Feedback AAD 2017

A Paradigm Shift in the Pathogenesis and Treatment of Atopic Dermatitis

There is a large unmet need for safe and effective therapy in atopic dermatitis (AD) for both adults and children. It remains the most common inflammatory skin disease in children, and its prevalence is rising. One-third of patients have moderate-to-severe disease.

Like psoriasis, AD is characterized by abnormalities in immune response and in skin barrier function, with increases in markers of proliferation such as K-16 and KI-67 and increased epidermal thickness. Similarities also exist in the presence of T cells and dendritic cells in the epidermis and dermis. This has prompted the question – Can the psoriasis model, where a deeper understanding of pathogenesis has led to translational research in therapeutics, be applied to AD?

This question was explored in a presentation by Emma Guttman, Dermatology Director at the Center for Excellence in Eczema and Laboratory for Inflammatory Skin Disease and a professor and vice chair of Dermatology, Mount Sinai School of Medicine, New York, New York, USA.

Until recently, the molecular phenotypes and immune pathways involved in AD were not sufficiently well defined. In recent years, however, the role of cytokines in AD in adults has come into focus. Key cytokines include IL-4 and IL-13, which have been linked to barrier disruption of the skin, inhibition of antimicrobial peptides, and the “itch cytokine” IL-31. The cytokines IL-17 and IL-22 have also been linked to hyperplasia that occurs in AD. The sum of these cytokines are all Th2-driven.

An important research question is whether this model applies to the 85% of cases of AD that begin before 5 years of age. Guttman described a collaborative research study, conducted with Amy Paller, in infants and children with recent onset of AD that was designed to investigate this question. This study evaluated blood and skin samples from children with AD below the age of 5 (most <3 years of age) who had been diagnosed with AD for less than 6 months, and compared them to samples from healthy age-matched controls, as well as adults with AD.

Even this early in the disease course, hyperplasia and epidermal thickness was similar in children with AD and their adult cohorts. K-16 gene expression was significantly higher. Increase in inflammatory Th2 cytokines (the interleukins IL-13, IL-5, IL-31) was also noted in lesional and nonlesional skin of children with AD; moreover, in some cases, they were significantly higher than in adult cohorts with AD. In many cases, these differences were most marked in nonlesional skin.

The results of this study point to early and potent Th2 activation in the blood and skin of children with AD, confirming the systemic nature of new onset AD. Selective activation of Th2 in blood may direct B-cells towards immunoglobulin E (IgE) class switching, potentially explaining the “atopic march” that often follows on the heels of AD in children. The question of whether appropriate systemic immune manipulations in children with AD can prevent the progression of the atopic march is a potential avenue of research.

Guttman described the results of a 4-week phase 1b study of dupilumab, a fully human IL-4Rα monoclonal antibody (mAb) which potently inhibits both IL-4 and IL-13 signaling. A total of 67 patients received weekly injections of dupilumab 75 mg, 150 mg, 300 mg, or placebo; 18 of these patients participated in a biopsy study. Improvements in Eczema Area and Severity Index (EASI)-50 scores were noted, along with changes in inflammatory biomarkers and markers of proliferation (including a dramatic decrease in K-16). In an extension of the study, dupilumab appeared to reverse barrier defects and decreased epidermal thickness. These findings confirm the importance of IL-4 and IL-13 as pathogenic cytokines in AD, and support the view of AD as an immune-driven disease, potentially reversible like psoriasis.

Further phase 2 and 3 studies with dupilumab support its efficacy in patients with moderate to severe AD, as demonstrated by significant improvements from baseline in Eczema Area and Severity Index (EASI)-75 and EASI-90 scores versus placebo.

Another important avenue of research is that other cytokines, such as IL-22, IL-23, and IL-17, play a part in the pathogenesis of AD, and the potential role of therapeutic agents that target these cytokines. Agents that target IL-17, IL-22, and IL-12/IL-23 are currently being studied in patients with AD.

Guttman also reviewed the current state of knowledge regarding the systemic nature of AD. Just as psoriasis is increasingly recognized as a systemic disease, there is emerging evidence for AD as a systemic disease, including epidemiologic data demonstrating an association between adult AD, cardiovascular disease and heart attacks, as well as imaging studies showing increased risk for silent coronary artery disease in patients with severe AD.

Our understanding of the molecular mechanisms underlying AD is still evolving. Unlike psoriasis, the AD phenotype cannot be explained by a single cytokine pathway, and it remains unclear how many immune axes must be targeted and to what extent. Further clinical trials with IL-17/IL-23, IL-22, and IL-4/IL-13 antagonists, along with mechanistic studies, are needed to determine the relative contribution of each immune axis to AD. Given emerging evidence regarding the systemic nature of AD, identifying effective systemic treatments is more urgent than ever, particularly for patients with severe disease.