Sodium in the Skin and Atopic Dermatitis: The SIS-AD Study

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ABSTRACT Atopic dermatitis (AD) rates have tripled since the 1950s, and are highest in urban and industrialized areas, likely due to changing environmental and dietary factors. Atopic dermatitis is now the most burdensome skin disease globally, and disease course and response to new immunomodulatory treatments remain highly variable. There is a critical need to identify modifiable factors that could improve patient outcomes. The central hypothesis of this proposal is that excess dietary sodium (consumed primarily as salt) is concentrated in the skin as a physiologic response to poor barrier function and water loss, and that high levels of skin sodium exacerbate the clinical phenotype of atopic dermatitis. The rationale for this project is that the skin serves as an osmoregulatory organ, storing large amounts of sodium; and that high sodium concentrations trigger inflammation, including TH2 pathways specific to atopic dermatitis. Our long-term goals are to understand how skin sodium influences inflammation and to test whether reducing salt intake or storage improves atopic dermatitis. The first specific aim will focus on reasons for sodium storage in the skin and will evaluate the impact of dietary sodium intake and skin barrier function on skin sodium concentration. The second specific aim will focus on the implications of skin sodium and will examine the extent to which skin sodium is associated with atopic dermatitis severity and persistence. It will also define functional immune profiles associated with high skin sodium both in skin and in the blood. To achieve these aims, we will perform a longitudinal cohort study of 90 men and women age > 50 at enrollment. Enrollment will be stratified by sodium intake and atopic dermatitis status and severity at baseline. Diet will be evaluated using food frequency questionnaires and urine biomarkers prior to each study visit, and skin sodium concentration will be measured using a novel, non- invasive sodium MRI technique. Participants will be followed for two years after enrollment. Our multidisciplinary team combines expertise in clinical and translational research, nutritional and cardiovascular epidemiology, immunology, and advanced imaging. This proposal is innovative in its application of cutting-edge techniques to image sodium in the skin and to define immune cell subsets in the skin and blood. It also tests a new conceptual model that links developments in the understanding of sodium physiology and immune stimulation with epidemiologic trends in atopic dermatitis. It is significant because the results will be used to design a clinical trial that would represent a fundamentally new approach to AD management that addresses disease triggers rather than focusing only on immunosuppression. Moreover, it will improve our understanding of sodium physiology in ways that could ultimately impact the management of patients with hypertension and cardiovascular disease.