EDF Guideline AE 2018 - Modified - 190508

EDF Guideline AE part I and II final – 24.01.18 (modified 08.05.
19) 1
EDF-Guidelines for Treatment of Atopic Eczema (Atopic Dermatitis)

Part I
Developed by the Guideline Subcommittee “Atopic Eczema” of the

European Dermatology Forum
Subcommittee Members:
Prof. Dr. Andreas Wollenberg, Munich (Germany) Prof. Dr. Magdalena Czarnecka-Operacz, Poznan (Poland)
Dr. Sébastien Barbarot, Nantes (France) Prof. Dr. Torsten Schäfer, Immenstadt (Germany)
Prof. Dr. Thomas Bieber, Bonn (Germany) Prof. Dr. Peter Schmidt-Grendelmeier, Davos (Switzerland)
PD Dr. Stephanie Christen-Zaech, Lausanne (CH) Prof. Dr. Dagmar Simon, Bern (Switzerland)
Prof. Dr. Mette Deleuran, Aarhus (Germany) Prof. Dr. Zsuzsanna Szalai, Budapest (Hungary)
Dr. A Fink-Wagner, Konstanz (Germany) Prof. Dr. Jacek C. Szepietowski, Wroclaw (Poland)
Prof. Dr. Uwe Gieler, Gießen (Germany) Prof. Dr. Alain Taieb, Bordeaux (France)
Prof. Dr. Giampiero Girolomoni, Verona (Italy) Prof. Dr. Antonio Torrelo, Madrid (Spain)
Prof. Dr. Susanne Lau, Berlin (Germany Prof. Dr. Thomas Werfel, Hanover (Germany)
Prof. Dr. Antonella Muraro, Padova (Italy) Prof. Dr. Johannes Ring, Munich (Germany)
Members of EDF Guideline Committee:

Prof. Dr. Werner Aberer, Graz (Austria) Prof. Dr. Gillian Murphy, Dublin (Ireland)
Prof. Dr. Martine Bagot, Paris (France) Prof. Dr. Alexander Nast, Berlin (Germany)
Prof. Dr. Nicole Basset-Seguin, Paris (France) Prof. Dr. Martino Neumann, Rotterdam (Netherlands)
Prof. Dr. Ulrike Blume-Peytavi, Berlin (Germany) Prof. Dr. Tony Ormerod, Aberdeen (United Kingdom)
Prof. Dr. Lasse Braathen, Bern (Switzerland) Prof. Dr. Mauro Picardo, Rome (Italy)
Prof. Dr. Sergio Chimenti, Rome (Italy) Prof. Dr. Annamari Ranki, Helsinki (Finland)
Prof. Dr. Alexander Enk, Heidelberg (Germany) Prof. Dr. Johannes Ring, Munich (Germany)
Prof. Dr. Claudio Feliciani, Parma (Italy) Prof. Dr. Berthold Rzany, Berlin (Germany)
Prof. Dr. Claus Garbe, Tübingen (Germany) Prof. Dr. Rudolf Stadler, Minden (Germany)
Prof. Dr. Harald Gollnick, Magdeburg (Germany) Prof. Dr. Sonja Ständer, Münster (Germany)
Prof. Dr. Gerd Gross, Rostock (Germany) Prof. Dr. Wolfram Sterry, Berlin (Germany)
Prof. Dr. Michael Hertl, Marburg (Germany) Prof. Dr. Eggert Stockfleth, Bochum (Germany)
Prof. Dr. Dimitrios Ioannides, Thessaloniki (Greece) Prof. Dr. Alain Taieb, Bordeaux (France)
Prof. Dr. Gregor Jemec, Roskilde (Denmark) Prof. Dr. George-Sorin Tiplica, Bucharest (Romania)
Prof. Dr. Lajos Kemény, Szeged (Hungary) Prof. Dr. Elke Weisshaar, Heidelberg (Germany)
Dr. Gudula Kirtschig, Tübingen (Germany) Prof. Dr. Sean Whittaker, London (United Kingdom)
Prof. Dr. Robert Knobler, Vienna (Austria) Prof. Dr. Fenella Wojnarowska, Oxford (United Kingdom)
Prof. Dr. Annegret Kuhn, Muenster (Germany) Prof. Dr. Andreas Wollenberg, Munich (Germany)
Prof. Dr. Marcus Maurer, Berlin (Germany) Prof. Dr. Christos Zouboulis, Dessau (Germany)
Prof. Dr. Dieter Metze, Muenster (Germany) Prof. Dr. Dr. Torsten Zuberbier, Berlin (Germany)
Prof. Dr. Kai Munte, Rotterdam (Netherlands)
Chairman of EDF Guideline Committee:

Prof. Dr. Alexander Nast, Berlin (Germany)
Expiry date: 31.01.2021
EDF Guideline AE part I and II final – 24.01.18 (modified 08.05.19) 2
1 Consensus based European Guidelines for Treatment of Atopic Eczema

2 (Atopic Dermatitis) in Adults and Children
3 Part I
4
5 Wollenberg A1, Barbarot S2, Bieber T3, Christen-Zaech S4, Deleuran M5, Fink-Wagner A6, Gieler U7,
6 Girolomoni G8, Lau S9, Muraro A10, Czarnecka-Operacz M11, Schäfer T12, Schmid-Grendelmeier P13,
7 Simon D14, Szalai Z15, Szepietowski JC16, Taïeb A17, Torrelo A18, Werfel T19, Ring J20
8
9 For the European Dermatology Forum (EDF), the European Academy of Dermatology and
10 Venereology (EADV), the European Academy of Allergy and Clinical Immunology (EAACI), the
11 European Task Force on Atopic Dermatitis (ETFAD), European Federation of Allergy and Airways
12 Diseases Patients‘ Associations (EFA), the European Society for Dermatology and Psychiatry
13 (ESDaP), the European Society of Pediatric Dermatology (ESPD), Global Allergy and Asthma
14 European Network (GA2LEN) and the European Union of Medical Specialists (UEMS)
15
16 Correspondence to:
17 Prof. Dr. med. Dr. h.c. Andreas Wollenberg
18 Department of Dermatology and Allergology
19 Ludwig-Maximilian University
20 Frauenlobstr. 9-11, D-80337 Munich
21 Email: [email protected]
22
1 Department Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany and Klinik Thalkirchner Straße,
Munich, Germany
2 Department of Dermatology, Centre Hospitalier Universitaire CHU Nantes, Nantes, France
3 Department of Dermatology and Allergy, and Christine Kühne-Center for Allergy Research and Education, University Bonn,
Bonn, Germany
4 Pediatric Dermatology Unit, Departments of Dermatology and Pediatrics, Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland
5 Department Dermatology, Aarhus University Hospital, Aarhus, Denmark
6 Patient representative, European Federation of Allergy and Airways Diseases Patients‘ Associations (EFA) corporate
Relations and Fundraising Manager and Co-Founder of Global Allergy and Asthma Patient Platform (GAAPP), Konstanz,
Germany
7 Department of Dermatology and Dept. of Psychosomatics and Psychotherapy, University of Gießen and Marburg GmbH,
Gießen, Germany
8 Department of Medicine, Section of Dermatology, University of Verona, Verona, Italy
9 Pediatric Pneumology and Immunology, Universitätsmedizin Berlin, Germany
10 Centro di Specializzazione Regionale per lo Studio e la Cura delle Allergie e delle Intolleranze Alimentari presso l’Azienda
Ospedaliera, Università di Padova, Italy

11 Department of Dermatology, Medical University, Poznan, Poland
12 Dermatological Practice, Immenstadt, Germany
13 Allergy Unit, Department of Dermatology, University of Zurich, Switzerland and Christine Kühne Center for Allergy research
and Educaction CK-CARE, Davos, Switzerland

14 Department Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
15 Department of Dermatology, Heim Pál Children's Hospital, Budapest, Hungary
16 Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland
17 Department of Dermatology & Pediatric Dermatology, Hôpital St André, Bordeaux, France
18 Department of Dermatology, Hospital Niño Jesus, Madrid, Spain

19 Department Dermatology and Allergy, Hannover Medical School, Hannover, Germany
20
Department Dermatology and Allergy Biederstein, Technische Universität München, Munich, Germany and Christine
Kühne-Center for Allergy Research and Education (CK-CARE), Davos
1 Declaration of Conflict of Interest

2
3 A. Wollenberg has been an advisor, speaker or investigator for ALK Abelló, Almirall, Anacor, Astellas,
4 Beiersdorf, Bencard, Bioderma, Chugai, Galderma, Glaxo SmithKline, Hans Karrer, LEO Pharma,
5 L’Oreal, Maruho, MedImmune, Novartis, Pfizer, Pierre Fabre, Regeneron and Sanofi.
6
7 S.Barbarot has been an advisor, speaker or investigator for Bioderma, La Roche Posay, Sanofi-
8 Genzyme, Novalac, Ferring, Abbvie, Novartis, Janssen.
9
10 T. Bieber has been advisor, speaker or investigator for Abbvie, Allmirall, Anacor, Astellas, Bayer,
11 Celgene, Chugai, Daiichi-Sankyo, Galderma, Glaxo SmithKline, Leo Pharma, Novartis, Pfizer, Pfizer,
12 Pierre-Fabre, LÓréal, La Roche-Posay, Regeneron, and Sanofi.
13
14 S. Christen-Zaech has been an advisor, speaker or investigator for Galderma, L’Oreal, La RochePosey,
15 Pierre Fabre, Permamed, Procter and Gamble, and Sanofi-Genzyme.
16
17 M. Deleuran has been an advisor, speaker or investigator for AbbVie, Leo Pharma, MEDA, Pierre-Fabre,
18 LÓréal, La Roche-Posay, Pfizer, Regeneron and Sanofi.
19
20 A. Fink-Wagner has been working with, or an advisor or speaker for ALTANA, Novartis, Nycomed,
21 Hoffmann-La Roche and Teva.
22
23 U. Gieler has been has been advisor or speaker for Allmirall, Astellas, Bayer, Celgene, Galderma, Glaxo
24 SmithKline, Leo Pharma, Lilly, Novartis, Pfizer, Pierre-Fabre, La Roche-Posay and Sanofi -Aventis.
25
26 G. Girolomoni has been an advisor, speaker or investigator for AbbVie, Abiogen, Allmirall, Amgen, Bayer,
27 Biogen, Boehringer Ingelheim, Celgene, Eli-Lilly, Galderma, Hospira, Janssen, Leo Pharma, Menlo
28 therapeutics, Merck, MSD, Mundipharma, Novartis, Otsuka, Pfizer, Pierre Fabre, Regeneron, Sandoz,
29 Sanofi and Sun Pharma
30
31 S. Lau has received grants from Allergopharma and Symbiopharm, and a honorarium from Merck as
32 member of a drug monitoring committee, ALK and DBV Technologies.
33
34 A. Muraro has has been a speaker for Meda, Nestlè and Stallergenes.
35
36 M. Czarnecka-Operacz has been an advisor, speaker or investigator for Allergopharma, Allmiral,
37 Bioderma, Berlin Chemie, Mennarini, Novartis, Pierre Fabre, Galderma, Janssen and Leo Pharma.
38
39 T. Schäfer has been speaker for Abbott, Bencard, Dr Pfleger, Norvatis and Syneron-Candela.
40
41 P. Schmid-Grendelmeier has been an advisor or speaker for ALK-Abello, Allergopharma, La Roche-
42 Posay, MEDA, Novartis, Sanofi and Stallergenes.
43
44 D. Simon has been an advisor, speaker or investigator for Roche, Novartis, Galderma, Glaxo SmithKline,
45 Merz Pharma (Schweiz), Almirall, Sanofi, and Eli Lilly.
46
47 Z. Szalai has been advisor for Pfizer, speaker or investigator for Bayer, Novartis, Pierre Fabre, Sanofi,
48 Leo.
49
50 J.C. Szepietowski has been a Consutant and Advisor for AbbVie, Celgene, Dignity Sciences, Leo
51 Pharma, Novartis, Pierre-Fabre and Sandoz; Investigator for AbbVie, Actelion, Amgen, GSK, Janssen,
52 Merck, Novartis, Regereron, Takeda, Trevi; Speaker for AbbVie, Actavis, Astellas, Janssen, Leo Pharma,
53 Novartis, SunFarm, Sandoz, Eli Lilly.
54
55 A. Taïeb has been an advisor for Anacor, Bioderma, Chugai, Galderma, Roche and Pierre Fabre.
56
1 A. Torrelo has been advisor, speaker or investigator for AbbVie, Anacor, Astellas, Bayer, Beiersdorf AG,
2 Galderma, Meda, Novartis, Pierre Fabre.
3
4 T. Werfel has received support for research projects from AbbVie, Astellas, Janssen/JNJ, Meda,
5 Regeneron/Sanofi, Takeda, Ziarco, and has been an advisor for AbbVie, Allmiral, LEO Pharma, Lilly,
6 MSD, Novartis, Regeneron/Sanofi, Roche, Stallergen and Ziarco.
7
8 J. Ring has been advisor, speaker or investigator for ALLERGIKA, ALK Abello, Almirall-Hermal, Anacor,
9 Astellas, Bencard/Allergy Therapeutics, Galderma, GSK-Stiefel, LEO Pharma, Meda, MSD, Novartis,
10 Phadia-ThermoFisher, and Sanofi.
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30 Table R1 (online repository)

1
2 Assignment of guideline sections to draft authors
3
4 Part I
5 Introduction (Andreas Wollenberg & Johannes Ring)
6 Method of guideline formation (Andreas Wollenberg & Johannes Ring)
7 Patient perspective (Antje Fink-Wagner, patient representative)
8 General measures and avoidance strategies (Susanne Lau & Thomas Werfel)
9 Basic emollient treatment and bathing (Jacek Szepietowski & Alain Taieb)
10 Dietary intervention (Antonella Muraro & Johannes Ring)
11 Topical anti-inflammatory therapy (Thomas Bieber & Giampiero Girolomoni)
12 Phototherapy (Alain Taieb & Magda Operacz)
13 Antipruritic therapy (Jacek Szepietowski & Uwe Gieler)
14
15 Part II
16 Antimicrobial therapy (Peter Schmid-Grendelmeier & Stephanie Christen-Zäch)
17 Systemic anti-inflammatory treatment (Mette Deleuran & Andreas Wollenberg)
18 Other systemic treatment (Dagmar Simon & Antonio Torrelo)
19 Allergen specific immunotherapy (Magda Operacz & Johannes Ring)
20 Complementary medicine (Torsten Schaefer & Johannes Ring)
21 Psychosomatic counselling (Uwe Gieler & Zsuzsanna Szalai)
22 Educational interventions (Zsuzsanna Szalai & Sebastien Barbarot)
23 Conclusion and future options (Andreas Wollenberg & Johannes Ring)
24
25 Table R2: Members of the guideline panels (role in the guidelines development,
26 discipline, institution)
27
Name Role in the guideline development, discipline / content expertise, Institutions represented
institution / geographic location
Expert panel
Sebastien Barbarot Expert panel member; Assistant Professor of Dermatology, European Academy of
Department of Dermatology, Centre Hospitalier Universitaire (CHU) Dermatology and Venerology
Nantes, Nantes, France (EADV), European Task Force
on Atopic Dermatitis (ETFAD)
Thomas Bieber Expert panel member; Professor of Dermatology, Department of European Dermatology Forum
Dermatology and Allergy, and Christine Kühne-Center for Allergy (EDF), European Academy of
Research and Education, University Bonn, Bonn, Germany Dermatology and Venerology
(EADV), European Task Force
Stephanie Christen- Expert panel member; Pediatric dermatologist, Head of Pediatric European Society for Pediatric
Zäch Dermatology Unit, Departments of Dermatology and Pediatrics, Dermatology (ESPD),
Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland European Academy of
Dermatology and Venerology
Mette Deleuran Expert panel member; Professor of Dermatology and Head; European Dermatology Forum
Department Dermatology, Aarhus University Hospital, Aarhus, (EDF), European Society for
Denmark Pediatric Dermatology (ESPD),
European Academy of
Antje Fink-Wagner Expert panel member; Patient representative; EFA corporate European Federation of
Relations and Fundraising Manager and Co-Founder of GAAPP, Allergy and Airways Diseases
Konstanz, Germany Patients‘ Associations (EFA),
Global Allergy and Asthma
Patient Platform (GAAPP)
Uwe Gieler Expert panel member; Professor of Psychosomatics and Dermatology, European Dermatology Forum
Department of Dermatology and Dept. of Psychosomatics and (EDF), European Academy of
Psychotherapy, University of Gießen and Marburg GmbH, Gießen, Dermatology and Venerology
Germany (EADV), European Task Force
Giampiero Girolomoni Expert panel member; Professor of Dermatology, Department of European Dermatology Forum
Medicine, Section of Dermatology, University of Verona, Verona, Italy (EDF) European Academy of
(EADV)
Susanne Lau Expert panel member; Professor of Pediatric Allergy, Pediatric European Academy of Allergy
Pneumology and Immunology, Universitätsmedizin Berlin, Germany and Clinical Immunology
(EAACI)
Antonella Muraro Expert panel member; Professor of Allergy, Food Allergy Referral European Academy of Allergy
Centre , Veneto Region; Department of Women and Child Health , and Clinical Immunology
Padua University Hospital, Padua, Italy (EAACI)
Magda Czarnecka- Expert panel member; Professor of Dermatology and Head; European Dermatology Forum
Operacz Department of Dermatology, Medical University, Poznan, Poland (EDF); European Union of
Medical Specialists (UEMS);
European Academy of Allergy
and Clinical Immunology
(EAACI)
Torsten Schaefer Expert panel member; Dermatologist, Dermatological Practice, European Academy of Allergy
Immenstadt, Germany and Clinical Immunology
(EAACI)
Peter Schmid- Expert panel member; Professor of Dermatology and Allergy, Allergy European Academy of Allergy
Grendelmeier Unit, Department of Dermatology, University of Zurich, Switzerland and Clinical Immunology
and Christine Kühne Center for Allergy research and Educaction CK- (EAACI), European Academy
CARE, Davos, Switzerland of Dermatology and
Venerology (EADV)
Dagmar Simon Expert panel member; Professor of Dermatology, Department European Academy of
Dermatology, Inselspital, Bern University Hospital, University of Bern, Dermatology and Venerology
Bern, Switzerland (EADV); European Task Force
on Atopic Dermatitis (ETFAD);
(EAACI)
Zsuzsanna Szalai Expert panel member; Dermatologist and Pediatrician, Head, European Society for Pediatric
Department of Dermatology, Heim Pál Children's Hospital, Budapest, Dermatology (ESPD),
Hungary European Academy of
Jacek Szepietowski Expert panel member; Professor of Dermatology, Department of European Dermatology Forum
Dermatology, Venereology and Allergology, Wroclaw Medical (EDF), European Academy of
University, Wroclaw, Poland Dermatology and Venerology
(EADV); European Society for
Dermatology and Psychiatry
(ESDaP)
Alain Taieb Expert panel member; Professor of Dermatology, Department of European Dermatology Forum
Dermatology & Pediatric Dermatology, Hôpital St André, Bordeaux, (EDF), European Academy of
France Dermatology and Venerology
Antonio Torrelo Expert panel member; Professor of Pediatric Dermatology, European Society for Pediatric
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 European Dermatology Forum
Dermatology and Allergy, Hannover Medical School, Hannover, (EDF), European Academy of
Germany Allergy and Clinical
Immunology (EAACI),
European Academy of
Steering group
Johannes Ring Chairman, moderation of the consensus conference; Professor European Dermatology Forum
emeritus of Dermatology and Allergy; Klinik für Dermatologie, (EDF), European Academy of
Allergologie und Venerologie, Technical University Munich; Munich, Allergy and Clinical
Germany and Christine Kühne-Center for Allergy Research and Immunology (EAACI),
Education (CK-CARE), Davos European Academy of
on Atopic Dermatitis (ETFAD),
Global Allergy and Asthma

European Network (GA2LEN)
Andreas Wollenberg Organization, drafting and writing of the guideline text and figures; European Dermatology Forum
Consultant Dermatologist and Professor of Dermatology, Department (EDF), European Society for
Dermatology and Allergy, Ludwig-Maximilian University, Munich, Pediatric Dermatology (ESPD),
Germany and Klinik Thalkirchner Straße, Munich, Germany European Academy of
on Atopic Dermatitis (ETFAD),
(EAACI)
1
1 List of Abbreviations
2 AAD American Academy of Dermatology

3 AD Atopic dermatitis
4 AE Atopic eczema
5 AEGIS 3-trimethylsilylpropyl-dimethyloctadecyl ammonium chloride
6 AH Antihistamines
7 AGREE Appraisal of Guidelines Research and Evaluation
8 APT Atopy patch test
9 ASIT Allergen-specific Immunotherapy
10 AZA Azathioprine
11 BB-UVB Broadband ultraviolet B
12 BCC Basal Cell Carcinoma
13 BO Borage oil
14 CAM Complementary alternative medicine
15 CAP-FEIA CAP Fluorescence Immunoassay
16 CHM Chinese herbal medicine
17 DBPC Double-blind placebo-controlled
18 DBPCFC Double-blind placebo-controlled food challenge
19 DHA Docosahexaenoic acid
20 EADV European Academy of Dermatology and Venereology
21 EASI Eczema Area and Severity Score, a signs score
22 EAT Enquiring About Tolerance
23 EC Eczema coxsackium
24 EC-MPS Enteric-coated mycophenolate sodium
25 EDF European Dermatology Forum
26 EFA European Federation of Allergy and Airways Diseases Patients‘
27 Associations
28 EH Eczema herpeticum
29 EPO Evening primrose oil
30 ETFAD European Task Force on Atopic Dermatitis
31 EU European Union
32 EV Eczema vaccinatum
33 FA Food allergy
34 FTU Fingertip unit
35 GAAPP Global Allergy and Asthma Patient Platform
36 HBD Human-ß-defensin
37 HDM House Dust Mite
38 HTA Health Technology Assessment
39 H1R Histamin 1 receptor
40 IA Immunoadsorption
41 ICAM1 Intercellular Adhesion Molecule 1
42 IGA Investigators Global Assessment, a signs score
43 IgE Immunoglobulin E
44 IgG Immunoglobulin G
45 IL Interleukin
46 IVIG Intravenous immunoglobulins
47 IFN-α Interferon alpha
48 IFN-ƴ Interferon gamma
1 JAK Janus kinase

