLQI).
A 10-item questionnaire was used in purposes.
this study, similar to the adult DLQI
This is a simple scoring method. This method can
questions. The questionnaire was
be used for clinical trials and clinical practice.
designed for a child. It may sometimes
require parent’s help. Each question
was scored individually. The CDLQI
score was calculated by adding the
scores of the 10 questions. Scores
range from 0-30, 0 being the best
score.
 13

II. The role of microbiological and endocrine testing in evaluating patients with
adult acne and acne vulgaris in adolescents to adults

The most prevalent bacterium implicated in the clinical course of acne is

Propionibacterium acnes (P. acnes), a gram-positive anaerobic bacterium that normally
inhabits the skin. Studies have found that in patients affected with acne, the population
of P. acnes is higher than in the unaffected general population. Routine microbiologic
testing is unnecessary in the evaluation and management of patients with acne. In
patients who exhibit acne-like lesions, microbiologic testing may be helpful. Gram-
negative folliculitis is an uncommon complication often observed following long-term
systemic treatment of acne.
Adrenal and gonadal androgens play an integral role in the pathogenesis of acne.
Laboratory evaluation is indicated for those with acne and additional signs of androgen
excess. Most people with acne have normal levels of androgenic hormones, despite the
importance of androgens in this disorder. However, in females, acne severity and other
virilizing signs are associated with subtle differences in circulating androgens. These
include elevated free testosterone and DHEA-S, and reduced sex hormone-binding
globulin (SHBG). Presently, routine endocrinologic testing is not indicated for the
majority of patients with acne. Laboratory tests like free testosterone DHEA-S, LH and
FSH may be helpful.
 14

Table 2a. Microbiological Testing

Level
of Author(s)/Date/ Method of
Study Population Results Conclusions
Evi- Study Design Assessment
dence
Cove et al., Br J Dermatol Ages 18-20 years. Degree of acne This study showed no difference in There is no co-relationship
II 1980; 102: 277-80.16 (1) 35 patients with was graded on a the number of microorganisms between the severity of acne
2 separate studies to determine mild acne and 35 simple scoring between mild and moderate study and the number of bacteria.
levels of P. acnes and patients with system: groups. There is no direct relationship
Micrococcaceae. moderate acne bacteria sampled There was no significant decrease in between the size of the
were compared for using scrub bacterial populations after 3 months bacterial population and the
(1) This study compared
level of P. acnes method. of tetracycline. extent of acne severity.
bacterial populations on
and Micro- CFU (colony- There was not a significant decrease Greater numbers of bacteria
foreheads of patients with mild
coccaceae. forming units) were in the number of P. acnes or are not associated with
to moderate acne.
(2) 12 patients on determined by Micrococcaceae after the 3 months of increasing severity of acne. The
(2) This study compared
250 mg of plating out ten-fold treatment of either bacterium. effectiveness of oral
bacterial populations and acne
tetracycline twice serial dilutions. There was a significant decrease in tetracycline in treating acne
grade pre-treatment and post-
daily for 3 months Colonies were the acne grade in patients after 4 cannot be explained by the
treatment with tetracycline
were compared for counted after 7 weeks of therapy. reduction in the number of
250 mg twice daily for 3 months.
bacterial days or 48 hours viable bacteria.
populations of P. anaerobically for P.
acnes and acnes and
Micrococcaceae. Micrococcaceae.

Level
of Author(s)/Date/
Evi- Study Design
dence
Bojar et al., Drugs 1995; 49
II Suppl 2: 164-7.17
Double-blinded, randomized
clinical study to assess 1%
nadifloxacin compared to 2%
erythromycin to determine the
susceptibility of all cutaneous
microorganisms isolated before
and after treatment of patients
with mild/moderate facial acne.
15
Method of
Study Population Results Conclusions
Assessment
86 volunteers with Used the scrub Significant reduction in the number of It was demonstrated that topical
mild/moderate technique. propionibacteria with both 1% 1% nadifloxacin is clinically as
acne: nadifloxacin and 2% erythromycin effective as and
1% nadifloxacin after 12 weeks. microbiologically superior to 2%
(n=43); The carriage of Micrococcaceae was erythromycin.
2% erythromycin reduced in the nadifloxacin treated Widespread incidence of
(n=43). group only. erythromycin-resistant
propionibacteria may limit future
Minimum inhibitory concentration
(MIC)values were determined. usefulness of erythromycin as a
therapeutic agent.
After 12 weeks of treatment with
nadifloxacin, no resistant bacteria
were isolated.
Erythromycin-resistant P. acnes and
erythromycin-resistant
Micrococcaceae were isolated from
27.9% and 97.7% erythromycin-
treated subjects respectively.

Level
of Author(s)/Date/
Evi- Study Design
dence
Eady et al., Br J Dermatol
II 1989; 121: 51-7.18
Controlled study to determine
the incidence of erythromycin-
resistant propionibacteria in
various groups treated with
antibiotics for acne.
16
Method of
Study Population Results Conclusions
Assessment
51 patients on oral Bacterial samples 42-51 bacteria were isolated from the This study showed that the use
erythromycin and were obtained by skin surface of both erythromycin- of oral erythromycin has
53 patients on detergent scrub and clindamycin-treated patients developed more resistant
topical clindamycin technique. compared to 3% of controls. bacteria than the use of topical
were included in the MIC of each Patients responding to erythromycin clindamycin.
study; 100 control antibiotic was carried less erythromycin-resistant
This study suggests that use of
subjects. recorded as the bacteria compared to patients who
oral erythromycin should be
lowest did not respond or those who had
limited to patients with no
concentration relapsed.
previous exposure to the drug
yielding no growth.
There was an increased incidence of and therapy should be
erythromycin-resistant bacteria in discontinued after 6 months to
clindamycin patients who had used allow any resistant bacteria to
erythromycin previously compared to be overgrown by sensitive
those who received no erythromycin. bacteria. The use of benzoyl
peroxide alone for a short
period may eradicate resistant
bacteria.
 17

Level
of Author(s)/Date/ Method of
Study Population Results Conclusions
Evi- Study Design Assessment
dence
Harkaway et al., Br J Dermatol 60 subjects (30 Cultures obtained After 12 weeks of treatment with the These results showed that
II 1992; 126: 586-90.19 male, 30 female) from the forehead erythromycin group, the aerobic flora topical erythromycin excretes a
ages 18-30 years. at 0, 4, 8, 12 and dominated by S. epidermis (2/3) selective pressure.
Controlled trial to examine the 2% erythromycin 16 weeks of which was completely erythromycin- Erythromycin-resistant strains
development of antibiotic (n=20) treatment. resistant. were suppressed the same as
resistance in coagulase- 5% benzoyl There was also an increased sensitive strains.
negative staphylococci during peroxide (n=20) resistance to tetracycline and The use of benzoyl peroxide
treatment with of erythromycin, 5% benzoyl clindamycin. interferes with the selection or
benzoyl peroxide or combination peroxide + 3% the induction of erythromycin-
of the two for 16 weeks. erythromycin (n=20) Treatment with benzoyl peroxide and
resistant bacteria.
the combination of benzoyl peroxide
+ erythromycin resulted in significant
decrease in the number of aerobic
bacteria without any change in
resistance pattern to erythromycin or
other antibiotics.
 18

Table 2b. Endocrine testing

Level
of Author(s)/Date/ Study Population/
Method of Assessment Results Conclusion
Evi- Study Design Intervention
dence
Lawrence et al., Moderate to severe acne Testosterone concentration 29% of women with acne had elevated This study shows
Clin Endocrinol (simple acne) (n=24); was measured by testosterone levels and 41% had free testosterone that a deficiency in
I
(Oxf) 1981; 15: 87- chromatography and RIA. elevated values. SHBG and an
Moderate to severe acne
91.20 elevation in derived
and with hirsutism and/or Testosterone concentrations were higher in both free testosterone is
Controlled cohort trial irregular menstrual cycles acne groups compared with controls. a frequent finding in
to determine levels of (complicated acne)
There was no correlation between the women with severe
SHBG, testosterone (n=23);
concentration of testosterone and SHBG. acne.
and free testosterone
Unaffected women as
in women with
controls (n=15);
moderate to severe
acne and hirsutes. No patients or controls
were receiving oral
contraceptives.
Lucky et al., J 871 fourth and fifth grade The degree of facial acne No racial differences in acne or hormonal levels The results suggest
Pediatr 1997; 130: girls were in this study was classified annually as were found. that the early
I
30-9.22 Black (n=439) mild, moderate or severe. development of
There were more comedones at early age in girls
White (n=432) comedonal acne
5-year longitudinal Blood samples were obtained who later developed severe acne.
may be the best
cohort study to Subjects were placed in 3 at first, third and fifth years of
Those who developed severe inflammatory acne predictor of later
determine which groups based on severity study.
had more inflammatory and comedonal lesions more severe
factors in early of acne at year 5.
Facial comedonal and from -36 months to +36 months from menarche disease.
pubertal girls might
Mean acne scores, level nodular inflammatory lesions compared with girls who developed mild acne.
be predictive of later The DHEAS
of sex steroid hormones were recorded in the following
severe facial acne. Girls who developed mild acne had significantly concentration is
and testosterone-estrogen way:
later menarche than girls who developed severe higher in those girls
binding globulin (TEBG)
Mild – up to 10 lesions; given acne. destined to have
were compared among
a numerical value of 5. severe acne.
the 3 groups. Girls who developed severe comedonal acne had
Moderate – 11-25 lesions; significantly increased DHEAS and somewhat
given a numerical value of 17. increased testosterone and free testosterone.
Severe – more than 25 There were no differences in estradiol,
lesions; given a numerical progesterone and TEBG.
value of 25.
 19

III. Topical agents in the treatment of adult acne and acne vulgaris in
adolescents and adults

The effectiveness of topical therapy for acne is well-known. Topical retinoids are the
most effective comedolytic agents and since the microcomedo is thought to be the
precursor of all other acne lesions, they are appropriate for comedonal and inflammatory
acne. The effectiveness of topical retinoids (adapalene, tazarotene, tretinoin and
isotretinoin) is well documented. Topical retinoids such as tretinoin and adapalene
correct abnormalities in follicular keratinocytes. Topical isotretinoin is not available in the
United States. Salicylic acid and azelaic acid are weaker comedolytic agents, but may
be useful when retinoids are not tolerated. Topical antimicrobials include benzoyl
peroxide and topical antibiotics. Topical antibiotics such as clindamycin, tetracycline, and
erythromycin are bacteriostatic for P. acnes and are effective for mild to moderate
inflammatory acne. Benzoyl peroxide is bactericidal and improves both inflammatory and
non-inflammatory lesions. It is an oxidizing agent that works by introducing oxygen into
follicles, which then kills P. acnes. This is why P. acnes does not develop resistance to
benzoyl peroxide. In addition, there is increasing resistance to antibiotics by P. acnes.
Combining benzoyl peroxide with antibiotics reduces or eliminate this resistance. Sulfur,
resorcinol, aluminum chloride and sodium sulfacetamide are weaker antimicrobial
agents which can be useful in selected circumstances. Topical zinc alone is ineffective
but may enhance the activity of antimicrobial agents. Combination therapy, involving
benzoyl peroxide or retinoids and oral antibiotics, is effective treatment for acne.

Table 3a. Use of Topical Retinoids
Level of Author(s)/Date/
Evidence Study Design
Christiansen et al.,
Dermatologica 1974; 148:
I
82-9.25
Double-blinded,
randomized clinical trial to
evaluate the effect of
topical tretinoin in patients
with of acne.
Chalker et al., J Am Acad
Dermatol 1987; 17: 251-
I
4.28
Multicenter, randomized,
double-blinded, controlled
clinical trial to determine
the efficacy of 0.05%
topical isotretinoin gel in the study.
treatment of acne
compared its vehicle.
Study Population/
Intervention
256 patients with acne were
randomized to receive 1 of the
following daily for 12 weeks:
Tretinoin 0.02% cream,
Tretinoin 0.05% cream,
Placebo vehicle control.
Patients were evaluated at
baseline, 2, 4, and 8 weeks of
treatment.
231 patients completed the
study.
313 subjects (age range 13-30
years) with at least 12
inflammatory lesions, 12 non-
inflammatory lesions, and no
more than 3 facial nodulocystic
lesions.
268 subjects completed the
Subjects were randomized to
receive 0.05% isotretinoin or
vehicle gel twice daily for 12-14
weeks.
Subjects were evaluated at 0, 2,
5, 8, 10-11, and 12-14 weeks of
treatment.
20
Method of
Assessment Results Conclusions
The effect of There was a statistically significant Tretinoin is very
treatment was reduction in comedones and papules successful in reducing
determined by compared to placebo. comedones and
counting the papules.
0.05% cream had a quicker onset of
comedones,
action and had quantitatively greater A very high rate of
papules, pustules
effect than 0.02% cream. adverse effects was
and cysts and
seen.
scoring each type of Pustule and cyst counts were not
acne lesion at significantly different for all the 3
baseline and at 2, 4, groups.
and 8 weeks.
Local adverse reactions such as
erythema and peeling were noted by
40% of placebo group, and 81% and
86% in the 0.05% and 0.02% groups
respectively.
Facial inflammatory At 8 weeks, the non-inflammatory 0.05% isotretinoin gel
and non- lesion count was significantly is effective in the
inflammatory reduced in the isotretinoin-treated treatment of acne.
lesions were group compared to the placebo
More adverse effects
counted and overall group.
were observed in the
acne grade
Inflammatory and non-inflammatory treated group than in
assigned using
lesion counts were reduced by 55% the placebo group.
Cook’s et al.
and 46% respectively in the treated
method (0-8). 7
group compared to 25% and 14%
reduction in the placebo group.
Mean acne severity grade was
reduced by 40% after 12 weeks
isotretinoin treated vs. placebo
peeling: 71% 51%
erythema: 76% 62%
 21

Level of Author(s)/Date/ Study Population/ Method of

Evidence Study Design Intervention Assessment Results Conclusions
Shalita et al., Cutis 1999; 446 subjects (14-44 years) with Percentage of There was significant reduction in Tazarotene 0.1% and
63: 349-54.38 mild to moderate facial acne change was non-inflammatory and total lesion 0.05% aqueous gels
I
were randomized to receive determined by count at week 12. were safe and effective
Multicenter, double-blinded,
tazarotene 0.1% gel, tazarotene lesion count and in reducing acne lesion
randomized, parallel-group, 0.1% gel tazarotene had of 68%,
0.05% gel, or vehicle-only global evaluation count.
controlled trial to evaluate 0.05% gel tazarotene had 51% and
placebo daily for 12 weeks. response to
the safety and efficacy of placebo had 40% reduction of non- Both concentrations
Patients were evaluated at 0, 4, treatment methods.
tazarotene in the treatment inflammatory and total lesion counts. had acceptable
8, and 12 weeks of treatment.
of acne. Pharmacokinetics tolerability.
333 subjects completed the and safety analyses
There were few
study. were conducted.
adverse events.

