Gout, Urate Lowering Therapy and Uric Acid Levels among US Adults

Abstract

Objective

Evidence strongly suggests the delivery of gout care is suboptimal. The 2012 American College of Rheumatology (ACR) guidelines emphasize a serum uric acid (SUA) target of <6 mg/dl when utilizing urate lowering therapy (ULT). However, the proportion and characteristics of Americans with gout on ULT, or with a ULT indication, achieving this target is unknown.

Methods

We identified US adults with gout on ULT, and those with an indication for ULT, using the National Health and Nutrition Examination Surveys from 2007–2010. A ULT indication, by ACR guidelines, comprised chronic kidney disease stages 2–5 (CKD), a history of nephrolithiasis, or current ULT use. Demographic and clinical factors associated with a SUA ≥6 mg/dl were determined using Poisson regression.

Results

In 2007–2010, an estimated 4.5 million US adults with gout had an indication for ULT; two-thirds had a SUA ≥6 mg/dl. In adjusted analyses among those with gout and CKD or nephrolithiasis, those 70 years and older were less likely (prevalence ratio [PR] 0.77; 95% CI 0.61– 0.97) to have a SUA ≥6 mg/dl. Regarding those taking ULT, hypertension was related to a reduced prevalence (PR=0.51; 95%CI 0.30–0.87) whereas diabetes mellitus (PR=1.42; 95%CI 1.06–1.90) and obesity (PR=1.74; 95%CI 1.19–2.56) were each associated with a higher prevalence of a SUA value ≥6 mg/dl.

Conclusion

Half of all Americans with gout on ULT, and two-thirds with an indication for ULT, have a SUA above target. This study furnishes a meaningful baseline for assessing the effectiveness of the ACR guidelines in future years.

INTRODUCTION

Gout is an acute, debilitating form of arthritis, responsible for much human suffering and high health costs (1). The prevalence of gout is rising, estimated to affect over 3.5% of United States (US) adults in 2007–2010 (2,3). Serum uric acid (SUA) is the principal mediator of gout, such that pharmacologic interventions to prevent gout recurrence have largely focused on urate-lowering therapy (ULT) (3,4).

Despite the rising burden of disease and substantial toll that recurrent gout attacks exact on affected persons, there is growing evidence that the management of gout is suboptimal (5). One quality indicator advanced a decade ago to improve gout treatment is to check a SUA level at least once during the first 6 months of xanthine oxidase inhibitor use; such quantification serves as an objective parameter by which to appropriately adjust (by escalating or diminishing) drug dosage (6). However, the inappropriate dosing and inadequate monitoring of ULT is viewed as a glaring deficiency in current clinical practice and an appropriate target for corrective efforts. To optimally manage gout, the 2012 guidelines disseminated by the American College of Rheumatology (ACR) recommend that persons with gout, particularly those with tophi, frequent attacks (≥2 attacks/year), chronic kidney disease (stages 2–5), or a history of nephrolithiasis, achieve a SUA below 6 mg/dl (3,4).

At present, the proportion of adults with gout in the general US population meeting this SUA target is unknown. Given the 2012 gout treatment guidelines, we sought to determine: (1) the proportion of US adults with gout who have an indication for ULT; (2) the proportion of US adults with an indication for ULT who are above target (i.e., with a measured SUA ≥ 6 mg/dl); and (3) demographic and clinical characteristics associated with a SUA ≥ 6 mg/dl among US adults with gout and either (a) chronic kidney disease (stage 2–5) or history of kidney stones or (b) currently taking ULT.

METHODS

Study Population

The National Health and Examination Surveys (NHANES) are large, cross-sectional studies conducted by the National Center for Health Statistics (NCHS) that utilize a complex, multistage sampling design to represent the sex, racial, and ethnic distribution of the US. In the present report, we examined the continuous NHANES (2007–2010), which queried participants about their gout status. Participants lacking a SUA measurement, missing gout medication data, or those with unknown gout status were excluded. Informed consent was obtained per NCHS and the NHANES protocol (7).

Gout, Gout Medication Use, and Uric Acid Goals

Gout status was ascertained based on self-report to the following question: “Has a doctor or other health professional ever told you that you had gout?” Further, NHANES staff documented medication use in the prior 30-day period using medication bottles brought to the mobile examination center, specifically identifying use of colchicine and ULT (allopurinol, probenecid, or combination colchicine-probenecid). SUA was measured via an oxidation reaction (7). The target SUA level, among those for whom ULT is indicated, was defined using the ACR guideline as a SUA <6.0 mg/dl (360 μmol/L) for both women and men (4).

