Guidelines For Treatment of Atopic Eczema (Atopic Dermatitis) Part II

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DOI: 10.1111/j.1468-3083.2012.04636.x
GUIDELINES
Guidelines for treatment of atopic eczema (atopic

dermatitis) Part II
J. Ring,,* A. Alomar, T. Bieber, M. Deleuran, A. Fink-Wagner, C. Gelmetti, U. Gieler,
J. Lipozencic, T. Luger, A.P. Oranje, T. Schafer, T. Schwennesen, S. Seidenari,
D. Simon, S. Stander, G. Stingl, S. Szalai, J.C. Szepietowski, A. Taeb,
T. Werfel, A. Wollenberg, U. Darsow, For the European Dermatology Forum (EDF), and the
European Academy of Dermatology and Venereology (EADV), the European Task Force on Atopic
Dermatitis (ETFAD), European Federation of Allergy (EFA), the European Society of Pediatric
Dermatology (ESPD), and the Global Allergy and Asthma European Network (GA2LEN)
Department of Dermatology and Allergy Biederstein, Christine Kuhne-Center for Allergy Research and Education (CK-CARE),
Technische Universitat Munchen, Munich, Germany and Division of Environmental Dermatology and Allergy, Helmholtz Zentrum
Munchen TUM, ZAUM-Center for Allergy and Environment, Munich, Germany
Department of Dermatology, Hospital de Sant Pau, Universitat Autonoma Barcelona, Barcelona, Spain
Department of Dermatology and Allergy, University Bonn, Bonn, Germany
Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark
EFA Project and Fundraising Officer, Konstanz, Germany
Istituto di Scienze Dermatologiche, Universita` di Milano, Milano, Italy
Department for Psychosomatics and Psychotherapy, University of Gieen and Marburg GmbH, Gieen, Germany
Department of Dermatology and Venereology, University Hospital Center Zagreb, Zagreb, Croatia
Competence Center Chronic Pruritus, Department of Dermatology, University Hospital of Munster, Munster, Germany
Department of Pediatric Dermatology, Erasmus MC Sophia Children s Hospital, Rotterdam, The Netherlands
Institute for Social Medicine, University Lubeck, Lubeck, Germany
Deutscher NEURODERMITIS Bund (DNB), Hamburg, Germany
Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy
Department of Dermatology, Universitatsklinik fur Dermatologie, Bern, Switzerland
Department of Dermatology, University of Vienna, Vienna, Austria
Department of Dermatology, Heim Pal Childrens Hospital, Budapest, Hungary
Department of Dermatology, Venereology and Allergology, Wroclaw Medical University, Wroclaw, Poland
Department of Dermatology & Pediatric Dermatology, Hopital St Andre, Bordeaux, France
Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany
Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany

*Correspondence: J. Ring: E-mail: [email protected]
Abstract
The existing evidence for treatment of atopic eczema (atopic dermatitis, AE) is evaluated using the national
standard Appraisal of Guidelines Research and Evaluation. The consensus process consisted of a nominal group
process and a DELPHI procedure. Management of AE must consider the individual symptomatic variability of the
disease. Basic therapy is focused on hydrating topical treatment, and avoidance of specific and unspecific
provocation factors. Anti-inflammatory treatment based on topical glucocorticosteroids and topical calcineurin
inhibitors (TCI) is used for exacerbation management and more recently for proactive therapy in selected cases.
Topical corticosteroids remain the mainstay of therapy, but the TCI tacrolimus and pimecrolimus are preferred in
certain locations. Systemic immune-suppressive treatment is an option for severe refractory cases. Microbial
colonization and superinfection may induce disease exacerbation and can justify additional antimicrobial treatment.
Adjuvant
therapy
includes
UV
irradiation
preferably
with
UVA1
wavelength
or
UVB
311 nm.
Dietary
recommendations should be specific and given only in diagnosed individual food allergy. Allergen-specific
immunotherapy to aeroallergens may be useful in selected cases. Stress-induced exacerbations may make
psychosomatic counselling recommendable. Eczema school educational programs have been proven to be helpful.
Pruritus is targeted with the majority of the recommended therapies, but some patients need additional antipruritic
therapies.
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Journal of the European Academy of Dermatology and Venereology 2012 European Academy of Dermatology and Venereology
Ring et al.
Conflict of interest
A. Alomar has been speaker for Almirall, Astellas, Leti. T. Bieber has been advisor, speaker or investigator for ALK
Abello, Astellas, Bencard, Galderma, Glaxo SmithKline, Leo, Novartis, Stallergenes. U. Darsow has been speaker,
investigator and or been a member of advisory boards for Allergopharma, ALK Abello, Bencard, GSK, Hermal,
Novartis Pharma, Stallergenes, Stiefel. M. Deleuran has been a speaker, participated in clinical trials and or been a
member of advisory boards for Merck, Novartis, Astellas, Leo Pharma, NatImmune, Pergamum, Pierre Fabre and
Janssen-Cilag. A.-H. Fink-Wagner received honorarium from Pharmaxis and Chiesi during the last 3 years and was
employed before that by Nycomed. J. Ring has been advisor, speaker or investigator for ALK Abello, Allergopharma,
Almirall-Hermal, Astellas, Bencard, Biogen-Idec, Galderma, Glaxo SmithKline, Leo, MSD, Novartis, Phadia, PLS
Design, Stallergenes. S. Stander was or is advisor, speaker and or investigator for Aesca Pharma, Almirall Hermal,
Astellas Pharma, Beiersdorf AG, Birken, Essex Pharma, GSK, Pierre Fabre, Maruho, 3M Medica, Mundipharma,
Novartis Pharma, Serentis, and Serono. Z. Szalai is investigator of clinical trials for Astellas, Novartis, Pfizer, Abbott,
Pierre Fabre. A. Taeb has received consulting and clinical trial honoraria from Pierre Fabre, Astellas,
Almirall Hermal, Leo and Novartis. T. Werfel has been advisor, speaker or investigator for ALK Abello, Astellas and
Novartis. A. Wollenberg has received research funding and lecture honoraria from, conducted clinical trials for, or is
a paid consultant to Astellas, Basilea, GSK, Loreal, Merck, Novartis, MSD. Other authors declared no conflict of
interest.
Phototherapy
As most patients affected by AE improve during the sunny summer season, artificial UV radiation is frequently employed in the
treatment of AE.
A recent study has confirmed that 74.4% of the patients affected
by mild-moderate AE had complete resolution during summer
holidays, 16.3% had improvement and only 9.3% had no modification of AE severity, confirming the seasonability of the disease,
with improvement during summertime and worsening in the
other seasons: More, seaside holidays produced a significantly
greater improvement than mountains holidays, with complete resolution of the disease in 91.2% vs. 11.1% of patients (P < 0.01).1
While this difference cannot be explained on the sole basis of UV
exposure, these data support the hypothesis on the positive effect
of UV radiation on AE.
Various pathways and means through which the energy of UV
radiation from natural or artificial sources is ultimately transformed into biological effects within the skin have been suggested,
including cutaneous sensory nerves, neuropeptides, neurotrophins
and certain nerve-related receptors.2 The known mechanism of
action targets immunomodulation through apoptosis of inflammatory cells, inhibition of Langerhans cells and alteration of
cytokine production.3 In addition, UV has an antimicrobial
effect reducing the colonization of S. aureus,4 due to its antiinflammatory effect and improves skin barrier.5 A different
explanation could be supported by the role of Vitamin D: a recent
study demonstrated that a 2-week course of heliotherapy significantly improved vitamin D balance by increasing serum calcidiol
concentration, and caused a marked healing of AE.6
Present UV sources include equipments able to emit selective
spectres of radiations:
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UVA + UVB (approx. 280400 nm).

