Author Archives: David Leverenz

BeSt

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Team: BeSt, aka “The BeSt Rheumatology Study”

Region: RA Revamp

Base article: Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. 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;52(11):3381-3390. doi:10.1002/art.21405 

Authors: Medical University of South Carolina Rheumatology Fellowship. Jake Altier, MD, 1st Year Fellow, M; Lauren Berry, MD, 1st Year Fellow; Sean Carter, MD, 2nd Year Fellow; Bradley Collins, DO, 2nd Year Fellow; Jessica English, MD, 2nd Year Fellow; Rachael Werner, MD-PhD, 1st Year Fellow; Faye Hant, DO, MSCR, Professor of Medicine

Team Overview

Our team truly deserves to be named BeSt in Bracket! Prior to the BeSt study, there had been evidence that early more aggressive treatment of Rheumatoid Arthritis (RA) was likely superior to prior, more defensive based strategies. It was not known yet, however, which “offensive” aka preventative strategy in early disease was best. Combination therapy and use of biologics had been shown to slow progression of joint damage more than DMARD monotherapy. It is in the BeST study, our all-star pick, that this was better clarified as this multicenter randomized control trial compared clinical and radiographic outcomes of 4 different treatment strategies to evaluate the optimal strategy for preventing long term joint damage and functional decline in rheumatoid arthritis.

508 patients from the Netherlands with early rheumatoid arthritis (defined by the 1987 ACR criteria – duration of 2 years or less, age over 18, and active disease with 6+ swollen joints, 6+ tender joints, and either ESR >28mm/hour or global health score greater than 20) were allocated to 1 of 4 treatment strategies: sequential disease-modifying antirheumatic drug monotherapy (group 1), step-up combination therapy starting with methotrexate and adding other conventional DMARDs if insufficient (group 2), initial combination therapy of methotrexate and sulfasalazine with tapered high-dose prednisone (group 3), and initial combination therapy methotrexate with the tumor necrosis factor antagonist, infliximab (group 4). Treatment adjustments were made every 3 months based on DAS44. If low disease activity (of £ 2.4) was not reached, therapy would be adjusted per the pre-determined treatment protocol. Results after intention to treat analysis showed that initial combination therapy (methotrexate and sulfasalazine) with prednisone (Group 3) or methotrexate and infliximab (Group 4) resulted in earlier functional improvement and less radiographic damage after 1 year than either (Group 1) sequential monotherapy or (Group 2) step-up combination therapy. A fast break down the court as opposed to a leisurely pass inbound may clearly be the best offensive strategy against the hard pressing disease that is erosive rheumatoid arthritis.

Impact on Rheumatology

Besides being the BeST trial, our trial made waves in the field of rheumatology by proving that the best defense against joint damage is often an aggressive offense. Our study changed the way providers treat rheumatoid arthritis by showing improvement in patient functionality and reduced joint damage radiographically with initiation of combinations of multiple csDMARDs or TNFi +csDMARD therapy at diagnosis and highlights the importance of having a treat to target gameplan. This strategy opposed the slow titration of monotherapy approach used for RA at the time. Not only did the BeST trial revolutionize treatment for providers, but it also had huge implications for patient care by inhibiting joint damage progression without jeopardizing patient safety. The importance of the BeSt trial in our field cannot be outdone – it trailblazed and transformed the approach to early RA treatment.

Chances in the Tournament

The BeST Study opens the tournament against the Ticora trial in Rheumatoid Arthritis. Both teams came into play around the same time with the goal of hitting hoops hard and early from the start of the game. The BeSt study, as the name implies, was called into play to assess clinical and radiographic outcomes of various treatment strategies. The TiCora trial, on the other hand, passed up on some star players, like infliximab, the team captain of the BeSt study, with a similar plan of action in mind – looking at a stepwise approach in training to target objective measures.

The BeSt Study’s future in the tournament lies within its team captain, Infliximab, which the TiCora trial could not recruit in time. Having Infliximab’s skills and participation set our team apart from the TiCora Trial and helps unite and enhance our scoring ability. The TiCora study may try to undermine and break up our defense, but they likely overlooked that we also applied interval retraining and practice with optimization of treatment strategies based on objective data, similar to a ”treat to target” approach, one could say.   While there is not a clear training strategy that the BeSt Study recommends, our focus has been a cohesive and early interdisciplinary training with emphasis on treating to a target, which remains the foundational pillar in the offense against all rheumatic conditions.