2 LEAP Learning Early About Peanut Allergy
3 LTC4 Leukotriene C4
4 LTD4 Leukotriene D4
5 LTE4 Leukotriene E4
6 MCV Molluscum contagiosum virus
7 MMF Mycophenolat Mofetil
8 MTX Methotrexate
9 mTLSS modified Total Lesion Symptom Score
10 NB-UVB Narrow band Ultraviolet B
11 OFC Oral food challenge
12 OTC Over the counter
13 PDE 4 Phosphodiesterase 4
14 PE Patient education
15 PO-SCORAD Patient-oriented Scoring of Atopic Dermatitis
16 PUVA Psoralen and ultraviolet A
17 RCT Randomized controlled trial
18 ROS Reactive oxygen species
19 SASSAD Six Area Six Signs Atopic Dermatitis score
20 SCC Squamous Cell Carcinoma
21 SCIT Subcutaneous Immunotherapy
22 SCORAD Scoring of Atopic Dermatitis, a composite score
23 SLIT Sublingual Immunotherapy
24 SPT Skin prick test
25 TCI Topical calcineurin inhibitors
26 TCS Topical corticosteroids
27 TPMT Thiopurine methyltransferase
28 TSH Thyroid-stimulating hormone
29 Th1 T helper 1 cells
32 UV-light Ultraviolet light
33 VOCs Volatile organic compounds
34 VZV Varicella-zoster Virus
35 QoL Quality of life
36 TSLP Thymic stromal lymphopoietin
37
1 Abstract
2 This guideline was developed as a joint interdisciplinary European project, including physicians
3 from all relevant disciplines as well as patients. It is a consensus based guideline, taking
4 available evidence from other guidelines, systematic reviews, and published studies in to
5 account.
6 This first part of the guideline covers methods, patient perspective, general measures and
7 avoidance strategies, basic emollient treatment and bathing, dietary intervention, topical anti-
8 inflammatory therapy, phototherapy and antipruritic therapy, whereas the second part covers
9 antimicrobial therapy, systemic treatment, allergen specific immunotherapy, complementary
10 medicine, psychosomatic counselling and educational interventions.
11 Management of AE must consider the individual clinical variability of the disease, highly
12 standardized treatment rules are not recommended. Basic therapy is focused on treatment of
13 disturbed barrier function by hydrating and lubricating topical treatment, besides further
14 avoidance of specific and unspecific provocation factors. Topical anti-inflammatory treatment
15 based on glucocorticosteroids and calcineurin inhibitors is used for flare management and for
16 proactive therapy for long term control. Topical corticosteroids remain the mainstay of therapy,
17 whereas tacrolimus and pimecrolimus are preferred in sensitive skin areas and for long term
18 use. Topical phosphodiesterase inhibitors may be a treatment alternative when available.
19 Adjuvant therapy includes UV irradiation, preferably with UVB 311 nm or UVA1. Pruritus is
20 targeted with the majority of the recommended therapies, but some patients may need additional
21 antipruritic therapy. Antimicrobial therapy, systemic anti-inflammatory treatment,
22 immunotherapy, complementary medicine and educational intervention will be addressed in part
23 II of the guideline.
24
25 Key words: Atopic eczema, atopic dermatitis, pruritus, immunomodulation, emollients
26
1 Table of contents
2
3 Part I
4 Introduction
5 Method of guideline formation
6 Patient perspective
7 General measures and avoidance strategies
8 Basic emollient treatment and bathing
9 Dietary intervention
10 Topical anti-inflammatory therapy
11 Phototherapy
12 Antipruritic therapy
13
14 Part II
15 Antimicrobial therapy
16 Systemic anti-inflammatory treatment
17 Other systemic treatment
18 Allergen specific immunotherapy
19 Complementary medicine
20 Psychosomatic counselling
21 Educational interventions
22 Conclusion and future options
23
1 Introduction
2
3 Atopic eczema (AE; atopic dermatitis, eczema, “Neurodermitis” in German speaking
4 countries, endogenous eczema, neurodermatitis) is an inflammatory, pruritic, chronic or
5 chronically relapsing skin disease occurring often in families with other atopic diseases
6 (bronchial asthma and/ or allergic rhinoconjunctivitis). AE is one of the most common non-
7 communicable skin diseases which affects up to 20% of children and 2-8% of adults in most
8 countries of the world. In many instances AE begins in childhood, while severe cases may
9 persist in adulthood. About one third of adult cases develop in adulthood. AE is often the
10 first step in the development of other atopic diseases, such as allergic rhinoconjunctivitis or
11 asthma and food allergy (FA).
12 Though several diagnostic criteria have been proposed over time, the classical Hanifin &
13 Rajka criteria are still the most widely used criteria worldwide (1). There is no pathognomonic
14 laboratory biomarker for diagnosis of AE. The most typical feature, the elevation of total or
15 allergen-specific IgE levels in serum or the detection of IgE-mediated sensitization in skin
16 tests, is not present in all individuals suffering from AE; the term “intrinsic” (non-IgE-
17 associated) AE has been introduced to distinguish the latter group from “extrinsic” (IgE-
18 associated) forms of AE (2). The controversy in terminology is going on until today, and has
19 practical implications regarding avoidance strategies for AE management.
20 Apart from a strong genetic influence (80% concordance in monozygous twins, 20% in
21 heterozygous twins), there are other characteristic features in pathophysiology. These
22 include an immune deviation towards the T helper 2 (Th2) pathway in the initiation phase
23 with consequent increased IgE production; an increased production of mediators from
24 various inflammatory cells, a deficient skin barrier function (“dry” skin) due to abnormal lipid
25 metabolism and epidermal structural protein formation of filaggrin and protease inhibitors;
26 an abnormal microbial colonization with pathogenic organisms such as Staphylococcus
27 aureus or Malassezia sp. (compared to Staphylococcus epidermidis in normal individuals)
28 and subsequently increased susceptibility to skin infection; and an obvious, strong
29 psychosomatic influence.
30 After establishing the diagnosis of AE, the overall disease severity must be determined by
31 evaluating both objective signs and subjective symptoms. As signs-only scores are lacking
32 the subjective part of pruritus and sleep disturbance, composite scores assessing signs and
33 symptoms must be used to assess overall disease severity (3). The classical composite
34 score is the “Scoring of Atopic Dermatitis” (SCORAD) developed by the European Task
35 Force of Atopic Dermatitis (ETFAD) (4). AE with a SCORAD above 50 is regarded as severe,
36 while SCORAD values below 25 are considered as mild AE (3, 5). The Patient-oriented
37 SCORAD (PO-SCORAD) is a tool for assessing AE severity independent of the physician,
38 and the results correlate well with SCORAD (6). In contrast, the Eczema Area and Severity
39 Score (EASI) is a signs-only score assessing visible lesions only, but not the subjective
40 symptoms. The Patient-Oriented Eczema Measures for Eczema (POEM) are a symptoms-
41 only score to measure subjective symptoms, but not objective signs in clinical trials. The
42 Investigators Global Assessment (IGA) is frequently used, but more a global assessment
43 than a validated score. In contrast to SCORAD, POEM and EASI, it is a based on a single
1 global assessment by the investigator only. The HOME group is an initiative of

2 methodologists, industry representatives and physicians interested in outcome measures
3 for AE, which has done considerable work in recommending instruments for measurement
4 of the previously identified domains of AE such as signs, symptoms, quality of life and long
5 term control (7).
6 Most AE cases can be regarded as mild, whereas less than 10% of patients suffer from
7 severe eczematous skin lesions. This percentage of severe cases seems to be higher in the
8 adult AE population (8). This guideline covers most of the important and relevant strategies
9 for management of AE.
10
11
1 Methods
2
3 The guideline committee decided that these guidelines should strictly concentrate on
4 therapeutic regimens and omit longer chapters on clinical entity, diagnosis or
5 pathophysiology of the disease. This is a consensus-based S2k guideline, though it has an
6 additional strong focus on evidence from the literature. Consensus was achieved among the
7 nominated members of the European interdisciplinary expert group.
8 Base of the guideline
9 This is an update of the 2012 guideline on atopic dermatitis (8, 9). The former, first version
10 of this guideline had been based on the evidence-based national guideline from Germany
11 (10), the HTA report (11), as well as the position paper of the ETFAD (12), which were
12 compared and assessed. The former committee had decided that all these documents
13 fulfilled enough criteria to be used as the base of the first version of the European Guidelines
14 on Treatment of Atopic Eczema (8, 9).
15 Data base and literature search
16 For this consensus-based guideline, no systematic literature review has been performed.
17 During the kick-off meeting in Copenhagen in 2015, subgroups of two authors were
18 determined among the expert panel to be responsible for the draft of specific sections of the
19 guideline by virtue of their clinical and scientific expertise (Table R1). Discrepancies between
20 the two respective authors were escalated to the steering committee. The subgroups were
21 in charge of the search for best available evidence, the summary thereof and of critically
22 appraising the evidence to inform the drafted recommendations. Specific inclusion or
23 exclusion criteria for the selection of the evidence (such as the limitation to a certain study
24 design) were not defined and the authors were encouraged to include the ‘best available
25 evidence’.
26 Data were included only, if a reference had been published as a full paper in a peer reviewed
27 journal by March 2017, but not based on an abstract or a conference presentation only.
28
29 Classification of presented studies with regard to study type
30 To give the reader a general impression of the quality of the evidence presented in this
31 guideline, grades of evidence were assigned using the system employed in the 2012 version
32 of the guideline (table 1) (8, 9). These need to be interpreted with caution, however, as the
33 literature search that was undertaken followed a targeted rather than systematic approach.
34
35 Recommendation levels (table 2) were given only for those therapies available in Europe by
36 September 2017, though the label did not have to specifically include AE as a licensed
37 indication. Therapies not available in Europe by September 2017 could be mentioned in the
38 manuscript, but no formal therapeutic recommendation would be given for these. High level
39 evidence with a potential to significantly change current treatment paradigms published after
1 these deadlines could be included upon vote during the final meeting of the guideline
2 committee in Geneva in 2017.
3 The expert panel tried to use standardized language for the recommendations given, but
4 would prefer a consensus vote on non-standardized language over standardized language,
5 if the highly variable clinical presentation of AE would suggest that a non-standardized
6 wording be more useful in clinical reality from a patient’s or physicians perspective (see table
7 3 for standardized wording of recommendations).
8
9 Consensus process
10 The committee designated all recommendation statements, as well as some especially
11 important areas as those requiring consensus. Consensus conferences were held in
12 Copenhagen in October 2015, in Vienna in September 2016 and in Geneva in September
13 2017. Johannes Ring acted as the moderator during all face-to-face meetings.
14 All sections with recommendations were discussed within the whole group and consensus
15 was defined as approval by at least 75 % of the panel members. All consented
16 recommendations are marked with grey boxes.
17 External review
18 According to the EDF standard operation procedure, all EDF members were invited to
19 review the guidelines prior to the last internal review. The comments of the participating
20 societies were forwarded to the chapter authors and considered during the last internal
21 review.
22 Update of the guidelines
23 These guidelines will require updating approximately every three years, but advances in
24 medical sciences may demand an earlier update.
25 Target group
26 This guideline has been prepared for physicians, especially dermatologists, pediatricians,
27 allergists, general practitioners and all specialists taking care of patients suffering from AE.
28 Patients and relatives should also be able to get reliable information and advice with regard
29 to evidence-based therapeutic modalities.
30
1 AE management from a patient’s perspective

2
3 Due to the variety of different AE therapies and different individual reactions, patients and
4 their caregivers need clear and easy to understand strategies for their individual needs in
5 therapy, and in order to become comfortable to take over responsibility for the treatment of
6 their chronic condition. Patients and caregivers need to be trained to understand and apply
7 the existing therapeutic options and best disease management immediately after a
8 diagnosis of AE. Health Care Professionals need to be reimbursed for education, as the
9 training of patients and caregivers is an imperative prerequisite for the essential
10 concordance between the patient and the treating physician. Free access to care and
11 medication is essential from a patient’s perspective. A multidisciplinary approach including
12 psychological advice is needed to overcome the painful, itching and stigmatizing flare-ups
13 and their impact on quality of life. Rehabilitation may play a key role.
14 Patients and caregivers should be able to identify their individual symptoms, become aware
15 of the need and benefit of sufficient amounts of basic management (topical treatment,
16 avoidance of specific and unspecific trigger factors) and to understand certain needs of anti-
17 inflammatory treatment based on topical glucocorticosteroids (TCS) and topical calcineurin
18 inhibitors (TCI). This will lead to a fast and effective short-term management of
19 exacerbations, as well as long term control by proactive therapy. Movement of patients and
20 caregivers towards unapproved complementary alternative medicine (CAM) and non-
21 compliance often result in worsening of the disease and should be avoided.
22 Cases of severe AE should be discussed openly and in detail between the treating physician
23 or multidisciplinary team and the patient or caregiver, since many patients cannot overlook
24 the therapeutic options, even if they have access to transparent guidelines. Patients and
25 caregivers should actively be involved in therapeutic decisions at all stages in order to
26 achieve therapeutic success.
27 Patients with a not well controlled AE should be informed about new therapeutic options and
28 possible side effects. Guidelines for patients and caregivers should be in place.
29

2
3 The identification of individual trigger factors is crucial in the management of AE and their
4 avoidance allows longer phases of remission or total clearance of symptoms. It is important
5 to differentiate between the genetic predisposition towards hypersensitive, dry skin with
6 barrier dysfunction – largely corresponding to ichthyosis vulgaris – which cannot be "cured"
7 and the inflammatory skin lesions which can very well be treated and disappear.
8 In avoidance recommendations, one must distinguish between primary, secondary and
9 tertiary prevention measures. Among provocation factors, specific and non-specific elicitors
10 must be distinguished.
11
12 Non-specific provocation factors
13 Numerous factors and substances from the environment can irritate the sensitive skin of
14 patients with AE and can elicit eczema flares. They may be physical, like mechanic irritants
15 (e.g. wool), chemical (acids, bleaches, solvents, water) or biological (allergens, microbes) in
16 nature. Information on unspecific irritants and their role in aggravating AE is a crucial
17 prerequisite for long-term management of patients with AE. Here also the adequate skin
18 care and hygiene procedures in cleansing and dressing have to be discussed with the
19 patient (see also, “Educational program, eczema school").
20 Negative effects of air pollutants upon the development and maintenance of AE, like tobacco
21 smoke or volatile organic compounds (VOCs) in indoor environments and traffic exhaust in
22 the outdoor air must be mentioned. There is evidence from epidemiological trials that
23 exposure to indoor chemicals, such as formaldehyde, increases skin barrier disturbance
24 (13); a mixture of volatile organic compounds has been shown to increase the intensity of
25 atopy patch test reactions to aero-allergens in patients with AE (14).
26 Exposure to traffic exhaust has been shown to be associated with an increased risk to
27 develop AE in pre-school children (15, 16). Moreover, diesel exhaust particles may favor
28 alloknesis and skin scratching, and thus worsen AE (17).
29 Exposure to environmental tobacco smoke measured as urinary cotinin / creatinin ratio was
30 associated with a significant elevated risk to develop AE which was especially pronounced
31 in children of parents with an atopic background (18). The prevalence of smoking was higher
32 in severe AE, as shown in a recent cross sectional study investigating the entire Danish
33 population (19). A systematic review of 86 studies confirmed the association of smoking and
34 AE in adolescents and adults in all continents of the earth (20). It remains unclear, however,
35 if smoking is a provocation factor in AE or if the burden of AE leads to more frequent smoking
36 habits (20).
37 Avoidance strategies regarding tobacco smoke as well as traffic exhaust exposure in young
38 children have been introduced in the recent S3 Guideline for primary prevention of atopic
39 diseases in Germany (21).
40
1 Specific allergen avoidance

2 Aeroallergens
3 Aeroallergens can elicit eczematous skin lesions in sensitized patients with AE, which can
4 be explained by increased permeability of the skin for inhalant allergens in patients with skin
5 barrier defects (22). Positive atopy patch tests are associated with specific IgE and positive
6 histories of flare-ups of AE to seasonal allergens (23).
7 Many airborne allergens eliciting AE are derived from house dust mites (HDM) of the species
8 Dermatophagoides pteronyssinus and D. farinae. The enzymatic activity of major mite
9 allergens is found to destroy tight junctions of the epithelial cells in the bronchial mucosa
10 and may thus also deteriorate the skin barrier dysfunction in patients with AE (24).
11 House dust mites are living in a complex eco-system consisting of air humidity, temperature
12 and presence of organic material. They accompany humans and are most commonly
13 present in dust from mattresses or bedroom floors. Normal cleaning measures help only
14 little in decreasing house dust mite allergens present in settled and airborne dust indoors.
15 Encasings of mattresses and beddings protect humans from house dust mites in mattresses.
16 There are also mite-proof pyjamas ("eczema overalls"). Some studies are showing a clear-
17 cut benefit from house dust mite avoidance strategies in the improvement of AE (25, 26). A
18 recent meta-analysis was not in favor of house dust mite avoidance in established AE (27).
19 Rehabilitation programs in mite-free environments – like in alpine climate – have shown to
20 lead to significant and long-lasting improvement of AE (28).
21 Pollen in the outdoor air also can elicit flares of AE as has been shown in a nested case
22 control study in pre-school children (29). A challenge of sensitized patients with grass pollen
23 in a challenge chamber led to exacerbation of AE in winter in a proof-of-concept study (30).
24 Pollen avoidance is difficult under everyday conditions in most parts of Europe except when
25 air conditioning with pollen filters is used in the indoor environment. In high altitude mountain
26 climate pollen counts are usually lower than in the average living areas.
27
28 Animal epithelia
29 Many patients are aware that contact with animals may lead to a deterioration of skin
30 symptoms. While in former times avoidance of pets was a central feature in primary
31 prevention recommendations for atopy, this has been modified as follows: cat epithelia
32 exposure is regarded by most authors as a risk factor, so it should be avoided (31, 32).
33 There is no evidence that dogs increase the risk of AE in children; recent studies suggest
34 that dogs might even protect from AE, possibly due to exposure to non-pathogenic microbes
35 (33-35). Once a patient is sensitized to a pet and shows symptoms after contact, avoidance
36 is necessary.
37 Furthermore, the exposure towards bacteria is increased if dogs live in a household, which
38 may have a protective effect in terms of primary prevention and immune regulation.
39 However, if AE has developed, there may be a risk of bacterial superinfection if skin lesions
40 are present and dogs have a close contact to the patient (36). Staphylococcus aureus, which
41 heavily colonizes the lesions of AE, produces extracellular proteases, which cause barrier
42 breakdown in the skin and thus facilitate the uptake of allergens and specific sensitization.
1
2 Dietary Recommendations
3 See chapter "Dietary intervention"
4
5 Vaccinations
6 It is a common misconception that AE patients and especially children diagnosed with AE
7 should avoid routine vaccinations. There is no evidence, that recommended vaccinations in
8 infancy and early childhood have an impact on the development of AE or other atopic
9 diseases (37). All children diagnosed with AE should be vaccinated according to the local
10 or national vaccination plan. Vaccinations should not be administered during acute flares –
11 in those cases two weeks of well-conducted TCS therapy followed by a normal vaccination
12 procedure are recommended (37). Patients on immunosuppressive therapy with
13 cyclosporine or related drugs should consult a specialist before live vaccination is performed
14 (37). The only exception from this rule has been the intracutaneous smallpox vaccination
15 with an attenuated live vaccine, which is contraindicated in AE patients due to risk of life-
16 threatening eczema vaccinatum (38). A safe and effective alternative regimen with a highly
17 attenuated MVA vaccine may circumvent these problems for AE patients in the future (39).
18
19 Clothing and textiles - contact allergens
20 Smooth clothing and avoidance of irritating fabrics and fibers is essential in the avoidance
21 of primary skin irritation. Silk garments with an AEGIS-coating are lightweight and
22 comfortable to wear, but do not improve eczema severity over standard of care treatment
23 (40). Too occlusive clothing inducing heat sensations should be avoided.
24 Obviously, contact allergens relevant to the patient should also be avoided. This is of special
25 relevance if type IV allergy to ingredients of emollients has been diagnosed by classical
26 patch tests. Emulsifiers, fragrances and preservatives are the main cause of contact allergy
27 to cosmetics (41).
28
29 Occupational aspects
30 Special recommendations must be given in individual counseling programs regarding the
31 choice of profession. There is common consensus that occupations involving contact with
32 strongly sensitizing substances should be avoided by patients with AE (42). Professions with
33 skin irritating tasks are not recommended to atopic individuals with a history of persistent or
34 relapsing hand eczema. The risk of contact sensitization is slightly increased in patients with
35 AE (43).
36
37 Summary of evidence
38 There is some evidence that house dust mite avoidance strategies, especially encasings,
39 can reduce house dust mite and house dust allergen content in indoor air and therefore
1 improve AE. The latter is controversial, since a recent meta-analysis would not confirm this
2 effect. (2b)
3 There is evidence that house dust mite avoidance and high altitude climate may give benefit
4 to patients suffering from AE. (2b, 3b)
5 There is a rationale for using protective clothes (eczema overalls), although good studies
6 are missing. (-)
7 In spring and summertime pollen exposure may exacerbate AE in the air-exposed skin
8 areas. (-)
9 Vaccination does neither improve nor worsen the natural course of AE (2a).
10 Recommendations
11 Pollen avoidance measures can be recommended during the pollen season. (-, D)
12 House dust mite avoidance measures may be tried in selected cases. (-, D)
13 When classical patch tests are positive, relevant contact allergens should be avoided. (-, D)
14 All children diagnosed with AE should be vaccinated according to the national vaccination
15 plan (2a, B).
16
1 Basic therapy of disturbed skin barrier function and emollient therapy

