Am J Clin Dermatol 2006; 7 (2): 121-131

ORIGINAL RESEARCH ARTICLE 1175-0561/06/0002-0121/$39.95/0

© 2006 Adis Data Information BV. All rights reserved.

Safety, Efficacy, and Dosage of 1% Pimecrolimus

Cream for the Treatment of Atopic Dermatitis in
Daily Practice
Jann Lübbe,1 Sheila F. Friedlander,2 Bernard Cribier,3 Marie-Anne Morren,4 Amaro García-Díez,5
Carlo Gelmetti,6 Heidelore Hofmann,7 Ronald H. Houwing,8 Stephen Kownacki,9 Richard G.B. Langley,10
Marie Virtanen,11 Klaus Wolff,12 Steve Wisseh,13 Claire McGeown,14 Beatrice Abrams,13 Dirk Schneider14 on
behalf of the NOBEL (New Online Based ELidel) Study Group
1 Clinique et Policlinique de Dermatologie et Vénéréologie, Hôpital Cantonal Universitaire, Geneva, Switzerland
2 Children’s Hospital, San Diego, California, USA
3 Clinique Dermatologique, Strasbourg, France
4 Department of Dermatology, University Hospital Leuven, Leuven, Belgium
5 Hospital Universitario de la Princesa, Madrid, Spain
6 Istituto di Scienze Dermatologiche, Università degli Studi di Milano, Milan, Italy
7 Klinik fuer Dermatologie und Allergologie Biederstein, Technische Universität München, Munich, Germany
8 St. Deventer Ziekenhuizen, Deventer, The Netherlands
9 Albany House Medical Centre, Wellingborough, UK
10 Queen Elizabeth II HSC Centre for Clinical Research, Dalhousie University, Halifax, Nova Scotia, Canada
11 Hudkliniken, Akademiska Sjukhuset, Uppsala, Sweden
12 Universitaetsklinik fuer Dermatologie, Vienna, Austria
13 Novartis Pharmaceutical Co., East Hanover, New Jersey, USA
14 Novartis Pharma AG, Basel, Switzerland

