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.

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.

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.

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