2 (“skin care”)
3
4 Emollient therapy and skin care
5 Dry skin is one of the characteristic symptoms of AE. There is now scientific evidence in
6 humans and mice of genetically driven skin barrier anomalies that facilitate allergen
7 penetration into the skin with an increased proneness to irritation and subsequent cutaneous
8 inflammation. Filaggrin deficiency is the best-defined anomaly, which gives rise to a
9 deficiency in small water binding molecules resulting from normal filaggrin catabolism (44).
10 Besides that, a lack of stratum corneum intercellular lipids and an inadequate ratio between
11 compounds (cholesterol, essential fatty acids, ceramides) enhance trans-epidermal water
12 loss leading to epidermal micro-fissuring. Barrier disruption leads to inflammation, and
13 protease-antiprotease imbalance is a crucial intermediate step (45).
14
15 Cleansing and bathing
16 The skin must be cleansed thoroughly, but gently and carefully to get rid of crusts and
17 mechanically eliminate bacterial contaminants in the case of bacterial super-infection.
18 Cleansers with or without antiseptics (the duration of action of antiseptics is very limited,
19 thus mechanical cleansing is probably more important) in non-irritant and low allergen
20 formulas available in various galenic forms (syndets, aqueous solutions) may be used. It is
21 easier to perform this first stage of gentle cleansing of skin on the nappy mattress rather
22 than directly in the bathtub in infants (3). A further cleansing followed by a rapid rinse is
23 performed in the bath (27-30°C). The short duration of the bath (only 5 minutes) and the use
24 of bath oils (2 last minutes of bathing) are aimed at avoiding epidermal dehydration. Topical
25 emollients are preferentially applied directly after a bath or a shower following gentle drying
26 when the skin is still slightly humid (see next section on emollient therapy).
27 Adding antiseptics such as sodium hypochlorite to the bath-water is an additional option for
28 treatment of AE because of its bacterial count inhibiting activities (46, 47). A study showed
29 that children bathing in 0,005% bleach experienced an improvement of their AE (47, 48). In
30 a recent study sodium hypochlorite baths did not show superiority to water baths concerning
31 the severity of AE, but allowed a reduction in topical corticosteroid and antibiotic usage (49).
32 Salt baths may be beneficial because of removing the dead keratin material (50). Salt baths
33 are useful especially in heavily impetiginized or ichthyotic skin. A recent study suggested
34 usage of fragrance-free baby oil as a soap substitute, especially in populations where
35 specially designed emollients are not affordable (51).
36 Bath oils are a valuable addition for skin care especially in babies and children. Bath
37 additives containing potentially allergenic proteins such as from peanut or colloidal oat
38 should be avoided in the most vulnerable age group before the age of 2 (3) It should be
39 emphasized that most bath oils commercially available in Europe are practically free of these
40 protein allergens.
41 Recommendations
1 Adding antiseptics such as sodium hypochlorite to the bath-water may be useful for
2 treatment of AE (1b, A).
3
4 Emollient therapy
5 By tradition, emollients are defined as topical treatment with vehicle-type-substances lacking
6 active ingredients. These emollients are extremely helpful for AE patients, and contain
7 usually a humectant (promoting stratum corneum hydration, such as urea or glycerol) and
8 an occludent (reducing evaporation, such as petrolatum). Recently, marketing of non-
9 medicated “emollients” containing active ingredients have softened the delineation of
10 emollients from topical drugs. Throughout this guideline, “emollients” are defined as “topical
11 formulations with vehicle-type-substances lacking active ingredients”, whereas “emollients
12 plus” refers to “topical formulations with vehicle-type substances and additional active, non-
13 medicated substances”.
14 The direct sole use of emollients on inflamed skin is poorly tolerated and it is better to treat
15 the acute flare first. Emollients are the mainstay of management. Hydration of the skin is
16 usually maintained by at least twice daily application of moisturizers with a hydrophilic base,
17 e.g. 5% urea (52). According to the acuity of the skin condition, lipophilic bases are also
18 helpful. The use of barrier ointments, bath oil, shower gel, emulsions or micellar solutions
19 enhancing the barrier effect is also recommended. The cost of high quality (low in contact
20 allergens) emollient therapies often restrict their use because such therapies are considered
21 to be non-prescription drugs (except for e.g. Finland and Switzerland, where prescription
22 and reimbursement are usual) and the quantities required are usually high (up to 100 g per
23 week in young children, and up to even 500 g in adults). The use of pure oil products such
24 as coconut oil instead of emulsions will dry out the skin, increase the transepidermal water
25 loss and is therefore not recommended.
26 The applied amount of topicals may also follow the fingertip unit rule: A fingertip unit (FTU)
27 is the amount of ointment expressed from a tube with a 5-mm diameter nozzle and measured
28 from the distal skin-crease to the tip of the index finger (~0.5 g); this is an adequate amount
29 for application to two adult palm areas, which is approximately 2% of an adult body surface
30 area (53).
31 A better molecular and biochemical knowledge of the skin in AE should provide access to
32 barrier improving topical agents. There is increasing evidence-based proof for the use of
33 emollients (54).
34
35 Ingredients and possible risks of emollients
36 Urea may cause irritation or stinging sensation especially if applied to lesional skin. Some
37 dermatologists are reluctant to use urea under the age of two years. Toddlers should be
38 treated with lower concentrations than adults (3). Glycerol seems better tolerated (less
39 smarting effect) than urea plus sodium chloride (55). Usually, the recommendation is to use
40 emollients immediately after bathing and soft pad drying. A small study suggests that an
41 emollient applied alone without bathing may have a longer duration as measured by
42 capacitance (56).
1 Propylene glycol is easily irritating in young children aged less than two years and should
2 not be used for toxicity reasons in these young children. There is concern that the large
3 preventive use of emollients containing intact proteins such as peanut allergens (57) or
4 colloidal oat meal (58) may increase the risk of skin sensitization and allergy. Only emollient
5 preparations devoid of proteinaceous allergens and haptens known to cause contact allergy
6 frequently (such as lanolin/wool wax alcohol or methylisothiazolinone) should be used,
7 especially in the most vulnerable age group before the age of two years.
8 Emollients containing tannin- and ammonium bituminosulphonate (ichthammol) may be a
9 useful addition to the basic treatment regimen, especially in mild disease or if TCS treatment
10 is not possible from a patient’s perspective, e.g. corticophobia (steroid phobia) (59).
11 Sole use of emollients without sufficient topical anti-inflammatory therapy involves a
12 considerable risk for disseminated bacterial and viral infection of AE, which is already
13 increased in AE patients (60).
14
15 Emollients “plus”
16 In the last years, several non-medicated products for topical treatment of AE are available
17 on the market, which contain active ingredients, but are neither fulfilling the definition of nor
18 needing a license as a topical drug. These products may contain for example saponins,
19 flavonoids and riboflavins from protein free oat plantlet extracts, or bacterial lysats from
20 Aquaphilus dolomiae or Vitreoscilla filiformis (61). These lysats both improve AE lesions and
21 influence the skin microbiome of AE patients (62, 63). In vitro and clinical research data from
22 different laboratories have provided some background information on molecular targets and
23 possible mode of action of these active emollients “plus” (64-66).
24
25 Evidence of emollient efficacy
26 Certain moisturizers could improve skin barrier function in AE and reduce skin susceptibility
27 to irritants. It was clearly demonstrated that long-term emollient therapy improves AE-
28 associated xerosis (67). Simple stand-alone emollient application for one week may improve
29 mild to moderate AE (68). A comparative study showed that an over-the-counter moisturizer
30 could be as clinically effective as more expensive barrier creams in the management of mild
31 to moderate childhood AE (69). Another study in adult AE patients suggested an effect of
32 coconut oil on staphylococcus aureus carriage (70). In addition, the daily use of emollients
33 from birth may significantly reduce the incidence of AE in a high-risk population (71, 72). As
34 the major limitation of these two promising trials is their relatively short duration of half a
35 year, longer trials are currently performed.
36
37 Evidence of steroid sparing effects of emollients
38 1. Short-term (3-6 weeks)
39 Several studies in children (54, 73) and one in a mixed children-adult population (74) showed
40 a variable but consistent evidence of short-term steroid sparing effect in mild to moderate
41 AE.
1 2. Long-term-maintenance therapy
2 Maintenance of stable disease can be obtained with emollients used twice weekly or more
3 frequently in a subset of patients, after an induction of remission with topical corticosteroids.
4 Several studies showed comparable results for intermittent emollient therapy and time to
5 relapse, using comparable study designs in adults and children (75, 76).
6
7 Recommendations
8 Emollients should be prescribed in adequate amounts and these should be used liberally
9 and frequently, in a minimum amount of 250 g per week for adults (3b,C).
10 Emollient bath oils and soap substitutes should also be used. Emollients with a higher lipid
11 content are preferable in winter time (3b,C).
12 A regular use of emollient has a short and long term steroid sparing effect in mild to moderate
13 AE. An induction of remission with topical corticosteroids or topical calcineurin inhibitors is
14 required first (2a,B).
2
3 Food allergens, pre- and probiotics
4 Food allergy has been well documented in approximately one third of children with
5 moderate-severe AE (77). Among food allergens, cow’s milk, hen’s egg, peanut, soy, nuts
6 and fish are most frequently responsible for AE exacerbation in young children, with age-
7 dependent variations in causally incriminated food (78). In older children, adolescents and
8 adults pollen associated food allergy should be taken into account (79, 80).
9
10 Response patterns to food allergens
11 Three different clinical reaction patterns in patients with AE have been described, depending
12 on the type of symptoms and their time of onset (78, 81).
13 Immediate-type, non-eczematous reactions are usually IgE mediated, occur within 2 hours
14 after the administration of the allergen, with skin manifestations such as urticaria,
15 angioedema, flush, and pruritus or other immediate type reactions of the gastrointestinal
16 tract, the respiratory tract, or the cardiovascular system in the sense of anaphylaxis.
17 Cutaneous manifestations occur in 74% of patients. In addition, children might develop a
18 transient morbilliform rash 6 to 10 hours after the initial immediate reaction, disappearing
19 within a few hours and considered as “late-phase” IgE-mediated response (81, 82).
20 Isolated eczematous delayed-type reactions typically occur 6 to 48 hours after the
21 administration of the allergen with flares of eczema on predilection sites of AE, suggestive
22 for a non-anaphylactic pattern.
23 A combination of the two above-mentioned patterns with an immediate-type reaction
24 followed by an eczematous delayed-type reaction has been described in approximately 40%
25 of children (83).
26 Sensitization to food can be identified by means of a detailed clinical history in combination
27 with in vivo tests (skin prick tests, prick-prick tests) and in vitro tests (serum specific IgE). In
28 addition, patch tests proved to be useful for studying delayed food-related skin responses.
29 In vitro tests are valuable when skin prick tests (SPT), cannot be applied (e.g.
30 dermographism or UV- and drug induced skin hypo-reactivity, eczema at the test site, lack
31 of compliance for SPT in infancy, etc.). Moreover, in vitro specific IgE to food allergens gives
32 better quantitative data for the grade of sensitization which helps to estimate the probability
33 of the risk of a clinical reaction (although precise decision points are not available) and it
34 offers the opportunity to test single recombinant allergens which may have a better
35 diagnostic specificity than testing with food extracts for some foods (e.g. omega-5-gliadin in
36 wheat allergy, Gly m 4 in pollen-related soy allergy).
37 Atopy patch test (APTs) are performed with self-made food material using a 1/10 dilution in
38 saline of the fresh food applied for 24-48 hours on non-lesional skin (84). Food APT is not
39 standardized for routine use. So far, APTs have demonstrated to improve the accuracy of
40 skin testing in the diagnosis of allergy to cow’s milk, eggs, cereals, and peanuts in patients
41 with AE (85-88). Whereas immediate-type reactions are associated with SPT positivity,
1 delayed reactions are related to positive responses to APTs. However, double-blind

2 placebo-controlled food challenge (DBPCFC) remains the “gold standard” for the diagnosis
3 of FA (89).
4 Oral food challenge (OFC) should always be performed under medical supervision with
5 emergency equipment available, particularly after long-lasting elimination of the culprit food.
6 Practically, OFC should be performed according to standardized protocols considering
7 variables associated with food matrix, doses and time intervals (90). In AE the major flaw is
8 that DBPCFC might not offer the opportunity to exclude placebo reactions or coincidental
9 influences of other trigger factors of AE during the prolonged challenge period. Therefore in
10 AE the evaluation of delayed reactions after 24 hours or 48 hours by trained personal is
11 mandatory (83). Challenge tests based on repeated exposure to food enable the
12 assessment of delayed adverse responses (83).
13 Unfortunately, the effects of dietary interventions on the course of AE have been studied
14 only in a few controlled studies. In a systematic review (11) eight randomised, controlled
15 studies examining the effect of an elimination diet on existing AE were identified and
16 summarized in the following way: a) Elimination diets are difficult to carry out even in a
17 motivating atmosphere during a clinical study. b) The drop-out-rate in AE studies is
18 particularly high in studies on diets. c) There is no convincing evidence that a milk- or egg-
19 free elimination diet is beneficial in general, when unselected groups of patients with AE
20 were studied. d) There is no evidence for a benefit in the use of elementary or few food
21 restricted diets in unselected patients with AE.
22 A Cochrane systematic review based on nine randomized controlled trials concluded that
23 eliminating egg from the diet in those who had positive specific IgE to eggs proved beneficial
24 (91). The American Academy of Dermatology recommended egg restriction in the subset of
25 patients with AE who were found to be clinically allergic to eggs (92), but this approach
26 should also be followed for other food allergens proven relevant in individual patients.
27 Although progress has been considerable, there are no simple strategies to prevent the
28 development of AE and food allergy in infants. The recent publication of randomized trials,
29 such as the Learning Early About Peanut Allergy (LEAP) (93) and Enquiring About
30 Tolerance (EAT) (94) studies, have given some support to the notion that early oral ingestion
31 of food may protect from sensitization and allergy later in life. The oral introduction early in
32 the first year of life at a “window of opportunity“ of time between 4 and 6 months of age may
33 actually protect children by facilitating the induction of tolerance (95). Epidemiological
34 studies have shown a significant association between the diversity of foods given in the first
35 year of life and protection form atopic eczema (96).
36
37 Pre- and probiotics
38 Probiotics such as lactobacillus mixtures have been studied in AE, and have been shown to
39 induce improvement (97). Other studies failed to show significant effects (98, 99). In a study
40 with 800 infants the effect of a prebiotic mixture was investigated and found to have
41 beneficial effects in preventing the development of AE (100).
1 Non-pathogenic bacterial strains like Vitreoscilla filiformis or Aquaphilus dolomiae have been
2 used as sources for bacterial lysates for topical therapy of AE (see chapter: Topical therapy).
3 Previous systematic reviews on probiotics for the treatment of AE have consistently
4 concluded a lack of effect in children (101). On the basis of the existing literature, with only
5 one group showing positive results in a controlled study, the guideline group decided not to
6 give a recommendation for treatment with lactobacilli in AE. It may well be that a preventive
7 effect of pre- or probiotic mixtures will be shown in the future; consultation of the S3 guideline
8 on “prevention on allergy” is recommended (21).
9
11 Food sensitization occurs in about 50 % of children with severe AE. The relevance can be
12 evaluated by oral provocation tests, best performed as double-blind placebo-controlled food
13 challenge. (1a)
14 Food allergy plays a role for disease exacerbation in 30 % of AE children, most often against
15 basic foods such as hen’s egg or cow’s milk. Pollen-associated food allergy can occur in all
16 ages. (2a)
17 Food elimination diets represent a major impairment in quality of life and are not easy to
18 perform. (2a)
19 There is evidence that elimination of basic foods in food allergic children can improve the
20 AE. (1a)
21 The persistence of food allergy can be evaluated by oral provocation after 1 or 2 years. (3a)
22 There are no long-term studies to the effect of food elimination diets in AE. (-)
23 There is conflicting data on prevention or improvement of AE during uptake of pro-biotics
24 such as lactobacillus preparations (1b).
25 Recommendations
26 Patients with moderate to severe AE should observe a therapeutic diet eliminating those
27 foods that elicitated clinical early or late reactions upon controlled oral provocation tests.
28 (2b, B)
29 Primary prevention of food allergy associated AE is recommended with exclusive breast milk
30 feeding until 4 months of age. (2-3,C)
31 If breast milk is lacking in low risk children (general population), conventional cow’s milk
32 formula is recommended. (2-3,C)
33 If breast milk is lacking in high-risk children (one first degree relative with physician
34 diagnosed allergic symptoms), a documented hypoallergenic formula is recommended. (1,
35 B)
36 Introduction of complementary foods is recommended between 4 and 6 months of age in
37 low and high-risk children irrespective of an atopic heredity. (1-2, B)
38 A certain diversity of foods selected should be observed during the introduction between 4
39 and 6 months of age (1, D)
40

2
3 Topical treatment: overall principles
4 Effective topical therapy depends on three fundamental principles: sufficient strength,
5 sufficient dosage and correct application (3). Many formulations are available especially for
6 corticosteroids, and the choice of formulation has a strong impact on the efficacy of the
7 resulting drug. Topical treatment should always be applied on hydrated skin, especially
8 when using ointments. Patients with acute, oozing and erosive lesions and children
9 sometimes do not tolerate standard topical application, and may first be treated with 'wet
10 wraps' until the oozing stops. Wet wrap medications are highly effective in acute AE and
11 improve tolerance. The use of wet-wrap dressings with diluted corticosteroids for up to 14
12 days (usual is rather up to 3 days) may be a safe crisis intervention treatment of severe
13 and/or refractory AE with temporary systemic bioactivity of the corticosteroids as the only
14 reported serious side effects (102-105). However, this treatment approach is not
15 standardized yet, and the evidence that it is more effective than conventional treatment with
16 topical steroids in AE is not of high quality. Simple or occlusive medications in less sensitive
17 skin areas and for brief time periods may also increase efficacy and speed up lesion
18 resolution. Even without wet wraps, topical therapy may be time consuming, and deserves
19 attention. One well-conducted treatment per day is usually sufficient but acute flares may
20 require a few days with higher treatment frequency.
21 By tradition, anti-inflammatory topical therapy has been administered to lesional skin only
22 and has been stopped or tapered down once visible lesions were cleared. This traditional,
23 reactive approach has now an alternative, which is the proactive treatment concept.
24 Proactive therapy is defined as a combination of predefined, long-term, anti-inflammatory
25 treatment applied usually twice a week to previously affected areas of skin in combination
26 with liberal use of emollients on the entire body and a predefined appointment schedule for
27 clinical examinations (106). The proactive regimen is started after all lesions have
28 successfully been treated by a regular anti-inflammatory therapy (by either steroids or topical
29 calcineurin-inhibitors) in addition to ongoing emollient application on previously unaffected
30 skin. Clinical trial data are available for a number of steroid products as well as for tacrolimus
31 ointment (107), but topical steroids are usually approved only for a very limited period of
32 time such as a few weeks. Studies investigating topical steroids for proactive treatment are
33 usually conducted only for 16 weeks, whereas studies with tacrolimus ointment have shown
34 good results for 52 weeks in both children and adults. The duration of the proactive
35 management is usually adapted to the severity and persistence of the disease (108). The
36 applied amount of anti-inflammatory topicals should also follow the fingertip unit rule (see
37 chapter: Emollient therapy).
38
39 Glucocorticosteroids
40 Topical glucocorticosteroids (TCS) are a first-line anti-inflammatory treatment, applied on
41 inflammatory skin according to the needs (pruritus, sleeplessness, new flare). Numerous
42 substances are available in a variety of formulations. Anti-inflammatory effects in AE were
1 reported by different investigators (109, 110). With mild disease activity, a small amount of
2 topical corticosteroid twice to thrice weekly (monthly amounts in the mean range of 15 g in
3 infants, 30 g in children and up to 60–90 g in adolescents and adults, roughly adapted to
4 affected body surface area), associated with a liberal use of emollients generally allows a
5 good maintenance. Such monthly amounts of even potent topical steroids usually do not
6 have adverse systemic or local effects. Twice weekly application of fluticasone or
7 methylprednisolone aceponate significantly reduced the risk of relapses of AE in a proactive
8 strategy (109-112).
9 Several factors should be considered when choosing a topical corticosteroid, including
10 potency, galenic formulation, patient age and body area to which the medication will be
11 applied. The potency of topical corticosteroids is grouped by potency according to Niedner
12 from mild (group I) to super-potent (group IV) (113). Prescribers should know this
13 classification, as they should know that the US-American classification is different and
14 ranges from VII (weakest) to I (strongest). In France, this classification is even different.
15 Super potent TCS (group IV) are not recommended for AE treatment, especially not in
16 children (3). Potent and very potent corticosteroids of group III and IV are more likely to
17 cause depression of adrenal function than group I and II treatments, but their systemic
18 effects will decrease more quickly due to more rapid restitution of the skin barrier (114).
19 Treatment of the face and especially the eyelid region should be restricted to mild TCS
20 (group I and II). Chidren should be treated with less potent TCS than aduts. In addition, there
21 are different generations of substances, which may differ in their risk-benefit ratio.
22 Itch is the key symptom for evaluation of response to treatment, and tapering should not be
23 initiated before the itch has largely improved. Two applications per day may be necessary
24 to reduce the itch, but one well-conducted, correctly dosed treatment per day may be
25 sufficient (115, 116). Dose tapering is usually applied to avoid withdrawal rebound, although
26 no controlled studies have demonstrated its usefulness. Tapering strategies consist of
27 switching to a less potent corticosteroid, or keeping a more potent one while reducing the
28 frequency of application (intermittent regimen). The most constructive way to spare steroids
29 and avoid steroid-related side-effects is to use them intensively during the acute flares (3).
30 Continuous emollient skin care combined with early anti-inflammatory intervention is also
31 very important to stabilize the disease and prevent flares (117).
32 Side-effects of topical corticosteroids comprise a variety of skin changes mostly in the sense
33 of skin atrophy – except from contact allergy to glucocorticosteroid substances. The skin
34 changes manifest as thinning of the skin, development of teleangiectasias (rubeosis
35 steroidica), spontaneous scars (“pseudocicatrices stellaires”, ecchymosis, striae distensae
36 (stretch marks). A “dirty neck” (cutis punctata linearis colli) and hypertrichosis may develop.
37 In infants, inappropriate use of TCS in the diaper area can lead to granuloma gluteale
38 infantum or even iatrogenic Cushing’s disease. The risk of ocular complications by topical
39 corticosteroids seems to be low. Development of glaucoma or cataract has been described
40 after systemic glucocorticosteroid application (118).
41 The use of potent topical corticosteroids in sensitive skin areas (face, neck, folds) should be
42 limited in time to avoid skin atrophy (119). Monitoring by physical examination for cutaneous
43 side effects during long term use of potent topical corticosteroids is very important. The
44 special aspects and potential adverse effects of topical corticosteroids in pregnancy have
1 been recently revieved (120). The application of topical corticosteroids to the eyelids and
2 periorbital region, even over longer periods of time in adults with AE was not associated to
3 the development of glaucoma or cataracts (118). Application of very potent topical
4 corticosteroids even for brief time periods may result in the drug becoming systemically
5 available and potent enough to induce adrenal gland suppression (121).
6 In the face a special skin condition called rosacea-like perioral dermatitis is often started by
7 inappropriate, long term use of TCS. The skin seems to become “addicted” to TCS (“red
8 face syndrome” or „corticosteroid addiction syndrome“). This is characterized by rosacea
9 like disease with persistent erythema, burning and stinging sensation. It has been reported
10 mostly on the face and genital area of women primarily in the setting of long-term
11 inappropriate use of potent topical corticosteroids (122).
12 Patient fear of side effects of corticosteroids (corticophobia) is quite common and should be
13 recognized and adequately addressed to improve adherence and avoid undertreatment
14 (123-125).
15 The simultaneous combination of topical corticosteroids with topical calcineurin inhibitors at
16 the same site does not seem to be useful. At least in pediatric patients with severe AE, the
17 efficacy and safety profile of pimecrolimus cream 1% combined with fluticasone were similar
18 to that of fluticasone alone (126). Treating sensitive body areas such as the face with topical
19 calcineurin inhibitors while treating other affected body areas with a topical corticosteroid
20 may be a useful and cost effective strategy. Initial treatment with topical corticosteroids may
21 be considered in patients with acute flare to minimize topical calcineurin inhibitor site
22 reactions (108).
23
25 Topical corticosteroids have a significant effect improving skin lesions compared to vehicle.
26 (1b)
27 The efficacy of topical glucocorticosteroids can be increased by using wet wraps. (1b)
28 Recommendations
29 Topical corticosteroids are important anti-inflammatory drugs to be used in AE, especially in
30 the acute phase. (-, D)
31 Topical corticosteroids with an improved risk-benefit ratio are recommended in AE. (-, D)
32 Diluted topical corticosteroids may be used under wet wraps for short-term periods in acute
33 AE to increase their efficacy. (1b, A)
34 Proactive therapy, e.g. twice weekly application in the long-term follow-up, may help to
35 reduce relapses. (1b, A)
36 Proactive therapy with TCS may be used safely for at least 20 weeks, which is the longest
37 duration of trials (1b, A).
38 Patient fear of side effects of corticosteroids (corticophobia) should be recognized and
39 adequately addressed to improve adherence and avoid undertreatment. (4C)
1 Topical calcineurin inhibitors

