JEADV ISSN 1468-3083

Blackwell Publishing Ltd

ORIGINAL ARTICLE

Cyclosporin in the treatment of patients with atopic eczema a systematic review and meta-analysis
J Schmitt,* N Schmitt, M Meurer
Department of Dermatology, University Hospital Carl Gustav Carus, Technical University Dresden, Germany Department of Clinical Pharmacology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Germany

Keywords atopic dermatitis, cyclosporin, immunosuppression, meta-analysis, systemic treatment *Corresponding author, Department of Dermatology, University Hospital Carl Gustav Carus, Technical University Dresden, Fetscherstr. 74, D-01307 Dresden, Germany, tel. +049-351-4583860; fax +049-351-4585326; E-mail: jochen.schmitt@uniklinikum-dresden.de Received: 14 February 2006, accepted13 July 2006 DOI: 10.1111/j.1468-3083.2006.02023.x

Abstract
Objective To systematically assess the effectiveness of systemic cyclosporin in patients with severe atopic eczema. Study design Systematic review and meta-analysis of controlled and uncontrolled trials. Electronic (MEDLINE, Cochrane databases) and hand search of published work. Independent standardized assessment of eligibility and data abstraction by two reviewers. Methods For the qualitative review data on study design, study population, methodology, results, tolerability and methodological quality was independently extracted by two reviewers. Qualitatively homogeneous studies were pooled using a random-effects model. The mean relative change in objective disease severity was chosen as the main outcome measure for the quantitative analysis. Publication bias was explored by regressing treatment effect on sample size. Sensitivity analysis included meta-regression of study-specic covariates (inclusion of children, study type, concomitant topical therapy, study quality). Results Fifteen studies including 602 patients met the eligibility criteria. In all studies analysed, cyclosporin consistently decreased the severity of atopic eczema. Twelve studies appeared homogeneous enough to be pooled. After 2 weeks of treatment we found a dose-related response with a pooled mean decrease in disease severity of 22% (95%-CI 836%) under low-dose cyclosporin ( 3 mg/kg) and 40% (95%-CI 2951%) at dosages 4 mg/kg. After 68 weeks the relative effectiveness was 55% (95%-CI 4862%). Conclusions Due to evidence of publication bias the quantitative results need to be interpreted with caution. Effectiveness of cyclosporin is similar in adults and children, but tolerability might be better in children. As data to adequately evaluate the long-term effectiveness and safety of cyclosporin in patients with atopic eczema are unavailable, long-term registries are encouraged.

Introduction
Atopic eczema (AE) is a common inammatory skin disorder that affects up to 20% of children and up to 10% of adults in developed countries.14 Although most cases of AE are mild in terms of objective clinical activity, this condition adversely affects most aspects of everyday life in the majority of patients.57 AE imposes a high economic burden both in terms of total cost and out-of-pocket expenses.8,9 It is also
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the most common cause of occupational skin disease in adults.10 Most patients with AE can be treated effectively with emollients and topical anti-inammatory agents such as topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI).1,11 In a subgroup of patients, however, the activity of skin lesions and concurrent symptoms cannot be sufciently controlled with these conventional treatments.12

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Cyclosporin is a lipophilic cyclic polypeptide that effectively inhibits the transcription of interleukin 2 and several other cytokines. This leads to an inhibition of the activation of T cells, which play a key role in the pathogenesis of AE.1315 In several smaller randomized controlled trials (RCT) and uncontrolled studies cyclosporin has been used in children and adults with severe AE. Based on the results of the RCTs on adult patients cyclosporin has been approved for the short-term treatment of adults with severe AE in whom conventional therapy is ineffective or inappropriate. However, several aspects of cyclosporin treatment in patients with AE have not been systematically addressed yet, although they are critically relevant for clinical practice. We undertook a systematic review of all published studies on cyclosporin in severe AE to clarify the following research questions. (1) What is the quantitative effect of cyclosporin therapy on AE severity? (2) What is the doseresponse effect? (3) Is the effectiveness of cyclosporin similar in adults and children? (4) Is the safety of cyclosporin comparable in adults and children? (5) Are the results of RCTs and uncontrolled studies similar? (6) What is the role of concurrent topical anti-inammatory treatment?

Published work search and study selection

An electronic published work search was performed using MEDLINE, the Cochrane Skin Group specialized register and the Cochrane central register of controlled trials (each from its inception until August 2005). Articles in all languages were considered potentially eligible. For the condition of interest we used the keywords (atopic and (eczema OR dermatitis)) OR neurodermatitis, for the treatment (study OR trial OR comparison) and (treatment OR drug OR therapy) and (cyclosporin OR cyclosporin OR cyclosporine). We limited the published work search to papers on humans and excluded reviews. Twenty-six articles matched these criteria. One additional paper was found by hand-searching the reference lists of these 26 articles. Each of these 27 articles was reviewed for eligibility by two independent reviewers (JS, NS) using a standardized eligibility form. Disagreements were resolved by discussion. Exclusion criteria comprised no original data reported, studies not carried out in humans, in vitro studies, no clinical endpoint studied, case reports or case series on fewer than ve patients, and no full-text article (e.g. letter). Sixteen articles met the eligibility criteria, two of which reported on the same study, so that 15 studies were included in this systematic review (g. 1).

Data extraction and quality assessment

Fifteen articles were abstracted using standardized data abstraction and quality assessment forms designed for this systematic review. The abstraction forms were pilot-tested and modied on a limited sample of key articles. Relevant data of each study was independently extracted by two

Methods
We systematically reviewed all studies (with n > 4) evaluating the efcacy or the clinical effectiveness of cyclosporin in patients with AE.

g. 1 Articles evaluated for inclusion in the systematic review.

