Written By: University of Colorado Rheumatology Fellows

Based on: Orange DE, et. al. RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares. NEJM. 2020;383:218-28

Topic Overview

Rheumatoid arthritis (RA), like many systemic autoimmune disorders, is characterized by periods of disease exacerbation and quiescence. Despite advances in our understanding of disease pathophysiology, little is known about the immunologic drivers of disease flares in RA. Previous studies have utilized cross-sectional analyses of RA patients with varying disease duration and clinical disease activity. This study offers unique insight into the immunologic changes, including in so-called PRIME (preinflammatory mesenchymal) cells, that occur directly preceding, during, and following disease flares, by utilizing a longitudinal design of four patients over years of intensive monitoring with frequent acquisition of transcriptional profiles and patient reported clinical data. A major strength of this paper lies in its unique methodology, as it generates detailed immunologic data that can be tightly correlated with concurrent clinical disease findings. 

Implications for Patients, Providers, & Researchers

Current implications: This paper describes immunologic changes in a small number of RA patients (n = 4). As such, applicability to wider populations (e.g., seropositive versus seronegative RA patients, early RA versus established RA, on csDMARD versus bDMARD therapy) is uncertain. The paper generates data that contributes to our understanding of immunologic underpinnings of RA flares, which can be helpful in patient education and counseling. Most importantly, this paper describes a methodology (proof of concept for the use of longitudinal transcriptomics) that can be utilized in the investigation of other autoimmune illnesses characterized by disease flares (SLE, vasculitis, etc…), and in studies investigating pre-clinical disease periods and the transition to overt clinical findings (e.g. pre-RA or incomplete lupus).

Future implications: Most immediately, this paper describes a clinical measurement tool that could provide educational benefit for patients and providers through explanation of how a flare may be happening (though not necessarily yet why). It holds potential in terms of personalized and precision medicine in the assessment and treatment of RA, and can be utilized in different stages of disease and perhaps even provide indication of transition between phases of disease (e.g. pre-clinical autoimmunity to clinical RA). Additionally, by understanding how flares may be occurring, this can further inform the process of identifying targets for novel therapies—a development that impacts both researchers and clinicians. This paper may highlight a new therapeutic target for treatment of RA (PRIME cells as the target).

Will PRIME Win its First Round Match-up?

PRIME certainly measures up against its competitor, R4RA. The latter is less ‘adaptable’ in future practice compared to PRIME as it relies on synovial biopsy. While the methodology described in both papers can be considered invasive, blood draws are certainly cheaper, less labor intensive, much more tolerable for patients when considering personalized medicine as opposed to acquiring tissue samples.

Could PRIME Win it All?

PRIME will have a very steep hill to climb to win it all. On one hand, the paper demonstrates the power of words (authors coining the term ‘PRIME’ cells) and a novel methodological approach. Anointing these cells as PRIME cells provides a better hook for readers than something along the lines of “A unique transcription profile found in CD45-CD31-PDPN+ synovial fibroblasts immediately precedes RA flares”. On the other hand, several competitors in the field offer immediate changes to clinical practice, and hence are likely to win out over the ‘delayed gratification’ of PRIME.

References

1. Orange DE, et. al. RNA Identification of PRIME Cells Predicting Rheumatoid Arthritis Flares. NEJM. 2020;383:218-28
2. Gravallese EM, Robinson WH. PRIME Time in Rheumatoid Arthritis. NEJM. 2020;383:278-279

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Written by: Vanderbilt University Medical Center Rheumatology Fellowship

Based on: Humby et al. Rituximab versus tocilizumab in anti-TNF inadequate responder patients with rheumatoid arthritis (R4RA): 16-week outcomes of a stratified, biopsy-driven, multicentre, open-label, phase 4 randomised controlled trial. Lancet.2021;397(10271):305-17 (pubmed link)

