Efficacy and tolerability of topical pimecrolimus and tacrolimus in th
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《英国医生杂志》
1 School of Pharmacy and Pharmaceutical Sciences, University of Manchester, Manchester M13 9PL, 2 Peninsula Technology Assessment Group, Universities of Exeter and Plymouth, 3 Department of Dermatology, University of Nottingham
Correspondence to: D M Ashcroft darren.ashcroft@manchester.ac.uk
We included randomised controlled trials that compared topical pimecrolimus or topical tacrolimus at a licensed therapeutic dose with vehicle or another active treatment (for example, topical corticosteroids) in patients with atopic dermatitis, and that reported efficacy outcomes or adverse events.
Outcome measures
For efficacy, we used the investigators' rating of the global degree of improvement. The trials used different scales to rate the degree of improvement. For pimecrolimus, we used the proportion of patients who were rated by the investigator as clear or almost clear as the primary outcome measure, whereas for the tacrolimus trials the primary outcome was the proportion of patients who achieved at least 90% improvement from baseline (defined as clear or excellent improvement in the trials).
Secondary outcome measures included patients' global assessments of feeling better or much better, the proportions of patients with flares of atopic dermatitis, and improvements in quality of life. We assessed tolerability to the drug by considering overall rates of withdrawal, withdrawal due to adverse events, and the proportions of patients with burning of the skin and skin infections.
Search strategy
Randomised controlled trials fulfilling the eligibility criteria were suitable for inclusion in our review, regardless of language or publication status. We systematically searched Medline, Embase, the Cochrane Skin Group specialised register, and the Cochrane central register of controlled trials to December 2004 using the search terms "pimecrolimus", "Elidel", "SDZ ASM 981", "tacrolimus", "Protopic", and "FK506". We also searched the reference lists of all retrieved trials along with the websites for the European Agency for the Evaluation of Medicinal Products and the US Food and Drug Administration.
Trial eligibility was determined by two authors (DMA, PD), who also independently extracted the data, which was checked by RG. Trials were rated for methodological quality (in duplicate by DMA and PD) using the Jadad scale and scored out of a maximum of five.8
Data synthesis
Not all of the trials reported on all the outcomes of interest. For each comparison and outcome we undertook separate meta-analyses. We grouped the topical corticosteroids on the basis of their potencies: mild (aclometasone dipropionate 0.1%, hydrocortisone acetate 1%) and potent (betamethasone valerate 0.1%, hydrocortisone butyrate 0.1%, triamcinolone acetonide 0.1%). We also stratified the analysis of efficacy data by the duration of treatment.
We summarised dichotomous data as rate ratios (relative risks) and combined these by using a random effects model.9 Results are given with 95% confidence intervals. We also computed homogeneity statistics to test the agreement of the individual trial results with the combined meta-analytical summary.10 11 Analyses were carried out in RevMan version 4.2.6.
Results
Tacrolimus 0.1% is as effective as potent topical corticosteroids and more effective than mild topical corticosteroids, such as hydrocortisone acetate 1%, for treating atopic dermatitis. This means that topical tacrolimus may be useful for resistant atopic dermatitis at sensitive sites such as the face, where the use of more potent topical steroids carries a high risk of thinning of the skin and telangiectasia. Tacrolimus 0.1% may also be useful for patients who depend on the constant use of potent steroids, although it would be helpful to see trial evidence on how effective it is in such a subgroup of treatment "failures."
Pimecrolimus has been found to be less effective than betamethasone valerate 0.1%, a commonly used potent topical corticosteroid. The efficacy of pimecrolimus compared with less potent topical corticosteroids is not known. In practice, pimecrolimus is being aimed at patients with mild atopic dermatitis, yet this is being done in the absence of randomised controlled trials that compare it with existing therapy for such a group—that is, short bursts of 1% hydrocortisone to treat acute flares. Pimecrolimus prevented more flares than vehicle, but it remains to be seen whether the early use of mild topical steroids may be as effective. In the absence of such key comparisons, it is unclear as to what role, if any, pimecrolimus has for atopic dermatitis.
