Rheumatoid arthritis (RA) is the prototypical inflammatory arthropathy. The primary site of disease is the synovium, which becomes inflamed and proliferates to form pannus: a mass of T cells, B cells, fibroblasts and activated macrophages. The boggy, inflamed pannus invades cartilage and bone, giving rise to the clinical features of pain and stiffness followed by joint swelling, instability and destruction.

RA is a classic autoimmune disease, involving both the cellular and humoral components of immunity. This chapter will cover basic details of the key cells, cytokines and mechanisms involved in the pathogenesis of RA.

T cells

T cells are the basis of cellular immunity and are up-regulated in RA synovial tissue. CD4+ T helper (TH) cells are divided into the subsets TH1, TH2 and TH17, each with a characteristic cytokine-producing profile. TH17 cells are the dominant cell population in RA, producing interleukin-17 (IL-17), which is responsible for cytokine production, osteoclast activation and matrix metalloproteinase (MMP) release.

T cell activation depends on antigen-presenting cells (e.g. dendritic cells) and requires two separate signals:

• Signal 1: antigen-specific binding between the T cell receptor and MHC II / antigen complexes on the surface of antigen-presenting cells; indeed RA is associated with HLA-DR4 and DR-1 alleles that contain a shared amino acid motif in the MHC II antigen binding site, commonly known as the shared epitope, and
  
• Signal 2: co-stimulatory binding between the T cells CD28 protein with ligands (CD80/86) on antigen-presenting cells. T cells may also express cytotoxic T lymphocyte antigen 4 (CTLA-4) which binds CD80/86 without providing a stimulatory signal and acts as an endogenous inhibitor.

• Induction of pro-inflammatory cytokines (e.g. IL-1, IL-6, IL-17 and TNFα) to enlist and coordinate lymphocyte and macrophage recruitment.
  
• Activation of synovial fibroblasts and osteoclasts to erode cartilage and bone.
  
• B cell proliferation and antibody production.

Regulatory T cells (Tregs) home into the site of inflammation and may act locally to resolve inflammation, probably through the release of IL-10 and/or transforming growth factor β.

B cells

B cells are responsible for

• Autoantibody production.
  
• Cytokine release.
  
• Antigen presentation.
  
• Modulation of T cells.

The most crucial role for B cells in RA is likely to be the development of antibodies against self-IgG molecules (rheumatoid factor, RF) and cyclic citrullinated peptides (anti-CCP antibodies – see Chapter 23 for their clinical utility). Anti-CCP antibodies may play a role in disease pathogenesis and/or perpetuation, or merely represent byproducts of the inflammatory process. There is increasing evidence of an association between anti-CCP antibodies, the shared epitope and cigarette smoking. Smoking may promote the citrullination of selfpeptides which are subsequently presented to T cells by antigen-presenting cells with the high-risk HLA-DR shared epitope. As a consequence, cell-mediated immunity against citrullinated antigens is enhanced (via T cell activation and expansion) and B cells secrete anti-CCP antibodies.

Macrophages

Macrophages initiate and perpetuate inflammation both in tissue and the circulation by:

• Cytokine production, most notably TNFα (see below).
  
• Antigen presentation to T cells.
  
• Promoting adhesion and migration of leucocytes.
  
• Degradation of collagen matrix.
  
• Angiogenesis.

Fibroblasts

Fibroblasts account for the majority of the cells in RA synovial tissue, and their uncontrolled growth is a major factor in pannus formation. RA synovial fibroblasts are quite different from those in normal tissue as they lack the normal control mechanisms that prevent cellular proliferation (such as tumour suppressor genes) and instead express protooncogenes and anti-apoptotic molecules. Synovial fibroblasts produce pro – inflammatory cytokines and chemokines, thereby attracting activated inflammatory cells into the joint. In addition, they produce matrix-degrading enzymes which erode cartilage.

TNFα is probably the dominant cytokine for most patients with RA. It is present in high concentrations in synovial fluid and rheumatoid synovium and is responsible for key pathological processes such as cellular activation and cytokine, MMP and prostaglandin release. In addition it is responsible for the systemic effects and weight loss seen in very active disease. TNFα blockade using monoclonal antibodies has revolutionised the treatment of RA (see Chapters 36 Medical management of inflammatory disease and 23 Rheumatoid arthritis).

IL-1, -6 and -17 are also crucial mediators in inflammatory disease and blocking antibodies are either available or in development.

Inflammation, cartilage and bone loss are closely linked.

Cartilage destruction in RA is driven by matrix metalloproteinases (MMPs) from synovial fibroblasts, neutrophil polymorphs and chondrocytes. Bone thinning (osteopaenia) and erosions are caused by activated osteoclasts, cells of monocyte/macrophage lineage that are specifically designed for bone resorption (see also Chapter 31 Disorders of bone metabolism). Osteoclastogenesis requires macrophage colony stimulating factor (M-CSF) and the receptor activator of NFκβ ligand (RANKL) from synovial fibroblasts and activated T cells; its expression is up-regulated by cytokines in inflamed synovial tissue. The non-signalling decoy receptor for RANKL, osteoprotegerin (OPG), diminishes osteoclast activation and bone resorption; as a result the ratio between RANKL and OPG is a crucial determinant of inflammatory bone loss. A monoclonal antibody against RANKL (denosumab) increases bone mineral density in post-menopausal women and may diminish bone erosion in RA.