BMJ  2005;330:516 (5 March), doi:10.1136/bmj.38376.439653.D3 (published 24 February 2005)

Primary care

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

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

Abstract

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.

Data sources Electronic searches of Cochrane Library, Medline, and Embase.

Study selection Randomised controlled trials of topical pimecrolimus or tacrolimus reporting efficacy outcomes or tolerability.

Data extraction 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. Tolerability: overall rates of withdrawal, withdrawal due to adverse events, and the proportions of patients with burning of the skin and skin infections.

Data synthesis 4186 of 6897 participants in 25 randomised controlled trials received pimecrolimus or tacrolimus. Both drugs 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). In comparison, 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 favoured 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.

Introduction

Atopic dermatitis affects 15-20% of children in developed countries,¹ and 1-3% of adults. Traditionally the treatment of atopic dermatitis has included emollients and occasional topical corticosteroids to control flares. Corticosteroids may be associated with several local and systemic adverse events, such as thinning of the skin.

Two new topical agents, pimecrolimus and tacrolimus, were developed to provide alternatives to topical corticosteroids without the adverse events. We undertook a systematic review and meta-analysis of randomised controlled trials of pimecrolimus and tacrolimus in atopic dermatitis to determine whether they offer any advantages over existing treatments for atopic dermatitis in terms of efficacy, improved tolerability, and fewer short term or long term adverse effects.

Methods

We included randomised controlled trials that compared topical pimecrolimus or topical tacrolimus at a licensed therapeutic dose with vehicle or another active treatment in patients with atopic dermatitis, and reported efficacy outcomes or adverse events.

Outcome measures
For efficacy, we used the investigators' rating of the global 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 tacrolimus the primary outcome was the proportion of patients who achieved at least 90% improvement (clear or excellent) from baseline.

Secondary outcome measures included patients' global assessments of feeling better or much better, the proportions of patients with flares, and improvements in quality of life. Tolerability to the drug was assessed from overall rates of withdrawal, withdrawal due to adverse events, and the proportions of patients with burning of the skin and skin infections.

Search strategy
We 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 and 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. Trials were rated for methodological quality using the Jadad scale.

Data synthesis
Some trials did not report on all the outcomes of interest. For each comparison and outcome we undertook separate meta-analyses. We grouped topical corticosteroids as mild (aclometasone dipropionate 0.1%, hydrocortisone acetate 1%) or 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 using a random effects model.² We also computed homogeneity statistics to test the agreement of the individual trial results with the combined meta-analytical summary.^{3 4}

Results

Overall, we identified 25 randomised controlled trials, totalling 6897 patients with atopic dermatitis (see bmj.com for details of trials).^w1-w23 Eleven trials studied the effects of pimecrolimus 1% cream applied twice daily, one trial directly compared pimecrolimus and tacrolimus 0.03% in children,^w20 and 14 trials investigated the effects of tacrolimus 0.1% or tacrolimus 0.03% applied twice daily.

Vehicle controlled studies
Pimecrolimus 1% versus vehicle
Five trials (783 patients) reported on the proportion of patients clear or almost clear at three weeks.^{w1 w2 w4 w7} Pimecrolimus was significantly more effective than vehicle (pooled rate ratio 2.72, 95% confidence interval 1.84 to 4.03; fig 1). Three of the trials reported on the same outcome after six weeks' treatment and found that pimecrolimus remained significantly more effective (2.03, 1.50 to 2.74). At six months, one trial (251 patients) found no significant difference (rate ratio 1.46, 0.98 to 2.19).^w3 In three vehicle controlled trials (1156 patients), pimecrolimus resulted in significantly fewer patients with flare at six months (pooled rate ratio 1.92, 1.56 to 2.36). At 12 months pimecrolimus remained significantly more effective than vehicle at preventing flares (two trials: 1.84, 1.50 to 2.24).

View larger version (44K): [in this window] [in a new window]   Fig 1 Investigators' global assessment of response (clear or almost clear) with pimecrolimus 1% compared with control

 

Tacrolimus versus vehicle
One trial (136 children) directly compared tacrolimus 0.03% and tacrolimus 0.1% with vehicle control, and reported on the proportion of children clear or achieving excellent improvement at three weeks.^w9 Tacrolimus 0.03% was significantly more effective than vehicle (rate ratio 2.13, 1.24 to 3.68), but there was no significant differences in response between tacrolimus 0.1% and vehicle (1.57, 0.88 to 2.81). On the basis of the patients' global assessment of response as better or much better, both tacrolimus 0.03% and tacrolimus 0.1% were significantly more effective than vehicle (1.47, 1.06 to 2.04 and 1.76, 1.31 to 2.36, respectively). Three trials (656 patients) also reported on the same outcomes after 12 weeks' treatment and found that tacrolimus 0.03% and tacrolimus 0.1% were significantly more effective than vehicle (pooled rate ratios for proportion of patients clear or achieving excellent improvement 4.50, 2.91 to 6.96 and 5.62, 3.67 to 8.61, respectively; fig 2).

