Team Name: Origin of sJIA, aka “Still Swole.”

Region: Origin Story

Base Article: Still GF. On a Form of Chronic Joint Disease in Children. Med Chir Trans. 1897;80:47-60.9. PMID: 20896907

Authors: Montefiore Medical Center Pediatric Rheumatology Fellowship. Malki Peskin, MD; 3rd year Pediatric Rheumatology fellow; Jessica Perfertto, MD; 2nd year Pediatric Rheumatology fellow; Faith-Andrea Ikalina, MD; 2nd year Med-Peds Rheumatology fellow; Samar Sohail, MD; 1st year Pediatric Rheumatology fellow.

Team Overview

Back in the 1800s, when pathologists measured lymph nodes by comparing them to nut sizes, pediatricians age-stratified patients based on tooth-eruption, and rheumatologic treatment included electric currents, doctors knew that children could get rheumatoid arthritis (RA), a chronic, progressive, enlargement of joints that led to damage and limitation. What was not known was that chronic arthritis in childhood could also be associated with extra-articular manifestations and represented an entirely different entity. If only children weren’t historically looked at as little adults, maybe little Alice C would not have remained hospitalized and bed-bound with fever for 2 years. Perhaps little Jane R could have received anakinra sooner, shrinking her lymph nodes from hazelnuts to pine nuts.

Dr. Still first characterized in 1897 what was later to become known as Still’s disease and what is now known as systemic JIA (sJIA). He described a case-series of 22 patients at the Hospital for Sick Children in England and contrasted this entity with its cousin RA. Unlike RA patients with mostly small joint involvement, these children typically had painless swelling of the knees and wrists, as well as earlier involvement of the C-spine. If you listened closely, he reported “creaking” of the tendons or cartilage but “never any bony grating”. He also noted that the female predominance of RA was not seen in this new disease, with boys and girls affected almost equally. Extra-articular manifestations included fevers, lymphadenopathy, splenomegaly, serositis, and anemia. Fevers were either high and intermittent, or continuous mild pyrexia. Dr. Still stressed the impressive splenomegaly and the hazelnut-sized lymphadenopathy as a major distinction. Serositis was also described as “adherent pericardium” and was noted in some symptomatic children, but was otherwise found on autopsy.

Implications

Dr. Still clearly demonstrated that there are marked clinical and pathological differences between adult RA and this new and distinct disease in children. We can also thank him for starting the complicated classification schema for JIA as he also described a different disease that appeared “identical in every respect” to adult RA, likely an early description of what is now known as polyarticular JIA.

Fortunately, as we continue to learn about sJIA, our knowledge no longer comes from autopsies as it did in 25% of Dr. Still’s patients. This point in and of itself should sway you to understand just how revolutionary this description truly was. Noticing that these patients seemed different was the first step towards the development of life-altering therapies which now save sJIA patients on a daily basis.

Despite the medical advances in the 127 years since Dr. Still’s revolutionary publication, children are often still considered little adults in the world of rheumatology research. In rheumatology, we constantly strive to improve our evidence base to enhance our understanding and management of diseases, despite being a realm of rare diseases. The challenges and limitations are even more pronounced in pediatrics. We inherently assume similarity in most of our diseases with their adult counterparts and therefore extrapolate data from adult drug trials to treat our children. Pharmacokinetic and safety differences aside, if pediatric rheumatic diseases differ in more ways than temporal relation to dental eruption as astutely noted by Dr. Still, it is imperative that we continue to work towards trials and observational studies in our pediatric population rather than extrapolations.

Chances in the Tournament

We are still the underdogs in this tournament given that we remain the only pediatric team. However, this revolutionary article’s eloquent Victorian descriptions of this new disease process marked the turning point at which patients with systemic JIA and by extension, the still-eponymous adult-onset Still’s disease, could be researched and treated differently. Dr. Still was a visionary as he was the first to realize that rheumatic diseases differ in children compared to adults in more than just age, though these children were not paid heed until after the 1940s.

Let’s do better than our Victorian counterparts – this is your chance to vote for little Alice C, Jane R, and their modern counterparts. Let’s continue Dr. Still’s efforts to work towards a world where we recognize that children need dedicated, targeted research to continue to improve outcomes. Just as it’s shocking to hear of children with JIA wasting away in a hospital bed for years or being examined in the morgue, hopefully as we continue research in pediatric rheumatology, the current state of affairs for children with rheumatic diseases will be shocking to readers 127 years from now.

Back to the full list of scouting reports.

References

1. Still GF. On a Form of Chronic Joint Disease in Children. Med Chir Trans. 1897;80:47-60.9.
2. Newton S, Maher D. A brief history of still’s disease. Still’s disease, the 411. https://sdthe411.com/2020/12/10/a-brief-history-of-stills-disease/. Published December 10, 2020. Accessed January 11, 2023.
3. Schaller, J. The History of Pediatric Rheumatology. Pediatr Res. 2005;58: 997–1007.

Team: Pathogenic ANCA, aka “The Most Villainous Protein (MVP)”

Region: Ab Workout

Base Article: Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. J Clin Invest. 2002;110(7):955-963. doi:10.1172/JCI15918. PMID 12370273.

Authors: University of North Carolina Rheumatology Fellowship Program; Katherine Yates, MD, First Year Rheumatology Fellow; Prarthana Jain, DO, MPH, First Year Rheumatology Fellow; Astia Allenzara, MD, Second Year Rheumatology Fellow

Team Overview

While teamwork makes the dreamwork, it never hurts to have a most villainous protein (MVP) on the team. The Most Villainous Protein team is lucky enough to have recruited an anti-MPO protein. This antibody has revolutionized the game by providing evidence that antineutrophil cytoplasmic antibodies (ANCAs) are directly pathogenic in crescentic glomerulonephritis and small vessel vasculitis¹. Some have compared this protein’s impact to that of Michael Jordan’s last second, National Championship game winning jumper in 1982; legendary.

