The Scouting Reports are Here!

Below you will find the 2021 RheumMadness Bracket and scouting reports reviewing each topic in the tournament. Over 40 adult rheumatology fellows from 14  fellowship programs collaborated to create these scouting reports.  A huge thank you to all those who submitted a scouting report; they are all fantastic, educational, and engaging reads!

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Use the links below to access each scouting report

Belimumab for Lupus Nephritis Scouting Report

Written by: Aki Udupa, Ryan Anderson, Isaac Smith, Poorva Apte, Megan Milne, Catherine Sims, Lisa Criscione-Schreiber, and David Leverenz

Based on: Furie et al. NEJM.2020;383(12):1117-28

Topic Overview

Are you ready for a BLySfull scouting report? Don’t look so BAFFled! You’ve come to the right place! With the burden of disease unacceptably high and so few tolerable and effective current therapies available for our patients, the urgency to identify novel therapeutic targets to treat systemic lupus erythematous cannot be overstated. Comprising up to half of this at-risk population is a particularly vulnerable subset of patients with lupus nephritis, who, left untreated, are at high risk for progression to ESRD and death1.

B cells are key orchestrators of the abnormal immune response in lupus and lupus nephritis; they facilitate the activation of autoreactive T cells via self-antigen presentation, promote the release of inflammatory cytokines, and produce harmful autoantibodies2. Autoreactive B cells are, at least in part, enabled by B-lymphocyte stimulator (BLyS), a cytokine which promotes B cell proliferation, differentiation, and survival2,3. BLyS is elevated in lupus patients, is locally expressed at the level of the kidney in lupus nephritis, and levels may correlate with disease activity 1-4.

Belimumab, a fully human monoclonal IgG1 antibody, neutralizes BLyS and subsequently depletes the autoreactive B cell pool contributing to the pathogenic autoimmune milieu of lupus. This medication has been FDA approved for the treatment of serologically and clinically active lupus since 2011 and has recently been awarded the title of the first FDA approved treatment for lupus nephritis. Approval was based on the results of a two year phase III double blind randomized placebo controlled trial by Furie and colleagues titled BLISS-LN1. This study sought to examine the effect of adding intravenous belimumab to standard of care lupus nephritis induction and maintenance regimens on renal response in patients with serologically and clinically active lupus plus biopsy proven active lupus nephritis1. Remarkably, the use of belimumab significantly improved the primary efficacy renal response, with a significantly greater proportion of patients in the belimumab group achieving reduced proteinuria, stable renal function, and less need for rescue therapy such as steroids.

Implications for Patients, Providers, & Researchers

Current implications: Previously, belimumab was primarily shown to work for patients with milder forms of lupus activity, such as skin and joint disease. The BLISS-LN study proves that belimumab also works for lupus nephritis when added on to standard induction regimens, and the recent FDA stamp of approval means that this treatment option is available right now! This is a huge win for patients with lupus nephritis.

Future implications: While we are excited about a new FDA-approved medication for SLE nephritis, this study also makes us wonder what other SLE manifestations may benefit from belimumab (i.e. neuropsychiatric). As with all other rheumatologic medications, trials of belimumab with pregnant women have not yet been performed. If this medication were studied and deemed safe in pregnant women, it would be wonderful to have an alternative to Azathioprine (AZA) for SLE nephritis during pregnancy. It will also be interesting to see if initiation of belimumab prior to pregnancy improves maternal and/or fetal outcomes (pregnancy loss, HTN, pre-eclampsia, heart block etc.) as compared to AZA/hydroxychloroquine. Another natural next step is to evaluate the effectiveness of this medication in children to see if belimumab may prevent progression of renal disease. Long term data will need to be evaluated in the future focusing on outcome measures such as proteinuria, serum creatinine, and new dependence on hemodialysis (HD). This will be important to know for patient expectations, anticipatory guidance, and financial burden of care. Finally, prior studies have suggested a possible increase in depression in patients treated with belimumab, though this was not seen in BLISS-LN. We would like to see additional studies that have a baseline assessment of depression prior to belimumab initiation. Lupus patients have a higher rate of depression than the general public and the addition of a weekly injection or monthly infusion may increase burden of care and make depression worse. These confounding variables are important to stratify before determining that belimumab is the cause of depression as opposed to a potential bystander.

Will BLISS-LN Win its First Round Match-up?

Belimumab is the clear favorite in the first-round match-up against anifrolumab. Though its competitors are often “BLYS”-fully ignorant, when it comes to shooting “BAFF”-kets, there is none better than belimumab. Leading experts in the field have been keeping a close eye on the upcoming match-up, and in the words of one prominent lupologist, “What is anifrolumab anyway? Only FDA-approved medications should be allowed to compete.” While it is true that anifrolumab isn’t even a prescribable medication, supporters of the drug turn to sports history to defend their position. “Our inspiration for TULIP 2 came from one of the greatest athletes of all time, Tom Brady. If you’re not getting the results you want, deflate the endpoint, and you’ll be sure to score a win.” Reviewers and practitioners of evidence-based medicine alike will need to be vigilant to ensure the goal-posts aren’t moved again leading up to the first round match-up. In spite of these concerns, APRIL showers are just around the corner, and belimumab is expected to rain destruction on its competitor. After all is said and done, belimumab will reign supreme.

Could BLISS-LN Win it All?