The main reason for developing new drugs as an alternative to topical steroids is to overcome possible side effects from steroids, such as thinning of the skin or adrenal gland suppression. We found no clear evidence that these newer, more expensive products offer such an advantage when compared with standard practice. Other studies have suggested that skin thinning is not a problem with these newer agents.37 38 One preliminary randomised controlled trial of pimecrolimus applied to normal skin for four weeks found no thinning of the skin.37 Such a study is, however, difficult to generalise to people with atopic dermatitis who apply preparations over the course of a year. A non-randomised prospective study of 119 participants that compared 0.1% topical tacrolimus with "conventional steroid based therapy" and normal controls found no evidence of decreased skin collagen synthesis or skin thinning in the tacrolimus group as measured by ultrasonography at one year.38 Skin collagen synthesis was also not decreased with conventional topical steroids, although a minor degree of skin thinning was found (mean decreased thickness of 8.2% compared with baseline); its clinical significance is difficult to interpret.
Strengths and limitations of the review
In contrast to an earlier review that identified 16 studies,39 we examined 25 clinical trials, using a wider range of clinically relevant outcome measures, and focused on direct comparisons with other active treatments, rather than making indirect inferences from placebo controlled trials.
One limitation of our systematic review is that our analyses of rates of withdrawals and adverse events were based on data pooled from trials of different durations. Some caution is therefore needed in their interpretation. Other potential sources of heterogeneity in the results are the patient population (infants, children, adults), the severity of the disease, and the choice of topical corticosteroid. The use of investigators' global assessments of response to treatment also causes some concern. Despite such assessments of response to treatment being widely used as outcome measures in clinical trials of atopic dermatitis, further research is needed to fully determine their validity, reliability, and sensitivity to change.40 41
Recommendations for future research to inform clinical practice
Our systematic review shows that there is little evidence to help deal with the clinically important questions of how pimecrolimus and tacrolimus compare for efficacy, side effects, tolerability, and cost with existing optimal treatments, such as short bursts of topical corticosteroids for flare-ups of disease followed by periods of rest using only emollients. Although some comparative data are available for tacrolimus to inform practice, the clinical role of pimecrolimus is uncertain owing to a lack of relevant comparative data. The lack of key comparative data highlights deficiencies in the current licensing systems for medicines in Europe and the United States, which require only evidence of efficacy and safety above placebo and vehicle, thus allowing more new drugs to reach the market. This leaves doctors, commissioners, and the public confused about how and when to use such new drugs in relation to standard practice.
Pragmatic randomised controlled trials lasting at least 12 months are needed to compare tacrolimus, pimecrolimus, and 1% hydrocortisone acetate in children and adults with mild to moderate atopic dermatitis. Outcome data should include clearing capacity, relapse, quality of life, adverse events (including skin thinning), and costs. In particular, it seems important to determine how well these agents work in people who fail to respond adequately to topical corticosteroids, given that they may be used as second line agents.42 Experience of long term use of topical pimecrolimus and tacrolimus is limited and the risk of rare but more serious adverse effects remains uncertain. Further long term surveillance of these agents is needed, given concerns about the theoretical risk of visceral and skin cancers from preclinical studies in animals.43
What is already known on this topic
Atopic dermatitis affects 15-20% of children in developed countries
Topical corticosteroids and emollients have been the mainstay of therapy
Topical pimecrolimus and tacrolimus have been developed as alternative treatments
What this study adds
Tacrolimus 0.1% is as effective as potent corticosteroids for treating atopic dermatitis and more effective than mild preparations such as hydrocortisone acetate 1%
Pimecrolimus is less effective than potent corticosteroids; it has not been compared with mild corticosteroids
Both agents caused more burning of the skin than topical corticosteroids, but no differences were observed in rates of skin infections
Contributors: All authors designed the review and revised the manuscript, which was drafted by DMA. DMA, PD, and RG decided on the inclusion of trials, extracted data, and assessed study quality. DMA and PD carried out the statistical analyses. All authors interpreted the findings. DMA is guarantor.
Funding: RG and KS were funded by the NHS health technology assessment programme.
Competing interests: None declared.
Ethical approval: Not required.
