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
disease with frequent flaring that can involve extensive areas of defined, and the term ‘dry’ skin is applied when fine scaling is
the skin.14,15,40 Although most physicians apply twice daily TCS present. It should be remembered that scaling is an intrinsic
to AD, MPA permits once-daily administration.8,26,41 On the other component in the definition of eczema and that many patients
hand, physicians use different formulations according to exten- with mild AD have a finely scaling process with slight or minimal
sion, area of the skin involved, exudation, and chronicity of erythema that can be confused with simply ‘dry’ skin.48 The use
lesions, and thus the availability of MPA in formulations including of emollients in active eczema can reduce scaling temporarily
ointment, fatty ointment, cream, lotion and milk/emulsion, all with but will not improve the disease and can cause irritation and fur-
equal efficacy, make it convenient for any patient age, skin condi- ther worsening of eczema. Physicians should be trained in the
tion, location of lesions, and disease severity.6 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-
Utilities of MPA According to the New
ence, patients who are instructed to treat minor flares of AD
Discoveries in AD
with TCS have better control of the disease, better quality of
For many years, most experienced dermatologists felt that AD life, and use much less topical treatment than when flare-ups
was primarily a skin disorder, most likely related to skin barrier and mild eczema are left untreated until they worsen or spread,
deficiency. However, extensive study of immunologic pathome- thus necessitating longer and more extensive therapy.
chanisms has led many researchers to consider immune sys-
tem imbalance as the primary abnormality in AD. The recent Achieving control of AD
discovery that filaggrin null mutations lead to genetic suscepti- Because AD is a chronic disease, both physicians and patients
bility to AD and can be responsible for at least a significant pro- may have feelings of frustration and surrendering. In children,
portion of AD patients (up to 40% in certain European the expectation for a remission when the child grows up may
populations) has shifted the paradigm of understanding and lead to a wait-and-see policy that can cause damage to children
management of AD.42,43 Filaggrin null mutations are also a first- in the form of continuous sensitization through damaged skin,
line risk factor for developing asthma and other allergic dis- mood changes, disturbance of academic achievements, and
eases.44 Because filaggrin is mostly expressed in the skin, the frustration from chronic suffering.
current opinion is that primary skin barrier defects lead to It is the author’s opinion and experience that every patient
increased exposure to environmental irritants and allergens, with AD should be brought into complete control, no matter if
causing irritant and allergic eczema.45 Eczema itself further the disease is mild or severe. The reasons are simple: (i) we
impairs skin barrier that becomes fully inefficient to prevent the have good and effective therapies that can be used safely; (ii)
entry of external molecules that are massively presented to the good control leads to a better quality of life; and (iii) control of
skin immune system, thus worsening the patient’s condition and the disease decreases the risk of further overexposure to aller-
leading to a circle of eczema and sensitization. gens and infectious agents. We can definitely change the life of
our patients with an appropriate approach to AD.
Combining emollient and pharmacologic treatment in AD Most patients with AD can be easily brought into control
The use of emollients has been recommended in an extensive with the use of only TCS. Because we have effective and
liberal use for all patients with AD. This seems reasonable in safe 4th generation TCS, their use for any flare-up, as early
view of the recent knowledge that primarily skin barrier defects as possible, on the whole affected area and for as many days
are the origin of AD. However, whereas the use of emollients is as necessary to achieve complete healing is encouraged. An
beneficial for patients with controlled AD and in the areas not insufficient use of TCS will lead to inefficiency and frustration.
affected by eczema, it is the author’s experience, as well as If the whole area with eczema is not treated, active eczema
others’, that the direct application of emollients on the skin will remain and treatment will be ineffective; it is important for
affected with eczema is poorly tolerated and causes itch and physicians and patients to recognize eczema and use 4th
irritation.46 In the author’s opinion, atopic eczema should be generation TCS on every affected area, whether severe or
brought into control before emollients are liberally used, and for mild. If TCS treatment is withdrawn before eczema is under
this, pharmacological therapy is necessary. The 4th generation complete control, the risk of rebound is very high; rebound is
topical CCS are the first-line drugs that should be used in order usually more linked to an insufficient treatment than to TCS
to achieve a complete healing of eczema because of their effec- themselves.
tiveness and safety profile. Once the skin is clinically healthy, Patients must be reassured that using 4th generation TCS is
emollients can be used according to the physician and patient safe and will not cause any harm when properly used. Cortico-
preferences. phobia49 will lead to the use of noneffective remedies, simply
It is generally accepted that the skin of the patients with AD on the basis that they will not cause any harm. In the author’s
is dry, and the concept of ‘dry’ skin has been equivalent to ‘ato- opinion, using ineffective remedies is harmful because AD is
pic’ skin.47 From a clinical point of view, ‘dryness’ is not well harmful itself in terms of affecting quality of life, inducing further
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
9 Which are the first-line drugs for the treatment of the atopic corticoid therapy with few side effects. Jahrb Dermatol 1992; 3:
dermatitis flares: 247–263.
