Original Article | 20
Copyright © University of Medicine, Tirana
AJMHS 2014; Vol. 45, No. 1: 20-29 © 2014
Efficacy, Safety and Adherence to Different Pulse Therapies of
Oral Itraconazole in the Treatment of Facial Seborrheic
Dermatitis
Ermira Demiraj1, Ermira Vasili2, Leonard Deda3
1
2
Department of Dermatology-Venereology, Regional Hospital Durrës, Albania
Department of Dermatology-Venereology, “Mother Teresa” University Hospital Centre, Tirana, Albania
3
Department of Biomedical and Experimental Sciences, University of Medicine, Tirana, Albania
Background: Seborrheic dermatitis is a
common chronic and relapsing disease.
Malassezia yeasts have been implicated in the
pathogenesis of this disease. Systemic antifungal
agents are known to be effective in the treatment
of Malassezia yeast infections.
Aims: To evaluate the efficacy of itraconazole
in the treatment of mild to severe facial
seborrheic dermatitis.
Study design: This is an open, randomized,
comparative clinical study.
Methods: Thirty six patients with severe facial
seborrheic dermatitis were randomly allocated in
three groups to receive one of three therapeutic
regimens. In all groups, the treatment was
initiated after a month wash-out period. During
this period all topical treatments with antiseborrheic agents were stopped, excluding
locally applied moisturizing agents. Itraconazole
200 mg/day was administered for 7 consecutive
days in all patients. Four weeks later, patients
were instructed to take 200 mg/day for 2 days
every 4 weeks (Group I), a single dose of 200
mg itraconazole every 2 weeks (Group II), or a
single dose of 100 mg itraconazole every week
(Group III) for a 20 weeks period.
Three clinical parameters (erythema, scaling,
itching) were assessed using a 0–3 score. The
patients were evaluated in the 1st, 2nd, 4th, and the
20th week. Adherence to treatment was assessed
using 4-items self-reported questionnaire.
Results: Significant improvement was reported
in all three clinical parameters (erythema,
scaling, and itching) in all groups, at the end of
the initial phase of the treatment (week 1 and 4).
Maintenance therapy did not lead to any further
significant improvement (week 8). In the 20th
week, clinical improvements were still
maintained in group II and III, but they were
partially lost in group I.
Adherence to treatment was found lower in
Group I. No adverse events were reported during
the study. No blood test abnormalities were
found during and at the completion of the
treatment.
Conclusion: Treatment with itraconazole in
patients with severe facial seborrheic dermatitis
was safe and beneficial. However, long-term
clinical improvement during the maintenance
therapy might be compromised for different
reasons, including the adherence to treatment.
Address for correspondence: Leonard Deda, MD, Department of Biomedical and Experimental
Sciences, University of Medicine Tirana, Albania
e-mail: [email protected]
21
Demiraj et al. Different Pulse Therapies of Oral Itraconazole
Key Words: seborrheic dermatitis, itraconazole,
pulse therapy, adherence.
the disease. According to a survey, the most
commonly used drugs are the corticosteroids
(59.9%) and imidazole-based antifungals
(35.1%) (7).
Recently, oral systemic antifungals have been
introduced in the therapy of SD as effective and
safe agents. A marked reduction in inflammation
is observed when seborrheic dermatitis is treated
with itraconazole (8, 9). Itraconazole is very
effective both in vitro and in vivo against
Malassezia species. It also possesses antiinflammatory activity. Its high lipophilicity
accounts for its presence in the skin structures
above the therapeutic concentration for some
weeks even after the cessation of therapy (a
reservoir effect) (10). This dual antifungal and
anti-inflammatory effect, in combination with its
pharmacokinetic profile, may account for the
prolonged therapeutic action of pulse low doses
(9).
In the recent medical literature different pulse
therapies of oral itraconazole have been reported
(8, 9, 10, 11). During the first week the therapy
is given continuously, aiming at rapid
controlling of signs and symptoms. Afterwards,
the pulse therapy which may be given for
several months, follows, which aims mainly at
the maintenance of the response. Using the
lowest effective dosage of itraconazole is crucial
for adverse events to be avoided.
