ARTICLE
Auteur(s) : Mohsen
Alirezai1, Sheru A George2, Ian
Coutts2, Diane I Roseeuw3, Jean-Pierre
Hachem3, Nabil Kerrouche4, Farzaneh
Sidou4, Pascale Soto4
1Service de dermatologie, Hôpital Saint Eloi,
Montpellier, France
2Department of Dermatology, Amersham Hospital, Amersham,
UK
3AZ-VUB Dermatologie, Brussels, Belgium
4Galderma, Sophia Antipolis, France
accepté le 23 Août 2006
Acne vulgaris is a common, chronic and recurrent disease.
Management of the moderate to moderately severe forms often
requires aggressive combination therapy to account for the multiple
associated etiological factors and a long-term therapeutic strategy
[1-5]. The recurring nature of acne suggests that many patients may
benefit from continuing on a maintenance therapy [5]. Ideally,
regular use of topical retinoids should help ensure visible acne
lesions remain in remission [6].The goal of maintenance therapy
should be to prevent acne recurrence by targeting the early stages
of comedogenesis, thereby suppressing the development of
subclinical microcomedones, the precursor of mature acne lesions
[5, 6]. Topical retinoids are effective, generally well-tolerated
comedolytic agents that can be applied to a broad epidermal surface
and therefore make a rational choice for maintenance therapy.
Furthermore, topical retinoids are well suited to prevent the
formation of microcomedos, as they are the only acne medication
that regulate the keratinisation process from within the duct [7].
Recently published guidelines recommend the use of topical
retinoids with or without benzoyl peroxide for maintenance
following initial combination treatment with an antimicrobial [5].
Despite support from leading guidelines and the variety of
medications available for the treatment of acute acne, there are
relatively few well-controlled studies providing evidence for
long-term or maintenance therapy.Most of the available clinical
evidence for successful maintenance therapy is with adapalene
[8-10], a naphthoic acid derivative, receptor-selective retinoid
with anti-inflammatory, comedolytic, and anticomedogenic properties
[11-16]. The efficacy and safety of adapalene in the treatment of
acne vulgaris have been extensively studied in numerous clinical
trials [17, 18] either alone or in combination with antimicrobials
and have consistently demonstrated a more favourable tolerability
profile than other topical retinoids, including all tazarotene [19,
20] and tretinoin [20-23] formulations. For the treatment of
inflammatory acne, the efficacy of a combination therapy of
adapalene plus antibiotic therapy is significantly better and
faster than therapy with antibiotic therapy alone (oral or topical)
for the treatment of inflammatory acne [8, 9, 24-27]. Furthermore,
several studies have shown clinical benefit of continued treatment
with adapalene gel 0.1% as a maintenance therapy following the
combination therapy with an antibiotic [8-10].The present study is
intended to confirm these previous studies and provide further
support for recommendations from the current guidelines. In an
initial study, the efficacy and safety of adapalene was evaluated
when used in combination with oral lymecycline by moderate to
moderately severe acne subjects for 12-weeks [24]. Lymecycline, a
semisynthetic tetracycline antibiotic, is a first-line antibiotic
for acne with improved oral absorption, enhanced tissue
penetration, and slower elimination relative to tetracycline [25].
Subjects were randomised to receive lymecycline 300 mg and
either adapalene gel 0.1% or vehicle once-daily. At week 12, the
combination of adapalene-lymecycline produced significantly larger
reductions in total, inflammatory, and non-inflammatory lesions
relative to lymecycline alone, similar to results from other
adapalene-antimicrobial studies [8, 9, 26, 27].In the present
study, the maintenance effect of adapalene gel 0.1% was evaluated
relative to its gel vehicle in those subjects who showed at least
moderate improvement from the previous adapalene-lymecycline
combination therapy study. The results of this maintenance study
are presented herein.