2 Two topical calcineurin inhibitors (TCI), tacrolimus ointment and pimecrolimus cream, are
3 licensed for AE treatment. The efficacy of both formulations has been demonstrated against
4 vehicle in clinical trials for short-term (127, 128) and long-term use (129, 130). In addition,
5 proactive tacrolimus ointment therapy has been shown to be safe and effective for up to 1
6 year in reducing the number of flares and improving the quality of life in both adults and
7 children (131, 132). The anti-inflammatory potency of 0.1% tacrolimus ointment is similar to
8 a corticosteroid with intermediate potency (133, 134), whereas the latter is clearly more
9 effective than 1.0% pimecrolimus cream (135).
10 The efficacy of long-term monotherapy with tacrolimus ointment has been shown in children
11 and adults (133, 134, 136). Less data are available for children under 2 years of age (137,
12 138). Pimecrolimus cream has been studied in infants and children in a combination regimen
13 with topical corticosteroids (139, 140), the latter being given if a flare occurred. Both topical
14 calcineurin inhibitors are approved in the EU from 2 years of age and above. High quality
15 long-term safety data have recently been published on a 4-year tacrolimus and 5-year
16 pimecrolimus studies (141, 142). The cost effectiveness of proactive therapy with tacrolimus
17 has been demonstrated for moderate AE and is even higher in severe AE in a recent study
18 on adult patients (143), whereas the cost effectiveness of first-line treatment with topical
19 calcineurin inhibitors has not been demonstrated conclusively. However, in children with AE,
20 twice-weekly treatment with tacrolimus 0.03% ointment has been observed to reduce the
21 number of flares and to prolong flare free intervals, and may be cost-saving in children with
22 moderate or severe AE (144, 145).
23 In addition, the long-term, effective treatment of patients with AE may have a beneficial effect
24 also on respiratory symptoms and serum IgE (146). In adults, long-term treatment with 0.1%
25 tacrolimus ointment appears to be at least as effective as a corticosteroid regimen for the
26 trunk and extremities and more effective in the face and neck area. Both topical tacrolimus
27 and corticosteroids decrease skin recall activity, and decrease serum IgE in patients with
28 treatment response.
29 Safety data of both topical calcineurin inhibitors have been reported in many clinical trials
30 and registries, demonstrating the safety of these drugs in daily routine use. The most
31 frequently observed side effect is a transient warmth, tingling or burning sensation at the
32 application site during the first days of application (127, 135). It starts about 5 min after each
33 application of the drug and may last up to 1 h, but intensity and duration typically disappear
34 within few days (147). Some patients experience a transient worsening of skin conditions.
35 These side effects are more common with tacrolimus ointment than with pimecrolimus
36 cream and when they are applied on acutely inflamed skin. In some patients they are severe
37 enough to induce prompt treatment discontinuation. Initial treatment with topical
38 corticosteroids should thus be considered in patients with acute flare to minimize these site
39 reactions (108).
40 Generalized viral infections such as eczema herpeticum or eczema molluscatum have been
41 observed during topical calcineurin inhibitor treatment (148, 149), but a high number of
42 clinical trials failed to demonstrate an increased frequency or showed only a transient
43 increase (reviewed in (150-153)). In contrast to corticosteroids, none of the topical
1 calcineurin inhibitors induces skin atrophy (154, 155). This favours their use over topical
2 corticosteroids in delicate body areas such as the eyelid region, the perioral skin, the genital
3 area, the axilla region or the inguinal fold and for topical long-term management. Clinical
4 and preclinical data do not indicate an increased risk of lymphoma (156). In contrast, severe
5 AE as such may carry an independent significant risk for lymphoma (156). The use of topical
6 calcineurin inhibitors is also not associated with increased risk of non-melanoma skin
7 cancer, other malignancies or photocarcinogenicity (142, 157-161). However, given that the
8 long-term use of cyclosporine is associated with an increased photocarcinogenicity risk in
9 solid organ transplant patients, UV protection e.g. with sunscreens has been advised (3).
10 The use of topical calcineurin inhibitors under wet wraps or on erosive lesions may increase
11 systemic absorption.
12 Clinicians should be aware of the black-box warning on the use of topical calcineurin
13 inhibitors, and may discuss this with patients to improve adherence.
14
16 TCI have a significant effect compared to vehicle in short-term and long-term treatment of
17 AE. (1b)
18 Tacrolimus 0,1% ointment is more potent than pimecrolimus cream. (1b)
19 Tacrolimus ointment and to lesser extent pimecrolimus cream may cause burning sensation
20 and transiently worsen AE especially when given on acutely inflamed skin. (1a)
21 TCI do not cause skin atrophy, glaucoma or cataract. (1a)
22 Recommendations
23 Topical calcineurin inhibitors (TCI) are important anti-inflammatory drugs to be used in AE.
24 (-, D)
25 Instead of treating acute flares with TCI, initial treatment with topical corticosteroids before
26 switching to a TCI should be considered. (-, D).
27 TCIs are especially indicated in sensitive skin areas (face, intertriginous sites, anogenital
28 area). (1b, A)
29 Proactive therapy with twice weekly application of tacrolimus ointment may reduce relapses.
30 (1b, A)
31 Effective sun protection should be recommended in patients treated with TCI. (-, D)
32
33 Upcoming topical therapies
34 Topical selective phosphodiesterase 4 inhibitors
35 Crisaborole is a topical phosphodiesterase 4 inhibitor effective in the treatment of AE
36 lesions, which has recently been approved for treatment of mild to moderate AE in patients
37 2 years of age and older in the United States of America (162, 163). Study data published
38 have focused on treatment of individual skin lesions using global eczema scores, as well as
39 on safety aspects, but do not include SCORAD data or EASI data of the patients treated.
1 From the published data of the global scores and the individual items of an eczema score,
2 a relatively low efficacy of crisaborole is probable (162). The efficacy of crisaborole is
3 significantly higher than the efficacy of its vehicle. However, the efficacy of crisaborole in
4 comparison to TCI or TCS is difficult to determine. Crisaborole ointment is currently not
5 licensed in Europe.
6 Other topical phosphodiesterase 4 inhibitors under investigation include OPA-15406 and
7 E6005 (164, 165).
8
9 Topical Janus-Kinase (JAK) inhibitors
10 First promising phase II clinical trial data with the topical JAK- inhibitor tofacitinib have been
11 published (166), but the topical development program was halted. Further similar
12 compounds are in the pipeline for topical as well as for systemic therapy, but none is
13 currently licensed in Europe.
1 Phototherapy
2
3 As most patients affected by AE improve during the sunny summer season, artificial UV
4 radiation is frequently employed in the treatment of AE. On the contrary, a small group of
5 patients will exacerbate following UV radiation.
6 A recent study has confirmed that 74% of patients affected by mild-moderate AE had
7 complete resolution during summer holidays, 16% had improvement and only 9% had no
8 modification of AE severity, confirming the seasonality of the disease, with improvement
9 during summertime and worsening in the other seasons: Seaside holidays produced a
10 significantly greater improvement than mountains holidays, with complete resolution of the
11 disease in 91% versus 11% of patients (P<0.01)(167). While this difference cannot be
12 explained on the sole basis of UV exposure, these data support the hypothesis on the
13 positive effect of UV radiation on AE.
14
15 Photobiology of AE treatment
16 Various pathways and means through which the energy of UV radiation from natural or
17 artificial sources is ultimately transformed into biologic effects within the skin have been
18 suggested, including cutaneous sensory nerves, neuropeptides, neurotrophins, and certain
19 nerve-related receptors (168). In general the effects of UV-light sources on the skin act
20 immunosuppressive, immunomodulating, anti-inflammatory as well as antipruritic, which is
21 obviously an overlapping effect. The known mechanisms of action target immunomodulation
22 through apoptosis of inflammatory cells, inhibition of Langerhans cells and alteration of
23 cytokine production (169). In addition, UV has an antimicrobial effect reducing the
24 colonization of S. aureus, (170) due to its anti-inflammatory effect and improves skin barrier
25 (171). A different explanation could be supported by the role of Vitamin D: a recent study
26 demonstrated that a 2-week course of heliotherapy significantly improved vitamin D balance
27 by increasing serum calcidiol concentration, and caused a marked healing of AE (172).
28 Suppression of Th2 associated cytokines such as IL-5, 13 and 31 have been observed under
29 UVA1 therapy (169). Induction of apoptosis of T-helper cells most probably are related to
30 generation of reactive oxygen species (ROS) (173, 174). Depletion and loss of function of
31 antigen-presenting cells within the epidermis and dermis support immunosuppression via
32 UV light source. Reduction of ICAM1 expression on keratinocytes has been observed and
33 further enhanced via IL-10 induced reduction of γ-IFN (175, 176).
34
35 Light sources and current treatment regimen for AE
36 Heliotherapy uses the exposure to natural sun light under controlled conditions and is part
37 of the therapeutic treatment in so called “climate therapy” at low altitude (Dead Sea)
38 predominantly with UVA (177), at sea level or at high altitude (e.g. Davos) with
39 predominantly UVB (178). The dose in heliotherapy is slowly increased by increasing the
40 time of sun exposure in moderate increments.
1 The following alternative modalities of UV treatment have been used in AE: UVB (mostly
2 narrowband (NB-UVB) of 311-313 nm and less frequently broadband (BB-UVB), UVA
3 (especially UVA1 of 340-400 nm), combined UVAB, and photochemotherapy where UV can
4 be combined with previous oral or topical administration of photosensitizing drugs such as
5 psoralens - the PUVA photochemotherapy regimen, but the long-term risks of skin cancer
6 noted in psoriasis have drastically limited this modality in Europe. In contrast, classical
7 broad-spectrum UVB phototherapy does not show increased risk for BCC and SCC (179,
8 180).
9 Other light therapies have been introduced. Short wave visible light (> 380 nm) (“Blue light”)
10 may have some effects, as indicated in uncontrolled pilot studies (181). There are no
11 controlled studies for this modality. Photopheresis is used in some centers for treatment of
12 selected cases. Positive effects in patients with severe refractory AE have been described.
13 Other devices such as 308 nm monochromatic excimer laser expand the therapeutic options
14 in patients with localized and therapy-resistant AE even though they can treat only limited
15 surfaces (182, 183). Pulsed-dye laser for the treatment of chronic AE is still experimental
16 (184).
17 Currently the mainstay for phototherapy in Europe is NB-UVB and UVA1. Following
18 concerns relative to PUVA, long-term risks of UV-light therapies have to be considered in
19 particular in children and even more in adults who have received systemic
20 immunosuppressants. Until now, no clinical studies have shown an increase of non-
21 melanoma skin cancer with NB-UVB and UVA1 (185, 186).The benefit/risk ratio of UVA1
22 medium-high dose (>20-70 J/cm2) is considered as better than that of high or low dose (187-
23 190). Comparison of middle-high UVA1 and NB-UVB does not show significant differences
24 with regard to efficacy and tolerability.
25 Taking into account the individual tolerability, NB-UVB has been indicated for chronic
26 moderate forms of AE (191) and is currently preferred to BB-UVB because it is less
27 erythemogenic, while high dose UVA1 has been prescribed for more severe phases (192).
28 Furthermore, as highlighted in a recent study, there is a small but significant proportion of
29 psoriasis and AE patients who do not tolerate NB-UVB but demonstrate an excellent clinical
30 response to BB-UVB (193).
31
32 Practical aspects of AE treatment
33 In practice, the choice of a certain UV treatment is limited by the availability of the
34 phototherapy equipment: e.g. UVA1 devices are expensive to buy and to maintain. The
35 biggest drawbacks of UV therapy are that the patient must travel between 3 and 5 times per
36 week and for 6-12 weeks to a site that offers this therapy. In addition, UV light does not
37 effectively treat hairy areas as scalp and skin folds. As a rule, phototherapy is not indicated
38 in the acute stage of AE (except UVA1, which is also effective in managing AE flares), but
39 is more apt to treat chronic, pruritic, lichenified forms and should not be prescribed in those
40 patients who experience a worsening of AE during sun exposure.
41 At the beginning of phototherapy, a co-medication of topical steroids and emollients should
42 be considered to prevent a possible flare-up. UV therapy has to comply with special
1 requirements with regard to personnel, documentation, UV protection especially of the eyes,

2 contraindications and technical aspects.
3 In practice, when prescribed, phototherapy is usually a part of a total treatment plan, i.e. a
4 second-level treatment used especially in adults and much less in children. Phototherapy
5 can improve and even clear AE; it can decrease bacterial colonization and reduce the
6 strength and/or the amount of topical anti-inflammatory drugs needed, but the beneficial
7 effects vary from person to person.
8
10 Narrow-band UVB has a better safety and efficacy profile compared to broad-band UVB.
11 (1a)
12 Medium-dose UVA1 is similar in efficacy to narrow-band UVB. (1b)
13 High-dose UVA1 is more effective in severe phases of AE. (1b)
14 All UV treatments pose theoretically a long-term risk for development of skin aging and skin
15 cancer, which is best demonstrated for PUVA. (2a)
16 New devices such as 308 nm excimer laser or visible blue light therapy may expand
17 therapeutic options, but have not been assessed properly in AE. (-)
18 Recommendations
19 Medium-dose UVA1 and narrow-band UVB are recommended for treatment of AE in adult
20 patients. (1b, A)
21 Narrow-band UVB is preferred over broad-band UVB for AE treatment if available. (1a, A)
22 Co-treatment with topical steroids and emollients should be considered at the beginning of
23 phototherapy to prevent flare-up. (C)
24 PUVA therapy is not a first choice therapy for safety profile reasons. (1b, A)
25 New devices such as 308 nm excimer laser are not recommended for treatment of AE
26 patients. (-,D)
27 Though phototherapy is rarely used in pre-pubertal children, it is not contraindicated; its use
28 depends rather on feasibility and equipment (NB-UVB). (-,D)
1 Anti-pruritic therapy
2
3 Itch is the most important clinical symptom in AE, with particular impact on emotional
4 dimensions of perception as compared to other pruritic dermatoses (194, 195). Concerning
5 pruritus accompanying AE, only few studies investigated the antipruritic effect only. Pruritus
6 was in most studies part of the total symptom score, such as in SCORAD or PO-SCORAD
7 (4, 6). For example, topical and systemic corticosteroids, topical calcineurin inhibitors,
8 cyclosporine and UV-irradiation have significant influence on pruritus while only single
9 studies specifically investigated the relief of pruritus intensity.
10 Antipruritic therapy in AE is multidimensional treating the symptom itself, the contributing
11 factors such as dry skin, inflammation and the related scratch lesions. Therefore, several
12 general measures can also be recommended (see: “Basic Therapy” and “Psychosomatic
13 counseling”).
14
15 Topical Therapy
16 Glucocorticosteroids
17 Topical corticosteroids have anti-inflammatory activity rather than acting as direct anti-
18 pruritic agents (196). However, several studies described the anti-inflammatory effect of
19 topical corticosteroids in AE, in which pruritus was one parameter among others studied.
20 Recent meta-analysis revealed 6 RCT with topical corticosteroids (desonide hydrogel
21 0.05%, clobetasole propionate lotion, fluticasone propionate 0.05% cream, prednicarbate
22 0.25% ointment, hydrocortisone 1% and methylprednisolone aceponate 0.1% cream) and
23 showed that those agents significantly reduce itch in AE patients by 34% in comparison to
24 the vehicle usage (197). Topical corticosteroids have a rapid antipruritic effect and can also
25 be used in “proactive” therapy (108).
26 Calcineurin inhibitors
27 Topical calcineurin inhibitors relieve significantly pruritus in AE. Itch is completely relieved
28 after the first days of treatment both in adults and children. 22 RCTs were meta-analysed
29 (16 – pimecrolimus 1% cream, 3 – tacrolimus 0.3% ointment, 1 – tacrolimus 0.1% ointment,
30 1 – tacrolimus 0.03% and 1- tacrolimus 0.01% ointment). Topical calcineurin inhibitors
31 appeared to reduce AE itch significantly by 36% compared to vehicle application (197).
32 Pimecrolimus blocks via TRPV1 the re-accumulation and synthesis of substance P (SP), a
33 major mediator of pruritus in inflammatory skin lesions.
34 Antihistamines
35 5% doxepin cream exhibited antipruritic effects in 3 controlled studies in AE; one RCT
36 assessed the efficacy of cromoglycate 4% lotion (197). The meta-analysis of those studies
37 documented that the use of topical antihistamines markedly reduced itch of AE by 27% in
38 patients in comparison to the vehicle. However, topical doxepin therapy is not licensed and
39 not used in any European country due to an increased risk of contact allergy, especially
40 when the treatment exceeds eight days.
1 Cannabinoid receptor agonist

2 Topical cannabinoid receptor agonists have been described to exhibit antipruritic and
3 analgesic properties. One cosmetic product containing the cannabinoid agonist N-
4 palmitoylethanolamin was used in a multicenter, large cohort, open label study as adjuvant
5 treatment in AE (74). 2456 patients including over 900 children applied the cream twice
6 daily. Pruritus and the need to use corticosteroids were reduced up to 60%.
7 Opioid receptor antagonists
8 One double-blind, vehicle-controlled, randomized cross-over trial was performed with topical
9 μ-opioid receptor antagonist nalmefene. The drug was used during two 7-days periods
10 separated by the wash-out period. The study did not show significant efficacy in reducing
11 the itch intensity in AE (198).
12 Polidocanol
13 Case series described the efficacy of a combination of the anaesthetic polidocanol and 5%
14 urea (199). In children with AE, the combination showed a pruritus improvement of 30% in
15 comparison with an emollient (200). Polidocanol is not licensed for AE in Europe, but OTC
16 products are available.
17 Anesthetics
18 Local anaesthetics such as benzocaine, lidocaine, as well as a mixture of prilocaine and
19 lidocaine are widely used as short-term effective topical antipruritics. In experimental
20 studies, the antipruritic effect of local anaesthetics was demonstrated in AE (201). None of
21 these substances is licensed for AE in Europe, but some OTC products are available.
22 Capsaicin
23 Capsaicin, is a naturally occurring alkaloid and the principal pungent of hot chilli peppers.
24 Capsaicin binds to the TRPV1 ion channel, which is present on many itch-mediating C-
25 fibers. Capsaicin has been advocated to be antipruritic in various dermatoses. Concerning
26 AE, experimental studies (202) and case series (203) report on clear itch reduction. No
27 controlled study has been published.
28
30 There is evidence that topical corticosteroids are effective in the initial phase of AE
31 exacerbation to control pruritus. (1a)
32 There is evidence that topical calcineurin inhibitors are effective in AE until clearance of
33 eczema to control pruritus. (1a)
34 There is not enough RCT evidence to demonstrate the efficacy of topical antihistamines,
35 including doxepin in the treatment of AE itch. (1a)
36 There is no evidence from RCTs that the topical cannabinoid receptor agonist N-
37 palmitoylethanolamin is effective as an adjuvant antipruritic therapy in AE. (4)
38 There is no evidence that the topical μ-opioid receptor antagonist nalmefene is effective in
39 the management of pruritus in AE. (2b)
1 There is no evidence that topical anaesthetics and capsaicin is an effective adjuvant

2 antipruritic therapy in AE. (4)
3 Recommendations
4 Topical corticosteroids are recommended to control pruritus in the initial phase of AE
5 exacerbation. (1a,A)
6 Topical calcineurin inhibitors are recommended to control pruritus in AE until clearance of
7 eczema. (1a,A)
8 Topical polidocanol may be used to reduce pruritus in AE patients. (-,D)
9 Routine clinical use of topical antihistamines including doxepin, topical cannabinoid receptor
10 agonists, topical µ opioid receptor antagonists or topical anaesthetics, cannot be
11 recommended as an adjuvant antipruritic therapy in AE. (4,C)
12 There is not enough data available to recommend the use of capsaicin in management of
13 itch in AE patients. (4,B)
14
15 UV therapy
16 UV irradiation relieves pruritus in AE, which has been demonstrated in several studies. A
17 recent systematic review of 19 available RCTs suggests the usage of narrow-band UVB and
18 UVA1 as the most effective in the treatment of AE, including reduction of itch intensity (204).
19 There is no “anti-itch-specific” data for UV therapy available, which would differ from the
20 general recommendations for UV treatment of AE. (See chapter “UV therapy”).
21 Recommendations
22 There is evidence that UV-therapy can be used in AE to relief pruritus. Narrow-band UVB
23 and UVA1 seem to be most preferable treatment modalities. (2a,B)
24
25 Systemic therapy
26 Antihistamines
27 Antihistamines (AH) have been used for decades, in an attempt to relieve pruritus in patients
28 with AE. However, only a few randomized controlled trials have been conducted and they
29 have in the majority shown only a weak or no effect in decreasing pruritus (205-213).
30 According to a Cochrane search, randomized controlled trials investigating the efficacy of
31 AH monotherapy in eczema patients are lacking (214).
32 The first generation of sedative AH such as hydroxyzine, clemastine fumarate and
33 dimethindene maleate may allow a better sleep in acute situations with exacerbations of
34 eczema (evidence level D). A significant, but clinically small, antipruritic effect of
35 fexofenadine 60 mg twice daily has been described (215). An effect on itch of a high dosage
36 of 20 to 40 mg cetirizine daily has been observed, but this effect was primarily attributed to
37 sedation (211). In the recent meta-analysis of antipruritics in AE (197) only one RCT study
38 on systemic AH fulfilled the criteria for inclusion and did not show significant improvement
39 of itch in comparison to placebo (211).
1 In general, AH are safe to use, also for a long period of time (216). There are limited
2 evidence-based data for the antipruritic effect of AH (H1-antagonists) in AE in general, and
3 the effect of both first and second generation AH on pruritus in patients suffering from AE is
4 very limited. AH may decrease urticaria when associated with AD, but this is rarely seen in
5 clinical reality. The ETAC pediatric cetirizine studies showed an effect of AH on food induced
6 urticaria (217). (See also chapter “Other systemic treatment”)
7 Apremilast
8 The oral inhibitor of phosphodiesterase 4 (PDE4) apremilast is discussed in part II of the
9 guideline (see chapter “other systemic treatment”).
10 Leukotriene receptor antagonists
11 The leukotriene receptor antagonists zafirlukast and zileuton are discussed in part II of the
12 guideline (see chapter “other systemic treatment”).
13 Opioid receptor antagonists
14 The µ-opioid receptor antagonist nalmefene was applied in controlled, randomized studies
15 in AE. A dosage of 10 mg and 20 mg each once per day showed significant relief of pruritus
16 in three studies (218-220). In open label trials and one double-blind, placebo-controlled
17 study trial, the only orally active µ-opioid antagonist naltrexone 25 - 150 mg per day showed
18 considerable antipruritic effects (221, 222). Common side effects include anxiety, arthralgia,
19 dizziness, drowsiness, fatigue, vomiting and headache. None of these substances is
20 currently licensed for treatment of AE itch.
21 Selective serotonin reuptake inhibitors
22 The antipruritic effect of the selective serotonin reuptake inhibitors paroxetin and fluvoxamin
23 was investigated in an open label trial in dermatological patients. A few patients with pruritus
24 due to AE were included, who responded with considerable reduction of pruritus. In these
25 patients, the pruritus was reduced about half in intensity (maximal antipruritic effect score,
26 45.0 +/- 7.1%) (223).
27 Cyclosporine A
28 See chapter “Systemic Immunosuppression”
29 Intravenous Immunoglobulin therapy
30 See chapter “Other systemic treatment”
31 Mycophenolate mofetil
32 See chapter “Systemic Immunosuppression”
33 Nemolizumab
34 See chapter “Biologics”
35
37 There is conflicting evidence regarding efficacy of antihistamines (H1-antagonists) for
38 treatment of pruritus in AE, with the majority of studies showing only a weak or no effect on
1 pruritus. Antihistamines in general, and especially second generation agents, show a good
2 safety profile. (1b)
3 The opioid receptor antagonists naltrexone and nalmefene may reduce itch in AE patients.
4 Common side effects include anxiety, arthralgia, dizziness, drowsiness, fatigue, vomiting
5 and headache. (1b)
6 The selective serotonin reuptake inhibitors paroxetine and fluvoxamine may be effective in
7 the treatment of AE-induced itch. Side effects include constipation, diarrhea, dizziness,
8 drowsiness, ejaculatory and erectile dysfunction, decreased libido, insomnia, nausea and
9 headache. (4)
10 Recommendations
11 There is not enough evidence to support the general use of both first and second generation
12 H1R-antihistamines for treatment of pruritus in AE. These may be tried for treatment of
13 pruritus in AE patients, if standard treatment with TCS and emollients is not sufficient. (1b,
14 A)
15 Long term use of sedative antihistamines in childhood may affect sleep quality and is
16 therefore not recommended. (-,D)
17 The opioid receptor antagonists naltrexone and nalmefene are not recommended for routine
18 treatment of itch in AE patients. (-,D)
19 The selective serotonin reuptake inhibitors paroxetine and fluvoxamine are not
20 recommended for routine treatment of itch in AE patients. (4,C)
1 Tables
2
3 Table 1 Grades of evidence
4
5 1a) Meta-analysis of randomized clinical trials (RCT)

6 1b) Single RCTs
7 2a) Systematic review of cohort studies
8 2b) Single cohort studies and RCTs of limited quality
9 3a) Systematic review of case control studies
10 3b) Single case control study
11 4) Case series, case cohort studies or cohort studies of limited quality
12 Recommendations (see Table 2) were classified based on the grade of evidence.
Table 2 Classification of strength of recommendation

Recommendation strength Evidence grade
A 1a, 1b
B 2a, 2b, 3a, 3b
C 4
D Expert opinion
Table 3 Language of recommendations

Wording in standard Free text explanation
situations
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 This intervention is not adequate for most patients,
patients only 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
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 skin atrophy initial burning/stinging initial burning/stinging
teleangiectasia teleangiectasia
striae distensae striae distensae
suitable for long term treatment sometimes no yes yes
suitable for proactive therapy yes yes yes* no
suitable for children > 2 years of age yes sometimes, see text yes* yes*
suitable for babies yes diluted use yes yes

< 2 years of age
suitable during pregnancy yes yes possible with possible with
strict indication strict indication
suitable during lactation yes yes possible with possible with
strict indication strict indication
 off label use * licensed use

Table 5: Upcoming topical drugs for treatment of atopic eczema

Substance Target Substance Development Registration Trial data Adverse drug Recommendation
code class phase status effect signals
Crisaborole AN2728 phospho- PDE4 blocker IV app. USA more effective application
diesterase 4 than vehicle, no site pain
comparative
study
OPA-15406 phospho- PDE4 blocker
diesterase 4
E6005 phospho- PDE4 blocker
diesterase 4
 see full text