Lucky et al., J Am Acad
Dermatol 1998; 38: S17-
I
23.41
Multicenter, double-blinded,
randomized, parallel-group,
vehicle-controlled trial to
evaluate the safety and
efficacy of tretinoin with
polyolprepolymer-2
compared with
commercially available
0.025% tretinoin gel in the
treatment of acne.
215 patient study; patients were
randomized to receive any one
of the treatments.
The formulation tested ethanol
gel containing 0.025% tretinoin
gel and polyolprepolymer-2, (n-
71) vehicle control (n-70) and
commercially available 0.025%
tretinoin gel (n-72).
Evaluations were performed at
day 0, 7, 14, 28, 56 and 84.
Efficacy The efficacy of both treatments was Both treatments
assessments were comparable and more effective than demonstrated
measured by lesion the control vehicle. comparable efficacy.
counts and Physical
The gel containing polyolprepolymer-
Global Evaluation
2 caused significantly less peeling
(PGE).
and drying than the commercially-
available gel by day 84 of the study.

Table 3b. Use of Benzoyl Peroxide
Level of Author(s)/Date/
Evidence Study Design
Belknap, Cutis 1979; 23:
856-9.42
I
Randomized, controlled
clinical trial to compare the
effectiveness of topical
benzoyl peroxide and
tretinoin in the treatment of
acne.
Schutte et al., Br J
Dermatol 1982; 106: 91-
I
4.48
A multicenter, randomized,
double-blinded, placebo-
controlled study to
determine the effect of a
5% benzoyl peroxide lotion
in the treatment of acne
compared to its base.
Study Population/
Intervention
69 patients ages 15-30 with
acne.
Patients were randomly
assigned to receive 0.05%
vitamin A acid cream or benzoyl
peroxide 5% gel treatments for 8
weeks.
Subjects were evaluated at
baseline and after 2, 4, and 8
weeks for the response to the
treatments.
65 patients ages 17-23 years
with acne.
Patients were randomly
assigned 5% benzoyl peroxide
lotion or placebo/base.
22
Method of
Results Conclusions
Assessment
Patients were A significantly higher percentage of The benzoyl peroxide
evaluated by total patients in the benzoyl peroxide group showed
lesion counts. group exhibited excellent overall improvement earlier
response compared to the retinoic than the retinoic acid
Overall evaluation
acid group. group.
of clinical response
was done for each Both treatment groups were effective Statistically, there was
patient. in reducing lesions. no significant
difference between the
There was significantly less peeling two drugs after 8
in the benzoyl peroxide compared to weeks.
the vitamin A acid group after 4
This study should
weeks.
have used proper
controls especially
because the trial is
comparing gel versus
cream. Each treatment
should have had its
respective vehicle as a
control.
Patients were The control preparation had no effect This study indicates
evaluated by lesion on the number of papules or that 5% benzoyl
count before the pustules. peroxide lotion does
start of therapy and have a rapid effect in
There was a significant reduction of
after 5 days after resolving inflamed
lesions seen in the treatment group
treatment. lesions.
and there was significantly reduced
Facial fluorescence facial prophyrin fluorescence. The mechanism of
by ultraviolet action of benzoyl
photography was peroxide lotion should
done. be studied.
The degree of Larger populations of
redness and scaling patients are required
was recorded. in studies to prove
safety and efficacy.
 23

Level of Author(s)/Date/ Study Population/ Method of

Evidence Study Design
Smith et al., Cutis 1980;
25:90-2.50
I
A multicenter, randomized,
double-blinded, controlled
study to evaluate the effect
of 20% benzoyl peroxide
lotion in the treatment of
acne.
Intervention
59 patients (mean age 20 years,
range 18-30) with at least 10
inflammatory lesions and 3 or
fewer nodulocystic lesions were
selected for the study.
The patients were randomized to
receive 20% benzoyl peroxide
lotion or placebo lotion base
twice daily for 12 weeks:
Benzoyl peroxide 20% lotion
(n=29);
Placebo control lotion (n=30).
Subjects were evaluated at
baseline and every 2 weeks.
Results Conclusions
Assessment
Patients were Benzoyl peroxide treated group had This study showed
evaluated for an excellent response compared to that 20% benzoyl
efficacy by counting the placebo group. peroxide is effective in
all lesions on the reducing the lesions of
Redness and peeling were observed
face. acne.
in both groups but more in the active
Erythema and treated group. There was some
peeling were also improvement in the
assessed. placebo group also.
Study with a larger
number of population
is required to prove
safety and efficacy.
 24

Table 3c. Use of Topical Antibiotics

Level of Author(s)/Date/ Study Population/ Method of

Evidence Study Design
Bernstein and Shalita, J
Am Acad Dermatol 1980;
I
2: 318-21.52
Randomized, placebo-
controlled trial to evaluate
the effectiveness of topical
2% erythromycin compared
to its vehicle in the
treatment of acne.
Results Conclusions
Intervention Assessment
348 patients (age range 13-30 Efficacy was There was a significant reduction in Topical erythromycin is
years) with inflammatory acne assessed by total papulopustule count in the treatment effective in the
were randomized to receive 2% lesion count and group compared to the placebo treatment of
erythromycin solution (n=178) or papulopustule group. papulopustular acne.
placebo control (n=170) twice count.
Comedones and cysts and total Vehicle base
daily for 8 weeks.
Physician global lesions were not significantly different preparation contained
Patients were evaluated at severity rating was after 8 weeks in both groups. alcohol and
baseline and after 2, 4, 8 and 12 assessed at polyethylene which are
Fewer adverse effects were noted in
weeks. baseline and after local irritants.
the active preparation compared to
2, 4, and 8 weeks of
the placebo group.
treatment.

Jones and Crumley, Arch
Dermatol 1981; 117: 551-
I
3.53
Randomized, double-
blinded, placebo-controlled
trial to evaluate the
effectiveness of topical 2%
erythromycin compared to
its vehicle in the treatment
of acne.
175 subjects (ages 12 years and
over) with inflammatory acne
were randomized to receive 2%
erythromycin (n-90) solution or
placebo control (n-85) twice daily
for 12 weeks.
Efficacy was The total count of inflammatory Topical 2%
assessed by total pustules was significantly reduced erythromycin
lesion count and after therapy in the 2% erythromycin demonstrated
inflammatory group. significantly better
papulopustule results than the blank
After 12 weeks, there was a 56%
count. vehicle.
papule reduction in the treated group
compared to 33% in the blank Study confirms the
vehicle group. effectiveness of topical
erythromycin in the
62% of subjects in the topical 2%
treatment of acne.
erythromycin group had good to
excellent response compared to 27% Adverse effects were
in the blank vehicle. similar in both groups.
 25

Level of Author(s)/Date/ Study Population/ Method of

Results Conclusions
Evidence Study Design Intervention Assessment
Lesher et al., J Am Acad 225 subjects (range 14-30 years) Facial inflammatory Erythromycin group had 46% mean This study showed that
Dermatol 1985; 12: 526- with at least 10 inflammatory lesions were lesion count reductions compared to 2% erythromycin
I
31.55 lesions, 10 non-inflammatory counted and overall 19% in the placebo group after 12 ointment was
lesions, and no more than 3 severity grade was weeks of treatment. significantly more
Multicenter, double-blinded,
nodulocystic lesions were assessed using effective than its
controlled clinical trial to Topical 2% erythromycin group had a
randomized to receive topical Cook’s et al. 7 placebo control in
assess the effectiveness of 40% reduction in mean acne severity
2% erythromycin ointment grading scale for decreasing
topical 2% erythromycin in grade compared to 23% reduction for
(n=112) or placebo vehicle acne severity 0-8 inflammatory acne
the treatment of acne. the vehicle group.
control (n=113) twice daily for 12 scale. lesions.
weeks. No significant differences were noted
between groups for side effects.
Subjects were evaluated at
baseline and after 2, 4, 8, 10,
and 12 weeks of treatment.

Pochi et al., Cutis 1988; 187 patients (range 13-48 years)
41: 132-6.56 with mild to moderate acne were
I
randomized to receive topical
Multicenter, double-blinded,
2% erythromycin gel (n=93)
controlled clinical trial to
compared to placebo vehicle
assess the effectiveness of
control (n=94) twice daily for 8
topical 2% erythromycin gel
weeks.
compared to its vehicle in
the treatment of acne. Patients were evaluated at
baseline, 4 and 8 weeks after
treatment.
Facial lesions were 2% erythromycin gel proved to be 2% erythromycin gel
counted at each significantly more effective than the was effective and well
visit and a grade placebo in the reduction of the tolerated in the
was based on number of inflammatory and non- treatment of acne.
percentage of inflammatory lesions.
A strong placebo effect
overall
After 8 weeks, 60% of the treated was noted.
improvement.
group had a good to excellent
Adverse effects response compared to 36% of the
were evaluated on vehicle group.
mild-to-severe
Side effects were generally mild and
scale.
transient, with no significant
differences noted between the
groups.

Dobson and Bellknap, J 253 patients were randomized to Total lesion count The reduction in the number of This study
Am Acad Dermatol 1980; receive either topical 1.5% was used for inflammatory lesions, papules, and demonstrated a
I
3: 478-82.57 erythromycin solution (n=127) or evaluation of the pustules was significantly greater in statistically significant
placebo vehicle control (n=126) treatment. the erythromycin treated group. benefit in the patients
Multicenter, double-blinded,
twice daily for 12 weeks. with acne receiving
controlled clinical trial to Global physician The global evaluation of the clinical
1.5% erythromycin
assess the effectiveness of Patients were evaluated at evaluation was also response correlated well with the
solution compared to
topical 1.5% erythromycin baseline and at 2, 4, 8, 10 and performed after 2, reduction in the lesion counts.
its vehicle.
solution compared to its 12 weeks of treatment. 4, 8, 10 and 12
vehicle in the treatment of weeks of treatment. No serious or
acne. irreversible adverse
effects were seen.

Level of Author(s)/Date/
Evidence Study Design
Mills et al., Acta Derm
Venereol 2002; 82: 260-
I 58
5.
Randomized, single-
blinded, controlled clinical
trial to assess the
effectiveness of topical
2% erythromycin gel
compared to its vehicle in
the treatment of acne and
to determine the bacterial
resistance associated with
its use.
Leyden et al., J Am Acad
Dermatol 1987; 16: 822-
I
7.62
Multicenter, randomized
parallel-group clinical trial
to assess the effectiveness
of topical 2% erythromycin
in the treatment of acne.
Study Population/
Intervention
208 patients were randomized to
receive either topical 2%
erythromycin gel or placebo
vehicle control twice daily for 12
weeks.
Patients were evaluated at
baseline and after 2, 4, 8, 10 and
12 weeks of treatment.
To study the regression of any
bacteriologic changes at 12
weeks, the patients on active
treatment were switched over to
placebo. The patients on
placebo continued their placebo
treatments.
102 patients (14 to 34 years)
were randomized to receive
either topical 2% erythromycin
gel or 1% clindamycin phosphate
solution twice daily for 12 weeks.
Patients were evaluated at
baseline and at 4, 8, and 12
weeks of treatment.
26
Method of
Results Conclusions
Assessment
Acne severity was The prevalence of erythromycin Resistance
evaluated by total coagulase-negative staph on the development was
lesion count and the face was high at 87% at baseline. At confined to the
use of photographs. the end of 12 weeks of erythromycin, macrolide class of
coagulase-negative staph increased antibiotics.
Bacteriologic
to 98% in the erythromycin-treated
samples were also No anti-acne efficacy
group.
assessed at was observed.
baseline and at 4, Nearly all bacteria were highly
This suggests that
12, 16 and 24 resistant (MIC > 128ug/ml).
topical treatment with
weeks of treatment.
erythromycin may
result in higher
carriage rates and
dissemination of
erythromycin-resistant
S. aureus from nares.
Acne severity was Both medications significantly Topical antibiotics
evaluated by total reduced the number of papules and have advantages over
facial lesion count. open and closed comedones. systemic therapy
because of direct local
Global physician There was no significant difference of
application on the
evaluation was also lesion count detected between the
affected areas of the
performed. treatment groups after 8 and 12
skin and a resultant
weeks of treatment.
decrease in systemic
At the end of 12 weeks, about 50% side effects.
of patients had a good to excellent
response.
Side effects included peeling,
erythema, burning, and itching.

Level of Author(s)/Date/
Evidence Study Design
Becker et al., Arch
Dermatol 1981; 117: 482-
I
5.65
Multicenter, double-blinded,
controlled clinical trial to
evaluate the effectiveness
of topical clindamycin
hydrochloride and
clindamycin phosphate
compared to placebo in the
treatment of acne.
27
Study Population/ Method of
Results Conclusions
Intervention Assessment
413 patients (14-29 years) with Acne severity was 86% of patients in the clindamycin Both clindamycin
acne were randomized to evaluated by hydrochloride group, 77% of the phosphate and
receive either 1% clindamycin counting pustules, clindamycin phosphate group, and clindamycin
phosphate solution (n=123), 1% papules, and 56% of the placebo group reported hydrochloride
clindamycin hydrochloride nodules over the improvement. treatment had
solution (n=120) or placebo entire face. significant reduction in
Side effects included peeling,
vehicle control (n=112) twice lesion count when
Mean change in erythema, burning, and itching.
daily for 8 weeks. compared to baseline
lesion count in each
and placebo group.
Patients were evaluated at group was reported.
baseline and after 2, 4, 6, and 8
weeks of treatment.