Methods
Study design and subjects
The efficacy and safety of adapalene gel 0.1% (Differin®
Gel 0.1%, Galderma International) as a maintenance therapy were
compared to its gel vehicle in a randomised, multicentre,
vehicle-controlled, investigator-blind, parallel group study
conducted at 19 centres in Europe. Male and female acne subjects,
12 to 30 years of age, were enrolled if they showed at least
moderate improvement (on the following 7-point scale of disease
improvement: Worse; No change; Slight improvement: approximately
1-24% improvement; Moderate improvement: 25-49% improvement; Marked
improvement: 50-74% improvement; Almost clear: 75-99% improvement;
Clear: 100% improvement) from the starting point of a previous
12-week treatment with either adapalene plus lymecycline or gel
vehicle plus lymecycline [24]. In this prior combination study, a
total of 242 subjects, with a global severity grade ranging from 4
to 10 on the Leeds Revised Acne Grading System [28] and with at
least 15 inflammatory facial lesions (no more than 3 nodules) and
at least 20 non inflammatory facial lesions, were randomized to
receive lymecycline 300 mg once-daily in the morning and
either adapalene or gel vehicle once-daily in the evening for 12
weeks. Eligible subjects completing that study were re-randomised
consecutively in a 1: 1 ratio to receive either adapalene gel 0.1%
or adapalene gel vehicle once-daily in the evening for an
additional 12 weeks as part of the current study. The randomisation
schedule remained blinded from those involved in the clinical
conduct of the study. The integrity of the blinding was ensured by
packaging the topical medication in identical tubes and requiring a
third party other than the investigator/evaluator to dispense the
medication.
Exclusion criteria prohibited enrollment of subjects with acne
requiring isotretinoin therapy or other dermatologic conditions
necessitating interfering treatment. Women were excluded if they
were pregnant, nursing, or planning a pregnancy, as were men with
facial hair that would interfere with the assessments. Subjects
were provided with a daily facial moisturizer to use as needed for
the symptomatic relief of skin dryness or irritation.
Evaluations for this study occurred at baseline and at weeks 4,
8, and 12. The final visit from the previous 12-week combination
study served as the baseline visit for this study. A urine
pregnancy test was required at entry and at the final study visit
for all females of childbearing potential. Subjects were free to
withdraw from the study at any time and for any reason. Subjects
not completing the entire study were to be fully evaluated when
possible.
This study was conducted in accordance with the ethical
principles originating from the Declaration of Helsinki and Good
Clinical Practices (GCPs), ICH guidelines, and in compliance with
local regulatory requirements. This study was reviewed and approved
by Independent Ethics Committees. All subjects provided their
written informed consent prior to entering the study.
Efficacy and safety variables
The main objective was to evaluate the maintenance success rate at
the end of the maintenance study, defined as the percentage of
subjects who maintained at least 50% of the improvement (in terms
of percent reduction of lesions [total, inflammatory and non
inflammatory]) from the previous 12-week combination therapy study
(e.g., a subject entering the maintenance phase after having lost
60% lesions [from 80 to 32 lesions] was considered as a failure if
the % reduction at the end of the maintenance study was inferior to
30% [56 lesions]. Other efficacy variables included median of
percent reduction in lesion count (total, inflammatory and non
inflammatory) from starting point of the previous combination
study, and global severity of the disease by use of the Leeds
Revised Acne Grading System [28].
Safety and tolerability were assessed through evaluations of
local facial tolerability and adverse events. At each visit, the
investigator rated erythema, scaling, dryness, and stinging/burning
on a scale ranging from 0 (none) to 3 (severe). Mean scores at each
post baseline visit and worst score (worst observation recorded for
a subject during the post baseline period) were calculated. Adverse
events were also evaluated at each visit.
Statistical analyses
In this study, the safety population was defined as all subjects
randomised and treated at least once. The intent-to-treat (ITT)
population included all randomised subjects who were dispensed
study medication. To evaluate the effect of major deviations or of
data exclusions, the ITT population was analysed using a worst case
method to impute missing values. All subjects with missing data
were considered failure subjects. Therefore, at week 12, for the
maintenance rate variable, the “failure” value was attributed to
missing data. To be consistent with maintenance rate, the median of
percent reduction of failure subject population was attributed to
missing data for the descriptive analyses of lesions.
Analyses for the maintenance rate were performed on the week 12
data for the ITT-worst case population. To evaluate the efficacy of
the maintenance therapy between the two treatment arms, the success
rate in terms of lesions (total, inflammatory and non inflammatory)
were analysed by the Cochran-Mantel-Haenzsel (CMH) test controlling
for previous treatment using ridit scores, at week 12. Global
severity was analysed using the Cochran-Mantel-Haenzsel (CMH) test
controlling for “analysis centre” and previous treatment. Percent
reduction from starting point of the previous combination study in
lesions counts was descriptively analysed on ITT-worst case
population. All tests were two-sided and used the 0.05 level to
declare significance.