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reviewers (JS, NS). Disagreements were resolved by consensus. Recorded data included information on study characteristics (setting, study design), study population, details of cyclosporin treatment (duration, initial dosage, doseadjustment regimen), study endpoints, results, tolerability and quality assessment. In all studies (RCTs and uncontrolled studies), the study result was expressed as mean relative change in clinical severity since baseline. Exclusively, the active treatment groups of RCTs were considered n order to be able to compare results of RCTs and uncontrolled studies. In crossover RCTs, we only considered the study period prior to cross-over to avoid information bias due to carry-over effects.16,17 Additionally, data on comparative efcacy of cyclosporin (against placebo or active comparators) were abstracted from reports on RCTs. As surrogate variables for drug safety, frequencies of typical adverse events of cyclosporin (increase in serum creatinine, hypertension, infections, gastrointestinal symptoms, paraesthesia, headache) were abstracted from the articles included. To be comparable across studies, safety data are presented in events per month of cyclosporin treatment. Chronic events, such as hypertension, were only counted once. Additionally, the frequencies of withdrawals due to adverse events were abstracted. Study quality assessment was solely based on the methods and the results sections and included the following seven criteria: adequate case denition,1,18,19 denition of eligibility criteria,2 description of study population,3 randomization and blinding,4 use of validated outcomes,5 adequate followup rate,6 and conduct of intention-to-treat analysis.7 Overall study quality was rated good if at least six criteria were appropriately met, moderate if four or ve criteria were met, and otherwise poor. As quality assessment is subjective and because it is not easy to distinguish between study quality and reporting quality, we did not exclude studies we found to be of poor quality. The overall quality score was used in the sensitivity analysis to explore whether study results systematically differ by study quality. The abstracted information was entered directly into a Microsoft Excel (Microsoft Corp., Redmond, WA, USA) spreadsheet, and later imported to Stata statistical software 8.0 (StataCorp, College Station, TX, USA) for Windows (Microsoft).20

continuous cyclosporin treatment was dened the primary quantitative outcome. Only studies that used a composite score of clinical severity including both intensity and extent of AE were included in the quantitative analysis. If the mean relative change in clinical severity was not mentioned in the paper, we derived relative changes in severity from absolute severity scores (and corresponding standard deviations (SD) or standard errors (SE)) at baseline and follow-up. Articles from which relative changes in severity could not be extracted were excluded from the quantitative analysis. A random-effects model (DerSimonialLairad method) was used to pool the results of individual studies.21 To explore the research question whether a doseresponse relationship exists, a separate meta-analysis was performed for mean relative effectiveness after 2 weeks of cyclosporin treatment. For this analysis, studies were stratied by initial cyclosporin dose (up to 3 mg/kg bodyweight (BW) vs. more than 3 mg/kg (BW). Subpopulations from studies comparing higher and lower cyclosporin dosages were included in the corresponding strata. Publication bias was explored by regressing treatment effect on sample size.22 Sensitivity analysis was performed to evaluate the inuence of each individual study on the pooled estimate. As part of the sensitivity analysis highly inuential studies were excluded and the remaining studies examined separately. Heterogeneity was assessed using 2 tests (Qstatistic).21 Heterogeneity based on study-specic covariates (study type, inclusion of children, overall study quality, concomitant treatment, follow-up rate) was examined by meta-regression.21 Meta-analysis was performed using Stata statistical software 8.0 for Windows (Microsoft).20

Results
Qualitative analysis
Overall, 15 studies met all eligibility criteria, totalling 602 patients with AE.2337 (g. 1) Eight studies (57%) were RCTs, two of which were open-label studies on different cyclosporin dosing regimens,23,28 three of which were doubleblind parallel group RCTs,26,33,34 and three of which were double-blind cross-over RCTs.27,29,30 One study compared cyclosporin against topical tacrolimus 0.1%,34 three compared cyclosporin against placebo.27,30,33 Seven trials were uncontrolled open-label studies.24,25,31,32,3537 All 15 studies were performed in Europe. Sample size ranged from 10 to 106 patients with the majority (80%) of studies including less than 50 patients.23,25,27,2937 Three studies included only children, four studies both children and adults, and eight studies exclusively adults (Table 1).

Quantitative methods
Based on the results of the qualitative analysis we sought to compare qualitatively homogeneous studies quantitatively by means of formal meta-analysis. The relative change from mean clinical severity at baseline to mean clinical severity after 68 weeks of
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Table 1 Summary of Study Characteristics Number of participants n = 33 n = 24 n = 46 n = 78 n = 14 n = 43 n = 106 n = 30 n = 43 n = 27 n = 100 n = 23 n = 10 n = 10 n = 15 Age range of participants 1756 years 1948 years 1768 years 1870 years 2064 years 216 years 18 years or older 1345 years 1680 years 216 years 12 years or older 1370 years 1745 years 115 years 35.5 years (median) Inclusion criteria regarding severity of atopic eczema inadequately controlled by conventional therapies no denition of severity of AE resistant to conventional therapies resistant to conventional therapy and/or signicantly disabling no denition of severity of AE refractory to topical steroids refractory to conventional therapies and BSA 30% or more inadequately controlled by topical steroids no denition of severity of AE refractory to topical steroids disabling AE, inadequately controlled by topical steroids no denition of severity of AE resistant to conventional therapies SCORAD > 50 and oSCORAD > 40 and refractory to topical steroids resistant to conventional therapies

Reference Sowden et al. 199127 Munro et al. 199430 van Joost et al. 199433 Zonneveld et al. 199628 Zurbriggen et al. 199929 Harper et al. 200023 Czech et al. 200026 Pacor et al. 200434 Granlund et al. 199532 Berth-Jones et al. 199625 Berth-Jones et al. 199724 Atakan and Erdem 199837 Caproni et al. 200036 Bunikowski et al. 200131 Pacor et al. 200135

Country U.K. U.K. Netherlands Netherlands Switzerland U.K. Germany Italy Finland U.K. U.K. Turkey Italy Germany Italy

Study design double-blind crossover RCT* double-blind crossover RCT double-blind parallel group RCT open label RCT double-blind crossover RCT open label RCT double-blind parallel group RCT double-blind parallel group RCT open uncontrolled study open uncontrolled study open uncontrolled study open uncontrolled study open uncontrolled study open uncontrolled study open uncontrolled study

Comparators CyA vs. placebo CyA vs. placebo CyA vs. placebo two dosages of CyA two formulations of CyA (Neoral vs. Sandimmun) continuous vs. intermittent long-term treatment two dosages of CyA CyA vs. topical tacrolimus 0.1% Not applicable Not applicable Not applicable Not applicable Not applicable Not applicable Not applicable

*randomized controlled trial. atopic eczema. Scoring atopic dermatitis (SCORAD) Index.41 SCORAD Index excluding pruritus and sleep loss. body surface area.