References
Williams H, Robertson C, Stewart A, Ait-Khaled N, Anabwani G, Anderson R, et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the international study of asthma and allergies in childhood. J Allergy Clin Immunol 1999;103: 125-38.
Lewis-Jones MS, Finlay AY, Dykes PJ. The infants' dermatitis quality of life index. Br J Dermatol 2001;144: 104-10.
Kiebert G, Sorensen SV, Revicki D, Fagan SC, Doyle JJ, Cohen J, et al. Atopic dermatitis is associated with a decrement in health-related quality of life. Int J Dermatol 2002;41: 151-8.
Herd RM. The morbidity and cost of atopic dermatitis. In: Williams HC, ed. Atopic dermatitis, Cambridge: Cambridge University Press, 2000.
Emerson RM, Williams HC, Allen BR. What is the cost of atopic dermatitis in preschool children? Br J Dermatol 2001;144: 514-22.
Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol 2000;142: 931-6.
Beattie PE, Lewis-Jones MS. Parental knowledge of topical therapies in the treatment of childhood atopic dermatitis. Clin Exp Dermatol 2003;28: 549-53.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17: 1-12.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: 177-88.
Deeks JJ, Altman D, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey Smith G, Altman DG, eds. Systematic reviews in health care. London: BMJ Publishing, 2001: 285-312.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: 557-60.
Eichenfield LF, Lucky AW, Boguniewicz M, Langley RGB, Cherill R, Marshall K, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002;46: 495-504.
Ho VC, Gupta A, Kaufmann R, Todd G, Vanaclocha F, Takaoka R, et al. Safety and efficacy of nonsteroid pimecrolimus cream 1% in the treatment of atopic dermatitis in infants. J Pediatr 2003;142: 155-62.
Kapp A, Papp K, Bingham A, Folster-Holst R, Ortonne J-P, Potter PC, et al. Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol 2002;110: 277-84.
Luger T, Van Leent EJM, Graeber M, Hedgecock S, Thurston M, Kandra A, et al. SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 2001;144: 788-94.
Meurer M, Folster-Holst R, Wozel G, Weidinger G, Junger M, Brautigam M. Pimecrolimus cream in the long-term management of atopic dermatitis in adults: a six-month study. Dermatology 2002;205: 271-7.
Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, et al. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 2002;110: e2.
Barba JF, Beirana A, Cohen V, Dominguez L, Duran C, Leon G, et al. Pimecrolimus cream 1% is effective, well tolerated and safe in infants and children with atopic eczema of the face. J Eur Acad Dermatol Venereol 2003;17: P2.35.
Ling M, Gottlieb AB, Abrams K. Pimecrolimus cream 1%; bid and qid application were equally effective and well tolerated. 11th congress of the European Academy of Dermatology and Venereology, Prague. J Eur Acad Dermatol Venereol 2002;16: P2-27.
Boguniewicz M, Fiedler VC, Raimer S, Lawrence ID, Leung DYM, Hanifin JM. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. J Allergy Clin Immunol 1998;102: 637-44.
Hanifin JM, Ling MR, Langley R, Breneman D, Rafal E. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy. J Am Acad Dermatol 2001;44: S28-38.
Paller A, Eichenfield LF, Leung DYM, Stewart D, Appell M. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001;44: S47-57.
Reitamo S, Rustin M, Ruzicka T, Cambazard F, Kalimo K, Friedmann PS, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J Allergy Clin Immunol 2002;109: 547-55.
Reitamo S, Van Leent EJM, Ho V, Harper J, Ruzicka T, Kalimo K, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol 2002;109: 539-46.
Ruzicka T, Bieber T, Schopf E, Rubins A, Dobozy A, Bos JD, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 1997;337: 816-21.
Reitamo S, Harper J, Bos JD, Cambazard F, Bruijnzeel-Koomen C, Valk P, et al. 0.03% tacrolimus ointment applied once or twice daily is more efficacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis: results of a randomized double-blind controlled trial. Br J Dermatol 2004;150: 554-62.