Results
Subject disposition and baseline characteristics
A total of 136 subjects were enrolled in this study. They were
re-randomised to receive either adapalene gel 0.1% (73 subjects) or
its gel vehicle (63 subjects; ( figure 1 )). One subject in
the adapalene group had missing data from the initial study
starting point and was therefore not included in the efficacy
analysis. Subject disposition was similar between the two treatment
groups. Discontinuation rates were higher in the vehicle group
(20.6%) relative to the adapalene group (6.8%). The most common
reason for discontinuation was subject request (2.7% and 14.3% for
the adapalene and vehicle groups, respectively). A total of 118
subjects (87%) completed the study.
Baseline subject characteristics of the ITT population are
summarised in table 1( Table 1 ).
Demographic characteristics and baseline dermatological scores were
comparable between the two treatment groups. There were slightly
more females (63.5% vs. 53.4%), more Caucasians (90.5% vs. 84.9%),
and slightly fewer subjects with mild baseline acne (76.2% vs.
86.3%) in the vehicle group relative to the adapalene group.
Table 1 Subject demographics and baseline disease
characteristics (ITT population)
|
Adapalene Gel 0.1% n = 73
|
Gel Vehicle n = 63
|
Total n = 136
|
|
Demographics
|
|
Gender
|
|
|
|
|
Female
|
39 (53.4%)
|
40 (63.5%)
|
79 (58.1%)
|
|
Male
|
34 (46.6%)
|
23 (36.5%)
|
57 (41.9%)
|
|
Race
|
|
|
|
|
Black/Negroid
|
8 (11.0%)
|
4 (6.3%)
|
12 (8.8%)
|
|
Other or mixed
|
1 (1.4%)
|
2 (3.2%)
|
3 (2.2%)
|
|
White/Caucasoid
|
62 (84.9%)
|
57 (90.5%)
|
119 (87.5%)
|
|
Yellow/Mongoloid
|
2 (2.7%)
|
–
|
2 (1.5%)
|
|
Skin phototype
|
|
|
|
|
I
|
3 (4.1%)
|
1 (1.6%)
|
4 (2.9%)
|
|
II
|
19 (26.0%)
|
23 (36.5%)
|
42 (30.9%)
|
|
III
|
27 (37.0%)
|
23 (36.5%)
|
50 (36.8%)
|
|
IV
|
15 (20.5%)
|
9 (14.3%)
|
24 (17.6%)
|
|
V
|
4 (5.5%)
|
3 (4.8%)
|
7 (5.1%)
|
|
VI
|
5 (6.8%)
|
4 (6.3%)
|
9 (6.6%)
|
|
Age (in years)
|
|
|
|
|
Mean±STD
|
19.1 ± 5.56
|
18.6 ± 4.31
|
18.9 ± 5.01
|
|
Median
|
17.9
|
17.3
|
17.5
|
|
(Min,Max)
|
(13,45.1)
|
(12.2,31.3)
|
(12.2,45.1)
|
|
Disease characteristics at starting point of combination
study
|
|
Lesion count
|
|
|
|
|
Total
|
|
|
|
|
Mean
|
101.1
|
99.7
|
–
|
|
Median
|
80.0
|
74.0
|
–
|
|
Inflammatory
|
|
|
|
|
Mean
|
33.6
|
32.9
|
–
|
|
Median
|
27.5
|
28.0
|
–
|
|
Noninflammatory
|
|
|
|
|
Mean
|
67.6
|
66.8
|
–
|
|
Median
|
48.5
|
40.0
|
–
|
- Global severity grade
- (Revised Leeds Scale)
|
|
|
|
|
4-7: moderate
|
64 (87.6%)
|
59 (93.5%)
|
–
|
|
5-8: moderately severe
|
9 (12.3%)
|
4 (6.4%)
|
–
|
|
Disease characteristics at starting point of maintenance
study
|
|
Mediana percent reduction in lesion count
|
|
|
|
|
Total
|
72.5%
|
69.2%
|
–
|
|
Inflammatory
|
76.2%
|
75.0%
|
–
|
|
Noninflammatory
|
71.3%
|
66.7%
|
–
|
- Global severity grade
- (Revised Leeds Scale)
|
|
|
|
|
1-3: mild
|
63 (86.3%)
|
48 (76.2%)
|
–
|
|
4-7: moderate
|
10 (13.7%)
|
15 (23.8%)
|
–
|
aDistribution of lesion % reduction being skewed, it was
estimated using the median.
