atopic dermatitis

REVIEW ARTICLE

Advances in the Diagnosis and Therapeutic Managementof Atopic Dermatitis

Christian Vestergaard • Mette Deleuran

Published online: 13 May 2014! Springer International Publishing Switzerland 2014

Abstract Atopic dermatitis is a very prevalent diseasethat affects children as well as adults. The disease has a

severe impact on quality of life for the patients and their

families. The skin in atopic dermatitis patients is a site ofboth a severe inflammatory reaction dominated by lym-

phocytes and decreased skin barrier function. The treat-

ment of the disease is mainly aimed at reducing theinflammation in the skin and/or restoring the skin barrier

function. However, most of the treatments used today

singularly aim at reducing the inflammation in the skin.Depending on the severity of the disease, the anti-inflam-

matory treatment may be topical or systemic, but basic

treatment, no matter the severity, should always be emol-lients. In addition, new studies have shown good effects of

psychosocial interventions, such as eczema schools, for

patients and their families. This review covers the latesttrends in the treatment of atopic dermatitis.

Key Points

Atopic dermatitis is both an inflammatory skin

disease and a disease of the skin barrier function.

Anti-inflammatory treatment is topical but systemic

therapy may be added in severe cases. Treatment

should always be combined with skin barrierregeneration (moisturizer), and occasionally with

antibacterials.

New emerging biological therapies for atopic

dermatitis are promising.

1 Introduction

Atopic dermatitis (AD) is a chronic or chronically relaps-

ing eczematous disease that affects between 15 and 20 %of all children in affluent countries [1]. The classical

symptoms are intense pruritus in the affected areas, often

with clinically visible eczema, typically in the flexuralareas of the body [2]. The lesions may be complicated with

bacterial super-infection with Staphylococcus aureus or

viral infections such as Herpes simplex virus [3]. In 60 %of paediatric cases, the onset of the disease is before the

age of 1 year and in 85 % of the cases before the age of 5

years [4]. Apart from the impact on the patient, the diseaseaffects the quality of life of the patient’s family to the same

degree as having a child with diabetes mellitus [5].

Classically, the diagnosis of AD is made on the basis ofthe Hanifin and Rajka [6] criteria from 1980, and it is a

clinical diagnosis. There is a long-standing discussion onwhether IgE-mediated allergies are part of the pathogenesis

C. Vestergaard ! M. Deleuran (&)Department of Dermatology, Aarhus University Hospital,P.P. Ørumsgade 11, 8000 Aarhus C, Denmarke-mail: [email protected]

Drugs (2014) 74:757–769

DOI 10.1007/s40265-014-0219-3

of AD and this debate is even more pertinent after the

finding of the importance of filaggrin mutations as the basisof approximately one-third of all AD patients in Northern

Europe, but with much higher variations in the rest of the

world [7, 8].The severity of AD dictates the level of treatment. In

mild to moderate cases, topical immunomodulators or

steroids may be used both in a proactive manner to preventflare-ups, and as treatment of acute eczema. In moderate to

severe cases, systemic immunomodulatory therapy may benecessary even in children [9]. However, in all cases the

basic therapy is moisturizers to alleviate the dry skin and

the impaired skin barrier function [10].This review will discuss the latest trends in diagnosis,

pathogenesis and treatments of AD.

2 The Diagnosis of Atopic Dermatitis (AD)

In the clinic the diagnosis of AD is made on the basis of

The Hanifin and Rajka [6] criteria from 1980 (Table 1), of

which the patient must have at least three major and threeminor criteria. The distribution of the eczema depends on

the age of the patient. In the infantile stage, the face, the

scalp and the extensor sides of the extremities are typicallyaffected whereas in the childhood phase the eczema is

typically located in the flexural folds of the extremities as

well as the hands and the face. In teenagers and adults theflexural areas are still the most common sites but the hands

and feet are often involved as well as the face and neck

[11]. The latter is often described as head and neck der-matitis and can be a sign of sensitisation to Malassezia

furfur, which is a skin commensal [12]. In severe cases, the

entire skin organ may be involved and the patients maydevelop erythroderma. The affected skin shows a typical

eczema with a maculopapular rash, with or without vesi-

cles, desquamation and excoriations [1]. In certain cases,the eczema may present itself as a nummular eczema with

sharply demarcated edges, as a pityriasiform lichenoid

eczema or as a follicular-type AD, characterized by plaque-shaped, lichenoid desquamation eczema, which is common

in the Japanese population [13]. Post-inflammatory hypo-

pigmentation is often seen in healed skin in fair skin typesand hyperpigmentation in darker skin types.

