Failure of Management: Treatment Gaps at the Root of Dismal Gout Care

Experts might use words like “suboptimal” or “insufficient” to describe gout management in the United States. To be fair, many gout specialists and rheumatologists use those exact words. But they also say that gout management in the U.S. is “crummy” or outright “sucks.” They say these things not behind closed doors or at dinner meetings, but from the dais of national and international rheumatology conferences. This suggests that gout management is beyond problematic.

The confounding thing is that, as far as chronic diseases go, gout is relatively straightforward. “Gout is simply a disease of increasing urate burden over time,” Brian F. Mandell, MD, PhD, a rheumatologist at the Cleveland Clinic, told Healio Rheumatology.

Mandell — who has spoken out previously regarding the failure of physicians to properly treat and advise patients with gout — addressed one common misconception that lies at the heart of gout mismanagement. “Many patients believe that the attacks and flares of gout are the disease itself,” he said. “There has to be a better understanding that these attacks and flares are just a symptom of the disease. Flares happen because uric acid is constantly accruing in the body.”

Better understanding may be coming. The American College of Rheumatology and the Arthritis Foundation are currently updating guidelines for gout management, the last iteration of which was published in 2012. The document will cover considerable ground, but perhaps the most newsworthy message is that the authors recommend using a treat-to-target strategy with urate-lowering therapy (ULT).

“We believe that since the last guidelines, enough studies have been published to support the idea that lowering serum urate to below 6 mg/dL has shown meaningful improvements in flares and reducing tophi,” Tuhina Neogi, MD, PhD, professor of epidemiology at the Boston University School of Public Health and chief of rheumatology at the Boston Medical Center, said in a presentation during the most recent ACR Annual Meeting. “This recommendation has been very controversial, because another professional organization says that a treat-to-target strategy is not supported by data.”

That professional organization is the American College of Physicians: Its guidelines call for a more conservative ULT strategy, placing more focus on treating pain and flares.

To be fair, clinicians spend a significant amount of time managing flares. But this is in part because many doctors treating the disease are unaware of the fundamentals of urate accrual. “Too often, gout management begins and ends with the flare, since this is what drives patients to seek care,” Ted R. Mikuls, MD, MSPH, Umbach Professor of Rheumatology and vice chair of research at the University of Nebraska Medical Center, told Healio Rheumatology. “But this really should just be the beginning of several steps in management.”

Those steps include understanding how to use diagnostic imaging, management of comorbidities like chronic kidney and heart disease, and understanding the therapeutic armamentarium, all of which are covered in the guidelines, and all of which have proven to be questionable areas in gout.

Forthcoming Recommendations

The experts who developed the guidelines understood that many of the doctors treating gout have questions large and small. In response, beyond the treat-to-target approach, they made other recommendations abundantly clear. The document is still undergoing a review process and is expected to be published in early 2020, but the highlights are available to interested clinicians.

“There are strong recommendations for ULT,” Nicola Dalbeth, MD, an academic rheumatologist at the University of Auckland, in New Zealand, said in a presentation about the guidelines at the ACR Annual Meeting. For example, ULT is strongly recommended in patients with more than two flares per year, those with subcutaneous tophi, and those with radiographic damage, among others. “We strongly recommend allopurinol over other urate-lowering therapies as first line agents for all patients.”

For patients who are unable to tolerate allopurinol, a conditional recommendation calls for a switch to febuxostat, as opposed to uricosuric drugs.

As for switching to pegloticase (Krystexxa, Horizon) when necessary, Neogi suggested that this decision should be based on clinical activity. “If the patient has frequent flares or ongoing tophi, switch to pegloticase,” she said. “If there are no flares and no tophi, do not switch to pegloticase.”

But allopurinol should be the mainstay, and the data support starting at a low dose, such as 100mg per day or lower in those with renal insufficiency and titrating upward until the target is met including to above 300 mg per day as needed, Neogi added. “The concerns that titrating up to higher doses are detrimental are unsupported by any data,” she said. Febuxostat should begin at 40 mg daily or lower and be titrated upward, as well.

Even when clinicians follow these protocols, flares happen. “There is a strong recommendation for low-dose colchicine over high-dose for managing gout flares,” Dalbeth said. “The guideline also states that when ULT is indicated while the patient is experiencing a flare, we conditionally recommend starting ULT during the gout flare.”

The guideline development team understood that there are many gray areas in gout management, and they scoured the evidence in an attempt to offer guidance to clinicians in as many of those instances as possible. “For those who have previously experienced a flare, but have had less than two in a year, we conditionally recommend initiating ULT,” Dalbeth said. “For patients experiencing their first gout flare, we conditionally recommend against ULT except in the case of patients with chronic kidney disease 3 or a serum urate level of 9 or higher.”