Table 3d. Use of Other Topical Agents
Level of Author(s)/Date/
Evidence Study Design
Zouboulis et al., Br J
Dermatol 2000; 143: 498-
I
505.70
Multicenter, randomized,
single-blinded, controlled
clinical trial to compare the
efficacy and safety of 1%
clindamycin/0.025%
tretinoin gel formulation
(CTG) to 1% clindamycin
lotion (CLN) for the
treatment of acne.
Chalker et al., J Am Acad
Dermatol 1983; 9: 933-6.72
I
Randomized, double-
blinded, placebo-controlled
clinical trial to determine if
topical erythromycin and
benzoyl peroxide were
effective in the treatment of
acne. This study also
compared the combination
to its vehicle base.
Study Population/
Intervention
209 patients (aged 14-26 years) Acne severity was
were randomized to receive
either CTG once (n=104) or CLN
(n=105) twice daily for 12 weeks.closed comedones,
Patients were evaluated at
baseline and after 2, 4, and 8
weeks of treatment to assess the
efficacy of both treatments.
165 subjects (age 15-30 years)
with grade 3 acne on the Cook et
al. scale7 were randomized to
receive one of the following
topicals twice daily for 10 wks.
3% erythromycin/5% benzoyl
peroxide gel (n=44);
5% benzoyl peroxide gel (n=44);
3% erythromycin gel (n=45);
placebo gel base, vehicle control
(n=44).
All patients were evaluated at
baseline and every 2 weeks for
10 weeks.
28
Method of
Results Conclusions
Assessment
At week 12 there was significantly A single daily topical
evaluated by greater reduction of inflamed lesions application of 1%
counting open and from baseline to week 12 in the CTG clindamycin/0.025%
group compared to the CLN group. tretinoin gel formulation
pustules, papules, was superior to 1%
50% reduction in total lesion count
and nodules. Acne clindamycin lotion
was observed by day 60 in 77% of
severity grade by applied twice daily for
patients on CTG compared with 56%
Cook et al. 7 was the reduction of acne.
receiving CLN.
also used.
CTG had a rapid effect
Both treatments were well tolerated.
on the onset of
improvement
compared to CLN.
Patients were There was no statistically significant The combination of 3%
evaluated at each difference between the groups for the erythromycin/
visit by lesion count. first 8 weeks. 5% benzoyl peroxide
gel was more effective
Grading method of At week 10, the active groups were
than the individual
Cook et al.7 was statistically different.
constituents or
also used.
Mean comedonal and pustule counts placebo.
were reduced in all active treatment
The most dramatic
groups.
effect was on
Combination therapy consistently combined inflammatory
improved papule and inflammatory lesions (papules and
lesion counts. pustules).
Adverse effects were not reported.

Level of Author(s)/Date/
Evidence Study Design
Tschen et al., Cutis 2001;
67: 165-9.73
I
Randomized, double-
blinded, parallel-group
clinical trial to evaluate the
effectiveness of benzoyl
peroxide and clindamycin
separately and in
combination.
Lookingbill et al., J Am
Acad Dermatol 1997; 37:
I
590-5.75
Multicenter, randomized,
double-blinded, placebo
controlled clinical trial to
determine the safety and
efficacy of combination
clindamycin/benzoyl
peroxide when compared
with clindamycin, benzoyl
peroxide or placebo
separately.
Study Population/
Intervention
287 patients (ages13-30 years)
with moderately severe acne
were randomly selected to
receive one of the following
topicals twice daily for 10 weeks:
(1) 5% benzoyl peroxide/1%
clindamycin phosphate gel
(n=95);
(2) 5% benzoyl peroxide gel
(n=95);
(3) 1% clindamycin phosphate
gel (n=49);
(4) placebo control (n=48).
Safety and efficacy was
evaluated at baseline and at 2,
4, 6, 8, and 10 weeks of
treatment.
334 subjects (ages 13-30 years)
were randomly assigned to
receive one of the following
topicals once daily:
1% clindamycin phosphate/5%
benzoyl peroxide gel;
1% clindamycin phosphate gel;
5% benzoyl peroxide gel;
placebo vehicle gel control.
Safety and efficacy evaluations
were performed at baseline and
at 2, 5, 8 and 11 weeks.
29
Method of
Results Conclusions
Assessment
Total improvement All study groups demonstrated There was greater
in lesion counts significant improvement from efficacy obtained with
from baseline was baseline. the combination
monitored. therapy and it was as
The number of lesions was reduced
safe as the other
Patients’ global to a greater extent in patients treated
treatments.
evaluations were with the combination of 5% benzoyl
measured at week peroxide/1% clindamycin phosphate
10. gel compared to the other
treatments.
Some patients reported adverse
effects.
The study evaluated All three active treatments were Topical clindamycin/
lesion counts, significantly superior to the placebo benzoyl peroxide
assessed global in global improvement and in combination gel is well-
responses and reducing both inflammatory and non- tolerated and superior
irritant effects. inflammatory lesions. to the other treatments.
The combination gel was significantly This has an advantage
superior to the two individual agents. over the combination of
erythromycin/benzoyl
peroxide gel because it
is not required to be
refrigerated.

Level of Author(s)/Date/
Evidence Study Design
Hjorth and Graupe, Acta
Derm Venereol Suppl
I
(Stockh) 1989; 143: 45-
8.79
Multicenter, randomized,
double-blinded, placebo-
controlled clinical trial to
compare the 20% azelaic
acid cream with its base
and compare it to oral
tetracycline treatment.
30
Study Population/ Method of
Results Conclusions
Intervention Assessment
First study had subjects with Total lesion count Both studies demonstrated significant 20% azelaic acid
moderate to severe acne. was monitored at clinically relevant reduction in the cream is an effective
monthly intervals. initial number of lesions during treatment for
Patients were randomized to
therapy. inflammatory acne and
receive one of the following
is well tolerated.
topicals twice daily: No significant difference in either
treatment was observed after 5
20% azelaic acid cream (n-164);
months.
placebo capsules (n-126).
Second study had patients
receiving oral tetracycline
1-g/day for the first month,
0.75-g/day for the second month
and 0.5-g/day for the third month
(n-169); and cream base (n-
135).
Patients with moderate acne
were treated for 5 months and
patients with severe acne were
treated for 6 months.
 31

IV. The efficacy and safety of systemic antibacterial agents in the treatment of adult acne
and acne vulgaris in adolescents to adults

Oral antibiotic therapy has been used for the treatment of moderate and severe acne for many years.
Systemic antibiotics have been shown to be effective as monotherapy and also in combination with
other therapies. Many clinical trials have shown the effectiveness of antibiotics like tetracyclines,
erythromycin, doxycycline, minocycline, trimethoprim with or without sulfamethoxazole and
azithromycin. These systemic antibiotics suppress P. acnes growth, and because of this, there is a
decrease in the production of inflammatory factors. The prevalent and long-term use of antibiotics has
led to the emergence of resistance to P. acnes. To minimize the development of bacterial resistance,
antibiotics should be used for a short period of time and combination therapy should be used.
 32

Table 4a. Use of Tetracyclines

Level of Author(s)/Date/ Study Population/ Method of

Evidence Study Design
Smith et al., South Med
J 1976; 69: 695-7.90
I
Randomized, double-
blinded study to evaluate
(1) patients treated with
topical and oral placebo;
(2) patients receiving
topical placebo and
systemic tetracycline
0.5-gm/day;
(3) patients treated with a
new topical tetracycline
preparation and an oral
placebo.
Intervention
135 subjects (age 18-35 years)
with acne grade 2 and over,
according to Cooke et al., 7
were randomized to receive
one of the following:
(1) topical placebo and
systemic placebo treatment;
(2) topical placebo/systemic
tetracycline 0.5-gm/day;
(3) new topical tetracycline and
oral placebo.
New topical tetracycline
consists of tetracycline
hydrochloride 0.22% with 4-
epi-tetracycline 0.28% and n-
decylmethyl sulfoxide in
ethanol/water; this was applied
twice daily.
Assessment Results Conclusion
All subjects were Oral and systemic groups both had This study confirms
evaluated with achieved statistically significant that tetracycline in
visual grading and improvement after 4, 7, 10, and 12 oral dose of
photographs to weeks of treatment compared to 0.5-gm/day is
assure critical placebo. effective treatment for
evaluation. acne after 4 weeks of
The topical treatment was effective,
therapy.
but somewhat less than the oral
tetracycline, but significantly better
than the placebo after seven weeks
of treatment.
Slight yellowish discoloration was
observed in 25% of subjects.

Gratton et al., J Am
Acad Dermatol 1982; 7:
I
50-3.91
A multicenter,
randomized, double-
blinded, placebo-
controlled study to
compare oral tetracycline,
topical clindamycin and
placebo for treatment of
acne.
305 patients (age range 18-35 Severity was Both oral tetracycline and topical Both oral tetracycline
years) with moderate to severe defined by papule, clindamycin significantly reduced and topical
acne were randomized to pustule and the papule and pustule counts clindamycin are
receive one of the following nodulocystic lesion compared to placebo. effective in the
three groups twice daily for 8 count. treatment of moderate
The most frequent side effect
weeks: to severe acne.
Efficacy was reported in the patients was
(1) 250 mg oral tetracycline evaluated with diarrhea.
hydrochloride (n=103); lesion count and
physicians’ overall
(2) 1% topical clindamycin
evaluation of
phosphate solution (n=97);
therapy.
(3) placebo (n=97).
Subjects were evaluated at
baseline and after 2, 4, 6, and
8 weeks.
 33

Level of Author(s)/Date/ Study Population/ Method of

Evidence Study Design Intervention Assessment Results Conclusion
Blaney and Cook, Arch 75 patients (age range 11-25 All subjects were Both oral and topical tetracycline Both oral and topical
Dermatol 1976; 112: 971- years) with moderate to severe evaluated with showed significant improvement tetracyclines are
I
3.95 acne were randomized to visual grading compared to placebo. effective in the
receive 1 of the following twice photographs to treatment of moderate
Randomized, double- No significant difference was
daily for 13 weeks: assure critical to severe acne.
blinded, placebo- apparent between the effects of
evaluation.
controlled study (1) Topically applied mixture of topical and oral administration of Larger numbers of
comparing the effect of tetracycline hydrochloride and Blood chemistry tetracycline hydrochloride. patients are required
topical and oral n-decylmethyl sulfoxide and analysis was to assess safety and
The treatments were generally well
tetracycline to placebo in orally administered lactose; performed. efficacy.
tolerated except for mild burning
the treatment of acne.
(2) Topically applied placebo and yellow tinted skin.
liquid and orally administered
lactose;
(3) Topically applied placebo
liquid and orally administered
500 mg/day of tetracycline
hydrochloride capsules.
Patients were evaluated at
baseline and after 2, 4, 6, 8
and 13 weeks of treatment.
 34

Table 4b. Use of Macrolides

Level of
Author(s)/Date/
Evi-
Study Design
dence
Skidmore et al.,
Arch Dermatol 2003;
I 102
139: 459-64.
Multicenter, randomized,
double-blinded, placebo-
controlled, parallel-group
clinical trial to determine
the effectiveness of
subantimicrobial-dose
(SD) doxycycline in the
treatment of acne.
Gammon et al., J Am
Acad Dermatol 1986; 14:
I 108
183-6.
Double-blinded,
randomized study to
compare the efficacy of
systemic erythromycin
with systemic tetracycline
in the treatment of acne.
Study Population/
Intervention
51 patients (age 18 years or
older) with moderate acne
were randomized to receive
20 mg doxycycline or placebo
twice daily for 6 months.
Patients were evaluated at
baseline and after 2, 4, and 6
months of treatment.
200 patients (age 14-30 years)
with moderate to moderately
severe acne were randomized
to receive one of the following:
Erythromycin 333 mg 3 times
daily for 4 weeks, then 333 mg
once daily for 8 weeks, plus
tetracycline placebo (n=100);
Tetracycline 500 mg twice daily
for 4 weeks, then 500 mg once
daily for 8 weeks, plus
erythromycin placebo (n=100).
Patients were evaluated at
baseline and after 2, 4, 8, and
12 weeks of treatment.
Method of
Results Conclusions
Assessment
Efficacy was At 6 months, the doxycycline group Systemic 20 mg
measured by had a significantly greater doxycycline is
noting change in percentage of reduction in the effective in the
inflammatory, non- number of comedones, treatment of moderate
inflammatory inflammatory and non-inflammatory acne.
lesions, and by lesions than the placebo group.
20 mg doxycycline is
physician global
Physician global assessment well tolerated.
assessment
scores showed greater
scores.
improvement in the treatment
Clinical laboratory group.
and microbiological
No significant difference was noted
samples were
in the microbial count between both
assessed at 6
groups.
months.
To evaluate safety Erythromycin and tetracycline There was no
and efficacy, treatment groups had significant statistically significant
papule, pustule, decreases in lesion counts starting difference between
and open and from the second week of treatment. the two groups; both
closed comedo drugs are effective.
Closed comedo counts decreased
counts were made.
more rapidly with tetracycline
Patients reported
treatment.
adverse effects.
Some patients had gastrointestinal
discomfort. Some developed
Candida vaginitis.
 35

Level of
Author(s)/Date/
Evi-
Study Design
dence
Christian and Krueger,
Arch Dermatol 1975;
I 111
111: 997-1000.
Randomized, double-
blinded, placebo-
controlled clinical trial to
determine the
effectiveness of
clindamycin in the
treatment of acne.
Study Population/ Method of
Results Conclusions
Intervention Assessment
91 patients (average age 20 Efficacy was Clindamycin treatment resulted in Clindamycin appears
years) with moderate acne measured by significant reduction in comedones to be effective in the
were randomized to receive noting change in and pustules compared to the treatment of moderate
clindamycin or placebo for a lesion count. placebo group. to severe acne.
13-week course of treatment.
Improvement was Some patients receiving
Patients were assigned 150 mg defined as at least clindamycin had severe diarrhea
st
clindamycin 4 times for the 1 50% reduction in and rash.
nd
week, 3 times for the 2 week the number of
and then 2 times for the rest of papules or
the time (weeks 3-13). pustules.
Patients were evaluated at
baseline and after 1, 2, 4, 6, 10
and 13 weeks of treatment.