Renal Gout: Chronic Kidney Disease and History of Kidney Stones

Renal gout was defined as the presence of chronic kidney disease, stages 2–5, or history of kidney stones among participants with gout. Chronic kidney disease, stages 2–5, was based on stages established by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (9), using both a creatinine-based estimated glomerular filtration rate (eGFR) and single albuminuria assessments (albumin-to-creatinine ratio ≥30 mg/g) (9). A history of nephrolithiasis was based on an affirmative response to the following question: “Have you ever had kidney stones?”

Indications for Urate-Lowering Therapy

The 2012 ACR guidelines identified the following categories of adults with gout to be started on ULT therapy: any patient with (a) a tophus or tophi, (b) frequent attacks of acute gouty arthritis (≥ 2 attacks per year), (c) chronic kidney disease stage 2–5, or (d) past urolithiasis. Further, the ACR guidelines recommend that all those with an indication for ULT achieve a SUA <6 mg/dl to improve the signs and symptoms of disease (4). Thus, using the NHANES dataset we defined an indication for ULT as follows: (a) current ULT use, (b) chronic kidney disease, stage 2–5, or (c) a history of kidney stones. We considered current ULT use a surrogate for US adults with gout who have tophi or frequent flares, as clinical features of gout activity that prompt a clinician to commence ULT. Of note, having a SUA ≥ 6 mg/dL in a participant with gout was not considered an indication for ULT unless the participant had concomitant CKD or a history of nephrolithiasis.

Demographic Characteristics and Comorbid Conditions

Age, sex, and race/ethnicity were recorded for all participants. Race/ethnicity was dichotomized as non-Hispanic white versus other. Obese was defined as a body mass index ≥ 30 kg/m². Hypertension was defined by a systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg or use of antihypertensive medications. A low level of high density lipoprotein cholesterol (HDLc) was defined as <40 mg/dl for men and <50 mg/dl for women. Serum total cholesterol levels were also measured. Diabetes was defined by self-report. Diuretic medications included loop diuretics, potassium-sparing diuretics, thiazide diuretics, carbonic anhydrase inhibitors, or miscellaneous diuretics. Alcohol consumption was categorized as never (<12 drinks throughout lifetime) or ever (≥ 12 drinks throughout lifetime).

Statistical Analyses

All analyses were performed following NCHS recommendations. We used the sample weights, primary sampling units, and strata available in each survey to account for the NHANES complex sampling design. Furthermore, standard errors were determined for all metrics using the Taylor series (linearization) method. Analyses were performed using Stata 11.1 (StataCorp LP, College Station, TX).

Characteristics of the gout population in NHANES 2007–2010 were determined using weighted means (standard errors) or prevalence estimates. We estimated in a nested fashion the total number of US adults (in millions) with gout, those with an indication for ULT, and those with a SUA ≥ 6 mg/dl. Finally, we used Poisson regression to identify demographic and comorbid conditions associated with a SUA ≥ 6 mg/dl among US adults with renal gout or those using a ULT agent. Note that these strata were not mutually exclusive. All models were adjusted for age, dichotomized at the approximate median age in the cohort (≥ 70 vs. <70 years), male sex (vs. female sex), non-Hispanic white (vs. Other race), obesity (body mass index ≥ 30 vs. <30 kg/m²), low HDLc (vs. elevated HDLc), hypertension (vs. no hypertension), diabetes (vs. no diabetes), diuretic use (vs. no diuretic medication use), and alcohol use (ever vs. never drank alcohol).

RESULTS

There were 10,977 adults, age 20 years or older, who participated in NHANES 2007–2010. Among this group, 514 participants had been told by a doctor or health professional that they had gout. Approximately 47% of those with gout also had either chronic kidney disease, stage 2–5, or a history of kidney stones (Table 1). A smaller proportion, only 29% were on ULT, predominantly allopurinol.

Table 1.

Demographic and treatment characteristics of the overall US gout population, US adults with renal gout (CKD stage 2–5 or nephrolithiasis), and US adults with gout on urate-lowering therapy.

	All Gout (N = 514)	Renal Gout (N = 272)*	Currently Using ULT (N = 147)
	Mean (SE) or %	Mean (SE) or %	Mean (SE) or %
Age, years	61.5 (0.9)	67.2 (1.2)	65.4 (1.6)
Age ≥ 70 years, %	32.4	50.8	40.3
Male, %	71.6	72.1	81.0
Non-Hispanic white, %	77.0	79.1	83.4
Obese (body mass index ≥ 30 kg/m2), %	55.5	54.0	61.9
Low HDL cholesterol, %	43.0	39.6	47.7
Hypertension, %	68.1	76.4	78.2
Self-reported Diabetes, %	23.3	30.9	30.6
Diuretic medications, %	27.8	36.9	44.0
Ever drank alcohol, %	89.2	84.5	89.3
Serum uric acid, mg/dl	6.7 (0.1)	6.8 (0.1)	6.0 (0.1)
Serum uric acid ≥ 6 mg/dl, %	66.3	68.9	49.3
Chronic kidney disease stage 2–5, %	34.2	72.3	49.2
History of kidney stones, %	21.7	45.9	26.0
Chronic kidney disease stage 2–5 or a history of kidney stones	47.4	100.0	61.6
Gout medications, %	31.6	41.1	100.0
Allopurinol	27.8	36.4	96.1
Probenecid	0.9	0.9	3.1
Colchicine	7.0	8.3	15.0
Urate-lowering therapy†	29.0	37.7	100.0
US adults with an indication for a uric acid <6 mg/dl‡, %	58.5	100.0	100.0