The development team, of course, hopes that the guidelines will ease some of the significant challenges posed by gout management in the U.S., but there is still work to be done.

Stigma and Misinformation

The most recent estimate from the CDC puts gout prevalence at 8.3 million individuals, or 3.9% of the population. Of more concern is that prevalence has increased by 1.2% in the past 2 decades.

For N. Lawrence Edwards, MD, professor of medicine in the division of clinical immunology at the University of Florida in Gainesville, the most critical statistic is that of those nearly 9 million Americans with gout, just 1.1 million are adequately treated with the appropriate therapies. “We have urate-lowering therapies, and they work,” he said at the Congress of Clinical Rheumatology West 2019. “But still we do an absolutely crummy job of managing this disease.”

Among the many reasons for this shortfall is the stigma surrounding gout, according to Edwards. “Many patients believe that gout is a disease of the obese or over-imbibers,” he said. He dispelled two myths straight off the bat. “Can diet and exercise cure gout? Short answer: No. Is this really a self-inflicted disease? Spoiler alert: It’s genetic.”

This kind of widespread misinformation among patients partially explains how incidence of gout increased from 45 per 100,000 in 1977 to 1978, to 63.3 per 100,000 in 1995 to 1996 according to the Rochester Epidemiology Project, while numbers from 2010 showed that hospitalizations from gout comprised 2.3% of all hospitalizations in the U.S., and 13.1% of those from arthritis or other rheumatic diseases.

While those numbers tell the broad story of the impact that stigma and misinformation can have, the effects are also felt in the doctor-patient relationship in the clinic. “The more we talk about diet, the less patients listen about the drugs that will stop the progress of this disease,” Edwards said. “Diet accounts for only about 1% of uric acid variability.”

Plugging Other Knowledge Gaps

With diet and exercise largely off the list of culprits of gout mismanagement, many researchers, including Abhishek and Doherty, have set their sights on other explanations. Their findings published in Rheumatology underscored Mandell’s point that poor adherence to ULT is a problem, with data showing treatment discontinuation at 358 days among men and 379 days among women. Other studies show ULT adherence after 12 months of treatment as low as 22%.

One explanation for poor ULT adherence rates is that, in many cases, rheumatologists do not treat gout, according to Mandell. He noted that gout is often managed by non-rheumatology health care providers who are unaware that treatment should be continual. “They may simply not be aware that the flares are just the symptom, and that ULT must be ongoing to reduce urate levels and keep them low.”

Until the guidelines emerge and a campaign to disseminate the information is undertaken, education can help, according to Abhishek and Doherty. In their study where patients received tailored, individualized attention on ULT, 100% wanted to try the drugs, 92% continued treatment at 1 year, and 91% continued through 5 years.

“Some physicians do not, or are unable to, take the time to engage in patient education about the underlying cause of gout being hyperuricemia, and the importance of using ULT to lower serum urate,” Neogi said. “Another reason is that some do not take gout seriously enough, which is to the detriment of people with gout.”

Mandell pointed out that both physicians and nurses provided care and participated in the educational component of the Abishek/Doherty study. “Nurses, actually, have about a 96% rate of urate lowering,” he said. This information may provide guidance for treatment paradigms that give nurses who are committed to providing gout education to patients and their families a more hands-on role in the future.

Tough Decisions

In further discussing the care given by rheumatologists to patients with gout, Mandell did not let his specialty off the hook. “Even when you look at care among rheumatologists, it is not always ideal,” he said.

To be fair, the specifics of clinical decision-making are not always cut-and-dried. “If you have a patient who is 85 or 90 years old who just started having attacks, you may not want to treat their urate, because it is a long-term approach” Mandell said. “They may not live long enough for ULT to dissolve the deposits and the initial mobilization flares may outweigh the potential long-term benefits.”

Even in younger patients, clinicians can find themselves in the weeds in deciding who, and when, to treat. “The current guidelines recommend integrating ULT when a patient has two or more attacks per year,” Mandell said, referencing the 2012 document. “But if a patient has one attack, they may have a second one right away, or it may be 15 years before their next one, or they may never have one. It can be very unpredictable.”

The new recommendations will attempt to untangle many of these scenarios, but it is impossible to cover everything. “We simply do not have hard data for every possibility and eventuality like this,” Mandell said. “Even if a patient has two attacks relatively close together, we have no ability to predict, with accuracy, the likelihood of having a third or fourth.”

But all of this focus on flares runs contrary to the simple biologic reality of gout. “While we are deciding when the next flare may occur, uric acid continues to build, and it takes time to dissolve these crystals,” Mandell said.

