Atopic dermatitis and the atopic march: what is new?
ABSTRACT Objective. In this paper the authors review the management of atopic dermatitis (AD) and the association between AD and allergic respiratory diseases. Data Sources. PubMed databases, researching articles in the last 15 years. Results. Studies about atopic march are cross-sectional population studies at different ages. They show that the most important predisposing factor for atopy is a decrease of the filaggrin's expression. Conclusions. The most modern theories seem to show that the most important factor which starts the atopic march is represented by an impaired epidermal barrier. It causes an increase in skin permeability to allergens that could induce sensitization even in the airways. The major predisposing factor is a primary inherited epithelial barrier defect resulting from filaggrin gene mutation, but other factors may play a role in this complex mechanism. Further studies are needed to focus on AD treatment and preventive strategies.
Article: Does improvement management of atopic dermatitis influence the appearance of respiratory allergic diseases? A follow-up study.[show abstract] [hide abstract]
ABSTRACT: Atopic dermatitis (AD) is often the prelude to allergic diseases. The aim of this study was 1) to evaluate if an integrated management regime could bring about a change in the evolution of the disease in comparison to the results of a previous study; 2) to determine whether the refinement of allergic investigations allowed to identify more promptly the risk factors of evolution into respiratory allergic diseases. The study included 176 children affected by AD and previously evaluated between 1993 and 2002 at the age of 9-16 months, who underwent a telephonic interview by means of a semi-structured, pre-formed questionnaire after a mean follow-up time of 8 years. According to the SCORAD, at first evaluation children had mild AD in 23% of cases, moderate in 62%, severe in 15%. AD disappeared in 92 cases (52%), asthma appeared in 30 (17%) and rhinoconjunctivitis in 48 (27%). The factors significantly related to the appearance of asthma were: sensitization to food allergens with sIgE > 2 KU/L (cow's milk and hen's egg; P < 0.05); to inhalant allergens with sIgE > 0.35 KU/L (P < 0.05). Logistic regression analysis showed that inhalant sensitization was positively related to the occurrence of asthma (OR = 4.219). While AD showed similar rates of disappearance to those of our previous study, the incidence of asthma was reduced, at the same follow-up time, from 29% to 15% (P = 0.002), and the incidence of rhinoconjunctivitis from 35% to 24% (P = 0.02). Comparing the results with those of the previous study, integrated management of AD does not seem to influence its natural course. Nevertheless, the decrease in the percentage of children evolving towards respiratory allergic disease stresses the importance of early diagnosis and improvement management carried out by specialist centers. The presence of allergic sensitization at one year of age might predict the development of respiratory allergy.Clinical and Molecular Allergy 01/2010; 8:8. · 1.39 Impact Factor
[show abstract] [hide abstract]
ABSTRACT: Recently, loss-of-function mutations in FLG, the human gene encoding profilaggrin and filaggrin, have been identified as the cause of the common skin condition ichthyosis vulgaris (which is characterised by dry, scaly skin). These mutations, which are carried by up to 10% of people, also represent a strong genetic predisposing factor for atopic eczema, asthma and allergies. Profilaggrin is the major component of the keratohyalin granules within epidermal granular cells. During epidermal terminal differentiation, the approximately 400 kDa profilaggrin polyprotein is dephosphorylated and rapidly cleaved by serine proteases to form monomeric filaggrin (37 kDa), which binds to and condenses the keratin cytoskeleton and thereby contributes to the cell compaction process that is required for squame biogenesis. Within the squames, filaggrin is citrullinated, which promotes its unfolding and further degradation into hygroscopic amino acids, which constitute one element of natural moisturising factor. Loss of profilaggrin or filaggrin leads to a poorly formed stratum corneum (ichthyosis), which is also prone to water loss (xerosis). Recent human genetic studies strongly suggest that perturbation of skin barrier function as a result of reduction or complete loss of filaggrin expression leads to enhanced percutaneous transfer of allergens. Filaggrin is therefore in the frontline of defence, and protects the body from the entry of foreign environmental substances that can otherwise trigger aberrant immune responses.Journal of Cell Science 06/2009; 122(Pt 9):1285-94. · 6.11 Impact Factor
Article: Filaggrin null mutations are associated with increased asthma exacerbations in children and young adults.[show abstract] [hide abstract]