A hallmark of AD, and one of the minor criterion in the

Hanifin and Rajka criteria, is dry skin or xerosis, though theprevalence varies between 48 and 100 % compared with

14–40 % in healthy controls [11, 14]. Furthermore, sweat-

induced itch, skin reactions upon food intake, hand eczema,positive skin prick testing, facial erythema and disease

activity influenced by environmental factors are more

prevalent among patients with AD than among healthycontrols [11]. Other signs of AD that are not included in the

Hanifin and Rajka criteria are earlobe rhagades (fissures at

the base of the earlobes), atopic winter feet (juvenileplantar dermatitis), and retro-auricular fissuring.

3 Pathogenesis of AD

Until recently, AD has been perceived as a disease drivenby T helper 2 (Th2; lymphocytes that express interleukin

[IL]-4, IL-5, IL-6 and IL-10), based on the IL-4-dominatedresponse achieved when peripheral blood mononuclear

cells (PBMCs) from AD patients are stimulated with, for

example, lipopolysaccharide (LPS) [15]. This perceptionwas supported by the fact that approximately 80 % of all

AD patients had increased serum concentrations of

immunoglobulin E (IgE) [16]. However, over the lastdecade this has changed immensely. The perception of IgE

as a central molecule in the pathogenesis has been chal-

lenged and it has been suggested that it may just be anepiphenomenon to the severe inflammation taking place

[8]. The Th2 paradigm has also been questioned as a result

of animal experiments, which show that neither Th2 lym-phocytes nor the Th2 pathway are a prerequisite for AD-

like eczema [17, 18]. Lastly, the skin barrier function has

drawn much more attention after the milestone publicationshowing that lack of filaggrin, due to loss of function

mutations in the FLG gene, increased the risk of having AD

13.4-fold [19].

3.1 Inflammation of the Skin in AD

Classically, the inflammation in AD is described as a

biphasic response with an initial Th2-dominated cytokine

profile; for example, high production of IL-4, IL-5 and IL-13 followed by a mixed Th1/Th2 response (e.g., additional

production of IL-2 and interferon-c [IFN-c]) [20]. IL-22

that originates from the Th22 lymphocytes has beenimplied in the acute phase of AD as it increases the epi-

dermal growth but down-regulates the skin barrier function

[21, 22], along with IL-31, which also induces pruritus[23]. Furthermore, the keratinocytes play an active role in

the production of inflammatory signals, as they produce the

skin-specific CC-chemokine-ligand 27 (CCL27) and theTh2 inducing CCL17 [24, 25]. The latter can also be

induced in dermal dendritic cells by thymic stromal lym-

phopoietin (TSLP), which is also produced by the kerati-nocytes. Another cytokine produced by the dendritic cells

in the dermis of AD patients is IL-25 (IL-17E) [26]. This

cytokine is known to induce a Th2 response and has beenfound increased not only in AD patients, but also in the

airway epithelium of asthma patients. Interestingly, IL-25

is released from mast cells when the FceRI receptors arecross-linked by antigens binding to IgE [27]. This may

758 C. Vestergaard, M. Deleuran

provide a link between food allergies and the flare-ups of

AD.

IL-33 is a member of the IL-1 family, and is describedas a member of the ‘alarmin’ family [28]. It is released

from keratinocytes upon mechanical stimuli, and binds to

the ST2 receptors that are expressed on mast cells and Th2lymphocytes, which suggests that IL-33 may be involved in

the early events of AD [29, 30].In the chronic stages of AD, a more mixed response can

be observed. As already mentioned, more Th1 lymphocytes

can be observed in the skin. The expression of IFN-c ispreceded by IL-12, a cytokine that can be induced in

monocytes by IL-4 [31]. However, recent results have

demonstrated that Th17 lymphocytes, which are usuallyassociated with psoriasis, are part of the T lymphocyte

infiltrate found in chronic lesions of AD skin [32]. IL-17 is

described as a master regulator of antimicrobial peptides(AMPs) and may be a key to the decreased expression of

AMPs in AD skin, and the following increased numbers of

skin infections [33].

