Joint pathology in rheumatoid arthritis (RA) is highly heterogeneous. It can be classed into three distinct types of synovial histopathologies termed ‘pauci-immune’, ‘diffuse’ and ‘follicular’, where the latter is characterised by lymphoid-rich follicles called ectopic lymphoid-like structures (ELS). This heterogeneity influences disease progression and severity, hence patients respond differently to cytokine-targeted therapies (e.g. anti-TNF and anti-IL-6R). At present, biomarkers for RA are lacking. While disease-specific autoantibodies such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA; anti-CCP) correlate with disease severity, they unreliably predict underlying joint pathology. Identifying cytokine-regulated networks that determine the development of distinct RA synovial pathotypes has the potential to define biomarkers for patient stratification and identify novel therapeutic targets for the treatment of RA.
Antigen-Induced arthritis was established in cytokine receptor deficient mice (Il27ra-/- and Il6ra-/-) that develop distinct synovial pathotypes. Synovium was dissected at time points relating to early and chronic inflammation and global transcriptomic changes in the inflamed joint were analysed using RNA sequencing.
Histopathological characterisation confirmed the exacerbated synovitis and lymphoid-rich pathology associated with ELS in Il27ra-/- mice. Conversely, Il6ra-/- mice displayed a low inflammatory phenotype reminiscent of ‘pauci-immune’ joint pathology. RNA-seq data identified increased expression of IL-17 and IL-1 pathways in ELS-associated disease, and gene signatures linked with leukocyte activation, B cell maturation and chemotaxis. In contrast, the ‘pauci-immune’ signature observed in Il6ra-/- mice was enriched with anti-inflammatory genes and genes involved in fibroblast activation and tissue remodelling.
This data provides novel insight into IL-27 and IL-6 regulated pathways that determine synovial pathology. Evaluation of the global transcriptomic changes between distinct synovial pathotypes has identified cytokine-regulated pathways, transcription factors and gene targets that may aid patient stratification and treatment.