Next scouting report: TICORA 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

  1. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. 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;52(11):3381-3390. doi:10.1002/art.21405
  2. Grigor C, Capell H, Stirling A, McMahon AD, Lock P, Vallance R, Kincaid W, Porter D. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004 Jul 17-23;364(9430):263-9. doi: 10.1016/S0140-6736(04)16676-2. PMID: 15262104.

TEAR Triple Rx

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Team: TEAR Triple Rx, aka “FEAR THE TEAR.”

Region: RA Revamp

Base article: Moreland LW, O’Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012;64(9):2824-2835. doi:10.1002/art.34498. PMID: 22508468

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

  1. 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.
  2. 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
  3. Nurmohamed MT, Dijkmans BA. Are biologics more effective than classical disease-modifying antirheumatic drugs? Arthritis Res Ther. 2008;10(5):118
  4. 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.
  5. 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.

Infliximab for RA

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Team: Infliximab for RA, aka “Flexing our way in with Infliximab”

Region: TNF Takedown

Base article: Maini R, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999 Dec 4;354(9194):1932-9. PMID: 10622295.

Authors: University of California San Diego Rheumatology Fellowship Program. Rashmi Dhital, MBBS, second year rheumatology fellow; Neha Singh, DO, first year rheumatology fellow; Manmeet Kaur, MD, first year rheumatology fellow; Brian A. Pedersen, MBBS, Rheumatologist, Assistant Professor of Medicine; Arthur Kavanaugh, MD, Rheumatologist, Professor of Medicine

Team Overview

Imagine a world of rheumatoid arthritis (RA) with only methotrexate (MTX) and no tumor necrosis factor alpha inhibitors (anti-TNFα). Yup, it’s like being on the bubble on Selection Sunday. The first anti-TNFα to have ever been trialed in human patients with RA and the first anti-TNFα to have obtained FDA approval in any disease was infliximab, a drug we proudly share on the court with our gastroenterology colleagues.

Before the publication of the ATTRACT Trial, MTX had become a standard disease-modifying antirheumatic agent (DMARD) for the treatment of RA. But many patients did not respond to treatment with MTX or other agents available at the time (e.g. sulfasalazine, hydroxychloroquine, gold injections),1 either alone or in combination. TNFα was increasingly being recognized as a key, central inflammatory mediator in RA based on ex vivo analyses showing that neutralization of TNFα in vitro reduced the production of other pro-inflammatory cytokines (e.g. IL-1), leading to a novel concept of affecting multiple cytokines through a single cytokine blockade. After demonstration of notable improvement in arthritic mice, a chimeric human-murine monoclonal antibody was genetically engineered to create what we know now as infliximab.2 The first trial of an anti-TNFα in RA using this novel agent was conducted in 1992 and proved to be successful with demonstrable clinical and serological improvements.3 This led to a paradigm shift in the use of biologics with far-reaching influence beyond RA as companies refocused their efforts from sepsis and put the full-court press into anti-TNFα therapy for RA and other inflammatory diseases such as Crohn disease and psoriasis.

Shortly thereafter, investigators began to fiddle with the concept of MTX and Infliximab combination therapy. Our base article highlights the results of the ATTRACT trial, which enrolled 428 from 37 international centers from 1997 – 1998, was a large multinational study that paved way for what has now become the standard for conducting clinical trials.4 This phase III trial comparing infliximab to placebo in patients already on MTX was a game changer.

