ORIGINAL ARTICLES

When does atopic dermatitis warrant

systemic therapy? Recommendations
from an expert panel of the
International Eczema Council
Eric L. Simpson, MD, MCR,a Marjolein Bruin-Weller, MD, PhD,b Carsten Flohr, MD, PhD, MSc,c
Michael R. Ardern-Jones, DPhil(PhD), FRCP(MD),d Sebastien Barbarot, MD, PhD,e Mette Deleuran, MD, DMSc,f
Thomas Bieber, MD, PhD, MDRA,g,h Christian Vestergaard, MD, PhD, DMSc,i Sara J. Brown, MD, FRCPE,j,k
Michael J. Cork, PhD, FRCP,l Aaron M. Drucker, MD, FRCPC,m Lawrence F. Eichenfield, MD,n,o,p
Regina Foelster-Holst, MD,q Emma Guttman-Yassky, MD, PhD,r Audrey Nosbaum, MD, PhD,s
Nick J. Reynolds, MD, FRCP,t,u Jonathan I. Silverberg, MD, PhD, MPH,v,w,x Jochen Schmitt, MD, MPH,y
Marieke M. B. Seyger, MD, PhD,z Phyllis I. Spuls, MD, PhD,aa Jean-Francois Stalder, MD,e
John C. Su, MD, MEpi, MA, MSt,bb,cc Roberto Takaoka, MD,dd Claudia Traidl-Hoffmann, MD,ee,ff
Jacob P. Thyssen, MD, PhD, DmSci,gg Jorien van der Schaft, MD, PhD,hh Andreas Wollenberg, MD, DrMed, DrHC,ii
Alan D. Irvine, MD, DSc,jj and Amy S. Paller, MSc, MDv,kk,ll
Portland, Oregon; Utrecht, Nijmegen, and Amsterdam, The Netherlands; London, Southampton, Dundee,
Sheffield, Newcastle upon Tyne, and Dublin, United Kingdom; Nantes, France; Aarhus and Hellerup,
Denmark; Davos, Switzerland; Providence, Rhode Island; San Diego, California; Bonn, Kiel, Dresden, and
Munich, Germany; New York and Rochester, New York; Lyon, France; Chicago, Illinois; Melbourne,
Australia; and S~ ao Paulo, Brazil

Background: Although most patients with atopic dermatitis (AD) are effectively managed with topical
medication, a significant minority require systemic therapy. Guidelines for decision making about
advancement to systemic therapy are lacking.

Objective: To guide those considering use of systemic therapy in AD and provide a framework for
evaluation before making this therapeutic decision with the patient.

From the Department of Dermatology, Oregon Health and Science University, Newcastle upon Tynet; Newcastle Dermatology,
University, Portlanda; National Expertise Center for Atopic Royal Victoria Infirmary, Newcastle upon Tyneu; Department
Dermatitis, Department of Dermatology and Allergology, of Dermatology,v Department of Preventive Medicine,w and
University Medical Center Utrechtb; Unit for Population-Based Department of Medical Social Sciences,x and Department of
Dermatology Research, St John’s Institute of Dermatology, Pediatrics, Northwestern University Feinberg School of Medi-
Guy’s and St Thomas’ National Health Service Foundation Trust cine, Chicagokk; Center for Evidence-Based Healthcare, Techni-
and King’s College Londonc; Clinical Experimental Sciences, sche Universit€at Dresdeny; Department of Dermatology,
Faculty of Medicine, University of Southamptond; Department Radboud University Nijmegen Medical Centrez; Department of
of Dermatology, Nantes University Hospitale; Department of Dermatology, Academic Medical Centre, Amsterdamaa; Depart-
Dermatology, Aarhus University Hospitalf; Department of ment of Dermatologybb and Department of Paediatrics, Mon-
Dermatology and Allergy, University of Bonng; Christine ash University, Eastern Health and Murdoch Childrens Research
K€uhne-Center for Allergy Research and Education, Davosh; Institute, University of Melbournecc; Department of Derma-
Department of Dermatology Aarhus University Hospitali; Skin tology, University of S~ao Paulo Medical Schooldd; Institute of
Research Group, School of Medicine, University of Dundeej; Environmental Medicine, UNIKA-T, Technical University of
Department of Dermatology, Ninewells Hospital and Medical Munich and Helmholtz Zentrum M€ uncheneGerman Research
School, Dundek; Sheffield Dermatology Research Department Center for Environmental Health (GmbH), Munichee; CK CARE,
of Infection, Immunity and Cardiovascular Disease, The Univer- Christine-K€uhne-Center for Allergy Research and Education,
sity of Sheffieldl; Department of Dermatology, Alpert Medical Davosff; Department of Dermatology and Allergy, Herlev-Gen-
School of Brown University, Providencem; Department of tofte Hospital, University of Copenhagen, Hellerupgg; Depart-
Dermatologyn and Department of Pediatrics, University of ment of Dermatology and Allergology, University Medical
California, San Diegoo; Rady Children’s Hospital, San Diegop; Centre Utrechhh; Department of Dermatology and Allergy,
Dermatology, Venereology and Allergology, University of Ludwig-Maximilian-University Munichii; Trinity College Dublin,
Schleswig-Holstein, Kielq; Icahn School of Medicine at Mount National Children’s Research Centre, Paediatric Dermatology
Sinai Medical Center, New Yorkr; Department of Allergy and Our Lady’s Children’s Hospital, Dublinjj; and Ann and Robert H.
Clinical Immunology, University Hospital Lyon Sud, Hospices Lurie Children’s Hospital of Chicago.ll
Civiles de Lyons; Institute of Cellular Medicine, Newcastle

623
624 Simpson et al J AM ACAD DERMATOL
OCTOBER 2017

Methods: A subgroup of the International Eczema Council determined aspects to consider before
prescribing systemic therapy. Topics were assigned to expert reviewers who performed a topic-specific
literature review, referred to guidelines when available, and provided interpretation and expert opinion.

