Written By: C. Allen Witt (Duke University) & the RheumMadness Leadership Team

Based on: Rangan et al. Management of adults with primary frozen shoulder in secondary care (UK FROST): a multicentre, pragmatic, three-arm, superiority randomised clinical trial. Lancet.2020;396(10256):977-89 (pubmed link)

Topic Overview

Adhesive Capsulitis (Frozen Shoulder) results in gradual loss of passive and active range of motion in the glenohumeral joint and is usually accompanied by severe pain. Plain radiographs usually only show evidence of osteopenia though there are some non-specific inflammatory or post-inflammatory soft tissue findings on Ultrasound and MRI. It occurs in 8.2% of men and 10.1% of women of working age. This condition is sually self-limited with functional limitation and pain lasting 2-3 years but 40% of patients have persistent mild symptoms and 6% with severe pain and loss of function at 4 years².

Current UK national physiotherapy guidelines recommend exercise and manual therapy either in isolation or to supplement steroid injection (CSI) , manipulation under anesthesia (MUA) or arthroscopic capsular release (ACR). The purpose of this trial was to determine any potential difference in efficacy or cost effectiveness of CSI + early structured physiotherapy vs MUA vs ACR.

This was a multicenter, pragmatic, superiority randomized trial comparing the three parallel groups. All patients were referred to secondary care for primary frozen shoulder. Patients with symptoms secondary to trauma, radiographic evidence of other cause or unable to tolerate surgery were excluded. Participants were randomly allocated in a respective 2:2:1 ratio to arthroscopic capsular release, manipulation under anesthesia, or steroid injection then early structured physiotherapy. Procedural groups also got the same physiotherapy post procedure. Primary outcome was the Oxford Shoulder Score (OSS), a 12 item patient-reported measure of pain and function. Other outcomes included visual analogue scale (0-100) of patient-perceived extent of recovery. All outcome measures conducted at 3, 6, and 12 months after randomization. Cost Effectiveness of each therapy in the UK health system was also an outcome measure, taking into account for each group the cost of initial intervention, hospitalizations and any further interventions in the 12-month period. In terms of results, there was no clinical difference in effectiveness between the three groups. Capsular Release was associated with greater risk of adverse events. Manipulation under anesthesia was considered most cost effective based on elaborate statistical modeling. Patients who got early physiotherapy were more likely to pursue additional therapies, but also the only group without any serious adverse effects.

Implications for Patients, Providers, & Researchers

Current implications:

Steroid injection and 12 weeks of appropriate physiotherapy is just as effective as the most popular procedural options for patients referred to secondary care for primary frozen shoulder. This has enormous implications for patients who are concerned about or at higher risk for adverse events from procedures. For providers this means that prior to referral to surgery there should at least be a discussion about starting PT or re-starting PT, perhaps with a different therapist than was originally used. If patients are insistent on procedure, it seems that manipulation may be the most reasonable option given relative safety and cost effectiveness. This is a practice changing study for a difficult-to-treat, painful and disabling condition that affects a large proportion of workers. If the cost-effectiveness data translates well into healthcare settings beyond the UK, these findings could lead to large savings in healthcare expenditures without changing efficacy of treatment or patient perception of wellness.

Future implications:

60% of all the patients in this study had already completed PT for the same shoulder with same symptoms. Patients had on average, 10.5 months of symptoms prior to randomizations, so the endpoint of 12 months means ~2 years post onset. This implies that not all PT is created equal and/or multiple rounds of PT are often required. No additional training was necessary and standard therapies for were used for the structured PT but the protocol was developed specifically for the study and was based on a survey of UK shoulder specialist physiotherapists³. If, as this study has shown, early PT can be safer and just as effective for patients then perhaps we should more closely examine the regimens and delivery models for PT. It would be interesting to see this same structured early PT program implemented nearer to onset of symptoms in a research study which may help answer the important question of whether these patients could start benefiting earlier in the course.

Will UK Frost for Frozen Shoulder Win its First Round Match-up?

