ARTICLE
Auteur(s) : Maria Victoria Barrera, Silvia Habicheyn,
Maria Victoria Mendiola, Enrique
Herrera Ceballos
Department of Dermatology, University Hospital Virgen de la
Victoria, Campus Universitario Teatinos s/n, 29010 Malaga.
Spain
accepté le 28 Juillet 2008
Psoriasis is an inflammatory skin disease that has significant
physical and psychological impact [1]. Etanercept is a tumor
necrosis alfa (TNF-α) antagonist, whose efficacy and safety in the
treatment of psoriasis and psoriatic arthritis have been proven in
several clinical trials in the short and medium term [2-4].
Postcommercialization surveillance and clinical studies of this
drug in patients suffering from rheumatoid arthritis have recorded
long-term safety data [5]. Data continue to be collected from
patients with psoriasis in whom treatment has not been interrupted
[6-8]. Now considered an important option for therapy, this new
drug represents a qualitative advance in the management of patients
with psoriasis and has had an extremely beneficial impact on
quality of life.
Our study aimed to evaluate the efficacy and safety of
etanercept in the daily practice of treating patients with
moderate-to-severe plaque psoriasis. It also examined the effect of
discontinuing and readministering the drug.
Materials and methods
We performed a retrospective and observational study that collected
data on all patients with moderate-to-severe plaque psoriasis who
were treated with etanercept in the psoriasis unit of the
dermatology service of the Hospital Universitario “Virgen de la
Victoria” in Malaga, Spain, from November 1, 2003 until March 30,
2007. A total of 66 patients who had already received systemic
therapy or psoralen UV-A have undergone treatment with etanercept
following the summary of product characteristics, that is, at
25 mg or 50 mg twice weekly (BIW) for a maximum of 24
weeks. The patients were evaluated every 6 weeks. At week 12, all
patients who began treatment at 50 mg had their dose reduced
to 25 mg. The following variables had were analyzed at each
visit: outcome of the psoriasis area severity index (PASI) [PASI
50, PASI 75, PASI 90], joint pain, and nail involvement. Data on
concomitant conditions and adverse events were recorded during the
treatment period. Patients who responded to treatment at week 24
(achieved at least 50% improvement in PASI relative to baseline)
interrupted etanercept until the disease recurred (loss of at least
half of the improvement [assessed using PASI] achieved during 24
weeks of treatment). They were readministered etanercept for
another treatment cycle (administration-discontinuation) at
25 mg or 50 mg BIW.
The efficacy analysis examined the parameters of interest for
each treatment cycle at baseline, week 12, week 24, and the final
visit (that is, the last week the patient had been followed up
during each cycle).
Given that the dose with which the patients had begun each
retreatment cycle was independent of the dose with which the
patient had started the study, outcome was studied for each of the
cycles independently according to the dose (25 mg BIW or
50 mg BIW) with which the patient had begun the cycle.
Descriptive analyses of both qualitative and quantitative
variables were carried out. The qualitative variables were analyzed
using absolute and relative frequencies, whereas the quantitative
variables were studied using the mean, standard deviation, and
confidence intervals in the case of a normal distribution, or using
the median, minimum, maximum, and interquartile range if the
variables did not follow a Gaussian distribution. The association
between visits was analyzed using the Wilcoxon test for
quantitative variables and the McNemar test or sign test for
ordinal non-dichotomous or dichotomous discrete variables,
respectively. A Kaplan-Meier survival model was used to study the
psoriasis time free from the first relapse depending on the initial
dose. Survival values were compared using the log-rank test. The
assumptions of normality and homoscedasticity necessary to use the
parametric tests were checked. Statistical significance was set at
P <.05. The statistical analysis was carried out using SPSS
version 13.0.
Results
Of the 66 patients enrolled in the study, 55.4% were men. Mean age
was 46.7 years. Figure
1 illustrates follow-up during the 3 treatment cycles. We
can see the dose at the beginning of each cycle, the suspension of
or withdrawal from treatment, and, in the case of a relapse, the
mean time from the last visit to the relapse.