Broadband ultraviolet B (BB-UVB = approx.
280320 nm).
Narrow-band UVB (nbUVB = peak: 311313 nm).
UVA1 (340400 nm).
Treatment with longer wavelengths has not been sufficiently
studied for AE and should therefore not be applied. When prescribed, phototherapy is usually a part of a total treatment plan,
i.e. a second-level treatment used especially in adults and much
less in children. Phototherapy in children younger than 12 years
should not be applied.
As a rule, phototherapy is not indicated in the acute stage of
AE (except UVA1, which is also effective in managing AE flares),
but is more apt to treat chronic, pruritic, lichenified forms and
should not be prescribed in those patients who experience a
worsening of their dermatosis during sun exposure. In practise,
the choice of a certain UV treatment is limited by the availability
of the phototherapy equipments: e.g. UVA1 devices are expensive to buy and to maintain. The biggest drawbacks of UV therapy are that the patient must travel between three and five times
per week and for 612 weeks to a site that offers this therapy. In
addition, UV light does not effectively treat hairy areas as scalp
and skin folds.
In short, taking into account the individual tolerability, narrowband UVB has been indicated for chronic moderate forms of AE7
and is currently preferred to broadband UV because it is less
erythemogenic, whereas high dose UVA1 has been prescribed for
more severe phases.8 Medium-dose UVA1 appears to be similar in
terms of efficacy as narrow-band UVB.9 Furthermore, as highlighted in a recent study, there is a small but significant
proportion of psoriasis and AE patients who do not tolerate
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Guidelines for treatment of atopic eczema
narrow-band UVB, but demonstrate an excellent clinical response

to broad-band UVB.10
Topical steroids and emollients should be considered at the
beginning of phototherapy to reduce a possible flare-up, whereas
topical immunosuppressors as tacrolimus and pimecrolimus
should be avoided. UV can also be combined with a previous (oral
or topical) administration of photosensitizing drugs (psoralens):
the so called PUVA (photochemotherapy). All UV treatments and,
even more, photochemotherapy pose a long-term risk for development of skin cancer, together with the proven prematurely ageing
of the skin. UV therapy has to comply with special requirements
with regard to personnel, documentation, UV protection especially
of the eyes, contraindications and technical aspects. Photochemotherapy is not the first choice for AE because of the proven carcinogeneity and the fact that most AE patients are young. During
systemic photochemotherapy, patients must wear UVA-blocking
sunglasses and also after treatment for some time when exposed to
sunlight because psoralens are eliminated slowly. Although simple
UV regimens are generally well tolerated (a transient sensation of
warmth should be considered normal), PUVA has a number of
side effects, which may include nausea, headache, fatigue, burning
skin, itching and irregular skin pigmentation as well as an
increased risk of skin cancer,11 so the risk-benefit ratio of this
treatment must be carefully weighted. However, it has been demonstrated that PUVA provides a better short- and long-term
response than medium-dose UVA1 in patients with severe AE.12 It
has been recently observed that PUVA therapy may reduce epidermal hyperinnervation of AE by normalization of axonal guidance
molecules as semaphorin 3A and nerve growth factor in the epidermis.13
Photopheresis is used in some centres for treatment of selected
cases. Possible effects in patients with severe refractory AE have
been described.
New devices as 308 nm monochromatic excimer light expand
the therapeutic options in patients with localized and therapyresistant AE, even though they can treat only limited surfaces.14,15
There are no prospective trials on AE patients comparing narrowband UVB and UVA1 with more complex regimens, such as heliotherapy, balneophototherapy, psoralen plus UVA (PUVA) and
extracorporeal photophoresis.16 Pulsed-dye laser for the treatment
of chronic AE is still experimental.17
In conclusion, phototherapy can improve and even clear AE; it
can decrease bacterial colonization and reduce the strength and or
the amount of topical anti-inflammatory drugs needed, but the
beneficial effects vary from person to person.
Recommendations
Narrow-band UVB is to be preferred to broad-band UVB (1a, A).

Medium-dose UVA1 is similar in efficacy as narrow-band UVB
(1b, A).
High dose UVA1 is to be preferred in severe phases (1b, A).
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Topical steroids and emollients should be considered at the

beginning of phototherapy to reduce flare-up (C).
All UV treatments pose a long-term risk for development of
skin cancer (2a, B).
PUVA therapy is not a first choice therapy. It provides a better
short- and long-term response than medium-dose UVA1 (1b, A).
New devices as 308 nm excimer laser expand therapeutic
options, but have been not assessed properly in AE (-, D).
Systemic immunosuppressive treatment

Oral glucocorticosteroids
Oral glucocorticosteroids are used in many European countries

for treatment of AE. Well known side effects limit their use especially for long-term treatment. Funding of expensive clinical trials
in the near future is unlikely.
Controlled clinical trial data demonstrating efficacy There is
one controlled trial available that demonstrates equal efficacy of
therapy with systemic glucocorticosteroids as ciclosporin.18
Broad experience from clinical use by many experts indicates
efficacy.
Evaluation summary Short-term treatment with oral glucocorticosteroids is effective (-, D).
Recommendations
Systemic steroids have a largely unfavourable risk benefit ratio for

treatment of AE. (-, D).
Short-term (up to 1 week) treatment may be an option to treat
an acute flare in exceptional cases of atopic eczema. Restrictive
use, largely limited to adult patients with severe atopic eczema, is
recommended (-, D).
The recommended daily dose should be adjusted to body weight.
Long term use in AE patients is not recommended. The indication for oral steroids in children should be handled even more
cautiously than in adults (-, D).
Ciclosporin A
Ciclosporin is licenced in many European countries for treatment

of AE. Ciclosporin inhibits the production of NF-AT dependent
proinflammatory cytokines in T cells.
Controlled clinical trial data demonstrating efficacy
Ciclosporin vs. placebo meta-analysis A meta-analysis of
pooled data from eight RCTs19 clearly demonstrated the efficacy

of ciclosporin in AE. Body surface area, erythema, sleep loss and
glucocorticosteroid use were reduced in the ciclosporin group.
The authors concluded that ciclosporine is more effective than placebo, but there is prompt relapse if ciclosporin is stopped. All
scores are back to pretreatment values 8 weeks after end of ciclosporin therapy.
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Ring et al.
Three RCTs have been published after this meta-analysis:19

Ciclosporin dosis finding study for AE treatment in adult
patients A fixed dosage ciclosporin regimen was evaluated
in 106 adults with severe AE.20 Initial treatment was performed

with 300 mg day or 150 mg day and reduced after 2 weeks to
50% of the initial daily dose until a final evaluation was performed after 8 weeks. Clinical efficacy was detectable after
2 weeks in both treatment groups, but the higher dose was significantly more effective (P < 0.05). The authors recommended
to start therapy with 150 mg day because this regimen showed
a lower incidence of serum creatinine increase.
Continuous or intermittent ciclosporin therapy study of AE in
children Forty children aged 216 years were randomized to
either a continuous long-term or an intermittent short-term

ciclosporin regimen.21 Both groups showed significantly better
results in clinical scores and quality of life assessments. Enhanced
sustained improvement was seen in the continuously treated group.
As the intermittent therapy was sufficient in some patients but
associated with a lower cumulative ciclosporin dose, the authors
recommended choosing the regimen on an individual basis.
Ciclosporin or UV Therapy for AE Ciclosporin was tested
against a combined UVA/UVB regimen in a 1 year, open label,
multicenter trial involving 72 patients.22 Ciclosporin therapy
induced a significantly higher number of days in remission, as
compared to UV therapy.
Compounding of Ciclosporin Microemulsions of ciclosporin
show an earlier onset and higher peak value of efficacy compared
with traditional formulations.23 The clinical efficacy evaluated after
8 weeks of therapy was identical for both formulations.
Drug safety profile of ciclosporin Patients receiving ciclosporin
should be monitored for blood pressure and renal parameters, as
ciclosporin is known to induce structural and organic kidney damage. Nephrotoxic effects are more likely to occur if the daily dose
exceeds 5 mg kg body weight, serum keratinine values are elevated
or elderly patients are treated.
Self-willed reduction in the recommended ciclosporin dose may

reduce the clinical efficacy of ciclosporin and is not recommended
(2b, B).
A microemulsion of ciclosporin has the advantage of an earlier
onset and peak level of clinical efficacy, which may be useful in
short-term treatment (1b, A).
Ciclosporin is effective in children and adolescent atopic eczema
patients (2b, B). As an intermittent dosage regimen will lead to
lower cumulative doses of ciclosporin and is effective in some AE
patients, an individualized dosage regimen is recommended for
underage patients (-, D).
Long-term intermittent ciclosporin therapy for 1 year is more
effective than an intermittent UVA UVB therapy following a two
to three time weekly regimen (1b, A).
Recommendations
Ciclosporin may be used in chronic, severe cases of AE in adults