14 Fritsch P. Clinical experience with methylprednisolone
A Topical corticosteroids
aceponate (MPA) in eczema. J Dermatolog Treat 1992; 3
B Topical calcineurin inhibitors (Suppl. 2): 17–19.
C Emollients 15 Mensing H, Lorenz B. Experience with methylprednisolone
D Oral antihistamines aceponate (MPA) in patients suffering from acute and chronic
10 Which of the following is false for the management of atopic eczema. Results of a large observational study. Z Hautkr 1998;
73: 281–285.
dermatitis:
16 Kecske s A, Jahn P, Wendt H, et al. Activity of topically applied
A Safe and effective therapies are available for atopic der- methylprednisolone aceponate in relation to other topical
matitis glucocorticosteroids in healthy volunteers. Arzneimittelforschung
B Control of atopic dermatitis leads to a better quality of life 1993; 43: 144–147.
C Control of atopic dermatitis decreases further exposure to 17 Kecske s A, Heger-Mahn D, Kuhlmann RK, et al. Comparison of
the local and systemic side effects of methylprednisolone
allergens
aceponate and mometasone furoate applied as ointments with
D Atopic dermatitis should be left untreated because most equal anti-inflammatory activity. J Am Acad Dermatol 1993; 29:
cases will eventually resolve 576–580.
18 Kungurov NV, Kokhan MM, Keniksfest JV, et al. Difference
topical therapy of the atopic eczema in children and adults
References (poster 2–3). J Eur Acad Dermatol Venereol 2001; 15(Suppl. 2):
107.
1 Blume-Peytavi U, Wahn U. Optimizing the treatment of atopic
19 Brazzini B, Pimpinelli N. New and established topical
dermatitis in children: a review of the benefit/risk ratio of
corticosteroids in dermatology: clinical pharmacology and
methylprednisolone aceponate. J Eur Acad Dermatol Venereol
therapeutic use. Am J Clin Dermatol 2002; 3: 47–58.
2011; 25: 508–515. €uber U. Dermatocorticosteroids: structure, activity,
20 Ta
2 Ruzicka T. Methylprednisolone aceponate in eczema and other
pharmacokinetics. Eur J Dermatol 1994; 4: 419–429.
inflammatory skin disorders – a clinical update. Int J Clin Pract
21 Wozniacka A, Sysa-Jedrzejowska A. Topical steroids – a new
2006; 60: 85–92.
approach after 50 years. Med Sci Monit 2001; 7: 539–544.
3 Toepert M, Olivar A, Opitz D. New developments in
22 Luger T, Loske K, Elsner P, et al. Topical skin therapy with
corticosteroid research. J Dermatolog Treat 1990; 1(Suppl. 3):
glucocorticosteroids – therapeutic index. J Deutsch Dermatol
S5–S9.
Ges 2004; 7: 629–634.
4 Ta€uber U. Pharmacokinetics and bioactivation of MPA. J Eur
23 Mori M, Pimpinelli N, Giannotti B. Topical corticosteroids and
Acad Dermatol Venereol 1994; 3(Suppl. 1): 23–31.
unwanted local effects. Improving the benefit/risk ratio. Drug Saf
5 Zentl HJ, Toepert M. Preclinical evaluation of a new topical
1994; 10: 406–412.
corticosteroid methylprednisolone aceponate. J Eur Acad
24 Hengge UR, Ruzicka T, Schwartz RA, et al. Adverse effects of
Dermatol Venereol 1994; 3(Suppl. 1): 32–38.
topical glucocorticosteroids. J Am Acad Dermatol 2006; 54: 1–15.
6 Luger TA. Balancing efficacy and safety in the management of
25 Ortonne J-P. Skin atrophogenic potential of methylprednisolone
atopic dermatitis: the role of methylprednisolone aceponate.
aceponate (MPA). J Eur Acad Dermatol Venereol 1994; 3
J Eur Acad Dermatol Venereol 2011; 25: 251–258.
