Peripheral glucocorticoid signaling in Kawasaki disease

To the editor

Kawasaki disease (KD) is an acute self-limiting inflammatory disorder, associated with systemic vasculitis. It is the leading cause of childhood-acquired heart disease in the developed world.^1,2 The most important complication of KD is coronary artery vasculitis. Without treatment, this causes coronary artery aneurysms (CAA) in 15–25% of KD patients, while a further 2–3% develop myocardial infarction, ischemic heart disease, or sudden death.¹ Treatment with intravenous immunoglobulin (IVIG) plus aspirin can resolve inflammation and reduce the occurrence of CAA.^1,2 However, in about 20% of cases IVIG fails to resolve the inflammation, leading to persistent vasculitis: these patients have increased risk of developing CAA unless they receive additional treatment.^1,2 Recently, IVIG plus adjuvant glucocorticoid hormones (GCs) has been shown to be an effective therapy for these patients,^3,4 suggesting that GCs may complement IVIG treatment in severe KD. However, this remains controversial with others reporting that additional GCs did not improve coronary artery outcomes and may even cause CAA due to impaired vascular remodeling.^5,6 An insight into how endogenous glucocorticoids might contribute to disease resolution could be useful for consideration of glucocorticoid therapy. Here we hypothesized that failure to appropriately regulate endogenous GC signaling in inflammatory cells may contribute to persistent inflammation in KD. Intracellular GC levels in peripheral tissues are controlled by pre-receptor metabolism by 11β-hydroxysteroid dehydrogenase (11β-HSD). 11β-HSD1 converts intrinsically inert cortisone to active cortisol, increasing intracellular GC levels available to activate glucocorticoid receptor (GR).⁷ We have previously shown that the direction of regulation of 11β-HSD1 by dexamethasone in peripheral blood mononuclear cells (PBMC) is associated with the cytotoxic effects of GCs in acute lymphoblastic leukemia, with upregulation in glucocorticoid-sensitive cells but downregulation or no change in patient cells that are resistant to the pro-apoptotic effects of GC.⁸ Therefore, the aim of this study was to establish whether 11β-HSD1 in PBMC is associated with acute inflammation in KD.

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