EDF-guideline_Atopic-Eczema_update2018


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��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Consensus based European Guidelines for Treatment of Atopic Eczema
(Atopic Dermatitis) in Adults and Children
Part I
Wollenberg A
, Barbarot S
Bieber T
, Christen
Zaech S
, Deleuran M
, Fink
Wagner A
, Gieler U
Girolomoni G
, Lau S
, Muraro A
, Czarnecka
Operacz M
, Schäfer T
, Schmid
Grendelmeier P
Simon D
, Szalai Z
Department Dermatology and Allergy, Ludwig
Maximilian University, Munich, Germany
and Klinik
Thalkirchner Straße,
Munich, Germany
Department of Dermatology
ntre Hospitalier Universitaire CHU Nantes,
Nantes, France
Department of
Dermatology and Alle
rgy, and Christine Kühne
Center
for Allergy Research and Ed
ucation, University Bonn,
Bonn,
Germany
Pediatric Dermatology Unit, Departments of Dermatology and
Pediatrics, Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland
Department Dermatology, Aarhus University Hospital, Aarhus, Denmark
Patient representative,
European Federation of Allergy and Airways Diseases Patients‘ Associations
EFA
cor
porate
Relations and Fundraising Manager and Co
Founder of
Global Allergy and Asthma Patient Platform
GAAPP
, Konstanz,
Germany
Department of Der
matology and Dept. of
Psychosomatics and Psychotherapy, University of Gießen and Marburg GmbH,
Gießen, Germany
Department of Medicine, Section of Dermatology, University of Verona, Verona, Italy
Pediatric Pneumology and Immunology, Universitätsmedizin Berlin, Germany
Centro di Specializzazione Regionale per lo Studio e la Cura delle Allergie e delle Intolleranze Alimentari
presso l’Azienda
Ospedaliera,
Università di Padova
, Italy
Department of Dermatology, Medical University, Poznan, Poland
Dermato
logical Practice
Immenstadt
Germany
Allergy Unit, Department of Dermatology, University of Zurich, Switzerland an
d Christine Kühne Center fo
r Allergy researc
and Educaction CK
CARE, Davos
, Switzerland
Department Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Department of Dermatology, Heim Pál Children's Hospital, Budapest, Hungary
Department of Dermatology,
Venereology and Allergology, Wroclaw Medical Uni
versity, Wroclaw, Poland
Department of Dermatology & Pediatric Dermatology, Hôpital St André, Bordeaux, France
Department of Dermatology, Hospital Niño Jesus, Madrid, Spain
Department Dermatology and Allergy, Hannover Medical School, Hannover,
Germany
Department Dermatology and Allergy Biederstein, Technische Universität München, Munich, Germany
and
Christine
Kühne
Center for Allergy Re
search and Education (CK
CARE), Davos
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Declaration of Conflict of Interest
A. Wollenberg has been an advisor, speaker or investigator for ALK Abelló, Almirall, Anacor, Astellas,
Beiersdorf, Bencard, Bioderma, Chugai, Galderma, Glaxo SmithKline, Hans Karrer, LEO Pharma,
L’Oreal,
Maruho,
MedImmune, Novartis,
Pfizer, Pierre Fabre, R
egeneron and Sanofi.
S.Barbarot has been an advisor, speaker or investigator for Bioderma, La Roche Posay, Sanofi
Genzyme, Novalac, Ferring, Abbvie, Novartis, Janssen.
T. Bieber has been advisor, speaker or investigator for Abbvie, Allmirall, Anacor,
Astellas, Bayer,
Celgene, Chugai, Daiichi
Sankyo, Galderma, Glaxo SmithKline, Leo Pharma, Novartis, Pfizer, Pfizer,
Pierre
Fabre, L´Oréal, La Roche
Posay, Regeneron, and Sanofi.
S. Christen
Zaech has been an advisor, speaker or investigator for Galderma,
L’Oreal, La RochePosey,
Pierre Fabre, Permamed, Procter and Gamble, and Sanofi
Genzyme.
M. Deleuran has been an advisor, speaker or investigator for AbbVie, Leo Pharma, MEDA, Pierre
Fabre,
L´Oréal, La Roche
Posay, Pfizer, Regeneron and Sanofi.
A. Fink
gner has been working with, or an advisor or speaker for ALTANA, Novartis, Nycomed,
Hoffmann
La Roche and Teva.
U. Gieler has been has been advisor or speaker for Allmirall, Astellas, Bayer, Celgene, Galderma, Glaxo
SmithKline, Leo Pharma, Lilly, Novartis
, Pfizer, Pierre
Fabre, La Roche
Posay and Sanofi
Aventis.
G. Girolomoni has been an advisor, speaker or investigator for AbbVie, Abiogen, Allmirall, Amgen, Bayer,
Biogen, Boehringer Ingelheim, Celgene, Eli
Lilly, Galderma, Hospira, Janssen, Leo Pharma,
Menlo
therapeutics, Merck, MSD, Mundipharma, Novartis, Otsuka, Pfizer, Pierre Fabre, Regeneron, Sandoz,
Sanofi and Sun Pharma
S. Lau has received grants from Allergopharma and Symbiopharm, and a honorarium from Merck as
member of a drug monitoring committ
ee, ALK and DBV Technologies.
A. Muraro has has been a speaker for Meda, Nestlè and Stallergenes.
M. Czarnecka
Operacz has been an advisor, speaker or investigator for Allergopharma, Allmiral,
Bioderma, Berlin Chemie, Mennarini, Novartis, Pierre Fabre, G
alderma, Janssen and Leo Pharma.
T. Schäfer has been speaker for Abbott, Bencard, Dr Pfleger, Norvatis and Syneron
Candela.
P. Schmid
Grendelmeier has been an advisor or speaker for ALK
Abello, Allergopharma, La Roche
Posay, MEDA, Novartis, Sanofi and St
allergenes.
D. Simon has been an advisor, speaker or investigator for Roche, Novartis, Galderma, Glaxo SmithKline,
Merz Pharma (Schweiz), Almirall, Sanofi, and Eli Lilly.
Z. Szalai has been advisor for Pfizer, speaker or investigator for Bayer, Novartis,
Pierre Fabre, Sanofi,
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;A. Torrelo has been advisor, speaker or investig
ator for AbbVie, Anacor, Astellas, Bayer, Beiersdorf AG,
Galderma, Meda, Novartis, Pierre Fabre.
T. Werfel has received support for research projects from AbbVie, Astellas, Janssen/JNJ, Meda,
Regeneron/Sanofi, Takeda, Ziarco, and has been an advisor for A
bbVie, Allmiral, LEO Pharma, Lilly,
MSD, Novartis, Regeneron/Sanofi, Roche, Stallergen and Ziarco.
J. Ring has been advisor, speaker or investigator for ALLERGIKA, ALK Abello, Almirall
Hermal, Anacor,
Astellas, Bencard/Allergy Therapeutics, Galderma, GSK
Stiefel, LEO Pharma, Meda, MSD, Novartis,
Phadia
ThermoFisher, and Sanofi.
Table R1 (online repository)
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�� &#x/MCI; 0 ;&#x/MCI; 0 ; &#x/MCI; 1 ;&#x/MCI; 1 ;1 &#x/MCI; 3 ;&#x/MCI; 3 ;Assignment of guideline sections to draft authors
Part I
Introduction
(Andreas Wollenberg & Johannes Ring)
Name
Role in the guideline development, discipline / content expertise,
institution / geographic location
Institutions represented
Expert panel
Sebastien
Barbarot
Expert panel member; Assistant Professor of Dermatology,
Department of Dermatology, Centre Hospitalier Universitaire (CHU)
Nantes, Nantes, France
European Academy of
Dermatology and Venerology
(EADV), European Task Force
on Atopic Dermatitis (ETFAD)
Thomas
Bieber
Expert panel member; Professor of Dermatology, Department of
Dermatology and Allergy, and Christine Kühne
Center for Allergy
Research and Education, University Bonn, Bonn, Germany
Euro
pean Dermatology Forum
(EDF), European Academy of
Dermatology and Venerology
(EADV), European Task Force
on Atopic Dermatitis (ETFAD)
Stephanie
Christen
Zäch
Expert panel member; Pediatric dermatologist, Head of Pediatric
Dermatology Unit, Departments of
Dermatology and Pediatrics,
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
Dermatology (ESPD),
European Academy of
Dermatology and Venerology
(EADV), European Task Force
on Atopic Dermatitis (ETFAD)
leuran
Expert panel member; Professor of Dermatology and Head;
Department Dermatology, Aarhus University Hospital, Aarhus,
Denmark
European Dermatology Forum
on Atopic Dermatitis (ETFAD)
Antje
Fink
Wagner
Expert panel member;
Patient representative
; EFA corporate
Relations and Fundraising Manager and Co
Founder of GAAPP,
Konstanz, Germany
European Federation of
Allergy an
d Airways Diseases
Patients‘ Associations (EFA),
Global Allergy and Asthma
Patient Platform (GAAPP)
Uwe
Gieler
Expert panel member; Professor of Psychosomatics and Dermatology,
Department of Dermatology and Dept. of Psychosomatics and
European Dermatology Forum
(EDF), European Academy of
��EDF Guideline AE
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Psychotherapy,
University of Gießen and Marburg GmbH, Gießen,
Germany
Dermatology and Venerology
(EADV), European Task Force
on Atopic Dermatitis (ETFAD)
Giampiero
Girolomoni
Expert panel member; Professor of
Dermatology, Department of
Medicine, Section of Dermatology, University of Verona, Verona, Italy
European Dermatology Forum
(EDF) European Academy of
Dermatology and Venerology
(EADV)
Susanne
Lau
Expert panel member; Professor of Pediatric Allergy, Pediat
ric
Pneumology and Immunology, Universitätsmedizin Berlin, Germany
European Academy of Allergy
and Clinical Immunology
(EAACI)
Antonella
Muraro
Expert panel member; Professor of Allergy, Food Allergy Referral
Padua University Hospital, Padua, Italy
European Academy of Allergy
and Clinical Immunology
(EAACI)
Magda
Czarnecka
Operacz
Expert panel member; Professor of Dermatology and Head;
Department of Dermatology, Medical University, Poznan,
Poland
European Dermatology Forum
(EDF); European Union of
Medical Specialists (
UEMS);
European Academy of Allergy
and Clinical Immunology
(EAACI)
Torsten
Schaefer
Expert panel member; Dermatologist, Dermatological Practice,
Immenstadt, Germany
European
Academy of Allergy
and Clinical Immunology
(EAACI)
Schmid
Grendelmeier
Expert panel member; Professor of Dermatology and Allergy, Allergy
Unit, Department of Dermatology, University of Zurich, Switzerland
and Christine Kühne Center for Allergy
research and Educaction CK
CARE, Davos, Switzerland
European Academy of Allergy
and Clinical Immunology
(EAACI), European Academy
of Dermatology and
Venerology (EADV)
Dagmar
Simon
Expert panel member; Professor of Dermatology, Department
Dermatology, Inse
lspital, Bern University Hospital, University of Bern,
Bern, Switzerland
European Academy of
Dermatology and Venerology
(EADV); European Task Force
on Atopic Dermatitis (ETFAD);
European Academy of Allergy
and Clinical Immunology
(EAACI)
Zsuzsanna
Szalai
Expert panel member; Dermatologist and Pediatrician, Head,
Department of Dermatology, Heim Pál Children's Hospital, Budapest,
Hungary
Dermatology (ESPD),
European Academy of
Dermatology and Venerology
(EADV), European Task Fo
rce
on Atopic Dermatitis (ETFAD)
Jacek
Expert panel member; Professor of Dermatology, Department of
Dermatology, Venereology and Allergology, Wroclaw Medical
University, Wroclaw, Poland
European Dermatology Forum
(EDF), European Academy of
Dermatology and Venerology
(ESDaP)
Alain
Taieb
Expert panel member; Professor of Dermatology, Department of
Dermatology & Pediatric Dermatology, Hôpital St André, Bordeaux,
France
European Dermatolog
y Forum
(EDF), European Academy of
Dermatology and Venerology
(EADV), European Task Force
on Atopic Dermatitis (ETFAD)
Antonio
Torrelo
Expert panel member; Professor of Pediatric Dermatology,
Department of Dermatology, Hospital Niño Jesus, Madrid, Spain
Dermatology (ESPD),
European Task Force on
Atopic Dermatitis (ETFAD)
Thomas
Werfel
Expert panel member; Professor of Dermatology, Department
Dermatology and Allergy, Hannover Medical School, Hannover,
Germany
European
Dermatology Forum
(EDF), European Academy of
Allergy and Clinical
Immunology (EAACI),
European Academy of
Dermatology and Venerology
(EADV), European Task Force
on Atopic Dermatitis (ETFAD)
Steering group
Johannes
Ring
Chairman, moderation of the
consensus conference; Professor
emeritus of Dermatology and Allergy; Klinik für Dermatologie,
Allergologie und Venerologie, Technical University Munich; Munich,
Germany and Christine Kühne
Center for Allergy Research and
Education (CK
CARE), Davos
European
Dermatology Forum
(EDF), European Academy of
Allergy and Clinical
Immunology (EAACI),
European Academy of
Dermatology and Venerology
(EADV), European Task Force
on Atopic Dermatitis (ETFAD),
��EDF Guideline AE
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Global Allergy and Asthma
Andreas
Wollenberg
Organization, drafting and writing of the guideline text and figures;
Consultant Dermatologist and Professor of Dermatology, Department
Dermatology and Allergy, Ludwig
Maximilian University, Munich,
Germany and Klinik Thalkirchner Straße, Munich
, Germany
European Dermatology Forum
(EAA
CI)
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;List of Abbreviations
American Academy of Dermatology
Atopic dermatitis
Atopic eczema
AEGIS
Eczema vaccinatum
Food allergy
FTU
Fingertip unit
GAAPP
Global Allergy and Asthma Patient Platform
HBD
Human
defensin
HDM
House Dust Mite
HTA
Health Technology Assess
ment
H1R
Histamin 1 receptor
Immunoadsorption
ICAM1
Intercellular Adhesion Molecule 1
Investigators Global Assessment, a signs score
IgE
Immunoglobulin E
IgG
Immunoglobulin G
Interleukin
IVIG
Intravenous immunoglobulins
IFN
Interferon alpha
IFN
Interferon gamma
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;JAK
Janus kinase
LEAP
Learning Early About Peanut Allergy
LTC4
Leukotriene C4
LTD4
Leukotriene D4
LTE4
Leukotriene E4
MCV
Molluscum contagiosum virus
VOCs
Volatile organic compounds
VZV
Varicella
zoster Virus
QoL
Quality of life
TSLP
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Abstract

