ARTICLE
Auteur(s) : MWF Van Duijnhoven, EMGJ de Jong, WJ
Gerritsen, MC Pasch, PCM Van de Kerkhof
Dept of Dermatology, University Medical Centre St Radboud, PO
Box 8101, 6500HB Nijmegen, The Netherlands
accepté le 17 Juin 2005
Memory T cells (CD4+CD45RO+ and CD8+CD45RO+) have been shown to be
important in the immunopathogenesis of psoriasis [1, 2]. Alefacept
(Amevive, BiogenIdec Cambridge, Mass. USA) is a selective
biological agent, consisting of the first extracellular domain of
lymphocyte function-associated antigen-3 (LFA3) fused to
the hinge, CH2 and CH3 sequences of
IgG1. Alefacept binds with the LFA3 segment
to the CD2 on the surface of the T cell, thereby inhibiting T-cell
activation and proliferation [3-6]. Alefacept preferentially
targets memory T cells (CD45RO+), as memory T cells, in contrast to
naive T cells (CD45RA+), bear significant levels of
CD2[7, 8]. In addition, the F-c portion of IgG1 of
alefacept binds to FCγRIII on accessory cells and induces apoptosis
of the memory T cells [9, 10] The clinical response in patients
with chronic plaque psoriasis was correlated to some extent with
decreases in circulating blood lymphocyte counts [11].Phase II and
Phase III trials have demonstrated the efficacy and safety of
alefacept through either 12 weekly injections of 7.5 mg i.v. or 15
mg i.m, followed by 12 weeks follow up. Clinical improvement
correlated with reduction of the number of memory T cell subsets
[10], without impairing immune responses to a neo antigen or recall
antigen [12]. Repeated courses of alefacept proved to be well
tolerated and had a consistent efficacy [13]. In the phase III
study of i.v. administration, two repeated courses of alefacept
proved to result in a better clinical improvement as compared to
one course [14]. A remarkable observation was the prolonged
remission following alefacept treatment. After one course of
alefacept, patients who achieved a 75% or greater reduction in PASI
at any time during one course maintained their 50% or greater
improvement status for a median duration of 241 days. In patients
who received 2 courses of alefacept and reached a 75% or greater
improvement of PASI at any time during these 2 courses, more than
50% of them had maintained their 50% or greater improvement status
at the final end point (48 weeks).In view of the prolonged
remission periods in patients who have been treated with one
alefacept course and the empowered efficacy of the second treatment
course, alefacept can be regarded as a disease modifier, resulting
in prolonged reduction of severity.The question arises as to what
extent the long-term safety and efficacy is valid if alefacept
treatment is combined with other available treatments. In this
report we described 10 patients who suffered from severe psoriasis
in terms of the extent of lesions, poor improvement by available
systemic treatments and presence of contraindications for these
treatments. These patients participated in a multi-centre study to
find out the safety of repeated courses of alefacept in combination
with the available antipsoriatic treatments, in patients with
moderate to severe psoriasis. In view of the remarkable results in
these patients, we wish to report as a case report the responses of
these patients to available antipsoriatic treatments in the past
before alefacept treatment, versus the responses to these
treatments during alefacept treatment. After a brief presentation
of the design of the trial we will describe the history of the 10
patients and their responses to alefacept.
Methods
A multi-centre study was designed to determine the safety and
tolerability of repeated courses of alefacept, administered as a
15 mg intramuscular injection (i.m.) to patients with chronic
plaque psoriasis in the context of standard dermatology practice.
Patients, at least 16 years of age, were included in this
multicentre study after having given informed consent. Patients
were included only if they required a systemic treatment. Patients
with erythrodermic or pustular disease were also eligible to enter
the study. In the Nijmegen department no patients with
erythrodermic or pustular disease were included. Alefacept was
administered as a 15 mg IM injection once a week for 12 weeks,
followed by a 12-week follow-up period. Patients were eligible to
receive up to 3 treatment courses of alefacept during this study.
Each of these courses consisted of 12 once- weekly alefacept doses
and a 12-week follow-up period. During the follow-up periods no
alefacept was administered. Safety parameters, including physical
examination, liver functions, creatinine, cholesterol
triglycerides, white blood cell counts, CD4+ and CD8+ cells,
antinuclear factor, rheumatoid factor, tuberculin tests and
monitoring for infections, for concomitant therapies and for
adverse events, were assessed with variable frequency, ranging from
once weekly to once a month. Efficacy parameters, including
physician global assessment psoriatic arthritis scores and a nail
involvement score, were assessed at day 1, 43, 92, 120 and 162.
