Team: TEAR Triple Rx, aka “FEAR THE TEAR.”
Region: RA Revamp
Authors: UT Southwestern Rheumatology Fellowship Program. Avni Amratia, MD, first year rheumatology fellow; Kubra Bugdayli, MD, second year rheumatology fellow; Yusuf Chao, MD, second year rheumatology fellow; Prajwal Dara, MD, first year rheumatology fellow; Omkar Dhamankar, MD, first year rheumatology fellow; Joad Eseddi, MD, second year rheumatology fellow; Nagendra Pokala, MD, second year rheumatology fellow; James Roberts, MD, first year rheumatology fellow; Bonnie Bermas, MD, Professor of Medicine; Haidy Galous, MD, Assistant Professor of Medicine; Swathi Reddy, MD, Assistant Professor of Medicine; Andreas Reimold, MD, Professor of Medicine; Andres Guillermo Quiceno, MD, Associate Professor of Medicine
Team Overview
Oral disease modifying anti-rheumatic drugs (DMARDs) have long been the foundation of rheumatoid arthritis (RA) therapy, with methotrexate as the cornerstone. American College of Rheumatology guidelines recommend initial treatment of RA patients with methotrexate monotherapy with the addition (“step-up”) of hydroxychloroquine and sulfasalazine for refractory disease. The combination of these three medications is called “triple therapy.” In 1998, the superstar kid on the block was etanercept, the first TNF-inhibitor to be approved by the FDA for the treatment of moderate to severe RA. Etanercept revolutionized RA therapy for those patients who failed the typical game plan. Subsequent TNF-inhibitors were developed and most often prescribed in conjunction with methotrexate (double therapy). The dramatic response to TNF-inhibitors led many physicians to move from using it as a “Hail Mary” to the belief that TNF-inhibition plus methotrexate must be superior to triple therapy. However, there were no head-to-head trials to evaluate this supposition. The TEAR trial was a randomized double-blind controlled study specifically designed to answer this question: the triple-double so to speak. Additionally, since traditional RA treatment started with methotrexate monotherapy with subsequent step-up to combination treatment, it was unknown whether immediate combination therapy upfront (a kind of full court press) would be more effective than a step-up approach in controlling disease activity, preventing functional limitations, and limiting radiographic progression.
The study included players with early (<3 years) and active (at least 4 swollen and 4 tender joints) disease who met 1987 ACR criteria for RA. Players were biologic naïve and had previously received no more than 2 months of hydroxychloroquine or sulfasalazine. The study was performed in a 2×2 factorial design with 4 treatment arms: (1) immediate treatment with methotrexate (MTX) and etanercept (ETN); (2) immediate treatment with triple therapy; (3) step up from MTX to MTX+ETN if DAS28-ESR ≥3.2 at week 24; and (4) step up from MTX to triple therapy if DAS28-ESR ≥3.2 at week 24. Matching placebos were used. All players, coaches, and referees were blinded throughout the 2-year study period. The primary outcome was DAS28-ESR between weeks 48 and 102. At week 24, of the two step-up groups, a high field goal percentage (28%) of players achieved DAS28-ESR <3.2 on methotrexate monotherapy and did not require step-up in therapy; in comparison, DAS28-ESR <3.2 was achieved by a greater proportion of players randomized to immediate combination therapy with either MTX+ETN (41%) or triple therapy (43%). The immediate treatment groups also had a larger reduction in DAS28-ESR at week 24 compared to the step-up groups. However, by week 48, the mean DAS28-ESR was similar in all groups.
The primary outcome was similar between all groups. Around 56% of all players achieved remission by DAS28-ESR, with no significant difference among the four groups. There was also no significant difference in rate of remission based on timing (step-up versus immediate combination) or type of medication received. There were no major differences across treatment groups in terms of adverse events or serious adverse events.
Impact on Rheumatology
The TEAR trial remains one of the most elegantly designed RCTs in RA and to this day shapes the winning strategy for the treatment of RA patients. This trial established that methotrexate alone can be a superstar against RA, leading to a low disease activity in a considerable portion of patients. If methotrexate alone is not enough to slow down RA, both etanercept (the expensive free agent) and triple therapy (the affordable veteran) are viable co-stars. Triple therapy is an excellent option for patients who prefer oral medications, cannot perform injections at home, have contraindications to or cannot afford biologics. Additionally, this strategy may limit excessive early medication (and salary cap) burden. Finally, although immediate combination therapy may lock down active disease faster, by week 48 both strategies had similar results. For this reason, initial methotrexate monotherapy with step-up therapy for continued active disease is a reasonable option.
Chances in the Tournament
The TEAR Trial is undoubtedly in the running for G.O.A.T status. The final score in the first round could come down to the buzzer depending on the matchup. BeST is a misnomer and would be blown away by the sheer number of players on TEAR. If the TICORA trial “steps-up” to the second round, it might be a “tight” matchup. Ultimately, as a first-tier RA trial, TEAR should easily make the final four. After that it’s anyone’s tournament: FEAR THE TEAR!
Next scouting report: BeSt Trial
Back to the full list of scouting reports.
See the Q&A on theMednet.org for the RA Revamp Region: What target do you utilize in clinical practice for defining disease remission in RA?
References
- Moreland LW, Baumgartner SW, Schiff MH, Tindall EA, Fleischmann RM, Weaver AL, et al. Treatment of rheumatoid arthritis with a recombinant human tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med. 1997;337(3):141–7.
- Smolen JS, Van Der Heijde DM, St Clair EW, Emery P, Bathon JM, Keystone E, et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum. 2006;54(3):702–10
- Nurmohamed MT, Dijkmans BA. Are biologics more effective than classical disease-modifying antirheumatic drugs? Arthritis Res Ther. 2008;10(5):118
- Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, van Zeben D, Kerstens PJ, Hazes JM, Zwinderman AH, Ronday HK, Han KH, Westedt ML, Gerards AH, van Groenendael JH, Lems WF, van Krugten MV, Breedveld FC, Dijkmans BA. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum. 2005 Nov;52(11):3381-90. doi: 10.1002/art.21405. PMID: 16258899.
- Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, et al. Effect of a treatment strategy of tight control for rheumatic arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364:263–9.
