Pharmacodynamic biomarkers and differential effects of TNF- and GM-CSF-targeting biologics in rheumatoid arthritis.
Int J Rheum Dis
; 22(4): 646-653, 2019 Apr.
Article
em En
| MEDLINE
| ID: mdl-30358109
ABSTRACT
AIM:
The aim of our study was to identify pharmacodynamic biomarkers and assess differential effects of tumor necrosis factor (TNF)- and non-TNF-targeting agents on rheumatoid arthritis (RA) patients with an inadequate response to anti-TNF agents (anti-TNF-IR) in comparison with biologic-naïve patients.METHODS:
EARTH EXPLORER 2, a phase IIb trial, evaluated golimumab, an anti-TNF antibody, and mavrilimumab, an granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor antibody, in disease-modifying antirheumatic drug (DMARD)-IR and anti-TNF-IR patients. Our current study assessed peripheral protein markers and gene expression levels in association with clinical response post-treatment in two disease strata.RESULTS:
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 interleukin (IL)-6, C-reactive protein, IL2RA, and matrix metalloproteinase 1, 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 to 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.CONCLUSION:
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Artrite Reumatoide
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Fator Estimulador de Colônias de Granulócitos e Macrófagos
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Fator de Necrose Tumoral alfa
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Monitoramento de Medicamentos
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Mediadores da Inflamação
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Antirreumáticos
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Proteômica
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Biomarcadores Farmacológicos
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Anticorpos Monoclonais
Tipo de estudo:
Clinical_trials
/
Prognostic_studies
Limite:
Adult
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Int J Rheum Dis
Assunto da revista:
REUMATOLOGIA
Ano de publicação:
2019
Tipo de documento:
Article