Team: NORD-STAR, aka the “NORD All Stars”

Base Article: Østergaard M, van Vollenhoven RF, Rudin A, et al. Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis: 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial. Ann Rheum Dis. 2023;82(10):1286-1295. doi:10.1136/ard-2023-224116

Authors: Vanderbilt Rheumatology Fellowship Program

1. Michael Libre, medical student, Vanderbilt University School of Medicine
2. Yash Pershad, medical student, Vanderbilt University School of Medicine
3. Genessis Maldonado, MD, Fellow, Division of Rheumatology and Immunology, Vanderbilt University Medical Center
4. Tyler Reese, MD, Assistant Professor of Medicine, Division of Rheumatology and Immunology, Vanderbilt University Medical Center

Team Overview

Rheumatoid arthritis (RA) treatment is more divisive than Christian Laettner.

The Scandinavian NORD-STAR trial demonstrated that crossing up RA treatment paradigms by starting with biologics can do more than just break the ankles of RA – first line biologics can euro-step their way to superior clinical remission rates than conventional therapy.

In NORD-STAR, active conventional treatment and biologics faced off head-to-head for the first time in treatment-naïve RA. The star-studded final four included the seasoned veteran active conventional therapy and the rising stars abatacept, certolizumab, and tocilizumab.

In a 48-week matchup, abatacept and certolizumab left conventional therapy behind on fast-breaking the pain and stiffness of RA. They threw down slam dunks, significantly outperforming active conventional therapy in achieving 48-week clinical remission. Although tocilizumab got close to hitting a buzzer-beater, it didn’t quite statistically outshine active conventional therapy in the box score. When it came to guarding against radiographic progression, it was a tie game—everybody on the NORD-STAR court proved they could block advancement of structural joint damage.

When it comes to picking the most “practically perfect” paper, bracketologists will want to check the advanced stats: RA affects 1.3 million Americans and is among the most common concerns a rheumatologist will manage day-to-day.

Although this year’s challengers are fierce, you’ll want to bet on this early RA game-changer. Even if you love to root for the mid-majors focusing on individual RA therapies or the Cinderellas making advancements in rarer diseases, betting on NORD-STAR is as good as betting on Coach K.

Want to learn more?

See the Q&A on theMednet.org about the following question: How do you approach selecting biologic therapy vs non-biologic DMARD (such as methotrexate) as initial therapy in patients with new RA diagnosis with significant erosive disease?

Next Report: RA-ILD Review

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Team: SAPHYR

Base Article: Spiera RF, Unizony S, Warrington KJ, et al. Sarilumab for Relapse of Polymyalgia Rheumatica during Glucocorticoid Taper. N Engl J Med. 2023;389(14):1263-1272. doi:10.1056/NEJMoa2303452

Authors: The Medical University of South Carolina Fellowship Program

1. Jessica English, MD, 3^rd year fellow
2. Lauren Berry, MD, 2^nd year fellow
3. Rachael Werner, MD, PhD, 2^nd year fellow
4. Jake Altier, MD, 2^nd year fellow
5. Gretchen Santana, MD, 1^st year fellow
6. Rashi Vora, MD, 1^st year fellow
7. Faye Hant, DO, Program Director

Team Overview

Lace up those sneakers and whip off your warmup suit, because the NEJM SAPHYR study on Sarilumab for Relapse of Polymyalgia Rheumatica during Glucocorticoid Taper is not just a game; it’s a “gem” of a trial and the BIG DANCE that’s making PMR rethink its moves!

In this biochemical court, sarilumab takes charge, showcasing its anti-inflammatory moves like a point guard with pinpoint accuracy. It’s late in the third quarter and team placebo/glucocorticoid taper (58 patients, 52 week taper) has met its randomized, double blind match against sarilumab/short glucocorticoid taper (600 patients, 14 week taper), armed with its signature interleukin-6 receptor inhibition, giving the team a much-needed boost. It’s a full court press with sarilumab boxing out the inflammatory offense, spreading the zone and evading screens. Sarilumab works on both sides of the ball, juking out those inflammatory cytokines and taking it straight to the hole – allowing for sustained remission of PMR signs and symptoms in 28% of its players (17/60 patients) versus 10% of its opponent placebo team (6/58 patients, difference 18%; 95% CI 4-32; P=0.02) while needing only a third of the amount of cumulative glucocorticoids compared to placebo (777 mg vs 2044 mg; P<0.001). Nothing but net! Sarilumab is the breakout rookie of the year orchestrating these anti-inflammatory plays.

