Team: RAVE Trial, aka “Team PR3 (Perpetually Raining 3’s)”

Region: Jump ball

Base article: Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232. PMID: 20647199.

Authors: Wake Forest Rheumatology Fellowship Program. Khiem Vu, MD, Second-Year Rheumatology Fellow, Rachel Wolfe, MD, Assistant Professor, Jon Golenbiewski, DO, Assistant Professor.

Team Overview

For many years, the combination of cyclophosphamide (CYC) and high dose steroids was standard of care for remission induction in ANCA-associated vasculitis (AAV). Introduced in the early 1970s by then 32-year-old Anthony Fauci and his mentor Sheldon Wolff, this CYC-based regimen transformed what used to be a near-death sentence into a manageable, chronic disease. Nevertheless, CYC is associated with significant infectious risk as well as other potential life-changing side effects including infertility, hemorrhagic cystitis and secondary malignancies, amongst others. As such, better treatment options were needed.

A major shift occurred after the publication of the 2010 Rituximab (RTX) in ANCA-Associated Vasculitis (RAVE) trial in the NEJM by Stone et al. A multicenter, randomized, double-blind, double-dummy, non-inferiority trial, it compared RTX with steroids to oral CYC with steroids for remission induction in 197 patients with newly diagnosed and relapsing AAV over 6 months. The results of this study have changed the standard of care ever since; the RTX-based regimen was found to be noninferior to CYC in achieving steroid-free, complete disease remission at 6-month follow up. Additionally, RTX was superior to CYC in achieving remission for relapsing cases of AAV at baseline. Moreover, there was no significant increase in adverse effects in RTX compared to CYC treatment arm.

Impact on Rheumatology

The 2010 RAVE trial is one of the most important developments in modern rheumatology. The preference of RTX over CYC for severe AAV (whether new-onset or relapsing) continues to this day, as reflected in the first ever 2021 joint guideline by the American College of Rheumatology/Vasculitis Foundation for the management of AAV. The toppling of CYC from its four decades of “G.O.A.T” status underscores that accepting the status quo is incompatible in a field like rheumatology, and we should always strive for improving the care of our patients.

Chances in the Tournament

It’s quite clear that we are the team to beat! We are the only team in the tournament with RAVE reviews, what a very impressive feat! Siding with another team would be like choosing CYC over Rituximab; sure, it works and may get you the “W”, but why would you choose a team that will do nothing but trouble you? Although we are confident in our chances in the tournament, we do expect to run into some tough competition from the other non-inferiority trials. There has been lots of talk about a lupus nephritis trial that also aimed to dethrone CYC, but with a different agent, mycophenolate. However, we are only modestly impressed, at best. After all, “The enemy of my enemy is [not always] my friend”. Should you choose to go with another team, the ref will surely blow their whistle for a travel; naysayers tread lightly, as you will watch your bracket unravel.

Next scouting report: HCQ Withdrawal

Back to the full list of scouting reports.

See the Q&A on theMednet.org for the Jump Ball region: Is there a role for monitoring serum ANCAs to assess ANCA associated vasculitis disease activity?

References

1. Chung SA, Langford CA, Maz M, Abril A, Gorelik M, Guyatt G, Archer AM, Conn DL, Full KA, Grayson PC, Ibarra MF, Imundo LF, Kim S, Merkel PA, Rhee RL, Seo P, Stone JH, Sule S, Sundel RP, Vitobaldi OI, Warner A, Byram K, Dua AB, Husainat N, James KE, Kalot MA, Lin YC, Springer JM, Turgunbaev M, Villa-Forte A, Turner AS, Mustafa RA. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Arthritis Rheumatol. 2021 Aug;73(8):1366-1383. doi: 10.1002/art.41773. Epub 2021 Jul 8. PMID: 34235894.
2. Cohen, Ben. “The Mentor who made Dr. Anthony Fauci”. The Wall Street Journal. April 16, 2020. https://www.wsj.com/articles/the-mentor-who-made-dr-anthony-fauci-11587040520
3. Fauci AS, Wolff SM. Wegener’s granulomatosis: studies in eighteen patients and a review of the literature. Medicine (Baltimore). 1973;52(6):535-561.
4. Maugh, Thomas. “Researchers find new therapy for vasculitis”. Los Angeles Times. July 14, 2010. https://www.latimes.com/archives/la-xpm-2010-jul-14-la-heb-vasculitis-20100714-story.html.
5. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232. PMID: 20647199

Team: HCQ Withdrawal, aka “2legit2quit- Hydroxychloroquine- Why you ‘Can’t Touch This’  drug”

Region: Jump Ball

Base Article: Canadian Hydroxychloroquine Study Group. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med. 1991;324(3):150-154. doi:10.1056/NEJM199101173240303. PMID 1984192

Authors: Belinda Birnbaum, MD- Rheumatologist, Bryn Mawr Medical Specialists Association; Jay Ghadiali, MD- Rheumatologist, Bryn Mawr Medical Specialists Association. Bryn Mawr, PA.