Results: We recommend a systematic and holistic approach to assess patients with severe signs and
symptoms of AD and impact on quality of life before systemic therapy. Steps taken before commencing
systemic therapy include considering alternate or concomitant diagnoses, avoiding trigger factors,
optimizing topical therapy, ensuring adequate patient/caregiver education, treating coexistent infection,
assessing the impact on quality of life, and considering phototherapy.

Limitations: Our work is a consensus statement, not a systematic review.

Conclusion: The decision to start systemic medication should include assessment of severity and quality of
life while considering the individual’s general health status, psychologic needs, and personal attitudes
toward systemic therapies. ( J Am Acad Dermatol 2017;77:623-33.)

Key words: atopic dermatitis; azathioprine; biologic; consensus statement; cyclosporine; eczema;
methotrexate; quality of life; systemic therapy.

Drs Irvine and Paller contributed equally to this article. investigator for BBSRC Case with AstraZeneca, Stiefel/GlaxoS-
Corporate sponsorship was provided to the International Eczema mithKline, Bristol Myers Squib, Genentech, Innovate UK with
Council by Abbvie, Amgen, Celgene, Chugai, Galderma, Glaxo- Stiefel/GlaxoSmithKline, and Wellcome Trust/GlaxoSmithKline
SmithKline/Stiefel, the Leo Foundation, Leo Pharma, Lilly, and a consultant with honorarium for Genentech. Dr Schmitt is
MedImmune/Astrazeneca, Pfizer, Sanofi, Genzyme and Regen- an investigator for ALK, Merck Sharp and Dohme, Novartis,
eron Pharmaceuticals, and Valeant. The sponsors had no Pfizer, and Sanofi and a consultant with honorarium for
influence on the content and viewpoints in this article. The Novartis and Roche. Dr Spuls is a consultant with honorarium
cost of publication was covered by the International Eczema for AbbVie, Anacor, Leo Pharma, and Novartis and an investi-
Council. gator for Leopharma and Schering Plough; she reports also
Disclosure: Dr Simpson is an investigator for GlaxoSmithKline, having been involved in performing clinical trials with many
Novartis, Regeneron, Vanda, and Tioga and a consultant with pharmaceutical industries that manufacture drugs used for the
honorarium for Celgene, Galderma, Dermira, Genentech, Glaxo- treatment of psoriasis and atopic dermatitis. Dr Thyssen is a
SmithKline, Pfizer, Regeneron, and Sanofi. Dr Bruin-Weller is an consultant with honorarium for Leo Pharma, Roche, and
investigator for Roche and an investigator and consultant for Sanofi-Genzyme. Dr Wollenberg is a consultant with honorium
Abbvie and Regeneron/Sanofi, with all fees paid to her for Almiral, Anacor, Astellas, Bioderma, Celgene, Chugai (travel
institution. Dr Flohr is a consultant with honorarium for grant), Galderma, Hans Karrer, Leo Pharma, L’Oreal, MEDA,
Roche/Genentech and Sanofi/Regeneron. Dr Barbarot is a MedImmune, Merck Sharp and Dohme, Novartis, Pierre Fabre,
consultant with honorarium for Pierre Fabre Laboratory and Pfizer, Regeneron, and Sanofi-Adventis and he received
Sanofi-Genzyme, a speaker/educator with honorarium for research funding from Beiersdorf and Leo Pharma. Dr Irvine is
Bioderma, and an investigator with Pierre Fabre Laboratory. a consultant with honorarium for AbbVie, Anacor, Chugai
Dr Deleuran is an investigator for AbbVie and Sanofi Genzyme Pharma, Genentech, and Sanofi Regeneron. Dr Paller is a
and a consultant with honorarium for CKCare Foundation, La consultant with honorarium Anacor, Eli Lilly, Galderma, Glax-
Roche Posay, Leo Pharma, Meda Pharma, Pierre Fabre, Regen- oSmithKline/Stiefel, Pierre Fabre, Puricore, Regeneron/Sanofi,
eron, and Sanofi Genzyme. Dr Bieber is an investigator or Roivant, and Valeant and an investigator for Astellas and Pfizer.
consultant or lecturer for Sanofi, Regeneron, Novartis, Roche, Drs Ardern-Jones, Vestergaard, Brown, Silverberg, Seyger,
Astellas, Galderma, Pfizer/Anacor, GlaxoSmithKline, Lilly, and Stalder, Su, Takaoka, Traidl-Hoffmann, and Van der Schaft
L9Or eal. Dr Cork is a consultant with honorarium and investi- have no conflicts of interest to declare.
gator for Regeneron and Sanofi. Dr Drucker is a consultant with Accepted for publication June 19, 2017
honorarium for Astellas Canada, Prime Inc, Sanofi, and Spire Reprints not available from the authors.
Learning and an investigator for Sanofi and Regeneron. Dr Correspondence to: Eric L. Simpson, MD, MCR, Department of
Eichenfield is a consultant with honorarium for Anacor/Pfizer, Dermatology, Oregon Health and Science University, Portland,
Galderma, Genentech, Lilly, Regeneron/Sanofi, and Valeant and OR. E-mail: [email protected]. Alan D. Irvine, MD, DSc, Trinity
an investigator for Regeneron/Sanofi. Dr Foelster-Holst is an College Dublin, National Children’s Research Centre, Paediatric
investigator (with fees paid to her institution) for Astellas, Dermatology, Our Lady’s Children’s Hospital, Dublin, United
Novartis Pharma, Phamanet, Pierre Fabre, and Regeneron and a Kingdom. E-mail: [email protected]. Amy S. Paller, MSc, MD,
consultant with honoraria for ALK/Abbott, Ardeypharm, Astel- Department of Dermatology, Northwestern University
las, Johnson and Johnson, La Roche Posay, and Neubourg Skin Feinberg School of Medicine, 676 N St Clair, Suite 1600,
care GMBH and Co. Dr Guttman is a consultant with honorar- Chicago, IL 60611. E-mail: [email protected].
ium for AbbVie, Allergan, Amgen, Anacor, Bristol-Myers Squibb, Published online August 10, 2017.
Celgene, Celsus Therapeutics, Dermira, Drais, Eli Lilly, Escalier, 0190-9622
Galderma, Genentech, Glenmark, LEO Pharma, Mitsubushi Ó 2017 by the American Academy of Dermatology, Inc. Published
Tanabe, Novartis, Pfizer, Regeneron, Sanofi, Stiefel/GlaxoS- by Elsevier Inc. All rights reserved. This is an open access article
mithKline, and Vitae and principal investigator for under the CC BY-NC-ND license (http://creativecommons.org/
Bristol-Myers Squibb, Celgene, Dermira, Janssen Biotech, LEO licenses/by-nc-nd/4.0/).
Pharma, Merck, Novartis, and Regeneron. Dr Nosbaum is a http://dx.doi.org/10.1016/j.jaad.2017.06.042
consultant with honorarium for Sanofi. Dr Reynolds is an
J AM ACAD DERMATOL Simpson et al 625
VOLUME 77, NUMBER 4

Most patients with atopic dermatitis (AD) have section subheadings of this consensus statement)
mild-to-moderate disease1 that responds adequately were assigned to expert reviewers from 9 countries,
to optimized emollient use, avoidance of irritants each of whom performed a literature review,
and disease triggers, and standard topical anti- referred to guidelines when available, and
inflammatory therapies. However, many patients provided interpretation and expert opinion on that
with AD may not have adequate disease control topic area.
with these regimens of care or with phototherapy.
For pediatric and adult pa- RESULTS
tients with moderate-to- This expert review group
severe AD that does not CAPSULE SUMMARY recommends a systematic
respond to topical therapy approach to assess patients
and for which phototherapy
d Physicians should optimize topical
with severe signs and/or
is not a viable option, sys- therapy before considering systemic
symptoms of AD and/or
temic therapy is needed to medications for atopic dermatitis.
impact on quality of life
control skin inflammation, d Patients who fail to respond should be before systemic therapy. We
reduce symptoms, prevent evaluated for exacerbating factors such reviewed the strengths and
flares, and improve quality as cutaneous infection and for weaknesses of methods to
of life (QoL). The decision alternative diagnoses such as allergic measure disease severity
to initiate a systemic medica- contact dermatitis. and discussed issues to
tion for AD can be difficult, d The decision to start systemic therapy address before determining
given the known risks of depends on disease severity, impact on that nonsystemic treatment
traditional immunosuppres- quality of life, and risks and benefits of had failed. Finally, we sum-
sants. In a study from systemic therapies for the individual marized the key steps to
Germany, 10% of patients patient. follow before choosing to
with AD received systemic start a systemic agent
therapy with oral corticoste- (Fig 1). Consensus across
roids,2 although the proportion of children with AD these areas is detailed in the following sections.
requiring systemic therapy is likely lower.3,4
Recent guidelines and systematic reviews from Severity-based scoring systems alone cannot
national societies provide evidence-based sum- determine the need for systemic therapy: a
maries of the safety and efficacy of systemic agents holistic assessment is needed
used for AD treatment,5-9 and others discuss how One approach for identifying a candidate for
systemic treatments can be used effectively.10 systemic therapy is to utilize a disease severity score.
Nevertheless, the question of when a patient is a More than 20 AD scoring systems quantify disease
candidate for systemic therapy has received little severity.12,13 The 2 most extensively validated are the
11
attention. Scoring of Atopic Dermatitis (SCORAD), which in-
Clinicians, patients, and caregivers consider many corporates the intensity of disease signs and extent
factors when deciding whether a systemic agent along with the patient-reported sleep loss and itch,
should be used. Most reviews state that failure to and the Eczema Area and Severity Index.14 Scoring
respond to adequate topical therapy, need for systems are used primarily in clinical trials and are
prolonged use of high-potency topical steroids, or too time-consuming for routine clinical practice.
repeated flares makes a patient eligible, but there are Moreover, these tools assess only part of the complex
no universally accepted definitions of recalcitrance. thinking that underlies treatment selection.
Given the lack of clarity in decision making and in an Assessment of the impact of AD on the patient,
effort to prevent overtreatment or undertreatment, a however, needs to include consideration of both
group of experts on AD management, all councilors severity and quality of life. Even if the extent of
or associates of the International Eczema Council disease is small (eg, just the face, hands, or genital
(IEC), conferred to provide consensus guidance for area), the impact on the individual patient may still
clinicians in recognizing when a child or adult is be severe, negatively affecting a patient’s emotional
considered a candidate for systemic therapy. state, social functioning, activities of daily living, or
any combination of these. Furthermore, extent of AD
METHODS is hard to quantify because lesions are diffuse and
Authors participated in a face-to-face meeting to less circumscribed than in psoriasis, for example.
delineate broad topic areas for consideration before Using a SCORAD higher than 25 to define moderate-
prescribing systemic therapy. Topic areas (the to-severe disease is favored by many European
626 Simpson et al J AM ACAD DERMATOL
OCTOBER 2017

disruption can be assessed by using formal tools

Abbreviations used:
such as the Patient-Oriented Eczema Measure, visual
AD: atopic dermatitis analogue scales, or numeric rating scales.25
IEC: International Eczema Council
NB-UVB: narrowband ultraviolet B Treatment burden includes the time spent on treat-
QoL: quality of life ment and the costs of medications, physician visits
SCORAD: SCORing Atopic Dermatitis Score related to AD flares, and medication monitoring. If
TCI: topical calcineurin inhibitors
TCS: topical corticosteroid the impact on QoL from symptoms and/or treatment
burden is significant in the eyes of the patient despite
efforts to establish an appropriate and feasible plan
of topical care (further discussed later), systemic
dermatologists,15,16 but our expert panel identified therapy should be considered and may be more
several drawbacks to the use of a single scoring acceptable to patients and providers alike.
system in identifying candidates for systemic
treatment. Alternative or concomitant diagnoses should
A single, static (1 point in time) measurement of be considered before advancing to systemic
severity may overestimate or underestimate the true therapy
AD severity experienced by the patient, given the The diagnosis of AD is usually made clinically.
characteristic exacerbations and remissions of AD.17 However, a correct diagnosis can sometimes be
Serial measurements can provide information about challenging, particularly if clinical features are atyp-
baseline severity, flares, and therapeutic response. It ical (Table I). Careful history taking, examination,
is important to gauge the severity and frequency of and (sometimes) accompanying biopsy, laboratory
disease flares by using a variety of methods, as assessments such as potassium hydroxide, scabies
flares are a major determinant of quality of life and microscopic examinations, or patch testing26 should
disillusionment with current therapy.18 Self- be undertaken.
assessment scores such as the Patient-Oriented
Eczema Measure and Patient-Oriented SCORAD Ensure that adequate education has been
enable patient-derived assessment of the course delivered to improve adherence to topical
of the disease between consultations.19-21 therapy
Documentation of severe, extensive disease and/or It is important to ascertain whether failure of
QoL impairment at several time points with adequate topical treatment is due to the severity of the disease
topical therapy enables a holistic rationale for mov- (lack of efficacy of topical therapy) or lack of
ing to systemic therapy. adherence to the treatment when making the deci-
sion to begin systemic therapy. Adherence to optimal
Assess disease impact on QoL topical management is challenging and can be
AD can severely affect social lives and emotional exhausting for some patients and caregivers. Most
well-being, as well as academic and occupational prevalent is the fear of patients, caregivers, and
endeavors.22 Validated QoL measures can be useful, health professionals about use of topical anti-
but their use in the clinic may not be practical. For inflammatory medications.27 However, the smell
example, Heinl et al identified the best-validated and stains from tar preparations, the ‘‘feel’’ of a
instrument for measuring QoL with pediatric AD to topical ointment (vs an oil or cream), and the
be the Childhood Atopic Dermatitis Impact Scale, messiness of certain topicals under clothes are
which contains more than 30 items.23 In some patient concerns that can be discussed and accom-
practice settings, shorter, yet validated QOL scales, modated to improve adherence. In addition to ste-
such as the Dermatology Life Quality Index or roid phobia,28 there is fear of topical calcineurin
Skindex-16, may be useful to help document the inhibitors (TCIs) related to the black box warning
impact of the disease, which may not be readily mandated by the US Food and Drug Administration
apparent through routine questioning. Chernyshov in 2005. Although the black box warning was
et al recently reviewed the pros and cons of the initiated because of the theoretical risk of malig-
various instruments available for QOL measurement nancy, no signal for cancer risk has emerged;
in AD.24 Alternatively, clinicians may assess and nevertheless, the black box remains and requires
document QoL by using simple, open-ended ques- US pharmacists to warn patients.
tions, such as How is your atopic dermatitis affecting If failure of therapy is due to lack of adherence
you? or How does your atopic dermatitis affect your and/or topical corticosteroid (TCS) phobia, the first-
life at home or at school/work? The frequency and line intervention of choice is patient education.29-32 If
intensity of symptoms, such as itch, pain, and sleep adherence to topical therapy cannot be optimized
J AM ACAD DERMATOL Simpson et al 627
VOLUME 77, NUMBER 4

Fig 1. Algorithm to decide when systemic immunomodulatory therapy is warranted in patients

with atopic dermatitis.

despite proper education, the decision to start sys- patients with AD. However, several factors poten-
temic therapy rests on the clinician’s understanding tially provoke flares, most commonly, irritants such
of the reasons for continued nonadherence and as detergents, sweat, saliva, aeroallergens, contact
whether those reasons can justify the risk and allergens, and psychologic stress.33
expense of systemic therapy for a particular patient.
The need for overly complex topical regimens that Patients need a trial of intensive topical
are not feasible for a particular patient may justify therapy
moving to systemic therapy. We advocate comprehensive patient education
There are no evidence-based recommendations and a period of intensive topical therapy (if needed
for environmental trigger avoidance measures in in a daycare setting), followed by reassessment of the
628 Simpson et al J AM ACAD DERMATOL
OCTOBER 2017

Table I. Differential diagnoses to consider in pediatric and adult patients with severe atopic dermatitis
Condition Clinical features Diagnostic work-up
Children and adults
Contact dermatitis (irritant or Atypical or localized distribution Patch testing for allergic contact
allergic)
Severe, suberythrodermic psoriasis Less pruritus and lack of eczematous Biopsy
change such as oozing/crusting
Severe seborrheic dermatitis Lack of pruritus with greasy scale in Clinical diagnosis
scalp and folds in infants
Scabies infestation Inguinal, axillary, and genital papules. Mineral oil scraping
Palmoplantar vesicles and burrows
in infants.
Widespread tinea corporis Annular papulosquamous lesions Skin scraping for microscopy and
without eczematous change culture
Children
Zinc deficiency Erosive plaques on face and groin Zinc levels and genetic testing
with fussiness
Netherton syndrome/other Erythroderma, hair abnormalities, and Genetic testing
ichthyoses failure to thrive
Immune deficiencies (eg, severe Sinopulmonary infections and failure Genetic and immunologic testing, as
combined immunodeficiency, to thrive well as total IgE (hyperIgE
agammaglobulinemia, Wiskott- syndrome)
Aldrich syndrome, hyperIgE
syndrome)
Adults
Cutaneous T-cell lymphoma Lack of classic eczematous skin Skin biopsy and T-cell rearrangement
changes such as oozing and studies
crusting

IgE, Immunoglobulin E.