The BLISS-LN trial is a strong contender to win the tournament. Other trials in this tournament may boast that their interventions significantly limit steroid exposure. BLISS-LN demonstrates that belimumab is both a steroid-sparing agent and an effective disease-modifying agent in controlling a major rheumatic disease. Belimumab does not just have the potential to be steroid-sparing. It is potentially life-sparing. Belimumab decreased renal-related events or death in a well-selected treatment group of lupus nephritis patients. The same cannot be said for trials that had to alter primary endpoints or did not find positive results in the initial study population. BLISS-LN clearly represents a new frontier for the treatment of lupus nephritis. The discerning rheumatologist can easily foresee that belimumab, which has already undergone the rigors of FDA-approval, will change the management of lupus nephritis. The well-designed, clinically meaningful BLISS-LN trial is responsible for this major innovation.


  1. Furie, Richard, et al. “Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.” The New England Journal of Medicine, vol. 383, no. 12, 2020, pp. 1117–1128., doi:10.1056/NEJMoa2001180. Accessed 7 Mar. 2021.
  2. Furie, Richard et al. “Biologic activity and safety of belimumab, a neutralizing anti-B-lymphocyte stimulator (BLyS) monoclonal antibody: a phase I trial in patients with systemic lupus erythematosus.” Arthritis research & therapy vol. 10,5 (2008): R109. doi:10.1186/ar2506
  3. Furie, Richard et al. “A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus.” Arthritis and rheumatism vol. 63,12 (2011): 3918-30. doi:10.1002/art.30613
  4. Neusser, M., Lindenmeyer, M., Edenhofer, I. et al. Intrarenal production of B-cell survival factors in human lupus nephritis. Mod Pathol 24, 98–107 (2011).

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Anifrolumab Scouting Report

Written By: Sarah Compton, Sam Minkin, Whitney Elg-Salsman, Ana Tucker, and Jen Schmidt; MUSC Rheumatology Fellowship

Based on: TULIP-1 and TULIP-2 trials of anifrolumab

Topic Overview

Type I interferons are cytokines that link innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus (SLE) with increased interferon-stimulated gene expression seen in most patients with SLE. Anifrolumab is a fully human IgG1K monoclonal antibody to type 1 interferon receptor subunit 1, and inhibits signaling by all type I interferons, which results in enhanced blockage of the type I interferon pathway. Anifrolumab has undergone two phase 3 trials- TULIP 1 and TULIP 2. TULIP 1 was a double-blind, randomized, controlled phase 3 trial performed internationally in multiple centers. The trial was designed to assess the efficacy and safety of IV anifrolumab versus placebo in adults with SLE who are receiving standard of care treatment. Patients were randomly assigned to high or low dose anifrolumab or placebo. Patients were also randomized according to their interferon gene signature. Patients had to have moderate to severe SLE and be on stable doses of medication. Patients with lupus nephritis and neuropsychiatric manifestations were excluded. Primary endpoint of SLE-Responder index-4 (SRI-(4)) was not reached. Secondary endpoints were not formally statistically assessed but there were improvements in oral corticosteroid dose, cutaneous lupus erythematosus disease area and severity index (CLASI) responses, and the British Isles Lupus Assessment Group-based composite lupus assessment (BICLA) responses. TULIP 2 used only high dose anifrolumab against placebo which did meet its primary endpoint of the BICLA response after changing from the SRI-(4). SRI-(4) was enticing given its promise shown in the phase 2 MUSE trial as well as its use in the belimumab phase 3 trial. Adverse effects were shown in a high proportion in both groups, but a higher incidence of herpes zoster was shown in the anifrolumab group.

Implications for Patients, Providers, & Researchers

Current implications: Limited application at this time pending additional studies, but in patients with active cutaneous manifestations of SLE who have failed or have contraindications or intolerance to multiple therapies and remain on glucocorticoids could consider for off label use.

Future implications: We hope for this team FDA approval of anifrolumab in the coming future. We also envision this medication will be used for those patients that are steroid dependent and those with cutaneous manifestations. We would like to see anifrolumab be put up against lupus nephritis and neuropsychiatric manifestations to help us better understand how it will work in our patients with these manifestations. Those patients that are unable to have control of their disease despite standard medications will benefit from this medication.

Will Anifrolumab Win its First Round Match-up?

This team is definitely the underdog against FDA-approved belimumab. Breaking way as the first FDA approved drug for SLE in 60 years, some may say belimumab is already the champion. This team has promise though as it too was able to meet its primary endpoint in BICLA response after some trial and error. This team was also able to improve oral corticosteroid dose and skin manifestations.

Could Anifrolumab Win it All?

Chances are somewhat slim for anifrolumab to win it all in the tournament, but anifrolumab did make a comeback in the TULIP 2 trial using the secondary endpoint, BICLA response, from the first trial by proving significance. The primary endpoint was changed prior to unblinding the study to BICLA response from SRI-(4) which some may say is sneaky or others genius. Who knows?- anifrolumab may have the fairytale ending it deserves. With the demonstration of inhibition of interferon type 1 in those with a high interferon signature its unique mechanism of action, steriod sparing effects and improvement in cutaneous manifestations of SLE make this distinctive player one to watch in the armamentarium to treat the cruel mystery that is lupus.