ABSTRACT: Filaggrin (FLG) null mutations are important genetic predisposing factors for atopic asthma and have recently been shown to influence controller and reliever medication needs in asthmatic children. Our objective was to study the role of FLG null alleles in asthma exacerbations. FLG mutations R501X and 2282del4 were assayed in 1135 individuals ranging from 3 to 22 years old with asthma from Tayside and Dumfries, Scotland. Asthma exacerbations over the previous 6 months were also studied. The FLG mutations were significantly associated with greater risk of exacerbations in children with asthma. Exacerbations were significant for the R501X but not the 2282del4 mutation and the combined genotype compared to the wild-type with odds ratios of 1.97 (95% CI, 1.19-3.22; P = 0.009) and 1.61 (95% CI, 1.08-2.40; P = 0.021), respectively. Individuals with FLG null alleles were more likely to require oral steroids (31.4%vs 19.5%; OR = 1.89; P = 0.021) for their exacerbations. There was also a 1.71-fold increased risk (42.6%vs 30%; P = 0.041) of school absence owing to asthma exacerbations in asthmatic individuals with FLG null mutation. On sub-group analysis, the effect of FLG mutations on asthma exacerbations is significant (P = 0.045) only for participants with relatively mild asthma controlled on inhaled steroids, with inhaled albuterol according to need. In addition to their effect on asthma medication requirements reported previously, there is an association between the presence of FLG null mutations and the risk of asthma exacerbations in asthmatic children and young adults.Allergy 03/2008; 63(9):1211-7. · 6.27 Impact Factor
Hindawi Publishing Corporation
Journal of Allergy
Volume 2011, Article ID 279425, 5 pages
AtopicDermatitis and theAtopic March: What Is New?
1Division of Dermatology, Department of Internal Medicine, Geriatrics and Nephrology, University of Bologna, Via Massarenti 1,
40138 Bologna, Italy
2Department of Pediatrics, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
Correspondence should be addressed to Annalisa Patrizi, firstname.lastname@example.org
Received 8 April 2011; Accepted 14 June 2011
Academic Editor: Fabienne Ranc´ e
Copyright © 2011 Annalisa Patrizi et al. This is an open access article distributed under the Creative Commons Attribution
License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly
Objective. In this paper the authors review the management of atopic dermatitis (AD) and the association between AD and allergic
respiratory diseases. Data Sources. PubMed databases, researching articles in the last 15 years. Results. Studies about atopic march
are cross-sectional population studies at different ages. They show that the most important predisposing factor for atopy is a
decrease of the filaggrin’s expression. Conclusions. The most modern theories seem to show that the most important factor which
starts the atopic march is represented by an impaired epidermal barrier. It causes an increase in skin permeability to allergens
that could induce sensitization even in the airways. The major predisposing factor is a primary inherited epithelial barrier defect
resulting from filaggrin gene mutation, but other factors may play a role in this complex mechanism. Further studies are needed
to focus on AD treatment and preventive strategies.
Atopic dermatitis (AD) is the commonest chronic cutaneous
disease of childhood in the first years of life . AD is often
the first manifestation of allergic diseases. Literature data
[2, 3] show a progression from AD to asthma: the so-called
atopic march. In this paper we will focus reader’s attention
about the relationship between AD and respiratory allergic
AD has a long history. It was firstly described in 1892
by Besnier  who named it “prurigo diath´ esique”. In
order to highlight a possible association between the skin
flare and genetic constitution, in 1927 Brocq suggested the
term “constitutional eczema”. Wise and Sulzberger in 1933
changed this name into “atopic dermatitis”, finally adopted
by Hanifin and Rajka in 1980 . This is the current
denomination adopted in the USA, while in Europe the most
common definition is atopic eczema. In 2004 the World
Allergy Organisation (WAO) Committee suggested to call
“atopic eczema” any inflammatory condition determined
by an IgE reaction, suggesting that the presence of eczema
in atopic patients could be associated with or herald the
development of some allergic diseases such as rhinitis and
AD may be the first manifestation of allergic diseases and
may be the first step of the so-called atopic march. A crucial
role is played by filaggrin (filament-aggregating protein) that
is involved in the epidermal barrier function. It is important
and allergens . Filaggrin aggregates the keratin filaments
and this process is essential for the formation of a normal
stratum corneum and for the hydration of the skin. The
filaggrin gene (FLG), located on chromosome 1q21 in
the epidermal differentiation complex, encodes profilaggrin,
a phosphorylated protein, precursor of filaggrin protein.