View larger version (47K): [in this window] [in a new window]   Fig 2 Investigators' global assessment of response (clear or excellent improvement) with tacrolimus (0.03% and 0.1%) compared with control

 

Comparative efficacy of topical pimecrolimus
Pimecrolimus 1% versus potent corticosteroid
One trial (87 patients) compared pimecrolimus 1% with betamethasone valerate 0.1% and reported on the proportion of patients clear or almost clear.^w4 Betamethasone valerate 0.1% was significantly more effective than pimecrolimus 1% after three weeks (rate ratio 0.22, 0.09 to 0.54; see fig 2).

Pimecrolimus 1% versus potent corticosteroid (trunk) and mild corticosteroid (face)
One trial (658 adults; moderate to severe atopic dermatitis) compared pimecrolimus 1% with a combined regimen of triamcinolone acetonide 0.1% (trunk and limbs) and hydrocortisone acetate 1% (face, neck, and intertriginous areas).^w22 On the basis of the proportions of patients moderately clear or better, the combined regimen was significantly more effective than pimecrolimus 1% after treatment for one week, three weeks, and six months, but there were no significant differences between treatment groups at 12 months.

Pimecrolimus 1% versus tacrolimus 0.03%
One direct comparison of pimecrolimus 1% against tacrolimus 0.03% (141 children; moderate atopic dermatitis) found no significance difference in the proportion of children clear or almost clear at six weeks (0.71, 0.45 to 1.12).^w20

Pimecrolimus 1% four times daily versus pimecrolimus 1% twice daily
One crossover trial (49 patients; moderate to severe atopic dermatitis) found no significant difference in the proportion of patients clear or almost clear with four times daily versus twice daily application of pimecrolimus 1% cream at three weeks (0.96, 0.40 to 2.33).^w8

Comparative efficacy of topical tacrolimus
Tacrolimus versus mild topical corticosteroids
Two trials (1183 children; moderate to severe atopic dermatitis) compared tacrolimus with hydrocortisone acetate 1%.^{w13 w15} Both tacrolimus 0.03% and tacrolimus 0.1% were significantly more effective than hydrocortisone acetate 1% on the basis of the proportion of patients clear or achieving excellent improvement at three weeks (2.56, 1.95 to 3.36 and 3.05, 2.12 to 4.40, respectively). Another trial (143 patients; atopic dermatitis of face and neck) compared tacrolimus 0.1% with aclometasone dipropionate 0.1% (mild corticosteroid).^w17 Tacrolimus 0.1% was significantly more effective at treating facial atopic dermatitis than aclometasone dipropionate 0.1% (rate ratio for proportion of patients achieving at least marked improvement (> 75%) at one week 3.94, 2.21 to 7.00).

Tacrolimus versus potent topical corticosteroids
One trial (570 adults; moderate to severe atopic dermatitis) compared tacrolimus (0.03% and 0.1%) with hydrocortisone butyrate 0.1% (potent corticosteroid) and reported on the proportions of patients clear or achieving an excellent improvement at three weeks.^w12 Tacrolimus 0.03% was significantly less effective than hydrocortisone butyrate 0.1% (0.73, 0.58 to 0.92), whereas tacrolimus 0.1% was as effective (0.95, 0.78 to 1.17).

Two trials compared tacrolimus 0.1% with potent topical corticosteroids (betamethasone valerate 0.1%, hydrocortisone butyrate 0.1%) and reported on the proportions of patients achieving at least marked improvement (> 75%) at three weeks.^{w12 w16} Tacrolimus 0.1% was as effective as the potent topical corticosteroids (pooled rate ratio 1.08, 0.97 to 1.21).

Tacrolimus versus potent corticosteroid (trunk) and mild corticosteroid (face)
One trial (968 adults; moderate to severe atopic dermatitis) compared tacrolimus 0.1% with a combined regimen of hydrocortisone butyrate 0.1% (trunk and extremities) plus hydrocortisone acetate 1% (head and neck).^w21 At 12 weeks, tacrolimus 0.1% was significantly more effective than the combined regimen on the basis of the proportions of patients clear or achieving an excellent improvement (1.67, 1.41 to 1.98).

