Review Article
Topical calcineurin inhibitors in atopic dermatitis: A systematic review and meta-analysis

https://doi.org/10.1016/j.jdermsci.2009.02.002Get rights and content

Abstract

Objectives

To build a critical appraisal of the available literature to evaluate the effectiveness of topical calcineurin inhibitors in treatment of atopic dermatitis (AD), in comparison to topical corticosteroids (TCs) and/or placebo.

Review methods

Design: systematic review and meta-analysis. Data sources: electronic search of MEDLINE Pubmed along the last 10 years (1997–2006). Study selection: randomized control trials of TCIs reporting efficacy outcomes, in comparison to TCs or vehicle (placebo) or both. Data synthesis: of 210 articles, 19 studies were included, 10 for tacrolimus and 9 for pimecrolimus, involving 7378 patients of whom 2771 applied tacrolimus, 1783 applied pimecrolimus, and 2824 were controls. Both drugs were significantly more effective than a vehicle. However, two long-term trials comparing demonstrated the value of pimecrolimus in reduction of flares and steroid-sparing effect after 6 months. Compared to TCs, both 0.1% and 0.03% tacrolimus ointments were as effective as moderate potency TCs, and more effective than a combined steroid regimen. Tacrolimus was more effective than mild TCs.

Conclusions

TCIs in AD are more effective than placebo. Although less effective than TCs, pimecrolimus has its value in long-term maintenance and as a steroid-sparing agent in AD, whenever used early enough, at first appearance of erythema and/or itching. In treatment of moderate to severe AD, topical tacrolimus is as effective as moderately potent TCs, and more effective than mild preparations. Chronic AD lesions of the face and flexures are the most justified indication for topical calcineurin inhibitors.

Introduction

Atopic dermatitis (AD) is one of the most common chronic diseases of childhood [1] that may persist in adulthood with distinctive clinical features and disease course [2]. Treatment should be tailored to an individual's needs, bearing in mind age, sex, social conditions, sites of involvement and severity. Choice of therapy should reflect an understanding of the underlying immune abnormalities of this complex chronic skin disease [3]. First-line therapy has generally consisted of care for dry skin, avoidance of triggers, application of topical corticosteroids (TC), topical antiseptics and administration of oral antibacterials and sedating antihistamines [4].

Corticosteroids continue to be one of the main pillars of dermatological therapy of atopic dermatitis. However, their use is limited by local and systemic adverse effects. Cutaneous complications such as striae, atrophy, and telangiectasia limit the long-term use of these agents. Tachyphylaxis is also one of the clinical concerns. Application on large surface areas, especially in infants, carries the risk of percutaneous systemic absorption, resulting in hypothalamic pituitary axis suppression [3], [5].

An enormous demand for anti-inflammatory agents not belonging to the corticosteroid group is increasing [6]. In the last few years the therapeutic arsenal for AD has expanded with two distinct groups of drugs: topical immunomodulators and leukotriene inhibitors [6].

Tacrolimus (FK 506) and pimecrolimus (ASM 981) are topical immunomodulators classified as calcineurin inhibitors. They belong to this group of substances with a high capacity to inhibit T lymphocyte activation. Although they also act on other cells playing a role in AD (mastocytes, Langerhans’ cells, B lymphocytes), their action on T lymphocytes seems to be the most important [6], [7], [8]. Questions remain regarding the place of topical calcineurin inhibitors (TCIs) as a treatment for AD and how to use them most effectively, from both therapeutic and pharmacoeconomic standpoints [4].

The aim of this work was to build a critical appraisal of the available literature to evaluate the effectiveness of topical tacrolimus and pimecrolimus in the treatment of atopic dermatitis, in comparison to topical corticosteroids and/or placebo. This study was designed in the form of a systematic review and meta-analysis.

Section snippets

Methodology

The methods used to carry out this systematic review adhered to the guidelines stated by the Centre of Research and Dissemination (CRD) report for carrying out systematic reviews. The items of the report were adapted to meet the quality requirements for reports of systematic reviews and meta-analyses, as summarized by the QUOROM statement check list according to Moher et al. [9].

Results

The applied search strategy identified 210 articles, of which 191 were excluded. Nineteen randomized controlled trials (RCTs) were included: 10 for pimecrolimus, and 9 for tacrolimus, with a total of 7378 patients involved in the trials. The included studies used topical corticosteroids or vehicle as a comparator. Vehicle is the base of the cream or ointment without the active ingredient; thus it was used as a placebo.

Discussion

This systematic review and meta-analysis was undertaken to assess how the effectiveness of TCIs measures up to topical corticosteroids and/or placebo. In this systematic review, the overall comparison between pimecrolimus and vehicle favored pimecrolimus. Pimecrolimus cream 1% was found to be more effective than vehicle in AD, at three and six weeks. However, in one study with long-term management of patients no significant difference was found between both groups in treatment response at 6 and

Conclusion

This study concludes that pimecrolimus is superior in efficacy than vehicle but equivalent to mildly potent topical steroids, and less effective than moderately potent TCs. On the other hand, tacrolimus is more effective than mild TCs and equally effective to moderately potent topical steroids. Based on this we suggest that pimecrolimus could be used in milder cases of AD, or in long-term maintenance for prevention of flares of the disease and for its assumed steroid-sparing effect. Tacrolimus

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