Efficacy evaluation
The maintenance success rates for total, inflammatory, and non
inflammatory lesion counts at end point (week 12, ITT population,
worst case) are shown in ( figure 2 ). These rates
reflect the percentage of subjects maintaining at least 50% of
improvement from the previous combination study. After 12 weeks,
maintenance treatment with adapalene gel 0.1% resulted in higher
success rates in total (84.7% vs. 63.5%; P = 0.0049), inflammatory
(76.4% vs. 66.7%; P = 0.21), and non inflammatory (84.7% vs. 55.6%;
P < 0.001) lesions compared to treatment with vehicle ( (figure 2) ). The same
trend in favour of adapalene gel 0.1% was observed for the percent
reduction from initial state in lesion counts ( (figure 3) ).
For the global severity assessment, at baseline, 86.3% in the
adapalene group and 76.2% in the vehicle group had mild acne (Leeds
global severity score 1 to 3). Global severity remained stable in
the adapalene group, whereas it worsened slightly in the vehicle
group: at the end of the study, 82.2% vs. 68.3% of subjects
presented mild acne and 17.8% vs. 31.7% of subjects presented
moderate acne for the adapalene and vehicle groups, respectively;
P = NS. ( Figure
4 ) illustrates the effect of 12 weeks of maintenance
therapy with adapalene gel 0.1% following 12 weeks of combination
therapy with adapalene gel 0.1% plus lymecycline on moderate to
moderately severe facial acne lesions.
Safety evaluation
Severity scores for erythema, scaling, dryness, and
stinging/burning are summarised graphically in ( figure 5 ). As expected,
local cutaneous tolerability of study treatments was excellent for
both groups. Mean tolerability scores for erythema, scaling,
dryness, and stinging/burning were less than 1 (mild) for all study
visits. Worst scores at any time during the study for these
tolerability parameters were also all less than 1 (mild). Most
subjects in both groups experienced mild or no irritation.
The number of subjects experiencing adverse events was similar
in both treatment groups: 25% and 22% for the adapalene and vehicle
groups, respectively. A total of 5 treatment-related adverse events
occurred in 4 (5.5%) of the adapalene subjects (adverse events:
headache [2]), eczema [2], and erythema & desquamation [1]).
Two of these adverse events were severe (eczema and erythema &
desquamation). There were no treatment related adverse events in
the vehicle group. One subject in the vehicle group experienced a
serious adverse event deemed unrelated to study treatment (wisdom
teeth extraction). There were 2 adverse events in the adapalene
group that led to study discontinuation; skin infection (unlikely
related) and erythema & desquamation (related).
Discussion
The goal of maintenance therapy is the prevention of the recurrence
of acne lesions through the suppression of subclinical
microcomedones [5, 6]. Currently, there are relatively few studies
available to help guide evidence based decisions for the long-term
management of this disease. The current study adds to our limited,
but growing foundation of clinical data supporting the potential of
maintenance therapies with topical retinoids. In this 12-week
study, adapalene gel 0.1% was evaluated as a maintenance therapy in
subjects who showed at least moderate improvement in their moderate
to moderately severe acne in a previous 12-week
adapalene-lymecycline combination therapy study [24].
Overall, the results of this study demonstrate a clinical
benefit of continued adapalene use as a maintenance therapy for
acne. Adapalene provided numerically better results relative to gel
vehicle for all efficacy assessments, including maintenance success
rates, global severity, global improvement from baseline, and the
percent reduction in lesion counts (total, inflammatory, and non
inflammatory) from baseline of the previous combination study. At
week 12, adapalene was significantly superior relative to the
vehicle for success rates of total and non inflammatory lesions. A
“success” was defined as a subject maintaining at least 50% of
improvement from the previous study, with missing data considered
as a failure (worst case). Adapalene was safe and well tolerated
during this study, consistent with its well-documented profile
[19-23].