Team Overview

Every Rheumatologist should know that 1991 was a remarkable year.  The first World Wide Web website launched, the former U.S.S.R disbanded, The Duke Blue Devils started their basketball reign with their first NCAA championship, and MC Hammer topped the charts. But it was also the year that one study  would lay the foundation for lupus management for decades.. It’s time to pay homage to one of the GOATs in rheumatology.

In 1991, Dr. Esdaile and his Canadian Colleagues demonstrated that the necessity of hydroxychloroquine (HCQ) was not mere hypothesis or hyperbole but plain-spoken truth; hydroxychloroquine was purposeful to lupus patients, and its withdrawal would prove problematic [1].

We 21st-century rheumatologists take it as a given that HCQ,  once started, should rarely be stopped.  But that wasn’t always the case. While it was known for decades that antimalarials work for lupus [2], the doubters didn’t feel comfortable keeping patients on it long term (the doubters were not just ophthalmologists, but rheumatologists too). Our authors had a hunch it was necessary and safe so they conducted a randomized controlled trial.  Stable patients with SLE on hydroxychloroquine for at least six months were randomized to either continuation of HCQ,  or to the withdrawal of it,  taking a placebo for 24 weeks.

What was the bottom line?   The relative risk of a clinical flare-up was 2.5 times higher (95 percent confidence interval, 1.08 to 5.58) in the patients taking a placebo than in those continuing to take hydroxychloroquine (16 of 22 patients vs. 9 of 25 had flare-ups), and the primary outcome, the time to a flare-up was shorter (P = 0.02).  The secondary outcomes were a change in the prednisone dose and development of a a severe flare. The lupus patients on placebo had to increase their prednisone more and had more severe flares than patients who were taking hydroxychloroquine.  These measurements did not reach statistical significance.  Long-term hydroxychloroquine helps our lupus patients.  Not only is it necessary to initiate hydroxychloroquine at disease diagnosis, but also to continue hydroxychloroquine to prevent flares and progression.

Impact on Rheumatology

The impact of long-term hydroxychloroquine use cannot be understated. There is no other drug available to rheumatologists today with so much benefit and so few adverse events.  Can you think of another DMARD (maybe methotrexate?),that you prescribe more frequently than hydroxychloroquine? Yeah, we didn’t think so.  Can you imagine a time when maintaining a patient on HCQ wasn’t obvious? We can’t, but we are a Gen X and a Millennial. (To any boomer blue ribbon panelists, we think you look great)

Hydroxychloroquine is timeless. No matter what other drug we use for lupus, we know this will always be part of our armamentarium.  It is the steady workhorse we need. Any player or coach knows that a solid defense wins games,  no matter how flashy an offense is.  In that sense, hydroxychloroquine is the tenacious D of rheumatology.

Chances in the Tournament:

When looking at the other contenders, we would like you to ask yourself this question- Where would you be as a rheumatologist without Hydroxychloroquine?  When put this way,  we see our chances as excellent!

While RAVE offered rituximab for ANCA-associated vasculitis,  and ALMS offered mycophenolate mofetil for lupus nephritis, they merely added options to an already available drug, cyclophosphamide. Two trials show the same thing; The drug they are rooting for is better or non-inferior to something else…meh.  Are they a cornerstone for maintenance without causing diarrhea or infusion reactions?  Are they prescribed without the headache of prior authorizations and complicated instructions over proper administration?  No, no they are not.    And let’s talk about cost-effectiveness.  Fans of the Michael Lewis book  “Moneyball” or fans of the movie can learn how the Oakland Athletics won the World Series despite having one of the lowest payrolls in all of Major League Baseball.  Hydroxychloroquine is the “Moneyball” of rheumatology. Sure, it doesn’tfill the stands and stadiums like the high-cost players (yes, you Rituximab; and mycophenolate mofetil, you are no bargain), but it gets the job done and can win championships so we are optimistic. As years have passed, we find more ways it helps our patients. It provides better pregnancy outcomes, it reduces thrombotic events [3,4].  What will it do next?  Cure a global pandemic?  Yeah, no. Not that

More like the song, and unlike MC Hammer’s parachute pants, you can’t touch Hydroxychloroquine; it is too legit.  When the ref tosses up that jump ball, we will easily take possession and win.

Next scouting report: ALMS Trial

Back to the full list of scouting reports.

See the Q&A on theMednet.org for the Jump Ball region: Do you ever consider discontinuing hydroxychloroquine SLE patients in longstanding remission except in cases of overt toxicity?

