Arthritis Care & Research Vol. 67, No. 4, April 2015, pp 588 –592 DOI 10.1002/acr.22469 © 2015, American College of Rheumatology
BRIEF REPORT
Gout, Urate-Lowering Therapy, and Uric Acid Levels Among Adults in the United States STEPHEN P. JURASCHEK,1 LARA C. KOVELL,2 EDGAR R. MILLER III,1
AND
ALLAN C. GELBER1
Objective. Evidence strongly suggests that 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 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 an SUA >6 mg/dl. In adjusted analyses among those with gout and CKD or nephrolithiasis, those age >70 years were less likely (prevalence ratio [PR] 0.77, 95% confidence interval [95% CI] 0.61– 0.97) to have an 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 an SUA value >6 mg/dl. Conclusion. Half of all Americans with gout receiving ULT, and two-thirds with an indication for ULT, have an 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 pain and high health costs (1). The prevalence of gout is rising; estimates show it has affected more than 3.5% of 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).
Dr. Juraschek’s work was supported by an NIH/National Heart, Lung, and Blood Institute Cardiovascular Epidemiology Training Grant (T32-HL-007024). Dr. Gelber’s work was supported by the Donald B. and Dorothy Stabler Foundation. 1 Stephen P. Juraschek, MD, PhD, Edgar R. Miller III, MD, PhD, Allan C. Gelber, MD, MPH, PhD: Johns Hopkins Bloomberg School of Public Health, Welch Center for Prevention, Epidemiology and Clinical Research, and Johns Hopkins University School of Medicine, Baltimore, Maryland; 2Lara C. Kovell, MD: Johns Hopkins University School of Medicine, Baltimore, Maryland. Address correspondence to Allan C. Gelber, MD, MPH, PhD, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Building, Center Tower, Suite 4100, Baltimore, MD 21224. E-mail: [email protected]. Submitted for publication August 5, 2013; accepted in revised form September 2, 2014.
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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 an 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 dose (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 (ⱖ2 attacks/year), chronic kidney disease (CKD; stage 2–5), or a history of nephrolithiasis, achieve an SUA value ⬍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 the following: 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 ⱖ6 mg/dl), and 3) demographic and clinical characteristics associated
Target Serum Uric Acid Levels and ULT in Gout
Significance & Innovations ●
Among adult Americans with gout who are taking urate-lowering therapy (ULT), half (49%) have a serum uric acid (SUA) level ⱖ6 mg/dl.
●
Among Americans with gout and chronic kidney disease (stage 2–5) or a history of nephrolithiasis, two-thirds have an SUA level ⱖ6 mg/dl.
●
Among Americans with gout taking a ULT agent, older age and hypertension were each associated with a lower prevalence of SUA ⱖ6 mg/dl, whereas diabetes mellitus and obesity were each related to a higher prevalence of SUA ⱖ6 mg/dl.
with an SUA ⱖ6 mg/dl among US adults with gout and either CKD (stage 2–5) or history of kidney stones, or currently taking ULT.
Methods Study population. The National Health and Nutrition 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 population. In the present report, we examined the continuous NHANES (2007–2010), which queried participants about their gout status. Participants lacking an SUA measurement, missing gout medication data, or those with unknown gout status were excluded. Informed consent was obtained per the NCHS and the NHANES protocols (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 and 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 an SUA value ⬍6.0 mg/dl (360 mol/liter) for both women and men (4). Renal gout: CKD and history of kidney stones. Renal gout was defined as the presence of CKD, stage 2–5, or history of kidney stones among participants with gout. CKD, stage 2–5, was based on stages established by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (8), using both a creatinine-based estimated glomerular filtration rate and single albuminuria assessments (albumin:creatinine ratio ⱖ30 mg/gm) (9). A history of nephrolithiasis was based on an affirmative response to the following question: “Have you ever had kidney stones?”