One cycle of treatment was administered to 37.9% of patients (n
= 25), 2 cycles to 27.3% (n = 18), 3 cycles to 28.8% (n = 19), and
4 cycles to 3.0% (n = 2). The remaining 2 patients received
continuous therapy for 104 and 140 weeks, respectively.
During the first cycle, the percentage of patients starting
therapy with 50 mg BIW was 40.9% (n = 27), during the second
cycle it was 52.6% (n = 14), during the third it was 66.7% (n =
14), and during the fourth cycle it was 50% (n = 1) (table 1). The PASI (figure 2) fell
significantly from a mean score of 25.65 at baseline to 5.19 during
the last follow-up visit of the first cycle. This fall in PASI was
significantly lower at weeks 12 and 24 for patients who started
treatment with 50 mg BIW compared with those who started with
25 mg BIW. During cycles 2 and 3, the mean PASI also fell
significantly from 15.70 to 4.86 and from 17.47 to 3.18,
respectively. No significant differences were observed in the PASI
value according to the dose for any of the cycle visits.
At the end of the first cycle, 91.4% of the patients (n = 32) had
reached a PASI 50, 71.4% (n = 25) a PASI 75, and 48.6% (n = 17) a
PASI 90. In the subpopulation of patients who had started cycle 1
with 25 mg BIW, 92.3% (n = 24) of patients reached a PASI 50,
73.1% (n = 19) a PASI 75, and 46.2% (n = 12) a PASI 90. In the
subpopulation of patients who had started cycle 1 with 50 mg
BIW, 88.9% (n = 8) reached PASI 50, 66.7% (n = 6) reached PASI 75,
and 55.6% (n = 5) reached PASI 90. The frequency of patients who
reached PASI 50 at week 12 and PASI 75 and 90 at week 24 was
significantly greater than that of patients who started the cycle
with 25 mg BIW.
At the end of the second cycle, 90.9% of the patients (n = 10)
had reached a PASI 50, 45.5% (n = 5) a PASI 75, and 18.2% (n = 2) a
PASI 90. In the subpopulation of patients who started the cycle
with 25 mg BIW, 100.0% (n = 6) reached a PASI 50, 33.3% (n =
2) reached a PASI 75, and 16.7% (n = 1) reached PASI 90. In the
subpopulation of patients who started the cycle with 50 mg
BIW, 80% (n = 4) reached a PASI 50, 60% (n = 3) reached PASI 75,
and 20% (n = 1) reached PASI 90.
At the end of the third cycle, 83.3% of the patients (n = 5)
reached a PASI 50, 66.7% (n = 4) a PASI 75, and 33.3% (n = 2) a
PASI 90. In the subpopulation of patients who started the cycle
with 25 mg BIW, the only patient we had reached PASI 50, PASI
75, and PASI 90. In the subpopulation of patients who started the
cycle with 50 mg BIW, 80.0% (n = 4) reached PASI 50, 60.0% (n
= 3) reached PASI 75, and 20.0% (n = 1) reached PASI 90.
Table 1 Starting dose per treatment cycle
|
Starting doses per cycle
|
|
N
|
%
|
|
Cycle I
|
25 mg/2w
|
39
|
59.1
|
|
50 mg/2w
|
27
|
40.9
|
|
Total
|
66
|
|
Cycle II
|
25 mg/2w
|
18
|
47.4
|
|
50 mg/2w
|
20
|
52.6
|
|
Total
|
38
|
|
Cycle III
|
25 mg/2w
|
7
|
33.3
|
|
50 mg/2w
|
14
|
66.7
|
|
Total
|
21
|
|
Cycle IV
|
25 mg/2w
|
1
|
50.0
|
|
50 mg/2w
|
1
|
50.0
|
|
Total
|
2
|
Joint pain
We observed that joint pain improved significantly during cycles 1
and 2, both in the total sample and in the 2 subpopulations. No
significant differences were observed according to dose during any
week of the study. Joint pain improved during the third cycle,
although not significantly.
