Lower limits on serum urate levels applied in gout management may be based on a misreading of data on mortality risks, researchers say.
Low urate levels may not in themselves pose a risk of death but may be a sign of some other illness, said Joshua Baker, MD, MSCE, associate professor of rheumatology and epidemiology at the University of Pennsylvania in Philadelphia.
“It points us towards being more reassured that we can be aggressive in treating gout without a concern about long-term effects for our patients,” he told Medscape Medical News. He and colleagues published their findings online Aug. 16 in Arthritis & Rheumatology.
Previous research has linked high levels of urate with excessive fat and low levels of urate with loss of skeletal muscle mass. And epidemiologic studies have shown a U-shaped relationship between urate levels and mortality, suggesting that very high and very low levels of urate could be harmful.
Based on this correlation, and the theory that urate could have antioxidant benefits, some professional societies have recommended not lowering urate levels below a defined threshold when treating gout. For example, the European Alliance of Associations for Rheumatology has recommended a lower limit of 3 mg/dL.
But the evidence doesn’t entirely support this caution. For example, in a clinical trial of pegloticase (Krystexxa) in patients with refractory gout, patients whose mean serum urate dropped below 2 mg/dL did not die in higher proportions than patients with higher urate levels.
To better understand the risk of low urate, Baker and colleagues analyzed data on 13,979 participants in the National Health and Nutrition Examination Survey (NHANES) during 1999-2006. The dataset included whole-body dual energy x-ray absorptiometry (DXA) body composition measures as well as urate levels.
The researchers argue this measurement reveals more about a person’s overall health than body mass index (BMI), which doesn’t distinguish between mass from fat and mass from muscle.
They defined low lean body mass, or sarcopenia, as an appendicular lean mass index relative to fat mass index z-score of -1. And they defined low urate as less than 2.5 mg/dL in women and less than 3.5 mg/dL in men.
They found that 29% of people with low urate had low lean body mass, compared with 16% of people with normal urate levels. The difference was statistically significant (P = .001).
They found an association between low urate and increased mortality (hazard ratio [HR], 1.61; 95% CI, 1.14-2.28; P = .008). But that association lost its statistical significance when the researchers adjusted for body composition and weight loss (HR, 1.30; 95% CI, 0.92-1.85; P = .13).
Baker thinks the association between elevated mortality and low urate can be explained by conditions such as cancer or lung inflammation that might on one hand increase the risk of death and on the other hand lower urate levels by lowering muscle mass. “Low uric acid levels are observed in people who have lost weight for unhealthy reasons, and that can explain relationships with long-term outcomes,” he said.
Proportions of muscle and fat could not account for the risk of mortality associated with high levels of urate, the researchers found. Those participants with urate levels above 5.7 mg/dL had a higher risk of death with higher levels of urate, and this persisted even after statistical adjustment for body composition.
The study sheds light on an important area of controversy, said Mehdi Fini, MD, assistant professor of medicine at the University of Colorado in Denver, who was not involved in the research.
But body composition does not entirely explain the relationship between urate and mortality, he told Medscape Medical News. Medications used to lower urate can cause side effects that might increase mortality, he said.
Also, he said, it’s important to understand the role of comorbidities. He cited evidence that low urate is associated with renal, cardiovascular, and pulmonary conditions. Safe levels of urate might differ depending on these factors. So rather than applying the same target serum level to all patients, perhaps researchers should investigate whether lowering urate by a percentage of the patient’s current level is safer and more effective, he suggested.
He agreed with an editorial that also appeared in Arthritis & Rheumatology saying that there is no evidence for a benefit in lowering urate much below 5 mg/dL. “No matter what, I think we should just be careful,” Fini said.
Fini and Baker report no relevant financial relationships. Baker acknowledged support from a VA Clinical Science Research & Development Merit Award and a Rehabilitation R&D Merit Award.
Arthritis Rheumatol. Published August 16, 2022. Abstract.
Laird Harrison writes about science, health, and culture. His work has appeared in national magazines, in newspapers, on public radio, and on websites. He is at work on a novel about alternate realities in physics. Harrison teaches writing at the Writers Grotto. Visit him at www.lairdharrison.com or follow him on Twitter: @LairdH.
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