Implications

Now what makes our article an all-star? Patients enrolled in this trial had advanced and recalcitrant disease, as evidenced by mean duration of 7.2 to 9.0 years, significant disease activity with failure of over three DMARDs and incomplete response to methotrexate at a median dose of 15 mg/week (range 10–35), and a history of joint surgery in 1/3 of patients. Over 72% of the patients were receiving ≥ 15mg MTX weekly! Despite enrolling very severe and active patients, the primary endpoint as measured by ACR-20 response at 30 weeks was met with even the lowest dose 3mg/kg q8 weeks. This dosing is still being followed to this day. In addition, this article provided reassurance surrounding the low immunogenicity of the chimeric antibody in combination with MTX eventually leading to its FDA approval for RA in combination with MTX in 1999. Not only did the ATTRACT trial prove the efficacy of infliximab as measured by ACR 20 response, but it also showed that infliximab therapy halted radiographic progression of disease (the findings later published in NEJM in 2000).5 This was quite impressive considering that there was no evidence of MTX or other DMARDs doing this despite being called “disease modifying.” We can say that this trial was the first to use x-ray vision to assess disease response and monitor disease progression in the TNF realm!  After over two decades of anti-TNFs, they still remain on the forefront of therapy for RA with a well-established efficacy/safety profile.

Chances in the Tournament

Like a slam dunk in the paint, we feel infliximab is the most ATTRACTive option! With infliximab, we have an infusion option (which neither MTX nor etanercept offers!) and dose flexibility (several effective doses and frequencies recognized as early as in this trial: 3-10 mg/kg every 4-8 weeks). This means ease for patients who have difficulty self-administering injections and difficulty with medication adherence—a benefit for both providers and patients. Infliximab remains an ATTRACTive anti-TNFα option among rheumatologists (as the trial name suggests!) and deserves another “One Shining Moment.”

Next scouting report: TEAR Triple Rx

Back to the full list of scouting reports.

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

References:

  1. O’Dell JR, Haire CE, Erikson N, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med. 1996;334(20):1287-1291. doi:10.1056/NEJM199605163342002
  2. Knight DM, Trinh H, Le J, et al. Construction and initial characterization of a mouse-human chimeric anti-TNF antibody. Mol Immunol. 1993;30(16):1443-1453. doi:10.1016/0161-5890(93)90106-l
  3. Elliott MJ, Maini RN, Feldmann M, et al. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum. 1993;36(12):1681-1690. doi:10.1002/art.1780361206
  4. Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet Lond Engl. 1999;354(9194):1932-1939. doi:10.1016/s0140-6736(99)05246-0
  5. Lipsky PE, van der Heijde DM, St Clair EW, et al. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med. 2000;343(22):1594-1602. doi:10.1056/NEJM200011303432202

Etanercept + MTX

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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 theMednet.org for the TNF Takedown Region: Do you use conventional DMARDs aside from methotrexate to prevent anti-drug antibody development for patients on infliximab?

References

  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.

Etanercept for RA

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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 theMednet.org for the TNF Takedown Region: Do you use conventional DMARDs aside from methotrexate to prevent anti-drug antibody development for patients on infliximab?

References:

  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

The All Star Season Begins on Feb 22, 2023

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The All Star Season is almost here! Here’s the timeline:

  • On Wednesday, February 22, we will reveal the 22 teams in the bracket and release scouting reports reviewing each team in the tournament. This year, the scouting reports were authored by 131 collaborators from 19 fellowship programs and 2 private practice groups, including 79 fellows, 41 faculty, 5 residents, and 6 medical students. What an amazing collaboration!
  • For those of you in training programs or other groups, consider using these scouting reports and their associated base articles for a journal club or didactic session.
  • Along with the scouting reports, we will release new RheumMadness podcast episodes where we dive deeper into each team and interview the authors of the scouting reports about why they think their team will win. The RheumMadness podcast series is available on all major podcasting apps.
  • You can submit your brackets anytime between Wednesday, February 22 and Wednesday, March 22, 2023.  That means you have 4 WEEKS to learn about the teams and make your picks.
  • Submitting a bracket is FREE and easy. We will provide detailed instructions to submit your brackets when the tournament begins.
  • Results from each round of the tournament will be announced as follows:
    • Thursday, March 23: Round 1 (Round of 22)
    • Saturday, March 25: Round 2 (The Seronegative Sixteen)
    • Monday, March 27: Round 3 (The Entheseal Eight)
    • Saturday, April 1: Round 4 (The IgG Four)
    • Monday, April 3: Round 5 (the Interleukin Two, AKA the finale)

RheumMadness on theMednet!