disease impact on severity and quality of life.15 approach has been shown to significantly reduce
Authors agreed that the general approach should relapses, ultimately requiring less total TCS/TCI with
be an intensive clearance period with a TCS followed negligible side effects.39 Patients who flare
by a safe and individualized regimen of intermittent frequently, despite TCS induction followed by a
TCSs, TCIs, or emollients to prevent flares. The proactive approach, are candidates for systemic
strength of prescribed TCSs should be appropriate therapy. Overuse of topical therapy (potency, fre-
for patient age and the body locations being treated. quency, and duration) despite controlled disease
Exact treatment protocols varied among the authors, represents an indication for systemic therapy.
but there was general consensus that the use of more Finally, the need for repeated courses of oral or
potent TCSs (medium- to high-potency, class I to III intramuscular steroids, a management strategy
in the United States, and class III to IV in Europe) discouraged by AD treatment guidelines, would be
once or twice daily for 1 to 4 weeks provides a useful another indication for initiating more appropriate
way to gain control of severe disease, followed by a systemic therapy.
taper in application frequency. Patient age should be
taken into consideration, with use of the strongest
steroid classes restricted to adolescents and adults. Infection should be sought and treated as
Wet-wrap therapy and use of therapy after soaking in appropriate
a bath (particularly in cases in children) may also be Bacterial or viral infections should be identified
useful adjunctive measures to the application of TCSs and treated before considering systemic therapy.
or TCIs to quickly reduce disease severity but will Many individuals affected by AD have skin and
increase the potency of the treatment.34 nasal colonization with Staphylococcus aureus,40
Should a patient improve during this induction increasing the risk of cutaneous infection.41
period, it may be possible to maintain disease control Furthermore, AD flares are accompanied by a shift
by utilizing a medium-strength TCS or TCI applied 2 in the microbiome, with an increased percentage of S
to 3 times weekly to normal-appearing skin at a site aureus and reduced bacterial diversity.42 Certain
of frequent flares (proactive therapy).35-38 This viral infections have also been associated with AD
 VOLUME 77, NUMBER 4
J AM ACAD DERMATOL
Table II. Most common on-label and off-label systemic therapies in AD
Estimated efficacy
(% reduction
Drug (in alphabetical Approved in composite
order) for AD? severity scores) Dose range Common or serious side effects Monitoring required*
Azathioprine No 26%-39%5 Adult: 1-3 mg/kg/day; Hematologic abnormalities, CBC, CMP, thiopurine
Pediatric: 1-4 mg/kg/day skin and other malignancies, methyltransferase
hepatosplenic lymphoma,
and CNS infections such as
PML
Cyclosporine No in 53%-95%5 Adult and pediatric: Renal insufficiency, CBC, CMP, magnesium,
United States, 2.5-5 mg/kg hypertension, and drug uric acid, lipids, and
yes in Europe interactions blood pressure
Dupilumab Yes 73%62 Adult: 600 mg loading Injection site reactions and None
followed by 300 mg/wk conjunctivitis
Methotrexate No 42%5 Adult: 7.5-25 mg weekly Hepatoxicity, hematologic CBC, CMP
Pediatrics: 0.2-0.7 mg/kg abnormalities, teratogen,
weekly gastrointestinal intolerance,
nausea, and fatigue
Mycophenolate No Unknown 1.0-1.5 g orally twice daily Gastrointestinal, teratogen CBC, CMP
Pediatric: 30-50 mg/kg daily

AD, Atopic dermatitis; CBC, complete blood count with differential and platelets; CMP, complete metabolic panel with basic chemistries and liver function tests; CNS, central nervous system; PML,
progressive multifocal leukoencephalopathy.
*See published review by Sidbury et al7 for more complete and detailed information regarding dosing and drug monitoring.

Simpson et al 629
630 Simpson et al J AM ACAD DERMATOL
OCTOBER 2017

exacerbation (eczema herpeticum, eczema cox- Optimal benefit requires a prolonged course (;24
sackium, and molluscum).43 phototherapy treatments) to induce sustained remis-
Systemic antibiotics are usually required for treat- sion, and adherence to phototherapy can be partic-
ment of cutaneous bacterial infection, especially ularly challenging. Phototherapy is often poorly
before initiation of systemic therapy,11 as persistent tolerated in highly inflamed AD and may be better
infection may impair treatment responses.44 Systemic tolerated after acute disease control with intensive
antibiotics should be avoided in the absence of signs topical or wet-wrap therapy.
of infection (ie, these should not be used as a systemic Typically, 2 or 3 treatments per week of NB-UVB
treatment for AD and do not effectively reduce S are used for 6 to 12 weeks57 or longer.7 If no
aureus colonization).45 Antiseptic baths, most response is seen within 8 to 12 weeks, or if AD
commonly with 0.005% sodium hypochlorite (dilute recurrently flares during phototherapy, we recom-
bleach), reduce disease severity46 and could be mend discontinuation. If AD improves with photo-
considered before systemic therapy, although this therapy but relapses rapidly, the safety risks of
approach is not universally adopted and may have a frequent retreatment or use of maintenance photo-
greater ameliorative effect on the barrier and inflam- therapy must be weighed against those of systemic
mation than on S aureus colonization. Topical or even therapy. For many patients, the inconvenience of
systemic antifungal treatment could be considered for office-based phototherapy is untenable and home
head and neck dermatitis, which is postulated to be phototherapy may be a useful option; 1 study of
driven by secondary yeast colonization, although the patients with psoriasis showed results of home
results of clinical trials have been conflicting.47 phototherapy similar to those of in-office use.58
Phototherapy should be discontinued if cyclo-
Possible allergic triggers should be considered
sporine or other systemic treatments (eg, azathio-
and managed as appropriate
prine or mycophenolate mofetil) are initiated to
Patients with AD have a higher rate of allergic
avoid the synergistic risk of inducing skin malig-
sensitization, including both type I reactions to
nancy. Combining methotrexate with phototherapy
aeroallergens (eg, animal dander and grass pollens)
is thought to be associated with lower risk than other
and type IV delayed allergic responses to contact
immunosuppressants and has been used for psoria-
allergens. Fragrances, preservatives (particularly pro-
sis treatment.59
pylene glycol and methylchlorothiazolinone) and
emulsifiers in emollients and topical steroid creams
Factors to consider when choosing a systemic
are a frequent source of contact allergens for patients
agent
with AD.25,48-51 If the patient’s history and physical
Each patient’s situation is unique, and several
examination results suggest allergic triggers that
factors influence the discussion between patient/
exacerbate disease, further investigation to identify
caregiver and physician that leads to therapeutic
these triggers is appropriate (eg, referral to allergy
decision making.60 These include existent comorbid-
services for skin prick testing or patch testing).
ities and results of baseline investigations; patient age;
Phototherapy should be considered before the anticipation of pregnancy and family planning issues
use of other systemic therapy if accessible and for both male and female patients; and the patient’s
practical previous clinical experience, including with systemic
Phototherapy is recommended as second-line or agents.61 Sharing information about treatment effi-
adjuvant therapy in selected patients for moderate- cacy and potential side effects with the patient and
to-severe AD, especially in adults and older chil- family is also important. The most commonly used
dren.7,52 Systematic reviews have identified the systemic medications for AD are summarized in
greatest efficacy for narrowband ultraviolet B (NB- Table II. A shared decision-making process should
UVB) (311-313 nm) and ultraviolet A-1 (340- then be undertaken, weighing these factors previ-
400 nm).53,54 Psoralen with ultraviolet A radiation is ously discussed herein with the risks and benefits of
associated with a greater risk of cutaneous malig- the individual agents. The actual choice of any 1
nancy and should be considered only in adults for systemic agent is beyond the scope of this article.
whom NB-UVB has shown inadequate efficacy.55
Phototherapy is also efficacious in the pediatric A future consideration: will the availability of
population,7,56 but the long-term risk of skin cancer, targeted immunomodulation with fewer safety
especially in fair-skinned individuals, is not fully risks lower the threshold for utilization of
understood, suggesting the need for caution in this systemic agents?
population, especially in patients who might receive Several emerging therapies are showing evidence
systemic immunosuppressive medication later in life. of efficacy and short-term safety that are potentially
J AM ACAD DERMATOL Simpson et al 631
VOLUME 77, NUMBER 4

