Molecular and Cellular Heterogeneity in Rheumatoid Arthritis: Mechanisms and Clinical Implications

Abstract

Rheumatoid arthritis is an autoimmune disease that exhibits significant clinical heterogeneity. There are various treatments for rheumatoid arthritis, including disease-modifying anti-rheumatic drugs (DMARDs), glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), and inflammatory cytokine inhibitors (ICI), typically associated with differentiated clinical effects and characteristics. Personalized responsiveness is observed to the standard treatment due to the pathophysiological heterogeneity in rheumatoid arthritis, resulting in an overall poor prognosis. Understanding the role of individual variation in cellular and molecular mechanisms related to rheumatoid arthritis will considerably improve clinical care and patient outcomes. In this review, we discuss the source of pathophysiological heterogeneity derived from genetic, molecular, and cellular heterogeneity and their possible impact on precision medicine and personalized treatment of rheumatoid arthritis. We provide emphasized description of the heterogeneity derived from mast cells, monocyte cell, macrophage fibroblast-like synoviocytes and, interactions within immune cells and with inflammatory cytokines, as well as the potential as a new therapeutic target to develop a novel treatment approach. Finally, we summarize the latest clinical trials of treatment options for rheumatoid arthritis and provide a suggestive framework for implementing preclinical and clinical experimental results into clinical practice.

Keywords: genetics; heterogeneity; interaction; mechanism; pathophysiology; precision medicine; responsiveness; rheumatoid arthritis.

Figure 1

Mechanism of cell-cytokine interaction in RA. Various factors (e.g., smoking, dust, genetic factors, and microorganisms) lead to the production of exogenous and endogenous antigens. Antigen-presenting cells (primarily dendritic cells) present exogenous and endogenous antigens to CD4+ T cells that differentiate into T cells with different functions, including Th1, Th2, and Th17. These cells cooperate with mast cells, macrophages, and monocytes to secrete multiple pro-inflammatory mediators that act on FLSs and osteoclasts, which in turn can secrete various biological mediators to aggravate the circulation. The anti-inflammatory mechanism (red represents anti-inflammatory mediators) is active but insufficient to inhibit the pro-inflammatory process (black represents pro-inflammatory mediators). Briefly, the interaction of various cell subgroups and cell mediators forms a complex network that promotes the development of RA, including bone destruction, angiogenesis, and synovial inflammation. DC, dendritic cells; IL, interleukin; TNF-α, tumor necrosis factor-α; mDCs, myeloid DCs; pDCs, plasmacytoid DCs; GM-CSF, granulocyte-macrophage colony-stimulating factor; M-CSF, macrophage colony-stimulating factor; CXCL, chemokine CXC ligand; CCL, CC-chemokine ligand; MMP, matrix metalloproteinase; MCP-1, monocyte chemoattractant protein-1; PGE2, prostaglandin E2; APRIL, a proliferation-inducing ligand; RF, rheumatoid factor; ACPA, anti-citrullinated protein antibody; FLS, fibroblast-like synoviocyte; TGF, transforming growth factor; VEGF, vascular endothelial growth factor; MC, mast cell.