3.2 Barrier Function and Filaggrin

AD patients have a decreased skin barrier that leads to anincreased trans-epidermal water loss (TEWL) [34, 35] but

also to an increased risk for the patient to acquire allergies[36]. The composition of the skin barrier is very complex,

but one of the major constituents of the barrier is the out-

ermost layer of the epidermis, the stratum corneum. Thekeratinocytes in this layer have undergone apoptosis,

excluded their nuclei and have become completely filled

with keratin [37]. Keratin filaments are tightly cross-linkedby filaggrin molecules and thus a lack of filaggrin leads to a

poorer aggregation of keratin. Filaggrin is encoded by the

FLG gene as profilaggrin, which is made up by 8–12 fil-aggrin repeats [38]. Heavy phosphorylation protects

Table 1 The Hanifin and Rajkacriteria for the diagnosis ofatopic dermatitis [6]

Must have three or more basic features:

Pruritus

Typical morphology and distribution:

Flexural lichenification or linearity in adults

Facial and extensor involvement in infants and children

Chronic or chronically relapsing dermatitis

Personal or family history of atopy (asthma, allergic rhinitis, atopic dermatitis)

Plus three or more minor features:

Xerosis

Ichthyosis/palmar hyperlinearity/keratosis pilaris

Immediate (type I) skin test reactivity

Elevated serum IgE

Early age of onset

Tendency towards cutaneous infections (esp. Staphylococcus aureus and Herpes simplex)/impaired cell-mediated immunity

Tendency towards non-specific hand or foot dermatitis

Nipple eczema

Cheilitis

Recurrent conjunctivitis

Dennie–Morgan infraorbital fold

Keratoconus

Anterior subcapsular cataracts

Orbital darkening

Facial pallor/facial erythema

Pityriasis alba

Anterior neck folds

Itch when sweating

Intolerance to wool and lipid solvents

Perifollicular accentuation

Food intolerance

Course influenced by environmental/emotional factors

White dermographism/delayed blanch

Diagnosis and Management of Atopic Dermatitis 759

filaggrin from breakdown [39] until it reaches the stratum

granulosum, in which several proteases including matrip-tase, prostasin, as well as caspase 14 are situated [40–42].

In 2006, Palmer et al. [19] described the significantly

increased risk (OR 13.4) of developing AD in patientsheterozygous for loss of function mutations in the FLG

gene. Filaggrin mutations exist globally but they vary from

population to population. Although defects in this gene todate have the best correlation with developing AD,

between 44 and 85 % of patients with AD do not havemutations in the filaggrin gene [34].

Inflammation itself is also able to induce functional

filaggrin defects through down-regulation of filaggrinproduction or filaggrin maturation [43]. IL-4 and Il-13,

both classical Th2-type cytokines, down-regulate filaggrin

on a transcriptional level [44]. IL-25, which may be con-sidered as a Th2-inducing cytokine, also down-regulates

filaggrin expression on a transcriptional level [26]. IL-22

that is produced by skin homing T lymphocytes (Th22) anddendritic cells from the skin down-regulate filaggrin and

profilaggrin on both mRNA and protein levels [21]. IL-31,

which is produced mainly by Th2 lymphocytes but alsomast cells, dendritic cells and monocytes, is strongly

associated with itch, since blocking of this cytokine may

alleviate this symptom [23]. IL-31 also induces IL-20 andIL-24 in HaCaT cells and through this down-regulates fil-

aggrin expression [45]. Cytokines typically associated with

a Th1 response, such as tumour necrosis factor (TNF)-a[46] and IL-17A, also down-regulate filaggrin [47].

4 Treatment of AD

The main goal of therapy for AD is relief from the itch andpossibly inhibition of the inflammatory reaction in the skin.

Treatment modalities can be divided into basic therapy,

topical therapy and systemic therapy. Basic therapyincludes non-pharmacological therapies such as emollients

and baths, and avoidance strategies of both specific and

non-specific provoking factors. Topical therapy includestreatment with topical glucocorticoids and topical calci-

neurin inhibitors (TCIs) and this may be used either as

acute therapy or as proactive treatment. Systemic therapyincludes the use of immunosuppressants such as systemic

glucocorticoids, azathioprine, cyclosporine A, methotrex-

ate, and in some instances mycophenolate. Phototherapyand coal tar baths are classic dermatological treatments and

do have an effect in AD. Biologics have so far not been

registered for the treatment of AD, as they have in psori-asis, but early studies indicate that this may happen in the

future. Other modalities such as psychosomatic counselling

and education through eczema schools also have increasingevidence and are recommended.

4.1 Basic Treatment

4.1.1 Emollients

Emollients are the mainstay of therapy in AD and should

be applied concomitantly with any other therapy chosen.Although the mechanism of action for emollients is largely

unknown, several studies have shown that application of

emollients, both in the short and long term, have a steroid-sparing effect [48]. However, the use of emollients only

without specific treatment of the inflammatory reaction

may increase the risk of disseminating skin infections [49].Emollients containing intact proteins such as oats and

peanut may increase the risk of allergies [50, 51].

