Intrinsic and Extrinsic Subtypes Compared in Atopic Dermatitis

Intrinsic AD is associated with a more complex inflammatory mechanism that involves Th2, Th1, Th17, and Th22 while extrinsic AD is a Th2-based disease.

Extrinsic atopic dermatitis (AD) is a Th2-based disease, and intrinsic AD is associated with a more complex inflammatory mechanism, involving Th2, Th1, Th17, and Th22, according to data from a study published in Clinical, Cosmetic and Investigational Dermatology.

Investigators conducted a review to assess the differences between the extrinsic and intrinsic subtypes of AD in epidemiology, skin barrier function, allergens, and inflammatory response.

Environmental factors may only have a minor effect on the prevalence of extrinsic and intrinsic AD. In addition, the distinction between the 2 subtypes is not permanent, and intrinsic AD may develop into extrinsic type over time. Several studies have found a female preponderance of intrinsic AD in children and adults, and others found that women with intrinsic AD were more likely to have worsening symptoms during pregnancy vs those with extrinsic AD, which suggests that female sex hormones have a greater effect on intrinsic AD compared with extrinsic AD.

Extrinsic AD has also been shown to be associated with increased transepidermal water loss (TEWL) but decreased capacitance. For patients with intrinsic AD, the barrier function and sensory reactivity to external pruritic stimuli remain normal. Intrinsic AD may evolve into an inflammatory pattern once a secondary barrier defect has occurred, and control of itch is especially important for primary management of patients with intrinsic AD along with anti-inflammatory therapy, according to the investigators.

There is still much work to be done to understand the patho-mechanisms and heterogeneity of AD, which potentially contribute to future endotypic- and genetically based management of AD.

Patients with extrinsic AD have increased levels of Th2 cytokines (interleukin [IL]-4, IL-5, and IL-13), and those with intrinsic AD have elevated Th1 but low CCL17/thymus and activation-regulated chemokine levels. Extrinsic AD is associated with increased eosinophil levels and eosinophilic cationic protein (ECP) serum levels. Other studies have found that for extrinsic AD, Th2 cytokines were correlated positively with disease severity and negatively with barrier products such as loricrin, periplakin, and filaggrin. For intrinsic AD, Th1 and CCL20 levels were associated with disease severity.

Evidence has shown that both AD subtypes produce similar levels of mRNA of Th2 cytokines (IL-4, IL-13, and IL-31). Also, upregulation of interferon-γ could suppress immune globulin E (IgE) production, leading to the normal immune globulin E level in intrinsic AD. Other research has found that the severity of extrinsic AD is significantly correlated with serum total IgE levels, researchers noted.

Patients with intrinsic AD have been shown to have increased sweat concentration of nickel, inversely related to serum IgE, which is consistent with research showing a normal IgE level and high metal allergy incidence in intrinsic AD. Bacterial superantigens have been suggested to bind to Toll-like receptor-2 (TLR-2) on monocytes and upregulate FcεRI, initiating a flare-up in extrinsic AD. A high incidence of metal allergy in intrinsic AD may be associated with the absence of suprabasin, according to another study.

“Although the distinction between intrinsic and extrinsic AD subtypes has expanded our understanding about the pathogenesis of AD, there is still much work to be done to understand the patho-mechanisms and heterogeneity of AD, which potentially contribute to future endotypic- and genetically based management of AD,” stated the study authors.


Liu L, Song G, Song Z, et al. Intrinsic atopic dermatitis and extrinsic atopic dermatitis: similarities and differences. Clin Cosmet Investig Dermatol. Published online December 7, 2022. doi: