Combination Regimens of Topical Calcipotriene in Chronic Plaque Psoriasis Systematic Review of Efficacy and Tolerability

EVIDENCE-BASED DERMATOLOGY: ORIGINAL CONTRIBUTION Combination Regimens of Topical Calcipotriene in Chronic Plaque Psoriasis Systematic Review of Efficacy and Tolerability

Darren M. Ashcroft, PhD; Alain Li Wan Po, PhD; Hywel C. Williams, PhD; Christopher E. M. Griffiths, MD

Objective: To examine the efficacy and tolerability of sporine vs cyclosporine alone (6 weeks), 1.2 (95% CI, calcipotriene combined with phototherapy or systemic 0.9-1.6); and calcipotriene plus psoralen–UV-A vs pso- therapies compared with monotherapy for the treat- ralen–UV-A alone (12 weeks), 1.2 (95% CI, 0.9-1.6). Pa- ment of chronic plaque psoriasis. tients were also no more likely to obtain marked improvement or better with calcipotriene plus UV-B therapy Design: Quantitative systematic review of 11 random- than with UV-B therapy alone (RR, 1.0; 95% CI, 0.8-1.1 ized controlled trials involving a total of 756 patients with at 8 weeks in the patient assessment). There is limited plaque psoriasis. evidence that use of calcipotriene might reduce the cumulative exposure to phototherapy and systemic treat- Main Outcome Measures: Rate ratios (RRs) for marked ment. During the short duration of these trials, there were improvement or clearance in patient and investigator over- no significant differences in withdrawal rates or adverse all assessments of response; mean difference in percent- effects between the combined regimens and their corre- age change in Psoriasis Area and Severity Index; and RRs sponding monotherapy control interventions. for clearance in patient and investigator overall assessments of response. Adverse effects were estimated with Conclusions: Overall, there is insufficient evidence to the RR and the rate difference in terms of withdrawal rate, support any large effects in favor of combination treat- proportion of patients experiencing adverse events, and ment. In the patient assessments, the results do not show proportion of patients with cutaneous and noncutane- an adjuvant effect, but there is some evidence that use ous adverse effects. of calcipotriene might reduce cumulative exposure to systemic therapy to obtain clearance. There were no long- Results: Antipsoriatic effects of acitretin, cyclosporine, term morbidity data on the effectiveness of any of the com- and psoralen–UV-A phototherapy were enhanced with binations studied. Given that psoriasis is a chronic the addition of topical calcipotriene using the Psoriasis recurrent disease for most patients, longer trials are needed Area and Severity Index as the outcome, but this is not to determine whether the addition of topical calcipotri- translated into an increase in the number of patients who ene to systemic therapy improves the risk-benefit ratio achieve at least marked improvement. At the end of treat- by reducing the long-term risk of toxic effects. Equally ment, the RRs for marked improvement or clearance in important is the need to examine the impact of such com- patient assessments were as follows: calcipotriene plus binations on the duration of remission after treatment. acitretin vs acitretin alone (12 weeks), 1.4 (95% confidence interval [CI], 1.0-1.9); calcipotriene plus cyclo- Arch Dermatol. 2000;136:1536-1543

T HAS BEEN ESTIMATED that 23% of lessen the risk of serious adverse effects. The patients with psoriasis have dis- use of combined regimens also raises sev- ease for which topical therapy is eral important questions: Are there any im- either impractical or not suffi- provements in efficacy? Do patients expe- ciently effective.1 These patients rience longer duration of remission after Iare often treated with phototherapy, pho- treatment? Are there any reductions in the tochemotherapy, or systemic treatments. overall therapy costs (economic issues)? The usefulness of these treatment mod- alities is often restricted by their toxic effects. The dose-dependent nature of many See also page 1547 of the adverse effects has led to the devel- The affiliations of the authors opment of combined treatment with topi- Calcipotriene is one of the most appear in the acknowledgment cal therapies in an attempt to reduce the to- widely prescribed treatments for psoria- section at the end of the article. tal dose of the systemic agent and thereby sis in many countries, and its efficacy in

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 MATERIALS AND METHODS calcipotriene (Leo Pharmaceuticals, Buckinghamshire, England) and the reference lists of all retrieved RCTs. The INCLUSION AND EXCLUSION CRITERIA search was most recently updated in January 1999. Trial eligibility was determined by 2 authors (D.M.A. and The following selection criteria were used to identify stud- A.L.W.P. There were no language restrictions. Abstracts were ies for inclusion in this analysis. considered; relevant information not included in the published reports was obtained by contacting the principal au- Types of Studies thor of the trial or the manufacturer.

Only RCTs were included. Quality scoring was restricted METHODS OF REVIEW to this threshold criterion because of broad support for the clinical importance of these items but less so on other items Dichotomous Outcomes often included in quality scores. Efficacy was estimated with the rate ratio (RR), defined as Types of Participants the proportion of patients achieving the outcome in the treatment group relative to the control group. If the treatment Patients with chronic plaque psoriasis were eligible for in- makes no difference to the rate of events, the RR is 1. Ben- clusion. Exclusion criteria included guttate, pustular, or eficial interventions will have an RR greater than 1. A 95% erythrodermic psoriasis. confidence interval (CI) for the RR that crosses unity indicates that there was no significant difference in the rate Types of Interventions of the outcome between the treatment groups (PϾ.05). Ad- verse effects were estimated with the RR (or relative risk) Calcipotriene, 0.005% cream or ointment, used in combina- and the rate difference. When there were no events in 1 tion with phototherapy or systemic antipsoriatic therapies. group we added 0.5 to each cell of the 2ϫ2 table. In all cases, we used an intention-to-treat analysis, whereby Types of Outcome Measures the denominator was the number of patients randomized. The Rothman method was used for 95% CI estimation of Assessment of Efficacy. The efficacy criteria were (1) the the individual RR and rate difference.5 proportion of patients showing marked improvement or clearance in patient and investigator overall assessments Continuous Outcomes of response; (2) the proportion of patients with clearance in patient and investigator overall assessments of re- The percentage change in PASI from baseline was analyzed sponse; and (3) the mean percentage change from base- as the weighted mean difference, defined as the difference line in the Psoriasis Area and Severity Index (PASI).4 between mean values in the treatment and control groups Patient overall assessment of response was the pri- for individual trials and the mean difference weighted for trial mary outcome measure in this analysis. size for groups of trials.2 In estimating the weighted pooled difference in effect, the inverse of the squared SE (sampling Assessment of Tolerability. The proportion of patients variance) of the difference in response was used as the weight. experiencing cutaneous, noncutaneous, and any adverse The method of DerSimonian and Laird,6 as imple- effects and the number of withdrawals due to adverse mented by Whitehead and Whitehead,7 was used to cal- effects were examined. culate the pooled estimates and their corresponding 95% CIs. Heterogeneity between trials was examined using ␹2 SEARCH STRATEGY tests, with PՅ.05 indicating significant heterogeneity. Het- FOR IDENTIFICATION OF STUDIES erogeneity refers to nonhomogeneous treatment effects from the different trials being considered.The statistical power The RCTs were identified by computerized searches (from of the ␹2 tests for heterogeneity is, in many cases, low be- 1987) of the Cochrane Controlled Trials Register, cause of the small number of combined trials. If there was EMBASE, MEDLINE, and the BIDS Index to Scientific and no evidence of statistical heterogeneity, summary esti- Technical Proceedings. Textwords applied to the search in- mates of the effect from each trial were pooled using a fixed cluded calcipotriol, MC903, calcipotriene, Dovonex, Daivonex, effects model. A random effects model was used if PՅ.05. and Psorcutan. This was supplemented by searching the Results from fixed or random effects modeling are shown information database maintained by the manufacturer of as appropriate in the tables and figures.

mild to moderate psoriasis has already been shown in a to investigate the efficacy and tolerability of combining meta-analysis of 37 clinical trials.2 Concurrent use of cal- calcipotriene with phototherapy or systemic agents in the cipotriene with systemic agents is commonplace in many treatment of chronic plaque psoriasis. dermatology departments. Results from a survey3 of dermatologists using such regimens suggest that it is pos- RESULTS sible to improve efficacy over systemic monotherapy. Sev- eral studies have been published on combining calci- CHARACTERISTICS OF ELIGIBLE TRIALS potriene with other antipsoriatic treatments. To clarify these issues in a more objective manner, we conducted Eleven RCTs8-18 that met the study’s inclusion criteria were a systematic review of randomized controlled trials (RCTs) identified. In all, this represented 756 patients random-

