TY - JOUR
T1 - Serum biomarkers of glucocorticoid response and safety in anti-neutrophil cytoplasmic antibody-associated vasculitis and juvenile dermatomyositis
AU - Conklin, Laurie S.
AU - Merkel, Peter A.
AU - Pachman, Lauren M.
AU - Parikh, Hemang
AU - Tawalbeh, Shefa
AU - Damsker, Jesse M.
AU - Cuthbertson, David D.
AU - Morgan, Gabrielle A.
AU - Monach, Paul A.
AU - Hathout, Yetrib
AU - Nagaraju, Kanneboyina
AU - van den Anker, John
AU - McAlear, Carol A.
AU - Hoffman, Eric P.
N1 - Funding Information:
Supported by research grants from the National Institutes of Health (NICHD U54HD090254 Research in Pediatric Developmental Pharmacology Center [JvdA, YH, EPH, LSC]; NIAMS 1R43AR073547-01 [EPH, LMP], NIAMS R43AR073541-01 [JMD, PAM]). Research also supported by a grant from the Foundation to Eradicate Duchenne [EPH]. The Vasculitis Clinical Research Consortium (VCRC) (U54 AR057319) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Science (NCATS). The VCRC is funded through collaboration between NCATS , and the National Institute of Arthritis and Musculoskeletal and Skin Diseases , and has received funding from the National Center for Research Resources ( U54 RR019497 ) [PAM]. The Myositis Center is supported by the Cure JM Foundation , and hosts the Juvenile Myositis Registry and Biological Sample Repository [LMP]. KN is supported by the National Institutes of Health (R21AI128248-02, R56NS097229-01 and K26OD011171), the Myositis Association and the US Department of Defense (W81XWH-11-1-0809).
Funding Information:
Supported by research grants from the National Institutes of Health (NICHD U54HD090254 Research in Pediatric Developmental Pharmacology Center [JvdA, YH, EPH, LSC]; NIAMS 1R43AR073547-01 [EPH, LMP], NIAMS R43AR073541-01 [JMD, PAM]). Research also supported by a grant from the Foundation to Eradicate Duchenne [EPH]. The Vasculitis Clinical Research Consortium (VCRC) (U54 AR057319) is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Science (NCATS). The VCRC is funded through collaboration between NCATS, and the National Institute of Arthritis and Musculoskeletal and Skin Diseases, and has received funding from the National Center for Research Resources (U54 RR019497) [PAM]. The Myositis Center is supported by the Cure JM Foundation, and hosts the Juvenile Myositis Registry and Biological Sample Repository [LMP]. KN is supported by the National Institutes of Health (R21AI128248-02, R56NS097229-01 and K26OD011171), the Myositis Association and the US Department of Defense (W81XWH-11-1-0809).
PY - 2018/12
Y1 - 2018/12
N2 - Glucocorticoids are standard of care for many chronic inflammatory conditions, including juvenile dermatomyositis (JDM) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We sought to define pharmacodynamic biomarkers of therapeutic efficacy and safety concerns of glucocorticoid treatment for these two disorders. Previous proteomic profiling of patients with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease (IBD) treated with glucocorticoids identified candidate biomarkers for efficacy and safety concerns of glucocorticoids. Serial serum samples from patients with AAV (n = 30) and JDM (n = 12) were obtained during active disease, and after treatment with glucocorticoids. For AAV, 8 of 11 biomarkers of the anti-inflammatory response to glucocorticoids were validated (P-value ≤0.05; CD23, macrophage-derived cytokine, interleukin-22 binding protein, matrix metalloproteinase-12, T lymphocyte surface antigen Ly9, fibrinogen gamma chain, angiopoietin-2 [all decreased], and protein C [increased]), as were 5 of 7 safety biomarkers (P-value ≤0.05; afamin, matrix metalloproteinase-3, insulin growth factor binding protein-5, angiotensinogen, leptin [all increased]). For JDM, 10 of 11 efficacy biomarkers were validated (P-value ≤0.05; all proteins except fibrinogen gamma chain) and 6 of 7 safety biomarkers (P-value ≤0.05; AAV proteins plus growth hormone binding protein). The identified efficacy biomarkers may be useful as objective outcome measures for early phase proof-of-concept studies when assessing novel anti-inflammatory drugs in JDM and AAV, and likely in other inflammatory disorders. Similarly, safety biomarkers may also be helpful assessing toxicity of alternatives to glucocorticoids.
AB - Glucocorticoids are standard of care for many chronic inflammatory conditions, including juvenile dermatomyositis (JDM) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We sought to define pharmacodynamic biomarkers of therapeutic efficacy and safety concerns of glucocorticoid treatment for these two disorders. Previous proteomic profiling of patients with Duchenne muscular dystrophy (DMD) and inflammatory bowel disease (IBD) treated with glucocorticoids identified candidate biomarkers for efficacy and safety concerns of glucocorticoids. Serial serum samples from patients with AAV (n = 30) and JDM (n = 12) were obtained during active disease, and after treatment with glucocorticoids. For AAV, 8 of 11 biomarkers of the anti-inflammatory response to glucocorticoids were validated (P-value ≤0.05; CD23, macrophage-derived cytokine, interleukin-22 binding protein, matrix metalloproteinase-12, T lymphocyte surface antigen Ly9, fibrinogen gamma chain, angiopoietin-2 [all decreased], and protein C [increased]), as were 5 of 7 safety biomarkers (P-value ≤0.05; afamin, matrix metalloproteinase-3, insulin growth factor binding protein-5, angiotensinogen, leptin [all increased]). For JDM, 10 of 11 efficacy biomarkers were validated (P-value ≤0.05; all proteins except fibrinogen gamma chain) and 6 of 7 safety biomarkers (P-value ≤0.05; AAV proteins plus growth hormone binding protein). The identified efficacy biomarkers may be useful as objective outcome measures for early phase proof-of-concept studies when assessing novel anti-inflammatory drugs in JDM and AAV, and likely in other inflammatory disorders. Similarly, safety biomarkers may also be helpful assessing toxicity of alternatives to glucocorticoids.
KW - Anti-inflammatory
KW - Biomarker
KW - Glucocorticoids
KW - Juvenile dermatomyositis
KW - Vasculitis
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U2 - 10.1016/j.steroids.2018.10.008
DO - 10.1016/j.steroids.2018.10.008
M3 - Article
C2 - 30352204
AN - SCOPUS:85055355706
VL - 140
SP - 159
EP - 166
JO - Steroids
JF - Steroids
SN - 0039-128X
ER -