Tacrolimus 0.03% versus tacrolimus 0.1%
Six trials (1502 patients) directly compared tacrolimus 0.03% with tacrolimus 0.1%.^w9-w13 Three trials reported on the proportions of patients clear or achieving excellent improvement at three weeks and found no significant difference in response between strengths of tacrolimus (pooled rate ratio 0.89, 0.67 to 1.19; see fig 2). At 12 weeks in the three remaining trials, however, tacrolimus 0.1% was significantly more effective than tacrolimus 0.03% (0.80, 0.65 to 0.99). On the basis of the participants' global assessment of response of better or much better, there were no significant differences in response between strengths (three weeks: 0.84, 0.69 to 1.00; 12 weeks: 0.93, 0.83 to 1.03).

Quality of life
Information on quality of life was patchy, with a lack of common outcome measures. In two trials of pimecrolimus compared with vehicle, the parent's index of quality of life in atopic dermatitis was completed for a subset of patients; children who received pimecrolimus were judged to have a significantly improved quality of life than those receiving vehicle.⁵ In one trial (192 adults; moderate to severe atopic dermatitis), patients receiving pimecrolimus had a significantly improved quality of life than those receiving vehicle, assessed using the quality of life index—atopic dermatitis and the dermatology life quality index.^w5

In three trials (985 patients), significant improvements in overall quality of life were found separately for infants, children, and adults treated with tacrolimus (0.03% and 0.1%) compared with vehicle.⁶ In adults, tacrolimus 0.1% also resulted in a significantly greater improvement in quality of life compared with tacrolimus 0.03%, but no significant differences were found between strengths in infants or children.

Withdrawal from treatment
Significantly more patients withdrew from treatment with vehicle than with pimecrolimus 1% or tacrolimus 0.03% or 0.1% (table). No significant differences were found in rates of withdrawals due to adverse events between pimecrolimus 1% and vehicle, but there were significantly higher rates with tacrolimus (0.03% and 0.1%) (pooled rate ratios 0.50, 0.30 to 0.84 and 0.47, 0.28 to 0.80, respectively).

View this table: [in this window] [in a new window]   Comparison of risk of withdrawals and adverse events in trials of pimecrolimus and tacrolimus for treating atopic dermatitis

 

We found no significant differences in rates of withdrawals due to adverse events between any of the comparisons of pimecrolimus or tacrolimus (0.03% and 0.1%) with topical corticosteroids. Direct comparisons of tacrolimus 0.03% against tacrolimus 0.1% also showed no significant differences in withdrawals between the strengths (pooled rate ratio for overall withdrawals 0.75, 0.49 to 1.14 and for withdrawals due to adverse effects 0.99, 0.59 to 1.64).

Adverse effects
The most common adverse effects reported related to skin irritation and skin burning. No significant difference was found between pimecrolimus 1% and vehicle in the incidence of skin burning (pooled rate ratio obtained from six trials was 0.87, 0.70 to 1.09). However, we found a significantly higher rate of skin burning with pimecrolimus 1% than with betamethasone valerate 0.1% (5.26, 1.92 to 14.30) or a combined regimen of triamcinolone acetonide 0.1% and hydrocortisone acetate 1% (2.38, 1.66 to 3.40).

Tacrolimus (0.03% and 0.1%) was significantly more likely to cause skin burning than vehicle (pooled rate ratios 1.89, 1.43 to 2.50 and 2.08, 1.35 to 3.18, respectively). Both strengths were also significantly more likely to cause skin burning than mild or potent topical corticosteroids (see table). None of the trials reported on key adverse effects such as thinning of skin.

Discussion

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.

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

Pimecrolimus, however, 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. It prevented more flares than vehicle, but it remains to be seen whether the early use of mild steroids may be as effective.

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. We found no evidence that these newer, more expensive products offer such an advantage when compared with standard practice. No thinning of the skin was found in one preliminary randomised controlled trial of pimecrolimus applied to normal skin for four weeks.⁷ Such a study is 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 at one year in the tacrolimus group.⁸

Strengths and limitations of the review
In contrast to an earlier review of 16 studies,⁹ we examined 25 clinical trials, using a wider range of clinically relevant outcome measures, and focused on direct comparisons with active treatments, rather than making indirect inferences from placebo controlled trials.

