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Darren M Ashcroft a Centre for Evidence-Based
Pharmacotherapy, School of Life and Health Sciences, Aston University,
Birmingham B4 7ET, b Department of Dermatology, Queen's Medical
Centre, Nottingham NG7 2UH, c Section of
Dermatology, University of Manchester, Hope Hospital, Salford M6 8HD
Correspondence to: A Li Wan Po a.liwanpo{at}aston.ac.uk
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Abstract |
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Objectives:
To evaluate the comparative efficacy and
tolerability of topical calcipotriol in the treatment of mild to
moderate chronic plaque psoriasis.
Psoriasis affects 1%-2% of the population in the United
Kingdom.
1 2
Despite the availability of several
treatments, psoriasis is often difficult to treat owing to its sporadic
course, variable response to treatments, and adverse effects. In the
absence of a permanent cure the goal of treatment is to minimise the
extent and severity of the condition so that it no longer disrupts
substantially the patient's quality of life.3
In recent years calcipotriol, a synthetic vitamin D3
analogue, has become one of the most widely prescribed treatments for psoriasis in the United Kingdom. To assess its usefulness compared with
the more traditional topical treatments for psoriasis we undertook a
systematic review of trials of topical calcipotriol in the treatment of
mild to moderate chronic plaque psoriasis.
Criteria for considering studies for review
Design:
Quantitative systematic review of randomised controlled trials.
Subjects:
6038 patients with plaque psoriasis reported in 37 trials.
Main outcome measures:
Mean difference in percentage
change in scores on psoriasis area and severity index, and response
rate ratios for both patients' and investigators' overall assessments
of marked improvement or better. Adverse effects were estimated with
the rate ratio, rate difference, and number needed to treat.
Results:
Calcipotriol was at least as effective as potent topical corticosteroids, calcitriol, short contact dithranol, tacalcitol, coal tar, and combined coal tar 5%, allantoin 2%, and
hydrocortisone 0.5%. Calcipotriol caused significantly more skin
irritation than potent topical corticosteroids (number needed to treat
to harm for irritation 10, 95% confidence interval 6 to 34).
Calcipotriol monotherapy also caused more irritation than calcipotriol
combined with a potent topical corticosteroid (6, 4 to 8). However, the
number needed to treat for dithranol to produce lesional or
perilesional irritation was 4 (3 to 5). On average, treating 23 patients with short contact dithranol led to one more patient dropping
out of treatment owing to adverse effects than if they were treated
with calcipotriol.
Conclusions:
Calcipotriol is an effective treatment
for mild to moderate chronic plaque psoriasis, more so than calcitriol, tacalcitol, coal tar, and short contact dithranol. Only potent topical
corticosteroids seem to have comparable efficacy at eight weeks.
Although calcipotriol caused more skin irritation than topical
corticosteroids this has to be balanced against the potential long term
effects of corticosteroids. Skin irritation rarely led to withdrawal of
calcipotriol treatment. Longer term comparative trials of calcipotriol
versus dithranol and topical corticosteroids are needed to see whether
these short term benefits are mirrored by long term outcomes such as
duration of remission and improvement in quality of life.
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Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
![]()
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
Conclusions
References
We included only randomised controlled trials of calcipotriol.
Patients with chronic plaque psoriasis treated with calcipotriol
0.005% cream or ointment were eligible for inclusion.
Search strategy
We systematically searched (1987 to January 1999) Medline, Embase,
the Cochrane controlled trials register, and BIDS index to scientific
and technical proceedings using the textwords calcipotriol, MC903,
calcipotriene, Dovonex, Daivonex, and Psorcutan. Reference lists of all
retrieved randomised controlled trials were also searched and the
manufacturer of calcipotriol contacted. Trial eligibility was
determined by two authors, who also independently extracted the data.
Any disagreements were resolved by discussion. Abstracts were
considered; relevant information not included in the published reports
was obtained by either contacting the principal author of the trial or
the manufacturer.
Methods of the review
We grouped the topical corticosteroids on the basis of their
potencies: moderate (clobetasone butyrate 0.05%), potent
(betamethasone valerate 0.1%, betamethasone dipropionate 0.1%,
desoxymethasone 0.25%, fluocinonide 0.05%, halobetasol 0.05%), and
very potent (clobetasol propionate 0.05%, diflorasone diacetate 0.05%).
Outcomes
Dichotomous outcomes
Efficacy was estimated with the
rate ratio, defined as the proportion of patients achieving at least
marked improvement in the calcipotriol group compared with the control
group. Adverse effects were also estimated with the rate ratio, the
rate difference, and the number needed to treat. We performed an
intention to treat analysis. In all cases we used the Mantel-Haenszel
method for interval estimation of the individual rate ratio and rate
difference.5
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We calculated the mean difference in
effect (di) and 95% confidence interval for each
trial. When the standard errors or standard deviations and sample sizes
were not provided or could not be calculated on the basis of the data
reported, we used the pooled interstudy standard error from studies
reporting variances.6 In estimating the weighted pooled
difference in effect (d), the inverse of the squared standard error
(sampling variance) of the difference in response was used as the
weight (
i). For interval estimation and calculation
of the 95% confidence interval of the pooled estimates, we used the
inverse variance method.
