After years of treating atopic dermatitis with
topical, oral, and systemic steroids, safer
treatments are now available in the form of topical
immunomodulating drugs, specifically
pimecrolimus and tacrolimus. Research conducted
on these products and personal experience
with the agents was shared at several seminars
presented at the American Academy of Dermatology
2002 meeting to help physicians understand
more about new agents and where they fit within
the current spectrum of treatment options.
Update on Current Treatment Options
In a symposium entitled, "Eczema & Atopic Dermatitis,"
Sakari Reitamo, MD, from the Department of
Dermatology at the University of Helsinki's Hospital
for Skin and Allergic Diseases, presented an overview
of current treatment options based on a paper by
Hoare C, Li Wan Po A, and Williams H. (Health
Technol Assess. 2000; 4( 37): 1-191) entitled "Systematic
Review of Treatments for Atopic Eczema."
In conducing the review, the authors looked at
1165 randomized controlled trials for solid evidence
of effectiveness. Eighty percent were excluded for
quality issues. The remaining 272 discussed 47 different
interventions. The authors felt that reasonable evidence
was found only in randomized, controlled trials
of the efficacy of short-term topical corticosteroids
and oral cyclosporine, as well as psychological
approaches and ultraviolet (UV) therapy as first-line
therapy, and azathioprine and methotrexate as second-line
treatments. "Of course we know that oral steroids
work, but there are really no controlled studies available,"
Dr. Reitamo said.
Insufficient evidence was found to support the use of
oral antihistamines, Chinese herbs, house dust mite reduction,
evening primrose oil, massage therapy, hypnotherapy,
emollients, topical coal tar, maternal allergen
avoidance, or dietary restriction in established eczema.
Nor was evidence found to support twice-daily as
opposed to once-daily steroids, or topical antibiotic/
steroid combinations versus topical steroids alone.
"We really don't know if we should use a short dose of
potent steroids or weaker steroids longer term. Also,
some dermatologists dilute the topical steroids, but there
is no evidence that this should be done," he explained.
The Hoare paper also makes recommendations for
future research, one of which is the comparison of
tacrolimus and pimecrolimus with topical steroids in
studies of 4 months or longer and taking into account
disease severity. Dr. Reitamo explained that these studies
are under way and should be available next year. "The
real question is where the immunomodulators fit in with
topical corticosteroids, UV phototherapy, and oral
immunosuppressive agents," he said.
The findings of a recent study (Granlund H, et al.
Acta Derm Venereol. 2001; 81( 1): 22-27) on the effectiveness
of intermittent UV phototherapy compared
with oral cyclosporine concluded that cyclosporine is
more effective than UV treatment when measured by
percent improvement in clinical score and quality of
life. "However, it is only about a 50% improvement,
and when you stop therapy, disease activity recurs
quite quickly. The question is, can topical
immunomodulators improve on this," said Dr.
Reitamo. "Can they replace corticosteroids as first-line
therapy, or should they be used as second-line
treatments?"
Immunomodulators vs steroids
Dr. Reitamo presented three studies comparing
immunomodulators to steroids. In a double-blind,
randomized, dose-finding study of 260 adult patients,
pimecrolimus 0.05%, 0.2%, 0.6%, and 1.0% were compared
to 0.1% betamethasone-17-valerate cream and
vehicle (Luger T, et al. Br J Dermatol. 2001; 144: 788-794).
Treatment was given bid for up to 3 weeks.
Results were determined by change in pruritus and EASI
scores (Figure 1).
Figure 1
|
The study noted a clear dose-response relationship
for pimecrolimus, with all but the lowest dose being
significantly more effective than vehicle (P= 0.041,
0.001, and 0.008, respectively). The 1.0% cream was
found to be safe, well tolerated, and the most effective
concentration in the study. Therefore, it was selected
for use in phase III studies. Betamethasone was more
effective than all concentrations of pimecrolimus.
In two studies comparing tacrolimus to corticosteroids
(Reitamo S, et al. J Allergy Clin Immunol.
2002; 109: 539-546,547-555), the first, conducted in
children aged 2 to 15, compared tacrolimus ointment
0.1% and 0.03% to hydrocortisone acetate ointment
1.0%. In the second study, conducted in adults, the
comparator was 0.1% hydrocortisone butyrate. All medications
were given bid for 3 weeks. Follow-up was done
2 weeks after stopping treatment. Results were tabulated
using the modified EASI scoring system (mEASI).
