Molecular Phenotyping Mild Atopic Dermatitis

A recent study explored phenotypic differences between mild atopic dermatitis (AD) and moderate to severe AD, highlighting important differences that have relevancy for clinical practice and research.

“This is the first time that patients with mild AD have been characterized and is also the first study that compared mild AD with moderate to severe AD,” said corresponding author Emma Guttman, MD, PhD, professor of dermatology and immunology and incoming system chair of the Department of Dermatology (effective January 2021) at Icahn School of Medicine at Mount Sinai in New York, discusses her recent study on phenotypic differences between mild atopic dermatitis (AD) and moderate to severe atopic dermatitis. 

In the study, Dr Guttman and her colleagues collected skin and blood samples from 20 patients with mild/limited AD, 17 with moderate AD, 24 with severe AD, and 20 healthy controls. They assessed immune and barrier markers in lesional, nonlesional, and control skin using quantitative real-time polymerase chain reaction and immunohistochemistry, and in blood using the OLINK proteomic assay.

Compared with controls, the researchers found all patients with AD had increased cellular markers of epidermal hyperplasia and T-cell/dendritic cell infiltration. They also noted that downstream T_H2, T_H22, T_H1, T_H17-related mediators increased with disease severity in both lesional and nonlesional skin. In addition, all patients with AD had comparably upregulated regulatory T cell-related mediators (IL-10, FOXP3), without displaying the severity-based gradient in other immune axes.

T_H2 (IL-13, CCL17, CCL26) and T_H22 (IL-22) cytokines were also significantly elevated in both lesional and nonlesional skin in all patients, regardless of severity. However, patients with mild/limited disease only had increases in T_H1 (IFNG, CXCL9, CXCL10) and T_H17 (IL-17A, CCL20, CXCL1) markers in lesional skin. When samples were clustered along a severity spectrum, nonlesional mild/limited AD skin was clustered with healthy control skin. This shows that “nonlesional skin is abnormal only in patients with moderate to severe AD, not in patients with mild disease,” explained Dr Guttman.

Blood profiles also distinguished patients with mild/limited AD from moderate to severe disease. Samples from patients with moderate to severe disease were found to have gradual increases in T_H1/T_H2/T_H17-related and atherosclerosis/cardiovascular (CV) risk (CCL7, FGF21, IGFBP1) proteins, whereas samples from patients with mild/limited AD lacked significant differences in these proteins compared with controls. 

“Basically, patients with mild AD do not have any inflammation in their blood, no systemic immune activation,” said Dr Guttman. “This emphasizes why patients with mild disease can likely be treated with just topicals, whereas patients with moderate to severe disease actually need systemic treatment.”

In an interview with The Dermatologist, Dr Guttman discussed these findings and their implications for clinical practice and research.

The Dermatologist: What is the significance of your study’s findings?

Dr Guttman: Until now, mild disease was not studied as extensively as moderate to severe disease.

In our study, the molecular profile showed the same immune abnormalities occur in both mild and moderate to severe disease. We showed that the molecules upregulated in moderate and severe disease, which are the T_H2 axis and T_H22 axis like IL-13 and IL-22, are also upregulated in mild disease. Also, the profile of lesional skin of mild AD is very similar to lesional skin of moderate and severe AD.

The difference is in the nonlesional skin. Nonlesional skin in patients with mild AD is closer to non-AD skin, whereas nonlesional skin in moderate and severe AD is closer to lesional skin. The other difference is in blood. Patients with moderate and severe AD have increases in inflammatory biomarkers in their blood, whereas patients with mild AD have no such increase in inflammation in their blood.

The Dermatologist: Does having this molecular profile for mild AD open up the possibility of more developments in topical therapies?

Dr Guttman: Absolutely. Another important aspect we found for mild AD is that there are increases in molecules that keep inflammation in check. The large increases in regulatory molecules in mild patients potentially account for why the inflammation is in check in mild patients, and why they do not develop that systemic immune abnormality.

Basically, this tells us that patients with mild AD can be treated with only topicals, whereas moderate to severe disease requires systemic treatment.

The Dermatologist: Does this suggest that patients with mild AD may not have the same increased CV risk seen in patients with moderate to severe AD?

Dr Guttman: Yes, absolutely. Our study definitely suggests that. While we found that patients with moderate and severe disease have increases in inflammatory molecules in their blood including those that are associated with CV risk factors, we did not find these same markers in patients with mild disease.

That is why we think that the ones with moderate and severe disease need to be treated with systemic therapies, in order to lower their CV risk. However, that is not something we would need to do for patients with mild disease.

The Dermatologist: What other research is needed to expand the understanding and treatment of mild AD?

Dr Guttman: We need to do a large study on mild AD, particularly to assess these markers in infants.

Also, we need to do more studies on treatments that boost the regulatory function of the body to see if these are able to turn the disease around, which is based on the finding that there are more regulatory markers in mild AD.

In this study, patients were predominately of European American descent, so these results will need to be replicated in different ethnicities.

The Dermatologist: What key takeaways would you like to leave with our audience?

Dr Guttman: Our study assessed patients who had mild disease all of their life. The findings show that we can address mild AD potentially with only topicals. Also, it is important that we treat patients with moderate to severe AD with systemic medications in order to control the inflammation.

Reference

He H, Del Duca E, Diaz A, et al. Mild atopic dermatitis lacks systemic inflammation, and shows reduced non-lesional skin abnormalities. J Allergy Clin Immunol. Published online October 1, 2020. doi:10.1016/j.jaci.2020.08.041