Bone erosion in rheumatoid arthritis: mechanisms, diagnosis and treatment

Abstract

Bone erosion is a central feature of rheumatoid arthritis and is associated with disease severity and poor functional outcome. Erosion of periarticular cortical bone, the typical feature observed on plain radiographs in patients with rheumatoid arthritis, results from excessive local bone resorption and inadequate bone formation. The main triggers of articular bone erosion are synovitis, including the production of proinflammatory cytokines and receptor activator of nuclear factor κB ligand (RANKL), as well as antibodies directed against citrullinated proteins. Indeed, both cytokines and autoantibodies stimulate the differentiation of bone-resorbing osteoclasts, thereby stimulating local bone resorption. Although current antirheumatic therapy inhibits both bone erosion and inflammation, repair of existing bone lesions, albeit physiologically feasible, occurs rarely. Lack of repair is due, at least in part, to active suppression of bone formation by proinflammatory cytokines. This Review summarizes the substantial progress that has been made in understanding the pathophysiology of bone erosions and discusses the improvements in the diagnosis, monitoring and treatment of such lesions.

Figure 1

Autoantibodies against citrullinated proteins and osteoclastogenesis. Plasma cells produce ACPA with specificity for citrullinated vimentin, which bind to osteoclast precursor cells and stimulate the release of TNF, which in turn enhances the differentiation of these cells into mature osteoclasts. During the osteoclast differentiation process, production of the PADI2 enzyme is induced by calcium. The activity of PADI2 leads to citrullination of vimentin, which is abundantly expressed on the surface of osteoclast-lineage cells. Abbreviations: ACPA, anti-citrullinated protein antibodies; PADI2, peptidyl-arginine deiminase type 2.

Figure 2

Evolution of bone erosion in the course of RA. During the preclinical phase of RA, ACPA are produced early on by plasma cells. ACPA can stimulate osteoclast differentiation and lead to initial bone loss. These early changes may initiate in the bone marrow adjacent to the joint. Synovitis at the onset of clinical disease leads to production of cytokines, which stimulate osteoclastogenesis by inducing expression of RANKL, and synergize with RANKL to enhance bone erosion. Established RA is characterized by the presence of large bone erosions filled with inflamed, synovially derived pannus tissue. Abbreviations: ACPA, anti-citrullinated protein antibodies; RA, rheumatoid arthritis; RANKL, receptor activator of nuclear factor κB ligand.

Figure 3

Site of action of antirheumatic drugs on osteoclast differentiation and bone erosion. Inhibitors (green boxes) of TNF, IL-1 and IL-6R block the expression of RANKL by mesenchymal cells and T cells; they also directly interfere with osteoclastogenesis. Abatacept inhibits osteoclast differentiation by directly engaging CD80 and CD86 on the surface of osteoclast precursor cells. T-cell activation is targeted by small-molecule tyrosine kinase inhibitors such as tofacitinib, an inhibitor of JAK. B cells differentiate into plasma cells, which are a source of RANKL. B cells are depleted by an antibody against CD20 (rituximab) and are inhibited by small-molecule tyrosine kinase inhibitors such as fostamatinib, an inhibitor of SYK. Abbreviations: IL-6R, IL-6 receptor; JAK, Janus kinase; RANKL, receptor activator of nuclear factor κB ligand; SYK, spleen tyrosine kinase.

Figure 4

Disruption of bone homeostasis by synovitis. Inflammation within synovial tissue induces osteoclastogenesis through increased expression of RANKL, and by the production of proinflammatory cytokines that drive osteoclastogenesis and synergize with RANKL. In addition, expression of Dkk-1 by synovial fibroblasts leads to inhibition of osteoblast differentiation and consequently of bone formation. Dkk-1 itself induces expression of another anti-anabolic molecule, sclerostin, by osteocytes. Abbreviations: Dkk-1; Dickkopf-related protein 1; RANKL, receptor activator of nuclear factor κB ligand.