Full text of DOI:10.2165/00128071-200203060-00002

Am J Clin Dermatol 2002; 3 (6): 381-388
1175-0561/02/0006-0381/$25.00/0
LEADING ARTICLE
© Adis International Limited. All rights reserved.
Topical Noncorticosteroid Immunomodulation
in the Treatment of Atopic Dermatitis
Sakari Reitamo, Anita Remitz, Hannele Kyllönen, Johanna Saarikko and Håkan Granlund
Department of Dermatology, Hospital for Skin and Allergic Diseases, University of Helsinki, Helsinki, Finland
At present, the first-line drugs for treating atopic dermatitis are topical corticosteroids. They are effective
Abstract
when used short-term; however, long-term use of the corticosteroids is associated with suppressive effects on
the connective tissue, seen as skin atrophy or resistance to therapy. Currently, two topical noncorticosteroid
immunomodulators tacrolimus (FK506) and pimecrolimus (SDZ ASM 981) are under development, or already
on the market in some countries for atopic dermatitis. These two compounds show structural similarity. In
T lymphocytes they bind to the same cellular receptor, the FK-binding protein (FKBP) or macrophilin-
12. Tacrolimus shows a 3-fold greater affinity to FKBP compared with pimecrolimus. The tacrolimus/
pimecrolimus–FKBP complex further binds to calcineurin, an enzyme vital for the early activation of T cells.
The consequence of calcineurin binding is a lack of activation of both T helper cell types 1 and 2. Further effects
of these compounds have been suggested on other inflammatory cells, such as Langerhans cells and mast
cells/basophils. In contrast to corticosteroids, no suppressive effects on connective tissue cells have been ob-
served. Taken together, treatment of inflammation results in healing of the barrier function of the skin. This
again results in reduced bioavailability of the drug, as compared with systemic use.
Placebo-controlled studies have shown the efficacy of both tacrolimus (at 0.03 and 0.1%) and pimecrolimus
(at 0.6 and 1%). The main adverse event in these studies has been a burning sensation and increased pruritus at
the site of application. Typically, these adverse events are observed only during the first days of treatment.
Long-term safety studies, of up to one year, have not revealed any new adverse events. So far, long-term use of
topical noncorticosteroid compounds has not been associated with signs of immune deficiency. Although there
is currently no evidence for clinically relevant, prolonged adverse effects, some of these, such as an increased
risk of photocarcinogenesis, need to be monitored. There is evidence from tacrolimus studies that monotherapy
results in better long-term results when compared with combination therapy with corticosteroids. Tacrolimus
and pimecrolimus could replace topical corticosteroids as the first-line treatment of atopic dermatitis.
Atopic dermatitis is a common disease of unknown etiology.
Both genetic and environmental factors play a role in its clinical
manifestations. The disease is characterized by itchy, dry skin, a
chronically relapsing course, and susceptibility to cutaneous in-
fections.[1,2] The therapies used so far for the treatment of atopic
dermatitis include topical corticosteroids as first-line therapy,
systemic corticosteroids, natural or artificial ultraviolet (UV)
therapies, and immunosuppressive agents such as azathioprine,
methotrexate, and cyclosporine as second-line therapy.[3] Of these
treatments, efficacy in placebo-controlled trials has only been
demonstrated for topical corticosteroids and oral cyclospor-
ine.[4,5] Like other secondary treatments for atopic dermatitis,
cyclosporine diminishes, but does not abolish, the need for topical
corticosteroid treatment.[6,7] Attempts to develop a topical formu-
lation of cyclosporine with efficacy in atopic dermatitis have
failed.[8,9] In contrast, similar formulations of tacrolimus were
effective in dinitroclorobenzene-induced atopic dermatitis.[10]
Early clinical studies demonstrated the efficacy of tacrolimus
ointment in atopic dermatitis.[11,12] Today, the new topical non-
corticosteroid immunomodulators, tacrolimus (FK506) and
pimecrolimus (SDZ ASM 981) have shown efficacy and an ex-
cellent safety profile in clinical studies as topical monotherapy
for atopic dermatitis (figure 1).[13-17] Therefore, they are the first
potential candidates to supplant topical corticosteroids as the pri-
mary treatment of atopic dermatitis.
In this review, we compare the mode of action of the new

382
Reitamo et al.
Cl
HO
O
O
O
O
O
O
OH
OH
N
N
O
O
O
O
O
O
OH
OH
O
O
O
O
O
O
Tacrolimus
Fig. 1. Molecular structures of tacrolimus and pimecrolimus.
Pimecrolimus
noncorticosteroid immunomodulatory agents, with an emphasis
on human studies, and review key clinical studies performed for
efficacy and safety with topical tacrolimus and pimecrolimus.
polypeptides, of the size 15 to 20kD, can penetrate atopic skin
and cause an immune reaction of the skin.[21,22] In atopic skin
these environmental polypeptides can be bound to CD1a+ anti-
gen-presenting cells of the epidermis, such as Langerhans cells
(LC) and inflammatory dendritic epidermal cells (IDEC), which
both contain increased densities the high-affinity receptor to im-
munoglobulin E (FcεRI) on their cell surface.[23] This facilitates
the binding of the exogenous environmental polypeptides with
the help of free specific immunoglobulin E to the antigen-
presenting cells. This ‘antigen-focusing’is an especially effective
way to present specific antigen to T cells.[24] An additional T cell
activation is caused by nonspecific polyclonal T cell activation
by superantigens, such as staphylococcal enterotoxins, shown to
be common in atopic dermatitis skin[25,26] (figure 3).
1. How Do Topical Noncorticosteroid
Immunomodulators Work in Atopic Dermatitis?
1.1 Altered Immunity in Atopic Dermatitis
Patients with atopic dermatitis show signs of altered immu-
nity in their skin and peripheral blood.[2,18] The skin of most pa-
tients with atopic dermatitis is colonized with microbes such as
Staphylococcus aureus and Malassezia furfur (Pityrosporum
ovale/orbiculare). The incidence of viral infections with herpes
simplex, viral warts and molluscum contagiosum is increased.
The majority of the patients show diminished delayed-type hy-
persensitivity reactions to recall antigens of bacterial or fungal
origin. Most patients have increased levels of immunoglobulin
(Ig) E in both the peripheral blood and the skin. This IgE has
specificity to various exogenous environmental antigens, and
also sometimes to intrinsic antigens.
1.3 T Helper Cell Subtypes
The lesional skin of atopic dermatitis contains a large number
of T cells which show characteristic cytokine profiles. In a fresh
lesion the infiltrate is characterized by cells of the T helper cell
type 2 (Th2) cytokine profile, whereas the chronic lesion the T
helper cells show a cytokine profile mainly of T helper cell type
1 (Th1).[18] Using a mouse model of atopic dermatitis, Spergel et
al.[27] showed that both Th1 and Th2 cytokines are necessary to
develop a mature atopic dermatitis lesion. T cells are activated
via a calcium-dependent pathway in which calcineurin depho-
sphorylates the nuclear factor of activated T cell protein (NF-
ATp) (for further information see Schreiber and Crabtree[28] and
Sigal and Dumont[29]). NF-ATp then migrates to the T cell nu-
cleus, where it leads to the transcription of interleukin (IL)-2 and
other cytokines. This early activation leads to secretion of IL-2
receptor and through an autocrine pathway leads to activation and
proliferation of T cells which can be selectively inhibited by the
topical noncorticosteroid immunomodulating agents.[30,31]
1.2 The Role of Exogenous Antigens
The skin in patients with atopic dermatitis differs in several
aspects from normal skin (figure 2). The 500 dalton (D) rule has
been proposed as a model for the penetration of small molecules.
According to this rule, molecules which are larger than 500D
cannot penetrate normal epidermis.[19] It should be emphasized
that this rule is not universally accepted. Tacrolimus has a molec-
ular size of 822D, and pimecrolimus of 810D; they do not pene-
trate normal skin. In atopic dermatitis, both the dry skin and vis-
ibly inflamed skin show impaired barrier properties, which can
be measured as increased transepidermal water loss.[20] Studies
using the atopy patch test have demonstrated that large exogenous
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Am J Clin Dermatol 2002; 3 (6)

Topical Noncorticosteroid Immunomodulation in AD
383
1.4 Effects of Tacrolimus and Pimecrolimus
dendritic cells could represent a target of tacrolimus in therapy
for atopic dermatitis.