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Patients, No. Patient Treatment Age, Treatment Combination Control Trial Design Mean, y Duration, wk Follow-up Combination Control Treatment Treatment Calcipotriene + UV-B Phototherapy vs Calcipotriene Kragballe,8 1990 Open-B 47 8 . . . CPT bid + UV-B (3ϫ/wk) CPT bid 20 20 Molin et al,9 1993 Open-B 43.7 8 8 wk CPT bid + UV-B (3ϫ/wk) CPT bid 101 101 Kerscher et al,10 1994 Open-B 43.5 2 . . . CPT bid + UV-B (5ϫ/wk) CPT bid 20 20 Bourke et al,11 1997† Open-P 40 4 . . . CPT 100 g/wk + CPT 100 g/wk 10 10 UV-B (3ϫ/wk) Calcipotriene + UV-B vs Placebo + UV-B Molin,12 1997 DB-B 46.9 8 8 wk CPT bid + UV-B (3ϫ/wk) Vehicle bid + 77 77 UV-B (3ϫ/wk) Bourke et al,11 1997† Open-P 40 4 . . . CPT 100 g/wk + UV-B (3ϫ/wk) 10 10 UV-B (3ϫ/wk) Ramsay,13 1998 SB-P 44.5 12 12 wk CPT bid + UV-B (2ϫ/wk) Vehicle bid + 84 80 UV-B (3ϫ/wk) Calcipotriene + PUVA vs Placebo + PUVA Frappaz and Thivolet,14 1993 DB-P 46.2, 47 12 . . . CPT bid + PUVA (3ϫ/wk) Vehicle bid + 54 53 PUVA (3ϫ/wk) Speight and Farr,15 1994 SB-B 50 6 6 mo CPT bid + PUVA (2ϫ/wk) Vehicle bid + 13 13 PUVA (2ϫ/wk) Aktas et al,16 1995 Open-P 36.4, 32.1 6 . . . CPT bid + PUVA (4ϫ/wk) Placebo bid + 10 10 PUVA (4ϫ/wk) Calcipotriene + Acitretin vs Placebo + Acitretin van de Kerkhof et al,17 1998 DB-P 48.1, 47.1 12 . . . CPT bid + acitretin Vehicle bid + 76 59 acitretin Calcipotriene + Cyclosporine vs Placebo + Cyclosporine Grossman et al,18 1994 DB-P 44.2, 43.3 6 . . . CPT bid + cyclosporine Placebo bid + 35 34 cyclosporine

*Open-B indicates open, bilateral comparison; Open-P, open, parallel group; DB-B, double-blind, bilateral comparison; DB-P, double-blind, parallel comparison; SB-P, single-blind, parallel group; SB-B, single-blind, bilateral comparison; CPT, calcipotriene, 50 µg/g; bid, twice daily; PUVA, psoralen–UV-A; and ellipses, no follow-up. †Three-armed trial.

ized to treatment. Table 1 shows details of these trials. tigator overall assessment. Comparing the proportion of One trial11 was a 3-armed parallel group study, and the patients showing marked improvement or clearance, there remaining 10 trials were 2-armed head-to-head compari- was no significant difference between the combined regi- sons, 5 of which involved a bilateral (right/left) design. men and calcipotriene alone. The RRs at 8 weeks were The duration of randomized treatment ranged from 2 to 1.1 (95% CI, 0.9-1.2) in the patient assessment and 1.1 12 weeks. Two non-English publications were re- (95% CI, 1.0-1.2) in the investigator assessment. trieved.10,16 All trials were randomized and controlled. Five Likewise, compared with UV-B monotherapy in one trials were open, 2 were single-blind, and 4 were double- trial12 of 77 patients, there was no significant difference blind. One trial10 did not report the variance of the in response with a combined regimen of calcipotriene and percentage change in PASI from baseline, necessitating UV-B (3 times weekly). The RRs for marked improve- variance imputation. ment or clearance at 8 weeks were 1.0 (95% CI, 0.8-1.1) in both patient and investigator overall assessments of EFFICACY response, whereas the corresponding RRs for clearance were 1.1 (95% CI, 0.7-1.8) and 1.0 (95% CI, 0.6-1.7), Results of the efficacy analyses are shown in Figures 1, respectively. At the end of treatment (8 weeks), the mean 2, 3, 4, and 5. difference in the percentage change in PASI was −1.9% (95% CI, −9.2% to 5.4%). Calcipotriene and UV-B Phototherapy One trial13 of 164 patients compared calcipotriene and UV-B (2 times weekly) with placebo cream and UV-B Combined calcipotriene and UV-B phototherapy proved (3 times weekly). The efficacy results were essentially simi- more effective than calcipotriene monotherapy on the ba- lar between the 2 treatment groups. There was a signifi- sis of the proportion of patients whose psoriasis cleared cant difference only in the patient overall assessment of and the mean difference in the percentage change in PASI clearance; the RR at the end of treatment (12 weeks) was (Figures 3, 4, and 5). The RRs for clearance at 8 weeks 0.6 (95% CI, 0.4-0.9). The mean difference in the per- were 2.1 (95% CI, 1.2-3.7) in the patient overall assess- centage change in PASI was −4.1% (95% CI, −14.5% to ment of response and 2.3 (95% CI, 1.6-3.4) in the inves- 6.3%).