Abstract Introduction: Although several controlled clinical trials have demonstrated the efficacy and good tolerability of
1% pimecrolimus cream for the treatment of atopic dermatitis, the results of these trials may not apply to real-life
usage. The objective of this study was to evaluate the safety and efficacy of a pimecrolimus-based regimen in
daily practice.
Methods: This was a 6-month, open-label, multicenter study in 947 patients aged ≥3 months with atopic
dermatitis of all severities. The investigators incorporated 1% pimecrolimus cream into patients’ standard
treatment protocols on the basis of their clinical diagnosis. Use of topical corticosteroids was allowed at the
discretion of the physician. Safety and tolerability were evaluated by monitoring adverse events. Efficacy was
evaluated by recording changes in the Investigators’ Global Assessment scores and pruritus scores at each visit.
Results: No clinically unexpected adverse events were reported. The discontinuation rate for adverse events was
2.3%. The disease improvement rate was 53.7% at week 1 and 66.9% at week 24. The pimecrolimus-based
regimen was particularly effective for the treatment of lesions involving the face (improvement rate: 61.9% at
week 1 and 76.7% at week 24). The greatest therapeutic response was experienced by pediatric patients with
mild or moderate disease. Nonetheless, 64% and 65% of infants and children, respectively, with severe/very
severe facial disease at baseline were clear/almost clear of signs of atopic dermatitis on their face at week 24. In
patients aged <18 years, most of the improvement occurred within the first week of treatment, while in adults a
progressive improvement was observed over the entire study period. Worsening of disease by the end of the
study occurred in 9.5% of patients and was most frequent in adults (12.6%). The discontinuation rate for
unsatisfactory therapeutic effect was 4.8%. The mean number of treatment days was 135.6 (SD 53.2). The mean
drug consumption (non-US centers only) was 4.2g per treatment day. Drug consumption decreased over time as
disease improved. In total, 47% of patients who completed the study never used topical corticosteroids over 6
months.
122
Conclusion: In daily practice, incorporation of 1% pimecrolimus cream into patients’ standard treatment
regimen is well tolerated and improves atopic dermatitis in approximately two-thirds of patients. Disease
improvement is particularly evident on the face. The greatest therapeutic response is experienced by pediatric
patients with mild or moderate disease. In these patients, most of the improvement is observed within 1 week
from the start of treatment.
Atopic dermatitis (AD) has become a disease of public impor-
tance[1-8] because of its increasing prevalence,[1-5] economic bur-
den,[6] and negative impact on patients’ health and quality of
life.[7,8]
For more than half a century, AD has been managed by using an
emollient to moisturize skin and a topical corticosteroid of appro-
priate potency to treat flares.[1,9-12] Although topical corticosteroids
are safe in the short-term, their long-term unrestricted use is
associated with adverse effects such as skin atrophy and suppres-
sion of the hypothalamic-pituitary-adrenal axis.[1,13-18] The risk of
adverse effects from use of topical corticosteroids is elevated in
patients of young age with extensive disease or facial involvement.
The mid- or high-potency topical corticosteroids most effectively
used to treat acute exacerbations of AD should be avoided on body
regions where the skin is particularly thin and more susceptible to
the atrophogenic effects of topical corticosteroids, such as the face
and intertriginous areas. Topical corticosteroid treatment of large
body areas with active lesions, or their use on body regions where
the skin is thin, also increases the risk of systemic absorption,
especially in young pediatric patients.[17,18] Other factors that limit
effective management of AD with topical corticosteroids include
the occurrence of contact allergic reactions,[19,20] decreasing effect
with repeat administration (tachyphylaxis),[21-23] and disease re-
bound after discontinuation.[24]
In order to prevent the occurrence of adverse effects, short-term
courses of topical corticosteroids have been advocated in the
management of AD, although this disease is a long-term, chronic
inflammatory skin disorder.[1,25,26] This problem and patients’ per-
sisting fear of adverse effects have resulted in poor satisfaction
with topical corticosteroids,[27-31] and many patients and physi-
cians have stressed the need for safer anti-inflammatory options
with a tolerability profile suitable for the long-term management
of AD.[27,31] One percent pimecrolimus cream (Elidel® 1, Novartis
Pharma GmbH, Wehr, Germany) was developed to meet this
need.[32-38] This agent is a topical calcineurin inhibitor that blocks
the release of inflammatory cytokines critically involved in the
pathogenesis of AD.[32-34] Its favorable pharmacologic profile is
characterized by negligible systemic absorption and lack of
atrophogenic potential.[35-38]
Numerous controlled clinical trials in adult and pediatric pa-
tients[38-45] have indicated that twice daily treatment with 1%
1 The use of trade names is for product identification purposes only and does not imply endorsement.
© 2006 Adis Data Information BV. All rights reserved.
Lübbe et al.
pimecrolimus cream induces rapid and sustained improvement of
AD and is well tolerated, even when the drug is used extensively
and for prolonged periods of time.[41,43,44,46,47] However, controlled
study settings may not reflect real-life drug usage because patients
are enrolled on the basis of strictly defined criteria, and concomi-
tant medications commonly used in clinical practice are not al-
lowed. This study was therefore designed to evaluate the safety
and efficacy of a pimecrolimus-based regimen in daily practice
worldwide. One percent pimecrolimus cream was used on the
basis of the physicians’ clinical diagnosis, and complemented
standard skin care and treatment modalities, including topical
corticosteroid use, that varied from center to center and from
country to country. This approach was chosen because it reflected
the expected real-life usage of the drug.
Patients and Methods
Study Design
This was a 6-month, open-label, single-arm, multicenter, pro-
spective study designed to evaluate the safety and efficacy of 1%
pimecrolimus cream in clinical practice. It was conducted in
patients ranging from 3 months to 81 years of age with a clinical
diagnosis of AD of any severity, as assessed by the investigators.
The main exclusion criteria included: pregnant or nursing women
unless the use of 1% pimecrolimus cream was clearly needed in
the physician’s opinion; subjects who had active viral infections at
the treatment site; subjects with systemic malignancy or active
lymphoproliferative disorders; subjects with skin conditions that
could interfere with evaluation (such as generalized erythroderma
and psoriasis, or current skin malignancies); subjects who were
receiving phototherapy or immunosuppressive therapy; subjects
who had used investigational drugs in the previous 8 weeks;
subjects who had used tacrolimus ointment; and subjects with
known or suspected hypersensitivity to pimecrolimus or any com-
ponent of the cream.
Ethics committee approval was obtained for all centers prior to
study implementation. All patients or legal guardians provided
signed informed consent.
To obtain an adequate sample of AD patients under daily
practice situations, it was planned to enroll at least 700 patients.
The study consisted of six visits (combined screening/baseline,
Am J Clin Dermatol 2006; 7 (2)
1% Pimecrolimus Cream for Atopic Dermatitis in Daily Practice
weeks 1, 4, 8, 16, and 24) and two telephone calls (weeks 12 and
20). The baseline was defined as day 1 prior to the first application
of the study medication.
Treatment
To examine the safety and efficacy of 1% pimecrolimus cream
use in typical clinical settings, physicians were allowed to incorpo-
rate the study medication into their established or preferred AD
treatment protocols (pimecrolimus-based regimen). In particular,
emollients, other non-medicated interventions, and appropriate
antimicrobial agents for the treatment of dermatologic infections
were allowed as per the physician’s normal practice. Topical
corticosteroids could be used to treat severe flares at the discre-
tion of the physician, without limitations. The only prohibited
concomitant treatments were topical tacrolimus, phototherapy,
and immunosuppressants. Patients were instructed to apply 1%
pimecrolimus cream twice daily to all affected areas at the first
signs or symptoms of AD. Treatment was to be continued for as
long as signs or symptoms of the disease persisted, and resumed
upon recurrence of early signs or symptoms of AD to prevent
progression to severe flare.
One percent pimecrolimus cream was the only treatment pro-
vided for free. Use of 1% pimecrolimus cream, emollients, and
any concomitant medication was recorded during the entire period
of the study. For 1% pimecrolimus cream, drug consumption was
based on tube weights (the weight of dispensed tubes minus the
weight of returned tubes), and treatment days were defined as the
number of days of pimecrolimus use from the start of treatment,
regardless of dosing (once or twice daily).
Assessment
Safety and tolerability were evaluated by continuous monitor-
ing of adverse events and by assessment of physical condition and
vital signs at each visit.
Efficacy parameters were assessed at baseline and at each
subsequent study visit. The investigators ranked the disease sever-
ity by using the Investigators’ Global Assessment (IGA),[41,43,44,47]
a 6-point scale ranging from 0 (clear) to 5 (very severe disease).
The primary efficacy parameter was the IGA assessment of the
whole body and, separately, of the face. Any reduction in the
whole-body or facial IGA scores from baseline defined whole-
body or facial disease improvement, respectively. The secondary
efficacy parameter was pruritus assessment; investigators used a
4-point scale ranging from 0 (absent) to 3 (severe) to record the
intensity of overall itching/scratching, reported by patients or their
caregivers, in the 24 hours preceding each assessment.[41,43]
© 2006 Adis Data Information BV. All rights reserved.
123
Statistical Methods
Only descriptive analyses were performed, unless otherwise
specified, using SAS version 8.2 software (SAS Inc., Cary, NC,
USA). The analyses of demographic, baseline, and safety data
were based on the safety population (all patients who received at
least one application of study medication). The incidence of ad-
verse events was calculated and summarized by severity and age
groups. The evaluation of effectiveness was based on the intent-to-
treat population (safety population patients having baseline and at
least one post-baseline efficacy measurement). Missing post-base-
line efficacy measurements were imputed using the last-observa-
tion-carried-forward approach. To eliminate potential bias due to
overestimation of the treatment effect, all patients who were clear
of disease at baseline (whole-body IGA score of 0, facial IGA
score of 0, or pruritus absent) were excluded from the whole-body
IGA, facial IGA, and pruritus analyses, respectively. Efficacy
results were presented as percentages of patients who improved or
became clear/almost clear of signs of AD (IGA of 0 or 1), with
95% CIs, for all patients combined as well as by age group
(infants: <2 years, children: 2–12 years, adolescents: 13–17 years,
adults: ≥18 years) and by the baseline level of disease severity
(mild, moderate, severe/very severe).
Results
Patients and Treatment Exposure
A total of 947 patients with a median age of 8 years (range: 3
months to 81.2 years) [table I] were recruited at 112 centers in 12
countries, including the US (48 centers), Canada (6 centers), and
Western Europe (58 centers). There were no major differences
across age groups in terms of demographic or clinical characteris-
tics (table I). The sole exception was sex, because females repre-
sented about 41% of the infant population, but their numbers
exceeded those of males in the other age groups, particularly in the
group aged 13–17 years (table I). This may indicate that the
clinical expression of AD occurs at an earlier age in boys than in
girls. Because the response to 1% pimecrolimus cream is not
known to be associated with sex, these differences were not
considered to have an impact on the validity of the study.
A total of 150 patients (15.8%) discontinued the study prema-
turely. The reasons for discontinuation were: lost to follow-up in
49 patients (5.2%); unsatisfactory therapeutic effect in 45 patients
(4.8%); withdrawal of consent in 23 patients (2.4%); adverse
events in 22 patients (2.3%); protocol violations in 10 patients
(1.1%); and administrative problems in 1 patient (<1.0%).
The overall exposure to 1% pimecrolimus cream, as expressed
by the mean number of treatment days, was 135.6 (SD 53.2). The
minimum number of treatment days in the population was 1,
indicating that every patient used 1% pimecrolimus cream at least
Am J Clin Dermatol 2006; 7 (2)
124 Lübbe et al.

