Pharmacology and therapeutics

Methylprednisolone aceponate for atopic dermatitis

Antonio Torrelo, MD

Department of Dermatology, Hospital Abstract

~o Jesu
Infantil Nin s, Madrid, Spain Background The 4th generation topical corticosteroids (TCS) have demonstrated a most
favorablerisk–benefit ratio. Methylprednisolone aceponate (MPA) is a non-halogenated
Correspondence
Antonio Torrelo, MD
corticosteroid with a methyl group at C6, which confers higher intrinsic activity. MPA is
Department of Dermatology, Hospital included in the group of potent TCS (category III/IV).
~o Jesu
Infantil Nin s Methods A literature review is carried out of the clinical efficacy, pharmacokinetics, and
Mene ndez Pelayo 65, 28009-Madrid adverse effects of MPA, especially for the treatment of atopic dermatitis (AD).
Spain
Results Several clinical studies support the use of MPA in infants and children, with
E-mail: atorrelo@aedv.es
minimal local or systemic adverse effects reported. The pharmacokinetic profile and the
Conflicts of interest: The author has acted low rate of adverse effects of MPA are most suitable for the treatment of atopic dermatitis
and has been paid as a consultant and (AD), a chronic disease with frequent flaring that can involve extensive areas of the skin.
lecturer for Bayer AG in the last 3 years, a Conclusions Most patients with AD can be easily brought into control with the use of only
company manufacturing the product being
TCS. Achieving a complete healing of eczema is key in AD, and once the skin is clinically
studied, and on issues related and
unrelated to the product. The author has
healthy, emollients can be used according to the physician and patient preferences.
not received any payment for writing this Physicians should be trained in the recognition of early or subtle manifestations of active
article. eczema that are most suitably treated with topical TCS to achieve a most rapid and
satisfactory control of the disease. If the whole area with eczema is not treated, active
doi: 10.1111/ijd.13485
eczema will remain and treatment will be ineffective. Insufficient use of TCS will lead to
inefficiency and frustration.

1980s, new TCS molecules that could retain the high potency
Introduction
of action and had a much lower profile of adverse effects were
In this article, the author will review the most important features researched, and hence the so-called 4th generation TCS, were
regarding the treatment of atopic dermatitis (AD) with topical marketed in the late 80s and early 90s. They include mometa-
corticosteroids (TCS), with special emphasis on the 4th genera- sone furoate, hydrocortisone-17-butyrate-21-propionate, predni-
tion TCS methylprednisolone aceponate (MPA). Recent carbate, and methylprednisolone aceponate (MPA), and they
advances in the pathogenesis of AD justify a shift in the para- demonstrate a most favorable risk-benefit ratio.1 Interestingly,
digm of therapy of the disease with the most potent and safe 25 years after the marketing of the 4th generation TCS, no
available first-line agents such as MPA. improvement in the synthesis of new corticosteroid molecules
has been produced, which gives an idea that the available 4th
generation TCS meet a high standard of efficacy and safety.
A Brief History of Topical Corticosteroids

Hydrocortisone was the first topical corticosteroid (TCS) avail-

able for the treatment of cutaneous diseases, and its use meant
a revolution in dermatology in the 1950s. Patients with condi-
tions such as eczema, which was mostly untreatable, obtained
a relief never achieved before. After the introduction of this low-
potency agent, the pharmaceutical companies synthetized
higher potency TCS during the 60s and 70s, usually by includ-
ing a halogen atom (halogenation) or methylation in the basic
molecule of the steroid scaffold. An extensive use of these
agents was associated with the apparition of adverse skin and
less frequently systemic reactions that partially occluded the
therapeutic effects of the TCS and led to a generalized opinion
that TCS were even more harmful than beneficial. During the
Pharmacological Properties of MPA
Methylprednisolone aceponate is a nonhalogenated corticos-
teroid with a methyl group at C6, which confers higher intrinsic
activity.2 The ester groups in C17 and C21 render the molecule
highly lipophilic, convenient for more efficient penetration within
the stratum corneum and low serum concentrations2,3 (Fig. 1).
