Pharmacodynamic biomarkers and differential effects of TNF‐ and GM‐CSF‐targeting biologics in rheumatoid arthritis

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.