Table I. Baseline demographic and clinical characteristics of all patients and by age group
All patients (n = 947) Age groups (years)
<2 (n = 177) 2–12 (n = 414) 13–17 (n = 75) ≥18 (n = 281)
Age (years)
mean 15.1 1.1 6.1 15.5 37.2
median 8.0 1.0 5.5 15.6 34.0
Sex (%)
male 47.4 59.3 47.1 37.3 43.1
female 52.6 40.7 52.9 62.7 56.9
Race (%)
Caucasian 77.7 64.4 73.2 85.3 90.7
Black 11.6 20.9 13.8 6.7 3.9
Oriental 5.4 8.5 6.0 5.3 2.5
other 5.3 6.2 7.0 2.7 2.8
Whole-body IGA (%)
0 = clear 1.4 2.3 1.4 0 1.1
1 = almost clear 5.9 7.9 4.6 10.7 5.3
2 = mild disease 34.7 40.1 35.3 32.0 31.3
3 = moderate disease 41.7 32.2 43.5 41.3 45.2
4 = severe disease 13.2 15.8 11.4 14.7 13.9
5 = very severe disease 3.1 1.7 3.9 1.3 3.2
Facial IGA (%)
0 = clear 27.9 15.3 35.3 29.3 24.6
1 = almost clear 18.5 20.3 20.0 24.0 13.5
2 = mild disease 24.0 23.7 23.4 21.3 25.6
3 = moderate disease 21.0 26.6 16.4 16.0 25.6
4 = severe disease 7.0 10.7 3.9 8.0 8.9
5 = very severe disease 1.7 3.4 1.0 1.3 1.8
Pruritus score (%)
0 = absent 4.6 6.8 3.4 6.7 4.6
1 = mild 31.0 32.2 26.1 33.3 37.0
2 = moderate 37.6 32.8 40.6 37.3 36.3
3 = severe 26.7 28.2 30.0 22.7 22.1
IGA = Investigators’ Global Assessment.