superior to those of traditional immunosuppressive REFERENCES

therapy.62 Prospective registries will be useful to 1. Silverberg JI, Simpson EL. Associations of childhood eczema
severity: a US population-based study. Dermatitis. 2014;25:
assess long-term safety and efficacy profiles, ideally 107-114.
allowing comparisons between conventional systemic 2. Schmitt J, Schmitt NM, Kirch W, Meurer M. Outpatient care
immunosuppressants and novel emerging agents. The and medical treatment of children and adults with atopic
Treatment of Atopic Eczema Registry Taskforce has eczema. J Dtsch Dermatol Ges. 2009;7:345-351.
just reached consensus on a core data set for prospec- 3. McAleer MA, Flohr C, Irvine AD. Management of difficult and
severe eczema in childhood. BMJ. 2012;345:e4770.
tive registries for phototherapy and systemic therapies 4. Emerson RM, Williams HC, Allen BR. Severity distribution of
to facilitate comparison and pooling of data, should atopic dermatitis in the community and its relationship to
more than 1 registry be established.63 secondary referral. Br J Dermatol. 1998;139:73-76.
If proven both efficacious and safer than conven- 5. Roekevisch E, Spuls PI, Kuester D, Limpens J, Schmitt J.
tional immunosuppressive therapies (both short- Efficacy and safety of systemic treatments for
moderate-to-severe atopic dermatitis: a systematic review.
and long-term therapy), systemic biologic and J Allergy Clin Immunol. 2014;133:429-438.
small-molecule therapies could lower the bar toward 6. Nankervis H, Thomas KS, Delamere FM, Barbarot S,
use for more moderate disease, not only to improve Rogers NK, Williams HC. Programme Grants for Applied
disease response and quality of life, but also to Research. Scoping systematic review of treatments for eczema.
potentially prevent disease progression and future Southampton, UK: NIHR Journals Library; 2016.
7. Sidbury R, Davis DM, Cohen DE, et al. Guidelines of care for
comorbidities. The long-term safety and accessibility the management of atopic dermatitis: section 3. Manage-
of these newer interventions will enter into the ment and treatment with phototherapy and systemic agents.
decision-making equation for patients in the future. J Am Acad Dermatol. 2014;71:327-349.
8. Saeki H, Nakahara T, Tanaka A, et al. Clinical practice
guidelines for the management of atopic dermatitis 2016. J
CONCLUSION Dermatol. 2016;43:1117-1145.
This article provides a framework of thinking to 9. Galli E, Neri I, Ricci G, et al. Consensus Conference on Clinical
Management of pediatric Atopic Dermatitis. Ital J Pediatr.
inform patients and physicians confronted with the 2016;42:26.
possibility of commencing systemic therapies for se- 10. Flohr C, Irvine AD. Systemic therapies for severe atopic
vere AD in adult or pediatric practice. We purposely dermatitis in children and adults. J Allergy Clin Immunol.
offered no definitive Boolean yes/no guidelines, but 2013;132:774-774.e6.
have instead offered guidance on the complex con- 11. Arkwright PD, Motala C, Subramanian H, et al. Management
of difficult-to-treat atopic dermatitis. J Allergy Clin Immunol
siderations in making this decision (Fig 1). The deci- Pract. 2013;1:142-151.
sion to start a systemic agent should ideally include 12. Schmitt J, Langan S, Deckert S, et al. Assessment of clinical
assessments of severity and quality of life, while also signs of atopic dermatitis: a systematic review and recom-
allowing consideration of individual factors. Some of mendation. J Allergy Clin Immunol. 2013;132:1337-1347.
these additional individual factors are patient prefer- 13. Ganemo A, Svensson A, Svedman C, Gronberg BM,
Johansson AC, Wahlgren CF. Usefulness of Rajka and Lange-
ences, impact on personal life, prior topical therapy, land eczema severity score in clinical practice. Acta Derm
financial implications, and comorbidities. The ultimate Venereol. 2016;96:521-524.
decision to commence systemic therapy will depend 14. Schmitt J, Langan S, Williams HC, Network ED-E. What are the
on the joint exploration of these many factors by the best outcome measurements for atopic eczema? A system-
patient/caregiver and providers, taking into account atic review. J Allergy Clin Immunol. 2007;120:1389-1398.
15. Wollenberg A, Oranje A, Deleuran M, et al. ETFAD/EADV
the patient’s psychologic needs, disease severity, and Eczema task force 2015 position paper on diagnosis and
personal attitudes to systemic therapies. treatment of atopic dermatitis in adult and paediatric
patients. J Eur Acad Dermatol Venereol. 2016;30:729-747.
We acknowledge the following IEC associates and 16. Oranje AP, Glazenburg EJ, Wolkerstorfer A, de Waard-van der
councilors for their important contributions to the concepts Spek FB. Practical issues on interpretation of scoring atopic
in this article: Lisa Beck, Rochester, New York; Robert dermatitis: the SCORAD index, objective SCORAD and the
Bissonnette, Montreal, Canada; Anna De Benedetto, three-item severity score. Br J Dermatol. 2007;157:645-648.
Gainesville, Florida; Kyu Han, Seoul, South Korea; 17. Haeck IM, ten Berge O, van Velsen SG, de Bruin-Weller MS,
Emmilia Hodak, Tel Aviv, Israel; Kenji Kabashima, Kyoto, Bruijnzeel-Koomen CA, Knol MJ. Moderate correlation be-
Japan; Kwan Hoon Lee, Yonsei, Korea; Thomas Luger, tween quality of life and disease activity in adult patients
Muenster, Germany; Cheng-Che E. Lan, Kaohsiung, with atopic dermatitis. J Eur Acad Dermatol Venereol. 2012;26:
Taiwan; Johannes Ring, Munich, Germany; Seong Jun 236-241.
18. Zuberbier T, Orlow SJ, Paller AS, et al. Patient perspectives on
Seo, Seoul, South Korea; Georg Stingl, Vienna, Austria;
the management of atopic dermatitis. J Allergy Clin Immunol.
and Alain Taieb, Bordeaux, France. Sara J. Brown holds a 2006;118:226-232.
Wellcome Trust Senior Research Fellowship in Clinical 19. Charman CR, Venn AJ, Ravenscroft JC, Williams HC. Trans-
Science (106865/Z/15/Z). We appreciate the assistance of lating Patient-Oriented Eczema Measure (POEM) scores into
Margaret Jung, IEC executive director, in organizing clinical practice by suggesting severity strata derived using
councilor responses. anchor-based methods. Br J Dermatol. 2013;169:1326-1332.
632 Simpson et al J AM ACAD DERMATOL
OCTOBER 2017

