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Clinical Updates

Yoshiki Tokura

Intrinsic Atopic Dermatitis (AD): A New Concept of AD Classification

Yoshiki Tokura

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 3.


Table 1. Subtypes of AD

Fig 1. Subtypes

AD=atopic dermatitis; FLG=filaggrin; IgE=immunoglobulin E.


Table 2. Nomenclature of AD classifications

Table 2. Nomenclature

AD=atopic dermatitis; IgE=immunoglobulin E.


Table 3. Characteristics of intrinsic AD2

Table 3. Characteristics of AD

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.


Fig 1aFig1b

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 intrinsic AD.

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.



  1. Novak N, Bieber T. Allergic and nonallergic forms of atopic diseases. J Allergy Clin Immunol 2003;112:252-62.
  2. Tokura Y. Extrinsic and intrinsic types of atopic dermatitis. J Dermatol Sci 2010;58:1-7.
  3. 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.
  4. 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.
  5. 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.
  6. 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 Immunol 2013;132:361-70.
  7. Koga C, Kabashima K, Shiraishi N. Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol 2008;128:2625-30.
  8. 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.
  9. Shanon J. Pseudo-atopic dermatitis. Contact dermatitis due to chrome sensitivity simulating atopic dermatitis. Dermatologica 1965;131:176-90.
  10. 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.