once during the study. One percent pimecrolimus cream was used
every day by 54.8% of patients. The remaining patients used 1%
pimecrolimus cream intermittently, with 22.0% having treatment-
free periods of >15 treatment days. Study drug consumption data
could be obtained only in the non-US centers (n = 510). The mean
consumption of 1% pimecrolimus cream was 4.2g per treatment
day (SD 5.3). Figure 1a shows that study drug consumption was
influenced by the level of disease severity at baseline and the
patient’s age: the greater the severity of AD and the older the
patient, the more study drug was used. As expected, study drug
consumption was also influenced by the percentage of total body
surface area affected by AD at baseline. The mean consumption of
1% pimecrolimus cream per treatment day ranged from 3.0g in
patients with <5% of total body surface area affected by AD to
10.2g in patients with ≥60% of total body surface area affected by
the disease. The mean consumption of 1% pimecrolimus cream
decreased over time for all levels of disease severity (figure 1b).
About one-third of patients were using AD-specific treatments
at study enrollment. The most frequently used were topical corti-
costeroids (12.6% of patients), topical antibacterials, and hista-
mine H1 receptor antagonists (antihistamines) [≤3.0% of patients].
During the 6-month study period, >85.0% of patients received
concomitant medications for AD. Topical corticosteroids were
used at least once by 53.0% of all patients, and the most frequently
used were hydrocortisone (not otherwise specified as to ester/
strength; 13.2% of patients) and mometasone furoate (10.6% of
patients). The proportions of patients who used topical corticoste-
roids at least once during the study were similarly distributed

© 2006 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2006; 7 (2)
1% Pimecrolimus Cream for Atopic Dermatitis in Daily Practice 125

Mild
across all age groups. The actual number of days of topical Moderate
a
corticosteroid use in these patients could not be determined. The Severe/very severe
10
other commonly used medications were antibacterials, antihista-

Mean grams per treatment day

9
mines for topical use, and amino alkyl ethers, such as
8
diphenhydramine hydrochloride.
7
At study enrollment, emollients were used for AD by 87.6% of
6
patients, most frequently after bathing or showering (79.9% of
5
patients). By week 24, the percentage of patients who used emol-
4
lients immediately after bathing or showering had decreased to
3
53.3%. There was also a decrease in the percentage of patients
2
who used emollients at least once daily at times other than bathing
1
or showering on areas of the skin affected by AD (from 67.7% at <2 2−17 ≥18 Overall
enrollment to 44.4% at the end of the study). Age group (y)

Safety and Tolerability b

Very severe
10
Severe
The most frequently reported adverse events were naso- 9

Mean grams per treatment day

Moderate
pharyngitis (12.7%), upper respiratory tract infection (10%), 8 Mild

cough (7.2%), headache (7.2%), application site burning (7.0%), 7

and pyrexia (6.5%) [table II]. Some adverse events, such as 6

nasopharyngitis, upper respiratory tract infection, otitis media,
vomiting, and diarrhea were more frequent in infants (table II),
who are commonly affected by these disorders. Other adverse
events such as asthma, conjunctivitis, and sinusitis (table II) are
disorders commonly observed in patients with AD.[1,48]
Impetigo was the most frequent bacterial infection, with an
overall incidence of 2.2%. This adverse effect occurred more
frequently in patients aged 2–12 years (3.6% of patients) [table II].
Herpes simplex infections occurred in 2.1% of all patients and
were more frequent in adults (4.6%) [table II]. In total, there were
six cases of eczema herpeticum (three in infants, two in children,
and one in adults). Of these, five cases were suspected to be related
to treatment and two cases were reported as serious adverse
events, as described below. Molluscum contagiosum and skin
papilloma occurred in 1.2% and 0.3% of patients, respectively.
Ten of the 11 patients affected by molluscum contagiosum and
two of the three patients with skin papilloma were children. The
third case of skin papilloma was reported in the adult group.
There were three nonserious cases of lymphadenopathy in
topical corticosteroid users (two in adults and one in adolescents).
Only one of these events was suspected to be related to treatment,
and this resolved spontaneously. The other two events followed an
upper respiratory tract infection and an ear infection, respectively,
and resolved in 5–9 days.
Concerning local tolerability, the most frequent application site
reaction was burning (7.0% of patients) [table II], which was
suspected to be related to treatment in all cases. In 0.5% of
patients, this adverse event was reported as severe and led to
premature discontinuation. Pruritus was reported in 4.6% of pa-
tients and in 2.9% was considered to be related to treatment. Only
one patient discontinued prematurely due to this event. All of the
5
4
3
2
1
0
>0−12 >12−24
Weeks of treatment
Fig. 1. Mean consumption of 1% pimecrolimus cream: (a) by level of
disease severity at baseline and age group; and (b) by week of treatment.
application site reactions were most frequently reported during the
first 6 weeks of treatment.
The overall incidence of serious adverse events was low
(3.1%). Two of these events were the two cases of eczema
herpeticum mentioned above, one of which required hospitaliza-
tion. Both occurred in patients aged <2 years and were suspected
to be related to treatment. The affected patients recovered fully
after antiviral treatment and continued in the study. The patient
who was hospitalized had used topical corticosteroids (triamci-
nolone for 70 days and fluticasone propionate for 21 days) over the
previous 4 months. The only serious adverse events leading to
premature discontinuation were exacerbation of AD and multiple
sclerosis; none was considered to be related to treatment.
Disease Improvement in the Intent-to-Treat Population
Use of the pimecrolimus-based regimen was associated with a
rapid improvement of the disease in most patients. Furthermore,
the improvement rate remained high throughout the study: the
percentage of patients who had a decrease in the whole-body IGA
score from baseline was 53.7% (95% CI 50.4, 57.1) at week 1 and
66.9% (95% CI 63.9, 69.9) at week 24. The pimecrolimus-based

© 2006 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2006; 7 (2)
126 Lübbe et al.