  1. Furie, R. A., Morand, E. F., Bruce, I. N., Manzi, S., Kalunian, K. C., Vital, E. M., Lawrence Ford, T., Gupta, R., Hiepe, F., Santiago, M., Brohawn, P. Z., Berglind, A., & Tummala, R. (2019). Type I interferon inhibitor anifrolumab in active systemic lupus erythematosus (TULIP-1): a randomized, controlled, phase 3 trial. The Lancet Rheumatology. doi:10.1016/S2665-9913(19)30076-1
  2. Morand EF, Furie R, Tanaka Y, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 01 2020;382(3):211-221. doi:10.1056/NEJMoa1912196

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Avacopan Scouting Report

Written By: Kaitlin Lima, Michael Lopker, Yoon Qiu, Julia Sun; Northwestern University

Based on: Jayne et al. NEJM.2021;384:599-609 (NEJM link)

Topic Overview

The ANCA-associated vasculitides are life-threatening autoimmune diseases with significant morbidity and mortality from both organ damage and treatment related toxicity. The alternative complement pathway has been implicated in the pathogenesis of ANCA-associated vasculitis, which culminates in production of C5a. Avacopan is an oral small molecule C5a-receptor antagonist that selectively blocks the effect of C5a, including blocking neutrophil chemoattraction and activation. Avacopan protects against development of glomerulonephritis after exposure to antimyeloperoxidase antibodies in mouse models, and Phase II trials in humans showed safety compared to standard of care.

The ADVOCATE trial1 was a phase 3 randomized controlled trial of 331 MPO or PR3 positive patients with new or relapsing disease in which patients received either avacopan 30 mg twice a day (n=166) OR corticosteroids (n=165) on a tapering schedule in addition to rituximab or cyclophosphamide at the investigators’ discretion. Avacopan was found to be noninferior to prednisone for remission at week 26 (defined as Birmingham Vasculitis Activity Score (BVAS)=0 and no corticosteroid use in the previous four weeks) with 72.3% in avacopan group vs 70.1% in prednisone group. Avacopan had superior sustained remission at week 52 (65.7% vs 54.9%). There was a trend towards higher eGFR and decreased albuminuria in the avacopan group, which mirrors other studies in mice2 and humans3,4. Serious adverse events were similar in the two groups.

Implications for Patients, Providers, & Researchers

Current implications: The ADVOCATE trial has made the previously unthinkable possible: inducing disease remission in ANCA-vasculitis without glucocorticoids. With the use of Avacopan in ANCA-vasculitis, patients with new or relapsing active disease, the amount of glucocorticoid use was significantly reduced with superior results at week 52. This resulted in fewer glucocorticoid-related side effects (as demonstrated by significantly lower Glucocorticoid Toxicity Index) while not compromising ability to achieve remission.

Future implications: The success of the ADVOCATE trial opens the door to the evaluation of other complement-directed treatments for ANCA-vasculitis. A monoclonal antibody (IFX-1) to C5a is in stage 2 clinical trials and there are case reports suggesting efficacy using eculizumab in refractory ANCA-vasculitis.

Will Avacopan Win its First Round Match-up?

In what is best represented as a #2 ADVOCATE vs #15 PEXIVAS matchup, PEXIVAS is the clear underdog. This negative trial won’t have nearly the impact of ADVOCATE, as knowing when NOT to use plasma exchange in a small subset of ANCA-associated vasculitis will clearly impact fewer patients. It did have an important secondary finding: that reduced-dose steroid regimens are non-inferior to standard regimens. While a reduced-dose regimen is a substantial step forward in reducing morbidity, a complete steroid sparing regimen is a giant leap. PEXIVAS is also not unique in this finding.

Could Avacopan Win it All?

Avacopan has a “blood blood” chance at making it to the final showdown – rheumatologists have been craving steroid-free treatment options for our most challenging diseases and this trial does not disappoint. If ADVOCATE can overcome the group of death second round matchup against SLE therapeutics, its path to the championship game is almost assured. Avacopan compared to prednisone was superior for sustained remission at week 52, had lower glucocorticoid toxicity, and a trend higher eGFR and decreased albuminuria with similar adverse events. While questions remain including durability and the use of avacopan for minor relapses, the prospect of almost completely eliminating steroids from the treatment regimen of this life-threatening condition represents a likely paradigm shift for the field of rheumatology.


  1. Jayne et al. NEJM. 2021;384:599-609
  2. Xiao et al. J Am Soc Nephrol. 2014;25:225-231.
  3. Jayne et al. J Am Soc Nephrol. 2017;28:2756-2767.
  4. Merkel et al. ACR Open Rheumatol 2020;2:662-671.

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IgG4-RD Classification Criteria Scouting Report

Written By: Guy Katz, MD; Ian Cooley, MD; Duncan F Moore, MD; Naomi Patel, MD; Massachusetts General Hospital Rheumatology Fellowship

Based on: Wallace ZS et al; American College of Rheumatology/European League Against Rheumatism IgG4-Related Disease Classification Criteria Working Group. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol. 2020 Jan;72(1):7-19.