Stoughton et al., Cutis
115
1980; 26: 424-5, 429
I
Randomized, double-
blinded, placebo-
controlled clinical trial to
determine the
effectiveness of
clindamycin and
tetracycline in the
treatment of acne.
50 patients (age 18-30 years)
with moderate acne were
randomized to receive one of
the following for 8 weeks:
Topical 1% clindamycin
phosphate and placebo
capsules or oral tetracycline
250 mg twice daily and placebo
lotion for a 13-week course of
treatment.
Evaluations Topically applied 1% clindamycin The use of topically
included counts of phosphate was found to be applied 1%
all types of lesions superior to the oral tetracycline at 6 clindamycin is an
and severity rating. weeks, determined by the reduction alternative to the use
of papules and patient evaluation. of oral tetracycline.
Open comedones
were analyzed for At other times of the study, there
the number of P. was no significant difference
acnes. between the two groups in the
number of pustules.
 36

Table 4c. Use of Trimethoprim-Sulfamethoxazole

Level of
Author(s)/Date/ Study Population/ Method of
Evi- Results Conclusions
Study Design Intervention Assessment
dence
Hersle, Dermatologica 43 patients (age 13-25 years) Overall Statistically significant improvement Trimethoprim-
117
1972; 145: 187-91. with acne were randomized to assessment was was achieved with 80 mg sulfamethoxazole is
I
receive 80 mg trimethoprim made by lesion trimethoprim and 400 mg effective treatment for
Randomized, double-
and 400 mg sulfamethoxazole count and sulfamethoxazole treatment acne compared to
blinded, placebo-
or placebo 1 time daily for 5 laboratory tests. compared to the placebo. placebo after 5 weeks
controlled cross-over
weeks. After 5 weeks, the of treatment.
clinical trial to compare Acne lesions had decreased from
active preparation was given to
the effectiveness of 100% to 38% in the active
the placebo group and the
systemic trimethoprim- treatment group compared to
active treatment group
sulfamethoxazole or 100% to 91% (not significant) in the
received the placebo.
placebo in the treatment placebo group.
of acne. Patients were evaluated at 5
and 10 weeks.
 37

V. The effectiveness and potential side effects of hormonal agents in the treatment of adult
acne and acne vulgaris in adolescents to adults

Androgenic hormones play an important role in the pathogenesis of acne vulgaris. Studies have
shown that hormonal overproduction can contribute to the development of acne. Androgenic
hormones stimulate the sebaceous glands, which can then increase sebum production. Many young
women with polycystic ovary syndrome (PCOS) first seek medical attention for acne. Indications for
hormonal abnormalities may include menstrual irregularities, other signs of virilization such as
hirsutism, androgenic alopecia, very early or very late onset acne, or failure to respond to
conventional therapy or relapse after isotretinoin. Hormonal treatment is an alternative treatment for
women with acne. Combined oral contraceptives have been evaluated and shown to be effective in
the treatment and management of acne in women especially with clinical signs of hyperandrogenism.

Table 5a. Effectiveness of Contraceptive Agents
Level of
Author(s)/Date/ Study
Evi-
Design
dence
Lucky et al., J Am Acad
Dermatol 1997; 37: 746-
I 122
54.
A multicenter,
randomized, double-
blinded, placebo-
controlled study to
evaluate the efficacy of
combination oral
contraceptive in the
treatment of acne.
Thiboutot et al., Fertil
124
Steril 2001; 76: 461-8.
I
A multicenter,
randomized, double-
blinded, placebo-
controlled study to
evaluate the efficacy of a
low-dose oral
contraceptive in the
treatment of acne.
38
Study Population/ Method of
Results Conclusions
Intervention Assessment
257 women (age 15-49 years) with Efficacy was assessed The oral contraceptive An oral contraceptive
moderate acne and without by facial lesion count, treatment group showed containing 0.035 mg
hirsutism were randomized to investigator’s global statically significant greater ethinyl estradiol
receive combination treatment listed assessment, patient improvement than the combined with
below for 3 weeks, followed by 1 self-assessment, and placebo group. triphasic regimen of
week of inactive drug/placebo, each analysis of within-cycle norgestimate is safe
The mean total lesion
month for 6 months: variation (cycle 6) in and effective
count decrease was 53.1%
lesion counts. treatment of
Ethinyl estradiol 0.035 mg and in the treatment group
moderate acne
norgestimate 0.180/0.215/0.250 mg) compared to 26.8% in the
vulgaris in women.
tablets, or placebo tablets. placebo group.
Adverse events were
Patients were evaluated at baseline Physician global
minor.
and monthly for 6 cycles, then 3 assessment showed 93.7%
times during the last month. improvement in the
treatment group compared
to 65.4% in the placebo
group.
350 women (age 14 and older) with Total lesion count, Inflammatory, non- Low-dose oral
moderate facial acne and regular inflammatory and non- inflammatory and total contraceptive
menstrual cycles were randomized inflammatory lesion lesion count was containing 20-g
to receive 100-g levonorgestrel and count was performed, significantly lower in the ethinyl estradiol and
20-g ethinyl estradiol contraceptive using physician global treatment group compared 100-g levonorgestrel
tablets or placebo. Patients received assessment and to the placebo group. is an effective and
21 days of active drug followed by 7 patient self- safe treatment for
Global assessment
days of placebo for 6 cycles. assessment. moderate acne.
showed that 57.9% of the
Patients were evaluated at baseline women in the treated group
and at 1, 3, and 6 months. were considered cleared
compared to 46.7% in the
placebo group.
 39

Level of
Author(s)/Date/ Study Study Population/ Method of
Evi- Results Conclusions
Design Intervention Assessment
dence
Leyden J et al., 350 women (age 14 and older) with Patients were The inflammatory and non- Low-dose oral
J Am Acad Dermatol moderate facial acne and regular evaluated by acne inflammatory lesion count contraceptive
I 125
2002; 47: 399-409. menstrual cycles were randomized lesion count, physician in the patient group containing 20-g
to receive 100-g levonorgestrel and global assessment and receiving ethinyl estradiol ethinyl estradiol and
A multicenter randomized
20-g ethinyl estradiol contraceptive patient self- was significantly lower 100-g levonorgestrel
double-blinded, placebo- nd
tablets or placebo tablets. Patients assessment. starting from the 2 cycle is an effective and
controlled study to
received 21 days of active drug compared to the placebo safe treatment for
compare the effect of 2
followed by 7 days of placebo for 6 group. moderate acne.
contraceptive
cycles.
preparations in the There was 81.7%
treatment of acne. Patients were evaluated at baseline improvement in the treated
and once during each treatment group compared to 68.1%
cycle. in the placebo group by
using physician global
assessment and patient
self-assessment.
 40

Table 5b. Effectiveness of Spironolactone

Level of Author(s)/Date/ Study Population/ Method of

Results Conclusions
Evidence Study Design Intervention Assessment
Muhlemann et al., Br J 29 women with moderate to severe Acne severity was Acne severity decreased Spironolactone is a
Dermatol 1986; 115: acne were randomized to receive assessed; inflamed significantly with the use of useful alternative
II 132
227-32. either 200 mg spironolactone or lesions were counted. spironolactone in the therapy for women
placebo for 3 months. After 3 treatment group compared with moderate acne.
A randomized, double- Improvement was
months, patients were given placebo to the placebo group.
blinded, placebo- defined as greater than
for 1 month and crossed over for
controlled, cross-over 50% reduction in the The beneficial effect of
further 3 months of placebo or
study to compare the number of lesions. spironolactone was
200 mg spironolactone.
effectiveness of Photographs were also observed by all assays.
spironolactone and Patients were evaluated at baseline used to assess the 86% of patients noted
placebo in the treatment and after 12 weeks of treatment. efficacy of the improvement with
of acne. treatment. spironolactone compared
to 24% on placebo.

Table 5c. Effectiveness of Anti-Androgens
Level of Author(s)/Date/
Evidence Study Design
Greenwood et al., Br
Med J (Clin Res Ed)
II 134
1985; 291: 1231-5.
A randomized, double-
blinded, placebo-
controlled trial to
compare the effect of
systemic estrogen +
cyproterone acetate and
tetracycline in the
treatment of acne.
Miller et al., Br J
Dermatol 1986; 114:
II 135
705-16.
Randomized, double-
blinded, controlled trial to
compare the effect of
anti-androgen treatment
in women with acne.
41
Study Population/ Method of
Results Conclusions
Intervention Assessment
Women (age range 16-30 years) with To assess efficacy, Combination of 2 mg Combination of 2 mg
acne were randomized to receive one grading and counting cyproterone acetate + 50 cyproterone acetate
of the following treatments for 6 of lesions was µg ethinyl estradiol with + 50 µg ethinyl
months: performed. 500 mg tetracycline was estradiol is as
significantly better effective as oral
(1) Combination of 2 mg cyproterone Sebum secretion
(improvement 82%) antibiotics treatment
acetate + 50 µg ethinyl estradiol for 21 rates and bacterial
compared to tetracycline for moderately
days with 500 mg tetracycline twice counts were taken
alone (68%). The severe acne.
daily; before and during
estrogen + cyproterone
treatment.
(2) 2 mg cyproterone acetate + 50 µg acetate treated group
ethinyl estradiol for 3 weeks and had 74% improvement.
placebo tablets twice daily; Sebum secretion rates
(3) Placebo tablets for 3 weeks and were reduced only in the
tetracycline 500 mg twice daily. cyproterone acetate +
50 µg ethinyl estradiol
Women were assessed at baseline and group.
every 2, 4 and 6 months.
90 women (age 16-36 years) were To assess efficacy, There was improvement The addition of CPA
randomized to receive one of the lesion count was in all three groups in total to estrogen adds
following three treatments for 6 cycles: performed on the and in facial acne grades significantly to the
face, back and chest. during the 6-month therapeutic effects in
Group D (Diane): 2 mg cyproterone
assessment period. acne.
acetate + 50 µg ethinyl estradiol; Sebum secretion
rates, photographic More rapid and complete Anti-androgen and
Group C (high dose CPA): 50 mg assessment and response was seen in estrogen
cyproterone acetate + 50 µg ethinyl bacterial counts were the groups receiving combination is more
estradiol; performed before and CPA. effective than
Group M (Minovlar): 1 mg of during treatment for standard estrogen
Adverse effects were
norethisterone acetate and 50 µg anaerobes and and progesterone
mild but difficult to asses.
ethinyl estradiol. aerobes. contraceptives.
All the treatments were taken daily from
days 5-25 of the cycle.
Patients were evaluated at baseline
and every 2 months for 6 months.
 42

Table 5d. Effectiveness of Oral Corticosteroids

Level of Author(s)/Date/ Study Population/ Method of

Results Conclusions
Evidence Study Design Intervention Assessment
Nader et al. J Am Acad 158 women (age 16-40 years) who Changes in acne and In 39.9% of patients, acne Pretreatment
II Dermatol 1984; 11: 256- had been identified as hyper- testosterone completely cleared. In testosterone levels
137 androgenic were treated with oral measurements were 50.6%, it was significantly were significantly
9.
prednisone (7.5-15 mg) twice daily performed. improved and in 9.5%, higher in those
This study was
for at least 6 months. Subjects were there was no effect on whose acne did not
conducted to determine if
categorized according acne after treatment. clear.
lowering androgen levels Changes in acne severity and serum
to whether their acne
by treatment with testosterone levels were recorded There were significant Lowering the
completely cleared,
glucocorticoid would periodically. differences between the androgen levels is
improved, or did not
clear acne. mean testosterone levels associated with
improve.
for the patients whose clearing acne.
acne had cleared and
those whose did not clear.
 43

VI. The effectiveness and potential side effects of isotretinoin in the treatment of adult acne
and acne vulgaris in adolescents to adults

Isotretinoin is a member of the retinoid class of compounds related to retinol (vitamin A). The
effectiveness of systemic isotretinoin therapy in the treatment of acne has been demonstrated. Oral
isotretinoin is approved for the treatment of severe recalcitrant nodulocystic acne or for the treatment
of moderate acne that had failed to respond to conventional antibiotic therapies. Isotretinoin is the
only treatment that has an effect on all the factors involved in the pathogenesis. It suppresses sebum
production, which in turn reduces the bacterial population. Isotretinoin also normalizes desquamation
and is anti-inflammatory.
The approved dosage is 0.5-2.0 mg/kg/day, usually for a 20-week treatment period. Its absorption is
greater when the drug is taken with food because it is lipid soluble.
Isotretinoin has many side effects. Most of the side effects are temporary and resolve after reducing
or withdrawal of the drug. Side effects such as suicide and depression have been reported in studies
but a causal relationship has not been demonstrated. The treating physician should monitor for signs
and symptoms of psychiatric disturbance among acne patients before, during and after isotretinoin
therapy. Large, well designed, well implemented, and carefully analyzed epidemiological studies must
be conducted to evaluate the psychiatric side effects of isotretinoin for the treatment of acne.
Because of the teratogenic effects of isotretinoin on the fetus, the FDA and the manufacturers have
approved a new risk management program for isotretinoin. Prescribers, patients, pharmacies, drug
wholesalers and manufacturers in the U.S. are required to register and comply with the iPLEDGE
program. This program requires mandatory registration of all patients receiving this drug. Detailed
information can be found on the iPLEDGE web site (https://www.ipledgeprogram.com).
 44

6. Use of Isotretinoin

Level of
Author(s)/Date/ Study Population/ Method of
Evi- Results Conclusions
Study Design Intervention Assessment
dence
Strauss et al. J Am 150 patients (age 5-49 years) Clinical side effects There was an increase in side There was no
Acad Dermatol 1984; with treatment-resistant were monitored. effects with higher doses of significant difference in
I 144
10: 490-6. nodulocystic acne were Plasma cholesterol isotretinoin. clinical response
Multicenter, randomized to receive 0.1, 0.5, and triglyceride between dosages 0.1,
Laboratory abnormalities were
randomized, double- or 1 mg/kg/day isotretinoin for levels were 0.5, or 1 mg/kg/day of
greater than 10%. The most
blinded study to 20 weeks. Therapy could be evaluated by isotretinoin.
frequent abnormality was in the
determine whether stopped when 70-80% laboratory analysis.
blood lipids, especially
there is a dose- reduction in lesions was 10% of patients treated
Lesion counts for triglycerides.
dependent clinical observed. with 1 mg/day required
face and trunk were
response and dose- a second course of
Patients were evaluated at monitored.
related incidence of therapy.
baseline and at 2, 4, 8, 12, 16,
clinical and laboratory
and 20 weeks and at 2-3
side effects of 0.5, 1 mg/kg/day dose
months after treatment was
isotretinoin therapy. of isotretinoin is
discontinued.
recommended for the
management of
nodulocystic acne.
 45

Level of
Author(s)/Date/ Study Population/ Method of
Evi- Results Conclusions
Study Design Intervention Assessment
dence
Goulden et al., Br J 80 consecutive patients (age Acne severity was At the end of 6 months, total acne The study suggests
Dermatol 1997; 137: 25 years and over) with assessed on the grades and inflamed lesion count that intermittent doses
I 150
106-8. unresponsive acne or rapid face, chest and back were significantly reduced. Acne of isotretinoin may be a
relapse after three or more using the Leeds had resolved in 88% of patients. cost-effective
This study was 9
courses of conventional objective technique. alternative to full dose
conducted to assess 9% of patients who failed to
antibiotic therapy were Inflamed lesion count isotretinoin therapy in
the efficacy of improve significantly were treated
randomized to receive and sebum excretion selected groups of
intermittent moderate with full dose regimen of
0.5 mg/kg of isotretinoin per rate were measured. patients with acne.
dose of systemic isotretinoin.
day for 1 week in every 4 Fasting lipids and
isotretinoin as a This study did not have
weeks for 6 months. liver functions were 4% of patients had relapse after 6
treatment for severe a control population.
compared during and months of treatment. 39% had
acne. Patients were evaluated at
after therapy. relapse after 12 months. There was
baseline and every 3 months
higher rate of relapse in patients
during therapy and for 12 Pregnancy test had
with truncal acne.
months following treatment. to be negative before
the start of the Mild cheilitis was the principal side
treatment. Patients effect.
were on
contraception
throughout the
treatment and for
one month following
treatment.
Side effects were
monitored at each
visit.

