Efficacy and tolerability of topical pimecrolimus and tacrolimus in the treatment of atopic dermatitis: meta-analysis of randomised controlled trials

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Ashcroft DM, Dimmock P, Garside R, Stein K, Williams HC. BMJ 2005;330:516-24.

Context Atopic dermatitis affects 15-20% of children and its treatment utilizes significant health care resources. Concerns about the safety of topical corticosteroids may affect patients' adherence to treatment.

Objective To determine the efficacy and tolerability of topical pimecrolimus and tacrolimus compared with other treatments for atopic dermatitis.

Design Systematic review and meta-analysis.

Main Outcome Measures Measures of efficacy: investigators' global assessment of response; patients' global assessment of response; proportions of patients with flares of atopic dermatitis; and improvements in quality of life. Measures of tolerability: overall rates of withdrawal; withdrawal due to adverse events; and proportions of patients with burning of the skin and skin infections.

Study Identification The authors electronically searched the Cochrane Library, Medline, and Embase for randomized controlled trials of topical pimecrolimus or tacrolimus. Trials were rated for methodologic quality and data was extracted by two authors.

Studies Reviewed 25 trials met inclusion criteria (11 for pimecrolimus and 14 for tacrolimus). 6897 participants were involved.

Results Both pimecrolimus and tacrolimus were significantly more effective than a vehicle control. Tacrolimus 0.1% was as effective as potent topical corticosteroids at three weeks and more effective than combined treatment with hydrocortisone butyrate 0.1% (potent used on trunk) plus hydrocortisone acetate 1% (weak used on face) at 12 weeks (number needed to treat (NNT)=6). Tacrolimus 0.1% was also more effective than hydrocortisone acetate 1% (NNT=4). Tacrolimus 0.03% was more effective than hydrocortisone acetate 1% (NNT=5), but less effective than hydrocortisone butyrate 0.1% (NNT= −8). Direct comparisons of tacrolimus 0.03% and tacrolimus 0.1% consistently favored the higher strength formulation, but efficacy differed significantly between the two strengths only after 12 weeks' treatment (rate ratio 0.80, 95% confidence interval 0.65 to 0.99). Pimecrolimus was far less effective than betamethasone valerate 0.1% (NNT= −3 at three weeks). Pimecrolimus and tacrolimus caused significantly more skin burning than topical corticosteroids. Rates of skin infections in any of the comparisons did not differ.

Conclusions Both topical pimecrolimus and topical tacrolimus are more effective than placebo treatments for atopic dermatitis, but in the absence of studies that show long-term safety gains, any advantage over topical corticosteroids is unclear. Topical tacrolimus is similar to potent topical corticosteroids and may have a place for long term use in patients with resistant atopic dermatitis on sites where side effects from topical corticosteroids might develop quickly. In the absence of key comparisons with mild corticosteroids, the clinical need for topical pimecrolimus is unclear. The usefulness of either treatment in patients who have failed to respond adequately to topical corticosteroids is also unclear.

Comment Topical tacrolimus was initially studied in patients with moderate to severe atopic dermatitis. While it does seem to be moderately effective for these patients, it is clear that these agents are being used in patients with more mild disease. As pointed out by these authors, topical pimecrolimus appears to have no significant benefits over topical steroids. Topical tacrolimus may offer some benefit to some areas of the skin (notably the face and other areas where one would want to minimize high potency steroids) in patients with more significant disease. However, for most patients with atopic dermatitis, emollients and moderate potency corticosteroids will be effective, and at a lower cost. Concerns about the side effects of topical corticosteroids (skin thinning, potential for adrenal gland suppression) and general “steroid phobia” can affect adherence to treatment and need to be addressed with patients and families.

The long-term impact of topical tacrolimus and pimecrolimus is also unknown at this point. In March 2005, the US Food and Drug Administration issued a public health advisory regarding “a potential cancer risk from these agents, based on animal studies, a small number of case reports, and the drugs' mechanism of action.” Taken together, these concerns and the modest effectiveness of these agents would warrant limited use of in selected patients. At a minimum, a full discussion with families regarding benefits and risks is a necessity.