This guideline was developed as a joint interdisciplinary European project, including physicians
from all relevant disciplines as well as patients. It is a consensus based guideline, taking
available evidence from other guidelines, systematic reviews, and
published studies in to
account.
This first part of the guideline covers methods, patient perspective, general measures and
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Table of contents

Part I
Introduction
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Introduction

Atopic eczema (AE; atopic dermatitis, eczema, “Neurodermitis” in
German speaking
countries, endogenous eczema, neurodermatitis) is an inflammatory, pruritic, chronic or
chronically relapsing skin disease occurring often in families with other atopic diseases
(bronchial asthma and/ or allergic rhinoconjunctivitis). AE is
one of the most common non
communicable skin diseases which affects up to 20% of children and 2
8% of adults in most
countries of the world. In many instances AE begins in childhood, while severe cases may
persist in adulthood. About one third of adult ca
ses develop in adulthood. AE is often the
first step in the development of other atopic diseases, such as allergic rhinoconjunctivitis or
asthma and food allergy (FA).
Though several diagnostic criteria have been proposed over time, the classical Hanifin &
Rajka criteria are still the most widely used criteria worldwide
. There is no pathognomonic
laboratory biomarker for diagnosis of AE. The most typical feature, the elevation of total or
allergen
only score to measure subjective symptoms,
but not objective signs in clinical trials. The
Investigators Global Assessment (IGA) is frequently used, but more a global assessment
than a validated score. In contrast to SCORAD, POEM and EASI, it is a based on a single
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;global assessment by the invest
igator only. The HOME group is an initiative of
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Methods

The guideline committee decided that these guidelines should strictly concentrate on
therapeutic regimens and omit longer chapters on clinical entity, diagnosis or
pathophysiology of the disease
. This is a consensus
based S2k guideline, though it has an
additional strong focus on evidence from the literature. Consensus was achieved among the
nominated members of the European interdisciplinary expert group.
Base of the guideline
This is an update of the 2012 guideline on atopic dermatitis
. The former, first version
of this guideline had been based on the evidence
based national guideline from Germany
, the HTA report
, as well as the position paper of the ETFAD
, which were
compared and assessed. The former committee had decided that all these
documents
fulfilled enough criteria to be used as the base of the first version of the European Guidelines
on Treatment of Atopic Eczema
Data base and literature search
For this consensus
based guideline, no systematic literature review has been performed.
During the kick
��EDF Guideline AE
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This guideline has been prepared for physicians, especially dermatologists, pediatricians,
allergists, general practitioners and all specialists taking care of patients suffering from AE.
to evidence
based therapeutic modalities.
��EDF Guideline AE
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AE management from a
atient’s perspective
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;General measures and avoidance strategies
The identifica
tion of individual trigger factors is crucial in the management of AE and their
avoidance allows longer phases of remission or total clearance of symptoms. It is important
to differentiate between the genetic predisposition towards hypersensitive, dry skin
with
barrier dysfunction
largely corresponding to ichthyosis vulgaris
which cannot be "cured"
and the inflammatory skin lesions which can very well be treated and disappear.
In avoidance recommendations, one must distinguish between primary, secondar
y and
tertiary prevention measures. Among provocation factors, specific and non
specific elicitors
must be distinguished.
Non
specific provocation factors
Numerous factors and substances from the environment can irritate the sensitive skin of
patients
with AE and can elicit eczema flares. They may be physical, like mechanic irritants
(e.g. wool), chemical (acids, bleaches, solvents, water) or biological (allergens, microbes) in
nature. Information on unspecific irritants and their role in aggravating AE
is a crucial
prerequisite for long
term management of patients with AE. Here also the adequate skin
care and hygiene procedures in cleansing and dressing have to be discussed with the
patient (see also, “Educational program, eczema school").
Negative effe
cts of air pollutants upon the development and maintenance of AE, like tobacco
smoke or volatile organic compounds (VOCs) in indoor environments and traffic exhaust in
the outdoor air must be mentioned. There is evidence from epidemiological trials that
posure to indoor chemicals, such as formaldehyde, increases skin barrier disturbance
; a mixture of volatile organic compounds has been shown to increase the intensity of
atopy patch test reactions to aero
alle
rgens in patients with AE
Exposure to traffic exhaust has been shown to be associated with an increased risk to
develop AE in
pre
school children
. Moreover, diesel exhaust particles may favor
alloknesis and skin scratching, and thus worsen AE
Exposure to environmental tobacco smoke measured as urinary cotinin / creatinin ratio was
associated with a significant elevated risk to develop AE which was especially prono
unced
in children of parents with an atopic background
. The prevalence of smoking was higher
in severe AE, as shown in a recent cross sectional study investigating the entire Danish
population
. A systematic review of 86 studies confirmed the association of smoking and
AE in adolescents and adults in all continents of the earth
. It remains unclear, however,
if smoking is a provocation factor in AE or if the burden of AE leads to more frequent smoking
habits
Avoidance strategies regarding tobacco smoke as well as traffic exhaust exposure in young
children have been introduced in the recent S3 Guideline for primary prevention of atopic
diseases in Germany
.

