Comprehensive transcriptome analysis of synovium and peripheral blood reveals major disease heterogeneity early in the RA disease process prior to therapeutic intervention

We report the first comparative analysis between histology, RNA-seq of synovium and matched peripheral blood, and clinico-radiological parameters in early rheumatoid arthritis (RA). Using a novel modular approach, we describe underlying pathways associated with three pre-dominant RA pathotypes. Myeloid was associated with macrophages, lymphoid with B and plasma cells, and fibroid with minimal inflammatory cell infiltration. Synovium RNA-seq was better correlated with the pathotypes than blood RNA-seq, but peripheral blood signatures, including type I interferon, were detected as associated with particular myeloid or lymphoid pathotypes. This study describes the molecular heterogeneity of RA and provides major new insights into the cross compartmental molecular pathways that underlie RA.