Abbreviations: CKD, chronic kidney disease; ULT, urate-lowering therapy

^*Renal gout defined by self-reported gout and chronic kidney disease (stages 2–5) or nephrolithiasis

^†Allopurinol, probenecid, or combination colchicine-probenecid

^‡Defined as chronic kidney disease, stage 2–5, a history of kidney stones, or current urate-lowering therapy

Of the 7.7 million adults with gout in the US, 58.5% or 4.5 million have an indication for ULT (Figure 1). Furthermore, among those with gout currently on ULT, 49% had a SUA ≥ 6 mg/dl. An even higher proportion had a SUA ≥ 6 mg/dl among US adults with CKD, stage 2–5, (69%), or with a history of nephrolithiasis (70%). Overall, 2.9 million US adults had both an indication for ULT and a SUA ≥ 6 mg/dl, representing 38% of the total gout population in the US, and approximately two-thirds of those with both gout and a ULT indication (Figure 1).

Figure 1.

Flow chart representing the prevalence and population estimate in millions (mil) of (1) total gout; (2) gout with an indication for urate-lowering therapy (ULT) according to guidelines established by the American College of Rheumatology, i.e., chronic kidney disease (CKD) stage 2–5 or nephrolithiasis, or current ULT use; and (3) gout with an indication for ULT and a uric acid ≥ 6 mg/dl. Estimates with black lettering represent the entire US population, while estimates in gray lettering represent a proportion of gout or a subpopulation of gout. Note some participants had more than one indication for ULT such that the three categories depicted in the third row of the figure are not mutually exclusive. Modest discrepancies in percentage values are due to rounding.

Next, we examined factors associated with having a SUA value ≥ 6 mg/dl among participants with renal gout or those currently using a ULT agent (Table 2). In the former group, those older than 70 years of age were less likely (prevalence ratio [PR] 0.77; 95% CI 0.6 1–0.97) to have an elevated SUA value than their younger counterparts. As for the latter group, those with gout on ULT, older age was similarly related to a lower prevalence of a SUA value ≥ 6 mg/dl. Moreover, hypertension was associated with a reduced prevalence (PR=0.51; 95%CI 0.30–0.87), whereas diabetes mellitus (PR=1.42; 95%CI 1.06–1.90) and obesity (PR=1.74; 95%CI 1.19–2.56) were each associated with a higher prevalence of a SUA value ≥ 6 mg/dl.

Table 2.

Factors associated with having a uric acid concentration ≥ 6 mg/dl among persons with renal gout or those using urate-lowering therapy

	Renal Gout (N = 244)*	Currently Using ULT (N = 134)*
	Prevalence Ratio (95% CI)**	Prevalence Ratio (95% CI)**
Age ≥ 70 years	0.77 (0.61, 0.97)	0.57 (0.42, 0.77)
Male	1.21 (0.92, 1.59)	1.14 (0.77, 1.67)
Non-Hispanic white	0.96 (0.79, 1.17)	1.04 (0.71, 1.54)
Obese (body mass index ≥ 30 kg/m2)	0.98 (0.83, 1.16)	1.74 (1.19, 2.56)
Low HDL cholesterol	1.16 (0.94, 1.44)	0.84 (0.61, 1.18)
Hypertension	0.91 (0.70, 1.18)	0.51 (0.30, 0.87)
Diabetes	1.02 (0.87, 1.20)	1.42 (1.06, 1.90)
Diuretic medications	1.11 (0.93, 1.33)	1.53 (0.97, 2.42)
Ever drank alcohol	1.09 (0.66, 1.78)	1.51 (0.77, 2.98)

Abbreviations: ULT, urate-lowering therapy; Renal gout denotes those patients with gout and coexistent chronic kidney disease or nephrolithiasis; bold represents P <0.05

^*Unweighted number after excluding participants with missing covariate data

^**All models were adjusted for age (≥ 70 vs. <70 years), male (vs. female), non-Hispanic white (vs. Other race), obese (body mass index ≥ 30 vs. <30 kg/m²), low high-density lipoprotein cholesterol (vs. elevated high density lipoprotein cholesterol), hypertension (vs. no hypertension), diabetes (vs. no diabetes), diuretic use (vs. no diuretic medication use), and ever drank alcohol (vs. never drank alcohol).