No studies have been focused on the treatment
adherence. We consider treatment adherence an
important factor influencing especially the
efficacy of the maintenance phase of therapeutic
regimen, which is extended over time.
The aim of this study is to evaluate the efficacy,
safety and adherence to different pulse therapies
of oral itraconazole in severe forms of facial
seborrheic dermatitis in a sample of Albanian
population.
INTRODUCTION
Seborrheic dermatitis (SD) is a common papulosquamous disease of the skin. Its prevalence, in
different studies, has been reported in the range
of 2–5% (1), although if the mild forms are
included it may be present in 15-20% of the
population (2). It is a chronic, superficial,
inflammatory disease with a predilection for
skin areas with a rich supply of sebaceous
glands (i.e. the scalp, eyebrows, eyelids, nasolabial creases, ears, chest). The disease is
characterized by scaling on an erythematous
base. The scale often has a yellow, greasy
appearance. Itching also may be severe.
The exact physiopathology of seborrheic
dermatitis hasn’t been completely established
yet. However, the association of the disease with
the presence of Malassezia spp. yeast on the skin
of affected individuals is currently the dominant
view. This yeast is known to be present on all
human skin but may be present to a greater
extent in individuals with SD. It has been
described that this fungus is responsible for the
production of a lipase that is essential for its
growth in vitro and in vivo (3, 4). It is believed
that the fungus uses lipids from the human skin
surface to produce unsaturated and saturated
fatty acids that, in the outer layer of the skin of
susceptible individuals induce an inflammatory
response (5, 6). The fact that SD responds to
treatment with antifungal medication also
represents a strong evidence of the association
between Malassezia and SD.
The therapeutic arsenal for the control of SD is
extensive. The objective of treatment consists
mainly in controlling the inflammation and/or
proliferation of the microorganism, taking into
consideration the chronic and relapsing nature of
AJMHS, Vol. 45, No. 1, 2014
Demiraj et al. Different Pulse Therapies of Oral Itraconazole
MATERIALS AND METHODS
This
open,
randomized,
comparative,
interventional study was carried out for a period
of several months from October 2011 to May
2012 in the department of DermatologyVenereology, Regional Hospital of Durrës, in
Albania, after prior approval by the National
Ethics Committee. Written informed consent
was obtained from all patients before starting the
study.
Patients
Thirty-six adult patients with severe facial
seborrheic dermatitis, who had applied different
topical treatments, including corticosteroids, for
at least 1 month with no response, were recruited
for this study. Patients were excluded from the
study if they had any of the following
conditions: impaired renal and liver function,
pregnancy, lactation, or hypersensitivity to
itraconazole. In the study were included both
male and female adult patients of any age,
patient willing to give consent to take part in the
study, patient expected to be available for the
duration of study and able to comply with the
study visit.
Treatments
Patients were randomly allocated in three groups
to receive one of three therapeutic regimens. In
all groups, the treatment was initiated after a
month wash-out period. During this period all
topical treatments with anti-seborrheic agents
were stopped, excluding locally applied
moisturizing agents. Itraconazole 200 mg/day
was administered for 7 consecutive days in all
patients. Four weeks later, patients were
instructed to take 200 mg/day for 2 days every 4
weeks (Group I), a single dose of 200 mg
itraconazole every 2 weeks (Group II), or a
single dose of 100 mg itraconazole every week
(Group III) for a 20 weeks period. The patients
AJMHS, Vol. 45, No. 1, 2014
22
were evaluated in the 1st, 4th, 8th and the 20th
week. Up to the 8th week all the patients were
called by phone/mobile in order not to forget
taking their medicine.
Assessment of lesions
Efficacy was assessed primarily by clinical
assessment of the severity of the lesions in the
involved area. These assessments were
performed by the same doctor under standard
lighting. On the initial evaluation, the patients
were examined at three sites (scalp, face, and
chest), but only facial clinical findings were
graded numerically for erythema, scales and
itching using a four-point score from 0 to 3 (0,
absent; 1, mild; 2, moderate; 3, severe). Patients
enrolled into the study were required to have a
sum - Overall Clinical Assessment Score
(OCAS) - of at least 6.