4.2 Topical Treatment

The use of topical treatment is often the first choice ofpharmacological treatment in AD, either with glucocorti-

coids or calcineurin inhibitors. The effect of the drug is

determined by three factors: the strength of the drug, thedosage of the drug, and the application of the drug [52].

Dosing of topical treatment might seem difficult but when

using the fingertip unit (FTU) it is quite simple. One FTUequals the amount of ointment/cream that can be expressed

from the distal crease of the index finger to the fingertip

(approximately 0.5 g of cream). This covers the bodysurface area corresponding to two palms.

Topical treatment can be applied on a daily basis during

acute flares, and twice or thrice weekly as a proactivetreatment during periods of remission.

4.2.1 Topical Glucocorticoids

Glucocorticoids partly exert their action through binding to

steroid receptors in the cytosol of the cell. The receptorcomplex then translocates into the nucleus of the cell,

where it inhibits the expression of inflammatory cytokines

(transrepression), induces the expression of anti-inflam-matory cytokines (transactivation) and inhibits the pro-

duction of structural cytokines [53]. Topical steroids are

grouped according to potency into groups I–IV (Europe)and groups I–VII (US), and are effective against inflam-

mation in the skin. In Europe, group I corresponds to the

products with the weakest potency. This is in contrast tothe US, where group I topical corticosteroids corresponds

to the products with the strongest potency. The potency

reflects both the effect of the topical treatment but also therisk of side effects. One well performed treatment per day,

compared with two, is sufficient to obtain effect of thetreatment [54]. Once the symptoms are controlled, treat-

ment should be tapered either through decrease of appli-

cation frequency or of potency of the glucocorticoid.


Proactive treatment with application of fluticasone propi-

onate twice weekly during remission periods significantlyreduced flare-ups of the eczema [55].

The use of high-potency steroids increases the risk for

systemic side effects, although the risk for hypothalamus-pituitary-adrenal axis suppression is very low [56]. How-

ever, high-potency steroids also restore the skin barrier

significantly faster than low-potency steroids, and thusshorter treatment periods are needed [57]. The restoration

of the skin barrier through glucocorticoids is probably dueto the inhibition of the skin-disrupting effect of inflam-

mation, as shown by betamethasone valerate, which by

itself actually inhibits rate-limiting enzymes for lipid syn-thesis [58].

4.2.2 Topical Calcineurin Inhibitors

Tacrolimus and pimecrolimus are macrolides that exert

immunosuppression through inhibition of the calcium-dependent dephosphorylation of the transcription factor

nuclear factor of activated T cells (NFAT) that is required for

the transcription of inflammatory cytokines such as IL-2 [59].Both have efficacy in both long- [60, 61] and short-term [62,

63] studies, and have shown a high degree of efficacy in

proactive treatment over a 1-year period with regard toreduction of both severity and number of flare-ups. The

efficacy of 0.1 % tacrolimus equals that of a corticosteroid of

medium potency [64], whereas pimecrolimus is weaker [65].There have been controversies over the safety of the drugs,

especially with regard to the risk of non-melanoma skin

cancer and lymphoma. However, a follow-up study over6 years has shown no increased risk of lymphoma after the

use of TCIs and the photocarcinogenic effect of the drugs has

also been examined and found to be non-existent when usedtopically [66]. However, since the systemic use of calcineurin

inhibitors in solid organ transplant patients significantly

increases the risk for non-melanoma skin cancer, the use ofsunscreens is still recommended when using these drugs [64].

4.3 Antibacterials and Antiseptics

Most patients with AD are colonized with S. aureus on

both affected and unaffected skin [67]. A systematic reviewfound no clear evidence of benefit from the use of anti-

bacterial soaps, antibacterial bath additives or topical

antibacterials/antiseptics [68]. The studies included in thereview were, however, quite small. A randomized con-

trolled trial (RCT) in children with AD showed beneficial

effects of intranasal mupirocin ointment combined withbaths containing sodium hypochlorite (bleach baths) on

disease activity in children [69]. Oral antibacterials are not

recommended when the skin is not clinically infected, butshould be used as a short-term treatment for clinically

super-infected AD with oozing, crusts, pustules and/or

fissures. Cephalosporins, penicillinase-resistant penicillins,or clindamycin are preferred for this purpose [70, 71]. In

most countries, methicillin-resistant strains of S. aureus

(MRSA) are an increasing problem, and it is very difficultto clear the bacteria from patients with active skin disease.

