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British Journal of Dermatology 2004; 150: 554562.

Edited by Foxit Reader Copyright(C) by Foxit Corporation,2005-2010 For Evaluation Only.

Therapeutics 003% tacrolimus ointment applied once or twice daily is more efcacious than 1% hydrocortisone acetate in children with moderate to severe atopic dermatitis: results of a randomized double-blind controlled trial
S.REITAMO, J.HARPER,* J.D.BOS, F.CAMBAZARD, C.BRUIJNZEEL-KOOMEN, P . V A L K , C . S M I T H , * * C . M O S S , A . D O B O Z Y A N D R . P A L A T S I F O R T H E EUROPEAN TACROLIMUS OINTMENT GROUP
Department of Dermatology, Helsinki University Central Hospital, Helsinki *Department of Dermatology, Great Ormond Street Hospital for Children, London, U.K. Department of Dermatology, Academic Medical Centre, University of Amsterdam, the Netherlands Service de Dermatologie, Saint Etienne Cedex, France Department of Dermatology, University Hospital, Utrecht, the Netherlands Department of Dermatology, University Medical Centre St Radboud, Nijmegen, the Netherlands **Skin Therapy Research Unit, University Hospital Lewisham, London, U.K. Department of Paediatric Dermatology, Birmingham Childrens Hospital, Birmingham, U.K. Department of Dermatology, University of Szeged, Hungary Department of Dermatology, University Central Hospital Oulu, Oulu, Finland Additional members of the European Tacrolimus Ointment Study Group are listed in the appendix. Accepted for publication 4 August 2003

Summary

Background Topical corticosteroids are the usual treatment for atopic dermatitis (AD) in children but can have side-effects. Objectives This study compared the efcacy and safety of 003% tacrolimus ointment applied once or twice daily over a 3-week period with the twice daily application of 1% hydrocortisone acetate (HA) ointment in children with moderate to severe AD. Patients and methods Patients applied ointment daily to all affected body surface areas. The primary study endpoint was the percentage change in the modied Eczema Area and Severity Index (mEASI) between baseline and treatment end. Results Six hundred and twenty-four patients, aged 215 years, applied 003% tacrolimus ointment once daily (n 207), twice daily (n 210) or 1% HA twice daily (n 207). By the end of treatment, application of 003% tacrolimus ointment both once or twice daily resulted in signicantly greater median percentage decreases in mEASI (667% and 767%, respectively) compared with 1% HA (476%; P < 0001). Furthermore, the median percentage decrease in mEASI was signicantly greater for patients applying 003% tacrolimus twice daily compared with once daily (P 0007). Patients with severe AD beneted especially from twice daily application of 003% tacrolimus ointment compared with once daily application (P 0001). Transient mild to moderate skin burning occurred signicantly more often in the 003% tacrolimus groups (P 0028) but resolved in most cases within 34 days. Laboratory parameters showed no clinically relevant changes.

Correspondence: Dr Sakari Reitamo MD. E-mail: sakari.reitamo@hus.

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Conclusions 003% tacrolimus ointment applied once or twice daily is signicantly more efcacious than 1% HA in treating moderatesevere AD in children. Twice daily application of 003% tacrolimus ointment results in the greatest improvement in mEASI, and is especially effective in patients with severe baseline disease. Key words: atopic dermatitis, efcacy, paediatric, tacrolimus ointment 003%

Atopic dermatitis (AD) is a common, inammatory skin disease that typically runs a chronic course of exacerbations and remissions. Intense itching is the predominant symptom and excessive scratching can cause damaging excoriations, erosions and lichenication of the skin.1 The disease is most common during childhood with 8090% of cases occurring before 5 years of age,2 and there exists a genetic predisposition with symptoms being triggered by various environmental and psychological factors.3 AD can signicantly affect the childs quality of life as patients are often distressed by their appearance, have low self-esteem and sometimes cannot enjoy normal routine activities and social interactions. The exact pathogenesis of AD is unknown, but it is believed that immunoglobulin (Ig) E-mediated reactions and cellular responses are involved in causing inammation.1 Until now, topical corticosteroids have been the standard treatment of choice for acute outbreaks of AD, but their use can be associated with atrophogenic side-effects.4 An alternative, steroid-free, anti-inammatory agent that could provide a safe and effective long-term treatment for patients with AD would add to the treatment options for this complex disease. A new product is tacrolimus, a macrolide calcineurin inhibitor that prevents the expression of inammatory T-cell cytokines, such as interleukin (IL)-2, IL-3, IL-4 and tumour necrosis factor (TNF)-a.5 As tacrolimus has a relatively small molecular size, it is able to penetrate the skin effectively, and the topical ointment formulation was developed specially for the treatment of AD. In contrast to corticosteroids, tacrolimus ointment does not reduce collagen synthesis or skin thickness, and can be used safely on the thinner and more vulnerable regions of skin, such as the face and neck.6 Systemic absorption of the ointment is minimal7,8 and as, to date, there has been no evidence of systemic accumulation, it appears that the ointment can be applied safely over the long term to large affected body surface areas.9 Clinical studies undertaken in Europe, the U.S.A. and Japan have demonstrated that both the 01% and 003% ointment formulations applied twice daily are efcacious and welltolerated by adult612 and paediatric1316 patients alike.