In the skin, MPA is hydrolyzed by skin esterases into methyl-
prednisolone 17-propionate (MPP), the active metabolite of
MPA with a higher affinity for glucocorticosteroid receptors.4
This bioactivation is enhanced in inflamed skin because of
higher levels of esterases,4,5 which further concentrates MPP at
the therapeutic site. Once in the skin, MPP undergoes migration
1

ª 2017 The International Society of Dermatology International Journal of Dermatology 2017

2 Pharmacology and therapeutics Methylprednisolone aceponate for atopic dermatitis
Figure 1 Molecular structure of methylprednisolone aceponate
of the propionate group from C-17 to C-21, to form methylpred-
nisolone-21-propionate, which is in turn hydrolyzed and ren-
dered relatively inactive.4 Any MPP reaching systemic
absorption is rapidly inactivated by conjugation with glucuronic
acid to an inactive metabolite that is mainly excreted in the
urine.4
Efficacy of MPA
Methylprednisolone aceponate is included in the group of potent
TCS (category III/IV); triamcinolone acetonide and bethameta-
sone valerate are reference TCS also included in this group.6
Multiple double-blind studies, both placebo-controlled and com-
pared to reference TCS, have shown a high clinical efficacy of
MPA in the treatment of eczema after 1–4 weeks of application
once daily.7–17 Of note, once daily MPA is at least equally or
more effective than twice daily betamethasone valerate, a refer-
ence TCS, with treatment success superior to 90% of
patients.13,14 Direct comparison of MPA with other 4th genera-
tion TCS showed similar efficacy index than mometasone furo-
ate17 and prednicarbate.8 Most double-blind studies for efficacy
of MPA were carried out before its marketing and during mole-
cule development, more than 25 years ago. However, the
extensive use of MPA in Europe in the postmarketing period
after gaining experience for more than 25 years indicates that it
is a very effective therapy. It is generally accepted that potent
TCS are effective molecules that have been helping patients
with skin diseases for more than 60 years.
Most physicians generally believe that application of TCS
twice daily is superior to once daily, but this has been rarely
tested nor proven. Studies with MPA demonstrated that once-
daily application achieved similar efficacy to twice-daily (92%
vs. 90% of patients treated successfully).2,13,14
Different presentations of TCS can show different efficacy
rates. MPA once-daily was tested in cream and ointment pre-
sentations, and both showed identical success rates in
International Journal of Dermatology 2017
Torrelo et al.
eczematous disorders,1,15,18 comparable to twice-daily
betamethasone valerate.
Methylprednisolone aceponate efficacy studies have included
mostly patients with varied eczematous conditions including ato-
pic dermatitis, contact dermatitis, and others. Furthermore,
patients with age ranges from 2 months to 87 years have been
included, thus showing age-independent efficacy.1
Safety and Tolerability of MPA
Whereas the efficacy of a potent TCS such as MPA can be
easily demonstrated and generally affected, safety and tolerabil-
ity of a TCS must be thoroughly proven. Because TCS of high
and ultra-high potency are available, the physician’s greatest
concern about TCS is not efficacy but rather a favorable profile
of adverse effects. In the past, efficacy and adverse effects
were invariably linked, but 4th generation TCS showed that a
high therapeutic index (i.e., high potency with low adverse
effects) is possible, thus dissociating the concepts of ‘potent’
and ‘harmful’ TCS.19–22 Overall, studies involving animal mod-
els, healthy volunteers, and patients have demonstrated that
adverse effects with MPA are significantly lower than other
potent TCS and are similar to those of less potent TCS.8,10,17
The adverse effects of TCS are well known. They include
local effects from topical application and systemic effects from
percutaneous absorption of the TCS reaching significant blood
levels. The latter resemble the adverse effects of orally adminis-
tered corticosteroids.
Local adverse effects
The most common and largely studied adverse effect of TCS is
skin atrophy. The antiproliferative action of corticosteroids on
keratinocytes and fibroblasts leads to epidermal and dermal
thinning.23 Epidermal thinning is partly reversible, but atrophy of
the dermis and even subcutaneous tissue is often permanent.
Striae and telangiectasias are a reflection of permanent atrophy
and are often motive of concern for patients and physi-
cians.6,21,24 Skin atrophy is mostly an effect of long-term use of
TCS, but the epidermal and stratum corneum atrophy can be
induced even in short-term treatments.