"In the pediatric study, the effect of hydrocortisone
acetate was very modest, an improvement of about
36%. Tacrolimus had a better effect, with the 0.1%
tacrolimus ointment being the most effective with an
improvement of about 80%," said Dr. Reitamo.
The adult study showed no difference between hydrocortisone
butyrate and 0.1% tacrolimus at 3 weeks.
However, it was noted that patients used about 50%
more hydrocortisone butyrate than tacrolimus.
Monotherapy with topical immunomodulators
Dr. Reitamo suggested that topical immunomodulators
should be used as monotherapy. "I am afraid many of
their good sides will be lost by using them in combination
therapies," he said, citing concerns about the long-term
effects of corticosteroids on collagen synthesis. "I
think this is the real difference between the steroids and
the topical immunomodulatory agents. Patients who
regularly use corticosteroid monotherapy have low collagen
synthesis, which may appear as atrophy. Steroids
may also have undesirable immunological effects. This
may be why we have a disease that worsens and cannot
be controlled," he said.
Dr. Reitamo and colleagues looked at patients who were
switched to tacrolimus after using steroids for many years.
Collagen synthesis increased rapidly over 1 year and normalized
after 2 years. "If we had used steroids as well as
tacrolimus, we probably would not have seen this," he said.
"Lack of atrophogenicity is one of the reasons I feel that
these immunomodulators should be first-line treatments."
Conclusion
"Basically, tacrolimus is sufficient for moderately severe
atopic dermatitis, and pimecrolimus for less severe cases.
Data from Novartis suggest using pimecrolimus at the
first sign of disease, reserving steroids for exacerbations
of atopic dermatitis. Quite a few ongoing studies show
this treatment regimen can be used to promote clearance,
and many patients don't need anything else,"
Dr. Reitamo concluded.
Pimecrolimus
Pimecrolimus 1.0% was approved by the Food and Drug
Administration (FDA) in December 2001 for the
treatment of mild-to-moderate atopic dermatitis in
adults and children ages 2 and up. It is available as a
topical cream and is currently being tested as a systemic
agent.
Anne W. Lucky, MD, Volunteer Professor of Dermatology
and Pediatrics at Cincinnati Children's Hospital,
presented information and research on
pimecrolimus. She began by explaining that while
pimecrolimus and tacrolimus have similar molecular
structures, pimecrolimus is more lipophilic and goes
into the skin better than tacrolimus. However, systemic
absorption is negligible.
In preclinical studies, pimecrolimus has been
shown to inhibit allergic and irritant contact dermatitis
in animal models and has been shown to produce
little, if any, systemic immunosuppression. It is inactive
in rat models of graft versus host disease and in renal
allograft models. "This puts it in an entirely different
category than the systemic immunosuppressives that we have seen," she said.
Dr. Lucky presented combined data from two pivotal
US studies involving 236 children aged 2 to 17
years on pimecrolimus compared to 102 on placebo,
treated for 6 weeks (J Am Acad Dermatol.
2002; 46( 4): 495-504). End points were similar and included
Investigator's Global Assessment, EASI score,
relief of pruritus, and patient assessment.
In all end points, patients on pimecrolimus did significantly
better, as evaluated at first visit (day 8). Improvement
continued for the duration of the study,
with 36% of patients becoming clear or almost clear.
Pruritus significantly improved by first visit (day 8)
and continuing throughout the study. No differences
in number of skin infections or stinging and burning
were seen between the vehicle and treatment groups.
In a 1-year, multicenter, double-blind study to assess
the long-term safety and efficacy of pimecrolimus in
infants, 251 patients aged 3 to 23 months were randomized
(4: 1) to study medication or vehicle applied bid to
affected areas at first signs/ symptoms of atopic dermatitis
and until they resolve. In both treatment groups, emollients
were allowed for skin care as were -- for use according
to local label -- moderately potent corticosteroids
for flares not controlled by study medication. Corticosteroid
use was followed by a week of treatment
with study medication for residual disease.
Vehicle was used in the control group to maintain
the study blind. Primary efficacy analysis was on flare
incidence at 6 months, ranked allowing for
discontinuations.
In the 6-month results, presented at AAD 2002
(see page 8), pimecrolimus had significantly reduced
the incidence of flares compared with control. Most
pimecrolimus patients (70%) completed 6 months
without a flare, versus 33% in the control group.
