ARTICLE
Auteur(s) : Hamdi Ozcan1,
Muammer Seyhan1, Saim Yologlu2
1Inonu University, Medical Faculty, Department of
Dermatology 44280 Malatya – Turkey
2Inonu University, Medical Faculty, Department of
Biostatistics 44280 Malatya – Turkey
accepté le 17 Mars 2007
Seborrhoeic dermatitis (SD) is a chronic disease, seen in 2-5% of
adults. Although it is possible to encounter the disease at all
ages, it is common in infants within the first three months and in
adults between 30-60 years of age. It is more frequently seen in
males than in females [1, 2]. It has a chronic course with
recurrent exacerbations. SD typically involves skin regions in
which sebaceous glands are dense and in high activation. These
areas include the scalp, eyebrows, nasolabial folds, cheeks, ears,
presternal and interscapular regions, the axillary region and the
groin [2]. The severity of this papulosquamous disease varies from
the mild form (which is simple dandruff), to severe symptomatic
forms [1]. The skin lesions are sharply demarcated patches or thin
plaques, which vary from pink-yellow to dull red to red-brown in
color with bran-like to flaky greasy scales [3].The etiology of SD
is unknown but many factors may contribute to the development of
this disorder. These factors may be exogenous such as stress and
winter seasons, or endogenous such as the differences in the sebum
lipid composition and hormonal influence (androgens). Furthermore
immunological, nutritional, environmental factors and life style
may also predispose to the development of SD [4].Although topical
corticosteroid creams and antifungal drugs are frequently used in
SD treatment, there is no curative therapy [5, 6]. Plewing and
Jansen [7] suggested that topical metronidazole could be used as an
alternative drug in the treatment of SD. There are only three
studies about the treatment of SD with topical metronidazole in the
literature. Parsad et al. [8] and Siadat et al. [9] performed
double-blind placebo controlled studies and both reported that
topical metranidazole %1 was effective in SD treatment. However, in
a similar study, Koca et al. [2] reported that topical
metronidazole 0.75% gel was effective in the treatment of SD but
the effectiveness was not different from the placebo. Since there
are few studies and conflicting results available so far in the
literature on this issue as mentioned above, we planned this study
to determine the efficacy of topical metronidazole 0.75% gel in the
treatment of SD.
Materials and method
Among applicants at the Dermatology Clinic of the University
Hospital, patients diagnosed as SD, older than 18 years of age, and
accepting to participate were enrolled in the study. Patients who
had taken antimicrobials or used topical corticosteroids,
antifungals, tar, zinc pyrithione, selenium, or salicylates within
two weeks prior to study entry, or who had taken retinoids or
systemic antifungals within one month prior to study entry, were
excluded. Patients who used antiepileptics and antipsychotics were
not included in the study. Pregnant and lactating women were also
excluded.
Overall, 67 patients with mild to moderate SD, diagnosed
according to clinical findings, participated in this randomized,
double-blind study investigating the efficacy and tolerability of
metronidazole 0.75% gel versus placebo. The metronidazole 0.75% gel
and the placebo (vehicle gel) was prepared in identical containers
by a pharmacologist, and all containers were numbered according to
the random number list. The randomization list was kept by the
pharmacologist until the end of the study. The prepared drugs were
given to the patients in order of entry into the study. All
patients were evaluated at each visit by the same dermatologist.
The drugs were applied topically, twice a day, for one month.
The study was reviewed and approved by the local ethics
committee. Patients were informed about the study and a written
informed consent was obtained. In each group age, gender, duration
of disease, family history, smoking and alcohol usage, previous
treatment and drug usage for other diseases were recorded.
Scalp, eyebrows, bridge of the nose, nasolabial folds, posterior
aspects of the ear and the chest were examined. Erythema, scales,
papule and pruritus were scored numerically from 0 to 3 in these
six regions (0: absent, 1: mild, 2: moderate and 3: severe). The
maximum score for each of erythema, scales, papule or pruritus was
18 (6 regions × 3) and maximum total severity score for individuals
was 72 (6 × 3 × 4).
