Treatment of Rheumatoid Arthritis with a Recombinant Human Tumor Necrosis Factor Receptor (p75)-Fc Fusion Protein

Larry W. Moreland, Scott W. Baumgartner, Michael H. Schiff, Elizabeth A. Tindall, Roy M. Fleischmann, Arthur L. Weaver, Robert E. Ettlinger, Stanley Cohen, William J. Koopman, Kendall Mohler, Michael B. Widmer, Consuelo M. Blosch

Abstract

Background. Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. This study evaluated the safety and efficacy of a novel TNF antagonist -- a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc).

Methods. In this multicenter, double-blind trial, we randomly assigned 180 patients with refractory rheumatoid arthritis to receive subcutaneous injections of placebo or one of three doses of TNFR:Fc (0.25, 2, or 16 mg per square meter of body-surface area) twice weekly for three months. The clinical response was measured by changes in composite symptoms of arthritis defined according to American College of Rheumatology criteria.

Results. Treatment with TNFR:Fc led to significant reductions in disease activity, and the therapeutic effects of TNFR:Fc were dose-related. At three months, 75 percent of the patients in the group assigned to 16 mg of TNFR:Fc per square meter had improvement of 20 percent or more in symptoms, as compared with 14 percent in the placebo group (P<0.001). In the group assigned to 16 mg per square meter, the mean percent reduction in the number of tender or swollen joints at three months was 61 percent, as compared with 25 percent in the placebo group (P<0.001). The most common adverse events were mild injection-site reactions and mild upper respiratory tract symptoms. There were no dose-limiting toxic effects, and no antibodies to TNFR:Fc were detected in serum samples.

Conclusions. In this three-month trial TNFR:Fc was safe, well tolerated, and associated with improvement in the inflammatory symptoms of rheumatoid arthritis. (N Engl J Med 1997;337:141-7.)

Source Information

From the University of Alabama at Birmingham, Birmingham (L.W.M., W.J.K.); the Physician's Clinic of Spokane, Spokane, Wash. (S.W.B.); the Denver Arthritis Clinic, Denver (M.H.S.); Portland Medical Associates, Portland, Oreg. (E.A.T.); the Metroplex Clinical Research Center, Dallas (R.M.F., S.C.); the Arthritis Center of Nebraska, Lincoln (A.L.W.); Tacoma, Wash. (R.E.E.); and Immunex Corporation, Seattle (K.M., M.B.W., C.M.B.). Address reprint requests to Dr. Moreland at the Arthritis Clinical Intervention Program, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, 1717 6th Ave. S., Rm. 068, Birmingham, AL 35294-7201.