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 Favors Control Favors Combination Favors Control Favors Combination Treatment Treatment Treatment Treatment CPT + UV-B vs CPT CPT + UV-B vs CPT

Molin et al,9 1993 n = 101/101 8 wk Kragballe,8 1990 n = 20/20 8 wk Molin et al,9 1993 n = 101/101 CPT + UV-B (3×/wk) vs Placebo + UV-B (3×/wk) Pooled (Fixed) 1.1 (0.96-1.23); P = .19 χ2 = 0.01 (P >.05) Molin,12 1997 n = 77/77 8 wk CPT + UV-B (3×/wk) vs Placebo + UV-B (3×/wk) CPT + UV-B (2×/wk) vs Placebo + UV-B (3×/wk) Molin,12 1997 n = 77/77 8 wk Ramsay,13 1998 n = 84/80 6 wk × × Ramsay,13 1998 n = 84/80 7 wk CPT + UV-B (2 /wk) vs Placebo + UV-B (3 /wk)

13 Ramsay, 1998 n = 84/80 8 wk Ramsay,13 1998 n = 84/80 6 wk Ramsay,13 1998 n = 84/80 10 wk Ramsay,13 1998 n = 84/80 7 wk Ramsay,13 1998 n = 84/80 12 wk Ramsay,13 1998 n = 84/80 8 wk CPT + PUVA vs Placebo + PUVA

Frappaz and Thivolet,14 1993 n = 54/53 6 wk Ramsay,13 1998 n = 84/80 10 wk

14 Frappaz and Thivolet, 1993 n = 54/53 8 wk Ramsay,13 1998 n = 84/80 12 wk Frappaz and Thivolet,14 1993 n = 54/53 10 wk CPT + Acitretin vs Placebo + Acitretin Frappaz and Thivolet,14 1993 n = 54/53 12 wk van de Kerkhof et al,17 1998 n = 76/59 6 wk CPT + Acitretin vs Placebo + Acitretin

van de Kerkhof et al,17 1998 n = 76/59 6 wk van de Kerkhof et al,17 1998 n = 76/59 8 wk

van de Kerkhof et al,17 1998 n = 76/59 8 wk van de Kerkhof et al,17 1998 n = 76/59 10 wk van de Kerkhof et al,17 1998 n = 76/59 10 wk van de Kerkhof et al,17 1998 n = 76/59 12 wk van de Kerkhof et al,17 1998 n = 76/59 12 wk CPT + Cyclosporine vs Placebo + Cyclosporine CPT + Cyclosporine vs Placebo + Cyclosporine

Grossman et al,18 1994 n = 35/34 6 wk Grossman et al,18 1994 n = 35/34 6 wk 0.1 110 0.1 110 Rate Ratio (Log Scale) Rate Ratio (Log Scale)

Figure 1. Mean rate ratios for marked improvement or clearance between Figure 2. Mean rate ratios for marked improvement or clearance between treatment groups by patient overall assessment. Includes the trial, number of treatment groups by investigator overall assessment. Includes the trial, patients receiving combination/control treatment, and treatment duration. number of patients receiving combination/control treatment, and treatment CPT indicates calcipotriene; PUVA, psoralen–UV-A. Error bars represent 95% duration. CPT indicates calcipotriene; PUVA, psoralen–UV-A. Bars represent confidence intervals. 95% confidence intervals.

Calcipotriene and Psoralen–UV-A Therapy RRs for clearance at 12 weeks in patient and investigator overall assessments were equal at 7.0 (95% CI, 0.9-53.6). Three trials14-16 compared calcipotriene and psoralen–UV-A (PUVA) with placebo ointment and PUVA in 140 patients. Calcipotriene and Cyclosporine There was no significant difference in the proportion of patients reporting marked improvement or clearance in the One trial18 compared calcipotriene and cyclosporine with patient assessment; the RR at 12 weeks was 1.2 (95% CI, placebo ointment and cyclosporine in 69 patients. The cal- 0.9-1.6). The corresponding RR for clearance was 2.1 (95% cipotriene and cyclosporine combination was signifi- CI, 1.0-4.2). In contrast, the PASI results show an improved cantly more effective than placebo and cyclosporine on the response to PUVA with calcipotriene. At the end of treat- basis of the proportion of patients cleared and the per- ment (12 weeks), the mean difference in the percentage centage change in PASI. At the end of treatment (6 weeks), change in PASI was 15.7% (95% CI, 3.6%-27.8%). the RRs for clearance in patient and investigator overall assessments were 3.2 (95% CI, 1.1-8.7) and 3.9 (95% CI, Calcipotriene and Acitretin 1.2 -12.6), respectively, and the mean difference in the percentage change in PASI was 22.1% (95% CI, 7.4%-36.8%). 17 One trial of 135 patients compared calcipotriene and ac- There were no significant differences in the proportion of itretin with placebo ointment and acitretin. On the basis patients with marked improvement or clearance; the RRs of the proportion of patients showing at least marked im- were 1.2 (95% CI, 0.8-1.6) and 1.4 (95% CI, 1.0-1.9) in provement and the percentage change in PASI, calcipo- patient and investigator assessments, respectively. triene had a significant additional effect to acitretin at ev- ery assessment point during treatment. At the end of WITHDRAWAL FROM TREATMENT treatment (12 weeks), the RRs for marked improvement or clearance were 1.4 (95% CI, 1.0-1.9) in the patient as- Table 2 summarizes the data for withdrawal from treat- sessment and 1.6 (95% CI, 1.2-2.3) in the investigator as- ment for any reason and as a result of adverse effects. All sessment. The mean difference in the percentage change the pooled RRs for withdrawal from treatment have 95% in PASI was 23.3% (95% CI, 9.8%-36.8%). In contrast, the CIs that span unity, indicating that we have no conclu-