Studies about FLG have underlined the link between early
childhood eczema and the subsequent development of
asthma. This is due to defective epidermal barrier function
2 Journal of Allergy
leading to increased allergen penetration and sensitization.
Smith and coworkers in 2006  demonstrated an associ-
ation between ichthyosis vulgaris and a mutation in FLG,
located on chromosome 1q21 (R501X and 2282del4).
In their study 15 families have been studied; AD was
present in 44% of individuals heterozygous for this gene
and in 76% of homozygous individuals; none of the family
member without mutation had AD. Actually it is thought
that the frequency of null FLG mutations (5 in total) is 9%
in the European population .
Further studies confirmed both filaggrin polymorphisms
as a major risk factor for AD [10–15]. The International
Study of Asthma and Allergies in Childhood showed that in
a group of German children the presenceof filaggrin variants
increased more than 3 times the risk of developing AD and
more than 2 times the risk of developing rhinitis regardless
of the presence of AD .
Of course, ascertaining the precise contribution of FLG
mutations to the overall prevalence of these atopic diseases
is confounded by temporal and disease severity factors in
conjunction with putative environmental effects.
AD and asthma present common immunological fea-
tures, including elevated IgE levels, TH2 cytokines, lesional
and peripheral eosinophilia, and common environmental
The hypothesis that asthma is secondary to allergic
sensitization, occurring after epidermal skin barrier disrup-
tion, has been confirmed by the fact that asthma is found
only in the subset of filaggrin mutation carriers with AD,
however the precise mechanisms through which filaggrin
mutations contribute to asthma and allergic rhinitis still
Eczema is a very frequent skin disease. The prevalence of this
condition ranges from 7% to 30% in children and from 2%
to 10% in adults. In the last decades it has been increased
with a percentage double or triple higher, in the developed
In about 70–80% of patients, AD is associated with
increased total IgE serum levels. Atopic diseases have differ-
and food allergies have the highest incidence in the first 2
years of life. Sensitization to inhalant allergens is rare at that
time of life. In later childhood, the prevalence of AD, food
allergies, and food allergen sensitization decreases and the
prevalence of asthma, allergic rhinitis, and sensitization to
inhalant allergens rises .
Several studies have evaluated the association between
AD and respiratory allergy, in particular Kulig et al. 
have shown that, at the age of 5 years, 50% of children with
AD have developed allergic respiratory diseases; Ricci et al.
 have studied 252 children with AD, aged 6–36 months:
the mean followup of these patients was 16.9 ± 2.9 years
(range 13–22 years); in the first 10 years asthma appeared
in 34.1% of cases and RC in 57.6%; they concluded that the
severity and good control of AD was predicable for the onset
of asthma. Ohshima et al.  in a 4-year follow-up study
of 169 children with AD have shown that, at the end of the
study, 35% of children developed asthma. van der Hulst et
al.  in their systematic review have confirmed that young
children with AD had a high risk of developing asthma in
According to a recent study by Spergel more than 50%
of children with AD may develop asthma and approximately
75% allergic rhinitis during the first 6 years of life .
In AD, typical lesions of acute eczema can be observed
in a first time, then lichenification is prevalent due to the
itching. Classically AD shows different clinical features in
3 different ages: first year of life (first step), childhood
(second step), and adolescence/adulthood (third step). In
the first step eczematous, exudating lesions mainly affect
3/5-month-old children. Lesions are located on the scalp
and on the face where the central area is typically spared.