(1a, A).
Well known side effects of ciclosporin limit its use in AE
(-, D).
An initial daily dose of 2.53.5 mg kg day and a maximal daily
dose of 5 mg kg day, divided upon two single doses, are recommended. A dose reduction of 0.51.0 mg kg day every 2 weeks is
recommended, as indicated by clinical efficacy (-, D).
Ciclosporin trough levels do not need to be assessed during
therapy (-, D).
Ciclosporin may be used off label in children and adolescent
patients showing a refractory or severe course of disease (2b, B). A
detailed patient monitoring, especially of the renal status, is advisable.
Although there are no controlled studies available regarding the
efficacy of vaccination during ciclosporin therapy, there is no evidence for a failure during ciclosporin either. Hence, a traditional
cessation of therapy of 2 weeks before and 46 weeks after vaccination seems possible. Clinically, there is no evidence for this recommendation (-, D).
A combination therapy of ciclosporin with UV therapy is not
indicated because the incidence of cutaneous malignancies may be
increased (-, D).
Azathioprine
Summary of evidence-based data Many RCTs indicate the
efficacy of ciclosporin vs. placebo in AE (1a, A).

The duration of therapy is guided by clinical efficacy and tolerance of the drug. Both short-term and long-term therapy may be
useful in AE (-, D).
Dose reduction should be considered according to clinical efficacy. Long-term treatment prescribing the lowest clinically useful
dose may be advisable in selected cases (-, D).
Side effects of cyclosporin argue against a long-term treatment
of AE with ciclosporin cessation of therapy should be attempted
after 2 years of therapy (-, D).
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Azathioprine is used since many years in Great Britain and the

United States for treatment of AE in adult patients. Funding of
expensive clinical trials in the near future is unlikely.
Controlled clinical trial data demonstrating efficacy Efficacy
of azathioprine was tested in a randomized, controlled, 6-month,
crossover clinical trial involving 37 patients aged 1773 years.24
The drop-out rate was high (12 patients on azathioprine, 4 patients
on placebo). Azathioprine (2.5 mg kg bw day) or placebo was
given for 3 months each in a crossover design. The SASSAD skin
severity score was reduced by 26% in the azathioprine group and
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3% in the placebo group (P < 0.01). Pruritus, sleep loss and fatigue improved significantly during azathioprine but not during
placebo treatment.
Another randomized double-blinded, placebo-controlled,
12 weeks, clinical trial involved 63 outpatients with AE.25 Following a low dose introduction phase, azathioprine was dosed in 42
patients according to the results of a thiopurine methyltransferase
(TPMT) polymorphism, which may be indicative for the myelotoxicity of azathioprine the other 21 patients received placebo.
Patients with a normal TPMT activity were treated with
2.5 mg kg bw day azathioprine, whereas patients with a reduced
TPMT activity (heterozygous phenotype) received 1.0 mg kg
bw day azathioprine. The azathioprine regimen was clearly effective in AE, as the disease activity dropped by 37% in the azathioprine group and by 20% in the placebo group. None of the
patients showed myelotoxic symptoms.
A retrospective, uncontrolled study investigated 48 children and
adolescents aged 616 years diagnosed with severe AE.26 After
3 months of therapy, 28 patients showed very good and 13
patients showed good improvement of their symptoms, whereas 7
patients showed little or no improvement. None of the patients
showed myelotoxic symptoms, TPMT activity was determined in
all patients before treatment. All patients were started on 2 mg kg
bw day and the dose was increased to 3 mg kg bw day in 14
patients due to insufficient clinical response. The mean time to
achieve clinical response was 4 weeks.
A retrospective, uncontrolled study in a heterogenous group of
17 children and adults from Hong Kong with a mean age of
16 years showed significant improvement of SCORAD after 3 and
6 months and significant reduction in total serum IgE levels.27
Mycophenolate mofetil (MMF)
Mycophenolate mofetil is an immunosuppressant drug licenced in

many European countries for treatment of systemic lupus erythematosus and prevention of transplant rejection.
Controlled clinical trial data demonstrating efficacy There is
one controlled trial with enteric-coated MMF vs. Ciclosporin A as
long-term treatment showing almost equal efficacy.28
In addition, uncontrolled trial data and some case reports indicate its clinical efficacy in AE.29,30
There is one uncontrolled retrospective report involving 14 children indicating efficacy in this age group31: MMF 4050 mg
kg day in younger children and 3040 mg kg day in adolescents.
Drug safety profile of MMF Gastrointestinal adverse events,
such as nausea or diarrhoea, are the most relevant side effect of
MMF. They are most common during initiation of treatment and
tend to disappear during long-term treatment. Leucopenia or
thrombopenia may also occur.
Summary of evidence-based data Positive case reports and
uncontrolled clinical trial data indicate that MMF may be effective
in AE (4, C).
Recommendations
MMF may be used (off label) for treatment of AE in adults in a

dose up to 2 g day, if ciclosporin is not effective or not indicated
(4, C). There are no trial data for its use in children or adolescents
(-, D).
Methotrexate (MTX)
Drug safety profile of azathioprine The authors of the Berth-
Jones study concluded that azathioprine would be an effective

and clinically useful drug for treatment of severe AE, but would
be associated with a high rate of unwanted drug effects.24 Leucocyte counts and liver enzymes must be controlled during therapy. The higher dose caused gastrointestinal symptoms in 14
patients; leucopenia in two and elevated liver enzymes in eight
patients.
Summary of evidence-based data Azathioprine is effective for
treatment of severe atopic eczema (1b, A).
Recommendations
Azathioprine may be used (off label) in AE patients, if ciclosporin

is either not effective or contraindicated (1b, A).
Patients should be screened for TPMT activity before starting
azathioprine therapy to reduce the risk for bone marrow toxicity
by dose adaptation. The suggested dose range is 13 mg kg
bw day (1b, A).
There are no published prospective clinical trial data regarding
treatment of children and adolescents (-, D).
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The immunosuppressant MTX is frequently used in psoriasis, but

there are only little published data on its use in AE. Some clinicians are using this drug in AE with good success since many
years. Funding of expensive clinical trials in the near future is
unlikely.
Controlled clinical trial data demonstrating efficacy A randomized trial with MTX vs. Azathioprine showed comparable
effects in severe atopic eczema.32
An open 24-week dose escalation clinical trial involving 12
adult patients investigated the efficacy of increasing doses
MTX.33 The starting dose of 10 mg week was increased weekly
in steps of 2.5 mg week until clinical efficacy was seen. The
skin score SASSAD improved by 52% during 24 weeks. The
median dose administered was 15 mg MTX week. Improvement remained stable in nine patients 12 weeks after the end
of treatment.
An uncontrolled, retrospective report involving 20 adult AE
patients treated with 10 mg week to 25 mg week MTX showed
response in 16 patients after 812 weeks.34 First improvement was
observed after a period ranging from 2 weeks to 3 months (mean
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Ring et al.
9.95 3.17 weeks). Treatment was more effective in adult onset