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The duration of active treatment ranged between six weeks and 12 months. Inclusion criteria regarding severity of AE were relatively homogeneous across studies: ve studies included patients refractory to (or inadequately controlled by) topical steroids.2325,31,34 Six studies included patients refractory to (or inadequately controlled by) conventional therapies.2628,33,35,36 Four of these studies did not provide a precise denition of conventional therapy;2628,35 the other studies specically named TCSs,33 psoralen and ultraviolet A (PUVA) therapy33 or systemic steroids.33,36 Two studies dened objective, score-orientated eligibility criteria in addition to one of the criteria stated above.26,31 Four studies did not describe eligibility criteria regarding severity of AE29,30,32,37 (Tables 1, 2a and 2b). All studies except the one by Czech et al.26 used bodyweight-dependent dosing regimens of cyclosporin. Nine studies (60%) used higher initial cyclosporin dosages (45 mg/kg BW)23,25,27,29,30,32,33,35,36 four studies low initial cyclosporin dosages (2.53 mg/kg BW)24,31,34,37 and two studies compared higher and low cyclosporin dosages.26,28 This heterogeneity in cyclosporin dosage was particularly present at the beginning of the studies, as most protocols included individual adjustments to the minimum effective dose. Eleven study protocols allowed concomitant therapy with topical glucocorticosteroids,2332,37 two exclusively allowed antihistamines33,34 and two did not provide information on concomitant therapies35,36 (Tables 2a and 2b). As primary outcome measurement, all studies except the ones by Pacor et al.35 and Munro et al.30 applied composite scores including both intensity and extent of AE. Although different measurements of disease severity were used, we considered all studies using such a composite score homogeneous, because all scores are so-called investigator-assessed, objective measurements of disease severity, that measure the intensity of at least six typical morphological aspects of AE on four-point Likert scales at different anatomical regions of the integument and provide a summary score ranging roughly from 0 to 100 with higher scores indicating more severe disease27,3842 (Tables 2a and 2b). The relative effectiveness also appeared homogeneous across studies: All studies found a decrease in mean severity of AE after cyclosporin treatment. After 68 weeks of continuous treatment with cyclosporin most studies found a reduction in mean severity of AE by about 50% (range 2990%)2529,3134,36,37 (Tables 2a and 2b). In terms of comparative efcacy, cyclosporin was superior to placebo in all placebo-controlled RCTs27,30,33 (Table 2a). In the only study that compared cyclosporin against another active treatment, cyclosporin and topical tacrolimus 0.1% twice daily were equally efcacious.34 In the studies comparing different dosing regimens of cyclosporin, higher
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initial dosages consistently led to more rapid response after 2 weeks of treatment.26,28 Due to individual adjustments to the minimum effective dosage, the response did not differ signicantly by the initial cyclosporin dose at consecutive study visits (Table 2a). The study comparing two different formulations of cyclosporin observed a more rapid response (after 2 weeks) in the group treated with the microemulsion (Neoral) compared patients receiving the older formulation Sandimmun. After 8 weeks of treatment, the mean decrease was similar in both groups.29 Long-term effectiveness of cyclosporin treatment in patients with AE was evaluated in three of the included studies, each of which had a follow-up time of approximately 1 year.23,24,28 Mean relative improvement was about 50% in each study. However, with drop-out rates of 62%,24 35%28, respectively, 28%23 and failure to perform an intention-to-treat analysis, these results might be explained by emigrative selection bias.43 Only three studies focused on relapse rates after discontinuation of cyclosporin treatment.23,32,37 Relapse was consistently dened as increase in disease severity to more than 75% of the patients baseline score. Protocols allowed topical steroids after discontinuation of cyclosporin.23,32,37 About 50% of patients relapsed within 2 weeks, and about 80% within 6 weeks after discontinuation in the study by Granlund et al. [32]. Seventy-three per cent of the patients relapsed within 24 weeks in the study by Atakan and Erdem.37 Harper et al. reported 86% of patients relapsing within 9 months follow-up.23 Health-related quality of life (HRQL) was assessed in three studies included in this review.23,25,26 These studies consistently found signicant improvements in HRQL.23,25,26 Two studies applied the Dermatology Life Quality Index, respectively, the Childrens Dermatology Life Quality Index, both of which are frequently used HRQL assessments with adequate psychometric properties.23,26,4446 A non-validated HRQL assessment was used by the other investigators.25 Study quality assessment is summarized in Table 3. Two studies were judged to have good,29,33 ve moderate,25,27,31,34,36 and eight poor23,24,2830,32,35,37 overall study quality. With respect to internal validity a low follow-up rate (< 80%) combined with no intention-to-treat analysis appears particularly problematic. This combination was present in ve studies, most of which had long follow-up periods.23,24,27,28,30 Lack of clear case denition,2325,30 missing denition of inclusion criteria,29,30,32,34,37 or missing description of socio-demographic characteristics of the study population23,24,2831,3537 are other quality criteria that were not appropriately met by several studies.43 Information on adverse events and withdrawals of patients treated with cyclosporin are summarized in Table 4. To be comparable across studies, safety data is provided in events per patient month of cyclosporin treatment. An

