Background/Purpose:  While several transcriptional profiling studies of synovial biopsies have been reported from RA patients with advanced disease, there is relatively little data available from patients with early disease before treatment with DMARDs or on the effects of treatment with DMARDS. Such data may advance our understanding of RA pathogenesis and promote precision-medicine based treatments for early disease.

Methods:  Biopsies from subjects with early RA (<12 months from diagnosis at baseline with an average disease duration of 17.6 weeks) before and after triple DMARD (tDMARD) therapy were collected by arthroscopy (n=19 paired samples at baseline and 6 months post-treatment). These biopsies as well as those from subjects with normal synovium (n=28) or those diagnosed with osteoarthritis (n=15) were profiled by total RNA sequencing. Comparison of RA biopsies before and after treatment and comparison with non-RA controls were performed. Pathway enrichment and upstream regulator analysis were used to understand gene changes and to generate hypotheses for future experimental confirmation.

Results:  Over 5000 genes were identified with differential expression between baseline RA samples and normal controls (with 5% FDR and 2 fold-change cutoffs). A subset comprising less than 500 of these genes was modulated by tDMARD treatment in the subjects (n=17) who achieved good or moderate response at 6 months as assessed by EULAR criteria. The gene set whose expression was modulated by treatment was enriched for genes involved in immune system and T cell activation pathways. Interestingly, many genes with increased expression in RA samples remained elevated after treatment compared to normal controls. Based on this finding, we also identified gene expression patterns in treated patients with low disease activity (DAS28 < 3.2) that differentiates them from normal controls. These gene signatures may help identify novel drug targets to improve rates of treatment induced disease remission.

Conclusion:  Through genome-wide transcriptomics profiling, we identified signatures that characterize synovial tissue from RA patients with early disease. Analysis of gene expression after 6 months of tDMARD treatment highlight consistent alterations in expression of genes related to immune response and T cell activation. Our results provide novel insight into the biology of joints from early RA patients and the mechanism of tDMARD action in this patient population with high unmet clinical need.

« Back to 2016 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/transcriptional-profiling-of-early-ra-synovial-tissue-reveals-the-impact-of-triple-dmard-treatment-on-t-cell-activation-pathways/