AE than in childhood onset.
Drug safety profile of MTX Drug safety data for MTX are largely
derived from clinical experience from other low dose indications
for MTX, indicating liver toxicity and teratogenicity as main areas
of concern. There are no AE specific safety data available for
MTX.
Summary of evidence-based data An open, uncontrolled clini-
cal trial indicates that MTX may be effective in AE (4, C).
The high rate of unwanted drug effects and the high treatment
costs are limiting the potential use of IFN-c in chronic diseases
(-, D).
Recommendations
IFN-c and IFN-a should not be used for treatment of AE (-, D).
Alitretinoin
Alitretinoin is a retinoid binding both retinoid and rexinoid receptors, thus delivering anti-inflammatory and antiproliferative
effects. It is licenced in some European countries for the treatment
of chronic hand eczema irrespectively of its pathogenesis.
Recommendations
MTX may be used (off label) for treatment of AE in adults, if ciclosporin is not effective or not indicated (4, C). There are no trial
data for its use in children or adolescents (-, D).
Interferon gamma (IFN-c)
Some interferons may interact with the dystorted immune system of AE patients. IFN gamma (IFN-c) is a TH1 cytokine
which has been shown to antagonize TH2 immune responses
in vitro.
Controlled clinical trial data demonstrating efficacy A 12week multicentric study involving 83 patients aged 265 years
compared the efficacy of subcutaneous injection of 50 mg m2
IFN-c with placebo in AE patients, who were allowed to continue
topical glucocorticosteroid treatment.35 Significantly more IFN-c
treated patients showed 50% improvement of the skin score compared with placebo. Erythema and scratch marks were significantly
reduced by 30%, whereas induration, dryness, itch and lichenification were not.
A high dose (1.5 Mio IE) and a low dose (0.5 Mio IE) three
times weekly IFG-g regimen were compared with placebo in 51
severe AE patients.36 Both IFG-g regimen had improved the AE
after 12 weeks as compared to placebo, but there was no difference
between both IFN-c treatment arms.
A randomized, prospective casecontrol study involving 44 AE
patients treated with IFN-a, IFN-c, thymopentin or null therapy.37
IFN-a was effective in 11 of 13 treated patients, whereas IFN-c
showed improvement in 2 of 10 patients. Thymopentin and null
therapy were ineffective.
Drug safety profile of IFN-c The high rate of IFN-c induced
unwanted drug effects included headache (60%), muscle pain
(32%) and fever (39%), all of which were significantly more frequent compared with placebo.
Summary of evidence-based data IFN-c seems to be moderately effective in adult patients with severe AE (1b, A).
Some uncontrolled observations and empirical knowledge do
not confirm the efficacy data from clinical trials (-, D).
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Controlled clinical trial data demonstrating efficacy
There is one large, multicentric randomized, placebo-controlled

clinical trial involving 1032 patients with chronic hand eczema,
about one third of which are probably atopic hand eczema
patients.38 Improvement of eczema symptoms was seen in 75% of
the patients. The response rate of hyperkeratotic hand eczema
(49%) and pulpitis sicca type patients (44%) was higher than the
dyshidrosiform subtype of hand eczema (33%). The patient group
suffering from atopic hand eczema has not been analysed separately,
and extrapalmar symptoms have not been assessed in this trial.
Six patients with AE and prominent hand involvement have
been treated with alitretinoin for 12 weeks in an uncontrolled,
open label trial.39 Palmar and extrapalmar lesions improved during the trial, as shown by the mTLSS hand eczema score and the
SCORAD.
Drug safety profile of alitretinoin As alitretinoin is teratogenic,
all women of childbearing potential must adhere to a strict birth
control programme. Headache is the most frequent clinical side
effect of alitretinoin, especially in the first 2 weeks of treatment.
Serum lipid and TSH elevation may also occur.
Summary of evidence-based data Direct evidence from an
uncontrolled clinical trial, as well as indirect evidence from a large,
double-blinded, placebo-controlled clinical trial indicates that alitretinoin may be effective in atopic hand eczema (4, C).
Recommendations
Alitretinoin may be used for atopic hand eczema in adult patients

of non-child-bearing potential unresponsive to topical steroid
therapy (1b, A).
Bystander improvement of extrapalmar AE lesions is likely, if
alitretinoin is used to treat chronic hand eczema (4, C).
There are no trial data for its use in children or adolescents
(-, D).
Biologics
Biological agents (Biologics) present a relatively new group of
therapeutics created by using biological processes that include
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recombinant therapeutic proteins, such as antibodies or fusion

proteins. Biologics specifically target inflammatory cells and mediators. In AE, biologics are used to reduce inflammation by modulating the number, activation and function of immune cells or the
action of cytokines or disease relevant antibodies. A number of
case reports, pilot studies and retrospective analyses on the effect
of biologics in patients with moderate to severe AE refractory to
topical and or systemic therapy have been published recently.
However, representative, randomized, placebo-controlled studies
evaluating the efficacy and safety of biologics in AE are still not
available.
T cells play a key pathogenic role in AE therefore targeting their
activation is a major approach of biologics. Alefacept is a fusion
protein of lymphocyte function protein (LFA)-3 (CD58) and
immunoglobulin (Ig) G that inhibits costimulation and induces
apoptosis of T cells. A 12-week course of alefacept 15 mg weekly
was reported to significantly reduce skin symptoms, pruritus and
concomitant topical steroid therapy.40 Another study demonstrated a clinical improvement in six of nine patients.41
The anti-CD11a antibody efalizumab shown to be effective in
AE by blocking the recruitment of T cells is no longer available
because of the risk of progressive multifocal leukoencephalopathy
(PML). Whereas early observations stated a significant improvement upon efalizumab therapy,42 a recent retrospective analysis
revealed a slight effect in 511 patients only.43 The depletion of B
cells by an anti-CD20 antibody, rituximab (2 1000 mg), resulted
in a rapid reduction in skin inflammation in all patients with a
sustained effect over 5 months in five of six patients. These results
suggest a pathogenic role of B cells in AE.44 However, a report on
two cases of severe AE receiving rituximab could not confirm
these findings.45
Inflammation in AE is characterized by a T-helper 2 cytokine
expression including interleukin (IL) 5 and eosinophil infiltration. Upon short-term therapy with the anti-IL-5 antibody
mepolizumab (2 750 mg), a moderate improvement of clinical
symptoms was observed, although a rapid depletion of eosinophils
in the peripheral blood was noted.46 Mepolizumab had no effect
on atopy patch test reactions.47 Based on the promising results in
AE and the experiences in bronchial asthma therapy, long-term
trials with anti-IL-5 antibodies seem indicated.
The majority of AE patients has elevated serum IgE levels, but
the pathogenic role of IgE in AE remains unknown. First case
reports gave inconsistent results on the effect of anti-IgE antibody
(omalizumab) treatment in severe AE.48,49 Upon low-dose antiIgE therapy (10 cycles of 150 mg), 6 of 11 AE patients with serum
IgE levels >1000 kU L before therapy responded as shown by a
decrease of SCORAD more than 50% in two and between 25%
and 50% in four patients.50 However, in a placebo-controlled
study in 20 patients, omalizumab administered for 16 weeks failed
to improve AE symptoms and itch despite a depletion of free
serum IgE and reduction in IgE receptor saturation.51 Recent studies reported that accompanying AE significantly improved in
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patients receiving omalizumab because of severe bronchial

asthma.5254
Anti-TNF-alpha (infliximab) has been shown to significantly
decrease skin symptoms and pruritus in patients with severe AE
during induction therapy.55 However, a sustained improvement
was seen only in two of nine patients during maintenance therapy.55 A patient with severe AE and concomitant contact allergy
responded well to anti-TNF-alpha.56 To note, some authors
observed AE-like skin eruptions in patients treated with anti-TNFalpha,57,58 whereas others did not.59
None of the biologics has been approved for the therapy of AE
yet. At present, the use of biologics in AE is advisable only in
patients with severe AE refractory to other topical and or systemic
treatment. Beside the lack of efficacy and safety data in AE, the
potential side effects as well as the costs have to be taken in
account before using biologics. On the other hand, treatment with
biologics provides important information on pathogenic mechanisms in AE. Today, more biologics are under investigation for
treatment of allergic diseases.
Recommendations
In patients with severe AE refractory to topical and systemic treatment, a therapy with biologics (omalizumab, rituximab or alefacept) can be considered (4, C).
Allergen-specific immunotherapy (ASIT)

