Abstract
Beyond classic “allergic”/atopic comorbidities, atopic dermatitis (AD) emerges as systemic disease with increased cardiovascular risk. To better define serum inflammatory and cardiovascular risk proteins, we used an OLINK high-throughput proteomic assay to analyze moderate-to-severe AD (n = 59) compared to psoriasis (n = 22) and healthy controls (n = 18). Compared to controls, 10 proteins were increased in serum of both diseases, including Th1 (IFN-γ, CXCL9, TNF-β) and Th17 (CCL20) markers. 48 proteins each were uniquely upregulated in AD and psoriasis. Consistent with skin expression, AD serum showed up-regulation of Th2 (IL-13, CCL17, eotaxin-1/CCL11, CCL13, CCL4, IL-10), Th1 (CXCL10, CXCL11) and Th1/Th17/Th22 (IL-12/IL-23p40) responses. Surprisingly, some markers of atherosclerosis (fractalkine/CX3CL1, CCL8, M-CSF, HGF), T-cell development/activation (CD40L, IL-7, CCL25, IL-2RB, IL-15RA, CD6) and angiogenesis (VEGF-A) were significantly increased only in AD. Multiple inflammatory pathways showed stronger enrichment in AD than psoriasis. Several atherosclerosis mediators in serum (e.g. E-selectin, PI3/elafin, CCL7, IL-16) correlated with SCORAD, but not BMI. Also, AD inflammatory mediators (e.g. MMP12, IL-12/IL-23p40, CXCL9, CCL22, PI3/Elafin) correlated between blood and lesional as well as non-lesional skin. Overall, the AD blood signature was largely different compared to psoriasis, with dysregulation of inflammatory and cardiovascular risk markers, strongly supporting its systemic nature beyond atopic/allergic association.
Highlights
Beyond classic “allergic”/atopic comorbidities, atopic dermatitis (AD) emerges as systemic disease with increased cardiovascular risk
When results were adjusted for BMI (Fig. 1b, Supplementary Table S2) and for the presence of asthma and the cardiovascular risk factors such as arterial hypertension, diabetes mellitus, and hypercholesterolemia (Supplementary Figure S1, Supplementary Table S3), the observed differences between AD and psoriasis, compared to controls, were largely preserved
While several studies have described a limited set of biomarkers being increased in the blood of AD patients[31,32,33], the current study is the first to investigate a broad array of immune and cardiovascular risk proteins in serum of moderate-to-severe AD patients, compared to psoriasis and controls
Summary
Beyond classic “allergic”/atopic comorbidities, atopic dermatitis (AD) emerges as systemic disease with increased cardiovascular risk. Emerging data suggests that similar to chronic plaque-type psoriasis, another chronic inflammatory skin disease, AD patients harbor increased cardiovascular risk factors, including higher rates of cardiovascular disease in some populations[10,11,12,13,14,15] that is independent of genetic risk[14]. In vitro data suggests that IL-17 can contribute to pro-inflammatory changes in endothelial cells, and inhibition of IL-17 in a mouse model of atherosclerosis showed significantly ameliorated disease[23,24]. Many of these “psoriasis” mediators are found in AD5,25,26. Patients with asthma are demonstrated to be at increased risk for atherosclerosis[28], implying that chronic inflammation across diseases in general, rather than a specific cytokine, may be primarily responsible for increased cardiovascular risk[29]
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