Gout is associated with a 20% increase in lower extremity amputations, according to a study of US veterans published in JAMA Network Open. Further, the increased risk was independent of comorbidities —such as diabetes—that are already well-established risk factors for lower extremity amputation.

Worldwide, gout is the most common form of inflammatory arthritis, and affects up to 4% of all adults, particularly older men and those of racial and ethnic minorities. Studies estimate that gout accounts for more than 200,000 visits to emergency departments and costs the US in excess of $6 billion annually. But the effects of gout are even further reaching, according to Ted R. Mikuls, MD, MSPH, and colleagues. “Although gout alone poses a substantial burden, it also has strong associations with comorbidities and increased mortality,” they wrote. “Cardiovascular disease, hypertension, chronic kidney disease (CKD), and diabetes are all overrepresented in patients with gout. Compared with the general population, patients with gout demonstrate a greater than 25% increase in the rate of acute myocardial infarction and are more likely to develop diabetes. Notably, these comorbidities also portend an increased risk of undergoing lower extremity amputation (LEA).

Diabetes, for example, is associated with a sixfold greater likelihood of receiving LEA, whereas advanced forms of CKD portend between a two to four-fold increase in the rate of amputation.”

Using inpatient and outpatient data from the national Veterans Health Administration (VHA), the study team sought to determine the incidence of lower extremity amputation


1l Patients with gout had higher rates of lower extremity amputations compared with those without gout, even after adjusting for comorbidities and other risk factors.

2l In patients with gout, poor control of serum urate levels was associated with a higher incidence of lower extremity amputations.

in 5.9 million patients, among whom 556,521 had gout (mean age, 67; 99.0% men; 16.0% Black non-Hispanic), and approximately 5.4 million did not (mean age, 67; 99.0% men; 10.4% Black non-Hispanic; 59.4% White nonHispanic). Patients with gout were matched with up to 10 patients without gout by birth year, sex, and year of enrollment in the VHA. All were followed until death or September 2015, whichever occurred first. Those with gout were more likely to be Black or African American and to have obesity and other comorbidities when compared with patients without gout.

Amputation More Likely in Patients With Gout

In all, 4,970 lower-extremity amputations were performed from January 1, 2000, to July 31, 2015 in patients with gout (incidence rate [IR], 1.46 procedures per 1,000 patient-years; 95% CI, 1.42-1.50), and 24,583 lower extremity amputations were performed in comparator patients (IR, 0.77 procedures per 1,000 patient-years; 95% CI, 0.76-078).

Patients with gout were more likely to need amputation, even after adjustment (adjusted HR [aHR], 1.20; 95% CI, 1.16-1.24). This was highest for below-the-knee amputations (aHR, 1.59; 95% CI, 1.39-1.81), but was also high for toe (aHR, 1.27; 95% CI, 1.18- 1.37), trans-metatarsal (aHR, 1.11; 95% CI, 1.06-1.16), and above-the-knee (aHR, 1.22; 95% CI, 1.15-1.30) procedures. The most common procedures were trans-metatarsal, followed by above-the-knee, toe, and below the knee. Patients with gout but without diabetes had a 1.56-fold increased rate of lower extremity amputation, but the highest rate was seen in those with both conditions (aHR, 3.36; 95% CI, 3.02-3.75), which was similar to rates seen in patients with only diabetes (aHR, 3.21; 95% CI, 3.00-3.43).

The Role of Serum Urate

Dr. Mikuls and colleagues also found that among patients with gout, poor serum urate control—defined as a mean of greater than 7 mg/dL in the preceding year—was associated with a 25% to 37% increase in the incidence of amputation. Urate-lowering therapy (ULT), however, was not associated with the rate of lower-extremity amputation. The frequency rates for lower extremity amputations were 39.3% in patients with adequate or indeterminate serum urate and adequate or indeterminate ULT, 10.9% in those with suboptimal serum urate and adequate or indeterminate ULT, 42.7% in those with adequate or indeterminate serum urate and suboptimal ULT, and 7.1% in those with suboptimal serum urate and suboptimal ULT.

LEA Procedures & Prevention

“This study found that US veterans with gout were 20% more likely to undergo LEA than those without gout,” concluded Dr. Mikuls and colleagues. “This increase was independent of comorbidities and other risk factors and was apparent across different LEA types. Among those with gout, suboptimal serum urate con-trol was associated with a higher rate of LEA. Further investigation is needed to understand the indications for LEA procedures conducted in gout in addition to identifying potential means of prevention as a way of ultimately improving long-term outcomes in this population.” Limitations of the study include its observational design; use of administrative data; possible bias due to misclassification, missing data, and loss to follow-up; and the changing status and severity of patient comorbidities.