The efficacy of specific immunotherapy in AE has been shown in
a number of case reports and smaller cohort studies,60 (reviewed
by Darsow et al.61) and more recently in a larger multicenter trial
with subcutaneous house dust mite immunotherapy.62 Due to
these data it became clear that ASIT can be applied for the treatment of allergic rhinitis or mild asthma also in those patients
who suffer in addition from AE as eczema was obviously not
worsened during or after ASIT. More and larger prospective studies are now being performed which shall respond to the question
whether AE alone may be an indication for the initiation of ASIT.
Experience in a pair of monozygotic twins with AE (with spring
and summer exacerbations) treated either with grass pollen ASIT
or placebo in a double-blind fashion showed significant improvement and decrease in serum IgE in the patient treated with
ASIT.63 Several open uncontrolled study designs also demonstrated advantages of ASIT in patients with AE, these data were
often published in national or non-anglosaxon journals. Some
investigators in the 1970s and 1980s also showed improvement of
AE in controlled trials (review61). A double-blind controlled trial
of ASIT with Dermatophagoides pteronyssinus in children with AE
was published in 1992 by Glover and Atherton63a This study
failed to demonstrate superiority over placebo after a standard 8
months course of treatment with tyrosin-adsorbed house dust
mite extracts in 24 children with AE and immediate hypersensitivity to this allergen. However, in a second study phase children
were randomly allocated to continue with active treatment or
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Ring et al.
placebo for a further 6 months. The numbers were too small to

permit confident conclusions, but the clinical scores suggested
that prolonged hyposensitization may be more effective than placebo with regards to several objective parameters of eczema severity. The authors noted that a high placebo effect led to problems
in comparing the active treatment. In the placebo-controlled
study of Kaufman and Roth,64 the skin condition of 13 of 16 treated patients improved, whereas only in 4 of 10 placebo-treated
patients this effect was noted. Similar results were reported by
Warner et al.65 and Zachariae et al.66 showing improvement of
eczematous skin lesions under ASIT with house dust mite
extracts.
Oral ASIT for D. pter. was not effective in a controlled study
enrolling 60 children with AE which were followed for 3 years.67
In contrast, Mosca et al.68 could show the effect of s.c. conventional ASIT (n = 41; 76% improved) and sublingual route
immunotherapy (SLIT; n = 48; 64% improved). This study also
reported on medication used and adverse drug reactions. The latter occurred in 1520% (both groups). Mastrandrea69,70 reported
a 6-year study in 35 selected AE cases undergoing SLIT, with
average 72% remission of AE after 2 years. However, this observational study also lacked a control group. Pajno et al.71 performed
a controlled study applying SLIT with house dust allergens in
children with AE. The outcome of this intervention was positive
only in patients with mild-to-moderate AE but not with severe
AE.
Noh and Lee72 reported in a pilot study the improvement of AE
together with changes in T-cell subpopulations induced by IFN-c
pretreatment before ASIT with house dust mite allergens. Patients
receiving placebo, IFN-c only or ASIT only showed no treatment
effect.
Werfel et al.62 investigated 89 patients with AE showing a sensitization to house dust mite (CAP-FEIA > 4). Patients were
injected weekly with three different doses of HDM allergen extract.
With higher allergen doses, a beneficial SCORAD decrease
occurred after 8 weeks compared to a control group with very low
allergen dose. The effect was maintained over 1 year and was
accompanied by lower glucocorticosteroid use. A smaller DBPC
study involving 20 patients with HDM- or grass pollen sensitization also showed objective and subjective symptom relief73 under
ASIT.
Even if the results of the studies are interpreted very carefully
with regard to the therapeutical effects of ASIT, it is remarkable
that exacerbations of the skin disease during this specific treatment
were rare. In contrast, the treatment was well tolerated in most
patients. The same was true for studies in patients with coexistent
AE who were treated with ASIT for respiratory atopic diseases and
experienced not more often flares of eczematous skin lesions. One
also has to keep in mind that eczema flares were seen in the control or placebo groups, too.
The role of allergens in the pathophysiology of AE has
been proven in controlled studies on allergen avoidance and
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atopy patch testing.7476 In respiratory atopic diseases, ASIT

plays an important role not only for treatment but also for
the prevention of further sensitizations and progress to more
severe respiratory disease (change from rhinitis to bronchial
asthma).
Hypothetically, patients with a positive atopy patch test and
corresponding history of eczema flares may be candidates for ASIT
with the eliciting allergen. The performed studies point to the
safety of ASIT also in AE, if the treatment is performed according
to the guidelines. However, the final judgement on the efficacy of
ASIT in this diagnosis is still not possible due to the lack of large,
controlled and randomized clinical trials with modern allergen
vaccines.61 As ASIT works in the sense of a biological response
modifier, it may require a longer time to exert all its effects on
inflammatory reactions as usually selected for pharmacotherapeutic trials.69 The issue of combining ASIT with immunomodulating
(pre) treatment may also deserve further investigations in AE
patients. Thus, the addition of anti-IgE treatment (with a monoclonal, commercially available antibody) to ASIT has been shown
to result in increased improvement in patients with respiratory
atopy.77
Recommendations
ASIT may have positive effects in selected, highly sensitized

patients with AE. The best evidence so far is available for ASIT
with house dust mite allergens (2a,B).
There is no contraindication of performing ASIT in patients
with respiratory allergic diseases (allergic rhinoconjunctivitis, mild
allergic bronchial asthma) associated with AE (2b,B).
Complementary and alternative medicine in

atopic eczema
There is evidence of growing interest of so called complimentary
alternative medicine (CAM) as treatment for AE.7880 This chapter
summarizes the available RCT-based evidence on specific treatment modalities.
For that purpose the electronic database PubMed was systematically searched for available randomized, controlled trials of
complementary, alternative treatment modalities used for AE. The
search covered the period from 1966 up to October 2009 and
included the terms atopic dermatitis or eczema and complementary or alternative medicine as well as specific modalities, such as
acupuncture, homeopathy, bioresonance or phytotherapy. Statements for the consensus process are given in bold letters at the
end of each chapter. If not specified otherwise these are based on
RCT (1a) evidence.
Definition
CAM has been defined as diagnosis, treatment or prevention

which complements mainstream medicine by contributing to a
common whole, by satisfying a demand not met by orthodoxy or
by diversifying the conceptual frameworks of medicine.79
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USA
of age prescribed CAM significantly more often in the UK and the

USA.
34
UK
26
Sweden
25
Netherlands
Specific CAM modalities
20
Germany
46
France
49
Denmark
23
Belgium
31
0
10
20
30
40
50
60
Figure 1 Results from population-based studies reporting use

of complementary medicine (% of patients) in the USA and
selected European countries.82
The underlying concept, rationale and practise of the different

CAM modalities will not be described in detail. The interested
reader is kindly referred to the corresponding literature.81
Usage of CAM in the general population
With respect to single countries, France (49%) and Germany

(46%) seem to exhibit the highest usage of CAM in Europe82
(Fig. 1). The growing interest in CAM in the public was demonstrated by a study from the United States, indicating an increase
in the usage of CAM from 33.8% to 42.1% between 1990 and
1997.83 A recently published telephone survey of the British
Broadcasting Corporation revealed that 20% of a random sample
of 1204 adults reported experiences with CAM in the preceding
year.
Usage of CAM for AE or allergies
A few studies have investigated the patterns of use of CAM in

patients with AE or related disorders. A study from Switzerland
investigated 202 inpatients with atopic disorders of which 37%
claimed to have used CAM previously. The most frequently used
techniques were homoeopathy (48%), diet (35%) and herbalism
(28%), autologous blood injection (28%), phytotherapy (20%)
and acupuncture (18%).84
A study from Norway investigated 444 inpatients with AE of
which 51% reported the previous use of CAM. The most popular
modalities were homoeopathy (34%), herbalism (19%), food supplements (18%), diet change (18%) and acupuncture (11%).85
A German population-based telephone survey in adults with
allergies revealed that 26.5% have used CAM.86 The most common
procedures were homoeopathy (35.3%), autologous blood injection
(28.1%), acupuncture (16.6%) and bioresonance (10.0%).
Utilization of CAM by dermatologists
A British health service research survey compared the treatment

patterns of dermatologists in Japan, the USA and the UK.87 The
highest prevalence of utilization of CAM was reported by Japanese
dermatologists (27%). Interestingly, dermatologists over 45 years
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Essential fatty acids With respect to polyunsaturated fatty acids