FK506 Ointment Study Group. Phase III comparative study of FK506 ointment vs betamethasone valerate ointment in atopic dermatitis (trunk/extremities) . Nishinihon J Dermatol 1997;59: 870-9.
Nakagawa H. Comparative study of FK506 (tacrolimus) ointment vs aclometasone dipropionate ointment in atopic dermatitis (face and neck lesions) ( 1266). J Invest Dermatol 1998;110: 683.
Kang S. Tacrolimus ointment for adults with moderate to severe atopic dermatitis: a dose escalation study ( 1253). J Invest Dermatol 1998;110: 681.
Hanifin JM. Use of tacrolimus ointment in 3-6 year-olds with atopic dermatitis: dose escalation study ( 1245). J Invest Dermatol 1998;110: 681.
Kempers S, Boguniewicz M, Carter E, Jarrat M, Pariser D, Stewart D, et al. Comparison of pimecrolimus cream 1% and tacrolimus ointment 0.03% in paediatric patients with atopic eczema. J Eur Acad Dermatol Venereol 2003;17: P2-41.
Reitamo S. 0.1% tacrolimus ointment is an effective treatment for adults with moderate or severe atopic dermatitis. J Eur Acad Dermatol Venereol 2003;17: P20-31.
Luger TA, Lahfa M, Folster-Holst R, Gulliver WP, Allen R, Molloy S, et al. Long-term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids in adults with moderate to severe atopic dermatitis. J Dermatol Treat 2004;15: 169-78.
Pacor ML, Di Lorenzo G, Martinelli N, Mansueto P, Rini GB, Corrocher R. Comparing tacrolimus ointment and oral cyclosporine in adult patients affected by atopic dermatitis: a randomized study. Clin Exp Allergy 2004;34: 639-45.
Whalley D, Huels J, McKenna SP, Van Assche D. The benefit of pimecrolimus (Elidel, SDZ ASM 981) on parents' quality of life in the treatment of pediatric atopic dermatitis. Pediatrics 2002;110: 1133-6.
Drake L, Prendergast M, Maher R, Breneman D, Korman N, Satoi Y, et al. The impact of tacrolimus ointment on health-related quality of life of adult and pediatric patients with atopic dermatitis. J Am Acad Dermatol 2001;44: S65-72.
Queille-Roussel C, Paul C, Duteil L, Lefebvre MC, Rapatz G, Zagula M, et al. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study. Br J Dermatol 2001;144: 507-13.
Kyllonen H, Remitz A, Mandelin JM, Elg P, Reitamo S. Effects of 1-year intermittent treatment with topical tacrolimus monotherapy on skin collagen synthesis in patients with atopic dermatitis. Br J Dermatol 2004;150: 1174-81.
Iskedjian M, Piwko C, Shear NH, Langley RG, Einarson TR. Topical calcineurin inhibitors in the treatment of atopic dermatitis: a meta-analysis of current evidence. AmJClin Dermatol 2004;5: 267-79.
Charman C, Williams H. Outcome measures of disease severity in atopic eczema. Arch Dermatol 2000;136: 763-9.
Charman C, Chambers C, Williams H. Measuring atopic dermatitis severity in randomized controlled clinical trials: what exactly are we measuring? J Invest Dermatol 2003;120: 932-41.
National Institute for Clinical Excellence. Technology appraisal guidance 82: tacrolimus and pimecrolimus for atopic eczema. London: NICE, 2004.
Williams H. New treatments for atopic dermatitis. BMJ 2002;324: 1533-4.(Darren M Ashcroft, senior clinical lectu)
Correspondence to: D M Ashcroft darren.ashcroft@manchester.ac.uk
We included randomised controlled trials that compared topical pimecrolimus or topical tacrolimus at a licensed therapeutic dose with vehicle or another active treatment (for example, topical corticosteroids) in patients with atopic dermatitis, and that reported efficacy outcomes or adverse events.
Outcome measures
For efficacy, we used the investigators' rating of the global degree of improvement. The trials used different scales to rate the degree of improvement. For pimecrolimus, we used the proportion of patients who were rated by the investigator as clear or almost clear as the primary outcome measure, whereas for the tacrolimus trials the primary outcome was the proportion of patients who achieved at least 90% improvement from baseline (defined as clear or excellent improvement in the trials).