Table II. Most frequent adverse events (incidence ≥2%) in all patients and by age group
Adverse event All patients (%) [n = 947] Age groups (years)
<2 (%) [n = 177] 2–12 (%) [n = 414] 13–17 (%) [n = 75] ≥18 (%) [n = 281]
Nasopharyngitis 12.7 22.0 13.0 10.7 6.8
Upper respiratory tract infectiona 10.0 18.6 12.8 6.7 1.4
Cough 7.2 8.5 11.4 2.7 1.4
Headache 7.2 0 5.3 10.7 13.5
Application site burning 7.0 2.3 6.5 9.3 10.0
Pyrexia 6.5 13.6 8.7 0 0.7
Asthmaa 5.3 6.8 7.2 2.7 2.1
Otitis mediaa 4.6 14.7 4.1 0 0.4
Pruritus 4.6 5.6 2.9 6.7 6.0
Ear infectiona 4.0 9.6 4.1 0 1.4
Conjunctivitis 3.1 4.0 4.1 0 1.8
Influenza 3.0 2.8 3.1 1.3 3.2
Vomitinga 3.0 7.9 3.1 1.3 0
Diarrheaa 2.9 6.2 3.1 1.3 0.7
Sinusitisa 2.7 2.3 3.9 1.3 1.8
Bronchitisa 2.3 4.0 1.7 2.7 2.1
Dermatitis atopic (worsening) 2.2 4.0 1.2 4.0 2.1
Impetigoa 2.2 1.7 3.6 1.3 0.7
Pharyngolaryngeal pain 2.2 0.6 3.1 2.7 1.8
Herpes simplex infections 2.1 0.6 1.0 2.7 4.6
a Not otherwise specified as to type.

regimen was particularly effective for the treatment of lesions
involving the face: a decrease in the facial IGA score was observed
in 61.9% (95% CI 58.1, 65.7) of patients after 1 week of treatment
and in 76.7% (95% CI 73.5, 79.9) of patients at week 24.
The improvement in active skin lesions was associated with
marked symptom relief in the majority of patients: while 64.3% of
patients suffered from moderate or severe pruritus at baseline
(table I), 70.7% reported absent or mild pruritus at week 24.
In total, 47.0% of the patients who completed the study did not
need to use topical corticosteroids over the 6-month study period.
The group of patients who did not use topical corticosteroids
tended to have less severe disease at baseline than the group of
patients who did (p < 0.045 by comparison of the whole-body
IGA, facial IGA, and pruritus scores with the Mantel-Haenszel
row mean test). Other parameters, including demography, expo-
sure to 1% pimecrolimus cream, and the number of discontinua-
tions, were similar in the group of patients who used topical
corticosteroids at least once over the 6-month study period com-
pared with the group of patients who never used topical corticoste-
roids.
Disease Improvement by Age Group
The pimecrolimus-based regimen was effective across all ages,
but disease improvement occurred earlier and was more frequent
in pediatric patients than in adults (table III and table IV). At week
1, the reduction in disease severity for the whole body was more
pronounced in infants and children than in the other age groups
(table III). At week 24, children showed the greatest benefit from
treatment (table III). Pediatric patients were also more responsive
to the pimecrolimus-based regimen than adults in terms of facial
involvement (table III). However, by the end of the study, the
majority of patients in all age groups were clear/almost clear of
signs of AD on the face (table IV).
Disease Improvement by Baseline Disease Severity
At week 1, a decrease in whole-body IGA scores was observed
in 42.6% (95% CI 37.1, 48.2) of mild, 57.7% (95% CI 52.6, 62.8)
of moderate, and 77.1% (95% CI 70.2, 84.1) of severe/very severe
patients. These improvement rates increased to 59.0% (95% CI
53.7, 64.4), 71.3% (95% CI 66.9, 75.8), and 83.4% (95% CI 77.5,
89.4), respectively, by week 24. Notably, 25.2% (95% CI 18.2,
32.1) of patients with a whole-body IGA score of 4 or 5 at baseline
were clear or almost clear of signs of AD (whole-body IGA score
of 0 or 1) at the end of the treatment period.
Further analysis of the data at week 24 by age groups showed
that AD improvement for all levels of baseline disease severity
was substantial regardless of age (figure 2). The improvement rate
was higher when considering only changes in facial IGA scores:

© 2006 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2006; 7 (2)
1% Pimecrolimus Cream for Atopic Dermatitis in Daily Practice 127