Level of
Author(s)/Date/ Study Population/
Evi-
Study Design Intervention
dence
Strauss et al., J Am 600 patients (≥12 yrs.) were
Acad Dermatol 2001; randomized to receive 1 of the
I 153
45: 196-207. following for 20 weeks:
Multicenter, double- Group (1) 0.4 mg/kg
blinded, randomized, micronized isotretinoin once
parallel-group clinical daily without food and placebo
study to compare the capsules twice daily with food
safety of micronized (n=300);
isotretinoin and
standard isotretinoin in Group (2) 1 mg/kg standard
isotretinoin in 2 divided doses
the treatment of
severe, recalcitrant, daily with food and 1 placebo
nodular acne. capsule daily without food
(n=300);
All patients were evaluated at
baseline and at 8, 16, and 20
weeks after treatment.
All patients underwent lab
evaluation that included CBC,
LFTS and serum lipids profile.
492 patients completed the
study.
46
Method of
Results Conclusions
Assessment
Photographs were Both treatment groups had an Micronized one-daily
taken at baseline equivalent reduction in the number dose of isotretinoin
and were used for of total nodules. was equivalent to the
comparison in the standard twice-daily
Adverse events occurred in 5.3% of
assessment of acne isotretinoin for the
patients who had to discontinue
severity by both treatment of
therapy.
patient and recalcitrant nodular
Adverse events: Group 1 Group 2
physician. acne.
Lesion counts of Mild 85.3% 87.3% The authors conclude
nodules, papules that the psychiatric
Moderate 80.3% 85.3%
and pustules were adverse events in this
performed. Severe 34.3 % 35.3% study do not support a
causal relationship
Efficacy was Most adverse events were
between the symptoms
measured by change mucocutaneous: (cheilitis, peeling
skin, dry/bleeding nose, dry/irritated and isotretinoin use.
in the nodular lesions
eyes and facial rash). Headache They are more likely to
from baseline to
was also seen in 13-16% of be due to underlying
week 20.
patients. Back pain was seen in 3- factors not assessed in
Mood assessments 5% of patients. this trial.
were also performed.
Adverse events classified as This study did not have
psychiatric disorders occurred in 1- a control placebo
3.7% of patients. group for comparison.
Triglycerides were abnormally
elevated for 16-26%, and 2-3% had
abnormal liver enzymes. There was
a slight reduction in total white
blood cells, neutrophils or
lymphocytes.
 47

Level of
Author(s)/Date/ Study Population/ Method of
Evi- Results Conclusions
Study Design Intervention Assessment
dence
Goldsmith et al., J Three goals for the conference: Consensus Dr. Lookingbill recommended Effective contraception
Am Acad Dermatol conferences of starting isotretinoin at 0.5 is essential in
I 159 (1) To bring scientific clarity to
2004; 50: 900-6. experts in the field of mg/kg/day for the first 4 weeks to minimizing the risk of
unresolved questions
acne. avoid flares and then increase to isotretinoin-associated
Summary and regarding isotretinoin use;
full dosage of 1.0 mg/kg/day. teratogenicity.
recommendations of
(2) To present the best data on
AAD consensus There is no dose of oral isotretinoin Physicians prescribing
clinical use and adverse
conference on the safe that is safe from possible isotretinoin must
effects;
and optimal use of teratogenic side effects during ensure that
isotretinoin treatment. (3) To develop pregnancy. The rate of contraceptive
recommendations malformation of fetus with retinoid counseling is provided.
regarding future research. exposure is about 20% compared
The association
to 2% in the unexposed population.
between isotretinoin
and depression or
suicide is not
determined.
Individuals who have
risk factors for
depression or suicide
should be monitored
closely when being
treated with
isotretinoin.

Jick et al. Arch To determine the rates and Results were There were 1,777 patients with The authors in this
Dermatol 2000; 136: relative risk (RR) of psychotic expressed as relative depression or psychosis. 61% had study do not provide
I 163
1231-6. symptoms, data was analyzed risk. RR was anxiety disorder, 29% had mood evidence that the use
for history of 7,195/340 estimated comparing disorders, 6% had affective of isotretinoin is
This population-based
isotretinoin patients and isotretinoin users, disorders and 3% had non-affective associated with an
cohort study was
13,700/676 oral antibiotic (ages oral antibiotic users disorders. The RR for current increased risk for
conducted to
10-29 years) patients from and non-users. isotretinoin use compared to the depression, suicide, or
determine the
Canada/ UK respectively. non-exposed period was 1.0. The other psychiatric
proposed association
RR for recent isotretinoin use, disorders.
between isotretinoin
current use and recent antibiotic
therapy and the risk of Depression can be
use was 0. 9, 1.3, and 0.9
depression or undiagnosed so it is
respectively.
psychotic symptoms. not possible to
definitively exclude all
subjects with a history
of major depression.
 48

Level of
Author(s)/Date/ Study Population/ Method of
Evi- Results Conclusions
Study Design Intervention Assessment
dence
Marqueling and Zane, A literature review was Searches were done Nine articles were reviewed; 6 The authors conclude
Semin Cutan Med performed. Data from articles using computerized studies were conducted that although the
I
Surg 2005; 24: 92- that met inclusion and databases, prospectively and 3 retrospectively. studies reviewed in this
164
102. exclusion criteria were MEDLINE using article do not support a
Some data supported the
reviewed for this study. PubMed, EMBASE, causal association
The aim of this paper possibility that isotretinoin therapy
BIOSIS previews, between isotretinoin
was to review the may have a positive impact on
and PsychINFO. use and an increased
published clinical psychiatric well-being.
risk of depression or
evidence assessing the
suicidal behavior, the
proposed association
evidence may not be
between isotretinoin
sufficiently compelling
use and the risk of
to rule out a weak
depression/suicide
association.
among patients with
acne vulgaris treated Factors like age,
with isotretinoin. gender and prior
psychiatric history
appear to be much
stronger predictors of
depression and
suicidal behavior.
The available data on
suicidal behavior
during isotretinoin
treatment are
insufficient to establish
a meaningful causative
association.

Level of
Author(s)/Date/ Study Population/
Evi-
Study Design Intervention
dence
Chia et al., Arch 132 patients (age 12-19 years)
Dermatol 2005; 141: with moderate to severe acne
I 165
557-60. participated in the cohort study
comparing depressive
A cohort study,
symptoms in adolescents
controlled, comparing
receiving isotretinoin therapy
depressive symptoms
(3-4 months) and those
in adolescents
receiving conservative therapy
receiving isotretinoin
(topical antibiotic, topical
therapy (3-4 months)
retinoid and twice daily oral
and those receiving
antibiotic).
conservative therapy.
Depressive symptoms were
evaluated at baseline and 3-4
months after therapy.
101 patients completed the
study and 31 patients were
unavailable for follow-up.
49
Method of
Results Conclusions
Assessment
Acne severity was CES-D scores were no higher in The authors conclude
determined by the isotretinoin group than in the that this cohort study
physician clinical conservative therapy group. indicates that there is
assessment. no increase in the
Due to the small number of cases
Patients were prevalence of
with new-onset of depression, it
evaluated for depressive symptoms
was not possible to perform a
depressive in the isotretinoin
multivariate analysis of incidence.
symptoms using the treated group
Center for compared to the group
Epidemiological treated with maximal
Studies Depression conservative therapy.
Scale (CES-D). The incidence of
Mean CES-D scores suicidal ideation in the
were compared isotretinoin and control
between treatment group was 0 and 1.4%
groups. respectively. This
study showed that the
isotretinoin therapy
improved the
depressive symptoms.
The study had a very
small sample size and
was not randomized.
Genetic factors and
environmental factors
of the subjects were
not taken into account.
The participants were
from private practice
and university clinics.
 50

VII. The effectiveness and potential side effects of miscellaneous therapies in the treatment
of adult acne vulgaris in adolescents to adults

Intralesional corticosteroid injections are effective in the treatment of individual acne nodules.
Chemical peels have been used in dermatology for the treatment of acne scars. Chemical peel is a
nonsurgical procedure. Both glycolic acid-based and salicylic acid-based preparations have been
used in the treatment of acne. There is limited evidence from published clinical trials regarding the
efficacy and safety of peeling regimens and comedo removal for the treatment of acne.
 51

Table 7a. Use of Intralesional Steroids

Level of Author(s)/Date/ Study Population/ Method of

Results Conclusions
Evidence Study Design Intervention Assessment
Levine and (1) 9 patients (age 16 – 35 years) with Flattening of cysts Triamcinolone acetonide was Triamcinolone
Rasmussen, Arch cystic acne were randomly assigned to was measured on effective in reducing the acetonide at
III
Dermatol 1983; 119: receive intralesional injections of a 0-3 scale in severity of nodulocystic acne. 0.63 mg/ml was
168
480-1. triamcinolone acetonide in 3 different both treatments. None of the concentrations of effective.
concentrations of 0.63 mg/ml, betamethasone had a Betamethasone
Randomized,
1.25 mg/ml and 2.5 mg/ml. significant effect. phosphate even at
blinded, controlled
3.0 mg/ml had no
study to evaluate the All patients were on
Patients were evaluated at baseline, 3 effect on nodulocystic
effectiveness of tetracycline, topical
and 7 days, and also 4 weeks after acne lesions.
intralesional steroid medications.
treatment.
injections of To compare the
corticosteroid in the efficacy of two different
(2) 8 patients with cystic acne received
therapy of treatments, both
intralesional injections of saline placebo
nodulocystic acne. studies should have
control and betamethasone phosphate
been conducted in a
in 3 different concentrations 3.0 mg/ml,
similar manner.
1.5 mg/ml and 0.75 mg/ml. This was
not blinded.

Patients were examined 1 week and 1

month after treatment
Potter, J Invest 9 patients (age 19-25 years) with Blood samples Patients who received higher Intralesional
Dermatol 1971; 57: severe cystic acne were given were analyzed doses of intralesional steroid triamcinolone
III 169
364-70. intralesional treatment with 15–50 mg daily and plasma showed adrenal suppression, acetonide can produce
triamcinolone acetonide. cortisol was with the duration related to the adrenal suppression
This study evaluates
measured by dosage. lasting for a prolonged
the use of Patients were injected with
laboratory period of time.
intralesional steroids triamcinolone acetonide in numerous All patients were on
analysis to
in the treatment of inflammatory acne cysts. tetracycline, topical keratolytics A very small number of
evaluate adrenal
acne. and dietary precautions. patients were used to
Patients were evaluated at baseline suppression.
show efficacy or safety.
and daily for up to 14 days after
treatment.
 52

Table 7b. Use of Chemical Peels

Level of Author(s)/Date/ Study Population/ Method of

Results Conclusions
Evidence Study Design Intervention Assessment
Kim et al., Dermatol 26 patients (age 16-27 years) with mild- Cunliffe’s grading There was a decrease in Both 70% glycolic acid
9
Surg 1999; 25: 270- to-moderate facial acne were treated system (Leeds scale) the mean acne grading and Jessner’s solution
III 170
3. with each of the following was used to grade score in both treatments. appear to be effective
simultaneously three times every 2 acne. in reducing mean acne
A split-face There was no statistical
weeks on opposing sides of the face for grading score but there
randomized clinical Patient preference test difference between the 2
6 weeks: was no placebo group
trial to compare the was given at the end of treatment groups.
in this study to
efficacy and safety of (1) Jessner’s solution (resorcinol, each study.
Redness was noted as a compare safety or
70% glycolic acid salicylic acid and lactic acid, in
common side effect. efficacy.
and Jessner’s ethanol)
solution in the (2) 70% glycolic acid Some patients had
treatment of acne. eczema with oozing and
Patients were evaluated at baseline, and
crusting.
bi-weekly.
Wang et al. 40 subjects with moderate to moderately The improvements Significant resolution of Glycolic acid peels
Dermatol Surg severe acne were treated with either were measured by comedones, papules and have some potential
III 171
1997; 23: 23-9. 35% or 50% glycolic acid, depending physician assessment pustules was observed in for the treatment of
upon the degree of facial skin which included the the patients. moderate to
This study was
greasiness. counting of facial moderately severe
conducted to Consistent and repetitive
lesions. acne.
evaluate the safety A series of 4 peels at 3-week intervals treatment with glycolic
and efficacy of serial were performed - at week 1, 4, 7, and Patient self-evaluation acid peels was required
glycolic acid peels 10. was also used to for improvement.
for the treatment of evaluate safety.
Subjects were evaluated at baseline and
facial acne.
after 2, 5, 8, and 11 weeks.
 53

Table 7c. Use of Comedo Removal

Level of Author(s)/Date/ Study Population/ Method of

Results Conclusions
Evidence Study Design Intervention Assessment
Pepall et al., Br J 14 patients (age 16-66 years) with large Lesion counts and All patients considered the Whiteheads may
Dermatol 1991; 125: (2-3 mm) whiteheads were treated with photographs were treatment to be beneficial. be treated with
III 173
256-9. light cautery using topical anesthesia used to assess the cautery
This was confirmed by
EMLA cream. efficacy of the technique using
This study describes photography and lesion counts.
treatment. topical
a simple treatment The procedure was repeated at 2-week
95% of the whiteheads were anesthesia.
for the ablation of intervals.
cleared.
whiteheads by
Patients were evaluated at baseline,
cautery under local
after 2 weeks and many months after
anesthesia with
treatments.
EMLA cream.
 54

VIII. The effectiveness and potential side effects of complementary/alternative therapies in

the treatment of adult acne and acne vulgaris in adolescents to adults

There have been many clinical trials conducted studying the safety and efficacy of complementary
therapies for the treatment of acne. Some studies have suggested a correlation between increase in
stress and acne severity. This may be associated with increased sebum, free fatty acid and endocrine
activity, which are important for the pathogenesis of acne. Additional research is needed to
adequately assess the role of herbal therapy, hypnotherapy, and psychological approaches in the
treatment of acne.
 55

