Synovial Tissue: Turning the Page to Precision Medicine in Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease targeting the joints. Current treatment strategies are based on clinical, biological and radiological features, yet still fail to reach the goal of early low disease activity in a significant number of cases. Hence, there is a need for refining current treatment algorithms, using accurate markers of response to therapy. Because RA induces histological and molecular alterations in the synovium even before apparition of clinical symptoms, synovial biopsies are a promising tool in the search of such new biomarkers. Histological and molecular characteristics of RA synovitis are heterogeneous. Variations in synovial lining layer hyperplasia, in cellular infiltration of the sublining by immune cells of myeloid and lymphoid lineages, and in molecular triggers of these features are currently categorized using well-defined pathotypes: myeloid, lymphoid, fibroid and pauci-immune. Here, we first bring the plasticity of RA synovitis under scrutiny, i.e., how variations in synovial characteristics are associated with relevant clinical features (disease duration, disease activity, effects of therapies, disease severity). Primary response to a specific drug could be, at least theoretically, related to the representation of the molecular pathway targeted by the drug in the synovium. Alternatively, absence of primary response to a specific agent could be due to disease severity, i.e., overrepresentation of all synovial molecular pathways driving disease activity overwhelming the capacity of any drug to block them. Using this theoretical frame, we will highlight how the findings of previous studies trying to link response to therapy with synovial changes provide promising perspectives on bridging the gap to personalized medicine in RA.

Paired Rheumatoid Arthritis Synovial Biopsies From Small and Large Joints Show Similar Global Transcriptomic Patterns With Enrichment of Private Specificity TCRB and TCR Signaling Pathways

“…Several studies were performed in order to understand the mechanisms driving heterogeneity in histological, cellular and molecular changes in rheumatoid synovitis and investigate whether synovial cellular and molecular patterns can be linked to clinical outcomes (5)(6)(7)(8)(9)(10)(11). Thus, clinical variables such as disease activity, disease duration, ACPA status or response to specific therapies were associated with variations in cellular populations and molecular profiles in RA synovial biopsies (12). We and others reported that disease activity correlates with the expression of T cell-and myeloid-related transcripts in RA synovitis (2,6,11).…”

A Molecular Signature Response Classifier to Predict Inadequate Response to Tumor Necrosis Factor-α Inhibitors: The NETWORK-004 Prospective Observational Study

“…Many targeted therapeutic options are available in RA, but therapy selection is a challenge because these options have similar treatment outcomes. Precision medicine tools are greatly needed to identify which patients have the appropriate disease biology for each targeted therapy [ 1 – 3 , 7 , 8 ]. The blood-based MSRC analyzes gene expression data along with common clinical features to accurately identify targeted-therapy naïve and TNFi-exposed patients who were unlikely to have an adequate response to TNFi therapy.…”

“…Because clinical guidelines do not recommend one treatment over another [ 1 , 4 ], therapy selection is often driven by administrative decisions and TNFi therapies remain the prevailing treatment in nearly 90% of patients with RA [ 5 , 6 ]. Matching each patient with the right targeted therapy to reach treat-to-target goals of low disease activity (LDA) or remission is an unmet medical need in RA [ 1 , 7 , 8 ].…”

The Crucial Questions on Synovial Biopsy: When, Why, Who, What, Where, and How?

“…A synovial biopsy is often performed for research purposes for example in RA patients; synovium histological and molecular alterations are considered a target for identifying new biomarkers to help rheumatologists tailor their clinical and therapeutic decision according to patient characteristics (7). Recently, a multicenter randomized control trial highlighted the possibility to integrate molecular pathology into clinical practice to improve treatment allocation of specific targeted therapies (8).…”