589 Indications for ULT. The 2012 ACR guidelines identified the following categories of adults with gout to be started on ULT therapy: any patient with 1) a tophus or tophi, 2) frequent attacks of acute gouty arthritis (ⱖ2 attacks/year), 3) CKD stage 2–5, or 4) past urolithiasis. Further, the ACR guidelines recommend that all those with an indication for ULT achieve an SUA ⬍6 mg/dl to improve the signs and symptoms of disease (4). Therefore, using the NHANES data set, we defined an indication for ULT as follows: 1) current ULT use, 2) CKD stage 2–5, or 3) 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 an SUA ⱖ6 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 ⱖ30 kg/m2. Hypertension was defined by a systolic blood pressure ⱖ140 mm Hg or diastolic blood pressure ⱖ90 mm Hg or use of antihypertensive medications. A low level of high-density lipoprotein (HDL) cholesterol was defined as ⬍40 mg/dl for men and ⬍50 mg/dl for women. Serum total cholesterol levels were also measured. Diabetes mellitus 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 (ⱖ12 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, SEs were determined for all metrics using the Taylor series (linearization) method. Analyses were performed using Stata, version 11.1. Characteristics of the gout population in NHANES 2007–2010 were determined using weighted mean ⫾ SE 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 SUA ⱖ6 mg/dl. Finally, we used Poisson regression to identify demographic and comorbid conditions associated with SUA ⱖ6 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 (ⱖ70 versus ⬍70 years), male sex (versus female sex), non-Hispanic white (versus other race), obesity (body mass index ⱖ30 versus ⬍30 kg/m2), low HDL cholesterol (versus elevated HDL cholesterol), hypertension (versus no hypertension), diabetes mellitus (versus no diabetes mellitus), diuretic use (versus no diuretic medication use), and alcohol use (ever versus never drank alcohol).
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Results There were 10,977 adults, age ⱖ20 years, 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 CKD, stage 2–5, or a history of kidney stones (Table 1). A smaller proportion, only 29%, were on ULT, predominantly allopurinol. 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 receiving ULT, 49% had SUA ⱖ6 mg/dl. An even higher proportion had SUA ⱖ6 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 SUA ⱖ6 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). Next we examined factors associated with having an SUA value ⱖ6 mg/dl among participants with renal gout or those currently using a ULT agent (Table 2). In the former group, those age ⱖ70 years were less likely (prevalence ratio [PR] 0.77, 95% confidence interval [95% CI] 0.61– 0.97) to have an elevated SUA value than their younger counterparts. As for the latter group, i.e., those with gout receiving ULT, older age was similarly related to a lower prevalence of an SUA value ⱖ6 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 an SUA value ⱖ6 mg/dl. Parenthetically, when serum total cholesterol was substituted in the multivariate analyses for HDL cholesterol, results were fundamentally unchanged (see Supplementary Table 1, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22469/ abstract).