(Suppl. 1): S13–S18.
7 Korotky NG, Taganov AV, Shimanovsky NL. Use of Advantan in s A, Ta€uber U, et al. Methylprednisolone
26 Zaumseil R-P, Kecske
the treatment of atopic dermatitis in children. Pediatriya 2000; 5:
aceponate (MPA) – a new therapeutic for eczema: a
75–78.
pharmacological overview. J Dermatol Treat 1992; 3(Suppl. 2):
8 Rampini E. Methylprednisolone aceponate (MPA) – use and
3–7.
clinical experience in children. J Dermatol Treat 1992; 3(Suppl. €cke W-D, Merbold U, et al. Superior
27 Mirshahpanah P, Do
2): 27–29.
nuclear receptor selectivity and therapeutic index of
9 Bieber T, Vick K, Fo €lster-Holst R, et al. Efficacy and safety
methylprednisolone aceponate versus mometasone furoate. Exp
of methylprednisolone aceponate ointment 0.1% compared
Dermatol 2007; 16: 753–761.
to tacrolimus 0.03% in children and adolescents with an s A, Jahn P, Lange L. Local tolerability of topically
28 Kecske
acute flare of severe atopic dermatitis. Allergy 2007; 62:
applied methylprednisolone aceponate. J Am Acad Dermatol
184–189.
1993; 28: 786–788.
10 Ortonne JP. Safety aspects of topical methylprednisolone
29 Korotky NG, Taganov AV. The use of steroid Advantan
aceponate (MPA) treatment. J Dermatol Treat 1992; 3(Suppl.
(methylprednisolone aceponate) for management of
2): 21–25.
allergodermatoses in children. Vestn Dermatol Venereol 2000;
11 Grebenyuk VN, Balabolkin II. Progress in topical corticosteroid
3: 61–63.
therapy of atopic dermatitis in children. Pediatriya 1998; 5: 88–
30 Soennichsen N, Mekbib K. Die behandlung des atopischen
91.
ekzems (neurodermitis) im kindesalter mit 6-alpha-
12 Niedner R, Zaumseil R-P. Advantan milk ⁄ cream.ointment in
methylprednisoloneaceponat [in German]. Der Deutsche
children with atopic dermatitis and other inflammatory or
Dermatologe 1996; 44: 8.
eczematous dermatoses – an observational study in 558
31 Alchorne MM, Da CP, Cestari S, et al. A multicenter,
children. Aktuelle Derm 2004; 30: 200–203.
comparative, open-labelled, randomized study of tolerability and
13 Zaumseil R-P, Fuhrmann H, Kecske0 s A, et al.
efficacy of methylprednisolone aceponate and mometasone
Methylprednisolone aceponate (Advantan) – an effective topical
furoate in children from 2 to14 years of age suffering from dermatitis outpatients and their parents. PLoS ONE 2013; 8:
atopic dermatitis. Ped Mod 2003; 39: 275–280. e76493.
32 Nawata H, Okabe T, Yanase T, et al. Mechanism of action and 50 Peserico A, Sta €dtler G, Sebastian M, et al. Reduction of
resistance to glucocorticoid and selective glucocorticoid receptor relapses of atopic dermatitis with methylprednisolone aceponate
modulator to overcome glucocorticoid-related adverse effects. cream twice weekly in addition to maintenance treatment with
Clin Exp Allergy Rev 2008; 8: 53–56. emollient: a multicentre, randomized, double-blind, controlled
33 Newton R, Holden NS. Separating transrepression and study. Br J Dermatol 2008; 158: 801–807.
transactivation: a distressing divorce for the glucocorticoid 51 Van Der Meer JB, Glazenburg EJ, Mulder PG, et al. The
receptor? Mol Pharmacol 2007; 72: 799–809. management of moderate to severe atopic dermatitis in adults
34 Hoetzenecker W, Meingassner JG, Ecker R, et al. with topical fluticasone propionate. The Netherlands Adult Atopic
Corticosteroids but not pimecrolimus affect viability, maturation DermatitisStudy Group. Br J Dermatol 1999; 140: 1114–1121.