20. Coutanceau C, Stalder JF. Analysis of correlations between treatment to reduce risk of relapse in atopic dermatitis:
patient-oriented SCORAD (PO-SCORAD) and other assess- randomised, double blind, parallel group study. BMJ. 2003;
ment scores of atopic dermatitis severity and quality of life. 326:1367.
Dermatology. 2014;229:248-255. 38. Wollenberg A, Reitamo S, Girolomoni G, et al. Proactive
21. Stalder JF, Barbarot S, Wollenberg A, et al. Patient-oriented treatment of atopic dermatitis in adults with 0.1% tacrolimus
SCORAD (PO-SCORAD): a new self-assessment scale in atopic ointment. Allergy. 2008;63:742-750.
dermatitis validated in Europe. Allergy. 2011;66:1114-1121. 39. Wollenberg A, Ehmann LM. Long term treatment concepts
22. Drucker AM, Wang AR, Li WQ, Sevetson E, Block JK, and proactive therapy for atopic eczema. Ann Dermatol.
Qureshi AA. The burden of atopic dermatitis: summary of a 2012;24:253-260.
report for the National Eczema Association. J Invest Dermatol. 40. Graber CJ, Shane AL, Weintrub P, Chambers HF. Clonality of
2017;137:26-30. Staphylococcus aureus colonization over time in attendees of
23. Heinl D, Prinsen CA, Sach T, et al. Measurement properties of a camp for children with chronic dermatoses. Pediatr
quality-of-life measurement instruments for infants, children Dermatol. 2011;28:519-523.
and adolescents with eczema: a systematic review. Br J 41. Bieber T. Atopic dermatitis. N Engl J Med. 2008;358:
Dermatol. 2017;176:878-889. 1483-1494.
24. Chernyshov PV, Tomas-Aragones L, Manolache L, et al. 42. Kong HH, Oh J, Deming C, et al. Temporal shifts in the skin
Quality of life measurement in atopic dermatitis. Position microbiome associated with disease flares and treatment in
paper of the European Academy of Dermatology and children with atopic dermatitis. Genome Res. 2012;22:
Venereology (EADV) Task Force on Quality of Life. J Eur 850-859.
Acad Dermatol Venereol. 2017;31(4):576-593. 43. Wollenberg A, Wetzel S, Burgdorf WH, Haas J. Viral
25. von Kobyletzki LB, Thomas KS, Schmitt J, et al. What factors infections in atopic dermatitis: pathogenic aspects and
are important to patients when assessing treatment clinical management. J Allergy Clin Immunol. 2003;112:
response: an international cross-sectional survey. Acta Derm 667-674.
Venereol. 2017;97:86-90. 44. Hauk PJ, Hamid QA, Chrousos GP, Leung DY. Induction of
26. Chen JK, Jacob SE, Nedorost ST, et al. A pragmatic approach corticosteroid insensitivity in human PBMCs by microbial
to patch testing atopic dermatitis patients: clinical recom- superantigens. J Allergy Clin Immunol. 2000;105:782-787.
mendations based on expert consensus opinion. Dermatitis. 45. Bath-Hextall FJ, Birnie AJ, Ravenscroft JC, Williams HC. In-
2016;27:186-192. terventions to reduce Staphylococcus aureus in the manage-
27. Farrugia LL, Lee A, Fischer G, Blaszczynski A, Carter SR, ment of atopic eczema: an updated Cochrane review. Br J
Smith SD. Evaluation of the influence of pharmacists and GPs Dermatol. 2010;163:12-26.
on patient perceptions of long-term topical corticosteroid 46. Huang JT, Rademaker A, Paller AS. Dilute bleach baths for
use. J Dermatolog Treat. 2017;28:112-118. Staphylococcus aureus colonization in atopic dermatitis to
28. Mueller SM, Itin P, Vogt DR, et al. Assessment of ‘‘cortico- decrease disease severity. Arch Dermatol. 2011;147:246-247.
phobia’’ as an indicator of non-adherence to topical cortico- 47. Glatz M, Bosshard P, Schmid-Grendelmeier P. The role of
steroids: a pilot study. J Dermatolog Treat. 2017;28:104-111. fungi in atopic dermatitis. Immunol Allergy Clin North Am.
29. Stalder JF, Bernier C, Ball A, et al. Therapeutic patient 2017;37:63-74.
education in atopic dermatitis: worldwide experiences. 48. Correa da Rosa J, Malajian D, Shemer A, et al. Patients with
Pediatr Dermatol. 2013;30:329-334. atopic dermatitis have attenuated and distinct contact
30. Staab D, Diepgen TL, Fartasch M, et al. Age related, hypersensitivity responses to common allergens in skin. J
structured educational programmes for the management Allergy Clin Immunol. 2015;135:712-720.
of atopic dermatitis in children and adolescents: multicentre, 49. Dinkloh A, Worm M, Geier J, Schnuch A, Wollenberg A.
randomised controlled trial. BMJ. 2006;332:933-938. Contact sensitization in patients with suspected cosmetic
31. Ersser SJ, Cowdell F, Latter S, et al. Psychological and intolerance: results of the IVDK 2006-2011. J Eur Acad
educational interventions for atopic eczema in children. Dermatol Venereol. 2015;29:1071-1081.
Cochrane Database Syst Rev. 2014;(1):CD004054. 50. Malajian D, Belsito DV. Cutaneous delayed-type hypersensi-
32. Heratizadeh A, Werfel T, Wollenberg A, et al. Effects of tivity in patients with atopic dermatitis. J Am Acad Dermatol.
structured patient education in adults with atopic dermatitis: 2013;69:232-237.
multicenter randomized controlled trial. J Allergy Clin Immu- 51. Shaughnessy CN, Malajian D, Belsito DV. Cutaneous
nol. 2017; http://dx.doi.org/10.1016/j.jaci.2017.01.029 [E-pub delayed-type hypersensitivity in patients with atopic derma-
ahead of print]. titis: reactivity to surfactants. J Am Acad Dermatol. 2014;70:
33. Langan SM, Silcocks P, Williams HC. What causes flares of 704-708.
eczema in children? Br J Dermatol. 2009;161:640-646. 52. Tintle S, Shemer A, Suarez-Farinas M, et al. Reversal of atopic
34. Devillers AC, Oranje AP. Wet-wrap treatment in children with dermatitis with narrow-band UVB phototherapy and bio-
atopic dermatitis: a practical guideline. Pediatr Dermatol. markers for therapeutic response. J Allergy Clin Immunol.
2012;29:24-27. 2011;128:583-593. e1-4.
35. Paller AS, Eichenfield LF, Kirsner RS, et al. Three times weekly 53. Garritsen FM, Brouwer MW, Limpens J, Spuls PI. Photo
tacrolimus ointment reduces relapse in stabilized atopic (chemo)therapy in the management of atopic dermatitis:
dermatitis: a new paradigm for use. Pediatrics. 2008;122: an updated systematic review with implications for practice
e1210-e1218. and research. Br J Dermatol. 2014;170:501-513.
36. Hanifin J, Gupta AK, Rajagopalan R. Intermittent dosing of 54. Meduri NB, Vandergriff T, Rasmussen H, Jacobe H. Photo-
fluticasone propionate cream for reducing the risk of relapse therapy in the management of atopic dermatitis: a system-
in atopic dermatitis patients. Br J Dermatol. 2002;147: atic review. Photodermatol Photoimmunol Photomed. 2007;
528-537. 23:106-112.
37. Berth-Jones J, Damstra RJ, Golsch S, et al. Twice weekly 55. Ling TC, Clayton TH, Crawley J, et al. British Association of
fluticasone propionate added to emollient maintenance Dermatologists and British Photodermatology Group
J AM ACAD DERMATOL Simpson et al 633
VOLUME 77, NUMBER 4

