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