and immune function of murine epidermal Langerhans cells. J 52 Hanifin J, Gupta AK, Rajagopalan R. Intermittent dosing of
Invest Dermatol 2004; 122: 673–684. fluticasone propionate cream for reducing the risk of relapse in
35 Schwiebert LM, Beck LA, Stellato C, et al. Glucocorticosteroid atopic dermatitis patients. Br J Dermatol 2002; 147: 528–537.
inhibition of cytokine production: relevance to antiallergic 53 Berth-Jones J, Damstra RJ, Golsch S, et al. ; Multinational
actions. J Allergy Clin Immunol 1996; 97: 143–152. Study Group. Twice weekly fluticasone propionate added to
36 Boschetto P, Rogers DF, Fabbri LM, et al. Corticosteroid emollient maintenance treatment to reduce risk of relapse in
inhibition of airway microvascular leakage. Am Rev Respir Dis atopic dermatitis: randomised, double blind, parallel group study.
1991; 143: 605–609. BMJ 2003; 326: 1367.
37 Haapasaari KM, Risteli J, Koivukangas V, et al. Comparison of 54 Glazenburg EJ, Wolkerstorfer A, Gerretsen AL, et al. Efficacy
the effect of hydrocortisone, hydrocortisone-17-butyrate and and safety of fluticasone propionate 0.005% ointment in the
betamethasone on collagen synthesis in human skin in vivo. long-term maintenance treatment of children with atopic
Acta Derm Venereol 1995; 75: 269–271. dermatitis: differences between boys and girls? Pediatr Allergy
38 Albrecht G. Clinical comparison of methylprednisolone Immunol 2009; 20: 59–66.
aceponate and prednicarbate in chronic eczema. J Eur Acad 55 Thacßi D, Reitamo S, Gonzalez Ensenat MA, et al. Proactive
Dermatol Venereol 1994; 3(Suppl. 1): S42–S48. disease management with 0.03% tacrolimus ointment for
39 Sonnichsen N, Zaumseil R-P. Efficacy and tolerability of children with atopic dermatitis: results of a randomized,
methylprednisolone aceponate solution in eczematous diseases multicentre, comparative study. Br J Dermatol 2008; 159: 1348–
of the hairy scalp. Dermatology 1999; 5: 317–324. 1356.
40 Haria M, Balfour JA. Methylprednisolone aceponate. A review of 56 Wollenberg A, Reitamo S, Atzori F, et al. Proactive treatment of
its pharmacological properties and therapeutic potential in the atopic dermatitis in adults with 0.1% tacrolimus ointment. Allergy
topical treatment of eczema. Clin Immunother 1995; 3: 241–253. 2008; 63: 742–750.
41 Haneke E. The treatment of atopic dermatitis with 57 Bieber T. Atopic dermatitis. N Engl J Med 2008; 358: 1483–
methylprednisolone aceponate (MPA), a new topical 1494.
corticosteroid. J Dermatol Treat 1992; 3(Suppl. 2): 13–15. 58 Simpson EL, Chalmers JR, Hanifin JM, et al. Emollient
42 Palmer CN, Irvine AD, Terron-Kwiatkowski A, et al. Common enhancement of the skin barrier from birth offers effective atopic
loss-of-function variants of the epidermal barrier protein filaggrin dermatitis prevention. J Allergy Clin Immunol 2014; 134: 818–
are a major predisposing factor for atopic dermatitis. Nat Genet 823.
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. Answers to Questions
44 McAleer MA, Irvine AD. The multifunctional role of filaggrin in
allergic skin disease. J Allergy Clin Immunol 2013; 131: 280–
1 A
291.
45 O’Regan GM, Irvine AD. The role of filaggrin in the atopic 2 B
diathesis. Clin Exp Allergy 2010; 40: 965–972. 3 C
46 Gelmetti C, Wollenberg A. Atopic dermatitis – all you can do 4 C
from the outside. Br J Dermatol 2014; 170(Suppl. 1): 19–24. 5 D
47 Boralevi F, Saint Aroman M, Delarue A, et al. Long-term
6 D
emollient therapy improves xerosis in children with atopic
dermatitis. J Eur Acad Dermatol Venereol 2014; 28: 1456–1462. 7 D
48 Uehara M, Miyauchi H. The morphologic characteristics of dry 8 C
skin in atopic dermatitis. Arch Dermatol 1984; 120: 1186–1190. 9 A
49 Moret L, Anthoine E, Aubert-Wastiaux H, et al. TOPICOP©: a 10 D
new scale evaluating topical corticosteroid phobia among atopic