Animal models indicate a low atrophogenic potential of
MPA,25,26 higher than vehicle but significantly less than
mometasone furoate.27 The same was true for the incidence of
telangiectasias. In humans, although MPA is a potent topical
corticosteroid,16 it has been proven to show a low atrophogenic
potential,25,27 possibly lower than betamethasone valerate
cream and ointment, and similar to hydrocortisone butyrate. In
20 healthy volunteers, once-daily MPA cream did not cause any
significant reduction in skin thickness in comparison to vehicle,
whereas betamethasone valerate significantly reduced skin
thickness.2,25 Both under occlusive and nonocclusive conditions,
treatment with clobetasol propionate induced significantly more
pronounced atrophy and telangiectasias.28 In 20 healthy
ª 2017 The International Society of Dermatology
Torrelo et al. Methylprednisolone aceponate for atopic dermatitis
volunteers, a double-blind, 6-week, occlusive, randomized trial
showed that treatment with mometasone furoate resulted in a
higher incidence and severity of telangiectasias compared with
MPA.17
Visible signs of atrophy were observed in only two of more
than 1900 patients in clinical trials treated with MPA for
eczema,2 and it is even likely that these two patients had pre-
existing atrophy unmasked by the successful action of MPA.13
Common local adverse effects observed with MPA include
application site burning and pruritus.6 Although less common,
the following have occurred as well: application site dryness,
eczema, skin exfoliation, skin fissures, application site pain,
application site vesicles, application site pustules, application
site erosion, application site papules, application site erythema,
peripheral edema, skin atrophy, ecchymosis, impetigo, greasy
skin, and telangiectasia.6,10,14,15,25,26,28 In addition, it should be
noted that a specific therapy is required in bacterially infected
skin diseases and/or in fungal infections as local skin infections
can be potentiated by topical glucocorticoid use. Other con-
traindications include tuberculous or syphilitic processes in the
area to be treated, viral diseases (e.g., varicella, herpes zoster),
rosacea, perioral dermatitis, ulcera, acne vulgaris, atrophic skin
diseases, and postvaccination skin reactions in the area to be
treated.
Systemic adverse effects
These are related to absorption through the skin and are equal
to the effects of systemic corticosteroids. They include hyper-
glycemia, hypertension, leukocytosis, and others.24 Because
MPA has a rapid action and suffers inactivation of its metabo-
lites after absorption, a low risk of systemic effects is expected.
None of the effects mentioned above were observed in patients
treated with 0.1% MPA ointment for 3 months,10 although it
cannot be excluded that systemic effects due to absorption may
occur when topical preparations containing corticoids are
applied.
Systemic corticosteroids can suppress the hypothalamic–
pituitary–adrenal (HPA) axis, and there is a concern for topi-
cal corticosteroids producing this effect. The measurement of
cortisol levels reflects HPA axis function.6 MPA did not sup-
press cortisol after 43 days of treatment in rats.6,28 In 100
healthy volunteers, after daily application of 40 g of topical
0.1% MPA over 60% of the body surface, no changes in
cortisol levels were observed over 8 days.6,10,13 In adults
with atopic dermatitis involving 40–60% of the skin surface
treated with 30 g of 0.1% MPA ointment for 7 days, no
effects on the HPA axis were noted.6 In 45 adults with
chronic dermatoses, application of MPA ointment 1–3 times
daily for 4 months, showed no suppression of endogenous
cortisol secretion.6,10 These studies demonstrate that MPA
has a minimal effect on the HPA axis, in contrast with other
corticosteroids such as clobetasol propionate and betametha-
sone valerate.2,13
ª 2017 The International Society of Dermatology
Pharmacology and therapeutics 3
Safety in children
Children, especially infants, present a higher rate of skin sur-
face to volume ratio8 and thus are subject to a possible higher
amount of absorption of topical corticosteroids. Because of the
low profile of topical absorption, MPA cream, milk/emulsion, and
ointment have been approved for the treatment of children of all
ages. The milk/emulsion formulation of MPA is especially very
acceptable cosmetically and can be used safely and effectively
in infants aged 4 months and over.1,2
Several clinical studies support the use of MPA in infants and
children,7,8,29,30 with no local or systemic adverse effects
reported.8 Trials in children aged 4 months to 15 years with AD
reveal that adverse events were mostly absent after the applica-
tion of 0.1% MPA ointment once daily for 21 days. No effect on
plasma cortisol levels was seen after 7 days using nonocclusive
dressings in 20 children over 6 months of age with atopic der-
matitis. Mild burning sensation, usually attributed to the vehicle,
and infectious skin diseases were the most common adverse
effects.7,8,31
MPA for the Treatment of Atopic Dermatitis
Corticosteroids (CCS) bind to specific glucocorticoid receptors
(GR) in the cytoplasm and are translocated into the nucleus,
where they exert actions on DNA by activating (transactivation)
and repressing (transrepression) different genes.32,33 Transacti-
vation is usually linked to the metabolic properties of CCS,
whereas transrepression of inflammatory genes leads to thera-
peutic effects.33 The result is a decreased production of many
proinflammatory cytokines (including TNFa, IL-1a, IL-3, IL-5,
and granulocyte-macrophage colony stimulating factor) and
mediators (such as prostaglandins and leukotrienes).6,32
Furthermore, CCS inhibit function and maturation of den-
dritic cells and leukocyte migration, suppress eosinophil matura-
tion, reduce vascular leakage, and reduce collagen
synthesis.6,19,34–37 With all these anti-inflammatory actions,
MPA exerts a fast and effective action on the relief of AD, and
this has been demonstrated in randomized trials in children and
adults,7,15,38 as well as accumulated clinical experience for
more than 25 years. Hairy areas of the scalp treated for
2 weeks with once daily 0.1% MPA solution also experienced
complete remission or significant improvement by patients’ and
physicians’ global assessment.39
Sixty-seven percent of patients with severe AD flares were
clear of or experienced significant improvement in Investigator’s
Global Assessment scores after 3 weeks of once-daily treat-
ment with 0.1% MPA ointment, a similar proportion as with
0.03% tacrolimus ointment twice daily.9 However, MPA was
superior to tacrolimus in terms of itching, EASI score, and sleep
quality.9 The study concluded that MPA is recommended as a
first line treatment in AD.
