PHILADELPHIA—Existing urate-lowering therapies are generally safe and effective and should be used aggressively to reach target treatment goals, according to N. Lawrence Edwards, MD, who gave an update on therapeutic options for hyperuricemia here at the 2009 ACR/ARHP Annual Scientific Meeting. The symposium also focused on the relationship of hyperuricemia to both the metabolic syndrome and cardiovascular disease and how understanding the biologic activity of uric acid should guide therapy.
Dr. Edwards—professor, program director, and vice chair of the department of medicine at the University of Florida in Gainesville—said that most physicians do not prescribe a high enough dose of urate-lowering therapy because of concerns about toxicity and hypersensitivity reactions.
“Most recent studies have found no association between risk and dose,” he said. “Raise the dose to whatever it takes to get to target.” Most physicians, he said, do an inadequate job of managing gout because the condition is not treated aggressively enough.
Urate-Lowering Therapies
Therapies used for urate lowering will have no effect on pain but are necessary for renal function and to reduce gout attacks, Dr. Edwards said. Indications for urate lowering include multiple gout flares each year, advanced gouty arthritis, presence of tophi, gout with chronic kidney disease, recurring renal stones, and daily urinary urate excretion of 1,000 mg or more.
When the urate level is lower than 6.0 mg/dL, the patient’s flares can be eliminated, the tophi resolve, and quality of life improves. This level “improves renal function if you can get the patient off NSAIDs [nonsteroidal antiinflammatory drugs],” he said.
Current therapies for urate lowering include:
- Allopurinol: Most physicians prescribe a 300-mg allopurinol dose or lower, and only 3% of physicians prescribe a dose higher than 300 mg, even though the U.S. Food and Drug Administration (FDA) has approved doses up to 800 mg. A 300-mg or lower dose has been found ineffective in many cases, even though some published guidelines recommend the 300-mg dose. “If you adhere to these guidelines, you will be massively undertreating your patients,” Dr. Edwards said.
- Febuxostat: A new selective xanthine oxidase inhibitor and nonpurine analog, febuxostat is metabolized in the liver, orally administered, rapidly absorbed, and highly protein bound. A phase III trial, the CONFIRMS trial, found that more patients reached the target of lower than 6 mg/dL at six months with an 80-mg dose. The 40-mg dose outperformed the 80-mg dose in renally impaired patients, and 44% of patients reached a 5-mg/dL target with the higher dose, he said.1
- Pegloticase: Not yet approved by the FDA, pegloticase is a purified recombinant porcine urate oxidase that catalyzes the conversion of uric acid to allantoin, a more soluble and readily excretable form. Patients in the clinical trials were the “bad cases,” with longstanding disease, numerous comorbidities, inability to reduce serum urate below 6 mg/dL, reduced quality of life, chronic swollen and tender joints, and frequent flares; 75% had tophi. With injections given every two weeks, there was a “remarkable decline in baseline, resolution of tophi, and impressive lowering of uric acid,” Dr. Edwards said.
Pain Management
Gout management should also include pain control. The most effective pain reduction therapies include:
- NSAIDs and glucocorticoids.
- Colchicine: The Acute Gout Flare Receiving Colchicine Evaluation (AGREE) trial considered the efficacy of high-dose versus low-dose colchicine versus placebo and found less toxicity with the low dose.2
- Newer interleukin-1 inhibitors: anakinra, rilonacept, and canakinumab. All have been found effective for significant reduction in gout pain and chronic pain.
Cardiovascular Disease Link
Hyon Choi, MD, professor of medicine at Boston University School of Medicine, said that hyperuricemia is strongly associated with the metabolic syndrome. The metabolic syndrome is a cluster of symptoms that can include increased blood pressure; elevated insulin levels; high triglycerides, low HDL cholesterol, and high LDL cholesterol; and excess body fat around the waist.
Presence of the metabolic syndrome results in a three-fold increased risk of atherosclerotic cardiovascular disease and a five-fold increased risk of type 2 diabetes. Higher insulin levels are known to reduce renal excretion of urate, Dr. Choi said.