In this context, bleach baths are a useful supplementary

treatment [72].

4.4 UV Phototherapy

Ultraviolet (UV) phototherapy for AD has been used for

many years. Treatments include broadband (BB)-UVB,narrowband (NB)-UVB, UVA/B, UVA1 and psoralen (P)-

UVA. Most patients experience significant benefits. A

limitation is that the effectiveness of UV phototherapy isshort term, moderate and followed by recurrence of

symptoms within a few months, especially in patients with

severe AD.A recent systematic review included 19 RCTs and 905

patients. The studies were clinically and qualitatively het-

erogeneous, but the authors concluded that UVA-1 andNB-UVB appear to be the most effective treatment

modalities for the reduction of clinical signs and symptoms

of AD [73].UV treatments should not be started when the skin is

acutely inflamed and oozing, as this will often result in a

poor outcome of the treatment. The patient should betreated with emollients, topical corticosteroids and anti-

bacterials, if indicated, for some days before UV treatment

is started. This may not be necessary for high-dose UVA1.The carcinogenic effects of UV phototherapy limit their

use for long-term maintenance treatment.

There are limited data on the use of phototherapy forchildren with AD. Darne et al. [74] performed a prospec-

tive comparative cohort study including 55 children with

moderate to severe AD. Twenty-nine children were treatedwith NB-UVB for 12 weeks and 26 children served as

controls. There was a 61 % reduction in Six Area Six Sign

Atopic Dermatitis (SASSAD) score in the treated groupcompared with a 6 % increase in the unexposed cohort, and

the quality of life was improved in the treated group [74].

These data are supported by two other retrospectivestudies on the use of NB-UVB in children with AD [75,

76]. Further studies are needed to evaluate the long-term

safety in treating children with phototherapy.

4.5 Systemic Immunosuppressive Therapy

4.5.1 Corticosteroids

There are very limited data documenting the effect ofsystemic corticosteroids, but clinical experience shows that


they are rapidly effective in controlling the symptoms of a

severe flare in AD.If a patient has moderate to severe chronic disease, one

should consider starting another systemic immunosup-

pressive treatment in combination with topical treatment,while tapering the systemic corticosteroid, due to the

severe long-term side effects of systemic corticosteroids,

and the risk of flare after stopping the treatment [77].

4.5.2 Cyclosporine A

Cyclosporine A is the best-documented systemic treatment

for severe AD, licensed in many countries for this indica-tion in adults. A meta-analysis pooling data from eight

RCTs demonstrated its effectiveness compared with pla-

cebo [78], and this conclusion has been confirmed in a veryrecent systematic review including 14 trials [79]. Both

short-term and long-term use may help control severe AD

[80, 81].The advantage of cyclosporine A is its rapid onset of

action. While most patients experience very few subjective

side effects, they have to be carefully monitored due to therisk of severe side effects, in particular nephrotoxicity,

liver impairment and hypertension. The recommended dose

is between 2.5 and 5 mg/kg/day. It is beneficial to thepatient to start with 4–5 mg/kg/day to gain good control of

the disease and then taper off to the lowest effective dose.

When the drug is discontinued, around half of the patientsexperience a rapid relapse, half remain in remission for

about 3 months and a few patients experience a rebound

phenomenon [80].

4.5.3 Methotrexate

Many clinicians have used methotrexate for severe AD in

both adults and children, but until recently only a few open,

uncontrolled case series had documented its effectiveness inadults [82–84]. In 2010, an RCT compared the use of meth-

otrexate versus azathioprine for severe AD in adults. A total

of 42 patients were included and the treatment period was12 weeks [85]. The mean relative reduction in the eczema

severity score (SCORAD) was 42 and 39 %, respectively. No

serious adverse events were observed in the study.A recent RCT including 40 children has also demon-

strated its effect in children between 7 and 14 years of age

[86]. Methotrexate 7.5 mg/week was compared withcyclosporine A 2.5 mg/kg/day for 12 weeks. The mean

reduction in SCORAD was 49.3 and 44.7 %, respectively.

Both drugs were well tolerated.The primary side effects for methotrexate are cytopenias,

liver function abnormalities and gastrointestinal side effects.