More than 70% of pimecrolimus patients used no corticosteroids,
versus <40% in the control group, even
though pimecrolimus patients were involved in the
study longer. The pimecrolimus patients had superior
EASI scores and comparable adverse events. The researchers
concluded that pimecrolimus treatment was
significantly more effective than control in all secondary
efficacy assessments, with relief of pruritus seen
within the first week of treatment, thus offering significant
therapeutic advantages over conventional
treatment in the long-term management of atopic dermatitis
in this difficult-to-treat group.
Another long-term study (Pediatrics. 2002; 110( 1 pt
1): e2) involving 713 children aged 2 to 17 used the
same model. Again, half the patients on pimecrolimus
(50%) versus 28% of controls experienced no flares,
and 57% versus 31% needed no steroids. In this particular
study 12% of patients on pimecrolimus versus
6% on vehicle had viral skin infections. "This is
something we are all somewhat concerned about with
all the immunomodulators," she said.
Summary
"Pimecrolimus 1.0% cream is a welcome addition to
available treatments. Head-to-head studies with
pimecrolimus and tacrolimus are ongoing, so no one
can say yet that one is better than another.
Pimecrolimus does appear to be safe and effective in
patients as young as 3 months, but remember, this would
be off-label use, because it is FDA-approved for patients
over 2 years of age," Dr. Lucky reminded the audience.
"Pimecrolimus has low absorption and little systemic
immunosuppression. The way it was tested indicates
that it may be useful in preventing flares and reducing
the need for corticosteroids."
Tacrolimus
Amy S. Paller, MD, Chief of Dermatology at
Children's Memorial Hospital, Northwestern University
Medical School, presented a summary of information
and research about tacrolimus from the 37 clinical
trials involving 14,000 patients performed world-wide
to date. She focused on the pediatric trials,
which involved 6000 patients. Most of the trials used
the same parameters: physician assessment, percentage
of body surface area affected, EASI score, patient
assessment of pruritus, and total clinical score.
The first trial reported from the United States was a
3-week, double-blind, randomized, dose-finding study involving
180 children ages 7 to 16 with moderate-to-severe
atopic dermatitis (Boguniewicz M, et al. J Allergy Clin
Immunol. 1998; 102( 4 pt 1): 637-644). Tacrolimus
0.3%, 0.1%, and 0.03% were compared with vehicle.
This study and those that followed showed the same
trend in all parameters: a statistically significant difference
between vehicle and all concentrations of
tacrolimus, but no statistically significant difference
among the three concentrations. "So what we learned
from that study is that we really don't need the highest
concentration, which of course would elevate the risk
of increased absorption," Dr. Paller said.
Subsequent 12-week studies compared tacrolimus
0.03% and 0.1% to vehicle in similar patients with
moderate-to-severe atopic dermatitis. In all cases, success
(measured by 90% or greater clearance) was far greater
with tacrolimus than with vehicle. Good improvement
(50% or greater clearance) was seen in about 80% of
patients, versus 30% with vehicle. Significant improvement
in body surface area affected was also seen.
No statistical significance in the pruritus or total
clinical score was seen between the 0.03% and the
0.1% concentrations, although they were statistically
significant versus vehicle (Paller AW, et al. J Am Acad
Dermatol. 2001; 44( 1 suppl): S47-S57). "Although
there was no increased risk of side effects with the
0.1% compared to the 0.03%, it was this lack of statistical
significance in efficacy between these two
treatment arms that led to the FDA recommendation
of 0.03% in children," said Dr. Paller.
Dr. Paller reminded the audience of the need to assess
quality of life along with clinical changes. A quality-of-
life index, which has been validated in children,
but is not specific to atopic dermatitis, was used in the
newer studies. It showed a significant improvement in
quality of life in both toddlers and in children with
both concentrations of tacrolimus.
A longer-term trial of 255 children aged 2 to 15
with moderate-to-severe atopic dermatitis was published
in the same supplement (Kang S, et al. J Am
Acad Dermatol. 2001; 44 (1 suppl): S58-S64). In this
trial, the patients were given tacrolimus 0.1% bid and
evaluated every 3 months for up to 1 year. A dramatic
decrease in EASI score and body surface area affected
was seen in the first week, with a significant decrease
over the next 2 weeks and then gradual, continuing
decrease through 12 months. The same pattern was
noted with pruritus.
