Published in UAB Insight, Summer 2008
Diagnosis and New Treatments for Gout
ABSTRACT: A rational approach to hyperuricemia and gouty arthritis can ameliorate symptoms of acute attacks and decrease sequelae.
CME OBJECTIVE: The reader will be aware of how to terminate acute attacks, protect against further attacks, and treat chronic hyperuricemia to prevent disease progression.
Kenneth G. Saag, MD, MSc, grant and research support TAP Pharmaceuticals; consultant Savient Pharmaceuticals, TAP Pharmaceuticals
Gout, an inflammatory arthritis triggered by hyperuricemia and monosodium urate crystal deposition, strikes upwards of 1% of US adults and is on the rise worldwide. Known since ancient times, gout was long resistant to prevention and treatment. Today, with new therapeutic approaches and appropriate lifestyle modifications, people can significantly manage and remediate their disease.
Gout presents as acute, recurring, and often unbearably painful flare-ups in joints inflamed by buildups of urate crystals. Common sites are the large toe, heel, ankle, knee, elbow, and fingers. More men than women have gout, but among the elderly the disease is more equally distributed between the genders (most likely reflecting the postmenopausal loss of estrogen's uricosuric effect).
The most significant risk factor for gout is elevated serum urate. There are many complex factors associated with hyperuricemia, which can begin years before clinical onset of disease, says rheumatologist and clinical immunologist Kenneth G. Saag, MD, MSc, director of the UAB Center for Education and Research on Therapeutics of Musculoskeletal Disorders.
"Although cause-and-effect relationships are not well understood, gout is associated with a number of other diseases, such as hypertension, diabetes, obesity and metabolic syndrome, and cardiovascular disease [CVD]," he says.
"Currently, 46% of women and 59% of men at high risk of CVD take aspirin, which has a bimodal effect on uric acid levels." At low dosages (≤2 g/day), aspirin increases urate retention but is uricosuric at higher dosages (Arthritis Rheum. 2000;43:103-108).
Concomitant diuretic use can exacerbate aspirin's effects on urate levels. Drugs prescribed for kidney transplant patients - eg, cyclosporine and the immunosuppressive agent tacrolimus - and many chemotherapy agents contribute to hyperuricemia.
A number of studies have examined the role of purine foods, high protein intake, and dairy intake. Research strongly links meat and seafood consumption to hyperuricemia. Organ meats (liver, brains, kidney, and sweetbreads), anchovies, herring, and mackerel are particularly high in purines. Purine-rich vegetables such as beans and lentils, however, have little or no effect on serum urate levels.
Consumption of dairy products may protect against gout. Research has shown a nearly 50% reduction of gout risk among individuals with high-dairy intake independent of weight, age, hypertension, alcohol use, diuretic use, and chronic renal failure (N Engl J Med. 2004;350:1093-1103).
These associations remain highly significant in the majority of cases. Alcohol consumption, particularly of purine-rich beer, is a strong risk factor for gout. Interestingly, studies have suggested that wine intake does not significantly increase serum urate after adjusting for other risk factors such as age and obesity (Arthritis Rheum. 2004;51:1023-1029).
Treatment
Putative associations between gout and other increasingly prevalent diseases such as obesity and CVD create an urgent need to identify hyperuricemic patients well before the onset of gout's clinical manifestations.
Gout is best described by four stages: asymptomatic hyperuricemia with no clinical manifestations of gout; acute inflammation in the joint caused by urate crystallization; intercritical segments between acute flares; and advanced gout characterized by long-term gouty complications of uncontrolled hyperuricemia. Asymptomatic hyperuricemia may persist for years before detection and is potentially dangerous as it appears to be associated with hypertensive renal insufficiency.
Saag outlines three major treatment goals for gout: terminating the acute flare-up as rapidly as possible, protecting against further attacks by reducing crystal-mediated inflammation, and treating chronic hyperuricemia to prevent disease progression.
Lifestyle modifications recommended for prevention or treatment of gout are similar to those of other major chronic disorders and are expected to have greater benefits for gout patients with coexisting conditions such as diabetes and CVD.
"Hypertension control, changes in medication regimens, weight loss, dietary changes, and other lifestyle changes may help control hyperuricemia in some patients, especially early in the course of their disease," Saag says. Fewer than 20% of patients, however, adhere to such regimens. Pharmacologic agents may be necessary to achieve better disease control and may have reciprocal benefits for those with comorbid conditions.
Therapeutic Options
Several short- and long-term therapies can correct metabolic problems associated with gout and can lower serum urate sufficiently to deplete the total body urate pool and reduce tophi size.
Although Saag says there appear to be no quick fixes for terminating acute flare-ups, nonsteroidal anti-inflammatory drugs (NSAIDs), oral colchicine, corticosteroids, and synthetic adrenocorticotropic hormone can resolve symptoms. "These therapies should be initiated as rapidly as possible after flare-up onset," he says. "Although these agents resolve symptoms, their individual toxicities require cautious use."
When treating chronic gout physicians should first consider whether the patient exhibits recurrent attacks or gouty complications. Initiate treatment of recurrent attacks with prophylactic NSAIDs or colchicine and follow with careful monitoring of serum urate levels to gauge efficacy, Saag says.
In appropriate patients the uricosuric agent probenecid can reverse underexcretion of uric acid, the most common metabolic abnormality of gout. Patients taking probenecid must take multiple daily doses, drink at least 2 liters of fluid daily, and have satisfactory renal function and no history of nephrolithiasis.
Saag's UAB center is heavily involved in studying the safety and appropriate use of therapeutic agents for gout. Allopurinol (Zyloprim) is one of the most commonly used therapeutics for treating people with symptomatic gout with both uric acid overproduction and underexcretion. It offers the advantages of single daily dosing and demonstrated efficacy in patients with renal insufficiency. The drug's limitations include the potential need for higher doses in patients with profoundly elevated serum urate levels. Physicians may need to adjust doses according to renal function. In addition, lowering serum urate mobilizes deposited crystals, which initiates acute flare-ups.
Research has shown that febuxostat, a nonpurine selective inhibitor of xanthine oxidase, is a potent therapeutic for urate reduction. A potential advantage of this experimental agent is that physicians can administer febuxostat to patients with mild renal insufficiency without dose adjustment.
Saag and colleagues have demonstrated in different populations that quality of care for gout is uniformly low (Rheumatol. 2005;44[8]:1038-1042) and (J Rheumatol. 2006;33[3]:562-566). They have developed gout quality indicators evaluating safe and appropriate use of gout therapies (Athritis Rheum. 2004;50[3]937-943).
Exciting new approaches to gout may include use of new synthetic uricase agents with potential to provide more rapid relief to patients with large tophi and otherwise refractory disease, Saag says. "While many agents offer effective control of gout symptoms, the only curative approach to the disease is successful lowering of serum urate. This requires a concerted effort that includes close collaboration between doctors and their patients."
Gout Risk Factors
- Elevated serum uric acid level
- Male gender
- Longevity
- Purine-rich foods
- Alcohol
- High body mass index/obesity
- Hypertension/thiazide diuretics
- Cardiovascular disease/low-dose aspirin
- Diabetes
- Renal failure
- Kidney transplantation/calcineurin inhibitors
FOR MORE INFORMATION:
Dr. Kenneth Saag
1.800.UAB.MIST
mist@uabmc.edu