This study investigates whether 003% tacrolimus ointment applied only once daily is more efcacious than a common steroid treatment for children17 with moderate to severe AD.

Methods
This randomized, double-blind comparative study was conducted at 42 centres in 11 European countries. The ethics committee from each centre reviewed the protocol and granted approval prior to the start of the study. The study consisted of a screening visit conducted 27 days prior to the baseline visit (day 1, treatment allocation) and assessments made during the 3-week treatment phase on days 1, 4 and 8 and at weeks 2 and 3. A follow-up visit was conducted 2 weeks after the end of treatment. Following written informed consent from the parent guardian, male and female patients aged 2 15 years with a diagnosis of AD based on the criteria of Hanin and Rajka18 were enrolled in the study. The patients were required to have a grading of moderate to severe AD as dened by the scoring system of Rajka and Langeland.19 This technique rates separately the extent, course and intensity of the disease on a scale between 1 and 3 and then adds the three individual scores to determine overall severity (maximum 9). A score of 34 represents mild AD, 4575 moderate AD, and 89 denotes severe disease. Patients were also required to have disease involvement of 5100% of the total body surface area (BSA). Randomization was 1 : 1 : 1 stratied by centre and age of the patient (26 years and 715 years). All patients received two sets of tubes of ointment, one for morning and another for evening. The patients applied either a thin layer of 003% tacrolimus ointment once or twice daily or 1% hydrocortisone acetate (HA) ointment twice daily to all affected BSAs. To ensure blinding, the patients applying 003% tacrolimus ointment once daily also administered a vehicle control as the second daily application. The study ointment was supplied in identical tubes to ensure blinding and treatment was to continue uninterrupted for a minimum

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of 2 weeks. Cleared areas were to be treated for an additional 7 days postclearance. Prohibited therapies during the study included topical or systemic corticosteroids, antimicrobials and antihistamines, coal tar, topical nonsteroidal anti-inammatory drugs, ultraviolet (UV) treatments (UVA and UVB), hypnotics and sedatives, and systemic immunosuppressive agents, e.g. ciclosporin. The washout phase for these therapies ranged from a minimum of 5 days (for medicated topical agents, systemic antihistamines and sedatives) to a maximum of 6 weeks (for astemizole and UV treatments) prior to the start of the study. The washout period for systemic corticosteroids and nonsteroidal immunosuppressants was 4 weeks. Inhaled or intranasal corticosteroids were limited to 1 mg day)1. Bath oil and nonmedicated emollients were permitted. The primary study endpoint was the percentage change between baseline and the end of treatment in the modied Eczema Area and Severity Index (mEASI). The mEASI is a composite score comprising severity ratings of erythema, oedema induration papulation, excoriations and lichenication weighted according to the estimated percentage of affected BSA. The mEASI is identical to the Eczema Area and Severity Index (EASI)20 but includes an additional assessment of itch which is considered one of the primary symptoms of AD. For each body region (head neck, upper limbs, trunk and lower limbs), an affected area score of 06 was assigned for the percentage of affected BSA (0100%). The individual ratings for erythema, oedema induration papulation, excoriations and lichenication were then added (03 for each of the four symptoms) before the sum of the individual symptoms (maximum 12) was multiplied by the affected area score (maximum 6) to give a maximum of 72. In the patients aged 26 years, the head neck subtotal was multiplied by 02, the upper limb subtotal by 02, the trunk subtotal by 03, and the lower limb subtotal by 03 before being summed (maximum 72). The same applied to the patients aged 715 years except that the head and neck subtotal was multiplied by 01 and the lower limb subtotal by 04 to give a maximum of 72. Patients or parents assessed the intensity of itching during the previous 24 h by using a 10-cm visual analogue scale, 0 cm indicating no itch and 10 cm representing worst itch imaginable. The patients parents assessment of itch was converted from the visual analogue scale to an ordinal scale of 03 which was then multiplied by the investigators total affected area scale (06) to give a maximum score of 18. The maximum mEASI score is therefore 90 points.

