Abstract
Corticosteroids are extensively used in pediatrics, yet the burden of side effects is significant. Availability of a simple, fast, and reliable biochemical read out of steroidal drug pharmacodynamics could enable a rapid and objective assessment of safety and efficacy of corticosteroids and aid development of corticosteroid replacement drugs. To identify potential corticosteroid responsive biomarkers we performed proteome profiling of serum samples from DMD and IBD patients with and without corticosteroid treatment using SOMAscan aptamer panel testing 1,129 proteins in <0.1 cc of sera. Ten pro-inflammatory proteins were elevated in untreated patients and suppressed by corticosteroids (MMP12, IL22RA2, CCL22, IGFBP2, FCER2, LY9, ITGa1/b1, LTa1/b2, ANGPT2 and FGG). These are candidate biomarkers for anti-inflammatory efficacy of corticosteroids. Known safety concerns were validated, including elevated non-fasting insulin (insulin resistance), and elevated angiotensinogen (salt retention). These were extended by new candidates for metabolism disturbances (leptin, afamin), stunting of growth (growth hormone binding protein), and connective tissue remodeling (MMP3). Significant suppression of multiple adrenal steroid hormones was also seen in treated children (reductions of 17-hydroxyprogesterone, corticosterone, 11-deoxycortisol and testosterone). A panel of new pharmacodynamic biomarkers for corticosteroids in children was defined. Future studies will need to bridge specific biomarkers to mechanism of drug action, and specific clinical outcomes.
Highlights
Have existing biomarkers well-bridged to clinical outcomes, namely adrenal suppression, insulin resistance, bone turnover, and immune suppression[13]
Persistent suppression of adrenal function can lead to adrenal atrophy, and adrenal insufficiency where the adrenal cortex is unable to respond to increased circulating ACTH
Three proteins insulin (INS), soluble form of growth hormone receptor (GHBP) and leptin (LEP) that did not meet statistical significance in the cross-sectional data, but were found to be significant in one or both longitudinal sample sets of pre and post corticosteroid treated DMD or IBD patients were retained for analysis
Summary
Have existing biomarkers well-bridged to clinical outcomes, namely adrenal suppression, insulin resistance, bone turnover, and immune suppression[13]. Measure of first-in-morning serum cortisol >2 4 hours after the last corticosteroid dose is a reliable measure of adrenal suppression, but is non-specific for adrenal insufficiency and risk for adrenal crisis Corticosteroids induce both acute and chronic insulin resistance, and this is measured by fasting glucose and insulin levels[15]. One robust emerging proteomics platform is the SOMAscan technology, where specific aptamers (small protein-binding fragments of nucleic acid) have been developed as sensitive and reliable tests for 1,129 serum proteins measured simultaneously in
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