(PUFA), a distinction should be made between x-3 acids like
eicosapentaenoic acid and their metabolites and x-6 acids like
arachidonic acid and the corresponding metabolites. The supplementation with x-3 fatty acids is based on the assumption that the
inflammatory profile of x-6 fatty acids and their metabolites is
higher than that of x-3 fatty acids and their metabolites and that the
supplementation with x-3 fatty acids shifts the metabolic pathway
towards less inflammatory metabolites. x-3 PUFA were studied in
oral and topical administration in patients with AE. The most commonly used preparations were eicosapentaenoic acids, evening
primrose oil (containing 810% GLA, Epogam, Strathmann
GmbH, Hamburg, Germany), borage oil (containing at least 23%
GLA) and fish oil. The systematic review of treatments for AE published in 2000 summarizes available RCT evidence of supplementation with essential fatty acids.19 The authors describe a metaanalysis of 9 RCTs88 and another large study conducted by Bamford
et al.89 The meta-analysis concluded that primrose oil has a modest
beneficial effect. However, several trials had not been made available
to the public at this stage, which made a critical methodological
appraisal impossible. Results of the two largest and well-reported
studies on evening primrose oil could not show an effect superior to
placebo. The further 9 published RCTs have given conflicting evidence. Further meta-analyses and systematic reviews on evening
primrose oil and GLA supplementation are under way.
In a trial published by Ring and Kunz, 17 patients were treated
with eicosapentanoeic acids or placebo over 3 months.90 At the
end, all clinical parameters had improved significantly in both
with a slight superiority for placebo.
A study from India failed to show significant therapeutic effects
of primrose oil 500 mg day compared to 300 mg day sunflower
oil delivered in capsules over 5 months.91
Beside four smaller trials,9295 giving conflicting results, there
are only two other reported RCTs on the use of borage oil in atopic eczema. In the trial published by Henz et al.,96 160 adult
patients were treated with borage oil containing capsules or placebo over a 24 weeks period. No significant differences concerning
the clinical response as a function of corticosteroid usage was
found. However, subgroup analyses by centres or patients who
demonstrated an increase in erythrocyte dihomo-c-linolenic acids
revealed significant results in favour of supplementation with borage oil. This might indicate a beneficial effect on those who absorb
and metabolize GLA and justifies further trials.
A total of 140 patients, including 69 children, were treated by
an English working group with either borage oil capsules or placebo over 12 weeks. No significant differences in severity, symptoms, global assessment or use of medication were observed.97
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A study from Berlin compared the daily administration of 5.4 g

docosahexaenoic acid (DHA) in 21 patients who completed the
trial with an isoenergetic control of fatty acids (N = 23) over
8 weeks. The SCORAD dropped significantly in the DHA group,
however, significant differences to control were not observed.98
In a comparison of dietary hempseed oil with olive oil, some
parameters of skin physiology and symptoms improved under
hempseed oil, but obviously without significant difference to the
control group.99
A recent randomized trial in 20 hospitalized patients with AE
comparing infusions of fish oil to soybean oil revealed marked
improvements within 1 week in both groups, but a significantly
greater effect in those treated with fish oil.100 Some smaller RCTs
have also indicated a beneficial effect,101103 although the largest
and well-reported trial could show no difference between the fish
oil and the placebo.104
Primrose oil has also been used as topical treatment. Although
the pilot study has indicated some beneficial effects,105 further
studies were unable to establish a dose response relationship.106
Further studies could not prove a beneficial effect on skin barrier
function.107 However, large trials on that issue are lacking.
Recommendations
There is not enough evidence to support the use of oral or topical

applications of unsaturated fatty acids in the treatment of AE.
Phytotherapy
Herbal remedies are used either orally or topically since a long time
also for skin diseases, mainly because of their anti-inflammatory
and itch-relieving capacity. Detailed background information on
herbal therapy in dermatology is summarized in a recent review.108
Concerning the topical use we identified two RCTs investigating
the efficacy and safety of a chamomile preparation109 and a cream
containing hypericum extract respectively.110 The chamomile
extract containing commercial cream Kamillosan (MEDA Pharma
GmbH, Bad Homburg, Germany) was compared to either 0.5%
hydrocortisone cream or vehicle cream in a half-side comparison
in 69 patients with AE. With respect to the major outcome
parameters pruritus, erythema and desquamation, Kamillosan
was moderately superior to 0.5% hydrocortisone after a 2 week
treatment and not different to the vehicle cream. Results of statistical analysis were not given in this publication. The cream
containing hypericum extract standardized to 1.5% hyperforin
was compared with the corresponding vehicle cream in a halfside comparison in 18 patients with mild-to-moderate AE. Over
4 weeks the modified SCORAD index improved with both therapies, but the improvement was significantly higher under active
treatment. This promising result should be confirmed by larger
trials and in comparison with topical standard therapy.
A further study compared a topical preparation of Mahonia
aquifolium, Viola tricolor and Centella asiatica with the vehicle
cream in 88 patients and could not find significant differences.111
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A subgroup analysis revealed superiority of the plant preparation

under dry and cool weather conditions.
Plant extracts are prone to induce contact sensitization and subsequent contact allergy. This has been studied intensively and corresponding clinical reports exist.112,113 It was demonstrated that so
called phytocosmetic creams containing a mixture of plant extracts
also contain triamcinolone acetonide as an active ingredient.114
Beside negative results, there is only one RCT indicating a beneficial effect of hypericum as a topical phytotherapy. No recommendation can be given based on the available evidence.
Chinese herbal medicine
Chinese herbs are part of the traditional Chinese medicine which

consists of Chinese herbs administered orally or topically,
acupuncture, diet and exercise.115,116 Chinese herbal treatment is
promoted as treatment for AE, taken orally as decoction, usually
consisting of about 10 different herbs. The first randomized controlled trials of Chinese herbal medicine in the treatment of AE
outside China were published by Sheehan and coworkers117,118
and subsequently summarized in a systematic review.119 In a similar crossover design, 37 children and 31 adults received either an
active or a placebo plant mixture over an 8-week period. The
severity scoring included erythema, surface damage and percentage
area affected. The median percentage change for surface damage
in the childrens group was 63.1% for Chinese herbs, compared
with 6.2% for placebo. In a 1-year follow-up, the 23 children who
decided to stay on Chinese herbs showed overall better results than
those who quit this therapy.120 In the adult group the geometric
mean for surface damage at the end of Chinese herbs treatment
was 11.3 compared with 111 at the end of placebo.121 After 1 year
12 of the 17 adults, who decided to continue the herbal treatment
had a greater than 90% reduction in the clinical score which was
significantly better than those of the 11 patients, who chose not to
carry on taking the medication. Short-term toxicity was not
observed in these trials, but prior routine checks of haematological, renal and hepatic function were recommended. Serious
adverse effects including fatal hepatitis have been reported by independent investigators following these trials.115,122124 A further trial
investigating a commercial product of Chinese herbs (Zemaphyte, Phytopharma, UK) focused on immunological outcomes
and indicated relevant immunological as well as clinical effects.125
Zemaphyte was further evaluated and compared with placebo in a
crossover trial involving 37 patients.126 A trend towards clinical
improvement was observed in both groups without significant differences between groups.
The oral application of a combination of Eleutherococcus, Achillea millefolium and Lamium album was not superior to placebo
after 2 weeks.127
Although earlier reports indicated beneficial effects of Chinese
herbal medicine in the treatment of AE, consecutive trials could
not confirm these findings and further studies including larger
sample sizes are certainly needed.
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Recommendations
11
There is not enough evidence to support the use of Chinese herbs

in the treatment of AE.
A classical randomized placebo-controlled trial was initiated in