Methotrexate is teratogenic and women of childbearing agemust use a safe contraception method [87]. This also includes

men treated with methotrexate who have fertile female

partners. If well tolerated, the major advantage of metho-trexate is that it can be used for many years in chronic cases,

with a weekly dose between 7.5 and 25 mg in adults. The

recommended therapeutic dose range for children with pso-riasis is 0.2–0.7 mg/kg/week [88] and we use the same dose

interval in children with AD. Methotrexate treatment in

children should not exceed adult dosing.The patients should be informed about the slow onset of

action, which is up to 12 weeks, before the maximal effectcan be expected. If gastrointestinal side effects occur, or

the patient does not respond to the oral treatment, subcu-

taneous administration may be considered.

4.5.4 Azathioprine

Azathioprine is a frequently used immunosuppressive drug

in the management of severe AD in many countries, but

hardly ever used in other countries. This difference isprimarily based on clinical tradition. Main adverse effects

are cytopenias, gastrointestinal side effects, viral infec-

tions, and a small increase in skin carcinomas, especially inpatients with marked UV exposure. A typical maintenance

dose is between 1.5 and 3.0 mg/kg/day. Like methotrexate,

it has a slow onset of action.A few patients have a low level or lack of the enzyme

thiomethylpurine transferase (TPMT), with a resultant

increased risk of developing severe myelosuppression.Measurement of TPMT level before prescribing the drug, or

starting with a small test dose of azathioprine, under close

weekly laboratory monitoring, is necessary. Patients withnormal levels of TPMT can also develop myelosuppression.

A few controlled studies have so far been published docu-

menting the effect in adult patients with severe AD. Berth-Jones et al. [89] demonstrated a 26 % reduction in the SAS-

SAD score in the azathioprine-treated group compared with a

3 % reduction in the placebo group. The treatment period was3 months. The dropout rate was quite high, but a significant

reduction in pruritus, sleep loss and fatigue in the active group

was observed. In 2006, an RCT including 63 patients wasperformed. Forty-two patients were treated with azathioprine

for 12 weeks. Patients with normal levels of TPMT received

azathioprine 2.5 mg/kg/day and patients with reduced TPMTactivity received 1 mg/kg/day. A mean reduction of 37 % in

disease activity was observed in the azathioprine-treated

group compared with 20 % in the placebo group [90].Azathioprine is also effective in controlling severe AD

in children [91].

4.5.5 Mycophenolate

Mycophenolate mofetil can be considered as a third-linedrug in the treatment of severe AD. Standard doses are


between 0.5 and 1.5 g twice daily in adults. Clinical

experience, case reports and small open studies suggestbenefit in patients with severe AD [92, 93]. The most

prominent adverse events are cytopenias and gastrointes-

tinal problems, and it is very important to know that my-cophenolate is a teratogen [94, 95]. If gastrointestinal side

effects are a problem, a small open study suggests the use

of mycophenolate sodium as an alternative [96]. The drugis formulated in an enteric-coated form and none of the ten

patients studied discontinued the drug due to adverseevents. The effect of this drug has been confirmed in a

larger study comparing mycophenolate sodium with low-

dose cyclosporine A for adult patients with severe AD [97].

4.6 Biologics

During the last years, a limited number of studies have

been published indicating an effect of some biological

agents on AD. However, the future looks promising, asdifferent biological treatments for AD are in the pipeline,

but so far no specific biologic therapy for AD has been

approved by the drug agencies.

4.6.1 Interferon-c

The main adverse effects of IFNc are flu-like symptoms,

and this has limited the use of the drug. IFNc treatment for

severe, recalcitrant AD should be considered as a third-lineoption for patients who do not respond to or do not tolerate

other systemic treatments.

A double-blind, placebo-controlled study including 83patients demonstrated more than 50 % improvement in

physicians’ overall assessment in 45 % of patients treated

with daily subcutaneous injections of 50 lg/m2 IFNc for12 weeks compared with 20 % in the placebo group [98].

Two smaller studies have shown that the treatment can be

continued for up to 2 years [99, 100].

4.6.2 Anti-CD20

Rituximab is an anti-CD20 monoclonal antibody directed

against B cells. Six patients with severe AD were treated

with rituximab 1,000 mg intravenously at day 0 and 14. Allpatients experienced a significant improvement of their

eczema, and the treatment was well tolerated [101]. This

effect could not be confirmed in a case report of twopatients with severe AD [102].