Additional endpoints included the EASI score, the response rate (dened as the proportion of patients with at least 60% improvement in mEASI between baseline and treatment end), the physicians global evaluation of clinical response, the patients assessment of global response, the physicians assessment of affected BSA, and the patients assessment of quality of sleep. For the physicians global evaluation of clinical response, investigators were instructed to use cleared to indicate improvement of 100%, excellent for improvement of 9099%, marked for 7589%, moderate for 5074%, slight for 3049%, no appreciable improvement for 029% and worse for worsening of the condition. The patient or parent evaluated the change from baseline of the AD (how it looked, felt, appeared to others) as much better, better, slightly better, same, slightly worse, worse or much worse. At each assessment, the quality of sleep during the previous night was rated using a 10-cm analogue scale with 0 cm indicating slept badly and 10 cm indicating slept well. Safety assessments during the study included monitoring of adverse events and clinical laboratory assessments. An adverse event was dened as any undesirable experience that occurred to a patient during the study, regardless of whether it was related to the study drug. The intent-to-treat (ITT) population data were used for all of the statistical analyses, i.e. all randomized patients who received at least one application of ointment. The primary and secondary efcacy endpoints were analysed using Wilcoxon rank-sum tests. Descriptive P-values for pairwise comparisons of treatment groups were also calculated according to the Wilcoxon rank-sum test while Fishers exact test was used to compare the incidence of adverse events among the treatment groups.

Results
Efcacy There was little difference in the data reported for the 26-year-old and 715-year-old subgroups within each treatment group, and therefore only the collective data for each treatment regimen are discussed. In total, 624 patients were randomized to treatment and comprised the ITT population; 207 and 210 patients applied 003% tacrolimus ointment once or twice daily while 207 patients applied 1% HA twice daily. Fortyone patients (198%) were withdrawn from the 1% HA group and 26 patients (126%) and 21 patients

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Table 1. Demographic and baseline characteristics and reasons for withdrawal

Hydrocortisone acetate 1% n 207 Age in years (mean SD) All patients 7 2 4 1 26 years of age 3 9 1 3 715 years of age 108 28 Male female (%) 517 : 483 Ethnic group: n (%) Caucasian 179 (865) Black 9 (43) Oriental 6 (29) Other 13 (63) Overall duration of atopic dermatitis Mean years SD 6 3 4 0 Median years (minmax) 50 (< 115) Duration of current episode Mean months SD 275 374 Median months (minmax) 99 (021764) Severity of atopic dermatitis on day 1: n (%) Mild 0 Moderate 93 (449) Severe 114 (551) Total affected body surface area day 1: n (%) 0 to 25% 75 (362) > 25% to 50% 63 (304) > 50% to 75% 51 (246) > 75% to 100% 18 (87) Percentage affected BSA (day 1) Mean SD 389 242 Median (minmax) 360 (50990) Reasons for treatment discontinuation: n (%) Lack of efcacy 17 (82) Adverse event 6 (29) Prohibited therapy 1 (05) Withdrawal of consent 11 (53) Other 6 (29)

Tacrolimus ointment 003% Once daily 207 67 39 40 15 105 26 483 : 517 172 (831) 9 (43) 10 (48) 16 (77) 57 38 50 (< 115) 265 358 92 (021689) 0 108 (522) 99 (478) 89 53 43 22 (430) (256) (208) (106) Twice daily 210 69 42 36 14 110 27 452 : 548 172 (819) 6 (29) 13 (62) 19 (90) 61 40 50 (115) 281 400 79 (011718) 1 (05) 111 (529) 98 (467) 87 63 43 17 (414) (300) (205) (81)

372 260 315 (501000) 8 3 5 6 4 (39) (14) (24) (29) (19)