It has been known for quite some time that the anti-MPO antibody was an important player. Further tape review, however, has revealed just how impactful this protein can be. This is similar to how the most valuable player of all time, Michael Jordan, was an outstanding player during this time at UNC, but the full extent of his talent was not observed until further observations were made as he played in the NBA. The film to which we are referring is the definitive evidence, meeting all 8 Bradford Hill criteria, that anti-MPO antibodies cause glomerulonephritis and small vessel vasculitis. The Most Villainous Protein team has demonstrated through knockout mice lacking functioning B and T lymphocytes that the addition of anti-MPO antibodies results in the development of crescentic glomerulonephritis within days¹. This effect was dose dependent, with mice that received more anti-MPO developing necrotizing glomerulonephritis, hemorrhagic pulmonary capillaritis and granulomatous inflammation¹. Anti-MPO’s absence on the court is also noticeable: when anti-MPO was on the bench, anti-BSA splenocytes and anti-BSA IgG were unable to induce the same glomerular crescents¹.

Anti-MPO is an impactful player, but talent is not enough to win championships. What separates this protein on the assay is how this antibody also inspires its teammates. Just as Michael Jordan was known to push his UNC teammates, anti-MPO knows how to inspire and motive its teammates. Prime examples of this skill occurred during big games against several rival teams (immune complex glomerulonephritis or anti-GBM glomerulonephritis), where anti-MPO demonstrated the ability to bring the team together and activated both neutrophils and monocytes to win the games. Anti-MPO has been known to stimulate neutrophils to release injurious oxygen metabolites, proteases, and proinflammatory cytokines and allow neutrophiles to hold on tight and thwart its endothelial cell opponents^2,3,4. Anti-MPO’s presence on the court also encourages monocytes to undergo a respiratory burst, releasing a wave of proteinases and cytokines⁵. All this goes to show that The Most Villainous Protein team not only has the MVP, but also includes several other players that will likely go on to be inducted into the hall of fame.

Impact on Rheumatology

While anti-MPO has been known to be involved in causing glomerular and vascular inflammation, this team has provided definitive evidence for its pathogenic role. This exciting development is a game changer.

Knowing that anti-MPO antibodies have a pathogenic role has resulted in the study and development of new treatment strategies, including a reduced dose glucocorticoid regimen over a standard dose regimen and Rituximab over Cyclophosphamide for induction for active severe ANCA-associated vasculitis⁶. One could say that this discovery has rewritten the rule book.

Recently, there has been more attention paid to how anti-MPO influences its neutrophil and monocyte teammates. This increased focus will likely improve our understanding of other rheumatologic diseases and has the potential to inspire novel treatment strategies.

Chances in the Tournament

Anti-MPO is felt to be a top runner for the overall tournament MVP award as this protein presents a threat on multiple fronts including a definitive pathological role in inducing glomerulonephritis and vasculitis as well as stimulating its neutrophil and monocyte teammates. Any opponent will need to be prepared to withstand bursts of injurious oxygen metabolites, proteinases, and proinflammatory cytokines.

The Most Villainous Protein team has a formidable opponent in the first round with CCP & Enolase, but the more definitive role of anti-MPO will allow this MVP to roll over its first challenger in this tournament. Anti-MPO’s impact will likely be enough to carry The Most Villainous Protein team through the Ab Workout region, but it will be this protein’s inspiration and influence on its neutrophil and monocyte teammates that will help to carry the team through to the championship.

The Blue-Ribbon Panel will appreciate the application of the Bradford Hill criteria to prove anti-MPO antibodies’ causation of glomerulonephritis and vasculitis. The phenomenal demonstration of this pathogenic role is awe inspirating and has a significant impact on our understanding of the pathogenesis of ANCA glomerulonephritis and vasculitis and has led to the development of new treatment strategies. Furthermore, this discovery has the potential to continue to provide insights into pathogenesis and revolutionize management as more is learned about the role of neutrophils and monocytes.

Next scouting report: CYC for PAN

Back to the full list of scouting reports.

See the Q&A on theMednet.org for the Ab Workout Region: How do you approach follow up in patients with isolated positive ANA, but no current clinical signs or symptoms of systemic lupus erythematosus?

References

1. Xiao H, Heeringa P, Hu P, et al. Antineutrophil cytoplasmic autoantibodies specific for myeloperoxidase cause glomerulonephritis and vasculitis in mice. Journal of Clinical Investigation. 2002;110(7):955-963. doi:10.1172/JCI15918
2. Falk RJ, Terrell RS, Charles LA, Jennette JC. Anti-neutrophil cytoplasmic autoantibodies induce neutrophils to degranulate and produce oxygen radicals in vitro. Proceedings of the National Academy of Sciences. 1990;87(11):4115-4119. doi:10.1073/pnas.87.11.4115
3. Charles LA, Caldas MLR, Falk RJ, Terrell RS, Jennette JC. Antibodies Against Granule Proteins Activate Neutrophils In Vitro. Journal of Leukocyte Biology. 1991;50(6):539-546. doi:10.1002/jlb.50.6.539
4. Ewert BH, Jennette JC, Falk RJ. Anti-myeloperoxidase antibodies stimulate neutrophils to damage human endothelial cells. Kidney International. 1992;41(2):375-383. doi:10.1038/ki.1992.52
5. Casselman BL, Kilgore KS, Miller BF, Warren JS. Antibodies to neutrophil cytoplasmic antigens induce monocyte chemoattractant protein-1 secretion from human monocytes. J Lab Clin Med. 1995;126(5):495-502.
6. Chung SA, Langford CA, Maz M, et al. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis. Arthritis & Rheumatology. 2021;73(8):1366-1383. doi:10.1002/art.41773

Team: MSU and NLRP3, aka “The Inflammasome Slama Jam-masome”

Region: Mechanism Madness

Base article: Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440(7081):237-241. doi:10.1038/nature04516. PMID 16407889.