Topic Overview

R4RA (Humby et al, Lancet. 2021) is a biopsy-driven, multicenter, phase 4 randomized controlled trial that pits rituximab vs tocilizumab against each other in 161 patients with rheumatoid arthritis who have failed DMARD and TNFi therapy, either by intolerance or lack of efficacy. The patients are stratified by histology on synovial biopsy and RNA seq on synovial biopsy as either being “B-cell rich” or “B-cell poor.” This paper presents the 16 week outcomes, of which the primary outcome is difference in Clinical Disease Activity Index (CDAI) by 50% or more (CDAI50%). Other secondary endpoints were examined as well and include other disease activity measures (DAS-ESR, etc), functional outcomes (eg, HAQ), as well as quality of life outcomes (eg, SF-36). Ultimately, the authors show no statistically significant difference in achievement of the primary endpoint in patients who were characterized B-cell poor by histologic characterization (rituximab group with 17 [45%] of 38 patients and tocilizumab group with 23 [56%] of 41 patients; difference 11% [95% CI –11 to 33], p=0·31). However, there was a difference in patients characterized as B-cell poor by molecular RNA sequencing of the synovial sample (rituximab group 12 [36%] of 33 patients vs tocilizumab group 20 [63%] of 32 patients; difference 26% [2 to 50], p=0·035). Occurrence of adverse and serious adverse were not significantly different between treatment groups.

Implications for Patients, Providers, & Researchers

Current implications: Current treatment patterns in patients with RA rely on historical availability, insurance access, and relative contraindications. Historical response rates are limited in RA and could be optimized with a more targeted, personalized approach. There is an associated cost as well as side effect potential with multiple medications in patients with RA. R4RA provides that personalized approach, albeit with invasive testing. This is the first biopsy-driven trial in RA to show a differential treatment response. This paper confirms the translational suspicion that there are different endotypes of RA with corresponding differential responses to therapy. Researchers will continue to flesh this out and potentially find a less invasive means to sort these patients.

Future implications: It is not hard to see the future of a paper like this: Precision rheumatology! Our oncologic colleagues have been doing this for years, but the potential in selecting on the front end a treatment that will have more benefit in the patient in front of us is quite exciting.

Will R4RA Win its First Round Match-up?

R4RA stands a good chance to advance past the first round as its competitor, PRIME cells in RA (Orange et al, NEJM. 2020) is further from the bedside and does not suggest a therapeutic intervention and thusly cannot close a game down the stretch. R4RA needs to watch out though, as the PRIME illustration (Table 5) is sure to be a long-term teaching tool for future rheumatology fellows.

Could R4RA Win it All?

As exciting as the paper is, it will be a challenge for R4RA to win it all. While it might progress in the early rounds, it will find it difficult to overcome the powerhouses present in the AAV/SLE bracket. R4RA’s “Moneyball”-like approach in determining RA treatment therapy is clever, as it gives providers a biomarker to specifically guide therapy. This paper also adds to the few head-to-head trials we have in RA to help guide therapy. Ultimately though, synovial biopsy is invasive, and there will be questions about applicability of this trial to current care paradigms as well as limitations in it being an open label trial.

Reference(s)

1. Humby et al. Lancet.2021;397(10271):305-17
2. Orange et al. NEJM.2020;383(3):218-28

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Written by: Didem Saygin, Emily Peninger, Laarni Quimson, Marco Lopez-Velazquez, Kichul Ko – University of Chicago Fellowship Program

Based on: Mackenzie IS and the FAST Study Group. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020 Nov 28;396(10264):1745-1757.

Topic Overview

Gout is the most common inflammatory arthritis affecting 4% of adults¹. Hyperuricemia, a feature of gout, is associated with increased risk of cardiovascular (CV) disease. There are currently only two FDA-approved xanthine oxidase inhibitors for urate lowering therapy (ULT) in gout: allopurinol and febuxostat. Initial trials of gout comparing febuxostat with placebo/allopurinol suggested a higher rate of CV event with febuxostat. In this population with an already increased risk for CV disease, these results led to a blackbox warning for CV events with febuxostat and a change in recommendations for ULT in gout treatment guidelines.

The FAST trial is a large study conducted in Europe to assess the CV safety of febuxostat compared with allopurinol⁴. The study was a prospective, randomized, open-label, blinded endpoint, non-inferiority multi-center trial of febuxostat vs allopurinol. Eligible patients were 60 years or older, had gout, required ULT and had at least one CV risk factor. Patients who had a myocardial infarction (MI) or stroke in the previous six months, or class III/IV heart failure were excluded from the study. A total of 6128 patients were randomized to receive allopurinol vs febuxostat. The primary outcome was a composite of hospitalization for non-fatal MI or biomarker positive acute coronary syndrome, non-fatal stroke or death due to CV event. The study showed that febuxostat was non-inferior to allopurinol with respect to the primary outcome as well as secondary outcomes including CV death, all-cause death, hospitalization for non-fatal MI or biomarker positive acute coronary syndrome, and hospitalization for heart failure or transient ischemic attack based on both intention-to-treat and on-treatment analyses.