It is at this point that management can become extremely frustrating for both doctors and patients who lack fundamental knowledge about the disease and its treatments. “When you start to lower urate levels, you may actually have more attacks,” Mandell said. “Now patients might say, ‘This doctor gave me the drug that he said would cure it, but then I had two attacks. This drug is terrible.’ This needs to be explicitly explained to patients – the dissolving of the uric acid deposits can initially cause more flares before they stop completely.”

Troubling Comorbidities

When patients have that attitude, they naturally drop off the treatment radar. At this point, complications — including chronic kidney disease and heart disease — are considerably more likely to arise. However, parsing out those associations can be tricky.

Some data sets show associations between gout and heart disease, or gout and kidney disease. However, gout therapies have been associated with both nephrotoxicity and cardiovascular outcomes, so the links grow weaker. Further, whether heart disease impacts kidney disease or vice versa also has not been clearly established. Many experts are confounded, and the data can be equally confusing.

In their 2017 study published in the American Journal of Kidney Diseases, Vargas-Santos and Neogi addressed the complicated relationship between gout and chronic kidney disease (CKD). “Although the presence of CKD poses additional challenges in gout management, effective urate lowering is possible for most patients with CKD,” they wrote. However, they acknowledged that managing flares can be difficult due to “potential nephrotoxicity and/or contraindications in the setting of other common comorbid conditions.” Emerging data may support a renoprotective effect of treating asymptomatic hyperuricemia with ULT, according to the researchers.

“Whether ULT meaningfully changes gout-related risk of developing comorbid illnesses, such as cardiovascular disease or chronic kidney disease, is still unknown in my book,” Mikuls said.

The lack of large-scale interventional trials on the subject is the stumbling block for Mandell. “It is difficult to do this kind of study because there are so many variables,” he said.

Turning to the heart, findings by Reddy and Choi from the Health Professionals Follow-Up Study demonstrated that men with gout carried an increased risk for cardiovascular disease mortality compared with men without gout over 12 years of follow up (RR = 1.38; 95% CI, 1.15-1.66).

However, not all experts are convinced by numbers like this. “The association between gout and cardiovascular disease is hard to sort out because there are so many factors at play,” Mandell said, noting that this association has confounded experts for more than a century. “There are animal models showing that hyperuricemia can cause high blood pressure and kidney injury, but in humans we have not been able to demonstrate that therapeutic interventions that lower the serum urate reduce renal and cardiovascular disease.”

Regarding gout treatments, Lin and colleagues studied 8,047 patients, 1,422 of whom were treated with allopurinol, 4,141 with benzbromarone, and 2,484 with both drugs. Results published in International Journal of Cardiology showed that use of both drugs, whether alone or in combination, conferred a linear dose-response relationship between dose and coronary artery disease risk.

In the absence of hard data elucidating the myriad associations between gout and the heart, Mikuls advocates for ongoing ULT therapy. “By reducing flare burden with ULT, we successfully reduce patients’ exposure to medications such as glucocorticoids and NSAIDs that can adversely influence a patient’s risk for heart and/or renal disease in addition to other harmful cardiometabolic effects,” he said.

Exploring the Treatment Armamentarium

While ULT is indeed important, gout treatment generally begins with anti-inflammatory medications to treat the pain and swelling of attacks, continues through steroids or low-dose colchicine for long-term reduction in flare risk, and then culminates with ULT.

The guideline development team is confident that allopurinol, febuxostat and pegloticase can do the heavy lifting in lowering urate in those 9 million Americans living with gout.

“Pegloticase is used for individuals with refractory gout, often with a large tophaceous burden, particularly when the tophi are not resolving on oral ULT or are causing functional impairment, which can be the case even when the tophus burden is small, but in a bad location,” Mandell said. “Because pegloticase is so effective for resolving tophi, I like to think of it as induction therapy, followed by maintenance therapy with oral ULT.”

Strong efficacy data are available for other ULT drugs recommended in the guidelines, driving home Edwards’ message that they work. The issue, then, is not efficacy. The issue is regulatory. On Feb. 1, 2019, Ironwood Pharmaceuticals discontinued the marketing of lesinurad (Zurampic) as well as their combination lesinurad/allopurinol (Duzallo) product in the U.S. Although the manufacturer has stated this was strictly a financial decision unrelated to drug efficacy or safety, its removal has nonetheless left a gap in the gout armory.

“If it were ever to become available on the market again, it does offer an important additional option in the management of the hyperuricemia of gout,” Neogi said.