Assessment of efficacy
Clinical efficacy was determined by percent
reduction in OCAS measured at each visit
against baseline. Improvement was considered
excellent if OCA Score reduction was > 70%,
very good 51-70%, good 30-50% and poor <
30%. The patients were evaluated at the weeks
1, 4, 8 and 20 and the severity score was
determined at each visit.
Assessment of safety
The patients were asked for the occurrence of
any adverse events at each visit. The patients
were asked to report immediately to the
investigator any adverse events. Blood samples
were taken for routine hematologic and
biochemical analyses at the beginning of the
study, as indicated during the course of the
treatment and at the completion of the treatment.
Assessment of adherence
Adherence to treatment was assessed at last visit
using 4-items self-reported questionnaire.
23
Demiraj et al. Different Pulse Therapies of Oral Itraconazole
Patients were asked to answer the following
questions:
1. Did you forget to take in due time your
seborrheic dermatitis medicine in the last three
months?
2. Did you have any problems remembering to
take your seborrheic dermatitis medication in the
last three months?
3. When you feel better, do you sometimes stop
taking your seborrheic dermatitis medication?
4. Do you consider this dosing regimen as
inappropriate to your case?
The scoring scheme was “Yes” = 1 and “No” =
0. Adherence was considered the highest if the
total score was 0 and the poorest if the total
score was 4.
RESULTS
Thirty-six adult outpatients with a clinical
diagnosis of SD (15 men, 21 women; mean age
30.5 ± 9.03 years; age range 18–54 years)
entered the study. Thirty-two patients were
evaluated at the end of the 20th week. Four
patients left the study for personal reasons but
unrelated to the study. The demographic and
clinical characteristics of the patients are shown
in Table 1and Figure 1.
Statistical analysis
Tabulated data are expressed as arithmetic mean
± standard deviation. Within group comparisons
versus baseline values were done using
Wilcoxon's signed test. For statistical
comparisons between groups Kruskal–Wallis
test was used. Categorical data were compared
using Fisher’s exact test. Differences are
considered statistically significant if P < 0.05.
Table 1.
Demographic and clinical characteristics of the
evaluated patients at baseline
Figure 1. Clinical characteristics of patients at
baseline
Age (years)
Male
Female
OCAS
Mean±SD
n (%)
n (%)
Mean±SD
Group I
29.1 ± 7.4
4 (40%)
6 (60%)
6.8 ± 0.79
Group II
29.3 ± 8.6
5 (45.5%)
6 (54.5%)
6.6 ± 0.80
Group III
30.3 ± 8.7
4 (36.4%)
7 (63.6%)
6.9 ± 0.83
OCAS = Overall Clinical Assessment Score
AJMHS, Vol. 45, No. 1, 2014
Demiraj et al. Different Pulse Therapies of Oral Itraconazole
24
Figure 2. a-c. Changes in the mean clinical
scores during the study. a) Group I, b) Group II,
c) Group III
In the 1st week significant improvement was
evident in three clinical parameters: erythema,
desquamation and pruritus for all treatment
groups. In the 4th week a further improvement
but not a significant one, compared to the
improvement made in the first week, was also
noted in three clinical parameters for all
treatment groups. In the 4th versus baseline the
score for erythema was reduced by 66.7%,
66.7% and 68.0% in Group I, Group II and
Group III, respectively; the score for
desquamation was reduced by 69.6%, 66.7% and
69.7% in Group I, Group II and Group III,
respectively; the score for pruritus was reduced
by 50.0%, 50.5% and 55.6% in Group I, Group
II and Group III, respectively and the Overall
Clinical Assessment Score was reduced by
62.7%, 62.1% and 65.2% in Group I, Group II
and Group III, respectively. These results are
shown in Figure 2.
AJMHS, Vol. 45, No. 1, 2014
25
The improvement in all clinical parameters (i.e.
erythema, desquamation and pruritus) as
evaluated by Overall Clinical Assessment Score
(OCAS) was substantially maintained during all
the study period for all treatment groups.
