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4 Articles in this Series
Introduction
Diagnosing and Treating Sjogren's Syndrome More than Meets the Eye
Retaining Mobility May Lead to Pain Reduction
Treatment Uncertainty Remains for Asymptomatic Hyperuricemia
Vitamin D Supplementation May Improve Chronic Widespread Pain

Treatment Uncertainty Remains for Asymptomatic Hyperuricemia

With Michael Pillinger, MD, and Jasvinder Singh, MD, MPH

Asymptomatic hyperuricemia may be more common than has been realized, which has stimulated debate about if and how to manage patients who present with elevated uric acid levels,1 according to Michael Pillinger, MD, professor of medicine and biochemistry and molecular pharmacology at the New York University Langone Medical Center in New York City, who raised the topic in a presentation at the American College of Rheumatology.Association of Rheumatology Health Professionals 2017 Annual Meeting in San Diego, California.

“The lack of consensus reflects the scarcity of research,” said Dr. Pillinger, "and the data to support any decision to treat remains quite limited." In his presentation, the scope of the problem, associated risks, and when to potentially consider treatment for elevated uric acid given the risk of developing gout, were addressed.1

 

Asymptomatic hyperuricemia is more common in aging men of all ethnicities but treatment remains controversial.

Assessing Asymptomatic Hyperuricemia By the Numbers

To put the problem into clear perspective, while the estimated prevalence of gout in the United States is about 3.9%, which means about 19 million people may be affected, while the prevalence of individuals with hyperuricemia is about 13.2%, said Dr. Pillinger. Of those with elevated uric acid, the vast majority at risk for gout are male.2

The condition is found fairly equally among Caucasians, African-Americans, Mexican Americans and other ethnicities.2 In addition to sex, age also plays a significant role in the development of hyperuricemia, Dr. Pillinger said. Hyperuricemia may have an early onset, at least in males, but levels off until about age 50 when it increases.

The presentation of gout, on the other hand, does not seem to become a significant health threat in those without a genetic predisposition until age 40, and then we typically see a linear increase in the prevalence.1,2 The occurrence of both hyperuricemia and gout also are a function of age, said Dr. Pillinger.

To Treat or Not to Treat 

The conundrum facing clinicians is whether to prophylactically treat a patient with elevated uric acid when there are no signs or symptoms of gout. Would treatment offer any benefit or should physicians simply avoid intervening with regard to asymptomatic hyperuricemia? The American College of Rheumatology 2012 guidelines, unfortunately, offer no recommendation with regard to this complicated question.The authors cited insufficient evidence to render an informed decision.

On the other hand, the Japan Society of Gout and Nucleic Acid Metabolism recommended that clinicians intervene to reduce serum urate level even in the asymptomatic stage of hyperuricemia in order to prevent gouty arthritis and other issues.According to these guidelines, cases ''with a serum level of not less than 9.0 mg/dL, (or 8.0 mg/dL or more in cases with urinary calculus renal disease, hypertension, etc) drug therapy should be considered."

“Patients with asymptomatic but elevated uric acid levels often have occult urate deposit in their joints,” said Dr. Pillinger, which has led some experts to suggest an association between gout, hyperuricemia, and osteoarthritis of the knee. A pattern of onset has led some to believe that the urate deposition on cartilage may predispose some individuals to develop osteoarthritis.

Treatment Strategy Given Cardiac, Renal, and Metabolic Comorbidities

“Another concern that complicates the question of active treatment stems from the high risk of renal, cardiac, and metabolic comorbidities among patients with hyperuricemia,” Dr. Pillinger said, "in comparison to individuals without an elevated uric acid, but still a lower incidence than those with gout."

Even so, the research regarding the risk of renal disease with hyperuricemia remains mixed.1 Yet, an alternative view has surfaced: while hyperuricemia may be associated with progression to renal disease, lowering a patient’s urate level offers no significant benefit with regard to progression of kidney disease.4

Researchers also have looked at the development of nephrolithiasis in patients with asymptomatic hyperuricemia, but to date, there has been no evidence of an impact in women and only a slight effect in men.1

Three contributory factors to stone formation include low urine volume, low urinary pH, and hyperuricosuria. However, in these patients, alkalinizing the urine will likely work better than lowering the serum urate,1 according to Dr. Pillinger.

“The condition of hyperuricemia has also been strongly linked with hypertension, “Dr. Pillinger said, “However, lowering uric acid levels have not shown any lessening in blood pressure levels in affected adults.”

Furthermore, if the clinician decides to treat asymptomatic hyperuricemia in order to lower serum urate with the goal of reducing the risk of stone formation, the process should focus on blocking the production of uric acid, not promoting uricosuria,1 said Dr. Pillinger.

“As long as the pH is above 6, the risk for kidney stones appears to remain low,” said Dr. Pillinger.

He also tackled the question of whether lowering urate might improve cardiovascular morbidity and mortality, but the research to date did not account for risk of developing gout, so the findings remain confounding.1

Is It Enough to Watch and Wait?

"This conundrum of waiting or deciding to treat remains problematic," Dr. Pillinger said, "There may be some adverse effects in a person who has a low urate level." In addition, when considering whether to treat a patient or not, the issues of cost and side effects should, of course, be factored into any plan.

The difficulty in trying to find an answer is that there simply isn't a sufficient evidence basis for a clear clinical determination of treatment of asymptomatic hyperuricemia. Bigger, prospective studies are needed to provide a clearer way forward, said Dr. Pillinger. Meanwhile, any treatment decisions will continue to be based on theoretical risks against theoretical benefits, said Dr. PIllinger,

The questions about management remain important since growing evidence in the past few decades seems to suggest that "hyperuricemia even in the absence of gout may be associated with hypertension, cardiovascular morbidity and mortality, and metabolic syndrome," said Jasvinder Singh, MD, MPH, professor of medicine and epidemiology at the University of Alabama at Birmingham who moderated the session and shared this observation with Practical Pain Management following the presentation.

Dr. Pillinger reports consulting for Astra-Zeneca, IronWood, Horizon, SOBI and has contracted research with Takeda. Dr. Singh has received research grants and consulting fees from Takeda and Savient, and he has also received consulting fees from Regeneron, Merz, Bioiberica, Crealta, and Allergan. In addition, Dr. Singh is a member of the executive of OMERACT, an organization that develops outcome measures in rheumatology and receives arms-length funding from 36 companies.

Sources:

  1. Pillinger M. Treatment considerations for Asymptomatic Hyperuricemia. American College of Rheumatology/Association of Rheumatology Health Professionals 2017 Annual Meeting, November 3-8, 2017 in San Diego, California.
  2. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007-2008. Arthritis Rheum. 2011;63(10):3136-41.
  3. Yamanaka H. Japanese guideline for the management of hyperuricemia and gout: second edition. Nucleosides Nucleotides Nucleic Acids. 2011;30 (12) 1018-29. 
  4. Rincon-Choles H, Jolly SE, Arrigain S, et al. Impact of Uric Acid Levels on Kidney Disease Progression. Am J Nephrol. 2017;46:315–322.
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