Biomarker research
Ex vivo JAK and TNF inhibitor-modulated immune signatures guide first-line therapy selection in rheumatoid arthritis
By Corrales S, Pérez-Sánchez C, Cerdó T and 19 others.
Abstract
Background
Rheumatoid arthritis (RA) is a heterogeneous autoimmune disease for which selecting the most appropriate first targeted therapy remains challenging. We integrated ex vivo immune-cell functional assays, targeted proteomics, clinical outcomes, and a three-dimensional (3D) synovial model to identify treatment-associated molecular signatures and evaluate their relationship with subsequent response to Janus kinase inhibitors (JAKi) or tumour necrosis factor inhibitors (TNFi).
Methods
Peripheral blood mononuclear cells and neutrophils from 48 b/tsDMARDs-naïve RA patients were cultured with autologous serum and treated ex vivo with Baricitinib or Etanercept to assess proliferation, adhesion, NETosis, and 92 inflammation-related proteins. The resulting JAKi- and TNFi-modulated protein signatures were subsequently evaluated in pretreatment serum from four independent RA treatment cohorts (n = 223; naïve and non-naïve). Unsupervised clustering was used to identify molecular subgroups, which were related to longitudinal DAS28-CRP outcomes at 3, 6, and 12 months. Logistic regression, neural network, and random forest models were evaluated using repeated nested cross-validation in naïve patients to discriminate treatment-specific 6-month remission outcomes. In a subset of naïve remission achievers, paired baseline and 6-month sera were applied to a 3D synovial micromass model.