The study isn’t just turning the page on polymyalgia rheumatica; it’s rewriting the playbook on medical challenges with a pharmacological play that’s leaving providers and patients alike high fiving in the clinic.

Game on!

Want to learn more?

See the Q&A on theMednet.org about the following question: What characteristics make a patient with PMR a good candidate for sarilumab?

Next report: Comparing ULT

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Team: INBUILD, aka “OFEVolution”

Base Article: Flaherty KR, Wells AU, Cottin V, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019;381(18):1718-1727. doi:10.1056/NEJMoa1908681

Authors: Ochsner Rheumatology Fellowship Program

1. Alexandra Reese, MD, first year rheumatology fellow at Ochsner Medical Center
2. Chandana Keshavamurthy, MBBS, MD, FACR, Associate Program Director at Ochsner Medical Center
3. Robert Quinet, MD, FACR, Program Director at Ochsner Medical Center
4. William Davis, MD, FACR, Department Head, Rheumatology
   Vice Chair of Education, Department of Internal Medicine at Ochsner Medical Center

Team Overview

The INBUILD trial is a multinational, randomized, double-blind, placebo-controlled, parallel-group trial that studied the efficacy and safety of an antifibrotic drug, nintedanib (OFEV ). Nintedanib is a multitargeted intracellular tyrosine kinase inhibitor that inhibits the critical pathways involved in the progression of lung fibrosis. Like in a FIFA league, 153 sites from 15 countries joined together to fight this disease in patients who were progressively declining despite treatment; specifically, these patients had already lost > 10% of their lung volume despite being on immunosuppressants. In patients with progressive fibrosing ILD from autoimmune causes, nintedanib slowed the decline in lung function. Nintedanib effectively won the Premier League when it gained approval for IPF, the FA Cup when it got approved for systemic sclerosis-ILD, and now the Champions League! It works in unclassifiable ILDs, autoimmune ILDs, chronic hypersensitivity pneumonitis, sarcoidosis, myositis, Sjogren’s syndrome, coal workers pneumoconiosis, and idiopathic forms of interstitial pneumonia such as idiopathic non-specific interstitial pneumonia. Because of the INBUILD trial, we are seeing nintedanib BUILT into treatment plans for our rheumatologic patients suffering from fibrosing ILD. Have you heard of the magic number in sports? Well, our magic number is 57, since the drug slowed lung function decline by 57% yearly compared to the placebo. This medication is breathing life into our patients who were previously left without many options. A warm EMBRACE while gazing at the NORT-STAR is lovely, but feeling like you can breathe, stay active and INBUILD your dreams is much better!

Want to learn more?

See the Q&A on theMednet.org about the following question: Do you generally recommend starting nintedanib prior to immunosuppressive therapy in a patient with CTD-ILD?

Next report: SAPHYR

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Team: PRODERM, aka the “Dermato Dunks”

Base Article: PRODERM trial. Aggarwal R, et al. Trial of Intravenous Immune Globulin in Dermatomyositis. N Engl J Med. 2022 Oct 6;387(14):1264-1278. PMID: 36198179.

Authors: Medical College of Wisconsin Fellowship Program

1. Bonit Gill DO, first year rheumatology fellow, Medical College of Wisconsin
2. Mahum Mirza DO, first year rheumatology fellow, Medical College of Wisconsin
3. Rohan Mehta DO, second year rheumatology fellow, Medical College of Wisconsin
4. Desh Nepal MD, second year rheumatology fellow, Medical College of Wisconsin
5. Michael Putman, MD, MSCI, Assistant Professor, Associate Rheumatology Fellowship Program Director, Medical College of Wisconsin

Team Overview

It’s not every day a drug comes in and shakes up our Rheumatology world! Albeit a rare disease, Dermatomyositis can wreak havoc on the immune system, and can lead to progressive weakness and diffuse rashes.  Dermatomyositis has been historically treated with steroids and DMARDs for many years but it’s time for a new player on the roster. The PRODERM trial shows the efficacy of IVIG in adults with Dermatomyositis. Although IVIG had been used off label in the past, this is the first study done to confirm its worth.