Secondary outcome measures included patients' global assessments of feeling better or much better, the proportions of patients with flares of atopic dermatitis, and improvements in quality of life. We assessed tolerability to the drug by considering overall rates of withdrawal, withdrawal due to adverse events, and the proportions of patients with burning of the skin and skin infections.
Search strategy
Randomised controlled trials fulfilling the eligibility criteria were suitable for inclusion in our review, regardless of language or publication status. We systematically searched Medline, Embase, the Cochrane Skin Group specialised register, and the Cochrane central register of controlled trials to December 2004 using the search terms "pimecrolimus", "Elidel", "SDZ ASM 981", "tacrolimus", "Protopic", and "FK506". We also searched the reference lists of all retrieved trials along with the websites for the European Agency for the Evaluation of Medicinal Products and the US Food and Drug Administration.
Trial eligibility was determined by two authors (DMA, PD), who also independently extracted the data, which was checked by RG. Trials were rated for methodological quality (in duplicate by DMA and PD) using the Jadad scale and scored out of a maximum of five.8
Data synthesis
Not all of the trials reported on all the outcomes of interest. For each comparison and outcome we undertook separate meta-analyses. We grouped the topical corticosteroids on the basis of their potencies: mild (aclometasone dipropionate 0.1%, hydrocortisone acetate 1%) and potent (betamethasone valerate 0.1%, hydrocortisone butyrate 0.1%, triamcinolone acetonide 0.1%). We also stratified the analysis of efficacy data by the duration of treatment.
We summarised dichotomous data as rate ratios (relative risks) and combined these by using a random effects model.9 Results are given with 95% confidence intervals. We also computed homogeneity statistics to test the agreement of the individual trial results with the combined meta-analytical summary.10 11 Analyses were carried out in RevMan version 4.2.6.
Results
Tacrolimus 0.1% is as effective as potent topical corticosteroids and more effective than mild topical corticosteroids, such as hydrocortisone acetate 1%, for treating atopic dermatitis. This means that topical tacrolimus may be useful for resistant atopic dermatitis at sensitive sites such as the face, where the use of more potent topical steroids carries a high risk of thinning of the skin and telangiectasia. Tacrolimus 0.1% may also be useful for patients who depend on the constant use of potent steroids, although it would be helpful to see trial evidence on how effective it is in such a subgroup of treatment "failures."
Pimecrolimus has been found to be less effective than betamethasone valerate 0.1%, a commonly used potent topical corticosteroid. The efficacy of pimecrolimus compared with less potent topical corticosteroids is not known. In practice, pimecrolimus is being aimed at patients with mild atopic dermatitis, yet this is being done in the absence of randomised controlled trials that compare it with existing therapy for such a group—that is, short bursts of 1% hydrocortisone to treat acute flares. Pimecrolimus prevented more flares than vehicle, but it remains to be seen whether the early use of mild topical steroids may be as effective. In the absence of such key comparisons, it is unclear as to what role, if any, pimecrolimus has for atopic dermatitis.
The main reason for developing new drugs as an alternative to topical steroids is to overcome possible side effects from steroids, such as thinning of the skin or adrenal gland suppression. We found no clear evidence that these newer, more expensive products offer such an advantage when compared with standard practice. Other studies have suggested that skin thinning is not a problem with these newer agents.37 38 One preliminary randomised controlled trial of pimecrolimus applied to normal skin for four weeks found no thinning of the skin.37 Such a study is, however, difficult to generalise to people with atopic dermatitis who apply preparations over the course of a year. A non-randomised prospective study of 119 participants that compared 0.1% topical tacrolimus with "conventional steroid based therapy" and normal controls found no evidence of decreased skin collagen synthesis or skin thinning in the tacrolimus group as measured by ultrasonography at one year.38 Skin collagen synthesis was also not decreased with conventional topical steroids, although a minor degree of skin thinning was found (mean decreased thickness of 8.2% compared with baseline); its clinical significance is difficult to interpret.