After completing the 12 week follow-up for a course, the patient
was eligible for the next course if the disease had progressed to
require a systemic therapy, provided that the CD4 counts were
sufficiently high and no contra indications existed. Patients with
chronic plaque psoriasis, requiring systemic therapy were eligible
for the study provided that they had CD4 counts at or above 400
cells/mm3. The following exclusion criteria were used
for this study; unstable erythrodermic or pustular psoriasis,
guttate psoriasis, serious infections, HIV positive, within 5 years
of enrolment an invasive malignancy, except for a history of
squamous cell- or basal cell carcinoma of the skin, active
tuberculosis, inadequate contraception in female patients of child
bearing potential, pregnancy or breast-feeding, current enrolment
in any other investigational drug, previous use of alefacept.
Patients were permitted to receive one combination with an
established therapy per course. On a subsequent course, the patient
was permitted to change to a different alefacept combination. Low
potency topical corticosteroids were permitted during the entire
study. One topical treatment and UVB phototherapy were permitted
during the alefacept treatment course and subsequent follow-up.
Systemic retinoids could be continued throughout the study.
Cyclosporine had to be continued during the entire alefacept course
and tapered down over 6 weeks in the follow-up, whilst methotrexate
might overlap with alefacept only during the first 4 weeks of
treatment. Fumarates, photochemotherapy and other immunosuppressant
agents were not permitted.
The results of this multicentre study will be published after
completion of the entire follow-up following three courses.
Case reports
Case 1, male, 42 years old
The patient had a 28-year history of widespread chronic plaque
psoriasis. After various topical treatments, the severity of his
extensive psoriasis required phototherapy and systemic treatments.
The patient was treated with cyclosporine (2 months), methotrexate
(45 months), systemic tacrolimus (10 months) and mycophenylate (4
months). These treatments had resulted in a temporary and partial
improvement. However, pancytopenia, liver function impairment and
kidney impairment prohibited further use of these medications. As a
systemic treatment was really needed, the patient has been treated
subsequently with acitretin (43 months) which had a modest efficacy
but which did not result in a satisfactory improvement.
Subsequently, the patient was treated with alefacept, whilst
continuing acitretin. The patient received two courses of alefacept
of 12 weeks each. At the start the patient had a widespread
psoriasis although he was on acitretin treatment. His condition
improved during treatment with the combination from moderate-severe
to mild-moderate within 92 days. The first course was followed by a
follow-up period of 120 days during which the patient maintained
his favourable result. At that time the patient again had
moderate-severe disease, which required the second course, which
resulted in an improvement to mild-moderate within 92 days, an
improvement which was maintained for at least 120 days (most recent
visit). Side effects were limited to a transient decrease of CD4+
cells (338/μl) without clinical significance. The patients had one
episode of bronchitis. The patient had psoriatic arthritis and
joint complaints. These complaints were less during alefacept
treatment as compared to the period before alefacept.
In this patient the combination of alefacept and acitretin
resulted in a satisfactorily control of his psoriasis during 240
days.
Case 2, female, 68 years old
The patient had a 12-year history of extensive psoriasis, which
started following radiotherapy for a mamma carcinoma. The severity
of psoriasis required phototherapies or a systemic treatment. The
patient had been treated with acitretin (11 months), PUVA (7
months), UVB (10 months) and sulfasalazine (9 months). All
these treatments failed to achieve any marked improvement.
Methotrexate was effective during 54 months and resulted in
satisfactory improvement. However, liver fibrosis (grade IIIB)
necessitated discontinuation of this otherwise very effective
treatment in this patient. Cyclosporine was not considered as an
option in view of the previous history of mamma carcinoma and for
that reason cyclosporine is indicated for short-term interventions
and not as a long-term management option to treat the disease.
Several admissions to the inpatient department were required for
dithranol treatment, but the efficacy in this patient was limited
and individual treatment courses lasted for 3-4 months without a
substantial improvement.