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Table 2a Details of cyclosporin treatment and results of randomized controlled trials Treatment characteristics Duration of cyclosporin treatment 8 weeks Outcome measurement Results

Reference Sowden et al. 199127 Munro et al. 199430 van Joost et al. 199433 Zonneveld et al. 199628 Zurbriggen et al. 199929 Harper et al. 200023 Czech et al. 200026 Pacor et al. 200434

Initial dose 5 mg/kg BW

Allowed dose adjustment None

Concurrent treatment Topical steroids

Primary outcome Non-validated score

Components Erythema, purulence, excoriation, dryness, ssuring, lichenication, extent No composite score applied

Relative improvement compared to baseline 56% reduction in mean severity score

Comparative efcacy Mean severity score with CyA vs. placebo: 16.5 vs. 40.5; P < 0.01

8 weeks

5 mg/kg BW

None

Topical steroids Antihistamines

6 weeks

5 mg/kg BW

None

Extent, erythema, excoriation TBSA

About 90% reduction in mean extent 55% reduction in mean severity score After 2 weeks: 46% vs. 29% reduction in mean severity score in high- vs. low-dose group; P = 0.05 After 8 weeks: 70% reduction in mean severity score in both groups; P > 0.05 After 12 : weeks 50% reduction in mean SASSAD

Mean extent after CyA vs. placebo: 2% BSA vs. 14% BSA; P < 0.01 4% increase in mean severity score in placebo group; signicant superiority of CyA; P < 0.05 After 1 year: 70% vs. 60% of patients in high- vs. low-dose group rated overall efcacy as good or very good; P > 0.05 After 2 weeks: Signicant improvement in Neoral-treated group, but not in Sandimmun-treated group After 1 year: 42% vs. 56% mean SASSAD reduction after shourt couse vs. contiunous therapy; P > 0.05 After 8 weeks: 58% vs. 48% reduction in mean severity in high- vs. low-dose group; P > 0.05 89% reduction in mean SCORAD in tacrolimus group; no difference between groups; P > 0.05

1 years

3 mg/kg BW vs. 5 mg/kg BW 44.5 mg/kg BW

8 weeks

After 2 weeks adjustment of 1 mg/kg every other week None

Topical steroids, antibiotics, antihistamines Topical steroids

Non-validated score

Non-validated score

12 weeks short course vs. 1 years continuous 8 weeks

5 mg/kg BW

150 mg vs. 300 mg

After 4 weeks 25% dose reduction per month 50% dose reduction after 2 weeks None

Topical steroids

SASSAD*

Erythema, vesiculation, excoriation, dryness, inltration, ssures, extent Erythema, vesiculation, excoriation, dryness, ssuring, lichenication, extent Erythema, purulence, excoriation, dryness, ssuring, lichenication, extent Erythema, exudation, excoriation, dryness, lichenication, extent Erythema, inltration, vesiculation, excoriation, dryness, ssuration, extent Erythema, papulation, crusting, excoriation, lichenication, dryness, extent, pruritus, sleep loss

6 weeks

3 mg/kg BW

Topical steroids, antibiotics, antihistamines Antihistamines

TBSA

SCORAD

After 2 weeks: 45% vs. 33% reduction in mean severity in high- vs. low-dose group; P < 0.05 88% reduction in mean SCORAD

Cyclosporin for atopic eczema

*Six Area Six Sign Atopic Dermatitis (SASSAD) Score.42 6-Area, Total Body Severity Assessment (TBSA).33 bodyweight. Scoring atopic dermatitis (SCORAD) Index.41

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Table 2b Details of cyclosporin treatment and results of open-label uncontrolled studies Treatment characteristics Duration of cyclosporin treatment 6 weeks 6 weeks 48 weeks Outcome measurement Results Reference Granlund et al. 199532 Berth-Jones et al. 199625 Berth-Jones et al. 199724 Atakan and Erdem 199837 Caproni et al. 200036 Bunikowski et al. 200131 Pacor et al. 200135 Initial dose 5 mg/kg BW 5 mg/kg BW 2.5 mg/kg BW Allowed dose adjustment None None After 8 weeks adjustments to minimum effective levels Stepwise dose increase up to 5 mg/kg None After 2 weeks, 1 mg/kg change every other week Not reported Concurrent treatment 1% hydrocortisone ointment Topical steroids, antihistamines Topical steroids, antihistamines Topical steroids Not reported Topical steroids Not reported Primary outcome non-validated score SASSAD SASSAD Components Erythema, purulence, excoriation, dryness, ssuring, lichenication, extent Erythema, exudation, excoriation, dryness, lichenication, extent Erythema, exudation, excoriation, dryness, lichenication, extent Erythema, papulation, crusting, excoriation, lichenication, dryness extent, pruritus, sleep loss Erythema, papulation, excoriation, lichenication, dryness, extent, pruritus, sleep loss Erythema, papulation, crusting, excoriation, lichenication, dryness extent, pruritus, sleep loss No composite score applied Relative improvement compared to baseline 53% reduction in mean severity score 57% reduction in mean SASSAD 39% reduction in mean SASSAD 90% reduction in mean SCORAD 54% reduction in mean Costas Index 58% reduction in mean SCORAD About 90% reduction in mean extent score
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10 weeks 6 weeks 8 weeks 8 weeks

3 mg/kg BW 5 mg/kg BW 2.5 mg/kg BW 5 mg/kg BW

SCORAD Costas Index SCORAD Extent on 4-point Likert scale (assessed by patient)

*Six Area Six Sign Atopic Dermatitis (SASSAD) Score.42 bodyweight. Scoring atopic dermatitis (SCORAD) Index.41 Costas index of severity of atopic dermatitis.40

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Table 3 Summary of quality criteria and rating of overall study quality Clearly dened eligibility criteria Yes No Yes Yes No Yes Yes No No Yes Yes No Yes Yes Yes Adequate description of study population Yes No Yes No No No Yes Yes Yes Yes No No No No No