Its first opponent, PT vs CSI for Knee OA is similar in many ways; both represent a win for Physical therapy over procedural care. The CSI vs PT in Knee OA trial is a very clean 1:1 design that a great job of showing that PT is better than steroid injection. I’m not sure how practice changing this really will be though given that the study did not look at steroid injection + physical therapy which is a common treatment that I suspect will continue and may be superior to either treatment alone.   Also, UK FROST had a more robust sample size and so were able to clearly demonstrate the clinical soundness of avoiding surgery or procedure under anesthesia thus avoiding all the costs and morbidities that go along with it. It is a study that leads to reduction of truly serious adverse events and saves millions of dollars in healthcare costs. UK Frost will undoubtedly give CSI vs PT the proverbial “cold shoulder” on its way to the next round.

Could UK Frost Win it All?

It ticks all the boxes. Is it practice changing? Check. Is it practice changing in a way that will substantially save healthcare costs? Check. Will it lead to reduction in serious adverse effects and morbidity for patients? Check. That being said, it can be difficult for a team out of the MSK bracket to go all the way when it is not a classic autoimmune Rheumatological disease. For this reason, this team is a dark horse but its potential to add value to patient care is tremendous. I think it will clear the first round but may have difficulty contending with other trials looking at therapy for more traditional Rheum disorders (i.e. SEMIRA).

Reference(s)

1. Rangan A, Brealey SD, Keding A, Corbacho B, Northgraves M, Kottam L, Goodchild L, Srikesavan C, Rex S, Charalambous CP, Hanchard N, Armstrong A, Brooksbank A, Carr A, Cooper C, Dias JJ, Donnelly I, Hewitt C, Lamb SE, McDaid C, Richardson G, Rodgers S, Sharp E, Spencer S, Torgerson D, Toye F; UK FROST Study Group. Management of adults with primary frozen shoulder in secondary care (UK FROST): a multicentre, pragmatic, three-arm, superiority randomised clinical trial. Lancet. 2020 Oct 3;396(10256):977-989. doi: 10.1016/S0140-6736(20)31965-6. Erratum in: Lancet. 2021 Jan 9;397(10269):98. PMID: 33010843.
2. Hand C, Clipsham K, Rees JL, Carr AJ. Long-term outcome of frozen shoulder. J Shoulder Elbow Surg. 2008 Mar-Apr;17(2):231-6. doi: 10.1016/j.jse.2007.05.009. Epub 2007 Nov 12. PMID: 17993282.
3. Hanchard NCA, Goodchild L, Brealey SD, Lamb SE, Rangan A. Physiotherapy for primary frozen shoulder in secondary care: Developing and implementing stand-alone and post operative protocols for UK FROST and inferences for wider practice. Physiotherapy. 2020 Jun;107:150-160. doi: 10.1016/j.physio.2019.07.004. Epub 2019 Jul 19. PMID: 32026815.

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Written by: Dr. Ronak Patel, Dr. Chad Hille, and Dr. Chandana Keshavamurthy from Ochsner Medical Center

Based on: Deyle et al. NEJM.2020;382(15):1420-29 (pubmed link)

Topic Overview

Knee osteoarthritis is a very common problem in the United States and also a leading cause of disability. Unlike in Rheumatoid arthritis, where disease modifying agents are the norm, we have no such luxury in the management of osteoarthritis. There are many clinical trials which have shown promising results for compounds that:

• Arrest structural progression, which include cathepsin inhibitors, Wnt inhibitors, anabolic growth factors.
• Reduce pain which include nerve growth factor inhibitors.

To-date no drugs are approved by the FDA. Managing the symptoms is the main stay. This includes pain management and therapies which focus on improving the quality of life. Data from varying population cohorts suggest that nearly 40 to 50% of the patients in the cohort receive intra articular steroid injections prior to total knee replacements. In our day to day practice we offer physical therapy for many of our patients, but not all of them consistently respond to the treatment offered, similarly we offer intra articular corticosteroid injections often with varying results.