References

1. Canadian Hydroxychloroquine Study Group. A randomized study of the effect of withdrawing hydroxychloroquine sulfate in systemic lupus erythematosus. N Engl J Med. 1991;324(3):150-154. doi:10.1056/NEJM199101173240303
2. PAGE F. Treatment of lupus erythematosus with mepacrine. Lancet. 1951;2(6687):755-758. doi:10.1016/s0140-6736(51)91643-13. Clowse MEB, Eudy AM, Balevic S, et al. Hydroxychloroquine in the pregnancies of women with lupus: a meta-analysis of individual participant data. Lupus Sci Med. 2022;9(1):e000651. doi:10.1136/lupus-2021-000651
3. Petri M, Konig MF, Li J, Goldman DW. Association of Higher Hydroxychloroquine Blood Levels With Reduced Thrombosis Risk in Systemic Lupus Erythematosus. Arthritis Rheumatol. 2021;73(6):997-1004. doi:10.1002/art.41621
4. MC Hammer 2legit2quit official video https://youtu.be/HFCv86Olk8E (we recommend skipping to minute 8:30 for the actual song)

Team: HAQ, aka “Ask the PROs”

Region: The Whole Patient

Base article: Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980;23(2):137-145. doi:10.1002/art.1780230202. PMID: 7362664.

Authors: RheumMadness Leadership Team. Meridith Balbach, medical student, Vanderbilt University Medical Center; Courtney Bair, medical student, Duke University School of Medicine; Ben Lueck, medical student, Duke University School of Medicine; Lauren He, MD, chief internal medicine resident, University of Chicago; Ben Kellogg, MD, internal medicine resident, Duke University School of Medicine; Sabahat Usmani, MD, internal medicine resident, Weiss Memorial Hospital; Guy Katz, MD, rheumatology fellow, Massachusetts General Hospital; Michael Macklin, MD, rheumatology fellow, University of Chicago; Iman Qaiser, MD, rheumatology fellow, LSU Health Shreveport; Akrithi Udupa Garren, MD, assistant professor of medicine, Medstar / Georgetown Washington Hospital Center; David Leverenz, MD, assistant professor of medicine, Duke University School of Medicine.

Team Overview

Field goals. Rebounds. Assists. Steals. Turnovers. Basketball stats are a celebrated part of the game, arming fans with cold hard data to quantify the performance of a team or player. One must be wary, however, of measures that don’t translate into wins—not only in basketball, but in rheumatology, too.

In the late 20^th century, rheumatology coaches were grappling with finding measures that represented clinically meaningful buckets. Historically they had turned to outcomes such as the presence of synovitis, grip strength, morning stiffness; labs such as ESR; and radiographic changes to assess response to treatment.¹ In 1980, James Fries et al. entered the endpoints arena with an entirely new type of play—patient-reported outcomes (PROs).²

In “Measurement of Patient Outcome in Arthritis,” the authors recognize and address the need for clinically meaningful measures in the context of chronic disease—specifically, rheumatoid arthritis. Moving beyond pre-existing scales that often lacked reliability, validity, and feasibility, the authors sought to develop and validate a systematic PRO, coined as the Health Assessment Questionnaire (HAQ).^3-5 To do so, they administered self-evaluated and interview questionnaires in an initial cohort of 20 patients to assess dimensions of death, discomfort, disability, drug toxicity, and dollar cost, finding good reliability. Subsequent correlation of evaluator and self-administered HAQ assessing standardized task performance in 25 patients demonstrated validity.

The resulting validated instrument, now known as the HAQ disability index (HAQ-DI) or legacy HAQ, transformed the way rheumatologists view the (assessment) lineup—moving the patient from the role of oft-overlooked benchwarmer to coveted starter.

Impact on Rheumatology

Coach Fries et al. revolutionized the recruitment landscape, demonstrating principles of good PRO development and evolution.⁶ The HAQ, translated into 60+ languages and now cited more than 5000 times, spawned the development of derived PROs including the modified HAQ (MHAQ), simplified 10-item HAQ-II, and multidimensional HAQ (MDHAQ).⁷ Alongside its friendly rival (also published in 1980), the Arthritis Impact Measurement Scales (AIMS), it spurred exponential growth of additional PROs in rheumatology—as evidenced by dedicated Arthritis Care & Research special editions in 1992, 2003, and 2011—the last of which reported greater than 250 PROs.^1,8,9 No longer limited to rheumatoid arthritis, generic and disease-specific instruments cover a diversity of pathologies from systemic lupus erythematosus with the LupusQoL to systemic sclerosis with the scleroderma HAQ (SHAQ).^10,11

The HAQ provided evidence that well-crafted patient-reported outcomes might outperform “the so-called hard measures.”¹ Like an energized fanbase doing the wave, the rippling effects of this paradigm shift are apparent. Consider OMERACT (initially coined as “Outcome Measures in Rheumatoid Arthritis Clinical Trials”, now broadened to “Outcomes Measures in Rheumatology”), an international effort to achieve endpoint consensus. Recognizing the importance of patient experience, they included three PROs (pain, patient global assessment, and functional capacity) amongst their Core Set of variables to be collected in all rheumatoid arthritis clinical trials.¹² This recommendation has since been expanded to include additional PROs and disease-specific criteria for ANCA-associated vasculitis, idiopathic inflammatory myopathies, and more.^13,14

In the post-game interview, Fries reflected that “people almost didn’t notice that their thinking had shifted from a narrower medical model to a broader psychosocial model of health and illness.”¹ Indeed, the PROs inspired rheumatologists and other chronic disease specialists to become more patient-centered not only in their endpoints, but entire practice— fundamentally changing the game.

