Gout: Obesity's Stealth Disease Published: Jan 21, 2014 | Updated: Jan 22, 2014 By Nancy Walsh , Staff Writer, MedPage Today Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner The incidence of gout has been increasing considerably over the last several decades. The cornerstone of therapy is urate-lowering therapy with a xanthine oxidase inhibitor, usually allopurinol targeting a serum urate level of less than 6 mg/dL. Once known as "the disease of kings," gout today clearly is a disease of commoners as well, and although it's on the rise, treatment remains vastly underused. A recent estimate of the prevalence of gout in the U.S. set the number at about 8.3 million, or 3.9% of the population. "There are data suggesting that the incidence of gout in this country has doubled in the last 20 years and probably tripled in the past 40 years, making it by far the most common inflammatory arthritis," said N. Lawrence Edwards, MD, of the University of Florida in Gainesville. Reasons for this increase include the obesity epidemic, widespread use of medications such as diuretics that elevate urate levels, and greater longevity. "Historically, gout has been associated with overindulgence, in people who had access to foods of plenty, but now, in fact, gout is a condition of people with chronic illness such as kidney disease and heart disease, and regrettably it's often relegated to a lesser status given all the other challenges of management," explained Kenneth S. Saag, MD, of the University of Alabama at Birmingham. In a recent U.K. survey, only one in four patients with a new diagnosis of gout initiated urate-lowering therapy within a year. And among patients taking urate-lowering treatments, only 40% were adherent. This can have serious consequences, since increasing evidence is demonstrating that gout contributes significantly to the burden of cardiovascular morbidity and mortality.
A Disease of Misperceptions The most important hindrance to effective treatment of gout is the misperception by both clinicians and patients that it's an acute, intermittent -- and painful but relatively inconsequential -- disease rather than a chronic, destructive form of arthritis. "We now know that crystals are present in the joint long before the first symptomatic episode of gout, and that there's low-grade inflammation destroying the joint," Edwards told MedPage Today. "Because of a lack of appreciation of that destructive nature, many primary care physicians and even some rheumatologists are willing to just treat the acute attacks with the old standards of nonsteroidal anti-inflammatory drugs or colchicine and let it go at that," he added. However, gout today is considered largely curable and very effective treatments are available. "It's one of the few conditions in medicine where we know the cause and we can offer therapies that, if initiated early and used appropriately, can essentially fully reverse the process," Saag said in an interview. That process results from persistent levels of uric acid above the level of saturation and leads to crystal formation in the joints and soft tissues. When the monosodium urate crystals reach the joint space or bursa, the NALP3 inflammasome is activated and cytokines such as interleukin-1 and tumor necrosis factor are released, resulting in the acute episode.
Poor Use of Allopurinol Various groups including the American College of Rheumatology (ACR), the British Society for Rheumatology, and the European League Against Rheumatism have offered guidance for the treatment of gout. The cornerstone, according to all the recommendations, is urate-lowering therapy with a xanthine oxidase inhibitor, usually allopurinol. The ACR guidelines state that urate-lowering therapy should target a level below 6 mg/dL, and for some patients, below 5 mg/dL, starting with a low 100-mg-per-day dosage. Many physicians initiate therapy by just giving a set dose of allopurinol, typically 100 mg or 300 mg/day, depending on kidney function. "For years we used allopurinol poorly, and we still use it poorly," said Edwards, who heads the Gout and Uric Acid Education Society. Too often, clinicians assume that once they have given the patient a prescription for allopurinol, there's nothing else they can do. In fact, allopurinol can be escalated as high as 800 mg per day. The right dose for any given patient is the dose that gets their uric acid below 6 mg/dL, according to Edwards. And further, many clinicians never even go back to measure the uric acid after initiating treatment. "That's like starting them on metformin for diabetes and not checking to see if it's doing any good," he said. An additional reason for the underdosing of allopurinol has been concern about the potentially lethal systemic hypersensitivity reaction that occurs in about one in 500 to 1,000 new patient starts, usually in patients with kidney disease. The chance of this can be minimized by starting with the low dose, Edwards noted. The ACR guidelines also recommend that individuals at high risk for the hypersensitivity reaction, such as those with Han Chinese and Thai ancestry, undergo screening for the predisposing HLA-B*5801 allele. Patients who are unable to tolerate allopurinol today have an alternative in febuxostat. The ACR guidelines state that either allopurinol or febuxostat (Uloric) can be used first line, but febuxostat is more expensive, and in practice allopurinol is typically the favored option.
Urate and Consequences If unchecked, elevated serum urate can lead to an exceptionally disabling chronic arthritis that's associated with pain and the loss of ability to work or participate in normal activities of daily living, according to Saag. But it's now becoming clear that elevated urate -- even in the pre-gout stage -- is associated with other conditions, including hypertension, coronary heart disease, myocardial infarction (MI), and kidney disease, so there's increasing interest in trying to prevent or moderate elevated serum urate, Saag explained. And evidence is emerging that the association is independent of shared risk factors. For instance, in one report of men enrolled in the Health Professionals Follow-up Study, the relative risks for all-cause mortality, cardiovascular death, and fatal coronary heart disease among men with gout were 1.28 (95% CI 1.15-1.41), 1.38 (95% CI 1.15-1.66), and 1.55 (95% CI 1.24-1.93), respectively. "These associations were independent of age, body mass index, smoking, family history of MI, use of diuretics and aspirin, dietary risk factors, and risk conditions such as diabetes mellitus, hypercholesterolemia, and hypertension," the authors wrote in Circulation. In another prospective study conducted in Singapore, patients with gout had a 23% increased risk of all-cause mortality (HR 1.23, 95% CI 1.10-1.38), and 54% increase in risk for death from coronary heart disease (HR 1.54, 95% CI 1.23-1.93), and a seven times higher risk for death from renal disease (HR 7.21, 95% CI 4.48-11.60). "These associations were independent of major confounders in lifestyle and comorbidity factors, and were present in both men and women," the researchers stated. Serum urate also was linked with hypertension in young adults in the Coronary Artery Risk Development in Young Adults (CARDIA) cohort, which followed almost 5,000 participants for 20 years. That study found a 25% greater likelihood of developing hypertension in men with elevated serum urate (HR 1.25, 95% CI 1.15-1.36) and a 12% increase with each mg/dL increase in serum urate (HR 1.12, 95% CI 1.02-1.20). Moreover, the greater risk of developing hypertension was seen even at levels of serum urate below the threshold of 6.8 mg/dL, which is a generally accepted definition of hyperuricemia. For men, the increased risk began at levels of 5.80 mg/dL, and for women, at 3.60 mg/dL. "Our findings are in concordance with the growing body of data that supports a potentially causal role for elevated serum urate in the development of hypertension," Saag and colleagues wrote in Annals of the Rheumatic Diseases. Most recently, a group of French investigators found a 20% decreased risk of nonfatal first myocardial infarction in patients with gout treated with allopurinol. In their report, published online in Annals of the Rheumatic Diseases, the French researchers noted that uncertainty remains as to the precise mechanisms that link elevated urate with cardiovascular disease, "but may include oxidative stress generated by xanthine oxidase, the enzyme that catalyzes the formation of urate." "Indeed, allopurinol, a free radical scavenger, was found to improve both endothelial dysfunction and levels of some markers of oxidative stress," they observed. They called for randomized studies to directly assess the effects of xanthine oxidase inhibition on cardiovascular outcomes among individuals with gout.
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