Systematic review of comparative efficacy and tolerability of calcipotriol in treating chronic plaque psoriasis

Criteria for considering studies for review

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.

The primary efficacy criteria were the proportion of patients showing “marked improvement” or better in the patients' overall assessments and the mean percentage change in scores from baseline on the psoriasis area and severity index.4 The proportion of patients graded as marked improvement or better in the investigators' overall assessments of response was used as a secondary outcome measure. Adverse events were also recorded regarding lesional or perilesional irritation, facial or scalp irritation, exacerbation of psoriasis, and the number of withdrawals due to adverse effects.

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

Mean (95% confidence interval) differences in percentage change in scores on psoriasis area and severity index from baseline between treatments

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Continuous outcomes —We calculated the mean difference in effect (d_i) 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 (ω_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 χ² 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

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.

Topical corticosteroids —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 obtainedusing 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 betterthan 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' overallassessment 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 treatment ^w32; 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.

In contrast, short contact dithranol was significantly more irritant than calcipotriol. On average, treating four patients with dithranol led to one more patient experiencing lesional or perilesional irritation than if they were using calcipotriol. Facial or scalp irritation, however, occurred less frequently with dithranol than with calcipotriol.

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 treated^w6 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.

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.

Lesional or perilesional irritation is common but rarely requires withdrawal of calcipotriol. In contrast, short contact dithranol caused significantly more skin irritation. Importantly this contributed to a statistically higher withdrawal rate from dithranol than from calcipotriol. We did not have sufficient data to determine whether the newer dithranol formulations are any less irritant than the established products.

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.

Potential sources of heterogeneity in the results may include the formulation, choice of topical corticosteroid, and patient population (children or adults). Unfortunately, there were too few studies for further exploring these issues. However, calcipotriol seemedmore effective in adults than in children, an observation that needs further confirmation.

Future trials should examine efficacy over a much longer period than six to eight weeks (for example, up to six months) to capture the relapsing and remitting nature of the disease. Adverse effects may also not be detected during the short durations of the published randomised controlled trials. Number needed to treat values for adverse reactions werebased on data pooled from trials lasting four to 12 weeks. Caution in their interpretation is obviously required.