Chances in the Tournament

In our view, the first-round opponent of the PROs may be their toughest, with the LUMINA study drawing attention to socioeconomic-demographic disparities in SLE outcomes. However, the Blue Ribbon Panel might recognize that many of the salient findings of LUMINA rely on use of the Illness Behavior Questionnaire and Rheumatology Attitudes Index—that is, PROs.

After conquering the “Whole Patient” bracket, the PROs will conquer the winner of the “Origin Story” region. While RheumMadness fans may enjoy rooting for a Cinderella team, they must remember that such success is few and far between— an early case report of rheumatology disease is fascinating, but it’s best to bet on a #1 seed. From there, the success of the PROs largely depends on whether the Blue Ribbon Panel is more focused on impressive clinical trial data or paradigm shifts within the field. Given the theme of this year’s competition, the latter may be true, allowing this team to truly live up to its name.

The most important and transformational article ever written in the field of rheumatology? Just ask the PROs!

Next scouting report: Cortisone

Back to the full list of scouting reports.

See the Q&A on theMednet.org for The Whole Patient region: What target do you utilize in clinical practice for defining disease remission in RA?

References

1. Callahan LF. The History of Patient-Reported Outcomes in Rheumatology. Rheum Dis Clin North Am. May 2016;42(2):205-17. doi:10.1016/j.rdc.2016.01.012
2. Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. Feb 1980;23(2):137-45. doi:10.1002/art.1780230202
3. McCloy L, Jongbloed L. Robinson Bashall Functional Assessment for arthritis patients: reliability and validity. Arch Phys Med Rehabil. Aug 1987;68(8):486-9.
4. Lee P, Jasani MK, Dick WC, Buchanan WW. Evaluation of a functional index in rheumatoid arthritis. Scand J Rheumatol. 1973;2(2):71-7. doi:10.3109/03009747309098820
5. Convery FR, Minteer MA, Amiel D, Connett KL. Polyarticular disability: a functional assessment. Arch Phys Med Rehabil. Nov 1977;58(11):494-9.
6. Deshpande PR, Rajan S, Sudeepthi BL, Abdul Nazir CP. Patient-reported outcomes: A new era in clinical research. Perspect Clin Res. Oct 2011;2(4):137-44. doi:10.4103/2229-3485.86879
7. Maska L, Anderson J, Michaud K. Measures of functional status and quality of life in rheumatoid arthritis: Health Assessment Questionnaire Disability Index (HAQ), Modified Health Assessment Questionnaire (MHAQ), Multidimensional Health Assessment Questionnaire (MDHAQ), Health Assessment Questionnaire II (HAQ-II), Improved Health Assessment Questionnaire (Improved HAQ), and Rheumatoid Arthritis Quality of Life (RAQoL). Arthritis Care Res (Hoboken). Nov 2011;63 Suppl 11:S4-13. doi:10.1002/acr.20620
8. Katz PP. Introduction to special issue: patient outcomes in rheumatology, 2011. Arthritis Care Res (Hoboken). Nov 2011;63 Suppl 11:S1-3. doi:10.1002/acr.20585
9. Meenan RF, Gertman PM, Mason JH. Measuring health status in arthritis. The arthritis impact measurement scales. Arthritis Rheum. Feb 1980;23(2):146-52. doi:10.1002/art.1780230203
10. McElhone K, Abbott J, Shelmerdine J, et al. Development and validation of a disease-specific health-related quality of life measure, the LupusQol, for adults with systemic lupus erythematosus. Arthritis Rheum. Aug 15 2007;57(6):972-9. doi:10.1002/art.22881
11. Steen VD, Medsger TA. The value of the Health Assessment Questionnaire and special patient-generated scales to demonstrate change in systemic sclerosis patients over time. Arthritis Rheum. Nov 1997;40(11):1984-91. doi:10.1002/art.1780401110
12. Gossec L, Dougados M, Dixon W. Patient-reported outcomes as end points in clinical trials in rheumatoid arthritis. RMD Open. 2015;1(1):e000019. doi:10.1136/rmdopen-2014-000019
13. Merkel PA, Aydin SZ, Boers M, et al. The OMERACT core set of outcome measures for use in clinical trials of ANCA-associated vasculitis. J Rheumatol. Jul 2011;38(7):1480-6. doi:10.3899/jrheum.110276
14. Regardt M, Basharat P, Christopher-Stine L, et al. Patients’ Experience of Myositis and Further Validation of a Myositis-specific Patient Reported Outcome Measure – Establishing Core Domains and Expanding Patient Input on Clinical Assessment in Myositis. Report from OMERACT 12. J Rheumatol. Dec 2015;42(12):2492-5. doi:10.3899/jrheum.141243

Team: LUMINA

Region: The Whole Patient

Base article: Uribe AG, McGwin G Jr, Reveille JD, Alarcón GS. What have we learned from a 10-year experience with the LUMINA (Lupus in Minorities; Nature vs. nurture) cohort? Where are we heading? Autoimmun Rev. 2004 Jun;3(4):321-9. doi: 10.1016/j.autrev.2003.11.005. PMID: 15246029.