PDE: phosphodiesterase; app: approved;
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41 antagonists in pruritic dermatoses. Allergy. 1998;53(2):180-3.
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43 atopic dermatitis. A multi-crossover-designed study. Allergy. 1994;49(1):22-6.
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47 antihistamine in atopic dermatitis. Br J Dermatol. 1990;122(4):545-51.
48 210. Munday J, Bloomfield R, Goldman M, Robey H, Kitowska GJ, Gwiezdziski Z, et al. Chlorpheniramine
49 is no more effective than placebo in relieving the symptoms of childhood atopic dermatitis with a nocturnal
50 itching and scratching component. Dermatology. 2002;205(1):40-5.
51 211. Hannuksela M, Kalimo K, Lammintausta K, Mattila T, Turjanmaa K, Varjonen E, et al. Dose ranging
52 study: cetirizine in the treatment of atopic dermatitis in adults. Ann Allergy. 1993;70(2):127-33.
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2 loratadine syrup in childhood atopic dermatitis treated with mometasone furoate 0.1 per cent cream. J
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5 plasma tryptase levels in adult atopic dermatitis. J Dermatol Sci. 2006;43(2):127-34.
6 214. van Zuuren EJ, Apfelbacher CJ, Fedorowicz Z, Jupiter A, Matterne U, Weisshaar E. No high level
7 evidence to support the use of oral H1 antihistamines as monotherapy for eczema: a summary of a
8 Cochrane systematic review. Syst Rev. 2014;3:25.
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10 topical corticosteroid reduces the pruritus associated with atopic dermatitis in a 1-week randomized,
11 multicentre, double-blind, placebo-controlled, parallel-group study. Br J Dermatol. 2003;148(6):1212-21.
12 216. Simons FE, Early Prevention of Asthma in Atopic Children Study G. Safety of levocetirizine treatment
13 in young atopic children: An 18-month study. Pediatr Allergy Immunol. 2007;18(6):535-42.
14 217. Simons FE. Prospective, long-term safety evaluation of the H1-receptor antagonist cetirizine in very
15 young children with atopic dermatitis. ETAC Study Group. Early Treatment of the Atopic Child. The Journal
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17 218. Monroe EW. Efficacy and safety of nalmefene in patients with severe pruritus caused by chronic
18 urticaria and atopic dermatitis. J Am Acad Dermatol. 1989;21(1):135-6.
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20 220. Banerji D, Fox R, Seleznick M, Lockey R. Controlled antipruritic trial of nalmefene in chronic urticaria
21 and atopic dermatitis. The Journal of allergy and clinical immunology. 1988;81:81: 252.
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23 antagonist, in the treatment of pruritus in internal and dermatological diseases. J Am Acad Dermatol.
24 1999;41(4):533-9.
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26 naltrexone on pruritus in atopic eczema: a double-blind, placebo-controlled study. Journal of the European
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28 223. Stander S, Bockenholt B, Schurmeyer-Horst F, Weishaupt C, Heuft G, Luger TA, et al. Treatment of
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30 open-labelled, two-arm proof-of-concept study. Acta dermato-venereologica. 2009;89(1):45-51.
1 Consensus based European Guidelines for Treatment of Atopic

2 Eczema (Atopic Dermatitis) in Adults and Children
3 Part II
4
5 Wollenberg A21, Barbarot S22, Bieber T23, Christen-Zaech S24, Deleuran M25, Fink-Wagner A26,
6 Gieler U27, Girolomoni G28, Lau S29, Muraro A30, Czarnecka-Operacz M31, Schäfer T32, Schmid-
7 Grendelmeier P33, Simon D34, Szalai Z35, Szepietowski JC36, Taïeb A37, Torrelo A38, Werfel T39,
8 Ring J40
9
10 For the European Dermatology Forum (EDF), the European Academy of Dermatology and
11 Venereology (EADV), the European Academy of Allergy and Clinical Immunology (EAACI), the
12 European Task Force on Atopic Dermatitis (ETFAD), European Federation of Allergy and Airways
13 Diseases Patients‘ Associations (EFA), the European Society for Dermatology and Psychiatry
14 (ESDaP), the European Society of Pediatric Dermatology (ESPD), Global Allergy and Asthma
15 European Network (GA2LEN) and the European Union of Medical Specialists (UEMS)
16
17 Correspondence to:
18 Prof. Dr. med. Dr. h.c. Andreas Wollenberg
19 Department of Dermatology and Allergology
20 Ludwig-Maximilian University
21 Frauenlobstr. 9-11, D-80337 Munich
22 Email: [email protected]
23
21
Department Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany and Klinik Thalkirchner Straße,
Munich, Germany
22 Department of Dermatology, Centre Hospitalier Universitaire CHU Nantes, Nantes, France
23Department of Dermatology and Allergy, and Christine Kühne-Center for Allergy Research and Education, University
Bonn, Bonn, Germany
24Pediatric Dermatology Unit, Departments of Dermatology and Pediatrics, Centre Hospitalier Universitaire Vaudois,
Lausanne, Switzerland
25 Department Dermatology, Aarhus University Hospital, Aarhus, Denmark
26EFA corporate Relations and Fundraising Manager and Co-Founder of GAAPP, Konstanz, Germany
27Dept. of Dermatology and Dept. of Psychosomatics and Psychotherapy, University of Gießen and Marburg GmbH,
Gießen, Germany
28 Department of Medicine, Section of Dermatology, University of Verona, Verona, Italy
29 Pediatric Pneumology and Immunology, Universitätsmedizin Berlin, Germany
30 Centro di Specializzazione Regionale per lo Studio e la Cura delle Allergie e delle Intolleranze Alimentari presso
l’Azienda Ospedaliera, Università di Padova, Italy
31 Department of Dermatology, Medical University, Poznan, Poland
32Dermatological Practice, Immenstadt, Germany
33Allergy Unit, Department of Dermatology, University of Zurich, Switzerland and Christine Kühne Center for Allergy
research and Educaction CK-CARE, Davos, Switzerland
34 Department Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
35 Department of Dermatology, Heim Pál Children's Hospital, Budapest, Hungary
36 Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland
37 Department of Dermatology & Pediatric Dermatology, Hôpital St André, Bordeaux, France
38 Department of Dermatology, Hospital Niño Jesus, Madrid, Spain
39 Department Dermatology and Allergy, Hannover Medical School, Hannover, Germany
40
Department Dermatology and Allergy Biederstein, Technische Universität München, Munich, Germany and Christine
Kühne-Center for Allergy Research and Education (CK-CARE), Davos
1 Declaration of Conflict of Interest

2
3 A. Wollenberg has been an advisor, speaker or investigator for ALK Abelló, Almirall, Anacor,
4 Astellas, Beiersdorf, Bencard, Bioderma, Chugai, Galderma, Glaxo SmithKline, Hans Karrer, LEO
5 Pharma, L’Oreal, Maruho, MedImmune, Novartis, Pfizer, Pierre Fabre, Regeneron and Sanofi.
6
7 S.Barbarot has been an advisor, speaker or investigator for Bioderma, La Roche Posay, Sanofi-
8 Genzyme, Novalac, Ferring, Abbvie, Novartis, Janssen.
9
10 T. Bieber has been advisor, speaker or investigator for Abbvie, Allmirall, Anacor, Astellas, Bayer,
11 Celgene, Chugai, Daiichi-Sankyo, Galderma, Glaxo SmithKline, Leo Pharma, Novartis, Pfizer,
12 Pfizer, Pierre-Fabre, LÓréal, La Roche-Posay, Regeneron, and Sanofi.
13
14 S. Christen-Zaech has been an advisor, speaker or investigator for Galderma, L’Oreal, La
15 RochePosey, Pierre Fabre, Permamed, Procter and Gamble, and Sanofi-Genzyme.
16
17 M. Deleuran has been an advisor, speaker or investigator for AbbVie, Leo Pharma, MEDA, Pierre-
18 Fabre, LÓréal, La Roche-Posay, Pfizer, Regeneron and Sanofi.
19
20 A. Fink-Wagner has been working with, or an advisor or speaker for ALTANA, Novartis, Nycomed,
21 Hoffmann-La Roche and Teva.
22
23 U. Gieler has been has been advisor or speaker for Allmirall, Astellas, Bayer, Celgene, Galderma,
24 Glaxo SmithKline, Leo Pharma, Lilly, Novartis, Pfizer, Pierre-Fabre, La Roche-Posay and Sanofi -
25 Aventis.
26
27 G. Girolomoni has been an advisor, speaker or investigator for AbbVie, Abiogen, Allmirall, Amgen,
28 Bayer, Biogen, Boehringer Ingelheim, Celgene, Eli-Lilly, Galderma, Hospira, Janssen, Leo Pharma,
29 Menlo therapeutics, Merck, MSD, Mundipharma, Novartis, Otsuka, Pfizer, Pierre Fabre, Regeneron,
30 Sandoz, Sanofi and Sun Pharma
31
32 S. Lau has received grants from Allergopharma and Symbiopharm, and a honorarium from Merck
33 as member of a drug monitoring committee, ALK and DBV Technologies.
34
35 A. Muraro has has been a speaker for Meda, Nestlè and Stallergenes.
36
37 M. Czarnecka-Operacz has been an advisor, speaker or investigator for Allergopharma, Allmiral,
38 Bioderma, Berlin Chemie, Mennarini, Novartis, Pierre Fabre, Galderma, Janssen and Leo Pharma.
39
40 T. Schäfer has been speaker for Abbott, Bencard, Dr Pfleger, Norvatis and Syneron-Candela.
41
42 P. Schmid-Grendelmeier has been an advisor or speaker for ALK-Abello, Allergopharma, La Roche-
43 Posay, MEDA, Novartis, Sanofi and Stallergenes.
44
45 D. Simon has been an advisor, speaker or investigator for Roche, Novartis, Galderma, Glaxo
46 SmithKline, Merz Pharma (Schweiz), Almirall, Sanofi, and Eli Lilly.
47
48 Z. Szalai has been advisor for Pfizer, speaker or investigator for Bayer, Novartis, Pierre Fabre,
49 Sanofi, Leo.
50
51 J.C. Szepietowski has been a Consutant and Advisor for AbbVie, Celgene, Dignity Sciences, Leo
52 Pharma, Novartis, Pierre-Fabre and Sandoz; Investigator for AbbVie, Actelion, Amgen, GSK,
53 Janssen, Merck, Novartis, Regereron, Takeda, Trevi; Speaker for AbbVie, Actavis, Astellas,
54 Janssen, Leo Pharma, Novartis, SunFarm, Sandoz, Eli Lilly.
55
56 A. Taïeb has been an advisor for Anacor, Bioderma, Chugai, Galderma, Roche and Pierre Fabre.
1
2 A. Torrelo has been advisor, speaker or investigator for AbbVie, Anacor, Astellas, Bayer, Beiersdorf
3 AG, Galderma, Meda, Novartis, Pierre Fabre.
4
5 T. Werfel has received support for research projects from AbbVie, Astellas, Janssen/JNJ, Meda,
6 Regeneron/Sanofi, Takeda, Ziarco, and has been an advisor for AbbVie, Allmiral, LEO Pharma, Lilly,
7 MSD, Novartis, Regeneron/Sanofi, Roche, Stallergen and Ziarco.
8
9 J. Ring has been advisor, speaker or investigator for ALLERGIKA, ALK Abello, Almirall-Hermal,
10 Anacor, Astellas, Bencard/Allergy Therapeutics, Galderma, GSK-Stiefel, LEO Pharma, Meda, MSD,
11 Novartis, Phadia-ThermoFisher, and Sanofi.
12
1 List of Abbreviations
2 AAD American Academy of Dermatology
3 AD Atopic dermatitis
4 AE Atopic eczema
5 AEGIS 3-trimethylsilylpropyl-dimethyloctadecyl ammonium chloride
6 AH Antihistamines
7 AGREE Appraisal of Guidelines Research and Evaluation
8 APT Atopy patch test
9 ASIT Allergen-specific Immunotherapy
10 AZA Azathioprine
11 BB-UVB Broadband ultraviolet B
12 BCC Basal Cell Carcinoma
13 BO Borage oil
14 CAM Complementary alternative medicine
15 CAP-FEIA CAP Fluorescence Immunoassay
16 CHM Chinese herbal medicine
17 DBPC Double-blind placebo-controlled
18 DBPCFC Double-blind placebo-controlled food challenge
19 DHA Docosahexaenoic acid
20 EADV European Academy of Dermatology and Venereology
21 EASI Eczema Area and Severity Score, a signs score
22 EAT Enquiring About Tolerance
23 EC Eczema coxsackium
24 EC-MPS Enteric-coated mycophenolate sodium
25 EDF European Dermatology Forum
26 EFA European Federation of Allergy and Airways Diseases Patients‘
27 Associations
28 EH Eczema herpeticum
29 EPO Evening primrose oil
30 ETFAD European Task Force on Atopic Dermatitis
31 EU European Union
32 EV Eczema vaccinatum
33 FA Food allergy
34 FTU Fingertip unit
35 GAAPP Global Allergy and Asthma Patient Platform
36 HBD Human-ß-defensin
37 HDM House Dust Mite
38 HTA Health Technology Assessment
39 H1R Histamin 1 receptor
40 IA Immunoadsorption
41 ICAM1 Intercellular Adhesion Molecule 1
42 IGA Investigators Global Assessment, a signs score
43 IgE Immunoglobulin E
44 IgG Immunoglobulin G
45 IL Interleukin
46 IVIG Intravenous immunoglobulins
47 IFN-α Interferon alpha
48 IFN-ƴ Interferon gamma
1 JAK Janus kinase

2 LEAP Learning Early About Peanut Allergy
3 LTC4 Leukotriene C4
4 LTD4 Leukotriene D4
5 LTE4 Leukotriene E4
6 MCV Molluscum contagiosum virus
7 MMF Mycophenolat Mofetil
8 MTX Methotrexate
9 mTLSS modified Total Lesion Symptom Score
10 NB-UVB Narrow band Ultraviolet B
11 OFC Oral food challenge
12 OTC Over the counter
13 PDE 4 Phosphodiesterase 4
14 PE Patient education
15 PO-SCORAD Patient-oriented Scoring of Atopic Dermatitis
16 PUVA Psoralen and ultraviolet A
17 RCT Randomized controlled trial
18 ROS Reactive oxygen species
19 SASSAD Six Area Six Signs Atopic Dermatitis score
20 SCC Squamous Cell Carcinoma
21 SCIT Subcutaneous Immunotherapy
22 SCORAD Scoring of Atopic Dermatitis, a composite score
23 SLIT Sublingual Immunotherapy
24 SPT Skin prick test
25 TCI Topical calcineurin inhibitors
26 TCS Topical corticosteroids
27 TPMT Thiopurine methyltransferase
28 TSH Thyroid-stimulating hormone
32 UV-light Ultraviolet light
33 VOCs Volatile organic compounds
34 VZV Varicella-zoster Virus
35 QoL Quality of life
36 TSLP Thymic stromal lymphopoietin
37
1 Abstract
2
3 The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) was evaluated
4 using the national standard Appraisal of Guidelines Research and Evaluation (AGREE). The
5 consensus process consisted of a nominal group process and a Delphi procedure. This
6 second part of the guideline covers antimicrobial therapy, systemic treatment, allergen
7 specific immunotherapy, complementary medicine, psychosomatic counselling and
8 educational interventions, whereas the first part covers methods, patient perspective,
9 general measures and avoidance strategies, basic emollient treatment and bathing, dietary
10 intervention, topical anti-inflammatory therapy, phototherapy and antipruritic therapy.
11 Management of AE must consider the individual clinical variability of the disease. Systemic
12 immuno-suppressive treatment with cyclosporine, methotrexate, azathioprine and
13 mycophenolic acid are established options for severe refractory cases, and widely available.
14 Biologicals targeting the T helper 2 pathway such as dupilumab may be a safe and effective,
15 disease modifying alternative when available. Oral drugs such as JAK inhibitors and
16 Histamin4 receptor antagonists are in development. Microbial colonization and
17 superinfection may cause disease exacerbation and can require additional antimicrobial
18 treatment. Allergen-specific immunotherapy with aeroallergens may be considered in
19 selected cases. Psychosomatic counselling is recommended especially in stress-induced
20 exacerbations. Therapeutic patient education (“Eczema school”) is recommended for
21 children and adult patients.
22 General measures, basic emollient treatment, bathing, dietary intervention, topical anti-
23 inflammatory therapy, phototherapy and anti-pruritic therapy have been addressed in the
24 first part of the guideline.
25
26 Key words: Atopic eczema, atopic dermatitis, management, therapy, guideline
1 Table of contents
2
3 Part I
4 Introduction
5 Method of guideline formation
6 Patient perspective
8 Basic emollient treatment and bathing
11 Phototherapy
12 Antipruritic therapy
13
14 Part II
18 Allergen specific immunotherapy
19 Complementary medicine
20 Psychosomatic counselling
22 Conclusion and future options
23
2
3 In patients with AE, the inflammatory micro-milieu initiated by TSLP, IL-4 and IL-13 may
4 downregulate the cutaneous antimicrobial peptides such as cathelicidin LL-37, dermcidin,
5 human β-defensins HBD-1, HBD-2, and HBD-3 (1, 2). This is one of the reasons why these
6 patients are more susceptible to secondary skin infections, which tend to generalize (2). The
7 understanding of colonization and infection in AE has largely increased by structured
8 investigation of the human microbiome in the context of AE. Flares of AE are significantly
9 associated with a S. aureus-caused loss of diversity in the cutaneous microbiome, which is
10 not significant if patients have followed a proactive therapy regimen before the flare (3).
11
12 Anti-bacterial
13 In up to 90% of AE patients even the normal looking skin is extensively colonized by
14 Staphylococcus aureus. This bacterium is a major trigger of AE, as it leads to inflammation
15 through the release of superantigen toxins, which enhance T cell activation of superantigen
16 specific and allergen-specific T cells, expression of IgE anti-staphylococcal antibodies and
17 as it increases expression of IL-31 which leads to pruritus (4). Scratching favors binding of
18 S. aureus to the skin, and the increased amount of S. aureus derived ceramidase
19 aggravates the skin barrier defect. Moreover, superantigen production increases expression
20 of alternative glucocorticoid receptors that do not bind to topical corticosteroids, which leads
21 to resistance (5). Biofilm formation by AE-associated staphylococci most certainly also plays
22 a major role in the occlusion of sweat ducts and leads to inflammation and pruritus (6).
23 Recent investigations have shown that besides S. aureus the dysbalance of skin microbiome
24 may play an important role in AE pathophysiology (7, 8). New developments in emollients
25 are the incorporation of active compounds that repair the barrier function or influence the
26 microbiome of AE with bacterial lysates from Aquaphilus dolomiae or Vitreoscilla filiformis
27 species (9). A better understanding of the skin microbiome in AE is a promising direction for
28 the development of new treatment strategies.
29 A systematic review of 26 studies including 1229 participants showed no clear beneficial
30 evidence of antiseptic bath additives or soaps, or of antimicrobial agents added to topical
31 therapies in non-infected atopic dermatitis. Nevertheless, if there is no response to topical
32 glucocorticosteroids or calcineurin inhibitors, or evident infection, the use of topical
33 antiseptics can be considered, and these are preferred over topical antibiotics with regard
34 to the development of bacterial resistance (10). Sodium hypochlorite 0.005% is not only
35 antiseptic but enhances epidermal thickness and proliferation (11). Its intermittent use
36 showed a significant decrease of AE severity (12). Systemic antibiotics should only be used
37 in case of apparent and extensive bacterial superinfection. On the basis of current resistance
38 spectra, cephalexin, or another first-generation cephalosporin can be recommended.
39 Children with AE seem to have a much lower rate of community-acquired methicillin resistant
40 S. aureus infection compared to the general pediatric population (13). In any case treatment
41 with emollient and corticosteroids or topical calcineurin inhibitors should be continued.
1 Underestimated sources of bacteria are cream and ointment containers, of which up to 53%
2 are contaminated, up to 25% with S. aureus. Thus the following recommendations seem to
3 be useful (14): 1.) Keep open moisturizers in refrigerator; 2.) Use pumps or pour bottles
4 rather than jars; 3.) Avoid direct contact with hands and decant; 4.) Avoid sharing personal
5 hygiene items.
6 Antimicrobial textiles
7 Silver-impregnated textiles have shown significant antimicrobial activity, as well as
8 improvement of localized SCORAD in an unblinded, side-to-side controlled clinical trial (15).
9 In patients with uninfected AE, the use of silver impregnated textile compared to cotton
10 underwear did not reduce AE severity (16-18). However, some functional textiles (silver-
11 coated, acid-coated and silk textiles) as well as Chitosan, a natural biopolymer with
12 immunomodulatory and antimicrobial properties, may possibly improve AE manifestations,
13 as they decrease skin colonization by S. aureus, and they reduce itch (19). Some of these
14 newer options are still under investigation and there seem to be some concern about the
15 safety of silver-coated textiles in infants and toddlers. AEGIS-coated silk textiles did not
16 show clinical benefit in a well-controlled, multicenter clinical trial (20).
17
18 Anti-viral
19 Viral infections including herpes simplex, varicella zoster, molluscum contagiosum, smallpox
20 and coxsackie viruses occur more frequently in AE patients than in healthy individuals, with
21 a tendency to disseminated, widespread disease (21).
22 Eczema herpeticum (EH), a disseminated herpes simplex virus infection, is a potentially
23 serious complication of AE that requires immediate medical action. Patients, mostly children,
24 present with disseminated vesicles, fever and lymphadenopathy and can develop
25 complications such as keratoconjunctivitis, meningitis and encephalitis. Predisposing factors
26 of EH are early onset of AE, severe or untreated forms of AE, filaggrin deficiency and high
27 total serum-IgE level (21). Pre-treatment with topical corticosteroids does not seem to imply
28 an increased risk of developing EH whereas topical calcineurin inhibitor may do so and
29 should be discontinued immediately (22). Mainstay of EH therapy is a systemic treatment
30 with aciclovir or valaciclovir, in a majority of cases administrated intravenously (23).
31 Treatment should be started immediately once the clinical diagnosis is made (24).
32 Varicella-zoster virus (VZV) infection in an immunocompetent child is usually a mild, self-
33 limited disease. This infection is, however, known to facilitate secondary local or systemic
34 bacterial infection, which is cause for particular concern in AE children. Earlier studies
35 demonstrated the safety and efficacy of VZV vaccination in these children who appear to
36 benefit from this vaccination (25). Moreover, in children with AE, common childhood
37 immunization in the first year is not associated with an increased risk of more severe AE or
38 allergic sensitization; also immune response to VZV vaccine is comparable to healthy
39 children (26). Therefore parents of atopic children should be encouraged to fully immunize
40 their children.
41 Molluscum contagiosum virus (MCV) infection is in general benign and self-limited, but in
42 patients with AE dissemination is frequent and therefore treatment is recommended. A large
1 variety of topical treatments have been reported such as cantharidin, potassium hydroxide,
2 tretinoin cream, topical cidofovir, and others (27). Physical therapies including cryotherapy
3 and curettage are also effective, but not always well tolerated in pediatric patients (28).
4 Topical treatment of AE with TCS may be continued during MCV infection.
5 Eczema vaccinatum (EV) is a complication of smallpox vaccination known to occur in AE
6 patients. The vaccinia virus disseminates and causes an extensive rash and severe
7 systemic illness with a mortality rate estimate at 5-40% (29). Therefore smallpox vaccination
8 is contraindicated in patients with a history of or currently active AE (30). The existence of
9 an attenuated vaccine and three antiviral drugs, in addition to vaccinia immunoglobulin,
10 provides means of preventing or treating EV (31, 32). Should a smallpox outbreak
11 necessitate an emergency mass vaccination, the choice of vaccination strategies, such as
12 ring or mass vaccination, has to be determined by policymakers.
13 Eczema coxsackium (EC) is a disseminated form of coxsackie virus infection mostly
14 occurring in children with active AE lesions. The coxsackie virus A6 strain leads to atypical
15 disease manifestations, which are classified as diffuse form (lesions extended to the trunk),
16 acral form (lesions with a mainly acral distribution), or eczema coxsackium (disseminated
17 lesions on preexisting eczematous areas) (33). Symptomatic treatment includes use of
18 topical steroids and wet wrap therapy (34, 35).
19 Regional vaccination programs should be followed by all AE patients as recommended. The
20 denial of vaccination because of diagnosed AE is a misconception possibly leading to fatal
21 consequences (see chapter: general measures).
22
23 Anti-fungal
24 Despite its role as a commensal on healthy human skin, Malassezia spp. is attributed a
25 pathogenic role in AE, as it may interact with the local skin immune response and barrier
26 function. The precise mechanisms by which Malassezia spp. may contribute to the
27 pathogenesis of AE are not fully understood and remain to be elucidated (36). Several
28 randomized, placebo controlled trials investigated the benefit of topical or systemic
29 antifungal treatment for AE patients (37, 38). The ambiguous results of these clinical trials
30 might be attributed to a selection bias. It can be speculated that antifungal therapies are
31 more effective in certain subgroup of AE. It seems for example that antifungal therapy shows
32 beneficial effects in patients with a head-neck-type distributed AE and detectable IgE-
33 mediated sensitization against Malassezia (39). It has also been shown that sensitization
34 against this skin-colonizing yeast can correlate with disease activity (40). The most common
35 class of antifungal drugs prescribed for AE patients are azoles such as ketoconazole and
36 itraconazole which have also some anti-inflammatory properties (38). Due to a better benefit
37 side effect ratio imidazole derivates (fluconazole or itraconazole) should be prescribed
38 instead of ketoconazole for systemic treatment. In summary, antifungal treatment with either
39 topical ketoconazole or ciclopiroxolamine or systemic itraconazole or fluconazole can be
40 considered for those patients who suffer from head–neck dermatitis, particularly for those
41 who are characterized by clear IgE-sensitization to Malassezia spp.
42
2 Oral antibiotics have no benefit on the skin condition in AE as long as skin lesions are not
3 obviously superinfected. (1b)
4 A Cochrane review showed no clear beneficial evidence to antiseptic substances in non-
5 infected AE. (4)
6 Topical glucocorticosteroids and calcineurin inhibitors reduce the colonization rate of S.
7 aureus in AE. (4)
8 Antiseptic textiles have a moderate clinical effect on AE. (2b)
9 AEGIS-coated silk garments do not show clinical benefit over standard care (2b).
10 VZV vaccination is safe, efficacious and beneficial for children with atopic dermatitis. (2a)
11 An antifungal therapy may be efficient in some AE patients, mainly in those suffering from
12 the „head and neck“-variant of AE or with demonstrated IgE-sensitization to Malassezia spp.
13 (2b)
14 Recommendations
15 A short course of systemic antibiotics, such as cephalosporin, may be considered in AE
16 patients clinically infected with S. aureus. (2b, B)
17 The long-term application of topical antibiotics is not recommend due to the risk of increasing
18 resistances and sensitizations. (2, D)
19 Treatment with topical antiseptic drugs – including antiseptic baths e.g. with diluted sodium
20 hypochlorite - should be considered, if clinical signs of bacterial superinfection are present.
21 (4,C)
22 Treatment with topical antiseptic drugs – including sodium hypochlorite 0.005% baths – may
23 be considered in patients with treatment resistant, chronic course of AE. (2b,B)
24 Eczema herpeticum should be treated without delay using systemic antiviral therapy, such
25 as systemic aciclovir. (4,D)
26 VZV vaccination is recommended for children with atopic dermatitis. Parents of atopic
27 children should be encouraged to fully immunize their children. (2a,B)
28 Topical or systemic antifungal therapy may be effective in some AE patients, mainly in those
29 suffering from the „head and neck“ variant of AE or with demonstrated IgE-sensitization to
30 Malassezia spp. (2b,B)