All studies on antigen-presenting cells have so far been done
with tacrolimus only.[23,24] On the inflammatory epidermal and
dermal cells in the skin, tacrolimus and corticosteroids seem to
have quite opposing effects (figure 2). In Langerhans cells in
vitro, tacrolimus down-regulates the expression of FcεRI; in con-
trast, betamethasone up-regulates its expression.[24] The down-
regulation of FcεRI by tacrolimus is of potential clinical signifi-
cance in the therapy of atopic dermatitis. It is currently not known
whether the action of tacrolimus on FcεRI depends, as in T cells,
on NF-ATp.
Wollenberg et al.[32] showed, in an in vivo intervention study
with topical tacrolimus, that an increased proportion of CD1a+
cells in the epidermis of atopic dermatitis lesions decreased to
normal during clinical improvement with tacrolimus ointment.
The CD1a+ population consisted of LC and IDEC. An analysis
of the relative proportion of these cell types showed that the de-
crease in CD1a+ cells was mainly due to a decrease in IDEC. The
reduction of CD1a+ cells during treatment with tacrolimus oint-
ment was accompanied by down-regulation of FcεRI expression
in both IDEC and LC. The authors concluded that the CD1a+
Tacrolimus and pimecrolimus block the early activation of T
cells by binding to the FK506 binding protein (FKBP-12), a 12kD
macrophilin.[33,34] The FKBP-12/tacrolimus or pimecrolimus
complex inhibits calcineurin and thereby the dephosphorylation
of NF-ATp and expression of inflammatory T cell cytokines, such
as IL-2, IL-3, IL-4, IL-5, granulocyte-macrophage colony-stim-
ulating factor, interferon (IFN)-γ and tumor necrosis factor
(TNF)-α.
In vitro studies have also shown that both tacrolimus and
pimecrolimus, through a mechanism that involves binding to the
FK506-binding protein, also inhibit the release of inflammatory
mediators from mast cells and basophils.[35,36]
1.5 Staphylococcus aureus and Atopic Dermatitis
S. aureus is a contributing factor increasing the severity of
atopic dermatitis. S. aureus is found in more than 90% of atopic
dermatitis skin lesions.[18] At our center, in a study of 19 patients,
we found that staphylococcal colonization of atopic dermatitis
lesions significantly decreased after 1 week, 6 months and 12
months of treatment with 0.1% tacrolimus ointment compared
a
b
Exogenous
environmental
antigens
LC
LC
Epidermis
T
T
Dermis
T
T
D
D
collagen
collagen
M
M
F
F
c
d
Exogenous
environmental
antigens
LC
Epidermis
LC
T
T
Dermis
T
T
D
D
collagen
collagen
M
M
F
F
Fig. 2. The skin in atopic dermatitis: (a) normal skin; (b) skin in atopic dermatitis (inflammation); (c) skin in atopic dermatitis (treated with corticosteroids); and (d) skin in atopic
dermatitis [treated with tacrolimus (pimecrolimus?)]. D = dendritic cell (for example inflammatory epidermal dendritic cell); F = fibroblast; LC = Langerhans cells; M = monocyte/mac-
rophage; T = T cell.
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Am J Clin Dermatol 2002; 3 (6)

384
Reitamo et al.
atopic dermatitis increases degradation of collagen. The reduced
collagen synthesis can be seen in extreme cases as visual atrophy.
While it is clear that this atrophy is to a large part due to inhibitory
effects of external corticosteroids on collagen synthesis, other
intrinsic factors have to be considered. Many studies have shown
important inhibitory or stimulatory effects of inflammatory
cytokines on collagen or proteases causing collagen break-
down.[45-48] A study has shown that either type I or III collagen
can serve as a reservoir of inflammatory cytokines, such as IL-
2.[49] In addition, a recent study has suggested that the presence
of type I collagen causes direction of early maturation of Th cells
towards Th1, rather than Th2.[50] Taken together, at the present it
is not clear how much of the reduced collagen synthesis is due to
corticosteroids and how much due to inflammation. In future this
question may be answered using noncorticosteroid monotherapy.