The patient was given two courses of alefacept of 12 weeks each,
together with calcipotriol ointment once daily. The first course of
alefacept resulted in a modest improvement at day 43 which lasted
only to day 120. A second course of alefacept was given together
with dithranol treatment at the in patient department. After 43
days, an impressive improvement was reached. For the first time a
dithranol course virtually cleared the patient within one month,
whereas courses of dithranol treatment had previously lasted 3-4
months without substantial improvement. However, 120 days after
reaching virtually clearing, a relapse occurred which necessitated
readmission for dithranol treatment and a third course of
alefacept. No significant side effects were observed during
alefacept treatment.
In this patient alefacept treatment improved the efficacy of
dithranol treatment considerably. The total period of satisfactory
control was 197 days.
Case 3, male, 55 years old
This patient had a 39-year history of widespread chronic plaque
psoriasis. The severity required phototherapy or a systemic
treatment. Multiple courses of UVB phototherapy (as long as 228
months in total) had had a partial effect and the last courses were
not effective any more. Methotrexate (4 months) had had no effect.
Cyclosporine (19 months) had been effective, however kidney
impairment required discontinuation of the treatment.
The patient was treated with two courses of alefacept in
combination with calcipotriol ointment. The treatment had an
impressive effect and 43 days after the first alefacept injection
the disease severity was decreased from moderate-severe to only
minimal. At day 120 almost clearing was reached. At day 218 a
relapse occurred and the second course resulted in a similar fast
response, which was maintained for another 218 days (most recent
follow-up visit). Another observation was that itch had improved
substantially during alefacept treatment. The patient did not
experience any significant side effects during alefacept
treatment.
Although the patient was in an excellent condition with respect
to his skin for more than 393 days, the complaints with respect to
arthritis had not improved.
Case 4, male, 49 years old
This patient suffered from chronic plaque psoriasis for 36 years.
During the last two decades the patient had extensive psoriasis,
which was resistant to topical treatments. Several courses of
phototherapy with UVB (42 months in total) had resulted in a
temporarily improvement which was substantial, but of a relative
short duration. Methotrexate (96 months) had a moderate effect at
dosages above 20 mg per week; the efficacy of methotrexate was not
experienced as satisfactorily. Acitretin (49 months) had some
efficacy, which was satisfactorily during a few months of
combination of acitretin with UVB.
The patient was treated with alefacept. The first course was
started when the patient was still being treated with methotrexate,
which had an unsatisfactorily response, with widespread lesions
remaining. During the first course methotrexate was gradually
discontinued without an aggravation of disease severity.
Previously, discontinuation of methotrexate had always resulted in
severe relapses with severe expression of the disease. The second
course of alefacept was given 12 weeks after the last alefacept
injection of the first course and was given in combination with
phototherapy (UVB). Within 92 days after starting the second course
of alefacept with UVB, a significant improvement was experienced,
resulting in a mild expression of the disease during 117 days.
However, the patient indicated that the response to UVB during
alefacept was similar to UVB monotherapy in the past.
The patient had not experienced any significant side effects to
alefacept treatment. The patient experienced less complaints of his
psoriatic arthritis.
It is likely that alefacept had helped to prevent a relapse
following discontinuation of methotrexate.
Case 5, male, 61 years old
During the last 27 years the patient had psoriasis, involving a
large part of the body surface. The severity of the lesions
justified phototherapy or a systemic treatment. Several courses of
phototherapy, during 30 months in total, had had a good efficacy.
Methotrexate, during 3 months, had to be discontinued for reasons
of liver function abnormalities. Acitretin was given for a few
months without substantial improvement, and hair loss as a side
effect of retinoid treatment was the reason for discontinuation of
this treatment.
Two courses of alefacept in combination with calcipotriol
ointment were given. The first course of alefacept together with
calcipotriol ointment resulted in almost clearing at day 92, an
effect which was maintained for 274 days. At that time he had
recovered from his hair loss.
The second course of alefacept again resulted in almost clearing
within 92 days, an effect which persisted up to the most recent
visit (170 days). ( Figure 1 ) illustrates the
improvement in this patient. No significant side effects
occurred.
The patient experienced an excellent control of psoriasis during
344 days, which was in striking contrast to the years before
alefacept treatment.
Case 6, male, 47 years old
The patient had extensive chronic plaque psoriasis for the past 24
years. Topical therapies had resulted in an insufficient long-term
improvement of the skin conditions. Therefore, phototherapy and
systemic treatments were indicated. Many courses of phototherapy
(UVB) were given during 118 months in total, resulting in a
substantial improvement. Methotrexate (3 months) had no effect and
alcohol abuse restricted prolonged treatment.