2
3 Immunosuppressive treatment
4 Oral glucocorticosteroids
5 Oral glucocorticosteroids are used in many European countries for treatment of AE. Well
6 known side effects limit their use especially for long-term treatment. Funding of expensive
7 clinical trials in the near future is unlikely.
8 Controlled clinical trial data demonstrating efficacy: There is one controlled trial available
9 that demonstrates lower efficacy of therapy with systemic prednisolone compared to
10 ciclosporine in severe adult AE patients (41). Broad experience from clinical use by many
11 experts indicates some efficacy, as well as prompt rebound after withdrawal.
13 Short term treatment with oral glucocorticosteroids is moderately effective. (1b)
14 Systemic steroids have a largely unfavourable risk/benefit ratio for treatment of AE.
15 (1b)
16 Recommendations
17 Short-term (up to 1 week) treatment with oral glucocorticosteroids may be an option to treat
18 an acute flare in exceptional cases of AE. Restrictive use, largely limited to adult patients
19 with severe AE, is recommended. (-, D)
20 The daily dose should be adjusted to and not exceed 0,5 mg/kg body weight. (-, D)
21 Long-term use of oral glucocorticosteroids in AE patients is not recommended. The
22 indication for oral steroids in children should be handled even more cautiously than in adults.
23 (-, D)
24
25
26 Cyclosporine A
27 Cyclosporine is licensed in many European countries for treatment of AE and is therefore
28 considered to be the first line option for patients with severe disease who require systemic
29 immunosuppressive treatment.
30 Controlled clinical trial data demonstrating efficacy
31 Cyclosporine vs. Placebo: A meta-analysis and review of pooled data from 15 RCTs (42)
32 clearly demonstrated the efficacy of cyclosporine in AE with a 55% improvement on average
33 after 6-8 weeks of treatment. Body surface area, erythema, sleep loss and
34 glucocorticosteroid use were reduced in the cyclosporine group. Cyclosporine is more
35 effective than placebo, but there is often prompt relapse if cyclosporine is stopped. All scores
36 are back to pre-treatment values eight weeks after the end of cyclosporine therapy in most
37 patients.
1 Cyclosporine dose finding study for AE treatment in adult patients: A fixed dosage
2 cyclosporine regimen was evaluated in 106 adults with severe AE (43). Initial treatment was
3 performed with 300 mg/d or 150 mg/d and reduced after two weeks to 50% of the initial daily
4 dose until a final evaluation was performed after eight weeks. Clinical efficacy was
5 detectable after two weeks in both treatment groups, but the higher dose was significantly
6 more effective (p<0.05). The authors recommended to start therapy with 150 mg/d, because
7 this regimen showed a lower incidence of serum creatinine increase. It is recommended
8 today to start with a higher dose of 4-5 mg/kg/day to obtain a good initial result unless the
9 patient is old or suffers from relevant concomitant diseases (44). Some patients may tolerate
10 low dose cyclosporine therapy for a longer time than the usually recommended therapy
11 length of 2 years (45).
12 Continuous or intermittent cyclosporine therapy study of AE in children: Forty children aged
13 2-16 years were randomized to either a continuous long term or an intermittent short term
14 cyclosporine regimen (46). Both groups showed significantly better results in clinical scores
15 and quality of life assessments. Enhanced sustained improvement was seen in the
16 continuously treated group. As the intermittent therapy was sufficient in some patients but
17 associated with a lower cumulative cyclosporine dose, the authors recommended choosing
18 the regimen on an individual basis.
19 Cyclosporine or UV Therapy for AE: Cyclosporine was tested against a combined UV/UVB
20 regimen in a one year, open label, multicentre trial involving 72 patients (47). Cyclosporine
21 therapy induced a significantly higher number of days in remission, as compared to UV
22 therapy.
23 Compounding of Cyclosporine: Micro emulsions of cyclosporine show an earlier onset and
24 higher peak value of efficacy compared to traditional formulations (48). The clinical efficacy
25 evaluated after eight weeks of therapy was, however, identical for both formulations.
26 Drug safety profile of Cyclosporine: Patients receiving cyclosporine should be monitored for
27 blood pressure and renal parameters, as cyclosporine is known to induce structural and
28 organic kidney damage. Nephrotoxic effects are more likely to occur if the daily dose
29 exceeds 5 mg/kg body weight, serum creatinine values are elevated or elderly patients are
30 treated. Life vaccination is contraindicated during cyclosporine therapy.
31
33 Many RCTs indicate the efficacy of cyclosporine versus placebo in AE. (1a)
34 Cyclosporine is also effective in children and adolescent AE patients. (2b)
35 Self-willed reduction of the recommended cyclosporine dose may reduce the clinical efficacy
36 of cyclosporine and is not recommended. (2b)
37 A micro emulsion of cyclosporine has the advantage of an earlier onset and peak level of
38 clinical efficacy, which may be useful in short-term treatment. (1b)
39 Long-term intermittent cyclosporine therapy for one year is more effective than an
40 intermittent UVA/UVB therapy following a 2-3 times weekly regimen. (1b)
41 Recommendations
1 Cyclosporine may be used in chronic, severe cases of AE in adults. Treatment should not
2 exceed a two-year continuous regimen. Careful monitoring for potential severe side effects
3 must be performed. (1a, A)
4 Cyclosporine may be used (off label) in children and adolescent patients showing a
5 refractory or severe course of disease. A detailed patient monitoring, especially of the renal
6 status, is advisable. (2b, B)
7 The duration of cyclosporin therapy is guided by clinical efficacy and tolerance of the drug.
8 Both short-term and long-term therapy may be useful in AE. (-, D)
9 Common side effects of cyclosporine (e.g. nephrotoxicity, hypertension) argue against a
10 long-term treatment of AE with cyclosporine. Therefore, an interval of 3-6 months is usally
11 recommended. (-,D)
12 Cessation of therapy or switch to another systemic drug should be attempted after two years
13 of therapy, although many patients tolerate much longer therapy with low dose cyclosporine.
14 (-,D).
15 An initial daily dose of 5 mg/kg/d, divided upon two single doses, is recommended. A dose
16 reduction of 0.5-1.0 mg/kg/d every two weeks is recommended, once clinical efficacy is
17 reached. (-,D)
18 Dose reduction should be considered according to clinical efficacy. Long term treatment
19 prescribing the lowest clinically useful dose may be advisable in selected cases. (-,D)
20 Since an intermittent dosage regimen (e.g. “weekend therapy”) will lead to lower cumulative
21 doses of cyclosporine and is effective in some AE patients, an individualized dosage
22 regimen is recommended for underage patients. (-,D)
23 Cyclosporine trough levels do not need to be assessed routinely during therapy. (-,D)
24 Though there are no controlled studies available regarding the efficacy of vaccination during
25 cyclosporine therapy, there is no evidence for a failure during cyclosporine either. Hence, a
26 cessation of therapy of 2 weeks before and 4-6 weeks after vaccination may be advisable.
27 Clinically, there is no evidence for this recommendation. (-,D)
28 A combination therapy of cyclosporine with UV-therapy is not recommended, effective UV
29 protection should be used. (-,D)
30
31
32 Azathioprine (AZA)
33 Azathioprine is used (off label) for many years for treatment of AE in adult patients. Funding
34 of expensive clinical trials in the near future is unlikely.
35 Controlled clinical trial data demonstrating efficacy: Efficacy of AZA was tested in a
36 randomized, controlled, 6 month, crossover clinical trial involving 37 patients aged 17 to 73
37 years (49). The drop-out rate was high (12 patients on AZA, 4 patients on placebo). AZA
38 (2.5 mg/kg/d) or placebo was given for three months each in a crossover design. The
39 SASSAD skin severity score was reduced by 26% in the AZA group and 3% in the placebo
1 group (p<0.01). Pruritus, sleep loss and fatigue improved significantly during AZA, but not
2 during placebo treatment.
3 Another randomized double blind, placebo controlled, 12 weeks, clinical trial involved 63
4 outpatients with AE (50). Following a low dose introduction phase, azathioprine was dosed
5 in 42 patients according to the results of a thiopurine methyltransferase (TPMT)
6 polymorphism, which may be indicative for the myelotoxicity of azathioprine – the other 21
7 patients received placebo. Patients with a normal TPMT activity were treated with 2.5
8 mg/kg/d AZA, whereas patients with a reduced TPMT activity (heterozygous phenotype)
9 received 1.0 mg/kg/d AZA. The AZA regimen was more effective in AE, as the disease
10 activity dropped by 37% in the azathioprine group and by 20% in the placebo group. None
11 of the patients showed myelotoxic symptoms.
12 A prospective, randomized controlled trial showed equal clinically relevant improvement of
13 AZA 1.5-2.5 mg/kg/day compared to methotrexate 10-22.5 mg/week after 12 weeks of
14 treatment in adults with severe AE. Both treatments were safe in the short term (51).
15 Twelve children with severe, recalcitrant AE were treated with oral AZA and followed
16 prospectively. AZA therapy was associated with clinical improvement in all but 1 patient.
17 There were few adverse effects (52).
18 A retrospective, uncontrolled study investigated 48 children and adolescents aged 6 to 16
19 years diagnosed with severe AE (53). After three months of therapy, 28 patients showed
20 very good and 13 patients showed good improvement of their symptoms, while 7 patients
21 showed little or no improvement. None of the patients showed myelotoxic symptoms, TPMT
22 activity was determined in all patients before treatment. All patients were started on
23 2mg/kg/d AZA and the dose was increased to 3mg/kg/d in 14 patients due to insufficient
24 clinical response. The mean time to achieve clinical response was 4 weeks.
25 A retrospective, uncontrolled study in a heterogeneous group of 17 children and adults with
26 a mean age of 16 years showed significant improvement of SCORAD after 3 and 6 months
27 of AZA, and significant reduction of total serum IgE levels (54).
28 Safety profile of azathioprine The authors of the Berth-Jones study concluded, that AZA
29 would be an effective and clinically useful drug for treatment of severe AE, but would be
30 associated with a high rate of unwanted drug effects (49). Leukocyte counts and liver
31 enzymes must be controlled during therapy. The higher dose caused gastrointestinal
32 symptoms in 14 patients; leukopenia in 2 and elevated liver enzymes in 8 patients. Long-
33 term efficacy and safety data in AE patients are sparse, but AZA increased the risk of non-
34 melanoma skin cancer and lymphoma in inflammatory bowel disease patients (55).
36 AZA is effective for treatment of severe AE in adults. (1b)
37 One small prospective clinical trial in children showed efficacy of AZA. (4)
38
39
40 Recommendations
1 AZA may be used (off label) in adult AE patients, if cyclosporine is either not effective or
2 contraindicated. (1b,A)
3 AZA may also be used (off label) in children. (4, C)
4 Patients should be screened for TPMT activity before starting AZA therapy to reduce the
5 risk for bone marrow toxicity by dose adaptation. The suggested dose range is 1-3mg/kg
6 bw/d. (1b,A)
7 Alternatively, an initial AZA dose of 50mg/day in adults and a slow increase of the dose
8 under close monitoring of full blood and liver function count is possible. (-, D)
9 In pregnant women, AZA should only be used on strict indication. (-, D)
10 AZA should not be combined with UV therapy, effective UV protection should be used. (-,
11 D)
12
13
14 Mycophenolate Mofetil (MMF)
15 MMF is an immunosuppressant drug licensed in many European countries for the treatment
16 of systemic lupus erythematosus and prevention of transplant rejection.
17 Controlled clinical trial data demonstrating efficacy: There is one controlled trial with enteric-
18 coated mycophenolate sodium (EC-MPS) vs. Cyclosporine A as long-term treatment
19 showing almost equal efficacy (56). Some case reports or uncontrolled clinical trial data from
20 adults indicate that it would be clinically effective in AE (57, 58). There is one uncontrolled
21 retrospective report involving 14 children indicating efficacy in this age group, with MMF 40-
22 50 mg/kg/d in younger children and 30-40 mg/kg/d in adolescents (59) and another including
23 12 children (60). A fixed dose of 2g MMF per day for adults is common practice in Europe
24 (24).
25 Drug safety profile of MMF: Gastrointestinal adverse events such as nausea or diarrhoea
26 are the most relevant side effect of MMF. They are most common during initiation of
27 treatment and tend to disappear during long-term treatment. Leukopenia or
28 thrombocytopenia may also occur. Recent data indicate that MMF should be discontinued
29 6 weeks before a planned pregnancy (61).
31 Positive case reports and uncontrolled clinical trial data indicate that MMF may be effective
32 in AE. (4)
33 There is no randomized clinical trial data for use of MMF in children or adolescents. (-)
34 MMF and EC-MPS are both teratogenic substances. (3a)
35 Recommendations
36 MMF may be used (off label) for treatment of AE in adults in a dose up to 3 g/d, if
37 cyclosporine is not effective or not indicated. (4,C)
38 MMF may be used for treatment of AE in children or adolescents. (4, C)
1 As MMF and EC-MPS are both teratogenic, men and women of childbearing potential must
2 use effective contraception during therapy. (3a, B)
3
4
5 Methotrexate (MTX)
6 The immunosuppressant MTX is frequently used in psoriasis, but there is little published
7 data on its use in AE. Some clinicians have used this drug in AE with good responses since
8 many years. MTX can be given by oral, intravenous or subcutaneous application. Funding
9 of expensive clinical trials in the near future is unlikely.
10 Controlled clinical trial data demonstrating efficacy: A randomized trial with MTX vs.
11 Azathioprine showed comparable effects in severe AE (51).
12 Forty children with severe AE were randomly assigned to receive either methotrexate 7.5
13 mg weekly or cyclosporin 2.5 mg kg daily for 12 weeks. At week 12, patients in
14 the methotrexate group had a mean reduction in SCORAD which was not statistically
15 different from the cyclosporin treated group. Both drugs were associated with minor adverse
16 effects, none of which required changing the treatment regimen (62).
17 An open 24 week dose escalation clinical trial involving 12 adult patients investigated the
18 efficacy of increasing doses MTX (63). The starting dose of 10 mg/week was increased
19 weekly in steps of 2.5 mg/week until clinical efficacy was seen. The skin score SASSAD
20 improved by 52% after 24 weeks. The median dose administered was 15 mg MTX/week.
21 Improvement remained stable in 9 patients 12 weeks after end of treatment.
22 An uncontrolled, retrospective report involving 20 adult AE patients treated with 10 mg/week
23 to 25 mg/week MTX showed response in 16 patients after 8-12 weeks (64). First
24 improvement was observed after a period ranging from 2 weeks to 3 months (mean 9.95 w
25 +/- 3.17). Treatment was more effective in adult onset AE than in childhood onset.
26 Forty Children with severe AE were randomly assigned to receive either methotrexate 7.5
27 mg weekly or cyclosporin 2.5 mg/kg daily for 12 weeks. At week 12, patients in
28 the methotrexate group had a mean reduction in SCORAD which was not statically different
29 from the cyclosporin treated group. Both drugs were associated with minor adverse effects,
30 none of which required changing the treatment regimen (62).
31 Safety profile of MTX:
32 All available drug safety data for MTX is largely derived from clinical experience from other
33 low dose indications for MTX, indicating liver toxicity and teratogenicity as main areas of
34 concern. There is no AE specific safety data available for MTX.
36 An open, uncontrolled clinical trial, as well as broad clinical experience, indicate that MTX
37 may be effective in AE. (4)
38 MTX is a teratogenic substance. (3a)
1 Recommendations
2 MTX may be used (off label) for treatment of AE in both adults and children. (4,C)
3 The recommended dosing regimen is similar or slightly lower compared to psoriasis. (D,-)
4 As MTX is teratogenic, men and women of child bearing potential must use effective
5 contraception during therapy. (3a,B)
1 Biological agents
2 Biological agents (Biologics) have been used in dermatology for more than 10 years for
3 other inflammatory skin diseases, especially psoriasis, but so far no registered biologics for
4 AE are available in Europe. Biologics present a relatively new group of therapeutics created
5 by using biological processes that include recombinant therapeutic proteins such as
6 antibodies or fusion proteins. Biologics specifically target inflammatory cells and/or
7 mediators respectively. In AE, biologics may be helpful in reducing inflammation by
8 modulating the number, activation and function of immune cells or the action of cytokines or
9 disease relevant antibodies. Several case reports, pilot studies and retrospective analyses
10 on the effect of biologics in patients with moderate to severe AE refractory to topical and/or
11 systemic therapy have been published, and randomized, placebo-controlled studies
12 evaluating the efficacy and safety of a few biologics in AE are now available.
13
14 Approved biologic therapy
15 Dupilumab
16 Dupilumab, a fully human monoclonal antibody that blocks the common α-chain of the
17 receptor for interleukin-4 and interleukin-13, has been approved as first line treatment for
18 moderate-to-severe adult AE in the USA in March 2017 and in Europe in September 2017.
19 Dupilumab has previously shown efficacy in patients with asthma and elevated eosinophil
20 levels and now also in AE (65). Randomized, double-blind, placebo-controlled trials involving
21 adults who had moderate-to-severe AE were performed. In 4-week monotherapy studies,
22 dupilumab resulted in rapid and dose-dependent significant improvements in
23 pathophysiological and clinical parametres. Side-effect profiles were not dose-limiting and
24 mostly mild side effects were observed. In a 12 week double-blind study where topical
25 corticosteroids were combined with dupilumab or placebo, the group treated with dupilumab
26 had significantly better effect on both AE activity and pruritus (65). The positive outcome for
27 dupilumab treated moderate to severe adult AE patients was confirmed in a double blind,
28 placebo controlled study involving 380 randomly assigned to different dosages of dupilumab
29 or placebo (66). Recently, the two identical phase III SOLO studies in adults have completed
30 the clinical development program for dupilumab, again confirming the efficacy of dupilumab
31 monotherapy on skin signs and symptoms, and overall improvement of the QoL in AE. A
32 significant proportion of patients achieved an IGA score of clear and almost clear and at
33 least a 75% improvement in EASI score (67). The LIBERTY AD CHRONOS studies indicate
34 maintenance of efficacy over 1 year of continued treatment with dupilumab (68). The safety
35 profile of dupilumab was good, with conjunctivitis being the only adverse event that was
36 observed more frequently with dupilumab than with placebo. In view of all trials published
37 so far, about 1/3 of all treated patients are clear or almost clear in IGA from their AE. Up to
38 70% of patients achieve an EASI 75 or higher skin improvement, and it takes about 4 weeks
39 to reach the fullclinical outcome. Skin signs, QoL, and symptoms including pruritus
40 significantly improved as early as 2 weeks after treatment initiation. Several ongoing studies
41 involving both children and adolescents will show if these subgroups of the AE population
42 may experience equally positive effects, expanding the treatment indication for dupilumab
43 even further.
2 A number of large, randomized, placebo controlled clinical trials indicate that dupilumab is
3 effective in AE, with the response maintained for at least 1 year of continuous treatment in
4 the majority of patients. (1b)
5 Dupilumab-treated AE patients did not show systemic side effects in clinical studies, but
6 showed a higher incidence of conjunctivitis. (1b)
7 Recommendations
8 Dupilumab is recommended as a disease modifying drug for patients with moderate to
9 severe AE, in whom topical treatment is not sufficient and other systemic treatment is not
10 advisable. (1,a)
11 Dupilumab should be combined with daily emollients and may be combined with topical anti-
12 inflammatory drugs as needed. (2,b)
13
14 Upcoming biologic therapy
15 Nemolizumab
16 Nemolizumab, a humanized monoclonal antibody directed against the IL-31 receptor A, has
17 shown efficacy in patients with moderate to severe AE (69). There was a significant
18 improvement in the primary endpoint pruritus, as well as in the objective signs of the AE
19 with, however, less efficacy. Nemolizumab is currently not approved for any indication.
21 A randomized, placebo controlled clinical trial indicates that nemolizumab is effective in
22 treating pruritus in AE patients. (1b)
23 Nemolizumab-treated AE patients did not show systemic side effects in clinical studies, but
24 showed a higher incidence of peripheral edema. (1b)
25
26 Off label use of other traditional Biologicals
27 Rituximab
28 The depletion of B cells by an anti-CD20 antibody, rituximab (2x 1000 mg), resulted in a
29 rapid reduction of skin inflammation in all patients with a sustained effect over 5 months in
30 five of six patients. These results may suggest a pathogenic role of B cells in AE, although
31 CD20 may also play a role in some DC-T cell mediated reactions (70). A report on two cases
32 of severe AE receiving rituximab could not confirm these findings (71).
33 Mepolizumab
34 Inflammation in AE is characterized by a T helper 2 cytokine expression including interleukin
35 (IL) –5 and eosinophil infiltration. Upon short-term therapy with the anti-IL-5 antibody
36 mepolizumab (2 x 750 mg), a moderate improvement of clinical symptoms was observed,
37 although a rapid depletion of eosinophils in the peripheral blood was noted (72). The patients
38 were not stratified for eosinophilia in this study. Mepolizumab had no effect on atopy patch
1 test reactions (73). Based on the promising results in AE and the experiences in bronchial
2 asthma therapy, long-term trials with anti-IL-5 antibodies are now performed.
3 Omalizumab
4 Most AE patients have elevated serum IgE levels, but the pathogenic role of IgE in AE
5 remains unknown. In a placebo-controlled study in 20 patients, omalizumab administered
6 for 16 weeks failed to improve AE symptoms and itch despite a depletion of free serum IgE
7 and reduction of IgE receptor saturation (74). Other studies reported that accompanying AE
8 significantly improved in patients receiving omalizumab because of severe bronchial asthma
9 (75-77). First explorative open label trials did not indicate good efficacy (78). An open label
10 study on 20 adult patients with severe AE have indicated an increased efficacy of
11 omalizumab in patients with wild type filaggrin status and high levels of phosphatidylcholines
12 (79). An open label study involving 7 treatment refractory, pediatric AE patients treated with
13 omalizumab for 12 to 68 months showed significant improvement of their AE (80). By
14 contrast, a recent small, randomised, trial including 8 children with severe treatment
15 refractory AE treated for 24 weeks with omalizumab or placebo showed no significant clinical
16 differences between the two groups (81) and this was confirmed in another similar study
17 (82). In summary, the data concerning omalizumab are conflicting, and omalizumab cannot
18 be recommended for treatment of AE.
19 Ustekinumab
20 By blocking IL-12 and IL-23, ustekinumab can regulate Th1, Th17 and also Th22 pathways,
21 which are reportedly active in AE. Results regarding the use of ustekinumab in severe AE
22 have, however, been conflicting and only case reports have been published so far. Some
23 have reported significant improvement of AE (83) and some have not (84). The first two
24 randomised controlled trials comprising 79 and 33 patients in total have been completed,
25 and results are quite uniform showing no significant decrease in severity scores (85, 86).
26 Other substances
27 Some older biologics such as infliximab or efalizumab, which are outdated for use in atopic
28 dermatitis or withdrawn from the market, are not discussed anymore in this version of the
29 guideline.
30 On the other hand, a number of highly interesting substances are in progress and may soon
31 be registered for treatment of AE. Therefore, the committee decided to produce a table in
32 the addendum on potential new biologics or small molecules for AE “in the pipeline”, which
33 will be continuously updated by the guideline committee. Substances to be included in this
34 table will be, among others, the anti-IL 13 antibody tralokinumab, the anti-TSLP antibody
35 tezepelumab, and the Janus kinase (JAK) inhibitor upadacitinib.
36
38 None of the traditional biologics has been approved for the therapy of AE in Europe. At
39 present, the use of traditional biologics in AE should be tried only in patients with severe AE
40 refractory to other topical and/or systemic treatment. Beside the lack of efficacy and safety
41 data in AE, the potential side effects must be taken into account before using biologics. On
1 the other hand, treatment with biologics may provide important information on pathogenetic
2 mechanisms in AE. Today, the imminent availability of Th2-blocking biologics has further
3 reduced the clinical need for experimental therapy with traditional biologics. (-)
4 Recommendations
5 A therapy of AE with traditional biologics (rituximab, omalizumab or ustekinumab) cannot be
6 recommended. (4, C)
7 A therapy of AE with mepolizumab may be tried in selected cases unresponsive to standard
8 therapy. (-, D)
9