Discussion This study represents the first nationwide assessment of the US gout population with regard to the 2012 ACR gout treatment guidelines and its SUA treatment target. In 2007–2010, 2 of 3 US adults with gout had an SUA concentration ⱖ6 mg/dl. Notably, when restricted to those with gout and coexistent stage 2–5 CKD or nephrolithiasis (2 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, 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 an SUA value ⬍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
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 ULT*
Age, mean ⫾ SE years Age ⱖ70 years Male Non-Hispanic white Obese (BMI ⱖ30 kg/m2) Low HDL cholesterol Hypertension Self-reported diabetes mellitus Diuretic medications Ever drank alcohol Serum uric acid, mean ⫾ SE mg/dl Serum uric acid ⱖ6 mg/dl CKD, stage 2–5 History of kidney stones CKD stage 2–5 or history of kidney stones Gout medications Allopurinol Probenecid Colchicine ULT‡ US adults with indication for uric acid ⬍6 mg/dl§
All gout (n ⴝ 514)
Renal gout (n ⴝ 272)†
Currently using ULT (n ⴝ 147)
61.5 ⫾ 0.9 32.4 71.6 77.0 55.5 43.0 68.1 23.3 27.8 89.2 6.7 ⫾ 0.1 66.3 34.2 21.7 47.4 31.6 27.8 0.9 7.0 29.0 58.5
67.2 ⫾ 1.2 50.8 72.1 79.1 54.0 39.6 76.4 30.9 36.9 84.5 6.8 ⫾ 0.1 68.9 72.3 45.9 100.0 41.1 36.4 0.9 8.3 37.7 100.0
65.4 ⫾ 1.6 40.3 81.0 83.4 61.9 47.7 78.2 30.6 44.0 89.3 6.0 ⫾ 0.1 49.3 49.2 26.0 61.6 100.0 96.1 3.1 15.0 100.0 100.0
* Values are the percentage unless indicated otherwise. CKD ⫽ chronic kidney disease; ULT ⫽ urate-lowering therapy; BMI ⫽ body mass index; HDL ⫽ high-density lipoprotein. † Renal gout defined by self-reported gout and CKD. ‡ Allopurinol, probenecid, or combination colchicine/probenecid. § Defined as CKD stage 2–5, a history of kidney stones, or current ULT.
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gout and an indication for ULT: 65.5% Figure 1. Flow chart representing the prevalence and population estimate in millions (mil) of total gout; of 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 of gout with an indication for ULT and a uric acid level of ⱖ6 mg/dl. Estimates with black lettering represent the entire US population, while estimates in gray lettering represent a proportion of gout patients or a subpopulation of gout patients. Note, some participants had ⬎1 indication for ULT such that the 3 categories depicted in the third row of the figure are not mutually exclusive. Modest discrepancies in percentage values are due to rounding.
⬍6 mg/dl (4). Previous observational studies have cited inconsistent monitoring of SUA concentrations by health care providers (12). Moreover, the present findings suggest Table 2. Factors associated with having a uric acid concentration >6 mg/dl among persons with renal gout or those using ULT*
Age ⱖ70 years Male Non-Hispanic white Obese (BMI ⱖ30 kg/m2) Low HDL cholesterol Hypertension Diabetes mellitus Diuretic medications Ever drank alcohol
Renal gout (n ⴝ 244)†
Currently using ULT (n ⴝ 134)†
0.77 (0.61–0.97)‡ 1.21 (0.92–1.59) 0.96 (0.79–1.17) 0.98 (0.83–1.16) 1.16 (0.94–1.44) 0.91 (0.70–1.18) 1.02 (0.87–1.20) 1.11 (0.93–1.33) 1.09 (0.66–1.78)
0.57 (0.42–0.77)‡ 1.14 (0.77–1.67) 1.04 (0.71–1.54) 1.74 (1.19–2.56)‡ 0.84 (0.61–1.18) 0.51 (0.30–0.87)‡ 1.42 (1.06–1.90)‡ 1.53 (0.97–2.42) 1.51 (0.77–2.98)
* Values are the prevalence ratio (95% confidence interval); all models were adjusted for age (ⱖ70 vs. ⬍70 years), male (vs. female), non-Hispanic white (vs. other race), obese (body mass index [BMI] ⱖ30 vs. ⬍30 kg/m2), low high-density lipoprotein (HDL) cholesterol (vs. elevated HDL cholesterol), hypertension (vs. no hypertension), diabetes mellitus (vs. no diabetes mellitus), diuretic use (vs. no diuretic medication use), and ever drank alcohol (vs. never drank alcohol). ULT ⫽ urate-lowering therapy. † Renal gout denotes those patients with gout and coexistent chronic kidney disease or nephrolithiasis. Sample size is the unweighted number after excluding participants with missing covariate data. ‡ P ⬍ 0.05.