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Molin et al,9 1993 n = 101/101 8 wk Kragballe,8 1990 n = 20/20 8 wk Molin et al,9 1993 n = 101/101 CPT + UV-B (3×/wk) vs Placebo + UV-B (3×/wk) Pooled (Fixed) 2.3 (1.6-3.4); P < .001 χ2 = 0.0004 (P >.05) Molin,12 1997 n = 77/77 8 wk CPT + UV-B (3×/wk) vs Placebo + UV-B (3×/wk) CPT + UV-B (2×/wk) vs Placebo + UV-B (3×/wk)

12 Ramsay,13 1998 n = 84/80 6 wk Molin, 1997 n = 77/77 8 wk × × Ramsay,13 1998 n = 84/80 7 wk CPT + UV-B (2 /wk) vs Placebo + UV-B (3 /wk)

Ramsay,13 1998 n = 84/80 8 wk Ramsay,13 1998 n = 84/80 6 wk

Ramsay,13 1998 n = 84/80 10 wk Ramsay,13 1998 n = 84/80 7 wk

Ramsay,13 1998 n = 84/80 12 wk Ramsay,13 1998 n = 84/80 8 wk CPT + PUVA vs Placebo + PUVA Ramsay,13 1998 n = 84/80 10 wk Frappaz and Thivolet,14 1993 n = 54/53 6 wk Ramsay,13 1998 n = 84/80 12 wk Frappaz and Thivolet,14 1993 n = 54/53 8 wk CPT + PUVA vs Placebo + PUVA Frappaz and Thivolet,14 1993 n = 54/53 10 wk Speight and Farr,15 1994 n = 13/13 6 wk Frappaz and Thivolet,14 1993 n = 54/53 12 wk CPT + Acitretin vs Placebo + Acitretin CPT + Acitretin vs Placebo + Acitretin van de Kerkhof et al,17 1998 n = 76/59 6 wk van de Kerkhof et al,17 1998 n = 76/59 6 wk van de Kerkhof et al,17 1998 n = 76/59 8 wk van de Kerkhof et al,17 1998 n = 76/59 8 wk 17 van de Kerkhof et al,17 1998 n = 76/59 10 wk van de Kerkhof et al, 1998 n = 76/59 10 wk

van de Kerkhof et al,17 1998 n = 76/59 12 wk van de Kerkhof et al,17 1998 n = 76/59 12 wk

CPT + Cyclosporine vs Placebo + Cyclosporine CPT + Cyclosporine vs Placebo + Cyclosporine

Grossman et al,18 1994 n = 35/34 6 wk Grossman et al,18 1994 n = 35/34 6 wk 0.01 0.1 1 10 100 1000 0.01 0.1 1 10 100 1000 Rate Ratio (Log Scale) Rate Ratio (Log Scale)

Figure 3. Mean rate ratios for cleared psoriasis between treatment groups by Figure 4. Mean rate ratios for cleared psoriasis between treatment groups by investigator overall assessment. Includes the trial, number of patients patient overall assessment. Includes the trial, number of patients receiving receiving combination/control treatment, and treatment duration. CPT combination/control treatment, and treatment duration. CPT indicates indicates calcipotriene; PUVA, psoralen–UV-A. Error bars represent 95% calcipotriene; PUVA, psoralen–UV-A. Error bars represent 95% confidence confidence intervals. intervals.