Topic Overview

IgG4-related disease (IgG4-RD) is a systemic immune-mediated fibroinflammatory disease first described in the early 2000’s. Many of its manifestations have long been recognized and thought to represent idiopathic single organ system diseases. These are now unified by this underlying diagnosis, primarily on the basis of a common histopathology (characterized by storiform fibrosis, obliterative phlebitis, and an IgG4-rich lymphoplasmacytic infiltrate). While some clinical features can be quite suggestive, manifestations can be protean, and the disease is notoriously difficult to differentiate from other mimicking conditions (such as sarcoidosis, Sjogren’s syndrome, ANCA-associated vasculitis, and lymphoma). Both because it is a recently recognized disease, and because of the frequently challenging nature of arriving at the diagnosis, the development of effective classification criteria is invaluable for research and clinical purposes. These criteria were developed by a large multispecialty international group and feature a robust list of exclusion criteria in addition to inclusion criteria as well as a weighted scoring system, which yielded a sensitivity of 82.0-85.5% and specificity 97.8-99.2% in validation cohorts.

Implications for Patients, Providers, & Researchers

Current implications: These are the first-ever classification criteria for IgG4-RD. Researchers can immediately begin using them to generate standardized cohorts for prospective clinical trials and epidemiologic studies that will allow for robust, replicable, and generalizable research in this disease. Like other classification criteria, despite the fact that these criteria were developed primarily for research purposes, they have demonstrated remarkable clinical utility as well. The criteria present a user-friendly and comprehensive framework with which to approach the diagnosis of this rare, under-recognized, and treatable disease. The publication alone has already helped raise awareness and understanding of this disease.

Future implications: These criteria are likely to benefit clinicians, researchers, and patients for quite some time. Study of the pathophysiology of the disease itself has led to a broader understanding of autoimmunity and fibrosis. With these classification criteria, larger-scale study of this pathophysiology is likely to further our understanding of not only the disease itself but also many other autoimmune and fibrotic conditions, ranging from systemic sclerosis to cirrhosis. Additionally, these criteria feature exclusion criteria that are strongly associated with IgG4-RD mimickers rather than the disease itself. This focus on exclusion criteria is novel in rheumatology classification criteria, and future criteria in our field can make use of this framework both to improve specificity of the criteria themselves and to heighten clinicians’ awareness of specific features that should make them question a given diagnosis.

Will IgG4-RD Classification Criteria Win its First Round Match-up?

In its first round match-up, the IgG4-RD criteria will compete with the study describing three subtypes of relapsing polychondritis (RP). The excellent study on RP subtypes demonstrated that the most common forms of RP lack many of its characteristic features, thereby leading to significant delays in diagnosis. While this is tremendously important in the field of RP, the IgG4-RD classification criteria achieve a similar goal on a much larger scale in a disease that arguably has less widespread recognition and understanding. Additionally, the classification criteria have many implications that reach beyond the disease itself. Both because of its novelty and its potential impact, IgG4-RD Classification Criteria is likely to beat RP Subtypes in its first round match-up.

Could IgG4-RD Classification Criteria Win it All?

Alas, storiform fibrosis alone is not enough to confirm the ever-elusive diagnosis of IgG4-RD. As it can mimic many other conditions and be difficult to confirm, classification criteria are essential to identify patients and allow them to be properly treated. Drs. Stone and Wallace have both been leaders in the understanding of IgG4-RD and have again come through with criteria that have a whopping specificity of greater than 98%. It will likely win against RP subtypes in its first bracket, though it is hard to predict how it will fare against VEXAS, a worthy challenger that is so unlike the rest. As prednisone is a mainstay of therapy in IgG4-RD, it may be tough to compete with Avacopan, which demonstrated an unmatched steroid-sparing effect, and belimumab and anifrolumab, which show promise as new options in the treatment of SLE. However, once it makes it past the initial rounds, its novelty combined with its widespread applicability will likely lead it to win against more bread-and-butter topics like gout and rheumatoid arthritis.


  1. Wallace ZS, Naden RP, Chari S, Choi H, Della-Torre E, Dicaire JF, Hart PA, Inoue D, Kawano M, Khosroshahi A, Kubota K, Lanzillotta M, Okazaki K, Perugino CA, Sharma A, Saeki T, Sekiguchi H, Schleinitz N, Stone JR, Takahashi N, Umehara H, Webster G, Zen Y, Stone JH; American College of Rheumatology/European League Against Rheumatism IgG4-Related Disease Classification Criteria Working Group. The 2019 American College of Rheumatology/European League Against Rheumatism Classification Criteria for IgG4-Related Disease. Arthritis Rheumatol. 2020 Jan;72(1):7-19. doi: 10.1002/art.41120. Epub 2019 Dec 2. PMID: 31793250.
  2. Ferrada M, Rimland CA, Quinn K, Sikora K, Kim J, Allen C, Sirajuddin A, Goodspeed W, Chen M, Grayson PC. Defining Clinical Subgroups in Relapsing Polychondritis: A Prospective Observational Cohort Study. Arthritis Rheumatol. 2020 Aug;72(8):1396-1402. doi: 10.1002/art.41270. Epub 2020 Jul 8. PMID: 32249511.

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RP Subtypes Scouting Report

Written By: Page Bomar, Rami Diab, John Herion, Yael Klionsky; Wake Forest School of Medicine

Based on: Ferrada, M., et al., Defining Clinical Subgroups in Relapsing Polychondritis: A Prospective Observational Cohort Study. Arthritis Rheumatol, 2020. 72(8): p. 1396-1402.