virtually all pediatric and adult patients with severe or very severe
disease on their face at baseline (facial IGA score of 4 or 5)
experienced an improvement in facial lesions by the end of the
study (figure 2). Looking at the proportion of patients who became
clear or almost clear of signs of AD by week 24, the greatest
therapeutic response was experienced by infants and children with
mild or moderate disease (figure 3). Nonetheless, 64.0% (95% CI
45.2, 82.8) and 65.0% (95% CI 44.1, 85.9) of infants and children,
respectively, with severe/very severe facial disease at study enroll-
ment were clear or almost clear of signs of AD on their face at the
end of the treatment period (figure 3). As mentioned previously,
the consumption of 1% pimecrolimus cream and the number of
treatment days increased with the patients’ age and level of disease
severity at baseline. Therefore the results by age groups and level
of AD severity at baseline also reflect these differences in expo-
sure to treatment.
Patients Who Did Not Experience Disease Improvement
At the end of the study, 307 of 927 patients (33.1%) showed no
decrease in whole-body IGA: 23.6% of patients had the same
whole-body IGA score as at baseline, and 9.5% had an increase in
the whole-body IGA score from baseline, indicating worsening of
disease. Further analysis of these data, taking into account the
baseline level of disease severity, demonstrated that worsening of
disease occurred in 12.2% of patients with mild AD, 8.1% of
patients with moderate AD, and 2.6% of patients with severe/very
severe AD. Considering the different age groups, an increase in the
whole-body IGA score from baseline was observed in 9.9% of
infants, 6.7% of children, 12.2% of adolescents, and 12.6% of
adults. Whole-body worsening of disease by week 24 was less
frequent in patients who never used topical corticosteroids (5.7%)
than in those who used topical corticosteroids at least once during
the study (12.8%).
The percentage of patients experiencing worsening of disease
on the face by the end of the study was 6.8% (3.4% of infants,
5.6% of children, 13.5% of adolescents, and 9.0% of adults).
Among the 45 patients who discontinued prematurely for un-
satisfactory therapeutic effect, 24 (53.3%) were adults. The dis-
continuation rate for unsatisfactory therapeutic effect was lower in
patients who never used topical corticosteroids (3.6%) than in
those who used topical corticosteroids at least once during the
study (5.8%).
Discussion
This is the first study in which the safety and efficacy of 1%
pimecrolimus cream was verified in daily practice. Pediatricians,
general practitioners, and dermatologists from 12 countries partic-
ipated in the trial. They were allowed to incorporate 1%
pimecrolimus cream into their established or preferred AD treat-
ment regimens, rather than following a protocol-dictated treatment
modality. Although 1% pimecrolimus cream was the only treat-
ment made available for free, the pimecrolimus-based regimen
included skin care with emollients and the use of topical cortico-
steroids to treat severe flares at the discretion of the physicians,
without limitations. The safety profile of this pimecrolimus-based
regimen was good and consistent with the safety profile of 1%
pimecrolimus cream demonstrated in controlled clinical tri-
als.[38-45] There were no unexpected adverse events in any age

Table III. Disease improvement rate by week of treatment and age groupa,b
Week Age group (years)
<2 [n = 177] 2–12 [n = 414] 13–17 [n = 75] ≥18 [n = 281]
Whole-body improvement rate [% (95% CI)]
1 59.1 (51.3, 66.9) 59.7 (54.8, 64.7) 57.1 (45.5, 68.7) 40.6 (34.5, 46.6)
4 69.6 (62.7, 76.5) 67.4 (62.8, 72.0) 63.5 (52.5, 74.5) 54.2 (48.3, 60.0)
8 64.9 (57.8, 72.1) 68.9 (64.4, 73.4) 67.6 (56.9, 78.2) 57.0 (51.2, 62.9)
16 67.3 (60.2, 74.3) 66.2 (61.6, 70.8) 66.2 (55.4, 77.0) 58.5 (52.7, 64.3)
24 66.1 (59.0, 73.2) 70.9 (66.4, 75.3) 62.2 (51.1, 73.2) 62.8 (57.1, 68.5)

Facial improvement rate [% (95% CI)]

1 72.8 (65.3, 80.3) 62.7 (56.6, 68.7) 60.0 (46.4, 73.6) 53.9 (46.9, 60.9)
4 78.4 (71.7, 85.0) 76.4 (71.3, 81.5) 63.5 (50.4, 76.5) 65.4 (59.0, 71.8)
8 73.0 (65.8, 80.1) 78.7 (73.7, 83.6) 78.8 (67.7, 89.9) 68.7 (62.5, 75.0)
16 81.1 (74.8, 87.4) 76.4 (71.3, 81.5) 76.9 (65.5, 88.4) 75.4 (69.5, 81.2)
24 77.7 (71.0, 84.4) 79.4 (74.5, 84.3) 71.2 (58.8, 83.5) 73.9 (68.0, 79.9)
a All patients with a whole-body or facial IGA score of 0 at baseline (see table I) were excluded from the whole-body IGA and facial IGA analyses,
respectively.
b Any reduction in the whole-body or facial IGA score from baseline defined whole-body and facial improvement, respectively.
IGA = Investigators’ Global Assessment.

© 2006 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2006; 7 (2)
128 Lübbe et al.

