CYC in PAN

Team: CYC in polyarteritis nodosa (PAN), aka “Fauci’s Power Forward”

Region: Get in the Game

Base article: Fauci AS, Katz P, Haynes BF, Wolff SM. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med. 1979 Aug 2;301(5):235-8. doi: 10.1056/NEJM197908023010503. PMID: 36563.

Authors: Allegheny Health Network Rheumatology Fellowship. Zaina Shahid, MD, first year rheumatology fellow, Nicholas Wiemer, DO, second year rheumatology fellow, Sara Shahid, MD, first year rheumatology fellow, Michael Lucke, MD, Rheumatology Program Director,

Team Overview

Before 1970, the prognosis of systemic necrotizing vasculitis was abysmal, almost uniformly fatal. Dr. Walton in his survey of 56 patients with systemic vasculitis found the average survival time to be 5 months with 81% of the patients dead within one year of diagnosis.1 The 5-year survival rate of  a cohort of patients from 1946-1962 with a diagnosis termed periarteritis nodosa, the prototypical systemic necrotizing vasculitis, was only 15% in untreated patients. Corticosteroids were the mainstay of treatment improving survival rate to only 48% .2

It was in this grim setting that Drs. Anthony Fauci and Sheldon Wolff reported on 17 patients with severe necrotizing vasculitis studied over the course of 11 years.3 16 of these patients had been treated with corticosteroids for a mean duration of 22 months and had suffered from severe side effects. All 16 patients showed subjective and objective evidence of disease progression despite treatment with corticosteroids. 16 patients were treated with cyclophosphamide 2mg/kg oral per day. 1 patient chose to continue azathioprine. A taper of corticosteroids was initiated within 2 weeks of receiving cyclophosphamide with the goal of discontinuation. 14 patients showed definite remission within 3 weeks of cyclophosphamide therapy. The mean duration of cyclophosphamide induced remission was 22 months with notably no relapses while being on cyclophosphamide. At the end of the study period, remission was achieved in all 17 patients in the study!

Impact on Rheumatology

This dramatic response to cyclophosphamide represented the first important advancement in the management of necrotizing vasculitis. This momentous discovery had significant impact on the lives of patients with systemic vasculitis.  Before this break-through, the average survival time after diagnosis was 5 months.  Now, because of the use of cyclophosphamide and the work done by Drs. Fauci and Wolff, this previously devastating disease has an effective treatment improving the survival rate to almost 80% at 5 years.4 It was a joyous moment for rheumatologists and patients alike.  Cyclophosphamide remained the MVP for many years to come as standard induction treatment of vasculitis.  This legendary player went on to compete against other legends of the game, including rituximab.  However, rituximab has never been able to surpass cyclophosphamide as an offensive player.  Additionally, cyclophosphamide set the stage for innovative treatment in numerous other rheumatic conditions ranging from pulmonary disease in scleroderma, lupus nephritis, and refractory cutaneous and myositis diagnoses.  It also remains a treatment of choice for remission induction in some forms of severe vasculitis .5 This landmark trial continues to impact the field of Rheumatology 50 years since publication.

Chances in the Tournament

A breakout, offensive star like cyclophosphamide is sure to be game changer for this tournament.  A player of this skill hasn’t been seen since Cortisone played back in 1949 for Mayo.  Combined with the skill of Dr. Fauci, a fan favorite known for sinking shots while under immense pressure from the most imposing defenses, this team will be an overwhelming force in the games to come.

Next scouting report: CYC in Scleroderma

Back to the full list of scouting reports.

See the Q&A on theMednet.org for the Get in the Game region: Are there patients in whom you would avoid initiating of ULT during acute gout flare? 