39

40
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Specific allergen av
oidance
Aeroallergens
Aeroallergens can elicit eczematous skin lesions in sensitized patients with AE, which can
be explained by increased permeability of the skin for inhalant allergens in patients with skin
barrier defects
. Positive atopy patch tests are associated with specific IgE and positive
histories of flare
ups of AE to seasonal allergens
Many airborne allergens eliciting AE are derived from house dust mites (HDM) of the species
Dermatophagoides pteronyssinus
and
D. farinae
. The enzymatic activity of major mite
allergens is found to destroy tight junctions of the epithelial cells in the bronchial mucosa
and may thus also deteriorate the skin barrier dysfunction in patients with AE
House dust mites are living in a
complex eco
system consisting of air humidity, temperature
and presence of organic material. They accompany humans and are most commonly
present in dust from mattresses or bedroom floors. Normal cleaning measures help only
little in decreasing house dust m
is necessary.
Furthermore, the expo
sure towards bacteria is increased if dogs live in a household, which
may have a protective effect in terms of primary prevention and immune regulation.
However, if AE has developed, there may be a risk of bacterial superinfection if skin lesions
are prese
nt and dogs have a close contact to the patient
. Staphylococcus aureus, which
heavily colonizes
the lesions of AE, produces extracellular proteases, which cause barrier
breakdown in the skin and thus facilitate the uptake of allergens and specific sensitization.
��EDF Guideline AE
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Recommendations
Pollen avoidance measures can be recommended during the poll
en season. (
, D)
House dust mite
avoidance measures may be tried in selected cases. (
, D)
When classical patch tests are positive, relevant contact allergens should be avoided. (
, D)
All children diagnosed with AE should be vaccinated according t
o the national vaccination
plan (2a, B).
16
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Basic therapy of disturbed skin barrier function and emollient therapy
(“skin care”)
Emollient therapy and skin care
Dry skin is one of the characteristic symptoms of AE. There is now scientific evidence in
It should be
emphasized that most bath oils commercially available in Europ
e are practically free of these
protein allergens.
Recommendations
��EDF Guideline AE
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Adding antiseptics such as sodium hypochlorite to the bath
water may be useful for
treatment of AE (1b, A).
Emollient therapy
By tradition, emollients are defined as topical treatment
with vehicle
type
substances lacking
active ingredients. These emollients are extremely helpful for AE patients, and contain
usually a humectant (promoting stratum corneum hydration, such as urea or glycerol) and
an occludent (reducing evaporation, such as
age group, whereas toddlers should be treated with lower concentrations than adults
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Propylene glycol is easily irritating in young children aged less than two years and should
not be used for toxicity reasons in these young children.
There is concern that the large
preventive use of emollients containing intact proteins such as peanut all
ergens
or
colloidal oat meal
may increase the risk of skin sensitization and allergy. Only emollient
preparations devoid of proteinaceous allergens and haptens known to cause co
ntact allergy
. As
the major limitation of these two promi
sing trials is their relatively short duration of half a
year, longer trials are currently performed.
Evidence of steroid sparing effects of emollients
1. Short
term (3
6 weeks)
Several studies in children
and one in a mixed children
adult population
owed
a variable but consistent evidence of short
term steroid sparing effect in mild to moderate
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;2.
Long
term
maintenance therapy
Maintenance of stable disease can be obtained with emollients used twice weekly or more
frequently in a subset of patients, after an induction of remission with topical corticosteroids.
Several studies showed comparable results for intermittent emollient t
herapy and time to
relapse, using comparable study designs in adults and children
Recommendations
Emollients should be prescribed in adequate amounts and these should be used liberally
and frequently, in a minimum amount of 250 g per week for adults (3b,C).
Emollient bath oils and soap substitutes should also be used.
Emollients with a higher lipid
content are preferable in winter time (3b,C).
A regular use of emollient has a short and long term steroid sparing effect in mild to moderate
AE. An induction of remission with topical corticosteroids or topical calcineurin
inhibitors is
required first (2a,B).
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Dietary intervention
Food allergens, pre
and probiotics
Food allergy has been well documented in approximately one third of children with
moderate
severe AE
. Among food allergens, cow’s milk, hen’s egg, peanut, soy, nuts
and fish are most frequently responsible for AE exacerbation in young children, with age
dependent variations in causally incriminated food
. In older children, adolescents and
adults pollen associated food allergy should be taken into acco
unt
Response patterns to food allergens
Three different clinical reaction patterns in patients with AE have been described, depending
on the type of symptoms
Atopy patch test (APTs) are performed with
self
made food material using a 1/10 dilution in
saline of the fresh food applied for 24
48 hours on non
lesional skin
. Food APT is not
standardized for routine use. So far, APTs have demonstrated to improve the accuracy of
in testing in the diagnosis of allergy to cow’s milk, eggs, cereals, and peanuts in patients
with AE
Whereas immediate
type reactions are associated with SPT positivity,
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;delayed reactions are related to positive responses to APTs. However, double
blind
placebo
controlled food challenge (DBPCFC) remains the “gold standard” for the diagnosis
of FA
Oral food challenge (OFC) should always be performed under medical supervision with
emergency equipment available, particularly after long
lasting elimination of the culprit food.
Practically, OFC should be performed accor
ding to standardized protocols considering
variables associated with food matrix, doses and time intervals
. In AE the major flaw is
that DBPCFC might not offer the opportunity to exclude placebo reactions or coincidental
influences of other trigger factors of AE during the prolonged challenge period. Therefore in
AE the evaluation of delayed reactions after 24
hours or 48 hours by trained personal is
mandatory
. Challenge tests based on repeated exposure to food enable the
assessment of delayed adverse responses
Unfortunately, the effects of dietary interventions on the course of AE have been studied
only in a few controlled studies. In a systematic review
eight randomised, controlled
Probiotics such as lactobacillus mixtures have been studied in AE, and have been shown to
induce improvement
. Other studies failed to show significant effects
. In a study
with 800 infants the effect of a prebiotic mixture was investigated and found to have
beneficial effects in preventing the development of AE
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Non
pathogenic bacterial strains like
Vitreoscilla filiformis
or
Aquaphilus dolomiae
have been
used as sources for bacterial lysates for topical therapy of AE (see chapter: Topical therapy).
Previous systematic reviews on probiotics for the treatment of AE have consistently
concluded a lack of effect in children
. On the basis of the existing literature, with only
one group showing positive results in a controlled s
tudy, the guideline group decided not to
give a recommendation for treatment with lactobacilli in AE. It may well be that a preventive
effect of pre
or probiotic mixtures will be shown in the future; consultation of the S3 guideline
on “prevention on alle
rgy” is recommended
Summary of evidence
Food sensitization occurs in about 50 % of children with severe AE. The relevance can be
evaluated by oral provocation tests, best
performed as double
blind placebo
controlled food
challenge. (1a)
Food allergy plays a role for disease exacerbation in 30 % of AE children, most often against
basic foods such as hen’s egg or cow’s milk. Pollen
associated food allergy can occur in all
age
s. (2a)
Recommendations
foods that elicitated clinical early or late reactions upon controlled oral provocation tests.
(2b, B)
Primary prevention of food allergy associated AE is recommended with exclusive breast milk
feeding until 4 months of age. (2
3,C)
If breast milk is lacking in low risk children (general population), conventional cow’s milk
formula is recommended. (2
3,C)
If breast milk is lacking in high
risk children (one first degree relative with physician
diagnosed allergic symptoms), a documented hypoallergenic formula is recommended. (1,

low and high
risk children irrespective of an atopic heredity.
2, B)
ween 4
and 6 months of age
(1, D)
40
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Topical anti
inflammatory therapy
Topical treatment:
overall principles
Effective topical therapy depends on three fundamental principles: sufficient strength,
sufficient dosage and correct application
. Many formulations are available especially for
corticosteroids, and the choice of formulation has a strong impact on the efficacy of the
resulting drug. Topical treatment should always be applied on hydrated skin, especially
when using ointments. Patient
s with acute, oozing and erosive lesions and children
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;reported by different investigators
. With mild disease activity, a small
amount of
topical corticosteroid twice to thrice weekly (monthly amounts in the mean range of 15 g in
infants, 30 g in children and up to 60
90 g in adolescents and adults, roughly adapted to
affected body surface area), associated with a liberal use of em
ollients generally allows a
good maintenance. Such monthly amounts of even potent topical steroids usually do not
have adverse systemic or local effects. Twice weekly application of fluticasone or
infantum or even iatrogenic Cushing’s disease. The risk of ocular complications by topical
corticosteroids seems to be low. Development of glaucoma or cataract has been described
after systemic glucocorticosteroid application
The use of potent topical corticosteroids in sensitive skin areas (face, neck, folds) should be
limited in time to avoid skin atrophy
. Monitoring by physical examination for cut
aneous
side effects during long term use of potent topical corticosteroids is very important. The
special aspects and potential adverse effects of topical corticosteroids in pregnancy have
��EDF Guideline AE
part I and II
final
been recently revieved
The application of topical corticosteroids to the eyelids and
periorbital region, even over longer periods of time in adults with AE was not associated to
the development of glaucoma or cataracts
. Application of very potent topical
corticosteroids
even for brief time periods may result in the drug becoming systemically
available and potent enough to induce adrenal gland suppression
In the face a special skin condition called rosacea
like perioral dermatitis is often started by
inappropriate, long term use of TCS. The skin seems to become “addicted” to TCS (“red
face syndrome” or
„corticosteroid addiction syndrome“). This is character
ized by rosacea
like disease with persistent erythema, burning and stinging sensation. It has been reported
inappropriate use of potent topical corticosteroids
122
Patient fear of side effects of corticosteroids (corticophobia) is quite common and should be
recognized and adequately
addressed to improve adherence and avoid undertreatment
125
The simultaneous combination of topical corticosteroids with topical calcineurin inhibitors at
the same site does not seem to be useful. At least in pediatric patients with severe AE, the
Recommendations

Topical corticosteroids are
important anti
inflammatory drugs to be used in AE, especially in
the acute phase. (
, D)
Topical corticosteroids with an improved risk
benefit ratio are recommended in AE. (
, D)
AE to increase their efficacy. (1b, A)
Proactive therapy, e.g. twice weekly application in the long
term follow
up, may help to
reduce relapses. (1b, A)
Proactive therapy with TCS may be used safely for at least 20 weeks, which is the long
est
duration of trials (1b, A).
Patient fear of side effects of corticosteroids (corticophobia) should be recognized and
adequately addressed to improve adherence and avoid undertreatment. (4C)
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Topical calcineurin inhibitors
Two topical calcineurin inhibitors (TCI), tacrolimus ointment and pimecrolimus cream, are
licensed for AE treatment. The efficacy of both formulations has been demonstrated against
vehicle in clinical trials for short
term
127
128
and long
term use
130
. In addition,
proactive tacrolimus ointment therapy has been sh
own to be safe and effective for up to 1
year in reducing the number of flares and improving the quality of life in both adults and
children
132
. The anti
inflammatory potency of 0.1% tacrolimus ointment is similar to
a corticosteroid with intermediate potency
134
, whereas the latter is clearly more
effective than 1.0% pimecrolimus cream
The efficacy of long
term monotherapy with tacrolimus ointment has been sho
wn in children
and adults
. Less data are available for children under 2 years of age
137
. Pimecrolimus cream has been studied in infants and children in a combination regimen
with topical corticosteroids
140
, the latter being given if a flare occurred. Both topical
calcineurin inhibitors are approved in the EU from 2 years of age and above. High quality
long
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;calcineurin inhibitors induces skin atrophy
. This favours their use over topical
corticosteroids in delicate body areas such as the eyelid region, th
e perioral skin, the genital
area, the axilla region or the inguinal fold and for topical long
term management. Clinical
and preclinical data do not indicate an increased risk of lymphoma
156
. In contrast, severe
AE as such may carry an independent significant risk for lymphoma
. The use of topical
calcineurin inhibitors is also not associated with increased risk of non
melano
ma skin
cancer, other malignancies or photocarcinogenicity
157
161
. However, given that the
long
term use of cyclosporine is associated with an increased photocarcinogenicity risk in
solid
organ transplant patients, UV protection e.g. with sunscreens has been advised
Recommendations

Topical calcineurin
inhibitors (TCI) are important anti
inflammatory drugs to be used in AE.
, D)
Instead of treating acute flares with TCI, initial treatment with topical corticosteroids before
switching to a TCI should be considered. (
, D).
TCIs are especially indicated
in sensitive skin areas (face, intertriginous sites, anogenital
area). (1b, A)
Proactive therapy with twice weekly application of tacrolimus ointment may reduce relapses.
(1b, A)
Effective sun protection should be recommended in patients treated with TCI.
, D)
Upcoming topical therapies
Topical selective phosphodiesterase 4 inhibitors
Crisaborole is a topical phosphodiesterase 4 inhibitor effective in the treatment of AE
lesions, which has recently been approved for treatment of mild to moderate AE in pa
tients
2 years of age and older in the United States of America
. Study data published
have focused on treatment of individual skin lesions using global eczema scores, as well as
on safety aspects, but do not include SCORAD data or EASI data of the patients treated.
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;From
the published data of the global scores and the individual items of an eczema score,
a relatively low efficacy of crisaborole is probable
162
. The efficacy of crisaborole is
significantly higher than the efficacy of its vehicle. However, the efficacy of crisaborole in
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Phototherapy
As most patients affected by AE improve during the sunny summer season, artificial UV
radiation is frequently employed in the treatment of AE. On the contrary, a small group
of
patients will exacerbate following UV radiation.
A recent study has confirmed that 74% of patients affected by mild
moderate AE had
predominantly with UVA
177
, at sea level or at high
altitude (e.g. Davos) with
predominantly UVB
. The
dose in heliotherapy is slowly increased by increasing the
time of sun exposure in moderate increments.
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;The following alternative modalities of UV treatment have been used in AE: UVB (mostly
narrowband (NB
UVB) of 311
313 nm and less frequently broadband
(BB
UVB), UVA
(especially UVA1 of 340
400 nm), combined UVAB, and photochemotherapy where UV can
be combined with previous oral or topical administration of photosensitizing drugs such as
psoralens
the PUVA photochemotherapy regimen, but the long
term ri
sks of skin cancer
noted in psoriasis have drastically limited this modality in Europe.
In contrast, classical
broad
spectrum UVB phototherapy does not show increased risk for BCC and SCC
179
Other light therapies have been introduced.
Short wave visible light (� 380 nm) (“Blue light”)
may have some effects, as indicated in uncontrolled pilot studies
. There
are no
controlled studies for this modality.
Photopheresis is used in some centers for treatment of
selected cases. Positive effects in patients with severe refractory AE have been described.
Other devices such as 308 nm monochromatic excimer laser expand
the therapeutic options
in patients with localized and therapy
resistant AE even though they can treat only limited
surfaces
182
183
. Pulsed
dye laser for the treatment of chronic AE is still experimental
Currently the mainstay for phototherapy in Europe is NB
UVB and UVA1.
Following
concerns relative to PUVA, long
term risks of UV
light therapies have
to be considered in
particular in children and even more in adults who have received systemic
immunosuppressants. Until now, no clinical studies have shown an increase of non
melanoma skin cancer with
UVB and UVA1
185
186
.The benefit/risk ratio of UVA1
medium
high dose (�20
phototherapy
equipment
: e.g. UVA1 devices are expensive to buy and to maintain. The
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;requirements with regard to personnel, documentation, UV protection especially of the eyes,
contraindications and technical aspects.
In practice,
hen prescribed, phototherapy is usually a part of a total treatment plan, i.e. a
second
level treatment used especially in adults and much less in children.
Phototherapy
can improve and even clear AE; it can decrease bacterial colonization and reduce the
trength and/or the amount of topical anti
inflammatory drugs needed, but the beneficial
effects vary from person to person.
Summary of evidence
Narrow
Medium
dose UVA1 and narrow
band UVB are recommended for
treatment of AE in adult
patients. (1b, A)
Narrow
band UVB is preferred over broad
band UVB for AE treatment if available. (1a, A)
treatment with topical steroids and emollients should be considered at the beginning of
phototherapy to prevent flare
up.
(C)
New devices such as 308 nm excimer laser are not recommended for treatment of AE
patients. (
,D)
Though phototherapy is rarely used in pre
pubertal children, it is not contr
aindicated; its use
depends rather on feasibility and equipment (NB
UVB). (
,D)


��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Anti
pruritic therapy
Itch is the most important clinical symptom in AE, with particular impact on emotional
dimensions of perception as compared to other pruritic dermatoses
195
. Concerning
pruritus accompanying AE, only few studies investigated the antipruritic effect only. Pruritus
was in most studies part of the total symptom score, such as in SCORAD or PO
SCORAD
. For example, topical and systemic corticosteroids, topical calcineurin in
hibitors,
cyclosporine and UV
irradiation have significant influence on pruritus while only single
studies specifically investigated the relief of pruritus intensity.
Antipruritic therapy in AE is multidimensional treating the symptom itself, the contribu
ting
factors such as dry skin, inflammation and the related scratch lesions. Therefore, several
general measures can also be recommended (see: “Basic Therapy” and “Psychosomatic
counseling”).
Topical Therapy
Glucocorticosteroids
Topical corticosteroids have anti
inflammatory activity rather than acting as direct anti
pruritic agents
. However, several studies described the anti
inflammatory effect of
not used in any European country due to an increased risk of contact allergy, especially
when the treatment exceeds eight days.
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Cannabinoid receptor agonist
Topical cannabinoid receptor agonists have been described to exhibit antipruritic
and
the management of pruritus in AE. (2b)
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;There is no evidence that t
Recommendations
Topical corticosteroids are recommended to
control pruritus in the initial phase of AE
exacerbation. (1a,A)
Topical calcineurin inhibitors are recommended to control pruritus in AE until clearance of
eczema. (1a,A)
Topical polidocanol may be used to reduce pruritus in AE patients. (
,D)
Routine cli
nical use of topical antihistamines including doxepin, topical cannabinoid receptor
agonists,
topical µ opioid receptor antagonists
recommended as an adjuvant antipruritic therapy in AE. (4,C)
There is not enough data ava
ilable to recommend the use of capsaicin in management of
itch in AE patients. (4,B)
UV therapy
UV irradiation relieves pruritus in AE, which has been demonstrated in several studies. A
recent systematic review of 19 available RCTs suggests the usage of narrow
band UVB and
UVA1 as the most effective in the treatment of AE, including reduction of itch
intensity
There is no “anti
itch
specific” data for UV therapy available, which would differ from the
general recommendations for UV treatment of AE. (See chapter “UV therapy”).
Recommendations
There is evidence that UV
therapy can be used in AE to relief pruritus. Narrow
band UVB
and UVA1 seem to be most preferable treatment modalities. (2a,B)
Systemic therapy
Antihistamines
Antihistamines (AH) have been used for decades, in an attempt to relieve pruritus in patients
with AE. However, only a few randomized controlled trials have been conducted and they
have in the majority shown only a weak or no effect in decreasing pruritus
205
213
According to a Cochrane search, randomized controlled trials investigating the efficacy of
AH monotherapy in eczema patients are lacking
The first generation of sedative AH such as hydroxyzine, clemastine fumarate and
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;In general,
AH are safe to use, also for a long period of time
216
There are limited
evidence
based data for the antipruritic effect of AH (H1
antagonists) in AE in general, and
the effect of both first and second generation
AH on pruritus in patients suffering from AE is
very limited. AH may decrease urticaria when associated with AD, but this is rarely seen in
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;pruritus. Antihistamines in general, and especially second
generation agents, show a good
Recommendations
There is not enough evidence to support the general use
of both first and second generation
H1R
antihistamines for treatment of pruritus in AE. These
may be tried for treatment of
pruritus in AE patients, if standa
rd treatment with TCS and emollients is not sufficient. (1b,

Long term use of sedative antihistamines in childhood may affect sleep quality and is
therefore not recommended. (
,D)
The opioid receptor antagonists naltrexone and nalmefene are not
recommended for routine
treatment of itch in AE patients. (
,D)
recommended for routine treatment of itch in AE patients. (4,C)


��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Tables
Table 1 Grades of evidence
��EDF Guideline AE
part I and II
final
Table 2 Classification of strength of recommendation
Recommendation strength
Evidence grade
1a, 1b
2a, 2b,
3a, 3b
Expert opinion
Table 3 Language of recommendations
Wording in standard
situations
Free text explanation
must be used
This intervention should be done in all patients,
unless there is a real good reason not to do it
should be used
Most expert physicians would do it this way, but
some would prefer other possible action
may be used
It would be correct to do this intervention, but it
would also be correct not to do it; the choice
depends largely on the specific situation
is possible
Most expert physicians would do something else,
but it would not be wrong to do it
may be used in selected
patients only
This intervention is not adequate for most patients,
but for some patients there may be a reason to do it
is not recommended
Most exp
ert physicians would not choose this
intervention, but some specific situation may justify
its use
must not be used
This intervention is inadequate in most situations



��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Table
4:
Topical drugs for treatment of atopic eczema
TCS class II
TCS class III
Tacrolimus
Pimecrolimus
overall recommendation
+ default treatment
+ short term flare treatment
+ long term
maintenance
+ children, facial lesions
most important side effects
skin atrophy
teleangiectasia
striae distensae
skin atrophy
teleangiectasia
striae distensae
initial burning/stinging
initial burning/stinging
suitable for long term treatment
sometimes
yes
yes
suitable for proactive therapy
yes
祥s
祥s*
suitable for children� 2 years of age
yes
yes*
yes*
suitable for babies
2 years of age
yes
diluted use
yes
yes
suitable during
pregnancy
yes
yes
possible with
strict
indication
possible with
strict indication
suitable during lactation
yes
yes
possible with
strict indication
possible with
strict indication
off label use
* licensed use
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ; Table
5:
Upcoming topical drugs for treatment of atopic eczema
Substance
code
Target
Substance
class
Development
phase
Registration
status
Trial data
Adverse drug
effect signals
Recommendation
Crisaborole
AN2728
phospho
diesterase 4
PDE4 blocker
app. USA
more effective
than vehicle, no
comparative
study
application
site pain
15406
phospho
diesterase 4
PDE4 blocker
E6005
phospho
diesterase 4
PDE4 blocker
see full text
PDE
phosphodiesterase
app: approved;
��EDF Guideline AE
part I and II
final
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;References:
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part I and II
final
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Eczema (Atopic Dermatitis) in Adults and Children
Part II
Wollenberg A
, Barbarot S
, Bieber T
, Christen
Zaech S
, Deleuran M
Fink
Wagner A
Gieler U
, Girolomoni G
, Lau S
, Muraro A
, Czarnecka
Operacz M
, Schäfer T
, Schmid
Grendelmeier P
, Simon D
, Szalai Z
Department Dermatology and Allergy, Ludwig
Maximilian University,
Munich, Germany
and Klinik Thalkirchner Straße,
Munich, Germany
Department of Dermatology
Centre Hospitalier Universitaire
CHU Nantes,
Nantes, France
Department of
Dermatology and Allergy, and Christine Kühne
Center for Allergy Research and Ed
ucation,
University
Bonn, Bonn,
Germany
Pediatric Dermatology Unit, Departments of Dermatology and Pediatrics, Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland
Department Dermatology, Aarhus University Hospital, Aarhus, Denmark
EFA corporate
Relations and Fundraising Manager and Co
Founder of GAAPP, Konstanz, Germany
Dept.
of Dermatology and Dept. of Psychosomatics and Psychotherapy, University of Gießen and Marburg GmbH,
Gießen, Germany
Department of Medicine, Section of Dermatology,
University of Verona, Verona, Italy
Pediatric Pneumology and Immunology, Universitätsmedizin Berlin, Germany
Centro di Specializzazione Regionale per lo Studio e la Cura delle Allergie e delle Intolleranze Alimentari
presso
l’Azienda Ospedaliera,
Università di Padova
, Italy
Department of Dermatology, Medical University, Poznan, Poland
Dermato
logical Practice
, Immenstadt
Germany
Allergy Unit, Department of Dermatology, University of Zurich, Switzerland an
d Christine Kühne Center fo
r Allergy
esearc
h and Educaction CK
CARE, Davos
, Switzerland
Department Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
Department of Dermatology, Heim Pál Children's Hospital, Budapest, Hungary
Department of
Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland
Department of Dermatology & Pediatric Dermatology, Hôpital St André, Bordeaux, France
Department of Dermatology, Hospital Niño Jesus, Madrid, Spain
Department
Dermatology and Allergy, Hannover Medical School, Hannover, Germany
Department Dermatology and Allergy Biederstein, Technische Universität München, Munich, Germany
and
Christine
Kühne
Center for Allergy Re
search and Education (CK
CARE), Davos
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Declaration of Conflict of Interest
A. Wollenberg has been an advisor, speaker or investiga
tor for ALK Abelló, Almirall, Anacor,
Astellas, Beiersdorf, Bencard, Bioderma, Chugai, Galderma, Glaxo SmithKline, Hans Karrer, LEO
Pharma, L’Oreal,
Maruho,
MedImmune, Novartis,
Pfizer, Pierre Fabre, Regeneron and Sanofi.
S.Barbarot has been an advisor,
speaker or investigator for Bioderma, La Roche Posay, Sanofi
Genzyme, Novalac, Ferring, Abbvie, Novartis, Janssen.
T. Bieber has been advisor, speaker or investigator for Abbvie, Allmirall, Anacor, Astellas, Bayer,
Celgene, Chugai, Daiichi
Sankyo, Galderm
a, Glaxo SmithKline, Leo Pharma, Novartis, Pfizer,
Pfizer, Pierre
Fabre, L´Oréal, La Roche
Posay, Regeneron, and Sanofi.
S. Christen
Zaech has been an advisor, speaker or investigator for Galderma, L’Oreal, La
RochePosey, Pierre Fabre, Permamed, Procter a
nd Gamble, and Sanofi
Genzyme.
M. Deleuran has been an advisor, speaker or investigator for AbbVie, Leo Pharma, MEDA, Pierre
Fabre, L´Oréal, La Roche
Posay, Pfizer, Regeneron and Sanofi.
A. Fink
Wagner has been working with, or an advisor or speaker for
ALTANA, Novartis, Nycomed,
Hoffmann
La Roche and Teva.
U. Gieler has been has been advisor or speaker for Allmirall, Astellas, Bayer, Celgene, Galderma,
Glaxo SmithKline, Leo Pharma, Lilly, Novartis, Pfizer, Pierre
Fabre, La Roche
Posay and Sanofi
Aventi
G. Girolomoni has been an advisor, speaker or investigator for AbbVie, Abiogen, Allmirall, Amgen,
Bayer, Biogen, Boehringer Ingelheim, Celgene, Eli
Lilly, Galderma, Hospira, Janssen, Leo Pharma,
Menlo therapeutics, Merck, MSD, Mundipharma, Novartis,
Otsuka, Pfizer, Pierre Fabre, Regeneron,
Sandoz, Sanofi and Sun Pharma
S. Lau has received grants from Allergopharma and Symbiopharm, and a honorarium from Merck
as member of a drug monitoring committee, ALK and DBV Technologies.
A. Muraro has has been a
speaker for Meda, Nestlè and Stallergenes.
M. Czarnecka
Operacz has been an advisor, speaker or investigator for Allergopharma, Allmiral,
Bioderma, Berlin Chemie, Mennarini, Novartis, Pierre Fabre, Galderma, Janssen and Leo Pharma.
T. Schäfer has been s
peaker for Abbott, Bencard, Dr Pfleger, Norvatis and Syneron
Candela.
P. Schmid
Grendelmeier has been an advisor or speaker for ALK
Abello, Allergopharma, La Roche
Posay, MEDA, Novartis, Sanofi and Stallergenes.
D. Simon has been an advisor, speaker or i
nvestigator for Roche, Novartis, Galderma, Glaxo
SmithKline, Merz Pharma (Schweiz), Almirall, Sanofi, and Eli Lilly.
Z. Szalai has been advisor for Pfizer, speaker or investigator for Bayer, Novartis, Pierre Fabre,
Sanofi, Leo.
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ; &#x/MCI; 1 ;&#x/MCI; 1 ;1 &#x/MCI; 3 ;&#x/MCI; 3 ;A. Torrelo has been advisor, speaker or investigator for AbbVie, Anacor, Astellas, Bayer, Beiersdorf
AG, Gald
erma, Meda, Novartis, Pierre Fabre.
T. Werfel has received support for research projects from AbbVie, Astellas, Janssen/JNJ, Meda,
Regeneron/Sanofi, Takeda, Ziarco, and has been an advisor for AbbVie, Allmiral, LEO Pharma, Lilly,
MSD, Novartis, Regeneron/
Sanofi, Roche, Stallergen and Ziarco.
J. Ring has been advisor, speaker or investigator for ALLERGIKA, ALK Abello, Almirall
Hermal,
Anacor, Astellas, Bencard/Allergy Therapeutics, Galderma, GSK
Stiefel, LEO Pharma, Meda, MSD,
Novartis, Phadia
ThermoFisher
, and Sanofi.
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;List of Abbreviations
American Academy of Dermatology
Atopic dermatitis
Atopic eczema
AEGIS
Eczema vaccinatum
Food allergy
FTU
Fingertip unit
GAAPP
Global Allergy and Asthma Patient Platform
HBD
Human
defensin
HDM
House Dust Mite
HTA
Health Tech
nology Assessment
H1R
Histamin 1 receptor
Immunoadsorption
ICAM1
Intercellular Adhesion Molecule 1
Investigators Global Assessment, a signs score
IgE
Immunoglobulin E
IgG
Immunoglobulin G
Interleukin
IVIG
Intravenous immunoglobu
lins
IFN
Interferon alpha
IFN
Interferon gamma
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;JAK
Janus kinase
LEAP
Learning Early About Peanut Allergy
LTC4
Leukotriene C4
LTD4
Leukotriene D4
LTE4
Leukotriene E4
MCV
Molluscum contagiosum virus
VOCs
Volatile organic compounds
VZV
Varicella
zoster Virus
QoL
Quality of life
TSLP
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Abstract
The existing evidence for treatment of atopic eczema (atopic dermatitis, AE)
was evaluated
using the national standard Appraisal of Guidelines Research and Evaluation (AGREE). The
consensus process consisted of a nominal group process and a Delphi procedure. This
second part of the guideline covers antimicrobial therapy, systemic t
reatment, allergen
specific immunotherapy, complementary medicine, psychosomatic counselling and
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Table
of contents