Authors: Geisinger Medical Center Rheumatology Fellowship. Melissa Band, DO, 2nd year rheumatology fellow, David Bulbin, DO, RhmSUS, Program Director.

Team Overview

We know that gout has crystalized history for centuries – even historians have mentioned that the acute gout flares of many influential leaders, from King Henry VIII to Benjamin Franklin, may have played a role in the outcome of major historical events including the Constitution.¹ Prior to the understanding of gout pathophysiology, the disease put the “full court press” on the 1^st MTP, making the lives of those afflicted turn purines and pyrimidines into a uric acid “Havoc” defense.

These monosodium urate and calcium pyrophosphate crystals were known to increase the ill humors of joint inflammation, devastating the competition. However, scientists and physicians prior to Martinon et al. did not know how to crack this “Havoc” inflammatory response.

Martinon et al. was the sentinel study identifying the mechanism that swarmed the opponent. This was the advent of the offensive juggernaut stomping down the inflammation, which helped paved the way for further research and development of IL-1 inhibition for gout and autoinflammatory syndromes.

They extrapolated that increased production of the cytokine IL-1B, as identified in different autoinflammatory diseases, can also be a part of the pathogenesis of gout, the greatest offense to date for defeating the “Havoc” from IL-1. They studied this by injecting monosodium urate and calcium pyrophosphate crystals in mice deficient in the IL-1B pathway. They found that MSU or CPPD crystals engage caspase-1, activating the NLRP3 or NALP3 inflammasome’s “Havoc defense.” This resulted in production of IL-1B in acute gout flares, and the legend of Inflammasome Slama Jam-masome was born.

Impact on Rheumatology

The NLRP3 inflammasome’s impact has expanded far beyond the field of rheumatology, the playbook finally breaking the neutrophil’s IL-1 Havoc defense. This revolutionized the way the game was played and helped our understanding of defeating the powerful inflammatory driven defenses including the dreaded heart disease matchup zone, which is the leading cause of mortality in the United States.² Beyond coronary artery disease, the NLRP3 inflammasome’s defenses have held up strong against pericarditis as shown in the AIRTRAP trial and against the chronic smoldering effects of atherosclerosis in the CANTOS trial.^3,4

One of the NLPR3 inflammasome’s superstar players, the Inflammasome Slama Jam-masome Anakinra, has been a hidden gem that the offensive strategy turned into a juggernaut. Anakinra’s skillset is the perfect counterpoint to the effects of IL-1 and the inflammasome.⁵ He is quick in his decisions, weaving through the neutrophilic “Havoc” defense and throwing down a tomahawk jam posterizing the inflammasome. He is consistent, agile and the best weapon on the floor, washing out the fiery pain generated by IL-1. Anakinra is potential number one pick in the FDA draft, making life easier for fans with refractory gout relieving the competition. The Inflammasome Slama Jam-masome brought the playbook that stopped the “Havoc” dead in its tracks.

Chances in the Tournament

The NLRP3 inflammasome pathway in gout paved the way for Anakinra, the superstar diamond in the rough, that will lead the small conference Cinderella, Inflammasome Slama Jam-masome, through the competition of RheumMadness 2023. Coming from humble beginnings and its effect through history, the 11 seed in the tournament shocks the world in the first round. The understanding of NLRP3 was the move needed to escape defenses with fast paced, quick movement quelling the inflammation generated. “Abs before SLE” is a tough matchup, but they are no match for the heroics of the NLRP3 inflammasome. The Cinderella club has final four aspirations and will fly over the competition, leaving its mark on the history of RheumMadness.

Next scouting report: Abs before SLE

Back to the full list of scouting reports.

References

1. Marson, P., & Pasero, G. (2011). Some historical remarks on microcrystalline arthritis (gout and chondrocalcinosis). Reumatismo – The Italian Journal of Rheumatology, 63(4), 199–206. https://doi.org/10.4081/reumatismo.2011.199.
2. Abbott, RD., Brand, FN., Kannel, WB., & Catelli, WP (1988). Gout and coronary heart disease: The framingham study. Journal of Clinical Epidemiology, 41(3), 237-242. https://doi.org/10.1016/0895-4356(88)90127-8.
3. Brucato A, Imazio M, Gattorno M, Lazaros G, Maestroni S, & Carraro M (2016). Effect of anakinra on recurrent pericarditis among patients with colchicine resistance and corticosteroid dependence: the AIRTRIP randomized clinical trial. Journal of the American Medical Association. 316(18), 1906–1912. https://doi.org/10.1001/jama.2016.15826.
4. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, & Ballantyne C (2017). Anti-inflammatory therapy with canakinumab for atherosclerotic disease. The New England Journal of Medicine. 377(12), 1119–1131. https://doi.org/10.1056/NEJMoa1707914.
5. Saag KG, Khanna PP, Keenan RT, Ohlman S, Osterling Koskinen L, Sparve E, Åkerblad AC, Wikén M, So A, Pillinger MH, & Terkeltaub R (2021). A Randomized, Phase II Study Evaluating the Efficacy and Safety of Anakinra in the Treatment of Gout Flares. Arthritis & Rheumatology. 73(8), 1533-1542. https://doi.org/10.1002/art.41699.

