Molecular Portraits of Early Rheumatoid Arthritis Identify Clinical and Treatment Response Phenotypes

Abstract

Summary There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website ( https://peac.hpc.qmul.ac.uk/ ) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage.

Lactate Buildup at the Site of Chronic Inflammation Promotes Disease by Inducing CD4+ T Cell Metabolic Rewiring

“…Patients were enrolled in the Pathobiology of Early Arthritis Cohort (PEAC, details at http://www.peac-mrc. mds.qmul.ac.uk/index.php) at the Centre for Experimental Medicine and Rheumatology at Queen Mary University of London (REC 05/Q0703/198, London, UK), as previously described (Kelly et al, 2015;Humby et al, 2019;Lewis et al, 2019). All patients belonging to this cohort underwent baseline ultrasound-guided biopsy on the most inflamed accessible joint.…”

Molecular Remission at T cell level in Patients with Rheumatoid Arthritis

“…However, we couldn't show the signi cant bene t of achieving deep MR de ned by remission signature genes on clinical course, while those treated with TCZ in deep MR had a favorable trend. To date, although several studied tried to predict following change of disease activity using only transcriptome data, they failed to show robust predictability [6,29]. In our data, most patients even in non-deep MR we could follow were under good control during follow-up as shown in Figure 5A, which might make hard to detect statistical signi cance.…”

New Developments in Transcriptomic Analysis of Synovial Tissue

“…Investigation of key histological variables in the tissue samples showed concordance with the sequencing results, with the high-inflammatory samples possessing high levels of immune cell infiltrate. Additionally, in a longitudinal consortium study taking synovial biopsies at first presentation of new RA, significant correlations were observed between histological type, whole tissue bulk RNAseq-derived gene clusters, and clinical response to first therapy (38,39). This powerful approach elegantly demonstrates the predictive value of cellular gene clusters derived from whole tissue signatures.…”