Breakthrough Study Could Lead to New Options for Children With Atopic Dermatitis

Dr Guttman

A recent study from a team of researchers found significant differences in the skin phenotypes among pediatric patients with atopic dermatitis (AD) compared with adults with chronic, long-term AD. 

Specifically, the study showed Th2 and Th17/Th22-centered inflammation among pediatric AD without the Th1 activation and epidermal barrier abnormalities associated with adult AD. These findings were published online in the Journal of Allergy and Clinical Immunology.

The distinct phenotype of early-onset pediatric AD might have implications for the development of targeted treatment options for this patient population. “This study gives us additional information to determine what we need to do to treat children with AD that may be similar or different than adults with this disease,” said co-author Emma Guttman-Yassky, MD, PhD, from Icahn School of Medicine at Mount Sinai. 

Differences in Phenotype

One of the important aspects of this study, according to Dr Guttman-Yassky, was that “it puts to rest the idea that filaggrin is the initiator of AD and the entire atopic march.” 

In this study, she said, “We see that all the terminal differentiation markers in children, not just filaggrin, at the time of disease initiation are not downregulated like they are in adults.” Possibly, the increases in cytokines are the ones that are inhibiting the barrier measures overtime, with disease chronicity, she said.

For study, the researchers collected skin biopsies from 19 children between 2 months and 5 years of age with early-onset moderate to severe AD within the previous 6 months and from 18 healthy children matched for age, gender, and ethnicity during routine surgical procedures. They obtained tissues samples from 20 adults with lesional and nonlesional AD and 11 healthy controls from previously reported cohorts with similar disease severity. Samples were assessed using gene expression studies, along with immunohistochemistry and immunofluorescence. 

Their findings showed that pediatric patients had significant Th17 skewing but lacked Th1 upregulation, which is characteristic of chronic adult AD. In addition, “we saw abnormalities in claudins in children,” added Dr Guttman-Yassky.

“The phenotype of AD in early disease initiation has similar Th2 upregulation, that is similar to adults with AD, but it also has a Th17 axis activation that is very similar to adult psoriasis,” she said. 

In addition, they observed normal expression of epidermal differentiation genes compared with very low expressions of many epidermal differentiation and cornification products among adults with chronic AD. However, both patient populations had defects in lipid barrier and epidermal tight junctions.

“Studies show that children with early disease initiation have a phenotype that already has overt hyperplasia and very high levels of immune activation in the skin,” said Dr Guttman-Yassky. “We need to remember that these children are within 6 months of disease initiation and that AD has a short window of intervention in which we can perhaps also prevent the entire atopic march.” AD usually presents within the first 3 months of age followed by food allergies around 9 months followed by seasonal allergies and asthma. One thought, according to Dr Guttman-Yassky, is that “once the atopic dermatitis phenotype develops in its moderate to severe form in children, then we may need a systemic treatment in order to prevent the entire atopic march.”

Potential Treatment Targets

Dr Guttman-Yassky said that the study raises several questions and options for future therapies: can we successfully treat children by targeting only the Th2 axis or will therapies need to target more than 1 cytokine access because of the Th17 axis activation in children with AD. “This is a question we can only answer in the future with targeted treatments in children,” she said. Due to the dysregulation of Th17, some psoriasis treatments, such as IL-23 or IL-17 antagonists, may also potentially work in children with AD, she said, but this hypothesis will need to be studied and tested. 

Another possibility, which is being tested in children at high risk to develop eczema, is to determine if an emollient would be able to improve the skin barrier and prevent development of eczema and/or the atopic march. “But after AD is already formed in its severe form, how are we preventing the atopic march?” said Dr Guttman-Yassky. “This will probably be an immune-based systemic treatment and we will need to learn which one is the best in future studies.” 

Reference

Brunner PM, Israel A, Zhang N, et al. Early-onset pediatric atopic dermatitis is characterized by Th2/Th17/Th22-centered inflammation and lipid alterations [published online May 3, 2018]. J Allergy Clin Immunol. doi:10.1016/j.jaci.2018.02.040