that health professionals seeking to lower SUA in patients with gout and comorbid CKD or kidney stones should be aware that those age ⬍70 years are more likely to have an SUA value above the target level of 6 mg/dl. Furthermore, among those with gout and established ULT, those US adults who are obese and those with coexistent diabetes mellitus have a higher prevalence of an above-target SUA level. That pathophysiologic mechanisms or practice patterns influence these identified associations with hypertension, diabetes mellitus, 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 participant’s gout course, including disease duration, arthrocentesis-confirmed urate crystals, presence of tophi, and frequency of gout attacks, was not assessed with the NHANES questionnaire. Further, neither dose nor duration of ULT was available in the NHANES data set. 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. Moreover, receipt of a prescription for a ULT agent is intuitively
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a meaningful surrogate for more severe gout that 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. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Gelber had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Juraschek, Gelber. Acquisition of data. Juraschek.
Analysis and interpretation of data. Juraschek, Kovell, Miller, Gelber.
REFERENCES 1. Neogi T. Clinical practice: gout. N Engl J Med 2011;364:443– 52. 2. Juraschek SP, Miller ER III, Gelber AC. Body mass index, obesity, and prevalent gout in the United States in 1988 –1994 and 2007–2010. Arthritis Care Res (Hoboken) 2013;65:127– 32. 3. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum 2011;63:3136 – 41. 4. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 2012;64:1431– 46. 5. Singh JA, Hodges JS, Toscano JP, Asch SM. Quality of care for gout in the US needs improvement. Arthritis Rheum 2007;57: 822–9. 6. Mikuls TR, MacLean CH, Olivieri J, Patino F, Allison JJ, Farrar JT, et al. Quality of care indicators for gout management. Arthritis Rheum 2004;50:937– 43. 7. Centers for Disease Control. National Health and Nutrition Examination Survey (NHANES)–NHANES III (1988-1994) and NHANES 1999 –2010: manuals, brochures, and consent documents. 1988. URL: http://www.cdc.gov/nchs/nhanes.htm. 8. National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis Off J Natl Kidney Found 2012;39 Suppl 1:S1–266. 9. Juraschek SP, Kovell LC, Miller ER III, Gelber AC. Association of kidney disease with prevalent gout in the United States in 1988 –1994 and 2007–2010. Semin Arthritis Rheum 2013;42: 551– 61. 10. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811–21. 11. Juraschek SP, Kovell LC, Miller ER, Gelber AC. Dose-response association of uncontrolled blood pressure and cardiovascular disease risk factors with hyperuricemia and gout. PloS One 2013;8:e56546. 12. Li-Yu J, Clayburne G, Sieck M, Beutler A, Rull M, Eisner E, et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol 2001;28:577– 80. 13. Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial fluid after successful hypouricaemic treatment relates to the duration of gout. Ann Rheum Dis 2007;66:1056 – 8. 14. Zhu Y, Pandya BJ, Choi HK. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007– 2008. Am J Med 2012;125:679 – 87.
Applications Invited for Arthritis Care & Research Editor (2016 –2021 Term) The American College of Rheumatology Committee on Journal Publications announces the search for the position of Editor, Arthritis Care & Research. The official term of the next Arthritis Care & Research editorship is July 1, 2016 –June 30, 2021; however, some of the duties of the new Editor will begin during a transition period starting April 1, 2016. ARHP or ACR members who are considering applying should submit a nonbinding letter of intent by April 15, 2015 to the Managing Editor, Nancy Parker, at nparker@rheumatology .org and are also encouraged to contact the current Editor, Dr. Marian T. Hannan, to discuss details; initial contact should be made via e-mail to [email protected]. Applications will be due June 15, 2015 and will be reviewed during the summer of 2015. Application materials are available at http://www.rheumatology. org/Publications/Acr/Editor_Application_Cover_Materials.