References

  1. Hollander D, Manning RT. The use of alkylating agents in the treatment of Wegener’s granulomatosis. Ann Intern Med. 1967 Aug;67(2):393-8. doi: 10.7326/0003-4819-67-2-393. PMID: 6036397.
  2. Frohnert PP, Sheps SG. Long-term follow-up study of periarteritis nodosa. Am J Med. 1967 Jul;43(1):8-14. doi: 10.1016/0002-9343(67)90144-1. PMID: 4157287.
  3. Fauci AS, Katz P, Haynes BF, Wolff SM. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med. 1979 Aug 2;301(5):235-8. doi: 10.1056/NEJM197908023010503. PMID: 36563.
  4. Catherine King, Lorraine Harper, Mark Little, The complications of vasculitis and its treatment, Best Practice & Research Clinical Rheumatology, Volume 32, Issue 1,2018,Pages 125-136,ISSN 1521-6942 https://doi.org/10.1016/j.berh.2018.07.009.
  5. 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 Rheumatology. 2021 Aug;73(8):1366-1383. doi: 10.1002/art.41773. Epub 2021 Jul 8. PMID: 34235894.

CYC in Scleroderma

Team: CYC in Scleroderma, aka “CYC’d for SLS”

Region: Get in the Game

Base article: Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl J Med. 2006;354(25):2655-2666. PMID 16790698.

Authors: Louisiana State University Shreveport Rheumatology Fellowship. Iman Qaiser, MD, second year rheumatology fellow, Smita Maruvada, MD, second year rheumatology fellow, Jasmeen Uppal, MD, first year rheumatology fellow, Mohammad Hassaan Khan, MD, first year rheumatology fellow, Warda Maqsood, MD, first year rheumatology fellow, Sulman Hasan, MD, second year rheumatology fellow, Kinza Muzaffar, MD, Assistant Professor of Internal Medicine, Madiha Tariq, MD, Program Director Rheumatology, Overton Brooks VA Medical Center Shreveport, Sarwat Umer, MD, Professor of Internal Medicine, Louisiana State University Shreveport, Samina Hayat, MD, Professor of Internal Medicine, Louisiana State University Shreveport.

Team Overview

Scleroderma is a complex, multi-systemic disease. Forty percent of scleroderma patients have pulmonary involvement, mostly interstitial lung disease.1 Ventilatory restriction, along with pulmonary hypertension, is responsible for a staggering mortality rate of 42% within 10 years after disease onset! 2, 3 For a disease that has been such an Achilles heel for rheumatologists since the 1700s, management was still not clearly defined by the millennium and rheumatologists were still playing defense.4 In 2006, Tashkin et al went on offense against scleroderma lung disease and produced this slam-dunk of a study, also known as the Scleroderma Lung Study I or SLS-I, which showed the clear effectiveness of cyclophosphamide in improving and maintaining FVC (forced vital capacity) in scleroderma patients. Between the 158 patients who were randomized, the mean difference in FVC at 12 months between the cyclophosphamide and placebo group was 2.53%, favoring cyclophosphamide with P < 0.03. Not only that, cyclophosphamide also showed significant improvement in TLC (total lung capacity), functional ability, health-related quality of life and skin thickness. The study also clearly demonstrated the downside of cyclophosphamide, with adverse effects of cytopenias. 1

Impact on Rheumatology

While RA, gout and vasculitis got their fair share of glory throughout history, scleroderma was benched far too long. Scleroderma patients, often minority ethnic populations, would die young and suffer effects on every organ system. William Osler wrote in 1898 “On Diffuse Scleroderma”, comparing a scleroderma patient to Tithonus, who wished for eternal life, but forgot to ask for eternal youth: “Like Tithonus to ‘wither slowly’ and like him ‘beaten down and marred and wasted’ until one is literally a mummy, encased in an ever-shrinking, slowly-contracting skin of steel, is a fate not pictured in any tragedy, ancient or modern.” 5 Research into treatment for this cruel disease was long overdue by the 2000s, and the SLS-I team was just what the rheumatology league needed at that point in time.