Table 8a. Use of Herbal Agents

Level of Author(s)/Date/ Study Population/ Method of

Results Conclusions
Evidence Study Design Intervention Assessment
Bassett et al., 124 subjects with mild to moderate The severity of acne Both treatments were Tea tree oil may be
Med J Aust 1990; acne (age 12-35 years) were was assessed using effective in reducing the effective topical
II 174
153: 455-8. randomized to receive either topical tea the lesion counting number of inflamed lesions treatment but studies
tree oil in a 5% water-based gel (n=61) technique described but benzoyl peroxide was conducted double-
A randomized, or 5% topical benzoyl peroxide lotion by Burke and significantly better than tea- blinded and with
single-blinded study 9
(n=63) for 3 months. Cunliffe. Efficacy tree oil. proper controls would
to compare the was measured by better determine the
efficacy and safety of All subjects were evaluated at baseline Adverse effects were seen in
monitoring the safety and efficacy of
topical tea tree oil and every month for 3 months. both groups.
changes in the total tea-tree oil for the
and topical benzoyl inflamed and non- treatment of acne.
peroxide. inflamed lesion
counts during the
treatment.
Skin tolerance was
also assessed.
Paranjpe and 82 patients (age 18–28 years) with Facial lesions were Significant reduction in lesion This Ayurvedic
Kulkarni, J moderate facial acne were randomized counted and the count was seen only in the preparation Sunder
II
Ethnopharmacol to receive 2 tablets of one of the investigator Sunder Vati group 5 (60%). Vati may be of value in
175
1995; 49: 127-32. following, three times daily for 6 weeks: performed an the treatment of acne.
There was a significant.
overall clinical
Randomized, double- (1) Sookshama Triphala: composed of reduction in the total number A larger study group
evaluation of
blinded, placebo- dried fruit and mineral (n=16); of inflammatory lesions within and comparison to
patients’ overall
controlled clinical trial 2 weeks and further other known systemic
(2) Thiostanin: composed of dried fruit, change in facial
to compare the reduction during the 6 weeks therapies should be
mineral, and root (n=17); acne. Photographs
efficacy of 4 of treatment. evaluated to
were also used for
Ayurvedic (3) Placebo tablets (n=15); determine the efficacy
evaluating the 2/3 patients in group 5
formulations and and safety of the
(4) Shankhabhasma Vati: composed of patients. showed good to excellent
placebo in the Ayurvedic drugs.
a counch shell (n=14); clinical response.
treatment of acne
The mechanism of
vulgaris. (5) Sunder Vati: composed of stem
action of any of the
bark, dried fruit, and rhizome (n=20).
Ayurvedic
All patients were evaluated every 2 preparations is not
weeks. known at present.
 56

Level of Author(s)/Date/ Study Population/ Method of

Results Conclusions
Evidence Study Design Intervention Assessment
Lalla et al., J 53 patients (age 14-28 years) with mild Global assessment Group 1: 32% showed good Both combinations of
Ethnopharmacol to moderately severe acne were scale of Burke and to excellent, 63% slight to fair oral and topical
II 176
2001; 78: 99-102. randomized to receive one of the Cunliffe was used improvement. preparations showed
9
following for 4 weeks: for evaluation. significant
Randomized, double- Group 2: 58% good to
improvement of acne.
blinded, placebo- (1) Oral tablets containing active Overall change in excellent, 26% slight to fair
controlled clinical trial ingredients and topical gel preparations the facial acne from improvement. The study had too
to compare the (n=23); baseline to the end small a number of
Group 3: 100% slight to fair
effectiveness of oral of the trial was patients to evaluate
(2) Oral tablets containing active improvement
and topical forms of evaluated on a 4- safety and efficacy.
ingredients and topical cream
Ayurvedic point scale: good to Group 4: No improvement.
preparations (n=23);
preparation to excellent, slight to
placebo in the (3) Oral tablets containing active fair, variable, no
treatment of acne. ingredients and placebo topical change or worse.
preparations (n=5);
(4) Placebo tablets with placebo
topical preparation (n=2).
Patients were evaluated every week.
 57

Table 8b. Use of Psychological Approaches

Level of Author(s)/Date/ Study Population/ Method of

Results Conclusions
Evidence Study Design Intervention Assessment
Ellerbroeck, 38 patients (age 13-46 years) with acne The patient and At 16 weeks, 17 patients The author’s idea is
Perspect Biol Med who refused to be evaluated by a physician agreed were “cured” on the basis of that a “disease” is
III 177
1973; 16: 240-62. dermatologist. upon severity of a clear skin. determined by all the
acne. specific
This study describes Many patients in the trial had earlier The rest of the patients had
The presence and psycholinguistic and
the hypotheses pursued many different treatments. 80-90% improvement.
degree of behavioral events in
towards a unified All patients received 1 mg tablet of improvement were No adverse effects were the life history of the
field theory of human trifluoperazine daily. established by reported. patients.
behavior with clinical agreement of the
application to acne Patients also received staphylococcus The author used
patients and the
vulgaris. toxoid at first twice weekly and then psychotherapy for the
opinion of their
every month for 6 months. treatment of acne.
physician.
Good posture and a pleasant facial Control groups were
expression were emphasized. lacking in the study to
assess the efficacy of
Patients were seen every 4-6 weeks,
this therapy.
for up to 2 1/2 years and followed up to
4 years.
 58

Table 8c. Use of Hypnosis/Biofeedback

Level of Author(s)/Date/ Study Population/ Method of

Results Conclusions
Evidence Study Design Intervention Assessment
Hughes, et al. Study involved 30 subjects with acne Photographic method Biofeedback-assisted Biofeedback-assisted
J Psychosom Res who were receiving dermatological of Cook et al. was relaxation and cognitive relaxation and cognitive
II
1983; 27: 185- treatment. used to assess acne imagery treatments imagery may be
178 7
91. severity. resulted in a significant effective in the treatment
Patients received relaxation and
reduction in acne severity of acne.
A randomized, cognitive imagery treatments, attention-
compared to control
case-controlled comparison training, or normal Regular practice of
groups and
study to determine dermatological care only. relaxation-imagery is
dermatological treatment
if acne vulgaris can probably necessary in
groups.
be reduced by The treatment was for 12 sessions over order for patients to
psychological 6 weeks. maintain the improved
treatment like acne condition that was
biofeedback- All cases had a matched control group. observed at the end of
assisted relaxation the treatment.
and cognitive
imagery treatments.
 59

IX. The effectiveness of dietary restriction in the treatment of adult acne and acne vulgaris in
adolescents to adults

The role of diet in the development of acne and an association between diet and acne has not been
demonstrated. There are limited studies that directly evaluate the effectiveness of dietary restriction in
the treatment of acne in adolescents and adults. Various foods, including chocolate, fats, sugar, and
carbonated beverages have been thought to develop or worsen acne. Studies on diet and the
development of acne have been limited and inconclusive. It is difficult to conduct good clinical studies
because it is not possible to dissociate diet from genetic factors.
 60

Table 9. Effectiveness of Dietary Restriction

Level of Author(s)/Date/ Study Population/

Method of Assessment Results Conclusions
Evidence Study Design Intervention
Bett et al., Br Med 16 patients with acne (mean age Sugar intake was assessed No significant Patients with acne had a
179
J 1967; 3: 153-5. 19.5years) were compared to 16 by self-reported difference in similar amount of sugar
II
patients with other dermatologic questionnaire. sugar intake as the control
Cohort study to
diseases (mean age 20.0 years) and 16 consumption groups.
evaluate the Acne was diagnosed based
healthy volunteers (mean age 19.7 was noted
influence of sugar on the presence of From this study it is not
years). among the acne
consumption on the comedones, papules, possible to conclude that
patients
development of pustules, or cystic lesions of diet is not involved in the
compared to the
acne vulgaris. the face, back, or chest. causation of acne or that
two control
changes in diet would not
groups.
affect disease progress.
Further studies are required
to test this possibility.

Fulton et al., 65 adolescents and young adults with Comedones, papules, and There was no Dietary chocolate had no
JAMA 1969; 210: mild to moderate acne were randomized pustules on the left side of difference in effect on acne severity.
II 180
2071-4. to receive an enriched chocolate bar the face were counted severity of acne,
Larger double-blinded
(ten times the amount of chocolate in a weekly. sebum secretion
Randomized, studies with controlled
typical bar) or a control bar (which rates, or sebum
single-blinded, Improvement was defined dietary factors should be
appeared to be identical in size, shape, composition
controlled, as a 30% decrease in total conducted.
color and wrapping to the enriched between the
crossover study to lesion count. Worsening
chocolate bar but contained no treatment
determine the effect was defined as a 30%
chocolate) daily for 4 weeks. After 3 groups.
of consumption of increase in total lesion
weeks of rest, patients crossed over to
high amounts of count. Smaller differences Neither the
the other group.
chocolate on acne. were reported as no chocolate bar
change. nor the control
bar influenced
acne vulgaris.
 61

Graded References

1 Ebell MH, Siwek J, Weiss BD et al. Simplifying the language of evidence to improve patient
care: Strength of recommendation taxonomy (SORT): a patient-centered approach to grading
evidence in medical literature. J Fam Pract 2004; 53: 111-20.
2 Lehmann HP, Robinson KA, Andrews JS et al. Acne therapy: a methodologic review. J Am Acad
Dermatol 2002; 47: 231-40. II
3 Pochi PE, Shalita AR, Strauss JS et al. Report of the Consensus Conference on Acne
Classification. Washington, D.C., March 24 and 25, 1990. J Am Acad Dermatol 1991; 24: 495-
500. II
4 Doshi A, Zaheer A, Stiller MJ. A comparison of current acne grading systems and proposal of a
novel system. Int J Dermatol 1997; 36: 416-8. II
5. Allen, B.S. and J.G. Smith, Jr., Various parameters for grading acne vulgaris. Arch Dermatol,
1982. 118(1): p. 23-5. II
6 Lucky AW, Barber BL, Girman CJ et al. A multirater validation study to assess the reliability of
acne lesion counting. J Am Acad Dermatol 1996; 35: 559-65. III
7 Cook CH, Centner RL, Michaels SE. An acne grading method using photographic standards.
Arch Dermatol 1979; 115: 571-5. II
8 Gibson JR, Harvey SG, Barth J et al. Assessing inflammatory acne vulgaris--correlation between
clinical and photographic methods. Br J Dermatol 1984; 111 Suppl 27: 168-70. III
9 Burke BM, Cunliffe WJ. The assessment of acne vulgaris--the Leeds technique. Br J Dermatol
1984; 111: 83-92. II
10 Motley RJ, Finlay AY. Practical use of a disability index in the routine management of acne. Clin
Exp Dermatol 1992; 17: 1-3. III
11 Lewis-Jones MS, Finlay AY. The Children's Dermatology Life Quality Index (CDLQI): initial
validation and practical use. Br J Dermatol 1995; 132: 942-9. II
12 Martin AR, Lookingbill DP, Botek A et al. Health-related quality of life among patients with facial
acne -- assessment of a new acne-specific questionnaire. Clin Exp Dermatol 2001; 26: 380-5. III
13 Lasek RJ, Chren MM. Acne vulgaris and the quality of life of adult dermatology patients. Arch
Dermatol 1998; 134: 454-8. II
14 Mallon E, Newton JN, Klassen A et al. The quality of life in acne: a comparison with general
medical conditions using generic questionnaires. Br J Dermatol 1999; 140: 672-6. II
15. Gupta MA, Johnson AM, Gupta AK. The development of an Acne Quality of Life scale: reliability,
validity, and relation to subjective acne severity in mild to moderate acne vulgaris. Acta Derm
Venereol 1998; 78: 451-6. II
16 Cove JH, Cunliffe WJ, Holland KT. Acne vulgaris: is the bacterial population size significant? Br
J Dermatol 1980; 102: 277-80. II
17 Bojar RA, Hittel N, Cunliffe WJ et al. Direct analysis of resistance in the cutaneous microflora
during treatment of acne vulgaris with topical 1% nadifloxacin and 2% erythromycin. Drugs
1995; 49 Suppl 2: 164-7. II
18 Eady EA, Cove JH, Holland KT et al. Erythromycin resistant propionibacteria in antibiotic treated
acne patients: association with therapeutic failure. Br J Dermatol 1989; 121: 51-7. II
19 Harkaway KS, McGinley KJ, Foglia AN et al. Antibiotic resistance patterns in coagulase-negative
staphylococci after treatment with topical erythromycin, benzoyl peroxide, and combination
therapy. Br J Dermatol 1992; 126: 586-90. II
20 Lawrence DM, Katz M, Robinson TW et al. Reduced sex hormone binding globulin and derived
free testosterone levels in women with severe acne. Clin Endocrinol (Oxf) 1981; 15: 87-91. I
 62

21 Bunker CB, Newton JA, Kilborn J et al. Most women with acne have polycystic ovaries. Br J
Dermatol 1989; 121: 675-80. II
22 Lucky AW, Biro FM, Simbartl LA et al. Predictors of severity of acne vulgaris in young
adolescent girls: results of a five-year longitudinal study. J Pediatr 1997; 130: 30-9. I
23 Timpatanapong P, Rojanasakul A. Hormonal profiles and prevalence of polycystic ovary
syndrome in women with acne. J Dermatol 1997; 24: 223-9. II
24 Lucky AW. Endocrine aspects of acne. Pediatr Clin North Am 1983; 30: 495-9. II
25 Christiansen JV, Gadborg E, Ludvigsen K et al. Topical tretinoin, vitamin A acid (Airol) in acne
vulgaris. A controlled clinical trial. Dermatologica 1974; 148: 82-9. I
26 Bradford LG, Montes LF. Topical application of vitamin A acid in acne vulgaris. South Med J
1974; 67: 683-7. II
27 Krishnan G. Comparison of two concentrations of tretinoin solution in the topical treatment of
acne vulgaris. Practitioner 1976; 216: 106-9. II
28 Chalker DK, Lesher JL, Jr., Smith JG, Jr. et al. Efficacy of topical isotretinoin 0.05% gel in acne
vulgaris: results of a multicenter, double-blind investigation. J Am Acad Dermatol 1987; 17: 251-
4. I
29 Shalita A, Weiss JS, Chalker DK et al. A comparison of the efficacy and safety of adapalene gel
0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial. J Am Acad
Dermatol 1996; 34: 482-5. II
30 Clucas A, Verschoore M, Sorba V et al. Adapalene 0.1% gel is better tolerated than tretinoin
0.025% gel in acne patients. J Am Acad Dermatol 1997; 36: S116-8. II
31 Cunliffe WJ, Caputo R, Dreno B et al. Clinical efficacy and safety comparison of adapalene gel
and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials. J Am Acad
Dermatol 1997; 36: S126-34. II
32 Dunlap FE, Mills OH, Tuley MR et al. Adapalene 0.1% gel for the treatment of acne vulgaris: its
superiority compared to tretinoin 0.025% cream in skin tolerance and patient preference. Br J
Dermatol 1998; 139 Suppl 52: 17-22. II
33 Galvin SA, Gilbert R, Baker M et al. Comparative tolerance of adapalene 0.1% gel and six
different tretinoin formulations. Br J Dermatol 1998; 139 Suppl 52: 34-40. II
34 Grosshans E, Marks R, Mascaro JM et al. Evaluation of clinical efficacy and safety of adapalene
0.1% gel versus tretinoin 0.025% gel in the treatment of acne vulgaris, with particular reference
to the onset of action and impact on quality of life. Br J Dermatol 1998; 139 Suppl 52: 26-33. II
35 Mills OH, Jr., Berger RS. Irritation potential of a new topical tretinoin formulation and a
commercially-available tretinoin formulation as measured by patch testing in human subjects. J
Am Acad Dermatol 1998; 38: S11-6. III
36 Ioannides D, Rigopoulos D, Katsambas A. Topical adapalene gel 0.1% vs. isotretinoin gel 0.05%
in the treatment of acne vulgaris: a randomized open-label clinical trial. Br J Dermatol 2002; 147:
523-7. II
37 Kakita L. Tazarotene versus tretinoin or adapalene in the treatment of acne vulgaris. J Am Acad
Dermatol 2000; 43: S51-4. II
38 Shalita AR, Chalker DK, Griffith RF et al. Tazarotene gel is safe and effective in the treatment of
acne vulgaris: a multicenter, double-blind, vehicle-controlled study. Cutis 1999; 63: 349-54. I
39 Ellis CN, Millikan LE, Smith EB et al. Comparison of adapalene 0.1% solution and tretinoin
0.025% gel in the topical treatment of acne vulgaris. Br J Dermatol 1998; 139 Suppl 52: 41-7. II
40 Webster GF, Berson D, Stein LF et al. Efficacy and tolerability of once-daily tazarotene 0.1% gel
versus once-daily tretinoin 0.025% gel in the treatment of facial acne vulgaris: a randomized
trial. Cutis 2001; 67: 4-9. II
 63