Reference Sowden et al. 199127 Munro et al. 199430 van Joost et al. 199433 Zonneveld et al. 199628 Zurbriggen et al. 199929 Harper et al. 200023 Czech et al. 200026 Pacor et al. 200434 Granlund et al. 199532 Berth-Jones et al. 199625 Berth-Jones et al. 199724 Atakan & Erdem 1998,37 Caproni et al. 200036 Bunikowski et al. 200131 Pacor et al. 200135

Clear case deniton18,19 Yes No Yes Yes Yes No Yes Yes Yes No No Yes Yes Yes Yes

Double blind treatment Yes Yes Yes No Yes No Yes Yes No No No No No No No

Validated outcome No No Yes No No Yes Yes Yes No Yes Yes Yes Yes Yes No

Follow-up rate > 80% No No No No Yes No Yes Yes Yes Yes No Yes Yes Yes Yes

Intention-to treat analysis No No Yes No No No Yes No No No No No No No No

Overall study quality* Moderate Poor Good Poor Poor Poor Good Moderate Poor Moderate Poor Poor Moderate Moderate Poor

*Good: 67 quality criteria were appropriately met. Moderate: 45 quality criteria were appropriately met. Poor: 03 quality criteria were appropriately met.

increase in creatinine by more than 30% compared to baseline was found in up to 10.9% of patient months of active treatment with cyclosporin.32 Newly diagnosed hypertension was observed in up to 5.8%, infections in up to 12.4% and gastrointestinal symptoms in up to 40.3% of patient months.32,33 Other frequently observed adverse events included headache and paraesthesia. Withdrawals due to adverse events occurred in up to 4.6% of patient months.32 Adverse events and withdrawals due to adverse events were observed more frequently in adults than in children und were also more likely in patients treated with higher cyclosporin dosages (Table 4).

Quantitative analysis
Based on the results of the qualitative analysis, the studies by Munro et al.30 and by Pacor et al.35 were excluded as they did not apply a composite score including extent and intensity of AE as an outcome. Zonnenveld et al.28 did not report a measure of spread (SE, SD) of disease severity, so that the minimum requirements for inclusion in the meta-analysis were not met. The remaining 12 studies were judged homogeneous enough to be pooled in a formal meta-analysis. Figure 2 shows the mean relative change in disease severity and the corresponding 95% condence intervals (95%-CI) after 2 weeks of treatment stratied by cyclosporin

dosage. The pooled mean (95%-CI) benet was 40% (2951%) in studies with higher initial dosages (45 mg /kg bodyweight (BW)) compared to 20% (836%) in studies with initial cyclosporin dosages of 2.53 mg/kg (BW). The pooled statistical estimate of the relative change in severity of AE after 68 weeks of cyclosporin treatment was 60% (95%-CI 4675%). However, critical heterogeneity was detected (Q-statistic = 415.49; degrees of freedom (d.f.) = 13; P < 0.001). Sensitivity analysis identied the study by Pacor et al. (2004) as the major source of this heterogeneity.34 In this study, the SE of the mean change in severity at week 6 was about 10 times smaller than the spread of the data in all other studies. (Data not shown, but available from the Correspondence on request.) Therefore, despite the small case number this study had very much weight in the quantitative analysis and was excluded from the consecutive analysis.47 As apart from chance also a typing error might explain the small spread of the presented data, we asked the Correspondence34 to conrm the correctness of the data, but she did not reply. Figure 3 shows the pooled statistical estimate of the relative change in mean severity of AE after 68 weeks of cyclosporin therapy. The mean benet was 55% (95%-CI 4862%). The Q-statistic for heterogeneity was 23.62 (d.f. = 12; P = 0.01). The xed and random-effect models yielded virtually identical results. As graphically displayed in (g. 4) publication bias with selective publication of small studies with high response
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Table 4 Adverse events and withdrawals due to adverse events in patients treated with cyclosporin for atopic eczema Creatinine increase (n/percent per month of treatment) 0 2/4.2% not reported low-dose: 6/0.9% high-dose: 2/0.4% not reported not reported low-dose: 2/1.9% high-dose: 4/3.8% Withdrawls due to adverse event (n/percent per month of treatment) 0 1/2.1% 1/2.9% low-dose: 4/0.9% high-dose: 4/0.9% 0 0 low-dose: 0 high-dose: 3/2.8%

Reference Sowden et al. 199127 Munro et al. 199430 van Joost et al. 199433 Zonneveld et al. 199628 Zurbriggen et al. 199929 Harper et al. 200023 Czech et al. 200026

Age range of study population 1756 years 19 48 years 1768 years 1870 years 20 64 years 216 years 18 years or older

Initial dose (mg/kg BW) 5 5 5 3 resp. 5 44.5 5 xed dosages: 150 mg vs. 300 mg 3 5 5 2.5 3.0 5 2.5 5

Hypertention (n/percent per month of treatment) 0 0 2/5.8% low-dose: 4/0.9% high-dose: 7/1.5% not reported not reported low-dose: 2/1.9%* high-dose: 1/0.9%* 0 1/1.6% 0 5/0.5% 0 not reported 0 0 high-dose: 1.2 low-dose: 0.6 children: 0.0 adults: 1.6

Infections (n/percent per month of treatment) 3/4.5% 5/10.4% not reported not reported not reported 1/0.4% not reported

Gastrointestinal symptom (n/percent per month of treatment) 15/22.7% 1/2.1% not reported not reported not reported 7/2.8% low-dose: 6/5.6% high-dose: 8/7.4%

Paraesthesia (n/percent per month of treatment) 8/12.1% 7/14.6% not reported not reported not reported 3/1.2% not reported

Headache (n/percent per month of treatment) 3/4.5% 0 not reported not reported not reported 2/0.8% not reported