The RheumMadness team is excited to announce a collaboration with theMednet.org for our 2023 tournament. theMednet is a physician only site providing a space for physicians to tackle difficult clinical questions and see how colleagues are practicing. theMednet will be featuring select Q&A relevant to articles in our 2023 tournament and will provide a space for further discussion and polling around clinical application. Register here for a free account with full access to the theMednet site and find RheumMadness content!

Scouting Report Archive

Looking to find your favorite scouting report from a prior year?  See links below.

2022: Click here to access the bracket and scouting reports from RheumMadness, Planet of the Rheumatologists

2021: Click here to access the bracket and scouting reports from the first season of RheumMadness

Leadership Team 2022 – 2023

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Meet the leadership team tasked with creating the 2022 – 2023 tournament.

Faculty Leadership

  • David Leverenz, MD is the creator and director of RheumMadness.  He is an Assistant Professor of Medicine at Duke University School of Medicine, Department of Medicine, Division of Rheumatology and Immunology.
  • Akrithi Udupa Garren, MD is an Assistant Professor of Medicine at Medstar / Georgetown Washington Hospital Center.

Fellow Leaders

  • Guy Katz, MD is a rheumatology fellow at Massachusetts General Hospital.
  • Michael Macklin, MD is a rheumatology fellow at the University of Chicago.
  • Iman Qaiser, MD is a a rheumatology fellow at LSU Health Shreveport.

Resident Leaders

  • Lauren He, MD is a chief resident at the University of Chicago.
  • Ben Kellogg, MD is an internal medicine resident at Duke University.
  • Sabahat Usmani, MD is an internal medicine resident at Weiss Memorial Hospital in Chicago

Medical Student Leaders

  • Courtney Bair is a medical student at Duke University School of Medicine.
  • Meridith Balbach is a medical student at Vanderbilt University Medical Center.
  • Ben Lueck is a medical student at Duke University School of medicine.

Senior Mentorship Team

  • Lisa Criscione-Schreiber, MD, MEd is an advisor and mentor for RheumMadness. She is a Professor of Medicine at Duke University School of Medicine, Department of Medicine, Division of Rheumatology and Immunology.
  • Matthew Sparks, MD is the creator of NephMadness and serves an advisor and mentor for RheumMadness. He is an Associate Professor of Medicine at Duke University School of Medicine, Department of Medicine, Division of Nephrology.

Write a Scouting Report!

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Welcome back to RheumMadness, the place for everyone who is crazy about rheumatology to connect, collaborate, compete, and learn together.

Our theme for the 2023 tournament is RheumMadness: The All Star Season. This season, we will focus on the foundational science that has driven our field to where it is today. Each of the 16 teams in the tournament will represent one “all star” article competing to be named the most important and transformational article ever written in the field of rheumatology.

Apply to write a scouting report!

If you love RheumMadness, please consider applying to write one of the scouting reports for this year’s tournament. This year, we are taking the scouting reports to a whole new level by allowing the scouting report authors to choose their own team.

***Click here to submit your application (link to Qualtrics Survey)***

Here’s what we need in your application:

  1. The names and affiliations of all collaborators in your group who will write the scouting report. We recommend having at least 3 people in your group.
  2. The article that you would like to write about. The article must have been published at least 10 years ago (before 2013), and your group must not include any of the authors on the paper.

Deadline to apply: September 28 at 1:00 pm Eastern Time.

Anyone is welcome to apply to write a scouting report. We welcome applications from fellowship programs, community rheumatology practices, medical student interest groups, or even just a group of friends who share a passion for rheumatology.  In addition, if you’d like to help with a scouting report but you don’t have a group to work with, please email us!  We’d be happy to get you involved.  We are looking forward to a fantastic and fun season filled with collaborative learning about the best specialty in the world.

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We Have a Winner!

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The final round of the RheumMadness tournament is complete, and the winner is…

Reproductive health guide was an underdog in this matchup, with 13% of participants picking it to win compared to 26% of participants who picked the juggernaut CAR-T cells.

