AB0010 TRIPLE DMARD TREATMENT IN EARLY RHEUMATOID ARTHRITIS INCREASE SYNOVIAL ACTIVATED NATURAL KILLERS AND RESTING MAST CELLS BUT DECREASE PLASMA CELLS AND M1 MACROPHAGES

Abstract

Background:Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with cartilage and bone damage as well as disability and its optimal therapeutic success depends on understanding the underlying pathophysiology[1]. Since RA is a heterogenous disease, there is an urge to characterize new molecular mechanisms to aid the development of more effective and personalized therapy [2]. Genome-wide transcriptional effects of tDMARD in early RA synovial tissues showed alterations in gene expression of T cell activation and plasmablast/plasma cell differentiation[3].Objectives:Using publicly available synovial tissue transcriptomic data to compare the immune cells infiltration at baseline and after 6 months of tDMARD to identify subgroups that might not respond well to tDMARD.Methods:RNAseq dataset (GSE97165) of synovial biopsies taken from 19 early RA patients at baseline and after 6 months of tDMARD treatment were retrieved and reanalyzed. The raw RNAseq data were used for in silico prediction of the immune cells’ infiltration the synovial tissue using CIBERSORT analytical tool to evaluate the pre versus post tDMARD changes in immune population and/or activation status. Then, patients were divided according to the level of alteration in immune cells percentage after the treatment. Differentially expressed genes between the subgroups were defined and gene set enrichment analysis was performed to identify the underlying pathways in each group using BioJupies tools.Results:4 immune cells populations showed significant changes after 6 months of tDMARD indicating their role in disease pathophysiology or in response to the therapy. Resting mast cells and activated natural killer (NK) cells were increased in 84% and 74% of patients, respectively. On the other hand, M1 macrophages and plasma cells were decreased after treatment in 68% and 58% of patients, respectively. GSEA of differentially expressed genes between patients who showed increased activated NK cells in comparison to those who showed decreased or no change in NK cells after treatment identify novel pathways that can explain the heterogeneity in response to treatment specifically genes related to WNT signaling, estrogen metabolism and IL17 signaling.Figure 1.Percentage of infiltrating immune cells in the synovial tissue at baseline and after 6 months of tDMARD therapy in 19 early RA patients using CIBERSORT tool.Figure 2.Top wikiPathways enriched in the patients with decreased percentage of synovial infiltrating activated NK after 6 months of tDMARD therapy compared to those who showed increased or unchanged percentage.Conclusion:Synovial tissue NK cells, resting mast cells, plasma cells and M1 macrophages play major role in response to tDMARD. Genes related to WNT signaling, estrogen metabolism and IL17 signaling can help stratification of patients for a more effective personalized medicine in RA.