Pacor et al. 200434 Granlund et al. 199532 Berth-Jones et al. 199625 Berth-Jones et al. 199724 Atakam & Erdem 199837 Caproni et al. 200036 Bunikowski et al. 200131 Pacor et al. 200135 TOTAL (percent per month treatment)

13 45 years 16 80 years 216 years 12 years or older 1370 years 1745 years 115 years 35.5 years (median)

0 7/10.9% 0 45/4.1% 0 not reported 1/5.0% 0 high-dose: 2.8 low-dose: 2.0 children***: 2.5 adults: 3.2

0 8/12.4% 3/7.4% 48/4.4% 2/1.1% not reported not reported 0 high-dose: 5.9 low-dose: 1.8 children: 3.9 children: 9.1

1/4.4% 26/40.3% 13/32.2% 66/6.0% 4/2.3% not reported not reported 0 high-dose: 15.4 low-dose: 4.6 children: 17.5 adults: 18.1

0 16/24.8% 2/4.9% 16/1.5% 1/0.6% not reported not reported 0 high-dose: 9.6 low-dose: 0.7 children: 3.1 adults: 12.9

3/13.3% 8/12.4% 7/17.3% 26/2.4% 1/0.6% not reported not reported 0 high-dose: 7.0 low-dose: 5.4 adults: 9.1 adults: 5.8

0 3/4.6% 1/2.5% 14/1.3% 0 not reported 0 0 high-dose: 1.5 low-dose: 0.4 children: 0.8 adults: 1.6

*adverse events regarding cardiovascular system. xed dose 300 mg, respectively, 150 mg, equaling 2.55.5 mg/kg body weight (BW), respectively, 1.32.8 mg/kg BW. e.g. nausea, vomiting, abdominal pain, diarrhea. increase in creatinine by more than 30% compared to baseline. **randomized controlled trial. bodyweight. sustained rise in blood pressure above normal range. initial dose more than 3 mg/kg BW. initial dose up to 3 mg/kg BW. ***in studies exclusively including patients up to age 16 years. in studies exclusively including patients age 16 years or older.

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g. 2 Relative change in mean disease severity after two weeks of treatment with Cyclosporine (Mean and 95%-CI) stratied by initial Cyclosporine dosage.

rates appears to be present (P = 0.013).22 The results should therefore be interpreted with caution. By means of meta-regression, we did not detect any signicant inuence of study type (RCTs vs. uncontrolled studies) (P = 0.63), inclusion of children (P = 0.91), overall study quality (P = 0.76) or concomitant topical treatment with glucocorticosteroids (P = 0.82).

Discussion
We found consistent evidence that short-term use of cyclosporin effectively decreases the severity of AE in

patients who in the course of their disease could not be adequately controlled with conventional topical therapies.2337 As only small RCTs and uncontrolled studies have been performed on cyclosporin in AE this rst systematic review including more than 600 patients is essential from an evidence-based medicine perspective. With regard to the research questions outlined above, we conclude that the mean clinical improvement in disease severity after 68 weeks of cyclosporin treatment is about 55%. Because of evidence of publication bias the true benet might be somewhat lower. However, when interpreting our results it is important to consider that
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g. 3 Meta-Analysis (Forest Plot) of mean relative change in severity of atopic eczema compared to baseline after 68 weeks of continuous treatment with Cyclosporine.

g. 4 Scatterplot of sample size and mean relative improvement in disease severity after 68 weeks of continuous treatment with Cyclosporine.

most of these patients were not adequately controllable with standard topical treatments. Higher initial dosages (45 mg/kg) led to a more rapid response. After 2 weeks, the mean benet was about 40% at this dose. After treatment initiation at this dose, adjustments to the individual minimum effective levels are recommended according to the evidence available. Because of better pharmacokinetic properties the microemulsion formulation Neoral should be preferred. Our results appeared to be very robust and did not differ between RCTs and uncontrolled open-label studies. In our meta-analysis, concomitant treatment with topical steroids was not associated with increased effectiveness. However, it seems rational that the minimum effective dose of cyclosporin can be kept lower by concomitant
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topical anti-inammatory treatment. We are not aware of studies specically focusing on this assumption. The likelihood of adverse events like (reversible) increases in creatinine and/or blood pressure, gastrointestinal symptoms, infections, paraesthesia and headaches increased by cyclosporin dosage. Withdrawals from treatment due to adverse events were also more likely in patients treated with higher initial cyclosporin dosages (Table 4). Primarily because of small case numbers and short follow-up periods, the studies included in this review are inappropriate to assess adverse drug reactions (ADRs) with long latency or rare events. Additional problems derive from varying and non-standardized reporting of ADRs in clinical studies. Therefore, the presented data on safety should be interpreted with caution. Cyclosporin, especially after PUVA therapy, has been shown to increase the risk of squamous cell carcinoma in patients with psoriasis.48,49 We are not aware of reports on skin cancer in AE patients treated with cyclosporin. A recently published review did not nd an increased risk of lymphoma or internal malignancies in dermatological patients treated with cyclosporin. Nevertheless, lymphoma during long-term cyclosporin treatment in patients with AE, respectively, psoriasis has been observed sporadically.5055 Three patients developed lymphoproliferative disorders including CD30(+) lymphoma during long-term treatment (continuously over 2 3 years) with cyclosporin. Prior to cyclosporin, all of these patients had received other immunosuppressants including azathioprine, systemic steroids and oral photochemotherapy.5052 Lymphomatoid papulosis developed in one patient under long-term treatment with cyclosporin and resolved shortly after withdrawal.51 Coinciding lymphoma has also been reported in AE patients neither