However, the Blue Ribbon Panel felt differently, voting for Repro health guide in a 6 to 1 landslide. We are sure this won’t be controversial at all!

After the dust settled, the winning brackets in each category are: 

Congratulations to our winners! To see the final results of your bracket, head over to the Tourneytopia website.

Comments from the Panel

By popular demand, we have collected anonymous comments from our fabulous Blue Ribbon Panel about their experience on the panel and why they made the choices they did. Just in case anyone has anything they’d like to say to the panel, you can find each of their Twitter handles on the Blue Ribbon Panel page.

Comment 1: “As a member of the #RheumMadness 2022 Blue Ribbon Panel, my aim was to focus on impact. To me, that means papers that change how we approach a disease, a test, or a treatment. As a pediatric rheumatologist, I was thrilled to see that a paper that focused on pediatric rheumatology made it to the big dance. I voted for ideas or approaches that push us forward as a field, even if they are still works in progress. I was so impressed by the work the teams put into the scouting reports- they definitely worked hard to box out the other teams in the paint. I voted for the increasing positive ANA study, even though it didn’t make it out of the first bracket. I think understanding the relationship between positive autoantibodies, background prevalence of autoantibodies, and autoimmunity will be important moving forward. I learned a lot, had a blast following the competition, and will definitely be back next year to join in the tourney.”

Comment 2: “My dark horse in this race was Axolotl Limbs. I was pulling hard for these amazing amphibians. The more I read about how axolotls regenerated of cartilage, the more I could see the substantial impact leveraging this would have for millions (maybe billions?) of people. All in all, the close votes we have seen the BRP voting really highlight some of the subtle differences in what we individually value as important. For example, is more certain short-term gain more important than high possible (i.e. unrealized) long-term potential? That’s why we play folks!”

Comment 3: “I loved the opportunity to read the base articles as a panel member! I voted NOW over FUTURE, for collaborative efforts, and for tools and knowledge that are broadly applicable. I voted pragmatic over theoretical. My kids tell me this is “adulting” and it makes me boring. Oh well.

I voted for NETs. They are everywhere. Gout and COVID are just the beginning. CAR-T cells are in the future, one great case can’t be the winner. I went with the masses on DECT. Distinguishing between OA, crystal disease and SN disease is one of the hardest things we do. It lacks the luster of distorted vessels and giant cells lighting up the aorta but its use will help avoid mistreating. Also, AI seemed more Elizabeth Holmes than Steve Jobs right now.

I voted for the arthritic canines over adorable Aztec amphibians. Have you seen Fido enthusiastically chase squirrels after a dose of doggie meds? As much as I would love to heal my chronic ankle sprain, I’m taking the dog!!

And my winner….Talking with our patients is our greatest power, more than any therapy or diagnostic tool. To acknowledge the importance of reproductive health, especially right now, and to celebrate the immense collaboration it took, repro health guidelines get the W from me.”

Comment 4: “Many thanks for the invitation to be part of the this year’s RheumMadness event. The scouting reports are phenomenal and the Madness reigns. My personal approach was to generally prioritize practicality over promise. That said, it was tough to not get swept up in the sci-fi like mechanism and potential power of CAR-T cells. In the end, though, a document like the Repro Health Guide gives us an incredible tool in taking care of our patients with rheumatic disease in the now and has my vote. What a remarkable event that creates a yearly reading list for those of us in rheumatology! To many more years of Madness!”

Comment 5: “Repro Health Guidelines should hands down be the winner of the tournament. Like the report said, “we are de facto women’s health providers” reflecting the female predominance in our clinics. These guidelines will help patients and doctors immediately and for a long time to come, impacting clinical practice right now.

With RheumMadness, I always learn a lot about what is going on in the world of rheumatology, including subjects we may miss out on at times, like reports from the Cells region and Animals region. Things I read in RheumMadness are rarely forgotten just because it is so much fun and interactive.

Increasing ANA positivity is a fact we are already quite aware of as rheumatologists – it is our bread and butter. But false positive MRIs for axial spondyloarthropathy usually presents a challenge. More research is needed for MRIs, whereas ANA positivity will hardly change rheumatology practices. This upset was necessary.