We do know from various clinical trials of treatments for osteoarthritis that physical therapy offers short term and long term relief of symptoms, offers functional improvement, decreases the need for pain medications particularly opioids. There is however paucity of data to help decide to what extent and duration intra articular corticosteroid injections offer benefit. Not to mention, the complications from the intra articular corticosteroid injections, including but not limited to joint infections, accelerated degradation of articular cartilage, subchondral insufficiency fractures.

Despite the controversy behind using intra articular corticosteroid injections and the guideline recommendations for physical therapy and lifestyle modifications, we see that intra articular corticosteroid injections are overutilized and physical therapy is underutilized in clinical practice. There are previous trials that combine intra articular corticosteroid injection to physical therapy with no added benefit and yet these practices have become a part of the treatment paradigm in managing knee osteoarthritis.

Let’s Talk About the Randomized Controlled Trial

The trial was designed to compare physical therapy to intra articular corticosteroid injections in a primary care setting in the US military health system . This was not a placebo controlled trial. Patients who were active duty or retired service members of the military health system and their family members with good access to health care participated in the trial, hence noncompliance/significant drop out rates was not an issue here.

Patients were randomly assigned in a 1: 1 ratio to receive intra articular corticosteroid injection or to undergo physical therapy. The mean body mass index of the entire cohort was 31.5 /obesity which is always thought to be a risk factor for knee OA is definitely noted here.

All patients had to meet the criteria laid by the American College of rheumatology clinical classification criteria for osteoarthritis of the knee , they had to have radio graphic evidence of osteoarthritis on weight bearing views assessed by Kellgren Lawrence scale, grading system, grades 1-4.  This is an important highlight, since this gives an opportunity to review the benefits of the therapy intervention on varying severity of the knee osteoarthritis.

However it so happens that majority of patients in the intra articular corticosteroid injection arm had Kellgren Lawrence grade 2, while majority of patients in the physical therapy arm had grade 3 scores. Not many patients had grade 1 scoring and a very few of them in both arms had grade 4 scoring, and lot more patients in the physical therapy arm had grade 4 as compared to the patients in the corticosteroid arm. To summarize, patients in the physical therapy arm had severe radiographic knee osteoarthritis as opposed to the intra articular corticosteroid injection arm.

Patients had physical therapy interventions including instructions and images for exercises for common joint mobilizations, there were hands on, manual techniques offered by the physical therapist. Patients underwent up to 8 physical therapy treatment sessions over the initial four to six week period, and patients could ask for additional 1 to 3 sessions at four months and nine months intervals. Patients in this group attended a mean of 11.8 treatment visits (range being 4 to 22).  Patients could get up to three intra articular corticosteroid injections in the one year time period. Patients in this group received a mean of 2.6 injections, range being 1 to 4.

Also noted was an overlap in the treatment interventions. 9% patients in the physical therapy arm also received intra articular corticosteroid injections. 18% in the intra articular corticosteroid injection arm received physical therapy in addition. The majority of patients had symptoms for an average of 100 months.  Symptoms included new swelling, locking, giving way feeling. 60% patients in both arms had bilateral knee osteoarthritis.

Statistical analysis was performed with the use of intention to treat approach.

Very clear primary outcome measures were defined early on, the primary outcome being the total score on the Western Ontario and McMaster Universities osteoarthritis index also known as WOMAC at one year. WOMAC contains 24 items and is composed of 3 subscales of pain, physical function, stiffness. Scores range from zero to 240, higher scores indicate worse pain, function, stiffness.  The secondary outcomes were the time needed to complete the timed up and go test and the score on the global rating of change scale at one year. The trial was sufficiently powered to meet the primary and the secondary endpoints. 

Trial Results

156 patients with the mean age of 56 years were selected and each group had 78 patients with all well matched baseline characteristics including pain severity ,disability. The baseline WOMAC scores were also well matched.