However, a slight decline in the response was
evident in the 20th week for Group I compared to
two other groups (see Figure 3). Group II and
Group III showed a 12.5% lower OCAS Score,
which was not statistically significant. However,
this difference must be interpreted with caution
because as seen in Figure 4, in the 20th week
treatment efficacy was very good to excellent in
50%, 63.6% and 72.7% in Group I, Group II and
Group III, respectively.
Demiraj et al. Different Pulse Therapies of Oral Itraconazole
Improvement was considered excellent if OCA
Score reduction was > 70%, very good 51-70%,
good 30-50% and poor if < 30%. Treatment
efficacy for all groups is shown in figure 4.
Adherence to the treatment was assessed using a
simple, not validated, 4-items self-reported
questionnaire which was filled by each patient at
last (week 20) visit.
As shown in Table 2 adherence to treatment
(higher the score lower the adherence) was
found lower in Group III, where patients were
asked to take itraconazole monthly for two days.
Figure 3. Changes in the mean Overall Clinical
Assessment Scores during the study
Response to treatment was determined by
percent reduction in Overall Clinical Assessment
Score measured at each visit against baseline.
AJMHS, Vol. 45, No. 1, 2014
26
Demiraj et al. Different Pulse Therapies of Oral Itraconazole
Figure 4.a-c. Treatment efficacies for all
groups. a) Group I, b) Group II, c) Group III
4-items self-reported questionnaire
1. Did you ever forget to take in due time your seborrheic
dermatitis medicine during last three months?
2. Did you ever have any difficulties in remembering to take your
seborrheic dermatitis medication during last three months?
3. When you feel better, do you sometimes stop taking your
dermatitis medication?
4. Do you consider this dosing regimen as inappropriate to your
case?
Mean Score
Group I
Yes No
Group II
Yes No
Group III
Yes No
4
6
2
9
2
9
6
4
3
8
4
7
2
8
2
9
1
10
1
9
0
11
1
10
1.3
0.63
0.72
Scoring scheme “Yes” = 1 and “No” = 0.
DISCUSSION
Table 2. Adherence to treatment - 4-items selfreported questionnaire mean scores.
Topical treatment is a well established
therapeutic modality in the treatment of
seborrheic dermatitis. Topical steroids perhaps
are the most common used drugs. Ketoconazole
creams and shampoos are widely used in the
treatment of this condition. Indeed, the use of
AJMHS, Vol. 45, No. 1, 2014
27
Demiraj et al. Different Pulse Therapies of Oral Itraconazole
azoles topically in the treatment of mild disease
is also well established. Terbinafine solution is
also an effective treatment. However, especially
during prolonged use, topical steroids may cause
adverse effects such as skin atrophy, perioral
dermatitis or telangiectasia. High risk of relapse
and poor patient compliance represent another
problem with topical treatment. This has led to
the search for alternative therapeutic agents.
Systemic use of antifungal agents is also
beneficial especially in more severe cases of
seborrheic dermatitis. Itraconazole, a systemic
azole, has been reported to be an effective
treatment in seborrheic dermatitis patients.
every 2 weeks for 18 weeks. They reported
treatment to be beneficial in patients with
moderate to severe disease.
In another study reported by Kose et al. (8), 29
patients were treated with itraconazole 200
mg/day for 1 week and then, after a 3 week
interval, patients used itraconazole 200 mg/day
for the first 2 days of 2 months. Marked
improvement was observed in 83% of patients at
week 2 and in 61% of patients at the end of the
study. No drug-related systemic adverse event
was observed during the study.
Baysal et al. (9) treated 32 pa¬tients with a
combination therapy of itraconazole and
hydrocorti-sone cream. The patients applied 1%
hydrocortisone cream twice daily for 1 month.
In addition, they took itraconazole, 200 mg/day,
during the first week of the first month and then
hydrocortisone cream was stopped and
itraconazole (200 mg/day) was given on the first
2 days of the following 11 months. The patients
were followed for 2 months without medicine.
Twenty-eight patients completed the study.