7 8
We examined heterogeneity between trials with
2
tests. Provided no significant heterogeneity was identified, we pooled
the summary estimates for the effect from each trial using a fixed effects model. We used the DerSimonian random effects model if P
0.05
for the test for heterogeneity.7
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Results |
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We identified 62 reports of randomised controlled trials. We included 37 trials, randomising 6038 patients in the analysis (table A on website).w1-37 Of the remaining 25 trials, 12 duplicated results from reports already included9-20 and eight failed to meet our inclusion criteria (non-relevant outcomes,21-24 different concentrations or regimens,25-27 and scalp psoriasis28). A further five reports were excluded: four were abstracts for which we were unable to obtain the necessary patient data29-32 and one had insufficient primary data for analysis.33 In all cases we attempted to obtain the data by contacting the manufacturer and the principal author of the trial.
Comparative efficacy of topical calcipotriol
Placebo
Overall, 1185 patients participated in eight
placebo controlled trials of calcipotriol. At six and eight weeks
calcipotriol was more effective than placebo in adults (figure and figs
A and B on website). At eight weeks in one trial the rate ratio was 2.9 (95% confidence interval 1.7 to 5.0) in the patients' overall
assessment of response, and the mean difference in the percentage
change in scores on the psoriasis area and severity index was 44.1%
(27.8% to 60.4%).w5 Based on the results of one trial
calcipotriol was no better than placebo in children.w6
Calcipotriol was significantly
more effective than potent topical corticosteroids at six weeks but not
at eight weeks. In two trials the pooled mean difference in the
percentage change in scores on the psoriasis area and severity index at
six weeks was 6.5% (2.4% to 10.6%) (figure).w9 w10
Calcipotriol was also as effective as very potent topical
corticosteroids. In two trials the pooled mean difference in the
percentage change in psoriasis area and severity index scores was
10.2% (
0.7% to 21.1%).w15 w16 A combination regimen
of a potent topical corticosteroid plus calcipotriol, however, proved
more effective than calcipotriol monotherapy. In one trial the rate
ratio for marked improvement or better in the patients' overall
assessment at eight weeks was 0.8 (0.6 to 1.0).w37
Once daily calcipotriol
Two trials compared twice daily and
once daily regimens with calcipotriol in 480 patients.w22 w37 Efficacy based on the percentage change
in psoriasis area and severity index scores showed superiority for the
twice daily regimen; the pooled mean difference in effect was 5.5%
(1.2% to 9.8%).
Calcitriol and calcipotriol had a greater effect over twice
daily topical calcitriol (figure). At six and eight weeks in one parallel trial, the mean difference in percentage change in psoriasis area and severity index scores was 34.2% (9.8% to 58.7%) and 50.9% (30.6% to 71.2%) respectively.w24
Coal tar
One trial showed that at six weeks topical
calcipotriol was superior to coal tar.w26 The results were
consistent with those obtained using the patients' and the
investigators' overall assessments of at least marked improvement; the
corresponding rate ratios were 5.5 (1.3 to 22.7) and 4.3 (1.4 to 13.7).
Coal tar 5%, allantoin 2%, and hydrocortisone
0.5%
From the investigators' overall assessment in a
trial of 122 patients the rate ratio for marked improvement or better
was 1.5 (1.1 to 2.1), indicating that calcipotriol was significantly
better than coal tar 5%, allantoin 2%, and hydrocortisone 0.5% (fig
B on website).
"Short contact" dithranol
Calcipotriol was
significantly more effective than short contact dithranol on the basis
of all three response measures. At eight and 12 weeks the rate
ratios for marked improvement or better in the patients' overall
assessment were 1.5 (1.3 to 1.7) and 1.3 (1.0 to 1.6) and for the
investigators' overall assessment were 1.6 (1.4 to 1.8) and 1.2 (1.0 to 1.5).
Tacalcitol
From the patients' and investigators' overall
assessments in one trial, twice daily calcipotriol was more effective than once daily tacalcitol at eight weeks of
treatmentw32; both rate ratios were 1.4 (1.1 to 1.8).
Ultraviolet B phototherapy and calcipotriol
No
statistical difference was found between the treatments except for
scores on the psoriasis area and severity index (figure).
Withdrawal from treatment
Significantly more patients withdrew from placebo compared
with calcipotriol (table B on website). Surprisingly, more patients
withdrew from treatment with very potent topical corticosteroids. Most
patients (32 of 48) dropped out as a result of resolution of their
psoriasis. In contrast, short contact dithranol resulted in a
significantly higher overall withdrawal rate but also a higher
withdrawal rate due to adverse effects of treatment.