Nail involvement
We observed that nail involvement improved significantly during
cycle 1, both in the total sample and in the 2 subpopulations. No
significant differences were observed between the doses during any
week of the study. Nail involvement improved significantly during
cycle 2 in the total sample. This was not the case in the 2
subpopulations. During cycle 3, nail involvement improved, although
the data did not show this improvement to be significant.
Treatment cycles
At least 1 cycle of treatment was necessary in 57.6% (n = 38) of
patients who started the study: 59.0% (n = 23) of those who started
with doses of 25 mg twice weekly and 55.6% (n = 15) of those
who started with 50 mg twice weekly. No significant
differences were observed (figure 4).
Time until the first relapse
No statistically significant differences were observed in the mean
time till the first relapse in patients regardless of whether they
started cycle 1 with 25 mg or 50 mg BIW.
The mean time (relapse-free psoriasis) till relapse in patients
who started with 25 mg was 3.70 months compared with 6.13
months in patients who started with 50 mg (table 2). There were no statistically significant
differences (table 2 and figure 5). There were no
cases of relapse after interrupting treatment. There were no
conversions of the morphology of psoriasis and there were no severe
adverse events. The most frequent reactions were at the injection
site during the first month of treatment.
Table 2 Retreatment cycles
|
Median
|
95% CI
|
P (Log-rank)
|
|
Lower limit
|
Upper limit
|
|
25 mg/2
|
3.70
|
1.45
|
5.95
|
.810
|
|
50 mg/2
|
6.13
|
3.18
|
9.09
|
|
Total
|
4.90
|
2.40
|
7.41
|
|
Discussion
Although continuous therapy with etanercept has proven to have a
favorable risk profile in the treatment of patients with
moderate-to-severe plaque psoriasis, we must adapt treatment to
individual patient needs in order to optimize quality of life.
Therefore, very often, therapy still has to be administered
intermittently. With regard to timing of administration after a
relapse, one group of experts in a recent European consensus
document [9] recommended that reuse of the drug be based on
clinical criteria. We administered continuous therapy to 2 of our
66 patients during the study period after taking into consideration
the extent of the condition, its effect on quality of life, and
degree of reduction in the PASI response. Both for patients who
started treatment at 50 mg and for those who started at
25 mg, a significant decrease in PASI was observed during the
3 treatment cycles, both for the total sample and for the 2
subpopulations.
These results make etanercept a good option when classic
systemic treatments are contraindicated or have failed Furthermore,
etanercept has proven to maintain both efficacy and safety in the
retreatment of patients with psoriasis and the response rate is
similar to that obtained in the initial cycle when treatment is
reintroduced after a relapse.
As in other published studies [10,11] with a regimen of
50 mg BIW, we observed a greater and more rapid response rate
with no increase in toxicity. This supports the indication of the
European consensus [9] on starting this treatment at 50 mg
BIW, at least in patients whose clinical status is worse. Other
studies [12] have shown that the reduction in the dose of
etanercept from 50 mg to 25 mg after 12 weeks does not
lead to poorer control of the disease at week 24. In our
experience, even after the dose reduction at week 12, a significant
reduction in the PASI was observed in patients who started with
50 mg during cycle 1 and, although this value did not continue
to fall during cycle 2, it remained unchanged until the end of the
cycle. These data support the reduction of the dose of etanercept
after 3 months of treatment with no loss of efficacy.
To conclude, in our experience, etanercept has proven to be a
beneficial treatment for patients with moderate-to-severe plaque
psoriasis who had not responded to conventional therapy. It has
good tolerance, the management of the disease is easy, as is the
safety of the drug, and there are no fatal complications. Both
clinical efficacy and safety are maintained over time and in
successive retreatment cycles. Although our study examines several
cycles of reinitiation and discontinuation of treatment, further
studies will help us to determine the most efficacious and safest
regimen for etanercept in the treatment of psoriasis.
Acknowledgments
Financial support: none. Conflict of interest: none.
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