Etanercept + MTX

Team: Etanercept + MTX

Region: TNF Takedown

Base article: Weinblatt, M. E., et al. (1999). A trial of etanercept, a recombinant tumor necrosis factor receptor:FC Fusion protein, in patients with rheumatoid arthritis receiving methotrexate. New England Journal of Medicine, 340(4), 253–259. PMID: 9920948

Authors: University of Chicago Medical Center Rheumatology Fellowship Program. Michael Macklin, MD PharmD, 1st year rheumatology fellow; Lauren He, MD, chief resident; Hans Vitzthum von Eckstaedt, MD, 2nd year resident; Chelsea Thompson, MD, 1st year rheumatology fellow; John Byun, MD, 2nd year rheumatology fellow; Kichul Ko, MD, Assistant Professor of Medicine and Rheumatology Fellowship Program Director.

Team Overview

In the year 2000, what Vince Carter did for the All-Star Slam Dunk contest was what biologics did for Rheumatoid Arthritis (RA) management: completely redefined what we thought was even possible. The etanercept trial examining methotrexate (MTX) plus etanercept vs MTX alone for persistently active RA despite 6 months of first line therapy was one of the early trials confirming the efficacy and clinical utility of anti-tumor necrosis factor (TNF) therapy in RA. It also proved the safety of using a traditional disease-modifying antirheumatic drug (DMARD) in combination with a biologic DMARD to treat RA.

Before etanercept, no other targeted therapy was available. In fact, the anti-TNF drug class was the first of an ever-growing list of biologic and other targeted synthetic DMARDs used in the treatment of RA and other autoimmune diseases in our field today. This trial demonstrated that the combination etanercept/MTX therapy led to more patients obtaining improved outcome compared with MTX alone, and served as the basis for our current standard of care treatment – adding a biologic medication to the first line MTX when RA remains persistently active.

Impact on Rheumatology

This trial was a 24-week, double-blind placebo-controlled trial comparing combination MTX + etanercept to MTX + placebo. This trial demonstrated, for the first time, the superiority of etanercept (the first approved anti-TNF therapy in rheumatology) combined with MTX to the current standard of care in RA. Thus, it set the stage for the development of additional TNF inhibitors and further targeted therapies in a condition where the standard of care for resistant disease had stagnated for decades.

Similar to Vince’s “honey dip” dunk, it was likely hard to understand the significance and widespread implications of this moment. Compared with other early anti-TNF therapy trials, this study went beyond showing superiority of etanercept to placebo and provided evidence for the superiority of combination therapy vs MTX monotherapy. The downstream effects of the trial are seen in innumerable studies, historical and ongoing, which have looked at biologics such as anti-IL-6, anti-CD20, IL-17, and T-cell modulators (1,2,3). The treatment implications of this trial are still used in clinical practice today, again emphasizing the impact this had on one of our field’s most common diseases.

Chances in the Tournament

In TNF Takedown, we see the combination of etanercept and MTX as analogous to Michael Jordan and Scottie Pippen on the court: a dominant duo undefeated in Championship Series. Etanercept beat out infliximab to market, with our team showing superiority to standard of care therapy being more clinically useful than improvement over placebo overall, making us the TNF champ. Once we win the battle royale of the TNFs, we believe an exciting matchup would pitch our team against HCQ Withdrawal given the foundational nature of both in treating their respective diseases. Alternatively, the Origin of RA could provide an intriguing battle as the “fundamentals” can always pose challenges to “flashy” athleticism.

This year’s tournament has numerous strong teams. However, the pivotal influence of etanercept and MTX’s combination on both RA treatment and targeted therapy in rheumatology as a whole makes our team a top seed in the battle for rheumatologic supremacy.

Next scouting report: Infliximab for RA

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. Burmester GR, Rubbert-Roth A, Cantagrel AG, Hall S, Leszczynski P, Feldman D, Rangara MJ. A Randomized, Double-Blind, Parallel Group Study of the Safety and Efficacy of Tocilizumab SC Versus Tocilizumab IV, in Combination with Traditional Dmards in Patients with Moderate to Severe RA. Arthritis and rheumatism. 2012;64(Supplement 10):2545.
  2. Genovese MC, Durez P, Richards HB, Supronik J, Dokoupilova E, Mazurov V, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Annals of the rheumatic diseases. 2012 Epub 2012/06/26
  3. Kerschbaumer A, Sepriano A, Smolen JS, van der Heijde D, Dougados M, van Vollenhoven R, McInnes IB, Bijlsma JWJ, Burmester GR, de Wit M, Falzon L, Landewé R. Efficacy of pharmacological treatment in rheumatoid arthritis: a systematic literature research informing the 2019 update of the EULAR recommendations for management of rheumatoid arthritis. Ann Rheum Dis. 2020 Jun;79(6):744-759. PMID: 32033937; PMCID: PMC7286044.

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