Adverse events
Application site adverse events -- specifically burning
or stinging -- may be an issue with tacrolimus, particularly
during the first week, but occur in the minority
of patients. They are reported less often in children
than in adults. "The problem tends to decrease rapidly
after the first week and stay relatively low, but we all
know there are patients -- about 5% -- who absolutely
can't get through that first week," said Dr. Paller. "I
have rarely had to stop using it. I think if you warn
your patients up front, particularly if you start them
with some topical steroids at the same time, you can
really get them past that period."
The longer-term pediatric trial showed no increased
incidence of systemic infection. Chickenpox
was the only infection that was statistically significant,
occurring in five children using the 0.03% concentration,
and none using the 0.1% concentration. "I think most of us
would agree that the occurrence of chickenpox was probably
a fluke and was not related to the use of medication,"
Dr. Paller concluded.
No trial showed any increased risk for Staphylococcus
aureus, molluscum, or herpes infections. However, the relationship
between tacrolimus and cutaneous infections will
be examined in longer-term trials.
No trial showed tacrolimus to be associated with any
steroid-related adverse event, such as atrophy or telangiectasias.
Tacrolimus is not readily absorbed. The majority
of patients (80% to 85%) have shown undetectable levels of
tacrolimus in the blood. In the patients who do absorb
some drug, the highest level detected was 2.2 ng/ mL (5 to
20 ng/ mL is the range for immunosuppression).
"There seems to be a tendency that as the atopic dermatitis
improves, the barrier improves and we see less absorption,"
she said.
Lack of adverse effects on the eyes makes tacrolimus a
safe choice for treating eyelid dermatitis. However, Dr.
Paller reminded the audience that increased absorption
must be considered in patients with poor barrier function,
such as the ichthyoses. While topical tacrolimus can be used
successfully in these conditions, blood levels can quickly become
toxic. "Many of these patients have been able to get
away with relatively infrequent applications, which can lead
to improvement without toxicity," she suggested.
Personal experience with tacrolimus
Topical tacrolimus ointment was approved by the
FDA in December 2000 at concentrations of 0.03%
and 0.1% for adults, and 0.03% for children over age
2. Its availability more than 1 year in advance of
pimecrolimus enabled many dermatologists to gain
personal experience with the drug beyond that of
clinical studies.
Dr. Paller shared her personal experience with
tacrolimus. She agrees with studies that say the face
and neck respond best and fastest, and the hands and
feet respond less well. "In the hands, feet, and other
areas where absorption is not a concern, I supplement
tacrolimus with a more potent topical corticosteroid if
it is not effective as monotherapy," she said.
She believes in preparing patients for less-than-immediate
results. "It's important for patients to realize
that there may not be a lot of change in the first
week, or even in the first few weeks. We've had several
patients who, with continuing use, have shown much
more improvement in the second month or even the
third month than they did initially, although most
patients respond fairly quickly," she added.
Although the studies showed no statistical difference
between the 0.03% and 0.1% concentrations,
Dr. Paller has found they are not always interchangeable.
"I tend to start my pediatric patients on the
0.03% concentration. But it was clear when the studies
were completed that many patients who had done
beautifully on 0.1% did not do as well when transferred
to 0.03%. And several patients who did not do
as well as expected on 0.03% did very nicely on 0.1%.
I feel comfortable switching them to the higher dose,
because safety studies have not shown any increased
problem with the use of a stronger medication. Yet I
don't think it's necessarily appropriate to start with
0.1%, unless somebody is very severe," she said.
Summary
Two-to 3-year studies continue to show topical
tacrolimus is safe in adults and children aged 2 to 15.
"Although it is not approved for children less than 2
years of age, the medication can be used with caution
in younger children, especially on the face, which can
be a difficult area to treat. If used for more extensive
body surface area involvement, however, I advise you
to get tacrolimus levels. Be sure to advise the patient
not to put the medication on areas where blood may
be drawn, or you may get an artificially elevated level.
And in general, warn patients about excessive use,"
Dr. Paller said.
Selected Research Presented at AAD 2002
Pimecrolimus Cream Is Effective and Safe in Infants Aged 3 to 23 Months With Atopic Dermatitis
Ho V, Papp K, Halbert A, Cherrill R, et al
Background:
Pimecrolimus cream, a skin-selective inflammatory
cytokine inhibitor, is effective in the treatment
of adults and children aged 2 years or older with
atopic dermatitis (AD). Pimecrolimus is a nonsteroid,
so it does not cause skin atrophy and has no potential for
corticosteroid-related systemic side effects, even when
applied to large body surface areas. We report the first
study in which a topical non-steroid selective inflammatory
cytokine inhibitor was used in infants under 2 years
of age with AD.
