There are three types of joints in the body: synarthroses, amphiarthroses and diarthroses (synovial joints). Synarthroses are joints that have an interlocking suture line between adjacent bones (e.g. skull bones)—this provides a very strong bond. The synarthrosis grows during maturation of the developing brain and is eventually replaced by bony union between the adjacent bones. Amphiarthroses are joints that have fibrocartilage between adjacent bones—this allows for flexibility. They are found in the rib cage, the sacroiliac joint and between vertebral bodies—the intervertebral discs.

Synovial, or diarthrodial joints, are the commonest type of joint and are the most mobile. They possess a synovial membrane, have a cavity that contains synovial fluid, and are subclassified into ball and socket (e.g. hip), hinge (e.g. interphalangeal) and saddle (e.g. first carpometacarpal) types. These joints (Fig. 1.1) allow the cartilaginous surfaces of the joint ends to move efficiently and smoothly, with low frictional resistance. Different designs allow for different movements, including flexion (bending), extension (straightening), abduction (movement away from midline), adduction (movement towards midline), and rotation. They are more susceptible to inflammatory injury than are other types of joints.

Synovial joints are surrounded by a capsule that defines the boundary between articular and periarticular structures (Fig. 1.2). Reinforcing the capsule are ligaments and muscular tendons, which act across the joint. The joint capsule, ligaments and tendons are composed principally of type 1 collagen fibres—type 1 collagen is the major fibrous protein of connective tissue.

The synovium has a lining layer that consists of special cells called synoviocytes and is normally one to three cells thick. There is no basement membrane separating the synoviocyte layer from the subintima (Fig. 1.3). There are at least two different types of synoviocyte cell: type A and type B. Type A are of bone marrow-derived macrophage (phagocyte or ‘hungry cell’) lineage and type B are fibroblast-like mesenchymal (connective tissue) cells. Other cell types in this layer include dendritic cells—antigen-processing cells involved in generating an immune response. The synoviocytes lie in a stroma composed of collagen fibrils and proteoglycans (a diverse group of glycosylated proteins that are abundant in the extracellular matrix of connective tissues), which is continuous with the subintima. The latter may be fibrous, fatty or areolar (contain loose connective tissue). It contains a dense network of fenestrated capillaries (small blood vessels) that facilitate the exchange of molecules between the circulation and the synovium. The vessels are derived from branches of the arterial plexus that supplies the joint capsule and juxta-articular bone. There is also a lymphatic supply—a vascular system involved in removing large molecules from the synovium. The latter is innervated and pain sensitive, particularly during inflammation.

Normal synovial joints are highly effective in allowing low-friction movement between articulating surfaces. Articular cartilage is elastic, fluid-filled and supported by a relatively impervious layer of calcified cartilage and bone. Load-induced compression of cartilage forces interstitial fluid to flow laterally within the tissue through adjacent cartilage. This assists in protecting the cartilage against mechanical injury.

Synovial fluid (Fig. 1.4) is present in small quantities in normal synovial joints. It is a clear, relatively acellular, viscous fluid that covers the surface of synovium and cartilage. Synovial fluid is an ultrafiltrate of blood to which hyaluronic acid is added. Hyaluronic acid is secreted by synoviocytes and is the molecule responsible for synovial fluid viscosity, acting as a lubricant for synovial–cartilage interaction. Synovial fluid represents an important site for exchange of nutrients and metabolic by-products between plasma and the surrounding synovial membrane. The synovial cavity can be used to advantage as a site in which therapeutic agents are introduced, e.g. intra-articular corticosteroids to treat inflamed synovium, as well as for diagnostic aspiration.

Normal synovial fluid contains only small quantities of low molecular weight proteins compared with plasma. The barrier to the entry of proteins probably resides within the synovial microvascular endothelium (cells that line the synovial microcirculation).

Innate defence mechanisms include the protective effects of intact skin and mucosa in combating microbes. Normal skin acts as an impermeable barrier to most infectious agents. Mucus secreted by the membranes lining the inner surfaces of the body (e.g. nasal and bronchial mucosa) acts as a protective barrier that prevents bacteria adhering to epithelial cells.

A variety of white blood cells, including polymorphonuclear neutrophils (PMNs) and macrophages, can act as important lines of defence against microbial attack. These cells, derived from bone marrow precursors, are capable of eliminating microbes following their phagocytosis (uptake). The cells are rich in digestive enzymes that aid in elimination of these microbes. PMNs are short-lived cells, whereas macrophages may remain in connective tissues for prolonged periods. PMNs are principally involved in host defence against pus-forming bacteria, while macrophages are better at combating intracellular microbes, including certain bacteria, viruses and protozoa. No prior exposure to the microorganism is necessary for these leukocytes to act.

Another innate line of defence against microbes is the complement system. This comprises over 20 proteins. The complement system is able to respond rapidly to a trigger stimulus, resulting in activation of a sequential cascade in which one reaction is the enzymatic catalyst of the next (Fig. 1.7). The most important complement component is C3, which facilitates the uptake and removal of microbes by enhancing their adherence to the surface of phagocytic cells. Biologically active fragments of C3–C3a, and C5a are able to attract PMNs (called chemotaxis) as well as activating these cells. Activated complement components later in this sequence, C6, 7, 8 and 9, form a complex—the membrane attack complex—on the surface of target cells and this is able to punch holes in the cell membrane, resulting in target cell lysis.