Evaluation was performed before the treatment, once a week
during the treatment for a month and on the second and fourth weeks
after the cessation of the treatment. Cases were questioned
regarding the side effects on each visit. On the second and fourth
weeks of the treatment and four weeks after the cessation of the
drug, patient satisfaction and doctor evaluation [very bad, bad, no
change, little improvement (< 25%), mild improvement
(26-50%), improvement (51-75%), major improvement (76-99%) and
total cure (100%)] were examined.
The efficacy of each preparation was determined by reduction in
the total severity score at the end of the treatment and at the end
of the study.
Statistical analysis: Statistical analyses were performed with
SPSS for windows version 11.0 software. In this study, the
power-based calculation of sample size was 0.815.
Intention-to-treat analysis was performed. All cases were
randomized and were included in the statistical analysis even if
they did not attend the follow-up visits. Continuous variables were
reported as median ± interquartile range. Categorical values were
reported as percentages. Normality for continued variables in
groups was determined by the Shapiro-Wilk test. The variables did
not show a normal distribution (p < 0.05). So the Mann-Whitney U
test and Wilcoxon test were used for comparison of variables in the
studied groups. Pearson Chi-Square test and Fisher’s exact test
were used for categorical valuables. A value of p < 0.05 was
considered significant.
Results
Sixty-seven patients were enrolled in the study. Seven of the
patients (three patients from the metronidazole group and four
patients from the placebo group) did not attend to the follow-up
visits. All these patients were male. In each group, 30 patients
completed the study. Baseline characteristics of the patients are
summarized in table 1. Two patients in
the metronidazole group, one patient in the placebo group had
gastric compliants and one patient in the placebo group was
hypertensive. The patients in the placebo group had a shorter
duration of the disease, more frequent family history, less
previous treatment history, younger median age and lower baseline
total severity score than the metronidazole group. However, there
were no statistically significant differences between the two
groups, except family history.
Erythema, scales, papule and pruritus scores of two groups in
each visit are given in table 2.
Statistically significant decreased values for all parameters
(erythema, scales, papule, pruritus and total severity score) were
determined after the first week of the treatment in the
metronidazole group (p < 0.05). There were no statistically
significant differences for papule scores according to the baseline
value in metronidazole group after the cessation of the treatment
(p > 0.05). In the placebo group, statistically significant
decreases for erythema, scales, pruritus and total severity scores
were detected at the end of the first week but only at the fourth
week for papule score (p < 0.05). Although all scoring values
were decreased during the treatment, they increased rapidly with
the withdrawal of drug and placebo. There were no statistically
significant differences between the two groups for all parameters
(p > 0.05). The change of total severity scores in time is shown
in figure 1.
During treatment, side effects like burning, pricking, increase
in pruritus and erythema were observed in 11 (36.7%) patients in
the metronidazole group and 8 (26.7%) patients in the placebo group
(p = 0.40). At the end of the study, the patient’s satisfaction
scoring revealed worsening in three (10.0%), no change in 10
(33.3%), mild improvement in 15 (50.0%) and improvement in two
(6.7%) patients in metronidazole group. The same ratios in the
placebo group were two (6.7%), 15 (50.0%), 12 (40.0%) and one
(3.3%) patients, respectively.
Doctor evaluation at the end of the study determined worsening
three patients (10.0%), no change in 14 (40.0%), mild improvement
in 11 (36.7%), and improvement in 2 (6.7%) cases in the
metronidazole group. In the placebo group, the same evaluation
revealed, in the same order of presentation one (3.3%), 13 (43.3%),
15 (50%) and one (3.3%) cases, respectively. The dermatologist and
patient evaluations were similar and there was no significant
difference between the two groups (p > 0.05).