Topic Overview

Relapsing polychondritis (RP) is a heterogeneous systemic inflammatory disease characterized by multisystem involvement including tracheobronchial tree, upper airways, cranial cartilaginous structures (ears and nose), eyes, blood vessels, cardiac valves, and skin. Historically, diagnosis rests on fulfillment of the McAdams criteria. In spite of its potentially fatal presentation, diagnosis is curtailed by heterogeneity of presentation especially when the disease does not necessarily present with cranial chondritis. For this reason, RP may present as a diagnostic dilemma even to the astute physician. This being the case, diagnostic delay is not uncommon and can range anywhere from 1 to 20 years potentially leaving irreversible end organ damage throughout the course of the disease. Other causes of RP-related morbidity if left undiagnosed includes tracheomalacia and subglottic stenosis which may require ICU admission as well as hearing loss and its associated disability. It has recently been demonstrated that patients with RP broadly fall into 3 phenotypic classification schemes (types 1, 2, and 3). Type I RP is characterized by high prevalence of cranial chondritis including ear chondritis and saddle-nose deformity as well as upper airway involvement including tracheomalacia and subglottic stenosis but may also have associated inner ear involvement, synovitis, and inflammatory eye disease seemingly representing the most clinically active phenotypic variant with the greatest averaged elevation in markers of systemic inflammation. Type 2 RP, on the other hand though, shares features of tracheomalacia, synovitis, and inner ear disease, has a lower prevalence of cranial chondritis including auricular and nasal involvement as well as a lower prevalence of ocular inflammation. Finally, type 3 RP is said to have no airway involvement but rather ear chondritis, inner ear involvement, and synovitis.

Implications for Patients, Providers, & Researchers

Current implications: RP is a potentially severe and debilitating disorder which if left unrecognized and/or sub optimally treated can lead to devastating consequences including disability and even death. Having not only a diagnostic classification but this most recent simplified phenotypic classification scheme can help better diagnose and treat patients who present as a diagnostic challenge.

Future implications: This classification scheme opens up avenues for further research and suggests that different RP types are likely to behave differently from a clinical standpoint and may potentially even respond differently to treatment. Furthermore, could the use of this classification scheme lead to shorted median time to diagnosis, leading us into a future where RP patients receive earlier intervention and suffer less complication from disease? We think so.

Will RP Win its First Round Match-up?

RP certainly has the ability to advance through the first round, but it’ll come down to the final buzzer. Paired against IgG4 Related Disease, we find two studies focused on the rarest of the rare diseases. Both studies find strength in setting forth clinical guidance by which we can recognize and diagnose these diseases. IgG4’s validated classification criteria places emphasis on exclusion criteria that reduce the likelihood that patients have IgG4 related disease, but also has strong inclusion criteria in addition to objective measures for making clinical diagnosis. RP finds its strength in simplifying and categorizing the variety of presentations of disease, reminding us that up to one-third of RP cases exist in patients with underlying systemic disease (vasculitis, myelodysplastic disease) and that the classic presentation of RP is less common than we may believe. The clinical observations in RP may be enough to beat the full court press from IgG4 related disease pushing them into the second round.

Could RP Win it All?

The Madness is all about the little guys taking on the powerhouses, this is no exception. While RP has the ability to make it out of the first round, a potential face off against VEXAS is daunting. The clinical implications in RP are fantastic, but limitations in defining the disease’s full clinical picture may end their run early when facing the rheum world newcomer. Looking at a potential final four match up out of the ANCA/SLE region is a scary proposition for RP, but March is for miracles.


  1. Ferrada, M., et al., Defining Clinical Subgroups in Relapsing Polychondritis: A Prospective Observational Cohort Study. Arthritis Rheumatol, 2020. 72(8): p. 1396-1402.

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Anti-CD38 in Refractory SLE Scouting Report

Written By: Leah Bettner, Shruti Chandramouli, Amanda Lusa, Christopher Overton, and Enid Sun, University of North Carolina

Based on: Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, Enghard P, Richter U, Biesen R, Schneider U, Knebel F. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. New England Journal of Medicine. 2020 Sep 17;383(12):1149-55.

Topic Overview

SLE pathophysiology is characterized by the development of pathogenic autoantibodies by plasma cells. Currently there are SLE therapies that target early stages of B-cell development to prevent autoantibody production, including anti-CD20 and anti-BAFF monoclonal antibodies. However, long-lived plasma cells do not respond to these available treatments. As such, specifically targeting the plasma cell source of autoantibody production is therapeutically attractive. Plasma cells express the glycoprotein CD38. Daratumumab is a CD38-directed monoclonal antibody that is currently used to deplete malignant plasma cells in multiple myeloma. Extension of daratumumab as a viable treatment option for refractory SLE was upheld in this proof of concept report. Two patients with life-threatening SLE refractory to traditional treatment options were treated with a 4-week course of daratumumab followed by maintenance therapy with belimumab after four months. Treatment resulted in highly favorable response rates in major organ involvement including lupus nephritis, pericarditis, and autoimmune hemolytic anemia. Organ-specific response rates were accompanied by improvement in serum serological markers of disease activity and SLEDAI-2K scores over the course of 11-12 months of follow-up. Post-treatment flow cytometry and transcriptome analysis demonstrated that the benefits of anti-CD38 therapy extended beyond plasma cell targets. Treatment resulted in reduction of CD38 expressing natural killer cells, plasmacytoid dendritic cells, CD19+ B-cells, and decreased T-cell activation and interferon signaling. Overall this report suggests that daratumumab is a potential therapy for refractory SLE.