One course of alefacept treatment was started in combination
with calcipotriol ointment. Within 92 days an impressive
improvement was observed, resulting in a mild severity disease
classification. At day 162 the patient was virtually clear, which
was the first time in 20 years. No side effects to alefacept were
reported.
This improvement to alefacept was maintained during 442
days.
Case 7, female, 64 years old
The patient had a 10-year history of chronic plaque psoriasis of
moderate extent. Topical treatments were not effective and
therefore the patient had to be treated with phototherapy and
systemic treatments. Phototherapy (several courses, in total 6
months) and photochemotherapy (3 months) had not resulted in a
significant improvement. Methotrexate had to be discontinued for
reasons of liver function impairment.
The patient was treated with alefacept in combination with
calcipotriol ointment. The patient received one course of 12 weeks
and at day 92 of the treatment the patient was almost clear. Now
442 days later the patient is still almost clear. No side effects
were recorded.
Alefacept, in combination with calcipotriol has resulted in this
patient in a long-term improvement.
Case 8, male, 41 years old
The patient suffered from psoriasis for 23 years. He had extensive
plaque psoriasis and a psoriatic arthritis with joint complaints.
Topical treatments had not been effective. The patient was treated
with fumarates for 13 months without a substantial improvement. The
patient never received photo(chemo)therapy with UVB or PUVA,
methotrexate, cyclosporine or retinoids and had no
contraindications for these treatments.
The patient received two courses of alefacept. Both courses were
combined with a topical treatment with calcipotriol. The first
course resulted in a reduction of severity to mild disease and
almost clearing at day 43 till day 162. A second course had to be
given, resulting in only a temporary reduction to mild-moderate
psoriasis. No side effects were recorded. No improvement of the
psoriatic arthritis was experienced by the patient.
The patients was not as dissatisfied with the efficacy of
alefacept as he was with his previous treatments ( (figure 2) ).
Case 9, male, 49 years old
This patient had plaque psoriasis for 19 years. The patient
developed widespread disease with indurated plaques. Topical
treatments were not effective. Therefore phototherapy with UVB and
phototherapy with PUVA were given (8 months in total) with, at
first, a transient effect but without substantial improvement.
During 2 months the patient was treated with acitretin without any
improvement. Methotrexate, cyclosporine and fumarates had not been
considered although no contraindications existed.
The patient received two courses of alefacept in combination
with calcipotriol ointment. The first course had virtually no
visible effect, although the patient felt some improvement with
respect to tenderness of the skin. The second course resulted in a
partial improvement from moderate-severe disease to moderate
disease, 6 weeks after the first alefacept injection of the second
course, an improvement which remained 120 days (most recent visit).
No side effects of alefacept were experienced.
The patient interpreted the effect of alefacept as a limited
response.
Case 10, female, 45 years old
This patient had suffered from extensive psoriasis for 24 years.
Psoriatic arthritis caused joint pain. Topical treatments were not
sufficiently effective to provide adequate control. The patient
received several courses of phototherapy with UVB (total duration
21 months) and some courses of PUVA. These courses had a limited
efficacy. The patient was treated for 24 months with methotrexate
with a partial improvement but it was not completely
satisfactorily; liver function abnormalities further complicated
treatment. For a total of 107 months, she was treated with
fumarates, which resulted in an acceptable improvement. However,
liver function abnormalities and a drug rash to fumarates made
continuation of this treatment impossible. Cyclosporine was not
prescribed as a long-term control was aimed for. Several courses of
dithranol treatment were given at the in-patient department.
However, the improvement due to this treatment was limited and
required 2-4 months hospitalization. No other treatment options
were available. Even 11 months treatment with Chinese Herbs was
tried, also without a meaningful improvement.
Alefacept treatment was started and two courses were given, both
in combination with topical treatment with
clobetasol-17-propionate. The first course resulted in an
improvement, which she had not experienced with any treatment
before. After 43 days the severity was reduced to mild-moderate
severity. This improvement was maintained for 119 days and
aggravation occurred following an erysipelas. A second course of
alefacept was given in combination with topical
clobetasol-17-propionate, which was less effective. During this
course the patient experienced aggravation of a bronchitis (a
chronic aspecific hyperreactivity) and two alefacept injections
were not given. The patient was admitted again for in-patient
treatment with dithranol and, remarkably, dithranol resulted on
this occasion in almost clear within 8 weeks, a response to
dithranol which was never reached by this patient before alefacept
treatment. The patient did not experience an improvement of
arthritis during treatment.
