Disease activity drives transcriptomic heterogeneity in early untreated rheumatoid synovitis

Abstract

ObjectivesTranscriptomic profiling of synovial tissue from patients with early, untreated rheumatoid arthritis (RA) was used to explore the ability of unbiased, data-driven approaches to define clinically relevant subgroups.MethodsRNASeq was performed on 74 samples, with disease activity data collected at inclusion. Principal components analysis (PCA) and unsupervised clustering were used to define patient clusters based on expression of the most variable genes, followed by pathway analysis and inference of relative abundance of immune cell subsets. Histological assessment and multiplex immunofluorescence (for CD45, CD68, CD206) were performed on paraffin sections.ResultsPCA on expression of the (n=894) most variable genes across this series did not divide samples into distinct groups, instead yielding a continuum correlated with baseline disease activity. Two patient clusters (PtC1, n=52; PtC2, n=22) were defined based on expression of these genes. PtC1, with significantly higher disease activity and probability of response to methotrexate therapy, showed upregulation of immune system genes; PtC2 showed upregulation of lipid metabolism genes, described to characterise tissue resident or M2-like macrophages. In keeping with these data, M2-like:M1-like macrophage ratios were inversely correlated with disease activity scores and were associated with lower synovial immune infiltration and the presence of thinner, M2-like macrophage-rich synovial lining layers.ConclusionIn this large series of early, untreated RA, we show that the synovial transcriptome closely mirrors clinical disease activity and correlates with synovial inflammation. Intriguingly, lower inflammation and disease activity are associated with higher ratios of M2:M1 macrophages, particularly striking in the synovial lining layer. This may point to a protective role for tissue resident macrophages in RA.

Inclusion of Fibrinoid Necrosis increases the accuracy of synovial tissue assessment in predicting response to methotrexate: analysis of the UCLouvain Brussels ERA Cohort

“…The spread out of synovial biopsies, a safe and reliable procedure, opens perspectives of personalized medicine in RA. This was recently illustrated in two biopsy-driven clinical trials [2.3], investigating the response to bDMARD as second or third-line therapy, based on synovial pathotypes de ned by the presence of B lymphocytes, T lymphocytes, and synovial tissue macrophages (STMs) By contrast, we have recently shown that synovial transcriptomic patterns do not seem to segregate into distinct subgroups, rather correlate with disease activity, mitigating the potential of transcriptomic pro ling to predict therapeutic response [4]. To date, no studies have clearly demonstrated the ability of histology and pathotypes to predict the response to rst-line therapy in untreated Early Rheumatoid Arthritis (ERA).…”

Patterns and determinants of response to novel therapies in juvenile and adult-onset polyarthritis

“…Furthermore, it remains unclear whether the observed heterogeneity in synovial tissue patterns points to intrinsic biological differences between patients, to different stages of the same process, or is influenced by other factors (such as disease duration, disease activity or ongoing therapies) [ 58 , 102 , 106 , 116 , 117 ]. Thus, we have shown that clinical disease activity (and not distinct pathotypes) is the major driver of transcriptomic heterogeneity in the synovia of a large cohort of untreated early RA patients [ 118 ]. Although it remains plausible that the synovial representation of a drug target at least partially determines its clinical effect, many other factors influence individual response to therapy, as we will discuss in the following paragraphs ( Table 2 ).…”