Similar concerns exist for drugs that sit further down the bench. IL-1 inhibitors canakinumab (Ilaris, Novartis) and anakinra (Kineret, Sobi) are not currently FDA-approved for managing gout flares. “IL-1 inhibitors are an important option for patients with gout who are unable to use the other standard gout flare therapies due to contraindications or intolerances,” Neogi said.

Specifically, IL-1 inhibition is particularly important in controlling flares in patients with kidney and/or heart disease including congestive heart failure, or poorly controlled diabetes for whom conventional anti-inflammatory therapies such as NSAIDs, colchicine, or steroids may be contraindicated or less preferred, according to Neogi.

The issue for Mikuls is that many of the available therapies are often limited by unique clinical circumstances of the patient, underscoring the need for new treatments to address this unmet need. “As a gout provider, I am excited to see more tools in the management toolbox, as each new tool incrementally increases the number of gout patients we can help,” he said. “The opportunity that uricase-based therapies provide for medical debulking of advanced tophaceous disease has been a breakthrough in gout and serves as a prime example of how novel therapies empower effective gout management.”

Regardless of the drug, Edwards said to expect pushback from insurance carriers and other health care providers for one simple reason: “Urate-lowering therapy is lifelong,” he said. Insurance carriers may be loath to cover the drug indefinitely, and nonrheumatologists may be alarmed at the dosing and duration of these drugs, particularly allopurinol.

Impact of Diagnostic Technology

As the clinical community grapples with the basics of stigma and ULT adherence, research and development teams are hoping that technology may mitigate part of the problem. In Zeitschrift für Rheumatologie, Rech and colleagues reviewed literature from 2009 to 2017 for publications on dual energy computed tomography (DECT) for the evaluation and diagnosis of gout. Results from 77 papers showed that DECT had a sensitivity between 90% and 100%, along with a specificity of 83% to 89% for diagnosing gout.

“At present, advanced imaging is primarily helpful for aiding diagnosis when a crystal-proven diagnosis has not been made,” Neogi said. “Monitoring serum urate is the primary means of assessing response to treatment.”

While novel imaging methods may have utility, as Newberry and colleagues highlight in their review in Annals of Internal Medicine, there remain key concerns with their use as well. “Although DECT and ultrasonography also show promise for gout diagnosis, accessibility to these methods may be limited,” they wrote.

But does any of this matter? Assessing novel imaging techniques might be beside the point for Mandell. “We have more than enough information from the diagnostic tests that we currently have,” he said. “There is a place for DECT or musculoskeletal ultrasound in specific cases, but rheumatologists should be more interested in treating this disease and understanding why we do such a dismal job of treating it, than in sending more patients for expensive diagnostic tests.” – by Rob Volansky

• References:
• Abhishek A, Doherty M. Rheumatology. 2018;doi:10.1093/rheumatology/kex421.
• Lin HC, et al. Int J Cardiol. 2017;doi:10.1016/j.ijcard.2017.02.013.
• Newberry SJ, et al. Ann Intern Med. 2017;doi:10.7326/M16-0462.
• Rech HJ, Cavallaro A. Z Rheumatol. 2017;doi:10.1007/s00393-017-0341-1.
• Roddy E, Choi H. Rheum Dis Clin North Am. 2014; doi:10.1016/j.rdc.2014.01.001.
• Vargas-Santos AB, Neogi T. Am J Kidney Dis. 2017; doi:10.1053/j.ajkd.2017.01.055.

• For more information:
• Nicola Dalbeth, MD, can be reached at M&HS Building 502, 85 Park Rd., Grafton, Auckland 1023, New Zealand; email: n.dalbeth@auckland.ac.nz.
• N. Lawrence Edwards, MD, can be reached at 2000 SW Archer Rd., Gainesville, FL 32610.
• Brian F. Mandell, MD, PhD, can be reached at 9500 Euclid Ave. A50, Cleveland Clinic, Cleveland, OH 44195; email: mandelb@ccf.org.
• Ted R. Mikuls, MD, MSPH, can be reached at 986270 Nebraska Medical Center, Omaha, NE 68198-6270; email: tmikuls@unmc.edu.
• Tuhina Neogi, MD, PhD, can be reached at 650 Albany St., Suite X200, Boston, MA, 02118; email: tneogi@bu.edu.

Disclosure: Edwards and Neogi report no relevant financial disclosures. Dalbeth reports associations with Abbvie, Amgen, AstraZeneca, Dyve BioSciences, Hengrui, Horizon, Janssen, Kowa and Pfizer. Mandell reports being a clinical investigator for, and receiving consulting fees from, Horizon Pharma. Mikuls reports receiving research support from BMS and Horizon and consulting for Pfizer.