Patients with gout 20% more likely to undergo lower extremity amputation
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Patients with gout are 20% more likely to undergo lower extremity amputation versus those without gout, independent of comorbidities and other risk factors, according to data published in JAMA Network Open.
“I was initially interested in this study question based on my own clinical observation of patients with gout having undergone amputation — or in some cases multiple amputations — for presumed infection or non-healing ulcers only to later find tophaceous deposits as the culprit,” Ted R. Mikuls, MD, MSPH, of the U.S. Department of Veterans Affairs Nebraska-Western Iowa Health Care System, and the University of Nebraska Medical Center, in Omaha, told Healio.
“Beyond that possibility, it is well understood that gout patients suffer from high rates of comorbidity — conditions such as diabetes and chronic kidney disease — that have been associated with the use of amputation,” he added. “Given that amputation is associated with poor long-term outcomes, we were interested to understand whether these procedures are experienced more often in patients with gout, whether this is all explained by other health care conditions that accompany gout, and finally whether at least some of these procedures might be preventable.”
To analyze the rate of, and factors associated with, lower extremity amputation among patients with gout, Mikuls and colleagues conducted a matched cohort study of administrative data from the national Veterans Health Administration. The researchers included 5,924,918 patients who used U.S. Department of Veterans Affairs services from Jan. 1, 2000, to July 31, 2015, among whom 556,521 had gout. Patients with gout were matched with up to 10 control individuals based on age, sex and year of benefit enrollment.
Mikuls and colleagues used multivariable Cox proportional hazards regression models to examine the associations of gout with lower extremity amputation. In the analysis limited to patients with gout, the researchers examined factors associated with serum urate control and urate-lowering therapy. Main outcomes included overall lower extremity amputation, as well as toe, trans-metatarsal, below-the-knee and above-the-knee amputation.
According to the researchers, patients with gout were more likely to undergo amputation, compared with those without gout, with an increased rate that remained even after adjusting for variables (adjusted HR = 1.2; 95% CI, 1.16-1.24). The rate was highest for below-the-knee amputation (adjusted HR = 1.59; 95% CI, 1.39-1.81).
Among patients with gout, poor serum urate control — defined as a mean of greater than 7 mg/dL during the preceding year — was associated with a 25% to 37% increase in the rate of amputation. Meanwhile, treatment with urate-lowering therapy was not associated with lower extremity amputation rate.
“Our results show that patients with gout undergo lower extremity amputation at a 20% higher rate than patients without gout and this relationship is independent of other health conditions,” Mikuls said. “Moreover, we found that poor serum urate control is also independently associated with amputation, suggesting that at least some of these procedures might be preventable.”
“Together, these results suggest that clinicians should consider gout as a possible mimic in the context of a non-healing wound or suspected lower extremity infection when patients are being evaluated for possible amputation,” he added. “Further research defining the role of select laboratory testing or imaging and the potential preventive role of urate lowering therapy in this context are warranted.”
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Paul J. DeMarco, MD, FACP, FACR, RhMSUS
In their study, Mikuls and colleagues postulate whether gout should take a place alongside diabetes as an association with lower extremity ischemia leading to lower extremity amputation (LEA), identifying gout as a modifiable risk factor to prevent progression towards this life-saving but deforming surgical intervention.
This impressive endeavor studies 5,924,918 patients, 556, 521 of whom have gout and each of whom is matched with 10 other non-gout controls through a search of the VA database. Despite matched counterparts, there is discordance in the gout vs. non-gout cohorts for BMI ≥ 30 (64% vs. 48%), hypertension (78.2% vs. 42%), cardiovascular disease (36% vs. 21%) kidney disease (10% vs. 3%) and diabetes (29% vs. 18%). The model controls for these states, but the authors point out the model is unable to control for disease severity. Notwithstanding, there appears to be an increased risk of LEA in the gout cohort.
Diabetes has the strongest association with LEA, (adjusted HR = 3.21) while the association of gout is less robust (adjusted HR =1.13). When the effect of diabetes is removed from this cohort, the effect of gout on LEA compared to non-gout patients with other risk factors demonstrated a 1.56-fold increase; this is reflected in the smallest fraction of the cohort, again because of concomitant diabetes.
To compare hazard ratios in another manner, the hazard ratio of MACE in tofacitinib 5 mg bid vs. anti-TNF use in an RA cohort (HR = 1.24) earned all JAK inhibitors a black box warning from the FDA. A further comparison is seen with risk of pulmonary embolism with tofacitinib 5 mg twice daily (HR =2.93) and tofacitinib 10 mg bid (HR = 8.26).
While LEA appears more common in gout, there is no additive effect of gout to diabetes vs. diabetes alone. When comparing gouty arthritis in non-diabetics, the incidence is much lower, and not necessarily much greater than the non-gout, non-diabetes cohort. With an absence of an additive effect on LEA in diabetes, and a significantly lower incidence in gout alone, one must wonder about the true impact gout makes on LEA vs. the ability of gout to identify patients with more severe metabolic syndrome.
This analysis was unable to determine whether better urate control would affect the multiple comorbid conditions that may contribute to LEA. This paper raises the issue of a need for further study, which is always needed. If we shared this with American humorist Mark Twain, I wonder if he would invoke “lies, damn lies and statistics.” We will have to wait for a prospective, randomized, matched cohort to understand if approaching serum urate management will have any effect on the rate of LEA in this high-risk population.
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David A. McLain, MD, MACR, FACP, FRCP
Of all the complications of gout that I have heard of, lower extremity amputation (LEA) was not one of them. We know that gout is associated with many comorbidities including cardiovascular disease, chronic kidney disease, diabetes and hypertension and that gout patients have an excess of myocardial infarctions. These comorbidities, particularly diabetes and CKD, portend an increased risk of undergoing LEA.
In this VA database analysis study, LEA was increased in gout independent of diabetes and peripheral vascular disease. Poor uric acid control was also a risk factor for LEA, whereas a normal uric acid because of uricosuric drugs was not a risk factor. In my experience in the VA, the patients often have diabetes and are smokers, which is a terrible combination for LEA. In this study, the gout patients were 76% present or former smokers (with 5.7% missing data) and the patients without gout were 67% present or former smokers (with 16% missing data in this group).
The analysis was controlled for many variables, including age, sex, race, ethnicity, BMI, smoking history, as well as for comorbidities such as hypertension, cardiovascular disease, peripheral artery disease, cancer, cerebrovascular disease, chronic lung disease, dementia, diabetes, and kidney disease; yet, gout and poor uric acid control were still independently associated with LEA. This is an eye-opening study and hopefully more research will be done in this vein.
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