Team: Enolase & RA, aka “P. gingivalis and RA”

Region: Ab Workout

Base Article: Lundberg K, Kinloch A, Fisher BA, et al. Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase. Arthritis Rheum. 2008;58(10):3009-3019. doi:10.1002/art.23936. PMID 18821669.

Authors: University of South Florida Rheumatology Fellowship. Caroline Bresnan, MD, first year rheumatology fellow, Anastasiya Bagrova, MD, second year rheumatology fellow, Vanessa Osting, DO, MPH, FACR, Assistant Chief of Ambulatory Care Outpatient Services – James A. Haley VA Hospital, Joanne Valeriano-Marcet, MD, Rheumatology program director, Larry Young, MD, Chief of Rheumatology, James A. Haley VA Hospital.

Team Overview

Connections between rheumatologic diseases and human pathogens have been speculated about for decades. Rheumatoid arthritis (RA) was once thought to be caused by a streptococcal infection akin to rheumatic fever^1,4. This led to the development of sulfasalazine as a combination antibacterial and anti-inflammatory drug:² the dream team of medications at the time! Although this connection was disproved, the complex interplay of human genes and the environment, particularly in response to bacterial infection or colonization remains an area of intensive research to identify triggers of autoimmunity.

In the late 1990s, a team of Dutch researchers found the anti-citrullinated peptide antibody to be a highly specific autoantibody in RA, and subsequently developed the anti-CCP ELISA test³. Anti-CCP is one of the MVPs when it comes to RA diagnosis and prognosis. However, the origins of this autoantibody remained unclear.

To elucidate where antibodies to citrullinated peptides may come from, Lundberg et al (2008) examined the relationship between the oral bacterium Porphyromonas gingivalis (a cause of adult periodontitis) and RA. Patients with periodontitis are four times more likely to develop RA than the general population, which is truly a flagrant foul on the bacteria’s part. The authors identified the citrullinated protein a-enolase, which is found in the synovial fluid of RA patients, as a target of anti-citrullinated peptide antibodies. Interestingly, a-enolase is a highly conserved protein and is also made by P. gingivalis. Furthermore, P. gingivalis is the only human pathogen which produces an enzyme peptidyl arginine deaminase (PAD) that is responsible for citrullinating peptides. Our immune cells then target (or double-team, if you will) these citrullinated peptides with antibodies, thus creating a vicious cycle of chronic inflammation and potential for autoimmunity. To demonstrate that bacterial citrullinated peptides may be important in human RA, the researchers collected serum from RA patients, along with disease controls (Sjogren’s, SLE, and spondylarthritis, etc.), and healthy controls. They identified several forms of citrullinated a-enolase (CEP) to mix with the patient sera and found that 64% of RA patients, compared to 15% of controls had antibodies to the CEPs. The form of CEP to which the RA patient’s antibodies bound the most in this study was highly similar to that of P. gingivalis. They subsequently found that antibodies that reacted to the human enolase were cross-reactive to P. gingivalis enolase. These findings suggest that P. gingivalis promotes the development of anti-CCP positive RA by stimulating production of autoantibodies to human citrullinated a-enolase. This was the first study to identify a commensal bacterium as potentially contributing to pathogenesis in RA.

Impact on Rheumatology

This article was excitedly suggested by one of our attendings who clearly remembered hearing about this study during ACR as a fellow. The major impact from the article are not the findings themselves, although also important. It is the fact that this article suggested the role of commensal bacteria in the pathogenesis of autoimmune diseases. It was one of the first articles examining the role of microbiome in rheumatic disease. In the more recent years, microbiome dysregulation has been implicated in IBD, SLE, spondyloarthritis, even APLS⁵. The role of fecal microbiota transplant is currently being studied in several autoimmune diseases^6,7. While we have not yet reached the game changing state of being able to “fix” the abnormal microbiome to cure autoimmune disease, it is a very promising area of research for clinicians and patients. We bet every rheumatologist reading this report gets asked by their patients whether they can be cured with diet, supplements, or life-style modifications. Our paper gives a basis for advice about defensive moves, such as dental care, and provides hope that in the future we will be able to change the pace of play with a prescription for a diet instead of csDMARDs or biologics (not to mention, send the insurance companies and their “preferred medication lists” back to the bench forever).

Chances in the Tournament

We admit we are the dark horse of the tournament. While there are some truly five-star players masterfully crafting their game around us, we believe that our team is a top prospect for a come-from-behind, game-winning, three-pointer at the buzzer. What sets our article apart from the top seeded teams in our bracket is that our article takes a step back from just identifying pathogenic antibodies as a sole player, and examines pathogenesis of the disease itself. Furthermore, as discussed above, our article’s findings have far-reaching implications that can transcend the game by showing the role of microbiome in rheumatic disease and offer targets for cure and prevention.

Next scouting report: Pathogenic ANCA

Back to the full list of scouting reports.

See the Q&A on theMednet.org for the Ab Workout Region: How do you approach follow up in patients with isolated positive ANA, but no current clinical signs or symptoms of systemic lupus erythematosus?