Authors: Northwestern University Rheumatology Fellowship Program. Lakshmi Jayaram, MBBS, second year rheumatology fellow, Brian Jaros, MD, first year rheumatology fellow, Laura Arneson, MD, first year rheumatology fellow, Anisha Dua, MD, MPH, Associate Professor, Fellowship Program Director.

Team Overview

The LUMINA cohort was one of the first sources of prospective data highlighting the associations between ethnicity, social determinants of health, and SLE morbidity and mortality in the United States. Previous studies had demonstrated racial disparities in the prevalence and severity of SLE, though prior investigation had focused on genetic and behavioral factors underlying these disparities, and involved smaller cohorts with fewer racial groups (Ward 1990, Petri 1991, McCarty 1995, Jordan 2002, Petri 1991). This paper summarizes the findings from the first 10 years of the LUMINA (Lupus in Minorities: Nature vs. Nurture) cohort, which began enrolling patients with SLE of <5 years duration at the University of Alabama – Birmingham and the University of Texas – Houston in 1994; a site in Puerto Rico was added in 2001. At the time of this publication, the cohort included 587 patients with a mean follow-up time 40 months. Overall the study demonstrated higher disease activity and damage accrual among patients of African American or Texas Hispanic ethnicity, compared to patients of Caucasian or Puerto Rican Hispanic ethnicity, in association with both socioeconomic and genetic factors. Specifically, factors associated with higher disease activity on the SLAM (Systemic Lupus Activity Measure) at enrollment included African American ethnicity, lack of private health insurance, and particular HLA alleles. Damage measured by the SDI (SLICC/ACR Damage Index) was highest at enrollment among African American patients and accrued most rapidly among Texas Hispanic patients; it was also associated with education, poverty, and the HLA DR8 allele. Compared to Caucasian and Puerto Rican Hispanic patients, Texas Hispanic and African American patients were less likely to be on hydroxychloroquine at enrollment, were more likely to require corticosteroids and cyclophosphamide, and had a higher cumulative prevalence of lupus nephritis. In multivariate analysis, early mortality was predicted by disease activity, damage, and most strongly by poverty.

Impact on Rheumatology

The root of the word LUMINA is light. Much like its name, this landmark study has been shedding light on the importance of interplay between biologic and non-biologic factors in rheumatologic disease processes like SLE.

To start with, the LUMINA trial ignited an awareness amongst scientists in rheumatology to be cognizant of the importance of diversity and inclusion in their study samples. It earmarked the start of individualized care to rheumatology patients with consideration of immunogenetic, clinical, sociodemographic, and psychosocial factors.

There are multiple important nested case control studies that resulted from the parent study LUMINA. Fifty years ago, we learned about mortality in SLE related to atherosclerosis. Twenty-five years ago, we learned about increased myocardial infarctions in women with SLE. Now, thanks to LUMINA, we have learned that cardiovascular disease in SLE is multifactorial and related to age, gender, inflammatory marker levels, and baseline disease activity. The role of hydroxychloroquine in preventing damage accrual and reducing mortality in lupus patients is a major contribution of LUMINA. LUMINA also proved the factors contributing to adverse pregnancy outcomes ranged from renal involvement to African American ethnicity and fewer years of education- which in turn changed the landscape of counseling pregnant women with SLE. Disease burden aside, this paper also led to us to begin to understand socioeconomic barriers to accessing health care for underprivileged populations. In terms of tangible outcomes, the above studies resulted in development of multiple CDC (Centers for Disease Control)-funded SLE education and outreach programs to help increase awareness in vulnerable populations who have data indicating worse outcomes with disease.

Listed above are just a few of the many impactful advances that were derived from the LUMINA study- with the promise of many more such relevant studies. In the words of Dr. Suzanne Serrate-Sztein from NIAMS, the LUMINA cohort database can be considered “a national resource”.

Chances in the Tournament

While many of the competitor articles outline significant diagnostic, pathophysiologic or therapeutic advancements, only LUMINA summates components of each of these core domains into one landmark study. Beyond this, LUMINA demonstrates how these advancements are ultimately subject to various genetic and social determinants of health. In 20 years, the landscape of the tournament bracket will be filled with new pharmaceutical agents that have transcended these listed in 2023. However, the interaction of ethnicity, social determinants of health, and rheumatologic disease will continue to be a durable mainstay of conversation due to its lasting and pervasive effects on the way we care for patients. LUMINA represents a first major step in the initiation of this conversation, and for this reason we believe it will shoot the lights out in this year’s Rheum Madness competition.