Parenthetically, when serum total cholesterol was substituted in the multivariate analyses for HDL cholesterol, results were fundamentally unchanged (Supplementary Table).

DISCUSSION

This represents the first nation-wide assessment of the US gout population with regard to the 2012 ACR gout treatment guidelines and its SUA treatment target. In 2007–2010, two of three US adults with gout had a SUA concentration ≥ 6 mg/dl. Notably, when restricted to those with gout and coexistent stage 2–5 CKD or nephrolithiasis, two clear indications identified by the 2012 guidelines for use of ULT, nearly 70% had a measured SUA value above this treatment target level. Furthermore, among those already on ULT therapy, half did not achieve the target level established by the ACR guidelines.

The relationship between SUA and gout is well-characterized (10,11). Moreover, SUA is associated with the frequency of gout attacks (12), tophus mobilization and tophi size (1); maintaining a SUA <6 mg/dl can deplete intraarticular urate crystal concentrations (12) even after only 3 months of therapy (13). Guided by this evidence, the ACR has strongly recommended use of ULT to achieve a target SUA concentration, at a minimum, to a level <6 mg/dl (4). Previous observational studies have cited inconsistent monitoring of SUA concentrations by health care providers (12). Moreover, the present findings suggest that health professionals seeking to lower SUA in patients with gout and comorbid CKD or kidney stones should be aware that those under 70 years of age are more likely to have a SUA value above the target level of 6 mg/dl. Furthermore, among those with gout and established ULT use, those US adults who are obese and those with coexistent diabetes mellitus have a higher prevalence of an above target SUA level. The pathophysiologic mechanisms or practice patterns influence these identified associations with hypertension, diabetes and obesity is at this time conjecture. Yet, these patients may warrant greater vigilance in gout management.

There are important limitations to acknowledge. First, gout was assessed by self-report of a physician or health professional diagnosis of gout. Self-report is commonly used in large population-based epidemiologic studies. Second, detailed clinical information regarding the participants’ gout course, including disease duration, arthrocentesis-confirmed urate crystals, presence of tophi, and frequency of gout attacks, were not assessed with the NHANES questionnaire. Further, neither dose nor duration of ULT therapy was available in the NHANES dataset. As such, we cannot assess the above itemized clinical features of gout flares among NHANES participants. However, assessment of renal function and self-reported history of nephrolithiasis are ascertained in the NHANES protocol, constituting well-established indications for ULT therapy. Moreover, receipt of a prescription for a ULT agent is intuitively a meaningful surrogate for more severe gout which manifests with recurrent flares or tophaceous deposits. Additionally, use of febuxostat, a newer xanthine oxidase inhibitor (approved in 2009 by the Food and Drug Administration), was not captured in the NHANES protocol. Further, since the ACR recommends an even lower SUA target for patients with more severe disease (e.g. <5 mg/dl) (4), these findings may underestimate the prevalence of US adults with gout that should achieve tighter or more optimal SUA levels. Finally, participants’ indication for ULT is not described in the NHANES protocol, which could lead to misclassification. For example, participants taking allopurinol for tumor lysis syndrome prophylaxis may be misclassified as taking ULT for gout. However, this scenario is likely to be quite infrequent, if at all, among the total NHANES gout population.

Our study has several important strengths. The NHANES represent a major national resource to estimate disease prevalence in the US. With its complex sampling design ensuring a study population representative of the US, these reported data are less influenced by selection biases inherent among inpatient or clinic-based cohorts. NHANES includes rigorous and standardized data collection. Moreover, this valuable national epidemiologic resource, using the same definition of gout case status, has enabled several recent reports of the national burden of gout, related comorbidities and temporal trends (9, 11, 14).

In conclusion, a substantial proportion of US adults with clear indications for use of ULT, including those prescribed such agents by their health care provider, have an elevated SUA measurement. This may represent inadequate treatment due to poor compliance, limited duration of treatment or inadequate modification of lifestyle factors. Yet, these findings establish a meaningful baseline to assess efficacy of the new treatment guidelines intended to enhance the quality of care delivered to US adults with gout in this country.

SIGNIFICANCE AND INNOVATIONS.

1. Among adult Americans with gout who are taking urate-lowering therapy, half (49%) have a serum uric acid level ≥6 mg/dl.

2. Among Americans with gout and chronic kidney disease stages 2–5 or a history of nephrolithiasis, two-thirds have a serum uric acid ≥6 mg/dl.

3. Among Americans with gout on a ULT agent, older age and hypertension were each associated with a lower prevalence of SUA ≥6 mg/dl, whereas diabetes mellitus and obesity were each related to a higher prevalence of SUA ≥6 mg/dl.