Fast Facts: Rheumatoid Arthritis
Introduction
Rheumatoid arthritis (RA) is the commonest inflammatory joint disease, affecting approximately 1% of adults in the developed world. Here, we provide an easy-to-read and up-to-date overview of how RA is thought to develop, how it is diagnosed and monitored, and how it is treated, incorporating the major advances in these areas that have taken place since the first edition.
The pathogenesis of RA is starting to become unraveled and, more than in any other disease, this has led to powerful targeted treatments. Specifically, nine targeted biological therapies have, at the time of press, received approval by regulatory agencies. These target inflammatory mediators and the cells that coordinate the dysregulated immune and inflammatory responses that characterize RA. They are discussed in the closing chapters of the book, along with our thoughts on future directions of investigation and management. We also cover the new classification criteria for RA, and a new autoantibody class, anti-citrullinated peptide antibody (ACPA), is discussed in the context of its use for diagnosing RA
1.i Synovium The normal joint
The synovial membrane lines the non-weight-bearing aspects of the synovial cavity and is divided into the lining layer or intima and sublining layer or subintima. It is the target tissue of the dysregulated inflammation and immunity that characterizes rheumatoid arthritis (RA) (Figure 1.1). The synovial membrane intima is just one or two cell layers thick and contains two major cell types: type A synoviocytes, which bear macrophage markers, and type B synoviocytes, which have fibroblastic characteristics. The intima lacks the typical features of an epithelium and does not possess a basement membrane or tight intercellular contacts between synoviocytes. The matrix of the intima is rich in proteoglycans and glycosaminoglycans, in particular hyaluronic acid
Figure 1.1 Normal joint anatomy (left side of figure) and RA pathology (right).
The subintima is a loose vascular connective tissue stroma containing blood vessels, lymphatics and nerve endings within a matrix comprising varying proportions of lipid, collagen fibrils and more organized fibrous tissue
1.ii Synovial fluid
The synovial membrane secretes lubricating and nourishing synovial fluid, a viscous fluid containing a high concentration of hyaluronic acid. Other constituents include nutrients and solutes that diffuse from the blood vessels in the subintima. The precise physiology of synovial fluid production is unknown, but exchange of fluid between the circulation and the joint space is governed by a balance of hydrostatic, osmotic and convective forces. As well as providing an osmotic force within the synovial cavity, hyaluronic acid contributes to the lubricating properties of synovial fluid although other constituents are also important. .
iiiArticular cartilage.1
Articular cartilage comprises chondrocytes embedded in a hydrated matrix composed of collagen, proteoglycans and other matrix proteins. It is an avascular structure lacking lymphatics, and the synovial fluid is critical for providing nutrients to this tissue. Water makes up approximately 70% of normal cartilage by weight, whereas chondrocytes occupy only 5–10% by volume. Because of their low density, chondrocytes do not come into contact with one another directly but possess cellular processes which abut the matrix. These cells are critical to the integrity of articular cartilage because they synthesize collagen, proteoglycans and also other components such as fibronectin. Each cell is surrounded by a zone of secreted proteoglycans and a basket-like mantle of fibrillar collagen, but the highest collagen content occurs in the more distal intercellular matrix.
Collagens are fibrillar proteins that, together with proteoglycans, account for the biomechanical properties of articular cartilage. There are 14 different types of collagen, divided into three major groups. The predominant collagen in articular cartilage is type II, constituting approximately 90% in the adult, with types IX and XI contributing most of the remainder. All collagens are based on a triple helical structure (Figure 1.2), and the differences between collagens relate to the length of the triple helix, the presence of non-collagenous units within the molecule that impart extra flexibility, or the addition of non-collagenous side-chains such as carbohydrates. The triple helical structure of collagens accounts for their tensile strength. Collagen biosynthetic and degradative pathways are quite well characterized.
Introduction
Rheumatoid arthritis (RA) is the commonest inflammatory joint disease, affecting approximately 1% of adults in the developed world. Here, we provide an easy-to-read and up-to-date overview of how RA is thought to develop, how it is diagnosed and monitored, and how it is treated, incorporating the major advances in these areas that have taken place since the first edition.
The pathogenesis of RA is starting to become unraveled and, more than in any other disease, this has led to powerful targeted treatments. Specifically, nine targeted biological therapies have, at the time of press, received approval by regulatory agencies. These target inflammatory mediators and the cells that coordinate the dysregulated immune and inflammatory responses that characterize RA. They are discussed in the closing chapters of the book, along with our thoughts on future directions of investigation and management. We also cover the new classification criteria for RA, and a new autoantibody class, anti-citrullinated peptide antibody (ACPA), is discussed in the context of its use for diagnosing RA
1.i Synovium The normal joint
The synovial membrane lines the non-weight-bearing aspects of the synovial cavity and is divided into the lining layer or intima and sublining layer or subintima. It is the target tissue of the dysregulated inflammation and immunity that characterizes rheumatoid arthritis (RA) (Figure 1.1). The synovial membrane intima is just one or two cell layers thick and contains two major cell types: type A synoviocytes, which bear macrophage markers, and type B synoviocytes, which have fibroblastic characteristics. The intima lacks the typical features of an epithelium and does not possess a basement membrane or tight intercellular contacts between synoviocytes. The matrix of the intima is rich in proteoglycans and glycosaminoglycans, in particular hyaluronic acid
Figure 1.1 Normal joint anatomy (left side of figure) and RA pathology (right).
The subintima is a loose vascular connective tissue stroma containing blood vessels, lymphatics and nerve endings within a matrix comprising varying proportions of lipid, collagen fibrils and more organized fibrous tissue
1.ii Synovial fluid
The synovial membrane secretes lubricating and nourishing synovial fluid, a viscous fluid containing a high concentration of hyaluronic acid. Other constituents include nutrients and solutes that diffuse from the blood vessels in the subintima. The precise physiology of synovial fluid production is unknown, but exchange of fluid between the circulation and the joint space is governed by a balance of hydrostatic, osmotic and convective forces. As well as providing an osmotic force within the synovial cavity, hyaluronic acid contributes to the lubricating properties of synovial fluid although other constituents are also important. .
iiiArticular cartilage.1
Articular cartilage comprises chondrocytes embedded in a hydrated matrix composed of collagen, proteoglycans and other matrix proteins. It is an avascular structure lacking lymphatics, and the synovial fluid is critical for providing nutrients to this tissue. Water makes up approximately 70% of normal cartilage by weight, whereas chondrocytes occupy only 5–10% by volume. Because of their low density, chondrocytes do not come into contact with one another directly but possess cellular processes which abut the matrix. These cells are critical to the integrity of articular cartilage because they synthesize collagen, proteoglycans and also other components such as fibronectin. Each cell is surrounded by a zone of secreted proteoglycans and a basket-like mantle of fibrillar collagen, but the highest collagen content occurs in the more distal intercellular matrix.
Collagens are fibrillar proteins that, together with proteoglycans, account for the biomechanical properties of articular cartilage. There are 14 different types of collagen, divided into three major groups. The predominant collagen in articular cartilage is type II, constituting approximately 90% in the adult, with types IX and XI contributing most of the remainder. All collagens are based on a triple helical structure (Figure 1.2), and the differences between collagens relate to the length of the triple helix, the presence of non-collagenous units within the molecule that impart extra flexibility, or the addition of non-collagenous side-chains such as carbohydrates. The triple helical structure of collagens accounts for their tensile strength. Collagen biosynthetic and degradative pathways are quite well characterized.
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