Until now, most studies attributing the effect of corticoste-
roids on the dermis and collagen synthesis, have either used
healthy individuals or the corticosteroid effect has been measured
by ultrasound. The ultrasound does not seem a reliable method
for detecting inflamed skin, because even if total control of the
disease is achieved residual inflammation will make the skin ap-
pear thicker than without inflammation. Short-term treatment
with tacrolimus under occlusion did not have any effect on the
collagen synthesis of treated skin in healthy individuals and pa-
tients with atopic dermatitis. Betamethasone, in contrast, reduced
type I collagen synthesis to 20% and that of type III collagen to
30% of baseline value.[51] Betamethasone, but not tacrolimus,
also reduced skin thickness both in controls and patients with
atopic dermatitis. Pimecrolimus was studied under nonoccluded
condition in healthy individuals for 28 days.[52] No effect on skin
thickness was seen. However, the true clinical situation is long-
term treatment. We have noticed a more than 2-fold increase in
collagen synthesis in patients previously treated with corticoste-
roids after 1 year of tacrolimus treatment (H. Kyllönen et al.,
unpublished observations), suggesting that a repair is possible
after prolonged corticosteroid treatment.
a
b
MHC II
TCR
MHC II
Peptide
Staph.
enterotoxin
PKC
pathway
PKC
pathway
IP3 pathway
IP3 pathway
Fig. 3. Specific T cell activation through the major histocompatibility complex II (MHC II)/
T cell receptor (TCR) signal by (a) antigens processed by antigen presenting cells; and
(b) non-specific activation by staphylococcal superantigens. Both activate the same
pathways leading to the activation of T cells via inositol-3-phosphate (IP3)/calcineurin
pathway and protein kinase C (PKC) pathway. These pathways are inhibited by
tacrolimus. Staph. = Staphylococcus spp.
with baseline.[37] These decreases followed clinical improve-
ment. Tacrolimus has no inhibitory effect on bacteria in vitro,
including S. aureus;[38] thus decreases in colonization probably
reflect improvement of skin barrier function. Studies have shown
that the colonization of atopic dermatitis skin with superantigen-
producing S. aureus contributes to the severity of atopic skin
disease.[39-41] Superantigen-mediated activation of T cells are re-
sistant to corticosteroids, which may, in part, account for the in-
creased clinical severity.[25] Hauk and Leung[26] showed that
tacrolimus specifically blocks S. aureus superantigen-induced T
cell proliferation in peripheral blood mononuclear cells of pa-
tients with atopic dermatitis and healthy volunteers, compared
with dexamethasone. Antigen-processing by LC seems not to be
involved in this process. Interestingly, it was recently shown that
NF-ATp controls superantigen-induced shock.[42] This is impor-
tant, as the inhibitory effect of tacrolimus on T cells is mediated
through the same pathway, the calcineurin-mediated dephospho-
rylation of NF-ATp. The fact that this path is independent of the
glucocorticoid receptor could account for the positive therapeutic
response observed with tacrolimus ointment in patients with
atopic dermatitis who are clinically insensitive to topical cortico-
steroid therapy.
2. Clinical Efficacy
2.1 Efficacy Compared With Placebo
Several placebo-controlled studies with tacrolimus[13,14,20,53]
and pimecrolimus[16,17,54,55] have shown significant efficacy of
these compounds as compared with vehicle treatment. In the first
randomized, double-blind study with tacrolimus ointment in pa-
tients with moderate to severe atopic dermatitis, performed as a
multi-center study in Europe, ointments containing 0.03% (n =
54), 0.1% (n = 54), and 0.3% tacrolimus (n = 51), or a vehicle
control (n = 54) were applied twice daily in 13 to 60-year-old
patients.[13] Treatment duration was 3 weeks, and the treatment
area was less than 10% of body surface area (not more than
1000cm2). Efficacy was measured with a combined score for er-
1.6 The Dermis and Noncorticosteroid
Immunomodulation
Compared with healthy dermis, the dermis of patients with
moderate to severe atopic dermatitis shows decreased amounts of
collagens type I and III (H. Kyllönen et al., unpublished observa-
tions), the two collagens which form over 70% dry weight of the
skin (figure 2). Currently, it is not clear whether these reduced
amounts are solely due to decreased synthesis after corticosteroid
therapy[43] or UV-phototherapy,[44] or whether inflammation in
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Am J Clin Dermatol 2002; 3 (6)

Topical Noncorticosteroid Immunomodulation in AD
385
ythema, edema and pruritus. The median decrease in clinical
score was significantly greater than vehicle control for all the
tacrolimus concentrations used. There was no significant differ-
ence among the three concentrations. A similar double-blind,
multicenter study was performed in the US in 180 children aged
7 to 16 years old.[14] Results of this 3-week study was similar to
the European study with all tacrolimus ointments (0.03, 0.1 and
0.3%) being significantly more effective than vehicle treatment.