Next scouting report: HAQ

Back to the full list of scouting reports.

See the Q&A on theMednet.org for The Whole Patient region: What target do you utilize in clinical practice for defining disease remission in RA?

References:

1. Uribe AG, McGwin G Jr, Reveille JD, Alarcón GS. What have we learned from a 10-year experience with the LUMINA (Lupus in Minorities; Nature vs. nurture) cohort? Where are we heading? Autoimmun Rev. 2004 Jun;3(4):321-9. doi: 10.1016/j.autrev.2003.11.005. PMID: 15246029.

Team: ALMS Trial

Region: Jump Ball

Base article: Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. Journal of the American Society of Nephrology : JASN. 2009 May 2009;20(5)doi:10.1681/ASN.2008101028. PMID: 19369404.

Authors: University of Alabama at Birmingham Rheumatology Fellowship Program. Maria Salgado Guerrero, MD, second year fellow, Vijay Kannuthurai, MD, second year fellow, Mariana Urquiaga Changanaqui, MD, second year fellow, Joanna Potera, MD, first year fellow, T. Alex Edgil, MD, first year fellow, Haneen Abdalhadi, MD, first year  fellow, John Bridges, MD, fourth year combined adult/pediatric rheumatology fellow, Amanda S. Alexander, MD, Assistant Professor, University of Alabama at Birmingham.

Team Overview

2009 is remembered for all-time NBA great Kobe Bryant securing his 4th NBA Championship trophy; however, 2009 can also be remembered for one of the all-time great trials in Rheumatology history — the ALMS trial. Lupus nephritis affects more than half of patients with lupus and increases morbidity and mortality, especially in non-white patients ². Prior to the Aspreva Lupus Management Study (aka

the ALMS trial), high-dose cyclophosphamide using the “NIH protocol” was standard of care treatment for proliferative lupus nephritis ³. While dose-reduction was proven effective with the EuroLupus regimen, the high toxicity issues of cyclophosphamide remained ⁴. The ALMS trial was one of the largest lupus trials at its time of publication with 370 patients from 88 centers in 20 countries; and was particularly diverse with a group of patients from all over the world ¹. In this multinational cohort, no significantly detectable difference in response rate between MMF and cyclophosphamide was found. There were no significant differences in the rate of adverse events between the two treatment groups. An important subgroup analysis revealed that efficacy of cyclophosphamide in patients of Hispanic or African descent was reduced compared to other race/ethnicity subgroups, and that mycophenolate was consistently effective in all racial and ethnic groups.

Impact on Rheumatology

In a disease that disproportionately affects reproductive age women of color, the impact of a large and racially diverse study with implications related to lowering malignancy and infertility risks cannot be understated. Gonadal toxicity, infectious risk, bladder malignancy, and hematologic toxicity all pose serious possible complications to the use of cyclophosphamide in treating proliferative lupus nephritis. In addition, the inconvenience and higher resource burden of intravenous therapy are other factors that limit its use and accessibility for patients. This was one of the largest and most racially diverse studies for the treatment of lupus nephritis at its time. Dirk Nowitzki, Yao Ming, Giannis Antetokounmpo, the ALMS trial — all great examples how diversity improves the field as a whole. Because of these findings, these treatment principles can be extrapolated to diverse populations across the world affected by lupus nephritis. In place of hospital admission or infusion center access, this practice-changing study (we’re talking about practice!) showed equivalent benefit of therapy with oral medications without dedicated facilities and supervision by healthcare providers.

Chances in the Tournament

The ALMS trial is certainly a fan favorite—the saving grace for the struggling rheumatology fellow that hopes to avoid another sleepless night looking up cyclophosphamide dosing regimen and MESNA calculations. Why use cyclophosphamide after reading the ALMS trial? Hydroxychloroquine withdrawal won’t save rheum fellows any sleepless nights, so you might as well consider the first round a bye and go ahead and face the ALMS trial off against RAVE (another trial notably forcing patients to sit through infusions). No matter who wins the ALMS-RAVE match-up, cyclophosphamide is the loser.

Next scouting report: LUMINA

Back to the full list of scouting reports.

See the Q&A on theMednet.org for the Jump Ball region:

1. Do you ever consider discontinuing hydroxychloroquine SLE patients in longstanding remission except in cases of overt toxicity?
2. Is there a role for monitoring serum ANCAs to assess ANCA associated vasculitis disease activity?