41 Lucky AW, Cullen SI, Jarratt MT et al. Comparative efficacy and safety of two 0.025% tretinoin
gels: results from a multicenter double-blind, parallel study. J Am Acad Dermatol 1998; 38: S17-
23. I
42. Belknap BS. Treatment of acne with 5% benzoyl peroxide gel or 0.05% retinoic acid cream.
Cutis 1979; 23: 856-9. I
43 Bucknall JH, Murdoch PN. Comparison of tretinoin solution and benzoyl peroxide lotion in the
treatment of acne vulgaris. Curr Med Res Opin 1977; 5: 266-8. II
44 Montes LF. Acne vulgaris: treatment with topical benzoyl peroxide acetone gel. Cutis 1977; 19:
681-5. III
45. Hughes BR, Norris JF, Cunliffe WJ. A double-blind evaluation of topical isotretinoin 0.05%,
benzoyl peroxide gel 5% and placebo in patients with acne. Clin Exp Dermatol 1992; 17: 165-8.
II
46 Cunliffe WJ, Dodman B, Ead R. Benzoyl peroxide in acne. Practitioner 1978; 220: 479-82. III
47 Fyrand O, Jakobsen HB. Water-based versus alcohol-based benzoyl peroxide preparations in
the treatment of acne vulgaris. Dermatologica 1986; 172: 263-7. II
48 Schutte H, Cunliffe WJ, Forster RA. The short-term effects of benzoyl peroxide lotion on the
resolution of inflamed acne lesions. Br J Dermatol 1982; 106: 91-4. I
49 Yong CC. Benzoyl peroxide gel therapy in acne in Singapore. Int J Dermatol 1979; 18: 485-8. II
50 Smith EB, Padilla RS, McCabe JM et al. Benzoyl peroxide lotion (20 percent) in acne. Cutis
1980; 25: 90-2. I
51 Mills OH, Jr., Kligman AM, Pochi P et al. Comparing 2.5%, 5%, and 10% benzoyl peroxide on
inflammatory acne vulgaris. Int J Dermatol 1986; 25: 664-7. I
52 Bernstein JE, Shalita AR. Topically applied erythromycin in inflammatory acne vulgaris. J Am
Acad Dermatol 1980; 2: 318-21. I
53 Jones EL, Crumley AF. Topical erythromycin vs blank vehicle in a multiclinic acne study. Arch
Dermatol 1981; 117: 551-3. I
54 Prince RA, Busch DA, Hepler CD et al. Clinical trial of topical erythromycin in inflammatory acne.
Drug Intell Clin Pharm 1981; 15: 372-6. I
55 Lesher JL, Jr., Chalker DK, Smith JG, Jr. et al. An evaluation of a 2% erythromycin ointment in
the topical therapy of acne vulgaris. J Am Acad Dermatol 1985; 12: 526-31. I
56 Pochi PE, Bagatell FK, Ellis CN et al. Erythromycin 2 percent gel in the treatment of acne
vulgaris. Cutis 1988; 41: 132-6. I
57 Dobson RL, Belknap BS. Topical erythromycin solution in acne. Results of a multiclinic trial. J
Am Acad Dermatol 1980; 3: 478-82. I
58 Mills O, Jr., Thornsberry C, Cardin CW et al. Bacterial resistance and therapeutic outcome
following three months of topical acne therapy with 2% erythromycin gel versus its vehicle. Acta
Derm Venereol 2002; 82: 260-5. I
59 Padilla RS, McCabe JM, Becker LE. Topical tetracycline hydrochloride vs. topical clindamycin
phosphate in the treatment of acne: a comparative study. Int J Dermatol 1981; 20: 445-8. III
60 Thomas DR, Raimer S, Smith EB. Comparison of topical erythromycin 1.5 percent solution
versus topical clindamycin phosphate 1.0 percent solution in the treatment of acne vulgaris.
Cutis 1982; 29: 624-5, 8-32. II
61 Shalita AR, Smith EB, Bauer E. Topical erythromycin v clindamycin therapy for acne. A
multicenter, double-blind comparison. Arch Dermatol 1984; 120: 351-5. II
62 Leyden JJ, Shalita AR, Saatjian GD et al. Erythromycin 2% gel in comparison with clindamycin
phosphate 1% solution in acne vulgaris. J Am Acad Dermatol 1987; 16: 822-7. I
63 McKenzie MW, Beck DC, Popovich NG. Topical clindamycin formulations for the treatment of
acne vulgaris. An evaluation. Arch Dermatol 1981; 117: 630-4. II
 64

64 Kuhlman DS, Callen JP. A comparison of clindamycin phosphate 1 percent topical lotion and
placebo in the treatment of acne vulgaris. Cutis 1986; 38: 203-6. II
65 Becker LE, Bergstresser PR, Whiting DA et al. Topical clindamycin therapy for acne vulgaris. A
cooperative clinical study. Arch Dermatol 1981; 117: 482-5. I
66 Ellis CN, Gammon WR, Stone DZ et al. A comparison of Cleocin T Solution, Cleocin T Gel, and
placebo in the treatment of acne vulgaris. Cutis 1988; 42: 245-7. II
67 Glass D, Boorman GC, Stables GI et al. A placebo-controlled clinical trial to compare a gel
containing a combination of isotretinoin (0.05%) and erythromycin (2%) with gels containing
isotretinoin (0.05%) or erythromycin (2%) alone in the topical treatment of acne vulgaris.
Dermatology 1999; 199: 242-7. II
68 Mills OH, Jr., Kligman AM. Treatment of acne vulgaris with topically applied erythromycin and
tretinoin. Acta Derm Venereol 1978; 58: 555-7. II
69 Richter JR, Bousema MT, De Boulle KLV et al. Efficacy of a fixed clindamycin phosphate 1.2%,
tretinoin 0.025% gel formulation (Velac) in the topical control of facial acne lesions. J
Dermatolog Treat 1998; 9: 81-90. II
70 Zouboulis CC, Derumeaux L, Decroix J et al. A multicentre, single-blind, randomized
comparison of a fixed clindamycin phosphate/tretinoin gel formulation (Velac) applied once daily
and a clindamycin lotion formulation (Dalacin T) applied twice daily in the topical treatment of
acne vulgaris. Br J Dermatol 2000; 143: 498-505. I
71 Rietschel RL, Duncan SH. Clindamycin phosphate used in combination with tretinoin in the
treatment of acne. Int J Dermatol 1983; 22: 41-3. II
72 Chalker DK, Shalita A, Smith JG, Jr. et al. A double-blind study of the effectiveness of a 3%
erythromycin and 5% benzoyl peroxide combination in the treatment of acne vulgaris. J Am
Acad Dermatol 1983; 9: 933-6. I
73 Tschen EH, Katz HI, Jones TM et al. A combination benzoyl peroxide and clindamycin topical
gel compared with benzoyl peroxide, clindamycin phosphate, and vehicle in the treatment of
acne vulgaris. Cutis 2001; 67: 165-9. I
74 Leyden JJ, Hickman JG, Jarratt MT et al. The efficacy and safety of a combination benzoyl
peroxide/clindamycin topical gel compared with benzoyl peroxide alone and a benzoyl
peroxide/erythromycin combination product. J Cutan Med Surg 2001; 5: 37-42. II
75 Lookingbill DP, Chalker DK, Lindholm JS et al. Treatment of acne with a combination
clindamycin/benzoyl peroxide gel compared with clindamycin gel, benzoyl peroxide gel and
vehicle gel: combined results of two double-blind investigations. J Am Acad Dermatol 1997; 37:
590-5. I
76 Shalita AR. Treatment of mild and moderate acne vulgaris with salicylic acid in an alcohol-
detergent vehicle. Cutis 1981; 28: 556-8, 561. II
77 Cunliffe WJ, Holland KT. Clinical and laboratory studies on treatment with 20% azelaic acid
cream for acne. Acta Derm Venereol Suppl (Stockh) 1989; 143: 31-4. II
78 Katsambas A, Graupe K, Stratigos J. Clinical studies of 20% azelaic acid cream in the treatment
of acne vulgaris. Comparison with vehicle and topical tretinoin. Acta Derm Venereol Suppl
(Stockh) 1989; 143: 35-9. II
79 Hjorth N, Graupe K. Azelaic acid for the treatment of acne. A clinical comparison with oral
tetracycline. Acta Derm Venereol Suppl (Stockh) 1989; 143: 45-8. I
80 Elstein W. Topical deodorized polysulfides. Broadscope acne therapy. Cutis 1981; 28: 468-72.
III
81 Hurley HJ, Shelley WB. Special topical approach to the treatment of acne. Suppression of
sweating with aluminum chloride in an anhydrous formulation. Cutis 1978; 22: 696-703. II
82 Hjorth N, Storm D, Dela K. Topical anhydrous aluminum chloride formulation in the treatment of
acne vulgaris: a double-blind study. Cutis 1985; 35: 499-500. II
 65

83 Cochran RJ, Tucker SB, Flannigan SA. Topical zinc therapy for acne vulgaris. Int J Dermatol
1985; 24: 188-90. II
84 Stainforth J, MacDonald-Hull S, Papworth-Smith JW et al. A single-blind comparison of topical
erythromycin/zinc lotion and oral minocycline in the treatment of acne vulgaris. J Dermatolog
Treat 1993; 4: 119-22. II
85 Bojar RA, Eady EA, Jones CE et al. Inhibition of erythromycin-resistant propionibacteria on the
skin of acne patients by topical erythromycin with and without zinc. Br J Dermatol 1994; 130:
329-36. III
86 Thiboutot D. New treatments and therapeutic strategies for acne. Arch Fam Med 2000; 9: 179-
87. I
87 Lebrun CM. Rosac cream with sunscreens (sodium sulfacetamide 10% and sulfur 5%). Skinmed
2004; 3: 92. III
88 Tarimci N, Sener S, Kilinc T. Topical sodium sulfacetamide/sulfur lotion. J Clin Pharm Ther
1997; 22: 301. II
89 Lane P, Williamson DM. Treatment of acne vulgaris with tetracycline hydrochloride: a double-
blind trial with 51 patients. Br Med J 1969; 2: 76-9. II
90 Smith JG, Jr., Chalker DK, Wehr RF. The effectiveness of topical and oral tetracycline for acne.
South Med J 1976; 69: 695-7. I
91 Gratton D, Raymond GP, Guertin-Larochelle S et al. Topical clindamycin versus systemic
tetracycline in the treatment of acne. Results of a multiclinic trial. J Am Acad Dermatol 1982; 7:
50-3. I
92 Katsambas A, Towarky AA, Stratigos J. Topical clindamycin phosphate compared with oral
tetracycline in the treatment of acne vulgaris. Br J Dermatol 1987; 116: 387-91. II
93 Braathen LR. Topical clindamycin versus oral tetracycline and placebo in acne vulgaris. Scand J
Infect Dis Suppl 1984; 43: 71-5. III
94 Anderson RL, Cook CH, Smith DE. The effect of oral and topical tetracycline on acne severity
and on surface lipid composition. J Invest Dermatol 1976; 66: 172-7. III
95 Blaney DJ, Cook CH. Topical use of tetracycline in the treatment of acne: a double-blind study
comparing topical and oral tetracycline therapy and placebo. Arch Dermatol 1976; 112: 971-3. I
96 Rapaport M, Puhvel SM, Reisner RM. Evaluation of topical erythromycin and oral tetracycline in
acne vulgaris. Cutis 1982; 30: 122-6, 30, 32-5. II
97 Norris JF, Hughes BR, Basey AJ et al. A comparison of the effectiveness of topical tetracycline,
benzoyl-peroxide gel and oral oxytetracycline in the treatment of acne. Clin Exp Dermatol 1991;
16: 31-3. II
98 Sauer GC. Safety of long-term tetracycline therapy for acne. Arch Dermatol 1976; 112: 1603-5.
III
99 Baer RL, Leshaw SM, Shalita AR. High-dose tetracycline therapy in severe acne. Arch Dermatol
1976; 112: 479-81. III
100 Plewig G, Petrozzi JW, Berendes U. Double-blind study of doxycycline in acne vulgaris. Arch
Dermatol 1970; 101: 435-8. II
101 Harrison PV. A comparison of doxycycline and minocycline in the treatment of acne vulgaris.
Clin Exp Dermatol 1988; 13: 242-4. II
102 Skidmore R, Kovach R, Walker C et al. Effects of subantimicrobial-dose doxycycline in the
treatment of moderate acne. Arch Dermatol 2003; 139: 459-64. I
103 Hersle K, Gisslen H. Minocycline in acne vulgaris: a double-blind study. Curr Ther Res Clin Exp
1976; 19: 339-42. III
 66

