Intrinsic Atopic Dermatitis (AD): A New Concept of AD Classification
Wednesday, June 11, 2014
Although several criteria for the
definition of atopic dermatitis (AD) have been approved, variations
still exist in the diagnosis of AD because of its heterogeneous
aspects. The clinical phenotype of AD has been classified into the
extrinsic and intrinsic types (Table 1).1,2 They are
also referred to under several different names (Table 2): mixed AD
versus pure AD, allergic AD versus non-allergic AD and classical AD
versus atopiform dermatitis. The intrinsic-type AD is not a simple
non-allergic type; it is induced via an immunological mechanism.
The characteristics of intrinsic AD are summarized in
Table 1. Subtypes of
AD=atopic dermatitis; FLG=filaggrin;
Table 2. Nomenclature of AD
Table 3. Characteristics of
AD=atopic dermatitis; FLG=filaggrin;
IFN-γ=interferon-gamma; IgE=immunoglobulin E.
Extrinsic AD and intrinsic AD are
defined according to immunoglobulin E (IgE)-mediated sensitization
- specifically the presence or absence of specific IgE for
environmental and food allergens. The reported mean values of total
serum IgE in the intrinsic-type AD are from 22.2 to 134
kU/L,3,4 but values of <150 or 200 kU/L have also
been used to indicate the condition. IgE levels related to mite
allergen exposure can be used for categorization of extrinsic and
intrinsic AD as well as total IgE levels.5
The incidence of extrinsic AD and
intrinsic AD, respectively, have been reported as follows: 73%
versus 27% and 63% versus 37% both in German children, 88% versus
12% in Hungarian adults, 78.2% versus 21.8% in Dutch patients and
approximately 80% versus 20% in Korean patients.2 The
female predominance in intrinsic AD is well known and has been
observed by a number of studies, where as many as 76.5% of AD
patients were female.3
The skin manifestations of the two
types of AD are indistinguishable. However, intrinsic AD may lack
the features of filaggrin (FLG) gene mutation-associated
skin lesions, including ichthyosis vulgaris and palmar
hyperlinearity (Figure 1). Meanwhile, it has been reported in Dutch
patients that the Dennie-Morgan fold is present significantly more
often in the intrinsic type. The later onset of disease and milder
disease severity are also characteristics of intrinsic AD.
Figure 1. Extrinsic AD:
FLG gene-mutation-associated skin lesions.
Ichthyosis vulgaris (top) and palmar hyperlinearity (bottom).
(Images courtesy of Professor Yoshiki Tokura).
AD is well known as a Th2-polarized
disease. Extrinsic AD patients show high levels of Th2 cytokines,
such as IL-4, IL-5 and IL-13, whilst intrinsic AD is linked with
much lower levels of IL-4 and IL-13. Circulating interferon-gamma
(IFN-γ) T cell frequency was higher in intrinsic than extrinsic AD
in our study (Figure 3).4 A recent study using lesional
skin showed that higher activation of all inflammatory axes,
including Th2, was seen in patients with intrinsic AD,6
suggesting an important role of Th2 cells in the development of
intrinsic as well as extrinsic AD lesions.
Figure 3. Th1 cells are
increased in intrinsic AD. IFN-γ=interferon-gamma;
N.S.=non-significant; NS=normal subjects. (Figure courtesy of
Professor Yoshiki Tokura).
We found that Th17 cells, producing
IL-17A and IL-22, are increased in the peripheral blood of AD, and
Th17 cells infiltrate acute skin lesions more markedly than in the
chronic lesions.7 The frequency of circulating Th17
cells tends to be higher in intrinsic AD than in extrinsic
AD.4 In the lesional skin, positive correlations between
Th17-related molecules and SCORAD are only seen in patients with
With regard to chemokines, both groups
had higher levels of serum chemokine (C-C motif) ligand 17 (CCL17)
than healthy controls, but its value is significantly higher in
extrinsic than intrinsic AD.4 Upon external stimulation,
epidermal keratinocytes produce thymic stromal lymphopoietin
(TSLP), which stimulates Langerhans cells (LCs) possessing TSLP
receptors.8 Protein antigen is more responsible for the
cause of extrinsic AD than hapten. LCs initiate epicutaneous
sensitization with protein antigens and induce Th2-type immune
responses via TSLP signaling, further suggesting that LCs play a
mandatory role in extrinsic AD. In contrast, LCs may not be
stimulated to produce Th2 chemokines in intrinsic AD because of the
presence of preserved stratum corneum. Non-protein antigens are
considered to exert the Th1 response in intrinsic AD as circulating
IFN-γ Th1 cells are elevated in the patients.