References:

1. Appel GB, Contreras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. Journal of the American Society of Nephrology : JASN. 2009 May 2009;20(5)doi:10.1681/ASN.2008101028
2. Dooley MA, Hogan S, Jennette C, Falk R. Cyclophosphamide therapy for lupus nephritis: poor renal survival in black Americans. Glomerular Disease Collaborative Network. Kidney international. 1997 Apr 1997;51(4)doi:10.1038/ki.1997.162
3. McCune WJ, Golbus J, Zeldes W, Bohlke P, Dunne R, Fox DA. Clinical and immunologic effects of monthly administration of intravenous cyclophosphamide in severe systemic lupus erythematosus. The New England journal of medicine. 06/02/1988 1988;318(22)doi:10.1056/NEJM198806023182203 4. Houssiau FA, Vasconcelos C, D’Cruz D, et al. Immunosuppressive therapy in lupus nephritis: the Euro-Lupus Nephritis Trial, a randomized trial of low-dose versus high-dose intravenous cyclophosphamide. Arthritis and rheumatism. 2002 Aug 2002;46(8)doi:10.1002/art.10461

Team: Cortisone, aka “Rheum on the Rocks”

Region: Origin Story

Base article: Hench PS, Kendall EC, et. al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949;24(8):181-197.

Authors: University of Colorado Rheumatology Fellowship Program. Smarika Sapkota, MD, second year rheumatology fellow, David DeFrancisco, MD, first year rheumatology fellow, Jason Kolfenbach, MD, Associate Professor of Medicine.

Team Overview

Philip Hench and colleagues published their landmark article in 1949, during an era in which knowledge regarding the pathologic underpinnings of rheumatoid arthritis (RA) was limited, as were treatment options. Patients at that time were treated with aspirin (distributed by Bayer in 1899)², or much less commonly gold or sulfonamide compounds (1930s)³, often with limited success. The initial use of sulfonamide compounds such as sulfasalazine, as well as medications such as d-penicillamine (1950s), reflected a prevailing hypothesis that RA was a microbial-driven disease.

In this landmark study, Hench and colleagues demonstrated remarkable clinical and laboratory improvements in RA disease control through administration of their ‘Compound E’ (17-hydroxy-11-dehydrocorticosterone) to 14 patients with severe RA. This study was critical to the field of rheumatology not only for the discovery of an effective therapeutic agent (cortisone), but also because it supported a biochemical basis of disease rather than a microbial origin.

Prior to the publication of this study, Hench had studied the beneficial effects of pregnancy and jaundice on RA. The improved disease activity that he observed in these settings was a novel finding, as RA was previously thought to be an irreversible disease. Based on his observations, he sought to find a common biochemical denominator between pregnancy and jaundice that could lead to a potential therapeutic intervention for RA. After a series of trial-and-error experiments, the team settled on an adrenal hormone as the most likely ‘anti-rheumatic substance X’, and on September 21, 1948, they began treating their first patient with Compound E.

This study describes the subjective and objective responses of 14 patients following treatment with Compound E. Improvement was noted in muscle and joint pain, functional status, appetite, strength, and overall sense of well-being (including the first description of steroid-associated ‘euphoria’). In addition, reductions in ESR and serum gammaglobulin were reported, as well as improvement in disease-associated anemia. The biologic effect of Compound E was further supported by studies of drug withdrawal and subsequent re-institution upon disease flare.

Impact on Rheumatology

This landmark study provided the first evidence that corticosteroids could significantly improve the lives of patients suffering from RA, and its results suggested an alternative to the microbial theory of disease pathogenesis. This latter discovery shaped research in the decades to follow, helping to steer the field away from viewing RA as primarily the result of an infectious agent and shifting the focus toward therapeutics without anti-microbial properties. The experiments described in this study also relied upon collaboration with industry partners (Merck and Co.), a foreshadowing of the academic-industry relationship that drives many drug discoveries of today.

Following the improvement seen in patients with RA, Hench and colleagues then began to administer Compound E to lupus patients, with ‘encouraging results’, and describe a patient with myasthenia gravis who improved following treatment with ACTH. These point to the widespread applicability of corticosteroids in inflammatory/autoimmune disease.

Chances in the Tournament

Do we love this study? Let us count the ways: the discovery of the therapeutic potential of steroids, evidence of a biochemical basis of RA, initial descriptions of steroid-related side effects, and application to other diseases such as lupus and myasthenia gravis. Oh, and yes, the authors were awarded the Nobel Prize (the following year!) as a result of their decades long work in this area.

While we believe this study is a clear favorite to win the tournament, it may also be viewed by some readers as a ‘blue-blood’ that needs to step aside and make way for new therapies. Just as many fans have become tired of seeing Duke basketball play in the past 25 NCAA tournaments, or SEC football teams annually winning the championship game, some may feel that prednisone has already had its day in the sun.

It may also be tempting to overlook this study due to the side effects associated with corticosteroids, as well as numerous studies investigating the ability to reduce our dependence on them^4-6. Even so, it’s important to recognize that all medications have side effects, and as with any drug, medication risk can be mitigated by a cautious, conscientious prescriber, and balanced against the potential benefit. With this said, let’s recognize the many positives this precious gift provides to our patients with rheumatic disease and give credit where it’s due. So, the next time you are consulted on a patient with diffuse alveolar hemorrhage and a pulmonary-renal syndrome in the ICU, think of the value of corticosteroids, and the impact their discovery has had on the field of medicine.