371 237 320 (471000) 4 8 1 4 4 (19) (38) (05) (19) (19)

(100%) were withdrawn from the once and twice daily 003% tacrolimus groups, respectively (Table 1). Lack of efcacy was the main reason for withdrawal from the 1% HA group (17 patients; 82%) and the once daily 003% tacrolimus group (eight patients; 39%) while adverse events were the main cause of withdrawal in the twice daily 003% tacrolimus group (eight patients; 38%). Patient demographic characteristics were similar among the three treatment groups (Table 1). With respect to baseline disease status, more patients in the 1% HA group had severe AD (114 patients; P NS, v2-test) compared with the 003% tacrolimus once and twice daily groups (99 and 98 patients, respectively). The mean percentage of affected BSA measured at baseline was similar for each of the treatment groups (1% HA 389%; 003% tacrolimus once daily 372%; 003% tacrolimus twice daily 371%). Twenty-two patients (106%) in the 003% tacrolimus once daily group had an affected BSA of

75100% compared with 18 patients (87%) in the 1% HA group and 17 patients (81%) in the 003% tacrolimus twice daily groups. After 3 weeks of treatment, the median percentage decrease from baseline in mEASI was 787%, 700% and 472% for the twice daily 003% tacrolimus, once daily 003% tacrolimus and 1% HA groups, respectively (Fig. 1). A substantial improvement in mEASI was evident by day 4 for all three treatment groups, but by the end of week 1, both 003% tacrolimus ointment regimens showed signicantly greater median percentage decreases in mEASI compared with 1% HA, a difference which was maintained over the remaining treatment time (P < 0001, Wilcoxon rank-sum test). Furthermore by day 4, the patients applying 003% tacrolimus ointment twice daily experienced superior improvement compared with those applying the ointment once daily, and this improvement became signicantly greater after 2 weeks (P 0028), and

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Figure 1. Median percentage decrease from baseline in the modied Eczema Area and Severity Index (mEASI). EOT, end of treatment; HA, hydrocortisone acetate.

Figure 2. Response rate [ 60% improvement in modied Eczema Area and Severity Index (mEASI)] by baseline severity of atopic dermatitis (AD). HA, hydrocortisone acetate.

highly signicant after 3 weeks of treatment (P 0007, Wilcoxon rank-sum test). The data were also subanalysed according to the baseline disease severity of the patients. In all three treatment groups, the response rate of the patients who had severe disease at baseline was lower than for the patients with moderate baseline disease (Fig. 2). Although patients with moderate disease experienced signicantly more improvement in mEASI following once or twice daily application of 003% tacrolimus ointment compared with 1% HA ointment (P < 0001, Wilcoxon rank-sum test), there was little difference in

efcacy between once daily and twice daily 003% tacrolimus ointment application (Table 2). However, patients with severe AD at baseline responded signicantly better to twice daily application of 003% tacrolimus ointment compared with once daily application (median percentage decrease from baseline 755% vs. 541%; P 0001, Wilcoxon rank-sum test). The mEASI data were conrmed by all of the secondary endpoint measurements. The median percentage decrease in EASI between baseline and week 3 was signicantly higher for both 003% tacrolimus ointment regimens (twice daily 767%, once daily 667%) compared with 1% HA (476%; P < 0001, Wilcoxon ranksum test), and twice daily application of 003% tacrolimus ointment resulted in signicantly greater improvement compared with once daily application (P 0015, Wilcoxon rank-sum test). With respect to the physicians assessment of the percentage of affected BSA, a substantial decrease was evident by day 4 for all three treatment groups. By the end of week 1, patients applying 003% tacrolimus ointment either once or twice daily had greater improvement in affected BSA compared with the 1% HA group and this difference was signicant after 3 weeks of treatment (P < 0001, Wilcoxon rank-sum test). Again twice daily application of 003% tacrolimus ointment resulted in signicantly greater improvement compared with once daily application (P 0016, Wilcoxon rank-sum test). Both physicians and patients parents reported better efcacy with both of the 003% tacrolimus ointment regimens, with twice daily application being judged to result in greatest improvement (Table 3). Itch and assessment of sleep quality improved between day 1 and the end of treatment for all three treatment groups, but again the greatest improvement was reported by the patients applying 003% tacrolimus ointment twice daily. These patients experienced a mean decrease in itch of almost 60% and a mean increase of 45% in sleep quality over the 3-week period. Although the mean affected BSA at baseline was similar for the three treatment groups, patients in the