Figure 2
|
Methods:
A double-blind (DB), multicenter, vehicle-controlled
study evaluated the efficacy and safety of
pimecrolimus in 186 infants (3-23 months) with mild-to-moderate
AD. Patients were randomized 2: 1 to treatment
bid with pimecrolimus or corresponding vehicle, respectively,
for up to 6 weeks. After this DB phase,
patients entered a 20-week open-label (OL) extension in
which they were treated with pimecrolimus bid. Efficacy
assessments used included the Investigators' Global Assessment
(IGA), assessment of pruritus, and the Eczema
Area and Severity Index (EASI). Throughout the DB and
OL phases, monitoring of laboratory tests, vital signs,
and recordings of adverse events (AEs) were used to
assess safety.
Results:
109 (89%) of the pimecrolimus-treated patients
completed the 6-week DB phase versus only 33 (52%) of
the vehicle group. At 6 weeks, 54.5% of pimecrolimus-treated
patients had their AD cleared or almost cleared
(IGA scores of 0 or 1) versus 23.8% of vehicle-treated
patients (P< 0.001). At the end of the DB phase, the
mean reduction in EASI was significantly greater for
pimecrolimus-treated patients than for those receiving
vehicle (-61.78% vs +7.35%, respectively), and significantly
more pimecrolimus-treated patients had minimal
or no pruritus versus those in the vehicle group (72.4%
vs 33.3%, respectively; P< 0.001). Long-term control
of AD was achieved during the 20-week OL extension
and continuous improvement was consistent across all
measures.
Pimecrolimus was well tolerated throughout the DB
and OL study phases; by the end of the OL phase, only
2.9% of all patients discontinued due to AEs; none
discontinued during the DB phase. Comparably low
discontinuation rates similar to those in the vehicle
group have been observed in other pediatric studies with
pimecrolimus (Figure 2).
Conclusion:
This study demonstrates that pimecrolimus
effectively and safely controls pruritus and signs of AD in
infants as young as 3 months.
 |
Subjects n (%)
Days on second-line topical corticosteroid therapy
|
|
|
|
|
|
|
|
|
n |
0 |
1-7 |
8-14 |
15-21 |
22+ |
|
|
|
|
|
|
|
Pimecrolimus |
204 |
143 (70.1) |
16 (7.8) |
14 (6.9) |
9 (4.4) |
22 (10.8) |
|
|
Control |
46 |
18 (39.1) |
8 (17.4) |
5 (10.9) |
4 (8.7) |
11 (23.9) |
|
|
|
Table – Days on second-line topical corticosteroid therapy. Most patients (70%) in the pimecrolimus group used no topical corticosteroids.
Pimecrolimus Cream: A New Treatment Strategy That Reduced the Incidence of Flares and Use of Corticosteroids in the Long-term Management of Atopic Dermatitis in Infants 3 to 23 Months of Age
Kapp A, Bingham A, DeMoor A, Molloy S
Background:
Pimecrolimus cream, a skin-selective inflammatory
cytokine inhibitor, has been shown to be safe and
effective in the short-and long-term management of atopic
dermatitis (AD) in children aged 2 to 17 years. This study
compared a regimen for preventing progression to flares using
pimecrolimus to treat the first AD signs/ symptoms with
a conventional treatment (ie, emollients and reactive use
of corticosteroids [CS] for flares).
Methods:
This 1-year, multicenter, double-blind study
assessed long-term safety and efficacy in infants (3-23
months). The 6-month results are reported here. In
total, 251 patients were randomized (4: 1) to
pimecrolimus or corresponding vehicle, respectively,
to be applied bid to affected areas at first AD signs/
symptoms and until they resolve. In both treatment
groups, emollients were allowed for skin care, as
were -- for use according to local label -- moderately
potent CS for flares not controlled by study medication
(ie, Investigators' Global Assessment [IGA] 4 [severe],
5 [very severe]). CS use was followed by a week
of treatment with study medication for residual disease.
Vehicle was used in the control group to maintain
the study blind. Primary efficacy analysis was on
flare incidence at 6 months, ranked allowing for
discontinuations. Secondary analyses included IGA,
Eczema Area and Severity Index (EASI), and pruritus
assessment. Safety analyses included laboratory assessments,
vital signs, and monitoring of adverse events.