Strengths and limitations of the review
In contrast to an earlier review that identified 16 studies,39 we examined 25 clinical trials, using a wider range of clinically relevant outcome measures, and focused on direct comparisons with other active treatments, rather than making indirect inferences from placebo controlled trials.
One limitation of our systematic review is that our analyses of rates of withdrawals and adverse events were based on data pooled from trials of different durations. Some caution is therefore needed in their interpretation. Other potential sources of heterogeneity in the results are the patient population (infants, children, adults), the severity of the disease, and the choice of topical corticosteroid. The use of investigators' global assessments of response to treatment also causes some concern. Despite such assessments of response to treatment being widely used as outcome measures in clinical trials of atopic dermatitis, further research is needed to fully determine their validity, reliability, and sensitivity to change.40 41
Recommendations for future research to inform clinical practice
Our systematic review shows that there is little evidence to help deal with the clinically important questions of how pimecrolimus and tacrolimus compare for efficacy, side effects, tolerability, and cost with existing optimal treatments, such as short bursts of topical corticosteroids for flare-ups of disease followed by periods of rest using only emollients. Although some comparative data are available for tacrolimus to inform practice, the clinical role of pimecrolimus is uncertain owing to a lack of relevant comparative data. The lack of key comparative data highlights deficiencies in the current licensing systems for medicines in Europe and the United States, which require only evidence of efficacy and safety above placebo and vehicle, thus allowing more new drugs to reach the market. This leaves doctors, commissioners, and the public confused about how and when to use such new drugs in relation to standard practice.
Pragmatic randomised controlled trials lasting at least 12 months are needed to compare tacrolimus, pimecrolimus, and 1% hydrocortisone acetate in children and adults with mild to moderate atopic dermatitis. Outcome data should include clearing capacity, relapse, quality of life, adverse events (including skin thinning), and costs. In particular, it seems important to determine how well these agents work in people who fail to respond adequately to topical corticosteroids, given that they may be used as second line agents.42 Experience of long term use of topical pimecrolimus and tacrolimus is limited and the risk of rare but more serious adverse effects remains uncertain. Further long term surveillance of these agents is needed, given concerns about the theoretical risk of visceral and skin cancers from preclinical studies in animals.43
What is already known on this topic
Atopic dermatitis affects 15-20% of children in developed countries
Topical corticosteroids and emollients have been the mainstay of therapy
Topical pimecrolimus and tacrolimus have been developed as alternative treatments
What this study adds
Tacrolimus 0.1% is as effective as potent corticosteroids for treating atopic dermatitis and more effective than mild preparations such as hydrocortisone acetate 1%
Pimecrolimus is less effective than potent corticosteroids; it has not been compared with mild corticosteroids
Both agents caused more burning of the skin than topical corticosteroids, but no differences were observed in rates of skin infections
Contributors: All authors designed the review and revised the manuscript, which was drafted by DMA. DMA, PD, and RG decided on the inclusion of trials, extracted data, and assessed study quality. DMA and PD carried out the statistical analyses. All authors interpreted the findings. DMA is guarantor.
Funding: RG and KS were funded by the NHS health technology assessment programme.
Competing interests: None declared.
Ethical approval: Not required.
References
Williams H, Robertson C, Stewart A, Ait-Khaled N, Anabwani G, Anderson R, et al. Worldwide variations in the prevalence of symptoms of atopic eczema in the international study of asthma and allergies in childhood. J Allergy Clin Immunol 1999;103: 125-38.
Lewis-Jones MS, Finlay AY, Dykes PJ. The infants' dermatitis quality of life index. Br J Dermatol 2001;144: 104-10.
Kiebert G, Sorensen SV, Revicki D, Fagan SC, Doyle JJ, Cohen J, et al. Atopic dermatitis is associated with a decrement in health-related quality of life. Int J Dermatol 2002;41: 151-8.
Herd RM. The morbidity and cost of atopic dermatitis. In: Williams HC, ed. Atopic dermatitis, Cambridge: Cambridge University Press, 2000.
Emerson RM, Williams HC, Allen BR. What is the cost of atopic dermatitis in preschool children? Br J Dermatol 2001;144: 514-22.
