Gout Doubt: Experts Challenge New ACP Guidelines

Janis C. Kelly

November 02, 2016

New gout clinical guidelines published by the American College of Physicians (ACP) satisfy guideline criteria set by the Agency for Healthcare Research and Quality National Guideline Clearinghouse and the Institute of Medicine (IOM), but leave many gout experts outraged and saying the guidelines will harm patient care.

Specifically, the ACP guidelines turn away from recent "treat-to-target" emphasis on controlling serum uric acid (SUA) levels and recommend that for most patients, clinicians focus on relieving acute gout symptoms, rather than addressing underlying urate pathophysiology.

Writing on behalf of the Clinical Guidelines Committee, ACP Vice President for Clinical Policy Amir Qaseem, MD, PhD, MHA, and colleagues explain the ACP gout management and gout diagnosis guidelines in articles published online November 1 in the Annals of Internal Medicine. (Evidence reviews for management and diagnosis were simultaneously published online in the journal.)

The four main recommendations for the management of gout are to treat acute gout with corticosteroids, nonsteroidal anti-inflammatory drugs, or colchicine; to use low-dose colchicine (1.2 mg, then 0.6 mg 1 hour later) in treating acute gout; not to begin long-term uric acid-lowering therapy after a first gout attack or in patients with 2 or fewer attacks per year; and to discuss benefits, harms, costs, and individual preferences before initiating uric acid-lowering therapy in patients with recurrent gout attacks.

ACP: Evidence Is Insufficient for Monitoring of Serum Urate Levels

Notably, Dr Qaseem and colleagues write, "Evidence is insufficient for monitoring of serum urate levels in patients with gout.

"Target thresholds for serum urate levels rely on the chemistry of uric acid, which is soluble up to a concentration of about 404 μmol/L (6.8 mg/dL), above which precipitation may occur. However, this threshold is not absolute because patients with higher serum urate levels may still be asymptomatic, and some may have acute flares below this threshold. Although there is an association between lower urate levels and fewer gout flares, the extent to which use of urate-lowering therapy to achieve various targets can reduce gout flares is uncertain."

Gout expert Robert Terkeltaub, MD, professor of medicine at the University of California, San Diego, and president of the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN), told Medscape Medical News, "The guideline compromises gout-specific patient education, imperils good outcomes, and could set optimal treatment of the disease back decades."

The guideline...could set optimal treatment of the disease back decades. Dr Robert Terkeltaub

Dr Terkeltaub was not involved in the ACP guideline work, but was senior author on the 2012 American College of Rheumatology gout management guidelines.

Writing in an accompanying editorial, Robert M. McLean, MD, from the Northeast Medical Group in New Haven, Connecticut, a member of the ACP Clinical Guidelines Committee and a coauthor on the diagnostic guidelines, acknowledges that the guidelines run counter to those of the American College of Rheumatology (ACR), and will "likely will ignite controversy."

However, he continues, that is largely because the ACP committee chose to adhere to strict standards for guidelines: "Many professional organizations, including the ACR in its development of its gout recommendations, still develop 'guidelines' that are actually consensus expert panel opinions that do not clearly meet the current 2013 IOM and National Guideline Clearinghouse definitions and standards."

Hyperuricemia and Disease Control in Gout

That reasoning, however, does not appear to satisfy critics. In a second accompanying editorial, Tuhina Neogi, MD, PhD, from Boston University School of Medicine in Massachusetts, and Ted R. Mikuls, MD, MSPH, from the University of Nebraska Medical Center in Omaha, note that gout is so poorly managed that 70% of patients have recurrent flares.

"Elevation of serum urate levels to above 404 μmol/L (6.8 mg/dL) under normal physiologic conditions can lead to monosodium urate crystallization. Hyperuricemia is not a mere 'comorbid risk factor' of gout but rather the main pathophysiologic culprit that causes flares, tophi, and joint damage; therefore, management of hyperuricemia is a key tenet of disease control," they write.

Dr Qaseem and colleagues write, "There is no evidence from an experimental study that examined the health outcomes of treating to one serum uric acid level versus another, nor is there a trial comparing a strategy of basing treatment on attaining a specific urate level versus basing treatment on reduction in symptoms (such as gout flares)."

Dr Neogi told Medscape Medical News that the lack of randomized control trial data comparing "treat-to-target" vs "treat-to-avoid-symptoms" does not mean that no data are available to distinguish these two strategies.

"There is a large body of scientific knowledge other than randomized data to support a 'treat-to-target' strategy, while at the same time, the existing body of scientific knowledge raises concern regarding the 'treat-to-avoid-symptoms' approach contributing to poor outcomes in gout," she said.

Dr Neogi added, "Indeed, the ACP also recognizes uric acid as the cause of gout, and that lowering its levels is the treatment for gout. However, the ACP guidelines as written suggest that they cannot make a recommendation to physicians regarding what approach to use to lower uric acid. All international rheumatology society recommendations indicate that one should lower uric acid to well below the level at which it crystallizes.