The pharmacokinetic profile and the low rate of adverse effects
of MPA are most suitable for the treatment of AD, a chronic
International Journal of Dermatology 2017
4 Pharmacology and therapeutics Methylprednisolone aceponate for atopic dermatitis
disease with frequent flaring that can involve extensive areas of
the skin.14,15,40 Although most physicians apply twice daily TCS
to AD, MPA permits once-daily administration.8,26,41 On the other
hand, physicians use different formulations according to exten-
sion, area of the skin involved, exudation, and chronicity of
lesions, and thus the availability of MPA in formulations including
ointment, fatty ointment, cream, lotion and milk/emulsion, all with
equal efficacy, make it convenient for any patient age, skin condi-
tion, location of lesions, and disease severity.6
Utilities of MPA According to the New
Discoveries in AD
For many years, most experienced dermatologists felt that AD
was primarily a skin disorder, most likely related to skin barrier
deficiency. However, extensive study of immunologic pathome-
chanisms has led many researchers to consider immune sys-
tem imbalance as the primary abnormality in AD. The recent
discovery that filaggrin null mutations lead to genetic suscepti-
bility to AD and can be responsible for at least a significant pro-
portion of AD patients (up to 40% in certain European
populations) has shifted the paradigm of understanding and
management of AD.42,43 Filaggrin null mutations are also a first-
line risk factor for developing asthma and other allergic dis-
eases.44 Because filaggrin is mostly expressed in the skin, the
current opinion is that primary skin barrier defects lead to
increased exposure to environmental irritants and allergens,
causing irritant and allergic eczema.45 Eczema itself further
impairs skin barrier that becomes fully inefficient to prevent the
entry of external molecules that are massively presented to the
skin immune system, thus worsening the patient’s condition and
leading to a circle of eczema and sensitization.
Combining emollient and pharmacologic treatment in AD
The use of emollients has been recommended in an extensive
liberal use for all patients with AD. This seems reasonable in
view of the recent knowledge that primarily skin barrier defects
are the origin of AD. However, whereas the use of emollients is
beneficial for patients with controlled AD and in the areas not
affected by eczema, it is the author’s experience, as well as
others’, that the direct application of emollients on the skin
affected with eczema is poorly tolerated and causes itch and
irritation.46 In the author’s opinion, atopic eczema should be
brought into control before emollients are liberally used, and for
this, pharmacological therapy is necessary. The 4th generation
topical CCS are the first-line drugs that should be used in order
to achieve a complete healing of eczema because of their effec-
tiveness and safety profile. Once the skin is clinically healthy,
emollients can be used according to the physician and patient
preferences.
It is generally accepted that the skin of the patients with AD
is dry, and the concept of ‘dry’ skin has been equivalent to ‘ato-
pic’ skin.47 From a clinical point of view, ‘dryness’ is not well
International Journal of Dermatology 2017
Torrelo et al.
defined, and the term ‘dry’ skin is applied when fine scaling is
present. It should be remembered that scaling is an intrinsic
component in the definition of eczema and that many patients
with mild AD have a finely scaling process with slight or minimal
erythema that can be confused with simply ‘dry’ skin.48 The use
of emollients in active eczema can reduce scaling temporarily
but will not improve the disease and can cause irritation and fur-
ther worsening of eczema. Physicians should be trained in the
recognition of early or subtle manifestations of active eczema
that are most suitably treated with TCS to achieve a most rapid
and satisfactory control of the disease. In the author’s experi-
ence, patients who are instructed to treat minor flares of AD
with TCS have better control of the disease, better quality of
life, and use much less topical treatment than when flare-ups
and mild eczema are left untreated until they worsen or spread,
thus necessitating longer and more extensive therapy.
Achieving control of AD
Because AD is a chronic disease, both physicians and patients
may have feelings of frustration and surrendering. In children,
the expectation for a remission when the child grows up may
lead to a wait-and-see policy that can cause damage to children
in the form of continuous sensitization through damaged skin,
mood changes, disturbance of academic achievements, and
frustration from chronic suffering.