Part I
Introduction
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Antimicrobial therapy
In patients with AE, the inflammatory micro
milieu initiated by TSLP, IL
4 and IL
13 may
downregulate the cutaneous antimicrobial peptides such as cathelicidin LL
37, dermcidin,
human β
defensins HBD
1, HBD
2, and HBD
This is one of the reasons why these
patients are more susceptible to secondary skin infections, which tend to generalize
. The
understanding of colonization and infection in AE has largely increased by structured
investigation of the human microbiome in the context of AE. Flares
of AE are significantly
associated with a
S. aureus
caused loss of diversity in the cutaneous microbiome, which is
not significant if patients have followed a proactive therapy regimen before the flare
Anti
bacterial
In up to 90% of AE patients
even the normal looking skin is extensively colonized by
Staphylococcus aureus.
This bacterium
is a major trigger of AE, as it leads to inflammation
through the release of superantigen toxins, which enhance T cell activation of superantigen
specific and allergen
specific T cells, expression of IgE anti
staphylococcal antibodies and
as it increases e
xpression of IL
31 which leads to pruritus
Scratching favors binding of
S. aureus
to the skin, and the increased amount of
S. aureus
derived ceramidase
aggravates the skin barrier defect.
Moreover, superantigen production increases expression
of alternative glucocorticoid receptors that do not bind
to topical corticosteroids, which leads
to resistance
Biofilm formation by AE
associated staphylococci most certainly also plays
a major role in the occlusion of sweat ducts and leads to inflammation and pruritus
Recent investigations have shown that
besides
S. aureus
the
dysbalance of skin microbiome
may play an
important
role in AE pathophysiology
. New developments in emollients
are the incorporation of active compounds that repair the barrier function or influence the
microbiome of AE with bacterial lysates from Aquaphilus dolomiae or Vitreoscilla filiformis
species
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Underestimated sources of bacteria are cream and ointment containers, of which up to 53%
are contaminated, up to 25% with
S. aureus.
Thus the following recommendations seem to
be useful
: 1.) Keep open moistu
rizers in refrigerator; 2.) Use pumps or pour bottles
rather than jars; 3.) Avoid direct contact with hands and decant; 4.) Avoid sharing personal
hygiene items.
Antimicrobial textiles
Silver
impregnated textiles have shown significant antimicrobial activity, as well as
improvement of localized SCORAD in an unblinded, side
side controlled clinical trial
In patients with uninfected AE, the use of silver impregnated textile compared to cotton
underwear did not reduce AE severity
. However, some functional textiles (silver
coated, acid
coated and silk textiles) as well as
Chitosan
, a natural biopolymer with
immunomodulatory and antimicrobial properties, may possibly improve AE
manifestations,
as they decrease skin colonization
by
S. aureus,
and they reduce itch
. Some of these
newer options are still under investigation and there seem to be some concern about the
safety of silver
coated textiles in infants and toddlers. AEGIS
coated silk textiles did not
show clinical benefit in a well
contr
olled, multicenter clinical trial
Anti
viral
Viral infections including herpes simplex, varicella zoster, molluscum contagiosum, smallpox
and coxsackie viruses occur more frequently in AE patients than in healthy individuals, with
a tendency to disseminated, widespread disease
��EDF Guideline AE
part I and II
final
Eczema coxsackiu
m (EC)
is a disseminated form of coxsackie virus infection mostly
occurring in children with active AE lesions. The coxsackie virus A6 strain leads to atypical
disease manifestations, which are classified as diffuse form (lesions extended to the trunk),
ral form (lesions with a mainly acral distribution), or eczema coxsackium (disseminated
lesions on preexisting eczematous areas)
. Symptomatic treatment includes use of
Regional vaccination programs should be followed by all AE patients as recommended. The
denial of vaccination because of diagnosed AE is a
misconception possibly leading to fatal
consequences (see chapter: general measures).
Anti
fungal
Despite its role as a commensal on healthy human skin, Malassezia spp. is attributed a
pathogenic role in AE, as it may interact with the local skin immune response and barrier
function. The precise mechanisms by which Malassezia spp. may contribute to the
pathogenesis of AE are not fully understood and remain to be elucidated
. Several
randomized, placebo controlled trials investigated the benefit of topical or systemic
ifungal treatment for AE patients
. The ambiguous results of these clinical trials
might be attributed to a selection bias. It can be speculated that antifungal therapies are
more effective in certain subgroup of AE. It seems for example that antifungal therapy sho
ws
beneficial effects in patients with a head
neck
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Summary of evidence
Oral antibiotics have no benefit o
n the skin condition in AE as long as skin lesions are not
obviously superinfected. (1b)
A Cochrane review
showed no clear beneficial evidence to antiseptic substances in non
infected AE. (4)
Topical glucocorticosteroids and calcineurin inhibitors reduce
the colonization rate of S.
aureus in AE. (4)
Antiseptic textiles have a moderate clinical effect on AE. (2b)
AEGIS
coated silk garments do not show clinical benefit over standard care (2b).
VZV vaccination is safe, efficacious and beneficial for children
with atopic dermatitis. (2a)
An antifungal therapy may be efficient in some AE patients, mainly in those suffering from
the „head and neck“
variant of AE or with demonstrated IgE
sensitization to
Malassezia spp
(2b)
Recommendations
A short course of
systemic antibiotics, such as cephalosporin, may be considered in AE
patients clinically infected with S. aureus. (2b, B)
The long
term application of topical antibiotics is not recommend due to the risk of increasing
resistances and sensitizations. (2, D)
Treatment with topical antiseptic drugs
including antiseptic baths e.g. with diluted sodium
hypochlorite
should be considered, if clinical signs of bacterial superinfection are present.
(4,C)
Treatment with topical antiseptic drugs
including sodium
hypochlorite 0.005% baths
may
be considered in patients with treatment resistant, chronic
course of AE.
(2b,B)
as systemic aciclovir. (4,D)
VZV vaccination is recomm
ended for children with atopic dermatitis.
Parents of atopic
children should be encouraged to fully immunize their children.
(2a,B)
Topical or systemic antifungal therapy may be effective in some AE patients, mainly in those
suffering from the „head and neck“ variant of AE or with demonstrated IgE
sensitization to
Malassezia spp
. (2b,B)
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Systemic anti
inflammatory treatment
Immunosuppressive treatment
Oral glucocorticosteroids
Oral glucocorticosteroids are used in many European countries for treatment of AE. Well
known side effects limit their use especially for long
term treatment. Funding of expensive
clinical trials in th
e near future is unlikely.
Controlled clinical trial data demonstrating efficacy:
There is one controlled trial available
that demonstrates lower efficacy of therapy with systemic prednisolone compared to
ciclosporine in severe adult AE patients
. Broad experience from clinical use by many
experts indicates some efficacy, as well as prompt rebound after withdra
wal.
Summary of evidence
Short term treatment with oral glucocorticosteroids is moderately effective. (1b)
Systemic steroids have a largely unfavourable risk/benefit ratio for treatment of AE.
(1b)
Recommendations
Short
term (up to 1 week) treatment
with oral glucocorticosteroids may be an option to treat
an acute flare in exceptional cases of AE. Restrictive use, largely limited to adult patients
with severe AE, is recommended. (
, D)
The daily dose should be adjusted to and not exceed 0,5 mg/kg body
weight. (
, D)
term use of oral glucocorticosteroids in AE patients is not recommended. The
indication for oral steroids in children should be handled even more cautiously than in adults.
, D)
Cyclosporine A
Cyclosporine is licensed in many Europ
ean countries for treatment of AE and is therefore
considered to be the first line option for patients with severe disease who require systemic
immunosuppressive treatment.
Controlled clinical trial data demonstrating efficacy
Cyclosporine vs. Placebo:
A meta
analysis and review of pooled data from 15 RCTs
clearly demonstrated the efficacy of cyclosporine in AE with a 55% improvement on average
after 6
8 weeks of treatment. Body surface area, erythema, sleep loss and
glucocorticosteroid use were reduced
in the cyclosporine group. Cyclosporine is more
effective than placebo, but there is often prompt relapse if cyclosporine is stopped. All scores
are back to pre
treatment values eight weeks after the end of cyclosporine therapy in most
patients.
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Cyclospori
ne dose finding study for AE treatment in adult patients:
A fixed dosage
cyclosporine regimen was evaluated in 106 adults with severe AE
. Initial treatment was
performed with 300 mg/d or 150 mg/d and reduced after two weeks to 50% of the initial daily
dose until a final evalu
ation was performed after eight weeks. Clinical efficacy was
patient is old or suffers from relevant concomitant diseases
. Some patients may tolerate
low dose cyclosporine therapy for a longer time than the usually recommende
d therapy
length of 2 years
Continuous or intermittent cyclosporine therapy study of AE in childre
n:
Forty children aged
16 years were randomized to either a continuous long term or an intermittent short term
cyclosporine regimen
Recommendations