The results of the current study confirm data observed in
previous maintenance studies [8-10]. In a previous 16-week study,
Thiboutot and colleagues evaluated the maintenance effect of
adapalene gel 0.1% relative to its gel vehicle in those subjects
who showed at least moderate improvement in their severe acne from
the previous adapalene-doxycycline combination therapy study [10,
27]. After 16 weeks of treatment, adapalene provided statistically
significantly superior results relative to gel vehicle for all
efficacy assessments, including maintenance success rates for
total, inflammatory and non inflammatory lesions (same maintenance
definition as the current study). In the Thiboutot study, a
statistically significant difference between adapalene and vehicle
was first observed at 4 months. This observation may reflect the
time for the recurrence of visible acne based on the natural life
cycle of a comedone. Since these studies were not evaluating the
presence of subclinical microcomedones, the evaluations in both
these studies are limited to assessment of visible acne. Also, all
subjects received oral antibiotics in previous combination therapy
studies, so the antibiotic clearance time may have also affected
the time for acne recurrence. It is noteworthy that the current
study was only 12 weeks and therefore, based on the results of the
Thiboutot 16-week maintenance study, we may expect to observe
additional benefit with a longer study duration. These results
confirm those seen in recent open-label adapalene maintenance
studies [8, 9].
Despite the rising recommendations on the use of retinoids for
acne maintenance therapy [29], to our knowledge, no formal
definition of acne maintenance currently exists. In our study, like
in the Thiboutot study, it was agreed that maintaining at least 50%
improvement from a previous acute combination therapy would
represent the most realistic and easy criterion to measure the
efficacy of an acne maintenance treatment. This was based on the
definition of psoriasis relapse as proposed by a medical advisory
group [30, 31].
Together with the results of previous combination and
maintenance studies, these results support recommendations of
recent consensus guidelines from the Global Alliance to Improve
Outcomes in Acne [5, 8-10, 24, 26, 27]. The report states that an
effective strategy for the treatment of moderate to severe acne is
to utilise combination therapy at the onset of therapy with both a
topical retinoid and an oral antibiotic until reasonable clearing
has occurred. Then, the antibiotic therapy should be discontinued
to reduce the potential for developing resistance and the topical
retinoid continued to prevent recurrence. The guidelines consider
topical retinoids as the cornerstone of acne treatment, alone or in
combination, for all but the most severe cases of acne.
Topical retinoids have been associated with elevated skin
irritation, so careful consideration must be given to the
tolerability of a potential maintenance therapy. Cutaneous side
effects may decrease the likelihood of treatment adherence,
particularly when treating an “asymptomatic” condition [32]. Among
the currently available topical retinoids, adapalene is considered
the best tolerated therapy [33-35], and therefore is a rational
choice for maintenance therapy. Of the topical retinoids, adapalene
has the most robust data with the largest number of subjects
studied in long-term treatment [8-10]. Avoiding complicated
treatment regimens is also desirable for a maintenance therapy. In
contrast to some treatments, special treatment/washing regimens
[36, 37] are not necessary with adapalene use, which is well
tolerated even if applied immediately after washing [38].
In summary, this study has demonstrated a clear clinical benefit
of continued treatment with adapalene gel 0.1% as a maintenance
therapy for acne. Together with data from previous studies, these
results suggest adapalene should be used initially with antibiotic
therapy in moderate to moderately severe acne and then continued
for the long-term management of this disease to ensure acne lesions
remain in remission.
Acknowledgements
The authors would like to thank the following investigators:
Patrice Belperon, Angers, France; Isaac Bodokh, Cannes, France;
Alexandre Brunet, Angers, France; Elie Cattan, Pantin, France;
William Cunliffe, Leeds UK; Louis Dubertret, Paris, France; Dr
Colin John Fleming, Dundee, UK; Dr Bruno Haliloua, Paris, France;
Jean-Marie La Chapelle, Brussels, Belgium; Dr Julien Lambert,
Edegem, Belgium; Jean Meynadier, Montpellier, France; Dr. Gilles
Rostain, Nice, France; Mireille Ruer-Mular, Martigues, France; as
well as David Cox for editorial assistance.
Financial support: This study was funded by Galderma R&D,
Sohpia Antipolis, France
Conflict of interest: The investigating institutions received
payments for this research study. Three of the authors are
employees of Galderma (Kerrouche, Sidou and Soto)
References
1 Thiboutot D. Regulation of Human Sebaceous Glands. J Invest
Dermatol 2004; 123: 1-12.