4.6.3 Anti-IL-5

IL-5 is essential for eosinophil growth, differentiation and

migration, and these cells play a role in the pathogenesis ofAD. In an RCT, two single doses of 750 mg of

mepolizumab (an anti-IL-5 recombinant humanized

monoclonal antibody) were given 1 week apart, to patientswith moderate to severe AD. Forty patients participated in

the study and the effect was assessed on day 14. A decrease

in peripheral blood eosinophils and a moderate clinicalimprovement (\50 %) was observed [103].

4.6.4 Anti-IgE

Omalizumab is a humanized monoclonal mouse antibodydirected against IgE. It is registered for the treatment of

severe asthma, and it has also been shown to be effective in

chronic urticaria.Some reports describe a beneficial effect in patients with

moderate to severe AD [104–106]. However, a 2:1-ran-

domized, double-blind, placebo-controlled study including20 patients with an investigator global assessment score C2

did not reveal a superior effect of omalizumab over placebo

in reversing pre-existing chronic atopic disease in adults.The total treatment period was 16 weeks [107].

4.6.5 Anti-IL-4 Receptor

Dupilumab, a new human monoclonal antibody that targets

the IL-4Ra subunit and inhibits the effect of IL-14 and IL-13, has shown very promising results. In an RCT with

dupilumab 300 mg (n = 55) or placebo (n = 54) weekly

for 12 weeks, the Eczema Area and Severity Index (EASI)score improved significantly by 74 versus 23 % [108].

Another study showed that 100 % of patients (n = 21)

treated with dupilumab and topical corticosteroidsachieved EASI 50 compared with 50 % treated with pla-

cebo and corticosteroids (n = 10) [109].

4.6.6 Intravenous Immunoglobulins (IVIG)

IVIG treatment has been tried for both adults and childrenwith severe, treatment-refractory AD. Conflicting results

have been obtained, suggesting that the treatment may be

helpful in primarily paediatric cases of the disease.A small open study including ten adult patients showed

a very limited effect of the treatment after 2 months [110].

In 2011, Jee et al. [111] published an RCT including 40children, of whom 30 received IVIG with a 1-month

interval for 3 months compared with 10 children who

received placebo. A significant reduction in SCORAD wasobserved in the IVIG-treated group compared with the

placebo group after 3 months. Five patients in the active

group did not complete the study due to adverse effects.Another RCT compared a single dose of IVIG 2 g/kg in

six children with cyclosporine A 4 mg/kg/day in eight

children for 3 months. As expected, cyclosporine A wassignificantly more effective than IVIG, due to the single


dose of IVIG, but initially there was a good effect of both

treatments [112]. Concomitant treatment with topical cor-ticosteroids, antihistamines and antibacterials were allowed

in this study, and this may have influenced the outcome.

In conclusion, IVIG may be considered as a last resorttreatment in severe treatment-refractory AD in children.

4.7 Other Immunotherapies

4.7.1 Allergen-Specific Immunotherapy (ASIT)

Patients with severe AD often suffer from complicating type I

allergies and ASIT may be a useful complementary treatmentfor patients with moderate to severe chronic AD and com-

plicating allergic asthma and/or rhino-conjunctivitis.

An RCT by Werfel et al. [113] has shown that ASITwith house dust mite (HDM) preparations significantly

improved the disease activity, measured by SCORAD, in

patients sensitized to HDM, in a dose-dependent mannerover an observation period of 1 year. These results have

been confirmed in another study over 12 weeks using birch

pollen extracts in patients sensitized to this allergen [114].

4.7.2 Immunoadsorption

A pilot study including 12 patients with severe, treatment-

refractory AD was performed. All patients had a high

SCORAD and very high IgE values, in spite of a combi-nation of topical and systemic treatments [115]. Patients

were treated with a total of ten immunoadsorptions, in

order to reduce high titres of circulating antibodies. SerumIgE was reduced more than 90 % after each treatment, but

returned to initial concentrations shortly after the last

treatment. In spite of this, all patients experienced a highlysignificant reduction in SCORAD and pruritus. Larger

controlled trials with this promising but expensive and

time-consuming treatment are warranted.

4.8 Dietary Factors

4.8.1 Food Allergy

Food allergy is most prevalent in young children withmoderate to severe eczema. A Danish population-based

study found that 14.8 % of children suffered from food

allergy and of these, 90 % had AD [116]. An undetectedfood allergy may result in severe allergic reactions in the

child, including respiratory symptoms and anaphylaxis, but

it may also worsen the AD.It is quite rare that a teenager or adult develops food

allergy for the first time, and a substantial proportion of

children suffering from allergy against primarily milk andegg will grow out of their allergy during the first years of

life. In the Western world the most prevalent food allergies

are against milk, egg, peanut, hazelnut and fish [117].Children with AD should be considered for food allergy

evaluation if there is a suspicion found in the clinical his-

tory. Food provocation tests are conducted in order toconfirm or reject the diagnosis, to find the threshold of the

allergy, but also to investigate if a child has developed

tolerance to the food over time.