At one year, the group that underwent physical therapy met the primary and secondary outcome measures more than the group that had the intra articular corticosteroid injections.  The mean (±SD) baseline WOMAC scores were 108.8±47.1 in the glucocorticoid injection group and 107.1±42.4 in the physical therapy group. At 1 year, the mean scores were 55.8±53.8 and 37.0±30.7, respectively (mean between-group difference, 18.8 points; 95% confidence interval, 5.0 to 32.6), a finding favoring physical therapy.

Other outcome measures worth noting include the following :

• 10% patients in the physical therapy arm and 25% patients in the intra articular corticosteroid injections arm had no improvement from baseline, meaning they could not meet the 12% improvement in the minimal clinically important difference in the WOMAC score at one year.
• The median score on the global rating of change scale in both arms was above the clinically meaningful threshold of perceived improvement. But lot more patients in the intra articular corticosteroid injections arm than in the physical therapy arm did not report any perceived improvement on this scale.
• 14% of patients in the physical therapy arm and 33% of patients in the intra articular corticosteroid injections arm did not have a score on the global rating of change scale of plus three or higher at one year.

The authors therefore concluded that physical therapy did a better job in controlling pain and improving the functional disability at one year and is favored over intra articular corticosteroid injections.  Interestingly the mean cost for all knee related medical care during the one year trial was similar in the two groups.

WHAT ARE THE MAIN TAKE AWAY POINTS FROM THE STUDY?

The trial was designed to compare physical therapy to intra articular corticosteroid injections in patients with symptomatic clinical and radio graphic osteoarthritis in one or both knees and showed that physical therapy was more effective than glucocorticoid injections as assessed by the total WOMAC score and performance of functional tasks.

The advantages of this study is the long duration of follow up since previously short courses of physical therapy for four weeks at a time did show short term benefits but by one year the mean WOMAC scores would regress towards the baseline values.

What we also learned from this trial is the additional impact of educational sessions, periodic follow up visits with clinicians and change in interventions when necessary in managing our knee osteoarthritis patients. A dynamic world it is very similar to Rheumatoid arthritis!!!

Although intra articular corticosteroid injections do offer short term improvement , physical therapy shows both short term and long term benefits.

WILL THIS BE MY STANDARD OF CARE?

As with any trial there are definitely limitations and they are as follows,

• Patients who were assigned to physical therapy arm had more visits with the health care provider than patients assigned to the intra articular corticosteroid injections group.
• Patients had overlapping treatments which might have altered the trial conclusions.
• Significant number of patients in both arms did not meet the primary and secondary outcomes.
• Few patients despite all the interventions had their knees replaced.
• Few patients needed more than three intra articular corticosteroid injections and few patients needed more than the assigned number of physical therapy sessions.
• Most importantly this was an unblinded trial, hence bias cannot be ruled out.

CONCLUSIONS

Although physical therapy for patients with knee osteoarthritis will be the standard of care in my clinical practice, I will not discourage patients from getting intra articular steroid injections.

IMPLICATIONS FOR PATIENTS, PROVIDERS AND RESEARCHERS, CURRENT AND FUTURE

There are so many guidelines for management of knee osteoarthritis laid out by different societies. A treatment algorithm is truly lacking. A brief review is summarized here:

• Osteoarthritis research society international guidelines/OARSI emphasizes on core treatments including:
  • Arthritis education, structured land based exercise programs with and without dietary management, acquatic exercises.
  • Medical management includes topical NSAIDs, oral NSAIDs with PPIs if no contraindications, duloxetine, intraarticular corticosteroids, intra articular hyaluronic acid, topical capsaicin.
  • The society discourages the use of acetaminophen (paracetamol), oral and transdermal opiods.
• American college of rheumatology/ACR foundation recommends:
  • Exercises including balance exercises, weight loss, self efficacy and self management programs, tai chi, yoga, cognitive behavioural therapy.
  • Use of assisted devices like cane, tibiofemoral knee braces, patellofemoral braces, kinesiotaping.
  • Accupunture.
  • Thermal interventions including heat and cold, radiofrequency ablation.
  • Medical management includes topical and oral NSAIDs, intra articular glucocorticoid injections, topical capsaicin, acetaminophen, duloxetine, tramadol.
  • It discourages massage therapy, use of modified shoes and wedged insoles, pulsed vibration therapy, transcutaneous electrical stimulation.
  • It also discourages use of opiods, intra articular hyaluronic acid injections, intra articular botulinum injections, colchicine, fish oils, vitamin d and prolotherapy, platelet rich plasma treatment, stem cell injections, bisphosphonates, glucosamine, chondroitin sulfate, hydroxychloroquine, methotrexate, TNF inhibitors and IL-1 receptor antagonists.
• An American Academy of Orthopaedic Surgeons (AAOS) guideline suggests:
  • Encouraging patients with knee osteoarthritis to participate in self-management educational programs such as those conducted by the Arthritis Foundation and to incorporate activity modifications into their lifestyle (eg, walking instead of running or engaging in alternative activities).
  • The medications recommended are oral and topical NSAIDs,tramadol.
  • No guideline recommendations for use of Intra-articular hyaluronic acid, Glucosamine and/or chondroitin sulfate or hydrochloride.
• A recent review of Diagnosis and treatment of hip and knee osteoarthritis:
  • A review was published in JAMA, authored by Jeffrey N Katz et al, presented a table highlighting many therapies which we continue to use despite recommendations to the contrary. Follow this pubmed link to find the article.
• Well powered randomized controlled trials comparing different treatment options to lay out clear protocols is the need of the hour in osteoarthritis management.

Also worth noting that patients with persistent pain and functional loss and advanced radiographic changes are candidates for total knee replacement (TKR). More than 700 000 primary TKRs are performed annually in the US, more than 90% of which are for OA. 10% of TKRs need to be revised over 20 years. The failure rate is higher in younger and more active recipients, those with comorbidities, and those operated on in low-volume centers or by low-volume surgeons. Obesity, diabetes, chronic pain, anxiety and depression, cirrhosis, hepatitis C, delay in the timing of the TKA all either cause complications or lead to adverse outcomes.

WILL THIS ARTICLE WIN THE FIRST ROUND MATCH UP ? COULD THIS ARTICLE WIN AT ALL? YES I AM HOPEFUL.

• Osteoarthritis is the most common joint disease, affecting an estimated more than 240 million people worldwide, including an estimated more than 32 million in the US.
• Osteoarthritis is the most frequent reason for activity limitation in adults.
• It causes lot of joint dysfunction, pain, stiffness, functional limitation, loss of valued activities, such as walking and exercising.
• Knee osteoarthritis is the most common joint along with hip osteoarthritis which undergoes these changes.
• It is estimated that 30% of individuals older than 45 years have radiographic evidence of knee OA and of these 50% have symptomatic knee OA.
• Osteoarthritis also leads to substantial cost. 43% of the 54 million individuals in the US living with arthritis experience arthritis related limitations in daily activities. Wage losses due to OA amount to 65 billion $ and direct medical costs exceed 100 billion $. Persons with knee OA spend an average of about 15,000 $ over their life times on direct medical costs of OA.
• Osteoarthritis is commonly associated with comorbidities, which many stem from lack of physical activity, medication toxicity, and effects of inflammatory cytokines.
• Persons with knee OA have approximately 20% excess mortality compared with age matched controls, in part because of lower levels of physical activity.
• I am hoping that I have justified how important this study is in our day to day clinical practice.

References

1. Deyle et al. Physical Therapy versus Glucocorticoid Injection for Osteoarthritis of the Knee. NEJM.2020;382(15):1420-29 (pubmed link)
2. Jeffrey Katz et al. Diagnosis and Treatment of Hip and Knee Osteoarthritis. JAMA 2021;325(6):568-78. (pubmed link)
3. Guidelines for management of osteoarthritis by ACR,OARSI,AAOS

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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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