95 patients aged 18 to 80 years old with active Dermatomyositis, on a maximum dose of 20 mg of Prednisone and no more than two other DMARDs, were given either IVIG or placebo every 4 weeks for 4 cycles. By using a primary end point of a Total Improvement Score (TIS) of 20, it was seen that significantly more patients treated with IVIG improved (79%) compared with placebo (44%).

The PRODERM trial proves IVIG has what it takes to go from benchwarmer to the starting lineup. To say this is a game changer in practice is an understatement. Due to this study, Rheumatologists are much more inclined to offer IVIG at the time of Dermatomyositis diagnosis. The confirmation of IVIG’s efficacy rounds out an all-star treatment regimen for the syndrome. IVIG, which was once used as a 2^nd or 3^rd line agent, is now our number one draft pick. In patients with Dermatomyositis, there is no question IVIG is a slam dunk treatment choice.

Want to learn more?

See the Q&A on theMednet.org about the following question: How will you sequence therapies in dermatomyositis given the results of the ProDERM trial?

Next Report: INBUILD

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Team: EMBRACE, aka “EMBRACE Diversity”

Base Article: Ginzler E, Guedes Barbosa LS, D’Cruz D, et al. Phase III/IV, Randomized, Fifty-Two-Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2022;74(1):112-123. doi:10.1002/art.41900

Authors: Northwestern Rheumatology Fellowship

1. Laura Arneson, MD, rheumatology fellow, Northwestern University
2. Brian Jaros, MD, rheumatology fellow, Northwestern University
3. Stephanie Kao, MD, rheumatology fellow, Northwestern University
4. Natania Field, MD, PhD, rheumatology fellow, Northwestern University
5. Clarice Lin, MD, rheumatology fellow, Northwestern University

Team Overview

Systemic lupus erythematosus (SLE) disproportionately affects patients of Black / African ancestry in prevalence, morbidity, and mortality (1). However, this population has been under-represented in most clinical trials for SLE, leading to confusion about treatment for some of the patients who need it most (2). In particular, a pooled analysis of phase III data raised concern that belimumab was ineffective specifically in patients of Black / African ancestry (3). The EMBRACE trial entered the arena to address this question and set a new standard for racial equity in clinical trials.

EMBRACE was the first randomized, placebo-controlled trial for SLE that exclusively enrolled patients of self-identified Black race (4). 448 patients were randomized to belimumab vs. placebo. The primary endpoint of SRI-SLEDAI-2K at 52 weeks was numerically (though not statistically significantly) higher in the belimumab group (48.7%) vs. placebo (41.6%), with trends toward lower risk of severe flares and greater steroid tapering with belimumab. Patients with baseline SELENA-SLEDAI-SLEDAI-2K scores ≥ 10, positive anti-dsDNA antibodies, or low complement showed greater responses to belimumab, findings that can guide clinical practice.

Though the EMBRACE did not meet statistical significance, potentially due to under-enrollment, it provided reassurance that belimumab is a viable option for patients of Black / African ancestry. As a result, a cautionary statement was removed from the belimumab label (5). Most importantly, EMBRACE demonstrated how to re-center research to serve populations that have historically been excluded from its benefits.

Want to learn more?

See the Q&A on theMednet.org about the following question: How can ethnic representation in clinical research studies in childhood and adult SLE be improved?

Next Report: PRODERM

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References:

