ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2018; 103(8): 2998–3009.

Conventional glucocorticoid (GC) therapy in adrenal insufficiency (AI) does not fully mimic the endogenous cortisol circadian rhythm, and this may adversely affect long-term health. In the recent DREAM trial (Dual Release Hydrocortisone vs. Conventional Glucocorticoid Replacement in Hypocortisolism) patients with AI showed an atypical inflammation, with more classic monocytes and impaired innate immune responses. Treatment with once-daily modified-release hydrocortisone improved circulating immune cell profiles and reduced infections compared to standard GC replacement therapy.

The current study aimed to investigate whether patients with AI enrolled in the DREAM trial had an altered expression of circadian genes in PBMCs compared to control subjects. Furthermore, they investigated whether the pro-inflammatory state seen on conventional GC treatment was associated with dysregulation of such genes, whether the more physiological treatment restored clock gene expression, and whether restoration of clock gene expression correlated with clinical outcome.

Gene expression profiling of 84 circadian clock genes was performed in: A) 29 patients with AI on standard multiple daily hydrocortisone (HC) treatment; B) 26 patients with AI on modified release HC treatment; C) 16 control subjects. PBMCs were freshly isolated in the morning at baseline and 12 weeks after randomization (A, B, C). At baseline, 19 genes were differentially expressed in patients with AI compared to controls, for example downregulation of CLOCK and ARNTL, whereas PER3 and TIMELESS were upregulated. Most genes in the CREB pathway cluster (CAMK2D, CREB1, CREB3, MAPK1, PRKAR1A, PRKAR12A, and PRKCB) were under-expressed in patients with AI. The relative expression of several genes correlated with the metabolic and immune phenotype. At week 12, patients on once-daily modified release HC exhibited an increase in expression levels of ARNTL, ARNTL2, CLOCK and RORA and reduced the previously overexpressed PER3 and TIMELESS levels. Of the 19 differentially expressed genes, 16 were also modulated in lymphocytes sorted from the entire subset of pooled PBMCs. There was also a correlation between changes in expression of several clock genes (CAMK2D, CSNK1A1, GUSB, ONP3, PER3, PRF1, SP1, TIMELESS, WEE1) and changes in clinical outcome, such as glycated hemoglobin, blood pressure, and levels of circulating soluble CD16, ADAM17, pro-inflammatory monocytes and frequency of infections. This suggests that reprogramming of circadian gene expression/resynchronisation using once-daily modified release HC is linked to improvements in clinical outcome in patients with AI.