The Rat Adjuvant Arthritis Is an Experimental Model of Rheumatoid Arthritis

Rheumatoid arthritis is a systemic inflammatory disorder that mainly affects the diarthrodial joint. It is the most common form of inflammatory arthritis and affects about 1% of the population, in a female/male ratio of 2.5/1. The disease can occur at any age, but it is most common among those aged 40 to 70 years. The geographic distribution of rheumatoid arthritis is worldwide, with a notably low prevalence in rural areas (Goodson and Symmons 2002; Reginster 2002). Although it initially presents as a symmetrical polyarticular synovitis with prominent hand involvement, rheumatoid arthritis has multiple potential systemic manifestations. The clinical course of the disorder is extremely variable, ranging from mild, self-limiting arthritis to rapidly progressive multisystem inflammation with profound morbidity and mortality. Fever and weight loss can be part of the acute symptoms, while splenomegaly, vasculitis, neutropenia, and amyloidosis are some of the disease's complications, which may occur in patients with long-standing disease (Bowman 2002; Reginster 2002; Youssef and Tavill 2002).

Rheumatoid arthritis is a T-cell-driven autoimmune process associated with the production of autoantibodies. Rheumatoid arthritis is initiated by CD4+ T cells, which amplify the immune response by stimulating other mononuclear cells, synovial fibroblasts, chondrocytes, and osteoclasts. The release of cytokines, especially TNF-a, IL-1, and IL-6, causes synovial inflammation. In rheumatoid arthritis the inflammatory process, usually tightly regulated by mediators that initiate and maintain inflammation and mediators that shut the process down, becomes imbalanced leaving inflammation unchecked and resulting in the destruction of cartilage and bone. The etiology of rheumatoid arthritis (RA) is not known. Genetic susceptibility involving the HLA system along with environmental factors play a role. It is possible that the environmental factors are infectious agents such as Epstein Barr virus, cytomegalovirus, mycoplasmas, and parvovirus, or a response to microbial products. RA is a chronic multisystem disease with inflammatory synovitis of the joints serving as a major feature. Besides the pain and swelling in joints, morning stiffness, fatigue, and generalized weakness may occur and the clinical course may be variable. Therapy may consist of nonsteroidal anti-inflammatory drugs, Cox-2-specific inhibitors, glucocorticoids, disease-modiftying antirheumatic agents, the TNF-neutralizing agents, and immunosuppressive and cytotoxic drugs. In most studies of RA, sleep disturbances are often associated with pain. However, disease activity may lead to the release of cytokines affecting multiple neurobiological mechanisms.

Efforts to develop safer and more effective treatments for rheumatoid arthritis rely heavily on the availability of suitable animal models (Bendele 2001). Among these models, the rat's adjuvant arthritis is widely employed (Whitehouse 1988). Hallmarks of this rat model are reliable onset and progression of easily measurable, polyarticular inflammation, marked bone resorption and periosteal bone proliferation. Induction of adjuvant disease can be done with either Freund's complete adjuvant (FCA) supplemented with mycobacterium or by injecting synthetic adjuvants (Bendele 2001; Whitehouse 1988). The pathogenesis for development of adjuvant disease following injection of mycobacterial preparations is not fully understood, although a cross-reactivity of mycobacterial wall antigens with cartilage proteoglycans occurs.

After FCA injection to rats, the inflammatory disease of the joints shows four stages in its time-course: preclinical (first week), acute (weeks 2 to 4), post-acute (weeks 5 to 8), and recovery (weeks 9 to 11) (Calvino, Crepon-Bernard, and Le Bars 1987). The preclinical stage of FCA arthritis (first week) is characterized by discrete radiological lesions of the forepaws and slight increase in the threshold for struggle triggered by foot pressure, presumably due to an impending, initially painless, stiffness.

The acute stage or arthritis (weeks 2 to 4) is defined by signs of hyperalgesia, lack of mobility and a pause in body weight gain; during the acute period, hindpaw and forepaw joint diameters increase (Calvino et al. 1987). In the later, acute, stages of disease (day 12+), adjuvant arthritis rats are often relatively immobile due to severity of paw swelling.

At day 18th, an increase in scratching behavior and signs of hyperalgesia are clearly established as compared with the adjuvant's vehicle-injected group. FCA arthritis is induced most easily in inbred Lewis rats; it is also produced, to a milder extent, in Wistar and Sprague-Dawley rats (Holoshitz, Matiau, and Cohen 1984; Knight et al. 1992; Pearson 1956; Stenzel-Poore, Vale, and Rivier 1993; Tanaka, Ueta, Yamashita, Kannan, and Yamashita 1996).

The use of the adjuvant's arthritis model offers an opportunity to study pathological changes in a variety of tissues other than the joints. Among these, central nervous system (CNS) changes are most relevant (Dantzer 2001; Johnson 2002; Larson 2002).

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Arthritis Relief Now

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