title: Serum pharmacodynamic biomarkers for chronic corticosteroid treatment of children.
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.
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: Yetrib
authors.initials: Y
authors.lastname: Hathout
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: Laurie S
authors.initials: LS
authors.lastname: Conklin
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: Haeri
authors.initials: H
authors.lastname: Seol
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Brown
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Morgenroth
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Heier
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Damsker
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: John N
authors.initials: JN
authors.lastname: van den Anker
authors.affiliation: Department of Physical Medicine &Rehabilitation, University of California, Davis School of Medicine, Davis, CA 95618, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Henricson
authors.affiliation: Neurology Service, Department of Veterans Affairs Medical Center, Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Paula R
authors.initials: PR
authors.lastname: Clemens
authors.affiliation: Department of Pediatrics, Alberta Children's Hospital, Calgary, AB, T3B 6A8 Canada.
authors.forename: Jean K
authors.initials: JK
authors.lastname: Mah
authors.affiliation: Department of Physical Medicine &Rehabilitation, University of California, Davis School of Medicine, Davis, CA 95618, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: McDonald
authors.affiliation: Research Center for Genetic Medicine, Children's National Health Systems, Washington, DC 20010, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000293:Adolescent; D000305:Adrenal Cortex Hormones / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000378:metabolism; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D015212:Inflammatory Bowel Diseases / Q000097:blood* / Q000188:drug therapy*; D008137:Longitudinal Studies; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000097:blood* / Q000188:drug therapy*; D020543:Proteome / Q000378:metabolism
chemical_list: D000305:Adrenal Cortex Hormones; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D001798:Blood Proteins; D018836:Inflammation Mediators; D020543:Proteome