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.

Keywords: biologics; precision medicine; response to therapy; rheumatoid arthritis; synovial biopsies.

Figure 1

Correlations between myeloid and lymphoid scores in RA synovitis. Lymphoid and myeloid gene scores were calculated in 2 sets of 20 biopsies from patients with active RA, based on gene lists used by Dennis et al. (16), downloaded from https://arthritisresearch.biomedcentral.com/articles/10.1186/ar4555#MOESM3. Gene scores are the median values of the log2- transformed fold changes of each transcript belonging to the score compared to a reference group of 4 OA samples. Data set 1: synovial samples from RA patients with early disease, published in Ducreux et al. (23). Data Set 2: unpublished set of synovial samples, from RA patients with established disease. The characteristics of the patients in both data sets are displayed in Supplementary Table 1. Spearman correlation coefficient r = 0.7801.