sive evidence that patients were more likely to with- COMMENT draw from using the combined regimen than from using the control intervention. Comparing the withdrawal Overall, the addition of calcipotriene to several systemic rates due to adverse effects of treatment, we again found treatments (acitretin, cyclosporine, and PUVA) may pro- that the 95% CIs for the RRs crossed unity, indicating duce a small additive therapeutic effect in severe psoriasis that patients were no more likely to withdraw from us- without an increase in the incidence of short-term ad- ing the combined regimen than from using the control verse effects. However, the results of patient assessment sug- intervention. Despite this, indirect comparisons suggest gest that the magnitude of the effect observed is neither sta- that use of acitretin is most likely to cause withdrawal, tistically nor clinically meaningful. In other words, a whereas UV-B phototherapy is least likely. decrease in psoriasis severity, reflected in percentage change in PASI, may not be sufficient for the patient to classify the ADVERSE EFFECTS change as a categorical change, eg, from moderate to marked improvement in response RR as an outcome measure. Al- There were no significant differences in the proportion though the review does not exclude the possibility of small of patients experiencing adverse effects between the com- effects in favor of calcipotriene and UV-B combinations, bined regimens and their corresponding control inter- there is also insufficient evidence to support the claim that ventions (Table 2). In addition, the pooled RRs for cu- topical calcipotriene enhances the effect of UV-B. taneous and noncutaneous adverse effects all had 95% CIs that crossed unity, indicating that patients were no IMPLICATIONS OF RESULTS more likely to experience such effects from the addition of calcipotriene. However, results of the trials evaluated Theoretically, any treatment that improves the therapeu- suggest that acitretin was almost 3 times more likely to tic outcome (eg, time or likelihood of clearance) while mini- cause adverse effects during the randomized treatment mizing the risks of toxic effects would be advantageous. than PUVA therapy, which was associated with the low- Mostly on the basis of the results of single multicenter stud- est proportion of patients reporting adverse effects. ies, topical calcipotriene has not been shown to substan-