Germany including 60 patients.136 There was no difference between
placebo and verum homoeopathy in the outcome of AE.137
Acupuncture
Recommendations
Acupuncture has not been studied systematically or within randomized controlled trials as a treatment for AE. Case series of
patients including those with AE indicate some beneficial effects,
but studies implying a rigorous methodology are needed.128130
There is absence of evidence to support the use of homoeopathy

in the treatment of AE.
Recommendations
There is absence of evidence to support the use of acupuncture in

the treatment of AE.
Autologous blood therapy
We located one RCT comparing the reinjection of 13 ml autologous blood over 5 weeks to the injection of the equivalent amount
of sterile saline solution.131 Patients were recruited via press advertisement and finally 30 subjects participated. Over a 9 weeks
period, eczema severity as measured by SASSAD dropped significantly in the verum group from 23.2 to 10.4 and did not change
in the placebo group (21.022.5). Significant differences were not
observed in health related quality of life and the subjective assessment of pruritus skin appearance and sleep quality. The data suggest a beneficial effect of autologous blood therapy with respect to
the severity score. This finding should be confirmed in larger trials
and different settings.
Massage therapy aroma therapy
The effect of additional massage therapy applied daily for 20 min

over a 1-month period compared to standard therapy alone was
investigated in a randomized trial in 20 children.138 Greater
degrees of improvement in anxiety scores, tactile defensiveness
and coping index were reported by parents of children in the
active group. Furthermore, clinical signs such as scaling and excoriation improved significantly in the massage group. However,
appropriate statistical comparisons between groups were not performed. A further small crossover trial in eight children compared
massage with essential oils (aroma therapy) to conventional
massage.139 Both treatment groups improved significantly without
significant differences between groups. Given the small sample
size, conclusions on the beneficial effects of additional aroma therapy cannot be drawn.
Recommendations
There is insufficient evidence to support the use of massage aroma

therapy in the treatment of AE.
Recommendations
Salt baths
There is no evidence to support the use of autologous blood therapy in the treatment of AE.
Salt bath has been used for a long time to control chronic inflammatory skin diseases, especially psoriasis. Based on this experience
and anecdotal evidence, salt was recently recommended also in the
treatment of AE. The efficacy of salt bath alone, however, has not
been studied systematically in AE. In the current reports, salt baths
were investigated as part of a complex climatotherapy or in combination with UV therapy.140,141 A large clinical observation of
1408 patients with AE, who stayed 46 weeks in the Dead Sea area
revealed complete clearance of lesions in 90% of the patients.142
In another study from the Dead Sea area of 56 patients with
AE, bathing in diluted Dead Sea water was compared with bathing
in sweet water (20 min, twice a day) as part of the climatotherapy
regimen. As a result the severity index improved significantly in
both groups without significant differences between groups.143
Another uncontrolled trial investigated the use of narrow-band
UVB and bathing in Dead Sea salt solution. Significant improvement according to the SCORAD score was reported in per-protocol analysis (N = 143) or intention to treat analysis (N = 615).144
In a small trial from Germany, 12 patients were treated with
UVA B monotherapy and compared with 16 patients who
underwent UVA B phototherapy plus salt water baths.145 After 20
treatments, the SCORAD score improved markedly and significantly in the balneophototherapy group and only a marginal
Bioresonance
One RCT has been published so far, comparing bioresonance with

a sham procedure in 36 children with AE attending a specialized
rehabilitation unit in Davos, Switzerland.132 After 4 weeks, severity
score has improved in both groups with slight superiority of the
active group (differences 12.5 vs. 8.7). Statistical significant differences between groups did not occur. Although small benefits cannot be excluded, this study could not demonstrate a substantial
clinical effect and further studies under more usual outpatient
conditions are needed.
Recommendations
There is no evidence to support the use of bioresonance in the

treatment of AE.
Homoeopathy
Large case series illustrating the therapeutic benefits have been

published as papers or books.133,134 A recent uncontrolled trial of
17 patients with longstanding AE in Japan revealed a marked
improvement after the introduction of homoeopathic treatment.135
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Ring et al.
12
improvement was observed in the UVA B monotherapy group.

The patients of this small trial, however, were not randomized and
the baseline severity indicates that SCORAD of the patients in the
combination therapy group was much higher. In another German
trial, Dead Sea salt bath plus phototherapy were compared with
salt bath alone.146 However, results of the eight patients included
with AE were not given separately.
In a randomized trial from Japan, 100 patients were assigned to
get either Deep Sea water or physiological saline sprayed on the
skin for every 10 min, every day for 1 week.147 Clinical improvement was small in both groups and not statistically different.
Recommendations
At the moment there is not enough RCT evidence to support the

use of salt baths in the treatment of AE.
Vitamins and minerals
A total of six trials were identified investigating vitamins or minerals in the treatment of AE.148153 A recent study from Italy studied
96 patients who were randomized to either 400 IU of vitamin E
taken orally once a day, or placebo over the period of 8 months.152
According to the subjective assessment of the clinical outcome
after 12 months, marked differences between groups were
observed. A great improvement was reported by 46% in the vitamin E group compared with only 2% in the placebo group and
correspondingly, 87% of the placebo group reported worsening
and 8% did so in the vitamin E group. Unfortunately results of
statistical tests are not given in the publication. Similarly, a smaller
study of 49 patients comparing vitamin E plus vitamin B2 to vitamin E or vitamin B2 alone revealed a superiority of the combination treatment with respect to the physicians assessed overall
usefulness and global rating.150
A further trial in 60 adults with AE compared selenium or selenium plus vitamin E vs. placebo over a 12 weeks period.149 The
AE severity score fell in all 3 study arms without significant differences. A Hungarian study compared multivitamin supplementation in 2090 pregnancies to trace element supplementation in
2032 pregnancies over a 17-month period.148 AE occurred more
frequently in the multivitamin group (0.7% vs. 0.2%). Although
this unexpected result could be a chance finding as suggested by
the authors, detailed studies in the prospective setting are needed.
A small trial has investigated the zinc supplementation vs. placebo in 15 children over a 2-month period.154 The severity score
increased in both study groups without significant differences.
There is one published RCT comparing pyridoxine (vitamin
B6) vs. placebo in 41 children over a 4 weeks period.151 The median severity score increased in the pyridoxine group, whereas an
improvement was observed in the placebo group. None of the
differences were statistically significant.
In the only pilot study on Vitamin D so far, five children were
treated daily with 1000 IU for 1 month. Compared to six controls
the EASI score improved, but without statistical significance.153
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Recommendations
There is preliminary evidence that vitamins, especially vitamin

E and D, are useful in the treatment of AE, but further trials
are needed before an evidence-based recommendation can be
given.
Topical Vitamin B12
There are two smaller studies with half-side comparisons, which

indicate a beneficial effect of a preparation containing 0.07% vitamin B12 in avocado oil compared with a placebo preparation.
After application over 8 weeks in 41 adults the modified SASSAD
score dropped significantly more in the verum area. Similarly, the
global patients and physicians assessments were significantly better
for the area which was treated by verum in this German study.155
In the US, the preparation was tested in a similar design in 21 children and showed a significant superiority over placebo with
respect to the SCORAD.156 Large-scale studies should follow to
confirm these results.
Recommendations
The committee feels that these studies do not provide enough evidence to recommend this treatment.
Harms
Contrary to widespread assumptions of the public, CAM is not

free of side effects. Dietary regimens involving strong restrictions can lead to harmful sequels in terms of malnourishment.
Therapeutic procedures involving organic material from plants
or animals can be associated with severe toxic or allergic
reactions.
Psychosomatic counselling
Psychological and emotional factors are well known to influence
the clinical course of AE, which is reflected by the name neurodermitis in some countries for this disease. The itch-scratch cycle
is especially vulnerable to psychological influences and can show a
tendency to self-perpetuation.157159
It is also known that stress can elicit severe exacerbations of
eczematous skin lesions.160
At the same time psychosomatic disease in the sense of anxiety
or depression can be comorbidity features of AE.158
Quality of life is severely impaired in AE patients.161
Therefore, a variety of psychotherapeutic approaches including
psychosomatic counselling and behavioural therapy have been
studied.
Two randomized controlled trials compared the use of topical
corticosteroid alone with steroids together with a behavioural therapy programme which led to a significantly pronounced improvement of skin condition and itch-scratch behaviour.162
Autogenic training together with cognitive behavioural therapy
was studied in a standardized educational programme (see chapter
Education).163
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Behavioural therapy against itch was studied by Niebel164 showing a significant improvement in symptoms after 1 year.
Psychosomatic counselling and psycho education with regard to
relaxation techniques and behavioural therapeutical programmes
are part of several educational programmes used in AE (see Education).
Intrafamiliar psychodynamics are also well-known factors influencing the clinical course of AE.165,166
Most psychological training programmes include relaxation
techniques, habit training for social competence and communication as well as coping behaviour and improvement of self-control
with regard to disrupting the itch-scratch cycle.
Recommendations
Psychosomatic counselling can be a helpful adjuvant procedure in

the management of patients with AE including psychotherapeutical approaches and behavioural therapy techniques (3b, B).
Individual psychotherapeutic approaches can be helpful in individual patients (-, D).
Psychological and psychosomatic interventions are an essential
and helpful part of educational programmes (1a, A).
Educational interventions for atopic eczema