Through patch testing, approximately
20% AD patients are shown to be positive to metals. Patients with a
metal allergy occasionally exhibit a skin manifestation (Figure 4)
indistinguishable from AD under the name of 'pseudo-atopic
dermatitis'.9 Th1-inducing non-protein antigens, such as
metals, might be causative for intrinsic AD. Nickel (Ni), cobalt
(Co) and chrome (Cr) are the three major metals that can be
ingested orally as food and may be excreted from sweat at high
concentrations as well as urine. Intrinsic AD shows significantly
higher percentages of positive reactions than extrinsic AD to Ni
and Co.5 Furthermore, the prevalence of metal allergy to
one or more of the three metals was more than twice as high in
intrinsic AD (61.3%) than extrinsic AD (25.5%). The concentration
of Ni was also significantly higher in the sweat of intrinsic than
extrinsic AD patients.5 Thus, metal allergy is one of
the potential causes of intrinsic AD. Interestingly, Co allergy is
more prevalent in females than males, which is in accordance with
the female preponderance of intrinsic AD.
Figure 4. Intrinsic AD: metal
allergy-related skin manifestations. (Images courtesy of
Professor Yoshiki Tokura).
Recently, Ni and Co have been shown to
activate Toll-like receptor 4 (TLR4) signaling in
antigen-presenting cells.10 Thus, metals can interact
with not only major histocompatibility complex (MHC)/self-peptide
complex but also with TLR4. Ni, Co and Cr show a mixed Th1- and
Th2-type cytokine response in peripheral T cells from sensitized
patients, which is different from Th2-stimulatory protein
antigens.8 Women show a higher sensitization rate to Ni
than men, perhaps through wearing Ni-containing jewelry, which may
contribute to the female predominance of Ni allergy in intrinsic
AD. Ni- or Co-rich food items include peanuts, hazelnuts, almonds,
chocolate, etc. Excess intake of these foods allows metal ions to
be excessively administered. Metals are excreted through sweat, and
therefore, sweating may elicit dermatitis by serving as a
contactant. The concentration of Ni is higher in the sweat of
intrinsic than extrinsic AD patients.5
The risk of an 'atopic march' is
significantly lower in children with the intrinsic type. Again, it
appears that the intrinsic type is not related to the pure
Th2-dominant immunological state. Future studies on the intrinsic
type of AD may clarify its pathophysiology.
- Novak N, Bieber T. Allergic and nonallergic forms of atopic
diseases. J Allergy Clin Immunol 2003;112:252-62.
- Tokura Y. Extrinsic and intrinsic types of atopic dermatitis.
J Dermatol Sci 2010;58:1-7.
- Mori T, Ishida K, Mukumoto S, et al. Comparison of skin barrier
function and sensory nerve electric current perception threshold
between IgE-high extrinsic and IgE-normal intrinsic types of atopic
dermatitis. Br J Dermatol 2010;62:83-90.
- Kabashima-Kubo R, Nakamura M, Sakabe JI, et al. A group of
atopic dermatitis without IgE elevation or barrier impairment shows
a high Th1 frequency: Possible immunological state of the intrinsic
type. J Dermatol Sci 2012;67:37-43.
- Yamaguchi H, Kabashima-Kubo R, Bito T, et al. High frequencies
of positive nickel/cobalt patch tests and high sweat nickel
concentration in patients with intrinsic atopic dermatitis. J
Dermatol Sci 2013;72:240-5.
- Suárez-Fariñas M, Dhingra N, Gittler J, et al. Intrinsic atopic
dermatitis shows similar TH2 and higher TH17 immune activation
compared with extrinsic atopic dermatitis. J Allergy Clin
- Koga C, Kabashima K, Shiraishi N. Possible pathogenic role of
Th17 cells for atopic dermatitis. J Invest Dermatol
- Kabashima K. New concept of the pathogenesis of atopic
dermatitis: interplay among the barrier, allergy, and pruritus as a
trinity. J Dermatol Sci 2013;70:3-11.
- Shanon J. Pseudo-atopic dermatitis. Contact dermatitis due to
chrome sensitivity simulating atopic dermatitis.
- Raghavan B, Martin SF, Esser PR, et al. Metal allergens nickel
and cobalt facilitate TLR4 homodimerization independently of MD2.
EMBO Rep 2012;13:1109-15.