Table 1 Baseline characteristic features of the
patients.
|
- Metronidazol group
- (n = 33)
|
|
P-values
|
|
Age*
|
26.0 ± 11.5
|
26.0 ± 8.7
|
0.39
|
|
Disease duration (year)*
|
3.0 ± 3.0
|
2.0 ± 2.2
|
0.38
|
|
Baseline total severity score*
|
15.0 ± 11.0
|
13.0 ± 7.5
|
0.75
|
|
Gender
|
n
|
%
|
n
|
%
|
0.38
|
|
Male
|
21
|
63.6
|
25
|
73.5
|
|
|
Female
|
12
|
36.4
|
9
|
26.5
|
|
|
Family history
|
0
|
0
|
4
|
11.7
|
0.04
|
|
Smoker
|
11
|
33.3
|
11
|
32.3
|
0.93
|
|
Alcohol user
|
0
|
0
|
1
|
2.9
|
0.32
|
|
Previous treatment
|
17
|
51.5
|
14
|
41.1
|
0.39
|
|
Systemic disease
|
2
|
6.0
|
2
|
5.8
|
0.97
|
Table 2 Erythema, scales, papules, and pruritus scores
at each visit in the metronidazole and placebo-treated groups.
|
Baseline
|
1st week
|
2nd week
|
3rd week
|
4th week
|
6th week
|
8th week
|
|
Erythema
|
|
Metronidazole
|
3.0 ± 3.5
|
2.5 ± 3.0*
|
2.0 ± 2.5*
|
2.0 ± 3.2*
|
1.0 ± 2.0*
|
2.0 ± 2.2*
|
2.0 ± 2.2*
|
|
Placebo
|
3.0 ± 2.0
|
2.0 ± 1.0*
|
1.0 ± 2.0*
|
1.0 ± 3.0*
|
1.0 ± 2.0*
|
2.0 ± 3.0*
|
2.0 ± 3.2*
|
|
Scales
|
|
Metronidazole
|
5.0 ± 4.0
|
4.0 ± 2.2*
|
3.5 ± 3.0*
|
3.5 ± 3.0*
|
2.5 ± 2.5*
|
3.0 ± 2.2*
|
3.0 ± 3.5*
|
|
Placebo
|
6.0 ± 3.0
|
4.0 ± 2.2*
|
4.0 ± 2.2*
|
3.0 ± 2.2*
|
3.0 ± 2.0*
|
4.0 ± 3.0*
|
4.5 ± 4.0*
|
|
Papules
|
|
Metronidazole
|
1.0 ± 3.0
|
1.0 ± 2.0*
|
0.0 ± 2.0*
|
0.0 ± 1.2*
|
0.0 ± 1.0*
|
0.0 ± 2.0
|
0.0 ± 2.2
|
|
Placebo
|
1.0 ± 2.0
|
1.0 ± 2.0
|
1.0 ± 2.0
|
1.0 ± 2.0
|
0.0 ± 1.0*
|
0.0 ± 1.2
|
1.0 ± 2.0
|
|
Pruritus
|
|
Metronidazole
|
4.0 ± 5.0
|
3.0 ± 4.2*
|
2.5 ± 4.0*
|
2.5 ± 3.2*
|
2.0 ± 3.0*
|
3.0 ± 3.5*
|
2.5 ± 5.2*
|
|
Placebo
|
3.0 ± 4.2
|
2.0 ± 3.2*
|
1.0 ± 3.0*
|
1.0 ± 4.0*
|
1.0 ± 3.0*
|
2.0 ± 4.0*
|
2.0 ± 4.2
|
Discussion
SD is a chronic and recurrent disorder, and repetitive treatments
are often necessary. The topical (selenium sulfide, ketoconazole,
zinc pyrithione, sodium sulfacetamide, propylene glycol, ciclopirox
olamine, terbinafine) and systemic antifungals (terbinafine,
itraconazole) are used with great success to decrease the
colonization of lipophilic Malassezia species [10-19]. Furthermore,
topical steroids are commonly used due to their strong
anti-inflammatory effects. However, frequent relapses after the
cessation and side effects on long-term usage restrict usage of
corticosteroids [20]. In order to avoid these side effects, usage
of pimecrolimus and tacrolimus, which have anti-inflammatory
effects, have been recommended in recent years [20, 21].