Haters will say cyclophosphamide was already being used for scleroderma before 2006. True, there were some retrospective studies showing the benefit of cyclophosphamide, but we ask you what degree of confidence would these small studies give you when using a drug known to have high toxicity? 2 The SLS-I study changed the entire game. It was a well-strategized, 2-year long, double-blind, placebo-controlled, randomized, multi-center, prospective study  which drew solid conclusions regarding the efficacy, toxicity and risk-benefit ratio of cyclophosphamide in scleroderma. 1 It gave the rheumatologist that much needed alley-oop to score confidently against scleroderma.

The SLS-I study also laid down a game plan for the SLS-II and SLS-III trials. 6, 7 It was the dream team that all other teams aspired to. It’s clear, this team deserves to be named the most important and transformational article ever written in the field of rheumatology!

Chances in the Tournament

The SLS-I study got in the game when it was needed the most! While vasculitis and scleroderma are both devastating diseases, scleroderma did not get the attention it needed from cyclophosphamide until 27 years later! But when it did, SLS-I owned the court like it was their home! The impregnable strategy with which CYC was studied for scleroderma, makes our team a sure shot winner. Our opponents wouldn’t even be able to defend us man-to-man with their sample size of 17 compared to our 158! 8 Additionally, keeping score might be difficult for them, seeing as they did not use many objective measurements. After that easy win, we would be up against a team that discusses the timing of drug initiation of a drug that has been well studied for decades, in a disease that has been well known for centuries. 9 We question if they should even be in the game when they only made it to a conditional recommendation in the American College of Rheumatology guidelines. 10 Eventually, we would like to be able to jump ball with the RAVE trial, as rituximab is the hot, new player on the block. 11 But let’s see how much steam rituximab can handle when facing off with the MVP, the Michael Jordan, the OG of rheumatology: cyclophosphamide.

Though advances have been made in scleroderma research, there is still a lot that needs to be studied for this overwhelming disease. Our team paved the way forward for future players and researchers in how to deal with this systemic disease in an objective and calculated way, and in the process reach out to the crowds of patients rooting for us. SLS-1 is indeed an all-star in rheumatology!

Next scouting report: ULT During Flare

Back to the full list of scouting reports.

See the Q&A on theMednet.org for the Get in the Game region: Are there patients in whom you would avoid initiating of ULT during acute gout flare? 

References

  1. Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in
  2. scleroderma lung disease. N Engl J Med. 2006;354(25):2655-2666.
  3. Steen VD, Conte C, Owens GR, Medsger TA Jr. Severe restrictive lung disease in systemic sclerosis. Arthritis Rheum. 1994;37(9):1283-1289.
  4. White B, Moore WC, Wigley FM, Xiao HQ, Wise RA. Cyclophosphamide is associated with pulmonary function and survival benefit in patients with scleroderma and alveolitis. Ann Intern Med 2000;132: 947-54.
  5. Adigun R, Goyal A, Hariz A. Systemic Sclerosis. [Updated 2022 May 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK430875/
  6. OSLER W: On diffuse scleroderma; with special reference to diagnosis and to the use of thyroid extract. Jour. Cutan. & Gen. Urinary Dis., XVI: 49 & 127, (Feb. & Mar.), 1898.
  7. Tashkin DP, Roth MD, Clements PJ, et al. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Lancet Respir Med. 2016;4(9):708-719. doi:10.1016/S2213-2600(16)30152-7
  8. Khanna D, Spino C, Bernstein E, Goldin J, Tashkin D, et al. Combination Therapy of Mycophenolate Mofetil and Pirfenidone vs. Mycophenolate Alone: Results from the Scleroderma Lung Study III. In: ACR Convergence 2022, 10-14 November, 2022, Philadelphia, USA.
  9. Fauci AS, Katz P, Haynes BF, Wolff SM. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med. 1979;301(5):235-238.
  10. Taylor TH, Mecchella JN, Larson RJ, Kerin KD, Mackenzie TA. Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med. 2012;125(11):1126-1134.e7.
  11. FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout [published correction appears in Arthritis Care Res (Hoboken). 2020 Aug;72(8):1187] [published correction appears in Arthritis Care Res (Hoboken). 2021 Mar;73(3):458]. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180
  12. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-232.

