Tumor necrosis factor alpha (TNFα) is the name given to a serum factor that was derived in 1975 from endotoxin-treated mice and found to be capable of inducing necrosis of a methylcholanthrene-induced murine sarcoma [1
]. The molecular characterization of TNFα in the 1980s revealed that it is identical to cachectin, a previously described serum factor that was found to be responsible for weight loss and fever in experimental animal models [2
]. The diverse biologic activities of TNFα soon became apparent. Aside from its tumoricidal property, it was recognized that, following injection into animals or humans, TNFα causes signs and symptoms of shock, including multi-organ damage via pro-inflammatory effects on vascular endothelium. The realization that TNFα may play a role in rheumatoid arthritis (RA) followed four demonstrations: firstly, its ability to degrade cartilage and bone in vitro
; secondly, its arthritogenic properties in animal models; thirdly, its co-localization with TNF receptors in RA synovium and the pannus-cartilage junction; and fourthly, its pivotal role in regulating the production of interleukin (IL)-1 in cultured RA-derived synovial cells (a mixture of lymphoid cells, macrophages, dendritic cells, B cells, endothelial cells, and fibroblasts) [4
Support for the role of TNFα in RA, and hence its promise as a therapeutic target candidate, came from the observation that the clinical signs and tissue damage of collagen-induced arthritis in mice were ameliorated by administration of a monoclonal anti-TNFα antibody [6
]. In 1992, 20 patients with active RA despite treatment with disease-modifying antirheumatic drugs were the first to be treated with an anti-TNFα agent, infliximab (Remicade®
, Centocor, Inc, Malvern, Pa). In this open-label clinical trial by our group at the Kennedy Institute of Rheumatology Division, the safety and marked anti-inflammatory effect of intravenously administered infliximab was associated with a dramatic reduction in C-reactive protein (CRP) and erythrocyte sedimentation rate [7
]. A multicenter, randomized, placebo-controlled trial in Europe quickly followed and confirmed the anti-inflammatory effect of a single intravenous infusion of infliximab [8
]. However, most patients relapsed within 3 to 8 weeks demonstrating the requirement for repeat therapy [9
]. The duration of benefit before relapse was related to the size of the drug dose (1 or 10 mg/kg).
The efficacy and optimal dose of infliximab, as well as an enhanced therapeutic efficacy when coadministered with methotrexate (MTX), was subsequently established in a follow-up, randomized, controlled clinical trial [10
]. The consistency of a sustained therapeutic clinical response in long-term treatment (2 years) with infliximab plus MTX under double-blinded, placebo-controlled conditions has now been demonstrated in the international, multicenter Anti-Tumor necrosis factor Trial in Rheumatoid Arthritis with Concomitant Therapy (ATTRACT) [12
]. Patients were randomized to receive either four dose schedules of infliximab plus weekly doses of MTX (median dose 15 mg/wk) or MTX alone. Serial radiographs performed at 24, 54, and 102 weeks of this trial have revealed retardation or arrest (and even improvement in 39% to 54% of patients) of both joint space narrowing (which equates with cartilage loss) and bone erosion. These results are in contrast to the progressive damage in the control group of patients who were treated with MTX alone [12
]. These data are consistent with the hypothesis that TNFα plays a key role in the perpetuation of inflammation and destruction of cartilage and bone in RA.