Adverse effects
The most common adverse effects were lesional or perilesional
irritation, facial or scalp irritation, or exacerbation of psoriasis
(table B on website). For every 10 patients treated with calcipotriol
one more patient experienced lesional or perilesional irritation than
if they were treated with a potent topical corticosteroid. For every
six patients treated with calcipotriol alone, one more patient
experienced lesional or perilesional irritation than if they were
treated with calcipotriol and a moderate or potent topical corticosteroid.
Sensitivity analysis
Intention to treat and remaining patient analyses led to the same
conclusions. With placebo controlled trials we also examined the effect
of including one trial of only children treatedw6 and of
excluding one trial of a once daily regimen of
calcipotriol.w7 No qualitative differences in results were
identified except that inclusion of the only paediatric trial showed a
significant difference in efficacy on the basis of the investigators'
overall assessment of response (table). Exclusion of trials using half body comparisons or those with imputed variances did not change the
results qualitatively.
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Discussion |
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Calcipotriol is effective in the treatment of mild to moderate chronic plaque psoriasis. Overall, calcipotriol was superior to calcitriol, coal tar, combined coal tar 5%, allantoin 2%, and hydrocortisone 0.5%, short contact dithranol, and tacalcitol. Comparable effects were seen with potent topical corticosteroids after eight weeks of treatment.
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What is already known on this topic
Calcipotriol has become one of the most commonly prescribed antipsoriatic treatments, but until now there has not been any systematic assessment of its usefulness compared with other topical agents for psoriasis What this study addsCalcipotriol is a useful drug for treating mild to moderate psoriasis. It seems to be more effective than calcitriol, tacalcitol, coal tar, and short contact dithranol but it is associated with a high frequency of skin irritation Potent topical steroids are as effective as calcipotriol but this has to be balanced against possible long term systemic effects. The trials have generally been short term, and the advantage of calcipotriol in longer term trials over the cheaper alternatives, particularly regarding improved quality of life and lower relapse rates, has yet to be shown |
Implications
Once daily calcipotriol and a potent topical corticosteroid may be
more effective and better tolerated than twice daily calcipotriol. One
explanation might be that corticosteroids suppress the occurrence of
irritation induced by calcipotriol. With long term use, however,
topical corticosteroids have the potential to cause side effects such
as atrophy, striae, telangiectasia, and masking of local
infections.3 Systemic effects cannot be completely ignored.
Limitations
Only one trial included quality of life
assessments.w31 European investigators favoured a modified
psoriasis area and severity index as the primary measure of efficacy
whereas trials conducted in the United States tended to use an
investigators' overall assessment of improvement. Previously, we
proposed that a minimum core set of outcome measures should be included
in all psoriasis clinical trials, and we have acknowledged major
limitations with the psoriasis area and severity index.w34
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Conclusions |
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Pooled data from randomised controlled trials show that
calcipotriol is an effective and well tolerated treatment for mild to
moderate chronic plaque psoriasis. Although skin irritation is
comparatively common, this rarely requires withdrawal of calcipotriol treatment. Potent topical corticosteroids have also emerged as equally
effective agents when assessed at eight weeks, with less short term
side effects than calcipotriol. Future trials should focus on examining
the risk to benefit ratios from combined regimens of calcipotriol with
other antipsoriatic agents and include information on quality of life
and disease remission.
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Acknowledgments |
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We thank the following for information and unpublished data: Dr N K Veien, Professor J P Ortonne, Dr J F Bourke, Professor G Landi, Dr L Cresti and Dr D Crippa (Schering), Dr S Lovati, and Dr L Naldi; Mrs I Müller (Leo Pharmaceutical Products); Mr Q D Clarke, Mr P Menday, and Ms C Michell (Leo Pharmaceuticals), Dr A Herxheimer, Dr T F Poyner, Dr W Y Zhang, Dr R T Plott, and Dr S F Levy (Dermik Laboratories), and Dr S B Siskin (Bristol-Myers Squibb).
Contributors: DMA and ALWP designed the study, conducted the literature searches, abstracted the data, analysed the results, and wrote the paper. HCW and CEMG helped write the paper and provided clinical interpretation of the included trials and the results. ALWP and DMA will act as guarantors for the paper.
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Footnotes |
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Funding: A research grant from Boots Healthcare.
Competing interests: DMA is a recipient of a research grant from E Merck Pharmaceuticals who initially marketed tacalcitol in the United Kingdom. ALWP is the recipient of funding for studentships from Leo Pharmaceuticals (manufacturer of calcipotriol) and Merck Lipha. CEMG's department is the beneficiary of research grants from both Leo and E Merck. CEMG has also acted as a consultant to both companies on an ad hoc basis.
Additional figures and tables
appear on the BMJ's website
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References |
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(Accepted 7 December 1999)
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