ULT During Flare

Team: Urate-Lowering Therapy (ULT) During Flare, aka the “Unapologetically Uricase-Deficient Mammals!”

Region: Get in the Game

Base article: Taylor, T. H., Mecchella, J. N., Larson, R. J., Kerin, K. D., & MacKenzie, T. A. (2012). Initiation of Allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. The American journal of medicine, 125(11), 1126-1134. PMID 23098865.

Authors: Medical College of Wisconsin Rheumatology Fellowship Program. Desh Nepal, MD, First-year rheumatology fellow; Rohan Mehta, DO, First-year rheumatology fellow; Yiran Jiang, MD, Second-year rheumatology fellow; Alison Fernandes, MD, Second-year rheumatology fellow; Michael Putman, MD, MSCI, Assistant Professor, Associate Rheumatology Fellowship Program Director

Team Overview

The urate-lowering agent, allopurinol, was discovered in 1956 and approved for mass consumption 10 years later. Allopurinol has remained the treatment of choice for gout management ever since. Yet, before the publication of this double-blind, placebo-controlled randomized control trial [1], it was believed initiation of allopurinol during an acute flare would prolong or exacerbate the attack due to uric acid mobilization [2]. Such practice was based on the observation that after allopurinol initiation, patients had frequent gout flares even as uric acid levels improved [3]. Based on this, rheumatological societies published guidelines recommending benching allopurinol until the flare has subsided [4] [5]. Known as the “delayed initiation and step-up approach,” the pervading thesis was introduced to start allopurinol at a low dose with a gradual increase. Consequently, the patient would only first see allopurinol come into play in low-stakes outpatient follow-up in the office 10-14 days later. Here are a few limitations of this traditional approach that continues to be recommended in the current 2020 ACR guideline [6]:

Delayed initiation equals missed opportunities. Only 64% of post-discharge appointments are generally kept [7]. Delayed initiation leads to prolonged disease burden. Within the traditional approach, the time to achieve the target uric acid goal of <6 is increased. At an average  allopurinol dose of 100 mg to 300 mg, 66 % of patients were not at the uric acid goal of < 6 [8]. You miss 100% of the shots you don’t take! Even among patients initiated on treatment, only <40% achieve the uric acid goal [9].

Gout affects 9.2 million US adults and has an annual healthcare cost of 24 million dollars. When taken together, delayed initiation of low-dose urate-lowering therapy of the most common cause of inflammatory arthritis contributes to increased healthcare utilization [12], decreased quality of life [13] and persistent premature mortality in gout patients [14].

Results of this publication:

In patients with crystal-proven acute gout arthritis (onset < 7 days), upon early initiation of allopurinol at 300 mg/day along with indomethacin and colchicine (treatment group), pain (measured by visual analog scale) in the first 10 days, and patient-reported gout flare in first 30 days did not differ when compared to initial treatment with only indomethacin and colchicine with delayed allopurinol initiation at day 10 (placebo group). Early initiation of allopurinol helped achieve uric acid at goal by day three and remained at goal throughout the 30 days. Starting allopurinol on day ten meant the uric acid goal was reached only around day 30 [1].

Despite the limitations of being a small, single-center study, this adequately powered study highlights an essential step in synergistically utilizing urate-lowering agents and anti-inflammatory medications to optimize the game plan.

Impact on Rheumatology

Starting Allopurinol early in patients with acute gout arthritis represents a paradigm shift in decades of clinical practice. It helped transform the management of acute gout arthritis, and gout in general, from a theoretical to an evidence-based approach.

It is worth noting that > 90% of gout is managed by Primary care providers [15]. In a survey of PCP, only about 50% of PCP felt their gout management practices are optimal. So, the clarity on the timing and dose of allopurinol initiation, along with the use of indomethacin and colchicine, impacted not only rheumatology but also primary care practices. Again, finding a publication with such broad impact beyond the specialty alone is not common.

For the healthcare system, it has the potential to translate into decreased healthcare resource utilization. Most importantly, achieving optimal gout management will mean enhanced quality of life and improved premature mortality for patients.