Psychological and educational interventions enhance the effectiveness of conventional therapy for children with AE. These interventions are focused on the process of acquiring new knowledge
or skills through teaching and learning activities. Information
and formal teaching lead the recipients to become more accurately informed about the condition, and therefore better
equipped to understand the need for medical treatments and
good disease management. This improvement in disease control
will restore family dynamics, the patient and family will cope
better and have an overall improvement in quality of life. In
addition, education should aim to reduce doctors visits, facilitate
a better partnership between the doctor, and the patient, and the
parent. This leads to a decrease in the long-term costs of chronic
disease treatment.
Educational service delivery models
There are different educational programmes running all around

the world. These differ in number and certification of the educator, number of participants, age of patients, duration and frequency of interventions. The outcome of the patient education
depends on the education techniques, the skills of the educator
and the composition of the participants.
Multidisciplinary age related structured group training educational programmes: There is evidence that structured age related
programmes are significantly improving severity score, improving
coping behaviour, parents handling their affected children and
increasing disease knowledge.167171
Eczema workshops: Significantly more patients from the
eczema workshop improve from moderate-to-mild severity
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13
score.172,173 There is greater adherence to eczema management

(coping behaviour, parents handling their effected children) in
the eczema school compared with the standard dermatologist-led
clinic.171
Atopic eczema educator: There is no evidence that this kind of
intervention improves the severity, the quality of life or the disease
outcome. Itch-scratching cognitions are improving and parents
deal with their effected children better. The additional psychological benefit in the training group does not only depend on the
greater improvement of SCORAD values, the disease knowledge is
increasing.171,174,175
Nurse-led eczema workshops, single nurse-led interventions,
nurse-led care: The self-management techniques are improving.
There is evidence, that the benefits of nurse interventions are the
reduction in the severity of the condition and the use of topical
therapies are more effective. There is a reduction in referrals to the
general practitioner or dermatologists, and the disease knowledge
is increasing.171,172,176
Structured lay-led self-management education training programmes: They lead to a small statistically significant reduction in
disease status (pain itch, disability, fatigue) and a small statistically
significant improvement in depression, small improvement in psychological well being, there was no difference in quality of life.177
No evidence that such programmes improve psychological
health.178180
Forms of educational intervention tools
There are numerous kinds of intervention tools, which help to

improve understanding, and knowledge. The different health systems have different backgrounds.181,182
There is evidence that a special educational school enhances better knowledge of the disease, and has positive effects.183185
There is no evidence that demonstrations, lectures, question
and answer sessions and relaxation techniques result in significant
improvement of disease severity.186 The patients perceptions of
conventional medicine is improved.187
Direct telephone access to a nurse leads to a better understanding of self-management.184
Video-based education, films, audiotapes, books booklets, leaflets, handouts, questionnaires improve the disease knowledge, but
the evidence of usefulness needs further investigation.188191
There are no available controlled clinical trials in case of the use
of written action plans, the effect on adherence in paediatric AE
needs further investigation.184,192
Website information for educating patients is not sufficient
because the internet is not generally accessible. Internet access is
not common everywhere and the information is not necessarily
credible among adult patients. The current status needs further
investigations in each country.193,194
The health systems and possibilities are differing in each countries. Personal contact and the structured programmes such as the
educational schools show the most benefit.
2012 The Authors

Ring et al.
14
Recommendations
Educational programmes (training programmes, eczema

schools) for AE in children and adults are highly efficient and
established already in many countries. The multidisciplinary age
related structured group training educational programmes are
improving coping behaviour, parents handling their children.
The skin symptoms improve, and there is less need for
medication. These programmes have the most benefit and are
therefore recommended as an adjunct to conventional therapy of
AE (1a, A).
The eczema workshops lead to the improvement in severity
scores, there is greater adherence in eczema management, itchscratching cognition and there is additional psychological benefit
(2a, 2b B).
The nurse-led programmes result in more effective use of topical therapies and improvement in severity scores, but there is a
narrow range in their roles, although it is remarkable that this
intervention is sparing doctors time (2a, 2b B).
There is no evidence of change in severity scores due to the programmes led by an AE educator, nor the lay-led self-management
education programmes, which have weak effect in improvement,
but the disease knowledge is increasing (-, D).
Acknowledgements
The work was supported by Christine Kuhne-Center for Allergy
Research and Education (CK-CARE) Davos, Munich, Zurich.
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2012 The Authors


Guidelines For Treatment of Atopic Eczema (Atopic Dermatitis) Part II

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JEADV

Guidelines for treatment of atopic eczema (atopic

Department of Dermatology and Allergy, University Bonn, Bonn, Germany

Department of Dermatology, Aarhus University Hospital, Aarhus, Denmark

EFA Project and Fundraising Officer, Konstanz, Germany

Istituto di Scienze Dermatologiche, Universita` di Milano, Milano, Italy

Institute for Social Medicine, University Lubeck, Lubeck, Germany

Deutscher NEURODERMITIS Bund (DNB), Hamburg, Germany

Department of Dermatology, University of Modena and Reggio Emilia, Modena, Italy

Department of Dermatology, Universitatsklinik fur Dermatologie, Bern, Switzerland

Department of Dermatology, University of Vienna, Vienna, Austria

Department of Dermatology, Heim Pal Childrens Hospital, Budapest, Hungary

Department of Dermatology & Pediatric Dermatology, Hopital St Andre, Bordeaux, France

Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany

Department of Dermatology and Allergy, Ludwig-Maximilian University, Munich, Germany

2012 The Authors

UVA + UVB (approx. 280400 nm).

2012 The Authors

Guidelines for treatment of atopic eczema

narrow-band UVB, but demonstrate an excellent clinical response

Narrow-band UVB is to be preferred to broad-band UVB (1a, A).

Topical steroids and emollients should be considered at the

Systemic immunosuppressive treatment

Oral glucocorticosteroids are used in many European countries

Systemic steroids have a largely unfavourable risk benefit ratio for

Ciclosporin is licenced in many European countries for treatment

pooled data from eight RCTs19 clearly demonstrated the efficacy

2012 The Authors

Three RCTs have been published after this meta-analysis:19

in 106 adults with severe AE.20 Initial treatment was performed

either a continuous long-term or an intermittent short-term

Self-willed reduction in the recommended ciclosporin dose may

Ciclosporin may be used in chronic, severe cases of AE in adults

Summary of evidence-based data Many RCTs indicate the

efficacy of ciclosporin vs. placebo in AE (1a, A).

Azathioprine is used since many years in Great Britain and the

2012 The Authors

Guidelines for treatment of atopic eczema

Mycophenolate mofetil (MMF)

Mycophenolate mofetil is an immunosuppressant drug licenced in

MMF may be used (off label) for treatment of AE in adults in a

Drug safety profile of azathioprine The authors of the Berth-

Jones study concluded that azathioprine would be an effective

Azathioprine may be used (off label) in AE patients, if ciclosporin

The immunosuppressant MTX is frequently used in psoriasis, but

2012 The Authors

9.95 3.17 weeks). Treatment was more effective in adult onset

cal trial indicates that MTX may be effective in AE (4, C).

Controlled clinical trial data demonstrating efficacy

There is one large, multicentric randomized, placebo-controlled

Alitretinoin may be used for atopic hand eczema in adult patients

2012 The Authors

Guidelines for treatment of atopic eczema

recombinant therapeutic proteins, such as antibodies or fusion

patients receiving omalizumab because of severe bronchial

Allergen-specific immunotherapy (ASIT)

2012 The Authors