References:

1. Benedek TG. The history of bacteriologic concepts of rheumatic fever and rheumatoid arthritis. Semin Arthritis Rheum. 2006 Oct;36(2):109-23. doi: 10.1016/j.semarthrit.2006.05.001. Epub 2006 Jul 13. PMID: 16884972.
2. Pinals RS. History of enteric coated sulfasalazine in rheumatoid arthritis. J Rheumatol Suppl. 1988 Sep;16:1-4. PMID: 2903922.
3. Schellekens, G.A., Visser, H., De Jong, B.A.W., Van Den Hoogen, F.H.J., Hazes, J.M.W., Breedveld, F.C. and Van Venrooij, W.J. (2000), The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis & Rheumatism, 43: 155-163.
4. Svartz N. The origin of rheumatoid arthritis. Rheumatology. 1975;6:322-8. PMID: 1105749.
5. Clemente, J. C., Manasson, J., & Scher, J. U. (2018). The role of the gut microbiome in systemic inflammatory disease. Bmj, 360.
6. Huang, C., Yi, P., Zhu, M., Zhou, W., Zhang, B., Yi, X., … & Lu, Q. (2022). Safety and efficacy of fecal microbiota transplantation for treatment of systemic lupus erythematosus: An EXPLORER trial. Journal of Autoimmunity, 102844.
7. Stoll, M. L. (2022). Therapeutic alteration of the microbiota in rheumatic diseases: Hype or potential?. Best Practice & Research Clinical Rheumatology, 101806.

Team: Abs Before SLE, aka “Autoantibodies before SLE”

Region: Ab Workout

Base Article: Arbuckle MR, et al. Development of autoantibodies before clinical onset of systemic lupus erythematosus. N Engl J Med. 2003 Oct 16;349(16):1526-33. doi: 10.1056/NEJMoa021933. 

Authors: Massachusetts General Hospital Rheumatology Fellowship; Guy Katz, MD, third-year rheumatology fellow; Jacquelyn Nestor, MD, PhD, second-year rheumatology fellow; Steve Witte, MD, PhD, second-year rheumatology fellow; Zandra Walton, MD, PhD, first-year rheumatology fellow; Greg Challener, MD, first-year rheumatology fellow; Marcy Bolster, MD, rheumatology fellowship Program Director

Team Overview

Virtually every player with systemic lupus erythematosus (SLE) harbors autoantibodies as part of their offensive strategies. For decades, these autoantibodies have been powerhouses in the workup and long-term management for patients with SLE and many other systemic autoimmune diseases. Indeed, the ability to analyze the meaning of these tests in different clinical contexts is one of the defining skills of a rheumatologist. However, long after they were discovered to be associated with SLE, there remained critical questions surrounding these autoantibodies. What is their role in disease pathogenesis? When in the disease process do they develop? How should we counsel patients with positive autoantibodies and no clinical evidence of associated autoimmune disease? In the landmark article by Arbuckle et al., answers to these questions were finally uncovered, providing novel insights into SLE and autoimmunity.

Recruiting players from a powerful database of 30 million prospectively collected serum samples, patients with SLE (n=130) and four matched controls each were identified. These samples were then interrogated for the presence of antinuclear antibodies (ANA) at a titer of 1:120 titer or greater as well as antibodies to Ro (SSA), La (SSB), dsDNA, smith (Sm), RNP, and phospholipids. This team effort revealed that SLE-associated antibodies attracted the attention of scouts long before clinical disease manifestations and their tournament debut. Ro and La appeared, on average, starting the shot clock, over 3 years before diagnosis. Likewise, development of other antibodies also predated SLE debuts, and seroconversion cheered the players towards diagnosis with ANA and antiphospholipid antibodies appearing 3 years, dsDNA 2 years, Sm 1.5 years, and RNP nearly 11 months prior to diagnosis. Autoantibodies predicted future performance, with the vast majority of SLE players (about 90%) harboring positive antibodies for more than two years prior to the onset of symptoms. And these estimates on the lead time of antibody positivity prior to clinical disease onset and diagnosis are likely underestimated, as many of the earliest available samples already exhibited autoantibodies.

Impact on Rheumatology

The Arbuckle team not only filled important knowledge gaps in SLE pathophysiology, but it also changed the game for research on preclinical autoimmunity in numerous diseases, which is now one of the areas of investigation in rheumatology at the top of the standings. This team provided answers to real-world clinical questions that rheumatologists and patients encounter every day. Autoantibody positivity—particularly ANA—is one of the most common reasons for rheumatology referral. Only a minority of patients with positive ANA develop ANA-related systemic autoimmune disease, yet it is crucial to identify and provide a defense for those who will develop diseases such as SLE. Nearly two decades after its league debut, we continue to refer to this championship winning team for evidence-based plays on how to coach patients with positive autoantibodies in the absence of clinical manifestations of autoimmune disease. Using the offensive style from this study, clinicians can confidently rank patients with positive autoantibodies and coach them on their odds of developing autoimmune disease using specific game times.

This paper is a much-needed playbook of immune-related events prior to SLE tip-off, which was previously uncharted territory. It provided key plays—answering some of the most common clinical questions rheumatologists face—led to a momentum shift in our understanding of SLE pathogenesis, and it established the field of preclinical autoimmunity. The study directly impacts patients and clinicians every day, and its winning results have gone on to shape our understanding of the playbook of not just SLE, but of many autoantibody-associated autoimmune diseases.

Chances in the Tournament

Since its tournament debut in 2003, this manuscript has consistently been a dynasty in the field of rheumatology, and it is certain to be a fan favorite in RheumMadness 2023. Due to its clinical applicability and broad research implications that extend far beyond SLE, this landmark article has a strong chance of cutting down the net as the tournament champion. Its applicability to numerous autoimmune diseases will likely lead to its landslide victory in the Ab Workout Region, where the other teams apply more narrowly to individual diseases (anti-CCP and RA, ANCA and ANCA-associated vasculitis). If prior tournaments are any indication, landmark clinical trials from TNF Takedown, RA Revamp, Get in the Game, and Jump Ball are likely to be lay-ups in the tournament. However, the broad impact of this study—addressing more than a single disease—is the reason it is likely to be a slam dunk over these trials, none of which have been cited as many times (i.e., has as many wins) as the paper by Arbuckle et al.