The first course of alefacept was regarded as very successful
and the second course might have been counteracted by an erysipelas
and intercurrent bronchitis. It is of interest that the efficacy of
dithranol was enhanced by alefacept.
Discussion
Currently available systemic treatments for psoriasis have serious
limitations with respect to cumulative toxicity potential [15]. In
general, long-term management of moderate to severe psoriasis may
require a continuous long-term treatment or an interval treatment
with a short-term intervention in case of exacerbation of the
disease.
Of the currently available systemic therapies MTX and acitretin
can be used for long-term continuous treatment. Side effects have
been reported [16, 17]. Methotrexate is a first line treatment for
patients with moderate to severe psoriasis, if topical treatments
and phototherapy are not successful. Eight of the ten patients in
the present study had received MTX. In 4 of 10 patients MTX had
been given for more than two years. Two patients were satisfied
with the efficacy of MTX and 4 described the long-term efficacy as
questionable or none at all. In 5 patients, liver function
abnormalities required discontinuation of MTX. All eight MTX
treated patients discontinued MTX for reason of insufficient
long-term effects or liver function abnormalities. Two out of 10
patients had not received MTX although no contra-indications
existed. However these patients did not want treatment with MTX for
fear of side effects. Seven out of 10 patients had received
acitretin treatment and 2 of them had received acitretin for more
than 3 years. In 3 of them acitretin was not effective at all, in 2
of them a partial effect was observed and in 2 patients the
efficacy was uncertain. In two patients treatment was discontinued
for reason of hair loss or alcohol abuse. In one of the 3 remaining
patients acitretin might have been a treatment option and in 2 of
these patients contra-indications had prohibited acitretin
treatment.
In summary, long-term continuous treatment with available
treatments was no longer possible in 8 out of 10 patients. One
patient still had two treatment options and one patient only one
option. Therefore the need for development of other options, which
can provide a continuous long-term disease control, is of utmost
importance. In this respect the further commercial development of
fumarates is of importance [18-21]. Fumarate treatment is given in
the Netherlands as a compassionate use treatment. Three out of 10
patients had received fumarates: One patient had no effect
following 13 months treatment, and two patients had to discontinue
fumarates for reason of side effects (liver function disturbances,
a drug eruption and kidney function impairment). One patient had
contra-indications for fumarates. If fumarates had been available
as a routine treatment the number of patients without continuous
systemic treatment options would have decreased from 8 to 6, which
implies that in the majority of the 10 cases new systemic treatment
options still remain urgently needed.
Short-term intervention of relapses is another treatment
approach for patients with moderate to severe psoriasis.
Phototherapy with UVB and PUVA are treatments which can be used
exclusively as short-term intervention treatment, clearly with a
cumulative toxicity potential in view of their carcinogenicity
[22-24]. In the group of 10 patients, UVB phototherapy was given in
9 subjects. In 5 patients UVB had been given for a cumulative
duration of at least 20 months and in the remaining 4 patients the
efficacy had been too low. In fact, PUVA therapy might have been an
extra option as intervention therapy in two patients. So, 7 out of
the 10 patients also did not have the option of intervention
treatment with photo(chemo)therapy.
Cyclosporine can be given over a one year cumulative duration,
according to the guidelines of the Dutch Association of
Dermatologists. Long-term treatment has a serious risk for kidney
impairment [25, 26]. In 2 out of 10 patients cyclosporine had been
given, in one patient without efficacy and in the other resulting
in kidney damage. Taking into consideration that 7 patients had had
substantial cumulative doses of UVB and PUVA, only 2 patients were
eligible for cyclosporine.
This analysis demonstrates that 8 out of 10 patients had no
option for continuous long-term treatment, although interval
treatment to manage relapses was possible in 3 patients by
photo(chemo)therapy and in 2 patients by cyclosporine.
In the group of 10 patients presented in this report only one
patient had a slight and transient decrease of CD4 counts. No
patient had significant side effects to alefacept. Alefacept proved
to have a substantial benefit, transforming severe psoriasis into a
mild disease expression during one year or longer, in as many as 4
out of 10 patients. Table 1( Table 1 )
provides the long-term efficacy data. These patients indicated that
their long-term response to a treatment had been substantially
better with alefacept as compared to the responses to treatments
before alefacept.