Implications for Patients, Providers, & Researchers

Current implications: This study raises consideration for the following: 1) Plasma cells amongst other CD38+ cells contribute to SLE pathogenesis; 2) Targeting the CD38 glycoprotein promotes depletion of long-lived plasma cells and when used concomitantly with belimumab results in favorable clinical outcomes for patients with refractory SLE. This study highlights how the SLE treatment armamentarium would benefit from further research into plasma-cell depleting therapies.

Future implications: This study sets the stage for further investigation into a novel treatment modality for SLE. The exact mechanism of action of daratumumab in SLE pathophysiology remains speculative and warrants further evaluation to confirm its unique targeting mechanism and downstream immunologic and clinical effects. The current data is cautiously optimistic. However, the positive outcomes will likely prompt further investigation into larger safety studies and ultimately clinical trials. If larger randomized trials are ultimately pursued, concurrent treatment with belimumab might be considered as part of a multimodal B cell-targeting strategy. Clinicians treating patients with highly refractory SLE might consider daratumumab as an off-label therapeutic strategy and should stay tuned for potential future clinical trial enrollment options for anti-CD38 therapy.

Will Daratumumab Win its First Round Match-up?

Daratumumab is difficult to compare to its VEXAS opponent. The VEXAS study identifies a new systemic disease which will certainly prompt further studies into pathogenesis and ultimately treatment considerations. The Daratumumab study identifies a new treatment for an already well-defined systemic disease. A clear advantage Daratumumab has over VEXAS is the suspected far-reaching fan base of SLE patients who will show up to support the Daratumumab team. The VEXAS fan base is still to be determined and without the support of a crowd, our opponent might falter against Daratumumab.

Could Daratumumab Win it All?

While it is easy to underestimate this small but mighty Daratumumab team, the exciting future therapeutic implications for refractory SLE could help it win the entire tournament. Although the study reviewed only two cases, the fact that it was published in the high-impact New England Journal of Medicine shows that there is great potential for this team to go all the way. However, if Daratumumab gets past the first round against VEXAS, it will have to face formidable opponents RP Subtypes or IgG4-RD Classification Criteria, both important studies helping to classify multi-organ system, rare diseases with many overlapping manifestations. If successful, it will then have to face the powerhouse teams of SLE and ANCA, all of which have significant clinical implications. However, the potential to use daratumumab for the sickest of our SLE patients could help it win it all!


  1. Ostendorf L, Burns M, Durek P, Heinz GA, Heinrich F, Garantziotis P, Enghard P, Richter U, Biesen R, Schneider U, Knebel F. Targeting CD38 with daratumumab in refractory systemic lupus erythematosus. New England Journal of Medicine. 2020 Sep 17;383(12):1149-55.

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VEXAS Scouting Report

Written By: the RheumMadness Leadership Team

Topic Overview

VEXAS is a newly described adult-onset autoinflammatory syndrome caused by a mutation in the UBA1 gene on the X-chromosome that encodes the E1 enzyme, a key component of the ubiquitylation system. To date, VEXAS has exclusively been described in older patients, unlike other known autoinflammatory syndromes caused by a genetic mutation. This is because VEXAS is due to a somatic (a.k.a., acquired) mutation in blood cells that occurs later in life, rather than an inherited mutation that affects all cells from the beginning of fetal development. In this way, VEXAS is somewhat akin to an acquired mutation that leads to cancer, only instead of cancer this mutation leads to severe inflammation. VEXAS was discovered when researchers found three men with what appeared to be two different copies of the UBA1 gene on the X-chromosome. This was unexpected finding as men only have one X-chromosome and thus should only have one copy of each gene. Instead of attributing their findings to a sequencing error, the researchers evaluated the clinical phenotypes of these men and discovered that all three had cytopenias, strange vacuoles in the myeloid cells of the bone marrow, and intense inflammatory syndromes. Ultimately, they found 25 cases of this new syndrome and performed a variety of incredible experiments to describe it further. All patients had cytopenias and inflammatory syndromes including chondritis, vasculitis, and neutrophilic infiltrates of the lungs and skin. The syndrome was subsequently named for its major features: V for Vacuoles seen on bone marrow biopsy, E for E1 gene, X for X-chromosome, A for Autoinflammatory, and S for Somatic mutation.

Implications for Patients, Providers, & Researchers

Current implications: To date, VEXAS has only been described in 25 patients, so the current implications are somewhat small. However, the association between relapsing polychondritis and myelodysplasia in older men is already well recognized and VEXAS may explain this connection. Furthermore, the true incidence of VEXAS remains unknown. Perhaps additional clinical manifestations beyond those currently described will appear as more cases are reported. It is even possible that women with somatic UBA1 mutations could be affected, just to a lesser degree than men given their two X-chromosomes. Awareness of VEXAS is critical for practicing adult rheumatologists who are not used to looking for genetic causes of adult-onset inflammatory diseases.

Future implications: This team’s strength lies primarily in its future implications, as it is the first adult-onset inflammatory syndrome known to be caused by a somatic mutation. There are likely many more of these kinds of syndromes that have yet to be described. The methodology used by the VEXAS research team may prove foundational for future work in this area. Many rheumatologists have been dumbfounded by adult patients with severe inflammatory syndromes that are refractory to treatment; perhaps thanks to VEXAS over the next several decades we will start to learn the names (and targeted treatment options) for these conditions.