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treated with cyclosporin nor with other immunosuppressive drugs.52 From the data available it cannot be concluded that cyclosporin is associated with an increased risk of lymphoproliferative disorders. However, from an evidencebased medicine perspective epidemiological studies or registries are needed to clarify this issue. Cyclosporin is licensed for the short-term treatment of adults with severe AE in whom conventional therapy is ineffective or inappropriate. The presented data suggest that the effectiveness of cyclosporin is similar in adults and children, whereas the tolerability might be better in children. However, due to uncertainty concerning rare ADRs with long latencies, close long-term monitoring is important in all patients treated with cyclosporin, particularly in children. From the patients perspective, HRQL is most important.7,56 Only three studies included in this review assessed HRQL. These studies consistently found parallel improvements in HRQL and clinical disease severity.23,25,26 To be more meaningful, future studies on cyclosporin and other treatments of AE should include patient-orientated outcomes in addition to validated objective measurements of disease severity and an adequate HRQL questionnaire. In a few studies, analysing the stability of treatment effect about 50% of patients relapsed within 2 weeks, and about 80% within 6 weeks after discontinuation of cyclosporin treatment despite maintenance treatment with TCS.32 Studies on the long-term effectiveness of cyclosporin in severe AE are encouraged as the available data is limited by questionable internal validity.23,24,28 To be more meaningful, such studies should have high follow-up rates and include all patients treated in the statistical analysis.42 Intermittent short-term treatment of cyclosporin, as evaluated by Harper et al.23 might be a promising treatment regimen with good benet-torisk ratio. Unfortunately, in this study the follow-up rate was not large enough to adequately evaluate this hypothesis.23 Although some questions cannot be completely answered with the data available, this systematic review will assist physicians treating patients with severe and refractory AE to make an informed and evidence-based decision about whether and how to apply cyclosporin. Additionally, patients compliance and treatment satisfaction might be increased if they are informed about what is likely to happen and what not.

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References
1 Williams HC. Clinical practice. Atopic dermatitis. N Engl J Med 2005; 352: 23142324. 2 Williams H, Robertson C, Stewart A et al. Worldwide variations in the prevalence of symptoms of atopic eczema

17

18

in the International Study of Asthma and Allergies in Childhood. J Allergy Clin Immunol 1999; 103: 125138. Rystedt I. Long-term follow-up in atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1985; 114: 117120. Lammintausta K, Kalimo K, Raitala R, Forsten Y. Prognosis of atopic dermatitis. A prospective study in early adulthood. Int J Dermatol 1991; 30: 563568. Emerson RM, Williams HC, Allen BR. Severity distribution of atopic dermatitis in the community and its relationship to secondary referral. Br J Dermatol 1998; 139: 7376. Chamlin SL, Frieden IJ, Williams ML, Chren MM. Effects of atopic dermatitis on young American children and their families. Pediatrics 2004; 114: 607611. Fivenson D, Arnold RJ, Kaniecki DJ et al. The effect of atopic dermatitis on total burden of illness and quality of life on adults and children in a large managed care organization. J Manag Care Pharm 2002; 8: 333342. Carroll CL, Balkrishnan R, Feldman SR, Fleischer AB Jr, Manuel JC. The burden of atopic dermatitis: impact on the patient, family, and society. Pediatr Dermatol 2005; 22: 192 199. Kemp AS. Cost of illness of atopic dermatitis in children: a societal perspective. Pharmacoeconomics 2003; 21: 105 113. Dickel H, Bruckner TM, Schmidt A, Diepgen TL. Impact of atopic skin diathesis on occupational skin disease incidence in a working population. J Invest Dermatol 2003; 121: 3740. Ellis C, Luger T, Abeck D, Allen R et al. International consensus conference on atopic dermatitis II (ICCAD II): clinical update and current treatment strategies. Br J Dermatol 2003; 148: 310. Hanin JM, Cooper KD, Ho VC et al. Guidelines of care for atopic dermatitis, developed in accordance with the American Academy of Dermatology (AAD)/American Academy of Dermatology Association administrative regulations for evidence-based clinical practice guidelines. J Am Acad Dermatol 2004; 50: 391404. Borel JF, Feurer C, Gubler HU, Stahelin H. Biological effects of cyclosporin A: a new antilymphocytic agent. Agents Actions 1976; 6: 468475. Faulds D, Goa KL, Beneld P. Cyclosporin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in immunoregulatory disorders. Drugs 1993; 45: 9531040. Liu J. FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. Immunol Today 1993; 14: 290295. Curtin F, Elbourne D, Altman DG. Meta-analysis combining parallel and cross-over clinical trials. III: the issue of carryover. Stat Med 2002; 21: 21612173. Elbourne DR, Altman DG, Higgins JP et al. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol 2002; 31: 140149. Hanin J, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 1980; 92: 4447.

2007 The Authors JEADV 2007, 21, 606 619 Journal compilation 2007 European Academy of Dermatology and Venereology

617

Cyclosporin for atopic eczema

Schmitt et al.