��EDF Guideline AE
part I and II
final
Cyclosporine may be used in chronic, severe cases of AE in adults. Treatment should not
exceed a two
year continuous regimen. Careful monitoring for potential severe side effects
must be performed. (1a, A)
Cyclosporine may be used (off la
bel) in children and adolescent patients showing a
status, is advisable. (2b, B)
The duration of cyclosporin therapy is guided by clinical efficacy and tolerance
of the drug.
Both short
term and long
term therapy may be useful in AE. (
, D)
Common side effects of cyclosporine (e.g. nephrotoxicity, hypertension) argue against a
long
term treatment of AE with cyclosporine. Therefore, an interval of 3
6 months is us
ally
recommended. (
,D)
Cessation of therapy or switch to another systemic drug should be attempted after two years
of therapy, although many patients tolerate much longer therapy with low dose cyclosporine.
,D).
An initial daily dose of 5 mg/kg/d, divid
ed upon two single doses, is recommended. A dose
reduction of 0.5
1.0 mg/kg/d every two weeks is recommended, once clinical efficacy is
reached. (
,D)
Dose reduction should be considered according to clinical efficacy. Long term treatment
prescribing the l
owest clinically useful dose may be advisable in selected cases. (
,D)
Since an intermittent dosage regimen (e.g. “weekend therapy”) will lead to lower cumulative
doses of cyclosporine and is effective in some AE patients, an individualized dosage
regimen
is recommended for underage patients. (
,D)
Cyclosporine trough levels do not need to be assessed routinely during therapy. (
,D)
Though there are no controlled studies available regarding the efficacy of vaccination during
cyclosporine therapy, there is n
o evidence for a failure during cyclosporine either. Hence, a
cessation of therapy of 2 weeks before and 4
6 weeks after vaccination may be advisable.
Clinically, there is no evidence for this recommendation. (
,D)
A combination therapy of cyclosporine wit
h UV
therapy is not recommended, effective UV
protection should be used. (
,D)
Azathioprine (AZA)
Azathioprine is used (off label) for many years for treatment of AE in adult patients. Funding
of expensive clinical trials in the near future is unlikely.
Controlled clinical trial data demonstrating efficacy:
Efficacy of AZA was tested in a
randomized, controlled, 6 month, crossover clinical trial involving 37 patients aged 17 to 73
years
. The drop
out rate was high (12 patients on AZA, 4 patients on placebo). AZA
(2.5 mg/kg/d) or placebo was given for three months each in a crossover design. The
SASSAD skin severity score was reduced by 26% in the AZA group and 3% in the placebo
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;group (p
0.01). Pruritus, sleep loss and fatigue improved significantly during AZA, but not
during placebo treatment.
Another randomized double blind, placebo controlled, 12 weeks, clinical trial involved 63
outpatients with AE
. Following a low dose introduction phase, azathioprine was dosed
in 42 patients according to the results of a thiopuri
39
Recommendations


��EDF Guideline AE
part I and II
final
AZA may be used (off label) in adult AE patients, if cyclosporine is either not effective or
contraindicated. (1b,A)
AZA may also be used (off label) in children. (4, C)
Patients should be
screened for TPMT activity before starting AZA therapy to reduce the
risk for bone marrow toxicity by dose adaptation. The suggested dose range is 1
3mg/kg
bw/d. (1b,A)
Alternatively, an initial AZA dose of 50mg/day in adults and a slow increase of the dos
under close monitoring of full blood and liver function count
is possible. (
, D)
In pregnant women, AZA should only be used on strict indication. (
, D)
AZA should not be combined with UV therapy, effective UV protection should be used. (

Mycophe
nolate Mofetil (MMF)
MMF is an immunosuppressant drug licensed in many European countries for the treatment
of systemic lupus erythematosus and prevention of transplant rejection.
Controlled clinical trial data demonstrating efficacy:
There is one control
led trial with enteric
coated mycophenolate sodium (EC
MPS) vs. Cyclosporine A as long
term treatment
showing almost equal efficacy
. Some case reports or uncontrolled clinical trial data from
adults indicate that it would be clinically effective in AE
There is one uncontrolled
Recommendations

MMF may be used (off label) for treatment of AE in adults in a dose up to 3 g/d, if
cyclosporine is not effective or not
indicated. (4,C)
MMF may be used for treatment of AE in children or adolescents. (4, C)
��EDF Guideline AE
part I and II
final
As MMF and EC
MPS are both
teratogenic, men and women of childbearing potential must
use effective contraception during therapy.
(3a, B)
Methotrexate (MTX)
The immuno
suppressant MTX is frequently used in psoriasis, but there is little published
data on its use in AE. Some clinicians have used this drug in AE with good responses since
many years. MTX can be given by oral, intravenous or subcutaneous application. Funding
of expensive clinical trials in the near future is unlikely.
Controlled clinical trial data demonstrating efficacy:
A randomized trial with MTX vs.
Azathioprine showed comparable effects in severe AE
Forty children with severe
AE were randomly assigned to receive either
mg weekly or cyclosporin 2.5 mg
kg daily for 12 weeks.
At week 12, patients in
the
different from the cyclosporin treated group. Both drugs were associated with minor adverse
effects, none of which required cha
nging the treatment regimen
An open 24 week dose escalation clinical trial involving 12 adult patients investigated the
efficacy of increasing doses MTX
. The starting dose of 10 mg/week was increased
weekly in steps of 2.5 mg/week until clinical efficacy was seen. The skin score SASSAD
improved by 52% after 24 weeks. The median dose administered was 15 mg MTX/week
Improvement remained stable in 9 patients 12 weeks after end of treatment.
An uncontrolled, retrospective report involving 20 adult AE patients treated with 10 mg/week
to 25 mg/week MTX showed response in 16 patients after 8
12 weeks
. First
improvement was observed after a period ranging from 2 weeks to 3 months (mean 9.95 w
Forty Children with severe
AE were randomly assigned to receive either
mg weekly or cyclosporin 2.5 mg/kg daily for 12 weeks.
At week 12, patients in
the
from the cyclosporin treated group. Both drugs were associated with min
or adverse effects,
none of which required changing the treatment regimen
��EDF Guideline AE
part I and II
final
Recommendations

MTX may be used (off label) for treatment of AE in both adults and children. (4,C)
The recommended dosing regimen is similar or slightly lower compared to psoriasis. (D,
As MTX is teratogenic, men and
women of child bearing potential must use effective
contraception during therapy. (3a,B)
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Biological agents
Biological agents (Biologics) have been used in dermatology for more than 10 years for
other inflammatory skin diseases, especially psoriasis, but s
o far no registered biologics for
AE are available in Europe. Biologics present a relatively new group of therapeutics created
by using biological processes that include recombinant therapeutic proteins such as
antibodies or fusion proteins. Biologics spec
may experience equally positive effects, expanding the treatment indication for dupilumab
even further.
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Summary of evidence
A number of large, randomized, placebo controlled clinical trials indicate that dupilumab is
effective in AE,
with the response maintained for at least 1 year of continuous treatment in
the majority of patients. (1b)
Dupilumab
treated AE patients did not show systemic side effects in clinical studies, but
showed a higher incidence of conjunctivitis. (1b)
Recommendations

Dupilumab is recommended as a disease modifying drug for patients with moderate to
severe AE, in whom topical treatment is not sufficient and other systemic treatment is not
advisable. (1,a)
Dupilumab
should be combined with daily emollients and may be combined with topical anti
inflammatory drugs as needed. (2,b)
Upcoming biologic therapy
Nemolizumab
Nemolizumab, a humanized monoclonal antibody directed against the IL
31 receptor A, has
shown efficacy in patients with moderate to severe AE
. There was a significant
improvement in the primary endpoint pruritus, as well as in the objective signs of the AE
with, however, less efficacy. Nemolizumab
is currently not approved for any indication.
Summary of evidence
A randomized, placebo controlled clinical trial indicates that nemolizumab is effective in
treating pruritus in AE patients. (1b)
Nemolizumab
treated AE patients did not show systemic side
effects in clinical studies, but
showed a higher incidence of peripheral edema. (1b)
Off label use of other traditional Biologicals
Rituximab
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;test reactions
. Based on the promising results in AE and the experiences in bronchial
asthma
therapy, long
term trials with anti
5 antibodies are now performed.
Omalizumab
Most AE patients have elevated serum IgE levels, but the pathogenic role of IgE in AE
remains unknown. In a placebo
controlled study in 20 patients, omalizumab administered
By blocking IL
12 and IL
23, ustekinumab can regulate Th1, Th17 and also Th22 pathways,
which are reportedly active in AE.
Results regarding the use of ustekinumab in severe AE
have, however, been conflicting and only case reports have been published so fa
r. Some
have reported significant improvement of AE
and some have not
. The first two
randomised controlled trials comprising 79 and 33 patients in total have been completed,
and results are quite uniform showing no significant decrease in severity scores
Other substances
Some older biologics such as infliximab or efalizumab, which are outdated for use in atopic
dermatitis or
guideline.
On the other hand, a number of highly interesting substances are in progress and may soon
be registered for treatment of AE. Therefore, the committee decided to produce
a table in
the addendum on potential new biologics or small molecules for AE “in the pipeline”, which
will be continuously updated by the guideline committee. Substances to be included in this
table will be, among others, the anti
IL 13 antibody tralokinu
mab, the anti
TSLP antibody
tezepelumab, and the Janus kinase (JAK) inhibitor upadacitinib.
Summary of evidence
None of the traditional biologics has been approved for the therapy of AE in Europe. At
present, the use of traditional biologics in AE should be tried only in patients with severe AE
refractory to other topical and/or systemic treatment. Beside the lack o
��EDF Guideline AE
part I and II
final
Recommendations
A therapy of AE with traditional biologics (rituximab, omalizumab or ustekinumab) cannot be
recommended. (4, C)
therapy of AE with mepolizumab may be tried in selected cases unresponsive to standard
therapy. (
, D)
9
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Other systemic treatment
Alitretinoin
Recommendations

potential unresponsive to topical steroid therapy. (1b,A)
patients. (4,C)
Apremilast
Apremilast is a small molecule phosphodiesterase (PDE) 4 inhibitor that has been approved
for the treatment of psoriasis arthritis and moderate to severe plaques psoriasis. Blocking
PDE4 increa
ses intracellular adenosine monophosphate levels resulting in a downregulation
of proinflammatory cytokines such as IL
2, IL
5, IL
13 and increased production of the
regulatory cytokine IL
10. A pilot study investigating the effect of apremilast in patient
s with
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;moderate to severe AE has demonstrated moderate improvement of skin lesions, pruritus
and QoL
, but the drug development program of apremilast for AE has been stopped
Recommendations



