Poor serum urate control associated with increased incidence of LEAs

Gout is associated with a 20% increase in lower extremity amputations, according to a recent study of U.S. 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 over 200,000 visits to emergency departments and costs the U.S. in excess of $6 billion annually. But the effects of gout are even further reaching, according to Ted R. Mikuls, MD, MSPH, of the University of Nebraska Medical Center, Omaha, and colleagues.

“Although gout alone poses a substantial burden, it also has strong associations with comorbidities and increased mortality. 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 6-fold greater likelihood of receiving LEA, whereas advanced forms of CKD portend between a 2- to 4-fold increase in the rate of amputation,” they wrote.

Using inpatient and outpatient data from the national Veterans Health Administration (VHA), Mikuls et al sought to determine the incidence of lower extremity amputation in 5,924,918 patients, among whom 556,521 had gout (mean age: 67 years; 99.0% men; 16.0% Black non-Hispanic), and 5,368,397 did not (mean age: 67 years; 99.0% men; 10.4% Black non-Hispanic; 59.4% White non-Hispanic).

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 have obesity and other comorbidities compared with patients without gout.

In all, 4,970 lower-extremity amputations were performed from Jan. 1, 2000, to July 31, 2015 in patients with gout (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: 1.20; 95% CI: 1.16-1.24). This was highest for below-the-knee amputations (adjusted HR [aHR]: 1.59; 95% CI: 1.39-1.81), but was also high for toe (aHR: 1.27; 95% CI, 1.18-1.37), transmetatarsal (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 transmetatarsal ones, followed by above-the-knee, toe, and below-the-knee procedures.

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). This was similar to rates seen in patients with only diabetes (aHR: 3.21; 95% CI: 3.00-3.43).

Further, Mikuls and colleagues found that in 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%-37% increase in the incidence of amputation. Urate-lowering therapy (ULT), however, was not associated with the rate of lower-extremity amputation.

The frequency of lower extremity amputations was 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.

“This study found that U.S. veterans with gout were 20% more likely to undergo LEA than those without gout. This increase was independent of comorbidities and other risk factors and was apparent across different LEA types. Among those with gout, suboptimal serum urate control 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,” concluded Mikuls and colleagues.

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.

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

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

Liz Meszaros, Deputy Managing Editor, BreakingMED™

Funding for this study was provided by the Nebraska Arthritis Outcomes Research Center and the University of Nebraska Medical Center Division of Rheumatology and Immunology.

Mikuls is supported by grants from the Veterans Affairs Biomedical Laboratory Research and Development and from the National Institutes of Health, and reported receiving grants from and serving as a consultant for Horizon Therapeutics outside the submitted work and serving in the Core Leadership group for the 2020 American College of Rheumatology Gout Guidelines.

Cat ID: 158

Topic ID: 90,158,730,192,158,925,159