1. Feldman CH, Hiraki LT, Liu J, Fischer MA, Solomon DH, Alarcon GS, et al. Epidemiology and sociodemographics of systemic lupus erythematosus and lupus nephritis among US adults with Medicaid coverage, 2000–2004. Arthritis Rheum 2013;65:753–63.
2. Falasinnu T, Chaichian Y, Bass MB, Simard JF. The representation of gender and race/ethnic groups in randomized clinical trials of individuals with systemic lupus erythematosus. Curr Rheumatol Rep 2018; 20:20.
3. Benlysta prescribing information. Philadelphia (PA): GlaxoSmithKline; 2021. URL: https://www.gsksource.com/pharma/content/dam/ GlaxoSmithKline/US/en/Prescribing_Information/Benlysta/pdf/BENL YSTA-PI-MG-IFU-COMBINED.PDF.
4. Ginzler E, Guedes Barbosa LS, D’Cruz D, Furie R, Maksimowicz-McKinnon K, Oates J, Santiago MB, Saxena A, Sheikh S, Bass DL, Burriss SW, Gilbride JA, Groark JG, Miller M, Pierce A, Roth DA, Ji B. Phase III/IV, Randomized, Fifty-Two-Week Study of the Efficacy and Safety of Belimumab in Patients of Black African Ancestry With Systemic Lupus Erythematosus. Arthritis Rheumatol. 2022 Jan;74(1):112-123. doi: 10.1002/art.41900. Epub 2021 Dec 9. PMID: 34164944; PMCID: PMC9300099.
5. Sheikh, S.Z., Englund, T.R., Burriss, S.W., Bull, J., Harry, A., Groark, J.G., Hall, A.M., Miller, M. and Roth, D.A. (2022), EMBRACE: One Small Story in Lupus—One Giant Challenge in Clinical Trials. ACR Open Rheumatology, 4: 747-752. https://doi.org/10.1002/acr2.11477

Team: ARCTIC REWIND, aka the “TNF Inhibiting Tritons”

Base Article: Lillegraven S, Paulshus Sundlisæter N, Aga AB, et al. Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial. Ann Rheum Dis. 2023;82(11):1394-1403. doi:10.1136/ard-2023-224476

Authors: University of California San Diego Fellowship Program

1. Rashmi Dhital, MBBS, third year rheumatology fellow, UCSD
2. Neha Chiruvolu Singh, DO, second year rheumatology fellow, UCSD
3. Brian Pedersen, MBBS, rheumatology attending, UCSD

Team Overview

In the rheumatoid arthritis (RA) realm, where the game is all about controlling inflammation, TNF inhibitor (TNFi) therapy takes center court. This trial addressed the knowledge gap on TNFi tapering and withdrawal in RA patients with prolonged clinical remission – a period when patients anticipate medication reduction, and clinicians may consider tapering.

This pragmatic Norwegian study from 2013 to 2019 included RA patients in remission for over one year on stable TNFi therapy (+/- conventional disease-modifying antirheumatic drugs). Players were randomized to either continue their TNFi full court press at the current dose or begin to taper (halving TNFi for 4 months and withdrawing if still in remission). TNFi was restarted at full dose if a flare occurred.

The scoreboard tells an intriguing tale: the 12-month mark revealed a significant disparity in flare rates, 27/43 (63%) in the tapering group versus 2/41 (5%) in the stable TNFi group. During the initial 4 months of half-dose TNFi, 12% flared in the tapering group in contrast to none in the stable group. The tapering group was more likely to receive steroids. Upon reinstating treatment, however, both groups achieved comparable remission (tapering vs stable groups: Boolean [67% vs 63%] and DAS [88% vs 85%]).

This study provides valuable play-by-play insight for shared decision-making by addressing both flare risk and the possibility of regaining disease control. It also highlights the unmet need to identify predictors of who will flare and who will not upon medication tapering, and those for whom remission will not be recaptured.

Want to learn more?

See the Q&A on theMednet.org about the following question: Do you advocate to taper the TNFi or simply continue to monitor for long term adverse events? 

Next report: EMBRACE

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Team: LLDAS, aka “Treat to Target 4 SLE”

Base Article: Franklyn K, Lau CS, Navarra SV, et al. Definition and initial validation of a Lupus Low Disease Activity State (LLDAS). Ann Rheum Dis. 2016;75(9):1615-1621. doi:10.1136/annrheumdis-2015-207726

Authors: University of Manchester Fellowship Program

1. Sarah Dyball, MBBS, rheumatology registrar, The University of Manchester
2. Anastasia Madenidou, MBBS, rheumatology registrar, The University of Manchester
3. Mia Rodziewicz, MBBS, rheumatology registrar, The University of Manchester

Team Overview

In lupus, we cheer for LLDAS, oh so grand,
A paradigm shift, that is changing the land!
Practically perfect and so much more
For our patients it opens a door
Low disease activity in rheumatology is not new,
But lupus patients need it, it’s true!