104 Sheehan-Dare RA, Papworth-Smith J, Cunliffe WJ. A double-blind comparison of topical

clindamycin and oral minocycline in the treatment of acne vulgaris. Acta Derm Venereol 1990;
70: 534-7. III
105 Samuelson JS. An accurate photographic method for grading acne: initial use in a double-blind
clinical comparison of minocycline and tetracycline. J Am Acad Dermatol 1985; 12: 461-7. II
106 Poliak SC, DiGiovanna JJ, Gross EG et al. Minocycline-associated tooth discoloration in young
adults. JAMA 1985; 254: 2930-2. II
107 Goulden V, Glass D, Cunliffe WJ. Safety of long-term high-dose minocycline in the treatment of
acne. Br J Dermatol 1996; 134: 693-5. II
108 Gammon WR, Meyer C, Lantis S et al. Comparative efficacy of oral erythromycin versus oral
tetracycline in the treatment of acne vulgaris. A double-blind study. J Am Acad Dermatol 1986;
14: 183-6. I
109 Al-Mishari MA. Clinical and bacteriological evaluation of tetracycline and erythromycin in acne
vulgaris. Clin Ther 1987; 9: 273-80. III
110 Parsad D, Pandhi R, Nagpal R et al. Azithromycin monthly pulse vs daily doxycycline in the
treatment of acne vulgaris. J Dermatol 2001; 28: 1-4. II
111 Christian GL, Krueger GG. Clindamycin vs placebo as adjunctive therapy in moderately severe
acne. Arch Dermatol 1975; 111: 997-1000. I
112 Cunliffe WJ, Cotterill JA. Clindamycin as an alternative to tetracycline in severe acne vulgaris.
Practitioner 1973; 210: 698-700. III
113 Poulos ET, Tedesco FJ. Acne vulgaris: double-blind trial comparing tetracycline and
clindamycin. Arch Dermatol 1976; 112: 974-6. III
114 Panzer JD, Poche W, Meek TJ et al. Acne treatment: a comparative efficacy trial of clindamycin
and tetracycline. Cutis 1977; 19: 109-11. II
115 Stoughton RB, Cornell RC, Gange RW et al. Double-blind comparison of topical 1 percent
clindamycin phosphate (Cleocin T) and oral tetracycline 500 mg/day in the treatment of acne
vulgaris. Cutis 1980; 26: 424-5, 429. I
116 Macdonald RH, Macconnell LE, Dunsmore IR. Trimethoprim-sulphamethoxazole versus placebo
in acne vulgaris. Br J Clin Pract 1972; 26: 97-8. II
117 Hersle K. Trimethoprim-sulphamethoxazole in acne vulgaris. A double-blind study.
Dermatologica 1972; 145: 187-91. I
118 Cotterill JA, Cunliffe WJ, Forster RA et al. A comparison of trimethoprim-sulphamethoxazole with
oxytetracycline in acne vulgaris. Br J Dermatol 1971; 84: 366-9. III
119 Gibson JR, Darley CR, Harvey SG et al. Oral trimethoprim versus oxytetracycline in the
treatment of inflammatory acne vulgaris. Br J Dermatol 1982; 107: 221-4. III
120 Bottomley WW, Cunliffe WJ. Oral trimethoprim as a third-line antibiotic in the management of
acne vulgaris. Dermatology 1993; 187: 193-6. II
121 Miller YW, Eady EA, Lacey RW et al. Sequential antibiotic therapy for acne promotes the
carriage of resistant staphylococci on the skin of contacts. J Antimicrob Chemother 1996; 38:
829-37. I
122 Lucky AW, Henderson TA, Olson WH et al. Effectiveness of norgestimate and ethinyl estradiol in
treating moderate acne vulgaris. J Am Acad Dermatol 1997; 37: 746-54. I
123 Olson WH, Lippman JS, Robisch DM. The duration of response to norgestimate and ethinyl
estradiol in the treatment of acne vulgaris. Int J Fertil Womens Med 1998; 43: 286-90. I
124 Thiboutot D, Archer DF, Lemay A et al. A randomized, controlled trial of a low-dose
contraceptive containing 20 microg of ethinyl estradiol and 100 microg of levonorgestrel for acne
treatment. Fertil Steril 2001; 76: 461-8. I
 67

125 Leyden J, Shalita A, Hordinsky M et al. Efficacy of a low-dose oral contraceptive containing 20
microg of ethinyl estradiol and 100 microg of levonorgestrel for the treatment of moderate acne:
A randomized, placebo-controlled trial. J Am Acad Dermatol 2002; 47: 399-409. I
126 Thorneycroft IH, Stanczyk FZ, Bradshaw KD et al. Effect of low-dose oral contraceptives on
androgenic markers and acne. Contraception 1999; 60: 255-62. II
127 Worret I, Arp W, Zahradnik HP et al. Acne resolution rates: results of a single-blind, randomized,
controlled, parallel phase III trial with EE/CMA (Belara) and EE/LNG (Microgynon). Dermatology
2001; 203: 38-44. II
128 Rosen MP, Breitkopf DM, Nagamani M. A randomized controlled trial of second- versus third-
generation oral contraceptives in the treatment of acne vulgaris. Am J Obstet Gynecol 2003;
188: 1158-60. III
129 Thorneycroft H, Gollnick H, Schellschmidt I. Superiority of a combined contraceptive containing
drospirenone to a triphasic preparation containing norgestimate in acne treatment. Cutis 2004;
74: 123-30. I
130 Huber J, Walch K. Treating acne with oral contraceptives: use of lower doses. Contraception
2006; 73: 23-9. I
131 Goodfellow A, Alaghband-Zadeh J, Carter G et al. Oral spironolactone improves acne vulgaris
and reduces sebum excretion. Br J Dermatol 1984; 111: 209-14. III
132 Muhlemann MF, Carter GD, Cream JJ et al. Oral spironolactone: an effective treatment for acne
vulgaris in women. Br J Dermatol 1986; 115: 227-32. II
133 Hatwal A, Bhatt RP, Agrawal JK et al. Spironolactone and cimetidine in treatment of acne. Acta
Derm Venereol 1988; 68: 84-7. III
134 Greenwood R, Brummitt L, Burke B et al. Acne: double blind clinical and laboratory trial of
tetracycline, oestrogen-cyproterone acetate, and combined treatment. Br Med J (Clin Res Ed)
1985; 291: 1231-5. II
135 Miller JA, Wojnarowska FT, Dowd PM et al. Anti-androgen treatment in women with acne: a
controlled trial. Br J Dermatol 1986; 114: 705-16. II
136 Fugere P, Percival-Smith RK, Lussier-Cacan S et al. Cyproterone acetate/ethinyl estradiol in the
treatment of acne. A comparative dose-response study of the estrogen component.
Contraception 1990; 42: 225-34. III
137 Nader S, Rodriguez-Rigau LJ, Smith KD et al. Acne and hyperandrogenism: impact of lowering
androgen levels with glucocorticoid treatment. J Am Acad Dermatol 1984; 11: 256-9. II
138 Amichai B, Shemer A, Grunwald MH. Low-dose isotretinoin in the treatment of acne vulgaris. J
Am Acad Dermatol 2006; 54: 644-6. I
139 Goldstein JA, Socha-Szott A, Thomsen RJ et al. Comparative effect of isotretinoin and etretinate
on acne and sebaceous gland secretion. J Am Acad Dermatol 1982; 6: 760-5. II
140 King K, Jones DH, Daltrey DC et al. A double-blind study of the effects of 13-cis-retinoic acid on
acne, sebum excretion rate and microbial population. Br J Dermatol 1982; 107: 583-90. III
141 Peck GL, Olsen TG, Butkus D et al. Isotretinoin versus placebo in the treatment of cystic acne. A
randomized double-blind study. J Am Acad Dermatol 1982; 6: 735-45. I
142 Strauss JS, Stranieri AM. Changes in long-term sebum production from isotretinoin therapy. J
Am Acad Dermatol 1982; 6: 751-6. II
143 Jones DH, King K, Miller AJ et al. A dose-response study of I3-cis-retinoic acid in acne vulgaris.
Br J Dermatol 1983; 108: 333-43. II
144 Strauss JS, Rapini RP, Shalita AR et al. Isotretinoin therapy for acne: results of a multicenter
dose-response study. J Am Acad Dermatol 1984; 10: 490-6. I
145 Lester RS, Schachter GD, Light MJ. Isotretinoin and tetracycline in the management of severe
nodulocystic acne. Int J Dermatol 1985; 24: 252-7. III
 68

146 Chivot M, Midoun H. Isotretinoin and acne--a study of relapses. Dermatologica 1990; 180: 240-
3. III
147 Layton AM, Knaggs H, Taylor J et al. Isotretinoin for acne vulgaris--10 years later: a safe and
successful treatment. Br J Dermatol 1993; 129: 292-6. II
148 Lehucher-Ceyrac D, Weber-Buisset MJ. Isotretinoin and acne in practice: a prospective analysis
of 188 cases over 9 years. Dermatology 1993; 186: 123-8. I
149 Stainforth JM, Layton AM, Taylor JP et al. Isotretinoin for the treatment of acne vulgaris: which
factors may predict the need for more than one course? Br J Dermatol 1993; 129: 297-301. II
150 Goulden V, Clark SM, McGeown C et al. Treatment of acne with intermittent isotretinoin. Br J
Dermatol 1997; 137: 106-8. I
151 Strauss JS, Leyden JJ, Lucky AW et al. A randomized trial of the efficacy of a new micronized
formulation versus a standard formulation of isotretinoin in patients with severe recalcitrant
nodular acne. J Am Acad Dermatol 2001; 45: 187-95. I
152 McElwee NE, Schumacher MC, Johnson SC et al. An observational study of isotretinoin
recipients treated for acne in a health maintenance organization. Arch Dermatol 1991; 127: 341-
6. I
153 Strauss JS, Leyden JJ, Lucky AW et al. Safety of a new micronized formulation of isotretinoin in
patients with severe recalcitrant nodular acne: A randomized trial comparing micronized
isotretinoin with standard isotretinoin. J Am Acad Dermatol 2001; 45: 196-207. I
154 Lammer EJ, Chen DT, Hoar RM et al. Retinoic acid embryopathy. N Engl J Med 1985; 313: 837-
41. II
155 Dai WS, LaBraico JM, Stern RS. Epidemiology of isotretinoin exposure during pregnancy. J Am
Acad Dermatol 1992; 26: 599-606. I
156 Zech LA, Gross EG, Peck GL et al. Changes in plasma cholesterol and triglyceride levels after
treatment with oral isotretinoin. A prospective study. Arch Dermatol 1983; 119: 987-93. II
157 Bershad S, Rubinstein A, Paterniti JR et al. Changes in plasma lipids and lipoproteins during
isotretinoin therapy for acne. N Engl J Med 1985; 313: 981-5. II
158 Leachman SA, Insogna KL, Katz L et al. Bone densities in patients receiving isotretinoin for
cystic acne. Arch Dermatol 1999; 135: 961-5. II
159 Goldsmith LA, Bolognia JL, Callen JP et al. American Academy of Dermatology Consensus
Conference on the safe and optimal use of isotretinoin: summary and recommendations. J Am
Acad Dermatol 2004; 50: 900-6. I
160 Myhill JE, Leichtman SR, Burnett JW. Self-esteem and social assertiveness in patients receiving
isotretinoin treatment for cystic acne. Cutis 1988; 41: 171-3. II
161 Rubinow DR, Peck GL, Squillace KM et al. Reduced anxiety and depression in cystic acne
patients after successful treatment with oral isotretinoin. J Am Acad Dermatol 1987; 17: 25-32. I
162 Hull SM, Cunliffe WJ, Hughes BR. Treatment of the depressed and dysmorphophobic acne
patient. Clin Exp Dermatol 1991; 16: 210-1. III
163 Jick SS, Kremers HM, Vasilakis-Scaramozza C. Isotretinoin use and risk of depression,
psychotic symptoms, suicide, and attempted suicide. Arch Dermatol 2000; 136: 1231-6. I
164 Marqueling AL, Zane LT. Depression and suicidal behavior in acne patients treated with
isotretinoin: a systematic review. Semin Cutan Med Surg 2005; 24: 92-102. I
165 Chia CY, Lane W, Chibnall J et al. Isotretinoin therapy and mood changes in adolescents with
moderate to severe acne: a cohort study. Arch Dermatol 2005; 141: 557-60. I
166 Lehucher-Ceyrac D, de La Salmoniere P, Chastang C et al. Predictive factors for failure of
isotretinoin treatment in acne patients: results from a cohort of 237 patients. Dermatology 1999;
198: 278-83. I
 69

167 White GM, Chen W, Yao J et al. Recurrence rates after the first course of isotretinoin. Arch
Dermatol 1998; 134: 376-8. II
168 Levine RM, Rasmussen JE. Intralesional corticosteroids in the treatment of nodulocystic acne.
Arch Dermatol 1983; 119: 480-1. III
169 Potter RA. Intralesional triamcinolone and adrenal suppression in acne vulgaris. J Invest
Dermatol 1971; 57: 364-70. III
170 Kim SW, Moon SE, Kim JA et al. Glycolic acid versus Jessner's solution: which is better for
facial acne patients? A randomized prospective clinical trial of split-face model therapy.
Dermatol Surg 1999; 25: 270-3. III
171 Wang CM, Huang CL, Hu CT et al. The effect of glycolic acid on the treatment of acne in Asian
skin. Dermatol Surg 1997; 23: 23-9. III
172 Grimes PE. The safety and efficacy of salicylic acid chemical peels in darker racial-ethnic
groups. Dermatol Surg 1999; 25: 18-22. III
173 Pepall LM, Cosgrove MP, Cunliffe WJ. Ablation of whiteheads by cautery under topical
anesthesia. Br J Dermatol 1991; 125: 256-9. III
174 Bassett IB, Pannowitz DL, Barnetson RS. A comparative study of tea-tree oil versus benzoyl
peroxide in the treatment of acne. Med J Aust 1990; 153: 455-8. II
175 Paranjpe P, Kulkarni PH. Comparative efficacy of four Ayurvedic formulations in the treatment of
acne vulgaris: a double-blind randomized placebo-controlled clinical evaluation. J
Ethnopharmacol 1995; 49: 127-32. II
176 Lalla JK, Nandedkar SY, Paranjape MH et al. Clinical trials of ayurvedic formulations in the
treatment of acne vulgaris. J Ethnopharmacol 2001; 78: 99-102. II
177 Ellerbroek WC. Hypotheses toward a unified field theory of human behavior with clinical
application to acne vulgaris. Perspect Biol Med 1973; 16: 240-62. II
178 Hughes H, Brown BW, Lawlis GF et al. Treatment of acne vulgaris by biofeedback relaxation
and cognitive imagery. J Psychosom Res 1983; 27: 185-91. III
179 Bett DG, Morland J, Yudkin J. Sugar consumption in acne vulgaris and seborrhoeic dermatitis.
Br Med J 1967; 3: 153-5. II
180 Fulton JE, Jr., Plewig G, Kligman AM. Effect of chocolate on acne vulgaris. JAMA 1969; 210:
2071-4. II