Table 2. Modied Eczema Area and Severity Index percentage decrease from baseline to end of treatment (week 3) by baseline severity of atopic dermatitis Tacrolimus ointment 003% Hydrocortisone acetate 1% n Baseline severity Moderate Severe 92 112 Median (25% 75%) 597 (215 839) 416 (107 656) n 107 97 Once daily Median (25% 75%) 793 (571 913) 541 (180 800) n 110 96 Twice daily Median (25% 75%) 816 (607 918) 755 (523 868)

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Table 3. Physician and patient assessments of overall improvement of atopic dermatitis from baseline to end of treatment (week 3)

Hydrocortisone acetate 1% Physicians global evaluation of clinical response All patients (n) 206 Cleared or excellent (n %) 28 (136) moderate improvement (n %) 109 (529) Patients assessment of global response All patients (n) 205 Much better (n %) 43 (210) Better or much better (n %) 104 (507) Patients assessment of itch and quality of sleep Itch (n, mean SD) Day 1 207 (62 End of treatment (week 3) 204 (42 Quality of sleep (n, mean SD) Day 1 207 (56 End of treatment (week 3) 204 (70

Tacrolimus ointment 003% Once daily 205 57 (278) 152 (741) 206 87 (422) 138 (670) Twice daily 210 77 (367) 170 (810) 210 99 (471) 174 (829)

26) 31) 31) 32)

206 (63 27) 206 (33 30) 206 (59 32) 206 (75 30)

209 (61 26) 208 (26 26) 209 (56 31) 208 (81 24)

1% HA group applied considerably more ointment over the 3-week period (mean total ointment used 1752 g). The patients applying 003% tacrolimus ointment once daily required a mean total of 1120 g (mean 538 g placebo + mean 594 g tacrolimus ointment) while the patients in the 003% tacrolimus twice daily treatment group required a mean total of 1225 g ointment. Safety Skin burning and pruritus at the site of ointment application were the most common adverse events reported in all three treatment groups (Table 4) with most cases being mild to moderate in severity and decreasing over time (Fig. 3). Patients applying 003% tacrolimus ointment once or twice daily experienced signicantly more transient skin burning compared
Figure 3. Prevalence of skin burning over time. EOT, end of treatment; HA, hydrocortisone acetate.

Table 4. Incidence of most commona adverse events irrespective of causality Hydrocortisone acetate 1% 207 30 (145) 33 (159) 8 (39) 11 (53) 2 (10) 4 (19) 6 (29) 2 (10) 6 (29) 5 (24) Tacrolimus ointment 003% Once daily 207 48 (232) 38 (184) 8 (39) 6 (29) 6 (29) 5 (24) 2 (10) 3 (14) 3 (14) 3 (14) Twice daily 210 50 (238) 45 (214) 11 (52) 12 (57) 6 (29) 6 (29) 8 (38) 6 (29) 6 (29) 3 (14)

COSTART n Skin burning Pruritus Folliculitis Flu syndrome Skin erythema Fever Headache Rash Skin infection Pustular rash

Figure 4. Incidence of skin burning by baseline severity of atopic dermatitis (AD). HA, hydrocortisone acetate.

COSTART, coding symbols for thesaurus of adverse reaction terms. a At least 2% of patients in any treatment group.

with the 1% HA group (P 0028, Fishers exact test). As would be expected, the patients with severe AD at baseline experienced a higher incidence of skin burning compared with those with moderate disease (Fig. 4). Skin irritation led to discontinuation of treatment in two patients applying 003% tacrolimus ointment (one patient once daily and one patient twice daily).