2 Alitretinoin
3 Alitretinoin is a retinoid binding both retinoid and rexinoid receptors, thus delivering anti-
4 inflammatory and anti-proliferative effects. It is licensed in some European countries for the
5 treatment of chronic hand eczema irrespectively of its pathogenesis.
6 Controlled clinical trial data demonstrating efficacy
7 There is one large, multicenter randomized, placebo controlled clinical trial involving 1032
8 patients with chronic hand eczema, about one third of which are probably atopic hand
9 eczema patients (87). Improvement of eczema symptoms was seen in 75% of the patients.
10 The response rate of hyperkeratotic hand eczema (49%) and pulpitis sicca type patients
11 (44%) was higher than the dyshidrosiform subtype of hand eczema (33%). The patient group
12 suffering from atopic hand eczema has not been analyzed separately, and extrapalmar
13 symptoms have not been assessed in this trial.
14 Six patients with AE and prominent hand involvement have been treated with alitretinoin for
15 twelve weeks in an uncontrolled, open label trial (88). Palmar and extrapalmar lesions
16 improved during the trial, as shown by the mTLSS hand eczema score and the SCORAD.
17 Drug safety profile of alitretinoin
18 As alitretinoin is highly teratogenic, all females of childbearing potential must adhere to a
19 strict birth control program. Headache is the most frequent clinical side effect of alitretinoin
20 especially in the first two weeks of treatment. Serum lipid and TSH elevation may also occur.
22 Direct evidence from an uncontrolled clinical trial, as well as indirect evidence from a large,
23 double blinded, placebo controlled clinical trial indicates that alitretinoin may be effective in
24 atopic hand eczema. (4)
25 Alitretinoin is a teratogenic substance. (-)
26 There is no trial data for its use in children or adolescents. (-)
27 Recommendations
28 Alitretinoin may be used for atopic hand eczema in adult patients of non-child-bearing
29 potential unresponsive to topical steroid therapy. (1b,A)
30 Alitretinoin might lead to an improvement of both extrapalmar and hand lesions in AE
31 patients. (4,C)
32
33 Apremilast
34 Apremilast is a small molecule phosphodiesterase (PDE) 4 inhibitor that has been approved
35 for the treatment of psoriasis arthritis and moderate to severe plaques psoriasis. Blocking
36 PDE4 increases intracellular adenosine monophosphate levels resulting in a downregulation
37 of proinflammatory cytokines such as IL-2, IL-5, IL-13 and increased production of the
38 regulatory cytokine IL-10. A pilot study investigating the effect of apremilast in patients with
1 moderate to severe AE has demonstrated moderate improvement of skin lesions, pruritus

2 and QoL (89), but the drug development program of apremilast for AE has been stopped.
3 Recommendations
4 Apremilast may be used in selected cases unresponsive to standard therapy for treatment
5 of AE. (-,D)
6
7 Tofacitinib
8 So far only one small open label trial with the oral JAK inhibitor tofacitinib citrate has been
9 performed in 6 patients with moderate to severe, treatment refractory AE. After 8-29 weeks
10 of treatment they had a mean SCORAD reduction of 66 %. No adverse events were
11 observed (90).
12 Recommendations
13 There is not enough evidence to support the use of tofacitinib in AE. (4,C)
14
15
16 Immunoadsorption
17 Immunoadsorption (IA) has been used in patients with AE and high serum-IgE levels based
18 on the assumption that a reduction of IgE might result in a reduction of disease activity. An
19 investigator initiated open-label pilot study in patients with severe AE recalcitrant to topical
20 and systemic therapy showed that IA resulted in a significant decrease of SCORAD three
21 weeks after the first cycle of 5 IA and a further improvement after the second cycle one
22 month apart, and in parallel a reduction of skin-bound IgE (91). A recent study confirmed
23 these results and showed long-term clinical effect of IA in AE patients (92). Another pilot
24 study in severe AE showed a beneficial effect of immunoadsorption together with
25 subcutaneous application of omalizumab; the serum levels of free IgE and the SCORAD
26 decreased significantly (93).
27
28 Recommendations
29 Immunoadsoption might be considered for patients with severe AE and high serum IgE
30 levels if the technology is available. (4, C)
31
32
33 Mast cell stabilizers
34 Mast cell stabilizers inhibit mast cell degranulation and thus prevent the release of histamine
35 and other mediators. Oral cromolyn, ketotifen and pemirolast are used for asthma and other
36 allergic diseases, but have not shown any significant effect for the treatment of AE. In the
37 last five years, studies investigating these substances in AE have not been published.
1 Recommendations
2 Mast cell stabilizers are not recommended for the treatment of AE. (-)
3
4
5 Leukotriene antagonists
6 Montelukast is a cysteinyl-leukotriene receptor antagonist that blocks the action of LTD4,
7 LTC4 and LTE4. It has been used at doses of 10 mg daily (5 mg/day in children below 12
8 years), with some reduction in SCORAD indexes (94, 95). A systematic review stated that
9 limited evidence exists to recommend montelukast for the treatment of AE (96). Studies on
10 leukotriene antagonist zafirlukast for the treatment of AE have not been reported in the last
11 five years.
12 Recommendations
13 There is not enough evidence to support the use of leukotriene antagonists in AE. (2a,B)
14
15
16 Intravenous Immunoglobulin
17 Intravenous immunoglobulins (IVIG) are considered as immunomodulatory substances, but
18 not as immunosuppressive agents. IVIG have been tried for both adults and children with
19 severe, treatment refractory AE, but clinical trials did not indicate a high efficacy or quick
20 onset of action despite the high cost of treatment (97, 98). IVIG may be considered as a last
21 resort treatment in severe, treatment refractory AE in children only. It is likely that the
22 availability of novel biologics for AE may further reduce the indication for IVIG in AE.
23 Recommendations
24 The use of IVIG in AE is not recommended. (4,D)
25
26
27 H1R-blocking antihistamines
28 Traditional histamine 1 receptor (H1R) blocking antihistamines have been used for decades,
29 in an attempt to relieve pruritus in patients with AE. However, only a few randomized
30 controlled trials have been conducted and they have in the majority shown only a weak or
31 no effect in decreasing pruritus (99-104). According to a Cochrane search, randomized
32 controlled trials investigating the efficacy of antihistamine monotherapy in AE patients are
33 lacking (105).
34 The first generation of sedative antihistamines such as hydroxyzine, clemastine fumarate,
35 doxylamine, and dimetinden maleate may allow better pattern in acute situations with
36 exacerbations of AE (evidence level D). Concerning the newer non-sedating antihistamines,
37 studies using loratadine, cetirizine or fexofenadine demonstrated no or only a weak relief of
38 pruritus in AE (106-108). A significant, but clinically small, antipruritic effect of fexofenadine
1 60 mg twice daily has been described (109). An effect on itch of a high dosage of 20 to 40
2 mg cetirizine daily has been observed, but this effect was primarily attributed to sedation
3 (107).
4 The corticosteroid sparing effect of cetirizine in infants with severe AE has been attributed
5 to its decreasing effect on pruritus (110). A recent study reported a beneficial effect of the
6 non-sedating H1 antihistamine olopatadine in AE patients by decreasing nocturnal
7 scratching without affecting sleep quality (111). Possible mechanisms of action of second
8 generation antihistamines are a reduction of the urticarial component of AE, and blocking
9 histamine interaction with bradykinine, downregulation of transcription factors resulting in a
10 decrease of proinflammatory cytokine production (112).
11 In general, antihistamines are safe to use, also for a long period of time (113), and the major
12 advantage seems to be relief of the symptoms of co-morbidities such as allergic asthma,
13 rhino-conjunctivitis, urticarial dermographism and urticaria. Topical antihistamines have no
14 effect on itch beyond that of their cooling vehicles.
15
16 H4R-blocking antihistamines
17 Amongst the 4 histamine receptors described in humans, the histamine 4 receptor (H4R)
18 blocking antihistamines represent an additional promising treatment for AE (114). Clinical
19 trials have been performed with H4R blocking agents, but the results are not published yet.
20
21 Recommendations
22 There is not enough evidence to support the general use of both first and second generation
23 H1R-antihistamines for treatment of pruritus in AE. These may be tried for treatment of
24 pruritus in AE patients, if standard treatment with TCS and emollients is not sufficient. (1b,
25 A)
26 Long term use of sedative antihistamines in childhood may affect sleep quality and is
27 therefore not recommended. (-,D)
1 Allergen-specific immunotherapy
2
3 Allergen-specific immunotherapy (ASIT) has been investigated for treatment of AE, the two
4 relevant therapeutic regimens are subcutaneous immunotherapy (SCIT) and sublingual
5 immunotherapy (SLIT).
6
7 Introduction to allergen-specific immunotherapy for AE
8 Some efficacy of allergen-specific immunotherapy (ASIT) in AE has been shown in a number
9 of case reports and smaller cohort studies (115, 116), and more recently in a larger
10 multicenter trial with subcutaneous house dust mite immunotherapy (117). These data
11 showed that ASIT can be used for treatment of allergic rhinitis or mild asthma also in AE
12 patients, since the AE was obviously not worsened and sometimes even improved during
13 or after ASIT. A few prospective studies have been performed which address the question
14 if AE alone may be an indication for ASIT.
15 Even if the results of the studies are interpreted very carefully with regard to the therapeutic
16 effects of ASIT, it is remarkable that exacerbations of the skin disease during treatment were
17 rare, while the treatment was well tolerated in most patients. The same was true for studies
18 in patients with coexistent AE who were treated with ASIT for respiratory atopic diseases
19 and experienced not more often flares of eczematous skin lesions. The role of allergens in
20 the pathophysiology of AE has been proven in controlled studies on allergen avoidance and
21 atopy patch testing (118-120). In respiratory atopic diseases, ASIT plays an important role
22 not only for treatment, but also for the prevention of further sensitizations and progress to
23 more severe respiratory disease (change from rhinitis to bronchial asthma).
24 Hypothetically, patients with a positive atopy patch test and corresponding history of eczema
25 flares may be candidates for ASIT with the eliciting allergen. The performed studies point to
26 the safety of ASIT also in AE, if the treatment is performed according to the guidelines.
27 However, the final judgement on the efficacy of ASIT in this diagnosis is still not possible
28 due to the lack of large, controlled and randomized clinical trials with modern allergen
29 vaccines (116).
30 Evidence from controlled clinical trials
31 Experience in a pair of monozygotic twins with AE (with spring and summer exacerbations)
32 treated either with grass pollen ASIT or placebo in a double-blind fashion showed significant
33 improvement and decrease of serum IgE in the patient treated with ASIT (121). Several
34 open uncontrolled study designs also demonstrated advantages of ASIT in patients with AE,
35 these data were often published in national or non-anglosaxon journals. Some investigators
36 in the 1970s and 80s also showed improvement of AE in controlled trials (116).
37 Subcutaneous immunotherapy (SCIT)
38 A double-blind controlled trial of ASIT with Dermatophagoides pteronyssinus in children with
39 AE failed to demonstrate superiority over placebo after a standard 8-months’ course of
40 treatment with tyrosin-adsorbed house dust mite extracts in 24 house dust mite-allergic
41 children with AE (122). However, in a second study phase children were randomly allocated
1 to continue with active treatment or placebo for a further 6 months. The placebo effect was
2 high, and the numbers were too small to permit confident conclusions, but the clinical scores
3 suggested that prolonged ASIT may be effective with regards to several objective
4 parameters of AE severity (122).
5 A small placebo-controlled study showed AE improvement in 13 of 16 ASIT treated AE
6 patients, whereas only 4 of 10 placebo-treated AE patients improved (123). Similar results
7 were reported for AE lesions under ASIT with house dust mite extracts (124, 125). Oral ASIT
8 for D. pter was not effective in a controlled study enrolling 60 children with AE which were
9 followed for three years (126). Conventional s.c. ASIT (n=41; 76% improved) and sublingual
10 ASIT (SLIT; n=48; 64% improved) showed some efficacy, with adverse drug reactions
11 occurring in 15-20% of both groups (127). A controlled study applying SLIT with house dust
12 allergens was performed in 56 children with AE aged 5 to 16 years, but the outcome of this
13 intervention was positive only in patients with mild to moderate AE, but not with severe AE
14 (128).
15 A pilot study reported the improvement of AE together with changes in T cell subpopulations
16 induced by IFN gamma pretreatment before ASIT with house dust mite allergens. Patients
17 receiving placebo, IFN gamma only or ASIT only showed no treatment effect (129).
18 A large randomized, assessor-blinded clinical trial investigated 89 patients with AE showing
19 a sensitization to house dust mite (CAP-FEIA > 4) (117). Patients were injected weekly with
20 three different doses of HDM allergen extract. With higher allergen doses, a beneficial
21 SCORAD decrease occurred after 8 weeks compared to a control group with an “active
22 placebo” consisting of very low allergen dose. The effect was maintained over one year and
23 was accompanied by lower glucocorticosteroid use.
24 A smaller DBPC study involving 20 patients with HDM- or grass pollen sensitization also
25 showed objective and subjective symptom relief accompanied by immunological changes
26 under ASIT (130).
27 Another large, randomized double-blind placebo controlled study investigated 168 adult AE
28 patients for 18 months. The study did not reveal efficacy in the AE patients studied, but a
29 subgroup analysis showed statistical significance of SCORAD reduction in subgroup of
30 severe AE patients with SCORAD > 50 (131). Longer treatment duration was associated
31 with higher efficacy. The best outcome was observed during September to February, which
32 may be due to the use of indoor heating and subsequent high HDM exposure.
33 A systematic review and meta-analysis of randomized controlled trials published until
34 December 2012 assessed the efficacy of immunotherapy for AE. 8 randomized controlled
35 trials that comprised a total of 385 subjects were analyzed. It has been found that ASIT has
36 a significant positive effect on AE patients (odd ratio [OR], 5,35:95% CI, 1.61-17.77; number
37 needed to treat 3;95% CI, 2-9). ASIT showed also significant efficacy in long-term treatment
38 (OR, 6.42;95% CI, 1.31-7.48) for severe atopic dermatitis (OR, 3.13;95% CI, 1.31-7.48), and
39 when administered subcutaneously (OR, 4.27;95% CI, 1.36-13.39). This meta-analysis
40 provides moderate level evidence for the efficacy of SCIT in AE. However, these findings
41 are based on an analysis of a small number of patients, with considerable heterogenicity
42 among trials (132).
43 Sublingual immunotherapy (SLIT)
1 A first 18 months, placebo controlled study investigating the effects of SLIT on AE found a
2 significant decrease of the SCORAD starting from month 9 (128).
3 Another study analyzed 107 patients undergoing SLIT for 12 months. A total of 84 patients
4 finished the trial, compared to the placebo group (53,85%), the treatment group (77,78%)
5 showed improvement in symptoms (133).
6 Another group of authors has investigated SLIT in AE patients allergic to HDM in a murine
7 model (134). The mouse model induced by Der f allergen extract reflected the typical
8 hallmarks of AE in humans. In the Der f allergens-sensitized mice, SLIT treatment with Der
9 f vaccine significantly inhibited AE symptoms through correction of Th2 and Th1 cytokine
10 predominance, therefore according to the authors SLIT could be considered as an
11 alternative treatment for patients with extrinsic AE.
12
14 There is conflicting evidence regarding ASIT in AE, with more recent literature being more
15 in favour of it. ASIT may have positive effects in selected, highly sensitized patients with AE.
16 (2a)
17 The best evidence so far is available for ASIT with house dust mite allergens. (2a)
18 There is no contraindication for performing ASIT in patients with respiratory allergic diseases
19 (allergic rhinoconjunctivitis, mild allergic bronchial asthma) and concomitant AE. (2b)
20 Recommendations
21 ASIT is currently not recommended as a general treatment option for AE. (2a, B)
22 ASIT may be considered for selected patients with house dust mite, birch or grass pollen
23 sensitization, who have severe AE, and a history of clinical exacerbation after exposure to
24 the causative allergen or a positive corresponding atopy patch test. (2a, B)
25
1 Complementary and alternative medicine in atopic eczema

2
3 There is evidence of growing interest of so-called complementary alternative medicine
4 (CAM) as treatment for AE (135-137). CAM has been defined as “diagnosis, treatment or
5 prevention which complements mainstream medicine by contributing to a common whole,
6 by satisfying a demand not met by orthodoxy or by diversifying the conceptual frameworks
7 of medicine” (136). This chapter summarises available RCT-based evidence on CAM for
8 AE.
9
10 Essential fatty acids
11 The most commonly used preparations in the treatment of AE are polyunsaturated fatty
12 acids, evening primrose oil (EPO), borage oil (BO), or animal and fish oil. A systematic
13 review published in 2016 showed conflicting results on EPO (138-141). Four smaller trials
14 (142-145), as well as two larger trials (146, 147) and an Indian study on EPO (148) also
15 gave conflicting results.
16 Negative results were obtained in a trial on eicosapentaenoic acids from Germany (149)
17 A study from Berlin compared the daily administration of 5,4 g docosahexaenoic acid (DHA)
18 in 21 patients who completed the trial with an isoenergetic control of fatty acids (N=23) over
19 8 weeks. The SCORAD dropped significantly in the DHA group, however, significant
20 differences to control were not observed (150).
21 In a comparison of dietary hempseed oil with olive oil, some parameters of skin physiology
22 and symptoms improved under hempseed oil, but obviously without significant difference to
23 the control group (151).
24 A RCT in 20 hospitalised patients with AE comparing infusions of fish oil to soybean oil
25 revealed marked improvements within one week in both groups but a significantly greater
26 effect in those treated with fish oil (152). Some smaller RCTs have also indicated a beneficial
27 effect (153-155), although the largest and well reported trial did show a difference between
28 the fish oil and the placebo (156).
29 EPO has also been used as topical treatment. Although a pilot study has indicated some
30 beneficial effects (157), further studies were unable to establish a dose response
31 relationship (158). Additional studies could not prove a beneficial effect on skin barrier
32 function (159). Large trials on that issue, however, are lacking.
33 In one pilot study, the addition of gamma-linolenic acid to emollients was able to decrease
34 elevated TEWL in atopic eczema (160).
35 The most recent Cochrane review on EPO and BO included 19 studies on EPO and 8 on
36 BO (161). The authors concluded that EPO and BO lack effect on AE and that further studies
37 would be hard to justify.
39 There is partly conflicting, mostly negative evidence regarding the efficacy of oral or topical
40 applications of unsaturated fatty acids in the treatment of AE. (1a)
1 Recommendations
2 Oral application of unsaturated fatty acids is not recommended for treatment of AE. (1a, A)
3 Topical application of unsaturated fatty acids as an ingredient in emollients may be tried in
4 selected cases. (D,-)
5
6 Phytotherapy
7 Detailed background information on herbal therapy in dermatology is published (162). Two
8 RCTs investigated the efficacy and safety of topical chamomile preparation (163) and a
9 hypericum extract cream for AE (164).
10 The chamomile cream was moderately superior to 0.5% hydrocortisone cream regarding
11 pruritus, erythema and desquamation, but not different to the vehicle cream. The cream
12 containing hypericum extract standardized to 1.5% hyperforin was compared to the
13 corresponding vehicle cream in a half side comparison in 18 patients with mild to moderate
14 AE. The modified SCORAD index improved over 4 weeks with both therapies, but the
15 improvement was significantly higher under active treatment. A further study compared a
16 topical preparation of Mahonia aquifolium, Viola tricolor and Centella asiatica with the
17 vehicle cream in 88 patients and could not find significant differences (165). A subgroup
18 analysis revealed superiority of the plant preparation under dry and cool weather conditions.
19 Plant extracts are well known to induce contact sensitisation and subsequent contact allergy
20 (166, 167). It was demonstrated that so called “phytocosmetic creams” containing a mixture
21 of plant extracts may also contain triamcinolone acetonide as an active ingredient (168).
22 The concerns regarding side effects of phytotherapy with crude plant extracts must not be
23 generalized to emollients containing protein free oat plantlet extracts (169, 170). (see section
24 “Emollients plus” in chapter “Basic therapy”).
26 Beside many negative results, there is only one small RCT indicating a beneficial effect of
27 hypericum cream as a topical phytotherapy. (1b)
28 Topical use of crude plant extracts may cause contact sensitization and contact dermatitis.
29 (1a, A)
30 Recommendations
31 Topical use of crude plant extracts is not recommended for treatment of AE. (1b, C)
32
33 Chinese herbal medicine (CHM)
34 Chinese herbs are part of the traditional Chinese medicine which consists of Chinese herbs
35 administered orally or topically, acupuncture, diet and exercise (171, 172). CHM is promoted
36 as treatment for AE, taken orally as decoction, usually consisting of about 10 different herbs.
37 The first positive RCTs of CHM in the treatment of AE outside China were published by
38 Sheehan in 1992 (173). Serious adverse effects including fatal hepatitis have been reported
39 by independent investigators following these trials (171, 174-176). Further trials on
1 Zemaphyte, a commercial product of Chinese herbs, revealed conflicting results (177,

