Etanercept for RA

Team: Etanercept for RA

Region: TNF Takedown

Base Article: Moreland LW, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997 Jul 17;337(3):141-7. PMID: 9219699.

Authors: Ohio State University Rheumatology Fellowship Program: Jesse Reisner, DO, second year rheumatology fellow; Catherine Strahle, DO, second year rheumatology fellow; Jasmine Thai, MD, first year rheumatology fellow; Cristina Hurley, MD, first year rheumatology fellow.

Topic Overview

This article describes a multicenter, randomized, double-blind, placebo-controlled trial studying the efficacy of the then-novel recombinant human TNFR p75-Fc fusion protein (TNFR:Fc, or etanercept) in patients with rheumatoid arthritis who had previously failed other conventional synthetic disease-modifying antirheumatic drugs.  There was little known about the potential efficacy of the TNFR:Fc in RA before the trial.  While the role of TNF-alpha in the pathogenesis of RA was suspected and previous trials studying human monoclonal antibodies targeting TNF-alpha had shown benefit in RA, this was the first randomized clinical trial evaluating the use of TNFR:Fc.  In fact, the authors cite the 1996 safety & dose-finding study by Moreland, et al, which showed reduction in disease activity in a small number of patients with refractory RA, as the inspiration for their trial.

Patients were randomly assigned to one of four different treatment groups: TNFR:Fc twice weekly at a dose of 0.25mg per square meter of BSA, 2mg per square meter, 16mg per square meter, and a placebo group.  The primary endpoint was the percentage change in swollen and tender joint count from baseline to 3 months.  The group receiving TNFR:Fc achieved a significantly greater reduction in the number of swollen and tender joints, when compared to the placebo group. There was a linear dose response, demonstrating that those who received higher doses of the drug had greater improvement in measures of disease activity.  By contrast, the placebo group showed an initial improvement only through week two, then no improvement thereafter.  TNFR:Fc was found to be safe at all doses administered, with mild injection site reactions and mild URIs, but no serious adverse events.  In summary, the trial demonstrates significant dose-related positive outcomes, and an acceptable safety profile, with the use of TNFR:Fc in patients with refractory RA.

Impact on Rheumatology

This article was crucial in triggering the biologic renaissance in rheumatology. Etanercept became the first targeted biologic therapy to be approved by the FDA for rheumatoid arthritis in 1998 and later the first TNF-alpha inhibitor to be approved for juvenile idiopathic arthritis and ankylosing spondylitis.

Since the approval of etanercept, it would be an understatement to say that the treatment of rheumatic diseases has been transformed. In the last two decades, multiple alternative TNF-alpha inhibitors have been subsequently approved for a wide range of autoimmune diseases. For patients, this renaissance has generated dramatic improvement in disease control, quality of life, and decreased morbidity. The study was one of the first to demonstrate the feasibility of studying biologic medications for the treatment of rheumatic conditions, thereby catalyzing the expansion of our arsenal for the treatment of rheumatic diseases.

Chances in the Tournament

Although a drug derived from hamster ovaries may not sound intimidating, we expect etanercept to live up to its title as the first biologic approved for RA with victories in the first 2 rounds. Some may argue that combination therapy will triumph, as two is better than one. But who wants to take multiple medications? Not us! A matchup with the TEAR trial in the 3rd round could prove to be a close contest and etanercept will need to put on a clinic in order to send their opponent home. Either way, we are excited to see if this TNF could prove to be the ALPHA for the 2023 tournament.

Next scouting report: Etanercept + MTX

Back to the full list of scouting reports.

See the Q&A on for the TNF Takedown Region: Do you use conventional DMARDs aside from methotrexate to prevent anti-drug antibody development for patients on infliximab?


  1. Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, Ettlinger RE, Cohen S, Koopman WJ, Mohler K, Widmer MB, Blosch CM. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997 Jul 17;337(3):141-7. doi: 10.1056/NEJM199707173370301. PMID: 9219699.
  2. Moreland LW, Margolies G, Heck LW Jr, et al. Recombinant soluble tumor necrosis factor receptor (p80) fusion protein: toxicity and dose finding trial in refractory rheumatoid arthritis. J Rheumatol 1996;23:1849-1855

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