Three placebo-controlled studies comparing tacrolimus 0.03,
0.1% and vehicle with a 12-week duration have been performed
in the US.[53,54,56] The total number of patients in these three stud-
ies was over 900. Tacrolimus was significantly more effective
than placebo in all studies. No significant difference was ob-
served between the two tacrolimus concentrations studied. In all
five studies treatment efficacy compared to baseline was clearly
over 50%.[13,14,53,54,56] Pimecrolimus cream was compared to ve-
hicle in a proof-of-concept study in a single-center study per-
formed in Amsterdam.[16] The size of the lesion was 1 to 2% of
total body area. Pimecrolimus cream 1% was applied once or
twice daily. Pimecrolimus was significantly more effective than
vehicle treatment, whereas twice daily application was signifi-
cantly more effective than once daily.
In a randomized, double-blind multicenter three-week study
with 260 adult patients, pimecrolimus cream (0.05, 0.2, 0.6 and
1%) were compared with vehicle and betamethasone valerate
cream.[17] With the exception of the lowest concentration of
pimecrolimus, all other concentrations were more effective than
vehicle treatment. There was a dose-dependent increase of effi-
cacy with increasing concentration of pimecrolimus. The average
improvement with 1% pimecrolimus was slightly under 50%
(46.7%). When treatment efficacy was compared to clinical se-
verity of disease, treatment results were better in patients with
mild disease compared to those with moderate disease.Two inde-
pendent 6-week, randomized, multicenter trials studying a total
of 403 patients with mild to moderate atopic dermatitis compared
treatment with 1% pimecrolimus cream or vehicle cream.[57] Sig-
nificant improvement in clinical score relative to vehicle treat-
ment was observed with pimecrolimus treatment. The overall im-
provement was comparable to the adult study of 3 weeks.[17]
a finding not seen in US studies.[53,54,56] In adult patients with
moderate to severe atopic dermatitis, tacrolimus 0.03 and 0.1%
twice daily was compared to 0.1% hydrocortisone butyrate, a
midpotent to potent topical corticosteroid.[59] Tacrolimus 0.1%
showed similar efficacy as hydrocortisone butyrate, and both
these ointments were significantly more effective than 0.03%
tacrolimus ointment.
Comparisons of pimecrolimus cream (0.05, 0.2, 0.6 and 1%)
to betamethasone valerate cream in 260 adult patients with
mainly moderate atopic dermatitis showed that betamethasone
valerate was significantly more effective than pimecrolimus at all
concentrations studied (0.05 to 1%).[17]
Full reports of long-term comparative studies are not avail-
able. One such study, of pimecrolimus compared with triamcin-
olone acetate cream is available as an abstract and showed similar
efficacy of both treatments for those patients who completed the
study.[60] Over 50% of the patients on pimecrolimus did not com-
plete the study, which raises questions about an intent-to-treat
analysis as it would seem likely that patients with more severe
disease might have a less effective treatment result.[18,60,61]
We believe that the true test of these compounds will be in
long-term use, as this is a chronic disease that tends to need long-
term treatment. Although topical corticosteroids are often used
long-term for the treatment of atopic dermatitis they are only
approved for short-term use. Therefore, there is practically no
data available on whether we should use them until all symptoms
have vanished or sparingly to have best efficacy, while avoiding
adverse effects. The ongoing long-term comparative study of
tacrolimus/corticosteroid should shed light on this question.