2 178).
3 The oral application of a combination of Eleutherococcus, Achillea millefolium, and Lamium
4 album was not superior to placebo after two weeks (179).
5 The most recent Cochrane review on CHM included 28 studies encompassing 2306 patients
6 (180). When compared to placebo CHM showed higher clinical effectiveness (RR 2.09, 95%
7 CI 1.32 to 3.32) in 2 studies. The total effectiveness rate in CHM groups was found to be
8 superior (RR 1.43, 95% CI 1.27 to 1.61) when compared to conventional therapy in 21
9 studies. The authors assessed most studies at high risk of bias and found substantial
10 inconsistency between studies. Therefore it was concluded that there is no conclusive
11 evidence that CHM could reduce the severity of AE. A similar result was achieved by the
12 systematic review of Tan and co-workers (181). The most recent RCT showed significant
13 effects of CHM on SCORAD and QoL scores when compared to the placebo group (182).
15 There is no conclusive evidence to support the use of Chinese herbs in the treatment of AE.
16 (1a)
17 Recommendations
18 The use of Chinese herbs is not recommended for treatment of AE. (1a, A)
19
20 Acupuncture/Acupressure
21 Acupuncture has been studied considering allergen-induced itch as primary endpoint but
22 not systematically or within randomised controlled trials as a treatment for AE. Case series
23 of patients including those with AE indicate some beneficial effects but studies implying a
24 rigorous methodology are needed (183-186). There is initial evidence from a small pilot trial
25 that acupressure might be helpful in reducing pruritus and lichenification in AE patients
26 (187).
28 There is absence of evidence to support the use of acupuncture or acupressure in the
29 treatment of AE. (-)
30 Recommendations
31 The use of acupuncture or acupressure is not recommended for treatment of AE. (-, D)
32
33 Autologous blood therapy
34 One RCT compared the intramuscular re-injection of 1 to 3 ml autologous blood over 5
35 weeks to the injection of the equivalent amount of sterile saline solution (188). Patients were
36 recruited via press advertisement and finally 30 subjects participated. Over a 9 weeks
37 period, AE severity measured by SASSAD dropped significantly in the verum group from
38 23.2 to 10.4 and did not change in the placebo group (21.0 to 22.5). Significant differences
39 were not observed in health related quality of life and the subjective assessment of pruritus
1 skin appearance and sleep quality. The data suggest a beneficial effect of autologous blood
2 therapy with respect to the signs score. This finding should be confirmed in larger trials and
3 different settings.
5 There is very limited evidence supporting the use of autologous blood therapy in the
6 treatment of AE. (2b)
7 Recommendations
8 The use of autologous blood therapy is not recommended for the treatment of AE. (2b, B)
9
10 Bioresonance
11 One RCT has been published so far, comparing bioresonance with a sham (inactive pseudo-
12 ) procedure in 36 children with AE attending a specialized rehabilitation unit in Davos,
13 Switzerland (189). After 4 weeks, AE severity had improved in both groups with slight
14 superiority of the active group but without statistical significance. Further studies under more
15 usual outpatient conditions are needed.
17 Current evidence from a single trial does not indicate a substantial clinical effect of
18 bioresonance for treatment of AE. (2b)
19 Recommendations
20 The use of bioresonance for treatment of AE is not recommended. (2b, B)
21
22 Homoeopathy
23 Homeopathy is a system of alternative medicine created in 1796 by Samuel Hahnemann,
24 based on his doctrine of like cures like. Large case series illustrating the therapeutic benefits
25 of homeopathy have been published as papers or books (190, 191). A recent uncontrolled
26 trial of 17 patients with longstanding AE in Japan revealed a marked improvement after the
27 introduction of homoeopathic treatment (192). A classical randomised placebo controlled
28 trial was initiated in Germany including 60 patients (193), showing no difference between
29 placebo and verum homeopathy in the outcome of AE (194).
31 There is absence of evidence to support the use of homeopathy in the treatment of AE. (2b)
32 Recommendations
33 The use of homeopathy is not recommended for treatment of AE. (2b, B)
34
35 Massage therapy / aroma therapy
36 The effect of additional massage therapy for AE, applied daily for 20 minutes over a one
37 month period compared to standard therapy alone, was investigated in a randomised trial in
1 20 children (195). Greater degrees of improvement in anxiety scores, tactile defensiveness

2 and coping index were reported by parents of children in the active group. Furthermore
3 clinical signs such as scaling and excoriation improved significantly in the massage group.
4 Appropriate statistical comparisons between groups, however, were not performed. A further
5 small cross-over trial in 8 children compared massage with essential oils (aroma therapy) to
6 conventional massage (196). Both treatment groups improved significantly without
7 significant differences between groups. Given the small sample size, conclusions on the
8 beneficial effects of additional aroma therapy cannot be drawn.
10 There is insufficient evidence to support the use of massage / aroma therapy in the treatment
11 of AE. (4)
12 Recommendations
13 The use of massage / aroma therapy is not recommended for treatment of AE. (4, C)
14
15 Salt baths and thermal spring water balneotherapy
16 Salt bath has been used for a long time to control chronic inflammatory skin diseases,
17 especially psoriasis. Based on this experience and anecdotal evidence, salt was recently
18 recommended also in the treatment of AE. The efficacy of salt bath alone, however, has not
19 been studied systematically in AE. In the current reports, salt baths were investigated as
20 part of a complex climatotherapy or in combination with UV-therapy (197-204). From these
21 studies it cannot be concluded that salt baths provide a consistent and significant clinical
22 effect on AE. Conventional balneotherapy with or without synchronous UV therapy has been
23 shown to be effective in AE but was not considered as CAM in this chapter. Balneotherapy
24 with thermal spring water has been shown to be beneficial in children with mild to moderate
25 AE with an effect similar to mid-potency topical corticosteroids (205).
27 There is insufficient evidence to support the use of salt baths in the treatment of AE. (4)
28 Cohort studies indicate that thermal spring water balneotherapy with or without phototherapy
29 may be effective in mild to moderate AE (2a, 2b)
30
31 Recommendations
32 The use of salt baths is not generally recommended for treatment of AE. (4, C)
33 Thermal spring water balneotherapy may be considered in mild to moderate AE (B, 2a, 2b)
34
35 Vitamins and minerals
36 A total of 6 trials were identified investigating vitamins or minerals in the treatment of AE
37 (206-211). A placebo-controlled study from Italy studied oral vitamin E (400 IU) in 96
38 patients (210). Greater clinical improvement was reported for the vitamin E group but without
1 results of statistical tests. Similarly, a smaller study of 49 patients comparing vitamin E plus
2 vitamin B2 to vitamin E or vitamin B2 alone revealed a superiority of the combination
3 treatment with respect to the physician’s assessed overall usefulness and global rating
4 (208). A further trial in 60 adults with AE compared selenium or selenium plus vitamin E vs.
5 placebo over a 12 weeks period (207). The AE severity score fell in all 3 study arms without
6 significant differences. A Hungarian study compared multi-vitamin supplementation in 2090
7 pregnancies to trace element supplementation in 2032 pregnancies over a 17 month period
8 (206). AE occurred more frequently in the multi-vitamin group (0.7% vs. 0.2%). Although this
9 unexpected result could be a chance finding as suggested by the authors, detailed studies
10 in the prospective setting are needed. A small trial has investigated the zinc supplementation
11 vs. placebo in 15 children over a 2 month period (212). The severity score increased in both
12 study groups without significant differences. There is one published RCT comparing
13 pyridoxine (vitamin B6) vs. placebo in 41 children over a 4 weeks period (209). The median
14 severity score increased in the pyridoxine group whereas an improvement was observed in
15 the placebo group. None of the differences were statistically significant.
16 Following a pilot study on vitamin D (211) more RCTs on that subject were published
17 recently. Thereby vitamin D supplementation showed statistically significant improvement in
18 clinical scores in 20 i.e. 60 adults (213, 214) and 107 children (215), whereas another trial
19 in 60 adults failed to prove significant effects by vitamin D supplementation (216). Vitamin
20 D supplementation of mothers during lactation did also not improve facial eczema in 164
21 children studied (217). A further RCT in 45 adults patient showed equal and significant
22 reduction of the SCORAD score by vitamin D or E supplementation (34.8%, 35.7% resp.)
23 and an even higher reduction by the combination of both vitamins (64.3%) (218).
24
26 There is preliminary evidence that vitamins, especially vitamin E and D, may be useful in the
27 treatment of AE. (1b)
28 Recommendations
29 There is not enough evidence to recommend vitamin supplementation for routine use in AE
30 patients. (2b, B)
31 Topical Vitamin B12 in avocado oil
32 There are two smaller studies with half-side comparisons, which indicate a mild beneficial
33 effect of a preparation containing 0.07% vitamin B12 in avocado oil compared to a placebo
34 preparation (219, 220).
36 There is preliminary evidence that a topical preparation of Vitamin B12 in avocado oil may
37 be useful in the treatment of AE. (2b)
38 Recommendations
39 There is not enough evidence to recommend topical preparations of Vitamin B12 in avocado
40 oil for routine use in AE. (2b, B)
1
2 Harms of CAM
3 Contrary to widespread assumptions of the public, CAM is not free of side effects. Dietary
4 regimens involving strong restrictions can lead to harmful sequels in terms of
5 malnourishment. Therapeutic procedures involving organic material from plants or animals
6 can be associated with severe toxic or allergic reactions. Finally, patient’s and parent’s
7 adherence to assumingly effective CAM may delay or hinder a severely affected patient’s
8 access to effective or even lifesaving therapy.
9
1 Psychosomatic counseling
2
3 Psychological and emotional factors influence the clinical course of AE, which is mirrored in
4 the German term “neurodermitis”. Interventions including patient education, eczema action
5 plans, and a quick return for a follow-up visit improve adherence (221). The reason for
6 treatment failure in more than one-half of patients referred to specialist centers is that the
7 treatment is not being administered. Doctors often have insufficient time to educate patients
8 and their caregivers about the correct application of ointments and creams, and this
9 adversely affects compliance. Many countries have patient organizations and support
10 groups that provide useful supplementary literature (222).
11 Poor adherence to treatment
12 Poor adherence to treatment is a major factor limiting treatment outcomes (223), and may
13 have different causes: Stress can elicit severe exacerbations of eczematous skin lesions
14 (224-226). The itch-scratch cycle is especially vulnerable to psychological influences and
15 can show a tendency to self-perpetuation (227-229). Psychosomatic disease in the sense
16 of anxiety or depression can be a co-morbidity of AE (228, 230). Intrafamiliar
17 psychodynamics are also well-known factors influencing the clinical course of AE (231, 232).
19 A Cochrane review analyzed ten RCTs of psychological or educational interventions, in
20 addition to conventional therapy, for AE in children (233). One study of a psychological
21 intervention used biofeedback and hypnotherapy as relaxation techniques versus
22 discussion only. Three of the four educational studies identified significant improvements in
23 disease severity in the intervention groups. The fourth trial evaluated long-term outcomes
24 and found a statistically significant improvement (P < 0.01) in disease severity and parental
25 quality of life over 12 months in all studied age groups (three months to 18 years).
26 Heterogeneity in outcome measures and inadequate methodology limited data synthesis in
27 this review. The psychological and educational interventions were delivered by nurses or
28 multidisciplinary teams (234). Quality of life (QoL) is severely impaired in AE patients (235),
29 as shown in a recent review: Statistically significant improvements in QoL of AE patients by
30 patient education were reported in five studies, whereas the severity of skin disease
31 improved significantly in three studies out of ten studies evaluated. In conclusion, patient
32 education appears to be effective in improving QoL and in reducing the perceived severity
33 of skin disease (236-238). (See chapter: Educational interventions for AE)
34 Psychotherapeutic approaches
35 Most psychological training programs include relaxation techniques (239), habit training for
36 social competence and communication as well as coping behavior and improvement of self-
37 control with regard to disrupting the itch-scratch cycle.
38 Psychosomatic counseling: Randomized controlled trials compared the use of topical
39 corticosteroid alone with steroids together with a behavioral therapy program which led to a
40 significantly pronounced improvement of skin condition and itch-scratch behavior (240).
1 Behavioral therapy: Behavioral therapy against itch was studied, showing a significant
2 improvement in symptoms after one year (241-243). Especially habit reversal techniques
3 improve itch in atopic dermatitis (244).
4 Autogenic training: Together with cognitive behavioral therapy was studied in a
5 standardized educational program (see chapter “Education”) (245).
6 Relaxation: Relaxation methods may be more effective in reducing disease severity than
7 discussion only (246).
8 Parents who had negative treatment experiences in the past and possessed only poor
9 coping abilities with regard to scratch control benefitted the most from the training program.
10 The outcome of the education measure was independent of parents' schooling, vocational
11 level and income (247). Another publication stated that there is currently only limited
12 research evidence on the effect of educational and psychological approaches when used
13 alongside medicines for the treatment of childhood eczema (233). It is well possible that
14 there is limited research activity in this area of intervention, thus providing limited evidence
15 of the measurable effects of interventions.
17 Psychosomatic counseling can be a helpful adjuvant procedure in the management of
18 patients with AE including psychotherapeutical approaches and behavioral therapy
19 techniques. (3b)
20 Relaxation techniques may cause significant improvements in disease severity. (1a)
21 Individual psychotherapeutic approaches can be helpful in individual patients. (-)
22 Psychological and psychosomatic interventions are an essential and helpful part of
23 educational programs. (1a)
24 Recommendations
25 Psychosomatic counseling, psychotherapeutical approaches, behavioural therapy
26 techniques, autogenic training, relaxation techniques, psychological and psychosomatic
27 interventions are recommended in selected patients. (1a, A)
28 The indication should be confirmed by specialists in the field of psychodermatology. (-, D)
29
1 Educational interventions for atopic eczema

2
3 Adherence to treatment and poor quality of life (QoL) are key issues in patients with AE
4 (248). Patient education (PE) interventions can help patients and their families to better
5 understand their disease and cope with treatment in order to maintain or even improve QoL
6 and treatment adherence. The aim of PE is not simply to provide information by leaflets in
7 the waiting rooms, but entails the transfer of skills (e.g. self- management of the disease,
8 treatment adaptation) from a trained healthcare professional to the patient or their parents.
9 Additionally, PE should aim to reduce doctor's visits, facilitate a better partnership between
10 the doctor and the patient/parents and restore family dynamics. PE should also lead to a
11 decrease of the long-term costs of AE treatment. A recent study showed that parents with
12 negative treatment experiences in the past and poor coping abilities regarding scratch
13 control benefitted most from PE programs (247).
14 High-quality PE programs should ideally be evidence-based, tailored to a patient’s individual
15 educational and cultural background (rather than being standardized in form and content),
16 and have well-defined content and activities (233, 236, 249).
17 Educational service delivery models
18 There are different types of PE programs running all around the world. These differ in
19 number and certification of the educators, number of participants, age of patients, teaching
20 techniques, duration and frequency of interventions (233, 250). Thus, because the content
21 of the PE programs varies greatly, comparison between studies is difficult. For example,
22 while the intervention by Staab (237) entailed 2-h sessions, involving a trained
23 multidisciplinary team, once a week for 6 weeks, the intervention by Shaw et al (251)
24 involved a trained medical student running a single 15-min session. Most of the published
25 intervention programs are structured as follows:
26 Multidisciplinary age related structured group training educational programs (eczema
27 school): There is evidence that structured age related programs are significantly improving
28 severity score, improving coping behavior, parents handling their affected children and
29 increasing disease knowledge. (237, 241, 252-255). A recent multidisciplinary eczema
30 school program tailored to the adult situation showed also high efficacy (238).
31 Eczema workshops: Eczema workshops may improve the disease severity of patients with
32 AE (256, 257). There is also a greater adherence to eczema management (coping behavior,
33 parent's handling their affected children) in the eczema school, compared with the standard
34 dermatologist-led clinic (254).
35 Nurse-led eczema workshop: There is evidence that the benefits of nurse interventions
36 are the reduction in the severity of the condition and the better use of topical therapies.
37 There is a reduction in referrals to general practitioners or dermatologists, disease
38 knowledge and self-management techniques are improving (254, 256, 258, 259). The
39 relative effectiveness of nurse led programs compared to multidisciplinary age related,
40 structured programs is unclear.
1 Structured lay-led self-management education training programs: They lead to a small

2 statistically-significant reduction in disease status (pain/ itch, disability, fatigue) and a small,
3 statistically-significant improvement in depression and psychological well-being but there
4 was no difference in quality of life (260). There is no evidence that such programs improve
5 psychological health (261, 262).
6 E-health during follow-up of patients with AE
7 E-health intervention follows the initial diagnosis and treatment with face-to-face contact.
8 This is just as effective as usual face-to-face care with regard to quality of life and severity
9 of disease. However, when costs are considered, e-health is likely to result in substantial
10 cost savings. Therefore, e-health is a valuable service for patients with AE. (263, 264).
11 Forms of educational intervention tools
12 Depending of cultural backgrounds and health care systems, a wide variety of tools are used
13 in PE programs (practical demonstrations sessions as florescent cream advices (265),
14 written action plans (266), lectures, question and answer sessions, leaflets, online videos
15 etc.) but there is no evidence that a specific tool is more efficient than another (233).
17 PE programs for AE in children and adults are efficient and established already in many
18 countries. The multidisciplinary age related structured group training educational programs
19 (eczema school) have the most evidence-based benefit. (1a)
20 Eczema workshops lead to an improvement in severity scores, there is greater adherence
21 in eczema-management, itch-scratching cognition, and there is additional psychological
22 benefit. (2a, 2b)
23 Nurse led programs result in more effective use of topical therapies. (3b)
24 Nurse led programs result in an improvement of severity scores. (2a)
25 Nurse led programs may be sparing doctor's time. (2b)
26 There is some evidence that a direct-access, online model for follow-up dermatologic care
27 is equivalent to classical in-person care for patients with AE. (2a)
28 There is no evidence of change in severity scores due to lay-led self-management education
29 programs, which have weak effect in improvement although the disease knowledge is
30 increasing (-)
31 Recommendations
32 PE programs for AE in children and adults are recommended as an adjunct to conventional
33 therapy of AE. (1a, A)
34
1 Conclusion and Outlook

2
3 The complex pathophysiology of AE explains why the therapeutic strategies also comprise
4 multiple aspects and are complex in nature. Although there is a strong genetic preposition,
5 patients with AE must not be desperate. Labelling AE as “incurable” is not correct, since the
6 eczema with its symptoms can very well be treated and may disappear totally. Adequate
7 treatment needs the cooperation of the well-informed patient with the physician and time;
8 educational programs are extremely helpful.
9 In the recent past, new medications resulting from immunological research have been
10 licensed for AE. The appearance of biologics specific for immune mediators and receptors
11 are extremely promising and will be available soon for patients in many European countries
12 and the rest of the world.
13
1 Tables
2
3 Table 1 Grades of evidence
4
5 1a) Meta-analysis of randomized clinical trials (RCT)
6 1b) Single RCTs
7 2a) Systematic review of cohort studies
8 2b) Single cohort studies and RCTs of limited quality
9 3a) Systematic review of case control studies
10 3b) Single case control study
11 4) Case series, case cohort studies or cohort studies of limited quality
12 Recommendations (see Table 2) were classified based on the grade of evidence.
Table 2 Classification of strength of recommendation

Recommendation strength Evidence grade
A 1a, 1b
B 2a, 2b, 3a, 3b
C 4
D Expert opinion
Table 3 Language of recommendations

Wording in standard Free text explanation
situations
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 This intervention is not adequate for most patients,
patients only 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
Table 4: Systemic drugs for treatment of severe atopic eczema

cyclosporine methotrexate azathioprine mycophenolic corticosteroids dupilumab
acid
overall ++ acute flare ++ long term can be used ++ little toxicity outdated long term
recommendation intervention maintenance long term maintenance
time to respond 2 8-12 8-12 8-12 1-2 4-6
(weeks) #
time to relapse <2 > 12 >12 > 12 <2 >8
(weeks)
most important serum hematological hematological hematological Cushing’s conjunctivitis
side effects creatinine liver enzymes liver enzymes skin infections osteoporosis
blood pressure gastro-intestinal gastro-intestinal gastro-intestinal diabetes
starting dose 4-5 mg/kg/day 5-15 mg/week 50 mg/day MMF 1-2 g/day 0.2-0.5 600 mg loading
adult   (EC-MPA 1.44 mg/kg/day dose
g/day)
maintenance 2.5-3 most often 15/week; 2-3 mg/kg/day* MMF 2-3 g/day** not for 300 mg/
dose adult mg/kg/day can increase to max (EC-MPA 1.44 maintenance 2 weeks
25 mg/week g/day)
starting dose 5 mg/kg/day 10–15 mg/m2/week 25-50 mg/day MMF 20–50 0.2-0.5 no data yet
children mg/kg/day mg/kg/day
maintenance 2.5-3 increase 2.5- 2-3 mg/kg/day* increase daily total not for no data yet
dose children mg/kg/day 5mg/week, decrease dose by 500 mg maintenance
2.5mg/week to every 2–4 weeks up
effective/lowest to 30-50 mg/kg/day
effective dose
pregnancy possible teratogenic, conflicting data, teratogenic, possible no data yet
absolutely contra- possible with absolutely contra-
indicated strict indication indicated
fathering possible little information, little conflicting data possible no data yet
conflicting data,
information,
contra-indicated
possible with
strict indication
1 * TPMT heterozygote 1-1.5 mg/kg/day  see full text # time to reach most of expected full response
2 MMF: mycophenolate mofetil; EC-MPS: enteric-coated mycophenolic sodium
Table 5: Upcoming systemic drugs for treatment of atopic eczema

Substance Target Substance class Development Registration Trial data Adverse drug Recommendation
code phase status effect signals
Nemolizumab CD-14152 IL31R alpha IL31 blocker III  peripheral edema?
(formerly CIM-
331)
Tralokinumab CAT-354 IL13 Th2 blocker III
Lebrikizumab TNX-650 IL13 Th2 blocker II
Tezepelumab MEDI-9929 TSLP TSLP blocker II
Upadacitinib ABT-494 JAK1 JAK inhibitor II
PF-04965842 JAK1 JAK inhibitor III
ZPL-389 H4R H4R blocker II

(formerly PF-
03893787)
 see full text

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EDF Guideline AE part I and II final – 24.01.18 (modified 08.05.

EDF-Guidelines for Treatment of Atopic Eczema (Atopic Dermatitis)

Developed by the Guideline Subcommittee “Atopic Eczema” of the

Members of EDF Guideline Committee:

Chairman of EDF Guideline Committee:

1 Consensus based European Guidelines for Treatment of Atopic Eczema

9 Pediatric Pneumology and Immunology, Universitätsmedizin Berlin, Germany

Ospedaliera, Università di Padova, Italy

12 Dermatological Practice, Immenstadt, Germany

and Educaction CK-CARE, Davos, Switzerland

15 Department of Dermatology, Heim Pál Children's Hospital, Budapest, Hungary

17 Department of Dermatology & Pediatric Dermatology, Hôpital St André, Bordeaux, France

18 Department of Dermatology, Hospital Niño Jesus, Madrid, Spain

1 Declaration of Conflict of Interest

30 Table R1 (online repository)

Global Allergy and Asthma

2 AAD American Academy of Dermatology

1 JAK Janus kinase

1 global assessment by the investigator only. The HOME group is an initiative of

1 AE management from a patient’s perspective

1 General measures and avoidance strategies

1 Specific allergen avoidance

1 Basic therapy of disturbed skin barrier function and emollient therapy

1 delayed reactions are related to positive responses to APTs. However, double-blind

1 Topical anti-inflammatory therapy

1 Topical calcineurin inhibitors

1 requirements with regard to personnel, documentation, UV protection especially of the eyes,

1 Cannabinoid receptor agonist

1 There is no evidence that topical anaesthetics and capsaicin is an effective adjuvant

5 1a) Meta-analysis of randomized clinical trials (RCT)

Table 2 Classification of strength of recommendation

Table 3 Language of recommendations

Table 4: Topical drugs for treatment of atopic eczema

suitable for proactive therapy yes yes yes* no

suitable for babies yes diluted use yes yes

 off label use * licensed use

Table 5: Upcoming topical drugs for treatment of atopic eczema

 see full text

1 152. Bornhovd E, Wollenberg A. Topische Immunmodulatoren zur Ekzembehandlung. Allergo J

1 212. Chunharas A, Wisuthsarewong W, Wananukul S, Viravan S. Therapeutic efficacy and safety of

1 Consensus based European Guidelines for Treatment of Atopic

1 Declaration of Conflict of Interest

1 JAK Janus kinase

1 Systemic anti-inflammatory treatment

1 Other systemic treatment

1 moderate to severe AE has demonstrated moderate improvement of skin lesions, pruritus

1 Complementary and alternative medicine in atopic eczema

1 Zemaphyte, a commercial product of Chinese herbs, revealed conflicting results (177,

1 20 children (195). Greater degrees of improvement in anxiety scores, tactile defensiveness

1 Educational interventions for atopic eczema

1 Structured lay-led self-management education training programs: They lead to a small

1 Conclusion and Outlook

Table 2 Classification of strength of recommendation

Table 3 Language of recommendations

is not recommended Most expert physicians would not choose this

Table 4: Systemic drugs for treatment of severe atopic eczema

Table 5: Upcoming systemic drugs for treatment of atopic eczema

Lebrikizumab TNX-650 IL13 Th2 blocker II