Unacceptable disease burden, patients’ struggles are real,
Morbidity, damage, high disease activity are a big deal
International communities working to get the management strategy right
Treat to target   T2T goal, shining so bright!

You may wonder why so many components, why it took so long?
In SLEDAI, BILAG, SRI4, the steroids don’t belong
Clinical trials have only a 52-week aim,
But with LLDAS, reduced damage and mortality is the lifelong game!

SLEDAI-2k less than four,
Steroids above 7.5mg, is acceptable no more!
Physician assessment less than one, the target is right
LLDAS wins the world cup, on match night

No EMBRACE for belimumab’s trial,
Conflicting evidence won’t make you smile,
Our competitors pit one treatment with another,
But our paper stands out, like no other!

Want to learn more?

See the Q&A on theMednet.org about the following question: What is your approach to practical monitoring of lupus disease activity in clinical practice?

Next report: ARCTIC REWIND

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Team: VITAL, aka the “Simply D best”

Base Article: Hahn J, Cook NR, Alexander EK, et al. Vitamin D and marine omega 3 fatty acid supplementation and incident autoimmune disease: VITAL randomized controlled trial. BMJ. 2022;376:e066452. Published 2022 Jan 26. doi:10.1136/bmj-2021-066452

Authors: RheumMadness Leadership Team

1. Eric A. Wilson, MD, second year internal medicine resident at Duke University,
2. Sabahat Usmani, MD, chief internal medicine resident at Weiss Memorial Hospital,
3. Laura Arneson, MD, second year rheumatology fellow at Northwestern University,
4. Meridith Balbach, MD, first year internal medicine resident at Vanderbilt University,
5. Courtney Bair, fourth year medical student at Duke University,
6. Lauren He, MD, first year rheumatology fellow at University of Michigan,
7. John B. Kellogg, MD, first year rheumatology fellow at Duke University,
8. Benjamin D. Lueck, fourth year medical student at Duke University,
9. Michael Macklin, MD, second year rheumatology fellow at University of Chicago,
10. Iman Qaiser, MD, rheumatologist at Choctaw Nation
11. Amanda Rodriguez, DO, second year internal medicine resident at Lankenau Medical Center,
12. Akrithi Updupa Garren, MD, rheumatologist at Medstar Washington Hospital Center,
13. Matthew Sparks, Associate Professor of Medicine at Duke University,
14. Lisa Criscione-Schreiber, Professor of Medicine at Duke University
15. Guy Katz, MD, Physician Investigator and Assistant in Medicine at Massachusetts General Hospital, 
16. David Leverenz, MD, MEd, Assistant Professor of Medicine at Duke University

Team Overview

In this mammoth (25,871 participants) RCT, investigators explore whether vitamin D and/or omega 3 fatty acid supplementation can ward of autoimmune disease. Older adults (men >50 and women >55) were randomized to receive vitamin D (2000 IU daily) plus omega 3 (1 g/day), vitamin D plus placebo, omega 3 plus placebo, or placebo alone. Then, the development of autoimmune diseases (RA, PMR, psoriasis, thyroid, IBD, or “other”) was assessed at 5 years. Those receiving vitamin D had a statistically significant reduction in the 5-year cumulative incidence of autoimmune disease (HR 0.78, 95% CI 0.61-0.99, NNT ~500). In the omega 3 fatty acid arm, there was no statistically significant change (HR 0.85, 95% CI 0.67-1.08).

Albeit an interesting finding, it is far from a slam dunk endorsement for vitamin D to prevent autoimmunity. This trial was limited to older adults; thus, the results are not generalizable to younger patients susceptible to conditions like SLE, scleroderma, etc. Despite the impressive number of enrollees, the cumulative incidence of new autoimmune disease was low (155 cases in the placebo group, 123 in the vitamin D group), resulting in high NNTs.

With so many caveats, why is this study practically perfect? Because it addresses the commonly asked question: “what can I take to stay healthy?” The VITAL study suggests vitamin D might help, particularly in men >50 and women >55, but it also allows us to keep our recommendations realistic. With a NNT of ~500, it’s clear that vitamin D is no panacea.

Want to learn more?

See the Q&A on theMednet.org about the following question: Do you recommend Vitamin D and omega 3 fatty acid supplementation for prevention of autoimmune disease?

Next Report: GCA Score

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