group. Most adverse events were not considered to be related to
treatment and were mild or moderate in severity. Serious adverse
events were infrequent and the only two that led to premature
discontinuation were not considered to be related to treatment. In
terms of local tolerability, the reactions more frequently suspected
to be related to the application of 1% pimecrolimus cream were
skin burning and pruritus. In most cases, these local reactions were
transient and self-limited.
Patients with AD are more susceptible to skin infections than
healthy subjects.[49] Bacterial infections have been reported to
occur in 40% of AD patients.[50] The reported incidence of viral
infections in AD is 6–10% for herpes simplex,[51-53] 4% for mollus-
cum contagiosum,[52] and 4–17% for viral warts (skin papillo-
ma).[51,52] In this study, the most frequent bacterial infection of the
skin was impetigo, which affected 2.2% of patients overall, while
herpes simplex infections, molluscum contagiosum, and skin pap-
illoma occurred in 2.1%, 1.2%, and 0.3% of patients, respectively,
over the 6-month study period. Thus, the incidence of these skin
infections was low and consistent with that expected in a similar
population of patients with AD.[50-53]
In a survey of 63 patients with AD (aged 5 months to 69 years)
conducted at a single center in Germany,[54] the incidence of the
widespread form of herpes simplex infection (eczema herpeticum)
from 1982 to 1986 was about 12 cases per year. Therefore the
incidence of eczema herpeticum observed in this 6-month study
was also consistent with that expected for individuals with AD.
The evaluation of efficacy in this study was limited by the fact
that it was conducted in the context of a non-comparator, open-
label study design. Nonetheless, our findings provide new and
important information regarding the daily consumption of 1%
pimecrolimus cream and its beneficial effects in relation to the
level of disease severity and the patients’ age. The data shown in
figure 1 indicate that the mean consumption of 1% pimecrolimus
cream during the first 3 months of the treatment period ranged
from 3.4g per treatment day in patients with mild disease to 8.6g
per treatment day in patients with very severe disease. Irrespective
of the level of AD severity, the highest drug consumption was
recorded in adult patients. Consumption of 1% pimecrolimus
cream decreased over time as AD improved, and this was particu-
larly evident in patients who had severe or very severe disease at
baseline. The reduction in emollient use during the study may be
explained by a decrease in the patients’ perceived need for emol-
lients as the disease improved but should be discouraged in a real-
life situation because regular skin care with emollients is a helpful
supportive measure in the long-term management of AD.[25,26] A
large proportion of patients used topical corticosteroids at least
once during the treatment period. However, in 47% of patients,
AD was able to be controlled by a pimecrolimus-based regimen
that did not include any recourse to topical corticosteroids over 6
months.
Although all previous controlled clinical trials[38-45] demonstrat-
ed that treatment with 1% pimecrolimus cream was particularly
effective in patients with mild or moderate disease, the results of
the present study indicate that a substantial proportion of patients
with more severe AD also derive benefit from use of a
pimecrolimus-based regimen. Indeed, over 25% of patients with a
whole-body IGA of 4 or 5 at study enrollment, indicating severe or
very severe AD, were clear or almost clear of signs of AD by the
end of the study. The response rate to the pimecrolimus-based
regimen was particularly notable in infants and children. These

Table IV. Percentage of patients who were clear or almost clear of signs of atopic dermatitis by week of treatment and age groupa
Week Age group (years)
<2 [n = 177] 2–12 [n = 414] 13–17 [n = 75] ≥18 [n = 281]
Whole-body IGA of 0 or 1 [% (95% CI)]
1 36.4 (28.8, 44.0) 32.9 (28.2, 37.6) 37.1 (25.8, 48.5) 18.1 (13.4, 22.8)
4 48.0 (40.5, 55.4) 43.2 (38.4, 48.0) 39.2 (28.1, 50.3) 25.6 (20.5, 30.8)
8 51.5 (44.0, 59.0) 44.2 (39.4, 49.0) 44.6 (33.3, 55.9) 31.4 (25.9, 36.9)
16 50.9 (43.4, 58.4) 46.2 (41.3, 51.0) 37.8 (26.8, 48.9) 38.3 (32.5, 44.0)
24 53.8 (46.3, 61.3) 47.7 (42.8, 52.5) 43.2 (32.0, 54.5) 43.7 (37.8, 49.5)

Facial IGA of 0 or 1 [% (95% CI)]

1 55.9 (47.5, 64.2) 63.9 (57.9, 69.8) 60.0 (46.4, 73.6) 38.9 (32.0, 45.7)
4 68.2 (60.7, 75.7) 75.7 (70.5, 80.8) 65.4 (52.5, 78.3) 56.9 (50.2, 63.6)
8 70.9 (63.6, 78.3) 77.9 (72.9, 82.9) 73.1 (61.0, 85.1) 60.7 (54.1, 67.3)
16 74.3 (67.3, 81.4) 76.8 (71.7, 81.8) 71.2 (58.8, 83.5) 65.9 (59.5, 72.3)
24 75.7 (68.8, 82.6) 79.8 (75.0, 84.6) 71.2 (58.8, 83.5) 64.9 (58.5, 71.4)
a All patients with a whole-body or facial IGA score of 0 at baseline (see table I) were excluded from the whole-body IGA and facial IGA analyses,
respectively.
IGA = Investigators’ Global Assessment.

© 2006 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2006; 7 (2)
1% Pimecrolimus Cream for Atopic Dermatitis in Daily Practice 129

Mild
Moderate ate when treatment with 1% pimecrolimus cream should be
Severe/very severe stopped if it is not helpful. However, table III and table IV show
a Whole body that in patients aged <18 years, whole-body and facial improve-
100 ment occurred in most responsive patients within the first week of
90 treatment. In adults, a progressive increase in the improvement
80 rate was observed over the entire study period, but facial improve-
70
ment was evident in most responsive patients by the end of the
60
fourth week of treatment. Thus 1 week of treatment should be
50
40
sufficient to judge whether or not an individual patient will benefit
30 from the use of a pimecrolimus-based regimen on the face, irre-
Patients showing improvement (%)

20 spective of age. A longer treatment period may be needed for

10 adults with active lesions involving other body regions.
0
<2 2-12 13-17 ≥18
Conclusion
b Face
100 The results of this study indicate that incorporation of 1%
90 pimecrolimus cream into AD patients’ standard treatment regimen
80
in daily practice is well tolerated. During a 6-month treatment
70
period, AD improvement was observed in about two-thirds of
60
50 Mild
40 Moderate
Severe/very severe
30
20 a Whole body
10 100
0 90
<2 2-12 13-17 ≥18 80
Age groups (y) 70
Fig. 2. Disease improvement at week 24 by level of disease severity at 60
baseline and age group. The error bars are 95% CIs. Any reduction in the 50
Patients clear or almost clear of signs of AD (%)