2 Pawin H, Beylot C, Chivot M, Faure M,
Poli F, Revuz J, Dreno B. Physiopathology of acne
vulgaris: recent data, new understanding of the treatments. Eur J
Dermatol 2004; 14(1): 4-12.
3 Leyden JJ. A review of the use of combination therapies
for the treatment of acne vulgaris. J Am Acad Dermatol 2003; 49(3
suppl): S200-SS10; Review.
4 Thiboutot D. New treatments and therapeutic strategies
for acne. Arch Fam Med 2000; 9: 179-87.
5 Gollnick H, Cunliffe W, Berson D, et al.
Management of acne. A report from a Global Alliance to Improve
Outcomes in Acne. J Am Acad Dermatol 2003; 49(1 suppl): S1-S37.
6 Wolf JE. Maintenance therapy for acne vulgaris: the fine
balance between efficacy, cutaneous tolerability, and adherence.
Skinmed 2004; 3: 23-6.
7 Thielitz A, Helmdach M, Ropke E-M,
Gollnick H. Lipid analysis of follicular casts from
cyanoacrylate strips as a new method for studying therapeutic
effects of antiacne agents. Br J Dermatol 2001; 145: 19-27.
8 Zhang J, Li L, Tu Y, Zheng J. A successful
maintenance approach in inflammatory acne with adapalene gel, 0.1%
after an initial treatment in combination with clindamycin topical
solution,10r after monotherapy with clindamycin topical
solution,1%. J Dermatolog Treat 2004; 15: 372-8.
9 Cassano N, Amoruso A, Alessandrini G,
et al. Treatment of inflammatory acne with a combination
therapy with lymecycline and adapalene followed by maintenance
treatment with adapalene. Eur J Inflam 2004; 2: 45-52.
10 Thiboutot DM, Shalita AR, Yamauchi PS,
Dawson C, Kerrouche N, Arsonnaud S, Kang S.
Adapalene gel, 0.1%, as maintenance therapy for acne vulgaris: a
randomized, controlled, investigator-blind follow-up of a recent
combination study. Arch Dermatol 2006; 142(5): 597-602.
11 Gollnick H, Schramm M. Topical drug treatment in
acne. Dermatology 1998; 196: 119-25.
12 Brogden RN, Goa KL. Adapalene: a review of its
pharmacological properties and clinical potential in the management
of mild to moderate acne. Drugs 1997; 53: 511-9.
13 Michel S, Jomard A, Demarchez M. Pharmacology
of adapalene. Br J Dermatol 1998; 139(suppl 52): 3-7.
14 Vega B, Jomard A, Michel S. Regulation of
human monocyte toll-like receptor 2 (TLR2) expression by adapalene.
J Eur Acad Dermatol Venereol 2002; 16(suppl 1): 123-4;
[Abstract].
15 Shroot B, Michel S. Pharmacology and chemistry of
adapalene. J Am Acad Dermatol 1997; 36: S96-S103.
16 Cunliffe WJ, Holland DB, Clark SM,
Stables GI. Comedogenesis: some new aetiological, clinical and
therapeutic strategies. Br J Dermatol 2000; 142: 1084-91.
17 Cunliffe WJ, Poncet M, Loesche C,
Verschoore M. A comparison of the efficacy and tolerability of
adapalene 0.1 0el versus tretinoin 0.025 0el in patients with acne
vulgaris: a meta-analysis of five randomized trials. Br J Dermatol
1998; 139: 48-56.
18 Waugh J, Noble S, Scott LJ. Adapalene: a
review of its use in the treatment of acne vulgaris. Drugs 2004;
64: 1465-78.
19 Dosik JS, Homer K, Arsonnaud S. Cumulative
Irritation Potential of Adapalene 0.1% Cream and Gel compared with
Tazarotene Cream, 0.05% and 0.1%. Cutis 2005; 0075(5): 289-93.
20 Greenspan A, Loesche C, Vendetti N,
et al. Cumulative irritation comparison of adapalene gel and
solution with 2 tazarotene gels and 3 tretinoin formulations. Cutis
2003; 72: 76-81.
21 Dunlap FE, Mills OH, Tuley MR, Baker MD,
Plott RT. Adapalene 0.1 0el for the treatment of acne
vulgaris: its superiority compared to tretinoin 0.025ream in skin
tolerance and patient preference. Br J Dermatol 1998; 139:
17-22.