BRIEF REPORT
Gout, Urate-Lowering Therapy, and Uric Acid Levels Among Adults in the United States STEPHEN P. JURASCHEK,1 LARA C. KOVELL,2 EDGAR R. MILLER III,1
AND
ALLAN C. GELBER1
Objective. Evidence strongly suggests that 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 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 an SUA >6 mg/dl. In adjusted analyses among those with gout and CKD or nephrolithiasis, those age >70 years were less likely (prevalence ratio [PR] 0.77, 95% confidence interval [95% CI] 0.61– 0.97) to have an 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 an SUA value >6 mg/dl. Conclusion. Half of all Americans with gout receiving ULT, and two-thirds with an indication for ULT, have an 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 pain and high health costs (1). The prevalence of gout is rising; estimates show it has affected more than 3.5% of 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).
Dr. Juraschek’s work was supported by an NIH/National Heart, Lung, and Blood Institute Cardiovascular Epidemiology Training Grant (T32-HL-007024). Dr. Gelber’s work was supported by the Donald B. and Dorothy Stabler Foundation. 1 Stephen P. Juraschek, MD, PhD, Edgar R. Miller III, MD, PhD, Allan C. Gelber, MD, MPH, PhD: Johns Hopkins Bloomberg School of Public Health, Welch Center for Prevention, Epidemiology and Clinical Research, and Johns Hopkins University School of Medicine, Baltimore, Maryland; 2Lara C. Kovell, MD: Johns Hopkins University School of Medicine, Baltimore, Maryland. Address correspondence to Allan C. Gelber, MD, MPH, PhD, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Building, Center Tower, Suite 4100, Baltimore, MD 21224. E-mail: [email protected]. Submitted for publication August 5, 2013; accepted in revised form September 2, 2014.
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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 an 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 dose (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 (ⱖ2 attacks/year), chronic kidney disease (CKD; stage 2–5), or a history of nephrolithiasis, achieve an SUA value ⬍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 the following: 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 ⱖ6 mg/dl), and 3) demographic and clinical characteristics associated
Target Serum Uric Acid Levels and ULT in Gout
Significance & Innovations ●
Among adult Americans with gout who are taking urate-lowering therapy (ULT), half (49%) have a serum uric acid (SUA) level ⱖ6 mg/dl.
●
Among Americans with gout and chronic kidney disease (stage 2–5) or a history of nephrolithiasis, two-thirds have an SUA level ⱖ6 mg/dl.
●
Among Americans with gout taking a ULT agent, older age and hypertension were each associated with a lower prevalence of SUA ⱖ6 mg/dl, whereas diabetes mellitus and obesity were each related to a higher prevalence of SUA ⱖ6 mg/dl.
with an SUA ⱖ6 mg/dl among US adults with gout and either CKD (stage 2–5) or history of kidney stones, or currently taking ULT.
Methods Study population. The National Health and Nutrition 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 population. In the present report, we examined the continuous NHANES (2007–2010), which queried participants about their gout status. Participants lacking an SUA measurement, missing gout medication data, or those with unknown gout status were excluded. Informed consent was obtained per the NCHS and the NHANES protocols (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 and 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 an SUA value ⬍6.0 mg/dl (360 mol/liter) for both women and men (4). Renal gout: CKD and history of kidney stones. Renal gout was defined as the presence of CKD, stage 2–5, or history of kidney stones among participants with gout. CKD, stage 2–5, was based on stages established by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (8), using both a creatinine-based estimated glomerular filtration rate and single albuminuria assessments (albumin:creatinine ratio ⱖ30 mg/gm) (9). A history of nephrolithiasis was based on an affirmative response to the following question: “Have you ever had kidney stones?”