Implications for Patients, Providers, & Researchers

Current implications: Given the frequency of gout, increased risk of CV events in these patients and limited ULT options, the clinical implications of the FAST trial are undoubtedly large. The results of this study inform both patients and physicians regarding the CV safety of febuxostat compared to allopurinol. These results are particularly helpful in choosing a ULT for patients with gout who have CV risk factors and patients for whom allopurinol is contraindicated or not tolerated.

Future implications: The FAST trial provides a high-quality evidence for the FDA to consider removing the blackbox warning of febuxostat and for a change in future gout treatment guidelines.

Will FAST trial Win its First Round Match-up?

We believe that the FAST trial will easily win its first-round match-up against the ACR 2020 gout guidelines as the trial actually helps to clarify the uncertainties regarding CV safety of febuxostat and provides important results to inform newer gout guidelines with more robust evidence. The ACR guidelines may make some runs with a barrage of different shots with their numerous recommendations of varying degrees of evidence. However, the ‘analytics’ strongly favor high efficiency shots near the basket which the FAST trial provides with its high-quality data and straight-to-answer-the-question approach.

Could FAST trial Win it All?

The FAST trial can really win it all given the impact of its results. There are certainly heavy challenges that can come from novel therapies for systemic diseases with their jaw-dropping moves. Nonetheless, when it comes to efficiency and volume of shots made, the FAST trial can score high on both counts as a large randomized study that can affect countless gout patients with CV risks.

Reference(s)

1. M Chen-Xu, et al. Contemporary Prevalence of Gout and Hyperuricemia in the United States and Decadal Trends: The National Health and Nutrition Examination Survey, 2007-2016. Arthritis Rheumatol. 2019;71:991-999.
2. IS Mackenzie, et al. Long-term cardiovascular safety of compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomized, open-label, non-inferiority trial. Lancet. 2020;396:1745-1757

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Written by: Donna Jose, MD and Marven Cabling, MD; Loma Linda University Rheumatology Fellowship Program

Based on: FitzGerald JD, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020 Jun;72(6):744-760.

Topic Overview:

In May 2020, the American College of Rheumatology debuted the new guidelines for the management of gout. This latest set is a direct answer to criticisms on the prior guidelines released in 2012 where there were low quality evidence supporting some of its core recommendations, especially for treat to target strategy. This update reflects new data from recent studies and input from a panel of experts and patients.

Gout is the most common inflammatory arthritis, affecting about 9.2 million adults in the United States. Its incidence has doubled over the past 20 years. Even though the underlying etiology of the disease is well-elucidated and appropriate therapies exist, there are still significant gaps of care. The overall management of gout remains suboptimal with a chronic underutilization and poor patient adherence to the drugs that lower the uric acid burden. It is the hope of the ACR that the new guidelines would help improve gout management in our patients.

The 2020 ACR Guidelines has 42 recommendations, including 16 that are considered strong recommendations. The guidelines feature recommendations for the following key areas: indications for urate lowering therapy (ULT), approaches to the initiation and management of ULT, management of gout flares, asymptomatic hyperuricemia, and management of concomitant drugs and lifestyle modification.

Here is a quick summary of notable recommendations:

1. ULT is indicated for all patients with tophaceous gout, radiographic damage due to gout, or frequent gout flare (³2 per year).
2. Initiation of ULT is conditionally recommended in patients with >1 flare but <2 per year; or those with first flare and CKD³3, serum uric acid level of >9mg/dl or urolithiasis.
3. ULT is not indicated in patients with asymptomatic hyperuricemia (no prior flare or subcutaneous tophi), even in those with evidence of MSU crystal deposition on DECT or ultrasound imaging (conditional).
4. Allopurinol is the preferred first line ULT, including for those with moderate to severe chronic kidney disease. However, a lower starting dose is to be used (£100mg/day). Febuxostat is another option.
5. Prophylaxis using anti-inflammatory drugs (colchicine, NSAIDs or steroids) for 3-6 months to prevent mobilization flares is strongly recommended.
6. Treat to target strategy is strongly recommended (SU target of <6mg/dl)
7. Continue ULT indefinitely (conditional)
8. Test for HLA-B*5801 prior to starting allopurinol in patients of Southeast Asian descent or are African American as this allele is associated with a high risk for developing allopurinol hypersensitivity syndrome. (conditional)
9. For patients with gout taking febuxostat with a history of CVD or a new CV event, it is conditionally recommended to switch to an alternative ULT agent if available (conditional)
10. For gout flare: may use colchicine, NSAIDs, or glucocorticoids. IL-1 inhibitors or ACTH may be used as second line agent. Topical ice is recommended as adjuvant therapy.
11. The guidelines have also commented on weight loss, diet (including limiting alcohol, high purines and high fructose corn syrup), intake of vitamin C, use of HCTZ, aspirin, losartan and fibrates.