22 Caron D, Sorba V, Kerrouche N, Clucas A.
Split-face comparison of adapalene 0.1 0el and tretinoin 0.025 0el
in acne patients. J Am Acad Dermatol 1997; 36: S110-S112.
23 Egan N, Loesche MC, Baker MM. Randomized,
controlled, bilateral (split-face) comparison trial of the
tolerability and patient preference of adapalene gel 0.1% and
tretinoin microsphere gel 0.1 0.000000or the treatment of acne
vulgaris. Cutis 2001; 68(suppl 4): 20-4.
24 Cunliffe WJ, Meynadier J, Alirezai M,
et al. Is combined oral and topical therapy better than oral
therapy alone in patients with moderate to moderately severe acne
vulgaris? A comparison of the efficacy and safety of lymecycline
plus adapalene gel 0.1%, versus lymecycline plus gel vehicle. J Am
Acad Dermatol 2003; 49(3 suppl): S218-S226.
25 Cunliffe WJ, Grosshans E, Belaïch S,
Meynadier J, Alirezai M, Thomas L. A comparison of
the efficacy and safety of lymecycline and minocycline in patients
with moderately severe acne vulgaris. Eur J Dermatol 1998; 8:
161-6.
26 Wolf Jr. JE, Kaplan D, Kraus SJ,
et al. Efficacy and tolerability of combined topical treatment
of acne vulgaris with adapalene and clindamycin: A multicenter,
randomized, investigator-blinded study. J Am Acad Dermatol 2003;
49(3 suppl): S211-S217.
27 Thiboutot D, Shalita A, Yamauchi PS,
Dawson C, Arsonnaud S, Kang S. Combination therapy
with adapalene gel 0.1% and doxycycline for severe acne vulgaris: a
multicenter, investigator-blind, randomized, controlled study.
Skinmed 2005; 4(3): 138-46.
28 O’Brien SC, Lewis JB, Cunliffe WJ. The Leeds
Revised Acne Grading System. J Dermatol Treat 1998; 9: 215-20.
29 Dreno B, Bettoli V, Ochsendorf F,
Layton A, Mobacken H, Degreef H, European Expert
Group on Oral Antibiotics in Acne. European recommendations on the
use of oral antibiotics for acne. Eur J Dermatol 2004; 14(6):
391-9.
30 Gordon KB, Feldman SR, Koo JY, Menter A,
Rolstad T, Krueger G. Definitions of measures of effect
duration for psoriasis treatments. Psoriasis Forum 2002; 8:
1-5.
31 Carey W, Glazer S, Gottlieb AB,
Lebwohl M, Leonardi C, Menter A, Papp K,
Rundle AC, Toth D. Relapse, rebound, and psoriasis
adverse events: an advisory group report. J Am Acad Dermatol 2006;
54(4 Suppl 1): S171-S181.
32 Koo J. How do you foster medication adherence for better
acne vulgaris management? Skinmed 2003; 2: 229-33.
33 Haider A, Shaw JC. Treatment of acne vulgaris. JAMA
2004; 292: 726-35.
34 Brand B, Gilbert R, Baker MD, et al.
Cumulative irritancy comparison of adapalene gel 0.1
0.000000e+00rsus other retinoid products when applied in
combination with topical antimicrobial agents. J Am Acad Dermatol
2003; 49(3 Suppl): S227-S232.
35 Caron D, Sorba V, Clucas A, Verschoore M.
Skin tolerance of adapalene 0.1 0el in combination with other
topical antiacne treatments. J Am Acad Dermatol 1997; 36:
S113-S115.
36 Leyden J, Lowe N, Kakita I, et al.
Comparison of treatment of acne vulgaris with alternate-day
applications of tazarotene 0.1 0el and once-daily applications of
adapalene 0.1 0el: a randomized trial. Cutis 2001; 67(suppl 6):
10-6.
37 Bershad S, Kranjac Singer G, Paente JE,
et al. Successful treatment of acne vulgaris using a new
method: results of a randomized vehicle-controlled trial of
short-contact therapy with 0.1% tazarotene gel. Arch Dermatol 2002;
138: 481-9.
38 Dunlap FE, Baker MD, Plott RT, et al.
Adapalene 0.1 0el has low skin irritation potential even when
applied immediately after washing. Br J Dermatol 1998; 139(suppl
52): 23-5.
|
Version imprimable
Version PDF