Charman CR, Morris AD, Williams HC. Topical corticosteroid phobia in patients with atopic eczema. Br J Dermatol 2000;142: 931-6.
Beattie PE, Lewis-Jones MS. Parental knowledge of topical therapies in the treatment of childhood atopic dermatitis. Clin Exp Dermatol 2003;28: 549-53.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17: 1-12.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7: 177-88.
Deeks JJ, Altman D, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis. In: Egger M, Davey Smith G, Altman DG, eds. Systematic reviews in health care. London: BMJ Publishing, 2001: 285-312.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003;327: 557-60.
Eichenfield LF, Lucky AW, Boguniewicz M, Langley RGB, Cherill R, Marshall K, et al. Safety and efficacy of pimecrolimus (ASM 981) cream 1% in the treatment of mild and moderate atopic dermatitis in children and adolescents. J Am Acad Dermatol 2002;46: 495-504.
Ho VC, Gupta A, Kaufmann R, Todd G, Vanaclocha F, Takaoka R, et al. Safety and efficacy of nonsteroid pimecrolimus cream 1% in the treatment of atopic dermatitis in infants. J Pediatr 2003;142: 155-62.
Kapp A, Papp K, Bingham A, Folster-Holst R, Ortonne J-P, Potter PC, et al. Long-term management of atopic dermatitis in infants with topical pimecrolimus, a nonsteroid anti-inflammatory drug. J Allergy Clin Immunol 2002;110: 277-84.
Luger T, Van Leent EJM, Graeber M, Hedgecock S, Thurston M, Kandra A, et al. SDZ ASM 981: an emerging safe and effective treatment for atopic dermatitis. Br J Dermatol 2001;144: 788-94.
Meurer M, Folster-Holst R, Wozel G, Weidinger G, Junger M, Brautigam M. Pimecrolimus cream in the long-term management of atopic dermatitis in adults: a six-month study. Dermatology 2002;205: 271-7.
Wahn U, Bos JD, Goodfield M, Caputo R, Papp K, Manjra A, et al. Efficacy and safety of pimecrolimus cream in the long-term management of atopic dermatitis in children. Pediatrics 2002;110: e2.
Barba JF, Beirana A, Cohen V, Dominguez L, Duran C, Leon G, et al. Pimecrolimus cream 1% is effective, well tolerated and safe in infants and children with atopic eczema of the face. J Eur Acad Dermatol Venereol 2003;17: P2.35.
Ling M, Gottlieb AB, Abrams K. Pimecrolimus cream 1%; bid and qid application were equally effective and well tolerated. 11th congress of the European Academy of Dermatology and Venereology, Prague. J Eur Acad Dermatol Venereol 2002;16: P2-27.
Boguniewicz M, Fiedler VC, Raimer S, Lawrence ID, Leung DYM, Hanifin JM. A randomized, vehicle-controlled trial of tacrolimus ointment for treatment of atopic dermatitis in children. J Allergy Clin Immunol 1998;102: 637-44.
Hanifin JM, Ling MR, Langley R, Breneman D, Rafal E. Tacrolimus ointment for the treatment of atopic dermatitis in adult patients: part I, efficacy. J Am Acad Dermatol 2001;44: S28-38.
Paller A, Eichenfield LF, Leung DYM, Stewart D, Appell M. A 12-week study of tacrolimus ointment for the treatment of atopic dermatitis in pediatric patients. J Am Acad Dermatol 2001;44: S47-57.
Reitamo S, Rustin M, Ruzicka T, Cambazard F, Kalimo K, Friedmann PS, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone butyrate ointment in adult patients with atopic dermatitis. J Allergy Clin Immunol 2002;109: 547-55.
Reitamo S, Van Leent EJM, Ho V, Harper J, Ruzicka T, Kalimo K, et al. Efficacy and safety of tacrolimus ointment compared with that of hydrocortisone acetate ointment in children with atopic dermatitis. J Allergy Clin Immunol 2002;109: 539-46.
Ruzicka T, Bieber T, Schopf E, Rubins A, Dobozy A, Bos JD, et al. A short-term trial of tacrolimus ointment for atopic dermatitis. N Engl J Med 1997;337: 816-21.