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There was a low incidence of herpes simplex in all three treatment groups. One patient (05%) in the 1% HA group developed herpes simplex that was assessed as being related to treatment. Two patients (10%) in the once daily 003% tacrolimus group reported herpes simplex (both unrelated to treatment) and three patients (14%) in the twice daily 003% tacrolimus group also experienced herpes simplex (two cases assessed as being related to treatment). Flu syndrome and fever were the most common adverse events not at the application site and there were no signicant differences among the treatment groups. No treatment-related age differences in safety prole were apparent between the two age groups with the exception of skin burning which tended to occur more often in the 715-year-old age group. Six patients experienced serious adverse events during the treatment phase of the study. In the 1% HA group, one patient had abdominal pain (assessed as being unrelated to the study drug), one patient developed moderate leg pain attributed to an osteoarticular infection (possibly related), and one patient experienced lack of drug effect (unlikely relationship; occurred on day 2). In the twice daily 003% tacrolimus treatment group, one patient had lack of drug effect (unlikely relationship), one patient was hospitalized for a routine check-up because of failure to thrive (denitely unrelated) and one 003% tacrolimus-treated patient developed Kaposis varicelliform eruption together with a bacterial skin infection (possibly related). There were no serious adverse events reported for the patients in the once daily 003% tacrolimus treatment group. Adverse events leading to treatment discontinuation were reported in six patients in the 1% HA group (three patients with skin infection, one patient with exacerbation of untreated area, one with pustular rash and one patient with lack of drug effect). In the once daily 003% tacrolimus treatment group, three patients discontinued treatment because of adverse events. One patient had skin burning and pruritus, one patient had exacerbation of untreated area and the third patient developed pustular rash. Eight patients in the twice daily 003% tacrolimus treatment group discontinued treatment because of adverse events: one patient with skin burning, one patient with folliculitis and superimposed infection, two patients with herpes simplex (one patient had an additional bacterial infection), two patients with lack of drug effect, and two patients with skin infections. There were no clinically relevant changes in laboratory values throughout the study in the majority of

patients. One patient in the once daily 003% tacrolimus group had a low white blood cell count measured on day 16 which was assessed as having an unlikely relationship to the study drug. Leucopenia was reported on day 21 in one patient in the 003% tacrolimus twice daily group and was assessed as being possibly related to the study drug.

Discussion
This is the rst study of its kind to investigate whether the lower concentration of 003% tacrolimus ointment applied once or twice daily is more efcacious in treating moderate to severe AD than a low-potency steroid applied twice daily. These data demonstrated that, compared with the twice daily application of 1% HA, both once and twice daily application of 003% tacrolimus ointment resulted in signicantly greater improvement in the signs and symptoms of AD in children. The best clinical improvement was observed in patients who were applying 003% tacrolimus ointment twice daily, and this regimen was particularly effective in patients with severe baseline disease. As patients with moderate AD at baseline experienced little difference in efcacy between once and twice daily application of 003% tacrolimus ointment, a once daily treatment regimen would appear to be sufcient for these patients. A possible therapeutic option for the clinician would be to apply 003% tacrolimus ointment twice daily to bring severe AD under control to moderate levels, whereupon patients could then graduate to once daily application. Further studies may show whether once daily application of 003% tacrolimus ointment could be reduced further with time and accordant disease clearance, until only intermittent treatment as necessary would be required. The patients applying 003% tacrolimus ointment experienced larger and swifter decreases in affected BSA, and consequently, required less ointment to treat the lesions and maintain treatment efcacy. Successfully reducing ointment usage without compromising efcacy not only benets the patient and clinician, but also has important implications with respect to the cost of treatment for the healthcare provider. Therefore, the fact that children with moderate AD can be treated successfully with one daily application of 003% tacrolimus ointment before progressing to intermittent treatment will reduce considerably the cost of long-term treatment. The aim of any treatment is to improve the health and quality of life of the patient. The considerable improvement in the general disease symptoms experi-

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enced by the majority of the 003% tacrolimus-treated patients in this study means a substantial improvement in their quality of life. A study conducted in the U.S.A. reported signicantly better health-related quality of life benets in adults and children with AD who were treated with 003% and 01% tacrolimus ointment for a period of 12 weeks.21 Transient mild to moderate skin burning at the site of ointment application was the only adverse event that occurred signicantly more often in the 003% tacrolimus treatment groups. Previous studies have reported that the sensation of skin burning lasts only about 10 min14,15 and in this study, discomfort was not sufcient to warrant discontinuation of treatment in the majority of patients. As the lesions healed, the prevalence of skin burning decreased and the higher incidence of skin burning experienced by the patients with severe AD at baseline who were applying 003% tacrolimus ointment once daily is probably attributable to the slower healing of the skin in these patients. A weakness of the study is that 003% tacrolimus ointment was not compared with an equipotent corticosteroid. On account of the double-blinded design of the study, it was considered inappropriate to apply a more potent corticosteroid treatment, especially in such young patients, because of the potential for side-effects. Future studies with an open-label design will enable us to conduct a more equal comparison. In addition, it would have been interesting to follow-up these patients over a longer time period to see whether the clinical efcacy of both 003% tacrolimus ointment regimens was sustained or if the patients clinical condition relapsed. None the less these data present a good argument for applying 003% tacrolimus ointment either once or twice daily to children with moderate to severe AD. Physicians concerned about using the higher concentration of 01% tacrolimus ointment on their young patients may feel more comfortable about prescribing the lower concentration of tacrolimus ointment. Furthermore, the clinician can adjust the treatment schedule according to the baseline severity of their patients disease and their subsequent clinical improvement. In conclusion, 003% tacrolimus ointment is a safe and efcacious alternative to 1% HA ointment in children with moderate to severe AD and presents a exible therapeutic option for the clinician.