(a) whole-body or (b) facial Investigators’ Global Assessment (IGA) score 40

from baseline defined whole-body and facial improvement, respectively. 30
20
findings are important because young pediatric patients are those 10
with the greatest need for an effective and safe alternative to 0
<2 2-12 13-17 ≥18
topical corticosteroids for treatment of AD in the long-term.[27-30]
Another important finding of our study was that the pimecrolimus- b Face
based regimen was very effective at improving facial disease. 100
About 77% of all patients who completed this study experienced 90
an improvement of AD on their face by week 24, and >60% of 80
infants and children with severe or very severe disease on the face 70
60
at baseline had no or minimal facial involvement of AD at the end
50
of the treatment period. Given the well known reluctance to use
40
topical corticosteroids on the face because of the high risk of local 30
adverse effects, these data indicate that this regimen can meet a 20
key need among patients with AD. 10
In this study, the discontinuation rate due to unsatisfactory 0
<2 2-12 13-17 ≥18
therapeutic effect was <5%. Overall, one-third of patients did not Age groups (y)
experience disease improvement. Predictors of premature discon-
Fig. 3. Proportion of patients who were clear or almost clear of signs of
tinuations for unsatisfactory therapeutic effect and poor response atopic dermatitis (AD) [Investigators’ Global Assessment (IGA) score 0 or
to treatment were age ≥18 years and concomitant use of topical 1] at week 24 by level of disease severity at baseline and age group: (a)
corticosteroids. The study was not specifically designed to evalu- whole body; (b) face. The error bars are 95% CIs.

© 2006 Adis Data Information BV. All rights reserved. Am J Clin Dermatol 2006; 7 (2)
130
patients. This improvement was particularly evident on the face,
where applications of topical corticosteroids are not recommend-
ed. The greatest therapeutic response was experienced by pediatric
patients with mild or moderate disease. In these patients, most of
the improvement was observed within 1 week from the start of
treatment. Consumption of 1% pimecrolimus cream decreases as
disease improves, particularly in patients who have severe or very
severe disease when treatment is started.
Acknowledgements
This study was sponsored by Novartis. S.F. Friedlander has received
honoraria and clinical research support from Novartis. S. Kownacki has
attended advisory board meetings and lectured for Novartis, and has received
an honorarium from the sponsor. The Dalhousie University has received a
research grant from Novartis for the conduction of this study by R.G.B. Lang-
ley. K. Wolff and J. Lübbe have received research grants from Novartis.
S. Wisseh, C. McGeown, B. Abrams, and D. Schneider are employees of
Novartis. The other authors have no conflicts of interest to disclose. The
authors thank the following investigators, listed by country, for their contribu-
tion to the NOBEL study: Austria: P. Fritsch, W. Aberer, J. Auboeck, I. Mutz;
Belgium: M. De La Brassine, J.M. Lachappelle, J.-M. Naeyaert, J. Lambert,
M. Song; Canada: B. Krafchik, G. Searles, J. Prendiville, D. Marcoux,
W. Gulliver; France: P. Amblard, J.-M. Bonnetblanc; Germany: P. Hoeger,
U. Haustein, M. Sticherling, A. Wollenberg, R. Foelster-Holst, T. Ruzicka,
G. Heyer; Italy: A. Giannetti, M. Paradisi, L. Armenio, G.A. Vena, A. Fiocchi;
The Netherlands: E.R. Lonnee, P.G.J. van Aubel, A.F.E. Bots, L.W. Barkema,
J.J.M. van der Werf, G.J.M. van Doesburg; Spain: F. Javier, M. Casado,
M. Lecha, R.P. Vallverdu; Sweden: G. Lilja, H. Beitner, A. Svensson,
T. Andersson, A. Vahlquist; Switzerland: M. Anliker, L. Braathen,
M.H. Schoeni, R. Lauener, B. Wuethrich, T. Rufli, D. Hohl; UK: B. Bodalia,
S. Rowlands, T. Poyner, A. Hetherington, A. Fuat; USA: M. Spraker, N. Le-
vine, P. Qaqundah, J. Powers, A. Iravani, P. Darden II, A. Johnson, P. Murray,
M. Chambers, S. Kempers, M. Wells, M. Petrick, M. Scannon, R. Chesney,
S. Clark, D. Tashjian, T. Chu, R. Hopp, D. Henry, J. Bautista, L. Butler,
S. Galant, C. Kauffman, K. Loven, D. Pariser, W. Teer, E. Walter, S. Capper,
M. Levy, A. Nopper, V. Fiedler, T. Fleming, D. Hominck, T. Kahn, M. Noss,
J. Bagel, M. Blatter, L. Schneider, C. Smith, C. Johnson, R. Matheson,
R. Sidbury, L. Schachner, D. Schneider, R. Conti, A. Paller, A. Kimball.
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Correspondence and offprints: Dr Jann Lübbe, Clinique et Policlinique de
Dermatologie et Vénéréologie, Hôpital Cantonal Universitaire, CH-1211
Geneva 14, Switzerland.
E-mail: jann.lubbe@hcuge.ch
Am J Clin Dermatol 2006; 7 (2)