Apremilast may be used in selected cases unresponsive to standard therapy for treatment
of AE. (
,D)
Tofacitinib
So far only one small open label trial with the oral JAK inhibitor
tofacitinib
citrate has been
performed in 6 patients with moderate to severe, treatment refractory AE. After 8
29 weeks
of treatment they had a mean SCORAD reduction of 66 %. No adverse eve
nts were
observed
Recommendations
There is not enough evidence to support the use of
tofacitinib
in AE. (4,C)
Immunoadsorption
Immunoadsorption (IA) has been used in patients with AE and high serum
IgE levels based
on the assumption that a reduction of IgE might result in a reduction of disease activity. An
investigator initiated open
label pilot study in patients with severe AE r
ecalcitrant to topical
and systemic therapy showed that IA resulted in a significant decrease of SCORAD three
weeks after the first cycle of 5 IA and a further improvement after the second cycle one
month apart, and in parallel a reduction of skin
bound Ig
. A recent study confirmed
these results and showed long
term clinical effect of IA in AE patients
. Another pilot
Immunoadsoption might be considered for patients with severe AE and high serum IgE
levels if the technology is available. (4, C)
Mast cell stabilizers
Mast cell
stabilizers inhibit mast cell degranulation and thus prevent the release of histamine
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Recommendations
Mast cell stabilizers are not recommended for the treatment of AE. (
Leukotriene antagonists
Montelukast is a cysteinyl
leukotriene
receptor antagonist that blocks the action of LTD4,
LTC4 and LTE4. It has been used at doses of 10 mg daily (5 mg/day in children below 12
years), with some reduction in SCORAD indexes
. A systematic review stated that
limited evidence exists to recommend montelukast fo
r the treatment of AE
. Studies on
leukotriene antagonist zafirlukast for the treatment of AE have not been reported in the last
five years.
Recommendations
There is not enough evidence
to support the use of leukotriene antagonists in AE. (2a,B)
Intravenous Immunoglobulin
Intravenous immunoglobulins (IVIG) are considered as immunomodulatory substances, but
not as immunosuppressive agents. IVIG have been tried for both adults and children with
severe, treatment refractory AE, but clinical trials did not indicate a high effic
acy or quick
Recommendations
The use of IVIG in AE is not recommended. (4,D)
H1R
blocking antihistamines
Traditional histamine 1 receptor (H1R) blocking antihistamines have been used for decades,
in an attempt to relieve pruritus in patients with AE. However, only a few randomized
controlled trials have been conducted and they
have in the majority shown only
a weak or
no effect in decreasing pruritus
According to a Cochrane search, randomized
controlled trials investigating the efficacy of antihistamine monotherapy in AE patients are
lacking
e first generation of sedative antihistamines such as hydroxyzine, clemastine fumarate,
doxylamine, and dimetinden maleate
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;60 mg twice daily has been described
. An effect on itch of a high dosage of 20 to 40
Recommendations
There is not enough evidence to support the general use
of both first and second generation
H1R
antihistamines for treatment of pruritus in AE. These may be tried for treatment of
pruritus in AE patients,
if standard treatment with TCS and emollients is not sufficient. (1b,

Long term use of sedative antihistamines in childhood may affect sleep quality and is
therefore not recommended. (
,D)
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Allergen
specific immunotherapy
Allergen
specific
immunotherapy (ASIT) has been investigated for treatment of AE, the two
relevant therapeutic regimens are subcutaneous immunotherapy (SCIT) and sublingual
immunotherapy (SLIT).
Introduction to allergen
specific immunotherapy for AE
Some efficacy of allerg
specific immunotherapy (ASIT) in AE has been shown in a number
of case reports and smaller cohort studies
116
, and more recently in a larger
multicenter trial with subcutaneous house dust mite immunotherapy
. These data
showed that ASIT can be used for treatment of allergic rhinitis or mild asthma also in AE
children with AE
. However, in a second study phase children were randomly allocated
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;to continue with active treatment or placebo for a further
6 months. The placebo effect was
high, and the numbers were too small to permit confident conclusions, but the clinical scores
suggested that prolonged ASIT may be effective with regards to several objective
. Patients were injected weekly with
three different doses of HDM allergen extract. With higher allergen doses, a beneficial
SCORAD decrease occurred after 8 weeks compared to
a control group with an “active
placebo” consisting of very low allergen dose. The effect was maintained over one year and
was accompanied by lower glucocorticosteroid use.
A smaller DBPC study involving 20 patients with HDM
or grass pollen sensitization
also
showed objective and subjective symptom relief accompanied by immunological changes
under ASIT
130
Another large, randomized double
blind placebo controlled study investigated 168 adult AE
patients for 18 months. Th
e study did not reveal efficacy in the AE patients studied, but a
subgroup analysis showed statistical significance of SCORAD reduction in subgroup of
severe AE patients with SCORAD� 50
. Longer treatment duration was associated
with higher efficacy. The best outcome was observed during September to February, which
may be due to the use of indoor heating and subsequent high HDM exposure.
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;A first 18 months, placebo controlled study in
vestigating the effects of SLIT on AE found a
significant decrease of the SCORAD starting from month 9
128
Another study analyzed 107 patients undergoing SLIT for 12 months. A total of 84 patients
finished the trial, compared to the placebo group (53,85%), the treatment group (77,78%)
showed improvement in symptoms
133
Another group of authors has investigated SLIT in AE patients allergic to HDM
in a murine
model
134
. The mouse model induced by
Der f
allergen extract reflected the typical
hallmarks of AE in humans. In the
Der f
allergens
sensitized mice, SLIT treatment with
Der
vaccine significantly inhibited AE symptoms through correction of Th2 and Th1 cytoki
ne
predominance, therefore according to the authors SLIT could be considered as an
alternative treatment for patients with extrinsic AE.
Summary of evidence
There is conflicting evidence regarding ASIT in AE, with more recent literature being more
in
favour of it. ASIT may have positive effects in selected, highly sensitized patients with AE.
(2a)
The best evidence so far is available for ASIT with house dust mite allergens. (2a)
There is no contraindication for performing ASIT in patients with respira
tory allergic diseases
(allergic rhinoconjunctivitis, mild allergic bronchial asthma) and concomitant AE. (2b)
Recommendations
ASIT is currently not recommended as a general treatment option for AE. (2a, B)
ASIT may be considered for selected patients
with house dust mite, birch or grass pollen
sensitization, who have severe AE, and a history of clinical exacerbation after exposure to
the causative allergen or a positive corresponding atopy patch test. (2a, B)
25
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Complementary and alternative medicine in
atopic eczema
There is evidence of growing interest of so
called complementary alternative medicine
(CAM) as treatment for AE
137
. CAM has been defined as “diagnosis, treatment or
prevention which complements mainstream medicine by contributing to a common whole,
A study from Berlin compared the daily administration of 5
,4 g docosahexaenoic acid (DHA)
In one pilot study, the addition of gamma
linolenic acid to emollients was able to decrease
elevated TEWL in atopic eczema
160
The most recent Cochrane review on EPO and BO included 19 studies on EPO and 8 on
BO
. The authors concluded that EPO and BO lack effect on AE and that further studie
would be hard to justify.
Summary of evidence
There is partly conflicting, mostly negative evidence regarding the efficacy of oral or topical
applications of unsaturated fatty acids in the treatment of AE. (1a)
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Recommendations
Oral application of
unsaturated fatty acids is not recommended for treatment of AE. (1a, A)
Topical application of unsaturated fatty acids as an ingredient in emollients may be tried in
selected cases. (D,
Phytotherapy
Topical use of crude plant extracts is not recommended for treatment of AE. (1b, C)
Chinese herbal
medicine (CHM)
Chinese herbs are part of the traditional Chinese medicine which consists of Chinese herbs
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Zemaphyte
, a commercial product of Chinese herbs, revealed conflicting results
The oral application of a
combination of
Eleutherococcus, Achillea millefolium
, and
Lamium
album
was not superior to placebo after two weeks
The most recent Cochrane review on CHM included 28 studies encompassing 2306 patients
. When compared to placebo CHM showed higher clinical effectiveness
(RR 2.09, 95%
CI 1.32 to 3.32) in 2 studies.
The total effectiveness rate in CHM groups was found to be
superior (RR 1
.43, 95% CI 1.27 to 1.61) when compared to conventional therapy in 21
studies.
The authors assessed most studies at high risk of bias and found substantial
The use of Chinese herbs is not recommended for treatment of AE. (1a, A)
Acupuncture/Acupressure
Acupuncture has been studied considering allergen
induced itch as primary endpoint but
not systematically or within randomised controlled trials as a treatment for AE. Case series
of patients including those with AE indicate some beneficial effects but stu
dies implying a
The use of acupuncture or acupressure is not recommended for treatment of AE. (
, D)
Autologous blood therapy
One RCT compared the intramuscular re
injection of 1 to 3 ml autologous blood over 5
weeks to the injection of the equivalent amount of sterile saline solution
Patients were
recruited via press advertisement and finally 30 subjects p
articipated. Over a 9 weeks
period, AE severity measured by SASSAD dropped significantly in the verum group from
23.2 to 10.4 and did not change in the placebo group (21.0 to 22.5). Significant differences
were not observed in health related quality of lif
e and the subjective assessment of pruritus
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;skin appearance and sleep quality. The data suggest a beneficial effect of autologous blood
therapy with respect to the signs score. This finding should be confirmed in larger trials and
different settings.
Summ
ary of evidence
There is very limited evidence supporting the use of autologous blood therapy in the
treatment of AE. (2b)
Recommendations
The use of autologous blood therapy is not recommended for the treatment of AE. (2b, B)
Bioresonance
One RCT has been published so far, comparing bioresonance with a sham (inactive pseudo
) procedure in 36 children with AE attending a specialized rehabilitation unit in Davos,
Switzerland
. After 4 weeks, AE severity had improved in both groups with slight
superiority of the active group but without statistical
significance. Further studies under more
usual outpatient conditions are needed.
Summary of evidence
Current evidence from a single trial does not indicate a substantial clinical effect of
bioresonance for treatment of AE. (2b)
Recommendations
The use of
bioresonance for treatment of AE is not recommended. (2b, B)
Homoeopathy
Homeopathy is a system of alternative medicine created in 1796 by Samuel Hahnemann,
based on his doctrine of like cures like. Large case series illustrating the therapeutic benefits
of homeopathy have been published as papers or books
190
191
. A recent uncontrolled
trial of 17 patients with longstanding AE in Japan revealed a marked improvement after the
introduction of homoeopa
thic treatment
192
. A classical randomised placebo controlled
trial was initiate
d in Germany including 60 patients
Recommendations
The use of homeopathy is not recommended for treatment of AE. (2b, B)
Massage therapy / aroma therapy
The effect of additional massage therapy for AE, applied daily for 20 minutes over a one
month period compared to standard therapy alone, was investigated in a randomised trial in
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;20 children
195
The use of
massage / aroma therapy
is not recommended for treatment of AE. (4, C)
Salt baths and thermal spring water balneotherapy
Salt bath has been used for a long time to control chronic inflammatory skin diseases,
especially psoriasis. Based on this experience and anecdotal evidence, salt was recently
recommended also in the treatment of AE. The efficacy of salt bath alone, howeve
r, has not
been studied systematically in AE. In the current reports, salt baths were investigated as
part of a complex climatotherapy or in combination with UV
therapy
204
. From these
studies it cannot be concluded that salt baths provide a consistent and significant clinical
effect on AE. Conventional balneotherapy with or without synchronous UV therapy has been
shown to be effective in AE but was not considered as CAM in
this chapter. Balneotherapy
with thermal spring water has been shown to be beneficial in children with mild to moderate
AE with an effect similar to mid
potency topical corticosteroids
205
Summary of evidence
There is insufficient evidence to support the use of
salt baths
in the treatment of AE. (4)
Cohort studies indicate that thermal spring water balneotherapy with or without phototherapy
may be effective
in mild to moderate AE (2a, 2b)
Recommendations
The use of
salt baths
is not generally recommended for treatment of AE. (4, C)
Thermal spring
water balneotherapy may be considered in mild to moderate AE (B, 2a, 2b)
Vitamins and minerals
A total of 6 trials were identified investigating vitamins or minerals in the treatment of AE
211
. A placebo
controlled study from Italy studied oral vitamin E (400 IU) in 96
patients
210
. Greater clinical improvement was reported for the vitamin E group but without
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;resul
ts of statistical tests. Similarly, a smaller study of 49 patients comparing vitamin E plus
vitamin B2 to vitamin E or vitamin B2 alone revealed a superiority of the combination
treatment with respect to the physician’s assessed overall usefulness and glob
al rating
. A further trial in 60 adults with AE compared selenium or selenium plus vitamin E vs.
placebo over a 12 weeks period
207
. The AE severity score fell in all 3 study arms without
significa
nt differences. A Hungarian study compared multi
vitamin supplementation in 2090
pregnancies to trace element supplementation in 2032 pregnancies over a 17 month period
. AE occurred more frequently in the multi
vitamin group (0.7%
vs. 0.2%). Although this
Recommendations
There is not enough evidence to
recommend vitamin supplementation for routine use in AE
patients. (2b, B)
Topical Vitamin B12 in avocado oil
There are two smaller studies with half
side comparisons, which indicate a mild beneficial
effect of a preparation containing 0.07% vitamin B12 in avocado oil compared to a placebo
preparation
219
220
Summary of evidence
There is preliminary evidence that a topical preparation of Vitamin B12 in avocado oil may
be useful in the treatment of AE.
(2b)
Recommendations
There is not enough evidence to recommend topical preparations of Vitamin B12 in avocado
oil for routine
use in AE.
(2b, B)
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ; &#x/MCI; 1 ;&#x/MCI; 1 ;1 &#x/MCI; 3 ;&#x/MCI; 3 ;Harms of CAM
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Psychosomatic counseling
Psychological and emotional factors influence the clinical course of AE, which is mirrored in
the German term “neurodermitis”.
Interventions
including
patient education, eczema action
groups that provide useful supplementary literature
222
Poor adherence to treatment
Poor adherence to treatment is a major factor limiting treatment outcomes
223
, and may
have different causes:
Stress
can elicit severe exacerbations of eczematous skin lesions
226
. The
itch
scratch cycle
is especially vulnerable to psychological influences and
can show a tendency to self
A Cochrane review analyzed ten RCTs of psychologi
cal or educational interventions, in
addition to conventional therapy, for AE in children
233
One study of a psychological
intervention used biofeedback and hypnotherapy as relaxation techniques versus
discussio
n only. Three of the four educational studies identified significant improvements in
disease severity in the intervention groups. The fourth trial evaluated long
term outcomes
and found a statistically significant improvement (
0.01) in disease severity
and parental
quality of life over 12 months in all studied age groups (three months to 18 years).
this review. The psychological and educational interventions were deli
vered by nurses or
multidisciplinary teams
Quality of life (QoL) is severely impaired in AE patients
235
as shown in a recent review:
Statistically significant improvements in QoL of AE patients by
tient education were reported in five studies, whereas the severity of skin disease
improved significantly in three studies out of ten studies evaluated. In conclusion, patient
education appears to be effective in improving QoL and in reducing the perceive
d severity
of skin disease
236
238
. (See chapter: Educational interventions for AE)
Psychotherapeutic approache
Most psychological training programs include relaxation techniques
, habit training for
social competence and communication as well as coping behavior and improvement of self
control with regard to disrupting the itch
scratch cycle.
Psychosomatic counseling:
Randomize
d controlled trials compared the use of topical
��EDF Guideline AE
part I and II
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Behavioral th
erapy:
Behavioral therapy against itch was studied, showing a significant
improvement in symptoms after one year
241
243
. Especially habit reversal techniques
improve itch in atopic dermatitis
244
Autogenic training:
Parents who had negative treatment experiences in the past and possessed only poor
coping abilities with regard to scratch control benefitted the most from the training program.
The outcome of the educatio
n measure was independent of parents' schooling, vocational
level and income
247
. Another publication stated that there is currently only limited
research evidence on the effect of educational and psychological approac
hes when used
alongside medicines for the treatment of childhood eczema
233
It is well possible that
there is limited research activity in this area of intervention, thus providing limited evidence
of the measurable effects of interventions.
Summary
of evidence
Psychosomatic counseling can be a helpful adjuvant procedure in the management of
patients with AE including psychotherapeutical approaches and behavioral therapy
techniques. (3b)
Relaxation techniques may cause significant improvements in dis
ease severity.
(1a)
Individual psychotherapeutic approaches can be helpful in individual patients. (
Psychological and psychosomatic interventions are an essential and helpful part of
educational programs. (1a)
Recommendations
Psychosomatic
counseling, psychotherapeutical approaches, behavioural therapy
techniques, autogenic training, relaxation techniques, psychological and psychosomatic
interventions are recommended in selected patients. (1a, A)
The indication should be confirmed by special
ists in the field of psychodermatology. (
, D)
29
��EDF Guideline AE
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Educational interventions for atopic eczema
Adherence to treatment and poor quality of life (QoL) are key issues in patients with AE
Patient education (PE) interventions can help
decrease of the long
term costs of AE treatment.
A recent study showed that parents with
negative treatment experiences in the past and poor coping abilities regarding scratch
ntrol benefitted most from PE programs
247
High
quality PE programs should ideally
be evidence
based, tailored to a patient’s individual
educational and cultural background (rather than being standardized in form and content),
and have well
defined content and activities
236
Educational service delivery models
There are different types of PE programs running all around the world. These differ in
number and certification of the educators, number of participants, age of patients, teaching
techniques, duration and frequency of interventions
233
250
. Thus, because the content
of the PE programs
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Structured lay
led self
management education training progr
ams:
They lead to a
small
statistically
significant reduction in disease status (pain/ itch, disability, fatigue) and a small,
statistically
significant improvement in depression and psychological well
being but there
was no difference in quality of life
260
There is no evidence that such programs improve
psychological health
261
health during follow
up of patients with AE
health intervention follows the initial diagnosis and treatment with face
face contact.
This is just as effective as usual face
face care with regard to quality of life and severity
of disease. However, when costs are considered, e
health is likely
to result in substantial
cost savings. Therefore, e
health is a valuable service for patients with AE.
264
Forms of e
ducational
intervention tools
PE programs for AE in children and adults are recommended as an adjunct
to conventional
therapy of AE. (1a, A)
34
��EDF Guideline AE
part I and II
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�� &#x/MCI; 0 ;&#x/MCI; 0 ;Conclusion and Outlook
The complex pathophysiology of AE explains why the therapeutic strategies also comprise
��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Tables
Table 1 Grades of evidence
��EDF Guideline AE
part I and II
final
Table 2 Classification of strength of recommendation
ecommendation strength
Evidence grade
1a, 1b
2a, 2b, 3a, 3b
Expert opinion
Table 3 Language of recommendations
Wording in standard
situations
Free text explanation
must be used
This intervention should be done in all patients,
unless
there is a real good reason not to do it
should be used
Most expert physicians would do it this way, but
some would prefer other possible action
may be used
It would be correct to do this intervention, but it
would also be correct not to do it; the ch
oice
depends largely on the specific situation
is possible
but it would not be wrong to do it
may be used in selected
patients only
This intervention is not adequate for most patients,
but for some patients
there may be a reason to do it
is not recommended
Most expert physicians would not choose this
intervention, but some specific situation may justify
its use
must not be used
This intervention is inadequate in most situations