Next scouting report: CCP & Enolase

Back to the full list of scouting reports.

See the Q&A on theMednet.org for the Ab Workout Region: How do you approach follow up in patients with isolated positive ANA, but no current clinical signs or symptoms of systemic lupus erythematosus?

References

1. Arbuckle MR, et al. Development of autoantibodies before clinical onset of systemic lupus erythematosus. N Engl J Med. 2003 Oct 16;349(16):1526-33. doi: 10.1056/NEJMoa021933.

Team: Clonal Selection, aka “the Forbidden Clones.”

Region: Mechanism Madness

Base article: Burnet M. Auto-immune disease. I. Modern immunological concepts. Br Med J. 1959;2(5153):645-650. doi:10.1136/bmj.2.5153.645. PMID 13806210.

Authors: Vanderbilt University Medical Center Rheumatology Fellowship Program. Meridith Balbach, fourth year medical student; Robert Corty, MD PhD, first year rheumatology fellow; Ganiat Adeogun, MD, first year rheumatology fellow; Catherine Deffendall, MD, first year rheumatology fellow; Erin Chew, MD, second year rheumatology fellow; Sarah Luebker, DO, second year rheumatology fellow; Tyler Reese, MD, assistant professor of medicine; Kevin Byram, MD, assistant professor of medicine; Narender Annapureddy, MD, MSCI, associate professor of medicine; Leslie Crofford, MD, professor of medicine, Vanderbilt University Medical Center

Team Overview

Basketball coaches have long debated team-building strategy. The “Wooden school” recruits malleable players with potential and teaches them to play a winning system. The “Calipari school” simply recruits such highly skilled players that victories occur without much further training. In the 1950s, immunologists engaged in a similar debate on the mechanism by which the immune system produces antibodies.

The Lamarckian “instructive school” held that an antibody-producing cell ingests an antigen that “impresses its character” onto its respective antibody, coaching it so that it might make it into the big leagues of peripheral circulation.^1,2 Building on Ehrlich’s side chain theory (1898) and Jerne’s natural selection theory (1955), however, Coach MacFarlane Burnet stepped onto the court in 1957 with his Darwinian theory of clonal selection.^3,4 He posited that the immune system produces a diversity of candidates and subsequently recruits the most capable among them into the periphery, generating an all-star lineup.⁵

In this 1959 monograph, Burnet applies clonal selection theory to provide a working approach to autoimmune disease.⁶ He states that a high degree of mutability during the embryonic stage of development generates a diversity of antibody-producing cells, akin to Jerne’s preexisting repertoires while satisfying the newfound central dogma. From there, cells that react with self-antigen are eliminated by a homeostatic mechanism—now known as central tolerance.

The understanding that the “breakdown in that information service” which differentiates between self and non-self allows the emergence of self-reactive antibody or immunologically active cells is a slam dunk—one that revolutionizes our understanding of adaptive immunity. Burnet recognized that making a team from players with existing talents left the floor wide open for Forbidden Clones when that central tolerance is lost, predisposing to autoimmune disease.

Impact on Rheumatology

Incorporating clonal selection theory into our understanding of autoimmune disease represented a major paradigm shift in the 20^th century—and is sparking game-changing plays once again. An enhanced understanding of adaptive immunity spurred numerous innovations. Clonal selection theory contributed to the production of the first monoclonal antibody in 1975, now a cornerstone of treatment in numerous rheumatic diseases.⁷ It guided selection of antigens capable of eliciting a memory response in vaccine development, including the crowd-pleasing COVID-19 inoculations we now use to protect our most vulnerable patients.⁸ In parallel, it set a pick for understanding T cell selection—the importance of which is not lost on our oncology colleagues leveraging these principles with CAR T-cell therapy—or, increasingly, in refractory systemic lupus erythematosus.^9,10 Furthermore, it shifted the spotlight from antigen to antibody, prepping the rheumatology community to better understand the presence of autoantibodies prior to disease onset in lupus, rheumatoid arthritis, systemic sclerosis, and more.^11-13

Incredibly, the applications of Burnet’s seminal work, particularly understanding Forbidden Clones as opponents in rheumatic disease, is only growing—just take a look at the 2022 American College of Rheumatology Convergence meeting. Drs. Peter Campbell and Joanne Reed incorporated Forbidden Clones into their playbooks, directly citing Burnet’s work.^14-16 Both put forth somatic mutation as a key mechanism by which autoantibodies arise and become increasingly pathogenic, highlighting these cells as playmakers in autoimmune diseases such as Sjogren’s syndrome and vasculitis. This research exploring the evolution from benign seropositivity to antibody-driven pathology may yield a treatment targeting those Forbidden Clones.

Chances in the Tournament

Avoid making Forbidden Clones’ first-round opponent “NRLP3 in gout” your bracketbuster—it will be nothing but net as the Forbidden Clones take the “Mechanism Madness” region. Treatment implications of their base paper are reliant on understanding Forbidden Clones—just consider the need for concomitant methotrexate administration with pegloticase in gout to prevent the rise of a specific type of forbidden clone—that is, anti-pegloticase antibodies.^17,18

In the following round, they will take on the winner of the Ab Workout region. This is sure to be a tough matchup, but the Forbidden Clones will win big if the Blue Ribbon Panel considers that this base paper establishes the mechanistic underpinnings of how any potential opponent from the Ab Workout region might emerge. Our MVP (& Nobel Prize Winner) Burnet will guide his team to victory, just as he’s guided immunology and rheumatology over the last 60+ years.