There was a statistically significant and quite
constant decrease in the mean severity score at
the first, the 12th and the 14th months. On the
final evaluation at the 12th month 67.8% of
patients showed a complete improvement (>71%
improvement in OCA Score).
In the study of Das et al. (17) itraconazole was
given to 30 patients in a dose of 100 mg twice
daily for a week followed by 200 mg/day for
first 2 days of the following 2 months. The
clinical response was graded as markedly
effective, effective, or ineffective. Clinical
improvement (evaluated as markedly effective
or effective) was observed in 83.3% of cases.
Treatment was not effective in 17% of cases.
In the study of Khondker et al. (10) 37 patients
with seborrheic dermatitis were treated by oral
itraconazole (200 mg/ day for 7 days) in first
month and consecutively 200 mg/ day for the
The rationale for the use of itraconazole is based
on its antimycotic and anti-inflammatory
properties (12, 13, 14).
Perhaps, the first study (15) where patients with
seborrheic dermatitis were treated with
itraconazole orally (150mg or 200mg once per
week for 2-3 months), was reported in medical
literature in 1995. In that study, the clinical
response was found to be markedly effective or
effective in 67% of patients.
The largest study to date (16) was an open,
single center study involving 160 patients with
seborrheic dermatitis. Itraconazole 200mg/day
was administered for 7 consecutive days.
Patients were evaluated at baseline, day 7 and
day 37 following the end of therapy. The
treatment was judged to be effective by 148
patients (92.5%), with clinicians rating overall
improvement as excellent in 55 patients
(34.3%), good in 64 patients (40.0%), and
moderate in 30 patients (18.7%).
Shemer et al. (11) evaluated sixty patients with
moderate to severe seborrheic dermatitis in an
open non-comparative study. Itraconazole 200
mg/day was administered for 7 consecutive
days. Five weeks later, patients were instructed
to take a single dose of 200 mg itraconazole
AJMHS, Vol. 45, No. 1, 2014
Demiraj et al. Different Pulse Therapies of Oral Itraconazole
28
first 2 days of the following 11 months.
Improvement was shown in 70.27% of the cases.
On the other side, our results also clearly
demonstrated that systemic itraconazole has
remarkable efficacy in the treatment of
seborrheic dermatitis. Efficacy data obtained in
our study are in general in agreement with the
results reported in other studies. Furthermore, no
safety questions were encountered; no adverse
events related to drug were observed during the
study.
This is the first study where an attempt to assess
the adherence to oral itraconazole in seborrheic
dermatitis was done. It was a surprise to see a
good correlation, but statistically not significant,
between the adherence to treatment score and
the Overall Clinical Assessment Score, with
Group I showing lowest adherence to treatment
and lowest Overall Clinical improvement at
week 20, which partially explains the difference
in Overall Clinical Assessment Score and
percentage of patients achieving a very good to
excellent improvement between Group I, and
Group II and Group III. It is to be noted that it is
impossible to conclude since there are at least
two weak points in assessing the adherence to
treatment in this study. First, the number of
patients is too small, and second, the 4-items
self-reported questionnaire, which is mainly a
modification of four point Morisky Medication
Adherence Scale, has not been validated for this
purpose. However, it seems that patients adhere
in different ways to different pulse therapeutic
regimens delivering the same quantity of drug.
This topic deserves further investigations.
therapy of a single dose of 100 mg every week,
200 mg every 2 weeks or 200 mg/day for first 2
days every 4 weeks, is safe and beneficial in
patients with severe facial seborrheic dermatitis.
Physicians must be aware that patients’
adherence may be not the same for different
regimens. Although not conclusive, the evidence
supports the use of itraconazole as an alternative
therapy in patients who do not respond or do not
wish to use topical treatment. However, these
results should be confirmed in randomized,
double-blind, comparative clinical trials.
CONCLUSIONS
Though this is an open and uncontrolled study
on a limited number of cases it still is able to
demonstrate that the treatment with itraconazole,
200 mg/day for a week with a maintenance
AJMHS, Vol. 45, No. 1, 2014
Acknowledgements: Not available
Conflict of interest disclosure: Not available
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