2.3 Safety
Burning sensation of the skin was the only adverse event that
showed a higher incidence with tacrolimus ointment or
pimecrolimus cream, compared with the vehicle control in short-
term studies.[13,14,16,17] In long-term studies skin burning, ery-
thema and pruritus were common, but tended to occur only during
the first few days of treatment.[15,56,62] Burning and also erythema
of the face were aggravated by alcohol uptake in some patients.
The cause of burning is not known, and it is unclear whether any
treatment, e.g. antihistamines, could be useful in the prevention
of it. Using timed suction blisters of the skin, we have observed
that there is an early release of some neuropeptides which could
be responsible for these symptoms (Reitamo S et al., unpublished
observations). Uncontrolled safety studies of 1 year duration did
not show any safety concerns.[15,56,62] Bacterial colonization with
S. aureus was reduced to a great extent and there were no other
apparent signs of immune suppression. Using historical compar-
isons there was no apparent increase in herpes simplex infec-
tion.[15,63] Also, there was no decrease in recall antigen reac-
tions[15] and the number of pigment nevi had not increased
(Reitamo S et al., unpublished observations). Long-term compar-
2.2 Efficacy Compared With Corticosteroids
Short-term studies of 3 weeks duration have compared
tacrolimus with hydrocortisone acetate in children,[58] tacrolimus
with hydrocortisone butyrate in adults,[59] and pimecrolimus with
betamethasone valerate.[17] Tacrolimus 0.03 and 0.1% was com-
pared to 1% hydrocortisone acetate treatment in 2 to 15-year-old
children with moderate to severe atopic dermatitis in a 3 week
randomized, double-blind study.[58] Treatment was restricted to
60% of total body surface. Both tacrolimus concentrations were
significantly more effective than hydrocortisone acetate, with
tacrolimus 0.1% being significantly more effective than 0.03%,
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Am J Clin Dermatol 2002; 3 (6)

386
Reitamo et al.
a
b
Fig. 4. An 18-year-old patient with severe atopic dermatitis not responsive to corticosteroids: (a) before treatment with tacrolimus ointment; and (b) after 3 years of tacrolimus ointment
monotherapy.
ative studies for tacrolimus are ongoing. So far, however, the
main outcome seems to be that these compounds have a good
safety profile and can therefore be used long-term.[15,56,62] During
long-term studies with tacrolimus, some of our patients experi-
enced several months in which no treatment was necessary
(Reitamo S et al., unpublished observations). It would be of in-
terest to assess this prospectively. Long periods of clearance, in
which treatment would be unnecessary, would be a great advan-
tage over conventional corticosteroid treatment.
Laboratory profiles during several long-term studies have
been unremarkable.[15,56,62] Drug concentrations in the blood
have been shown to decrease a few days after starting therapy for
both tacrolimus and pimecrolimus.[13,64] During long-term treat-
ment about 75% of the patients did not show detectable blood
concentrations of tacrolimus.[15] The only exception has been
children with Netherton syndrome, an autosomal recessive dis-
ease characterized by congenital erythroderma, who despite a
good treatment results showed high tacrolimus trough blood con-
centrations.[65] Blood concentrations from pimecrolimus long-
term studies have not yet been reported. In a short-term study they
have been low.[64]
a period of many years, increase the risk of basal cell or squamous
cell carcinoma. Thus, patients receiving therapy with a topical
immunomodulator should be educated on adequate measures of
sun protection, and an important aim of post-marketing research
should be long-term safety.
3. Why Should Patients Be Treated
with Monotherapy?
We have experience from many patients who have used
cyclosporine, together with topical corticosteroids, who have sig-
nificantly improved after switching to tacrolimus monotherapy
(Reitamo S et al., unpublished observations). This suggests that
tacrolimus monotherapy can greatly improve the treatment of se-
vere atopic dermatitis (figure 4). When tacrolimus is used as long-
term treatment in a clinical research project which emphasizes
treatment of all atopic dermatitis until the skin is totally cleared
and pruritus as resolved, an improvement in patients with mod-
erate to severe atopic dermatitis of at least 90% can be expected
in half of the patients.[15] These findings need to be reperated in
a controlled study. Total use of tacrolimus ointment decreased
with time, and some patients also had treatment-free periods of
several weeks. After 12 months of monotherapy several patients
showed normalization of the transepidermal water loss and they
had no pruritus. In patients with at least 90% improvement, we
have observed also a decrease in serum and skin immunoglobulin
There has been no evidence of an increased risk of any type
of infection compared with historical data from the literature. In
terms of mode of action, topical tacrolimus and pimecrolimus
may decrease immune surveillance of treated skin, and thus, over
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Am J Clin Dermatol 2002; 3 (6)

Topical Noncorticosteroid Immunomodulation in AD
387
E levels (Reitamo S et al., unpublished observations). This im-
provement of the skin, apparently to normal, after long-term
tacrolimus treatment raises questions of whether all skin symp-
toms in atopic dermatitis are actually of a secondary nature, with
a primary disorder in the bone marrow cells. This would mean
that the disease would need redefining since pruritic dry skin has
been the central prerequisite for the diagnosis of atopic dermati-
tis.