Will VEXAS Win its First Round Match-up?

VEXAS stands a very good chance against its first-round opponent, anti-CD38 in refractory systemic lupus erythematosus, largely due to the groundbreaking scientific work of the VEXAS team. However, they do need to be on alert for anti-CD38’s ability to steal the ball and shoot three-pointers, as anti-CD38 is an actual treatment that could be considered for very sick patients with systemic lupus erythematosus, whereas targeted treatment options for VEXAS (bone marrow transplant? Gene therapy?) remain theoretical at best.

Could VEXAS Win it All?

It’s far-fetched but not impossible for this small but mighty Cinderella team to win the tournament, as the future implications truly are something special. Assuming VEXAS makes it through the first round, it might have to watch out for RP subtypes in the second round as that’s another excellent study from the same senior author (Peter Grayson), and who knows if it could make it through the juggernauts coming out of the ANCA and SLE regions. But the science of VEXAS alone could help it go all the way!


  1. Beck et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. NEJM. 2020;383:2628-38
  2. Check out the RheumMadness Podcast Episode on this topic!

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SEMIRA Scouting Report

Written by: Osman Bhatty MD, Padmini Parameswaran MD, Christon Grant MD, Mohamed Tageldin, MD, Michael Lucke, MD. Allegheny Health Network Division of Rheumatology

Based on: Burmester GR et al. Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial. Lancet. 2020 Jul 25;396(10246):267-276.


Glucocorticoids have long been a bittersweet player in the treatment of patients with rheumatoid arthritis (RA) pumping up the crowd with much needed symptom relief while simultaneously getting their share of boos with long term adverse side effects. In spite of widespread teaching that these medications should be in the game for the shortest amount of time and with the lowest dose possible, two-thirds of patients in clinical practice receive glucocorticoids for longer than 6 months! Possible reasons for the lack tapering may include inducing disease flares, adrenal insufficiency and withdrawal symptoms. A lack of evidence-based tapering strategies may also be adding to the hesitancy. In fact, a search of PubMed looking for double-blind, placebo-controlled trials pertaining to glucocorticoid tapering in rheumatoid arthritis yields only one result underscoring our dire need for further studies. The Steroid EliMination in Rheumatoid Arthritis (SEMIRA) trial is the first trial of its kind to investigate a scheme with tapering low dose steroids versus continuation in patients with RA and low disease activity. This multicenter, double blind, placebo-controlled, randomized study was done across 39 centers across 6 countries. Patients had a diagnosis of RA maintained on tocilizumab and a stable 5 mg prednisone dose for 4 weeks prior to randomization while having low disease activity using DAS28-ESR (<3.2). 246 patients were randomized to one of two groups; one in which 5 mg of prednisone was continued daily or a second in which they underwent a 1 mg taper every 4 weeks until tapering off by week 16. After 24 weeks the primary endpoint, change in DAS28-ESR from baseline, was lower in the continued prednisone group (-0.08 [-0.27-0.12]) compared to the tapered group (0.54 [0.35-0.73]. Of particular interest was the secondary endpoint which showed that 65% of patients in the tapered group became prednisone free without disease flare, adrenal insufficiency and remained in low disease activity. 77% of patients in the continued prednisone group were able to reach this endpoint as well.

Implications for Patients, Providers, & Researchers

Current implications: Talk about coming up in the clutch! Despite a mean disease duration of 9 years and a history of prior biologic use in one-third of patients, many were able to successfully discontinue steroid therapy by the end of the trial. In fact, when compared to the group continuing steroids, 8 patients would need to undergo steroid taper before one patient experienced a flare or loss of low disease activity. With this number needed to harm patients and providers should continue to view steroid taper as a natural next step in rheumatoid arthritis management. Also of note is that patients who flared were usually on prednisone 1 mg or 0 mg daily therefore even a failed attempt can be viewed as an opportunity to reduce their daily steroid maintenance dose by more than 50%. Swoosh!

Future implications: Providers should be reassured by the fact that no cases of adrenal insufficiency occurred in the prednisone withdrawal group. Given the high success rate, eventual withdrawal of steroid therapy can be viewed as a standard of care in all patients with rheumatoid arthritis. With the abundance of therapies available, patients who fail withdrawal should be offered therapy modification with the aim of one day attaining steroid-free remission.

Will SEMIRA win in its First Round Match-up?

We believe SEMIRA has the higher odds of winning its tough first round against the harms of short-term steroid study for numerous reasons. Firstly, our opponent’s study is a self-controlled case series from only one health care system that makes it more vulnerable to bias. SEMIRA on the other hand is the first of its kind and a good one at that – a double-blind, multicenter, randomized controlled trial across 6 countries to look at a glucocorticoid tapering regimen in stable RA patients with stable biologic therapy. Moreover, SEMIRA shows that an incredible two thirds of stable RA patients were able to be safely tapered off steroids. That’s a statistic that will be sure to bring the crowd to its feet! Additionally, a significant limitation in the harms of short terms steroid study is the lack of accounting for possible confounding factors, and the study relies on prescription data of Medrol dose packs, which is hardly the most commonly used modality for achieving RA disease control. Finally, the study did not have any patients with rheumatologic illnesses and therefore the applicability to patients with RA is questionable.

