7. The vasculopathy of JDM; evidence of persistent endothelial injury, hypercoagulability, subclinical inflammation and increased arterial stiffness

Abstract

Background/Purpose: Vasculopathy is considered central to the pathogenesis of Juvenile Dermatomyositis (JDM). The interplay between persistent JDM-vasculopathy, traditional cardiovascular risk factors, exposure to corticosteroids, and chronic inflammation could create a perfect storm for early atherogenesis. A major hurdle to the study of vasculopathy of JDM, monitoring of its trajectory over time and contribution to cardiovascular disease has been a lack of non-invasive biomarkers. Recently, we described 2 methods for detecting endothelial cell components in blood: circulating endothelial cells (CEC), and endothelial microparticles (EMP). We aim therefore to explore the vasculopathy of JDM by assessing: (i) biomarkers of endothelial injury (CEC and EMP), subclinical inflammation (cytokines) and hypercoagulability (MP-mediated thrombin generation); and (ii) structural arterial changes (indicative of premature atherosclerosis), and their relation to disease activity and treatment in children with JDM. Methods: 64 patients recruited to the UK JDM Cohort & Biomarker Study were included; median age 10.5 (range 6.9 - 13.7) years with median disease duration of 1.5 (0.3-4.7) years. 40 (62.5%) were females. Inactive disease was defined as per modified PRINTO criteria: no skin rashes, CK = 48, MMT8>=78, Physician 's global assessment <0.0001. Patients with active JDM had higher CEC than those with inactive JDM, p=0.02. CEC counts significantly correlated with levels of inflammatory cytokines/chemokines implicated previously in JDM disease pathogenesis: interferon regulated Monocyte Chemoattractant Protein-1 (MCP-1; r=0.63, p=0.02) and interleukin-8 (IL-8; r=0.65 and p=0.01). Total circulating MP counts were also significantly higher in active JDM, 1781 (981-2616) x103/ml compared to inactive JDM, 1116 (263-1393) x103/ml, p=0.02; and healthy controls 89 (25-236) x103/ml, p=0.0001. These circulating MPs were predominantly of platelet and endothelial origin. Enhanced MP mediated thrombin generation was demonstrated in active compared to inactive JDM (p=0.03) and controls (p=0.001). Lastly, children with JDM had increased carotid-radial PWV adjusted for age compared to healthy controls (p=0.005). Conclusion: Our data demonstrate: 1. Increased endothelial damage in children with active JDM, possibly driven by pro-inflammatory cytokines; 2. High levels of circulating MP with propensity to drive thrombin generation and hence occlusive vasculopathy; and 3. Increased arterial stiffness, suggestive of accelerated atherosclerosis in patients with JDM. Validation of these biomarkers in multicentre prospective studies will provide data regarding their prognostic relevance.