Deciphering transcriptomic heterogeneity in rheumatoid arthritis synovium
(2022)
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- Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease characterized by a predominant joint involvement. RA encompasses a wide spectrum of clinical disease severity spanning from limited, indolent oligoarticular involvement to severe, polyarticular destructive disease. Therapeutic armamentarium has greatly increased these last decades to involve drugs specifically targeting key inflammatory effectors. Again, response to therapy displays a wide heterogeneity across individuals, with some patients entering remission after 1st-line therapy while others suffer from “multi-resistant” RA. Importantly, accurate predictors of response to therapy are lacking. The target tissue of RA -the synovium- is the seat of alterations involving immune and resident cells. Just as clinical characteristics, features of synovial inflammation in RA are widely heterogenous from a cellular and molecular point-of-view. The development of minimally invasive biopsies techniques has enabled to study clinical correlates of synovial tissue heterogeneity in large cohorts of RA patients. While confounding factors (i.e. disease duration, ongoing treatment) may partially account for these variations, it remains unclear whether RA endotypes (commonly named “pathotypes”) can be defined based on synovial inflammatory pattern. The clinical benefit of defining such RA subgroups with different prognosis/response to therapy is evident and would represent a great step toward the grail of precision-medicine. Nevertheless, clinician scientists ought to temper their enthusiasm with a critical approach. In this thesis, I first explored the intra-patient heterogeneity (that is, across pairs of large and small joints) of synovial inflammatory features. I have shown that T cells infiltration and expression of TCR-signaling genes (and other RA-related pathways) are largely similar between pairs of joints from the same individuals. These observations have pathophysiological but also methodological implications: the location of the joint biopsy is not a confounding factor contributing to inter-patient heterogeneity in synovial signals. Then, I analyzed the cellular and molecular effects of T cell co-stimulation blockade therapy (abatacept) on RA synovitis using pre/post treatment biopsies. I took advantage of the large datasets previously acquired by our team to analyze the common transcriptomic effects of 5 drugs with different molecular targets (i.e. B cells, TNF⍺, IL6R). Interestingly, we found a large overlap between the effects of the different therapies: no matter their primary target, they all induced a correlated downregulation of a common set of genes involved in both lymphoid and myeloid cells activation. These observations argue in favor of a common pathogenic mechanism operating in RA synovitis, as opposed to differential (innate vs. adaptive) immune activation. Finally, I analyzed the synovial transcriptome in a large cohort of early, untreated RA patients using unbiased approaches. The main drivers of synovial transcriptomic heterogeneity were genes involved in B and plasma cell biology and RA-related inflammatory process. Interestingly, the synovial expression pattern of these genes strongly correlated with the systemic disease activity. Response to methotrexate therapy (despite several limitations) was mainly associated with baseline disease activity rather than with a specific gene expression pattern. In conclusion, I discuss three (non-exclusive) mechanistic models able to account for our observations on the link between synovial and clinical features in RA. Several questions are raised: Is RA a syndrome encompassing discrete, stable (sub)entities? Does RA synovitis rather represent a continuous spectrum of common mechanisms varying in intensity? Finally, could the differences in pro- and anti-inflammatory cell subtypes present in the synovium of RA patients represent a dynamic process of successive immune-regulatory mechanisms?
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Triaille, C. (2022). Deciphering transcriptomic heterogeneity in rheumatoid arthritis synovium. https://hdl.handle.net/2078.5/100062