Results:
Pimecrolimus significantly reduced the flare
incidence compared with control (P< 0.001). Most
pimecrolimus patients (70%) completed 6 months
without a flare versus 33% in the control group, and
>70% used no CS versus <40% in the control group,
even though pimecrolimus patients were in the study
longer (Table). Median time to first use of CS in the
control group was 28 days, while less than half the
pimecrolimus group used CS at all (P< 0.001).
Pimecrolimus treatment was significantly more effective
than control in all secondary efficacy assessments,
with relief of pruritus seen within the first week of
treatment. There were no significant differences
between treatment groups in any safety assessments.
Conclusions:
Pimecrolimus cream significantly
reduced the incidence of flares and dependence on CS
in infants as young as 3 months, thus offering significant
therapeutic advantages over a conventional treatment
in the long-term management of AD in this
difficult-to-treat patient group.
Pimecrolimus Cream Reduces the Number of Flares and the Need for Topical Corticosteroids in Children With Atopic Dermatitis: a 12-Month, Double-Blind, Controlled Study
De Prost Y, Wahn U, Bos JD, Paul C, et al
Background:
Pimecrolimus, an ascomycin macro-lactam
derivative, is a cell-selective inhibitor of inflammatory
cytokines. Pimecrolimus cream, developed for
the treatment of inflammatory skin disease, is safe and
effective in atopic dermatitis (AD). This study in children
with AD compared a treatment regimen for preventing
progression to flares, ie, pimecrolimus to treat
early AD signs/ symptoms, with a conventional control
treatment (emollients and reactive use topical corticosteroids
[CS]).
Figure 3
|
Methods:
This 12-month, multicenter, double-blind
study investigated the long-term efficacy and safety of
pimecrolimus in 713 children aged 2 to 17 years.
Patients were randomized 2: 1 to pimecrolimus cream
or corresponding vehicle, applied bid at first signs/
symptoms of AD and until they resolve. In both treatment
groups, emollients were allowed for skin care, as
were -- for use according to local label -- moderately
potent CS for flares not controlled by study medication
(ie, Investigators' Global Assessment [IGA] 4 [severe],
5 [very severe]). CS use was followed by a week
of treatment with study medication for residual disease.
Vehicle was used to maintain the study blind.
Key efficacy end points were flare incidence and CS
use; primary efficacy analysis was on flare incidence at
month 6. A recall-antigen test assessed delayed-type
hypersensitivity in patients completing the 12
months.
Results:
Pimecrolimus cream significantly reduced
the flare incidence at both 6 and 12 months compared
to control (P< 0.001)( Figure 3). Of
pimecrolimus-treated patients, 60% completed 6
months without a single flare versus 35% of controls.
Time to first use of second-line CS was significantly
longer for pimecrolimus than for control
(P< 0.001). Of pimecrolimus-treated patients, 57%
completed 1 year of treatment with no second-line
CS versus 32% in the control group. There were no
differences between groups in frequency of positive
antigens in the recall-antigen test: 73% in the
pimecrolimus group had <1 positive antigen versus
67% in the control group. There was no clinically
relevant difference in incidence of adverse events
between groups.
Conclusions:
The therapeutic regimen using
pimecrolimus was more effective than a conventional
treatment in reducing the incidence of AD flares in
children. More than half those treated with
pimecrolimus cream did not require CS over 1 year.
Pimecrolimus was safe and did not affect skin immune
response.
Pimecrolimus Cream Reduces the Need for Corticosteroids in the Long-term Management of Atopic Dermatitis in Adults
Meurer M, Bräutigam M
Background:
Pimecrolimus cream, a skin-selective inflammatory
cytokine inhibitor, is safe and effective in short-term
control of adults with atopic dermatitis (AD). This study assessed
the safety and efficacy of a new pimecrolimus-based
treatment regimen in the long-term management of moderate-
to-severe atopic dermatitis (AD) in adults.
Methods:
In a 24-week, multicenter, parallel-group,
double-blind, controlled study, 192 patients with AD were
randomized (1: 1) to either the pimecrolimus-based treatment
regimen or to a conventional treatment (ie, emollients
and corticosteroid [CS]). Emollients were allowed for dry
skin. First signs and symptoms of AD were treated bid with
either pimecrolimus or vehicle cream to prevent progression
to disease flares. Vehicle was included to maintain
the study blind. If flares (ie, disease exacerbation unacceptable
to the patient) were not prevented by study
medication, CS (prednicarbate 0.25% cream) bid for 7 days
followed by od for 7 days was prescribed. CS use was followed
by a week of treatment with study medication for residual
disease. Primary efficacy analysis was the percentage
of days with topical CS use due to disease flares. Secondary
analysis included the Eczema Area and Severity Index
(EASI) and pruritus assessment. Safety was assessed by
adverse events (AEs) and laboratory data.