It is the author’s opinion and experience that every patient
with AD should be brought into complete control, no matter if
the disease is mild or severe. The reasons are simple: (i) we
have good and effective therapies that can be used safely; (ii)
good control leads to a better quality of life; and (iii) control of
the disease decreases the risk of further overexposure to aller-
gens and infectious agents. We can definitely change the life of
our patients with an appropriate approach to AD.
Most patients with AD can be easily brought into control
with the use of only TCS. Because we have effective and
safe 4th generation TCS, their use for any flare-up, as early
as possible, on the whole affected area and for as many days
as necessary to achieve complete healing is encouraged. An
insufficient use of TCS will lead to inefficiency and frustration.
If the whole area with eczema is not treated, active eczema
will remain and treatment will be ineffective; it is important for
physicians and patients to recognize eczema and use 4th
generation TCS on every affected area, whether severe or
mild. If TCS treatment is withdrawn before eczema is under
complete control, the risk of rebound is very high; rebound is
usually more linked to an insufficient treatment than to TCS
themselves.
Patients must be reassured that using 4th generation TCS is
safe and will not cause any harm when properly used. Cortico-
phobia49 will lead to the use of noneffective remedies, simply
on the basis that they will not cause any harm. In the author’s
opinion, using ineffective remedies is harmful because AD is
harmful itself in terms of affecting quality of life, inducing further
ª 2017 The International Society of Dermatology
Torrelo et al. Methylprednisolone aceponate for atopic dermatitis Pharmacology and therapeutics 5

exposure to allergens and the likelihood of serious infectious prevention of the development of the atopic phase of atopic
complications, and should not be left untreated. dermatitis, and possibly other manifestations of the atopic
disease.
Use of MPA for AD in maintenance therapy
Because of the risk of relapse of AD, strategies for maintenance QUESTIONS (answers found after references)
or preventive treatment have been proposed. In one study, 221
adult patients with AD were treated once daily with 0.1% MPA 1 The first available topical corticosteroid was:
cream until control of the disease and were then randomized to A Hydrocortisone
twice weekly 0.1% MPA cream (weekends) on the previously B Methylprednisolone aceponate
affected areas + emollients vs. emollients alone for 16 weeks.50 C Clobetasol propionate
Patients in the MPA branch had a 3.5-fold lower risk of relapse D Betamethasone valerate
with maintenance therapy than with emollient alone and had 2 Which of the following is not a halogenated topical corticos-
lower EASI scores throughout the study.50 During 16 weeks of teroid:
maintenance therapy with MPA, no signs of skin atrophy, striae, A Betamethasone valerate
telangiectasias, irritation, or infection were observed.50 Similar B Methylprednisolone aceponate
studies have been carried out with other TCS, emphasizing C Clobetasol-17-propionate
their effectiveness and safety.51–54 A similar study with intermit- D Betamethasone dipropionate
tent tacrolimus treatment in children and adults with AD also 3 In which group of potency of topical corticosteroids is methyl-
indicated that maintenance therapy can reduce the incidence of prednisolone aceponate included:
flares.55,56 A I/IV (mild)
B II/IV (moderate)
Use of MPA in infants with AD C III/IV (potent)
AD may start in infancy, as early as 2 or 3 months of age. MPA D IV/IV (ultra-potent)
is approved for children from the age of 4 months, which is 4 Which is the main active metabolite of methylprednisolone
unique for this young age. MPA is suitable for the treatment of aceponate:
AD in infants because of its effectiveness, safety profile, and A Methylprednisolone aceponate itself
the convenience of the milk/emulsion formulation. B Methylprednisolone-6-propionate
Following the most currently accepted model for the devel- C Methylprednisolone-17-propionate
opment of AD,57 it is suspected that skin barrier defects in D Methylprednisolone-21-propionate
infants lead to increased passage through the skin of external 5 Which of the following topical corticosteroids shows a lower
agents that reach the upper dermis, thus causing a primary atrophogenic potential on the skin:
irritant eczema. This early, nonatopic eczema further impairs A Betamethasone valerate cream
the skin barrier, thus allowing for more and more external B Betamethasone valerate ointment
molecules, both irritants and allergens, to pass through the C Clobetasol-17-propionate ointment