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/28/2021 tially enhance the effect of systemic therapy. There were Favors Control Favors Combination relatively few studies, and it is possible that we could have Treatment Treatment missed small additive effects of calcipotriene, but the mag- CPT + UV-B vs CPT nitude of the effect observed suggests that the response is Molin et al,9 1993 n = 78/78 6 wk not clinically relevant to the patient. A recent review19 con- Molin et al,9 1993 n = 57/57 8 wk cluded that calcipotriene and UV-B combinations were more Molin et al,9 1993 n = 93/93 EOT CPT + UV-B (3×/wk) vs Placebo + UV-B (3×/wk) effective than UV-B alone. This conclusion cannot be veri- Molin and the Calcipotriol- fied by our results. The former review included nonran- UVB Study Group,12 1997 n = 69/69 6 wk Molin and the Calcipotriol- domized studies, and the results of primary studies were UVB Study Group,12 1997 n = 58/57 8 wk reported only as significant or not significant, with no at- Molin and the Calcipotriol- UVB Study Group,12 1997 n = 74/74 EOT tempt made to measure effect sizes or to pool results. CPT + UV-B (2×/wk) vs Placebo + UV-B (3×/wk) There was no increase in the incidence of withdrawal Ramsay,13 1998 n = 75/70 6 wk rates or adverse effects from combined treatment. Given Ramsay,13 1998 n = 69/68 7 wk that the adverse effects associated with systemic therapies Ramsay,13 1998 n = 66/59 8 wk are mostly dose dependent, the short duration of these RCTs Ramsay,13 1998 n = 67/50 10 wk 13 is unlikely to detect the most critical adverse effects of treat- Ramsay, 1998 n = 55/39 12 wk Ramsay,13 1998 n = 79/77 EOT 13.1% (–4.9%-31.2%); P = .16 ment. Longer trials are needed to establish whether use of CPT + PUVA vs Placebo + PUVA χ2 = 11.85 (P <.001) topical calcipotriene improves the risk-benefit ratio by re- Frappaz and Thivolet,14 1993 n = 35/38 6 wk Aktas et al,16 1995 n = 10/10 ducing the long-term risks of toxic effects. Is there a dose- Pooled (Random) sparing effect? It seems that combination therapy can de- Frappaz and Thivolet,14 1993 n = 17/27 8 wk crease the cumulative exposure to systemic therapy. Results Frappaz and Thivolet,14 1993 n = 9/17 10 wk of recent studies13 suggest that use of calcipotriene can re- Frappaz and Thivolet,14 1993 n = 5/11 12 wk duce the number of UV-B exposures and the cumulative Frappaz and Thivolet,14 1993 n = 46/45 EOT energy density. Other studies have shown significant re- CPT + Acitretin vs Placebo + Acitretin van de Kerkhof et al,17 1998 n = 69/49 6 wk 14 ductions in the cumulative exposure to UV-A and acitre- van de Kerkhof et al,17 1998 n = 66/46 8 wk 17 tin. As yet, the clinical relevance of the amount of energy van de Kerkhof et al,17 1998 n = 61/41 10 wk density saved has not been determined; however, from a van de Kerkhof et al,17 1998 n = 56/40 12 wk theoretical point of view, less UV exposure is likely to cause van de Kerkhof et al,17 1998 n = 76/59 EOT fewer UV-related adverse effects. Likewise, lowering the daily CPT + Cyclosporine vs Placebo + Cyclosporine Grossman et al,18 1994 n = 20/27 6 wk dose of systemic drugs would be likely to result in a re- Grossman et al,18 1994 n = 32/34 EOT duction in their dose-dependent adverse effects. This could –20 –10 04010 20 30 also result in considerable savings in time and total costs. Mean Difference Does use of topical calcipotriene prolong the duration of remission? The studies were not numerous enough Figure 5. Mean differences in percentage change in Psoriasis Area and for this analysis; only 4 trials reported relapse rates dur- Severity Index from baseline between treatment groups. Includes the trial, number of patients receiving combination/control treatment, and treatment ing posttreatment follow-up. Each trial used different re- duration. CPT indicates calcipotriene; EOT, end of treatment; and PUVA, lapse criteria and varied lengths of posttreatment follow- psoralen–UV-A. Error bars represent 95% confidence intervals. up. Because psoriasis is a chronic disease for most patients, differences in remission time after treatment might be a more important measure of a treatment’s relative efficacy combined use of topical calcipotriene and UV-B photo- than differences in the clearing capacity. We20 already pro- therapy were excluded because they reported on non- posed that the time to relapse would be a useful outcome relevant outcomes for this study. A further 5 trials26-30 were measure, but the definition of relapse would need to be excluded because of lack of randomization. Similar quali- precisely defined and universally agreed on so that the re- tative results were obtained in these trials, which gave sults of different trials could be compared directly. us some confidence about the robustness of our conclu- Other topical agents besides calcipotriene have also sions. Moreover, not all the trials reported the out- been shown to be effective adjuvant therapies in severe comes of interest. Therefore, to obtain the pooled esti- psoriasis. In practice, coal tar and topical corticoste- mates, the trials included in the different analyses do not roids are routinely used with many systemic therapies.3 necessarily match. In particular, we were unable to ex- Traditionally, coal tar has been used in combination with tract data on withdrawal rates from 5 trials that con- UV-B phototherapy in the Goeckerman regimen. In re- ducted bilateral (right/left) comparisons. cent years, anthralin, tacalcitol, and tazarotene have been There is no accepted definition of what constitutes reported21-23 to improve the outcome of second-line treat- meaningful clinical improvement in psoriasis. The PASI ments, and their risk-benefit profile should be com- was selected as an outcome measure in this analysis for pared with that of calcipotriene. several reasons. First, it was the most commonly used outcome measure in the trials. Second, most trials collected LIMITATIONS OF STUDY data on a variety of outcomes, and as such there is the potential for bias due to the selective publication of results Publication bias is a potential threat to the validity of any showing impressive treatment effects. Because we ob- systematic review. Although strenuous efforts were made tained PASIs for all but 2 of the included trials, the like- to locate all RCTs, many of our conclusions were drawn lihood of bias due to selective publication of outcomes is from single studies. Two recent trials24,25 addressing the minimal. However, we acknowledge that the PASI has sev-

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Withdrawal Adverse Effects

Total Adverse Effects Total Cutaneous Noncutaneous Calcipotriene + UV-B Phototherapy vs Calcipotriene Crude rate NR NR 2/20 vs 2/20 20/121 vs 20/121 0/20 vs 0/20 Weighted RR NR NR 1 (0.16-6.42) 1 (0.57-1.76) 1 (0.02-48.09) Weighted RD NR NR 0 (−0.19 to 0.19) 0 (−0.09 to 0.09) 0 (−0.09 to 0.09) (Calcipotriene + UV-B (3؋/wk) vs Placebo + UV-B (3؋/wk Crude rate 0/10 vs 0/10 NR NR NR NR RR 1 (0.02-46.06) NR NR NR NR RD 0 (−0.17 to 0.17) NR NR NR NR (Calcipotriene + UV-B (2؋/wk) vs Placebo + UV-B (3؋/wk Crude rate 14/84 vs 15/80 1/84 vs 4/80 46/84 vs 53/80 NR NR RR 0.89 (0.46-1.72) 0.24 (0.03-2.08) 0.83 (0.64-1.06) NR NR RD −0.02 (−0.14 to 0.10) −0.04 (−0.09 to 0.01) −0.11 (−0.26 to 0.03) NR NR Calcipotriene + PUVA vs Placebo + PUVA Crude rate 12/77 vs 15/76 1/77 vs 4/76 19/64 vs 19/63 NR 5/64 vs 0/63 Weighted RR 0.79 (0.41-1.54) 0.42 (0.08-2.29) 0.98 (0.59-1.63) NR 4.59 (0.46-45.63) Weighted RD −0.03 (−0.14 to 0.08) −0.04 (−0.10 to 0.03) 0 (−0.13 to 0.12) NR 0.07 (−0.001 to 0.15) Calcipotriene + Acitretin vs Placebo + Acitretin Crude rate 16/76 vs 21/59 9/76 vs 13/59 74/76 vs 56/59 62/76 vs 45/59 NR RR 0.59 (0.34-1.03) 0.54 (0.25-1.17) 1.03 (0.96-1.10) 1.07 (0.90-1.28) NR RD −0.15 (−0.30 to 0.01) −0.10 (−0.23 to 0.03) 0.02 (−0.04 to 0.09) 0.05 (−0.09 to 0.19) NR Calcipotriene + Cyclosporine vs Placebo + Cyclosporine Crude rate NR 1/35 vs 2/34 18/35 vs 19/34 13/35 vs 9/34 17/35 vs 16/34 RR NR 0.49 (0.05-5.11) 0.92 (0.59-1.43) 1.40 (0.69-2.85) 1.03 (0.63-1.69) RD NR −0.03 (−0.13 to 0.07) −0.04 (−0.28 to 0.19) 0.11 (−0.11 to 0.32) 0.02 (−0.22 to 0.25)

