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

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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 im- provement 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 cu- mulative 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 assess- ments 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 sys- temic 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% confi- dence 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 ef- fects. 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 (REPRINTED) ARCH DERMATOL / VOL 136, DEC 2000 WWW.ARCHDERMATOL.COM 1536 ©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/30/2021 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 pub- lished 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 treat- ment 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 in- dicates that there was no significant difference in the rate Types of Interventions of the outcome between the treatment groups (P..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 232 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 x2 SEARCH STRATEGY tests, with P#.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 x2 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 P#.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 der- matologists 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
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