guidelines for the safe and effective use of 60. Gore C, Johnson RJ, Caress AL, Woodcock A, Custovic A. The
psoralen-ultraviolet A therapy 2015. Br J Dermatol. 2016; information needs and preferred roles in treatment
174:24-55. decision-making of parents caring for infants with atopic
56. Darn e S, Leech SN, Taylor AE. Narrowband ultraviolet B dermatitis: a qualitative study. Allergy. 2005;60:938-943.
phototherapy in children with moderate-to-severe eczema: a 61. Garritsen TK, van den Broek MPH, van Zuilen AD, Fidder HH,
comparative cohort study. Br J Dermatol. 2014;170:150-156. de Bruin-Weller MS, Spuls PI. Pregnancy and fetal outcomes
57. Ring J, Alomar A, Bieber T, et al. Guidelines for treatment of after paternal exposure to azathioprine, methotrexate or
atopic eczema (atopic dermatitis) Part II. J Eur Acad Dermatol mycophenolic acid: a critically appraised topic. Br J Dermatol.
Venereol. 2012;26:1176-1193. 2017;176:866-877.
58. Koek MB, Buskens E, van Weelden H, Steegmans PH, 62. Simpson EL, Gadkari A, Worm M, et al. Dupilumab therapy
Bruijnzeel-Koomen CA, Sigurdsson V. Home versus outpa- provides clinically meaningful improvement in patient-reported
tient ultraviolet B phototherapy for mild to severe psoriasis: outcomes (PROs): a phase IIb, randomized, placebo-controlled,
pragmatic multicentre randomised controlled non-inferiority clinical trial in adult patients with moderate to severe atopic
trial (PLUTO study). BMJ. 2009;338:b1542. dermatitis (AD). J Am Acad Dermatol. 2016;75:506-515.
59. Soliman A, Nofal E, Nofal A, El Desouky F, Asal M. Combina- 63. Gerbens LA, Boyce AE, Wall D, et al. TREatment of ATopic
tion therapy of methotrexate plus NBUVB phototherapy is eczema (TREAT) Registry Taskforce: protocol for an interna-
more effective than methotrexate monotherapy in the tional Delphi exercise to identify a core set of domains and
treatment of chronic plaque psoriasis. J Dermatolog Treat. domain items for national atopic eczema registries. Trials.
2015;26:528-534. 2017;18:87.