Currently, MTX is the most widely used disease-modifying antirheumatic drug for the treatment of RA. However, MTX treatment rarely results in complete disease remission [15
] and only slows the progression of joint erosion [16
]. In addition, long-term treatment with MTX is associated with pulmonary [17
] and liver toxicities [18
] and other side effects. Therefore, a treatment option that facilitates reversal of joint damage and has longer effectiveness and fewer side effects is desirable.
Experimental arthritis models have contributed to the basic understanding of joint disease and to the development of effective antiarthritic agents [19
]. Several models have been used to mimic human RA, ranging from immunization with cartilage components to infection with joint trophic organisms [20
]. Blocking TNF-α [6
] or IL-1 [23
] in these models has routinely shown benefit, although some questions remain regarding the role of these cytokines in mitigating joint inflammation versus preventing cartilage degradation and bone erosion [25
Using the Tg197 mice, we have shown that maintenance anti-TNF-α therapy, initiated after joint inflammation and erosions have occurred, allows damaged joints to heal. Specifically, anti-TNF-α mAb proved equally effective in reversing joint synovitis and erosions both in young mice, where an active repair process to damage occurs, and aged mice, where the repair process has relatively slowed. However, the repair of cartilage damage was different between young and aged mice. Cartilage in young mice treated with anti-TNF-α was significantly improved relative to saline-treated and baseline mice. By comparison, treatment of aged mice with anti-TNF-α prevented further cartilage damage but did not improve histological scores relative to baseline values. Mechanistically, the therapeutic effect of anti-TNF-α appears to be due to either neutralization of soluble hTNF-α or inhibition of hTNF-α production in the diseased joint. Additionally, other proinflammatory cytokine mRNAs were decreased in the local diseased tissues either through suppression of inflammatory cell infiltration or inhibition of cytokine production. Moreover, anti-TNF-α treatment resulted in a modest inhibition of murine IL-1β production in the diseased joint, which is consistent with previous findings that anti-TNF-α antibody inhibits the generation of IL-1 in collagen-induced arthritis and IL-1, IL-6, and IL-8 in rheumatoid synovial cultures [26
]. Our study provides preclinical evidence supporting the use of anti-TNF-α mAb in ameliorating arthritic pathology.
The progressive arthritis observed in Tg197 mice is similar to the pathology in patients with RA. Recent clinical data indicate that the blockade of TNF-α significantly reduces the signs and symptoms of RA [28
]and inhibits the progression of structural damage [30
]. It remains to be seen whether extended anti-TNF-α therapy might permit regeneration of articular cartilage and bone in established human disease, where multiple etiological pathways may contribute to the RA disease syndrome [32
]. Nevertheless, it is likely that much of the RA pathology involves TNF-α activation, and the results from the Tg197 model provide a sound scientific rationale for the therapeutic benefits observed following anti-TNF-α treatment in RA patients.