Synovial Tissue Insights into Heterogeneity of Rheumatoid Arthritis

Rheumatoid arthritis is one of the most common rheumatic and autoimmune diseases. While it can affect many different organ systems, RA primarily involves inflammation in the synovium, the tissue that lines joints. Patients with RA exhibit significant clinical heterogeneity in terms of presence or absence of autoantibodies, degree of permanent deformities, and most importantly, treatment response. These clinical characteristics point to heterogeneity in the cellular and molecular pathogenesis of RA, an area that several recent studies have begun to address.

Single-cell RNA-sequencing initiatives and deeper focused studies have revealed several RA-associated cell populations in synovial tissues, including peripheral helper T cells, autoimmunity-associated B cells (ABCs), and NOTCH3⁺ sublining fibroblasts. Recent large transcriptional studies and translational clinical trials present frameworks to capture cellular and molecular heterogeneity in RA synovium. Technological developments, such as spatial transcriptomics and machine learning, promise to further elucidate the different types of RA synovitis and the biological mechanisms that characterize them, key elements of precision medicine to optimize patient care and outcomes in RA. This review recaps the findings of those recent studies and puts our current knowledge and future challenges into scientific and clinical perspective.