The effect of targeted rheumatoid arthritis therapies on anti-citrullinated protein autoantibody levels and B cell responses

Abstract

Rheumatoid arthritis (RA) is a complex inflammatory disorder associated with synovitis and joint destruction that affects an estimated 1·3 million Americans and causes significant morbidity, a reduced life-span and lost work productivity. The use of biological therapies for the treatment of RA is costly, and the selection of therapies is still largely empirical and not guided by the underlying biological features of the disease in individual patients. The synovitis associated with RA is characterized by an influx of B and T cells, macrophages and neutrophils and the expansion of fibroblast-like synoviocytes, which form pannus and lead to cartilage and bone destruction. RA is associated with synovial production of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) and with the production of inflammatory cytokines, including interleukin (IL)-1, IL-6, IL-17 and tumour necrosis factor (TNF)-α, which are targets for RA therapeutics. Recent ideas about the pathogenesis of RA emphasize a genetic predisposition to develop RA, a preclinical phase of disease that is associated with the production of ACPA and the development of symptomatic disease following inflammatory initiating events that are associated with expression of citrullinated epitopes in the joints of patients. However, we still have a limited understanding of the cytokine and intracellular pathways that regulate ACPA levels. In humans, therapy with biological agents affords a unique opportunity to better understand the cytokine and signalling pathways regulating ACPA levels and the impact of ACPA level changes on disease activity. In this study we summarize the effect of RA therapies on ACPA levels and B cell responses.

Figure 1

Citrullinated peptides serve as antigens when encountered by antigen-presenting cells (APC) including macrophages within the joint. APC present citrullinated peptides via class II major histocompatibility complex (MHC II) to T cells. Macrophages secrete cytokines including interleukin (IL)-1 and IL-6. Cytokines such as IL-6 stimulate B cells via binding to IL-6R, resulting in B cell activation and differentiation of B cells into antibody-producing plasma cells. Tocilizumab is a humanized monoclonal antibody that binds to and inhibits the IL-6R. IL-6 inhibitors that bind directly to IL-6 are now in development. Anakinra is an IL1 receptor antagonist (IL-1ra). T cell activation occurs via two signals delivered by APC. The first signal occurs when an antigen is presented by MHC II to a T cell receptor (TCR). The second signal occurs via co-stimulatory molecules CD80 and CD86 binding to CD28 on the surface of the T cell. Abatacept is a fusion protein composed of the Fc region of immunoglobulin (Ig)G1 fused to the extracellular domain of cytotoxic T lymphocyte-4 (CTLA-4). Abatacept binds CD80/CD86, which blocks CD28 activation. Abatacept is a selective co-stimulation modulator, as it inhibits the co-stimulation of T cells. Activated T cells secrete several cytokines, including tumour necrosis factor (TNF)-α and IL-17. TNF inhibitors neutralize TNF-α. TNF-α is a proinflammatory cytokine that mediates apoptosis . In addition, TNF-α is a growth factor for B lymphocytes inducing the production of IL-1 and IL-6 ,. Moreover, through nuclear factor kappa B (NF-κB) activation, TNF-α up-regulates MHC molecules, interferon (IFN)-γ production and TNF receptor 2 (TNFR2). Anti-IL-17 inhibitors are under investigation for the treatment of rheumatoid arthritis (RA) and have shown promising results in early-phase studies in RA patients. Activated T cells also stimulate B cells via CD40L (CD154) binding to CD40 on B cells. Rituximab is a chimeric monoclonal antibody that binds CD20, which is found primarily on the surface of B cells. Rituximab binding to B cells results in deletion of B cells.

Figure 2

Interleukin (IL)-6 signals through a receptor composed of a 130-kDa (gp130) protein subunit. Binding of IL-6 to its receptor initiates cellular events, including activation of Janus kinases (JAK) and signal transducers and activators of transcription (STAT). JAK inhibitors interfere with JAK/STAT signalling. Tofacitinib is a JAK inhibitor approved recently by the Food and Drug Administration (FDA) for the treatment of RA. Phosphorylated STAT-3 forms a dimer and translocates into the nucleus to activate the transcription of genes containing STAT response elements. STAT is essential for gp130-mediated cell survival. This signalling pathway induces B cells to differentiate into antibody-forming cells (plasma cells).