Pharmacodynamic Biomarkers and Differential Effects of TNF- and GM-CSF-Targeting Biologics in Rheumatoid Arthritis
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ABSTRACT: A major unmet need in rheumatoid arthritis (RA) is the choice of treatment options for patients with an inadequate response to anti-TNF agents (anti-TNF–IR). In order to identify pharmacodynamic biomarkers and assess differential effects of TNF- and non–TNF-targeting agents on RA patients with an inadequate response to anti-TNF–IR in comparison with biologic-naïve patients, peripheral protein markers and gene expression levels in association with clinical response posttreatment in two disease strata were assessed in disease-modifying antirheumatic drug (DMARD)-IR and anti-TNF-IR patients. Serum proteomics results indicated the existence of specific pharmacodynamic markers for golimumab and mavrilimumab, regardless of prior anti-TNF treatment. In contrast, both antibodies induced early and sustained suppression of RA disease markers, including IL-6, CRP, IL2RA, and MMP1, in DMARD-IR patients. Golimumab-induced early changes rapidly returned toward baseline concentrations in anti-TNF–IR patients, whereas mavrilimumab-induced changes were maintained through Day 169. RNA sequencing demonstrated gene expression changes at Day 169 after administration of mavrilimumab but not golimumab in anti-TNF–IR patients. Additionally, receiver operating characteristic curve and regression analysis showed the association of early IL-6 change and subsequent clinical responses to golimumab in anti-TNF-IR patients. Our results revealed golimumab- and mavrilimumab-specific pharmacodynamic biomarkers, and demonstrated differential biomarker-treatment relationships in anti-TNF–IR and DMARD-IR patients respectively. Early IL-6 change after anti-TNF antibody treatment may be a potential predictive biomarker for selection of different treatment regimens in anti-TNF-IR patients.
ORGANISM(S): Homo sapiens
PROVIDER: GSE120178 | GEO | 2019/06/13
REPOSITORIES: GEO
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