Abstract
The treatment of rheumatoid arthritis (RA) has been transformed with the introduction of biologic disease modifying anti-rheumatic drugs (bDMARD) and more recently, targeted synthetic DMARD (tsDMARD) therapies in the form of janus-kinase inhibitors. Nevertheless, response to these agents varies such that a trial and error approach is adopted; leading to poor patient quality of life, and long-term outcomes. There is thus an urgent need to identify effective biomarkers to guide treatment selection. A wealth of research has been invested in this field but with minimal progress. Increasingly recognized is the importance of evaluating synovial tissue, the primary site of RA, as opposed to peripheral blood-based investigation. In this mini-review, we summarize the literature supporting synovial tissue heterogeneity, the conceptual basis for stratified therapy. This includes recognition of distinct synovial pathobiological subtypes and associated molecular pathways. We also review synovial tissue studies that have been conducted to evaluate the effect of individual bDMARD and tsDMARD on the cellular and molecular characteristics, with a view to identifying tissue predictors of response. Initial observations are being brought into the clinical trial landscape with stratified biopsy trials to validate toward implementation. Furthermore, development of tissue based omics technology holds still more promise in advancing our understanding of disease processes and guiding future drug selection.
Highlights
Rheumatoid arthritis (RA) is a complex, genetically and biologically heterogeneous autoimmune disease
The treatment of patients with RA has evolved considerably in recent years owing to the successful development and widespread use of biologic disease modifying anti-rheumatic drug therapy, with more recent introduction of targeted synthetic DMARDs in the form of small molecules inhibitors
Personalized medicine, i.e., tailoring therapy to individual patient, has the potential to improve response rates, but has proven challenging to implement. If it is to be successful, the identification of reliable biomarkers will be of prime importance. In this mini-review, we summarize the evidence for synovial tissue heterogeneity, and tissue studies that have evaluated change in cellular and molecular markers following currently available biologic disease modifying anti-rheumatic drug (bDMARD) and targeted synthetic DMARDs (tsDMARD) that could aid treatment selection
Summary
Rheumatoid arthritis (RA) is a complex, genetically and biologically heterogeneous autoimmune disease. Multiple types of therapies will be discussed in detail below, these are summarized in Table 1 together with key findings which indicate response to biologic and synthetic targeted DMARDs. Tumor-Necrosis Factor-Inhibitors Synovial studies have offered useful insights into the mechanism of action of TNFi. TNFi have been shown to regulate chemokine and leukocyte trafficking [69] likely explaining the reduction in the synovial cellular infiltrate observed; with reductions in synovial tissue expression of IL-6, IL-8, granulocyte macrophage colony stimulating factor (GM-CSF), macrophage chemoattractant protein-1 (MCP-1), IL-1β, TNF, and vascular endothelial growth factor (VEGF) [70]. A more recent study in 33 early RA patients suggested higher expression of TNF-induced transcripts in early RA synovitis was associated with higher disease activity, and predicted poor response to firstline therapy (that comprised either methotrexate, tocilizumab or rituximab therapy) [65]. An exploratory study by Das et al suggested persistent synovial IL-6 mRNA expression
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