Another patient indicated that the overall extent of the lesions
was not reduced by alefacept treatment but the remarkable decrease
in the thickness of the plaques had been a substantial improvement
in the quality of life (case 9). The decrease of itch improved the
quality of life in another patient (case 3). This is in line with
the reported improvement of quality of life following alefacept in
multicentre studies [27, 28]. Four patients indicated that the
long-term efficacy during alefacept had not been better as compared
to the years that no alefacept was used, although two of these
patients indicated a major and clinically relevant improvement of
the short-term response to dithranol treatment.The most impressive
response with long-term reduction of disease severity to only mild
disease was seen in case 7. This patient had been treated with few
treatment options in the past and was not eligible for several
treatment options for reason of liver function abnormalities.
In 7 patients alefacept was combined with at least one course of
calcipotriol, one patient had two courses of
clobetasol-17-propionate and two patients had a course of dithranol
during or following alefacept treatment. Comparison of the
responses to topical treatments in combination with alefacept vs
these treatments without alefacept in the past, revealed a
remarkable modification of the response to dithranol. Before
alefacept, two patients had required 3-4 months of dithranol
treatment with only a modest improvement, in contrast to a major
improvement with only one month of dithranol treatment in
combination with alefacept. In one of these patients the long-term
response was not satisfactory, but the relatively short improvement
had been important to this patient. In a previous study by our
group it was shown that dithranol did not have a significant effect
on T-cell subsets, whilst decreasing epidermal proliferation
substantially and decreasing the clinical severity of the lesions
markedly [29]. It is attractive to speculate that the modes of
action of alefacept and dithranol may be complimentary.
The combination of alefacept with UVB (case 4) was not better as
compared to UVB monotherapy, however this patient, who was not
satisfied with the long-term response, indicated that the
discontinuation of methotrexate during alefacept was not
accompanied by a flare, whereas severe relapses following MTX
discontinuation had been observed in the years before
alefacept.
Considering the value of alefacept in combination with available
treatment in the long-term management of psoriasis, the present
cases illustrate that long-term satisfactory improvement is seen in
those patients without treatment options, 4 of 10 patients
realising improvement from moderate to severe psoriasis to only
mild disease for more than one year. Furthermore, alefacept proved
to improve markedly dithranol treatment in dithranol-unresponsive
patients and to reduce the relapse following discontinuation of
methotrexate.
The positioning of alefacept amongst other systemic treatments
for severe psoriasis is a challenge. Based on criteria such as the
percentage of patients reaching within 3 months the PASI 75,
alefacept is not superior to other systemic treatments. However,
the present communication illustrates that some patients with
severe psoriasis with restricted treatment options may benefit very
much for a prolonged duration from alefacept treatment. The
challenge is to identify those patients who are responders to
alefacept treatment. Better characterization of psoriasis subtypes,
and hopefully, pharmacogenetic approaches may help us.
Table 1 Long term efficacy data in 10 patients with
high need psoriasis treated with alefacept in combination with
other antipsoriatic treatments
|
Case
|
Combined treatment
|
Duration of improvement (days)
|
Remarks
|
|
1
|
1. Acitretin
|
120
|
|
|
2. Acitretin
|
120
|
|
2
|
1. Calcipotriol
|
-
|
|
|
2. Dithranol
|
120
|
Dithranol treatment highly effective
|
|
3
|
1. Calcipotriol
|
175
|
|
|
2. Calcipotriol
|
218
|
|
4
|
1. Methotrexate
|
-
|
MTX discontinuation without flare
|
|
2. UVB
|
117
|
|
|
5
|
1. Calcipotriol
|
274
|
|
|
2. Calcipotriol
|
170
|
|
6
|
1. Calcipotriol
|
442
|
|
|
7
|
1. Calcipotriol
|
442
|
|
|
8
|
1. Calcipotriol
|
119
|
|
|
2. Calcipotriol
|
-
|
|
9
|
1. Calcipotriol
|
-
|
|
|
2. Calcipotril
|
120
|
|
10
|
1. Clobetasol
|
119
|
|
|
2. Clobetasol/Dithranol
|
-
|
Dithranol treatment highly effective
|
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