4.8.2 Probiotics

There have been a number of studies dealing with the effect

of probiotics on AD. Most studies have shown beneficialeffects of the use of supplementation with probiotics in

mothers and infants in preventing development and

reducing the severity of AD [118].The results taken together are conflicting, however, due

to differences in study design, dosage and strain of the

probiotic [119].

4.8.3 c-Linolenic Acid

Studies on essential fatty acid supplementation in AD have

indicated beneficial effects in some patients with AD, but a

recent Cochrane Systematic Database review concludedthat oral borage oil and evening primrose oil, which both

contain c-linolenic acid, lack effect on eczema. Improve-

ment was similar to respective placebos used in theincluded trials [120].

4.9 Psychosomatic Approaches

A recent study by Chrostowska-Plak and co-workers

evaluated the relationship between pruritus and stress,health-related quality of life (HRQoL) and depression in

adult patients with AD, and it was shown that patients with

symptoms suggesting depression had more intense prurituscompared with the rest of the patients [121].

Psychological stress can induce exacerbations in eczema

activity [122], and illness representations and coping arehighly associated with self-rated physical impairment in

AD patients [123].

Further, it has been shown that psychological interventionshave a positive effect on itch and scratching behaviour. Stress

management programmes may therefore be a useful addition

to standard treatment in patients with AD [122].

4.9.1 Therapeutic Patient Education and Eczema Schools

Poor adherence to the treatment is frequent in patients with

AD. This may be due to fear of unwanted side effects, but

also to the time-consuming procedures related to topicaltreatment regimens.


The German Atopic Dermatitis Intervention Study

(GADIS), which included 823 children and adolescents,showed that age-related educational programmes are

effective in the long-term management of AD [124].

A position paper describing the objectives and recom-mendations for patient education in AD has recently been

published [125], and in spite of cultural and financial dif-

ferences between countries, a recent survey has shown thatthere is a consensus among experts to integrate education

into the treatment of AD [126].

5 Conclusion

AD is a multi-etiological disease. The skin is characterized

by an inflammatory reaction primarily made up of Th2/Th22 lymphocytes as well as Tc2 lymphocytes, but other

cell types such as dendritic cells, eosinophils and mast cells

may also play an important role. It is therefore safe toconsider AD as an inflammatory skin disease. Furthermore,

the research over the past 10–15 years has shown that a

decreased barrier function in the skin also plays a signifi-cant role in the pathogenesis of AD. Recent studies have

linked these etiologies together because the inflammatory

reaction can influence the barrier function and vice versa.Thus, the treatment for AD should ideally inhibit the

inflammatory reaction and re-establish the skin barrier

function. From this review of the latest trends in thetreatment of AD it is clear that most, if not all, of the

treatments are aimed at the inflammatory reactions. As

recommended by the EADV/ETFAD/EFA/ESPD andGA2LEN [52, 127], the basic therapy of AD should be

application of moisturisers and then, depending on the

severity, an anti-inflammatory treatment should be added.In mild to moderate cases, topical treatment with either

corticosteroids or calcineurin inhibitors may be used,

whereas in moderate to severe cases systemic immuno-suppressive drugs can be added. The evidence level for

most systemic drugs is low and the use of these varies

greatly between the countries of Europe [128]; however,some patients do need more than topical treatment.

Several studies have demonstrated that patient education

can have a very deep impact on the quality-of-life score forAD patients and their families, and thus psychosocial

interventions are of equal importance as the immunosup-

pressive drugs. Thus, this kind of treatment should beinstigated as soon as possible for patients with moderate to

severe AD.

No AD-specific biological treatments are registered atthe moment, but phase I and II trials are being carried out.

There is a dire need for effective biological treatments that

target this disease specifically, with fewer adverse events

than the traditional treatments we have described here,

especially for patients with severe, chronic disease.

Acknowledgments Mette Deleuran is an investigator, speaker and/or an advisor for AbbVie A/S, MSD, Pierre Fabre Dermo-cosmetique,Meda Pharma, Leo Pharma, and Regeneron. Christian Vestergaard isan investigator and/or speaker for Abbvie A/S, Leo Pharma, Novartisand Astellas. No sources of funding were used to prepare this review.

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