skin and gain contact with the immune system that, because D Methylprednisolone aceponate ointment
of overexposure to these substances and under genetic 6 Which of the following is a common systemic effect of the
unknown circumstances, will shift towards a Th2-enhanced topical application of methylprednisolone aceponate:
response. Immunologic sensitization will then cause truly ato- A Hyperglycemia
pic dermatitis and other allergic diseases according to the B Hypertension
‘atopic march’. If this situation could be overcome in early C Suppression of the HPA axis
infancy, by restoring the epidermal skin barrier, it is likely that D None of the above
AD will not develop. Certainly, double-blind studies have 7 At which age can methylprednisolone aceponate be used
demonstrated that early intervention with strict use of safely:
emollients in infants at risk of AD permits a reduction in the A 12 years and over
incidence of AD in almost 50% of children.58 In practice, B 6 years and over
however, most infants with AD are brought to pediatricians C 2 years and over
and dermatologists when early, active eczema is already D 6 months and over
present. In such cases, in the author’s experience, application 8 Which is the most commonly known gene mutation responsi-
of emollients will be poorly tolerated and can even ble for atopic dermatitis:
worsen eczema. It is very important to bring early AD under A SPINK5
control before emollients can be used. Maintaining the infants D Corneodesmosine
free of eczema and under appropriate use of emollients will C Filaggrin
lead to full control of the disease and most likely to D Desmoglein 1

ª 2017 The International Society of Dermatology International Journal of Dermatology 2017

6 Pharmacology and therapeutics Methylprednisolone aceponate for atopic dermatitis
9 Which are the first-line drugs for the treatment of the atopic
dermatitis flares:
A Topical corticosteroids
B Topical calcineurin inhibitors
C Emollients
D Oral antihistamines
10 Which of the following is false for the management of atopic
dermatitis:
A Safe and effective therapies are available for atopic der-
matitis
B Control of atopic dermatitis leads to a better quality of life
C Control of atopic dermatitis decreases further exposure to
allergens
D Atopic dermatitis should be left untreated because most
cases will eventually resolve
References
1 Blume-Peytavi U, Wahn U. Optimizing the treatment of atopic
dermatitis in children: a review of the benefit/risk ratio of
methylprednisolone aceponate. J Eur Acad Dermatol Venereol
2011; 25: 508–515.
2 Ruzicka T. Methylprednisolone aceponate in eczema and other
inflammatory skin disorders – a clinical update. Int J Clin Pract
2006; 60: 85–92.
3 Toepert M, Olivar A, Opitz D. New developments in
corticosteroid research. J Dermatolog Treat 1990; 1(Suppl. 3):
S5–S9.
4 Ta€uber U. Pharmacokinetics and bioactivation of MPA. J Eur
Acad Dermatol Venereol 1994; 3(Suppl. 1): 23–31.
5 Zentl HJ, Toepert M. Preclinical evaluation of a new topical
corticosteroid methylprednisolone aceponate. J Eur Acad
Dermatol Venereol 1994; 3(Suppl. 1): 32–38.
6 Luger TA. Balancing efficacy and safety in the management of
atopic dermatitis: the role of methylprednisolone aceponate.
J Eur Acad Dermatol Venereol 2011; 25: 251–258.
7 Korotky NG, Taganov AV, Shimanovsky NL. Use of Advantan in
the treatment of atopic dermatitis in children. Pediatriya 2000; 5:
75–78.
8 Rampini E. Methylprednisolone aceponate (MPA) – use and
clinical experience in children. J Dermatol Treat 1992; 3(Suppl.
2): 27–29.
9 Bieber T, Vick K, Fo €lster-Holst R, et al. Efficacy and safety
of methylprednisolone aceponate ointment 0.1% compared
to tacrolimus 0.03% in children and adolescents with an
acute flare of severe atopic dermatitis. Allergy 2007; 62:
184–189.
10 Ortonne JP. Safety aspects of topical methylprednisolone
aceponate (MPA) treatment. J Dermatol Treat 1992; 3(Suppl.
2): 21–25.
11 Grebenyuk VN, Balabolkin II. Progress in topical corticosteroid
therapy of atopic dermatitis in children. Pediatriya 1998; 5: 88–
91.
12 Niedner R, Zaumseil R-P. Advantan milk ⁄ cream.ointment in
children with atopic dermatitis and other inflammatory or
eczematous dermatoses – an observational study in 558
children. Aktuelle Derm 2004; 30: 200–203.
13 Zaumseil R-P, Fuhrmann H, Kecske0 s A, et al.
Methylprednisolone aceponate (Advantan) – an effective topical
International Journal of Dermatology 2017
Torrelo et al.
corticoid therapy with few side effects. Jahrb Dermatol 1992; 3:
247–263.
14 Fritsch P. Clinical experience with methylprednisolone
aceponate (MPA) in eczema. J Dermatolog Treat 1992; 3
(Suppl. 2): 17–19.
15 Mensing H, Lorenz B. Experience with methylprednisolone
aceponate (MPA) in patients suffering from acute and chronic
eczema. Results of a large observational study. Z Hautkr 1998;
73: 281–285.