Figure 4
|
Results:
CS use was significantly less frequent in the
pimecrolimus group than in the conventional treatment
control group (mean 14.8% vs 37.3% of days, P< 0.001,
Figure 4). In addition, patients in the pimecrolimus group
suffered significantly fewer disease flares compared with
control (mean 1.2 vs 2.6 flares, P< 0.001). At 24 weeks, a
significant decrease in disease severity was also observed in
the pimecrolimus group compared with control (mean
EASI scores -5.5 vs -2.0, P<0.001), and 58.3% of patients
in the pimecrolimus group had no or only mild pruritus
compared with 36.5% of controls (P<0.001). There were
no significant differences in the incidence of AEs between
the two treatment groups, and no clinically significant
differences in any other safety assessment were seen.
Conclusion
Pimecrolimus cream significantly reduced
the incidence of flares and the dependence on CS, thus
offering significant therapeutic advantages over a conventional
treatment (ie, emollients and topical CS) in the
long-term management of AD in adults.
Safety and Efficacy of Tacrolimus Ointment in Young Children 2 to 6 Years of Age With Atopic Dermatitis
Prose NS, Fleischer A, Koo J, Smith ML, Rico MJ, Zheng S, et al
Introduction:
Tacrolimus ointment 0.03% is a topical
immunomodulator indicated for short-term and intermittent
long-term therapy in the treatment of children
aged 2 to 15 years with moderate-to-severe atopic dermatitis
(AD). Clinical studies to date have shown
tacrolimus ointment to be safe and effective monotherapy
for atopic dermatitis in pediatric patients. Five US-based
clinical studies have evaluated the safety and efficacy of
tacrolimus ointment in children aged to 2 to 6 years with
moderate-to-severe AD. This study used the data from the
patients enrolled in these five studies to evaluate the safety
and effectiveness of tacrolimus ointment 0.03% and 0.1%
in pediatric patients aged 2 to 6 years.
Methods:
Of the 2624 pediatric AD patients aged 2 to 6
years enrolled in these trials, 1434 had safety data available.
Of these, 1390 had received tacrolimus ointment, and 96%
had received the 0.1% concentration. Efficacy was evaluated
with the Physician's Global Evaluation of Clinical Response.
Safety was evaluated by adverse events. All adverse
events, regardless of their relationship to the study drug
treatment, were recorded during the course of the study in
patients treated with at least one application of the
tacrolimus ointment. All adverse events were recorded,
using a modified version of the Coding Symbols for the
Thesaurus of Adverse Reactions Terms (COSTART). In
the 12-week controlled study, the incidence of adverse
events was calculated based on Kaplan-Meier estimates
and adjusted for treatment duration.
Figure 5
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Results:
In the controlled trials, no clinically meaningful
changes in mean or median values for any laboratory
parameters were noted (Figure 5). The adverse event profile
of the 2-to 6-year-old patients in the controlled trials
showed no apparent difference in the 0.1% tacrolimus ointment
group compared with vehicle. In the 0.03%
tacrolimus ointment group, pruritus rates were 47.2%
versus 26.6% in vehicle, and chickenpox rates were 7.8%
versus 0% in vehicle. This difference was not deemed to
be clinically significant, as the values fell within the
expected rates in the general pediatric population.
In the open-label trials, no increase in the incidence of
adverse events or infections was seen over time. No increase
in the risk of adverse events, including infections, was found
with up to 3 years of therapy with tacrolimus ointment.
Conclusions:
Both tacrolimus ointment concentrations
(0.03% and 0.1%) are effective treatment of atopic dermatitis
in children 2 to 6 years of age. Long-term treatment
with tacrolimus ointment did not increase the adverse event
rate, including infections, in this age group. Tacrolimus
ointment is a safe topical monotherapy for atopic dermatitis
in children 2 to 6 years of age.
Long-term Safety of Topically Applied Tacrolimus Ointment in Pediatric Patients 2 to 15 Years of Age With Atopic Dermatitis
Paller AS, Hanifin J, Eichenfield L, Rico MJ, Ayers M, et al
Figure 6
|
Introduction:
Atopic dermatitis (AD) is a chronic
inflammatory skin disease that frequently presents in children.