"Further, based on existing data in the literature, it is recognized that maintaining lower uric acid levels over a sufficient period of time leads to reduction in and/or cessation of recurrent gout flares, as well as reduction or resolution of tophi. Studies have shown benefits when serum urate is maintained below 6 mg/dL, and even more when it is maintained below 5 mg/dL, particularly for those who have tophi," she continued. "[T]he absence of existing randomized data should not preclude provision of reasonable guidance to physicians that, based on very well-understood biology, serum urate should be reduced to at least below 6.8 mg/dL."

Dr Neogi warned that the suggestion that "treat-to-avoid-symptoms" is an equally plausible strategy risks contributing to "recurrent gout flares, tophi, and joint damage."

The Rorschach of Gout

Dr Terkeltaub said that these differences might reflect "gout as a Rorschach test" for clinicians. He said that, in line with the ACP recommendations, primary care physicians often see gout as an intermittent disease for which the primary aim is to eradicate the acute attacks, whereas rheumatologists typically see gout as a chronic, progressive condition, requiring long-term management.

Dr Terkeltaub described acute gout attacks as "the tip of an iceberg." He said, "We can't afford to do advanced imaging in every patient to determine the body burden of tissue deposits of urate crystals, which is the iceberg under the tip of acute attack. Risk of flares is influenced by fluctuations in serum uric acid levels, and high uric acid levels are associated with formation of new crystals, facilitating accumulation of icebergs of crystal deposits in the joints. We understand that melting the tissue uric acid icebergs away is the key to successful long-term therapy. That requires turning up the therapeutic heat to melt the iceberg. Right now, the best 'temperature gauge' we have is to monitor the lowering of serum uric acid level to target, which remodels and starts the removal of urate crystal deposits in the tissues."

Dr Neogi added that monitoring serum uric acid is also key to dosing urate-lowering drugs. "For example, if one starts urate-lowering therapy in a patient who then has a flare 4 months later, without checking the serum urate, one won't know if the patient is actually taking the medication [if not, the serum urate would not have changed from baseline], whether the dose needs to be increased, or that no dose adjustment is needed because serum urate is now below 6 mg/dL and that flare is part of the expected physiologic response in the early part of urate-lowering therapy initiation."

What Will the Payers Think?

Dr Terkeltaub said, "Another concern is that the ACP recommendations are so flawed that it would be unfortunate if something as simple as getting uric acid levels done to routinely monitor serum uric acid were to be impacted at the third-party payer level. It runs counter to ACR guidance, EULAR guidance, and the 3e multinational recommendations, all of which are recent, as well to older guidelines for gout management, such as those from the British Society for Rheumatology. The ACP guideline is clearly the outlier."

Dr Neogi said that without adequate dosing of urate lowering therapy, which requires serum urate monitoring, third-party payers would likely end up paying more treating recurrent gout flares, hospital admissions, and other costs associated with gout complications.

"The ACP [Clinical Guidelines Committee] finds it difficult when it cannot endorse a widely disseminated recommendation from a fellow professional society because of a lack of adequate supporting evidence," concludes committee member Dr McLean in his editorial. "Yet, it believes that evidence must direct guideline recommendations. Specifying clinical options when evidence is lacking is the role of expert consensus panels or best-practice statements, but these documents must not masquerade as the type of evidence-based guidelines defined by the IOM. As we try to provide our patients with the best possible care, we must be clear about when the best clinical decision is defined by high-quality evidence and when it is suggested by consensus."

The ACP authors did not respond to requests for comment.

The ACP project was funded by the Agency for Healthcare Research and Quality, US Department of Health and Human Services. Funding for guideline development was from the ACP operating budget. Dr MacLean reports receiving personal fees from Takeda Pharmaceuticals speakers' bureau before 2015. Dr Manaker reports receiving personal fees from work as a grand rounds speaker, lecturer, consultant, and expert witness on documentation, coding, billing, and reimbursement to hospitals, physicians, departments, practice groups, professional societies, insurers, and attorneys (defense, plaintiff "qui tam," US attorneys general, and the Office of the Inspector General); personal fees from work as an expert witness in workers' compensation and medical negligence matters; and dividend income from stock held by his spouse in Pfizer and Johnson and Johnson. Dr Terkeltaub reports receiving consulting fees from SOBI, Ardea/Astra-Zeneca, Horizon, Aequus Biopharma, Revive, Relburn, Selecta, Proteothera, and CymaBay. Dr Neogi has disclosed no relevant financial relationships.

Ann Intern Med. Published online November 1, 2016. Management guidelines full text, Diagnosis guidelines full text, Management evidence review full text, Diagnosis evidence review, McLean editorial full text, Neogi editorial full text

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