19 Williams HC, Burney PG, Pembroke AC, Hay RJ. Validation of the U.K. diagnostic criteria for atopic dermatitis in a population setting. U.K. Diagnostic Criteria for Atopic Dermatitis Working Party. Br J Dermatol 1996; 135: 1217. 20 Stata Corporation. Stata statistical software: release 8.0. Stata Corporation, College Station, TX, 2002. 21 Stata Corporation. Stata 8 reference manual. College Station, TX, USA 2003. 22 Macaskill P, Walter SD, Irwig L. A comparison of methods to detect publication bias in meta-analysis. Stat Med 2001; 20: 641654. 23 Harper JI, Ahmed I, Barclay G et al. Cyclosporin for severe childhood atopic dermatitis: short course versus continuous therapy. Br J Dermatol 2000; 142: 5258. 24 Berth-Jones J, Graham-Brown RA, Marks R et al. Long-term efcacy and safety of cyclosporin in severe adult atopic dermatitis. Br J Dermatol 1997; 136: 7681. 25 Berth-Jones J, Finlay AY, Zaki I et al. Cyclosporine in severe childhood atopic dermatitis: a multicenter study. J Am Acad Dermatol 1996; 34: 10161021. 26 Czech W, Brautigam M, Weidinger G, Schopf E. A bodyweight-independent dosing regimen of cyclosporine microemulsion is effective in severe atopic dermatitis and improves the quality of life. J Am Acad Dermatol 2000; 42: 653659. 27 Sowden JM, Berth-Jones J, Ross JS et al. Double-blind, controlled, cross-over study of cyclosporin in adults with severe refractory atopic dermatitis. Lancet 1991; 338: 137 140. 28 Zonneveld IM, de Rie MA, Beljaards RC et al. The long-term safety and efcacy of cyclosporin in severe refractory atopic dermatitis: a comparison of two dosage regimens. Br J Dermatol 1996; 135: 1520. 29 Zurbriggen B, Wuthrich B, Cachelin AB, Wili PB, Kagi MK. Comparison of two formulations of cyclosporin A in the treatment of severe atopic dermatitis. A double-blind, single-centre, cross-over pilot study. Dermatology 1999; 198: 5660. 30 Munro CS, Levell NJ, Shuster S, Friedmann PS. Maintenance treatment with cyclosporin in atopic eczema. Br J Dermatol 1994; 130: 376380. 31 Bunikowski R, Staab D, Kussebi F et al. Low-dose cyclosporin A microemulsion in children with severe atopic dermatitis: clinical and immunological effects. Pediatr Allergy Immunol 2001; 12: 216223. 32 Granlund H, Erkko P, Sinisalo M, Reitamo S. Cyclosporin in atopic dermatitis: time to relapse and effect of intermittent therapy. Br J Dermatol 1995; 132: 106112. 33 van Joost T, Heule F, Korstanje M et al. Cyclosporin in atopic dermatitis: a multicentre placebo-controlled study. Br J Dermatol 1994; 130: 634640. 34 Pacor ML, Di Lorenzo G, Martinelli N et al. Comparing tacrolimus ointment and oral cyclosporine in adult patients affected by atopic dermatitis: a randomized study. Clin Exp Allergy 2004; 34: 639645.

35 Pacor ML, Biasi D, Di Lorenzo G, Carletto A, Corrocher R. Cyclosporin in atopic dermatitis. Recenti Prog Med 2001; 92: 390391. 36 Caproni M, Salvatore E, Cardinali C, Brazzini B, Fabbri P. Soluble CD30 and cyclosporine in severe atopic dermatitis. Int Arch Allergy Immunol 2000; 121: 324328. 37 Atakan N, Erdem C. The efcacy, tolerability and safety of a new oral formulation of Sandimmun Sandimmun Neoral in severe refractory atopic dermatitis. J Eur Acad Dermatol Venereol 1998; 11: 240246. 38 Charman C, Williams H. Outcome measures of disease severity in atopic eczema. Arch Dermatol 2000; 136: 763 769. 39 Chren MM. Giving scale new meaning in dermatology: measurement matters. Arch Dermatol 2000; 136: 788 790. 40 Costa C, Rilliet A, Nicolet M, Saurat JH. Scoring atopic dermatitis: the simpler the better? Acta Derm Venereol 1989; 69: 4145. 41 Severity scoring of atopic dermatitis: the SCORAD index. Consensus report of the European task force on atopic dermatitis. Dermatology 1993; 186: 2331. 42 Berth-Jones J. Six-area, six-sign atopic dermatitis (SASSAD) severity score: a simple system for monitoring disease activity in atopic dermatitis. Br J Dermatol 1996; 135: 2530. 43 Szklo M, Nieto J. Epidemiology Beyond the Basics. Jones and Barlett Publishers, Sidbury, MA, 2005: 205208. 44 Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) a simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 19: 210216. 45 Lewis V, Finlay AY. 10 years experience of the dermatology life quality index (DLQI). J Invest Dermatol Symp Proc 2004; 9: 169180. 46 Lewis-Jones MS, Finlay AY. The childrens dermatology life quality index (CDLQI): initial validation and practical use. Br J Dermatol 1995; 132: 942949. 47 Greenland S. Quantitative methods in the review of epidemiologic literature. Epidemiol Rev 1987; 9: 130. 48 Marcil I, Stern RS. Squamous cell cancer of the skin in patients given PUVA and cyclosporin: nested cohort cross-over study. Lancet 2001; 358: 10421045. 49 Behnam SM, Behnam SE, Koo JY. Review of cyclosporine immunosuppressive safety data in dermatology patients after two decades of use. J Drugs Dermatol 2005; 4: 189194. 50 Kirby B, Owen CM, Blewitt RW, Yates VM. Cutaneous T-cell lymphoma developing in a patient on cyclosporin therapy. J Am Acad Dermatol 2002; 47: S165S167. 51 Fletcher CL, Orchard GE, Hubbard V et al. CD30(+) cutaneous lymphoma in association with atopic eczema. Arch Dermatol 2004; 140: 449454. 52 Laube S, Stephens M, Smith AG, Whittaker SJ, Tan BB. Lymphomatoid papulosis in a patient with atopic eczema on long-term cyclosporin therapy. Br J Dermatol 2005; 152: 13461348.

618

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Schmitt et al.

Cyclosporin for atopic eczema

53 Sinha A, Velangi S, Natarajan S. Non-Hodgkins lymphoma following treatment of atopic eczema with cyclosporin A. Acta Derm Venereol 2004; 84: 327328. 54 Koo JY, Kadonaga JN, Wintroub BV, Lozada-Nur FI. The development of B-cell lymphoma in a patient with psoriasis treated with cyclosporine. J Am Acad Dermatol 1992; 26: 836840.

55 Corazza M, Zampino MR, Montanari A, Altieri E, Virgili A. Primary cutaneous CD30+ large T-cell lymphoma in a patient with psoriasis treated with cyclosporine. Dermatology 2003; 206: 330333. 56 Finlay AY. Quality of life in atopic dermatitis. J Am Acad Dermatol 2001; 45: S64S66.

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