No matter how old we get or how much we advance in our careers, there is always a little child inside of us, who just wants to have fun, play with like-minded kids (or colleagues), and have the chance for some trash-talk. RheumMadness is the creative innovation that provided all that with the additional benefit of learning, and whether we know it or not, we really needed it in our day-to-day grind!”

Comment 6: “Participating in the blue ribbon panel was really a fun and educational experience. I really enjoyed reviewing scouting reports on topics I wouldn’t otherwise learn about. It was a great way to interface with the growing knowledge base in rheumatology. I think it was great how the topics were grouped so that the initial advances were very comparable items. I do think it would be hard for some of the more obscure topics to compete against something as impactful as reproductive health guidelines that heavily influence patient care. I really appreciate the opportunity to be part of this panel and found the entire process really rewarding, fun and insightful.”

THANK YOU

Lastly, we would like to thank all our amazing collaborators who helped make RheumMadness possible.

  • Rheumatology Research Foundation for funding RheumMadness through the Clinician Scholar Educator Award.
  • Scouting Report Creators: There were 70 collaborators from 13  institutions involved in writing the scouting reports for RheumMadness 2022. These reports were amazing learning resources and a ton of fun to read. Thank you to these amazing collaborators for helping us learn together! Find links to each scouting report here.
  • Blue Ribbon Panel Members: Belinda Birnbaum, MD, Ashira Blazer, MD, Kevin Byram, MD, Anisha Dua, MD, MPH, Al Kim, MD, PhD, Laura Lewandowski, MS, MD, and Iman Qaiser, MD. Read more about the Blue Ribbon Panel here.
  • RheumMadness Leadership Team: David Leverenz, MD, Akrithi Garren, MD, Guy Katz, MD, Lauren He, MD, Ben Kellog, MD, Michael Macklin, MD, Courtney Bair, Matthew Sparks, MD, and Lisa Criscione-Schreiber, MD, MEd. Read more about the leadership team here.
  • NephMadness collaborators: This project was inspired by a similar project in nephrology called NephMadness, which is currently in its 10th year. We are thankful for their collaboration and mentorship, especially from Dr. Matt Sparks.

It takes a whole year to plan this tournament. If you want to get involved in the leadership team, help create a scouting report, suggest a team, or in some other way help out with RheumMadness, please contact us!

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IgG Four Results

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The third round of the RheumMadness tournament is complete! To see how your bracket is doing, head over to the RheumMadness Tourneytopia website. 

Results for reach matchup in the IgG Four are reviewed below, including how the 7-member Blue Ribbon Panel (BRP) voted compared to participant picks. Huge thanks to our amazing panel for their thoughtful consideration.

Overall, the IgG Four turned out as participants expected. The BRP voted for CAR-T cells (6) over Dog osteoarthritis (1) in a landslide. Likewise, 36% of participants picked CAR-T cells to win this round, compared to 5% who thought Dog osteoarthritis would make it to the championship.

The other matchup was similarly lopsided. The BRP voted for Repro health guide (5) over PET in LVV (2). Likewise, 31% of participants picked Repro health guide to win this round, compared to 8% who picked PET in LVV.

Despite all the upsets in the prior three rounds, this is the final matchup that most participants were expecting to see according to Tourneytopia statistics.

So who will win it all? It seems that the majority of participants think CAR-T cells will take the top spot, but will the Blue Ribbon Panel agree? And whose bracket will come out on top?

What’s up next?

Results for the Interleukin Two (finale) will be released on Monday, April 4 at 8pm ET.

Following these results, we will announce the winning participants (ie – top score) in teach of the following 3 categories: (1) Attending / APP, (2) Fellow, and (3) Resident / Medical Student.

The prize is a RheumMadness coffee mug and a lifetime of bragging rights!

While you wait, you can enjoy the following RheumMadness content:

  • New RheumMadness podcast episode where we recap the first two rounds of the tournament with Iman Qaiser (Blue Ribbon Panel member) and other members of the RheumMadness leadership team.
  • Join the conversation on Twitter by tweeting #RheumMadness

We will also release one more RheumMadness podcast episode next week. Stay tuned, the learning isn’t over yet!

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