Synovial Tissue Heterogeneity in Rheumatoid Arthritis and Changes With Biologic and Targeted Synthetic Therapies to Inform Stratified Therapy

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.

Identification of putative master regulators in rheumatoid arthritis synovial fibroblasts using gene expression data and network inference

“…Synovial fibroblasts are the main stromal cells in the synovial tissue of the joints. In healthy joints, they are found in the synovial lining and sublining layer (intima and subintima), forming a layer with a thickness of one to two cells, intercalated with tissue-resident macrophages 10,33 . In RA, synovial fibroblasts start to form thicker layers (15-20 cells thick) mainly due to a higher rate of proliferation and also due to a characteristic apoptosis-resistant phenotype.…”

“…In RA, inflammation and cellular infiltration cause hyperplasia of the synovial tissue leading to the pannus formation. The pannus is a tissue composed of MLS, FLS, leucocytes, plasma cells and mastocytes that mediates cartilage damage and bone erosion [7][8][9][10] .…”

mRNA level of ROCK1, RHOA, and LIMK2 as genes associated with apoptosis in evaluation of effectiveness of adalimumab treatment

“…Because of the dynamic development of molecular techniques, it has become possible to identify the gene transcripts that could act as new complementary molecular markers for detecting a lack of response to treatment as well as for deciding to change the therapy before adverse phenotypic changes occur [20][21][22]. This is because molecular changes are preceded by phenotypic changes [23] and the molecular marker systems entirely fit the strategy of personalized diagnostics and treatment [24,25].…”

Adalimumab changes the expression profile of selected BCL‐2 family genes

“…This is one of the key aspects of selecting the potential markers to determine the effectiveness of a therapy, as well as for detecting early drug resistance to the drug being used. Because molecular changes precede phenotypic changes, it is possible to implement another type of therapy before any adverse changes in the clinical picture of patients are observed (Ouboussad, Burska, Melville, & Buch, ; Póliska et al, ).…”