Porth's Essentials of Pathophysiology, 4e

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Disorders of the Skeletal System: Metabolic and Rheumatic Disorders

C h a p t e r 4 4

Genetic predisposition (HLA type) plus immunologic trigger

Rheumatic Disorders Arthritis is a descriptive term applied to more than 100 rheumatic disorders, ranging from localized, self-limit- ing conditions to those that are systemic immune-medi- ated processes. The term, which is used to describe any disorder that affects the joints, oversimplifies the nature of the varied disease processes, the difficulty in differen- tiating one form of arthritis from another, and the com- plexity of treatment of these usually chronic conditions. These diverse rheumatic conditions share inflammation of the joint as a prominent or accompanying symptom. In the systemic rheumatic diseases, such as rheumatoid arthritis, the inflammation is primary, resulting from an immune response, probably autoimmune in origin. In rheumatic conditions limited to a single or few diarthro- dial joints, such as osteoarthritis, the inflammation is secondary, resulting from the degenerative process and joint irregularities. Systemic autoimmune rheumatic diseases are a group of chronic disorders characterized by diffuse inflammatory vascular lesions and degenerative changes in connective tissue that share clinical features and may affect many of the same tissues and organs. They include rheuma- toid arthritis, systemic lupus erythematosus, and sys- temic sclerosis, all of which share an immune-mediated pathogenesis. Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic autoimmune sys- temic disease that affects all ethnic groups throughout the world, with women being affected more frequently than men. The onset of the disease can occur at any age, but its peak incidence is between 50 and 75 years of age. 34 Etiology. Although the cause of RA remains uncer- tain, evidence points to a genetic predisposition and the development of joint inflammation that is immu- nologically mediated. 3,4,35 It has been suggested that the disease is initiated in a genetically predisposed individual by the activation of a T-cell–mediated ■■ Paget disease is a disorder involving excessive osteoclastic activity, and bone destruction and repair, resulting in structural deformities of the long bones, spine, pelvis, and cranium. Symptomatic disease may be manifest as skeletal changes and symptoms related to expansion of the skull, jaw, clavicle, spine, and long bones of the leg. Systemic Autoimmune Rheumatic Diseases

T-cell–mediated immune response

RF antigen/IgG interaction

Complement fixation

Cytokine production TNF, IL-1

Angiogenesis in synovium

Inflammatory response

Recruitment of inflammatory cells

Synovial proliferation

Release of enzymes and prostaglandins

Pannus invasion

Destruction of articular cartilage and underlying bone

FIGURE 44-5. Disease process in rheumatoid arthritis. IL, interleukin;TNF, tumor necrosis factor.

response to an immunologic trigger, such as a micro- bial agent (Fig. 44-5). The importance of genetic fac- tors in the pathogenesis of RA is supported by the increased frequency of the disease among first-degree relatives and monozygotic twins. 4 In addition, specific major histocompatibility complex (MHC) alleles or human leukocyte antigen (HLA) types have been asso- ciated with RA (see Chapter 15). An increased preva- lence of RA has been associated with specific HLA DR alleles that share a sequence of amino acids located in the antigen-binding site of the DR molecule. This location is presumably the specific binding site of the immunologic trigger. 3 Cigarette smoking is a strong risk factor for the development of RA and may also influence the severity of the disease, especially in those with the shared epitope (HLA-DR4 marker) and a positive anti-citrullinated peptide antibody (ACPA) test, to be discussed. 35,36 Pathogenesis. The pathogenesis of RA can be viewed as an aberrant immune response that leads to synovial inflammation and destruction of the joint architecture. It has been suggested that the disease is initiated by the activation of CD4 + helper T cells, the local release of inflammatory mediators and cytokines (e.g., tumor necrosis factor [TNF], interleukin [IL]-1) that destroy the joint, and formation of antibodies directed against joint-specific and systemic autoantigens. Approximately