In more severe patients the extensor surfaces of limbs
are also involved. Parents usually refer to physician that
their babies are becoming restless and they cannot sleep at
night. In the second step flexural areas of arms and legs
are commonly affected. Lesions are typical of subacute or
chronic eczema, drier than those of the first step. Children
frequently complain a bothersome itching. In the third
step patients are adolescents or adult. Furthermore in this
step they present lichenified eczema usually localized in
one or a few skin areas such as the face, back of neck,
hands, wrists, and antecubital and popliteal fossae. Itching is
usually important. Inflammatory hyper pigmentation can be
observed in periocular and neck areas and the last has been
described as “dirty neck”. Similar lesions may be observed in
other areas as on feet.
Diagnosis of AD is not so easy  because of the
variety of clinical presentation, for this reason diagnostic
proposed in 1977 by Hanifin and Lobitz ; in 1980 the
diagnostic criteria by Hanifin and Rajka , were derived
from Sulzberger’s definition and from Hanifin and Lobitz’s
proposals. Furthermore Gu et al. refined these criteria in
order to develop diagnostic guidelines for adults, children,
and nonwhite ethnic groups suffering of AD .
In 1993, a consensus report of the European Task Force
on Atopic Dermatitis  defined a validated scale, the
SCORAD (SCORing Atopic Dermatitis), that considered
the extent and severity of the eczematous lesions and the
presence of two subjective symptoms: pruritus and loss of
sleep. Then Oranje and coworkers , proposed a new
SCORAD without patient’s prospective, a patient-oriented
SCORAD (PO-SCORAD) and the three-item severity (TIS)
 score. The TIS score fits well with the more detailed
objective SCORAD and can represent both as a prescreening
system and as a useful tool for epidemiological studies.
Recently in order to validate the PO-SCORAD index, a large
European population study has been developed .
Journal of Allergy3
Hanifin et al.  proposed in 2001 another scoring
system named EASI (Eczema Area and Severity Index),
which can be applied to both AD children and adults. It
considered four areas of the body: the head/neck, the trunk,
and the upper and lower extremities. Each of the four
body areas was separately assessed for erythema, induration/
papulation/edema, excoriation, and lichenification. A score
ranging from 0 to 3 was used to evaluate the severity of
each sign in each of the four areas. In 2004, Charman
et al.  published a new, validated score used both for
adults and children called POEM (Patient-Oriented Eczema
Measure), based on patients’ assessments of what constitutes
disease severity. It consists of questions about the frequency
of seven symptoms: itch, sleep disturbance, skin bleeding,
skin weeping/oozing, skin cracking, skin flaking, and skin
IGA (Investigator Global Assessment) is another severity
score tool that has been widely used in trials consisting of
adults and children. IGA is a simple, 6-point scale, ranging
from 0 (clear) to 5 (very severe disease), representing an
overall evaluation of dermatitis that can be performed by the
investigator at every consultation [30, 31].
A recent systematic review has identified 20 different
published outcome measures, but the authors state that only
EASI, SCORAD, and POEM have been adequately validated
and recommend using EASI or SCORAD for an objective
of eczema severity from the patient’s perspective .
to AD. Numerous differential diagnoses of AD should be
histiocytosis mainly in childhood, and contact dermatitis in
children and adults.
AD management is complex. Topical and systemic drugs are
needed to control the disease. The American Academy of
Dermatology has proposed detailed guidelines of care for
eczema [33–35] based on the assessment of clinical severity
by SCORAD or EASI indexes.
Recently, the PRACTALL (PRACTical ALLergy) con-
sensus paper proposed a simple, step-based algorithm for
only needs hydration; (ii) mild, moderate, and severe eczema
require, respectively, low-, mid-, and high-potency topical
corticosteroids; furthermore topical calcineurin inhibitors
TCIs can be helpful; (iii) systemic therapy is reserved to
resistant eczema. This algorithm has some limitations: TCIs
should not be used in children under 2 years and high-
potency corticosteroids have to be avoided in children and
in special sites such as the face.
The use of TCIs has been debated, in the last few years.