Could SEMIRA Win it All?

Is SEMIRA the Cinderella story at this year’s tournament? We think it’s very possible that SEMIRA can win the tournament and bring it all home! Let’s review the facts – SEMIRA is groundbreaking as the first randomized control trial evaluating prednisone taper in seven decades! Rheumatologists everywhere can unclutch their pearls now that we know adrenal insufficiency is not as big of a problem as once feared. Rheumatologists can also pop their collars and show off their kicks as improvising tapers can become a thing of the past with SEMIRA providing an evidence-based protocol. We’d say the outlook for SEMIRA is pretty good in the first and second rounds alone based on the very practical implications of the study – these are results that will be referred to on a daily basis! Finally, it may not bring the flashiness of the SLE and ANCA trials but we’d choose the solid and consistent performance of a trial like SEMIRA whose implications will be referred to daily rather than the pizzazz of trials dealing with diseases far less common.


  1. Burmester GR, Buttgereit F, Bernasconi C, Álvaro-Gracia JM, Castro N, Dougados M, Gabay C, van Laar JM, Nebesky JM, Pethoe-Schramm A, Salvarani C, Donath MY, John MR; SEMIRA collaborators. Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial. Lancet. 2020 Jul 25;396(10246):267-276. doi: 10.1016/S0140-6736(20)30636-X. PMID: 32711802.
  2. Haraoui B, Jovaisas A, Bensen WG, et al Use of corticosteroids in patients with rheumatoid arthritis treated with infliximab: treatment implications based on a real-world Canadian population. RMD Open 2015;1:doi: 10.1136/rmdopen-2015-000078

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Harms of Short Term Steroids (HoSTS) Scouting Report

Written By: Amna Batool, Susan Mansourian, Elise McVeigh, Saurav Suman, Kristine Lohr; University of Kentucky Fellowship Program

Based on: Yao et al, Ann Intern Med. 2020;173:325-330. doi:10.7326/M20-0432

Topic Overview

This study examines the side effects of a short course of oral corticosteroid burst dosing (up to14 days). The researchers reviewed the entire nationwide population of Taiwan using health insurance research database between the ages of 20-64 years that included more than 15 million adults, with over 2 million who received at least one steroid burst in the final analysis. The median dose of steroid was prednisone 10mg/day and the median duration of use was 3 days. The most common indication of steroid use were skin diseases and respiratory illness. Rheumatological diseases were not listed among the conditions requiring steroid burst.

The researchers specifically looked at the risk of severe adverse effects such as: GI bleeding, sepsis and heart failure up to 90 days after steroid use. The incidence rate per 1000 person – year among steroid users were: 27.1 for GI bleeding; 1.5 for sepsis, and 1.3 for heart failure. They found elevated risk of GI Bleeding (Incidence rate ratio (IRR): 1.8), sepsis (IRR: 1.99) and heart failure (IRR: 2.37) in people who received short steroid burst compared to those who did not receive it. This risk was significantly increased within 1st 5-30 days after the steroid dose and then gradually decreased afterwards over 31 – 90 days but still was significant. Final analysis adjusted for other concomitant medication that could confound the results such as NSAID and PPIs.

Implications for Patients, Providers, & Researchers

Current implications: This study emphasizes the elevated risk for side effects of even short course use of steroids, which is an important consideration that Rheumatology providers need to keep in mind when prescribing for disease flares. Evidence regarding short bursts of steroids regarding potential risks of treatment is limited. Thus, this study provides new insight into short-term risk following burst dosing.

Future implications: The future implications of this study include making Rheumatology providers more cognizant of the short-term risks associated with steroid burst for disease flares. Additionally, this study did not focus on rheumatologic disease patients, but should encourage Rheumatology researchers to specifically evaluate use of burst steroids in rheumatologic patients. Next steps may also implicate future research to determine optimal steroid burst duration to limit side effects and improve patient safety.

Will HoSTS Win its First Round Match-up?

“Harms of Short-Term Steroid” (HoSTS) and “SEMIRA” are both strong teams, with a lot of potential. However, in a match-up, HoSTS has the upper hand, because it is tackling the burning question that not only rheumatologists, but physicians of all fields, face on a daily basis: “Does this patient need a steroid taper today?” Granted, the study was not focused on rheumatological conditions perse. However, it managed to highlight the significant risk of steroids at doses and durations shorter than an average rheumatologist would prescribe, in a large population healthier than rheumatologists see every day! This will make rheumatologists as well as the general medical community, think twice before reaching for the electronic prescription pad!

SEMIRA on the other hand, has the advantage of focusing on RA patients, and is tackling the popular question of “Does this RA patient need a steroid taper today?” The trial highlights that steroid tapers are possibly used more often than required, however results do not offer a clear guidance regarding a taper regimen. Both teams need follow-up studies to tailor their outcome. However, in a match amongst the two, seems like winning the first round is a slam dunk for team HoSTS!

Could HoSTS Win it All?

It’s improbable but not impossible for Team Harms of Short Term Steroids (HoSTS) to win the tournament, as it could be a jumping point for additional research for something miraculous like a steroid alternative with less side effects. Assuming team HoSTS can pull through to the final face-off, it should be wary of the Avacopan trial as it may implicate the beginning of steroid alternatives.


  1. Yao et al, Ann Intern Med. 2020;173:325-330. doi:10.7326/M20-0432

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