Chances in the Tournament

This article is a dark horse on the surface – gout is often not considered by many fellows as a high-flying topic. It’s not as flamboyant as vasculitis, and it’s not as colorful and varied as systemic lupus erythematosus. However, astute viewers will agree this article represents the fundamental essence of the field of rheumatology – continuously reassessing and improving our management of even the oldest and most common diseases to truly impact our patients’ lives. In addition, rheumatology is a part of the healthcare ecosystem where primary care practices are the foundations, and this publication directly impacts primary care practices.

While there have been many developments in managing various rheumatic diseases that have led to significant outcome improvements, given the scale of gout prevalence, we would be hard-pressed to find another paradigm-defining change in rheumatology that has the potential for such a material impact on both disease burden (quality of life, mortality) and healthcare cost/utilization.

We hope our humble report conveys the importance of this advancement and give it the recognition it undoubtedly deserves!

Next scouting report: RAVE Trial

Back to the full list of scouting reports.

See the Q&A on theMednet.org for the Get in the Game region: Are there patients in whom you would avoid initiating of ULT during acute gout flare? 

References

  1. Taylor, T.H., et al., Initiation of allopurinol at first medical contact for acute attacks of gout: a randomized clinical trial. Am J Med, 2012. 125(11): p. 1126-1134 e7.
  2. Neogi, T., Clinical practice. Gout. N Engl J Med, 2011. 364(5): p. 443-52.
  3. Zhang, W., et al., EULAR evidence based recommendations for gout. Part II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis, 2006. 65(10): p. 1312-24.
  4. Jordan, K.M., et al., British Society for Rheumatology and British Health Professionals in Rheumatology guideline for the management of gout. Rheumatology (Oxford), 2007. 46(8): p. 1372-4.
  5. Yue, T.F. and A.B. Gutman, Effect of Allopurinol (4-Hydroxypyrazolo-(3,4-D)Pyrimidine) on Serum and Urinary Uric Acid in Primary and Secondary Gout. Am J Med, 1964. 37: p. 885-98.
  6. FitzGerald, J.D., et al., 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken), 2020. 72(6): p. 744-760.
  7. Kiefe, C.I., et al., Compliance with post-hospitalization follow-up visits: rationing by inconvenience? Ethn Dis, 1999. 9(3): p. 387-95.
  8. Li-Yu, J., et al., Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol, 2001. 28(3): p. 577-80.
  9. Pandya, B.J., et al., Relationship between physician specialty and allopurinol prescribing patterns: a study of patients with gout in managed care settings. Curr Med Res Opin, 2011. 27(4): p. 737-44.
  10. Singh, G., B. Lingala, and A. Mithal, Gout and hyperuricaemia in the USA: prevalence and trends. Rheumatology (Oxford), 2019. 58(12): p. 2177-2180.
  11. Kim, K.Y., et al., A literature review of the epidemiology and treatment of acute gout. Clin Ther, 2003. 25(6): p. 1593-617.
  12. Khanna, P.P., et al., Tophi and frequent gout flares are associated with impairments to quality of life, productivity, and increased healthcare resource use: Results from a cross-sectional survey. Health Qual Life Outcomes, 2012. 10: p. 117.
  13. Khanna, P.P., et al., Long-term therapy for chronic gout results in clinically important improvements in the health-related quality of life: short form-36 is responsive to change in chronic gout. Rheumatology (Oxford), 2011. 50(4): p. 740-5.
  14. Perez-Ruiz, F., et al., Tophaceous gout and high level of hyperuricaemia are both associated with increased risk of mortality in patients with gout. Ann Rheum Dis, 2014. 73(1): p. 177-82.
  15. Rott, K.T. and C.A. Agudelo, Gout. JAMA, 2003. 289(21): p. 2857-60.

RAVE Trial

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

HCQ Withdrawal

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)

HAQ

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 20th 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

LUMINA

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.

ALMS Trial

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

Cortisone

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 them4-6. 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.

Origin of RA

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.