589 Indications for ULT. The 2012 ACR guidelines identified the following categories of adults with gout to be started on ULT therapy: any patient with 1) a tophus or tophi, 2) frequent attacks of acute gouty arthritis (ⱖ2 attacks/year), 3) CKD stage 2–5, or 4) past urolithiasis. Further, the ACR guidelines recommend that all those with an indication for ULT achieve an SUA ⬍6 mg/dl to improve the signs and symptoms of disease (4). Therefore, using the NHANES data set, we defined an indication for ULT as follows: 1) current ULT use, 2) CKD stage 2–5, or 3) 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 an SUA ⱖ6 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 ⱖ30 kg/m2. Hypertension was defined by a systolic blood pressure ⱖ140 mm Hg or diastolic blood pressure ⱖ90 mm Hg or use of antihypertensive medications. A low level of high-density lipoprotein (HDL) cholesterol was defined as ⬍40 mg/dl for men and ⬍50 mg/dl for women. Serum total cholesterol levels were also measured. Diabetes mellitus 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 (ⱖ12 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, SEs were determined for all metrics using the Taylor series (linearization) method. Analyses were performed using Stata, version 11.1. Characteristics of the gout population in NHANES 2007–2010 were determined using weighted mean ⫾ SE 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 SUA ⱖ6 mg/dl. Finally, we used Poisson regression to identify demographic and comorbid conditions associated with SUA ⱖ6 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 (ⱖ70 versus ⬍70 years), male sex (versus female sex), non-Hispanic white (versus other race), obesity (body mass index ⱖ30 versus ⬍30 kg/m2), low HDL cholesterol (versus elevated HDL cholesterol), hypertension (versus no hypertension), diabetes mellitus (versus no diabetes mellitus), diuretic use (versus no diuretic medication use), and alcohol use (ever versus never drank alcohol).
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Results There were 10,977 adults, age ⱖ20 years, 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 CKD, stage 2–5, or a history of kidney stones (Table 1). A smaller proportion, only 29%, were on ULT, predominantly allopurinol. 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 receiving ULT, 49% had SUA ⱖ6 mg/dl. An even higher proportion had SUA ⱖ6 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 SUA ⱖ6 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). Next we examined factors associated with having an SUA value ⱖ6 mg/dl among participants with renal gout or those currently using a ULT agent (Table 2). In the former group, those age ⱖ70 years were less likely (prevalence ratio [PR] 0.77, 95% confidence interval [95% CI] 0.61– 0.97) to have an elevated SUA value than their younger counterparts. As for the latter group, i.e., those with gout receiving ULT, older age was similarly related to a lower prevalence of an SUA value ⱖ6 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 an SUA value ⱖ6 mg/dl. Parenthetically, when serum total cholesterol was substituted in the multivariate analyses for HDL cholesterol, results were fundamentally unchanged (see Supplementary Table 1, available in the online version of this article at http://onlinelibrary.wiley.com/doi/10.1002/acr.22469/ abstract).
Discussion This study represents the first nationwide assessment of the US gout population with regard to the 2012 ACR gout treatment guidelines and its SUA treatment target. In 2007–2010, 2 of 3 US adults with gout had an SUA concentration ⱖ6 mg/dl. Notably, when restricted to those with gout and coexistent stage 2–5 CKD or nephrolithiasis (2 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, 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 an SUA value ⬍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
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 ULT*
Age, mean ⫾ SE years Age ⱖ70 years Male Non-Hispanic white Obese (BMI ⱖ30 kg/m2) Low HDL cholesterol Hypertension Self-reported diabetes mellitus Diuretic medications Ever drank alcohol Serum uric acid, mean ⫾ SE mg/dl Serum uric acid ⱖ6 mg/dl CKD, stage 2–5 History of kidney stones CKD stage 2–5 or history of kidney stones Gout medications Allopurinol Probenecid Colchicine ULT‡ US adults with indication for uric acid ⬍6 mg/dl§
All gout (n ⴝ 514)
Renal gout (n ⴝ 272)†
Currently using ULT (n ⴝ 147)
61.5 ⫾ 0.9 32.4 71.6 77.0 55.5 43.0 68.1 23.3 27.8 89.2 6.7 ⫾ 0.1 66.3 34.2 21.7 47.4 31.6 27.8 0.9 7.0 29.0 58.5
67.2 ⫾ 1.2 50.8 72.1 79.1 54.0 39.6 76.4 30.9 36.9 84.5 6.8 ⫾ 0.1 68.9 72.3 45.9 100.0 41.1 36.4 0.9 8.3 37.7 100.0
65.4 ⫾ 1.6 40.3 81.0 83.4 61.9 47.7 78.2 30.6 44.0 89.3 6.0 ⫾ 0.1 49.3 49.2 26.0 61.6 100.0 96.1 3.1 15.0 100.0 100.0
* Values are the percentage unless indicated otherwise. CKD ⫽ chronic kidney disease; ULT ⫽ urate-lowering therapy; BMI ⫽ body mass index; HDL ⫽ high-density lipoprotein. † Renal gout defined by self-reported gout and CKD. ‡ Allopurinol, probenecid, or combination colchicine/probenecid. § Defined as CKD stage 2–5, a history of kidney stones, or current ULT.