Reitamo S, Harper J, Bos JD, Cambazard F, Bruijnzeel-Koomen C, Valk P, et al. 0.03% tacrolimus ointment applied once or twice daily is more efficacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis: results of a randomized double-blind controlled trial. Br J Dermatol 2004;150: 554-62.
FK506 Ointment Study Group. Phase III comparative study of FK506 ointment vs betamethasone valerate ointment in atopic dermatitis (trunk/extremities) . Nishinihon J Dermatol 1997;59: 870-9.
Nakagawa H. Comparative study of FK506 (tacrolimus) ointment vs aclometasone dipropionate ointment in atopic dermatitis (face and neck lesions) ( 1266). J Invest Dermatol 1998;110: 683.
Kang S. Tacrolimus ointment for adults with moderate to severe atopic dermatitis: a dose escalation study ( 1253). J Invest Dermatol 1998;110: 681.
Hanifin JM. Use of tacrolimus ointment in 3-6 year-olds with atopic dermatitis: dose escalation study ( 1245). J Invest Dermatol 1998;110: 681.
Kempers S, Boguniewicz M, Carter E, Jarrat M, Pariser D, Stewart D, et al. Comparison of pimecrolimus cream 1% and tacrolimus ointment 0.03% in paediatric patients with atopic eczema. J Eur Acad Dermatol Venereol 2003;17: P2-41.
Reitamo S. 0.1% tacrolimus ointment is an effective treatment for adults with moderate or severe atopic dermatitis. J Eur Acad Dermatol Venereol 2003;17: P20-31.
Luger TA, Lahfa M, Folster-Holst R, Gulliver WP, Allen R, Molloy S, et al. Long-term safety and tolerability of pimecrolimus cream 1% and topical corticosteroids in adults with moderate to severe atopic dermatitis. J Dermatol Treat 2004;15: 169-78.
Pacor ML, Di Lorenzo G, Martinelli N, Mansueto P, Rini GB, Corrocher R. Comparing tacrolimus ointment and oral cyclosporine in adult patients affected by atopic dermatitis: a randomized study. Clin Exp Allergy 2004;34: 639-45.
Whalley D, Huels J, McKenna SP, Van Assche D. The benefit of pimecrolimus (Elidel, SDZ ASM 981) on parents' quality of life in the treatment of pediatric atopic dermatitis. Pediatrics 2002;110: 1133-6.
Drake L, Prendergast M, Maher R, Breneman D, Korman N, Satoi Y, et al. The impact of tacrolimus ointment on health-related quality of life of adult and pediatric patients with atopic dermatitis. J Am Acad Dermatol 2001;44: S65-72.
Queille-Roussel C, Paul C, Duteil L, Lefebvre MC, Rapatz G, Zagula M, et al. The new topical ascomycin derivative SDZ ASM 981 does not induce skin atrophy when applied to normal skin for 4 weeks: a randomized, double-blind controlled study. Br J Dermatol 2001;144: 507-13.
Kyllonen H, Remitz A, Mandelin JM, Elg P, Reitamo S. Effects of 1-year intermittent treatment with topical tacrolimus monotherapy on skin collagen synthesis in patients with atopic dermatitis. Br J Dermatol 2004;150: 1174-81.
Iskedjian M, Piwko C, Shear NH, Langley RG, Einarson TR. Topical calcineurin inhibitors in the treatment of atopic dermatitis: a meta-analysis of current evidence. AmJClin Dermatol 2004;5: 267-79.
Charman C, Williams H. Outcome measures of disease severity in atopic eczema. Arch Dermatol 2000;136: 763-9.
Charman C, Chambers C, Williams H. Measuring atopic dermatitis severity in randomized controlled clinical trials: what exactly are we measuring? J Invest Dermatol 2003;120: 932-41.
National Institute for Clinical Excellence. Technology appraisal guidance 82: tacrolimus and pimecrolimus for atopic eczema. London: NICE, 2004.
Williams H. New treatments for atopic dermatitis. BMJ 2002;324: 1533-4.(Darren M Ashcroft, senior clinical lectu)