Metronidazole is an imidazole-derived potent antibacterial with
particular activity when used orally or parenterally. In addition
to its antimicrobial activity, metranidazole reduces oxidative
tissue damage by inhibiting neutrophil-generated inflammatory
mediators [22]. Metranidazole is used in the treatment of rosacea
for its anti-inflammatory activity. Although the fundamental
pathogenesis of rosacea remains unknown, inflammation is an
important process in this disorder. Recent evidence suggests that
this inflammation is associated with the generation of reactive
oxygen species (ROS) that are released by inflammatory cells such
as neutrophils. In vitro studies suggest that certain core
therapies for rosacea, including metronidazole and the
tetracyclines, show antioxidant effects and this may be one aspect
of their mechanism of action. [23, 24].
Metronidazole may be effective in the treatment of SD by
decreasing the oxygen radicals and inflammation. Parsad et al. [8]
conducted a double-blind placebo controlled study to determine the
effectiveness of metronidazole 1% gel for 8 weeks in the treatment
of SD. They determined marked to complete improvement in 14 out of
21 patients and moderate improvement in other three patients. They
concluded that metronidazole 1% gel was more effective than
placebo. In a similar study, Siadat et al. [9], evaluated the
efficacy of topical 1% metronidazole gel in facial SD. They
administered metronidazole or placebo for eight weeks. They
revealed statistically significant differences in the mean severity
scores between the two groups at the second week of the treatment,
and this difference continued until the end of the study. As a
consequence of this finding they reported that metronidazole 1% was
effective in the treatment of SD.
Koca et al. [2], administered metronidazole 0.75% gel in 48
patients and reported responses as perfect in 18, good in 14,
moderate in nine and poor in 10 patients. Responses of 30 patients
in the placebo group in the same order were 10, nine, 10 and four
patients, respectively. They did not find a statistically
significant difference in the mean severity scores of the two
groups. In the present study, in the metronidazole group at the end
of the study, two patients showed improvement, 11 a moderate
improvement, 14 no difference, and worsening in three patients;
this compared with one, 15, 13, and one patients, respectively, in
the placebo group. There was no statistically significant
difference (p < 0.05). This suggests that pharmaceutical vehicle
may be the cause of transient improvement in lesions, and
metronidazole itself may exert little or no effect on SD.
One point to remember is the difference of numeric expressions
of age, duration of disease, previous treatments and baseline
severity scores in favor of placebo group, although not
statistically significant. All these aspects taken together could
somewhat influence the outcome in favor of the placebo.
At the end of treatment three patients from the metronidazole
group and two patients from the placebo group were totally cured,
but with the withdrawal of the treatment their scores increased
again. Koca et al. reported higher effective results than our
study. This may be explained by the higher baseline scores (18.5
versus 15.0) of their groups, different regions of lesion
evaluation and longer duration of treatment. However, similar
results in the placebo group point out that metronidazole 0.75% gel
is not efficient enough. In contrast to the studies of Parsad et
al. [8] and Siadat et al. [9], no significant difference in
effectiveness was found in the studies of Koca et al. and ours.
This may be due to the different dosages of the gel. The treatment
period was four weeks in the present study but eight weeks in the
others. In these three studies the course of the disease after the
cessation of the drug was not evaluated. In the present study, the
patients were evaluated for four additional weeks after the
withdrawal of the drug and a rapid recurrence was observed shortly
after the end of the treatment.
In the present study, topical metronidazole 0.75% gel is well
tolerated but it is only as effective as placebo in the treatment
of SD. However, further studies are needed to show whether
different concentrations of metronidazole gel and different
durations of treatment will alter the course in face of
effectiveness.
Acknowledgements
Financial support: none. Conflict of interest: none.
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