16 Kecske s A, Jahn P, Wendt H, et al. Activity of topically applied
methylprednisolone aceponate in relation to other topical
glucocorticosteroids in healthy volunteers. Arzneimittelforschung
1993; 43: 144–147.
17 Kecske s A, Heger-Mahn D, Kuhlmann RK, et al. Comparison of
the local and systemic side effects of methylprednisolone
aceponate and mometasone furoate applied as ointments with
equal anti-inflammatory activity. J Am Acad Dermatol 1993; 29:
576–580.
18 Kungurov NV, Kokhan MM, Keniksfest JV, et al. Difference
topical therapy of the atopic eczema in children and adults
(poster 2–3). J Eur Acad Dermatol Venereol 2001; 15(Suppl. 2):
107.
19 Brazzini B, Pimpinelli N. New and established topical
corticosteroids in dermatology: clinical pharmacology and
therapeutic use. Am J Clin Dermatol 2002; 3: 47–58.
€uber U. Dermatocorticosteroids: structure, activity,
20 Ta
pharmacokinetics. Eur J Dermatol 1994; 4: 419–429.
21 Wozniacka A, Sysa-Jedrzejowska A. Topical steroids – a new
approach after 50 years. Med Sci Monit 2001; 7: 539–544.
22 Luger T, Loske K, Elsner P, et al. Topical skin therapy with
glucocorticosteroids – therapeutic index. J Deutsch Dermatol
Ges 2004; 7: 629–634.
23 Mori M, Pimpinelli N, Giannotti B. Topical corticosteroids and
unwanted local effects. Improving the benefit/risk ratio. Drug Saf
1994; 10: 406–412.
24 Hengge UR, Ruzicka T, Schwartz RA, et al. Adverse effects of
topical glucocorticosteroids. J Am Acad Dermatol 2006; 54: 1–15.
25 Ortonne J-P. Skin atrophogenic potential of methylprednisolone
aceponate (MPA). J Eur Acad Dermatol Venereol 1994; 3
(Suppl. 1): S13–S18.
s A, Ta€uber U, et al. Methylprednisolone
26 Zaumseil R-P, Kecske
aceponate (MPA) – a new therapeutic for eczema: a
pharmacological overview. J Dermatol Treat 1992; 3(Suppl. 2):
3–7.
€cke W-D, Merbold U, et al. Superior
27 Mirshahpanah P, Do
nuclear receptor selectivity and therapeutic index of
methylprednisolone aceponate versus mometasone furoate. Exp
Dermatol 2007; 16: 753–761.
s A, Jahn P, Lange L. Local tolerability of topically
28 Kecske
applied methylprednisolone aceponate. J Am Acad Dermatol
1993; 28: 786–788.
29 Korotky NG, Taganov AV. The use of steroid Advantan
(methylprednisolone aceponate) for management of
allergodermatoses in children. Vestn Dermatol Venereol 2000;
3: 61–63.
30 Soennichsen N, Mekbib K. Die behandlung des atopischen
ekzems (neurodermitis) im kindesalter mit 6-alpha-
methylprednisoloneaceponat [in German]. Der Deutsche
Dermatologe 1996; 44: 8.
31 Alchorne MM, Da CP, Cestari S, et al. A multicenter,
comparative, open-labelled, randomized study of tolerability and
efficacy of methylprednisolone aceponate and mometasone
ª 2017 The International Society of Dermatology
Torrelo et al. Methylprednisolone aceponate for atopic dermatitis
furoate in children from 2 to14 years of age suffering from
atopic dermatitis. Ped Mod 2003; 39: 275–280.
32 Nawata H, Okabe T, Yanase T, et al. Mechanism of action and
resistance to glucocorticoid and selective glucocorticoid receptor
modulator to overcome glucocorticoid-related adverse effects.
Clin Exp Allergy Rev 2008; 8: 53–56.
33 Newton R, Holden NS. Separating transrepression and
transactivation: a distressing divorce for the glucocorticoid
receptor? Mol Pharmacol 2007; 72: 799–809.
34 Hoetzenecker W, Meingassner JG, Ecker R, et al.
Corticosteroids but not pimecrolimus affect viability, maturation
and immune function of murine epidermal Langerhans cells. J
Invest Dermatol 2004; 122: 673–684.
35 Schwiebert LM, Beck LA, Stellato C, et al. Glucocorticosteroid
inhibition of cytokine production: relevance to antiallergic
actions. J Allergy Clin Immunol 1996; 97: 143–152.
36 Boschetto P, Rogers DF, Fabbri LM, et al. Corticosteroid
inhibition of airway microvascular leakage. Am Rev Respir Dis
1991; 143: 605–609.
37 Haapasaari KM, Risteli J, Koivukangas V, et al. Comparison of
the effect of hydrocortisone, hydrocortisone-17-butyrate and
betamethasone on collagen synthesis in human skin in vivo.