Implications for Patients, Providers, & Researchers:

Current Implications: Gout is certainly an old disease with most clinicians confident of its management. However, in reality, most of us can learn a few more things in caring for our patients with gout. It is easy to dismiss gout, either intentionally or not, as unimportant or easy to manage. Yet, the data on the quality indicators reveal that most of us do a suboptimal job in caring for our patients with gout. The new guidelines should serve as a reminder, if not a wake-up call, to up our game and improve the care we provide to our patients.

The strengths of this new set of guidelines lie in the team effort and collaboration between researchers, field experts and patient representatives. The voices and preferences of patients, cost of therapy have been reflected against emerging evidence, resulting in a robust set of new recommendations. It now includes an expanded indication for the use of ULT with greater emphasis on the use of allopurinol as the first choice for gout therapy.  A treat to target strategy with SU <6mg/dl is strongly recommended. This was recommended in the 2012 guidelines but now reemphasized based on newer and stronger evidence. Wider testing for the presence of HLA-B*5801 is recommended for certain populations due to higher risks of developing allopurinol hypersensitivity syndrome. Furthermore, bonus inclusions in the guidelines are some practical points such as dietary modifications, guidance on how to manage common drugs that may affect serum urate levels (hydrochlorothiazide, losartan, vitamin C and aspirin) and the use of ice compress as adjunct flare therapy.

Future implications: While the new guidelines are comprehensive, there are still questions that have been left unanswered. We look forward to the next iteration of the ACR guidelines in the future answering these questions:

• What is the best strategy for titrating ULT?
• What is the optimal serum uric acid threshold for patients with more severe gout?
• Would there be a different SU target based on patient’s race, sex or comorbidities?
• Would prolonged and profound hyperuricemia be safe especially since there has been a link to low SU<3mg/dl with neurodegenerative disorders?
• Would ULT be beneficial in patients with asymptomatic hyperuricemia and comorbidies such as CVD, CKD or hypertension?

Will the 2020 ACR Guideline for the Management of Gout win its first round match up?

Yep, just a simple yes. No question, the ACR Gout Guidelines will beat its first-round opponent, the FAST Trial. While the FAST trial is certainly important tackling the risks (or non-risks) of febuxostat in gout, the comprehensive nature of the ACR Guidelines and its wide implication in patient care will most surely knock the FAST trial off its feet. However, the FAST trial may possibly pull a fast one and swoop a win when you consider how the trial found non-inferiority of febuxostat over allopurinol for risk of cardiovascular events. This result contrasts with those of the CARES trial, which is one of the evidence used to conditionally recommend other ULTs over febuxostat in patients with cardiovascular disease.

Could the 2020 ACR Guideline for the Management of Gout win it all?

Optimistically speaking, it is possible. The 16 strong recommendations stated in the new guidelines were based on the gold standard RCT trials that compared treat to target regimens with usual care. These higher quality studies also details recommendations on lifestyle factors and use of concurrent medications, which together provides much needed information on how to better manage gout to improve quality of care for our patients. Other studies such as Avocapan and Belimumab for Lupus Nephritis provide new and exciting treatment options and might have a fair chance at winning it all but the extensive data and quality behind the new 2020 ACR guideline for gout management is unbeatable. This new guideline could pave the way to close the care gap in out gout patients with the assistance of evidence-based medicine.

Reference:

FitzGerald JD, et al. 2020 American College of Rheumatology Guideline for the Management of Gout. Arthritis Care Res (Hoboken). 2020 Jun;72(6):744-760.

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