Although the previous panels have traditionally focused on clinical practicality, they may be more focused on the fundamentals this year given the theme of the tournament. If the panel employs this logic, the Forbidden Clones have an excellent chance to cut down the nets. Just remember, Forbidden Clones don’t play by the rules— just as they bypass central tolerance, you may find yourself rooting for them as they bypass the competition.

Next scouting report: MSU & NLRP3

Back to the full list of scouting reports.

References

1. F B, F H. Chemische Untersuchung des Prazipitates aus Hamoglobin und Anti-Hamoglobin-Serum und Bemerkungen uber die Natur der Antikorper. Physiol Chem. 1930;192(45)doi:https://doi.org/10.1515/bchm2.1930.192.1-3.45
2. Pauling L. A Theory of the Structure and Process of Formation of Antibodies*. J. Am. Chem. Soc.; 1940. p. 2643–2657.
3. Ehrlich P. Croonian Lecture: On Immunity with Special Reference to Cell Life. Proceedings of the Royal Society of London; 1900. p. 424-448.
4. Jerne NK. THE NATURAL-SELECTION THEORY OF ANTIBODY FORMATION. Proc Natl Acad Sci U S A. Nov 15 1955;41(11):849-57. doi:10.1073/pnas.41.11.849
5. Burnet FM. A modification of Jerne’s theory of antibody production using the concept of clonal selection. Australian Journal of Science. 1957;20:67-69.
6. BURNET M. Auto-immune disease. I. Modern immunological concepts. Br Med J. Oct 10 1959;2(5153):645-50. doi:10.1136/bmj.2.5153.645
7. Liu JK. The history of monoclonal antibody development – Progress, remaining challenges and future innovations. Ann Med Surg (Lond). Dec 2014;3(4):113-6. doi:10.1016/j.amsu.2014.09.001
8. Clem AS. Fundamentals of vaccine immunology. J Glob Infect Dis. Jan 2011;3(1):73-8. doi:10.4103/0974-777X.77299
9. Bernard N. When humoral became cellular. Nature Immunology. 2016;17(9)doi:https://doi.org/10.1038/ni.3604
10. Mackensen A, Müller F, Mougiakakos D, et al. Anti-CD19 CAR T cell therapy for refractory systemic lupus erythematosus. Nat Med. Oct 2022;28(10):2124-2132. doi:10.1038/s41591-022-02017-5
11. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. Oct 16 2003;349(16):1526-33. doi:10.1056/NEJMoa021933
12. Nielen MM, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. Feb 2004;50(2):380-6. doi:10.1002/art.20018
13. Burbelo PD, Gordon SM, Waldman M, et al. Autoantibodies are present before the clinical diagnosis of systemic sclerosis. PLoS One. 2019;14(3):e0214202. doi:10.1371/journal.pone.0214202
14. Campbell P. Somatic mutations in normal & autoimmune lymphocytes 2022:
15. Reed J. Somatic Mutations Shape Autoantibody Response 2022:
16. Singh M, Jackson KJL, Wang JJ, et al. Lymphoma Driver Mutations in the Pathogenic Evolution of an Iconic Human Autoantibody. Cell. Mar 05 2020;180(5):878-894.e19. doi:10.1016/j.cell.2020.01.029
17. Lipsky PE, Calabrese LH, Kavanaugh A, et al. Pegloticase immunogenicity: the relationship between efficacy and antibody development in patients treated for refractory chronic gout. Arthritis Res Ther. Mar 04 2014;16(2):R60. doi:10.1186/ar4497
18. Botson JK, Tesser JRP, Bennett R, et al. Pegloticase in Combination With Methotrexate in Patients With Uncontrolled Gout: A Multicenter, Open-label Study (MIRROR). J Rheumatol. May 2021;48(5):767-774. doi:10.3899/jrheum.200460

Team: TICORA

Region: RA Revamp

Base article: Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364(9430):263-269. doi:10.1016/S0140-6736(04)16676-2. PMID 15262104

Authors: Angus B Worthing MD, attending, Arthritis & Rheumatism Associates, PC, Washington DC; Justin Peng MD, attending, Arthritis & Rheumatism Associates, PC, Washington DC; Dan El Bogdadi MD, attending, Arthritis & Rheumatism Associates, PC, Rockville, MD

Team Overview

When this team started playing, it was known that reducing rheumatoid arthritis activity correlated with less joint damage, and early combination oral DMARDs were starting to outperform monotherapy.^1,2,3,4,5 Targeted biologic therapy would become available after TICORA was already in process. Our game was entering an exciting era with promising new tools, but a winning formula for treating RA had not yet emerged.

TICORA provided that formula. It was the first blinded study to unveil what would become a standard player in any lineup: the all-star power-forward of an intensive, step-up, treat-to-target strategy in early RA. The intervention strategy included initial sulfasalazine, followed by addition and titration of methotrexate and hydroxychloroquine. At monthly evaluations, oral DMARDs were escalated with intra-articular and/or intramuscular glucocorticoids unless disease activity was low, patients declined or if contraindicated by drug toxicity. Clinical and radiographic evaluators were blinded. At the final buzzer, the box score showed this treat-to-target (T2T) approach outperformed routine care in all relevant stats.