Next scouting report: Origin of RA

Back to the full list of scouting reports.

References

1. Hench PS, Kendall EC, et. al. The effect of a hormone of the adrenal cortex (17-hydroxy-11-dehydrocorticosterone; compound E) and of pituitary adrenocorticotropic hormone on rheumatoid arthritis. Proc Staff Meet Mayo Clin. 1949;24(8):181-197.
2. Sneader W. The discovery of aspirin: a reappraisal. BMJ. 2000 Dec 23; 321(7276): 1591–1594.
3. Svartz N. The treatment of rheumatic polyarthritis with acid azo compounds. Rheumatism. 1948;4(1):180-185. Compounds
4. Stone JH, et. al. NEJM. 2017;377:317-28.
5. Jayne DR, et. al. NEJM. 2021;384:599-609
6. Walsh M, et. al. NEJM. 2020;382:622-31.

Team name: Origin of RA

Region: Origin Story

Base article: Landré-Beauvais AJ. The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800. Joint Bone Spine. 2001;68(2):130-143. doi:10.1016/s1297-319x(00)00247-5. PMID: 11324929.

Authors: Duke Rheumatology Fellowship Program. Courtney Bair, BA, third year medical student, Benjamin D. Lueck, fourth year medical student, Ann Cameron Barr, MD, first year rheumatology fellow, Sonali Bracken, MD, PhD, second year rheumatology fellow, Dahima Cintron, MD, first year rheumatology fellow, Lena Eder, MD, second year rheumatology fellow, Jeffrey Shen, MD, first year rheumatology fellow, Catherine Sims, MD, third year rheumatology fellow, Lisa Criscione-Schreiber, MD, MEd, Professor of Medicine, David Leverenz, MD, MEd, Program Director.

Team Overview

Team ‘Origins of RA’ is led by medical student captain Augustin Jacob Landré-Beauvais, a rookie looking to make a splash. In describing and deliberating on gout, he publishes a case series of nine patients he thought did not present with “ordinary gout,” and in doing so, he provides what is generally acknowledged as the first description of Rheumatoid Arthritis (RA).^1,2 Far ahead of his time in the year 1800, his distinction of RA from gout transforms the field.

But this team is far from all flash, they follow the fundamentals of the game. They not only clinically differentiate gout and RA, but go on to describe common pathologic findings of RA. In the face of adversity and with limited technology, they report autopsy findings clearly describing synovial involvement and bony erosions, defining hallmark pathologies of the disease. They even go further to recommend treatment strategies far ahead of their time, focusing on prevention of recurrent flares.

Impact on Rheumatology

What change had the biggest impact on modern basketball? Changing from 9 players on the court at a time to 5? Starting to use a regulated and standard sized ball? Introducing the three-point line? Like the game of basketball, the field of rheumatology and specifically the treatment of RA has drastically changed over time. In the management of RA, it is clear that nothing was more impactful than Augustin Jacob Landré-Beauvais first recognizing RA as its own disease process and not “ordinary gout”. Landré-Beauvais’s paper distinguished RA as a separate disease process and indicated the need for different and unique treatment options that didn’t include blood letting, astringent agents, and topical emollients, which were the standard treatment for gout at the time. Without this monumental discovery, we very well may still be treating RA with colchicine and allopurinol.

Chances in the Tournament

It is hard to overstate the contributions of team ‘Origins of RA’ as they totally changed the game and laid the foundation for those who come behind them. Given the all-around strength of the team, they must be considered a favorite in the tournament. They drew some tough early matchups against team “Origins of sJIA” and team “Cortisone,” but if they can make it out of their region, they look to be strong favorites against teams coming out of the TNF Takedown and RA Revamp regions.

Who is the most influential person to basketball? MJ? Chef Curry? The CEO of the NBA? How about James Naismith, who invented basketball in 1891, in graduate school as an assignment. Similarly, Landre-Beauvais, a medical student, was the first to distinguish gout from rheumatoid arthritis, serving as the foundation of our field and paving the way for description of other inflammatory arthritis subtypes. This distinction in causes of deforming arthritis had not been made for the past 2000 years. He noticed a pattern of patients with deforming arthritis that did not have the slam dunk features of gout and brought a new diagnosis to the game. ‘Nuff said.

Next scouting report: Origin of sJIA

Back to the full list of scouting reports.

References:

1. Landré-Beauvais AJ. The first description of rheumatoid arthritis. Unabridged text of the doctoral dissertation presented in 1800. Joint Bone Spine. 2001;68(2):130-143. doi:10.1016/s1297-319x(00)00247-5
2. Tsoucalas G, Sgantzos M. Primary asthenic gout by augustin-jacob landre-beauvais in 1800: is this the first description of rheumatoid arthritis? Mediterr J Rheumatol. 2017;28(4):223-226.

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.