Tacrolimus ointment 0.03% and 0.1% for adults
and 0.03% for children aged 2 to 15 years, is a topical
immunomodulator indicated for short-term and
intermittent long-term therapy in the treatment of
patients with moderate-to-severe AD. Clinical studies to
date have shown tacrolimus ointment to be a safe and effective
nonsteroidal treatment of AD in adult and pediatric
patients. This study was designed to evaluate the long-term
safety of tacrolimus ointment 0.1% in pediatric patients
when used bid, continuously, or intermittently. The interim
analysis for safety is presented here.
Method:
In an open-label, noncomparative, multicenter
extension study, 389 pediatric patients were given
tacrolimus ointment 0.1% to use bid on all affected areas
when AD was active and for one week after clearing.
Patients were permitted to restart tacrolimus ointment
therapy if AD recurred. Assessments were done at
baseline, week 1, month 3, and every 3 months during
treatment. All adverse events were recorded,
regardless of their relationship to study drug treatment,
using a modified version of the Coding Symbols
for the Thesaurus of Adverse Reactions Terms
(COSTART).
Results:
Duration of follow-up was more than 2 years
for 63% of patients and more than 3 years for 15% of
patients. Approximately 32% discontinued treatment
prematurely, primarily for administrative reasons (lost to
follow-up, patient request, noncompliance, etc). Patients
rarely discontinued due to an adverse event or lack of
efficacy. The most frequently occurring related adverse
events observed were local application site events. In
general, these events were of short duration and their
prevalence decreased after the first several days of treatment
(Figure 6).
Long-term treatment with tacrolimus ointment 0.1%
did not increase the adverse event rate, including infections.
Hazard rate analyses demonstrated no indication
of local or systemic immunosuppressive effects
with long-term use. The interim analysis demonstrates
a safety profile comparable with that of previous studies
in children.
Conclusion:
Tacrolimus ointment 0.1% is safe for the long-term
use of the treatment of atopic dermatitis in children.
The Experience of Tacrolimus Ointment in Adult Atopic Dermatitis Patients: Results of Two Large Open-Label Studies
Koo J, Abramovits W, Fivenson D, Horn T, Rico MJ, Jaracz E, et al
Introduction:
Tacrolimus ointment 0.03% and 0.1%
for adults and 0.03% for children aged 2 to 15 years is
a nonsteroidal topical immunomodulator indicated for
short-term and intermittent long-term therapy in the
treatment of patients with moderate-to-severe atopic dermatitis.
The safety and efficacy of tacrolimus ointment
monotherapy in pediatric and adult patients with atopic
dermatitis has been previously demonstrated. Safety data
were collected from two open-label, noncomparative,
multicenter, long-term studies to further evaluate the
long-term safety of tacrolimus ointment in a large cohort
of adult patients followed for up to 3 years. The goal was
to evaluate the safety of twice-daily applications of
tacrolimus ointment (0.1% and 0.03%) in patients 16
years of age with AD.
Figure 7
|
Methods:
Of the 8777 adult and pediatric patients
enrolled in two open-label, noncomparative, multicenter,
long-term studies of tacrolimus ointment (0.1% and
0.03% bid), 2582 adult patients were considered
evaluable for interim safety analysis. The majority of
these patients (99%) were treated with 0.1% tacrolimus
ointment. Patients applied tacrolimus ointment bid during
episodes of atopic dermatitis and for 1 additional
week after clearing. Patients were permitted to restart
tacrolimus ointment if the atopic dermatitis recurred.
Assessments were done at baseline, week 1 (extension
study) or month 1 (long-term study), month 3, and every
3 months during treatment. All adverse events were
recorded, regardless of their relationship to study drug
treatment, using a modified version of the Coding
Symbols for the Thesaurus of Adverse Reactions
Terms (COSTART).
Results:
In the interim analysis, median duration of
follow-up was 620 days (range, 37-1113 days) in the
extension study and 89 days (range, 1-391 days) in the
open-label safety study. The most frequently occurring related
adverse events were local application site events. There
was a lack of increased risk for any adverse event, including
infections, with long-term use of tacrolimus ointment (Figure
7). Hazard rate analyses demonstrated no increased risk
for any adverse event with long-term use of tacrolimus. No
indication of an immunosuppressive effect with long-term
use of tacrolimus was seen. Safety profiles were compatible
with those of previous studies.
Conclusion:
Long-term monotherapy with tacrolimus
ointment is a safe, nonsteroidal topical treatment of
atopic dermatitis in adult patients.
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