There are a variety of other humoral defence mechanisms mediated by soluble factors that assist in containing microbial infection. These include acute phase proteins such as C-reactive protein, alpha-1-antiprotease and alpha-2-macroglobulin and the interferons. The latter are a family of broad-spectrum antiviral agents that are synthesized by cells when infected by viruses. They limit the spread of virus to other cells.

Humans as well as many lower-order animals have developed more selective mechanisms to combat infection, involving humoral or antibody and cellular systems.

Antibodies are remarkable proteins produced by bone- marrow derived B lymphocytes, which are able to differentiate into plasma cells. Antibodies are adaptor molecules that are capable of binding to phagocytic cells, activating complement and binding to microbes. Each antibody has a unique recognition site for a particular microbe—the Fab end of the molecule, which binds microbes (Fig. 1.8). Molecules in the microorganism that evoke and react with antibodies are called antigens. The Fc end of the antibody molecule contains domains capable of binding and activating the first component of complement as well as binding to phagocyte Fc receptors. There are five antibody subtypes, classified by variations in the structure of the Fab region: IgG, IgM, IgA, IgD and IgE.

There is an enormous variety of B lymphocytes, each programmed to synthesize a single antibody specificity. These antibodies are expressed on the lymphocyte cell surface and act as a receptor for antigens. This process is highly selective; for example, antibodies that recognize tetanus toxoid antigen do not recognize influenza virus, and vice versa. On exposure to antigen, B lymphocytes with the corresponding cell surface antibody specificity, bind to the cell and deliver activation signals. This leads to their differentiation into plasma cells and synthesis and secretion of specific antibodies. The activated B lymphocytes also undergo proliferation, resulting in expansion of the number of clones capable of producing the same antibody. Antibody production in response to antigenic challenge is referred to as an acquired immune response.

Even after the elimination of a microbial antigen trigger, some B lymphocytes remain and have a ‘memory’ of this exposure. On subsequent challenge with the same antigen, the body responds by synthesizing antibody faster and in greater quantities than on the first exposure. This is the secondary immune response.

The ability to recognize a particular antigen and distinguish it from a different antigen is related to the ability to distinguish between self-antigen and non-self (i.e. foreign) antigens. There is an active process by which self-antigen fails to induce an immune response, known as tolerance. In some circumstances, tolerance is broken and the individual produces self-directed antibodies known as autoantibodies. These may give rise to autoimmune diseases. Another autoimmune disease, systemic lupus erythematosus, is discussed in Chapter 9.

Many microbes live inside host cells out of the reach of antibodies. Viruses can live inside host cells, such as macrophages, where they replicate. Thus a different form of immune defence, known as cell-mediated immunity, is required to combat intracellular infection. This involves T or thymus-derived lymphocytes. T cells only recognize antigen when it is presented on the surface of a host cell. There are T cell receptors present on the cell surface, distinct from antibody receptors, which recognize antigen. A further complexity is that antigen is recognized in association with another cell surface molecule known as the major histocompatibility complex (MHC) expressed on the target cell. The MHC plays an important role in organ transplant rejection.

A macrophage that has been infected with a virus is able to process small antigenic components of the virus and place these on its surface. A subpopulation of T lymphocytes, known as T helper cells, primed to that antigen, recognize and bind to the combination of antigen and class 2 MHC molecules. These T cells also secrete a range of soluble products known as lymphokines. The latter include gamma interferon, which stimulates microbicidal mechanisms in the macrophage that help to kill the intracellular microbe.

There is also another subpopulation of T lymphocytes, known as cytotoxic T cells, which recognize antigen expressed on the surface of target cells in association with MHC class 1 molecules (Fig. 1.9). The cytotoxic T cell comes into direct contact with the target cell and kills it. Just as is true for B cells, T cells selected and activated by binding antigen undergo clonal proliferation and mature to produce T helper and cytotoxic cells and produce memory cells. The latter can be reactivated upon further antigenic challenge.

For maximal T cell responses, second signals are usually required. Two of the co-stimulatory molecules through which these signals are provided are CD28 and CD40 ligand. Both of these molecules are expressed by synovial T cells in RA. One of the newer biological therapies for RA, Abatacept, specifically targets this interaction.

In summary, a wide range of innate and adaptive immunological mechanisms has evolved to protect the host against microbial infection. In some circumstances the host becomes a target for these responses, resulting in autoimmune disease.

To gain a better appreciation of the processes occurring within an inflamed joint, it is necessary to understand synovial pathology. However, in clinical practice a synovial biopsy is not routinely performed as part of the diagnosis of inflammatory arthritis.

In RA, the classical example of an inflammatory arthropathy, the synovium undergoes characteristic histological changes, but these are not disease-specific. Eventually, they may progress to destruction of articular cartilage and result in joint subluxation or ankylosis (bridging of adjacent bones).

In the early stages of RA, the synovium becomes oedematous (contains excess fluid), thickened, hyperplastic (cells multiply excessively) and develops villus-like projections as found in normal small intestine (Fig. 1.10A). The synovial lining layer undergoes cellular proliferation and becomes multilayered. One of the earliest histological changes is injury to the synovial microvasculature, with swelling of endothelial cells, widened interendothelial gaps and luminal occlusion. There is dense synovial cellular infiltration with prominent perivascular T lymphocytes, plasma cells and macrophages, but few neutrophils (Fig. 1.10B). Prominent fibrin deposition is characteristic. Lymphoid nodular aggregates composed principally of CD4 T (helper) cells may be found in the synovial stroma (Fig. 1.10C), but are more likely to develop later in the disease. By contrast, in the synovial fluid there is a predominance of neutrophils. RA often involves periarticular structures including tendon sheaths and bursae.