Sugiura et al.[66] showed recently that by treating only the
face with tacrolimus, and the rest of the body with corticosteroids,
there was, after an initial response, quite poor long-term results.
These results were dependent on the severity of dermatitis, with
treatment results inversely related to severity of dermatitis.[66] We
can confirm these findings from several patients treated outside
clinical trials.
who experience poor efficacy, so that any risks do not outweigh
the benefits. The clinical data collected so far indicates that there
is no increased risk of skin cancer, infection or other undesirable
immunosuppressive effects.
Acknowledgments
The authors have received grants from Fujisawa GmbH, Munich and
Novartis Pharma, Basel for clinical stuidies with tacrolimus ointment and
pimecrolimus cream. Håkan Granlund is currently employed by Novartis,
Finland.
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13. Ruzicka T, Bieber T, Schöpf E, et al. A short-term trial of tacrolimus ointment for
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Dermatol 1998; 134: 805-9
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18. Leung DYM. Atopic dermatitis: new insights and opportunities for therapeutic
intervention. J Allergy Clin Immunol 2000; 105: 860-76
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compounds and drugs. Exp Dermatol 2000; 9: 165-9
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Most of the patients undergoing pimecrolimus treatment in
clinical trials had either mild or moderate disease, although a few
had severe atopic dermatitis. From the available study in adults
it can be concluded that approximately half of such patients will
respond to pimecrolimus monotherapy.[17] The treatment results
with pimecrolimus in pediatric studies seem better.[54,55] How-
ever, these studies used vehicle as control therapy and corticoste-
roids were allowed as rescue therapy. Therefore, the results can-
not be directly compared with those from the adult studies.
4. Status of Marketing Approvals
For atopic dermatitis, tacrolimus ointment 0.1% has been on
the market in Japan for treatment of adults since 1999 and in the
US and Canada since 2001 as 0.03 and 0.1% ointment for adults
and 0.03% ointment for children. A marketing authorization ap-
plication for tacrolimus ointment 0.03 and 0.1%, has been ap-
proved by the European Agency for the Evaluation of Medicinal
Products (the drug is now available in many European countries).
Pimecrolimus cream 1% is being developed for atopic dermatitis.
In the US, pimecrolimus cream 1% was approved in 2001. In
Europe it should be available in Denmark in 2002.
5. Conclusions
The main advantage of topical noncorticosteroid im-
munomodulatory agents is that they do not cause skin atrophy and
therefore do not prevent healing of the skin. Tacrolimus and
pimecrolimus have a similar structure and mode of action, but
comparison of three 3-week clinical studies using the same effi-
cacy parameters and corticosteroid comparators, although no di-
rect comparison, suggest that tacrolimus is more effective.[17,58,59]
To avoid any possible risks associated with the use of these two
treatments, detailed knowledge of drug blood concentrations in
comparison with clinical outcome needs to be obtained. It seems
likely that the group of patients who would benefit least from
treatment would be those with severe and wide-spread disease
23. Wollenberg A, Kraft S, Hanau D, et al. Immunomorphological and ultrastructural
characterization of Langerhans cells and a novel, inflammatory dendritic epi-
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Correspondence and offprints: Dr Sakari Reitamo, Department of Dermatol-
ogy, Hospital for Skin and Allergic Diseases, Meilahdentie 2, Helsinki, 00250,
Finland.
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E-mail: sakari.reitamo@hus.fi
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Am J Clin Dermatol 2002; 3 (6)