Target Serum Uric Acid Levels and ULT in Gout
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gout and an indication for ULT: 65.5% Figure 1. Flow chart representing the prevalence and population estimate in millions (mil) of total gout; of 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 of gout with an indication for ULT and a uric acid level of ⱖ6 mg/dl. Estimates with black lettering represent the entire US population, while estimates in gray lettering represent a proportion of gout patients or a subpopulation of gout patients. Note, some participants had ⬎1 indication for ULT such that the 3 categories depicted in the third row of the figure are not mutually exclusive. Modest discrepancies in percentage values are due to rounding.
⬍6 mg/dl (4). Previous observational studies have cited inconsistent monitoring of SUA concentrations by health care providers (12). Moreover, the present findings suggest Table 2. Factors associated with having a uric acid concentration >6 mg/dl among persons with renal gout or those using ULT*
Age ⱖ70 years Male Non-Hispanic white Obese (BMI ⱖ30 kg/m2) Low HDL cholesterol Hypertension Diabetes mellitus Diuretic medications Ever drank alcohol
Renal gout (n ⴝ 244)†
Currently using ULT (n ⴝ 134)†
0.77 (0.61–0.97)‡ 1.21 (0.92–1.59) 0.96 (0.79–1.17) 0.98 (0.83–1.16) 1.16 (0.94–1.44) 0.91 (0.70–1.18) 1.02 (0.87–1.20) 1.11 (0.93–1.33) 1.09 (0.66–1.78)
0.57 (0.42–0.77)‡ 1.14 (0.77–1.67) 1.04 (0.71–1.54) 1.74 (1.19–2.56)‡ 0.84 (0.61–1.18) 0.51 (0.30–0.87)‡ 1.42 (1.06–1.90)‡ 1.53 (0.97–2.42) 1.51 (0.77–2.98)
* Values are the prevalence ratio (95% confidence interval); all models were adjusted for age (ⱖ70 vs. ⬍70 years), male (vs. female), non-Hispanic white (vs. other race), obese (body mass index [BMI] ⱖ30 vs. ⬍30 kg/m2), low high-density lipoprotein (HDL) cholesterol (vs. elevated HDL cholesterol), hypertension (vs. no hypertension), diabetes mellitus (vs. no diabetes mellitus), diuretic use (vs. no diuretic medication use), and ever drank alcohol (vs. never drank alcohol). ULT ⫽ urate-lowering therapy. † Renal gout denotes those patients with gout and coexistent chronic kidney disease or nephrolithiasis. Sample size is the unweighted number after excluding participants with missing covariate data. ‡ P ⬍ 0.05.