In 2005 , the Pediatric Advisory Committee of the Food
and Drug Administration (FDA) labeled pimecrolimus and
tacrolimus as dangerous, with a black-box warning about
their potential carcinogenicity. Sporadic case of cancer set
during treatment are reported. However, several groups [38–
41] have focused on the evidence of TCIs’ carcinogenetic
role and have agreed that data are inconclusive and further
studies must be done. Furthermore recent vehicle-controlled
trials indicate efficacy of proactive treatment with tacrolimus
in association with corticosteroides to prevent AE flares 
At present however tacrolimus (Protopic) and pimecrolimus
(Elidel) ointment have to be considered second-line treat-
ments for AD in children .
7.AD andQualityof Life
AD is a serious problem for patients and their families, in
fact, especially when severe, AD can be extremely disabling,
causing psychological stress that, in young children, can
involve the whole family. Clinicians should be aware of
the psychological problems related to this disease and their
impact on the child and parents’ quality of life (QOL) .
7.1. AD and Family Life. In 1998, Lawson et al.  focused
on QOL in the families of children affected by AD. They
worked out the Dermatitis Family Impact Questionnaire,
whose aim was to understand the family aspects most
influenced by the disease. Their results showed that 74%
of AD parents described a general burden of extra care,
for example, relating to household cleaning and washing,
preparing meals and shopping; 71% of parents described
psychological pressures including feelings of guilt, exhaus-
tion, frustration, resentment, and helplessness; night-time
itching and scratching caused delay in getting the child
to sleep and led to parental frustration and exhaustion in
64%. So for the 66% of families a “normal” family life
was not possible. Furthermore Lawson et al.  reported
that 63% of children with AD had current sleep problems
and most had had sleep disturbance at some time. Patients
with AD scratch more during sleep than patients with
other chronic dermatologic diseases. Pauli-Pott et al. in their
study  stated that mothers of children with AD were
more helpless, depressed, and overprotective than mothers
of healthy children.
3–84 months affected by AD were asked to complete two
validated questionnaires after clinical examination (Infants’
Dermatitis Quality of Life Index and Dermatitis Family
Impact questionnaire). Children’s QOL appeared slightly
moderately altered (mean score 10.2) compared with the
value of a control group (3.3), and itching, sleep problems,
and the influence of the disease on the child’s mood were
the cause of greatest discomfort for the child. Family QOL
appeared moderately altered (mean score 11) compared
with the value of the control group (7.4). The greatest
problem was the disturbed sleep of the family members.
Other important problems were the economic cost for the
management of the disease and the tiredness and irritability
caused by the disease in parents.
4Journal of Allergy
AD is a complex disease with needs a well standardized
clinical approach. Furthermore AD often preludes to other
atopic diseases. Our hope is that, in the next future, der-
matologists and paediatric allergists will have standardized
guidelines based on international consensus conferences.
Similarly to other chronic diseases such as allergic asthma,
the use of step-based therapy could be useful in the
management of the disease . The evaluation of the
quality of life of patients and their families represents a new
target, with a global consideration of problems no more
limited to the skin. Although the disease mainly affects
childhood, in some cases it may persist even in adulthood
and may be associated with asthma and/or allergic rhinitis.
The percentage of AD persistent cases is extremely variable,
ranging from 8–13% to 60–70% . On the other hand,
healing data reported in the literature widely vary: some
authors report 50–70% healing at the age of 10 years, others
 43.2% at the age of 3, and some refer to a general
improvement in AD severity in the first 5/7 years of life
. The relationship between asthma and AD is complex,
because different and unknown mechanisms are involved
in the atopic march. Further studies about loss of function
in filaggrin gene are needed to elucidate the risks related
to epidermal barrier defects. Potential targets for barrier
repair and prevention of atopic diseases will play a crucial
role in future therapy. Much data point towards a strong
correlation between AD in early infancy and the subsequent
appearance of asthma. The risk of developing asthma in
children with AD is highly variable: according to some
authors, the prevalence is 25%, while others suggest higher
values up to 80% [17, 19]. In a recent study conducted by
our team , the percentages of appearance of respiratory
allergies is lower; in fact only 37.5% of children with AD
have developed respiratory pathologies (rhinoconjunctivitis
in 27% of cases and asthma alone in 17%) after a long-term
respiratory allergies has been attributed to the good control
effective collaboration between dermatologists and pediatric
allergologists, sometimes with the aid of a psychologist.
Conflict of Interests
The authors declare no conflict of interests.
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