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Editorials |3 January 2017

To Treat or Not to Treat (to Target) in Gout Free

Tuhina Neogi, MD, PhD; Ted R. Mikuls, MD, MSPH

Tuhina Neogi, MD, PhD
From Boston University School of Medicine, Boston, Massachusetts; University of Nebraska Medical Center, Omaha, Nebraska.

Ted R. Mikuls, MD, MSPH
From Boston University School of Medicine, Boston, Massachusetts; University of Nebraska Medical Center, Omaha, Nebraska.

Article, Author, and Disclosure Information
Author, Article, and Disclosure Information
This article was published at www.annals.org on 1 November 2016.
  • From Boston University School of Medicine, Boston, Massachusetts; University of Nebraska Medical Center, Omaha, Nebraska.

    Grant Support: By grants P60 AR47785 (Dr. Neogi) and P50 AR060772 (Dr. Mikuls) from the National Institutes of Health.

    Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M16-2401.

    Requests for Single Reprints: Tuhina Neogi, MD, PhD, Clinical Epidemiology Unit and Rheumatology, Boston University School of Medicine, 650 Albany Street, Suite X200, Boston, MA 02118.

    Current Author Addresses: Dr. Neogi: Clinical Epidemiology Unit and Rheumatology, Boston University School of Medicine, 650 Albany Street, Suite X200, Boston, MA 02118.

    Dr. Mikuls: Department of Internal Medicine and Division of Rheumatology, University of Nebraska Medical Center, 986270 Nebraska Medical Center, Omaha, NE 68198-6270.

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Gout, the most common form of inflammatory arthritis, has a well-understood pathophysiology and effective treatments are available. Yet, gout is poorly managed, with approximately 70% of patients having recurrent flares (1). 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” (2) 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.
It is in this context that we review the American College of Physicians guidelines for gout diagnosis and management and the accompanying systematic literature reviews (2–5). We agree with the authors' conclusion that a high strength of evidence exists for use of colchicine, nonsteroidal anti-inflammatory drugs, and corticosteroids for gout flare management despite there being few placebo-controlled trials (none for corticosteroids), given “the known physiology of gout” and the fact that “symptoms result from an inflammatory reaction to the deposition of urate crystals, which occurs when the level of urate increases above its saturation point in the blood” (4). The authors also acknowledge evidence that urate-lowering therapy (ULT) reduces serum urate levels (a strong predictor of flares), and data from open-label extension studies of ULT trials support an association between lower serum urate levels and lower risk for flares. It is therefore puzzling that the strength of evidence for monitoring of serum urate levels, a prerequisite to ensuring adequate ULT dosing, was judged to be low. Using extrapolation similar to that applied to the assessment of gout flare management, we found at least moderate strength of evidence supporting monitoring of serum urate levels.
The authors suggest that a reactive “treat-to-avoid-symptoms” approach may be a reasonable strategy with ULT instead of a proactive “treat-to-target” strategy because the latter has not been adequately tested. However, the treat-to-avoid-symptoms approach has not been tested either. With this strategy, providers might consider suppressive anti-inflammatory therapy or treatment of each flare as a sufficient strategy without addressing underlying hyperuricemia. When patients never receive ULT or receive inappropriately low doses, ongoing urate deposition occurs, leading to progression of tophaceous deposits, further joint damage, and functional limitations. At this stage, such patients need much more aggressive (and expensive) treatment than they would have if their serum urate level had been appropriately targeted early on. Another concern is the confusion about what “treat to avoid symptoms” means, particularly because gout flares during ULT initiation are a common physiologic outcome. A patient having a flare 4 months into treatment might not be unexpected, but without checking serum urate levels, there is no way to know whether this relates to poor ULT adherence or a need for higher dosing. In addition, continuing a management strategy of starting allopurinol at an inappropriately high dose (specialty treatment guidelines do not recommend a starting dose of 300 mg/d) (6) will perpetuate the problem of unnecessarily increasing flare risk because this risk in the early treatment phase is directly proportional to the potency of the ULT used. Moreover, allopurinol doses of 300 mg/d or less leave more than half of all patients undertreated.
We acknowledge that the existing literature only indirectly addresses what the optimal serum urate target is. However, it is a disservice to our patients and primary care colleagues to suggest that treating to avoid symptoms is acceptable with ULT in the absence of evidence. At the very least, based on the biochemistry of urate, a treatment target below the physiologic threshold of urate crystallization (<6.8 mg/dL) would be appropriate, even if a lower target is not yet supported by randomized trials. A target of less than 6.8 mg/dL (or <357 µmol/L [<6 mg/dL] with assay variation taken into account) seems reasonable, based on the authors' own admission that serum urate levels exceeding this threshold are the cause of gout. As an example, no one would advocate for a treat-to-avoid-symptoms strategy for diabetes. Even though hypoglycemic agents have potential adverse effects, it is recognized that prevention of end-organ microvascular and macrovascular damage is important and that therapy is not aimed only at preventing symptoms of hyperglycemia. Suggesting that an unfavorable benefit–risk ratio for a treat-to-target strategy in diabetes should raise similar concerns for gout is unnecessarily alarmist. It is clear that low blood glucose levels can be detrimental, or even fatal; however, no such data exist for serum urate levels. In pegloticase trials (7), serum urate values as low as 59 to 119 µmol/L (1 to 2 mg/dL) were well-tolerated for several months without observed adverse effects. In fact, mean serum urate values around the turn of the 20th century in the United States averaged 178 to 238 µmol/L (3 to 4 mg/dL), levels that are rarely achieved with standard ULT using contemporary treatment paradigms. Testing of specific targets in a formal trial would provide insight, but whether a funding agency would be willing to support a large trial that would require 2 to 3 years of follow-up to adequately address this question is doubtful.
The discussion about ULT discontinuation is interesting but is based primarily on 2 reports from a single small observational cohort (8, 9). In the first report, about 40% of patients had recurrent gout flares within 6 to 60 months (median, 2 to 4 years) (8). In the second, only 27 patients had serum urate levels less than 416 µmol/L (<7 mg/dL); how long these patients were followed is unclear, and there were issues of loss to follow-up and lack of consent for joint aspiration to confirm gout recurrence (9). Discussions of ULT discontinuation based on such sparse data would be premature.
As for incremental harms and costs of continuing long-term ULT, particularly for patients who start allopurinol therapy without a hypersensitivity reaction in the first 180 days or so, the likelihood of developing a reaction later is exceedingly low (10). The costs of allopurinol and the requisite measurement of serum urate are minimal, particularly compared with the damage that can occur over time with urate deposition and the use of more aggressive and expensive therapy for tophaceous disease down the road.
In summary, although some approaches have not yet been formally tested in trials, a clear understanding of the pathophysiology of gout provides a strong foundation for rational recommendations while we await clarity on these important clinical issues.

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Neogi T, Mikuls TR. To Treat or Not to Treat (to Target) in Gout. Ann Intern Med. 2017;166:71–72. doi: 10.7326/M16-2401

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Published: Ann Intern Med. 2017;166(1):71-72.

DOI: 10.7326/M16-2401

Published at www.annals.org on 1 November 2016

©
2016 American College of Physicians
2 Citations

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Diagnosis of Gout: A Systematic Review in Support of an American College of Physicians Clinical Practice Guideline
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