��EDF Guideline AE
part I and II
final
�� &#x/MCI; 0 ;&#x/MCI; 0 ;Table
4:
Systemic drugs for treatment of severe atopic eczema
cyclosporine
azathioprine
mycophenolic
acid
corticosteroids
dupilumab
overall
recommendation
++ acute flare
intervention
++ long term
maintenance
can be
used
long term
++ little toxicity
outdated
汯ng⁴e牭
浡楮ten慮ce
time to respond
(weeks)
time to relapse
(weeks)
� 12
�12
� 12
most important
side effects
serum
creatinine
blood pressure
hematological
liver
enzymes
gastro
intestinal
hematological
liver enzymes
gastro
intestinal
hematological
skin infections
gastro
intestinal
Cushing’s
osteoporosis
diabetes
conjunctivitis
starting dose
adult
5 mg/kg/day

15 mg/week
50 mg/day

MMF 1
2 g/day
(EC
MPA 1.44
g/day)
0.2
0.5
mg/kg/day
600 mg loading
dose
maintenance
dose
adult
2.5
mg/kg/day
most often 15/week;
can increase to max
25 mg/week
3 mg/kg/day*
MMF 2
3 g/day**
(EC
MPA 1.44
g/day)
not for
maintenance
300 mg/
2 weeks
starting dose
children
mg/kg/day
15 mg/m
/week
50 mg/day
MMF 20
mg/kg/day
0.2
0.5
mg/kg/day
no data yet
maintenance
dose
children
2.5
mg/kg/day
increase 2.5
5mg/week, decrease
2.5mg/week to
effective/lowest
effective dose
3 mg/kg/day*
increase daily total
dose by
500 mg
every 2
4 weeks up
to 30
50 mg/kg/day
not for
maintenance
no data yet
pregnancy
possible
teratogenic,
absolutely contra
indicated
conflicting data,
possible with
strict indication
eratogenic,
absolutely contra
indicated
possible
no data yet
��EDF Guideline AE
part I and II
final
fathering
possible
little information,
conflicting data,
contra
indicated
little
information,
possible with
strict indication
conflicting data
possible
no data yet
* TPMT heterozygote 1
1.5 mg/kg/day
see full text
# time to reach most of expected
full response
MMF: mycophenolate mofetil; EC
MPS: enteric
coated mycophenolic sodium
��EDF Guideline AE
part I and II
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�� &#x/MCI; 0 ;&#x/MCI; 0 ; &#x/MCI; 1 ;&#x/MCI; 1 ; Table
5:
Upcoming systemic drugs for treatment of atopic eczema
Substance
code
Target
Substance class
Development
phase
Registration
status
Trial data
Adverse drug
effect signals
Recommendation
Nemolizumab
14152
(formerly
CIM
IL31R alpha
IL31 blocker
p敲iph敲al⁥de浡?
Tralokinumab
CAT
354
IL13
Th2 blocker
Lebrikizumab
TNX
650
IL13
Th2 blocker
Tezepelumab
MEDI
9929
TSLP
TSLP blocker
Upadacitinib
ABT
JAK1
JAK inhibitor
PF
04965842
JAK1
JAK inhibitor
ZPL
(formerly
PF
03893787)
H4R
H4R blocker
see full text
��EDF Guideline AE
part I and II
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�� &#x/MCI; 0 ;&#x/MCI; 0 ; &#x/MCI; 1 ;&#x/MCI; 1 ;References
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N, Meurer M. Cyclosporin in the treatment of patients with atopic eczema
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