study was supported by Fujisawa GmbH, Munich, Germany.

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Acknowledgments
We thank Claire Foster for editorial support and Ruthild Sautermeister for the statistical analyses. This

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21 Drake L, Prendergast M, Maher R 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: 6572.

Appendix
Additional members of the European Tacrolimus Ointment Study Group: A.Alomar MD (Hospital de la Santa Creu I Sant Pau, Barcelona, Spain); C.Bieder pital Armand Trousseau, Paris Cedex, France); MD (Ho J. Berth-Jones MD (Walsgrave Hospital, Coventry, U.K.); M.Blaszczyk MD (Academia Medyzna, Warsaw, Poland); P.J.Coenraads MD (Academisch Ziekenhuis Groningen, Groningen, the Netherlands); J-P.Denoeux MD (CHU-Groupe Hospitalier SUD, Amiens, France); K.Despontin MD (Centre Hospitalier de Luxembourg, pital Saint-Louis, Luxembourg); L.Dubertret MD (Ho Paris Cedex, France); P.Friedmann MD (University General Hospital, Southampton, U.K.); C.Gelmetti MD (Ospedale Maggiore di Milano, Milan, Italy); A.Giannetti MD (Policlinico, Modena, Italy); M.A.Gonzalez MD (Hospital San Joan de Deu, Barcelona, Spain); A.Green MD (Great Ormond Street Hospital for Chilpital A Morvan, dren, London, U.K.); G.Guillet MD (Ho Brest, France); R.Harvima MD (Kuopio University Hospital, Kuopio, Finland); K.Kalimo MD (University Hospital of Turku, Turku, Finland); H.Kyllo nen MD

(Helsinki University Central Hospital, Helsinki, Finland); B.Labeille MD (CHR de Valence, Valence Cedex, France); J-M.Lachapelle MD (Cliniques Universitaires St. Luc, Brussels, Belgium); C.Larsen MD (Marselisborg Hospital, Aarhus, Denmark); M-A.Morren MD (University Hospital Leuven, Leuven, Belgium); A.P.Oranje MD (Dijkzigt Hospital, Rotterdam, the Netherlands); pital Nord, St. Etienne, France); Y.de J-L.Perrot MD (Ho pital Necker-Enfants Malades, Paris Prost MD (Ho Cedex, France); L.de Raeve MD (AZV Universiteit Brussel, Brussels, Belgium); A.Remitz MD (Helsinki University Central Hospital, Helsinki, Finland); M.Rustin MD (Royal Free Hospital, London, U.K.); J.Saarinen MD (Kuopio University Hospital, Kuopio, Finland); J.Saarikko MD (Helsinki University Central Hospital, Helsinki, Finland); G.Sharpe FRCP (Department of Dermatology, University of Liverpool, U.K.); J-F.Stalder pital Hotel-Dieu, Nantes-Cedex, France); MD (Ho E.Suys MD (Dermatologie Handelskaai 1G, Kortrijk, pital Pellegrin-Enfants, Belgium); A.Taieb MD (Ho pital Claude Bordeaux, France); P.Thomas MD (Ho Huriez, Lille Cedex, France); K.Turjanmaa MD (Tampere University Hospital, Tampere, Finland); A.Vierucci MD (Ospedale Meyer, Florence, Italy); R.Willemze MD (Leids Universitair Medisch Centrum, Leiden, the Netherlands); A.Zambrano MD (Hospital Nino Jesus, Madrid, Spain).

2004 British Association of Dermatologists, British Journal of Dermatology, 150, 554562