Impact on Rheumatology

It’s hard to overstate TICORA’s effect on the game. As the first truly unbiased T2T trial design in rheumatology (credit an assist to its open-label predecessor FIN-RACo), TICORA helped power a fast-break of clinical trials with combinations and biologics. Research teams would emulate TICORA’s winning formula to test step-up, combination, and biologic treatment strategies using the same blinded, treat-to-target fashion.^6,7

T2T is now the key backbone of treatment strategy in major rheumatoid arthritis guidelines.^8,9 It has been drafted for use in ankylosing spondylitis, psoriatic arthritis, SLE, gout, and even fibromyalgia.^10,11,12,13 And although TICORA’s monthly visit intensity lost popularity, it drove higher remission rates compared to other T2T trials.

As rheumatologists began using T2T in practice, it not only improved patient outcomes but also revolutionized the clinic itself. Rheumatologists in the Mid-Atlantic US, for example, developed a clinical pathway to treat RA which guaranteed access to biologics for patients with active disease. When Medicare’s Quality Payment Program requested innovative Alternate Payment Model (APM) proposals to increase quality and reduce cost in the Medicare system, ACR incorporated T2T into its Alternative Payment Model of RA. ¹⁴ And ACR highlighted the Mid-Atlantic T2T pathway in the 2022 Innovation in Clinical Care Award given to our partner Dr. Herb Baraf.¹⁵ Therefore, TICORA was not only the original treat-to-target study in rheumatoid arthritis, but also provided a foundation for comparative clinical trials and treatment for RA and many other rheumatologic disease.

Chances in the Tournament

The TICORA Trial squad expects to make a deep run in the RheumMadness 2023 tournament. TICORA tips off against the BeST Trial, which provided novel data about early RA treatment using TICORA’s T2T game plan to compare early step-up combination treatment to 3 other strategies. But BeST has become less relevant now that those strategies – high-dose glucocorticoids, sequential monotherapy, and initial combination TNF plus methotrexate have generally moved to the back of the guideline playbook.¹⁶ TICORA Trial’s use of strong scoring fundamentals could put BeST Trial on the defensive. 2^nd round action against TEAR Triple Rx and a birth into the Interleukin 8 will have the Blue Ribbon Panel pick between TICORA’s fundamental X’s and O’s, and trick-shot triple therapy and TNFs. The BRP would be wise to heed hoops legend Larry Bird, who said, “First, master the fundamentals.” And how fitting would it be for the archetypal TICORA to face an Origin Story Bracket team in the Championship?

Whatever happens, this future Hall of Famer will be always be a slam dunk for rheumatology.

Next scouting report: Clonal Selection

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. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet. 2004;364(9430):263-269. doi:10.1016/S0140-6736(04)16676-2
2. Plant MJ, Williams AL, O’Sullivan MM, et al. Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid arthritis. Arthritis Rheum 2000; 43(7): 1473–77. doi: 10.1002/1529-0131(200007)43:7<1473::AID-ANR9>3.0.CO;2-N. PMID: 10902748
3. Haagsma CJ, van Riel PL, de Jong AJ, et al. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol. 1997;36(10):1082-8. doi: 10.1093/rheumatology/36.10.1082. PMID: 9374925.
4. Boers M, Verhoeven AC, Markusse HM, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet. 1997;350(9074):309-18. doi: 10.1016/S0140-6736(97)01300-7.
5. Sokka T, Mäkinen H, Puolakka K, et al. Remission as the treatment goal–the FIN-RACo trial. Clin Exp Rheumatol. 2006;24(6 Suppl 43):S-74-6. PMID: 17083766.
6. 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):3381-90. doi: 10.1002/art.21405. PMID: 16258899.
7. Moreland, L.W., O’Dell, J.R., Paulus, H.E., 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. https://doi.org/10.1002/art.34498
8. Smolen JS, Aletaha D, Bijlsma JWJ for the T2T Expert Committee, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Annals of the Rheumatic Diseases. 2010;69:631-637. http://dx.doi.org/10.1136/ard.2009.123919
9. Singh, J.A., Furst, D.E., Bharat, A., et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res. 2012;64: 625-639. https://doi.org/10.1002/acr.21641
10. Smolen JS, Braun J, Dougados M, et al. Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: Recommendations of an international task force. Ann. Rheum. Dis. 2014;73:6–16. doi: 10.1136/annrheumdis-2013-203419
11. van Vollenhoven RF, Mosca M, Bertsias G et al. Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann Rheum Dis. 2014;73(6):958-67. doi: 10.1136/annrheumdis-2013-205139. Epub 2014 Apr 16. PMID: 24739325.
12. Stamp, LK, Frampton C, Morillon MB, et al. Association between serum urate and flares in people with gout and evidence for surrogate status: a secondary analysis of two randomised controlled trials. The Lancet Rheumatology. 2022;4(1) e53–e60. https://doi.org/10.1016/S2665-9913(21)00319-2.
13. Häuser, W, Clauw, DJ, Fitzcharles, MA. Treat-to-Target Strategy for Fibromyalgia: Opening the Dialogue. Arthritis Care Res. 2017;69: 462-466. https://doi.org/10.1002/acr.22970
14. Nierengarten, MB. The ACR is exploring a rheumatology-specific APM. The Rheumatologist. 2017 at https://www.the-rheumatologist.org/article/acr-exploring-rheumatology-specific-apm/?singlepage=1 accessed January 11, 2023
15. Fusillo, P. The 2022 ACR awards of distinction. The Rheumatologist. 2022 at https://www.the-rheumatologist.org/article/the-2022-acr-awards-of-distinction/?singlepage=1 accessed January 11, 2023
16. Fraenkel, L, Bathon, JM, England, BR, et al. 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res. 2021;73: 924-939. https://doi.org/10.1002/acr.24596

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.

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

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, 2^nd year resident; Chelsea Thompson, MD, 1^st year rheumatology fellow; John Byun, MD, 2^nd 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.