*NR indicates not reported; RR, rate ratio; RD, rate (risk) difference; and PUVA, psoralen–UV-A.

eral major problems and recognize that the results must Based Pharmacotherapy, School of Life and Health Sci- be interpreted with caution.20 ences, Aston University, Birmingham (Prof Li Wan Po); the Department of Dermatology, Queen’s Medical Centre, CONCLUSIONS Nottingham (Prof Williams); and the Dermatology Cen- tre, University of Manchester, Hope Hospital, Salford (Prof Evidence for some superiority of combination treat- Griffiths), England. Dr Ashcroft has received funding from ment over systemic treatment alone was obtained. The E. Merck Pharmaceuticals, which initially marketed tacal- acitretin, cyclosporine, and PUVA treatment combina- citol in the United Kingdom. Prof Li Wan Po has received tions showed statistical significance in the difference in funding for studentships from E. Merck Pharmaceuticals and PASI from baseline. However, this is not translated into Leo Pharmaceuticals, manufacturers of calcipotriene. Prof an increase in the number of patients who achieve marked Griffith’s institution has been the beneficiary of research improvement or clearance. It has been suggested that topi- grants from Leo Pharmaceuticals and E. Merck Pharma- cal administration of calcipotriene enhances the effect of ceuticals. UV-B phototherapy.19 In studies that met our inclusion This study was supported by a research grant from Boots criteria, a beneficial effect greater than that of UV-B ir- Healthcare International, Nottingham, England (Dr radiation alone was not detected. Ashcroft). In practice, cumulative exposure to systemic agents The views expressed in this article are the personal views is substantial, increasing the lifetime risk of serious toxic of the authors. effects. There is some evidence that topical calcipotri- Reprints: Darren M. Ashcroft, PhD, Department of ene therapy can reduce cumulative exposure to sys- Medicines Management, Keele University, Keele, Stafford- temic treatments and thereby potentially lower the risks shire, ST5 5BG, England (e-mail: [email protected]). of toxic effects. The combination treatments did not result in aggravation or increased frequencies of short- REFERENCES term adverse effects. However, much longer clinical trials are warranted to identify the long-term efficacy and safety profile of the various combination therapies. 1. Liem W, McCullough JL, Weinstein GD. Is topical therapy effective for psoriasis? results of a survey of U.S. dermatologists [abstract]. J Invest Dermatol. 1992; 98:602. Accepted for publication June 15, 2000. 2. Ashcroft DM, Li Wan Po A, Williams HC, Griffiths CEM. Systematic review of com- From the Department of Medicines Management, Keele parative efficacy and tolerability of calcipotriol in the treatment of chronic plaque University, Keele (Dr Ashcroft); the Centre for Evidence- psoriasis. BMJ. 2000;320:963-967.

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Editor’s Comment

or information on evaluating systematic reviews, please see: Oxman AD, Cook DJ, Guyatt GH, for the Evidence-Based Working Group. Us- F ers’ guides to the medical literature, VI: how to use an overview. JAMA. 1994;272:1367-1371; and Greenhalgh T. How to read a paper: papers that sum- marise other papers (systematic reviews and meta-analyses). BMJ. 1997;315: 672-675. Available at: http://www.bmj.com/cgi/content/full/315/7109/672. Ac- cessibility verified October 17, 2000. Michael Bigby, MD Boston, Mass

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