that health professionals seeking to lower SUA in patients with gout and comorbid CKD or kidney stones should be aware that those age ⬍70 years are more likely to have an SUA value above the target level of 6 mg/dl. Furthermore, among those with gout and established ULT, those US adults who are obese and those with coexistent diabetes mellitus have a higher prevalence of an above-target SUA level. That pathophysiologic mechanisms or practice patterns influence these identified associations with hypertension, diabetes mellitus, 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 participant’s gout course, including disease duration, arthrocentesis-confirmed urate crystals, presence of tophi, and frequency of gout attacks, was not assessed with the NHANES questionnaire. Further, neither dose nor duration of ULT was available in the NHANES data set. 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. Moreover, receipt of a prescription for a ULT agent is intuitively
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a meaningful surrogate for more severe gout that 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. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Gelber had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Juraschek, Gelber. Acquisition of data. Juraschek.
Analysis and interpretation of data. Juraschek, Kovell, Miller, Gelber.
REFERENCES 1. Neogi T. Clinical practice: gout. N Engl J Med 2011;364:443– 52. 2. Juraschek SP, Miller ER III, Gelber AC. Body mass index, obesity, and prevalent gout in the United States in 1988 –1994 and 2007–2010. Arthritis Care Res (Hoboken) 2013;65:127– 32. 3. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum 2011;63:3136 – 41. 4. Khanna D, Fitzgerald JD, Khanna PP, Bae S, Singh MK, Neogi T, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 2012;64:1431– 46. 5. Singh JA, Hodges JS, Toscano JP, Asch SM. Quality of care for gout in the US needs improvement. Arthritis Rheum 2007;57: 822–9. 6. Mikuls TR, MacLean CH, Olivieri J, Patino F, Allison JJ, Farrar JT, et al. Quality of care indicators for gout management. Arthritis Rheum 2004;50:937– 43. 7. Centers for Disease Control. National Health and Nutrition Examination Survey (NHANES)–NHANES III (1988-1994) and NHANES 1999 –2010: manuals, brochures, and consent documents. 1988. URL: http://www.cdc.gov/nchs/nhanes.htm. 8. National Kidney Foundation K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis Off J Natl Kidney Found 2012;39 Suppl 1:S1–266. 9. Juraschek SP, Kovell LC, Miller ER III, Gelber AC. Association of kidney disease with prevalent gout in the United States in 1988 –1994 and 2007–2010. Semin Arthritis Rheum 2013;42: 551– 61. 10. Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811–21. 11. Juraschek SP, Kovell LC, Miller ER, Gelber AC. Dose-response association of uncontrolled blood pressure and cardiovascular disease risk factors with hyperuricemia and gout. PloS One 2013;8:e56546. 12. Li-Yu J, Clayburne G, Sieck M, Beutler A, Rull M, Eisner E, et al. Treatment of chronic gout. Can we determine when urate stores are depleted enough to prevent attacks of gout? J Rheumatol 2001;28:577– 80. 13. Pascual E, Sivera F. Time required for disappearance of urate crystals from synovial fluid after successful hypouricaemic treatment relates to the duration of gout. Ann Rheum Dis 2007;66:1056 – 8. 14. Zhu Y, Pandya BJ, Choi HK. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007– 2008. Am J Med 2012;125:679 – 87.
Applications Invited for Arthritis Care & Research Editor (2016 –2021 Term) The American College of Rheumatology Committee on Journal Publications announces the search for the position of Editor, Arthritis Care & Research. The official term of the next Arthritis Care & Research editorship is July 1, 2016 –June 30, 2021; however, some of the duties of the new Editor will begin during a transition period starting April 1, 2016. ARHP or ACR members who are considering applying should submit a nonbinding letter of intent by April 15, 2015 to the Managing Editor, Nancy Parker, at nparker@rheumatology .org and are also encouraged to contact the current Editor, Dr. Marian T. Hannan, to discuss details; initial contact should be made via e-mail to [email protected]. Applications will be due June 15, 2015 and will be reviewed during the summer of 2015. Application materials are available at http://www.rheumatology. org/Publications/Acr/Editor_Application_Cover_Materials.