Several studies have shown an independent association with serum uric acid and future risk of cardiovascular disease, stroke, and hypertension. The Coronary Artery Risk Development in Young Adults (CARDIA) study with 4,053 young adults found significantly higher body mass index, fasting insulin, and triglycerides and lower HDL cholesterol in patients with hyperuricemia.
The National Health and Nutrition Examination Survey III reported a 63% prevalence of the metabolic syndrome among patients with gout.3 In a Mexican case series, the prevalence was 82%, and in a Korean series, it was 44%.4,5
According to Dr. Choi, the British Columbia Linked Health Database found that women with gout have a 39% increased risk of myocardial infarction, whereas the increased risk for men was 11%.
Dr. Choi said that any patient with gout or hyperuricemia should trigger in the physician a “high clinical suspicion and investigation for potential coexistence of the metabolic syndrome and associated comorbidities.”
He stressed that, “every diagnosis of gout should raise a red flag to alert the physician to assess whether the patient is at risk for cardiovascular disease.”
Gout treatment should mirror treatment for hypertension, he noted, with lifestyle and dietary changes. The prevalence of gout has doubled since the 1970s, which could be related to the prevalence of high-fructose corn syrup in the American diet. Sweetened soft drinks should be eliminated because they have been found to increase the risk of gout twofold, Dr. Choi said.
Hypertensive patients with gout and the metabolic syndrome should be treated with losartan or amlodipine, which has a better risk–benefit ratio than diuretics for these patients, he said.
Biologic Activity of Uric Acid
According to Michael H. Pillinger, MD, associate professor of medicine and pharmacology at New York University Langone Medical Center in New York, uric acid seems to be a danger signal that drives the immune response. “A damaged, virally infected cell that is dying makes uric acid, and if it makes enough locally, you will get crystals forming and an immune response near the cell,” he said. “But it’s a fail-safe mechanism for not spreading the response where it doesn’t belong. Uric acid is a danger signal that acts as endogenous adjuvant when tissue is injured during immune presentation.”
In gout, the uric acid crystals activate complement by the alternative pathway, but also by the classical pathway through the accumulation of immunoglobulin. The crystals interact with macrophages, produce cytokine interleukin-1, and then generate other cytokines.
Dr. Pillinger said that uric acid has multiple and complex effects on cells, depending on their concentration and whether they are soluble or crystalline. Some effects have apparently been—and perhaps still are—evolutionarily advantageous. “Understanding uric acid biology may permit more rational targeting of future antiinflammatory and antihyperuricemic agents,” Dr. Pillinger concluded.
Kathy Holliman is a medical journalist based in New Jersey.
References
- Becker MA, MacDonald P, Chefo S, Jackson RL. Baseline characteristics of gout subjects influence orate-lowering efficacy during febuxostat and allopurinol treatment. #704. Presented at the ACR Annual Scientific Meeting. Oct. 19, 2009. Philadelphia.
- Terkeltaub RA, Furst DE, Bennett K, Kook KA, Crockett RS, Davis MW. High versus low dosing of oral colchicine for early acute gout flare: Twenty-four-hour outcome of the first multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-comparison colchicine study. Arthritis Rheum. 2010;62:1060-1068.
- Choi HK, Ford ES, Li C, Curhan G. Prevalence of the metabolic syndrome in patients with gout: The Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2007:57:109-115.
- Vazquez-Mellado J, Garcia CG, Vazquez SG, et al. Metabolic syndrome and ischemic heart disease in gout. J Clin Rheumatol. 2004;10:105-109.
- Rho YH, Choi SJ, Lee YH, et al. The prevalence of metabolic syndrome in patients with gout: A multicenter study. J Korean Med Sci. 2005;20:1029-1033.
- DeVera M, Rahman MM, Bhole V, et al. The independent impact of gout on risk for coronary heart disease among elderly women: A population-based study. #1509. Presented at the ACR Annual Scientific Meeting. Oct. 20, 2009. Philadelphia.