Acta Derm Venereol 1995; 75: 269–271.
38 Albrecht G. Clinical comparison of methylprednisolone
aceponate and prednicarbate in chronic eczema. J Eur Acad
Dermatol Venereol 1994; 3(Suppl. 1): S42–S48.
39 Sonnichsen N, Zaumseil R-P. Efficacy and tolerability of
methylprednisolone aceponate solution in eczematous diseases
of the hairy scalp. Dermatology 1999; 5: 317–324.
40 Haria M, Balfour JA. Methylprednisolone aceponate. A review of
its pharmacological properties and therapeutic potential in the
topical treatment of eczema. Clin Immunother 1995; 3: 241–253.
41 Haneke E. The treatment of atopic dermatitis with
methylprednisolone aceponate (MPA), a new topical
corticosteroid. J Dermatol Treat 1992; 3(Suppl. 2): 13–15.
42 Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common
loss-of-function variants of the epidermal barrier protein filaggrin
are a major predisposing factor for atopic dermatitis. Nat Genet
2006; 38: 441–446.
43 Irvine AD, McLean WH, Leung DY. Filaggrin mutations
associated with skin and allergic diseases. N Engl J Med 2011;
365: 1315–1327.
44 McAleer MA, Irvine AD. The multifunctional role of filaggrin in
allergic skin disease. J Allergy Clin Immunol 2013; 131: 280–
291.
45 O’Regan GM, Irvine AD. The role of filaggrin in the atopic
diathesis. Clin Exp Allergy 2010; 40: 965–972.
46 Gelmetti C, Wollenberg A. Atopic dermatitis – all you can do
from the outside. Br J Dermatol 2014; 170(Suppl. 1): 19–24.
47 Boralevi F, Saint Aroman M, Delarue A, et al. Long-term
emollient therapy improves xerosis in children with atopic
dermatitis. J Eur Acad Dermatol Venereol 2014; 28: 1456–1462.
48 Uehara M, Miyauchi H. The morphologic characteristics of dry
skin in atopic dermatitis. Arch Dermatol 1984; 120: 1186–1190.
49 Moret L, Anthoine E, Aubert-Wastiaux H, et al. TOPICOP©: a
new scale evaluating topical corticosteroid phobia among atopic
ª 2017 The International Society of Dermatology
Pharmacology and therapeutics 7
dermatitis outpatients and their parents. PLoS ONE 2013; 8:
e76493.
50 Peserico A, Sta €dtler G, Sebastian M, et al. Reduction of
relapses of atopic dermatitis with methylprednisolone aceponate
cream twice weekly in addition to maintenance treatment with
emollient: a multicentre, randomized, double-blind, controlled
study. Br J Dermatol 2008; 158: 801–807.
51 Van Der Meer JB, Glazenburg EJ, Mulder PG, et al. The
management of moderate to severe atopic dermatitis in adults
with topical fluticasone propionate. The Netherlands Adult Atopic
DermatitisStudy Group. Br J Dermatol 1999; 140: 1114–1121.
52 Hanifin J, Gupta AK, Rajagopalan R. Intermittent dosing of
fluticasone propionate cream for reducing the risk of relapse in
atopic dermatitis patients. Br J Dermatol 2002; 147: 528–537.
53 Berth-Jones J, Damstra RJ, Golsch S, et al. ; Multinational
Study Group. Twice weekly fluticasone propionate added to
emollient maintenance treatment to reduce risk of relapse in
atopic dermatitis: randomised, double blind, parallel group study.
BMJ 2003; 326: 1367.
54 Glazenburg EJ, Wolkerstorfer A, Gerretsen AL, et al. Efficacy
and safety of fluticasone propionate 0.005% ointment in the
long-term maintenance treatment of children with atopic
dermatitis: differences between boys and girls? Pediatr Allergy
Immunol 2009; 20: 59–66.
55 Thacßi D, Reitamo S, Gonzalez Ensenat MA, et al. Proactive
disease management with 0.03% tacrolimus ointment for
children with atopic dermatitis: results of a randomized,
multicentre, comparative study. Br J Dermatol 2008; 159: 1348–
1356.
56 Wollenberg A, Reitamo S, Atzori F, et al. Proactive treatment of
atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy
2008; 63: 742–750.
57 Bieber T. Atopic dermatitis. N Engl J Med 2008; 358: 1483–
1494.
58 Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient
enhancement of the skin barrier from birth offers effective atopic
dermatitis prevention. J Allergy Clin Immunol 2014; 134: 818–
823.
Answers to Questions
1 A
2 B
3 C
4 C
5 D
6 D
7 D
8 C
9 A
10 D
International Journal of Dermatology 2017