Antiarthritic activity of soluble tumor necrosis factor receptor type I forms in adjuvant arthritis: Correlation of plasma levels with efficacy

Objective, To determine the importance of tumor necrosis factor (TNF) in th e pathogenesis of adjuvant disease in rats and to determine plasma levels o f recombinant soluble TNF receptor type I (sTNF-RI) necessary for efficacy, to project dosing for human clinical trials. Methods. Rats with adjuvant arthritis were treated by continuous infusion w ith sTNF-RI forms to maintain blood levels of this TNF-alpha inhibitory pro tein. Tn addition, rats were given bolus injections of polyethylene glycol linked sTNF-RI and efficacy and plasma levels were determined. Effects of t reatment in the rats were monitored by sequential volume or diameter measur ement of ankle joints, final paw weights, and histologic evaluation of ankl e joints, with particular emphasis on bone erosive lesions. Results, In all studies and regardless of dosing methodology (bolus vs cont inuous infusion), minimal plasma levels for efficacy were in the 0.3-0.5 mu g/ml range. Higher plasma levels resulted in greater efficacy, with maxima l effects achieved when plasma levels were in the 5 mu g/ml range. Benefici al effects of treatment were seen on body weight, paw swelling, splenomegal y, hepatomegaly, and bone resorption. Conclusion. TNF-alpha is an important mediator of all aspects of rat adjuva nt disease including both the destructive processes in the joints as well a s the systemic manifestations of adjuvant disease. Studies using various fo rms of sTNF-RI consistently show that plasma levels of 0.3-0.5 mu g/ml are required for minimal efficacy and that higher plasma levels show dose-respo nsive enhanced efficacy.