One limitation of our study is that our analysis of rates of withdrawals and adverse events were based on data pooled from trials of different durations. Other potential sources of heterogeneity in the results may include the age of the patient population, the severity of the disease, and the topical corticosteroid. Despite investigators' global 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.^{10 11}

---

References w1-w23 are on bmj.com

This is the abridged version of an article that was posted on bmj.com on 24 February 2005: http://bmj.com/cgi/doi/10.1136/bmj.38376.439653.D3

Contributors: See bmj.com

Funding: RG and KS were funded by the NHS Health Technology Assessment programme.

Competing interests: None declared.

Ethical approval: Not required.

References

1. 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 Immunol1999; 103: 125-38.[CrossRef][Web of Science][Medline]
2. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials1986; 7: 177-88.[CrossRef][Web of Science][Medline]
3. 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.[Medline]
4. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ2003; 327: 557-60.
5. 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. Pediatrics2002; 110: 1133-6.[Medline]
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 Dermatol2001; 44: S65-72.[CrossRef][Web of Science][Medline]
7. 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 Dermatol2001; 144: 507-13.[Medline]
8. 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 Dermatol2004; 150: 1174-81.[CrossRef][Web of Science][Medline]
9. 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. Am J Clin Dermatol2004; 5: 267-79.[CrossRef][Web of Science][Medline]
10. Charman C, Williams H. Outcome measures of disease severity in atopic eczema. Arch Dermatol2000; 136: 763-9.
11. Charman C, Chambers C, Williams H. Measuring atopic dermatitis severity in randomized controlled clinical trials: what exactly are we measuring? J Invest Dermatol2003; 120: 932-41.[Free Full Text]

(Accepted 14 January 2005)

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    StumbleUpon    Technorati    What's this?

Relevant Articles

Atopic and non-atopic eczema

Sara Brown and Nick J Reynolds
BMJ 2006 332: 584-588. [Extract] [Full Text] [PDF]

Tacrolimus 0.1% matches potent steroids in eczema
BMJ 2005 330: 0. [Full Text]

Itching for a solution

Peter Lapsley
BMJ 2005 330: 522. [Extract] [Full Text] [PDF]

Related external webpages:

NHS Health Technology Assessment Programme

This article has been cited by other articles:

• Kato, A., Chustz, R. T., Ogasawara, T., Kulka, M., Saito, H., Schleimer, R. P., Matsumoto, K. (2009). Dexamethasone and FK506 Inhibit Expression of Distinct Subsets of Chemokines in Human Mast Cells. J. Immunol. 182: 7233-7243 [Abstract] [Full text]  
• Stern, R. S. (2006). Topical calcineurin inhibitors labeling: putting the "box" in perspective.. Arch Dermatol 142: 1233-1235 [Full text]  
• Phipatanakul, W. (2006). Efficacy and Tolerability of Pimecrolimus and Tacrolimus in the Treatment of Atopic Dermatitis: Meta-analysis of Randomised Controlled Trials. Pediatrics 118: S16-S17 [Abstract]  
• Brown, S., Reynolds, N. J (2006). Atopic and non-atopic eczema. BMJ 332: 584-588 [Full text]  
• Tlacuilo-Parra, A., Guevara-Gutierrez, E., Gutierrez-Murillo, F., Soto-Ortiz, A., Barba-Gomez, F., Hernandez-Torres, M., Salazar-Paramo, M. (2005). Pimecrolimus 1% cream for the treatment of discoid lupus erythematosus. Rheumatology (Oxford) 44: 1564-1568 [Abstract] [Full text]  
• Williams, H. C. (2005). Atopic Dermatitis. NEJM 352: 2314-2324 [Full text]  
• Yan, A. C. (2005). Topical Pimecrolimus and Tacrolimus versus Topical Corticosteroids for Atopic Dermatitis. AAP Grand Rounds 13: 62-63 [Full text]  
• Wooltorton, E. (2005). Eczema drugs tacrolimus (Protopic) and pimecrolimus (Elidel): cancer concerns. CMAJ 172: 1179-1180 [Full text]  
• (2005). Tacrolimus for Atopic Dermatitis. JWatch General 2005: 3-3 [Full text]  
• (2005). Tacrolimus and Pimecrolimus: Are They Better Than Steroids?. Journal Watch Dermatology 2005: 1-1 [Full text]  
• Lapsley, P. (2005). Itching for a solution. BMJ 330: 522-522 [Full text]  

Online poll

Find out more>>