Next Potential Therapeutic Targets in Rheumatoid Arthritis are Molecules Regulating Inflammatory Transition of Synovium

Abstract

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation and destruction. The affected synovium becomes the basis of the inflammatory milieu by recruiting immune cells including T cells, B cells, monocytes, macrophages and granulocytes etc., and activates osteoclasts leading to joint destruction and dysfunction. If this inflammatory environment can be restored, destructive arthritis in RA can be prevented.

With the introduction of molecular-targeted agents (MTAs) at the beginning of this century, RA has become a controllable disease. Nevertheless, effective drugs including MTAs require continuous administration. This is because they are still unable to eliminate the cause of the disease. Patients with refractory RA often show a decreased response to treatment over time, suggesting that there underlie the irreversible traits of cytokine dysregulation. For the treatment aiming a closer-to-cure condition, it is necessary to find new approach to restore such traits.

The RA synovium has two abnormalities: morphological and functional ones. The first is the loss of the single-cell-layer structure surrounding the joint cavity followed by abnormal proliferation to form a tumor-like tissue called pannus which is comparable to epithelial-mesenchymal transition (EMT), and the second is the autonomous activation of inflammation-related genes due to epigenetic changes in DNA and the decrease in immune regulatory response due to metabolic changes, etc. Especially, these functional abnormalities seem to be associated with traits of cytokine dysregulation in RA synovium.

Recent chromatin immunoprecipitation sequencing analysis with synovial fibroblasts has shown that EMT-like changes are linked to changes in cytokine production. In RA, compared to osteoarthritis, non-autoimmune joint disease, there were activating histone modifications at the IL-6 locus. Intriguingly, such activation changes were observed also in the loci of EMT marker genes, SNAI1 and COL1A1. These epigenetic changes in the RA synovium seem to be related to irreversible, fixed traits that continue the inflammatory response.

Candidate targets of the trait-restoring therapy for RA include molecules involved in epigenetic plasticity that can restore irreversible changes toward inflammatory nature in the RA synovium.